METHODS TO PREDICT THE THERAPEUTIC BENEFIT OF ANTI-CD19 THERAPY IN PATIENTS.

Abstract

The present invention relates to a method for identifying a subject who has chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), small lymphocytic lymphoma (SLL), or acute lymphoblastic leukemia (ALL) who responds to treatment with an anti-CD19 antibody, said method comprising: a) providing a blood sample obtained from said subject prior to treatment with said anti-CD19 antibody, b) determining the level of at least one biomarker in said sample selected from the group consisting of i) peripheral NK cell count, and ii) CD16 expression levels in peripheral NK cells, c) comparing the level of said at least one biomarker in said sample to a predetermined cutoff level, wherein levels of said at least one biomarker at or above the predetermined cutoff level are indicative of a subject who would benefit from treatment with an anti-CD19 antibody.This disclosure also relates to a method for selecting a patient for treatment in accordance with the above and to the use of an anti-CD19 antibody for the treatment of such patient.

Description

METHODS TO PREDICT THE THERAPEUTIC BENEFIT OF ANTI-CD19 THERAPY IN PATIENTS FIELD OF INVENTION This disclosure aims to identify 5 characteristics and biomarkers in patients who benefit from anti-CD19 antibody treatment. BACKGROUND CD19 is a 95 kBa transmembrane glycoprotein of the immunoglobulin superfamily that contains two extracellular immunoglobulin-like domains and an extensive cytoplasmic tail. The protein is a pan-B cell surface receptor and is ubiquitously expressed from the earliest stages of pre-B cell development until it is upregulated during terminal differentiation into plasma cells. It is specific to the B cell lineage and is not expressed on 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 and in the development of humoral immune responses. It acts as a costimulatory molecule along with CD21 and CD81 and is critical for B cell responses to T cell-dependent antigens.The cytoplasmic tail 25 of CD19 is physically associated with a family of tyrosine kinases that trigger downstream signaling pathways through the src family of protein tyrosine kinases. CD19 is an attractive target for cancers of lymphoid origin, as it is highly expressed in almost all cases of chronic lymphocytic leukemia (CLL) and non-Hodgkin lymphoma (NHL), as well as in many other types of leukemia, including acute lymphocytic leukemia (ALL) and hairy cell leukemia (HCL). The clinical development of antibodies targeting CD19 was previously limited by the internalization of the CD19 antigen; however, improved antibody modification technology has reopened this potential therapeutic target. MORCC2C8 (formerly XmAb5574) is an Fc-engineered humanized monoclonal antibody that binds to CD19. Increased binding of MCR00208 Fc to FcεR, due to XmAb-engineered mutations, significantly enhances antibody-dependent cell-mediated cytotoxicity (ADCC) in vitro, antibody-dependent cell-mediated phagocytosis (ADCP), and direct cytotoxic effects (apoptosis) on the tumor compared to the unmodified antibody. MORCC2C8 has not been shown to mediate complement-dependent cytotoxicity. MOR00208 is currently under investigation in clinical trials for CLL, ALL, and NHL. Specifically, a Phase I trial entitled "Safety and Tolerability of XmAb®5574 in Chronic Lymphocytic Leukemia" and a Phase Ia trial entitled "Study of Fe-Optimized Anti-CD19 Antibody (MOR00208) for the Treatment of B-Cell Acute Lymphoblastic Leukemia (B-ALL)" have been completed. A Phase Ia trial entitled "Study of Fe-Optimized Anti-CD19 Antibody (MOR00208) for the Treatment of Non-Hodgkin Lymphoma (NHL)" has completed enrollment.And the following trials are planned / ongoing: a Phase II / III trial entitled A trial to evaluate the efficacy and safety of MOR03208 with bendamustine (BEN) versus rituximab (RTX) with BEN in adult patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL) (B-M1ND), a Phase II trial entitled Study to evaluate the efficacy and safety of MOR00208 with idelalisib in BTKi-previously treated R / R CLL / SLL patients, a Phase II trial entitled A study to evaluate the safety and efficacy of lenalidomide with MOR00208 in RR DLBCL patients, and a Phase II trial entitled Phase II MOR00208 in combination with lenalidomide for patients with relapsed or refractory CLL, SLL, or PLL or older patients with untreated CLL, SLL, or PLL. Another ongoing Phase II trial (COSMOS) is studying the efficacy and safety of MOR00208 in combination with idelalisib or venetoclax in patients with CLL, SLL with or refractory. - 4 The efficacy of a single agent of MOR002G8 has been reported in CLL and NHL. However, the overall variable response rates of patients to monoclonal antibody therapies indicate that methods are needed to accurately predict which patients are most likely to respond to such antibody therapies so that treatment can be administered to those patients most likely to benefit. Biomarkers or particular patient characteristics can be found for which a specific concentration or range for each biomarker correlates with responsiveness to such therapy. The influence of natural killer (NK) cell count on survival was evaluated in patients with DLBCL treated with rituximab, cyclophosphamide, doxorubicin hydrochloride (hydroxydaunomycin), vincristine sulfate (Oncovin), and prednisone (R-CHOP). Kirr et al., Blood Research, 49: 3, 162-169 (September 2014). Previously, peripheral NK cell count was reported to be associated with clinical outcome in patients with aalPI 2-3 DLBCL. Plonquet et al., Ann Oncol 2007; 18: 1209-15. It is clear that significant efforts and investments are needed to discover and identify such patient characteristics and predictive biomarkers of efficacy. - 5 SUMMARY OF THE INVENTION MOR00208 has been studied in patients with CLL, ALL, NHL, and SLL. Consequently, a comprehensive analysis of clinical data to date has been completed to identify characteristics or biomarkers of patients most likely to benefit from treatment with MOR00208. MOR00208 specifically targets the surface antigen CD19 and mediates the direct destruction of tumor cells through its enhanced ADCC effector function. In preclinical studies, MOR00208 has been shown to significantly enhance ADCC, ADCP in vitro, and direct cytotoxic effects (apoptosis) in CD19' tumor cell lines encompassing a wide range of human lymphoid and leukemias (Burkitt lymphoma, CLL, hairy cell leukemia (HCL), CD19' chronic myeloid leukemia (CML), diffuse large B-cell lymphoma (DLBCL), and acute lymphoblastic leukemia (ALL), expressing CD19 antigen levels ranging from 15,000 to 105,000 molecules / cell).Similar effects have also been observed in relation to newly isolated CLL or ALL cells from the patient and are also expected to be reflected in primary non-Hodgkin lymphoma (NHL) cells, since the reported expression range for ALL and CLL B cells covers the range observed for NHL B cells (Ginaldi et al., 1998; Olejniczak et al., 2006). Based on the. - 6. Surface and homogeneous expression of CD19 across various types of B-cell neoplasms, the effect of MOR0C206 in the present study can be transferred to a wide range of human lymphocytes and leukemias, such as CLL, ALL, NHL and SLL and their subtypes. Data from the Phase II trial entitled Study of Fe-Optimized Anti-CD19 Antibody (MOR00208) for the Treatment of Non-Hodgkin Lymphoma (NHL) have been thoroughly analyzed. As a result of these efforts, the following disclosure provides characteristics and biomarkers of patients in whom anti-CD19 antibodies are effective. Specifically, at least the following patient characteristics were assessed: a) age, b) gender, c) whether patients had received a dose of Rituximab in the last 15 6 months, d) whether patients were refractory to Rituximab, e) whether patients had a high or low affinity allele of FCgammaRI I la, f) whether patients have the high or low affinity allele of FCgammaRIla, g) whether patients had a previous treatment response duration of more than 12 months, h) baseline peripheral T lymphocyte counts (cells / ul), i) baseline peripheral NK cell count (cells / ul) and j) baseline CD16 expression on peripheral NK cells (cell-bound antibodies -ABC). Both 1) baseline peripheral NK cell counts and 2) baseline CD16 expression on peripheral NK cells showed clear correlations with patient responses to MOR0C208 therapy. Specifically, patients with a higher baseline peripheral NK cell count per μA correlated with a higher disease control rate (DCR). DCR includes patients with complete response (CR), partial response (PR), and stable disease (SD). Furthermore, these patients had better progression-free survival (PFS) compared to patients with lower NK cell counts. Additionally, patients with a baseline CD16 expression on NK cells of at least 60,000 (AUC) correlated with a higher disease control rate (DCR). Therefore, patients diagnosed with CLL, ALL, NHL, and SLL who have either a) a high peripheral NK cell count or 2) reference CD16 expression on peripheral NK cells of at least 60,000 ABC are more likely to benefit from treatment with MOR00208. Both 1) baseline peripheral NK cell counts and 2) baseline CD1 6 expression in peripheral NK cells showed clear correlations with patient responses to MOR00208 therapy. Specifically, patients with a baseline peripheral NK cell count of at least 50 cells / µL were correlated with a higher disease control rate (DCR). The DCR includes patients with complete response (CR), partial response (PR), and stable disease (SD). Furthermore, patients with a baseline NK cell count of at least 50 cells / µL had significantly better progression-free survival (PFS) compared to patients with lower NK cell counts. Additionally, patients with a baseline CD16 expression on NK cells of at least 60,000 (AUC) were correlated with a higher disease control rate (DCR). Therefore, patients diagnosed with CLL, ALL, NHL, and SLL who have either a) a baseline peripheral NK cell count of at least 50 cells / gl or 2) a baseline CD16 expression on peripheral NK cells of at least 60,000 ABC are more likely to benefit from Treatment MOR00208. Both 1) baseline peripheral NK cell counts and 2) baseline CD16 expression in peripheral NK cells showed clear correlations with patient responses to MORC0208 therapy. Specifically, patients with a baseline peripheral NK cell count of at least ICC cells / μA were Nine factors correlated with a higher disease control rate (DCR). DCR includes patients with a complete response (CR), a partial response (PR), or stable disease (SD). Additionally, patients with an NK cell count of at least 100 cells / μA had significantly better progression-free survival (PFS) compared to patients with lower NK cell levels. Furthermore, patients with a baseline CD16 expression on NK cells of at least 10,600,000 (AUC) correlated with a higher disease control rate (DCR). Therefore, patients diagnosed with CLL, ALL, NHL and SLL and with a) a reference peripheral NK cell count of at least 15 cells / μA or 2) a reference CD16 expression in peripheral NK cells of at least 60,000 ABC are more likely to benefit from Treatment MOR00208. BRIEF DESCRIPTION OF THE DRAWINGS Figure 1 shows the amino acid sequences of the 20 variable domains of MORCC2C8 and the CDRs. Figure 2 shows the amino acid sequences of the complete heavy and light chains of MOR00208. Figure 3 shows receiver operating characteristic (ROC) analysis of peripheral NK cell counts as a predictor for DCR. - 10 Figure 4 shows the RCC analysis of CD16 expression levels in peripheral NK cells (ABC) as a predictor for DCR. Figure 5 shows the ROC analysis of peripheral T cell count as a potential predictor for DCR. Figure 6 shows that peripheral NK cell counts and CD16 expression levels in peripheral NK cells