Anti-CD19 therapy in combination with lenalidomide for the treatment of leukemia or lymphoma

Abstract

The present disclosure relates to a therapeutic combination of an anti-CD19 antibody and lenalidomide for use in treating patients with hematological cancers. Further, the present disclosure relates to extending overall survival and / or progression-free survival in patients with certain types of hematological cancers.

Description

[Technical Field]

[0001] The present disclosure relates to a therapeutic combination of an anti-CD19 antibody and lenalidomide for use in treating patients with hematological cancers. Further, the present disclosure relates to extending overall survival and / or progression-free survival in patients with certain types of hematological cancers. [Background technology]

[0002] CD19 is a 95-kDa transmembrane glycoprotein of the immunoglobulin superfamily containing two extracellular immunoglobulin-like domains and an extensive cytoplasmic tail. This protein is a pan-B lymphocyte surface receptor and is ubiquitously expressed from early stages of pre-B cell development until it is downregulated during terminal differentiation into plasma cells. It is B-lymphocyte lineage-specific and is not expressed on hematopoietic stem cells or other immune cells, except for some follicular dendritic cells. CD19 functions as a positive regulator of B-cell receptor (BCR) signaling and is important for B-cell activation and proliferation, as well as the development of humoral immune responses. It functions as a costimulatory molecule in conjunction with CD21 and CD81 and is important for B-cell responses to T-cell-dependent antigens. The cytoplasmic tail of CD19 physically associates with a family of tyrosine kinases that trigger downstream signaling pathways via the SRC family of protein tyrosine kinases. CD19 is an attractive target in cancers of lymphoid origin because it is highly expressed in almost all chronic lymphocytic leukemias (CLL) and non-Hodgkin's lymphomas (NHL), as well as many other different types of leukemia, such as acute lymphocytic leukemia (ALL) and hairy cell leukemia (HCL).

[0003] Tafasitamab (formerly MOR00208 and XmAb® 5574) is a humanized monoclonal antibody that targets the antigen CD19, a transmembrane protein involved in B-cell receptor signaling. Tafasitamab has been engineered with an IgG Fc region to enhance antibody-dependent cellular cytotoxicity (ADCC), improving a key mechanism for tumor cell killing and potentially increasing efficacy compared with conventional, i.e., non-enhanced, antibodies. Tafasitamab has been or is currently being studied in several clinical trials, including for CLL, ALL, and NHL. In some of these trials, tafasitamab is used in combination with idelalisib, bendamustine, or venetoclax.

[0004] The phase 2 L-MIND trial (NCT02399085) evaluated the efficacy of tafasitamab in combination with lenalidomide (LEN) in adult patients with relapsed or refractory diffuse large B-cell lymphoma (rr-DLBCL). L-MIND enrolled 81 patients with DLBCL who were ineligible for ASCT and had relapsed after or were refractory to one to three prior systemic regimens. Patients received tafasitamab (12 mg / kg) and lenalidomide (25 mg / day) concomitantly for up to 12 cycles (28 days each), followed by MOR00208 monotherapy (patients with stable or better disease) until disease progression. The primary endpoint was the objective response rate (central review). In this population of patients with relapsed or refractory DLBCL who were ineligible for stem cell transplantation, tafasitamab plus lenalidomide treatment induced an overall objective response in 60% of patients and a complete response in 42.5%, demonstrating that the combination of tafasitamab and lenalidomide is a promising treatment option.

[0005] The present disclosure relates to methods for extending progression-free survival in a population of patients with relapsed or refractory diffuse large B-cell lymphoma (rr-DLBCL) cancer; combining tafasitamab with lenalidomide to treat patients who have been pretreated with at least one or two lines of therapy (e.g., R-CHOP (rituximab and cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP)); and treating patients with relapsed or refractory diffuse large B-cell lymphoma (rr-DLBCL) cancer who have been pretreated with at least one or two lines of therapy (e.g., R-CHOP (rituximab and cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP)). Extending overall survival in patients with lymphoma (rr-DLBCL) cancer; Treating patients with relapsed or refractory diffuse large B-cell lymphoma (rr-DLBCL) with a combination of tafasitamab and lenalidomide, wherein the relapsed or refractory diffuse large B-cell lymphoma (rr-DLBCL) is germinal center B-cell (GCB) rr-DLBCL or non-germinal center B-cell (non-GCB) rr-DLBCL. Summary of the Invention

[0006] The present disclosure provides new therapeutic regimens for patients with certain hematological cancers. In particular, the present disclosure relates to the treatment of rr-DLBCL with a combination of an anti-CD19 antibody and lenalidomide. The present disclosure may provide: [Section 1] 1. A pharmaceutical composition comprising a therapeutic combination of an anti-CD19 antibody and lenalidomide for use in treating a patient with a hematological cancer, wherein said treatment extends overall survival and / or progression-free survival of said patient. [Section 2] 1. A pharmaceutical composition comprising an anti-CD19 antibody for use in treating a patient with a hematological cancer, wherein the anti-CD19 antibody is administered in combination with lenalidomide, and wherein the treatment extends the overall survival and / or progression-free survival of the patient. [Section 3] 1. A pharmaceutical composition comprising lenalidomide for use in treating a patient with a hematological cancer, wherein lenalidomide is administered in combination with an anti-CD19 antibody, and wherein the treatment extends overall survival and / or progression-free survival of the patient. [Section 4] Item 4. The pharmaceutical composition according to any one of Items 1 to 3, for use in treating patients with blood cancer, wherein the patients have received one line of prior treatment and have a 12-month overall survival rate of 80% or higher. [Section 5] Item 5. The pharmaceutical composition according to Item 4, for use in treating patients with blood cancer whose 12-month progression-free survival is 55% or more. [Section 6] Item 4. The pharmaceutical composition according to any one of Items 1 to 3, for use in treating patients with blood cancer, wherein the patients have received two or more lines of prior therapy and have a 12-month overall survival rate of 55% or higher. [Section 7] Item 7. The pharmaceutical composition according to Item 6, for use in treating patients with blood cancer whose 12-month progression-free survival rate is 35% or higher. [Section 8] 10. The pharmaceutical composition of any one of the preceding paragraphs for use in treating a patient with a hematological cancer, wherein the patient has a non-Hodgkin's lymphoma selected from the group consisting of follicular lymphoma, small lymphocytic lymphoma, mucosa-associated lymphoid tissue, marginal zone lymphoma, diffuse large B-cell lymphoma, Burkitt's lymphoma, and mantle cell lymphoma. [Section 9] Item 4. The pharmaceutical composition according to any one of Items 1 to 3, for use in treating a patient with blood cancer, wherein the patient has germinal center B-cell (GCB) DLBCL and has an overall survival rate of 60% or more at 12 months. [Section 10] Item 10. The pharmaceutical composition according to Item 9, for use in treating patients with blood cancer whose 12-month progression-free survival rate is 35% or higher. [Section 11] Item 4. The pharmaceutical composition according to any one of Items 1 to 3, for use in treating a patient with blood cancer, wherein the patient has non-germinal center B-cell (non-GCB) DLBCL and has an overall 12-month survival rate of 80% or higher. [Section 12] Item 12. The pharmaceutical composition according to Item 11, for use in treating patients with blood cancer whose 12-month progression-free survival rate is 70% or higher. [Section 13] Item 13. The pharmaceutical composition according to any one of Items 1 to 12, for use in treating a patient with blood cancer, wherein the anti-CD19 antibody comprises an HCDR1 region comprising the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region comprising the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region comprising the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region comprising the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region comprising the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region comprising the sequence MQHLEYPIT (SEQ ID NO: 6). [Section 14] Item 14. The pharmaceutical composition according to any one of Items 1 to 13, for use in treating a patient with blood cancer, wherein the anti-CD19 antibody has a variable heavy chain having the following sequence: EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPYNDGTKYNEKFQGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGTYYYGTRVFDYWGQGTLVTVSS (SEQ ID NO: 7) and a variable light chain of the following sequence: The pharmaceutical composition comprising DIVMTQSPATLSLSPGERATLSCRSSKSLQNVNGNTYLYWFQQKPGQSPQLLIYRMSNLNSGVPDRFSGSGSGTEFTLTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIK (SEQ ID NO: 8). [Section 15] Item 15. The pharmaceutical composition according to any one of Items 1 to 14, for use in treating a patient with blood cancer, wherein the anti-CD19 antibody has a heavy chain having the following sequence: EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPYNDGTKYNEKFQGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGTYYYGTRVFDYWGQG TLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT CPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKALPAPEEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 11) and a light chain having the sequence The pharmaceutical composition comprises DIVMTQSPATLSLSPGERATLSCRSSKSLQNVNGNTYLYWFQQKPGQSPQLLIYRMSNLNSGVPDRFSGSGSGTEFTLTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 12). [Section 16] 11. The pharmaceutical composition of any one of the preceding clauses for use in accordance with any one of the preceding clauses, wherein the anti-CD19 antibody is administered in an amount of 12 mg / kg per dose at least every other week, and lenalidomide is administered daily in an amount of 25 mg.

[0007] In a first aspect, the disclosure relates to a pharmaceutical composition comprising a therapeutic combination of an anti-CD19 antibody and lenalidomide for use in treating a patient with a hematological cancer, wherein the treatment prolongs the overall survival and / or progression-free survival of the patient. In another aspect, the disclosure relates to a pharmaceutical composition comprising an anti-CD19 antibody for use in treating a patient with a hematological cancer, wherein the anti-CD19 antibody is administered in combination with lenalidomide, and wherein the treatment prolongs the overall survival and / or progression-free survival of the patient. In another aspect, the disclosure relates to a pharmaceutical composition comprising lenalidomide for use in treating a patient with a hematological cancer, wherein the lenalidomide is administered in combination with an anti-CD19 antibody, and wherein the treatment prolongs the overall survival and / or progression-free survival of the patient.

[0008] In another aspect, the disclosure relates to a method for extending progression-free survival in a population of patients with hematological cancer, comprising administering to patients in the population an anti-CD19 antibody and lenalidomide.

[0009] In another aspect, the present disclosure relates to a therapeutic combination of an anti-CD19 antibody and lenalidomide for use in treating a hematological cancer patient population, wherein said treatment results in an increase in overall survival of patients within this population.

[0010] In a further aspect, the present disclosure relates to a therapeutic combination of an anti-CD19 antibody and lenalidomide for use in treating a hematological cancer patient population, wherein said treatment results in an increase in overall survival of said patients.

[0011] In a further aspect, the present disclosure relates to a therapeutic combination of an anti-CD19 antibody and lenalidomide for use in treating a hematological cancer patient population, wherein said treatment results in an increase in progression-free survival of said patients.

[0012] In one embodiment, an anti-CD19 antibody for use in treating patients with hematological cancer in therapeutic combination with lenalidomide comprises an HCDR1 region comprising the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region comprising the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region comprising the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region comprising the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region comprising the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region comprising the sequence MQHLEYPIT (SEQ ID NO: 6).

[0013] In a further embodiment, the anti-CD19 antibody for use in treating patients with hematological cancers in combination with lenalidomide has a variable heavy chain of the following sequence: EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPYNDGTKYNEKFQGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGTYYYGTRVFDYWGQGTLVTVSS (SEQ ID NO: 7) and a variable light chain of the following sequence: Contains DIVMTQSPATLSLSPGERATLSCRSSKSLQNVNGNTYLYWFQQKPGQSPQLLIYRMSNLNSGVPDRFSGSGSGTEFTLTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIK (SEQ ID NO: 8).

[0014] In another embodiment of the present disclosure, the anti-CD19 antibody is a human, humanized, or chimeric antibody. In another embodiment of the present disclosure, the anti-CD19 antibody is an antibody of the IgG isotype. In another embodiment, the antibody is an IgG1, IgG2, or IgG1 / IgG2 chimera. In another embodiment of the present disclosure, the isotype of the anti-CD19 antibody is engineered to enhance antibody-dependent cell-mediated cytotoxicity. In another embodiment, the heavy chain constant region of the anti-CD19 antibody comprises amino acids 239D and 332E, where Fc numbering is according to the EU index as in Kabat. In another embodiment, the antibody is an IgG1, IgG2, or IgG1 / IgG2, and the chimeric heavy chain constant region of the anti-CD19 antibody comprises amino acids 239D and 332E, where Fc numbering is according to the EU index as in Kabat.

[0015] In a further embodiment, the anti-CD19 antibody for use in treating patients with hematological cancers in combination with lenalidomide has a heavy chain having the sequence: EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPYNDGTKYNEKFQGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGTYYYGTRVFDYWGQG TLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH TCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKALPAPEEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 11) and a light chain having the sequence DIVMTQSPATLSLSPGERATLSCRSSKSLQNVNGNTYLYWFQQKPGQSPQLLIYRMSNLNSGVPDRFSGSGSGTEFTLTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 12).

