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The CD38-targeting antibody daratumumab has marked activity in multiple myeloma (MM). Natural killer (NK) cells play an important role during daratumumab therapy by mediating antibody-dependent cellular cytotoxicity via their FcγRIII receptor (CD16), but they are also rapidly decreased following initiation of daratumumab treatment. We characterized the NK cell phenotype at baseline and during daratumumab monotherapy by flow cytometry and cytometry by time of flight to assess its impact on response and development of resistance (DARA-ATRA study; NCT02751255). At baseline, nonresponding patients had a significantly lower proportion of CD16 +and granzyme B +NK cells, and higher frequency of TIM-3 +and HLA-DR +NK cells, consistent with a more activated/exhausted phenotype. These NK cell characteristics were also predictive of inferior progression-free survival and overall survival. Upon initiation of daratumumab treatment, NK cells were rapidly depleted. Persisting NK cells exhibited an activated and exhausted phenotype with reduced expression of CD16 and granzyme B, and increased expression of TIM-3 and HLA-DR. We observed that addition of healthy donor-derived purified NK cells to BM samples from patients with either primary or acquired daratumumab-resistance improved daratumumab-mediated MM cell killing. In conclusion, NK cell dysfunction plays a role in primary and acquired daratumumab resistance. This study supports the clinical evaluation of daratumumab combined with adoptive transfer of NK cells.