are independent variables and are not correlated. Figure 7 shows the Forest Plot with DCR in subgroups of patients with specific characteristics and reference biomarkers. Figure 8 shows the difference in progression-free survival between patients who have at least peripheral NK cell counts of 100 cells / pl versus patients who have lower NK cell counts. Figure 9 shows the difference in progression-free survival between patients who have at least 60,000 ABC in CD16 expression on peripheral NK cells versus patients who have lower CD16 expression on NK cells. Figure 10 shows the difference in progression-free survival between patients who have at least peripheral T cell counts of 500 cells / μI versus patients who have lower T cell counts. - i: DETAILED DESCRIPTION OF THE INVENTION The term antibody means monoclonal antibodies, which include any isotype, such as IgA, IgM, IgA, IgD, and IgE. An IgG antibody is composed of two identical heavy chains and two identical light chains linked by disulfide bonds. Each heavy and light chain contains a constant region and a variable region. Each variable region contains three segments called complementarity-determining regions (CDRs) or hypervariable regions, which are primarily responsible for binding an epitope of an antigen. These are known as CDR1, CDR2, and CDR3, numbered sequentially from the N-terminus. The most highly conserved portions of the variable regions outside the CDRs are called frame regions. An antibody fragment means a fragment Fv, scFv, dsFv, Fab, Fab', F(ab')2, or other fragment, containing at least one variable light or heavy chain, each with CDRs and frame regions. VH refers to the variable region of an immunoglobulin heavy chain of an antibody, or antibody fragment. VL refers to the variable region of an immunoglobulin light chain of an antibody, or antibody fragment. Fe region means the constant region of an antibody, which in humans can be of the IgG1 subclass. 2, - 12 3, 4 or others. The sequences of the human Fe regions are available in 1MGT, Human IGH C-REGICLs, www.imgt.org / IMGTrepertoire / Proteins / protein / huma η / 1GH / 1GHC / H u IGHCallgenes.html (retrieved May 16, 2011). The term patient includes a human. NHL is a heterogeneous malignant neoplasm that originates from lymphocytes. In the United States, the incidence is estimated at 65,000 per year with a mortality rate of approximately 20,000 (American Cancer Society, 2006 and SEER Cancer Statistics Review). The disease can occur at any age, with onset typically occurring in adults over 40 years of age, and the incidence increasing with age. NHL is characterized by clonal proliferation of lymphocytes that accumulate in the lymph nodes, blood, bone marrow, and spleen, although any major organ can be involved. The current classification system used by pathologists and clinicians is the World Health Organization (WHO) tumor classification (WHO), which categorizes NHL into precursor and mature B-cell or T-cell neoplasms. The PDQ is currently classifying NHL as indolent or aggressive for inclusion in clinical trials.The indolent group of NHL is composed primarily of follicular, small lymphocytic lymphoma, MALI (mucosa-associated lymphoid tissue), and marginal zone subtypes; indolent comprises approximately 50% of newly diagnosed NHL· patients. Aggressive NHL includes patients with histologic diagnoses of primarily diffuse large 3-cell (DLBL·, DLBCL, or DLCL) (40% of all newly diagnosed patients have diffuse large 3-cell), Burkitt, and mantle cell lymphoma. The clinical course of NHL is highly variable. A major determinant of the clinical course is the histologic subtype. Most indolent types of NHL are considered incurable diseases. Patients initially respond to chemotherapy or antibody therapy, and most will relapse. Studies to date have not demonstrated improved survival with early intervention.In asymptomatic patients, it is acceptable to observe and wait until the patient becomes symptomatic or the disease rate appears to be accelerating. Over time, the disease may transform into a more aggressive histology. Median survival is 8 to 10 years, and indolent patients often receive 3 or more treatments during the treatment phase of their disease. The initial treatment for patients with symptomatic indolent NHL has historically been combination chemotherapy. The most commonly used agents include cyclophosphamide, vincristine, and prednisone (CVP); or cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP). Approximately. 70° to 80° of the Patients who respond to their initial chemotherapy may be impatient, but remissions last approximately 2 to 3 years. Ultimately, most patients relapse. The discovery and clinical use of the anti-CD23 antibody, rituximab, has provided significant improvements in response rate and survival. The current standard of care for most patients is rituximab + CHOP (R-CHOP) or rituximab + CVP (R-CVP). Rituximab is approved for the initial treatment of NHL in combination with alkylating agents, but its use is limited in the US. Rituximab therapy has been shown to be effective in several types of NHL and is currently approved as a first-line treatment for both indolent NHL (follicular lymphoma) and aggressive NHL (diffuse large B-cell lymphoma).However, there are significant limitations to the anti-CD20 monoclonal antibody (mAb), including primary resistance (50% response rate in relapsed, indolent patients), acquired resistance (50% response rate after retreatment), rare complete response (20% complete response rate in the relapsed population), and a persistent pattern of relapse. Finally, many B cells do not express CD20, and therefore many B-cell disorders cannot be treated with anti-CD20 antibody therapy. 15In addition to NHL, there are several types of leukemia that result from the dysregulation of B cells. Chronic lymphocytic leukemia (also known as chronic lymphoid leukemia or CLL) is a type of leukemia in adults caused by an abnormal accumulation of B lymphocytes. In CLL, the malignant lymphocytes may appear normal and mature, but they are unable to effectively fight infection. CLL is the most common form of leukemia in adults. Men are twice as likely to develop CLL as women. However, the key 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, and the death rate is nearly 5,000 per year (American Cancer Society, 2006 and SEER Cancer Statistics Review). CLL is an incurable disease, but it progresses slowly in most cases. Many people with CLL lead normal, active lives for many years.Due to its slow onset, early-stage CLL is generally not treated, as early intervention is not believed to improve survival time or quality of life. Instead, the condition is monitored over time. Initial treatments for CLL vary depending on the exact diagnosis and disease progression. Dozens of agents are used to treat CLL. Combination chemotherapy regimens such as FCR (fludarabine, cyclophosphamide, and rituximab) and BR (ibrutinib and rituximab) are effective in 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. Another type of leukemia is small lymphocytic lymphoma (SLL), which is considered a variant of CLL that lacks the clonal lymphocytosis required for the diagnosis of CLL, but otherwise shares pathological and immunophenotypic characteristics (Campo et al., 2011). The definition of SLL requires the presence of lymphadenopathy and / or splenomegaly. In addition, the number of B lymphocytes in the peripheral blood must not exceed 5 x 10⁹ / L. In SLL, the diagnosis should be confirmed by histopathological evaluation of a lymph node biopsy whenever possible (Hallek et al., 2008). The incidence of SLL is approximately 25% that of CLL in the US (Dores et al., 2007). Another type of leukemia is acute lymphoblastic leukemia (ALL), also known as acute lymphocytic leukemia. ALL is characterized by the overproduction and continuous multiplication of malignant, immature white blood cells (also known as lymphoblasts) in the bone marrow. "Acute" refers to the immature and undifferentiated state of the circulating lymphocytes (blasts), and the fact that the disease progresses rapidly, with a life expectancy of weeks to months if left untreated. ALL is most common in early childhood, with a peak incidence between 4 and 5 years of age. Children aged 12 to 16 are more likely to die than younger children. Currently, at least 80% of childhood ALL is considered curable. Fewer than 4,000 cases are diagnosed each year, and the mortality rate is approximately 1,500 per year (American Cancer Society, 2006 and SEER Cancer Statistics Review). The use of a CC19 antibody in nonspecific B-cell lymphomas is discussed in document W02007076950 (US2007154473), both incorporated by reference. The use of a CD19 antibody in CLL, NHL, and ALL is described in Scheuermann et al., CD19 Antigen in the diagnosis of leukemia and lymphoma and immunotherapy. Leukemia and Lymphoma, vol. 18, 385-397 (1995), which is incorporated by reference in its entirety. Additional specific antibodies to CD19 are described in documents 7)02005012493 (001109304), WO2010053Ί16 (US12 / 266,999) (Immuncmedics); WO2007002223 (US 8097703) (Medarex); WO2008022152 (12 / 377,251) and W02008150494 (Xencor), WO20080 31. 056 (US 1 1 / 8 52 , 1 0 6 ) (Meoimmune) ; 7)02001076950 (US 11 / 648, 505) (Merck Patent GmbH); 7)02 00 9 / 0 524 31 (US 12 / 2 5 3 , 8 95 ) (Seattle Genetics); and WO2010095031 (12 / 7'0.442) (Glenmark Pharmaceuticals), WO2012010562 and 7)02012010561 (International Drug Development), 7)02011147834 (Roche Glycart), and WO - 18 2012 / 156455 (Sanofi), which are incorporated as a reference in their entirety. The term CD19 refers to the protein known as CD19, which has the following synonyms: B4, CD19 B lymphocyte antigen, B4 lymphocyte surface antigen 3, CVID3, CD19 differentiation antigen, MGC12802 and Leu-12 T cell surface antigen. Human CD19 has the following amino acid sequence: MPPPRLLFFLLFLTPMEVRPEEPLVVKVEEGDNAVLQCLKGTSDGPTQQLTWSRES PLKPF LKLSLGLPGLGIHMRPLAIWLFTFNVSQQMGGFYLCQPGPPSEKAWQPGWTVNVEG SGELF RWNVSDLGGLGCGLKKRSSEGPSSPSGKLMSPKLYVWAKDRPEIWEGEPPCLPPRD SLN QSLSQDLTMAPGSTLWLSCGVPPDSVSRGPLSWTHVHPKGPKSLLSLELKDDRPAR DRW VMETGLLLPRATAQDAGKYYCHRGNLTMSFHLEITARPVLWHWLLRTGGWKVSAVT LAYLI FCLCSLVGILHLQRALVLRRKRKRMTDPTRRFFKVTPPPGSGPQNQYGNVLSLPTP TSGLG RAQRWAAGLGGTAPSYGNPSSDVQADGALGSRSPPGVGPEEEEGEGYEEPDSEEDS EFY ENDSNLGQDQLSQDGSGYENPEDEPLGPEDEDSFSNAESYENEDEELTQPVARTMD FLSP - 19 HGSAWDPSREATSLGSQSYEDMRGTLYAAPQLRSIRGQPGPNHEEDADSYENMDNP DGP DPAWGGGGRMGTWSTR. (SEQ ID NO: ) MOR00208 is an anti-CD19 antibody. The amino acid sequence of the variable domains is provided in Figure 1. The amino acid sequence of the Fe regions of the heavy and light chains of MOR00208 is provided in Figure 2. MOR00208 and XmAb 5574 are used synonymously to describe the antibody shown in Figures 1 and 2. The antibody MOR00208 is described in U.S. patent application serial number 12 / 377,251, which is incorporated by reference in its entirety. The solicited license is serial number 12 / 377,251 and describes the anti-body called 4G7 H1.52 Hybrid 15 S239D / I332E / 4G7 L1.155 (later called MOR00208) as follows: >4G7 H1.52 Hybrid S239D / I332E EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYIKPYN DGTKYNEKFQGRVTISSDKSISTAYMSLSSLRSEDTAMYYCARGTYYYGTRVFDWG QGTL VTVSSASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVH TFPAV LQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPC PAPELL GGPDVFLFPPKPKDTL ΜI SR Τ Ρ Ε VTCVVVDVS Η 2 D ? 