Obinutuzumab versus Rituximab in transplant-eligible Mantle cell lymphoma patients.

Obinutuzumab (O) and Rituximab (R) are two CD antibodies that have never been compared in a prospective randomised trial in mantle cell lymphoma (MCL). Herein, we report the long-term outcome of the LYMA-101 (NCT02896582) trial, in which newly diagnosed MCL patients were treated with chemotherapy plus O before transplantation followed by O maintenance (O group). We then compared these patients to those treated with the same treatment design with Rituximab instead of O (R group) (NCT00921414). A propensity score matching (PSM) was used to compare the two populations (O vs R groups) in terms of MRD at the end of induction (EOI), PFS and OS. In LYMA-101, the estimated five-year PFS and OS since inclusion (n=85) were 83.4% (95%CI: 73.5-89.8%) and 86.9% (95%CI: 77.6-92.5%), respectively. At EOI, patients treated in the O group had more frequent bone marrow MRD negativity than those treated in the R group (83.1% vs 63.4% Chi2 p=0.007). The PSM resulted in 2 sets of 82 patients with comparable characteristics at inclusion. From treatment initiation, the O group had a longer estimated five-year PFS (p=0.029; 82.8% versus 66.6%, HR 1.99, IC95 1.05-3.76) and OS (p=0.039; 86.4% versus 71.4% (HR 2.08, IC95 1.01-4.16) compared to the R group. Causes of death were comparable in the 2 groups, the most common cause being lymphoma. Obinutuzumab prior to transplantation and in maintenance provides better disease control and enhances PFS and OS, as compared to Rituximab in transplant-eligible MCL patients.

Faster clinical decisions in B-cell acute lymphoblastic leukaemia: A single flow cytometric 12-colour tube improves diagnosis and minimal residual disease follow-up.

Assessing minimal residual disease (MRD) in B-cell precursor acute lymphoblastic leukaemia (BCP-ALL) is essential for adjusting therapeutic strategies and predicting relapse. Quantitative polymerase chain reaction (qPCR) is the gold standard for MRD. Alternatively, flow cytometry is a quicker and cost-effective method that typically uses leukaemia-associated immunophenotype (LAIP) or different-from-normal (DFN) approaches for MRD assessment. This study describes an optimized 12-colour flow cytometry antibody panel designed for BCP-ALL diagnosis and MRD monitoring in a single tube. This method robustly differentiated hematogones and BCP-ALL cells using two specific markers: CD43 and CD81. These and other markers (e.g. CD73, CD66c and CD49f) enhanced the specificity of BCP-ALL cell detection. This innovative approach, based on a dual DFN/LAIP strategy with a principal component analysis method, can be used for all patients and enables MRD analysis even in the absence of a diagnostic sample. The robustness of our method for MRD monitoring was confirmed by the strong correlation (r = 0.87) with the qPCR results. Moreover, it simplifies and accelerates the preanalytical process through the use of a stain/lysis/wash method within a single tube (<2 h). Our flow cytometry-based methodology improves the BCP-ALL diagnosis efficiency and MRD management, offering a complementary method with considerable benefits for clinical laboratories.

Humoral immune depression following autologous stem cell transplantation is a marker of prolonged response duration in patients with mantle cell lymphoma.

Rituximab maintenance (RM) after autologous stem cell transplantation (ASCT) is standard-of-care for young patients with mantle cell lymphoma (MCL). RM may enhance post-transplantation immune depression and risk of infections. We compared infection incidence and immune consequences of RM versus observation in transplanted MCL patients. All randomized patients included in the LyMa trial were eligible. The following parameters were collected prospectively: occurrence of fever, infection, hospitalization, neutropenia, hypogammaglobulinemia, CD4 lymphopenia and γ globulin (Ig) substitution. The post-ASCT period was divided into four periods in order to assess the possible effects of RM or ASCT on immune status. Each arm included 120 patients. Concerning infection incidence and all biological parameters, there was no difference between the two arms during the first year post ASCT. After this period, RM patients were more exposed to fever (P=0.03), infections (P=0.001), hypogammaglobulinemia (P=0.0001) and Ig substitution (P<0.0001). Incidences of hospitalization, neutropenia and CD4 lymphopenia were not different between the two arms. The number of rituximab injections was correlated with infections and hypogammaglobulinemia, P<0.0001 and P=0.001; but was not correlated with neutropenia and CD4 lymphopenia. Ig substitution did not modify infection incidence. Patients who presented hypogammaglobulinemia <6 g/L or <4 g/L had longer 3-years progression-free survival (PFS), this applies to RM patients (P=0.012 and P=0.03) and to the global cohort (P=0.008 and P=0.003). Hypogammaglobulinemia did not influence overall survival. Occurrence of infectious event, neutropenia and CD4 lymphopenia did neither influence PFS nor overall survival. Post-ASCT RM in MCL patients causes sustained hypogammaglobulinemia, which is independently correlated with improved PFS.