Introduction: Immune checkpoint blockade of programmed death-1 (PD-1) receptor and its ligand (PD-L1) has contributed to efficacy in many tumor types, with clinical responses observed in a proportion of patients (pts) with Hodgkin lymphoma and rare non-Hodgkin lymphoma subtypes. A recent study demonstrated that combination treatment with anti-PD-L1 and anti-CD38 agents contributed to a stronger anti-tumor immune response compared with anti-PD-L1 monotherapy. Isatuximab, an anti-CD38 monoclonal antibody, is approved for use in multiple myeloma. Cemiplimab, an anti-PD-1 monoclonal antibody, is approved for use in cutaneous squamous cell carcinoma, basal cell carcinoma, and non-small cell lung cancer. Methods: This Phase 1/2 open-label study (NCT03769181) was designed to assess the safety, tolerability, and efficacy of isatuximab in combination with cemiplimab (Isa+Cemi) in pts with relapsed and refractory classic Hodgkin's lymphoma (cHL), diffuse large B-cell lymphoma (DLBCL), and peripheral T-cell lymphoma (PTCL). The primary objectives of Phase 1 were to characterize the safety and tolerability of Isa+Cemi and to confirm the recommended Phase 2 dose. Phase 2 used a Simon's 2-stage design to assess the complete response rate in Cohort A1 (anti-PD-1/PD-L1 naïve cHL; n=18; median age, 36 years; 55.6% male; ≥2 prior regimens, 100%) and to assess the objective response rate in Cohorts A2 (cHL progressing after PD-1/PD-L1 therapy; n=12; median age, 33 years; 58.3% male; ≥2 prior regimens, 100%), B (DLBCL; n=17; median age, 64 years; 70.6% male; ≥2 prior regimens, 100%), and C (PTCL; n=11; median age, 69 years; 63.6% male; ≥2 prior regimens, 9.1%). Pts received Isa+Cemi for up to 96 weeks. In Phase 1, the isatuximab dose was 10 mg/kg every week (Cycle 1), every 2 weeks (Cycle 2-6), or every 3 weeks (Cycle 7+). The cemiplimab dose was 250 mg every 2 weeks (Cycle 1-6) or 350 mg every 3 weeks (Cycle 7+). An interim analysis was performed when the last pt in Phase 2 was followed up for 24 weeks. The efficacy evaluation was based on Simon's 2-stage design with 85% power at a 5% 1-sided alpha level for each cohort. At least 8 (44.4%) and 3 (30.0%) responses were required in Cohorts B and C, respectively, in Phase 2 Stage 1 to advance to Phase 2 Stage 2. Results: Isa+Cemi demonstrated a manageable safety profile with no new safety signals. No dose-limiting toxicities were observed, confirming the recommended Phase 2 dose. Treatment-emergent adverse events (TEAEs) were reported in 83.3% (Cohort A1) and 100% (Cohorts A2, B, C) of pts. Grade ≥3 TEAEs occurred in 5.6%, 8.3%, 70.6%, and 81.8% of pts in Cohorts A1, A2, B, and C, respectively. There were no pts in Cohorts A1 or A2 who reported TEAEs leading to definitive discontinuation; 5.9% and 27.3% of pts in Cohorts B and C experienced TEAEs leading to definitive discontinuation. No Grade 5 TEAEs with fatal outcome were reported in Cohorts A1 or A2. There were 4 deaths reported during the on-treatment period in Cohort B (progressive disease, n=2; intestinal perforation, n=1; urinary tract infection, n=1) and 2 in Cohort C (unknown, n=1; progressive disease, n=1). Infusion reactions were reported in 38.9%, 75.0%, 52.9%, and 72.7% of pts in Cohorts A1, A2, B, and C, respectively; there was 1 (9.1%) Grade ≥3 infusion reaction reported in Cohort C. Pharmacokinetics (PK) analyses suggested no effect of cemiplimab on isatuximab PK, and vice versa. Based on Lugano 2014 criteria, 55.6% (Cohort A1), 33.3% (Cohort A2), 5.9% (Cohort B), and 9.1% (Cohort C) of pts in the all-treated population achieved a complete or partial response. Median progression-free survival was 8.38 months (95% CI: 2.72-not calculable [NC]), 8.28 months (95% CI: 2.6-NC), 2.37 months (95% CI: 0.46-2.69), and 2.66 months (95% CI: 0.43-2.99) in Cohorts A1, A2, B, and C, respectively. Conclusion: In this study, Isa+Cemi had a manageable safety profile. Clinical efficacy was observed in pts with cHL, with increased responses observed in pts who had not previously received anti-PD-1/PD-L1 therapy compared with those who progressed on anti-PD-1/PD-L1 therapy. For Cohorts B (DLBCL) and C (PTCL), results of the interim efficacy analysis did not meet prespecified criteria to continue enrollment in Phase 2 Stage 2. Most pts with DLBCL were primary refractory/bulky and discontinued rapidly, which may have contributed to the lack of activity with this combination. Disclosures Carlo-Stella: ADC Therapeutics: Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Oncology: Honoraria; Celgene: Membership on an entity's Board of Directors or advisory committees; Karyopharm Therapeutics: Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Research Funding. Zinzani: TG Therapeutics Inc: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kyowa Kirin: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Sandoz: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ImmuneDesign: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Verastem: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Servier: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celltrion: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Merck Sharp & Dohme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; EUSA Pharma: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADC Therapeutics: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; BeiGene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Portola: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Sureda: Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Speakers Bureau; Roche: Other: Support for attending meetings and/or travel; Bluebird: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Consultancy; Kite, a Gilead Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; MSD: Consultancy, Honoraria, Speakers Bureau; BMS/Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Support for attending meetings and/or travel, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Casasnovas: TAKEDA: Consultancy, Research Funding; Gilead/Kite: Consultancy, Research Funding; BMS: Consultancy; Janssen: Consultancy; Amgen: Consultancy; ROCHE: Consultancy, Research Funding. Carpio: Regeneron, TAKEDA, Celgene, Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: Travels and accommodation. Bouabdallah: Abbvie: Honoraria; Sandoz: Consultancy, Honoraria; Kite/Gilead: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses; Roche: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses; Takeda: Consultancy, Honoraria, Other: Travel/Accommodations/Expenses. Cartron: Roche, Celgene-BMS: Consultancy; Danofi, Gilead, Novartis, Jansen, Roche, Celgene-BMS, Abbvie, Takeda: Honoraria. Kim: Celltrion: Research Funding; Dong-A Pharmaceutical: Research Funding; Kyowa Kirin: Research Funding; Sanofi: Research Funding; IGM Biosciences: Research Funding; Eisai: Research Funding; Johnson & Johnson: Research Funding; Roche: Research Funding. Cordoba: Incyte: Membership on an entity's Board of Directors or advisory committees; Pfizer: Research Funding; Kyowa-Kirin: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ADCTherapeutics: Membership on an entity's Board of Directors or advisory committees; AbbVie: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Koh: Pfizer: Consultancy; Jassen: Honoraria; AstraZeneca: Honoraria; Novartis: Honoraria; GSK: Honoraria; Roche: Honoraria; Takeda: Honoraria. Alves: Janssen, Cilag, Gilead, Takeda, Astrazeneca, Roche, Abbvie: Consultancy, Honoraria. Chamuleau: Gilead: Research Funding; Genmab: Research Funding; Celgene: Research Funding. Lopez-Guillermo: Roche, Gilead/Kite, Celgene, Novartis, Janssen, AbbVie, Spectrum: Consultancy, Honoraria, Research Funding. Van Der Poel: Roche, Janssen, Abbvie: Honoraria. Abbadessa: Sanofi: Current Employment. Meng: Sanofi: Current Employment. Ji: Sanofi: Current Employment. Lepine: Sanofi: Other: Contractual relationship. Saleem: Sanofi: Current Employment. Ribrag: PharmaMar: Honoraria, Membership on an entity's Board of Directors or advisory committees; GSK: Research Funding; Epizyme: Honoraria, Research Funding; Servier: Consultancy, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; MSD Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Argen-X: Research Funding; AstraZeneca: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Nanostring: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Astex Pharmaceuticals: Research Funding; Infinity Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees. OffLabel Disclosure: Based on the Phase III ICARIA-MM study, isatuximab (Sarclisa) is approved in a number of countries in combination with pomalidomide and dexamethasone for the treatment of adult patients with relapsed/refractory multiple myeloma who have received at least two prior therapies, including lenalidomide and a proteasome inhibitor. Based on the Phase III IKEMA study, isatuximab in combination with carfilzomib and dexamethasone is approved in the United States for the treatment of adult patients with relapsed or refractory multiple myeloma who have received one to three prior lines of therapy, and in the European Union for the treatment of adult patients with multiple myeloma who have received at least one prior therapy. Cemiplimab (Libtayo) is an anti-PD-1 antibody approved for the treatment of the following: 1) patients with metastatic cutaneous squamous cell carcinoma or locally advanced cutaneous squamous cell carcinoma who are not candidates for curative surgery or curative radiation; 2) patients with locally advanced or metastatic basal cell carcinoma previously treated with a hedgehog pathway inhibitor or for whom a hedgehog pathway inhibitor is not appropriate; and 3) patients with NSCLC and high tumor PD-L1 expression as determined by an FDA-approved test, with no EGFR, ALK, or ROS1 aberrations, and is locally advanced where patients are not candidates for surgical resection or definitive chemoradiation or metastatic.

Noninvasive diagnosis of multiple myeloma (MM) is a clinical challenge. CD38 is an established biomarker for MM, and the development of CD38-targeted radiotracers may improve the management of MM. By taking the advantages of bioorthogonal click chemistry, a nanobody (i.e., Nb1053-LLQS) specific for CD38 was successfully labeled with 18F. The diagnostic efficacy and specificity of the developed tracer (i.e., [18F]F-Nb1053) were evaluated by immuno-positron emission tomography (immunoPET) imaging in disseminated MM.1S-bearing models. [18F]F-Nb1053 was developed with high radiochemical purity (>98%) and excellent immunoreactivity. [18F]F-Nb1053 immunoPET successfully delineated disseminated MM lesions in preclinical MM models. The uptake in the humerus, femur, and tibia was 1.42 ± 0.50%ID/g, 1.35 ± 0.53%ID/g, and 1.48 ± 0.67%ID/g (n = 6), respectively. Tumor uptake of [18F]F-Nb1053 decreased after daratumumab premedication, indicating the superior specificity of the reported probe. This work successfully developed a novel CD38-specific probe [18F]F-Nb1053 that may potentially optimize the management of MM upon clinical translation.

