Conventional Chemoimmunotherapy Research Articles

Allogeneic hematopoietic cell transplantation is an effective treatment for patients with Richter syndrome: A systematic review and meta-analysis

Efficacy of conventional chemoimmunotherapy is limited in patients with Richter syndrome (RS) with anticipated median overall survival (OS) of less than 10 months. Allogeneic hematopoietic cell transplantation (allo-HCT) is commonly offered as a consolidative treatment option in RS. To our knowledge, there are no randomized controlled studies that have compared allo-HCT against other therapies in RS; available allo-HCT data are limited to small case series from single-institution or registry studies. We performed a systematic review and meta-analysis to assess the totality of evidence regarding the efficacy (or lack thereof) of allo-HCT for RS. We extracted data on post-allograft outcomes related to benefits (overall response rate [ORR], complete remission [CR], OS, and progression-free survival [PFS]). For harms, data were extracted on non-relapse mortality (NRM) and relapse post-allografting. Our search strategy identified 240 studies, but only four studies (n = 72 patients) met our inclusion criteria. Pooled ORR, CR, OS, and PFS rates were 79%, 33%, 49%, and 30%, respectively. Pooled NRM and relapse rates were 24% and 28%, respectively. Results of this systematic review and meta-analysis indicate that allo-HCT yields encouraging OS in RS, thus remaining a reasonable treatment option in fit patients whose disease demonstrates a chemosensitive response to pre-transplant salvage therapies. Novel strategies are certainly needed to reduce the risk of relapse to further improve outcomes in these patients.

Drug Review: Ibrutinib

AbstractIbrutinib is an irreversible BTK inhibitor, characterized by high selectivity and potency. It has revolutionized the therapy of B-cell lymphomas, especially chronic lymphocytic leukemia (CLL) and mantle cell lymphoma. Importantly, it has expanded the armamentarium for those patients who are refractory to conventional chemoimmunotherapy. This small-molecule inhibitor has shown efficacy in this difficult-to-treat subset – those with del(17p)/TP53-mutated CLL. Its immunomodulatory properties make it an excellent choice for combining with other immunotherapeutic agents such as venetoclax. The drug is not without drawbacks. The need for indefinite therapy and the presence of adverse effects such as infection, bleeding, hypertension, and arrhythmia temper our enthusiasm for this versatile drug. But overall, ibrutinib's favorable risk profile and lack of myelosuppression make it an ideal therapy for the elderly and those with multiple comorbidities.

SAKK38/07 study: integration of baseline metabolic heterogeneity and metabolic tumor volume in DLBCL prognostic model

AbstractSeveral functional parameters from baseline (18)F-fluorodeoxyglucose positron emission tomography (PET)/computed tomography have been proposed as promising biomarkers of treatment efficacy in diffuse large B-cell lymphoma (DLBCL). We tested their ability to predict outcome in 2 cohorts of DLBCL patients receiving conventional immunochemotherapy (rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, and prednisone [R-CHOP] regimen), either every 14 (R-CHOP14) or 21 days (R-CHOP21). Baseline PET analysis was performed in 141 patients with DLBCL treated with R-CHOP14 in the prospective SAKK38/07 study (NCT00544219) of the Swiss Group for Clinical Cancer Research (testing set). Reproducibility was examined in a validation set of 113 patients treated with R-CHOP21. In the SAKK38/07 cohort, progression-free survival (PFS) at 5 years was 83% for patients with low metabolic tumor volume (MTV) and 59% for those with high MTV (hazard ratio [HR], 3.4; 95% confidence interval [CI], 1.6-7.0; P = .0005), whereas overall survival (OS) was 91% and 64%, respectively (HR, 4.4; 95% CI, 1.9-10; P = .0001). MTV was the most powerful predictor of outcome also in the validation set. Elevated metabolic heterogeneity (MH) significantly predicted poorer outcomes in the subgroups of patients with elevated MTV. A model integrating MTV and MH identified high-risk patients with shorter PFS (testing set: HR, 5.6; 95% CI, 1.8-17; P < .0001; validation set: HR, 5.6; 95% CI, 1.7-18; P = .0002) and shorter OS (testing set: HR, 9.5; 95% CI, 1.7-52; P < .0001; validation set: HR, 7.6; 95% CI, 2.0-28; P = .0003). This finding was confirmed by an unsupervised regression tree analysis indicating that prognostic models based on MTV and MH may allow early identification of refractory patients who might benefit from treatment intensification. This trial was registered at www.clinicaltrials.gov as #NCT00544219.

Novel Therapies in Chronic Lymphocytic Leukemia: A Rapidly Changing Landscape

Treatment landscape of chronic lymphocytic leukemia (CLL) has changed since 2014 after the introduction of inhibitors of B-cell receptor signaling pathway (ibrutinib, acalabrutinib, idelalisib and duvelisib) and the inhibitor of the anti-apoptotic protein BCL-2 (venetoclax). In 2019, novel agents were upgraded from being a "great treatment option" to the "preferred choice" for all lines of treatment after number of randomized clinical trials proved their superiority compared to conventional chemoimmunotherapy (CIT) regimens. A growing number of next-generation molecules are in clinical trials with a promise of improved efficacy and less toxicity. This includes agents with expected better safety profile (zanubrutinib, umbralisib, etc.) or more importantly with a potential to overcome the resistance mechanism to early generation agents (ARQ-531, LOXO-305, or vecabrutinib). Early intervention has once again become an active topic of research and, if proven to provide an overall survival benefit, will eliminate the "watch and wait" strategy for asymptomatic CLL patients. Until then, treatment should only be offered to patients who meet the standard treatment indication in standard practice. With our upgraded therapeutic toolbox, there are and will be many unanswered questions. CLL field will need to define the optimal treatment sequence and most effective combinations with a goal of having a time-limited and chemotherapy-free regimen that provides longest remissions and potentially cure. Cellular immunotherapy with chimeric antigen receptor T-cell (CAR-T) may become available for high-risk CLL along with allogeneic stem cell transplant (allo-SCT). Financial toxicity of novel agents especially when used in combination will need to be an important aspect of research in coming years to avoid unnecessary overtreatment of patients. As current prognostic models (CLL-IPI, etc.) were developed and validated in the CIT era, there is ongoing effort to develop new models using clinical and molecular characteristics to accurately define high-risk CLL in the era of novel agents. We all need to keep in mind that access to the novel agents is currently limited to certain developed countries and every effort should be made to make sure patients around the world also benefit from these outstanding drugs.

A network meta-analysis of maintenance therapy in chronic lymphocytic leukemia.

