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EBMT 2019 – Preliminary in-human evaluation of a CD19/CD22 dual CAR-T construct for B-NHL

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On Wednesday 27 March 2019, Oral Session 20 (OS20) took place at the 45th Annual Meeting of the European Society of Blood and Marrow Transplantation (EBMT), Frankfurt, DE. During that session, Abstract OS20-2 was presented by Yongxian Hu from Zhejiang University, Hangzhou, CN. In an attempt to improve the response rates and lower the toxicity with chimeric antigen receptor T-cell (CAR-T) therapy in B-cell non-Hodgkin lymphoma (B-NHL), the preliminary clinical evaluation of a dual targeting CD19 and CD22 CAR-T construct was presented here. The primary aim of this study was to assess the safety of the dual CAR-T construct. The investigators also compared the efficacy of the dual CAR-T construct to a single-targeting CD19 CAR-T construct. The cytotoxicity of the dual CAR-T construct was assessed in vitro and in mouse models in vivo prior to this in-human preliminary trial. Study design & baseline characteristics N = 20 heavily pre-treated patients with B-cell lymphoma infused with either: CD19/CD22 dual CAR-T construct: n = 11 CD19 CAR-T construct: n = 9 Dual CAR-T construct structure: CAR with antigen recognition domains of both CD19 (anti-CD19 ScFv) and CD20 (anti-CD22 ScFv) 4-1BB costimulatory domain CD3z signaling domain Lymphodepletion: Fludarabine (Flu): 30 mg/m2 1−3 days prior to CAR-T infusion Cytoxan (CTX): 500 mg/m2 2−3 days prior to CAR-T infusion Peripheral blood mononuclear cell (PBMC) collection for CAR-T engineering occurred approximately 11 days prior to infusion Computed tomography (CT) or positron emission tomography (PET)-CT was used for disease assessment every 30 days following CAR-T infusion No statistically significant differences in baseline characteristics between the single CD19 CART and the dual CD19/CD22 CAR-T groups: Characteristic CD19 single CAR-T group (N = 9) Dual CD19/CD22 CAR-T group (N = 11) Median age (range) 47.8 (27−65) years 45.6 (25−65) years Male patients 55.6% 54.5% Disease type     DLBCL 88.9% 81. 8% Burkitt lymphoma 0% 9.1% SLL/CLL 11.1% 0% Lymphoblastic lymphoma 0% 9.1% Prior lines of treatment     2−3 22.2% 27.2% 4−5 33.3% 36.3% > 5 44.4% 36.3% Disease stage     I−II 22.2% 18.2% III−IV 77.8% 81.8% Refractory status at study entry     Primary refractory 44.4% 36.4% Refractory to ≥ 2 lines 55.6% 63.6% Relapse after auto-SCT 22.2% 18.2% Key results Average CAR-T cell infusion dose (range): CD19/CD22 dual CAR-T group: 5.2 x 106/kg (1.1−10 x 106/kg) CD19 CAR-T group: 5.8 x 106/kg (1.6−10 x 106/kg) Comparison: P > 0.05 Average peak CAR-T cell expansion after infusion (10.1 ± 3.32 and 9.2 ± 2.25 days): CD19/CD22 dual CAR-T group: 68.7% (6.9−78.6% in CD3+ T cells) CD19 CAR-T group: 36.8% (3.6−60.9% in CD3+ T cells) Grade 3−5 cytokine release syndrome (CRS): CD19/CD22 dual CAR-T group: 10% CD19 CAR-T group: 33% Neurotoxicity occurred in one patient infused with the dual CD19/CD22 CAR-T construct No patient died due to CAR-T-related adverse events Overall response rates (ORR): CD19/CD22 dual CAR-T group: 90% CD19 CAR-T group: 75% CR rates: CD19/CD22 dual CAR-T group: 70% CD19 CAR-T group: 50% Overall survival rates at Day 90 post infusion: CD19/CD22 dual CAR-T group: 90.0 ± 9.5% CD19 CAR-T group: 55.6% ± 16.6% The OS rates remain stable at Day 250 post infusion Conclusions Promising preliminary in-human results for the dual CD19/CD22 CAR-T construct with B-NHL patients achieving higher CR and ORR, with low severe CRS rates, compared to the standard CD19 single CAR-T construct. More in-human studies and of a larger scale with extended observation periods are needed to further validate these preliminary results.   Source:  Hu Y. et al. Novel CD19/CD22 dual targeting CAR-T cells have prominent anti-tumor activity against relapsed/refractory B-cell lymphoma. Abstract OS20-2: 45th EBMT Annual Meeting, Frankfurt, Germany