Integrative analysis of a phase 2 trial combining lenalidomide with CHOP in angioimmunoblastic T-cell lymphoma.

Angioimmunoblastic T-cell lymphoma (AITL) is a frequent T-cell lymphoma in the elderly population that has a poor prognosis when treated with cyclophosphamide, doxorubicin, vincristine, and prednisone  (CHOP) therapy. Lenalidomide, which has been safely combined with CHOP to treat B-cell lymphoma, has shown efficacy as a single agent in AITL treatment. We performed a multicentric phase 2 trial combining 25 mg lenalidomide daily for 14 days per cycle with 8 cycles of CHOP21 in previously untreated AITL patients aged 60 to 80 years. The primary objective was the complete metabolic response (CMR) rate at the end of treatment. Seventy-eight of the 80 patients enrolled were included in the efficacy and safety analysis. CMR was achieved in 32 (41%; 95% confidence interval [CI], 30%-52.7%) patients, which was below the prespecified CMR rate of 55% defined as success in the study. The 2-year progression-free survival (PFS) was 42.1% (95% CI, 30.9%-52.8%), and the 2-year overall survival was 59.2% (95% CI, 47.3%-69.3%). The most common toxicities were hematologic and led to treatment discontinuation in 15% of patients. This large prospective and uniform series of AITL treatment data was used to perform an integrative analysis of clinical, pathologic, biologic, and molecular data. TET2, RHOA, DNMT3A, and IDH2 mutations were present in 78%, 54%, 32%, and 22% of patients, respectively. IDH2 mutations were associated with distinct pathologic and clinical features and DNMT3A was associated with shorter PFS. In conclusion, the combination of lenalidomide and CHOP did not improve the CMR in AITL patients. This trial clarified the clinical impact of recurrent mutations in AITL. This trial was registered at www.clincialtrials.gov as #NCT01553786.

Treatment and outcome of Philadelphia chromosome-positive acute lymphoblastic leukemia in adults after relapse.

INTRODUCTION: Despite the significant progress that has been made over the last years in the front-line treatment of Philadelphia (Ph) chromosome-positive acute lymphoblastic leukemia (ALL), relapses are frequent and their treatment remains a challenge, especially among patients with resistant BCR-ABL1 mutations. AREAS COVERED: This manuscript reviews available data for the treatment of adult patients with relapsed/refractory Ph-positive ALL, with a focus on the role of tyrosine kinase inhibitors (TKIs), monoclonal antibodies, and immunotherapy. EXPERT OPINION: Although a majority of patients with first relapsed Ph-positive ALL respond to subsequent salvage chemotherapy plus TKI combination, their outcomes remain poor. The main predictor of survival is the achievement of major molecular response anytime during the morphological response. More treatment strategies to improve survival are under investigation. Monoclonal antibodies and bispecific antibody constructs hold considerable promise in improving the outcomes of patients with relapsed ALL including Ph-positive ALL.

Molecular response after obinutuzumab plus high-dose cytarabine induction for transplant-eligible patients with untreated mantle cell lymphoma (LyMa-101): a phase 2 trial of the LYSA group.