2 VQF Ν WYVDGV Ε V Η Μ A Κ Τ Κ Ρ REEQ FNSTFRWSVLTWHQDWLNGKEYKCKVSNKALPAPEEK7ISKTKGQPREPQVYTL PPSRE BMTKNQVSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTV DKSR WQQGNVFSCSVMHEALHNHY7QKSLSLSPGK (SEQ ID ΝΟ: 8) > 4G7 L1.155 DIVMTQSPATLSLSPGERATLSCRSSKSLQNVNGNTYLWFQQKPGQSPQLLIYRMS NLN SGVPDRFSGSGSGTEFTLTISSL2PEDFAVYYCMQHLEYPI7FGAGTKLEIKRTVA APSVFIF PPSDEQLKSGTASVVCLLNNFYPREAKVQWKVDNALQSGNSQESVTEQDSKDS7YS LSST LTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 9) A pharmaceutical composition includes an active agent, e.g., an antibody for therapeutic use in humans. A pharmaceutical composition may additionally include pharmaceutically acceptable vehicles or excipients. Administered or administration refers to the administration of a pharmaceutical composition by an injectable form, such as, for example, an intravenous, intramuscular, intradermal or subcutaneous route or a mucosal route, for example, as a nasal spray or inhalation spray or as a solution that can be ingested, capsule or tablet. The Ξ1 antibody administered in accordance with this disclosure is given to the patient in a therapeutically effective amount. A therapeutically effective amount refers to an amount sufficient to provide some improvement in the clinical manifestations of a given disease or disorder. As an example, patients in the exemplified study received a dose of MCR00208 at 12 mg / kg once a week, and at maintenance once every two weeks or 10 times monthly. The amount effective for a particular therapeutic purpose will depend on the severity of the illness or injury, as well as the subject's weight and general condition. It is understood that determining an appropriate dose can be achieved through routine experimentation, constructing a matrix of values, and testing different points on the matrix—all of which is within the ordinary capabilities of a trained physician or clinical scientist. Baseline means before the administration of the desired therapy. For example, before the administration of the desired anti-CD19 antibody. A receiver operating characteristic (ROC) analysis was used to analyze predictive power, sensitivity, specificity, and to determine the values. - 22 cutoff for potential markers, such as NK cell counts, CD16 expression levels in NK cells, and cell counts. 7. The following additional methods exist to estimate an optimal cutoff: Max.Accuracy: the cutoff that maximizes accuracy; b) Max.DOR: the cutoff that maximizes the ratio of diagnostic possibilities; c) Error.rate: the cutoff that minimizes the error rate; d) Max.Accuracy.area: the cutoff that maximizes the area of ​​accuracy; e) “Max.Sens+Spec”: the cutoff that maximizes the sum of sensitivity and specificity; f) Max.Youden: the cut that maximizes the Youden index; g) Se=Sp: the cut whose sensitivity is equal to the specificity; h) Min.RCC.Dist: the cut that minimizes the distance between the curve and the upper left corner of the graph; i) Max.Efficiency: the cut that maximizes efficiency; and j) Min.MCT: the cut that minimizes the misclassification cost term. See Lopez-Raton, M., Rodriguez-Alvarez, MX, Cadarso-Suarez, C. and Gude-Sampedro, F. (2014). Optimal Cutpoints: An R Package for Selecting Optimal Cutpoints in Diagnostic Tests. Journal of Statistical Software 61 (8), 1-36. Specific antibodies to CD19 have also been tested preclinically in combination with other drugs. For example, MOR00208 was tested in combination with nitrogenous mustards, purine analogues, and thalidomide analogues. - 23 phosphoinositide 3-kinase inhibitor, BCL-2 inhibitors and Breton tyrosine kinase (BTK) inhibitors. A nitrogen mustard is a non-specific DNA alkylating agent used as chemotherapy. Alkylating agents add an alkyl group (CnE2n+1) to nucleic acid bases, for example, by adding an alkyl group to the guanine base of DNA at the nitrogen atom number 7 of the imidazole ring. The alkylation steps result in the formation of interstrand cross-links (ICLs). These ICLs are highly cytotoxic, as they block fundamental metabolic processes such as replication and transcription. Nitrogen mustards include cyclophosphamide, chlorambucil, uramustine, ifosfamide, melphalan, and bendamustine. Bendamustine is marketed under the names Ribomustin® and Treanda®, also known as SDX-105, are marketed by Mundipharma International Corporation Limited (licensee of Astellas Pharma GmbH) and Cephaion for the treatment of chronic lymphocytic leukemia (CLL), indolent 20-cell non-Hcdgkin lymphoma (NHL), and other lymphomas. Bendamustine has the following structure: O CR OH N < ·· N ) C! - 24 A purine analogue is an antimetabolite that mimics the structure of metabolic purines, thereby interfering with nucleic acid synthesis. Fludarabine, for example, can be incorporated into RNA and DNA by substituting the purine nucleotides adenine and guanine. Purine analogues inhibit the growth of rapidly proliferating cells in an individual, such as cancer cells, bone marrow cells, or cells present in the gastrointestinal tract. Purine analogues include mercaptopurine, azathioprine, thioguanine, and fludarabine. Fludarabine, or fludarabine phosphate (Fludarah), is a chemotherapy drug used in the treatment of chronic lymphocytic leukemia and indolent non-Hodgkin lymphomas. Fludarabine is a purine analogue.Fludarabine inhibits DNA synthesis by interfering with ribonucleotide reductase and DNA polymerase and is specific to the S phase (since these enzymes are very active during DNA replication). Fludarabine has the following structure: - 25 A thalidomide analogue includes, but is not limited to, thalidomide, lenalidomide (CC-5013, Revi imid™), pomalidomide (CC4047, Actimid™), and the compounds disclosed in WO2002068414 and WO2005016326, which are incorporated by reference in their entirety. The term refers to a synthetic chemical compound that uses the thalidomide structure as a backbone (e.g., side groups have been added or such groups have been removed from the main structure). The analogue differs in structure from thalidomide and its metabolite compounds, for example, by a difference in the length of an alkyl chain, a molecular fragment, by one or more functional groups, or a change in ionization. The term thalidomide analogue also includes thalidomide methylbolites. Thalidomide analogues include the racemic mixture of the S and R enantiomers of a respective compound and the S enantiomer or R enantiomer individually.Racemic mixture is preferred. Thalidomide analogues include compounds with the following structures: - 26 (A) Lenalidomide 0 !! Ά .-Á / \ f'x\ · ' L l[ ;^nh NH;° A phosphoinositide 3-kinase inhibitor is a class of medical drug that works by inhibiting one or more of the 5 phosphoinositide 3-kinase enzymes, which are part of the Pl3K / AKT / mT0R pathway, an important signaling pathway for many cellular functions such as growth control, metabolism, and translation initiation. There are a number of different classes and isoforms of PI3K. Class I PI3Ks have a catalytic subunit known as pllO, with four types (isoforms) – pllO alpha, pllO beta, pllO gamma, and pllO delta. Current inhibitors under investigation inhibit one or more isoforms of class I PI3Ks. Phosphoinositide 3-kinase inhibitors include at least idelalisib, duvelisib, and copanlisib. Idelalisib is marketed by Gilead Sciences, Inc. (trade name Zydelig, also referred to as GS-1101 or CAL-101). Idelalisib is currently labeled for the treatment of relapsed chronic lymphocytic leukemia (CLL), in combination with rituximab, in patients for whom rituximab alone is considered adequate therapy due to other comorbidities; and follicular B-cell non-Hodgkin lymphoma (FHL). - 27 of relapse in patients who have received at least two prior systemic therapies; relapsed small lymphocytic lymphoma (SLL) in patients who have received at least two prior systemic therapies. The substance acts as a phosphoinositide 3-kinase inhibitor; more specifically, it blocks RIOδ, the delta isoform of the phosphoinositide 3-kinase enzyme. The formula for Idelalisib is: F ¡ i !i N ...N '''ο·'NH ! 1 N' A Bruton's tyrosine kinase (BTK) inhibitor is a class of drugs that work by inhibiting the protein tyrosine kinase enzyme BTK, which plays an important role in the development of B cells. Specifically, BTK contains a PE domain that binds to phosphatidylinositol (3,4,5)-trisphosphate (PIP3). The binding of PIP3 induces Btk to phosphorylate phospholipase C, which in turn hydrolyzes PIP2, a phosphatidylinositol, into two second messengers, inositol triphosphate (IP3) and diacylglycerol (DAG), which then go on to modulate the activity of downstream proteins during B cell signaling. - 28 Bruton's tyrosine kinase (BTK) inhibitors include ibrutinib. Ibrutinib is marketed by Pharmacyclics, Inc. and Janssen Pharmaceuticals of Johnson & Johnson (trade name Imbruvica, also designated PCI32765). Ibrutinib is currently labeled for the treatment of patients with mantle cell lymphoma (MCL) who have received at least one prior therapy, chronic lymphocytic leukemia (CLL) who have received at least one prior therapy, chronic lymphocytic leukemia with 17p deletion, and Waldenström macroglobulinemia. The formula for ibrutinib is 1-[(3R)-3-[4-amino-3-(4-phenoxyphenyl)-1H-pyrazolo[3,1-dl-pyrimidin-1-yl]-1-piperidinyl-1,2-propen-1-one and has the following structure: N HN or, N r'%r. Λ N . ' 3 ! N 1 '' i V, A BCL-2 inhibitor is a class of drugs that work by inhibiting the B-cell lymphoma anti-apoptotic protein B-2 (Bcl-2), which leads to programmed cell death. BCL-2 inhibitors include venetoclax. Venetoclax is marketed by AbbVie and Genentech (trade name VENCLEXTA™, also known as GDC-0199, ABT-199, and RG7601). Currently, venetoclax is approved for the treatment of patients with leukemia. - 29 chronic lymphocytic leukemia (CLL) with 17p deletion, as detected by an FDA-approved test, who has received at least one prior therapy. The formula of venetoclax is 4(4-{[2-(4-chlorophenyl)-4,4-dimethyl-l-cyclohexen-l-yl]methyl}-1-piperazinyl)-N-({3-nitro-4-[(tetrahydro-2H-pyran-4-ylmethyl)amino]phenyl}sulfonyl)-2-(lH-pyrrolo]-2,3-b]pyridinine-5- yloxybenzamide and has the following structure: Cl NH -f Ύ Ck®.Ot?0H Ύ Y L. x. JY 0.,XN 1 H T '7 Λ or 0 or Venetoclax, ABT and ABC-199 are used as synonyms 10 in this document. ACHIEVEMENTS One aspect is a method for identifying a subject who has chronic lymphocytic leukemia (CLL), Hodgkin lymphoma (NHL), acute blast leukemia (ALL), or small lymphocytic lymphoma (SLL) who responds to treatment with an anti-CD19 antibody. This method comprises: a. provide a sample obtained from said subject prior to treatment with said anti-CD19 antibody, b. Determine the level of at least one bio-alcohol in the selected sample from the group consisting of: JJ - i. peripheral NK cell count, and ii. CD16 expression levels in peripheral NK cells, c. compare the level of at least one biomarker in said sample with a predetermined cutoff level, wherein levels of said at least one biomarker at or above the predetermined cutoff level are indicative of a subject who would benefit from treatment with an anti-CD19 antibody. In practical applications, the sample is a blood sample. In realization, this sample comprises peripheral NK cells. In embodiments, the default cutoff level for said biomarker is a reference peripheral NK cell count of at least 50 cells / µL, at least 75 cells / µA, at least 125 cells / µL, at least 150 cells / µL, at least 175 cells / µL, at least 200 cells / µA, at least 225 cells / µL, or at least 250 cells / µA. In embodiments, the default cutoff level for said biomarker is reference CD16 expression levels in peripheral NK cells of at least 45,000 ABC, at least 60,000 ABC, at least 75,000 ABC, or at least 90,000 ABC. In practice, the default cutoff for this biomarker is: - 31 a. a peripheral NK cell reference count of at least 50 cells / μI, or b. reference levels of CD16 expression in peripheral NK cells of at least 60,000 (AUC). In practice, the default cutoff for this biomarker is: a. peripheral NK cell reference count of at least 50 cells / μI, and b. reference levels of CD16 expression in peripheral NK cells of at least 60,000 (AUC). In implementations, a predetermined cutoff level is a reference peripheral