[0016] Optionally, the therapeutic combination of an anti-CD19 antibody and lenalidomide results in a 12-month overall survival rate of 80% or greater for patients in a hematological cancer patient population. In one embodiment, patients in the treated population have received one line of prior therapy. In another embodiment, one line of prior therapy was treatment with rituximab. In one embodiment, one line of prior therapy was treatment with R-CHOP.

[0017] Optionally, the therapeutic combination of an anti-CD19 antibody and lenalidomide results in a 12-month overall survival rate of 55% or greater for patients in a hematological cancer patient population. In one embodiment, patients in the treated population have received two or more lines of prior therapy. In another embodiment, two or more lines of prior therapy included treatment with rituximab. In another embodiment, two or more lines of prior therapy included treatment with R-CHOP.

[0018] Optionally, the therapeutic combination of an anti-CD19 antibody and lenalidomide results in a 12-month overall survival rate of 60% or greater for patients in a hematological cancer patient population. In one embodiment, the patients in the treated population have germinal center B-cell (GCB) DLBCL.

[0019] Optionally, the therapeutic combination of an anti-CD19 antibody and lenalidomide results in an overall 12-month survival rate of 80% or greater for patients in a hematological cancer patient population. In one embodiment, the patients in the treated population have germinal center B-cell (non-GCB) DLBCL.

[0020] The present disclosure provides a new therapeutic regimen for patients with hematological cancers. In particular, the present disclosure relates to the treatment of rr-DLBCL in human subjects with a combination of an anti-CD19 antibody and lenalidomide. [Brief explanation of the drawings]

[0021] [Figure 1] Objective response rate by baseline characteristics: Two patients had double-hit or triple-hit DLBCL status, which was unknown at study entry. One patient developed "double-hit" DLBCL and achieved a best objective response of partial response. One patient developed "triple-hit" DLBCL and achieved a best objective response of complete response. (CI, confidence interval; DLBCL, diffuse large B-cell lymphoma; IHC, immunohistochemistry; IPI, International Prognostic Index; GCB, germinal center B cells; LDH, lactate dehydrogenase) [Figure 2]Swimmer plot of progression-free survival for patients with diffuse large B-cell lymphoma arising from transformation of low-grade lymphoma and double-hit or triple-hit lymphoma. CR, complete response; DHL, double-hit lymphoma; IRC, independent review committee; PR, partial response; SD, stable disease; THL, triple-hit lymphoma; TL, transformed low-grade lymphoma. DETAILED DESCRIPTION OF THE INVENTION

[0022] definition The term "CD19" refers to the protein known as CD19, which has the following synonyms: B4, B lymphocyte antigen CD19, B lymphocyte surface antigen B4, CVID3, differentiation antigen CD19, MGC12802, and T cell surface antigen Leu-12.

[0023] Human CD19 has the following amino acid sequence: (SEQ ID NO: 13)

[0024] The terms "tafasitamab," "MOR00208," and "XmAb5574" are used synonymously to describe the antibodies in Table 1. Table 1 shows the amino acid sequence of tafasitamab. Tafasitamab is described in U.S. Patent Application Serial No. 12 / 377,251, which is incorporated by reference in its entirety. U.S. Patent Application Serial No. 12 / 377,251 describes an antibody named 4G7H1.52 hybrid S239D / I332E / 4G7 L1.155 (later named MOR00208 and Tafasitamab).

[0025] As used herein, the term "antibody" refers to a protein comprising at least two heavy (H) chains and two light (L) chains interconnected by disulfide bonds that interact with an antigen. Each heavy chain is composed of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region is composed of three domains, CH1, CH2, and CH3. Each light chain is composed of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region is composed of one domain, CL. The VH and VL regions can be further subdivided into regions of hypervariability, termed complementarity-determining regions (CDRs), interspersed with more conserved regions, termed framework regions (FRs). Each VH and VL is composed of three CDRs and four FRs, arranged from the amino terminus to the carboxy terminus in the following order: FR1, CDR1, FR2, CDR2, FR3, CDR3, and FR4. The variable regions of the heavy and light chains contain binding domains that interact with an antigen. The term "antibody" includes, for example, monoclonal antibodies, human antibodies, humanized antibodies, camelized antibodies, and chimeric antibodies. Antibodies may be of any isotype (e.g., IgG, IgE, IgM, IgD, IgA, and IgY), class (e.g., IgG1, IgG2, IgG3, IgG4, IgA1, and IgA2), or subclass. Both the light and heavy chains are divided into regions of structural and functional homology.

[0026] As used herein, the phrase "antibody fragment" refers to one or more portions of an antibody that retain the ability to specifically interact with an antigen (for example, by binding, steric hindrance, or stabilization of spatial distribution). Examples of binding fragments include, but are not limited to, Fab fragments, i.e., monovalent fragments consisting of VL, VH, CL, and CH1 domains; F(ab')2 fragments, i.e., bivalent fragments containing two Fab fragments linked by a disulfide bridge at the hinge region; Fd fragments consisting of VH and CH1 domains; Fv fragments consisting of the VL and VH domains of a single antibody arm; dAb fragments consisting of the VH domain (Ward et al., (1989) Nature 341:544-546); and isolated complementarity-determining regions (CDRs). Furthermore, although the two domains of an Fv fragment, VL and VH, are encoded by separate genes, they may be joined by a synthetic linker, allowing them to be produced as a single protein chain using recombinant methods; the VL and VH regions pair to form a monovalent molecule (known as a single-chain Fv (scFv)); see, e.g., Bird et al., (1988) Science 242:423-426; and Huston et al., (1988) Proc. Natl. Acad. Sci. 85:5879-5883). Such single-chain antibodies are also intended to be encompassed by the term "antibody fragment." These antibody fragments are obtained using conventional techniques known to those skilled in the art, and the fragments are screened for utility in the same manner as intact antibodies. Antibody fragments may also be incorporated into single domain antibodies, maxibodies, minibodies, intrabodies, diabodies, triabodies, tetrabodies, v-NARs, and bis-scFvs (see, e.g., Hollinger and Hudson, (2005) Nature Biotechnology 23:1126-1136). Antibody fragments may be grafted onto scaffolds based on polypeptides such as fibronectin type III (Fn3) (see U.S. Pat. No. 6,703,199, which describes fibronectin polypeptide monobodies).Antibody fragments may also be assembled into single-chain molecules comprising a pair of tandem Fv segments (VH-CH1-VH-CH1) which, together with complementary light chain polypeptides, form a pair of antigen-binding sites (Zapata et al., (1995) Protein Eng. 8:1057-1062; and U.S. Patent No. 5,641,870).

[0027] "Administered" or "administration" includes, but is not limited to, delivery of a drug in an injectable form, such as intravenous, intramuscular, intradermal, or subcutaneous routes, or by a mucosal route, such as a nasal spray or aerosol for inhalation, or an ingestible solution, capsule, or tablet. Preferably, administration is by an injectable form.

[0028] The term "effector function" refers to a biological activity attributable to the Fc region of an antibody, which varies depending on the antibody isotype. Non-limiting examples of antibody effector functions include C1q binding and complement-dependent cytotoxicity (CDC); Fc receptor binding and antibody-dependent cell-mediated cytotoxicity (ADCC) and / or antibody-dependent phagocytosis (ADCP); down-regulation of cell surface receptors (e.g., B cell receptors); and B cell activation.

[0029] "Antibody-dependent cell-mediated cytotoxicity" or ADCC refers to a form of cytotoxicity in which antibodies coupled to Fc receptors (FcRs) present on certain cytotoxic cells (e.g., NK cells, neutrophils, and macrophages) enable these cytotoxic effector cells to specifically bind to antigen-bearing target cells and subsequently kill the target cells using cytotoxins. NK cells, the primary cells for mediating ADCC, express only FcγRIII, whereas monocytes express FcγRI, FcγRII, and FcγRIII.

[0030] The term "hematological cancer" includes blood-borne tumors and diseases or disorders involving abnormal cell proliferation and / or growth in tissues of hematopoietic origin, such as lymphoma, leukemia, and myeloma.

[0031] Non-Hodgkin's lymphoma (NHL) is a heterogeneous malignant tumor originating from lymphocytes. In the United States (US), the incidence rate is estimated at 65,000 per year, with a mortality rate of approximately 20,000 (American Cancer Society, 2006; and SEER Cancer Statistics Review). The disease can occur at any age, with onset typically beginning in adults over 40 years of age, and incidence rates increasing with age. NHL is characterized by the clonal proliferation of lymphocytes that accumulate in lymph nodes, blood, bone marrow, and spleen, although major organ involvement may occur. The current classification system used by pathologists and clinicians is the World Health Organization (WHO) Classification of Tumors, which categorizes NHL into precursor and mature B-cell or T-cell neoplasms. PDQ currently divides NHL into indolent or aggressive subtypes for clinical trial participation. The indolent NHL group is primarily composed of follicular subtypes, small lymphocytic lymphoma, mucosa-associated lymphoid tissue (MALT), and marginal zone lymphoma; indolent NHL comprises approximately 50% of newly diagnosed B-cell NHL patients. Aggressive NHL primarily includes patients with histologic diagnoses of diffuse large B-cell lymphoma (DLBL, "DLBCL," or DLCL) (40% of all newly diagnosed patients are diffuse large cell), Burkitt lymphoma, and mantle cell lymphoma ("MCL"). The clinical course of NHL is highly variable. The primary determinant of clinical course is the histologic subtype. Most indolent NHL types are considered incurable. Patients initially respond to either chemotherapy or antibody therapy, and most relapse. Previous studies have not demonstrated improved survival with early intervention. In asymptomatic patients, "watch and wait" is acceptable until the patient becomes symptomatic or the pace of disease appears to be accelerating. Over time, the disease may evolve into more aggressive histology. Median survival is 8 to 10 years, and indolent patients often receive three or more lines of therapy during their course of disease. Initial treatment for symptomatic indolent NHL patients has historically been combination chemotherapy.The most commonly used drugs include cyclophosphamide, vincristine, and prednisone (CVP) or cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP). Approximately 70% to 80% of patients respond to initial chemotherapy, with remissions lasting 2 to 3 years. Ultimately, the majority of patients relapse. The discovery and clinical use of the anti-CD20 antibody rituximab has significantly improved response and survival rates. The current standard of care for most patients is rituximab plus CHOP (R-CHOP) or rituximab plus CVP (R-CVP). Rituximab therapy has been shown to be effective in several types of NHL and is currently approved as first-line treatment for both indolent (follicular lymphoma) and aggressive (diffuse large B-cell lymphoma) NHL. However, anti-CD20 monoclonal antibodies (mAbs) have significant limitations, including primary resistance (50% response in relapsed indolent patients), acquired resistance (50% response rate upon retreatment), rare complete responses (2% complete responses in the relapsed population), and a persistent pattern of relapse. Finally, many B-cell disorders cannot be treated using anti-CD20 antibody therapy because many B cells do not express CD20.

[0032] In addition to NHL, there are several types of leukemia caused by dysregulation of B cells. Chronic lymphocytic leukemia (also known as "chronic lymphocytic leukemia" or "CLL") is a type of adult leukemia caused by the abnormal accumulation of B lymphocytes. In CLL, malignant lymphocytes may appear normal and mature but are unable to effectively fight infection. CLL is the most common form of leukemia in adults. Men are twice as likely as women to develop CLL. However, age is a major risk factor. More than 75% of new cases are diagnosed in patients over the age of 50. More than 10,000 cases are diagnosed each year, with a mortality rate of nearly 5,000 per year (American Cancer Society, 2006; and SEER Cancer Statistics Review). CLL is incurable, but in most cases it progresses slowly. Many people with CLL lead normal, active lives for many years. Because of the slow onset of the disease, early intervention is not believed to improve survival or quality of life, so early-stage CLL is generally not treated. Instead, the condition is monitored over time. Initial CLL treatment varies depending on the exact diagnosis and disease progression. There are dozens of drugs used in CLL therapy. Combination chemotherapy regimens such as FCR (fludarabine, cyclophosphamide, and rituximab) and BR (ibrutinib and rituximab) are effective for both newly diagnosed and relapsed CLL. Allogeneic bone marrow (stem cell) transplantation is rarely used as first-line treatment for CLL due to its risks.

[0033] Another type of leukemia is small lymphocytic lymphoma ("SLL"), which is considered a CLL variant that lacks the clonal lymphocytosis required for a CLL diagnosis, but otherwise shares pathological and immunophenotypic features (Campo et al., 2011). The definition of SLL requires the presence of lymphadenopathy and / or splenomegaly. Furthermore, the number of B lymphocytes in the peripheral blood should not exceed 5 × 109 / L. In SLL, the diagnosis should be confirmed by histopathological evaluation of lymph node biopsies whenever possible (Hallek et al., 2008). The incidence of SLL is approximately 25% of CLL cases in the United States (Dores et al., 2007).