BACKGROUND: Obinutuzumab monotherapy has shown promising efficacy in mantle cell lymphoma. We aimed to investigate the activity of obinutuzumab plus DHAP (dexamethasone, high-dose cytarabine, and cisplatin), measured by minimal residual disease quantitative (q)PCR status in the bone marrow after four cycles. METHODS: LyMa-101 was a prospective, open-label, single-arm, phase 2 trial. Participants were enrolled from 28 hospitals in France. Newly diagnosed patients with mantle cell lymphoma (aged 18 to <66 years) who were eligible for autologous stem-cell transplantation received four cycles of obinutuzumab plus DHAP (obinutuzumab 1000 mg/m2 intravenously on days 1, 8, and 15 at cycle 1 and day 1 at cycles 2, 3, and 4; dexamethasone 40 mg intravenously on days 1-4, cytarabine 2 g/m2 intravenously every 12 h on day 1, and according to local investigator, cisplatin 100 mg/m2 by continuous infusion over 24 h on day 1 or carboplatin area under the curve 5 or oxaliplatin 130 mg/m2) every 21 days before transplantation, and 3 years of obinutuzumab (1000 mg/m2 every 2 months) maintenance followed by minimal residual disease-based obinutuzumab on-demand maintenance. The primary outcome was minimal residual disease negativity in the bone marrow after four cycles of obinutuzumab plus DHAP at the end of induction, measured in the efficacy set (all minimal residual disease-informative [bone marrow or peripheral blood] patients who received at least one dose of obinutuzumab). Obinutuzumab plus DHAP was considered effective if bone marrow minimal residual disease negativity was 70% or more by intention to treat. The trial is closed to recruitment and registered with ClinicalTrials.gov, NCT02896582. FINDINGS: 86 patients were enrolled between Nov 29, 2016, and May 2, 2018. 81 patients completed induction, 73 underwent autologous stem-cell transplantation, and 69 started maintenance therapy. 55 (75%) of 73 patients in the efficacy set reached minimal residual disease negativity in bone marrow at end of induction. According to the protocol definition, 18 (25%) of 73 patients in the efficacy set were minimal residual disease-positive: 12 patients who were minimal residual disease-positive in the bone marrow, plus two patients who progressed during induction, and four patients who did not have minimal residual disease assessment. The most common grade 3-4 treatment-emergent adverse events were anaemia (grade 3, 26 [31%] of 85 patients; grade 4, three [4%] of 85 patients) and neutropenia (grade 3, 13 [15%] of 85 patients; grade 4, 32 [38%] of 85 patients). 58 serious adverse events occurred during the induction phase. There were no treatment-related deaths. INTERPRETATION: Obinutuzumab plus DHAP is a well tolerated regimen and has good activity for inducing minimal residual disease negativity in the bone marrow of transplant-eligible patients with mantle cell lymphoma. Obinutuzumab plus DHAP has potential activity as induction chemotherapy, with bone marrow minimal residual disease negativity potentially predicting long-term disease control. FUNDING: Roche SAS.

Thromboembolism prophylaxis in adult patients with acute lymphoblastic leukemia treated in the GRAALL-2005 study.

Patients undergoing treatment of acute lymphoblastic leukemia (ALL) are at risk for thrombosis, caused in part by the use of l-asparaginase (L-ASP). Antithrombin (AT) replacement has been suggested to prevent venous thromboembolism (VTE) and thus may increase exposure to ASP. We report herein the results of the prophylactic replacement strategy in the pediatrics-inspired prospective GRAALL-2005 study. Between 2006 and 2014, 784 adult patients with newly diagnosed Philadelphia- ALL were included. The incidence rate of VTE was 16%, with 69% of cases occurring during induction therapy. Most patients received AT supplementation (87%). After excluding patients who did not receive L-ASP or who developed thrombosis before L-ASP, AT supplementation did not have a significant impact on VTE. Administration of fibrinogen concentrates was associated with an increased risk of VTE, whereas transfusion of fresh frozen plasma had no effect. Heparin prophylaxis was associated with an increased risk of VTE. Prophylactic measures were not associated with an increased risk of grade 3 to 4 bleeding complications. The rate of VTE recurrence after L-ASP reintroduction was 3% (1 of 34). In ALL patients receiving L-ASP therapy, the use of fibrinogen concentrates may increase the risk of thrombosis and should be restricted to rare patients with hypofibrinogenemia-induced hemorrhage. VTE developed despite extensive AT supplementation, which suggests the need for additional prophylactic measures. Although this large descriptive study was not powered to demonstrate the efficacy of these prophylactic measures, it provides important insight to guide future trial design. This trial was registered at www.clinicaltrials.gov as #NCT00327678.

Human herpesvirus 6 infection after autologous stem cell transplantation: A multicenter prospective study in adult patients.