Hočkinov limfom, Hronična limfocitna leukemija, Nehočkinski limfom

BMT Societies Issue Recommendations on Posttransplant Maintenance in HL/NHL

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The American Society for Blood and Marrow Transplantation (ASBMT), Center for International Blood and Marrow Transplant Research (CIBMTR), and European Society for Blood and Marrow Transplantation (EBMT) have released consensus recommendations on the use of maintenance therapies after autologous transplantation for patients with Hodgkin (HL) or non-Hodgkin lymphoma (NHL).1 Use of maintenance therapy as a therapeutic strategy in posttransplant patients with HL and NHL is increasing in frequency, according to panel member Mehdi Hamadani, MD, of CIBMTR and Medical College of Wisconsin in Milwaukee. This joint panel was tasked with reviewing available data from clinical trials and summarizing evidence about the contemporary use of maintenance therapy in these patients to help guide therapy in a rapidly advancing field. “Clinical trials evaluating maintenance treatments in lymphoma patients undergoing autologous transplantation cannot keep pace with the speed of drug development; which effectively means, by the time these trials are published the results are no longer applicable to modern patient population[s],” Dr Hamadani told Cancer Therapy Advisor. For example, the large AETHERA clinical trial of brentuximab vedotin consolidation after autologous transplant in high-risk patients with HL showed that patients derived a disease-free survival benefit from that therapy.2 However, 1 of the main eligibility criteria for that trial was that patients could not have had prior exposure to brentuximab vedotin. “The problem is that in 2018, brentuximab got approval for frontline therapy in HL and is also now commonly used in second-line therapy,” Dr Hamadani said. “The population that the AETHERA trial used is becoming less relevant in the real world and we have no trial data available on how to handle those patients.” To issue its recommendations, the panel used the RAND-modified Delphi method, which generates consensus statements where at least 75% of a panel vote in favor of a recommendation. The panel issued 22 consensus recommendations. Several grade A recommendations, indicating good research-based evidence to support the recommendation, are discussed below. The first consensus statement for HL was use of post-autologous hematopoietic stem cell transplantation (HCT) consolidation/maintenance with brentuximab vedotin for 16 cycles in brentuximab vedotin-naive classic HL with at least 1 or more high-risk features as defined by the AETHERA study. A second grade A recommendation was rituximab maintenance therapy in patients with mantle cell lymphoma undergoing auto-HCT after first-line therapy. In these patients, a randomized trial has shown improved progression-free and overall survival with this maintenance regimen compared with observation alone.3 Rituximab maintenance was also recommended in rituximab-naive patients with follicular lymphoma. This recommendation was based primarily on data from the EBMT study,4 which showed that rituximab maintenance after transplant was safe and significantly prolonged progression-free (but not overall) survival. “However, the panel acknowledges that rituximab-naive status at the time of auto-HCT in patients with FL in the current era would be rare, thus limiting the clinical impact of this statement,” the panelists wrote. According to Henry Chi Hang Fung, MD, FACP, director of the Fox Chase-Temple University Hospital Bone Marrow Transplant Program in Philadelphia, Pennsylvania, these recommendations do not necessarily offer up any new data, but instead represent the opinion of bone marrow transplant experts. “These are all based on studies that have already been published, some quite some time ago,” Dr Fung noted. “Because these are from multiple transplant societies, the target audience is definitely transplant doctors, who are highly specialized.” “It is good to get everyone on the same page with recommendations like these, where there is consensus, and of equal importance are the areas where there is no consensus, like in DLBCL [diffuse large B-cell lymphoma],” Dr Fung said. Dr Fung was referring to a final grade A consensus statement recommending against post-transplant maintenance therapy in patients with DLBCL. According to Dr Hamadani, in patients with DLBCL, some clinicians may give maintenance therapy off-label, but there is a lack of evidence base for this. “Maintenance therapies, even with older drugs like rituximab, are not free from side effects and are expensive,” Dr Hamadani said. “We reviewed all trials looking at rituximab after transplant in DLBCL and the studies were negative. They don’t show any survival benefit.” Ongoing clinical trials looking at target therapies in DLBCL may change this recommendation in the future, but clinical trial data are not yet mature.   Source: www.cancertherapyadvisor.com

