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

Abstract

This invention provides a pharmaceutical composition for use in the treatment of patients with blood cancer. [Solution] A pharmaceutical composition comprising a therapeutic combination of an anti-CD19 antibody and lenalidomide is provided. The treatment is the pharmaceutical composition which extends overall survival and / or progression-free survival in patients with a particular type of hematological cancer.

Description

Technical Field

[0001] The present disclosure relates to a therapeutic combination of an anti-CD19 antibody and lenalidomide for use in the treatment of patients with blood cancer. Further, the present disclosure relates to the prolongation of overall survival and / or progression-free survival in patients having a specific type of blood cancer.

Background Art

[0002] CD19 is a 95 kDa transmembrane glycoprotein of the immunoglobulin superfamily that contains two extracellular immunoglobulin-like domains and an extensive cytoplasmic tail. This protein is a ubiquitous B-lymphocyte surface receptor that is expressed ubiquitously from the early stages of pre-B cell development until downregulated during the final differentiation into plasma cells. It is specific to the B-lymphocyte lineage and is not expressed in hematopoietic stem cells and 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 the humoral immune response. It functions as a co-stimulatory molecule in association with CD21 and CD81 and is important for the B-cell response to T-cell-dependent antigens. The cytoplasmic tail of CD19 is physically associated with a family of tyrosine kinases that induce downstream signaling pathways via the src family of protein tyrosine kinases. CD19 is highly expressed in almost all chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL), as well as many other different types of leukemia such as acute lymphocytic leukemia (ALL) and hairy cell leukemia (HCL), and thus is an attractive target for cancers of lymphoid origin.

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

[0004] The Phase 2 L-MIND trial (NCT02399085) evaluated the efficacy of tafacitamab 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 or were refractory to 1–3 systemic regimens. Patients received tafacitamab (12 mg / kg) and lenalidomide (25 mg / day) concurrently for up to 12 cycles (28 days each), followed by MOR00208 monotherapy (in patients with stable or better disease) until disease progression. The primary endpoint was objective response rate (central assessment). In this population of patients with relapsed or refractory DLBCL who are unsuitable for stem cell transplantation, combination therapy with tafacitamab and lenalidomide induced an overall objective response in 60% of patients and a complete response in 42.5%, demonstrating that the combination of tafacitamab and lenalidomide is a promising treatment option.

[0005] This disclosure aims to extend progression-free survival in a patient population with relapsed or refractory diffuse large B-cell lymphoma (rr-DLBCL); to treat patients who have previously received at least one or two lines of treatment (e.g., R-CHOP (rituximab and cyclophosphamide, adriamycin, vincristine and prednisone (CHOP))) with tafacitamab and lenalidomide; and to treat patients with relapsed or refractory diffuse large B-cell lymphoma (rr-DLBCL). The present invention relates to extending overall survival in patients with lymphoma (rr-DLBCL) cancer; to treating patients with relapsed or refractory diffuse large B-cell lymphoma (rr-DLBCL) using a combination of tafacitamab and lenalidomide, wherein the relapsed or refractory diffuse large B-cell lymphoma (rr-DLBCL) is either germline B-cell (GCB) rr-DLBCL or non-germline B-cell (non-GCB) rr-DLBCL. [Overview of the project]

[0006] This disclosure provides a novel treatment regimen for patients with certain hematological cancers. In particular, this disclosure relates to the treatment of rr-DLBCL with a combination of an anti-CD19 antibody and lenalidomide.

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

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

[0009] In another aspect, the disclosure relates to a therapeutic combination of an anti-CD19 antibody and lenalidomide for use in the treatment of a population of patients with hematological cancers, said treatment resulting in an extension of overall survival for patients in this population.

[0010] In a further embodiment, the disclosure relates to a therapeutic combination of an anti-CD19 antibody and lenalidomide for use in the treatment of a population of patients with hematological cancers, the treatment resulting in an extension of the overall survival of the patients.

[0011] In a further embodiment, the disclosure relates to a therapeutic combination of an anti-CD19 antibody and lenalidomide for use in the treatment of a population of hematological cancer patients, said treatment resulting in an extension of progression-free survival for said patients.

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

[0013] In a further embodiment, the anti-CD19 antibody for use in combination with lenalidomide to treat patients with hematological cancers is a variable heavy chain with the following sequence. EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPYNDGTKYNEKFQGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGTYYYGTRVFDYWGQGTLVTVSS(Sequence ID 7) and variable light chains in the following sequence Includes DIVMTQSPATLSLSPGERATLSCRSSKSLQNVNGNTYLYWFQQKPGQSPQLLIYRMSNLNSGVPDRFSGSGSGTEFTLTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIK (Sequence ID 8).

[0014] In another embodiment of this disclosure, the anti-CD19 antibody is human, humanized, or chimeric. In another embodiment of this disclosure, the anti-CD19 antibody is an IgG isotype antibody. In another embodiment, the antibody is IgG1, IgG2, or an IgG1 / IgG2 chimeric antibody. In another embodiment of this 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 the Fc numbering follows the EU index, as in the case of Kabat. In another embodiment, the antibody is IgG1, IgG2, or IgG1 / IgG2, and the chimeric heavy chain constant region of the anti-CD19 antibody comprises amino acids 239D and 332E, where the Fc numbering follows the EU index, as in the case of Kabat.

[0015] In a further embodiment, the anti-CD19 antibody for use in combination with lenalidomide to treat patients with hematological cancers has a heavy chain having the following sequence EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPYNDGTKYNEKFQGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGTYYYGTRVFDYWGQG TLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTH TCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKALPAPEEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK(Sequence ID 11) and light chain having the following sequence Includes DIVMTQSPATLSLSPGERATLSCRSSKSLQNVNGNTYLYWFQQKPGQSPQLLIYRMSNLNSGVPDRFSGSGSGTEFTLTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (Sequence ID 12).

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

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

[0018] If necessary, a therapeutic combination of anti-CD19 antibody and lenalidomide can increase the 12-month overall survival rate of patients in a population of hematological malignancies to over 60%. In one embodiment, patients in the treated population have germinal center B-cell type (GCB) DLBCL.

[0019] If necessary, a therapeutic combination of anti-CD19 antibody and lenalidomide can result in a 12-month overall survival rate of over 80% for patients in a population of hematological malignancies. In one embodiment, patients in the treated population have germinal center B-cell type (non-GCB) DLBCL.

[0020] This disclosure provides a novel treatment regimen for patients with hematological malignancies. In particular, this 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 drawing]

[0021] [Figure 1] Objective response rates based on baseline characteristics: Two patients showed double-hit or triple-hit DLBCL status, but this was unknown at the start of the study. One patient developed "double-hit" DLBCL and achieved the best objective response of partial response. One patient developed "triple-hit" DLBCL and achieved the 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 in patients with diffuse large B-cell lymphoma arising from transformation of low-grade lymphoma and double-hit lymphoma 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.

Mode for Carrying Out the Invention

[0022] Definition The term "CD19" refers to a protein known as CD19 having 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: MPPPRLLFFLLFLTPMEVRPEEPLVVKVEEGDNAVLQCLKGTSDGPTQQLTWSRESPLKPFLKLSLGLPGLGIHMRPLAIWLFIFNVSQQMGGFYLCQPGPPSEKAWQPGWTVNVEGSGELFRWNVSDLGGLGCGLKNRSSEGPSSPSGKLMSPKLYVWAKDRPEIWEGEPPCLPPRDSLNQSLSQDLTMAPGSTLWLSCGVPPDSVSRGPLSWTHVHPKGPKSLLSLELKDDRPARDMWVMETGLLLPRATAQDAGKYYCHRGNLTMSFHLEITARPVLWHWLLRTGGWKVSAVTLAYLIFCLCSLVGILHLQRALVLRRKRKRMTDPTRRFFKVTPPPGSGPQNQYGNVLSLPTPTSGLGRAQRWAAGLGGTAPSYGNPSSDVQADGALGSRSPPGVGPEEEEGEGYEEPDSEEDSEFYENDSNLGQDQLSQDGSGYENPEDEPLGPEDEDSFSNAESYENEDEELTQPVARTMDFLSPHGSAWDPSREATSLGSQSYEDMRGILYAAPQLRSIRGQPGPNHEEDADSYENMDNPDGPDPAWGGGGRMGTWSTR (SEQ ID NO: 13)