BackgroundChronic lymphocytic leukemia (CLL) is incurable through conventional chemoimmunotherapy regimens. Despite durable responses to front-line therapy and sustained remission rates in patients with CLL, a majority of patients eventually relapse in 5 years of initial treatment. The depth of the response may affect the length of response. Maintenance therapies were aimed to deep remissions and extend the period of disease quiescence. Lenalidomide, rituximab and ofatumumab had demonstrated some efficacy as a maintenance therapy compared to no intervention for CLL patients. The relative effect on disease control and safety between different maintenance therapies were unclear.MethodsWe performed a systematic literature review and network meta-analysis to evaluate relative effect on disease control and safety of current available maintenance therapies. We searched PubMed, Embase and Cochrane database up to March 6, 2019. Relevant reference of review article and conference abstract including European Hematology Association Annual Meeting (EHA 2018), American Society of Hematology Annual Meeting (ASH 2018) and American Society of Clinical Oncology Annual Meeting (ASCO 2018) were searched. Randomized controlled trials (RCT) involving current available maintenance therapy including “Lenalidomide”, “Rituximab”, “Ofatumumab”, “Ibrutinib”, “Idelalisib”, “Venetoclax”and “Obinutuzumab”were eligible. Outcomes of interest included progression-free survival (PFS), overall survival (OS) and serious adverse events (SAE) in CLL patients received subsequent maintenance therapy. Two authors CHL and CL) independently assessed eligibility for all identified citations and extracted data from the original trial reports. The selected studies’ risk of bias was assessed following the guidelines of Cochrane Collaboration Handbook.ResultsIn total, six phase III RCTs with total 1,615 CLL patients were identified. Maintenance therapy using lenalidomide, rituximab, and ofatumumab demonstrated a statistically significant effect in prolongation of progression-free survival (HR:0.37, 95% CI: 0.27–0.50 of lenalidomide; HR:0.50, 95% CI: 0.38–0.66 of rituximab; HR:0.52, 95% CI:0.41–0.66 of ofatumumab, separately) compared with no intervention; however, for overall survival, the effect of maintenance therapy showed no significant difference versus no intervention (HR: 0.89, 95% CI: 0.70–1.14). Lenalidomide showed the best efficacy for PFS (HR: 0.37, 95% CI: 0.27–0.50, Probability of being best treatment: 96%).ConclusionsOur network meta-analysis provided an integrated overview of relative efficacy and safety of different maintenance therapies in CLL. All maintenance therapies were effective in reducing the risk of disease progression versus no intervention. Based on current best evidence, maintenance therapy with lenalidomide is the most efficacious option.

CAR T-cell therapy in diffuse large B-cell lymphoma

SummaryDiffuse large B‑cell lymphoma (DLBCL) comprises 30–40% of non-Hodgkin’s lymphoma. Clinical factors such as a high International Prognostic Index (IPI) or molecular factors as cell of origin (COO) have an influence on the clinical outcome after conventional immunochemotherapy. Patients with resistant or relapsed (r/r) DLBCL have a poor prognosis with a median overall survival of 6,3 months and low complete response rates (CR 7%) to salvage chemoimmunotherapy. Currently, therapy with autologous chimeric antigen receptor T‑cells (CAR T‑cells) provide encouraging complete responses (CR) of up to 50%. However, high costs for approved products and elaborate logistics have to be encountered.

Conventional Immunochemotherapy (R-CHOEP) Vs High-Dose Immunochemotherapy (R-MegaCHOEP) in Younger Patients with High-Risk Aggressive B-Cell Lymphoma: 10-Year Long-Term Follow-up of a German Lymphoma Alliance (GLA) Study

Conventional Immunochemotherapy (R-CHOEP) Vs High-Dose Immunochemotherapy (R-MegaCHOEP) in Younger Patients with High-Risk Aggressive B-Cell Lymphoma: 10-Year Long-Term Follow-up of a German Lymphoma Alliance (GLA) Study

High Risk DLBCL in Younger Patients: Should ASCT be Declined in the Era Pos-Rituximab?

Introdution Optimal treatment of young patients with high-risk diffuse large B-cell lymphoma (DLBCL) remains a matter of debate. With the addition of rituximab, response rates (RR) and overall survival (OS) have improved significantly, but the best treatment option for this subset of patients with high risk DLBCL is not consensual. Historically, these patients are treated with conventional immunochemotherapy protocols (RCHOP - Rituximab + cyclophosphamide, doxorubicin, vincristine, and prednisone) followed by autologous stem cell transplantation (ASCT) as a consolidation treatment. Several studies tried to clear the exact role of ASCT, and others were design to answer about addition of other drugs to RCHOP, without conclusive results. Recently, our department review the protocol according to the state of the art, and an intensification of treatment was made for high risk DLBCL in young patients (&lt;65 years), without comorbidities. Since then, this group of patients is treated with the RCHOEP protocol (Rituximab + cyclophosphamide, doxorubicin, vincristine, and prednisone in addition to etoposide), omitting ASCT. Aim Comparison of conventional immunochemotherapy followed by ASCT with high dose immunochemotherapy in young, high risk patients with DLBCL. Analyze the impact of ASCT in the outcomes. Methods We evaluated 478 patients with confirmed diagnosis of DLBCL at our institution, between January 2012 and December 2017. 10 patients with CNS involvement and 108 patients with primary extranodal disease at diagnosis were excluded. A retrospective analysis was performed in the group of young, high risk patients with DLBCL. For study purpose 2 subgroups were defined: RCHOP plus ASCT (n=17) and RCHOEP (n=32) treated patients. Analysis of survival and statistical comparison between these two subgroups was made using the SPSS computing platform. Results In this study, 360 patients were analyzed. The median follow-up of the cohort was 46 months [4-86 months]. In the subgroup of RCHOP plus ASCT (n=17) the median age at diagnosis was 57 years [22-65]. LDH distribution showed a maximum of 3989 U/L and a minimum of 158 U/L, with a median value of 449 U/L. IPI median value was 3. 5 patients had involvement of extranodal areas and all presented at diagnosis with stage 3 (n=4) or 4 (n=13). Analysis of histological subtype (classified by Hans algorithm) , revealed 9 patients with germinal center DLBCL (GC DLBCL) and 8 patients with activated B Cell DLBCL (ABC DLBCL). Complete response (CR) was obtained in 15 patients and 3 patients relapsed. In the subgroup of RCHOEP (n=32) the median age at diagnosis was 51 years (31-63). LDH range between 150 and 2695 U/L, with a median value of 399 U/L. IPI median value was 3 with a minimum value of 2. 11 patients had involvement of extranodal areas and only 1 patient doesn´t presented with advanced disease at diagnosis. In concern to histological subtype, 18 patients had GC DLBCL and 14 patients had ABC DLBCL. CR was achieved in 28 patients and 4 patients relapse during follow up. Prior to analysis of survival a statistical comparison between the 2 subgroups was performed and did not identify any significant difference between the main demographic and analytical clinical variables (age at diagnosis, sex, ECOG, presence of B symptoms, LDH, hemoglobin concentration, clinical status, medullary involvement, presence of bulky mass, IPI score and histological subtype). As regards the analysis of survival in both subgroups, the median OS was not attained. The 2-year OS was 87,5% in the group of patients treated with RCHOEP and 82% in the subgroup of patients submitted to RCHOP plus ASCT, not presenting this difference statistical value. Conclusion No randomized trials have been conducted comparing R-CHOP and R-CHOEP and there is only one retrospective study population based cohort from the Danish Lyfo Registry comparing young high risk DLBCL treated with R-CHOP or R-CHOEP. This study aims to explore the RCHOEP potential comparing to RCHOP plus ASCT in this peculiar group of patients, as an alternative regimen. Despite the retrospective character of this study, our results demonstrates the non-inferiority of RCHOEP relatively to RCHOP plus ASCT. RCHOEP is an effective treatment for young patients with high risk DLBCL, an excellent alternative, with high efficacy and a tolerable toxicity. This result should be validated in a prospective randomized study. Disclosures No relevant conflicts of interest to declare.

