Final results on effectiveness and safety of Ibrutinib in patients with chronic lymphocytic leukemia from the non-interventional FIRE study.

We conducted an observational study (FIRE) to understand the effectiveness and safety outcomes of ibrutinib in patients with chronic lymphocytic leukemia (CLL) in France, after a maximum follow-up of five years. Patients were included according to the French marketing authorization in 2016 (i.e. patients with relapsed or refractory CLL or to previously untreated CLL patients with deletion 17p and/or tumor protein p53 mutations unsuitable for chemoimmunotherapy) and could have initiated ibrutinib more than 30 days prior their enrolment in the study (i.e. retrospective patients) or between 30 days before and 14 days after their enrolment (i.e. prospective patients). The results showed that in the effectiveness population (N = 388), the median progression-free survival (PFS) was 53.1 (95% CI: 44.5-60.5) months for retrospective patients and 52.9 (95% CI: 40.3-60.6) months for prospective patients and no difference was shown between the PFS of patients who had at least one dose reduction versus the PFS of patients without dose reduction (p = 0.7971 for retrospective and p = 0.3163 for prospective patients). For both retrospective and prospective patients, the median overall survival was not reached. The most frequent treatment-emergent adverse event of interest was infections (57.6% retrospective; 71.4% prospective). A total of 14.6% of the retrospective patients and 22.4% of the prospective patients had an adverse event leading to death. Our findings on effectiveness were consistent with other studies and the fact that patients with dose reductions had similar PFS than patients without dose reduction is reassuring. No additional safety concerns than those already mentioned in previous studies could be noticed.Trial registration ClinicalTrials.gov, NCT03425591. Registered 1 February 2018 - Retrospectively registered.

Long-term analysis of the RiBVD phase II trial reveals the unfavorable impact of TP53 mutations and hypoalbuminemia in older adults with mantle cell lymphoma; for the LYSA group.

Between 2011 and 2012, a phase II trial evaluated the use of the RiBVD (Rituximab, Bendamustine, Velcade and Dexamethasone) combination as first-line treatment for mantle cell lymphoma (MCL) patients aged over 65. We have now re-examined the classic prognostic factors, adding an assessment of the mutation status of TP53. Patients (n=74; median age 73 years) were treated with the RiBVD combination. Median Progression Free Survival (mPFS) was 79 months, and median Overall Survival (mOS) was 111 months. TP53 mutation status was available for 54/74 (73%) patients. TP53 mutations (TP53mt) were found in 12 patients (22.2%). In multivariate analysis, among the prognostic factors (PF) evaluated, only TP53mt and an albumin level below 3.6 g/dL (Alb<3.6 g/dL) were independently associated with a shorter mPFS. A hazard ratio (HR) of 3.16 (1.3-9.9, p=0.014) was obtained for TP53mt versus TP53wt, and 3.6 (1.39-9.5, p=0.009) for Alb<3.6 g/dL vs Alb≥3.6 g/dL. In terms of mOS, multivariate analysis identified three PFs: TP53mt (HR: 5.9 (1.77-19.5, p=0.004)), Alb<3.6 g/dL (HR: 5.2 (1.46-18.5, p=0.011)), and ECOG=2 (HR: 3.7 (1.31-10.6, p=0.014)). Finally, a score combining TP53 status and albumin level distinguished three populations based on the presence of 0, 1, or 2 PF. For these populations, mPFS was 7.8 years, 28 months and 2.5 months, respectively. Our prolonged follow-up confirmed the efficacy of the RiBVD regimen, comparing it favorably to other regimens. TP53mt and hypoalbuminemia emerge as strong PF that can be easily integrated into prognostic scores for older adult patients with MCL.

Biallelic deletion of 1p32 defines ultra-high-risk myeloma, but monoallelic del(1p32) remains a strong prognostic factor.

Cytogenetic abnormalities (CAs) are known to be the preponderant prognostic factor in multiple myeloma. Our team has recently developed a prognostic score based on 6 CAs, with which del(1p32) appears to be the second worst abnormality after del(17p). This study aimed to confirm the adverse effect of 1p32 deletion in patients with newly diagnosed multiple myeloma (NDMM). Among 2551 patients with newly diagnosed multiple myeloma, 11% were harboring del(1p32). Their overall survival (OS) was significantly inferior compared with patients without del(1p32) (median OS: 49 months vs 124 months). Likewise, progression-free survival was significantly shorter. More importantly, biallelic del(1p32) conferred a dramatically poorer prognosis than a monoallelic del(1p32) (median OS: 25 months vs 60 months). As expected, the OS of patients with del(1p32) significantly decreased when this abnormality was associated with other high-risk CAs [del(17p), t(4;14), or gain(1q)]. In the multivariate analysis, del(1p32) appeared as a negative prognostic factor; after adjustment for age and treatment, the risk of progression was 1.3 times higher among patients harboring del(1p32), and the risk of death was 1.9 times higher. At the dawn of risk-adapted treatment strategies, we have confirmed the adverse effect of del(1p32) in multiple myeloma and the relevance of its assessment at diagnosis.