[0024] "Tafasitamab", "MOR00208", and "XmAb5574" are used as synonyms 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 herein 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 consists of a heavy chain variable region (abbreviated herein as VH) and a heavy chain constant region. The heavy chain constant region consists of three domains CH1, CH2, and CH3. Each light chain consists of a light chain variable region (abbreviated herein as VL) and a light chain constant region. The light chain constant region consists of one domain CL. The VH and VL regions can be further subdivided into hypervariable regions called complementarity-determining regions (CDRs), interspersed with more conserved regions called framework regions (FRs). Each VH and VL consists of three CDRs and four FRs arranged from the amino terminus to the carboxyl 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 the antigen. The term "antibody" includes, for example, monoclonal antibodies, human antibodies, humanized antibodies, camelized antibodies, and chimeric antibodies. Antibodies may be 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 term “antibody fragment” refers to one or more portions of an antibody that possess the ability to specifically interact with an antigen (e.g., 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 disulfide crosslinks in the hinge region; Fd fragments consisting of VH and CH1 domains; Fv fragments consisting of VL and VH domains of a single arm of the antibody; dAb fragments consisting of a VH domain (Ward et al., (1989) Nature 341:544-546); and isolated complementarity-determining regions (CDRs). Furthermore, although the two domains of the Fv fragment, VL and VH, are encoded by separate genes, they may be joined by a synthetic linker that allows them to be constructed as a single protein chain using recombination, so that the VL and VH regions pair up to form a monovalent molecule (known as single-stranded 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-stranded antibodies are also intended to be included in the term “antibody fragment.” These antibody fragments are obtained using conventional techniques known to those skilled in the art, and these 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, for example, Hollinger and Hudson, (2005) Nature Biotechnology 23:1126-1136). Antibody fragments can be transplanted onto polypeptide-based scaffolds such as fibronectin type III (Fn3) (see U.S. Patent No. 6,703,199 describing fibronectin polypeptide monobodies).The antibody fragment may be incorporated into a single-chain molecule containing a pair of tandem Fv segments (VH-CH1-VH-CH1) that, together with a complementary light chain polypeptide, 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 "administered" means, but is not limited to, delivery of a drug in an injectable form, such as via an intravenous, intramuscular, intradermal, or subcutaneous route, or via a mucosal route, such as an inhaled nasal spray or aerosol, or an ingestible solution, capsule, or tablet. Preferably, administration is by an injectable form.

[0028] The term "effector function" refers to the biological activity that may be 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); downregulation 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 bound to Fc receptors (FcRs) present on certain cytotoxic cells (e.g., NK cells, neutrophils, and macrophages) allow these cytotoxic effector cells to specifically bind to antigen-carrying target cells, subsequently killing the target cells using cytotoxicity. Primary ADCC-mediated cells, such as NK cells, express only FcγRIII, while monocytes express FcγRI, FcγRII, and FcγRIII.

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

[0031] Non-Hodgkin lymphoma ("NHL") is a heterogeneous malignant tumor originating from lymphocytes. In the United States (US), the incidence is estimated at 65,000 cases 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 typical onset beginning in adults over 40 years of age, and the incidence increases with age. NHL is characterized by clonal proliferation of lymphocytes that accumulate in lymph nodes, blood, bone marrow, and the spleen, although major organs may be involved. The current classification system used by pathologists and clinicians is the World Health Organization (WHO) tumor classification, which classifies NHL into precursor and mature B-cell or T-cell neoplasms. PDQ currently divides NHL into painless and invasive types for participation in clinical trials. The painless NHL group consists mainly of follicular subtypes, small lymphocytic lymphoma, MALT (mucosa-associated lymphoid tissue), and marginal zone; painless accounts for approximately 50% of newly diagnosed B-cell NHL patients. Invasive NHL includes patients with histological diagnoses of diffuse large B-cell lymphoma (DLBL, "DLBCL," or DLCL) (40% of all newly diagnosed patients are diffuse large B-cell), Burkitt lymphoma, and mantle cell lymphoma ("MCL"). The clinical course of NHL is highly diverse. The primary determinant of the clinical course is the histological subtype. Most painless types of NHL are considered incurable. Patients initially respond to either chemotherapy or antibody therapy, and most relapse. Previous studies have not demonstrated improved survival rates with early intervention. In asymptomatic patients, "watch and wait" is acceptable until the patient becomes symptomatic or the disease appears to be progressing at an accelerating pace. Over time, this disease may develop a more aggressive histology. The median survival time is 8 to 10 years, and painless patients often receive three or more treatments during the course of treatment for the disease. Historically, the initial treatment for symptomatic painless NHL patients has been combination chemotherapy.The most commonly used drugs are cyclophosphamide, vincristine, and prednisone (CVP); or cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP). Approximately 70% to 80% of patients respond to initial chemotherapy, with remission lasting about 2 to 3 years. Ultimately, the majority of patients relapse. The discovery and clinical use of rituximab, an anti-CD20 antibody, has significantly improved response and survival rates. The current standard of care for most patients is rituximab + CHOP (R-CHOP) or rituximab + CVP (R-CVP). Rituximab therapy has been shown to be effective in several types of NHL and is now approved as a first-line treatment for both painless (follicular lymphoma) and aggressive NHL (diffuse large B-cell lymphoma). However, anti-CD20 monoclonal antibodies (mAbs) have significant limitations, including primary resistance (50% response rate in relapsed painless patients), acquired resistance (50% response rate upon retreatment), rare complete response (2% complete response rate in the relapsed population), and a persistent pattern of relapse. Finally, since many B cells do not express CD20, many B cell disorders cannot be treated with anti-CD20 antibody therapy.

[0032] In addition to NHL, there are several other types of leukemia caused by B-cell dysregulation. Chronic lymphocytic leukemia (also known as “chronic lymphocytic leukemia” or “CLL”) is a type of adult leukemia caused by an abnormal accumulation of B lymphocytes. In CLL, malignant lymphocytes may appear normal and mature, but they are unable to effectively fight infection. CLL is the most common form of adult leukemia. Men are twice as likely to develop CLL as women. However, the primary risk factor is age. More than 75% of new cases are diagnosed in patients over 50 years of age. 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 an incurable disease, but in most cases it progresses slowly. Many people with CLL live normal, active lives for many years. Because of its late onset, early CLL intervention is generally not considered to improve survival or quality of life, and therefore, early-stage CLL is not typically treated. Instead, the condition is monitored over time. Initial CLL treatment varies depending on the accurate diagnosis and disease progression. Dozens of drugs are used to treat CLL. 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 a first-line treatment for CLL due to its associated risks.

[0033] Another type of leukemia is small lymphocytic lymphoma ("SLL"), which is considered a CLL variant lacking the clonal lymphocytosis necessary for 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, diagnosis should be confirmed by histopathological evaluation of lymph node biopsy whenever possible (Hallek et al., 2008). The incidence of SLL is approximately 25% of CLL in the United States (Dores et al., 2007).

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

[0035] As used in this context, “subject,” “test subject,” or “patient” refers to any mammal, including rodents such as mice or rats, and primates such as cynomolgus macaques (Macaca fascicularis) and rhesus macaques (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 contains two constant domains, namely the CH2 domain and the 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] The drugs administered in accordance with this disclosure are administered to the patient in a therapeutically effective dose. “Therapeutic dose” means a dose sufficient to provide some degree of improvement in the clinical symptoms of a given disease or disorder. The dose effective for a particular therapeutic purpose also depends on the severity of the disease or disorder, as well as the subject's weight and overall condition. It is understood that determining an appropriate dose can be achieved by using routine experiments to construct a matrix of values ​​and testing different points within the matrix, all of which are within the normal skill of a trained physician or clinical scientist.

[0038] "Survival" refers to the period during which a patient is still alive, and includes overall survival and progression-free survival.

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

[0040] "Progression-free survival" or "PFS" refers to the period during which a patient is still alive without the cancer progressing or worsening. For the purposes of the clinical trials described in the Examples, progression-free survival (PFS) is defined as the time from the patient's first dose to the first occurrence of either the first demonstrated progressive disease, uncontrollable toxicity, or death from either cause. Disease progression may be demonstrated in a clinically accepted manner.