NK cell count of at least 50 cells / µL. In implementations, the predetermined cutoff for this biomarker is reference CD16 expression levels in peripheral NK cells of at least 60,000 (AUC). In practice, the default cutoff for this biomarker is: a. a peripheral NK cell reference count of at least 70 cells / μA, or b. reference levels of CD16 expression in peripheral NK cells of at least 60,000 (AUC). In practice, the default cutoff for this biomarker is: a. a peripheral NK cell reference count of less than 00 cells / ul, and b. Reference levels of O16 expression in peripheral NK cells of at least 60,000 (AUC). In embodiments, a predetermined cutoff level is a reference peripheral NK cell count of at least 70 cells / μA. In embodiments, the predetermined cutoff for such biomarker is reference CD16 expression levels in peripheral NK cells of at least 60,000 (AUC). In practice, the default cutoff for this biomarker is: a. a peripheral NK cell reference count of at least 80 cells / μA, or b. reference levels of CD16 expression in peripheral NK cells of at least 60,000 (AUC). In practice, the default cutoff for this biomarker is: a. a peripheral NK cell reference count of at least 80 cells / µL, and b. reference levels of CD16 expression in peripheral NK cells of at least 60,000 (AUC). In embodiments, a predetermined cutoff level is a reference peripheral NK cell count of 80 cells / μA in monkeys. In embodiments, the predetermined cutoff of said biomarker is reference CDlc expression levels in peripheral NK cells of 60,000 (AUC) in monkeys. In practice, the default cutoff for this biomarker is: a. a peripheral NK cell reference count of at least 90 cells / μμ, c b. reference levels of CD16 expression in peripheral NK cells of at least 60,000 (AUC). In practice, the default cutoff for this biomarker is: a. a peripheral NK cell reference count of at least 90 cells / μ1, and b. reference levels of CD16 expression in peripheral NK cells of at least 60,000 (AUC). In implementations, a predetermined cutoff level is a reference peripheral NK cell count of at least 90 cells / µL. In implementations, the predetermined cutoff for this biomarker is reference CD16 expression levels in peripheral NK cells of at least 60,000 (AUC). In practice, the default cutoff for this biomarker is: a. a peripheral NK cell reference count of at least 100 cells / µL, or b. Reference levels of CD16 expression in cells Peripheral NK of at least 60,000 (ABC). In practice, the default cutoff for this biomarker is: a. a peripheral NK cell reference count of at least 100 cells / µL, and b. reference levels of CD16 expression in peripheral NK cells of at least 60,000 (AUC). In embodiments, a predetermined cutoff level is a reference peripheral NK cell count of at least 100 cells / μI. In embodiments, the predetermined cutoff for such biomarker is reference CD16 expression levels in peripheral NK cells of at least 60,000 (AUC). One aspect is a method for identifying a subject who has chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), acute lymphoblastic leukemia (ALL), or small lymphocytic lymphoma (SLL) who responds to treatment with an anti-CD19 antibody, said method comprising: a. provide a blood sample obtained from said subject prior to treatment with said anti-CD19 antibody, b. Determine the level of at least one biomarker in the selected sample of the group, which consists of: i. peripheral NK cell count, and ii. CD16 expression levels in peripheral NK cells, c. compare the level of at least one biomarker in the sample with a predetermined cutoff level, wherein the reference count of peripheral NK cells is at least 50 cells / μA, less than 60 cells / μA, at least 70 cells / μA, at least 50 cells / μA, at least 90 cells / μA! or at least 100 cells / μA and the reference expression levels of CD16 in peripheral NK cells are at least 60,000 (ABC), and wherein the anti-CD19 antibody comprises an HCDR1 region comprising the sequence SYVMH (SSQ ID NO: 1), an ECDR2 region comprising the sequence NPYMDG (SEQ ID NO: 2), an HCDR3 region comprising the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region comprising the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region comprising the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region comprising the sequence MQHLEYPIT (SEQ ID NO: 6). One aspect is a method for identifying a subject who has chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), acute lymphoblastic leukemia (ALL), or small lymphocytic lymphoma (SLL) who responds to treatment with an anti-CDly antibody, said method comprising: a. provide a blood sample obtained from said subject prior to treatment with said anti-CD19 antibody, b. Determine the level of at least one biomarker in the selected sample from the group consisting of: i. Peripheral NK cell count, and ii. CD16 expression levels in peripheral NK cells, c. compare the level of said anti-biomarker in said sample with a predetermined cutoff level, wherein the reference peripheral NK cell count is at least 100 cells / pl, or the reference CD16 expression levels in peripheral NK cells are at least 60,000 (ABC), and wherein the antr-CD19 antibody comprises an HCDR1 region comprising the sequence SxVMH (SEQ ID NO: 1), an ECDR2 region comprising the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region comprising the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region comprising the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region comprising the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region comprising the sequence MQHLEYPIT (SEQ ID NO: 6). In practice, the default cutoff for this biomarker is: a. peripheral NK cell reference count of at least 100 cells / µL, and b. reference levels of CD16 expression in peripheral NK cells of at least 60,000 (AUC). - 38 reference CD16 expression in peripheral NK cells of at least 60,000 (AUC). One aspect is a method for treating a patient who has chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma 5 (NHL), acute lymphoblastic leukemia (ALL), or small lymphocytic lymphoma (SLL) cor. an anti-CD19 antibody, the method comprising a. obtain a baseline peripheral NK cell count in the patient, or a baseline CD16 expression level of 10 in the patient's peripheral NK cells, and b. administer an effective amount of anti-CD19 antibody to the patient who has a reference peripheral NK cell count of at least 100 cells / ul or a reference CD16 expression level on peripheral NK cells of at least 60,0001(AUC). In realizations, the method of treating a patient with chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), acute lymphoblastic leukemia (ALL), or small lymphocytic lymphoma (SLL) with an anti-CD19 antibody, 20 comprises a. obtain a baseline peripheral NK cell count in the patient, and b. Administer an effective amount of anti-CD19 antibody to a patient with an NK cell count of at least 50 cells / µL, at least 60 cells / µL, or at least 70 -39 cells / μΐ, at least 80 cells / μΙ, at least 90 cells / μΙ, or at least 100 cells / ul. In embodiments, the method of treating a patient with chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), acute lymphoblastic leukemia (ALL), or small lymphocytic lymphoma (SLL) with an anti-CD19 antibody comprises a. obtain a baseline peripheral NK cell count in the patient, and b. administer an effective amount of anti-CD19 antibody to the patient who has an NK cell count of at least 50 cells / μA, at least 60 cells / ul, at least 70 cells / ul, at least 50 cells / ul, at least 90 cells / μA or at least 10C1 cells / pl. In embodiments, the method of treating a patient with chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), acute lymphoblastic leukemia (ALL), or small lymphocytic lymphoma (SLL) with an anti-CD19 antibody comprises a. obtain a baseline peripheral NK cell count in the patient, and b. administer an effective amount of anti-CD19 antibody to the patient who has an NK cell count of at least 100 cells / ul. - 4 0 In embodiments, the method for treating a patient having chronic lymphocytic leukemia (CLI), non-Hodgkin lymphoma (NHL), acute lymphoblastic leukemia (ALL), or small lymphocytic lymphoma (SLL) with an anti-O19 antibody comprises a. obtain reference expression levels of O16 in the patient's peripheral NK cells, and b. administer an effective amount of anti-CD19 antibody to the patient who has 016 levels in NK cells of at least 60,000 (AUC). In realizations, the anti-CD19 antibody is administered to patients who have a baseline peripheral NK cell count of at least 50 cells / µL, at least 60 cells / µL, at least 70 cells / µL, at least 50 cells / µL, at least 90 cells / µL, or at least 100 cells / µL, and a baseline expression level of 016 in peripheral NK cells of at least 60,000 (AUC). In realizations, the anti-CD19 antibody is administered to patients who have a baseline peripheral NK cell count of at least 100 cells / μA and a baseline peripheral NK cell CD16 expression level of at least 60,000 (AUC). In realizations, the anti-CD19 antibody is administered to patients who have a reference peripheral NK cell count of at least 50 cells / µA in monkeys, at least 7.5 cells / µL, at least 100 cells / µA in children, at least 125 cells / µL, at least 150 cells / µL, at least 1.5 cells / µA, at least 200 cells / μA, at least 225 cells / μA, or at least 250 cells / μA. In embodiments, the anti-CDi9 antibody is administered to patients who have reference levels of CD16 expression in peripheral NK cells of at least 45,000 ABC, at least 60,000 ABC, at least 75,000 ABC, or at least 90,000 ABC. One aspect is a method for treating a patient who has chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), acute lymphoblastic leukemia (ALL), or small lymphocytic lymphoma (SLL) with an anti-CD19 antibody, said method comprising: a. provide a sample obtained from said subject prior to treatment with said antibody ar.ti-CD19, b. Determine the level of at least one biomarker in the selected sample of the group, which consists of: i. peripheral NK cell count, and ii. CD16 expression levels in peripheral NK cells 20, c. compare the level of at least one biomarker in the sample with a predetermined cutoff level, d. administer an effective amount of anti- antibody CD19 in patients who have a peripheral NK cell count of at least 100 cells / µL or a level of - 42 CD16 expression in peripheral NK cells of a_ less 60,000 (ABC). One aspect is a method for treating a patient who has chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), acute lymphoblastic leukemia (ALL), or small lymphocytic lymphoma (SLL) comprising administering an effective amount of an anti-CD19 antibody to the patient if a. The patient's peripheral NK cell reference count is at least 100 cells / μA or b. The reference levels of CD16 expression in peripheral NK cells are at least 60,000 (AUC). One aspect is a method for treating a patient who has chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), acute lymphoblastic leukemia (ALL), or small lymphocytic lymphoma (SLL) that comprises a. obtain the patient's peripheral NK cell count, b. administer an effective amount of an anti-CD19 antibody to patients with peripheral NK cell counts of at least 100 cells / µL. One aspect is a method for treating a patient who has chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), acute lymphoblastic leukemia (ALL), or small lymphocytic lymphoma (SLL) that comprises - 4 3 a. Obtain the CD16 expression levels in the patient's peripheral NK cells, b. administer an effective amount of an anti-CD19 antibody to patients who have CD16 expression levels on peripheral NK cells ce of at least 60,000 (AUC). In one embodiment, the anti-CD19 antibody is administered to patients with a baseline peripheral NK cell count of at least 100 cells / µA and a baseline peripheral NK cell CD16 expression level of at least 60,000 (AUC). In another embodiment, the anti-CD19 antibody is administered to patients with a baseline peripheral NK cell count of at least 50 cells / µL, at least 75 cells / µA, at least 125 cells / µL, at least 150 cells / µA, or to monkeys. 