OBJECTIVES: to prospectively evaluate the incidence and the clinical relevance on hematopoietic reconstitution of HHV-6 infection in autologous hematopoietic stem cell transplantation (ASCT) recipients. METHODS: HHV-6 DNA load was measured in whole blood specimens once during the 7 days before stem cell re-infusion and once a week after transplantation until hematopoietic recovery. Active HHV-6 infection was defined by 2 consecutive positive DNA loads. RESULTS: from July 2012 to February 2015, 196 adult patients undergoing ASCT were enrolled. Twenty-two (11.2%) patients developed active HHV-6 infection with a cumulative incidence of 19% at 40 days after transplantation. The onset of active HHV-6 infection occurred with a median of 13 days after stem cell re-infusion. HHV-6 infection was associated with an increased frequency of non-infectious complications (OR = 5.05; 95%CI 1.78-14.32; P < 0.001). Moreover, the severity of these non-infectious complications was higher in recipients exhibiting HHV-6 infection (OR = 4.62; 95%CI 1.32-16.2; p < 0.01). Delayed neutrophils 10 (IQR: 8-14) vs 8 (IQR: 6-11) days and platelets recoveries 15 (IQR: 11.8-18.5) vs 8 (IQR: 4-14) days were observed in patients with active HHV-6 infection compared to non-infected ones. CONCLUSIONS: in this study, 11.2% ASCT recipients presented active HHV-6 infection associated with significantly delayed hematologic reconstitution.

Cerebral venous thrombosis in adult patients with acute lymphoblastic leukemia or lymphoblastic lymphoma during induction chemotherapy with l-asparaginase: The GRAALL experience.

Central nervous system (CNS) thrombotic events are a well-known complication of acute lymphoblastic leukemia (ALL) induction therapy, especially with treatments including l-asparaginase (l-ASP). Data on risk factors and clinical evolution is still lacking in adult patients. We report on the clinical evolution of 22 CNS venous thrombosis cases occurring in 708 adults treated for ALL or lymphoblastic lymphoma (LL) with the Group for Research on Adult Acute Lymphoblastic Leukemia (GRAALL)-induction protocol, which included eight L-ASP (6,000 IU/m(2) ) infusions. The prevalence of CNS thrombosis was 3.1%. CNS thrombosis occurred after a median of 18 days (range: 11-31) when patients had received a median of three l-ASP injections (range: 2-7). Patients with CNS thrombosis exhibited a median antithrombin (AT) nadir of 47.5% (range: 36-67%) at Day 17 (range: D3-D28), and 95% of them exhibited AT levels lower than 60%. There were no evident increase in hereditary thrombotic risk factors prevalence, and thrombosis occurred despite heparin prophylaxis which was performed in 90% of patients. Acquired AT deficiency was frequently detected in patients with l-ASP-based therapy, and patients with CNS thrombosis received AT prophylaxis (45%) less frequently than patients without CNS thrombosis (83%), P = 0.0002). CNS thrombosis was lethal in 5% of patients, while 20% had persistent sequelae. One patient received all planned l-ASP infusions without recurrence of CNS thrombotic whereas l-ASP injections were discontinued in 20 patients during the management of thrombosis without a significant impact on overall survival (P = 0.4).

Autologous stem cell transplantation in mantle cell lymphoma: a report from the SFGM-TC.

Autologous stem cell transplantation (ASCT) is considered as an attractive treatment option for young mantle cell lymphoma (MCL) patients. This retrospective SFGM-TC study analyzed the outcome of 500 MCL patients treated with ASCT and investigated parameters that may modify the outcome of patients who proceeded to ASCT upfront (n=396). For all patients, median age at ASCT was 56 years (range, 26-71). Median follow-up was 34 months. Three-year progression free survival (PFS) and overall survival (OS)were 63.5% [95 % CI, 58.7­68.6 %] and 79.5 % [95 % CI, 75.3­83.4 %], respectively. Median time from ASCT to relapse was 22 months (range, 0­136 m). For patients transplanted upfront and in multivariate analysis, age (HR=2 [1.2­3.4], p=.01, and HR=2.3 [1.2­4.5], p=.01), disease status at time of ASCT (HR=1.7 [1.1­2.6], p=.01 and HR=1.8 [1.1­3.1], p=.03), and use of rituximab (HR=0.5 [0.3­0.8], p=.002 and HR=0.5 [0.3­0.9], p=.01) were statistically predictive for both PFS and OS. Also, first line treatment including anthracycline and high-dose cytarabine followed by ASCT conditioned with TAM improved PFS. To conclude, this study suggests that ASCT in MCL can provide a high response rate but may not be sufficient to cure MCL even when ASCT is performed upfront, highlighting the need for innovative approaches before ASCT, aiming to increase complete response rate, and after ASCT, to maintain response.