[0041] "Extended survival" or "improved survival" means an increase in overall survival or progression-free survival in patients treated in accordance with this disclosure compared to untreated patients and / or patients treated with one or more approved antitumor agents but not treated in accordance with this disclosure.

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

[0043] "Complete response" or "CR" refers to 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 reduction in the size of one or more tumors or lesions, or the extent of cancer within the body, in response to treatment.

[0045] "Efficacy data" refers to data obtained in comparative clinical trials that demonstrate the effective treatment of diseases such as cancer. Efficacy data for MOR00208 is shown in the examples provided herein.

[0046] "Combined" refers to the administration of one treatment in addition to another. Therefore, "combined" includes simultaneous (contemporary) and sequential administration in any order. A non-limiting example is administering the first therapy (e.g., a drug such as an anti-CD19 antibody) to the patient before administering the second therapy (e.g., a drug or a pharmaceutically acceptable salt thereof) (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, 8 weeks, 8 They may be administered simultaneously or subsequently (for example, for weeks, 9 weeks, 10 weeks, 11 weeks, or 12 weeks), simultaneously, or subsequently (for example, for 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 or more, 9 weeks, 10 weeks, 11 weeks, or 12 weeks or more). In some embodiments, the term “combination” means that the anti-CD19 antibody and the pharmaceutical or a pharmaceutically acceptable salt thereof are administered simultaneously or sequentially. In certain embodiments, the anti-CD19 antibody and the pharmaceutical or a pharmaceutically acceptable salt thereof are administered in separate compositions, i.e., the anti-CD19 antibody and the pharmaceutical or a pharmaceutically acceptable salt thereof are administered in separate unit dosage forms. It is understood that anti-CD19 antibodies and their pharmaceuticals or pharmaceutically acceptable salts 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 the compounds disclosed in WO2002068414 and WO2005016326, which are incorporated by reference. This term refers to synthetic compounds that use the thalidomide structure as a backbone (for example, with added or deleted side groups from the parent structure). These analogs differ structurally from thalidomide and its metabolites by differences in alkyl chain length, molecular fragmentation, one or more functional groups, or changes in ionization. The term "thalidomide analog" also includes thalidomide metabolites. Thalidomide analogs include the S- and R-enantiomers of each compound, as well as individual racemic mixtures of the S-enantiomer or R-enantiomer. A racemic mixture is preferred.

[0048] Examples of thalidomide analogs include compounds such as lenalidomide, which have the following structure: [ka]

[0049] Detailed description of this disclosure and embodiments In one embodiment, the present disclosure relates to a method for treating rr-DLBCL in human subjects, comprising administering a combination of an anti-CD19 antibody and lenalidomide to the target.

[0050] The use of CD19 antibodies in nonspecific 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 in its entirety by reference.

[0051] Additional antibodies specific to CD19 include O2005012493 (US Patent No. 7109304), WO2010053716 (US12 / 266,999) (Immunomedics); WO2007002223 (US Patent No. 8097703) (Medarex); WO2008022152 (12 / 377,251) and WO2008150494 (Xencor), WO2008031056 (US11 / 852,106) (Medimmune); WO 2007076950 (US11 / 648,505) (Merck Patent GmbH); WO 2009 / 052431 (US12 / 253,895) (Seattle This information is also found in 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.

[0052] The pharmaceutical composition includes an activator, for example, an antibody for therapeutic use in humans. The pharmaceutical composition may further include a pharmaceutically acceptable carrier or excipient.

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

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

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

[0056] In a further embodiment, 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 includes the administration of an anti-CD19 antibody in combination with lenalidomide.

[0057] In a further embodiment, the disclosure relates to the use of an anti-CD19 antibody in the preparation of a pharmacopoeia for the treatment of rr-DLBCL, wherein the treatment includes the administration of the anti-CD19 antibody in combination with lenalidomide. In another embodiment, the disclosure relates to a kit comprising a container containing an anti-CD19 antibody and instructions for the administration of the anti-CD19 antibody in combination with lenalidomide for the treatment of a target rr-DLBCL.

[0058] In yet another embodiment, 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 a target rr-DLBCL.

[0059] In all embodiments, and in specific embodiments, the patient had previously received anticancer treatment for hematological malignancy. In all embodiments, and in specific 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 Disclosure provides a therapeutic combination of an anti-CD19 antibody and lenalidomide for use in the treatment of a patient with hematological cancer, the patient having received one line of prior treatment, and the patient's 12-month overall survival rate is extended to 60%, 70%, 80%, 83%, 85%, or 87% or higher. In a further embodiment, the patient's 12-month progression-free survival is extended to 40%, 45%, 50%, 55%, 58%, or higher.

[0061] In another embodiment, the disclosure provides a therapeutic combination of an anti-CD19 antibody and lenalidomide for use in the treatment of patients with hematological cancers, the patients having received two or more lines of prior treatment, and the patients' 12-month overall survival rate is extended to 40%, 45%, 50%, 55% or higher. In a further embodiment, the patients' 12-month progression-free survival is extended to 30%, 35%, 40%, or higher.

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

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

[0064] In all embodiments, treatment involves administration of an anti-CD19 antibody and lenalidomide for up to 12 cycles (28 days each). In one embodiment, after treatment, MOR00208 monotherapy is continued until the disease progresses.

[0065] In all embodiments, the treatment comprises the administration of an anti-CD19 antibody and lenalidomide, the anti-CD19 antibody being administered intravenously at a dose of 12 mg / kg. In one embodiment, the intravenous administration takes approximately 2 hours or more.

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

[0067] In all aspects, treatment involved the co-administration of an anti-CD19 antibody and lenalidomide. Patients with hematological malignancies self-administered lenalidomide orally, starting with 25 mg daily on days 1-21 of each 28-day cycle. In cases of toxicity as defined in the protocol, gradual dose reduction of lenalidomide (decreasing by 5 mg / day at each stage, only once per cycle, without re-increasing) was permitted.

[0068] In certain embodiments, the disclosure relates to a method for treating a patient with hematological malignancy by administering to the patient an amount of anti-CD19 antibody and lenalidomide that improves progression-free survival (PFS) and / or overall survival (OS), wherein the patient has previously received one line of treatment. In one embodiment, one line of prior treatment was treatment with R-CHOP. In another embodiment, one line of prior treatment included treatment with rituximab. In one embodiment, the anti-CD19 antibody is tafacitamab. In one embodiment, the 12-month progression-free survival (PFS) rate is improved to more than 55%. In one embodiment, the 12-month overall survival (OS) rate is improved to more than 85%. In one embodiment, the 12-month progression-free survival (PFS) rate is improved to more than 55%, and the 12-month overall survival (OS) rate is improved to more than 85%. In one embodiment, the dose of tafacitamab to improve progression-free survival (PFS) and / or overall survival (OS) is 12 mg / kg per dose. In another embodiment, the dose of tafacitamab to improve progression-free survival (PFS) and / or overall survival (OS) is a regimen of up to 12 cycles, where for cycles 1-3, tafacitamab is administered weekly on days 1, 8, 15, and 22, and from cycle 4 onward, tafacitamab is administered every 14 days, on days 1 and 15 of each cycle. In one embodiment, the dose of lenalidomide to improve progression-free survival (PFS) and / or overall survival (OS) is 25 mg daily. In a further embodiment, the doses of tafacitamab and lenalidomide to improve progression-free survival (PFS) and / or overall survival (OS) are 12 mg / kg per dose of tafacitamab and 25 mg daily of lenalidomide. In another embodiment, tafacitamab is administered in a regimen of up to 12 cycles, with tafacitamab administered weekly on days 1, 8, 15, and 22 during cycles 1–3, and from cycle 4 onward, tafacitamab is administered every 14 days on days 1 and 15 of each cycle, while lenalidomide is administered daily on days 1–21 of each 28-day cycle, with gradual dose reduction of lenalidomide in case of toxicity as defined in the protocol (only once per cycle, decreasing by 5 mg / day at each step, with no further increases).