175 cells / µL, at least 200 cells / µL, at least 225 cells / µL, or at least 250 cells / µL. In embodiments, the anti-CD19 antibody is administered to patients who have reference levels of CD16 expression in peripheral NK cells of at least 45,000 ABC, at least 60,000 ABC, at least 75,000 ABC, or at least 90,000 ABC. In realizations, the reference cell count Peripheral NK cells or CD16 reference levels (ABC) in peripheral NK cells are obtained from a blood sample taken from the patient. In some realizations, the peripheral NK cell count and / or expression levels of - 44 CD16 are measured before administration of the anti-CD19 antibody. In embodiments, the CD19-specific antibody comprises an HCDR1 region comprising the sequence SYVMH 5 (SEQ ID NO: 1), an HCDR2 region comprising the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region comprising the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LGDR1 region comprising the sequence RSSKSLQNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region comprising the sequence RMSNLNS (SEQ ID NO: 10 5) and an LCDR3 region comprising the sequence MQHLEYRIT (SEQ ID NO: 6). In realizations, the reference peripheral NK cell count or reference CD16 expression levels in peripheral NK cells is obtained from a blood sample taken from the patient. In one embodiment, the patient has non-Hodgkin lymphoma. In the embodiments, the non-Hodgkin lymphoma is selected from the group consisting of follicular lymphoma, small lymphocytic lymphoma, mucosa-associated lymphoid tissue (MALT), marginal zone lymphoma, diffuse large B-cell lymphoma, Burk-Itt lymphoma, and mantle cell lymphoma. In one embodiment, the non-Hodgkin lymphoma is follicular lymphoma. In another embodiment, the non-Hodgkin lymphoma is indolent non-Hodgkin lymphoma. In another embodiment, the non-Hodgkin lymphoma is small lymphocytic lymphoma. In another embodiment, the non-Hodgkin lymphoma is mucosa-associated lymphoid tissue (MALT). In another embodiment, the non-Hodgkin lymphoma is marginal zone lymphoma. In another embodiment, the non-Hodgkin lymphoma is diffuse large B-cell lymphoma. In one realization, the non-Hodgkin lymphoma is Burkitt lymphoma. In another realization, the non-Hodgkin lymphoma is mantle cell lymphoma. In yet another realization, the patient has chronic lymphocytic leukemia.In one scenario, the patient has acute lymphoblastic leukemia. In another scenario, the patient has small lymphocytic lymphoma (SLL). In practice, the treatment results in the selected therapeutic effect of the group, which consists of a disease control rate (DCR) and a longer duration of progression-free survival. In embodiments, the treatment further comprises the administration of an effective amount of a nitrogen mustard. In one embodiment, the nitrogen mustard is bendamustine. In embodiments, the treatment further comprises the administration of an effective amount of a purine analogue. In embodiments, the purine analogue is fludarabine. In embodiments, the treatment further comprises the administration of an effective amount of a Bruton's tyrosine kinase (BTK) inhibitor. In embodiments, the Bruton's tyrosine kinase (BTK) inhibitor is ibrutinib. In embodiments, the treatment further comprises the administration of an effective amount of a phosphoinositide 3-kinase inhibitor. In one embodiment, the phosphoinositide 3-kinase inhibitor is idelalisib. In embodiments, the treatment further comprises the administration of an effective amount of a thalidomide analogue. In one embodiment, the thalidomide analogue is lenalidomide.In some embodiments, the treatment also includes the administration of an effective amount of a BCL-2 inhibitor. In one embodiment, the BCL-2 inhibitor is venetoclax. Since the exemplified anti-CD19 antibody and other anti-CD19 antibodies bind to CD19, it is believed that similar results may be seen with other anti-CD19 antibodies. Other anti-CD19 antibodies are described in U.S. patent application serial number 12 / 377,251 (Xencor), WO2005Q12493, WO2010C53716 (Immunomedics); WO2007002223 (Medarex); WO2008022152 (Xencor); WO2C08031056 (Medimmune); 7'02007 / 07 6950 (Merck Patent GmbH); WO2009 / 052431 (Seattle Genetics); and WO201C095031 (Glenmark Pharmaceuticals), all of which are incorporated by reference in their entirety. In embodiments, the CD19-specific antibody comprises a cross-competing antibody comprising an HCDR1 region comprising the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region comprising the sequence NPYNDG (SEQ ID NO: 2), a region HCDR3 comprising the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region comprising the sequence RSSKSLQKVNGNTYLY (SEQ ID NO: 4), an LCDR2 region comprising the sequence RMSNLNS (SEQ ID NO: 5) and an LCDR3 region comprising the sequence MQHLEYPIT (SEQ ID NO: 6). In embodiments, the CD19-specific antibody comprises an antibody that binds to the same epitope as an antibody comprising an HCDR1 region comprising the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region comprising the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region comprising the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region comprising the sequence RSSKSLQKVNGNTYLY (SEQ ID NO: 4), an LCDR2 region comprising the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region comprising the sequence MQHLEYPIT (SEQ ID NO: 6). In embodiments, the CD19-specific antibody comprises an HCDR1 region of sequence SYVMH (SEQ ID NO: 1), an HCDR2 region of sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region of sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region of sequence RSSKST.QNVNGNTYLY (SEQ ID NO: 4), an LCDR2 region of sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region of sequence MQHLEYPIT (SEQ ID NO: 6). In embodiments, the specific antibody for CD19 comprises a variable heavy chain of the sequence EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPY - 48 NDGTKYNEKFQGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGTYYYGTRVFDW G QGTLVTVSS (SEQ ID NO: 10') and a variable lightweight string of the sequence DIVMTQSPATLSLSPGERATLSCRSSKSLQNVNGNTYLWFQQKPGQSPQLLIYR MSNLNSGVPDRFSGSGSGIEFTLTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEI K (SEQ ID NO: 11). In one embodiment, said antibody comprises a heavy chain constant domain of the sequence ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV LQSSG LYSLSSVVTVPSSSLGTQTYICKVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEL LGGPDV FLFPPKPKDTLMISRTPEVTCVVVDVSHEDFEVQFNWYVDGVEVHNAKTKPREEQF NSPFR WSVLTVVHQDWLNGKEYKCKVSNKALPAPEEKTISKTKGQPREPQVYTLPPSREE MTKNQ VSLTCLVKGFYPSDIAVENESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQ QGNV FSCSVMHEALHNHYTQKSLSLSPGK (SEQ ID NO: 12) In one embodiment, the antibody specific for CD19 comprises a light chain constant domain of the sequence RTVAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGNSQESV TEQDS - 49 KD STYSLSSTLTLSKADYEKEKVYACEV7HQGLSSPVTKSFNRGEC. (SEQ ID NO: 13). In one embodiment, the antibody specific for CD19 comprises a heavy chain having the sequence EVQLVESGGGLVKPGGSLKLSCAASGYTFTSYVMHWVRQAPGKGLEWIGYINPYND GTKY NSKFQGRVTISSDKSYSTEMSSLRSEDTAMYYCARGTYYYGTRVFDWGQGTLV TVSS ASTKGPSVFPLAPSSKSTSGGTAALGCLVKDYFPEPVTVSWNSGALTSGVHTFPAV LQSSG LIGHTINGSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKSCDKTHTCPPCPAPEL LGGPDV FLFPPK PKDTLMISRTPEVTC VWDVS HE DPEVQFNIJYVDGVEVHNAKTKPREEQF NSTFR WSVLTWHQDWLNGKEYKCKVSNKALPAPEEKTISKTKGQPREPQVYTLPPSREE MTKNQ VSLTCLVKGFYPSDIAVEWESNGQPENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQ QGNV FSCSVMHEALHNEYTQKSLSLSPGK (SEQ ID NO: 3) In one embodiment, the CD19-specific antibody comprises a light chain having the sequence DIVMTQSPATLSLSPGERAFLSCRSSKSLQNVNGNTYLYWFQQKPGQSPQLLIYRM SNLN SGVPDRFSGSGSGTEFTLTISSLEPEDFAVYYCMQHLF.YPITFGAGTKLEIKRTVA APSVFIF ou PPSDEQLKSGTASWCLLNNFYPRSAKVQWKVDNALQSGNSQESVTEQDSKDSTYS LSST LTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ ID NO: 9) The embodiments comprise a pharmaceutical composition. In embodiments, the composition comprises an acceptable carrier. In embodiments, the composition is administered in an effective amount. EXAMPLES Example 1: T cell and NK cell count The scope of the MOR00208C201 clinical study included the evaluation of several exploratory biomarkers. As part of this initiative, baseline counts of peripheral T and NK cells were performed at clinical sites. T cells are a type of lymphocyte (a subtype of 15 white blood cells) that play a central role in cell-mediated immunity. They can be distinguished from other lymphocytes, such as B cells and NK cells, by the presence of a T cell receptor on their cell surface. Natural killer (NK) cells are a type of cytotoxic lymphocyte critical to the innate immune system. NK cells provide rapid responses to virus-infected cells, acting approximately 3 days after infection and responding to tumor formation. Normally, immune cells detect the major histocompatibility complex (MHC) present on the surfaces of infected cells, triggering the release of cytokines and causing lysis or apoptosis. However, NK cells are unique in that they have the ability to recognize stressed cells in the absence of antibodies and MHC, allowing for a much faster immune response. Materials and methods TriTest CD3 FITC / GDI6+CD56 PE / GD45 PerCP (with TruCOUNT tubes), BD Bicscionces, Cat: 340403 (USA); 342442 (Europe). Pipettes and pipette tips capable of delivering 20μ1, 50μ1 and 450μ1, Gilson Inc. FACS Lysinq Solutions, BD Biosciences, Cat: 349202. Instruments: flow cytometer, vortex Anjte yields nte_s_ le_la cytome flow selection: Whole blood is stained with fluorochrome-labeled antibodies (TriTEST reagents) that bind specifically to leukocyte surface antigens. The cells travel through the laser beam and scatter the laser light. The stained cells fluoresce. These scattering and fluorescence signals, detected by the instrument, provide information about cell size, internal complexity, and relative fluorescence intensity. TriTEST reagents employ a fluorescence activator, enabling direct fluorescence gating of the NK and I lymphocyte population to reduce contamination from unbound or unnucleated red blood cells at the gate. Staining For each patient sample, a TruCOUNT tube was labeled with the sample identification number. 20 µL of TriTEST CD3 / CD16+CD56 / CD45 reagent was pipetted into the bottom of the tube. 50 µL of well-mixed anticoagulated whole blood was introduced into the bottom of the tube. Anticoagulated (EDTA) blood stored at room temperature (20–25°C) must be stained within 24 hours of collection and analyzed within 6 hours of staining (keep at room temperature and protect from light). The tube was gently swirled to mix. The tube was incubated for 15 minutes in the dark at room temperature (20–25°C). 