Managing multiple myeloma (MM) patients receiving advanced (four or more) lines of treatment is a complex challenge. Therefore, real-world data are essential to better understand and address the medical need of this challenging population. We used the EMMY cohort, a French longitudinal real-world study, to describe the characteristics and outcomes of 2127 MM patients receiving advanced-line treatments between 2017 and 2020. A wide variety of treatments were used without a predominant combination showing an evolution over time. Patients exhibited median time to next treatment and overall survival ranging from 7.8 months (95% CI: 6.7-7.8) and 19.4 months (95% CI: 17.4-22.5) in Line 4 (L4) to 4.8 months (95% CI: 3.5-6) and 12.6 months (95% CI: 8.7-16.6) in L8, respectively. The EMMY study provides valuable insights into the real-world application of advanced-line treatments, demonstrating rapid disease progression and poor outcomes in these patients before the novel anti-B-cell maturation antigen (BCMA) directed therapies. These findings highlight the critical need for novel therapies in this population.

Background. High risk (HR) cytogenetic remains of poor prognosis, particularly in the RRMM setting. IFM 2010-02 studied pomalidomide and dexamethasone (Pd) and demonstrated limited activity, with a median TTP overall at 5.5 months, and at 7.3 vs 2.8 months in HR RRMM with deletion17p and t(4;14) respectively. We hypothesized that addition of Ixazomib (oral proteasome inhibitor) at increased dose density to Pd (IxPd) in HR RRMM would improve convenience, thus adherence to treatment, and in parallel improve efficacy with no increased toxicity compared to addition of a parental proteasome inhibitor (PI). Methods. Eligible patients had a RRMM, in L2, refractory to lenalidomide, but not to pomalidomide and ixazomib. HR was defined by presence of either del(17p) and/or t(4;14) at diagnosis or study entry. Patients received 17 induction cycles, 21-days long, consisting of ixazomib 3mg/day (d 1, 4, 8 and 11), pomalidomide 4mg/day (d1 to 14) and weekly dexamethasone, followed by a maintenance phase of 28-day cycles with ixazomib 4mg/day (d 1, 8 and 15) and pomalidomide 4mg/day (d 1 to 21), until progression. The primary endpoint was time to progression (TTP). The number of patients to be recruited was initially calculated based on an expected doubling of the median TTP obtained in IFM 2010-02 in either 2 HR RRMM population. No statistical comparison can be done across HR groups given that the study was powered to analyze the 2 groups as a whole. Results. Twenty-six patients were enrolled in the study. Median age at inclusion was 72 years (IQ. 67-78), median age at diagnosis was 70 years (IQ. 63-74). Twelve patients presented with del(17p), 9 with t(4;14), and 5 with del(17p) and t(4;14), all patients refractory to lenalidomide. One patient received the study medication but died with no post baseline efficacy assessment. Analyses were done on the remaining 25 patients and safety analysis were performed on all the 26 patients having received at least one dose of the study medication. Twenty-two patients had progressed on study (of whom 12 had died at end of study), 2 patients died before progression, and one patient had no death and no progression. Study treatment was permanently interrupted in 9 patients before progression or death, including 8 during the induction phase. With a median follow-up time of 27 months, the primary end-point median TTP for the efficacy analysis cohort (n=25) was 10.1 months (CI95%. 4.4;13). The median PFS and OS were 9.9 (CI95%. 4.2;12.7) months and 23.7 (CI95%. 12.7;inf) months, respectively. At end of induction, ORR and VGPR rate was (n=15) 60% and (n=7) 28%, CBR (n=18) 72%; at end of study the response rates were the same as end of induction. The median TTP and OS for del(17p) was 9.9 (CI95%. 3.3;inf) and 23.7 (CI95%.14.3;inf ) months, respectively; and was 10.5 (CI95%. 7.9;inf) months and not reached (CI95%. 27.1;inf), in the t(4;14) cohort respectively. Median TTP and OS for combined del(17p) and t(4;14) was 5.5 (CI95%. 2.7;inf) and 11.1 (CI95%. 9.9;inf) months respectively. The most common adverse events (10% occurrence) were neutropenia (n=15), thrombocytopenia (n=12), asthenia (n=10), anemia (n=8), rash (n=5), back pain (n=5), diarrhea (n=5), peripheral oedema (n=4), dizziness (n=3), general physical health deterioration (n=3), muscle spasms (n=3), pyrexia (n=3) and peripheral sensory neuropathy (n=3). There was no added safety concerns related to the combination of Ixazomib and Pomalidomide in the study protocol. Conclusion. The study IFM 2014-01 /IxPd in HR L2 Len refractory RRMM met its primary end point objective since we observed a doubling of the median TTP with the addition of Ixazomib to pomalidomide and dexamethasone in this very hard to treat population characterized with a very poor outcome. This data confirms the importance of proteasome inhibitors in HR RRMM. This phase 2 study needs confirmation in a larger cohort.