Autologous stem cell transplantation in mantle cell lymphoma: a report from the SFGM-TC.

Autologous stem cell transplantation (ASCT) is considered as an attractive treatment option for young mantle cell lymphoma (MCL) patients. This retrospective SFGM-TC study analyzed the outcome of 500 MCL patients treated with ASCT and investigated parameters that may modify the outcome of patients who proceeded to ASCT upfront (n = 396). For all patients, median age at ASCT was 56 years (range, 26-71). Median follow-up was 34 months. Three-year progression free survival (PFS) and overall survival (OS) were 63.5 % [95 % CI, 58.7-68.6 %] and 79.5 % [95 % CI, 75.3-83.4 %], respectively. Median time from ASCT to relapse was 22 months (range, 0-136 m). For patients transplanted upfront and in multivariate analysis, age (HR = 2 [1.2-3.4], p = .01, and HR = 2.3 [1.2-4.5], p = .01), disease status at time of ASCT (HR = 1.7 [1.1-2.6], p = .01 and HR = 1.8 [1.1-3.1], p = .03), and use of rituximab (HR = 0.5 [0.3-0.8], p = .002 and HR = 0.5 [0.3-0.9], p = .01) were statistically predictive for both PFS and OS. Also, first line treatment including anthracycline and high-dose cytarabine followed by ASCT conditioned with TAM improved PFS. To conclude, this study suggests that ASCT in MCL can provide a high response rate but may not be sufficient to cure MCL even when ASCT is performed upfront, highlighting the need for innovative approaches before ASCT, aiming to increase complete response rate, and after ASCT, to maintain response.

[Ruxolitinib prescription in myelofibrosis]. / Rationnel et modalités de prescription du ruxolitinib dans les myélofibroses.

Ruxolitinib is a JAK/STAT inhibitor, which has demonstrated clinical benefits in patients with intermediate-2 and high-risk myelofibrosis. Moreover, first results of recent clinical trials show a trend to better overall survival with ruxolitinib, which allows to hope that we will soon be able to change the natural evolution of this poor outcome disease. With such results, ruxolitinib quickly obtained the Food and Drug Administration (FDA) approval in the United States of America. In France, ruxolitinib is now available, allowing its administration to symptomatic myelofibrosis patients.

Allogeneic hematopoietic stem cell transplantation allows long-term complete remission and curability in high-risk Waldenström's macroglobulinemia. Results of a retrospective analysis of the Société Française de Greffe de Moelle et de Thérapie Cellulaire.

BACKGROUND: Patients with poor-risk Waldenström's macroglobulinemia have suboptimal response and early post-treatment relapse with conventional therapies. Hence, new therapeutic approaches such as allogeneic stem cell transplantation should be evaluated in these patients. DESIGN AND METHODS: We examined the long-term outcome of allogeneic stem cell transplantation in Waldenström's macroglobulinemia by studying the records of 24 patients reported in the SFGM-TC database and one transplanted in the bone marrow unit in Hamburg. RESULTS: Median age at the time of transplant was 48 years (range, 24-64). The patients had previously received a median of 3 lines of therapy (range, 1-6) and 44% of them had refractory disease at time of transplant. Allogeneic stem cell transplantation after myeloablative (n=12) or reduced-intensity (n=13) conditioning yielded an overall response rate of 92% and immunofixation-negative complete remission in 50% of evaluable patients. With a median follow-up of 64 months among survivors (range, 11-149 months), 5-year overall survival and progression-free survival rates were respectively, 67% (95% CI: 46-81) and 58% (95% CI: 38-75). The 5-year estimated risk of progression was 25% (95% CI: 10-36%), with only one relapse among the 12 patients who entered complete remission, versus 5 in the 12 patients who did not. Only one of the 6 relapses occurred more than three years post-transplant. CONCLUSIONS: Allogeneic stem cell transplantation yields a high rate of complete remissions and is potentially curative in poor-risk Waldenström's macroglobulinemia.