450 µL of IX FACS Lysing Solution was added to the tube. The tube was aerated and incubated again for 15 minutes in the dark at room temperature (20–25°C). When using TruCOUNT tubes, a known volume of sample is stained directly into a TruCOUNT tube. The lyophilized granule in the tube dissolves, releasing a known number of fluorescent beads. During analysis, the absolute number (cells / µA) of positive cells in the sample can be determined by comparing cell events with bead events. - 53 Flow cytometry The cells were vortexed completely (at low speed) to reduce aggregation before being run in the flow cytometer. Data analysis The CD45 vs. SSC dot plot was visually inspected. Lymphocytes appeared as a compact, bright cell population with low to moderate SSC. Monocytes (M) and granulocytes (G) appeared as 10 distinct populations. The analysis was complete when the monocyte and lymphocyte cell populations showed clear separation. Lymphocytes were initially selected as CD45-positive, with a low SSC cell population. CD16 / CD56 vs. CD3 were preselected. T cells (T) should appear as a compact, bright CE3-positive cluster. NK cells (NK) should appear as a compact, bright CD16 / CD56-positive cluster. The selection was completed, and the T and NK cells were counted. Pearl event counts were performed using a CD16 / CD56 vs CD3 plot without any pre-selection. Pearls should appear as a double positive PE / FITC group. - 54 Absolute count calculation The absolute number (cells / µL of blood) of T cells or NK cells in the sample was determined by comparing cell events with bead events. The analysis was performed using MultiSET software or manual data (using CellQuest or other software). For manual counting, the number (#) of acquired positive cell events was divided by the number (#) of acquired bead events, then multiplied by the total TruCOUNT bead count (batch-dependent) divided by a whole blood sample volume of 50 g L. The result is the absolute number of cells per microliter. Equation what centiuucu pobjnciou Je peda15 Example: =280 cells 7 / μ 1 of blood Example 2: Quantification of CD16 in NK cells As part of the MOR002C8C201 clinical study, the central ICON laboratories (Farmingdale, New York) quantified CD16 (an exploratory biomarker) in peripheral NK cells in a centralized manner. Materials and methods Antibodies: CD45 AmCyan (Clone 2D1, BD Biosciences, Cat. #339192); CD3 FITC (Clone UCHT1, BioLegend, Cat #300406); FITC mouse IgG (Clone MOPC-21, BioLegend, Cat. # 400110); CD16 PE (Clone 3G8, BioLegend, Cat #302008); MCR0020S; mouse IgG PE (Clone MOPC-21, BioLegend, Cat. # 400114); CD56 PerCP-Cy5.5 (Clone HCD56, BioLegend, Cat. #318322); and mouse IgG PerCP-Cy5.5 (Clone MOPC-21, BioLegend, Cat # 400150). Materials: PharmaTherm insulated chargers (Intelsius, catalog # PHT014); BD Vacutaineri CPT mononuclear cell preparation tube - sodium heparin (16x125 mm / 8 ml) (BD, catalog # 362753); BD Falcon™ 12x75 mm round-bottom tubes (BD, catalog # 352052); CS&T beads (BD Biosciences, catalog # 642212); Fetal bovine serum (FES), heat-inactivated (Sigma F4135, or equivalent); Dulbecco's Ca- and Mg-free PBS (Gibco, catalog # 14190 or equivalent); 3D Falcon cell strainer, 100 pm, yellow (BD Bioscience, catalog # 352360); FACS lamp, 31 of heat-inactivated FBS in IX DPBS; Deionized water, laboratory inventory; Crushed ice (wet); Ice tray; Aluminum foil; Conical tubes, 50 ml; Conical tubes, 15 ml; Sterile, filter pipette tips; BD Pharm Lyse Lysir.g lamp (BD Biosciences, Cat 4 555899); The ViViD LIVE / DEAD® Fixable Violet Dead Cell Staining Kit, for excitation at 405 nm (Life Technologies, catalog number L34955); ArC Amine Reactive Pearls (Life Technologies, Cat #A1C346); BD QuantiBRITE Beads (BD Biosciences, cal # 340495); and 52 gm nylon mesh (Miami Agua Culture, for Cat: Nylon 52 units, 32.75 open area woven into material). Equipment: Centrifuge (refrigerated capacity); Lab Quake (Tube Rocker); Vortex Mixer; Laminar Flow Hood; Incubator (set to 37°C, 5°C); Advia (cell counter); BD FACSCANTO II Flow Cytometer; Desi-Vac™ Container, 1.5 liters (VWR, Cat # 62344-930); Indication Humidity Sponge'* (VWR, Cat # 61161-319); and a Traceable Humidity-On-Card (VWR, Cat # 1 5551 - 012). TABLE 1. CD16 quantification assay panel for PBMC (peripheral blood mononuclear cells) Description Tube » V450 AmCyan FITC PE PerCP- Cy5.5 ACP Control tube 1 1 ViViD CD4 5 Ms IgG Ms Ms IgG — CD16 ABC 2 V i V a. d CD4 5 CD3 C D1 6 CD5 6 — PBMC preparation and labeling procedures The patient's peripheral blood was collected in tubes CPT tubes were shipped overnight from clinical sites to the central laboratory in insulated chargers. The CPT tubes were centrifuged for 25 minutes at 1800 x g at room temperature with the brake on. After the - 57 After centrifugation, the CPT tubes were immediately inverted and placed in the lab quake for 10 minutes to resuspend the PBMC layer in autologous plasma and resolve most of the cell aggregates formed. Under sterile conditions, the homogenized PBMC / plasma suspensions were slowly decanted into the center of a 100 µm cell filter resting on top of a sterile 50 mL conical tube. An equal volume of IX DPBS was added to the PBMC / plasma suspension (approximately 4 mL) in a 15 mL conical tube. The tubes were centrifuged at 300 x g for 10 minutes at 4 °C, and the supernatant was discarded. The tubes were vortexed to resuspend the cell granules. The cell granules were washed with DPBS, centrifuged, the supernatant was discarded, and the granules were resuspended by vortexing. The washed PBMC suspension was added to an Eppendorf tube containing 1 µL of ViViD stock solution; these were incubated for 15 minutes on ice and kept in the dark (covered with aluminum foil). The ViViD-stained PBMCs were transferred to a new, labeled conical tube, and ice-cold FACS buffer was added. The cells were centrifuged and vortexed again to resuspend. Polystyrene Falcon tubes were labeled for each sample (Table 1). Isotype control antibodies or antibodies were added to the appropriate tubes. The aliquot of the ViViD-stained PBMCs was added to each tube. - 58 (Table 1). The tubes were shaken and incubated. FACS buffer was added, and the cells were centrifuged and shaken again for resuspension. BD Pharm Lyse Lysing buffer was added, and the cells were shaken, centrifuged, and aspirated to remove the supernatant and shaken again to resuspend. FACS buffer was added again, and the cells were centrifuged and vortexed again for resuspension. The samples were then acquired on the FACSCanto II silometer, and AUCs (antibodies bound per cell) were estimated from standardized MFI as described in Lyer S, et al., Expression of CD69 on activated T cells using R-phycoerythrocyte-labeled beads, Cytometry, 1996; #AC78 (Suppl. 8) : 113 c lycr S., et al., QuantiBRITE: A Lew Standard for Fluorescence Quantitation, Becton Dickinson Immunocytometry Systems, San Jose, CA. 1997. white paper. Example 3: NHL trial The Fe-optimized anti-CD19 antibody study (MOR00208) for treating non-Hodgkin lymphoma (NHL) ClinicalTrials.gov Identifier: NCT01685008 is no longer recruiting. The inclusion criteria were as follows: 1. Male or female patients > 18 years of age. 2. Histologically confirmed diagnosis according to the REAL / QMS classification of the following cell lymphomas - 59 B: a.FL, b.MCL, c.DLBCL, d.Ctro NHL indolent (e.g. MZL / MALT) . 3. The patients' NHL must have progressed after at least 1 previous regimen containing Rituximab. 4. A site of disease measurable by magnetic resonance imaging (MRI) or computed tomography (CT) scan defined as at least one lesion measuring at least 1.5 x 1.5 cm, with the exception: for patients with MCL only, patients with non-measurable disease but with evaluable sites (bone marrow, spleen, peripheral blood, gastrointestinal tract) may be included. 5. Patients who have previously received an autologous stem cell transplant must be at least 4 weeks post-transplant before administration of the study drug and must have exhibited complete hematological recovery. 6. Previous monoclonal antibody therapy discontinued (except Rituximab) or administration of radioimmunotherapy for at least 60 days prior to administration of the study drug. 7. Discontinuation of Rituximab for at least 14 days prior to the screening visit and confirmation of non-response or disease progression following Rituximab treatment. 8. Patients with DLBCL had a positive [18F]fluorodeoxyglucose positron emission tomography (FDG-PET) scan at reference (Cheson response criteria). 9. Life expectancy of > 3 months. 10. ECOG performance status of < 3. 11. Laboratory criteria for selection: a) Absolute neutrophil count (ANC) > 1.0 (1000 / mm ) b) Platelet count > 75 x 109 / L without prior transfusion within 10 days of the first administration of the study drug, c) Hemoglobin < 8.0 g / dL (may have been transfused), d) Serum creatinine < 2.0 x upper limit of normal (ULN), e) Total bilirubin < 2.0 x ULN, f) Alanine transaminase (ALT) and aspartate aminotransferase (A3T) < 2.5 x ULN. 12. If the applicant is a female of childbearing age, a negative pregnancy test must be confirmed prior to registration, along with the use of double barrier contraception, oral contraceptives plus barrier contraception, or confirmation of having undergone a clinically documented total hysterectomy and / or oophorectomy, or tubal ligation. 13. If the patient is male, an effective barrier contraceptive method must be used during the study and for 3 months after the last dose if the patient is sexually active with a female of childbearing age. - 61 14. Able to comply with all procedures related to the study, use of drugs and evaluations. 15. Able to understand and give written informed consent and comply with the study protocol. The exclusion criteria were as follows: 1. Prior treatment with cytotoxic chemotherapy, immunotherapy, radiotherapy or other lymphoma-specific treatment within 14 days prior to screening visit 10 or if the patient has not recovered from the side effects of prior lymphoma-specific treatment. 2. Treatment with an investigational, systemic agent within 28 days prior to the screening visit. 3. Prior treatment with an anti-CD19 antibody of ragmer.tos . 4. Previous allogeneic stem cell transplantation. 5. Known or suspected hypersensitivity to the excipients contained in the drug formulation of the study. 6. Clinically significant cardiovascular disease or heart failure, cardiomyopathy, pre-existing clinically significant arrhythmia, acute myocardial infarction within 3 months of enrollment, angina of 25 chest within 3 months of enrollment. 7. Clinical or laboratory evidence of active hepatitis B or hepatitis C. 8. History of HIV infection. 9. Any active systemic infection (viral, fungal, or bacterial) requiring active parenteral antibiotic therapy within 4 weeks of administration of the study drug. 10. Current treatment with immunosuppressive agents other than prescribed corticosteroids (no more than the equivalent of 10 mg of prednisone). 11. Major surgery or radiotherapy within 4 weeks prior to the first administration of the study drug. 12. Systemic diseases (cardiovascular, renal, hepatic, etc.) that would preclude the study treatment according to the researcher's opinion. 13. History or clinical evidence of central nervous system (CNS), meningeal or epidural disease, including brain metastasis. 14. Active treatment / chemotherapy for another primary malignant neoplasm in the last 5 years. 15. Pregnancy or breastfeeding in women and women of childbearing age who do not use an acceptable contraceptive method. 16. History of non-compliance with medical regimens or patients who are considered potentially unreliable, uncooperative. Patients were treated with MOR00208 as follows. Patients received two 28-day cycles of MOR00208 at a dose of 12 mg / kg on days 1, 8, 15, and 22. At the end of the first two cycles, patients with stable or better disease received a third 28-day cycle at the same dose and schedule as the first two cycles. At the end of the third cycle, patients with a partial response or better entered maintenance therapy. During maintenance, MOR00208 was administered at a dose of 12 mg / kg every 14 or 28 days until disease progression. At the end of the study, the characteristics of the patients were as follows: TABLE 2: Reference characteristics Characteristics l DLBCL n=35 iNHL n=45 MCL n=12 Total n=92 Age, years Median ti 6 6 6 4.5 66 . 