Economic Burden of Neurologic Toxicities Associated with Treating Relapsed Refractory Diffuse Large B-Cell Lymphoma in the United States

Introduction: Chimeric antigen receptor T (CAR-T) cell therapies targeting CD19 antigen can yield durable remissions in relapsed or refractory diffuse large B-cell lymphoma (r/r DLBCL). Yet the use of CAR-T can be limited by potentially severe toxicities, principally cytokine release syndrome (CRS) and neurologic toxicities. Management of neurologic toxicities requires vigilant monitoring, supportive treatment and resource allocation. We found no studies reporting healthcare costs associated with treatment-related neurologic adverse events (NEAEs) in r/r DLBCL patients. The objective of this study was to develop an evidence-based list of r/r DLBCL treatment-related NEAEs and to estimate the healthcare costs associated with these NEAEs in a real-world setting. Methods: Grade 3 or higher NEAEs that occurred in ≥2% of patients were identified by reviewing U.S. drug prescribing information (PI), European Medicines Agency summaries of product characteristics, and published clinical trials for treatments of r/r DLBCL. Then, adult patients ≥18 years old with r/r DLBCL were identified from a U.S. administrative claims database containing de-identified claims for over 150 million people across over 11 years. Patients were included if they had: 1) evidence of treatment beyond first-line (2L+) during the identification period (07/01/14 - 12/31/18); and 2) ≥1 inpatient or ≥2 outpatient claims for DLBCL (ICD-9-CM codes: 200.7X; ICD-10-CM codes: C83.3X) during the study period (01/01/14 - 12/31/18) with ≥1 having occurred prior to or on the date when the 2L+ treatment was received. 2L+ treatments were selected based on National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines and clinical expert input. To maximize the identification of patients treated with CAR-T, treatments were categorized hierarchically into 4 groups: CAR-T therapy (axicabtagene ciloleucel, or tisagenlecleucel), high-intensity cytotoxic therapy (carboplatin, cisplatin, cyclophosphamide, or ifosfamide), low-intensity cytotoxic therapy (bendamustine, lenalidomide, or gemcitabine), and targeted monotherapy (rituximab, ibrutinib, or brentuximab vedotin). The index date was defined as the start date of the 2L+ treatment. Patients in the cytotoxic and targeted therapy groups were also required to have evidence of an earlier line of cytotoxic or targeted therapy. All patients were required to have ≥6-months continuous enrollment before the index date. The outcomes of interest were the rates of NEAEs and total healthcare costs for patients with and without NEAEs during the 30-day post index period. Costs were inflated to 2018 US dollars. Descriptive statistics were reported. Results: Twenty-three NEAEs were identified based on the review: 17 for CAR-T, 10 for conventional immunochemotherapy regimens, and 4 for both. In the claims database, a total of 349 adult patients with r/r DLBCL were identified, including 27 CAR-T therapy, 262 high-intensity cytotoxic therapy, 50 low-intensity cytotoxic therapy, and 10 targeted therapy users. Mean (median, SD) patient age was 72.3 (73; 10.3) years, with 47.9% being female and 83.4% having Medicare insurance. Patients were mainly from the South (44.1%) and the Midwest (31.5%). The mean (SD) Charlson comorbidity index was 4.4 (3.6) and mean (SD) number of chronic conditions was 7.3 (2.2). Forty-five (12.9%) patients had ≥1 NEAE at some point during the 30-day post-index period. Of these, 14 (31.1%) were CAR-T users. Eleven (40.7%) of the CAR-T users had encephalopathy. Mean total healthcare costs were $99,611 higher for patients with NEAEs [mean (SD): $153,435 (227,771)] than those without any NEAEs [$53,824 (96,170)]. Among patients with NEAEs, 72% of the healthcare costs were accrued in the inpatient setting. Among patients without NEAEs, 63% of the healthcare costs were for outpatient medical services. The trend of higher costs in patients with NEAEs was consistent across treatment groups. Conclusion: This is the first study of the economic burden of NEAEs associated with treating r/r DLBCL in a real-world setting with data that reflects the current range of treatment options. Patients with r/r DLBCL who have NEAEs incur substantially higher costs than those without such events. In this analysis, CAR-T is overrepresented for NEAEs, although the sample size is small. We intend to repeat the analysis when more claims data becomes available in the near future. Disclosures Broder: Partnership for Health Analytic Research (PHAR), LLC: Other: I am an employee of the Partnership for Health Analytic Research (PHAR), LLC, which was paid by Novartis to conduct the research described in this abstract.. Ma:Novartis Pharmaceuticals Corporation: Employment. Yan:Partnership for Health Analytic Research (PHAR), LLC: Other: T. Yan is an employee of Partnership for Health Analytic Research (PHAR), LLC, a health services research company paid to conduct this research.. Chang:Partnership for Health Analytic Research (PHAR), LLC: Other: E. Chang is an employee of Partnership for Health Analytic Research (PHAR), LLC, a health services research company paid to conduct this research.. Eldjerou:Novartis Pharmaceuticals Corporation: Employment. Hao:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership. Kuzan:Novartis Pharmaceuticals Corporation: Employment. Zhang:Novartis Pharmaceuticals Corporation: Employment, Equity Ownership.