Reduced peripheral blood dendritic cell and monocyte subsets in MDS patients with systemic inflammatory or dysimmune diseases.

BACKGROUND: Systemic inflammatory and autoimmune diseases (SIADs) occur in 10-20% of patients with myelodysplastic syndrome (MDS). Recently identified VEXAS (Vacuoles, E1 enzyme, X-linked, Autoinflammatory, Somatic) syndrome, associated with somatic mutations in UBA1 (Ubiquitin-like modifier-activating enzyme 1), encompasses a range of severe inflammatory conditions along with hematological abnormalities, including MDS. The pathophysiological mechanisms underlying the association between MDS and SIADs remain largely unknown, especially the roles of different myeloid immune cell subsets. The aim of this study was to quantitatively evaluate peripheral blood myeloid immune cells (dendritic cells (DC) and monocytes) by flow cytometry in MDS patients with associated SIAD (n = 14, most often including relapsing polychondritis or neutrophilic dermatoses) and to compare their distribution in MDS patients without SIAD (n = 23) and healthy controls (n = 7). Most MDS and MDS/SIAD patients had low-risk MDS. Eight of 14 (57%) MDS/SIAD patients carried UBA1 somatic mutations, defining VEXAS syndrome.Compared with MDS patients, most DC and monocyte subsets were significantly decreased in MDS/SIAD patients, especially in MDS patients with VEXAS syndrome. Our study provides the first overview of the peripheral blood immune myeloid cell distribution in MDS patients with associated SIADs and raises several hypotheses: possible redistribution to inflammation sites, increased apoptosis, or impaired development in the bone marrow.

Venous thromboembolism during systemic inflammatory and autoimmune diseases associated with myelodysplastic syndromes, chronic myelomonocytic leukaemia and myelodysplastic/myeloproliferative neoplasms: a French multicentre retrospective case-control study.

OBJECTIVES: Myelodysplastic syndromes (MDS) and chronic myelomonocytic leukaemia (CMML) are associated with systemic inflammatory and autoimmune diseases (SIADs) in 10-30% of cases. The aims of this study were (i) to evaluate the prevalence of venous thromboembolism VTE in patients presenting with both MDS/CMML and SIADs, (ii) to describe risk factors associated with thrombosis, and (iii) to analyse the impact of VTE on overall survival and transformation to acute myeloid leukaemia in comparison to patients with MDS/CMML-associated SIADs without VTE. METHODS: This retrospective multicentre case-control study was conducted among patients with MDS/CMML and dysimmune disorders and featured in the French retrospective database of the French Network of Dysimmune Disorders Associated with Hemopathies (MINHEMON), diagnosed with MDS/CMML and dysimmune disorders. RESULTS: During a median follow-up of 16 months (5-48) VTE occurred in 35 patients (21.6 %) whereas 127 patients did not. Among those with VTE, 8 patients (22.9%) experienced two or more VTE. Common prothrombotic risk factors were not significantly different in patients with or without VTE. CMML was more frequent in patients without VTE (37 % vs. 14.3%, p=0.01), whereas myelodysplasic/myeloproliferative neoplasm (MDS/MPN) was higher in VTE patients (20 % vs. 5.5 %, p=0.01). In a multivariate analysis, only MDS/CMML progression at the time of VTE (odds ratio 28.82, 95 % CI (5.52-530.70) was significantly associated with VTE. When treated with an anticoagulation therapy, bleeding occurred in 19.4% of cases (6/31). Overall survival was not significantly different between patients with and without VTE (p=0.68). Leukaemia-free survival between groups was not significantly different (p=0.83). CONCLUSIONS: VTE is a common complication in MDS/CMML-associated SIADSs with an increased risk of bleeding when treated by anticoagulants. In the MDS/CMML subgroup, SIADS flares and MDS/CMML progression seem to be prothrombotic risk factors.

Primary plasma cell leukemias displaying t(11;14) have specific genomic, transcriptional, and clinical features.