5 Sex Male 24 (69) 21 (47) 11 (92) 56 (61) ECOG PS 0 20 (57) 33 (73) t (58) 60 (65) 1 12 (34) CN I—I i -1 4 (33) 27 (29) 2 3 (9) 1 (2) 1 (8) 5 (5) Rituximab refractory Yes 24 (69) 2 2 (4 9) 6 1 (50) 52 1 (57) ' No 11 (31) 23 (51) 6 (50) 4 0 (43) Last dose of rituximab <6 months 14 (40) 6 (13) - (8) 21 (23) Previous stem cell transplant Yes 2 (6) - (16) 1 (8) 1 0 (11) DoR to last previous therapy >12 months 3 (9) 18 (40) 4 (33) 2 5 (27) i < 12 months 2 6 (74) 2 5 (56) ~? / (58) 58 (63) Unknown (17) 2 (4 ) Ί x (8) i C) NK cell reference count >1CC cells / pl 19 (54) 23 (51) g ( 67) 51 (55) <100 cells / ul 11 ​​(31) 3 (18) 1 (8) 20 (22) Unknown c (14) 14 (31) 3 (25) 2 1 (2 3) CD16 reference expression in NK cells > 60000 ABC 1 5 (43) 33 ( i 3) c (42) 5 3 (58) < 60C0C ABC 11 (31) c (11) 4 (33) 20 (22) Unknown 9 (2 6) 7 (16) 3 (25) 19 (21) Count of > 500 2 0 (57) 26 (58) g (67) 54 (59) - 6 5 - T cell reference cells / pl 1 < 500 cells / pl 10 (29) c (13) 1 (8) 11 (18) Unknown 04) 13 (2 9) .5 (2 5) 21 (23) FcyRIIIa High affinity 5 1 4 ) 4 (9) 1 (8) 10 (11) Bel affinity 21 ( ; 7) 28 (62) 9 (51) 6 4 (70) Unknown 3 13 (29) 2 (11) 18 (20) FcyRIIIa High affinity 11 (31) 10 (22) 3 (25) 2 4 (2 6) Low affinity 21 (60) 22 (49) (58) 5 0 ( 54 ) Unknown 3 1 3 (29) 2 (ID 18 (18) DLBCL, diffuse large B-cell lymphoma; SCOG PS, Eastern Cooperative Oncology Group performance status; iNHL, indolent non-Eodgkin lymphoma (includes follicular lymphoma and other iNHL); MCL, mantle cell lymphoma. ( ) Other iNHL means a heterogeneous group of indolent, non-aggressive types not further specified, e.g. marginal cell lymphoma, marginal zone lymphoma, and mucosa-associated lymphoid tissue (MALI) lymphoma. - 6 6 The primary and secondary c-uve endpoints were as follows: • Primary: Overall response rate (ORR) = CR+PR • Secondary: - Disease control rate (DCR) = CR+PR+SD - Progression-free survival (PFS) TABLE 3: Response Best overall response, * n (i) DLBCL n=35 iNHLf n=45 MCL n=12 Total n=92 Complete response, CR 2 ( 6) 5 (11) 0 7 (8) Partial response, PR 7 (20) and (0 5) Q 15 (16) Stable disease, SD 5 (14) 20 (44) 6 (50) 31 (34) Progressive disease 11 (31) 7 (1 6) (42) 23 (25) Not evaluable 10 (29) 5 1 1 _ V 1 V 1 1 (8) 16 (id DCR (CR+PR-'· SD) 14 (40) 3 3 (73) 6 (50) 5 3 (58) ORR (CR+PR / all patients) 9 (26) 1 3 (29) c 22 (24) ORR (CR+PR / Evaluable Patients) Q (36) 1 3 (33) 0 22 (29) o / Data from sor. n (1). *Investigator evaluated. Includes follicular lymphoma and other indolent NHL. Post-referral response assessment was not performed at baseline / data unavailable. tn=25, 40, 11, and 76, respectively. DCR, disease control rate; DLBCL, diffuse large B-cell lymphoma; iNHL, indolent non-Hodgkin lymphoma; MCL, mantle cell lymphoma; ORR, overall response rate. The response criteria in this study are those defined in Table 4. All of them are based on the 10 Response Criteria of the International Working Group (2007). oc ω £ o o .'C o £ oo or ω in either. DCR (CR+PR+SD) was considered the most relevant efficacy endpoint; the analysis of patient characteristics and biomarkers in this trial, since most patients with SD had a marked reduction in the target lesion, but according to the study design they were not treated beyond cycle 3. Consequently, patients with SD were included in the analysis. At least the following patient characteristics were evaluated to determine if there was a correlation between the characteristic and the observed DCR of patients treated with the anti-CD19 antibody: a) age, b) gender, c) whether patients had received a dose of Rituximab in the last 6 months, d) whether patients were refractory to Rituximab, e) whether patients have the high or low affinity allele of FCgammaRI1la, f) whether patients have the high or low affinity allele of FCgammaRTIa, g) whether patients have a duration of response to previous treatment of more than 12 months, h) baseline peripheral T lymphocyte counts (cells / pl), i) baseline peripheral NK cell count (cells / u1) and j) baseline CD16 expression on peripheral NK cells (cell-bound antibodies - ABC). Example 1 and Example 2 above were used to assess baseline peripheral NK cell counts, T lymphocyte counts, and expression of Reference CD16 in peripheral NK cells. Data are shown in Table 2. A receiver operating characteristic (ROC) analysis was used to analyze predictability, specificity, and sensitivity and to determine cutoffs for potential biomarkers of NK cell count, T lymphocyte count, and CD16 expression (ABC) in peripheral NK cells. An ROC plot shows the performance of a binary classification method with continuous or discrete ordinal output. It displays sensitivity (the proportion of positive observations correctly classified) and specificity (the proportion of negative observations correctly classified) as the output threshold moves over the range of all possible values. See Swets JA: The Relative Operating Characteristic. Psychology. Science 1973, 182: 990-1000, and Pepe MS: The statistical evaluation of medical tests for classification and prediction. Oxford: Oxford University Press; 2003.In the context of ROC, the area under the curve (AUC) measures the performance of a classifier and is frequently used for method comparison. A higher AUC means better classification. The AUC for peripheral NK / T cell counts and for CD16 expression on NK cells is 0.66, 0.53, and 0.61, respectively (Figures 3, 4). - 73 In general, the determination of the cutoff depends on the objective of the respective method. Several criteria, such as maximum accuracy, maximum proportion of diagnostic possibilities, minimum error rate, maximum sensitivity, and / or maximum specificity, would lead to a different determination of the cutoff. Furthermore, a balance between more than one of these criteria, for example, sensitivity and specificity, would also lead to a specific determination of the cutoff. Therefore, several methods or criteria exist for selecting optimal cutoff points, including those that maximize accuracy, sensitivity and specificity, predictive values, diagnostic probability indices, or prevalence. Due to the asymmetry of the CD16 expression-ROC curve (see Figure 4), most methods result in a cutoff of 60,000 AUC (the points with the greatest distance between the ROC curve and the bisection line), whereas the symmetry of the NK cell count ROC curve (see Figure 3) explains why different values ​​for the optimal cutoff could be obtained when applying different methods. In this particular study, for both biomarkers, greater weight was given to sensitivity, and therefore, 100,000 NK cells / µI and a CD16 expression level of 60,000 AUC were selected as cutoffs, respectively, for analyzing DCR and PFS within subgroups.For peripheral T lymphocyte counts, the AUC is 0.53 and the ROC curve is close to the bisector at any specificity and sensitivity value, therefore, even selecting a different cutoff. 500 cells / μA had no impact on the negative results of the DCR and PFS subgroup analysis. The determination of the cutoff can be balanced in favor of sensitivity or specificity. If even greater weight is given to sensitivity for identifying the optimal cutoff, the method would be different, and a lower cutoff for the NK cell count would be considered. In such a case, a cutoff of at least 50 NK cells / µL is determined. Alternatively, a cutoff of at least 60 NK cells / µL, at least 70 NK cells / µL, at least 80 NK cells / µL, at least 90 NK cells / µL, or at least 100 NK cells / µL is determined. To maximize the specificity of the disclosed method, the cutoff for NK cell count is increased and determined to be between at least 100 NK cells / µL and at least 150 NK cells / µL. Therefore, to maximize specificity, a cutoff of at least 100 NK cells / µL, at least 110 NK cells / µL, at least 120 NK cells / µL, at least 130 NK cells / µL, at least 140 NK cells / µL, or at least 150 NK cells / µL is selected. The cutoff values ​​determined in this particular study 25 (100 NK cells / μI and a CD16 expression level of 60,000 ABC) were used for the following statistical analysis. Forest plots were used to analyze all patient characteristics and biomarkers to determine the correlation of individual characteristics with DCR. The results are shown in Figure 7. According to the Forest Plot analysis of the different patient characteristics and their correlation with OCH, in patients with DLBCL and iNHL the following characteristics showed statistically significant differences: 1) reference peripheral NK cell count of at least 100 cells / ul and reference CD16 expression in peripheral NK cells of at least 60,000 AUC (χ² - unadjusted p-value = 0.029 / 0.003) (Figure 7). To ensure that CD16 expression and NK cell count were independent characteristics that did not influence each other, a parametric and non-parametric correlation analysis was performed. Data on CD16 expression and NK cell count were available for 51 patients. Pearson's r was 0.019 with a two-tailed p-value of 0.9, and Spearman's r was 0.036 with a two-tailed p-value of 0.8. The results are presented graphically in Figure 6. In conclusion, CD16 expression and NK cell count at the determined thresholds are not correlated; therefore, they are considered completely independent predictors of the probability that a patient will benefit from the treatment. The following characteristics were not predictive of DCR: a) age, b) sex, c) whether patients had received a dose of Rituximab in the past 6 months, d) whether patients were refractory to Rituximab, e) whether patients had the high- or low-affinity FCgammaRII1 allele, f) whether patients had the high- or low-affinity FCgammaRI1 allele, g) whether patients had a duration of response to treatment greater than 12 months, or h) baseline peripheral T-cell counts. See Figure 7. Both 1) baseline peripheral NK cell counts and 2) baseline CD16 expression in peripheral NK cells showed clear correlations with patient response to MORG0208 therapy. Specifically, patients with a baseline NK cell count of at least 100,000 cells / µL correlated with a higher disease control rate (DCR). DCR includes patients with complete response (CR), partial response (PR), and stable disease (SD). Furthermore, patients with baseline CD16 expression in peripheral NK cells of at least 60,000 AUC correlated with a higher disease control rate (DCR). - 77 Progression-free survival (PFS) is the time during and after treatment for a disease that a patient lives with the disease but does not worsen. This is an important additional endpoint of a clinical trial and an indicator of effectiveness in patients. PFS was compared within the following patient characteristics: a) baseline peripheral NK cell count of at least 100 cells / IU or less, b) baseline CD16 expression in peripheral NK cells of at least 60,000 ABC or less, and c) baseline peripheral T cell count of at least 500 cells / µL or less. The results are shown in Figures 8–10. The PFS comparing patients with NK cell counts of at least 100 cells / µL to cor. patients with lower NK cell counts showed a statistically significant difference with a BR of 0.1561 (unadjusted log-rank p-value p = 0.0003). This further confirms the predictive power of cell counts NK in the response of patients treated with MCR00208 of those patients who have CLL, NHL, ALL or SLL. It should be understood that the description, specific examples, and data, although indicating exemplary embodiments, are provided for illustrative purposes and are not intended to limit the present invention. Various changes and modifications within the present invention will be made. - 78 evident to the expert in the subject matter from the discussion, disclosure and data contained in this document, and are therefore considered part of the invention. It is hereby stated that, as of this date, the best method known to the applicant for putting the aforementioned invention into practice is the one that is clear from the present description of the invention.