[0034] Another type of leukemia is acute lymphoblastic leukemia (ALL), also known as acute lymphocytic leukemia. ALL is characterized by the overproduction and continued proliferation of malignant and immature white blood cells (also known as lymphoblasts) in the bone marrow. The "acute" refers to the undifferentiated, immature state of circulating lymphocytes ("blasts"). If left untreated, the disease progresses rapidly, with an average life expectancy of weeks to months. ALL is most common in childhood, with peak incidence between the ages of 4 and 5. Children aged 12 to 16 are more likely to die than others. Currently, at least 80% of childhood ALL cases are considered curable. Fewer than 4,000 cases are diagnosed each year, with a mortality rate of approximately 1,500 per year (American Cancer Society, 2006; and SEER Cancer Statistics Review).

[0035] As used in this context, "subject" or "patient" refers to any mammal, including rodents such as mice or rats, and primates such as cynomolgus monkeys (Macaca fascicularis) or rhesus monkeys (Macaca mulatta), or humans (Homo sapiens). Preferably, the subject or patient is a primate, most preferably a human patient, and even more preferably an adult human patient.

[0036] The term "Fc region" is used to define the C-terminal region of an immunoglobulin heavy chain. The Fc region of an immunoglobulin generally comprises two constant domains, a CH2 domain and a CH3 domain. Unless otherwise specified herein, the numbering of amino acid residues in the Fc region follows the EU numbering system, also known as the EU index, as described in Kabat et al., Sequences of Proteins of Immunological Interest, 5th Ed. Public Health Service, National Institutes of Health, Bethesda, MD, 1991.

[0037] Agents administered in accordance with the present disclosure are administered to patients in therapeutically effective amounts. A "therapeutically effective amount" refers to an amount sufficient to provide some improvement in the clinical symptoms of a given disease or disorder. The amount effective for a particular therapeutic purpose will also depend on the severity of the disease or injury, as well as the weight and general condition of the subject. It will be understood that determining the appropriate dosage can be accomplished using routine experimentation, constructing a matrix of values, and testing different points within the matrix, all of which are within the ordinary skill of a trained physician or clinical scientist.

[0038] "Survival" refers to the survival of a patient, and includes overall survival and progression-free survival.

[0039] "Overall survival" or "OS" refers to a patient remaining alive for a specified period of time, such as 12 months, 3 years, 5 years, etc., from the time of diagnosis or treatment. For purposes of the clinical trials described in the examples, overall survival (OS) is defined as the time from the date and time of a patient's first dose to the date and time of death from any cause.

[0040] "Progression-free survival" or "PFS" refers to the time that a patient remains alive without cancer progressing or worsening.For the purpose of the clinical trials described in the examples, progression-free survival (PFS) is defined as the time from the patient's first administration to the first documented progressive disease, or unmanageable toxicity, or death from any cause, whichever occurs first.Disease progression can be documented by any clinically accepted method.

[0041] "Extending survival" or "improving survival" means increasing overall survival or progression-free survival in patients treated in accordance with the present disclosure compared to untreated patients and / or compared to patients treated with one or more approved anti-tumor agents but not treated in accordance with the present disclosure.

[0042] "Objective response" refers to a measurable response, including a complete response (CR) or partial response (PR).

[0043] By "complete response" or "CR" is intended the disappearance of all signs of cancer in response to treatment. This does not necessarily mean that the cancer has been cured.

[0044] "Partial response" or "PR" refers to a decrease in the size of one or more tumors or lesions or the extent of cancer in the body in response to treatment.

[0045] "Efficacy data" refers to data obtained in controlled clinical trials that show that a drug effectively treats a disease such as cancer. Efficacy data for MOR00208 are presented in the Examples herein.

[0046] "In combination" refers to the administration of one therapy in addition to another therapy. Thus, "in combination" includes simultaneous (concurrent) and consecutive administration in any order. Non-limiting examples include administering a first therapy (e.g., an agent such as an anti-CD19 antibody) at least 1 minute, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 8 weeks, 9 months, 10 months, 11 months, 12 months, 13 months, 14 months, 15 months, 16 months, 17 months, 18 months, 19 months, 20 months, 21 months, 22 months, 23 months, 24 months, 25 months, 26 months, 27 months, 28 months, 29 months, 30 months, 31 months, 32 months, 33 months, 34 months, 35 months, 36 months, 37 months, 38 months, 39 months, 40 months, 41 months, 42 months, 43 months, 44 months, 45 months, 46 months, 47 months, 48 ​​months, 49 months, 50 months, 51 months, 52 months, 53 months, 54 months, 55 months, 56 months, 57 months, 58 months, 59 months, 60 months, 61 months, 62 months, 63 months, 64 months, 65 months, 66 months, 67 months, 68 months, 69 months, 70 months, 71 months, 72 months, 73 months, 74 months, 75 months, 76 months, The anti-CD19 antibody and the pharmaceutical agent or pharmaceutically acceptable salt thereof may be administered simultaneously or sequentially (e.g., 1 week, 9 weeks, 10 weeks, 11 weeks, or 12 weeks), simultaneously, or sequentially (e.g., 1 minute, 15 minutes, 30 minutes, 45 minutes, 1 hour, 2 hours, 3 hours, 4 hours, 5 hours, 6 hours, 7 hours, 8 hours, 12 hours, 24 hours, 48 ​​hours, 72 hours, 96 hours, 1 week, 2 weeks, 3 weeks, 4 weeks, 5 weeks, 6 weeks, 7 weeks, 8 weeks, 9 weeks, 10 weeks, 11 weeks, or 12 or more weeks). In some embodiments, the term "combination" means that the anti-CD19 antibody and the pharmaceutical agent or pharmaceutically acceptable salt thereof are administered simultaneously or sequentially. In certain embodiments, the anti-CD19 antibody and the pharmaceutical agent or pharmaceutically acceptable salt thereof are administered in separate compositions, i.e., the anti-CD19 antibody and the pharmaceutical agent or pharmaceutically acceptable salt thereof are each administered in separate unit dosage forms. It will be understood that the anti-CD19 antibody and the pharmaceutical agent or pharmaceutically acceptable salt thereof may be administered on the same day or on different days, in any order, according to an appropriate dosing protocol.

[0047] "Thalidomide analogs" include, but are not limited to, thalidomide itself, lenalidomide (CC-5013, Revlimid™), pomalidomide (CC4047, Actimid™), and compounds disclosed in WO2002068414 and WO2005016326, which are incorporated by reference in their entireties. The term refers to synthetic compounds that use the thalidomide structure as a backbone (e.g., side groups have been added or deleted from the parent structure). These analogs differ structurally from thalidomide and its metabolite compounds by differences in alkyl chain length, molecular fragments, one or more functional groups, or altered ionization. The term "thalidomide analogs" also includes metabolites of thalidomide. Thalidomide analogs include the S- and R-enantiomers of the respective compounds, as well as individual racemic mixtures of the S- or R-enantiomers. The racemic mixture is preferred.

[0048] Thalidomide analogs include compounds such as lenalidomide, which has the following structure: [ka]

[0049] Detailed Description of the Disclosure and Embodiments In one aspect, the disclosure relates to a method of treating rr-DLBCL in a human subject, comprising administering to the subject a combination of an anti-CD19 antibody and lenalidomide.

[0050] The use of CD19 antibodies in non-specific B-cell lymphoma is discussed in WO2007076950 (US2007154473), both of which are incorporated by reference. The use of CD19 antibodies in CLL, NHL, and ALL is described in Scheuermann et al., CD19 Antigen in Leukemia and Lymphoma Diagnosis and Immunotherapy, Leukemia and Lymphoma, Vol. 18, 385-397 (1995), which is incorporated by reference in its entirety.

[0051] Additional antibodies specific for CD19 are available from O2005012493 (U.S. Pat. No. 7,109,304), WO2010053716 (U.S. Pat. No. 12 / 266,999) (Immunomedics); WO2007002223 (U.S. Pat. No. 8,097,703) (Medarex); WO2008022152 (U.S. Pat. No. 12 / 377,251) and WO2008150494 (Xencor), WO2008031056 (U.S. Pat. No. 11 / 852,106) (Medimmune); WO 2007076950 (U.S. Pat. No. 11 / 648,505) (Merck Patent GmbH); WO 2009 / 052431 (U.S. Pat. No. 12 / 253,895) (Seattle Genetics); and WO2010095031(12 / 710,442) (Glenmark Pharmaceuticals), WO2012010562 and WO2012010561 (International Drug Development), WO2011147834 (Roche Glycart), and WO 2012 / 156455 (Sanofi), all of which are incorporated by reference in their entirety.

[0052] The pharmaceutical composition comprises an active agent, for example, an antibody for therapeutic use in humans. The pharmaceutical composition may further comprise a pharmaceutically acceptable carrier or excipient.

[0053] In one aspect, the present disclosure relates to a method of treating rr-DLBCL in a human subject, comprising administering to the subject a combination of an anti-CD19 antibody and lenalidomide, wherein the anti-CD19 antibody is administered at a dose of 12 mg / kg in all treatment cycles.

[0054] In another aspect, the disclosure relates to a method of improving survival in a human subject with rr-DLBCL, comprising administering to the subject an anti-CD19 antibody and lenalidomide.

[0055] In yet another aspect, the present disclosure relates to an anti-CD19 antibody for use in the treatment of rr-DLBCL in a human subject in combination with lenalidomide.

[0056] In a further aspect, the present disclosure relates to the use of an anti-CD19 antibody in the preparation of a medicament for the treatment of rr-DLBCL, wherein the treatment comprises administration of an anti-CD19 antibody in combination with lenalidomide.

[0057] In a further aspect, the disclosure relates to the use of an anti-CD19 antibody in the preparation of a medicament for the treatment of rr-DLBCL, wherein the treatment comprises administering the anti-CD19 antibody in combination with lenalidomide. In another aspect, the disclosure relates to a kit comprising a container containing an anti-CD19 antibody and instructions for administering the anti-CD19 antibody in combination with lenalidomide to treat rr-DLBCL in a subject.

[0058] In yet another aspect, the present disclosure relates to a kit comprising a container containing an anti-CD19 antibody and instructions for administering the anti-CD19 antibody in combination with lenalidomide to treat rr-DLBCL in a subject.

[0059] In all aspects, in certain embodiments, the patient has previously received anti-cancer treatment for the hematological cancer. In all aspects, in certain embodiments, administration of an anti-CD19 antibody in combination with lenalidomide improves survival, including overall survival (OS) and / or progression-free survival (PFS) and / or response rate (RR).

[0060] In another embodiment, the present disclosure provides a therapeutic combination of an anti-CD19 antibody and lenalidomide for use in treating a patient with a hematological cancer, wherein the patient has received one line of prior therapy, and wherein the patient's 12-month overall survival is extended to 60%, 70%, 80%, 83%, 85%, or 87% or greater. In a further embodiment, the patient's 12-month progression-free survival is extended to 40%, 45%, 50%, 55%, 58%, or greater.

[0061] In another embodiment, the present disclosure provides a therapeutic combination of an anti-CD19 antibody and lenalidomide for use in treating a patient with a hematological cancer, wherein the patient has received two or more lines of prior therapy, and wherein the patient's 12-month overall survival is extended to 40%, 45%, 50%, 55% or more. In a further embodiment, the patient's 12-month progression-free survival is extended to 30%, 35%, 40%, or more.

[0062] In another embodiment, the present disclosure provides a therapeutic combination of an anti-CD19 antibody and lenalidomide for use in treating a patient with a hematological cancer, wherein the patient has germinal center B-cell (GCB) DLBCL, and wherein the patient's 12-month overall survival is extended to greater than or equal to 50%, 55%, 60%, or 64%. In a further embodiment, the patient's 12-month progression-free survival is extended to greater than or equal to 30%, 35%, or 37%.

[0063] In another embodiment, the present disclosure provides a therapeutic combination of an anti-CD19 antibody and lenalidomide for use in treating a patient with a hematological cancer, wherein the patient has non-germinal center B-cell (non-GCB) DLBCL, and wherein the patient's 12-month overall survival is extended to greater than or equal to 70%, 75%, 80%, or 83%. In a further embodiment, the patient's 12-month progression-free survival is extended to greater than or equal to 60%, 65%, 70%, or 73%.

[0064] In all aspects, treatment involves administration of up to 12 cycles (28 days each) of anti-CD19 antibody and lenalidomide. In one embodiment, treatment is followed by MOR00208 monotherapy until disease progression.