Primary plasma cell leukemia (pPCL) is an aggressive form of multiple myeloma (MM) that has not benefited from recent therapeutic advances in the field. Because it is very rare and heterogeneous, it remains poorly understood at the molecular level. To address this issue, we performed DNA and RNA sequencing of sorted plasma cells from a large cohort of 90 newly diagnosed pPCL and compared with MM. We observed that pPCL presents a specific genomic landscape with a high prevalence of t(11;14) (about half) and high-risk genomic features such as del(17p), gain 1q, and del(1p32). In addition, pPCL displays a specific transcriptome when compared with MM. We then wanted to characterize specifically pPCL with t(11;14). We observed that this subentity displayed significantly fewer adverse cytogenetic abnormalities. This translated into better overall survival when compared with pPCL without t(11;14) (39.2 months vs 17.9 months, P = .002). Finally, pPCL with t(11;14) displayed a specific transcriptome, including differential expression of BCL2 family members. This study is the largest series of patients with pPCL reported so far.

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.

del(17p) without TP53 mutation confers a poor prognosis in intensively treated newly diagnosed patients with multiple myeloma.

Despite tremendous improvements in the outcome of patients with multiple myeloma in the past decade, high-risk patients have not benefited from the approval of novel drugs. The most important prognostic factor is the loss of parts of the short arm of chromosome 17, known as deletion 17p (del(17p)). A recent publication (on a small number of patients) suggested that these patients are at very high-risk only if del(17p) is associated with TP53 mutations, the so-called "double-hit" population. To validate this finding, we designed a much larger study on 121 patients presenting del(17p) in > 55% of their plasma cells, and homogeneously treated by an intensive approach. For these 121 patients, we performed deep next generation sequencing targeted on TP53. The outcome was then compared with a large control population (2505 patients lacking del(17p)). Our results confirmed that the "double hit" situation is the worst (median survival = 36 months), but that del(17p) alone also confers a poor outcome compared with the control cohort (median survival = 52.8 months vs 152.2 months, respectively). In conclusion, our study clearly confirms the extremely poor outcome of patients displaying "double hit," but also that del(17p) alone is still a very high-risk feature, confirming its value as a prognostic indicator for poor outcome.

Efficacy of lenalidomide in myelodysplastic/myeloproliferative neoplasms with ring sideroblasts and an extreme platelet count.

Lenalidomide is efficient in reducing red blood cell transfusion dependency and markedly lowering platelet counts in MDS/MPN-RS-T in the context of major platelet counts.

Antiplatelet Antibodies Do Not Predict the Response to Intravenous Immunoglobulins during Immune Thrombocytopenia.

Immune thrombocytopenia (ITP) is a rare autoimmune disease due to autoantibodies targeting platelet glycoproteins (GP). The mechanism of platelet destruction could differ depending on the specificity of antiplatelet antibodies: anti-GPIIb/IIIa antibodies lead to phagocytosis by splenic macrophages, in a Fcγ receptor (FcγR)-dependent manner while anti-GPIb/IX antibodies induce platelet desialylation leading to their destruction by hepatocytes after binding to the Ashwell-Morell receptor, in a FcγR-independent manner. Considering the FcγR-dependent mechanism of action of intravenous immunoglobulins (IVIg), we assumed that the response to IVIg could be less efficient in the presence of anti-GPIb/IX antibodies. We conducted a multicentric, retrospective study including all adult ITP patients treated with IVIg who had antiplatelet antibodies detected between January 2013 and October 2017. Among the 609 identified, 69 patients were included: 17 had anti-GPIb/IX antibodies and 33 had anti-GPIIb/IIIa antibodies. The response to IVIg was not different between the patients with or without anti-GPIb/IX (88.2% vs. 73.1%). The response to IVIg was better in the case of newly diagnosed ITP (odds ratio (OR) = 5.4 (1.2-24.7)) and in presence of anti-GPIIb/IIIa (OR = 4.82 (1.08-21.5)), while secondary ITP had a poor response (OR = 0.1 (0.02-0.64)). In clinical practice, the determination of antiplatelet antibodies is therefore of little value to predict the response to IVIg.

Clinical characteristics and outcomes of relapsed follicular lymphoma after autologous stem cell transplantation in the rituximab era.