Hronična limfocitna leukemija

Fixed Duration of Venetoclax-Rituximab in Relapsed/Refractory Chronic Lymphocytic Leukemia Eradicates Minimal Residual Disease and Prolongs Survival: Post-Treatment Follow-Up of the MURANO Phase III Study

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PURPOSE The MURANO study demonstrated significant progression-free survival (PFS) benefit for fixedduration venetoclax-rituximab compared with bendamustine-rituximab in relapsed/refractory chronic lymphocytic leukemia. With all patients off treatment, we report minimal residual disease (MRD) kinetics and updated outcomes. METHODS Patients were randomly assigned to 2 years of venetoclax plus rituximab during the first six cycles, or six cycles of bendamustine-rituximab. Primary end point was PFS. Safety and peripheral blood (PB) MRD status—at cycle 4, 2 to 3 months after end of combination therapy (EOCT), and every 3 to 6 months thereafter—were secondary end points. RESULTS Of 194 patients, 174 (90%) completed the venetoclax-rituximab phase and 130 (67%) completed 2 years of venetoclax. With a median follow-up of 36 months, PFS and overall survival remain superior to bendamustine-rituximab (hazard ratio, 0.16 [95% CI, 0.12 to 0.23]; and hazard ratio, 0.50 [95% CI, 0.30 to 0.85], respectively). Patients who received venetoclax-rituximab achieved a higher rate of PB undetectable MRD (uMRD; less than 1024) at EOCT (62% v 13%) with superiority sustained through month 24 (end of therapy). Overall, uMRD status at EOCT predicted longer PFS. Among those with detectable MRD, low-level MRD (1024 to less than 1022) predicted improved PFS compared with high-level MRD (1022 or greater). At a median of 9.9 months (range, 1.4 to 22.5 months) after completing fixed-duration venetoclax-rituximab, overall only 12% (16 of 130) of patients developed disease progression (11 high-level MRD, three low-level MRD). At the end of therapy, 70% and 98% of patients with uMRD remained in uMRD and without disease progression, respectively. CONCLUSION With all patients having finished treatment, continued benefit was observed for venetoclaxrituximab compared with bendamustine-rituximab. uMRD rates were durable and predicted longer PFS, which establishes the impact of PB MRD on the benefit of fixed-duration, venetoclax-containing treatment. Low conversion to detectable MRD and sustained PFS after completion of 2 years of venetoclax-rituximab demonstrate the feasibility of this regimen. Ceo tekst pročitajte ovde. Source: Journal of Clinical Oncology, Volume 37, Issue 4