Validation of the PRIMA-Prognostic Index for Patients Treated with Rituximab Plus Chemotherapy and Refinement of Prognostic Parameters for Patients on Rituximab Plus Lenalidomide in the Phase III Relevance Trial

Validation of the PRIMA-Prognostic Index for Patients Treated with Rituximab Plus Chemotherapy and Refinement of Prognostic Parameters for Patients on Rituximab Plus Lenalidomide in the Phase III Relevance Trial

Rituximab-CHOP and Central Nervous System Prophylaxis Using Intrathecal Methotrexate in Primary Breast Diffuse Large B-Cell Lymphoma: A Prospective, Multicenter, Single-Arm Phase II Study

Background: Primary breast diffuse large B-cell lymphoma (DLBCL) has poor outcomes with frequent extranodal failures, particularly in the central nervous system (CNS). To prevent CNS recurrence, we designed this phase II trial that addressed feasibility and activity of conventional immunochemotherapy and CNS prophylaxis. Methods: This prospective, multicenter, single-arm phase II study was conducted to evaluate efficacy and safety of 6 cycles of conventional rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone every 21 days (R-CHOP) with the addition of 4 doses of intrathecal methotrexate (IT MTX; 12mg) during the first 4 cycles of R-CHOP in patients with primary breast DLBCL. Primary breast lymphoma was defined as lymphoma involving one or both breasts as a sole extranodal site regardless of specific nodal involvement status. The primary end-point was 2-year progression-free survival (PFS). Secondary end-points included cumulative incidence of CNS recurrence, overall survival (OS), and safety. All patients provided written informed consents and the study was registered at www.clinicaltrials.gov as #NCT01448096. Results: Thirty-three patients with primary breast DLBCL were enrolled between Jan 2012 and Jul 2017 in the Consortium for Improving Survival of Lymphoma (CISL) member institutions. The median age was 50 years at diagnosis (range, 29-75) and all were female. Right breast involvement was more common than left (18 [55%] vs 14 [42%]) and bilateral breast involvement was found in one patient (3%). Nodal involvement was present in 16 patients (49%), primarily in regional nodes (14 patients). Thus, the Ann Arbor stage was IE in 17 (52%), IIE in 13 (39%), IIIE in 2 (6.1%), and IV in 1 (3.0%). ECOG performance status was ≥2 in 1 patient (3%) and serum LDH level was elevated in 9 (27%). Therefore, the IPI and the CNS-IPI risk were mainly low (28 patients, 85%; respectively). No patients had CNS involvement at diagnosis. 32 (97%) of the 33 patients completed R-CHOP as planned, and the remaining patient withdraw a consent after four cycles of R-CHOP because of poor tolerance. CNS prophylaxis using IT MTX was completed as planned in 31 patients (94%), but it was discontinued in 2 patients because of patient's refusal. These 2 patients received two and three IT MTX doses, respectively. 32 patients (97%) were evaluable for treatment response and all these patients achieved a complete response. At the cutoff date of this analysis (10 Jul 2019), all patients who entered a follow-up phase had at least 24.0 months of follow-up. With a median follow-up duration of 46.1 months (IQR 31.1-66.8), 6 patients had experienced treatment failure and 3 of these died. The 2-year PFS and OS were 81.3% (95% CI, 67.7-94.8) and 93.5% (95% CI, 84.9-100.0), respectively (fig 1A and B). Of the 6 patients with treatment failure, diseases involved CNS with or without lymph nodes in 4 patients and breasts in 2 patients (1 ipsilateral and 1 contralateral breast recurrence). 3 of the four patients with CNS recurrence had isolated CNS recurrences (2 brain parenchymal and 1 meningeal disease) and one had a concurrent meningeal and lymph nodal recurrence. All 4 patients with CNS recurrence had received prophylactic IT MTX as planned by protocol. The 2-year cumulative incidence of CNS recurrence, taking into account the competing risk of death, was 12.5% (95% CI, 0.3-23.2, fig 1C). Although the number of patients with intermediate CNS-IPI risk was small (5 patients, 15%), the cumulative incidence of CNS recurrence did not differ significantly according to the CNS-IPI risk group. All CNS recurrences occurred within the first 2 years after enrolment. Toxicities were generally manageable during the R-CHOP and IT MTX treatment. No deaths as a result of toxicity occurred during treatment. Conclusion: Our study shows that conventional R-CHOP with prophylactic IT MTX is feasible in patients with primary breast DLBCL. However, given a substantially high rate of CNS recurrence, further studies to properly define the best strategy for CNS prophylaxis should be needed in patients with primary breast DLBCL. Figure 1 Disclosures Yoon: F. Hoffmann-La Roche Ltd: Research Funding. Kim:Celltrion: Research Funding; Novartis: Research Funding; Donga: Research Funding; Kyowa-Kirin: Research Funding; Novartis: Research Funding; J + J: Research Funding; F. Hoffmann-La Roche Ltd: Research Funding.

How to approach CLL in clinical practice.

How to approach CLL in clinical practice.

Single-Agent Ibrutinib vs Real-World (RW) Treatments for Patients with Chronic Lymphocytic Leukemia (CLL) and del11q: Adjusted Comparison of RESONATE-2TM and RESONATETM with RW Databases