Objectives: Classic Hodgkin lymphoma (CHL) is not typically diagnosed by routine clinical flow cytometry in most laboratories. While the neoplastic Hodgkin lymphoma/ Reed Sternberg (HRS) cells in CHL may be identified by flow cytometry using special procedures, the methodology used is not common. We observed increased CD38 expression on T-cells compared to Bcells/non-T-cells in cases of CHL compared to normal samples and confirmed our observations in the context of retrospective and prospective analyses. We identified and characterized distinctive features of background non-neoplastic T cells associated with classic Hodgkin lymphoma utilizing common antibodies and analysis methods.

The efficacy of daratumumab depends partially on CD38 expression on multiple myeloma (MM) cells. We have previously shown that all-trans retinoic acid (ATRA) upregulates CD38 expression and reverts daratumumab-resistance ex vivo. We therefore evaluated the optimal dose, efficacy, and safety of daratumumab combined with ATRA in patients with daratumumab-refractory MM in a phase 1/2 study (NCT02751255). In part A of the study, 63 patients were treated with daratumumab monotherapy. Fifty patients with daratumumab-refractory MM were subsequently enrolled in part B and treated with daratumumab (reintensified schedule) combined with ATRA until disease progression. The recommended phase 2 dose of ATRA in combination with daratumumab was defined as 45 mg/m2. At this dose, the overall response rate (ORR) was 5%, indicating that the primary endpoint (ORR ≥15%) was not met. However, most patients (66%) achieved at least stable disease. After a median follow-up of 43 months, the median progression-free survival (PFS) for all patients was 2.8 months. Patients who previously achieved at least a partial response or minimal response/stable disease with prior daratumumab monotherapy had a significantly longer PFS compared with patients who immediately progressed during daratumumab as single agent (median PFS 3.4 and 2.8 vs 1.3 months). The median overall survival was 19.1 months. The addition of ATRA did not increase the incidence of adverse events. Flow cytometric analysis revealed that ATRA temporarily increased CD38 expression on immune cell subsets. In conclusion, the addition of ATRA and reintensification of daratumumab had limited activity in patients with daratumumab-refractory MM, which may be explained by the transient upregulation of CD38 expression. This trial was registered at www.clinicaltrials.gov as #NCT02751255.

BackgroundCAR-T cell therapy has shown highly effective clinical results in several diseases, but further improvement is necessary to target a wider range of antigens and tumors. In particular, excessive activation of CAR-T cells leads to cell exhaustion and reduction of naive/memory T cells’ population, which are important for long-term immune response. Therefore, suppressing non-antigen-specific activity is necessary for CAR-T cell production. However, when targeting tumor-related antigens that are also expressed on T cells, CAR-T cells recognize the antigens on the T cells, resulting in fratricide, poor cell growth, differentiation, and exhaustion during cell production process.In this study, we investigated a method for producing CAR-T cells targeting CD38 antigen that is common to T cells and tumor cells. CD38 is a suitable target antigen for CAR-T cell therapy because it is highly expressed in lymphocyte malignant tumors including B-cell non-Hodgkin’s lymphoma and multiple myeloma. However, as it is also intermediately expressed in normal blood cells, unwanted activation of CAR-T cells may be caused.MethodsWe tried to suppress the expression of CD38 in CAR-T cells by co-expressing CD38 siRNAs, and prevent activation during cell production by modifying the signal domain of anti-CD38-CAR to the newly developed JAK/STAT-CAR. JAK/STAT-CAR contains the intracellular domain of the IL-2 receptor β chain and the STAT3 binding motif, which have been shown to improve the proliferation of CAR-T cells and suppresses differentiation compared to conventional second-generation CAR-T cells.For further improvement, CAR-T cells were prepared in the presence of the tyrosine kinase inhibitor Dasatinib to suppress activation during the cell manufacturing process.ResultsCD38 siRNA co-expressing CAR-T cells showed decreased expression of CD38 and exhaustion markers, and the further reduction of exhaustion marker expression was observed in JAK/STAT CAR-T cells. However, compared to CAR-T cells targeting other antigens, CD38-CAR-T cells tended to be more exhausted and differentiated. As Dasatinib treatment maintained a high proportion of naive/memory T cells and was able to suppress exhaustion, combination of these approaches (CD38 siRNA-expressing CD38-JAK/STAT CAR-T cells with Dasatinib treatment) showed long-term persistence of antitumor activity in in vitro re-challenge assay.ConclusionsCD38 siRNA co-expressing CD38-JAK/STAT CAR-T cells produced in the presence of a tyrosine kinase inhibitor are expected to be suppressed excessive activation and maintain long-term antigen-specific activity. This approach is also expected to be applied to other CAR-T cell therapies targeting tumor-related antigens expressed on T cells.

Objective: Our study was performed on 49 chronic lymphocytic leukemia (CLL) patients followed in the outpatient clinic of the Istanbul University Cerrahpasa Medical Faculty Department of Hematology. We aimed to analyze the relationship between autoimmune phenomena and CLL. Methods: Twenty-five CLL patients with and 24 CLL patients without autoimmune phenomenon were included. Thirty-two of them were male and 17 were female. No statistically significant difference in the median age at diagnosis (60 vs 64) and in the median follow-up time (59 months vs 71 months) was detected. The initial diagnostic parameters were similar. Results: In our autoimmune phenomenon cohort, the most frequent autoimmune disease was autoimmune hemolytic anemia (AIHA) followed by immune thrombocytopenia (ITP) and pure red cell aplasia (PRCA). The direct antiglobulin positivity at the time of diagnosis was increased in the autoimmune phenomenon group (p=0.024). Additionally, the stage of CLL in patients of the autoimmune phenomenon group was more advanced than the other group (p=0.04). Although the number of autoimmune phenomena was not high enough, the CD38 positive cell ratio over 30% in the peripheral blood was more frequent in PRCA group (p=0.008). Conclusion: We could not determine a relationship between autoimmunity in CLL and KIR genotypes. We believe that a new study in a larger cohort with superior technical conditions should be planned to find accurate responses to our study. Istanbul University Scientific Research ProjectsIstanbul University [32784] This study was supported by Istanbul University Scientific Research Projects (Proje No: 32784) .