[0065] In all aspects, the treatment comprises administration of an anti-CD19 antibody and lenalidomide, wherein the anti-CD19 antibody is administered intravenously at a dose of 12 mg / kg. In one embodiment, the intravenous administration is over about 2 hours.

[0066] In some aspects, the treatment involves administration of an anti-CD19 antibody and lenalidomide for up to 12 cycles, where for cycles 1-3, the anti-CD19 antibody is administered weekly on days 1, 8, 15, and 22. In one embodiment, an additional loading dose of the anti-CD19 antibody is administered on day 4 of cycle 1. In another embodiment, for cycles 4 and beyond, the anti-CD19 antibody is administered every 14 days on days 1 and 15 of each cycle.

[0067] In all aspects of the study, treatment involved the coadministration of an anti-CD19 antibody and lenalidomide, with patients self-administering lenalidomide orally, starting at 25 mg daily on days 1-21 of each 28-day cycle. In the event of protocol-defined toxicity, escalating dose reductions of lenalidomide (5 mg / day reductions per step, no more than once per cycle, without re-escalation) were permitted.

[0068] In certain aspects, the present disclosure relates to a method of treating a patient with hematological cancer by administering to the patient an anti-CD19 antibody and lenalidomide in amounts that improve progression-free survival (PFS) and / or overall survival (OS), wherein the patient has received one prior line of therapy. In one embodiment, the one prior line of therapy was treatment with R-CHOP. In another embodiment, the one prior line of therapy included treatment with rituximab. In one embodiment, the anti-CD19 antibody is tafasitamab. In one embodiment, the 12-month progression-free survival (PFS) rate is improved to greater than 55%. In one embodiment, the 12-month overall survival (OS) rate is improved to greater than 85%. In one embodiment, the 12-month progression-free survival (PFS) rate is improved to greater than 55% and the 12-month overall survival (OS) rate is improved to greater than 85%. In one embodiment, the amount of tafasitamab to improve progression-free survival (PFS) and / or overall survival (OS) is 12 mg / kg per dose. In another embodiment, the amount of tafasitamab to improve progression-free survival (PFS) and / or overall survival (OS) is a regimen for up to 12 cycles, where for cycles 1-3, tafasitamab is administered weekly on days 1, 8, 15, and 22, and from cycle 4 onwards, tafasitamab is administered every 14 days on days 1 and 15 of each cycle. In one embodiment, the amount of lenalidomide to improve progression-free survival (PFS) and / or overall survival (OS) is 25 mg daily. In a further embodiment, the amounts of tafasitamab and lenalidomide to improve progression-free survival (PFS) and / or overall survival (OS) are 12 mg / kg per dose of tafasitamab and 25 mg daily of lenalidomide. In another embodiment, tafasitamab is administered in a regimen for up to 12 cycles, where during cycles 1-3, tafasitamab is administered weekly on days 1, 8, 15, and 22, and from cycle 4 onwards, tafasitamab is administered every 14 days on days 1 and 15 of each cycle, and lenalidomide is administered daily on days 1-21 of each 28-day cycle, with stepwise dose reductions of lenalidomide in case of protocol-defined toxicity (only once per cycle, with each step being a 5 mg / day reduction, with no re-escalation).

[0069] In certain aspects, the present disclosure relates to a method of treating a patient with hematological cancer by administering to the patient an anti-CD19 antibody and lenalidomide in amounts that improve progression-free survival (PFS) and / or overall survival (OS), wherein the patient has received two or more lines of prior therapy. In one embodiment, the patient has received two lines of prior therapy. In another embodiment, the two lines of prior therapy included treatment with R-CHOP. In another embodiment, the two lines of prior therapy included treatment with rituximab. In one embodiment, the anti-CD19 antibody is tafasitamab. In one embodiment, the 12-month progression-free survival (PFS) rate is improved to greater than 35%. In one embodiment, the 12-month overall survival (OS) rate is improved to greater than 55%. In one embodiment, the 12-month progression-free survival (PFS) rate is improved to greater than 35% and the 12-month overall survival (OS) rate is improved to greater than 55%. In one embodiment, the amount of tafasitamab to improve progression-free survival (PFS) and / or overall survival (OS) is 12 mg / kg per dose. In another embodiment, the amount of tafasitamab to improve progression-free survival (PFS) and / or overall survival (OS) is a regimen for up to 12 cycles, where for cycles 1-3, tafasitamab is administered weekly on days 1, 8, 15, and 22, and from cycle 4 onwards, tafasitamab is administered every 14 days, on days 1 and 15 of each cycle. In one embodiment, the amount of lenalidomide to improve progression-free survival (PFS) and / or overall survival (OS) is 25 mg daily. In a further embodiment, the amounts of tafasitamab and lenalidomide to improve progression-free survival (PFS) and / or overall survival (OS) are 12 mg / kg per dose of tafasitamab and 25 mg daily of lenalidomide.In another embodiment, tafasitamab is administered in a regimen for up to 12 cycles, where during cycles 1-3, tafasitamab is administered weekly on days 1, 8, 15, and 22, and from cycle 4 onwards, tafasitamab is administered every 14 days on days 1 and 15 of each cycle, and lenalidomide is administered daily on days 1-21 of each 28-day cycle, with stepwise dose reductions of lenalidomide in case of protocol-defined toxicity (only once per cycle, with each step being a 5 mg / day reduction, with no re-escalation).

[0070] In certain aspects, the present disclosure relates to a method of treating a patient with hematological cancer by administering to the patient an anti-CD19 antibody and lenalidomide in amounts that improve 12-month progression-free survival (PFS) and / or 12-month overall survival (OS), wherein the patient has germinal center B-cell (GCB)-rr-DLBCL. In one embodiment, the patient has germinal center B-cell (GCB)-rr-DLBCL and has received at least one line of prior therapy, wherein the prior therapy comprises treatment with R-CHOP. In one embodiment, the anti-CD19 antibody is tafasitamab. In one embodiment, the 12-month progression-free survival (PFS) rate is improved to greater than 35%. In one embodiment, the 12-month overall survival (OS) rate is improved to greater than 60%. In one embodiment, the 12-month progression-free survival (PFS) rate is improved to greater than 35%, and the 12-month overall survival (OS) rate is improved to greater than 60%. In one embodiment, the amount of tafasitamab to improve progression-free survival (PFS) and / or overall survival (OS) is 12 mg / kg per dose. In another embodiment, the amount of tafasitamab to improve progression-free survival (PFS) and / or overall survival (OS) is a regimen for up to 12 cycles, where for cycles 1-3, tafasitamab is administered weekly on days 1, 8, 15, and 22, and from cycle 4 onwards, tafasitamab is administered every 14 days, on days 1 and 15 of each cycle. In one embodiment, the amount of lenalidomide to improve progression-free survival (PFS) and / or overall survival (OS) is 25 mg daily. In a further embodiment, the amounts of tafasitamab and lenalidomide to improve progression-free survival (PFS) and / or overall survival (OS) are 12 mg / kg per dose of tafasitamab and 25 mg daily of lenalidomide.In another embodiment, tafasitamab is administered in a regimen for up to 12 cycles, where during cycles 1-3, tafasitamab is administered weekly on days 1, 8, 15, and 22; from cycle 4 onwards, tafasitamab is administered every 14 days on days 1 and 15 of each cycle; and lenalidomide is administered daily on days 1-21 of each 28-day cycle, with stepwise dose reductions of lenalidomide (5 mg / day reduction at each step, only once per cycle, with no re-escalation) in case of protocol-defined toxicity.

[0071] In certain aspects, the present disclosure relates to a method of treating a patient with hematological cancer by administering to the patient an anti-CD19 antibody and lenalidomide in amounts that improve 12-month progression-free survival (PFS) and / or 12-month overall survival (OS), wherein the patient has non-germinal center B-cell (non-GCB) rr-DLBCL. In one embodiment, the patient has non-germinal center B-cell (non-GCB) rr-DLBCL and has received at least one line of prior therapy, the prior therapy comprising treatment with R-CHOP. In one embodiment, the anti-CD19 antibody is tafasitamab. In one embodiment, the 12-month progression-free survival (PFS) rate is improved to greater than 70%. In one embodiment, the 12-month overall survival (OS) rate is improved to greater than 80%. In one embodiment, the 12-month progression-free survival (PFS) rate is improved to greater than 70%, and the 12-month overall survival (OS) rate is improved to greater than 80%. In one embodiment, the amount of tafasitamab to improve progression-free survival (PFS) and / or overall survival (OS) is 12 mg / kg per dose. In another embodiment, the amount of tafasitamab to improve progression-free survival (PFS) and / or overall survival (OS) is a regimen for up to 12 cycles, where for cycles 1-3, tafasitamab is administered weekly on days 1, 8, 15, and 22, and from cycle 4 onwards, tafasitamab is administered every 14 days, on days 1 and 15 of each cycle. In one embodiment, the amount of lenalidomide to improve progression-free survival (PFS) and / or overall survival (OS) is 25 mg daily. In a further embodiment, the amounts of tafasitamab and lenalidomide to improve progression-free survival (PFS) and / or overall survival (OS) are 12 mg / kg per dose of tafasitamab and 25 mg daily of lenalidomide.In another embodiment, tafasitamab is administered in a regimen for up to 12 cycles, where during cycles 1-3, tafasitamab is administered weekly on days 1, 8, 15, and 22; from cycle 4 onwards, tafasitamab is administered every 14 days on days 1 and 15 of each cycle; and lenalidomide is administered daily on days 1-21 of each 28-day cycle, with stepwise dose reductions of lenalidomide (5 mg / day reduction at each step, only once per cycle, with no re-escalation) in case of protocol-defined toxicity.

[0072] In another aspect, the disclosure relates to a method of improving or prolonging survival in a human subject with rr-DLBCL, comprising administering to the subject an anti-CD19 antibody and lenalidomide.

[0073] In yet another aspect, the disclosure relates to an anti-CD19 antibody for use in the treatment of rr-DLBCL in a human subject in combination with lenalidomide.

[0074] In a further aspect, the present disclosure relates to the use of an anti-CD19 antibody in the preparation of a medicament for the treatment of rr-DLBCL, wherein the treatment comprises administration of an anti-CD19 antibody in combination with lenalidomide.

[0075] In yet a further aspect, the present disclosure relates to the use of an anti-CD19 antibody in the preparation of a medicament for the treatment of rr-DLBCL, the treatment comprising administering the anti-CD19 antibody in combination with lenalidomide. In another aspect, the present disclosure relates to a kit comprising a container containing an anti-CD19 antibody and instructions for administering the anti-CD19 antibody in combination with lenalidomide to treat rr-DLBCL in a subject.

[0076] In yet another aspect, the present disclosure relates to a kit comprising a container containing an anti-CD19 antibody and instructions for administering the anti-CD19 antibody in combination with lenalidomide to treat rr-DLBCL in a subject.

[0077] In all aspects, in certain embodiments, the patient has previously received anti-cancer treatment for the hematological cancer. In all aspects, in certain embodiments, administration of an anti-CD19 antibody in combination with lenalidomide improves survival, including overall survival (OS) and / or progression-free survival (PFS) and / or response rate (RR).

[0078] In all aspects, treatment involves administration of up to 12 cycles (28 days each) of anti-CD19 antibody and lenalidomide. In embodiments, treatment is followed by anti-CD19 antibody monotherapy until disease progression.

[0079] In all aspects, the treatment comprises administration of an anti-CD19 antibody and lenalidomide, wherein the anti-CD19 antibody is administered intravenously at a dose of 12 mg / kg. In one embodiment, the intravenous administration is over about 2 hours.

[0080] In some aspects, the treatment involves administration of an anti-CD19 antibody and lenalidomide for up to 12 cycles, where for cycles 1-3, the anti-CD19 antibody is administered weekly on days 1, 8, 15, and 22. In one embodiment, an additional loading dose of the anti-CD19 antibody is administered on day 4 of cycle 1. In another embodiment, for cycles 4 and beyond, the anti-CD19 antibody is administered every 14 days on days 1 and 15 of each cycle.

[0081] In all aspects of the treatment, patients received an anti-CD19 antibody and lenalidomide, with patients self-administering lenalidomide orally, starting at 25 mg daily on days 1–21 of each 28-day cycle. In the event of protocol-defined toxicity, escalating dose reductions of lenalidomide (only once per cycle, with each reduction of 5 mg / day, without re-escalation) were permitted.

[0082] In one embodiment, the anti-CD19 antibody for use in combination with lenalidomide to treat patients with hematological cancers has a variable heavy chain of the following sequence: EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPYNDGTKYNEKFQGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGTYYYGTRVFDYWGQGTLVTVSS (SEQ ID NO: 7) and a variable light chain of the following sequence: DIVMTQSPATLSLSPGERATLSCRSSKSLQNVNGNTYLYWFQQKPGQSPQLLIYRMSNLNSGVPDRFSGSGSGTEFTLTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIK (SEQ ID NO: 8) or a variable heavy chain and a variable light chain having at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to the variable heavy chain of SEQ ID NO: 7 and to the variable light chain of SEQ ID NO: 8.