BACKGROUND:Patients with frailty and newly diagnosed multiple myeloma have worse outcomes due to higher rates of adverse events (AEs) and treatment discontinuation. This study evaluated a dexamethasone-sparing regimen of daratumumab plus lenalidomide versus lenalidomide plus dexamethasone in frail patients with newly diagnosed multiple myeloma. METHODS:In this prospective, randomised, open-label trial, conducted at 61 active Intergroup Francophone of Myeloma centres, patients aged 65 years or older with newly diagnosed multiple myeloma and an Eastern Cooperative Oncology Group proxy frailty score of 2 or more were randomly assigned 2:1 to receive daratumumab (1800 mg subcutaneously) plus oral lenalidomide (25 mg daily for 21 days of a 28 day cycle) and dexamethasone (20mg weekly) for two cycles (dexamethasone-sparing group) or lenalidomide (25 mg daily) and oral dexamethasone (20 mg weekly; control group), with stratification by International Staging System, age, and centre. The primary endpoint was progression-free survival. Efficacy was assessed in the intention-to-treat population and safety was assessed in all patients exposed to at least one dose of randomised intervention. This trial is registered with ClinicalTrials.gov, NCT03993912, and is complete. FINDINGS:From Oct 18, 2019 to July 20, 2021, 335 patients were screened, of whom 295 patients were randomly assigned (200 to lenalidomide plus daratumumab, 95 to lenalidomide plus dexamethasone). The median age was 81 years (IQR 77-84), with 180 (61%) aged older than 80 years, and 151 (51%) patients were female and 144 (49%) were male. Median follow-up was 46·3 months (IQR 46·0-52·7). Median progression-free survival was 53·4 months (95% CI 35·3-not reached) in the dexamethasone-sparing group versus 22·5 months (16·5-39·0) in the control group (hazard ratio [HR] 0·51, 95% CI 0·37-0·70, p<0·0001). The most common grade 3-5 AEs were neutropenia (110 [55%] of 200 patients in the dexamethasone-sparing group vs 23 [24%] of 95 patients in the control group), and infection (38 [19%] vs 20 [21%]). Serious adverse events occurred in 126 patients (63%) in the dexamethasone-sparing group and 66 patients (69%) in the control group. AEs leading to death occurred in 23 patients (12%) in the dexamethasone-sparing group and 12 patients (13%) in the control group, with 4 (2%) and 2 (2%) grade 5 treatment-emergent adverse events, respectively. INTERPRETATION:In the IFM2017-03 trial, use of lenalidomide plus daratumumab, with dexamethasone limited to the first 2 treatment cycles, reduced the risk of progression or death compared with lenalidomide plus dexamethasone, with no additional safety concerns. Lenalidomide plus daratumumab could therefore be considered as a treatment option for older patients with frailty and newly diagnosed multiple myeloma. FUNDING:The study was funded by Johnson & Johnson.