[0069] In certain embodiments, the disclosure relates to a method for treating a patient with hematological malignancy by administering to the patient an amount of anti-CD19 antibody and lenalidomide that improves progression-free survival (PFS) and / or overall survival (OS), wherein the patient has previously received two or more lines of treatment. In one embodiment, the patient received two lines of prior treatment. In another embodiment, two lines of prior treatment included treatment with R-CHOP. In yet another embodiment, two lines of prior treatment included treatment with rituximab. In one embodiment, the anti-CD19 antibody is tafacitamab. In one embodiment, the 12-month progression-free survival (PFS) rate is improved to more than 35%. In one embodiment, the 12-month overall survival (OS) rate is improved to more than 55%. In one embodiment, the 12-month progression-free survival (PFS) rate is improved to more than 35%, and the 12-month overall survival (OS) rate is improved to more than 55%. In one embodiment, the dose of tafacitamab to improve progression-free survival (PFS) and / or overall survival (OS) is 12 mg / kg per dose. In another embodiment, the dose of tafacitamab to improve progression-free survival (PFS) and / or overall survival (OS) is a regimen of up to 12 cycles, in which tafacitamab is administered weekly on days 1, 8, 15, and 22 for cycles 1-3, and from cycle 4 onward, tafacitamab is administered every 14 days, on days 1 and 15 of each cycle. In one embodiment, the dose of lenalidomide to improve progression-free survival (PFS) and / or overall survival (OS) is 25 mg daily. In a further embodiment, the amounts of tafacitamab and lenalidomide to improve progression-free survival (PFS) and / or overall survival (OS) are 12 mg / kg per dose of tafacitamab and 25 mg daily of lenalidomide.In another embodiment, tafacitamab is administered in a regimen of up to 12 cycles, with tafacitamab administered weekly on days 1, 8, 15, and 22 during cycles 1–3, and from cycle 4 onward, tafacitamab is administered every 14 days on days 1 and 15 of each cycle, while lenalidomide is administered daily on days 1–21 of each 28-day cycle, with gradual dose reduction of lenalidomide in case of toxicity as defined in the protocol (only once per cycle, decreasing by 5 mg / day at each step, with no further increases).

[0070] In certain embodiments, the disclosure relates to a method for treating a patient with hematological malignancy by administering to the patient an amount of anti-CD19 antibody and lenalidomide that improves 12-month progression-free survival (PFS) and / or 12-month overall survival (OS), wherein the patient has germinal center B-cell type (GCB) DLBCL. In one embodiment, the patient has germinal center B-cell type (GCB)rr-DLBCL. In one embodiment, the patient has germinal center B-cell type (GCB)rr-DLBCL and has received at least one line of prior treatment, the prior treatment including treatment with R-CHOP. In one embodiment, the anti-CD19 antibody is tafacitamab. In one embodiment, the 12-month progression-free survival (PFS) rate is improved to more than 35%. In one embodiment, the 12-month overall survival (OS) rate is improved to more than 60%. In one embodiment, the 12-month progression-free survival (PFS) rate is improved to over 35%, and the 12-month overall survival (OS) rate is improved to over 60%. In one embodiment, the dose of tafacitamab to improve progression-free survival (PFS) and / or overall survival (OS) is 12 mg / kg per dose. In another embodiment, the dose of tafacitamab to improve progression-free survival (PFS) and / or overall survival (OS) is a regimen of up to 12 cycles, where tafacitamab is administered weekly on days 1, 8, 15, and 22 for cycles 1-3, and every 14 days from cycle 4 onward, on days 1 and 15 of each cycle. In one embodiment, the dose of lenalidomide to improve progression-free survival (PFS) and / or overall survival (OS) is 25 mg daily. In a further embodiment, the amounts of tafacitamab and lenalidomide to improve progression-free survival (PFS) and / or overall survival (OS) are 12 mg / kg per dose of tafacitamab and 25 mg daily of lenalidomide.In another embodiment, tafacitamab is administered in a regimen of up to 12 cycles, with tafacitamab administered weekly on days 1, 8, 15, and 22 during cycles 1–3, and from cycle 4 onward, tafacitamab 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 a gradual dose reduction of lenalidomide in case of toxicity as defined in the protocol (decreasing by 5 mg / day at each step, only once per cycle, without re-increasing).

[0071] In certain embodiments, the disclosure relates to a method for treating a patient with hematological malignancy by administering to the patient an amount of anti-CD19 antibody and lenalidomide that improves 12-month progression-free survival (PFS) and / or 12-month overall survival (OS), wherein the patient has non-germinal center B-cell type (non-GCB) DLBCL. In one embodiment, the patient has non-germinal center B-cell type (non-GCB) rr-DLBCL. In one embodiment, the patient has non-germinal center B-cell type (non-GCB) rr-DLBCL and has received at least one line of prior treatment, the prior treatment including treatment with R-CHOP. In one embodiment, the anti-CD19 antibody is tafacitamab. In one embodiment, the 12-month progression-free survival (PFS) rate is improved to more than 70%. In one embodiment, the 12-month overall survival (OS) rate is improved to more than 80%. In one embodiment, the 12-month progression-free survival (PFS) rate is improved to over 70%, and the 12-month overall survival (OS) rate is improved to over 80%. In one embodiment, the dose of tafacitamab to improve progression-free survival (PFS) and / or overall survival (OS) is 12 mg / kg per dose. In another embodiment, the dose of tafacitamab to improve progression-free survival (PFS) and / or overall survival (OS) is a regimen of up to 12 cycles, where tafacitamab is administered weekly on days 1, 8, 15, and 22 for cycles 1-3, and every 14 days from cycle 4 onward, on days 1 and 15 of each cycle. In one embodiment, the dose of lenalidomide to improve progression-free survival (PFS) and / or overall survival (OS) is 25 mg daily. In a further embodiment, the amounts of tafacitamab and lenalidomide to improve progression-free survival (PFS) and / or overall survival (OS) are 12 mg / kg per dose of tafacitamab and 25 mg daily of lenalidomide.In another embodiment, tafacitamab is administered in a regimen of up to 12 cycles, with tafacitamab administered weekly on days 1, 8, 15, and 22 during cycles 1–3, and from cycle 4 onward, tafacitamab 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 a gradual dose reduction of lenalidomide in case of toxicity as defined in the protocol (decreasing by 5 mg / day at each step, only once per cycle, without re-increasing).

[0072] In another embodiment, the disclosure relates to a method for improving or extending survival in human subjects with rr-DLBCL, comprising administering an anti-CD19 antibody and lenalidomide to the target.

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

[0074] In a further embodiment, 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 includes the administration of an anti-CD19 antibody in combination with lenalidomide.

[0075] In a further embodiment, the disclosure relates to the use of an anti-CD19 antibody in the preparation of a pharmacopoeia for the treatment of rr-DLBCL, wherein the treatment includes the administration of the anti-CD19 antibody in combination with lenalidomide. In another embodiment, the disclosure relates to a kit comprising a container containing an anti-CD19 antibody and instructions for the administration of the anti-CD19 antibody in combination with lenalidomide for the treatment of a target rr-DLBCL.

[0076] In yet another embodiment, 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 a target rr-DLBCL.

[0077] In all embodiments, and in specific embodiments, the patient had previously received anticancer treatment for hematological malignancy. In all embodiments, and in specific 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 embodiments, treatment involves administration of an anti-CD19 antibody and lenalidomide for up to 12 cycles (28 days each). In embodiments, monotherapy with the anti-CD19 antibody is continued after treatment until the disease progresses.

[0079] In all embodiments, the treatment comprises the administration of an anti-CD19 antibody and lenalidomide, the anti-CD19 antibody being administered intravenously at a dose of 12 mg / kg. In one embodiment, the intravenous administration takes approximately 2 hours or more.

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

[0081] In all aspects, treatment involved the administration of an anti-CD19 antibody and lenalidomide. Patients with hematological malignancies self-administered lenalidomide orally, starting with 25 mg daily on days 1-21 of each 28-day cycle. In cases of toxicity as defined in the protocol, gradual dose reduction of lenalidomide (only once per cycle, decreasing by 5 mg / day at each stage, with no further increases) was permitted.

[0082] In one embodiment, the anti-CD19 antibody for use in combination with lenalidomide to treat patients with hematological cancers is a variable heavy chain with the following sequence. EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPYNDGTKYNEKFQGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGTYYYGTRVFDYWGQGTLVTVSS(Sequence ID 7) and variable light chains in the following sequence DIVMTQSPATLSLSPGERATLSCRSSKSLQNVNGNTYLYWFQQKPGQSPQLLIYRMSNLNSGVPDRFSGSGSGTEFTLTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIK (Sequence ID 8) Alternatively, it includes 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 with respect to the variable heavy chain of sequence number 7 and the variable light chain of sequence number 8.