[0083] In one embodiment, the anti-CD19 antibody for use in combination with lenalidomide to treat patients with hematological cancers has a variable heavy chain of the following sequence: EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPYNDGTKYNEKFQGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGTYYYGTRVFDYWGQGTLVTVSS (SEQ ID NO: 7) and a variable light chain of the following sequence: DIVMTQSPATLSLSPGERATLSCRSSKSLQNVNGNTYLYWFQQKPGQSPQLLIYRMSNLNSGVPDRFSGSGSGTEFTLTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIK (SEQ ID NO: 8) or a variable heavy chain and a variable light chain having at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to the variable heavy chain of SEQ ID NO: 7 and to the variable light chain of SEQ ID NO: 8, wherein the anti-CD19 antibody comprises an HCDR1 region comprising the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region comprising the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region comprising the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region comprising the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region comprising the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region comprising the sequence MQHLEYPIT (SEQ ID NO: 6). In another embodiment, the heavy chain region of the anti-CD19 antibody comprises amino acids 239D and 332E, wherein Fc numbering is according to the EU index as in Kabat.

[0084] In a further embodiment, the anti-CD19 antibody for use in treating patients with hematological cancers in combination with lenalidomide has a heavy chain having the sequence: EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPYNDGTKYNEKFQGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGTYYYGTRVFDYWGQG TLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT CPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKALPAPEEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 11) and a light chain having the sequence DIVMTQSPATLSLSPGERATLSCRSSKSLQNVNGNTYLYWFQQKPGQSPQLLIYRMSNLNSGVPDRFSGSGSGTEFTLTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 12) or a heavy chain and a light chain having at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98% or at least 99% identity to the heavy chain of SEQ ID NO: 7 and to the light chain of SEQ ID NO: 8.

[0085] In a further embodiment, the anti-CD19 antibody for use in treating patients with hematological cancers in combination with lenalidomide has a heavy chain having the sequence: EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPYNDGTKYNEKFQGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGTYYYGTRVFDYWGQG TLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT CPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKALPAPEEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 11) and a light chain having the sequence DIVMTQSPATLSLSPGERATLSCRSSKSLQNVNGNTYLYWFQQKPGQSPQLLIYRMSNLNSGVPDRFSGSGSGTEFTLTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 12) or a heavy chain and a light chain having at least 80%, at least 90%, at least 95%, at least 96%, at least 97%, at least 98%, or at least 99% identity to the heavy chain of SEQ ID NO: 7 and to the light chain of SEQ ID NO: 8, wherein the anti-CD19 antibody comprises an HCDR1 region comprising the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region comprising the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region comprising the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region comprising the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region comprising the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region comprising the sequence MQHLEYPIT (SEQ ID NO: 6). In another embodiment, the heavy chain region of the anti-CD19 antibody comprises amino acids 239D and 332E, wherein Fc numbering is according to the EU index as in Kabat.

[0086] In other embodiments, the disclosure is directed to an anti-CD19 antibody in combination with lenalidomide for use in treating a patient with a hematological cancer, wherein said patient has received one, at least one, two, or at least two lines of prior therapy, and after treatment with an anti-CD19 antibody in combination with lenalidomide, said patient (i) progression-free survival (PFS) of at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 13 months, at least 14 months, at least 15 months, at least 16 months, at least 17 months, at least 18 months, at least 19 months, at least 20 months, at least 24 months, at least 30 months, at least 36 months, at least 42 months, at least 48 months, or at least 54 months; (ii) an objective response rate (ORR) of at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 80%; (iii) duration of response (DoR) lasting at least 10 months, at least 12 months, at least 14 months, at least 16 months, at least 18 months, at least 20 months, at least 24 months, at least 30 months, at least 36 months, at least 42 months, at least 48 months, or at least 54 months; (iv) overall survival (OS) of at least 10 months, at least 12 months, at least 14 months, at least 16 months, at least 18 months, at least 20 months, at least 24 months, at least 30 months, at least 36 months, at least 42 months, at least 48 months, or at least 54 months; (v) A combination of one or more of the foregoing. In another embodiment of the present disclosure, the anti-CD19 antibody is administered in combination with lenalidomide in a dosing regimen as disclosed herein.

[0087] In other embodiments, the present disclosure is directed to an anti-CD19 antibody in combination with lenalidomide for the treatment of a patient with hematological cancer, wherein said patient has germinal center B-cell (GCB) DLBCL, and after said treatment said patient: (i) progression-free survival (PFS) of at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 13 months, at least 14 months, at least 15 months, at least 16 months, at least 17 months, at least 18 months, at least 19 months, at least 20 months, at least 24 months, at least 30 months, at least 36 months, at least 42 months, at least 48 months, or at least 54 months; (ii) an objective response rate (ORR) of at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 80%; (iii) duration of response (DoR) lasting at least 10 months, at least 12 months, at least 14 months, at least 16 months, at least 18 months, at least 20 months, at least 24 months, at least 30 months, at least 36 months, at least 42 months, at least 48 months, or at least 54 months; (iv) overall survival (OS) of at least 10 months, at least 12 months, at least 14 months, at least 16 months, at least 18 months, at least 20 months, at least 24 months, at least 30 months, at least 36 months, at least 42 months, at least 48 months, or at least 54 months; (vi) a combination of one or more of the foregoing. In another embodiment of the present disclosure, the anti-CD19 antibody is administered in combination with lenalidomide in a dosing regimen as disclosed herein.

[0088] In other embodiments, the present disclosure is directed to an anti-CD19 antibody in combination with lenalidomide for the treatment of a patient with hematological cancer, wherein said patient has non-germinal center B-cell (non-GCB) DLBCL, and after said treatment said patient: (i) progression-free survival (PFS) of at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 13 months, at least 14 months, at least 15 months, at least 16 months, at least 17 months, at least 18 months, at least 19 months, at least 20 months, at least 24 months, at least 30 months, at least 36 months, at least 42 months, at least 48 months, or at least 54 months; (ii) an objective response rate (ORR) of at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 80%; (iii) duration of response (DoR) lasting at least 10 months, at least 12 months, at least 14 months, at least 16 months, at least 18 months, at least 20 months, at least 24 months, at least 30 months, at least 36 months, at least 42 months, at least 48 months, or at least 54 months; (iv) overall survival (OS) of at least 10 months, at least 12 months, at least 14 months, at least 16 months, at least 18 months, at least 20 months, at least 24 months, at least 30 months, at least 36 months, at least 42 months, at least 48 months, or at least 54 months; or (vii) a combination of one or more of the foregoing. In another embodiment of the present disclosure, the anti-CD19 antibody is administered in combination with lenalidomide in a dosing regimen as disclosed herein.

[0089] In other embodiments, the present disclosure refers to an anti-CD19 antibody for the treatment of a patient with hematological cancer in combination with lenalidomide, wherein said combination treatment enhances one or more of the following characteristics: (i) progression-free survival (PFS), (ii) objective response rate (ORR); (iii) duration of response (DoR); (iv) overall survival (OS); (v) Time to progression (TTP).

[0090] In another embodiment, one or more of the features (i) to (v) are extended relative to a treatment comprising an anti-CD20 antibody. In a further embodiment, one or more of the features (i) to (v) are extended relative to a treatment comprising an anti-CD20 antibody and a chemotherapeutic agent. In a further embodiment, the anti-CD20 antibody is rituximab or a biosimilar thereof. In a further embodiment, one or more of the features (i) to (v) are extended relative to a treatment comprising an anti-CD20 antibody and one or more of cyclophosphamide, adriamycin, vincristine, or prednisone. In a further embodiment, one or more of the features (i) to (v) are extended relative to a treatment comprising R-CHOP.

[0091] In other embodiments, the disclosure refers to a therapeutic combination comprising an anti-CD19 antibody and lenalidomide for use in treating a patient with a hematological cancer, wherein the patient has received one, at least one, two, or at least two lines of prior therapy, and wherein administration of the anti-CD19 antibody results in an increase in progression-free survival (PFS), an improvement in objective response rate (ORR), an improvement in duration of response (DoR), an increase in overall survival (OS), or an increase in progression-free survival (TTP).

[0092] In other embodiments, the present disclosure refers to a therapeutic combination comprising an anti-CD19 antibody and lenalidomide for use in treating a patient with a hematological cancer, wherein the patient has received one, at least one, two, or at least two lines of prior therapy, and wherein administration of the anti-CD19 antibody results in improved progression-free survival (PFS) compared to administration of an anti-CD20 antibody, improved objective response rate (ORR) compared to administration of an anti-CD20 antibody, improved duration of response (DoR) compared to administration of an anti-CD20 antibody, improved overall survival (OS) compared to administration of an anti-CD20 antibody, or improved time to progression (TTP) compared to administration of an anti-CD20 antibody.

[0093] In other embodiments, the disclosure refers to a therapeutic combination comprising an anti-CD19 antibody and lenalidomide for use in treating a patient with a hematological cancer, wherein the patient has germinal center B-cell (GCB) DLBCL, and wherein administration of the anti-CD19 antibody results in an increased progression-free survival (PFS), improved objective response rate (ORR), improved duration of response (DoR), improved overall survival (OS), or improved progression-free survival (TTP).

[0094] In other embodiments, the disclosure refers to a therapeutic combination comprising an anti-CD19 antibody and lenalidomide for use in treating a patient with a hematological cancer, wherein the patient has germinal center B-cell (GCB) DLBCL, and wherein administration of the anti-CD19 antibody results in improved progression-free survival (PFS) compared to administration of an anti-CD20 antibody, improved objective response rate (ORR) compared to administration of an anti-CD20 antibody, improved duration of response (DoR) compared to administration of an anti-CD20 antibody, improved overall survival (OS) compared to administration of an anti-CD20 antibody, or improved time to progression (TTP) compared to administration of an anti-CD20 antibody.

[0095] In other embodiments, the disclosure refers to a therapeutic combination comprising an anti-CD19 antibody and lenalidomide for use in treating a patient with a hematological cancer, wherein the patient has non-germinal center B-cell (non-GCB) DLBCL, and wherein administration of the anti-CD19 antibody results in an increase in progression-free survival (PFS), an improvement in objective response rate (ORR), an improvement in duration of response (DoR), an improvement in overall survival (OS), or an improvement in progression-free survival (TTP).

[0096] In other embodiments, the disclosure refers to a therapeutic combination comprising an anti-CD19 antibody and lenalidomide for use in treating a patient with a hematological cancer, wherein the patient has non-germinal center B-cell (non-GCB) DLBCL, wherein administration of the anti-CD19 antibody results in improved progression-free survival (PFS) compared to administration of an anti-CD20 antibody, improved objective response rate (ORR) compared to administration of an anti-CD20 antibody, improved duration of response (DoR) compared to administration of an anti-CD20 antibody, improved overall survival (OS) compared to administration of an anti-CD20 antibody, or improved time to progression (TTP) compared to administration of an anti-CD20 antibody.

[0097] In other embodiments, the disclosure refers to an anti-CD19 antibody for use in treating a patient with a hematological cancer in combination with lenalidomide, wherein administration of said anti-CD19 antibody in combination with lenalidomide results in an increased progression-free survival (PFS) compared to administration of R-CHOP, an increased objective response rate (ORR) compared to administration of R-CHOP, an increased duration of response (DoR) compared to administration of R-CHOP, an increased overall survival (OS) compared to administration of R-CHOP, or an increased time to progression (TTP) compared to administration of R-CHOP.

[0098] In another embodiment, the hematological cancer patient has double-hit diffuse large B-cell lymphoma. In another embodiment, the hematological cancer patient has triple-hit diffuse large B-cell lymphoma.

[0099] In another embodiment, the hematological cancer patient has double-hit or triple-hit diffuse large B-cell lymphoma.

[0100] In another embodiment, the hematological cancer patient is a hematological cancer patient with diffuse large B-cell lymphoma arising from the transformation of an indolent lymphoma.

[0101] In one embodiment, the present disclosure provides an anti-CD19 antibody, wherein said anti-CD19 antibody is administered at a concentration of 12 mg / kg.

[0102] In a further embodiment, the anti-CD19 antibody is administered weekly, biweekly, or monthly. In a further embodiment, the anti-CD19 antibody is administered weekly for the first three months and then every other week for at least the next three months. In a further embodiment, the anti-CD19 antibody is administered weekly for the first three months. In a further embodiment, the anti-CD19 antibody is administered weekly for the first three months and then every other week for at least the next three months. In another embodiment, the anti-CD19 antibody is administered weekly for the first three months, every other week for the next three months, and monthly thereafter. In yet another embodiment, the anti-CD19 antibody is administered weekly for the first three months, every other week for the next three months, and monthly thereafter.