Multiple myeloma (MM) is incurable, so there is a significant unmet need for effective therapy for patients with relapsed or refractory disease. This situation has not changed despite the recent approval of the anti-CD38 antibody daratumumab, one of the most potent agents in MM treatment. The efficiency of daratumumab might be improved by combining it with synergistic anti-MM agents. We therefore investigated the potential of the histone deacetylase (HDAC) inhibitor ricolinostat to up-regulate CD38 on MM cells, thereby enhancing the performance of CD38-specific therapies. Using quantitative reverse transcription polymerase chain reaction and flow cytometry, we observed that ricolinostat significantly increases CD38 RNA levels and CD38 surface expression on MM cells. Super-resolution microscopy imaging of MM cells by direct stochastic optical reconstruction microscopy confirmed this rise with molecular resolution and revealed homogeneous distribution of CD38 molecules on the cell membrane. Particularly important is that combining ricolinostat with daratumumab induced enhanced lysis of MM cells. We also evaluated next-generation HDAC6 inhibitors (ACY-241, WT- 161) and observed similar increase of CD38 levels suggesting that the upregulation of CD38 expression on MM cells by HDAC6 inhibitors is a class effect. This proof-of-concept illustrates the potential benefit of combining HDAC6 inhibitors and CD38-directed immunotherapy for MM treatmen

Background The present study aimed to investigate the prognostic effect of CD38 in patients with esophageal squamous cell carcinoma (ESCC). Methods We performed a retrospective cohort study by consecutively recruiting 142 patients with ESCC. The clinicopathological features and expression of CD38, CD4, CD8, Ki-67, PD-L1 and PD-1 in tumor and immune cells were independently evaluated by two pathologists. Results CD38 was expressed in immune cells but not tumor cells and the median expression rate of CD38 in immune cells was 60%. Among ESCC patients with perigastric lymph node metastasis, the expression rate of CD38 was not associated with the disease-free survival (p = 0.207), but had a significant association with the overall survival (p = 0.042). The median overall survival was 13 months and not observed among patients with low and high expression rate of CD38, respectively. The crude and adjusted hazard ratio (HR) of high CD38 expression was 0.37 (95%CI 0.14, 0.95) and 0.21 (95%CI 0.06, 0.70). The expression rate of CD38 had a negative correlation with PD-L1 expressed in tumor cells and CD4 expressed in immune cells. Among patients without perigastric lymph node metastasis, the expression rate of CD38 showed a significant association with the disease-free survival (p

The prognosis of chronic lymphocytic leukemia (CLL) depends on different markers, including cytogenetic aberrations, oncogenic mutations, and mutational status of the immunoglobulin (Ig) heavy-chain variable (IGHV) gene. The number of IGHV mutations distinguishes mutated (M) CLL with a markedly superior prognosis from unmutated (UM) CLL cases. In addition, B cell antigen receptor (BCR) stereotypes as defined by IGHV usage and complementarity-determining regions (CDRs) classify ∼30% of CLL cases into prognostically important subsets. Subset 2 expresses a BCR with the combination of IGHV3-21–derived heavy chains (HCs) with IGLV3-21–derived light chains (LCs), and is associated with an unfavorable prognosis. Importantly, the subset 2 LC carries a single-point mutation, termed R110, at the junction between the variable and constant LC regions. By analyzing 4 independent clinical cohorts through BCR sequencing and by immunophenotyping with antibodies specifically recognizing wild-type IGLV3-21 and R110-mutated IGLV3-21 (IGLV3-21R110), we show that IGLV3-21R110–expressing CLL represents a distinct subset with poor prognosis independent of IGHV mutations. Compared with other alleles, only IGLV3-21*01 facilitates effective homotypic BCR–BCR interaction that results in autonomous, oncogenic BCR signaling after acquiring R110 as a single-point mutation. Presumably, this mutation acts as a standalone driver that transforms IGLV3-21*01–expressing B cells to develop CLL. Thus, we propose to expand the conventional definition of CLL subset 2 to subset 2L by including all IGLV3-21R110–expressing CLL cases regardless of IGHV mutational status. Moreover, the generation of monoclonal antibodies recognizing IGLV3-21 or mutated IGLV3-21R110 facilitates the recognition of B cells carrying this mutation in CLL patients or healthy donors., publishedVersion

CD38 is a multifunctional protein widely expressed in cells from the immune system and as a soluble form in biological fluids. CD38 expression is up-regulated by an array of inflammatory mediators, and it is frequently used as a cell activation marker. Studies in animal models indicate that CD38 functional expression confers protection against infection by several bacterial and parasitic pathogens. In addition, infectious complications are associated with anti-CD38 immunotherapy. Although CD38 displays receptor and enzymatic activities that contribute to the establishment of an effective immune response, recent work raises the possibility that CD38 might also enhance the immunosuppressive potential of regulatory leukocytes. This review integrates the current knowledge on the diversity of functions mediated by CD38 in the host defense to infection.

Immune thrombocytopenic purpura (ITP) is an autoimmune bleeding disorder associated with platelet destruction. Abnormalities in frequency and function of different immune cells can play a crucial role in this disease. The aim of this study was to evaluate the prognostic value of CD markers' expressions by immune cells in ITP. Peripheral blood samples were collected from 25 ITP patients before and after treatment. The expression of CD markers was evaluated by flow cytometry technique. The expression of CD38 and CD56 was significantly lower before treatment than after it (p = 0.025 and p = 0.036, respectively). Furthermore, a positive correlation was found between CD38 expression with platelet count before (r = 0.496, p = 0.012) and after treatment (r = 0.404, p = 0.045). No significant relationship was found between this marker and platelet count while CD4 expression was higher before treatment than after it (p = 0.002). In conclusion, CD38 may have independent prognostic value in ITP and we suggest that it can be a prognostic marker for this disease.