IntroductionIbrutinib, a first-in-class, oral, covalent inhibitor of Bruton's tyrosine kinase, is approved in many countries for treatment-naïve (TN) and previously treated CLL, supported by improved response rates, progression-free survival (PFS), and overall survival (OS) vs chlorambucil in RESONATE-2™ (NCT01722487; Burger JA, et al. N Engl J Med. 2015;373:2425-2437) and ofatumumab in RESONATE™ (NCT01578707; Byrd JC, et al. N Engl J Med. 2014;371:213-223). We analyzed survival outcomes for ibrutinib vs RW treatments for TN and relapsed/refractory (R/R) CLL by del11q status, an adverse prognostic factor linked with poor patient outcomes despite conventional chemoimmunotherapy. An adjusted comparison restricted to patients with confirmed del11q status was conducted using patient-level data from RESONATE-2™ and RESONATE™ and RW databases from 2 countries.MethodsThe Lyon-Sud RW database holds medical records for CLL patients diagnosed between 1980 and 2017 from the Centre Hospitalier Lyon-Sud, France; the Chronic Lymphocytic Leukemia Registry (CLLEAR) RW database holds medical records for CLL patients diagnosed between 1988 and 2017 from 7 academic centers in the Czech Republic. TN CLL database patients were selected using RESONATE-2™ criteria (which excluded those aged < 65 years or del17p positive). For the R/R group, patients ≥ 18 years of age or those with del17p were allowed per RESONATE™ inclusion criteria. PFS and OS outcomes by del11q status were compared between the ibrutinib arms of RESONATE-2™/RESONATE™ and physicians' choice (PC) treatment in the pooled RW databases (excluding ibrutinib). A multivariate Cox proportional hazards model was fitted on pooled RCT/RW data to estimate adjusted hazard ratios (HRs) for effect of ibrutinib vs RW PC treatment using age, sex, and treatment line as covariates. The unit of observation for the RW databases was the treatment line (rather than patient) number; RW patients receiving multiple lines of therapy contributed to multiple observations, and baseline was defined as the line-specific treatment start date.ResultsFor the RW TN cohort, 466 treatment lines were analyzed; 134 (28.8%) patients were del11q positive. In RESONATE-2™, 29/136 (21.3%) TN patients were del11q positive. The table below shows adjusted HRs for PFS and OS for patients with/without del11q. For the del11q-positive subgroup, adjusted HRs for ibrutinib vs RW PC first-line (1L) therapy were 0.02 (95% confidence interval [CI], 0.00-0.17; p = 0.0002) for PFS and not estimable for OS (no deaths on ibrutinib). For the del11q-negative subgroup, adjusted HRs were 0.34 (95% CI, 0.2-0.57; p < 0.0001) for PFS and 0.74 (95% CI, 0.37-1.49; p = 0.3957) for OS. For second-line (2L) PC treatment in the RW R/R cohort, 385 treatment lines were analyzed; 135 (35.1%) were from del11q positive patients. In RESONATE™, 13 (37.1%) 2L patients were del11q positive. For the del11q-positive subgroup, adjusted HRs for ibrutinib vs RW PC of 2L therapy were 0.03 (0.00-0.21; p = 0.0003) for PFS and 0.08 (0.01-0.46; p = 0.0050) for OS. For the del11q-negative subgroup, adjusted HRs were 0.27 (0.14-0.51; p < 0.0001) for PFS and 0.50 (0.24-1.05; p = 0.0670) for OS. For 2L and beyond (2L+) treatment in the RW R/R cohort, 727 treatment lines were analyzed; 291 (40.0%) were from del11q positive patients. In RESONATE™, 63/195 (32.3%) 2L+ patients were del11q positive. For the del11q-positive subgroup, adjusted HRs (95% CIs) for ibrutinib vs RW PC of 2L+ therapy were 0.13 (0.08-0.20; p < 0.0001) for PFS and 0.15 (0.08-0.26; p < 0.0001) for OS. For the del11q-negative subgroup, adjusted HRs were 0.20 (0.14-0.29; p < 0.0001) for PFS and 0.33 (0.21-0.52; p < 0.0001) for OS.ConclusionsAdjusted comparisons of the registration trial (RESONATE-2™/RESONATE™) and RW patient-level data suggest that OS and PFS improvements with ibrutinib vs PC therapies are pronounced for patients with CLL harboring del11q compared with those who are del11q negative. The findings inform physicians of the comparative effectiveness of ibrutinib in the RW for patients with this high-risk cytogenetic abnormality.Funding Source:This project was sponsored by Janssen Pharmaceutica NV, and Pharmacyclics LLC, an AbbVie Company. The real-world databases are independently owned. Writing assistance was provided by Emma Fulkes of PAREXEL and funded by Janssen Pharmaceutica NV. [Display omitted] DisclosuresSalles:Takeda: Honoraria; Acerta: Honoraria; Epizyme: Honoraria; Pfizer: Honoraria; Amgen: Honoraria; AbbVie: Honoraria; Gilead: Honoraria; Roche: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Servier: Honoraria; Janssen: Honoraria; Merck: Honoraria; Morphosys: Honoraria. Besson:Janssen Pharmaceutica NV: Employment. Doyle:Janssen Pharmaceutica NV: Employment. Garside:Janssen Pharmaceutica NV: Employment. Spacek:Roche: Consultancy, Honoraria; AbbVie: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Gilead: Consultancy, Honoraria. Doubek:Novartis: Consultancy; AbbVie: Consultancy, Research Funding; Roche: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Affimed: Research Funding; Gilead: Consultancy, Honoraria, Research Funding.

Early-onset invasive aspergillosis and other fungal infections in patients treated with ibrutinib

AbstractIbrutinib has revolutionized the management of chronic lymphocytic leukemia and is now being increasingly used. Although considered to be less immunosuppressive than conventional immunochemotherapy, the observation of a few cases of invasive fungal infections in patients treated with ibrutinib prompted us to conduct a retrospective survey. We identified 33 cases of invasive fungal infections in patients receiving ibrutinib alone or in combination. Invasive aspergillosis (IA) was overrepresented (27/33) and was associated with cerebral localizations in 40% of the cases. Remarkably, most cases of invasive fungal infections occurred with a median of 3 months after starting ibrutinib. In 18/33 cases, other conditions that could have contributed to decreased antifungal responses, such as corticosteroids, neutropenia, or combined immunochemotherapy, were present. These observations indicate that ibrutinib may be associated with early-onset invasive fungal infections, in particular IA with frequent cerebral involvement, and that patients on ibrutinib should be closely monitored in particular when other risk factors of fungal infections are present.

Ibrutinib.

Abnormal B-cell receptor (BCR) signalling is a key mechanism of disease progression in B-cell malignancy. Bruton's tyrosine kinase (BTK) has a pivotal role in BCR signalling. Ibrutinib (PCI-32765) is a small molecule which serves as a covalent irreversible inhibitor of BTK. It is characterized by high selectivity for BTK and high potency. Ibrutinib is currently approved by the FDA and EMA for use in chronic lymphocytic leukaemia in any line of treatment, for treatment of Waldenstrom macroglobulinemia in patients who have received previous treatments or are not suitable to receive immunochemotherapy as well as for second line treatment of mantle cell lymphoma and for patients with marginal zone lymphoma who have received at least one prior anti-CD20-based therapy. In addition, there is emerging clinical data on its efficacy in ABC subtype diffuse large B-cell lymphoma, multiple myeloma and primary central nervous system lymphoma. Ibrutinib has opened new options for treatment of those patients that have relapsed or have been refractory to more classical modes of treatment. Moreover, Ibrutinib has been shown to be effective in patients that have been known to have little sensitivity to classical immunochemotherapy. Having a favourable risk profile, the substance is, unlike conventional immunochemotherapy, also suitable for the less physical fit patients. Cases of primary and secondary resistance to Ibrutinib have emerged and there is an ongoing effort to identify their mechanism and develop strategies to overcome them. Beyond its direct effects on survival and apoptosis of malignant B-cells, there is increasing evidence that Ibrutinib is able to modulate the tumour microenvironment to overcome mechanisms of immune evasion. This has sparked interest in use of the substance beyond lymphoid malignancy. This chapter discusses structure, mechanism of action and toxicities of Ibrutinib and also presents important preclinical and clinical data as well as mechanisms of Ibrutinib resistance. Combination strategies with immunotherapeutic strategies such as immune checkpoint blockade and CAR T-cell therapy may be synergistic and are currently under investigation.