High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is a therapeutic option for patients with relapsed follicular lymphoma (FL). The clinical characteristics and outcomes of FL relapse after ASCT in the rituximab era have not yet been fully elucidated. We retrospectively reviewed 414 FL patients treated with ASCT between 2000 and 2014 in four hematology departments. All patients received rituximab as a first-line treatment. We specifically analyzed the clinical characteristics, treatment strategies at relapse, and outcomes of 95 patients (23%) who relapsed after ASCT. The patients (median age, 57 y) received a median of two lines of therapy (range, 2-6) prior to ASCT, with 92% in complete response (CR) or partial response (PR) before ASCT. Histological transformation at relapse after ASCT was observed in 20% of the patients. Treatment at relapse after ASCT consisted of chemotherapy with or without rituximab (n = 45/90, 50%), targeted agents (18%), rituximab monotherapy (14%), or consolidation allogeneic transplantation after induction chemotherapy (12%) and radiotherapy (6%). After relapse, the median progression-free survival (PFS) and overall survival (OS) were 1 year (95% CI, 0.541-1.579) and 5.5 years (95% CI, 1.910-9.099), respectively. In the multivariate analysis, histological transformation (HT) was associated with OS (P = .044; HR 2.439; 95% CI, 1.025-5.806), and a high FLIPI score at relapse was associated with PFS (P = .028; HR 2.469; 95% CI, 1.104-5.521). This retrospective study showed that the period of PFS of patients who relapsed after ASCT is short. A biopsy should be performed for these patients to document the HT. Our results indicate that new treatment strategies will need to be developed for these patients.

Development and Validation of a Cytogenetic Prognostic Index Predicting Survival in Multiple Myeloma.

PURPOSE: The wide heterogeneity in multiple myeloma (MM) outcome is driven mainly by cytogenetic abnormalities. The current definition of high-risk profile is restrictive and oversimplified. To adapt MM treatment to risk, we need to better define a cytogenetic risk classification. To address this issue, we simultaneously examined the prognostic impact of del(17p); t(4;14); del(1p32); 1q21 gain; and trisomies 3, 5, and 21 in a cohort of newly diagnosed patients with MM. METHODS: Data were obtained from 1,635 patients enrolled in four trials implemented by the Intergroupe Francophone du Myélome. The oldest collection of data were used for model development and internal validation. For external validation, one of the two independent data sets was used to assess the performance of the model in patients treated with more current regimens. Six cytogenetic abnormalities were identified as clinically relevant, and a prognostic index (PI) that was based on the parameter estimates of the multivariable Cox model was computed for all patients. RESULTS: In all data sets, a higher PI was consistently associated with a poor survival outcome. Dependent on the validation cohorts used, hazard ratios for patients in the high-risk category for death were between six and 15 times higher than those of patients in the low-risk category. Among patients with t(4;14) or del(17p), we observed a worse survival in those classified in the high-risk category than in those in the intermediate-risk category. The PI showed good performance for discriminating between patients who died and those who survived (Harrell's concordance index greater than 70%). CONCLUSION: The cytogenetic PI improves the classification of newly diagnosed patients with MM in the high-risk group compared with current classifications. These findings may facilitate the development of risk-adapted treatment strategies.

Carfilzomib Weekly plus Melphalan and Prednisone in Newly Diagnosed Transplant-Ineligible Multiple Myeloma (IFM 2012-03): A Phase I Trial.

PURPOSE: Carfilzomib is a novel generation proteasome inhibitor. The Carmysap trial demonstrated that twice-weekly KMP (carfilzomib, melphalan, prednisone) might challenge the MPV (melphalan, prednisone, bortezomib) standard. We sought to study KMP weekly, allowing to increase carfilzomib's dose with maintained efficacy and improved safety profile. PATIENTS AND METHODS: IFM2012-03, a phase I multicenter study of KMP weekly in elderly patients with newly diagnosed multiple myeloma (eNDMM), aimed to determine the MTD of carfilzomib. Carfilzomib was given intravenously at 36, 45, 56, and 70 mg/m2/day on days 1, 8, 15, and 22 with melphalan and prednisone, for nine 35-day induction cycles, followed by carfilzomib maintenance for 1 year. Three dose-limiting toxicities (DLT) determined MTD at the lower dose. RESULTS: Thirty eNDMMs were treated, 6 per cohort at 36, 45, and 56 mg/m2 and 12 at 70 mg/m². There was one DLT at 36 mg/m2 (lymphopenia), one at 45 mg/m2 (lysis syndrome), two at 56 mg/m2 (cardiac insufficiency and febrile neutropenia), and two at 70 mg/m2 (vomiting and elevated liver enzymes). The safety profile was acceptable; however, specific attention must be paid to the risk of cardiovascular events, especially for elderly patients. The overall response rate was 93.3%, with 46.6% complete response. CONCLUSIONS: The MTD dose of carfilzomib was 70 mg/m2 in this KMP weekly study in eNDMM. Response rates, and especially CR rate, were remarkable in this population, and would benefit from being assessed in a larger-scale study. The IFM2012-03 study demonstrated that the MTD of carfilzomib weekly is 70 mg/m2 in eNDMM, and 56 mg/m2 for patients older than 75 years. Carfilzomib used weekly in combination has a good efficacy and safety profile in eNDMM.