[0083] In one embodiment, the anti-CD19 antibody for use in combination with lenalidomide to treat patients with hematological cancers is a variable heavy chain with the following sequence. EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPYNDGTKYNEKFQGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGTYYYGTRVFDYWGQGTLVTVSS(Sequence ID 7) and variable light chains in the following sequence DIVMTQSPATLSLSPGERATLSCRSSKSLQNVNGNTYLYWFQQKPGQSPQLLIYRMSNLNSGVPDRFSGSGSGTEFTLTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIK (Sequence ID 8) Alternatively, the anti-CD19 antibody comprises 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 with respect to the variable heavy chain of SEQ ID NO: 7 and the variable light chain of SEQ ID NO: 8, wherein the anti-CD19 antibody comprises an HCDR1 region containing the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region containing the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region containing the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region containing the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region containing the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region containing 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, where the Fc numbering follows the EU index, as in the case of Kabat.

[0084] In a further embodiment, the anti-CD19 antibody for use in combination with lenalidomide to treat patients with hematological cancers has a heavy chain having the following sequence EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPYNDGTKYNEKFQGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGTYYYGTRVFDYWGQG TLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT CPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKALPAPEEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (Sequence ID 11) and light chain having the following sequence DIVMTQSPATLSLSPGERATLSCRSSKSLQNVNGNTYLYWFQQKPGQSPQLLIYRMSNLNSGVPDRFSGSGSGTEFTLTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (Sequence ID 12) Alternatively, it includes 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 with respect to the heavy chain of sequence number 7 and the light chain of sequence number 8.

[0085] In a further embodiment, the anti-CD19 antibody for use in combination with lenalidomide to treat patients with hematological cancers has a heavy chain having the following sequence EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPYNDGTKYNEKFQGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGTYYYGTRVFDYWGQG TLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT CPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKALPAPEEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (Sequence ID 11) and light chain having the following sequence DIVMTQSPATLSLSPGERATLSCRSSKSLQNVNGNTYLYWFQQKPGQSPQLLIYRMSNLNSGVPDRFSGSGSGTEFTLTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (Sequence ID 12) Alternatively, the anti-CD19 antibody comprises 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 with respect to the heavy chain of SEQ ID NO: 7 and the light chain of SEQ ID NO: 8, wherein the anti-CD19 antibody comprises an HCDR1 region containing the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region containing the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region containing the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region containing the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region containing the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region containing 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, where the Fc numbering follows the EU index, as in the case of Kabat.

[0086] In other embodiments, the present disclosure refers to an anti-CD19 antibody for use in the treatment of a hematological malignancy patient in combination with lenalidomide, wherein the patient has received one, at least one, two, or at least two lines of prior treatment, and after treatment with the anti-CD19 antibody in combination with lenalidomide, (i) A 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) 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; (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) Refers to an antibody having one or more of the combinations described herein. In another embodiment of the present disclosure, the anti-CD19 antibody is administered in combination with lenalidomide in a drug regimen such as that disclosed herein.

[0087] In other embodiments, this disclosure refers to an anti-CD19 antibody for the treatment of a hematological malignancy patient in combination with lenalidomide, wherein the patient has germinal center B-cell type (GCB) DLBCL, and after the treatment, the patient (i) A 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) 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; (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) having one or more of the combinations described herein. In another embodiment of the present disclosure, the anti-CD19 antibody is administered in combination with lenalidomide in a drug regimen such as that disclosed herein.

[0088] In other embodiments, this disclosure refers to an anti-CD19 antibody for the treatment of a hematological malignancy patient in combination with lenalidomide, wherein the patient has non-germinal center B-cell type (non-GCB) DLBCL, and after the treatment, the patient (i) A 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) 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; (iv) an 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) having one or more of the above combinations. In another embodiment of the present disclosure, the anti-CD19 antibody is administered in combination with lenalidomide in a drug regimen such as that disclosed herein.

[0089] In other embodiments, the present disclosure refers to an anti-CD19 antibody for the treatment of patients with hematological malignancies in combination with lenalidomide, the combination therapy extending one or more of the following features: (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 to a treatment comprising an anti-CD20 antibody. In a further embodiment, one or more of the features (i) to (v) are extended 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, one or more of the features (i) to (v) are extended compared 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 compared to a treatment comprising R-CHOP.

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

[0092] In other embodiments, the present disclosure refers to a combination of therapies comprising an anti-CD19 antibody and lenalidomide for use in the treatment of a patient with hematological cancer, wherein the patient has received one, at least one, two, or at least two lines of prior treatment, wherein the administration of the anti-CD19 antibody results in an improvement 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 time to progression (TTP) compared to the administration of an anti-CD20 antibody.

[0093] In other embodiments, the present disclosure refers to a combination of therapies comprising an anti-CD19 antibody and lenalidomide for use in the treatment of a patient with hematological malignancy, wherein the patient has germinal center B-cell type (GCB) DLBCL, and the administration of the anti-CD19 antibody results in an extension of 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 time to progression (TTP).

[0094] In other embodiments, the present disclosure refers to a combination of therapies comprising an anti-CD19 antibody and lenalidomide for use in the treatment of a patient with hematological malignancy, wherein the patient has germinal center B-cell type (GCB) DLBCL, and wherein the administration of the anti-CD19 antibody results in an improvement 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 time to progression (TTP) compared to the administration of an anti-CD20 antibody.

[0095] In other embodiments, the present disclosure refers to a combination of therapies comprising an anti-CD19 antibody and lenalidomide for use in the treatment of a patient with hematological malignancy, wherein the patient has non-germinal center B-cell type (non-GCB) DLBCL, wherein the administration of the anti-CD19 antibody results in an extension of 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 time to progression (TTP).

[0096] In other embodiments, the present disclosure refers to a combination of therapies comprising an anti-CD19 antibody and lenalidomide for use in the treatment of a patient with hematological malignancy, the patient having non-germinal center B-cell type (non-GCB) DLBCL, wherein the administration of the anti-CD19 antibody results in an improvement 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 time to progression (TTP) compared to the administration of an anti-CD20 antibody.

[0097] In other embodiments, the present disclosure refers to an anti-CD19 antibody for use in the treatment of patients with hematological malignancies in combination with lenalidomide, wherein the administration of the anti-CD19 antibody in combination with lenalidomide results in an extension of progression-free survival (PFS), an extended objective response rate (ORR), an extended duration of response (DoR), an extended overall survival (OS), or an extended time to progression (TTP) compared to the 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 resulting from a transformation of low-grade lymphoma.

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

[0102] In a further embodiment, the anti-CD19 antibody is administered weekly, bi-weekly, or monthly. In a further embodiment, the anti-CD19 antibody is administered weekly for the first three months and bi-weekly for at least the following 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 bi-weekly for at least the following three months. In another embodiment, the anti-CD19 antibody is administered weekly for the first three months, bi-weekly for the following three months, and monthly thereafter. In yet another embodiment, the anti-CD19 antibody is administered weekly for the first three months, bi-weekly for the following three months, and monthly thereafter.

[0103] Indications and patients This disclosure provides a therapeutic combination comprising an anti-CD19 antibody and lenalidomide for use in the treatment of hematological cancer patients having chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), small lymphocytic lymphoma (SLL), or acute lymphoblastic leukemia (ALL). In another embodiment, the hematological cancer patient has non-Hodgkin lymphoma. In a further embodiment, the non-Hodgkin 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 lymphoma, and mantle cell lymphoma. In a further embodiment, the non-Hodgkin 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 not eligible for high-dose chemotherapy (HDC) and / or autologous stem cell transplantation (ASCT). In another embodiment, the hematological cancer patient has relapsed or refractory diffuse large B-cell lymphoma (rr-DLBCL) and is not eligible for high-dose chemotherapy (HDC) and / or autologous stem cell transplantation (ASCT). In yet another embodiment, the hematological cancer patient has relapsed or refractory diffuse large B-cell lymphoma (rr-DLBCL) arising from low-grade lymphoma and is not eligible for high-dose chemotherapy (HDC) and / or autologous stem cell transplantation (ASCT). In a further embodiment, non-Hodgkin lymphoma is relapsed or refractory diffuse large B-cell lymphoma (rr-DLBCL) arising from low-grade lymphoma.