[0103] Indications and patients The present disclosure provides a therapeutic combination comprising an anti-CD19 antibody and lenalidomide for use in treating a patient with a hematological cancer, wherein the patient has chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL), small lymphocytic lymphoma (SLL), or acute lymphoblastic leukemia (ALL). In another embodiment, the patient with hematological cancer has non-Hodgkin's lymphoma. In a further embodiment, the non-Hodgkin's lymphoma is selected from the group consisting of follicular lymphoma, small lymphocytic lymphoma, mucosa-associated lymphoid tissue, marginal zone lymphoma, diffuse large B-cell lymphoma, Burkitt's lymphoma, and mantle cell lymphoma. In a further embodiment, the non-Hodgkin's lymphoma is relapsed or refractory diffuse large B-cell lymphoma (rr-DLBCL). In another embodiment, the hematological cancer patient has diffuse large B-cell lymphoma and is ineligible for high-dose chemotherapy (HDC) and / or autologous stem cell transplant (ASCT). In another embodiment, the hematological cancer patient has relapsed or refractory diffuse large B-cell lymphoma (rr-DLBCL) and is ineligible for high-dose chemotherapy (HDC) and / or autologous stem cell transplant (ASCT). In another embodiment, the hematological cancer patient has relapsed or refractory diffuse large B-cell lymphoma (rr-DLBCL) arising from an indolent lymphoma and is ineligible for high-dose chemotherapy (HDC) and / or autologous stem cell transplant (ASCT). In a further embodiment, the non-Hodgkin's lymphoma is relapsed or refractory diffuse large B-cell lymphoma (rr-DLBCL) arising from an indolent lymphoma.

[0104] In another embodiment, the hematological cancer patient has diffuse large B-cell lymphoma, and the patient is selected based on one or more of the following criteria: 1. Age > 18 years old 2. Histologically confirmed diagnosis of DLBCL 3. Tumor tissue must be provided for central pathology review and correlative studies. 4. Patients must have: Relapsed and / or refractory disease b. At least one bidimensionally measurable PET-positive disease area (lateral diameter ≥ 1.5 cm, perpendicular diameter ≥ 1.0 cm at baseline) c. Received at least one but no more than three prior systemic regimens for the treatment of DLBCL, with one line of treatment having included a CD20-targeted therapy d. Eastern Cooperative Oncology Group 0-2 5. Patients who are not considered eligible in the investigator's opinion or who are unwilling to undergo intensive salvage therapy, including ASCT 6. Patients must meet the following testing criteria at screening: Absolute neutrophil count ≥ 1.5 x 10 9 / L b. Platelet count ≧90×10 9 / L c. Total serum bilirubin ≤ 2.5 × ULN or ≤ 5 × ULN (in cases of liver damage due to Griebert syndrome or lymphoma) d. Alanine transaminase, aspartate aminotransferase, and alkaline phosphatase ≤ 3 x ULN or < 5 x ULN (in cases of liver involvement) e. Serum creatinine clearance ≥ 60 mL / min 7. Women of childbearing potential (FCBP) should: a. Not pregnant b. Refrain from breastfeeding and from donating blood or oocytes c. Agree to ongoing pregnancy testing d. Commit to continuous abstinence from heterosexual intercourse or agree to and be able to adhere to the use of double-barrier contraception 8. Men (if sexually active with FCBP) a. Effective barrier methods of contraception must be used b. Blood or sperm donation should be avoided. 9. In the opinion of the investigator, the patient must: Able and willing to receive appropriate prophylaxis and / or treatment for thromboembolic events b. Understand the reasons for adhering to the special terms of the pregnancy prevention risk management plan and are able to approve this in writing.

[0105] In another embodiment, the hematological cancer patient has double-hit diffuse large B-cell lymphoma.

[0106] In another embodiment, the hematological cancer patient has triple-hit diffuse large B-cell lymphoma.

[0107] In another embodiment, the hematological cancer patient has double-hit or triple-hit diffuse large B-cell lymphoma.

[0108] In another embodiment, the hematological cancer patient is a hematological cancer patient with diffuse large B-cell lymphoma arising from the transformation of an indolent lymphoma.

[0109] In another embodiment, the hematological cancer patient has diffuse large B-cell lymphoma, and the patient is excluded based on one or more of the following exclusion criteria: 1. Patients with: a. Other histological types of lymphoma b. Primary refractory DLBCL c. The history of "double / triple hit" genetics 2. Patients who have had any of the following within 14 days prior to dosing on Day 1: a. Uninterrupted CD20-targeted therapy, chemotherapy, radiation therapy, investigational anticancer therapy, or other lymphoma-specific treatment b. Have undergone major surgery or suffered a serious injury c. Received a live vaccine. d. Parenteral antimicrobial therapy as needed for active concurrent infections 3. Patients with the following: a. Previously treated with CD19-targeted therapy or IMiDs® (e.g., thalidomide, LEN) b. Have undergone ASCT within the 3 months prior to signing the informed consent form. c. Previous allogeneic stem cell transplant d. History of deep vein thrombosis / embolism and unwillingness / ability to undergo venous thromboembolic event prophylaxis throughout the treatment period e. Concurrent use of other anti-cancer or experimental treatments 4. History of malignancy other than DLBCL, unless the patient has been disease-free for more than 5 years prior to screening. 5. For patients with: Positive hepatitis B and / or hepatitis C serology. b. Known seropositivity or history of active viral infection with human immunodeficiency virus (HIV) c. CNS lymphoma involvement d. History or evidence of clinically significant cardiovascular, CNS, and / or other systemic disease that, in the opinion of the investigator, would prevent participation in the study or impair the patient's ability to give informed consent.

[0110] method In another embodiment of the present disclosure, the expected benefit from the therapeutic administration of an anti-CD19 antibody in combination with lenalidomide is improved progression-free survival (PFS), improved objective response rate (ORR), improved duration of response (DoR), improved overall survival (OS), or improved time to progression (TTP), or a combination thereof.

[0111] In another embodiment of the present disclosure, the expected benefit from the therapeutic administration of an anti-CD19 antibody in combination with lenalidomide is improved progression-free survival (PFS) compared to administration of an anti-CD20 antibody, improved objective response rate (ORR) compared to administration of an anti-CD20 antibody, improved duration of response (DoR) compared to administration of an anti-CD20 antibody, improved overall survival (OS) compared to administration of an anti-CD20 antibody, or improved time to progression (TTP) compared to administration of an anti-CD20 antibody, or a combination thereof.

[0112] In another embodiment of the present disclosure, the expected benefit from therapeutic administration of an anti-CD19 antibody in combination with lenalidomide is: (i) progression-free survival (PFS) of at least 8 months, at least 9 months, at least 10 months, at least 11 months, at least 12 months, at least 13 months, at least 14 months, at least 15 months, at least 16 months, at least 17 months, at least 18 months, at least 19 months, or at least 20 months; (ii) an objective response rate (ORR) of at least 30%, at least 40%, at least 50%, at least 60%, at least 70%, at least 80%, or at least 80%; (iii) duration of response (DoR) lasting at least 10 months, at least 12 months, at least 14 months, at least 16 months, at least 18 months, at least 20 months, at least 24 months, at least 30 months, at least 36 months, at least 42 months, at least 48 months, or at least 54 months; (iv) overall survival (OS) of at least 10 months, at least 12 months, at least 14 months, at least 16 months, at least 18 months, at least 20 months, at least 24 months, at least 30 months, at least 36 months, at least 42 months, at least 48 months, or at least 54 months; (v) A combination of one or more of the foregoing. In another embodiment of the present disclosure, the anti-CD19 antibody is administered in combination with a pharmaceutical agent as disclosed herein.

[0113] In another embodiment of the present disclosure, the expected benefit from therapeutic administration of an anti-CD19 antibody in combination with lenalidomide is improved progression-free survival (PFS) compared to administration of an anti-CD20 antibody and chemotherapy, improved objective response rate (ORR) compared to administration of an anti-CD20 antibody and chemotherapy, improved duration of response (DoR) compared to administration of an anti-CD20 antibody and chemotherapy, improved overall survival (OS) compared to administration of an anti-CD20 antibody and chemotherapy, or improved time to progression (TTP) compared to administration of an anti-CD20 antibody and chemotherapy. In a further embodiment, the anti-CD20 antibody is rituximab or a biosimilar thereof. In a further embodiment, the chemotherapeutic agent comprises one or more of cyclophosphamide, adriamycin, vincristine, or prednisone.

[0114] In another embodiment of the present disclosure, the expected benefit from the therapeutic administration of an anti-CD19 antibody in combination with lenalidomide is improved progression-free survival (PFS) compared to administration of R-CHOP, improved objective response rate (ORR) compared to administration of R-CHOP, improved duration of response (DoR) compared to administration of R-CHOP, improved overall survival (OS) compared to administration of R-CHOP, or improved time to progression (TTP) compared to administration of R-CHOP.

[0115] In another embodiment of the present disclosure, the expected benefit from the therapeutic administration of an anti-CD19 antibody in combination with lenalidomide is an increase in one or more of the following characteristics: (i) progression-free survival (PFS), (ii) Objective response rate (ORR) (iii) duration of response (DoR); (iv) overall survival (OS); (v) Time to progression (TTP).

[0116] In another embodiment, the increase in one or more of characteristics (i)-(v) is compared to a treatment comprising an anti-CD20 antibody. In a further embodiment, the increase in one or more of characteristics (i)-(v) is compared to a treatment comprising an anti-CD20 antibody and a chemotherapeutic agent. In a further embodiment, the anti-CD20 antibody is rituximab or a biosimilar thereof. In a further embodiment, the increase in one or more of characteristics (i)-(v) is compared to a treatment comprising an anti-CD20 antibody and one or more of cyclophosphamide, adriamycin, vincristine, or prednisone. In a further embodiment, the increase in one or more of characteristics (i)-(v) is compared to a treatment comprising R-CHOP.

[0117] In certain embodiments of the present disclosure, the hematological cancer patient predicted to benefit from therapeutic administration of an anti-CD19 antibody and lenalidomide has chronic lymphocytic leukemia (CLL), non-Hodgkin's lymphoma (NHL), small lymphocytic lymphoma (SLL), or acute lymphoblastic leukemia (ALL). In a further embodiment, the hematological cancer patient has non-Hodgkin's lymphoma. In a further embodiment, the hematological cancer patient has non-Hodgkin's lymphoma, the non-Hodgkin's lymphoma selected from the group consisting of follicular lymphoma, small lymphocytic lymphoma, mucosa-associated lymphoid tissue, marginal zone lymphoma, diffuse large B-cell lymphoma, Burkitt's lymphoma, and mantle cell lymphoma. In a further embodiment, the hematological cancer patient has relapsed or refractory diffuse large B-cell lymphoma (rr-DLBCL). In a further embodiment, the hematological cancer patient has relapsed or refractory diffuse large B-cell lymphoma (rr-DLBCL) and has received one, at least one, two, or at least two lines of prior therapy. In a further embodiment, the hematological cancer patient has relapsed or refractory diffuse large B-cell lymphoma (rr-DLBCL) and has received one line of prior therapy. In a further embodiment, the hematological cancer patient has relapsed or refractory diffuse large B-cell lymphoma (rr-DLBCL) and has received rituximab as a prior therapy. In a further embodiment, the hematological cancer patient has relapsed or refractory diffuse large B-cell lymphoma (rr-DLBCL) and has received R-CHOP as a prior therapy. In a further embodiment, the hematological cancer patient has relapsed or refractory diffuse large B-cell lymphoma (rr-DLBCL) and has received two lines of prior therapy. In a further embodiment, the hematological cancer patient has relapsed or refractory diffuse large B-cell lymphoma (rr-DLBCL) where the patient has non-germinal center B-cell (non-GCB) DLBCL. In a further embodiment, the hematological cancer patient has relapsed or refractory diffuse large B-cell lymphoma (rr-DLBCL) where the patient has germinal center B-cell (GCB) DLBCL.

[0118] In a further embodiment of the disclosure, the hematological cancer patient expected to benefit from therapeutic administration of an anti-CD19 antibody and lenalidomide is administered an anti-CD19 antibody comprising an HCDR1 region comprising the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region comprising the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region comprising the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region comprising the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region comprising the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region comprising the sequence MQHLEYPIT (SEQ ID NO: 6). EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPYNDGTKYNEKFQGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGTYYYGTRVFDYWGQGTLVTVSS (SEQ ID NO: 7) and a variable light chain of the following sequence: DIVMTQSPATLSLSPGERATLSCRSSKSLQNVNGNTYLYWFQQKPGQSPQLLIYRMSNLNSGVPDRFSGSGSGTEFTLTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIK (SEQ ID NO: 8).