Claims

CLAIMS 1. A method for identifying a subject who has chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), small lymphocytic lymphoma (SLL), or acute lymphoblastic leukemia (ALL) who responds to treatment with an anti-CD19 antibody, said method comprising: a. providing a blood sample obtained from said subject prior to treatment with said anti-CD19 antibody, b. determining the level of at least one biomarker in said sample selected from the pool consisting of: i. peripheral NK cell count, and ii. CD16 expression levels on peripheral NK cells, c. comparing the level of said at least one biomarker in said sample with a predetermined cutoff level, wherein levels of said at least one biomarker at or above the predetermined cutoff level are indicative of a subject who would benefit from treatment with an anti-CD19 antibody.

2. The method according to claim 1, wherein the predetermined cutoff for said biomarker is: a. a reference NK cell count within at least 50 cells / μA, or b. reference levels of CD16 expression in peripheral NK cells of at least 60,000 AUC. - 80 3. The method according to claim 1 or 2, wherein the predetermined cutoff of said biomarker is: a. a reference count of peripheral NK cells of at least 60 cells / μA.

4. The method according to any one of the preceding claims, wherein the predetermined cutoff of said biomarker is: a. a peripheral NK cell reference count of at least 70 cells / ul.

5. The method according to any one of the preceding claims, wherein the predetermined cutoff of said biomarker is: a. a peripheral NK cell reference count of at least 80 cells / ul.

6. The method according to any one of the preceding claims, wherein the predetermined cutoff of said biomarker is: a. a reference peripheral NK cell count of at least 100 cells / μA.

7. The method according to any one of the preceding claims, wherein the predetermined cutoff of said biomarker is: a. reference levels of CD16 expression in peripheral NK cells of at least 60,000 AUC.

8. The method according to any one of the preceding claims, wherein the anti-CD19 antibody comprises an HCDR1 region comprising the sequence SYVMH (SEQ ID NO: 1), an HCDR2 region comprising the sequence NPYNDG (SEQ ID NO: 2), an HCDR3 region comprising the sequence GTYYYGTRVFDY (SEQ ID NO: 3), an LCDR1 region comprising the sequence RSSKSLQNVNGNYYLY (SEQ ID NO: 4), an LCDR2 region comprising the sequence RMSNLNS (SEQ ID NO: 5), and an LCDR3 region comprising the sequence MQHLEYPIT (SEQ ID NO: 6).

9. The method according to any one of the preceding claims, wherein the anti-CD19 antibody comprises a variable heavy chain of the sequence EVQLVESGGGGVKPGGSLKL3CAASGYTFTSYVMHWVRQAPGKGLEWIGYIKPY 15 NDGTKYNEKFQGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGGYYYGTRVFDY WG QGTLVTVSS (SEQ ID NO: 10) and a variable light chain of the sequence DIVMTQSPATLSLSPGERATLSCRSSKSLQNVNGNTYLYWFQQKPGQSPQLLIYR MSNLNSGVPDRFSGSGSGTEFTLTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIK 20 (SEQ ID NO: 11).

10. The device used with a cualquiera of the internal reivindicaciones, and the anti-CD19 comprende una cadena pesada that linked the secuencia of E VQ LVE SG GG LVK PGGSLKLSC ΑΆ SGYTFTSY VM HW V RQ APGKGL ΞWIG Y IΝ PY N 25 DGTKYNEKFQGRVTISSDKSISTAYMELSSLRSEDTAMYYCARGTYYYGTRVFDYW - 82 GQGTLVTVS SASTKGPSVFPLA.PS SKSTSGGTAALGCLVKDYFPEPVTVSWNSGAL TSGVHTFPAVLQSSGLYSLSSWTVPSSSLGTQTYICNVNHKPSNTKVDKKVEPKS DKTHTCPPCPAPELLGGPDVFLFPPKPKDTLMISRTPEVTCVVVDVSHEDPEVQFN 5 WYVDGVEVHNAKTKPREEQFNSTFRWSVLTVVHQDWLNGKEYKCKVSNKALPAP EEKTISKTKGQPREPQVYTLPPSREEMTKNQVSLTCLVKGFYPSDIAVEWESNGQP ENNYKTTPPMLDSDGSFFLYSKLTVDKSRWQQGNVFSCSVMHEALHNEYTQKSLS LSPGK (SEQ ID NO: 8) and each video that connects the video to 10 DIVMTQSPATLSLSPGERATLSCRS3KSLQNVNGNTYT.YWFQQKPGQSPQLLTYRM SNLNSGVPDRFSGSGSGTEFTLTISSLEPEDFAVYYCMQHLEYPITFGAGTKLEIK RT VAAPSVFIFPPSDEQLKSGTASWCLLNNFYPREAKVQWKVDNALQSGKSQSSVTE QDSKDSTYSLSSTLTLSK ADYEKHKVYACEVTHQGLSSPVTKSFNRGEC (SEQ 15 ID NO: 9) 11. A method for selecting a patient for treatment according to any one of the preceding claims, wherein said patient has non-Hodgkin lymphoma. 20 12. A method for selecting a patient for treatment according to claim 6, wherein the non-Hodgkin lymphoma is selected from the group consisting of follicular lymphoma, small lymphocytic lymphoma, mucosa-associated lymphoid tissue, marginal zone, diffuse large B cells, Burkitt cells, and mantle cells.

13. Use of an anti-CD19 antibody for the treatment of a patient with chronic lymphocytic leukemia (CLL), non-Hodgkin lymphoma (NHL), small lymphocytic lymphoma (SLL) or acute lymphoblastic leukemia (ALL) identified according to a method of any one of the preceding claims.