[0104] In another embodiment, the hematological cancer patient has diffuse large B-cell lymphoma, and this patient is selected based on one or more of the following criteria: 1. Age > 18 2. Histologically confirmed diagnosis of DLBCL 3. Tumor tissue samples are needed for central pathology reviews and correlational studies. 4. The patient must have the following: a. Relapsed and / or refractory disease b. At least one two-dimensionally measurable PET-positive disease site (with a transverse diameter of 1.5 cm or more and a vertical diameter of 1.0 cm or more at baseline) c. You must have received at least one, but no more than three, prior systemic regimens for the treatment of DLBCL, and one of your treatment lines must include CD20-targeted therapy. d. Eastern Cooperative Oncology Group (USA) 0-2 5. Patients not considered in the opinion of a qualified researcher, or patients who do not wish to receive intensive salvage therapy, including ASCT. 6. Patients must meet the following screening criteria: a. Absolute neutrophil count ≥ 1.5 × 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 Grivert's syndrome or lymphoma) d. Alanine transaminase, aspartate aminotransferase, and alkaline phosphatase ≤3×ULN or <5×ULN (in cases of hepatic lesions) e. Serum creatinine clearance ≥ 60 mL / min 7. Women of childbearing potential (FCBP) should do the following: a. Not pregnant b. Please refrain from breastfeeding and from donating blood or oocytes. c. I consent to ongoing pregnancy testing. d. Commit to continuously abstaining from heterosexual intercourse, or agree to use and adhere to the use of double-barrier contraception. 8. Males (if sexually active in FCBP) a. It is necessary to use an effective barrier method of contraception. b. You should refrain from donating blood or sperm. 9. In the opinion of the principal investigator, the patient needs to do the following: a. The person is able to and desires to receive appropriate prevention and / or treatment for thromboembolic events. b. You understand the reasons for adhering to the special conditions of the pregnancy prevention risk management plan and can give written approval for this.

[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 resulting from a transformation of low-grade lymphoma.

[0109] In another embodiment, the hematological cancer patient has diffuse large B-cell lymphoma, and this patient is excluded based on one or more of the following exclusion criteria: 1. Patients with the following conditions: a. Lymphoma of other histological types b. Primary refractory DLBCL c. The history of "double / triple hit" genetics 2.1 Patients who had any of the following within 14 days prior to the medication administration on day 1: a. CD20-targeted therapy, chemotherapy, radiotherapy, investigational anticancer therapy, or other lymphoma-specific treatments that are not discontinued. b. Have undergone major surgery or suffered a serious injury. c. A live vaccine was administered. d. Parenteral antimicrobial therapy required for active co-infections 3. Patients who: a. Previously treated with CD19-targeted therapy or IMiDs® (such as thalidomide, LEN, etc.) b. The ASCT was received within three months prior to signing the informed consent form. c. Has previously undergone allogeneic stem cell transplantation. d. The patient has a history of deep vein thrombosis / embolism and is unwilling / unable to undergo venous thromboembolic event prevention throughout the treatment period. e. Concurrent use of other anti-cancer or experimental therapies 4. A history of malignant tumors other than DLBCL, unless the patient has not had the disease for more than 5 years prior to screening. 5. In the case of the following patients: a. Serological test for positive hepatitis B and / or hepatitis C. b. Known seropositivity or history of active HIV infection. c. Involvement of CNS lymphoma d. A history or evidence of clinically significant cardiovascular disease, CNS disease, and / or other systemic disease that, in the opinion of the principal investigator, would prevent the patient from participating in the study or impair the patient's ability to give informed consent.

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

[0111] In another embodiment of this disclosure, the expected benefits from therapeutic administration of an anti-CD19 antibody in combination with lenalidomide are 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 this disclosure, the expected benefits from therapeutic administration of an anti-CD19 antibody in combination with lenalidomide are: (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) 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; (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) one or more of the above combinations. In another embodiment of the present disclosure, the anti-CD19 antibody is administered in combination with a pharmaceutical product such as those disclosed herein.

[0113] In another embodiment of this disclosure, the expected benefits from therapeutic administration of an anti-CD19 antibody in combination with lenalidomide are 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) 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 this disclosure, the expected benefits from therapeutic administration of an anti-CD19 antibody in combination with lenalidomide are 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) compared to R-CHOP administration.

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

[0116] In another embodiment, one or more of the features (i) to (v) are compared with a treatment comprising an anti-CD20 antibody. In a further embodiment, one or more of the features (i) to (v) are compared with 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 compared with 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 compared with a treatment comprising R-CHOP.

[0117] In some embodiments of this disclosure, the hematological cancer patient expected to benefit from therapeutic administration of an anti-CD19 antibody and lenalidomide has chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), small lymphocytic lymphoma (SLL), or acute lymphoblastic leukemia (ALL). In further embodiments, the hematological cancer patient has non-Hodgkin lymphoma. In further embodiments, the hematological cancer patient has non-Hodgkin lymphoma, which 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 lymphoma, and mantle cell lymphoma. In further embodiments, 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 treatment. 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 treatment. In a further embodiment, the hematological cancer patient has relapsed or refractory diffuse large B-cell lymphoma (rr-DLBCL) and has received rituximab as prior treatment. 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 prior treatment. 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 treatment. In a further embodiment, the hematological cancer patient has relapsed or refractory diffuse large B-cell lymphoma (rr-DLBCL) in which the patient has non-germinal center B-cell type (non-GCB) DLBCL.

[0118] In a further embodiment of the present 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 containing the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region containing the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region containing the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region containing the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region containing the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region containing the sequence MQHLEYPIT (SEQ ID NO: 6). In another embodiment, the anti-CD19 antibody comprises a variable heavy chain of the following sequence EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPYNDGTKYNEKFQGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGTYYYGTRVFDYWGQGTLVTVSS(Sequence ID 7) and variable light chains in the following sequence Includes DIVMTQSPATLSLSPGERATLSCRSSKSLQNVNGNTYLYWFQQKPGQSPQLLIYRMSNLNSGVPDRFSGSGSGTEFTLTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIK (Sequence ID 8).

[0119] In a further embodiment, the anti-CD19 antibody is a heavy chain having the following sequence EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPYNDGTKYNEKFQGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGTYYYGTRVFDYWGQG TLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT CPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFNWYVDGVEVHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKALPAPEEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNHYTQKSLSLSPGK (Sequence ID 11) and light chain having the following sequence Includes DIVMTQSPATLSLSPGERATLSCRSSKSLQNVNGNTYLYWFQQKPGQSPQLLIYRMSNLNSGVPDRFSGSGSGTEFTLTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIKRTVAAPSVFIFPPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (Sequence ID 12).

[0120] In another embodiment, the disclosure relates to a method for treating patients with hematological cancers having rr-DLBCL, comprising administering an anti-CD19 antibody and lenalidomide to the subject.

[0121] In yet another aspect, the present disclosure relates to an anti-CD19 antibody for use in combination with lenalidomide in the treatment of patients with hematological malignancies having rr-DLBCL.