Nehočkinski limfom

Next-generation therapy for follicular lymphoma

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Morschhauser et al report the safety and efficacy of lenalidomide in combination with obinutuzumab and establish the recommended phase 2 dose (RP2D).1 Rituximab in combination with lenalidomide (R2) has favorable efficacy and toxicity in relapsed and untreated follicular lymphoma (FL) and is now entering the treatment landscape of FL.2⇓–4 Obinutuzumab, a glycoengineered type II anti-CD20 monoclonal antibody with enhanced antibody-dependent cellular cytotoxicity (ADCC), may be an attractive partner to lenalidomide that can exert immunomodulatory effects via natural killer (NK) and T cells for the treatment of relapsed or refractory (R/R) FL. The question is whether the potentially enhanced ADCC activity of obinutuzumab will translate into enhanced synergism with lenalidomide and result in an improved next-generation R2. Outcomes for FL have improved over the past few decades, and many patients diagnosed in the modern era can anticipate a normal life expectancy.5 However, FL remains a disease associated with continued risk for relapse. Currently, the greatest unmet need in new drug development is to alter the natural history among those who experience early relapse (<24 months) following frontline chemoimmunotherapy.6 Identifying effective, well-tolerated therapies that result in meaningful remission duration without negatively impacting quality of life remains fundamental to clinical research in this field. Providing insight into treatment selection and sequencing of therapy is also desirable given the list of therapeutic approaches is nearly as long as the natural history of this disease. With those ground rules, how do we interpret/incorporate the findings of this phase 1b dose-escalation study into the ever-expanding treatment landscape of FL? Obinutuzumab is US Food and Drug Administration (FDA) approved for R/R patients with FL based on the GADOLIN study, which compared obinutuzumab in combination with bendamustine followed by obinutuzumab maintenance to bendamustine alone in patients with rituximab-refractory indolent lymphoma. With a median progression-free survival (PFS) of 25.8 months vs 14.1 months, the obinutuzumab-containing arm was superior to chemotherapy alone.7 Neutropenia, an adverse event associated with obinutuzumab was one of the most common grade 3 or higher adverse events observed at 27.5%. GADOLIN provides a snapshot of the efficacy and safety of obinutuzumab in combination with bendamustine in rituximab-refractory. Though superior to chemotherapy alone, it is less clear whether obinutuzumab is superior to rituximab in this setting based on the study design. Targeted therapies have been promising in R/R FL. Idelalisib, a phosphatidylinositol 3-kinase δ (PI3Kδ) inhibitor, and copanlisib, a pan-PI3K inhibitor with predominant activity against α and δ isoforms, are both approved for the treatment of R/R FL patients who have failed at least 2 prior lines of therapy. Idelalisib was associated with a 57% objective response rate (ORR) and 11-month PFS among patients refractory to rituximab and an alkylating agent.8 Copanlisib was associated with an ORR of 59% and median PFS of 11 months.9 Though similar in efficacy, the safety profile of these 2 PI3K inhibitors is different, with less gastrointestinal toxicity and higher rates of hyperglycemia and hypertension associated with copanlisib. The toxicity profile of PI3K inhibitors (ie, pneumonitis, colitis, transaminitis, rash, and infection) has likely impacted the uptake of these drugs despite their efficacy profile in poor-risk patients. R2 is under active exploration for relapsed indolent lymphoma. The phase 3 AUGMENT study met its primary end point of superior PFS of R2 compared with rituximab monotherapy in relapsed follicular and marginal zone lymphoma. The details are forthcoming but will likely lead to FDA approval of R2 for R/R FL. The control arm is likely to impact the excitement surrounding this study, but it is important nonetheless to allow exploration of the impact of combination over R monotherapy. The MAGNIFY study is examining 12 cycles of R2 followed by R2maintenance vs rituximab maintenance in indolent and mantle cell lymphoma. Preliminary efficacy has been reported for the FL subgroup including cohorts of early-relapse or double-refractory (CD20 monoclonal antibody and alkylating agent) patients.4 R2 was associated with an ORR of 66% and 1-year PFS estimates of 70% for R/R FL. The early-relapse and double-refractory cohorts had less favorable but meaningful outcomes, with ORRs of 47% and 45% and 1-year PFS estimates of 49% and 65%, respectively. Neutropenia was one of the most common grade 3 or 4 adverse events at 29%. R2 appears to be an effective, manageable strategy for R/R FL. It remains unknown whether the greatest uptake will be in third-line or earlier lines of therapy. This leads us to the current study: obinutuzumab in combination with lenalidomide in R/R FL. This dose-escalation study established the RP2D of lenalidomide at 20 mg in combination with a fixed dose of obinutuzumab (1000 mg). Only 19 patients were evaluable for safety and efficacy and had favorable features. Mean age was 61.5 years, and most had excellent performance status (80% Eastern Cooperative Oncology Group 0), responded to prior rituximab (60%) or prior lymphoma therapy (80%), and had nonbulky disease (75% with lymph nodes <5 cm in size). With a median follow-up of 38.1 months, the 3-year PFS was 52% and ORR was 63%. The most common grade 3 or higher adverse event was neutropenia at 26%. Therefore, the combination appears effective and manageable, with no new safety signals. Commendable is the schedule (6 cycles of therapy). In an era where longer duration of therapy is commonly pursued, this is an important distinction for this study. Larger studies are necessary to understand whether this is a superior option to the available therapies, most importantly, its predecessor (R2). Where do we go from here? The importance of this study is establishing the RP2D for the potentially practice-changing trials. An important study, SWOG S1608, is a randomized phase 2 study exploring 3 arms for early-relapsing FL. One arm is obinutuzumab and lenalidomide. The other arms include a PI3Kδ inhibitor in combination with obinutuzumab and a chemoimmunotherapy arm. Understanding how to approach early-relapse FL is critical and will address the greatest unmet need. Obinutuzumab and lenalidomide have a critical role in one of the most important modern-day FL studies. Source: Blood 2018 132:1465-1467