Background:Systemic lupus erythematosus (SLE) is a chronic autoimmune disease characterized by pathogenic antinuclear autoantibodies, which are secreted by autoreactive plasma cells. Among novel plasma cell-depleting strategies, CD38 has been identified as promising target. The monoclonal anti-CD38 antibody daratumumab is approved for treatment of multiple myeloma and provided a therapeutically relevant depletion of plasma cells in patients with SLE1.Objectives:Beyond plasma cells, CD38 is widely expressed across innate and adaptive immune cells and additional cellular targets of anti-CD38 treatment, especially in patients with SLE, are largely unknown. Therefore, this study aimed to systematically characterize the expression of CD38 in peripheral blood leukocytes to identify potential target cells of CD38-directed therapies that may contribute to or limit therapeutic benefits in SLE.Methods:We analyzed the expression of CD38 on peripheral blood leukocytes in two different cohorts, comprising a total of 56 SLE patients and 39 healthy controls, by flow and mass cytometry. CD38 expression levels across major immune cells were analyzed for changes between controls and SLE, as well as for correlation across immune cell lineages, and with clinical and serological disease parameters.Results:We detected increased CD38 expression levels on circulating NK cells, plasmacytoid dendritic cells, CD4+ and CD8+ memory T cells, as well as IgD-CD27- and marginal zone-like B cells in SLE compared to healthy controls. In myeloid and NK cells, CD38 expression was associated with an activated cellular phenotype, reflected by co-expression of molecules such as HLA-DR, CD11c or Syk. In the B cell compartment, IgA- plasmablasts and plasma cells expressed more CD38 than their IgA+ counterparts. Also, HLA-DRhigh plasmablasts showed higher CD38 expression compared to HLA-DRlow plasma cells. The strongest differences in CD38 expression between controls and SLE were found in CD8+ central and effector memory T cells. Additionally, we detected an expansion in CD38high and CD38int cells in the T cell memory compartment, with some patients showing distinctly increased expression values. We observed a high intra-individual correlation of CD38 expression across immune cell lineages, yet without correlation of CD38 expression levels with clinical activity (SLEDAI-2K), serological markers of SLE or the type I interferon surrogate marker CD169 (SIGLEC-1).Conclusion:Our data indicate that not only pathogenic plasma cells are potential target cells of CD38-targeting antibodies. The highly dysregulated CD38 expression across innate and adaptive immune cells in SLE could be of pathophysiological importance with respect to the potential efficacy and side effects of such therapies. Since CD38 expression did not correlate with disease activity, it may be assumed that it is not a response protein solely induced and modulated by type I interferons. Nevertheless, our comprehensive characterization of CD38 expression in the immune system might have important implications for personalized approaches with emerging CD38-directed therapeutics.References:[1]Ostendorf, L. et al. Targeting CD38 with Daratumumab in Refractory Systemic Lupus Erythematosus. N. Engl. J. Med. 383, 1149–1155 (2020).Disclosure of Interests:None declared

Background To evaluate the clinical utility of LIM Domain Only 2 (LMO2) negative and CD38 positive in diagnosis of Burkitt lymphoma (BL). Methods LMO2 and CD38 expression determined by immunohistochemistry in 75 BL, 12 High-grade B-cell lymphoma, NOS (HGBL,NOS) and 3 Burkitt-like lymphomas with the 11q aberration. Results The sensitivity and specificity of LMO2 negative for detecting BL were 98.67 and 100%, respectively; those of CD38 positive were 98.67 and 66.67%, respectively. The sensitivity and specificity of a combination of both for detecting BL were 97.33 and 100%, respectively. In our study, the combined LMO2 negative and CD38 positive results had a higher area under the curve than either LMO2 negative or CD38 positive alone. Conclusions A combination of LMO2 negative and CD38 positive is useful for the diagnosis of Burkitt lymphoma.

Increasing efforts are being put into new treatment options for coeliac disease (CeD), a chronic disorder of the small intestine induced by gluten. Interleukin-2 (IL-2) and gluten-specific CD4 + T cells increase in the blood after four hours and six days, respectively, following a gluten challenge in CeD patients. These responses are unique to CeD and are not seen in controls. We aimed to evaluate different markers reflecting a recall response to gluten exposure that may be used to monitor therapy.CeD patients on a gluten-free diet underwent a one- (The frequency of gut-homing, tetramer-binding, CD4 + effector memory T (tetramer + β7 + TThe optimal time points for monitoring therapy response in CeD after a three-day oral gluten challenge is four hours for plasma IL-2 or six to eight days for the frequency of tetramer + β7 + T

Objective To investigate the ZAP-70 and CD38 expressions and their combined expressions in Sudanese B-CLL patients and their relationships with clinical and hematological characteristics as well as the disease staging at presentation. Results In the present cross-sectional descriptive study, analysis of ZAP-70 expression showed that 36/110 (32.7%) patients positively expressed ZAP-70 and insignificant higher presentation in intermediate and at advanced stages as well as no correlation was seen with hematological parameters and clinical features compared with negatively ZAP-70, on the other hand, 41/110 (37.3%) were CD38+ and no significant correlation was shown with the stage at presentation, clinical characteristics (except Splenomegaly, P = 0.02) and hematological parameters. However, in combined expressions of both ZAP-70 and CD38 together, 20/110 (18.2%) were concordantly ZAP-70+/CD38+, 53/110 (48.2%) concordantly ZAP-70−/CD38− and 37/110 (33.6%) either ZAP-70+ or CD38+, and these three groups showed insignificant correlation with clinical (except Splenomegaly, P = 0.03) and hematological parameters, and the stage at presentation. Our data showed the combined analysis of these two markers, lead to classify our patients into three subgroups (either concordant positive, negative or discordant expressions) with statistically insignificant correlation with clinical presentation (except Splenomegaly), hematological parameters and stage at presentation of B-CLL patients. Electronic supplementary material The online version of this article (10.1186/s13104-019-4319-8) contains supplementary material, which is available to authorized users.