[0119] In a further embodiment, the anti-CD19 antibody comprises a heavy chain having the sequence: EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPYNDGTKYNEKFQGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGTYYYGTRVFDYWGQG TLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT CPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKALPAPEEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 11) and a light chain having the sequence DIVMTQSPATLSLSPGERATLSCRSSKSLQNVNGNTYLYWFQQKPGQSPQLLIYRMSNLNSGVPDRFSGSGSGTEFTLTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 12).

[0120] In another aspect, the present disclosure relates to a method of treating a hematological cancer patient with rr-DLBCL, comprising administering to the subject an anti-CD19 antibody and lenalidomide.

[0121] In yet another aspect, the disclosure relates to an anti-CD19 antibody for use in treating a hematological cancer patient with rr-DLBCL in combination with lenalidomide.

[0122] In a further aspect, the present disclosure relates to the use of an anti-CD19 antibody in the preparation of a medicament for the treatment of a hematological cancer patient with rr-DLBCL, the treatment comprising administration of an anti-CD19 antibody in combination with lenalidomide.

[0123] In another embodiment, the hematological cancer patient has double-hit diffuse large B-cell lymphoma.

[0124] In another embodiment, the hematological cancer patient has triple-hit diffuse large B-cell lymphoma.

[0125] In another embodiment, the hematological cancer patient has double-hit or triple-hit diffuse large B-cell lymphoma.

[0126] In another embodiment, the hematological cancer patient is a hematological cancer patient with diffuse large B-cell lymphoma arising from the transformation of an indolent lymphoma. In another embodiment, the hematological cancer patient is a hematological cancer patient with diffuse large B-cell lymphoma arising from the transformation of an indolent lymphoma, including, but not limited to, follicular lymphoma or marginal zone lymphoma. In some embodiments, the diffuse large B-cell lymphoma arising from the transformation of an indolent lymphoma is transformed follicular lymphoma or transformed marginal zone lymphoma. In another embodiment, the hematological cancer patient is a hematological cancer patient with diffuse large B-cell lymphoma, where the diffuse large B-cell lymphoma is transformed lymphoma. In another embodiment, the hematological cancer patient is a hematological cancer patient with diffuse large B-cell lymphoma, where the diffuse large B-cell lymphoma is transformed indolent lymphoma. In another embodiment, the hematological cancer patient is a hematological cancer patient with diffuse large B-cell lymphoma, where such diffuse large B-cell lymphoma arises from transformation of a low-grade lymphoma or an indolent lymphoma. In a further embodiment, the hematological cancer patient with diffuse large B-cell lymphoma has relapsed or refractory diffuse large B-cell lymphoma (rr-DLBCL). In another embodiment, the hematological cancer patient has relapsed or refractory diffuse large B-cell lymphoma and is ineligible for high-dose chemotherapy (HDC) and / or autologous stem cell transplant (ASCT). In another embodiment, the hematological cancer patient has relapsed or refractory diffuse large B-cell lymphoma (rr-DLBCL) and is ineligible for high-dose chemotherapy (HDC) and / or autologous stem cell transplant (ASCT). In another embodiment, the hematological cancer patient has relapsed or refractory diffuse large B-cell lymphoma (rr-DLBCL) arising from an indolent lymphoma and is ineligible for high-dose chemotherapy (HDC) and / or autologous stem cell transplant (ASCT). In a further embodiment, the non-Hodgkin's lymphoma is relapsed or refractory diffuse large B-cell lymphoma (rr-DLBCL) arising from an indolent lymphoma. [Table 1-1] [Table 1-2] [Example]

[0127] Example 1: MOR00208 in combination with lenalidomide in relapsed or refractory diffuse large B-cell lymphoma Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) typically have poor outcomes and limited treatment options. MOR00208, an Fc-enhanced humanized anti-CD19 monoclonal antibody, has demonstrated preclinical and single-agent activity in patients with relapsed or refractory B-cell malignancies. Treatment of patients with relapsed or refractory DLBCL with MOR00208 in combination with lenalidomide was clinically investigated.

[0128] Patients and study design This open-label, single-arm, multicenter, phase 2 trial began in March 2016. Patients were enrolled at 35 centers in 10 countries across Europe and the United States through November 2017 (Supplementary Appendix). Adult patients (≥18 years of age) with histologically confirmed DLBCL (including indolent lymphoma with subsequent DLBCL relapse) who had relapsed after or were refractory to at least one but no more than three systemic regimens (including at least one anti-CD20 therapy) and were not candidates for high-dose chemotherapy followed by ASCT were eligible. Additional inclusion criteria were adequate organ function, Eastern Cooperative Oncology Group performance status of 0–2, and measurable disease at baseline. Exclusion criteria included any other histological type of lymphoma, a history of "double / triple-hit" DLBCL if known, prior treatment with anti-CD19 therapy or immunomodulatory agents such as thalidomide or lenalidomide, or primary refractory DLBCL (defined as lack of response during frontline therapy or progression within 6 months of treatment). Prior to the protocol amendment, only patients who relapsed within 3 months of a previous anti-CD20-containing regimen were defined as primary refractory and were excluded. Therefore, patients who relapsed or progressed between 3 and 6 months of frontline therapy were recruited before the protocol amendment and were considered primary refractory patients.

[0129] Treatment consisted of coadministration of MOR00208 and lenalidomide for up to 12 cycles (28 days each), followed by MOR00208 monotherapy (for patients with stable or better disease) until disease progression. MOR00208 was administered intravenously over approximately 2 hours at a dose of 12 mg / kg. In cycles 1–3, MOR00208 was administered weekly on days 1, 8, 15, and 22. An additional loading dose was administered on day 4 of cycle 1. Beginning with cycle 4, MOR00208 was administered every 14 days on days 1 and 15 of each cycle. Patients received oral lenalidomide, starting at 25 mg daily on days 1–21 of each 28-day cycle. In the event of protocol-defined toxicity, escalating dose reductions of lenalidomide (only once per cycle, with a 5 mg / day reduction at each stage, without further dose escalation) were permitted.

[0130] The primary endpoint was the objective response rate, defined as complete response plus partial response. Secondary endpoints included disease control rate (complete response + partial response + stable disease), duration of response, time to next treatment, progression-free survival, overall survival, time to progression, incidence and severity of adverse events, as well as immunogenicity (presence of anti-MOR00208 antibodies), pharmacokinetics, and biomarker analysis (measurements of B cells, T cells, and NK cells over time, including cell of origin).

[0131] The analysis of the primary endpoint was performed when all patients completed a minimum of 12 months of follow-up. Efficacy analyses were based on the complete analysis set, including all patients who received at least one dose of both MOR00208 and lenalidomide; safety analyses were based on patients who received at least one dose of either study drug. Sample size was determined assuming that combination therapy could improve the objective response rate from 20% (monotherapy) to 35% (combination therapy). Applying an exact binomial test with a two-sided significance level of 5% and a power of 85%, the estimated sample size was 73 patients. Assuming a dropout rate of 10%, a total sample size of 80 patients was estimated. Statistical analyses were performed using SAS® software, version 9.4 or later (SAS Institute, Cary, NC).

[0132] result: A total of 81 patients were enrolled and received at least one dose of either study drug (and were assessed for safety), and 80 received at least one dose of both MOR00208 and lenalidomide (and were assessed for efficacy). In total, 30 (37.0%) patients successfully completed 12 cycles of MOR00208 and lenalidomide therapy, and 28 (34.6%) were receiving MOR00208 monotherapy at the time of data cutoff.

[0133] The assessed objective response rate was 60.0% (95% confidence interval [CI], 48.4–70.8%), with 34 (42.5%) patients achieving a complete response and 14 (17.5%) achieving a partial response (Table 2). Overall agreement between both centrally and investigator-assessed objective response rates was 88.2%. Positron emission tomography scans, performed in 30 / 34 (88.2%) patients who achieved a complete response, confirmed the results obtained from computed tomography in all cases. The disease control rate was 73.8% (95% CI, 62.7–83.0% in 59 patients). The median time to response (partial or complete response) was 2 months (range, 1.7–16.8 months), and the median time to complete response was 7.1 months (range, 1.7–17.0 months). Analysis of objective response rates by patient baseline characteristics showed high and consistent response rates across most subgroups, including those refractory to previous therapy (Figure 1). [Table 2]

[0134] The median response duration was 21.7 months (95% CI, not reached 21.7 months), and the 12-month response rate was 71.6% (95% CI, 55.1%-82.9%). Among patients who achieved a complete response, the median response duration had not yet been reached. The 12-month and 18-month response rates were 93.2% (95% CI, 75.4%-98.3%). Among patients who achieved a partial response, the median response duration was 4.4 months (95% CI, 2.0%-9.1%). Median progression-free survival was 12.1 months (95% CI, not reached, 5.7 months). Patients who were progression-free at 12 months (50.2% [95% CI, 37.9-61.2%]) tended to remain progression-free at 18 months (45.8% [95% CI, 33.4-57.4%]). Median progression-free survival after discontinuation of lenalidomide was 12.7 months (95% CI, not reached, 2.3 months). Median overall survival had not yet been reached. 73.7% of patients (95% CI, 62.2-82.2%) were alive at 12 months.

[0135] safety The median duration of exposure to study treatment was 9.3 months (range, 0.2-32.1 months). The median duration of exposure to combination therapy or lenalidomide was 6.2 months (range, 0.1-12.5 months), and the median duration of exposure to MOR00208 monotherapy (after lenalidomide discontinuation) was 4.1 months (range, 0.1-20.8 months).

[0136] Treatment-emergent adverse events occurred in 81 (100%) patients. The most common treatment-emergent adverse event (all grades) and the most common grade 3 or higher adverse event were neutropenia, occurring in 40 (49.4%) and 39 (48.1%) patients, respectively. Neutropenia was managed with granulocyte colony-stimulating factor in 36 (44.4%) patients, with the majority (81% of grade 3 / 4 neutropenia) recovering to baseline levels within 1 week. The next most common grade 3 or higher events were thrombocytopenia (14 [17.3%] patients), febrile neutropenia (10 [12.3%]), leukopenia (7 [8.6%]), anemia (6 [7.4%]), and pneumonia / lung infection (6 [7.4%]). The majority of nonhematologic adverse events were grade 1 and 2. Diarrhea was the most common, occurring in 27 (33.3%) patients (grade 2 in 9 [11.1%] and grade 3 in 1 [1.2%]), with a median duration of 8 days. 29 (35.8%) patients experienced various types of rash, most of which were grade 2 or lower. Infusion-related reactions (all grade 1) were observed in 5 (6.2%) patients. All occurred once during the first infusion and did not require interruption of the infusion.

[0137] Serious adverse events occurred in 41 / 81 (50.6%) patients, of which 15 / 81 (18.5%) were suspected by the investigator to be related to treatment, mainly infections (8 [9.9%]) or febrile neutropenia (4 [4.9%]). In total, 14 / 81 (17.3%) patients discontinued lenalidomide and / or MOR00208 due to adverse events at any time during the study. Seven (8.6%) patients experienced adverse events of special interest (as defined by the protocol): three tumor flares (one each of grades 1 to 3), one grade 2 basal cell carcinoma, and three grade 3 allergic dermatitis.

[0138] Thirty deaths (37.0%) were recorded, eight occurring during study treatment and 22 occurring after treatment. Twenty-three deaths were related to lymphoma progression and seven were unrelated to disease progression. Treatment-related adverse events leading to death occurred in four patients (sudden death, respiratory failure, cerebrovascular accident, and progressive multifocal leukoencephalopathy), none of which were considered by the investigators to be related to study treatment.

[0139] Discontinuing lenalidomide (after cycle 13 per protocol, or earlier in the case of toxicity) reduced the incidence and severity of treatment-emergent adverse events with MOR00208 monotherapy. Grade 3 or 4 neutropenia occurred in 6 / 51 (11.8%) patients during this phase. In total, grade 3 or 4 adverse events were reported in 56 / 81 (70.0%) patients before lenalidomide discontinuation compared with 15 / 51 (29.4%) after lenalidomide discontinuation.

[0140] conclusion In this population of patients with relapsed or refractory DLBCL who were ineligible for stem cell transplantation, treatment with MOR00208 in combination with lenalidomide induced an overall objective response in 60% of patients and a complete response in 42.5%. Furthermore, responses were durable, with a median response duration of 21.7 months. Among patients who achieved a complete response, the response rate was 93.2% over an 18-month period. The median follow-up period was approximately 20 months, and median overall survival (OS) was not reached. In the context of other recently reported drug trials in similar populations, our results represent a promising treatment option. In particular, previous studies have reported objective response rates of 26% (SCHOLAR-1) (Blood 130, 1800-1808, 2017), 33% with lenalidomide plus rituximab (Leukemia 27, 1902-1909, 2013), 25% with ibrutinib monotherapy (Nat. Med. 21, 922-926, 2015), and 28% with lenalidomide monotherapy (Clin. Cancer Res. 23, 4127-4137, 2017).