Hočkinov limfom

A small change makes a big difference in Hodgkin lymphoma

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At first glance, it may not seem like much, a post hoc retrospective analysis of outcomes for patients with different levels of 18F-fluorodeoxyglucose (FDG) uptake on positron emission tomography (PET) scans after 2 cycles of chemotherapy for advanced-stage Hodgkin lymphoma (HL). But in fact, the results reported by Kobe et al1 in this issue of Blood have profound and beneficial consequences for 1 in 4 patients with advanced-stage HL who receive the intensive escalated-dose bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (eBEACOPP) regimen. Second only to the relatively recent arrival of novel, targeted agents for the treatment of relapsed and refractory disease,2 the introduction of PET represents the most important improvement in the management of HL in the last decade. Observational studies consistently found a very high prognostic value of early interim PET, suggesting that early PET could identify patients with excellent response who might benefit from a reduction of treatment intensity or duration without loss of efficacy.3,4 This would reduce the risk of overtreatment, which is an important challenge in a disease in which the vast majority of patients are young and curable and the cumulative late toxicities of treatment are substantial.5 PET could also identify poor responders who might benefit from intensification of treatment. Subsequently, a number of interventional studies have shown that early PET response–adapted therapy can reduce the overall treatment burden and improve progression-free survival in patients with advanced-stage HL who receive first-line treatment with the most commonly used regimen consisting of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD).6 Studies of early interim PET in cohorts treated with eBEACOPP have shown the same high negative predictive values as in cohorts treated with ABVD, but the positive predictive values have been lower. This is probably a consequence of the lower a priori risk of treatment failure in patients treated with this more intensive regimen. In the experimental arm of the German Hodgkin Study Group (GHSG) HD18 study, duration of treatment was reduced in patients who were PET negative after 2 cycles of eBEACOPP. The study showed noninferiority of abbreviated treatment of early PET-negative patients which, at the same time, resulted in a very clear reduction in the risk of acute treatment-related toxicity and the risk of secondary acute leukemias and myelodysplastic syndromes, the most feared complications related to eBEACOPP.7 After observing the important therapeutic consequences of interim PET, much effort was given to establishing uniform criteria for interpreting and reporting interim PET. These efforts led to agreement on a 5-point scale in which tumor FDG uptake is graded according to tracer uptake in different reference areas. This scale, named after the French seaside town Deauville where it was first established, was included in the international consensus guidelines for imaging and response assessment in lymphoma.8 Several studies have shown that the best cutoff between a negative and positive scan was between Deauville scores 3 and 4 (DS3 and DS4), which corresponds to the background uptake in the liver. Compared with a lower threshold, this results in a higher prognostic accuracy and at the same time a lower interobserver variation.9,10 Nevertheless, in the HD18 study, it was decided to include only DS1 and DS2 as negative results to reduce the potential risk of undertreatment. The report by Kobe et al is by far the largest study of early interim PET in advanced-stage HL. The results are very clear, showing no difference in progression-free and overall survival between patients with DS1-2 and DS3, respectively, when they were treated on the standard arm of the study with 6 cycles of eBEACOPP. Because ∼25% of all advanced-stage HL patients had FDG uptake with DS3 on early interim PET, the proportion of patients with a negative scan increased from 52% to 76% when the threshold between a negative and a positive result was lowered. The authors thoroughly stress that there is no direct evidence that we can reduce treatment of patients with DS3 on interim PET without impairing efficacy. However, the indications are so strong that the authors (as well as the GHSG) recommend restricting treatment to 4 cycles of eBEACOPP for patients with DS3 as well as for patients with DS1-2 on early interim PET. The GHSG has provided a wealth of evidence from 4 decades of randomized clinical studies. Most of their recommendations are based on strong evidence from those randomized clinical studies. The current change is an exception for which the group should be commended. The ongoing GHSG HD21 study for advanced-stage HL is a randomized study in which patients in the standard arm receive early PET response–adapted treatment based on the results of the HD18 study. So patients who are PET negative after 2 cycles of eBEACOPP receive a total of 4 treatment cycles and not 6 cycles, which was the previous standard. The definition of PET negative includes DS1, DS2, and DS3. In this way, the HD21 study hopefully will demonstrate that it is safe to include patients with a DS3 score in the PET-negative group and treat them accordingly. The study by Kobe et al represents an important improvement for patients with advanced-stage HL who are treated with eBEACOPP. At the same time, it is an inspiring example of how good and thorough retrospective analyses of clinical trials can sometimes provide data of the highest importance and clinical relevance. And in this case, provide new fuel for the long-lasting debate about ABVD vs eBEACOPP for first-line treatment of advanced-stage HL. Source: Blood 2018 132:2214-2215

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