Initiation of antiretroviral therapy (ART) in early compared with chronic HIV infection is associated with a smaller HIV reservoir. This longitudinal analysis of 63 individuals who commenced ART during primary HIV infection (PHI) investigates which pre-and post-therapy factors associate most closely with reservoir size (HIV DNA) following treatment initiation during PHI. The best predictor of reservoir size at one-year was pre-ART HIV DNA which was in turn significantly associated with CD8 memory differentiation (effector memory, naïve and T-betnegEomesnegsubsets), CD8 T cell activation (CD38 expression) and PD-1 and Tim-3 expression on memory CD4 T cells. No associations were found for any immunological variables following one-year of ART. HIV reservoir size is determined around the time of ART initiation in individuals treated during PHI. CD8 T cell activation and memory expansion are linked to HIV reservoir size, suggesting the importance of the initial host-viral interplay in eventual reservoir size.

Objective The objective of this study was to evaluate the cluster of differentiation-38 (CD38) expression in Sudanese patients with chronic lymphocytic leukemia (CLL) and to determine its association with clinical and laboratory characteristics of the disease. Results We conducted a cross-sectional study on 99 patients diagnosed with CLL in Khartoum Oncology Hospital in Khartoum, Sudan. Immunophenotyping and CD38 expression levels were measured with four-color flowcytometry. The results of physical examination and blood analyses were used for assigning a modified Rai clinical staging system. The collected data were analyzed using the Statistical Package for the Social Science, version 22 (SPSS Inc., Chicago, IL, USA). According to our findings, the frequencies of 7%, 20%, and 30% cutoff levels of CD38 expressions were 68.7%, 41.4%, and 36.4% respectively. CD38 cutoff level of 7% showed a significant association with hemoglobin concentration (P = 0.04), whereas other cutoff levels showed insignificant results. All the three cutoff levels showed insignificant associations with the other clinical and laboratory variables. In conclusion, the CD38 expression at a cutoff level of 7% seems to be more valuable clinically than higher cutoff levels in Sudanese CLL patients.

Transforming growth factor-β (TGF-β) plays an essential role in regulating immune responses through its immunossupressive effect on adaptive and innate immune cells. In addition, we and others have shown that alterations in cell-intrinsic metabolism profiles can significantly impact the function of immune cells. Previously, our group demonstrated that TGFβ-imprinting (TGFβi) decreases NK cell sensitivity to TGFβ through SMAD3 suppression and enhances a pro-inflammatory phenotype with hypersecretion of IFN-γ, TNF-α, and GM-CSF, which appeared to be mediated by an epigenetic mechanism. To evaluate this process, we conducted RNA-seq and ATAC-seq to evaluate the impact of chromosomal remodeling on gene expression. In addition to confirming low SMAD3 transcription, this data showed that TGFβi NK cells have decreased CD38 expression, which we confirmed at the protein level. Since CD38 is an ectoenzyme that regulates nicotinamide adenine dinucleotide (NAD+), a critical component of OXPHOS in both T and NK cells, we examined the effect of TGFβi on NK cell metabolism. TGFβi primary NK cells were generated from peripheral blood of healthy donors as previously described, and using a mitochondrial stress test assay, we observed higher oxygen consumption rates (OCR). However, in the glycolysis stress test assay we observed comparable extracellular acidification rates (ECAR) between Standard expanded and TGFbi NK cells, resulting in higher OCR/ECAR ratios in TGFbi NK cells. Since TGFβ has been shown to induce fragmented mitochondria, and inhibition of mitochondrial fragmentation improved mitochondrial metabolism, we evaluated subcellular structure of TGFβi NK cellsby transmission electron microscopy (TEM). We found no difference in mitochondrial fragmentation between STD and TGFβi NK cells. Together, these results show that TGFβi induces epigenetic reprograming of NK cells that results in increased OXPHOS through CD38 suppression. Moreover, the decreases CD38 expression in TGFβi NK cells could be a promising non-genetic alternative to generating CD38-negative NK cells to avoid fratricide in combination with DARA Figure Disclosures Lee: Kiadis Pharma Netherlands B.V: Consultancy, Current equity holder in publicly-traded company, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties.

Objective Daratumumab is a promising new antimyeloma agent. We report a single center "real-world" series of multiple myeloma (MM) and amyloidosis (AL) patients treated with daratumumab. Methods Forty-one patients were included: 7 second-line MM, 30 heavily pretreated (median number of therapies of 5) advanced MM, and 4 with AL. Results Second-line patients and advanced AL showed high rate of durable overall responses. However, advanced MM patients had a dismal prognosis with an overall response rate (ORR) of 36%, and a short median progression-free and overall survival of 2.3 and 6.6 months, respectively. Responses were particularly poor in patients with extramedullary plasmacytomas. Neither the addition of another agent to daratumumab nor changing to the next line of therapy produced significant durable responses in this patient population. Flow cytometry analysis demonstrated that CD38 expression level was not predictive of response. We show that CD38 expression dynamics by a commercially available anti-CD38 antibody after daratumumab administration was hindered by competitive binding of daratumumab. Conclusions Responses to daratumumab and combinations in patients with advanced MM, particularly with extramedullary disease, are low and short-lived, stressing the administration of this agent should be early in the course of the disease.