[0122] In a further embodiment, the disclosure relates to the use of an anti-CD19 antibody in the preparation of a pharmacopoeia for the treatment of a patient with hematological malignancy having rr-DLBCL, the treatment comprising the 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 resulting from a transformation of low-grade lymphoma. In another embodiment, the hematological cancer patient is a hematological cancer patient with diffuse large B-cell lymphoma resulting from a transformation of low-grade lymphoma, and the low-grade lymphoma may be, but is not limited to, follicular lymphoma or marginal zone lymphoma. In some embodiments, the diffuse large B-cell lymphoma resulting from a transformation of low-grade lymphoma is a transformed follicular lymphoma or a transformed marginal zone lymphoma. In another embodiment, the hematological cancer patient is a hematological cancer patient with diffuse large B-cell lymphoma, and such diffuse large B-cell lymphoma is a transformed lymphoma. In another embodiment, the hematological cancer patient is a hematological cancer patient with diffuse large B-cell lymphoma, and such diffuse large B-cell lymphoma is a transformed painless lymphoma. In another embodiment, the hematological cancer patient is a hematological cancer patient with diffuse large B-cell lymphoma, such diffuse large B-cell lymphoma resulting from a transformation of low-grade lymphoma or painless 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 not eligible for high-dose chemotherapy (HDC) and / or autologous stem cell transplantation (ASCT). In another embodiment, the hematological cancer patient has relapsed or refractory diffuse large B-cell lymphoma (rr-DLBCL) and is not eligible for high-dose chemotherapy (HDC) and / or autologous stem cell transplantation (ASCT). In another embodiment, the hematological cancer patient has relapsed or refractory diffuse large B-cell lymphoma (rr-DLBCL) arising from a low-grade lymphoma and is not eligible for high-dose chemotherapy (HDC) and / or autologous stem cell transplantation (ASCT). In a further embodiment, the non-Hodgkin lymphoma is relapsed or refractory diffuse large B-cell lymphoma (rr-DLBCL) arising from a low-grade lymphoma. [Table 1-1] [Table 1-2] [Examples]

[0127] Example 1: Combination therapy of MOR00208 and lenalidomide in relapsed or refractory diffuse large B-cell lymphoma Patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) typically have a poor prognosis and limited treatment options. MOR00208 is an Fc-enhanced humanized anti-CD19 monoclonal antibody that demonstrated preclinical and monotherapy activity in patients with relapsed or refractory B-cell malignancies. We clinically investigated the treatment of patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) with MOR00208 in combination with lenalidomide.

[0128] Patient and study design This open-label, single-arm, multicenter, phase 2 trial commenced in March 2016. Patients were enrolled at 35 sites (Supplemental Appendix) in 10 countries across Europe and the United States until November 2017. Adult patients (18 years of age or older) with histologically confirmed DLBCL (including painless lymphoma with subsequent DLBCL relapse) who had relapsed after three or fewer systemic regimens (with at least one anti-CD20 therapy) or were refractory to them, and who were not candidates for high-dose chemotherapy and subsequent ASCT. Additional inclusive criteria included adequate organ function, 0–2 Eastern Cooperative Oncology Group performance statuses, and measurable disease at baseline. Exclusion criteria include 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 no response to progression during or within 6 months of frontline treatment). Prior to the protocol revision, only patients who relapsed within 3 months of a previous anti-CD20 regimen were defined as primary refractory and excluded. Therefore, patients who relapsed or progressed between 3 and 6 months of frontline treatment were recruited before the protocol revision and were considered primary refractory patients.

[0129] Treatment consisted of co-administration of MOR00208 and lenalidomide for up to 12 cycles (28 days each), followed by MOR00208 monotherapy until disease progression (in patients with stable or better disease). MOR00208 was administered intravenously at a dose of 12 mg / kg over approximately 2 hours. 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. From cycle 4 onward, MOR00208 was administered every 14 days on days 22, on days 1 and 15 of each cycle. Patients received oral lenalidomide, starting with 25 mg daily on days 1-21 of each 28-day cycle. In case of toxicity as defined in the protocol, gradual dose reduction of lenalidomide (only once per cycle, decreasing by 5 mg / day at each stage, no further increases) was 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, progression-free survival, incidence and severity of adverse events, as well as immunogenicity (presence of anti-MOR00208 antibody), pharmacokinetics, and biomarker analysis (measurement of B cells, T cells, and NK cells over time, including cells of origin).

[0131] Analysis of the primary endpoint was performed when all patients completed a minimum of 12 months of follow-up. Efficacy analysis was based on a complete analysis set including all patients who received at least one dose of both MOR00208 and lenalidomide; safety analysis was based on patients who received at least one dose of either investigational 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 power of 85%, the estimated sample size was 73 patients. Assuming a dropout rate of 10%, the total sample size was estimated to be 80 patients. Statistical analysis was performed using SAS® software version 9.4 or later (SAS Institute, Cary, NC).

[0132] result: A total of 81 patients were enrolled, each receiving at least one dose of one of the investigational drugs (and their safety evaluated), and 80 patients receiving at least one dose of both MOR00208 and lenalidomide (and their efficacy evaluated). In total, 30 patients (37.0%) successfully completed 12 cycles of MOR00208 and lenalidomide therapy, and 28 patients (34.6%) were receiving MOR00208 monotherapy at the data cutoff.

[0133] The assessed objective response rate was 60.0% (95% confidence interval [CI], 48.4–70.8%), with 34 patients (42.5%) achieving complete response and 14 patients (17.5%) achieving partial response (Table 2). The overall agreement between both the central and investigator-assessed objective response rates was 88.2%. Positron emission tomography (PUT) scans performed in 30 / 34 (88.2%) patients who achieved 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 (ranging from 1.7 to 16.8 months), and the median time to complete response was 7.1 months (ranging from 1.7 to 17.0 months). An analysis of objective response rates based on patient baseline characteristics showed high and consistent response rates across most subgroups, including those resistant to previous treatments (Figure 1). [Table 2]

[0134] The median duration of response 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 complete response, the median duration of response 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 partial response, the median duration of response was 4.4 months (95% CI, 2.0–9.1 months). The median progression-free survival was 12.1 months (95% CI, less than 5.7 months). Patients who were progression-free at 12 months (50.2% [95% CI, 37.9–61.2%]) tended to maintain progression-free survival at 18 months (45.8% [95% CI, 33.4–57.4%]). The median progression-free survival after discontinuation of lenalidomide was 12.7 months (95% CI, less than 2.3 months). The 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 the treatment in the clinical trial 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 discontinuation of lenalidomide) was 4.1 months (range, 0.1–20.8 months).

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

[0137] Serious adverse events occurred in 41 / 81 (50.6%) of patients, of which 15 / 81 (18.5%) were suspected by the principal investigator to be treatment-related. These were primarily infections (8 [9.9%]) or febrile neutropenia (4 [4.9%]). In total, 14 out of 81 (17.3%) patients discontinued lenalidomide and / or MOR00208 at any point during the trial due to adverse events. Seven patients (8.6%) experienced particularly noteworthy adverse events (as defined in the protocol). Three patients experienced tumor flare (one each of grades 1 through 3), one experienced grade 2 basal cell carcinoma, and three experienced grade 3 allergic dermatitis.

[0138] Thirty deaths (37.0%) were recorded, with eight occurring during treatment and 22 occurring after treatment. Twenty-three deaths were associated with lymphoma progression, while seven were unrelated to disease progression. Treatment-related adverse events leading to death occurred in four patients (sudden death, respiratory failure, cerebrovascular event, and progressive multifocal leukoencephalopathy), but the principal investigator did not consider any of these to be related to the treatment in the study.

[0139] Discontinuation of lenalidomide (after cycle 13 according to the protocol, or earlier in cases of toxicity) resulted in a reduced incidence and severity of treatment-related adverse events with MOR00208 monotherapy. Grade 3 or 4 neutropenia occurred in 6 / 51 (11.8%) of patients at this stage. In total, grade 3 or 4 adverse events were reported in 56 / 81 (70.0%) of patients before lenalidomide discontinuation, compared to 15 / 51 (29.4%) of patients after lenalidomide discontinuation.

[0140] conclusion In this population of relapsed or refractory DLBCL patients ineligible for stem cell transplantation, combination therapy with MOR00208 and lenalidomide induced an overall objective response in 60% of patients and a complete response in 42.5%. Furthermore, the response was long-lasting, with a median duration of response of 21.7 months. In patients who achieved a complete response, the response rate over 18 months was 93.2%. The median follow-up period was approximately 20 months, and the median overall survival had not yet been reached. Given the context of other drug trials recently reported in similar populations, our results indicate a promising treatment option. In particular, previous studies have reported objective response rates of 26% (SCHOLAR-1) (Blood 130, 1800-1808, 2017), 33% with rituximab in addition to lenalidomide (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] In the L-MIND trial, lenalidomide monotherapy showed an objective response rate 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 MOR00208 monotherapy showed an objective response rate of 26% in relapsed or refractory DLBCL (Ann. Oncol. 29, 1266-1272, 2018). This demonstrates the benefits of adding MOR00208 to lenalidomide. The greater activity of L-MIND is likely based on the complementary mechanisms of action of both drugs. The increase in NK cell count observed after treatment (Blood 126, 50-60, 2015) as a result of lenalidomide-mediated lowering of the activation threshold may be a factor behind this synergistic effect. CD19 appears to be a useful alternative target for patients who have not been cured with previous anti-CD20-based immunochemotherapy, and a randomized phase 2 / 3 trial is underway to investigate the combination of chemotherapy with MOR00208 in patients previously exposed to rituximab (NCT02763319).