De novo acute lymphoblastic leukemia-like disease of high grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements: a case report and literature review

BackgroundB-cell lymphomas harboring the 8q24/MYC plus 18q21/BCL2 translocations are now referred to as high grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements (HGBL-MBR). Although HGBL-MBR is frequently found in cases with diffuse large B-cell lymphoma or Burkitt lymphoma-like B-cell lymphoma, acute lymphoblastic leukemia (ALL)-like disease of HGBL-MBR (AL-HGBL-MBR) has been reported incidentally.Case presentationA 69-year-old Japanese woman developed remittent fever and increasing systemic bone pain. The bone marrow examination revealed that more than 90% of nuclear cells were blastoid cells, which were positive for CD10, CD19, CD20, and surface IgMκ and negative for terminal deoxynucleotidyl transferase (TdT). Cytogenetic studies confirmed that the patient had de novo AL-HGBL-MBR with the extra copies of MYC and loss of chromosome 17p. She showed resistance to chemoimmunotherapy and died seven months after the diagnosis. The literature review identified further 47 de novo AL-HGBL-MBR cases within the last 32 years. The median age was 61 years (range, 27 − 86); the male/female ratio was 2.0. Thirty-eight cases (79%) presented a clinical picture of ALL at diagnosis; 14 (36%) of 39 available cases showed central nervous system involvement. Loss of 17p and translocations at 2p12–13, 3q27, 9p13 were frequently observed as additional cytogenetic abnormalities. Although the median survival of 46 available cases was only five months (range, 0.1–18), rituximab use significantly improved the survival of AL-HGBL-MBR (log-rank test, P = 0.0294).ConclusionOur patient and most reported de novo AL-HGBL-MBR cases showed resistance to conventional chemoimmunotherapy and disastrous consequences. AL-HGBL-MBL is a rare, but should be considered a distinct clinical condition in HGBL-MBR. Other therapeutic strategies, such as using inhibitors of MYC and BCL2, are needed to overcome the chemoresistance of AL-HGBL-MBR.

Bendamustine and Rituximab Versus Conventional Chemoimmunotherapy As a Frontline Treatment for Patients with Indolent B-Cell Lymphoma: A Cost-Effectiveness Analysis

Background: Indolent lymphomas are characterized by a chronic relapsing-remitting course. Bendamustine-Rituximab (BR) has been shown to improve overall response rate and progression free survival (PFS) in the upfront treatment of patients with indolent B-cell non-Hodgkin lymphoma (iNHL), as compared with conventional chemoimmunotherapy (Rummel et al., 2013; Flinn et al., 2014). The pan-Canadian Oncology Drug Review has recommended publicly funding BR, but concluded there is substantial uncertainty regarding the regimen's cost-effectiveness. The objective of our study was to assess the cost-effectiveness of BR as compared with Rituximab-Cyclophosphamide, Doxorubicin, Vincristine, Prednisone (RCHOP) as frontline treatment for patients with advanced iNHL from a Canadian perspective.Methods: A Markov model was developed to estimate the costs, life expectancy and quality-adjusted life-years (QALYs) associated with the two regimen options allowing determination of the incremental cost-utility ratio (ICUR). Model parameters were derived from peer-reviewed studies. Key health states included FT (frontline therapy), MR (2-year state of maintenance R), PF1 (1st progression-free state), PD1/2/3 (subsequent progressive disease states requiring salvage), PF2/3/4 (subsequent progression-free states post-salvage), palliation and death. To determine progression after FT, individual data elements were derived from the published literature, and transition probabilities were determined through parametric survival analysis. Age-related mortality was obtained from Statistics Canada. Cost data (in 2016 Canadian dollars) were obtained from current funding arrangements under the New Drug Funding Program of Cancer Care Ontario, the Ontario Health Insurance Plan Schedule of Benefits and Fees, and the published literature. Utility values for health states and utility decrements associated with treatment related adverse events (AEs) were derived from peer-reviewed studies. The analysis was performed from the health care provider perspective, with a lifetime time horizon (equivalent to 24 years) and cycle lengths of 6 months. Patients were treated with a maximum of 3 lines of salvage therapy (3rd salvage permitted in age-appropriate patients achieving at least 1 year remission from 2nd line salvage). In order to address uncertainty of model input variables, a probabilistic analysis in which model inputs were represented by probability distributions was utilized, permitting a Monte Carlo simulation with 5000 replications. Costs and utilities were discounted at a rate of 5% per annum. Subgroup analyses for the following iNHL histologies were performed using individualized parametric survival curves: follicular lymphoma (FL), mantle cell lymphoma (MCL), marginal zone lymphoma (MZL), lymphoplasmacytic lymphoma (LPL).Results: The average costs and QALYs for the two treatment strategies were as follows: $116,811 and 5.86 QALYs for RCHOP; $121,364 and 6.38 QALYs for BR. The incremental cost per QALY gained for using BR with respect to RCHOP was $8,812 (Figure 1). Subgroup analyses revealed robust ICUR results: $27,398 (FL), $8,924 (MCL), $10,012 (MZL), $6,565 (LPL). For the commonly accepted willingness to pay threshold (WTP) of $50,000 per QALY, BR was the more cost-effective strategy 92% of the time in the entire cohort (Figure 2). In the subgroup analyses, BR was the more cost-effective strategy 66%, 82%, 64%, 86% of the time in FL, MCL, MZL, LPL respectively. ICUR results were robust to sensitivity analyses of key variables including age at study entry, maximum allowable age for therapy, duration of AEs, probability of death from palliation state and discount rate.Conclusion: Our model suggests that BR is a cost-effective strategy for the frontline treatment of patients with iNHL as compared with RCHOP. The cost-effectiveness of BR may be driven by the upfront PFS advantage despite higher acquisition costs and is consistent in various iNHL histology subgroups. Our analysis supports the use of frontline BR for iNHL in the Canadian setting. [Display omitted] [Display omitted] DisclosuresBence-Bruckler:Lundbeck: Membership on an entity's Board of Directors or advisory committees.