had mutated immunoglobulin heavy chain variable gene (IGHV), 69 (51%) were ZAP70 negative and 76 (63%) had either 13q deletion or normal interphase cytogenetics, determined by fl uorescence in situ hybridization. Th e median time between the fi rst and last CD38 measurements was 3.4 years (range 0.2 – 11.3). CD38 expression was measured a median of 5.5 times (range 2 – 19). Patients with CLL were followed for a median of 7.7 years (range 1.3 – 30.4). During this time, 60 patients (44%) progressed and required therapy, while 76 patients (56%) did not need therapy. Of the 60 patients who were treated, 20 had received therapy prior to the fi rst CD38 measurement. What is the extent of CD38 variation in CLL lymphocytes over time in individual patients? As seen in Figure 1(A), the CD38 values in the entire cohort had a wide range, but in many patients these values remained relatively stable. For example, fi ve patients (4%) had fi rst CD38 values above 30% with subsequent CD38 values below 30%. Fourteen patients (10%) had fi rst CD38 values below 30% with later CD38 values above 30%. For the 60 patients who required therapy, two (3%) patients had a fi rst CD38 value above 30% with a subsequent CD38 value less than 30%, while nine patients (15%) had a fi rst CD38 value less than 30% and a subsequent CD38 value above 30%. Th e clinical outcomes (overall survival and time to therapy) of patients with CD38 values that were always less than the 30% cut-off were superior to those of patients with CD38 values always greater than 30% or both above and below 30% [Figures 1(B) and 1(C)]. Th ese results indicate that CD38 expression varies in approximately 15% of patients, crossing an established CD38 cut-off that has prognostic signifi cance, and that the clinical outcome of these patients is similar to that of patients with consistently high CD38 expression. What is the prognostic signifi cance of the fi rst, maximum and minimum CD38, as well as CD38 range? Evaluating these values as continuous variables, we found that an elevated fi rst CD38 measurement was associated with a signifi cantly more rapid time to therapy (TTT, hazard ratio [HR] 1.011, 95% confi dence interval [CI] 1.002 – 1.02, p 0.016, Wald test), and was associated with a trend toward a lower overall survival

The existence and identification of leukemia-initiating cells in adult acute B lymphoblastic leukemia (B-ALL) remain controversial. We examined whether adult B-ALL is hierarchically organized into phenotypically distinct subpopulations of leukemogenic and non-leukemogenic cells or whether most B-ALL cells retain leukemogenic capacity, irrespective of their immunophenotype profiles. Our results suggest that adult B-ALL follows the stochastic stem cell model and that the expression of CD34 and CD38 in B-ALL is reversibly and not hierarchically organized. Electronic supplementary material The online version of this article (doi:10.1186/s13045-016-0310-1) contains supplementary material, which is available to authorized users.

BACKGROUND In this study, we aimed to determine a cutoff level for CD38 that would aid us in identifying chronic lymphocytic leukemia patients in need of early therapy and predicting patients at sufficiently low risk who would likely exhibit a rapid improvement; we also aimed to find out if CD38 expression would show variability during disease course and determine the extent of CD38 expression. METHODS 124 patients were diagnosed with CLL. CD38 and ZAP-70 expression levels were measured with four color flowcytometry. Time from diagnosis to initial therapy was calculated for all patients. CD38 expression was studied for a second time during follow-up in 50 patients. RESULTS For cutoff levels of 7%, 20%, and 30%, CD38 expressions were 61.3%, 25%, and 24.2%, respectively. At all three cutoff levels there were significant correlations with all parameters except age between CD38+ vs. CD38- groups (p < 0.001). The comparative rates of starting therapy for cutoff levels of 7%, 20%, and 30% in CD38+ and CD38- groups were 77.5% vs. 6.25%; 100% vs. 30.7%, and 100% vs. 31.5%, respectively (p < 0.001). Multiple Cox Proportional Hazards Regression analysis: for a cutoff level of 7%, survival was affected by STAGE, ZAP70, and CD38. CONCLUSIONS A CD38 cutoff level of 7% determined by standardized laboratory techniques is an important prognostic marker. However, the number and frequency of repeat measurements of CD38 expression, and cutoff level of CD38 expression that significantly predict disease prognosis should be further determined by future cohort studies.

In order to determine if the expression of the activation marker CD38 can correlate with HIV disease progression independently of cycling, we performed a cluster-based multivariate correlation analysis of total circulating CD4+T cell counts and viral loads with frequencies of CD38 and Ki67 expression on CD4+lymphocytes from patients with untreated HIV infection, stratified in maturation subpopulations, and subpopulation subsets defined by the expression of CXCR5, CXCR3, and CCR4. The frequencies of the activated phenotypes %CD38+Ki67−and %CD38+Ki67+of the CXCR5−CXCR3−CCR4+(“pre-Th2”) central memory (TCM) cell subset clustered together, comprising a significant negative correlate of total circulating CD4+T cell counts and a positive correlate of viral load in multivariate analysis. Frequency of cycling-uncoupled CD38 expression in “pre-Th2”TCMcells was a negative correlate of total circulating CD4+T cell counts in univariate analysis, which was not the case of their %CD38+Ki67+. CXCR5+CXCR3−CCR4− TCMcells were underrepresented in patients, and their absolute counts correlated negatively with their %CD38+Ki67−but not with their % CD38+Ki67+. Our results may imply that CD38 expression either reflects or participates in pathogenic mechanisms of HIV disease independently of cell cycling.

Given the recent findings on the importance of CD38 signaling in the pathogenesis of colon cancer. We hypothesized that single nucleotide polymorphisms (SNP) in the CD38 gene may be related to colon cancer risk. CD38 has a genetic polymorphism, characterized by a C>G variation in the regulatory region of intron 1. The working hypothesis is that the presence of different alleles in colon cancer patients accounts for some of the clinical heterogeneity. CD38 is considered a marker of prognosis and as an indicator the activation and proliferation of cells. We hypothesized that single nucleotide polymorphisms (SNP) in the CD38 gene may be related to colon cancer risk. We evaluated one potentially functional CD38 SNP, intronic rs6449182 in two cases patients and controls. Genotyping was done using PCR-based assays in a total of 93 patients with colon cancer and 100 controls. We found that frequencies of variant allele (rs6449182 G) were significantly higher in colon cancer. Logistic regression analysis revealed an association between colon cancer and genotypes: rs6449182 CC [odds ratio (OR), 0.57; 95% confidence interval (95% CI), 0.32 – 1.01], rs6449182 CG (OR, 1.47; 95% CI, 0.83 – 2.60), and rs6449182 GG (OR, 2.26; 95% CI, 0.66 – 7.77). We observed that rs6449182 G carriers had more advanced clinical stage (P = 0.04). In conclusion, our data show that CD38 SNP may affect CD38 expression and contribute to the increased risk of colon cancer carcinogenesis.