[0141] The L-MIND trial demonstrates the benefit of adding MOR00208 to lenalidomide, given that single-agent lenalidomide demonstrated objective response rates ranging from 27.5% to 35% in patients with relapsed or refractory aggressive non-Hodgkin lymphoma (including DLBCL) (Clin. Cancer Res. 23, 4127–4137, 2017; Ann. Oncol. 22, 1622–1627, 2011; J. Clin. Oncol. 26, 4952–7, 2008) and single-agent MOR00208 demonstrated an objective response rate of 26% in patients with relapsed or refractory DLBCL (Ann. Oncol. 29, 1266–1272, 2018). The greater activity of L-MIND is likely due to the complementary mechanisms of action of both agents. The observed increase in NK cell numbers after treatment as a result of lenalidomide-mediated lowering of the activation threshold (Blood 126, 50-60, 2015) may be a factor behind this synergistic effect. CD19 appears to be a useful alternative target for patients not cured with previous anti-CD20-based immunochemotherapy, and a randomized phase 2 / 3 trial is underway to investigate the combination of MOR00208 with chemotherapy in patients previously exposed to rituximab (NCT02763319).

[0142] These data from this trial support the potential of MOR00208 in combination with lenalidomide as an effective and well-tolerated chemotherapy-free option for the treatment of patients with relapsed or refractory DLBCL who are ineligible for ASCT.

[0143] Example 2: MOR00208 in combination with lenalidomide in a subgroup with relapsed or refractory diffuse large B-cell lymphoma Of the 81 enrolled patients, 80 received MOR00208 plus lenalidomide and were included in the full efficacy analysis set (FAS). The median follow-up period was 17.3 months. In the FAS, the ORR was 60.0% (95% confidence interval [CI]: 48.4-70.8) (Table 3). The CR rate was 42.5% (n=34 / 80), of which 88.2% (n=30 / 34) were confirmed by PET. The median time to response (PR or CR) was 2.0 months, and the median time to CR was 7.1 months. The median DOR was 21.7 months (95% CI: 21.7-not reached [NR]); the median PFS was 12.1 months (95% CI: 5.7-NR); the median OS was NR (95% CI: 18.3-NR), and the median follow-up period was 19.6 months. The 12-month DOR and OS rates were 71.6% (95% CI: 55.1-82.9) (Table 3) and 73.7% (95% CI: 62.2-82.2) (Table 3), respectively.

[0144] Subgroup analysis showed that patients with a CR (best objective response) had a better outcome than those with a PR: median DOR was NR (95% CI: 21.7-NR) vs. 4.4 months (95% CI: 2.0-9.1); 12-month DOR rate was 93.2% (95% CI: 75.4-98.3) vs. 14.4% (95% CI: 1.1-43.7); and 12-month OS rate was 97.1% vs. 76.9%.

[0145] Patients with one prior line of treatment tended to have a better outcome than those with two or more prior lines: ORR, 70.0% vs. 50.0%. 12-month OS rates, 86.9% vs. 60.1%. However, 12-month DOR rates were similar regardless of the number of prior lines (one prior line: 70.5% [95% CI: 47.2-85.0] vs. two or more prior lines: 72.7% [95% CI: 46.3-87.6]).

[0146] For patients who were refractory to first-line or their last line of therapy, a similar ORR was observed compared with non-refractory patients (60.0% vs. 60.0%). The 12-month DOR was similar to that of the last line of therapy, regardless of refractory status. Additionally, the 12-month OS rate was higher in non-refractory patients (Table 3).

[0147] As expected, patients with low / low-intermediate International Prognostic Index (IPI) scores had better outcomes than patients with intermediate-high / high scores: ORR, 70.0% vs. 50.0%, 12-month DOR rate, 86.5% vs. 50.4%, and 12-month OS rate, 87.0% vs. 59.9%.

[0148] Based on the Hans algorithm, encouraging results were reported in patients with germinal center B-cell (GCB) DLBCL (n=37), with even better outcomes in patients with non-GCB DLBCL (n=21): ORR, 48.6% vs. 71.4%; 12-month DOR, 53.5% vs. 83.1%; and 12-month OS, 65.4% vs. 84.2% (Table 3). Given the historically poor activity of single-agent lenalidomide in the GCB subgroup (Clin. Cancer Res. 23, 4127-4137, 2017; Oncologist 21, 1107-12, 2016; Annals of Oncology 26, 2015), these results suggest greater activity and synergy for the combination of MOR00208 and lenalidomide. [Table 3]

[0149] Overall, the MOR00208+LEN combination followed by MOR00208 monotherapy has shown promising activity with durable responses in ASCT-ineligible patients with R / RDLBCL. L-MIND includes a significant subgroup of patients with poor prognosis. While the impact of these risk factors is clear, the clinical activity of MOR00208+LEN in these patients is encouraging, especially in those who were refractory to prior therapy.

[0150] Example 3: Updated MOR00208 plus lenalidomide subgroup Patients in the L-MIND study had a median age of 72 years (range 41–86) at enrollment and had received a median of two prior lines of therapy (range 1–4). All patients had received R-CHOP or equivalent chemoimmunotherapy prior to study enrollment. Due to the availability of additional data from central pathology review for two patients, baseline patient characteristics by immunohistochemistry and cell of origin by gene expression profiling have been updated since the primary analysis (Table 4). There was one patient each with double-hit and triple-hit DLBCL.

[0151] Clinically notable patient subgroups included 15 patients (18.5%) with primary refractory disease, 34 patients (42.0%) with rituximab-refractory disease, and 36 patients (44.4%) who were refractory to their last line of therapy. Most patients who were refractory to their last line of therapy had received two prior lines of therapy (71.4%), with the last prior line including chemotherapy in 94.4% of patients and rituximab in 80.0%. Baseline characteristics of the refractory subgroup were generally comparable to those of the overall population (Table 4), although patients in the refractory subgroup were more likely to have increased lactate dehydrogenase and germinal center B cells of origin by immunohistochemistry. [Table 4]

[0152] From medical history records in seven patients with transformed lymphoma and as current disease in one patient with B-cell lymphoma (progressing on cycle 1, day 1). Refractory subgroups may overlap. Primary refractory disease, defined as progression during first-line therapy and / or PD or SD response to first-line therapy or PD within 6 months after completion of first-line therapy. Rituximab-refractory, defined as PD or SD to any rituximab-containing regimen or PD during or within 6 months of completion of any rituximab-containing line of therapy. Last-treatment-refractory, defined as PD or SD to the most recent treatment administered prior to study enrollment.

[0153] Based on clinical history and central pathology, eight patients had DLBCL arising from transformation of low-grade lymphoma, with one patient each having double-hit and triple-hit lymphoma. Of the eight patients with transformed lymphoma, four experienced partial response and three experienced complete response. The patient with double-hit lymphoma (MYC and BCL2 translocation) was refractory to the last line of treatment prior to L-MIND (R-dexamethasone-cytarabine-cisplatin) and achieved partial response. The patient with triple-hit lymphoma (MYC, BCL2, and BCL6 translocation) previously responded to R-CHOP and experienced a 4.5-month complete response. One month after relapse, he began lenalidomide in addition to tafasitamab. This patient experienced a complete response with L-MIND and maintained remission for over 30 months. Swimmer plots for all these patients are shown in Figure 2. Overall, two patients with double-hit and triple-hit lymphoma and seven of eight patients with transformed lymphoma responded to treatment.

Claims

1. 1. A pharmaceutical composition comprising an anti-CD19 antibody for use in treating primary refractory diffuse large B-cell lymphoma (DLBCL) in a human subject, comprising: wherein said anti-CD19 antibody comprises an HCDR1 region comprising the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region comprising the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region comprising the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region comprising the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region comprising the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region comprising the sequence MQHLEYPIT (SEQ ID NO: 6), said anti-CD19 antibody is IgG1, IgG2, or IgG1 / IgG2, and the heavy chain constant region of said anti-CD19 antibody comprises amino acids 239D and 332E, wherein Fc numbering is according to the EU index of Kabat; wherein the antibody is administered in combination with lenalidomide.

2. 1. A pharmaceutical composition comprising an anti-CD19 antibody for use in treating non-germinal center B-cell (non-GCB) DLBCL in a human subject, comprising: wherein said anti-CD19 antibody comprises an HCDR1 region comprising the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region comprising the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region comprising the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region comprising the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region comprising the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region comprising the sequence MQHLEYPIT (SEQ ID NO: 6), said anti-CD19 antibody is IgG1, IgG2, or IgG1 / IgG2, and the heavy chain constant region of said anti-CD19 antibody comprises amino acids 239D and 332E, wherein Fc numbering is according to the EU index of Kabat; wherein the antibody is administered in combination with lenalidomide.

3. The pharmaceutical composition according to claim 2, wherein the non-GCB DLBCL is non-GCB relapsed or refractory DLBCL.

4. the anti-CD19 antibody comprising a variable heavy chain comprising the sequence EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPYNDGTKYNEKFQGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGTYYYGTRVFDYWGQGTLVTVSS (SEQ ID NO: 7); and 4. The pharmaceutical composition of any one of claims 1 to 3, comprising a variable light chain comprising DIVMTQSPATHLSPGERATLSCRSSKSLQNVNGNTYLYWFQQKPGQSPQLLIYRMSNLNSGVPDRFSGSGSGTEFTLTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIK (SEQ ID NO: 8).

5. The anti-CD19 antibody has the sequence EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPYNDGTKYNEKFQGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGTYYYGTRVFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTF PAVLQSSGLYSLSSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCV VVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKALPAPEEKTISKTKGQPREPQVYTLPPSR EEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 11), and a heavy chain comprising the sequence DIVMTQSPATTLSLSPGERATTLSCRSSKSLQNVNGNTYLYWFQQKPGQSPQLLIYRMSNLNSGVPDRFSGSGSGT 4. The pharmaceutical composition of any one of claims 1 to 3, comprising a light chain comprising EFTLTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 12).

6. 1. Use of an anti-CD19 antibody in the manufacture of a medicament for treating primary refractory diffuse large B-cell lymphoma (DLBCL) in combination with lenalidomide, comprising: wherein the anti-CD19 antibody comprises an HCDR1 region comprising the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region comprising the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region comprising the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region comprising the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region comprising the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region comprising the sequence MQHLEYPIT (SEQ ID NO: 6), wherein the anti-CD19 antibody is IgG1, IgG2, or IgG1 / IgG2, and the heavy chain constant region of the anti-CD19 antibody comprises amino acids 239D and 332E, wherein Fc numbering is according to the EU index of Kabat.

7. 1. Use of an anti-CD19 antibody in the manufacture of a medicament for treating non-germinal center B-cell (non-GCB) DLBCL in combination with lenalidomide, comprising: wherein the anti-CD19 antibody comprises an HCDR1 region comprising the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region comprising the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region comprising the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region comprising the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region comprising the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region comprising the sequence MQHLEYPIT (SEQ ID NO: 6), wherein the anti-CD19 antibody is IgG1, IgG2, or IgG1 / IgG2, and the heavy chain constant region of the anti-CD19 antibody comprises amino acids 239D and 332E, wherein Fc numbering is according to the EU index of Kabat.

8. The use according to claim 7, wherein the non-GCB DLBCL is non-GCB relapsed or refractory DLBCL.

9. the anti-CD19 antibody comprises a variable heavy chain comprising the sequence EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPYNDGTKYNEKFQGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGTYYYGTRVFDYWGQGTLVTVSS (SEQ ID NO: 7); 9. The use of any one of claims 6 to 8, comprising a variable light chain comprising the sequence DIVMTQSPATHLSPGERATLSCRSSKSLQNVNGNTYLYWFQQKPGQSPQLLIYRMSNLNSGVPDRFSGSGSGTEFTLTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIK (SEQ ID NO: 8).

10. The anti-CD19 antibody has the sequence EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPYNDGTKYNEKFQGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGTYYYGTRVFDYWGQGTLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHT FPAVLQSSGLYSLSSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTC VVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKALPAPEEKTISKTKGQPREPQVYTLPP a heavy chain comprising the sequence DIVMTQSPATTLSLSPGERATLSCRSSKSLQNVNGNTYLYWFQQKPGQSPQLLIYRMSNLNSGVPDRFSGSG; 9. The use of any one of claims 6 to 8, comprising a light chain comprising SGTEFTLTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 12).

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