Changing Demographics and Treatment Patterns in Patients the United States with Chronic Lymphocytic Leukemia in the First-Line Setting As Assessed Using a Novel Electronic Health Record Database

Introduction: Approximately 18,960 new cases of CLL and 4,660 deaths from CLL are estimated in the US in 2016, with an overall estimated 5-year survival rate of 82%. Despite this, CLL patients with unfavorable genetic features such as 17p deletion have relatively poor outcomes when treated with conventional chemoimmunotherapy (e.g. fludarabine and cyclophosphamide, or bendamustine plus rituximab); however, several new treatments have been approved by the FDA for the treatment of previously untreated CLL in the past 3 years, including obinutuzumab with chlorambucil and ibrutinib. The aim of this analysis was to assess demographics and treatment patterns in patients with previously untreated CLL since the introduction of new treatment options using a novel oncology electronic health record (EHR) database.Methods: A cohort of CLL patients was selected by identifying patients within Flatiron’s real-world oncology database. The Flatiron provider network comprises 230 clinics, 2,000 clinicians, and more than 1 million cancer patients throughout the United States (US). Patients included in the cohort were required to meet the following criteria: ≥2 clinic encounters on different days occurring on or after January 1, 2011; ≥1 medication order for an antineoplastic occurring on or after January 1, 2013; physician documentation of CLL; and, evidence in unstructured documents (ie, information not organized in a pre-existing data model, such as free text from a physician note/lab report) of having been treated specifically for CLL. The latter two criteria were assessed based on technology-enabled abstraction of unstructured data (e.g., pathology reports, clinician notes). Patients who lacked unstructured documents, absence of evidence of first-line treatment, or received CLL treatment at a practice outside of the Flatiron network were excluded. The cohort included patients of all ages treated between 2011 and 2015 from all 50 states of the US.The index date was defined as the date of the patient's CLL treatment initiation. Start of first-line therapy after January 1, 2011, was defined as the first episode of an eligible therapy given after or up to 14 days before the date of the patient's CLL treatment initiation. Line of therapy was the first eligible drug episode plus other eligible drugs given within 28 days. Therapies eligible for inclusion in lines of therapy were systemic treatment, as evidenced by an order or administration of an antineoplastic agent recorded in the EHR; radiotherapy and surgery were not included.For patients with documented transformation of CLL, the abstracted date of transformation ended any active line of therapy, and the patient was not considered eligible for any subsequent CLL lines of therapy. Any treatment that occurred after the date of transformation was not included as a CLL line of therapy (steroids were not included in the definition of CLL lines of therapy).Results: As of June 2016, the cohort consisted of 766 eligible CLL patients with a median age of 71 years, and 64% were male (Table 1). While distribution of first-line therapies initiated in 2011 to 2013 remained relatively constant by year, changes were observed during 2014 and 2015 following the introduction of obinutuzumab and ibrutinib (Figure 1); obinutuzumab monotherapy as first-line therapy increased from 8.2% in 2014 to 14.5% in 2015, and ibrutinib monotherapy or ibrutinib + rituximab increased from 10.5% in 2014 to 13.6% in 2015. Of note, fludarabine containing regimens declined from 19.8% in 2012 to 8.8% in 2015. Decreases were also observed with rituximab monotherapy from 21.0% to 16.2%, bendamustine + rituximab (BR) from 36.1% to 31.6%, and rituximab + fludarabine + cyclophosphamide (RFC) from 11.0% to 8.8%. Factors associated with chlorambucil treatment (as monotherapy or in combination) vs. chemoimmunotherapy included older age (75.9 years vs. 68.7 years and 62.6 years for BR and RFC, respectively) and Rai stage (78.1% of patients treated with chlorambucil had Rai stage 0-I disease vs. 70.1% and 71.7% treated with BR and RFC, respectively). A fifth of patients with 17p deletion were treated with ibrutinib. Updated data inclusive of 2016 treatments will be presented.Conclusion: Using a novel EHR database, the marked change in CLL treatments from 2011 to 2015 shows increased utilization of newer agents. Further follow-up and analysis will contrast treatment patterns beyond RCT data in a real-world setting. [Display omitted] [Display omitted] DisclosuresArnieri:F. Hoffmann La-Roche Ltd: Employment. Bernaards:F. Hoffmann La-Roche Ltd: Employment. Wilhelm:Roche: Equity Ownership; Genentech: Employment. Black:F. Hoffmann La-Roche Ltd: Employment. Hirst:F. Hoffmann La-Roche Ltd: Employment; AstraZeneca: Other: Previous employment . Taylor:F. Hoffmann La-Roche Ltd: Employment. Lambert:F. Hoffmann La-Roche Ltd: Employment. Green:F. Hoffmann La-Roche Ltd: Employment. Lu:F. Hoffmann La-Roche Ltd: Employment. Humphrey:Genentech, Inc.: Employment.

Myc and Bcl2 Overexpression and Traslocation Assessed By Immunohystochemistry (IHC) and FISH: Retrospective Analysis in a Series of De Novo DLBCL Homogeneously Treated with Rituximab-CHOP