CD38 expression on CD8+ cells seems to correlate well with HIV viral-loads, while the ex-pression levels are thought to be low in patients with tuberculosis. This study aimed at determining the levels of CD38 expression in HIV+ individuals who develop tuberculosis. Expression levels of CD8 and CD38 were analysed in peripheral blood collected from HIV (73), TB (32), HIV-TB (31) and healthy controls (20). The percentage of CD8+/CD38+ cells significantly increased during the first few years of seropositivity and decreased during 5 - 6 years. A decline in the expression of CD38, especially on CD8+ cells in a HIV+ individual within first 2 years of seropositivity, may be indicative of susceptibility to tuberculosis. This observation was reiterated when two patients developed TB during follow-up. CD38 on CD8 cells could perhaps be useful as an early biomarker for tuberculosis in HIV-positive individuals.

Objectives: The impact of modern prognostic markers on clinical course of chronic lymphocytic leukemia (CLL) in everyday practice has been not yet well-defined, especially in large series of patients. Therefore, the goal of the present study was to assess the influence of conventional as well as modern prognostic factors on overall survival (OS) and time to therapy (TTT) of CLL patients. Methods: We retrospectively analyzed data of all patients consecutively entered into the databases of five large academic centers in the Czech Republic. The total of 1300 patients was included in the analysis. Results and conclusion: Through the use of uniparametric analysis, it was determined that gender, clinical stage Rai II-IV, unmutated IgVH status, 17p deletion (for both 5% and 20% cut-off), 11q deletion, ZAP-70 positivity and high expression of CD38 had significant negative influence on OS. TTT was significantly influenced by gender, Rai stage, IgVH status, 11q deletion, 17p deletion, 13q deletion and by CD38 expression. Multiparametric analysis revealed that OS was significantly influenced by gender, age, IgVH status, and 17p deletion. If only patients who died of CLL were included, gender, age, Rai stage, IgVH status, and deletion 17p had significant influence on OS. Based on our results, the examination of biological prognostic markers can give an insight into the possible disease evolution in daily clinical practice. Biological prognostic markers are however not ready (maybe except deletion 17p in younger patients) to be used for guidance of therapy at least outside of clinical trials.

Pyrrolo-1,5-benzoxazepine-15 (PBOX-15) is a novel microtubule depolymerization agent that induces cell cycle arrest and subsequent apoptosis in a number of cancer cell lines. Chronic lymphocytic leukemia (CLL) is characterized by clonal expansion of predominately nonproliferating mature B cells. Here, we present data suggesting PBOX-15 is a potential therapeutic agent for CLL. We show activity of PBOX-15 in samples taken from a cohort of CLL patients (n = 55) representing both high-risk and low-risk disease. PBOX-15 exhibited cytotoxicity in CLL cells (n = 19) in a dose-dependent manner, with mean IC50 of 0.55 μmol/L. PBOX-15 significantly induced apoptosis in CLL cells (n = 46) including cells with poor prognostic markers: unmutated IgVH genes, CD38 and zeta-associated protein 70 (ZAP-70) expression, and fludarabine-resistant cells with chromosomal deletions in 17p. In addition, PBOX-15 was more potent than fludarabine in inducing apoptosis in fludarabine-sensitive cells. Pharmacologic inhibition and small interfering RNA knockdown of caspase-8 significantly inhibited PBOX-15–induced apoptosis. Pharmacologic inhibition of c-jun NH2-terminal kinase inhibited PBOX-15–induced apoptosis in mutated IgVH and ZAP-70− CLL cells but not in unmutated IgVH and ZAP-70+ cells. PBOX-15 exhibited selective cytotoxicity in CLL cells compared with normal hematopoietic cells. Our data suggest that PBOX-15 represents a novel class of agents that are toxic toward both high-risk and low-risk CLL cells. The need for novel treatments is acute in CLL, especially for the subgroup of patients with poor clinical outcome and drug-resistant disease. This study identifies a novel agent with significant clinical potential. [Cancer Res 2009;69(21):8366–75]

The MYC gene (at 8q24, previously referred to as C-MYC) rearrangement (R) with immunoglobulin heavy chain gene (IGH) [t(8;14)(q24;q32)] or light chain genes [t(2;8)(p12;q24) or t(8;22)(q24;q11.2)] ...

The individual prognosis of patients with chronic lymphocytic leukemia (CLL) is extremely variable. Although clinical stages remain the basis for assessing prognosis in CLL, a number of biological markers, particularly serum markers, cytogenetic abnormalities, IgVH mutations, CD38 and ZAP-70 expression in leukemic cells offer important, independent prognostic information. Before being incorporated into daily practice, however, these markers require standardization and validation in large, prospective trials. Meanwhile, treatment of patients with CLL not included in clinical studies should be decided on the basis of classical NCI/CLL Working Group criteria. An important area of research in CLL prognostication is the identification of markers useful for predicting response to therapy and its duration. Among them, del(17p), reflecting P53 abnormalities, is particularly important. Also relevant is del(11q), which points to ATM defects. There is also some correlation between IgVH mutational status, ZAP-70 and CD38 expression and response to therapy and its duration, although these relationships need further investigation. Finally, there is increasing evidence that response to therapy, particularly in those cases in which minimal residual disease is eradicated, is associated with longer survival.