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

[0143] Example 2: Combination therapy of MOR00208 and lenalidomide in a subgroup with relapsed or refractory diffuse large B-cell lymphoma. Of the 81 patients enrolled, 80 received MOR00208+LEN and were included in the full analysis set (FAS) for efficacy. The median follow-up period was 17.3 months. In the FAS, the objective response rate (ORR) was 60.0% (95% confidence interval [CI]: 48.4-70.8) (Table 3). The complete response (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 duration of response (DOR) was 21.7 months (95% CI: 21.7-Not reached [NR]); the median progression-free survival (PFS) was 12.1 months (95% CI: 5.7-NR); the median overall survival (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] In subgroup analysis, patients with complete response (CR) as their best objective response (BOR) showed better outcomes than those with partial response (PR). Median duration of response (DOR) was NR (95% CI: 21.7-NR) versus 4.4 months (95% CI: 2.0-9.1). The 12-month DOR rate was 93.2% (95% CI: 75.4-98.3) versus 14.4% (95% CI: 1.1-43.7); and the 12-month OS rate was 97.1% versus 76.9%.

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

[0146] In patients who were refractory to first-line or last-line treatment, an ORR similar to that of refractory patients was observed (60.0% vs. 60.0%). The 12-month DOR was similar to that of last-line treatment, regardless of the refractory status. Furthermore, the 12-month OS rate was higher in refractory patients (Table 3).

[0147] As expected, patients with low / low-intermediate International Prognostic Index (IPI) scores showed better outcomes than those 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, promising results were reported in patients with germinal center B-cell (GCB) DLBCL (n=37), and even better outcomes were observed in patients with non-GCB DLBCL (n=21): ORR, 48.6% vs. 71.4%; 12-month DOR rate, 53.5% vs. 83.1%; and 12-month OS rate, 65.4% vs. 84.2% (Table 3). Considering the historically low activity of lenalidomide monotherapy 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 synergistic effects of the MOR00208 and lenalidomide combination. [Table 3]

[0149] Overall, combination therapy with MOR00208+LEN followed by MOR00208 monotherapy has shown promising activity with sustained responses in patients with R / RDLBCL who are ineligible for ASCT. L-MIND includes a significant number of patient subgroups with poor prognosis. While the impact of these risk factors is clear, the clinical activity of MOR00208+LEN in these patients is promising, especially in patients who were resistant to previous treatments.

[0150] Example 3: Subgroup of updated MOR00208 in combination with lenalidomide Patients in the L-MIND study had a median age of 72 years (range 41–86) at enrollment and had received a median of 2 (range 1–4) prior lines of treatment. All patients had received R-CHOP or equivalent chemoimmunotherapy prior to trial enrollment. Due to the availability of additional data from the central pathology review for two patients, baseline patient characteristics of cells of origin by immunohistochemistry and gene expression profiling were updated since the primary analysis (Table 4). There was one patient each with double-hit and triple-hit DLBCL.

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

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

[0153] Based on medical history and central pathological diagnosis, eight patients had DLBCL resulting 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 (PR) and three experienced complete remission (CR). The patient with double-hit lymphoma (MYC and BCL2 translocation) was resistant to the previous last line of treatment with L-MIND (R-dexamethasone-cytarabine-cisplatin) and achieved a PR. The patient with triple-hit lymphoma (MYC, BCL2 and BCL6 translocation) had previously responded to R-CHOP and experienced CR for 4.5 months, and initiated lenalidomide in addition to tafacitamab one month after relapse. This patient experienced CR with L-MIND and maintained remission for more than 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 out of eight patients with transformed lymphoma, responded to treatment.

Claims

1. A pharmaceutical composition comprising a therapeutic combination of an anti-CD19 antibody and lenalidomide for use in the treatment of a patient with hematological cancer, wherein the treatment extends the patient's overall survival and / or progression-free survival.

2. A pharmaceutical composition comprising an anti-CD19 antibody for use in the treatment of a patient with hematological cancer, wherein the anti-CD19 antibody is administered in combination with lenalidomide, and the treatment extends the patient's overall survival and / or progression-free survival.

3. A pharmaceutical composition comprising lenalidomide for use in the treatment of a patient with hematological cancer, wherein lenalidomide is administered in combination with an anti-CD19 antibody, and the treatment extends the patient's overall survival and / or progression-free survival.

4. A pharmaceutical composition according to any one of claims 1 to 3 for use in treating a hematological cancer patient, wherein the hematological cancer patient has received one line of prior treatment and has a 12-month overall survival rate of 80% or more.

5. The pharmaceutical composition according to claim 4 for use in the treatment of patients with hematological cancers whose 12-month progression-free survival rate is 55% or higher.

6. A pharmaceutical composition according to any one of claims 1 to 3 for use in treating a hematological cancer patient, wherein the hematological cancer patient has received two or more lines of prior treatment and has a 12-month overall survival rate of 55% or more.

7. The pharmaceutical composition according to claim 6 for use in the treatment of patients with hematological cancers having a 12-month progression-free survival rate of 35% or more.

8. A pharmaceutical composition according to any one of the prior claims for use in the treatment of a hematological cancer patient having a non-Hodgkin 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 lymphoma, and mantle cell lymphoma.

9. A pharmaceutical composition according to any one of claims 1 to 3, for use in the treatment of a hematological cancer patient having germinal center B-cell type (GCB) DLBCL and having a 12-month overall survival rate of 60% or more.

10. The pharmaceutical composition according to claim 9 for use in the treatment of patients with hematological cancers having a 12-month progression-free survival rate of 35% or more.

11. A pharmaceutical composition according to any one of claims 1 to 3, for use in the treatment of a hematological cancer patient who has non-germinal center B-cell type (non-GCB) DLBCL and whose 12-month overall survival rate is 80% or higher.

12. The pharmaceutical composition according to claim 11 for use in the treatment of patients with hematological cancers having a 12-month progression-free survival rate of 70% or more.

13. The anti-CD19 antibody comprises an HCDR1 region containing the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region containing the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region containing the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region containing the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region containing the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region containing the sequence MQHLEYPIT (SEQ ID NO: 6), the pharmaceutical composition according to any one of claims 1 to 12 for use in the treatment of patients with hematological cancers.

14. A pharmaceutical composition according to any one of claims 1 to 13 for use in the treatment of patients with blood cancer, wherein the anti-CD19 antibody is a variable heavy chain having the following sequence EVQLVESGGGLLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPYNDGTKYNEKFQGRVTISSSDKSISISTAYMELSSLRRSEDTAMYYCARGTYYYGTRVFDYWGQGTLVTVSS (Sequence No. 7) and variable light chains in the following sequence The pharmaceutical composition comprising DIVMTQSPATLSLSSPGERAATLSCRSSKSSLQNVNGNTYLYWFQQKPGQSPQLLIYRMSNLNSGVPDRFSGSGSGTEFFTLTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIK (Sequence ID 8).

15. A pharmaceutical composition according to any one of claims 1 to 14 for use in the treatment of patients with hematological cancer, wherein the anti-CD19 antibody has the following heavy chain sequence EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPYNDGTKYNEKFQGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGTYYYGTRVFDYWGQG TLVTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAVLQSSGLYSLSSVVTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHT CPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSSHEDPEVQFNWYVDGVEVHNHNAKTKPREEQFNSTFRVVSVLTVVHQDWLNGKEYKCKVSNKALPAPEEEKTISKTKGQPREPQVYTLPPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSSCSVMHEALHNHYTQKSLSLSPGK (Sequence No. 11) and light chain having the following sequence The pharmaceutical composition comprising DIVMTQSPATLSLSPGERAATLSCRSSKSSLQNVNGNTYLYWFQQKPGQSPQLLIYRMSNLNSGVPDRFSGSGSGTEFTLTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIKRTVAAPSVFIFPPSDEQLKSGTATASVVCLLNNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDSTYSLSSSTLTLSKADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (Sequence ID 12).

16. The pharmaceutical composition according to any one of the prior claims, for use in accordance with any one of the prior claims, wherein the anti-CD19 antibody is administered at a dose of 12 mg / kg at least every other week, and lenalidomide is administered at a dose of 25 mg daily.

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