Introduction: MYC and BCL2 overexpression assessed by IHC and rearrangement detected by FISH are important prognostic factor in Diffuse Large B-Cell Lymphoma (DLBCL). Double Hit Lymphoma (DHL) patients have a poor prognosis with conventional therapy and Double expressor Lymphoma (DE) have worse outcome compared with conventional DLBCL although data are controversial. Aimed at a better knowledge of this issue, we performed a retrospective analysis to determine prevalence and outcome of Single Hit Lymphoma (SHL), DHL and DE in patients with de-novo DLBCL treated with Rituximab and CHOP.Methods: de novo DLBCL treated with R-CHOP between January 2003 and December 2013 were included in the study. BCL2 and BCL6 expression were evaluated by IHC at diagnosis while MYC expression was retrospectively investigated with Tissue Micro Arrays (TMA) technique; cases were considered positive for MYC, BCL2 or BCL6 expression by IHC if >40%, >40% or >25% of cells stained positive, respectively. FISH analysis for MYC and BCL2 rearrangements were performed with dual color break apart probes on TMA. PFS and OS were estimated with Kaplan-Meier method and compared between groups with the Cox model.We further evaluated in this series the IHC score proposed by Botto et al. (Blood 2014 124:2964) in DLBCL. The score was based on the assessment in IHC of the expression of MYC, BCL2 and BCL6. The three variable contributed with different risk in the multivariate analysis and an IHC sum additive score of 0-5 was calculated proportionally to the coefficient estimated (coefficient [Log hazard ratio] 0.92 for MYC+, 0.73 for BCL2+ and 0.48 for BCL6-), assigning an individual risk of 2 points for MYC or BCL2 positivity and 1 point for BCL6 negativity. Patients were stratified in three different risk groups; Low risk (0-1 point), Intermediate risk (2 points) and High risk (≥3 points).Results: Of a total of299 DLBCL screened, 267 were evaluable for survival analysis; median age was 65 years (range 20-90). 154 patients had complete immunohystochemical data and 101 were fully investigated by IHC and FISH. No significant differences in clinical presentation or in the outcome were seen between patients with or without available histologic tissue for IHC and FISH. Among 154 patients with complete IHC data we found 12 (8%) DLBCL without expression (DLBCL), 96 (62%) Single expressor (SE), 46 DE (30%). With a median follow up of 60 months, 5-year PFS rates were: DLBCL 90%, SE 60% and DE 43% respectively (fig 1) (HR 8.25 (95% CI: 1.12 -60.99) p 0.039); 5ys OS rates were 91%, 68% and 57% respectively (HR 5.72 (95% CI: 0.77 - 42.82) p 0.08).Applying the prognostic model (adjusted for IPI and age) defined in our previous pilot study we recorded 12/154 patients with low risk score, 61/154 with intermediate and 81/154 patients in high risk group. 5y-PFS rates were 91% vs 67% vs 45% (p=0.014) respectively (HR 1.74 (95% CI: 1.12 -2.69) p 0.014). Among 101 patients investigated by FISH we recorded 10 SHL (10%) and 8 DHL (8%). Clinical characteristics were superimposable among DLBCL, SHL and DHL with a prevalence of non GCB phenotype in DE group (56%). Among 101 patients fully investigated for FISH and IHC, 38 patients had MYC overexpression by IHC; 11 of them had also a MYC translocation. We found 3 cases with MYC rearrangement without protein overexpression. With a median follow up of 60 months PFS in DLBCL, SHL and DHL was 65%, 58% and 25% respectively (fig. 2); 5 ys OS was 70%, 77% and 25% respectively. The worse prognosis of DHL was statistically significant with an HR of 3.3 (95% CI: 1.37- 7.94, p 0.008) in terms of PFS and 3.9 (95% CI:1.59- 9.52 p 0.003) in terms of OS.Conclusion: Our data confirmed that our IHC prognostic score based on MYC, BCL2 and BCL6 expression, is a simple, reproducible and valid prognostic assessment that identify three groups with a different outcome in a large cohort of DLBCL. Moreover these data confirm intermediate prognosis for patients with DE lymphoma and poor prognosis of DHL treated with conventional chemoimmunotherapy. [Display omitted] [Display omitted] DisclosuresChiappella:Roche: Speakers Bureau; Celgene: Speakers Bureau; Janssen-Cilag: Speakers Bureau; Teva: Speakers Bureau; Pfizer: Speakers Bureau; Amgen: Speakers Bureau. Cavallo:Celgene: Honoraria; Onyx: Honoraria; Janssen-Cilag: Honoraria. Vitolo:Celgene: Honoraria; Gilead: Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria; Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

T Cells Bearing Anti-CD19- and/or Anti-CD38-Chimeric Antigen Receptors Effectively Abrogate Primary Double-Hit Lymphoma Cells

Patients with B-cell lymphomas bearing MYC translocation combined with an additional translocation involving other genes, such as BCL2, BCL3, or BCL6, whose category is defined as double-hit lymphoma (DHL), have dismal prognosis, because these cells are refractory to conventional immunochemotherapy. Recent studies have expanded the concept of a such disease entity to include double-expressing lymphomas (DEL) that co-overexpress MYC protein with those proteins, which have also poor prognosis. An adoptive T-cell immunotherapy with a chimeric antigen receptor (CAR) is clinically shown to have a powerful cytotoxicity in refractory neoplasias. Especially, several results showed that T cells transduced with an anti-CD19-CAR have successfully worked well in patients with refractory acute B-cell lymphoblastic leukemia and B-cell lymphoma as well as chronic B-cell lymphocytic leukemia. Thus, CAR T-cell therapy is a clinically promising tool for various refractory hematopoietic disorders. Accordingly, we examined whether anti-CD19- and/or anti-CD38-CAR-T cells, both of which we previously developed, could abrogate DHL cells. Here, we revealed that the remarkable cytotoxicity of anti-CD19- and/or anti-CD38-CAR T cells against DHL cells from patients. Firstly, DHL cell line cells (KPU-H1, a generous gift form Dr. Junya Kuroda, Kyoto Prefectural University of Medicine) were co-cultured with anti-CD19- and/or anti-CD38-CAR T cells at an effector (E) target (T) ratio of 1: 2 for three days. Cells harvested and stained with anti-CD19 and/or anti-CD38 antibody-APC or -PE were subjected to flow cytometry. Flow cytometric analysis showed that anti-CD19- or anti-CD38-CAR T cells almost killed KPU-H1 cells, respectively (specific cytotoxicity was >90%). Intriguingly, T cells expressing anti-CD19-CAR exerted a collaborative cytotoxicity against KPU-H1 cells with anti-CD38-CAR T cells in vitro. CD38-specific T cells were co-cultured with cytogenetic DHL (n=3) or DEL (n=2) cells from five patients carrying a poor prognosis for 3 days. We examined whether T cells retrovirally transduced with anti-CD19- and/or anti-CD38-CAR vector could show cytotoxicity against primary DHL cells obtained from patients. Anti-CD19 and/or ant-CD38-CAR T cells were co-cultured with primary DHL cells at an E: T ratio of 1: 2 for 3 days. Interestingly, anti-CD19 and anti-CD38-CAR T cells completely abolished these DHL cells from patients, respectively. Additionally, anti-CD19- and anti-38-CAR T cells were synergistically effective to eliminate DHL cells. These results showed that DHL cells, which are refractory or resistant to existing chemotherapeutic agents, can be efficiently abrogated by a clinical use of T cells with anti-CD19- and/or anti-CD38-CAR. These results might warrant adoptive immunotherapy with autologous T cells transduced with anti-CD19 and anti-CD38-CAR for patients with refractory DHL. DisclosuresNo relevant conflicts of interest to declare.