SummaryThe bendamustine–rituximab (BR) schedule is an efficient first‐line therapy in Waldenström macroglobulinaemia (WM). A previous analysis of 69 patients who received this treatment confirmed a high response rate and good progression‐free (PFS) and overall survival (OS). With a median follow‐up of 76.1 months (95% confidence interval [CI] 69.9–80.6), 5‐year outcome is still excellent at 66.63% (95% CI 56.09–79.17) for PFS and 80.01% (95% CI 70.82–90.41) for OS. The rate of secondary cancers is 17.66% (IQR 7.99–27.64) at 66 months. Relapsed patients who received ibrutinib as second‐line clearly benefited from this schedule. This confirms current recommendations suggesting BR long‐term efficacy as first‐line option in WM.

CD38-targeting immunotherapy is approved in combination with lenalidomide and dexamethasone in patients with newly diagnosed multiple myeloma (NDMM) that are transplant ineligible (TI) and is considered the best standard of care (SOC). To improve current SOC, we evaluated the added value of weekly bortezomib (V) to isatuximab plus lenalidomide and dexamethasone (IsaRd versus Isa-VRd). This Intergroupe Francophone of Myeloma phase 3 study randomized 270 patients with NDMM that were TI, aged 65-79 years, to IsaRd versus Isa-VRd arms. The primary endpoint was a minimal residual disease (MRD) negativity rate at 10-5 by next-generation sequencing at 18 months from randomization. Key secondary endpoints included response rates, MRD assessment rates, survival and safety. The 18-month MRD negativity rates at 10-5 were reported in 35 patients (26%, 95% confidence interval (CI) 19-34) in IsaRd versus 71 (53%, 95% CI 44-61) in Isa-VRd (odds ratio for MRD negativity 3.16, 95% CI 1.89-5.28, P < 0.0001). The MRD benefit was consistent across subgroups at 10-5 and 10-6, and was already observed at month 12. The proportion of patients with complete response or better at 18 months was higher with Isa-VRd (58% versus 33%; P < 0.0001), as was the proportion of MRD negativity and complete response or better (37% versus 17%; P = 0.0003). At a median follow-up of 23.5 months, no difference was observed for survival times (immature data). The addition of weekly bortezomib did not significantly affect the relative dose intensity of IsaRd. Isa-VRd significantly increased MRD endpoints, including the 18-month negativity rate at 10-5, the primary endpoint, compared with IsaRd. This study proposes Isa-VRd as a new SOC for patients with NDMM that are TI. ClinicalTrials.gov identifier: NCT04751877 .

Background. Elderly patients with newly diagnosed multiple myeloma (NDMM) have heterogeneous fitness and disparate tolerance to treatment. Frail patients develop more adverse events leading to higher rates of treatment discontinuation. The use of long term dexamethasone is associated with multiple side effects specially in elderly frail patients. In the phase 3 IFM2017-03 trial (NCT03993912) we investigate the efficacy and safety of daratumumab lenalidomide (DR) without long term dexamethasone to lenalidomide dexamethasone (Rd) in a frail population of patients with NDMM. Methods. The IFM2017-03 trial is a prospective, randomized, open-label study done at 90 IFM centers. Patients with NDMM over the age of 65 and with an ECOG proxy frailty score ≥ 2 were randomized 1:2 to receive 28-day cycles of lenalidomide (25mg/day, 21/28) and dexamethasone (20mg QW) - Rd arm - or daratumumab (1800mg SC QW for 8 weeks, Q2W for 16 weeks and Q4W thereafter), lenalidomide (25mg/day, 21/28) and 2 cycles of dexamethasone (20mg QW for 8 weeks) - DR arm - until progression or unacceptable toxicity. Randomization was stratified on ISS and age. The primary endpoint was progression free survival (PFS). Secondary endpoints were overall response rate, VGPR or better rate, overall survival (OS) and occurrence of grade 3 or more side effects. Results. In total, 295 patients were randomized (200 in DR arm and 95 in Rd arm). Median age was 81 years (range 68-92) with 84% of patients over the age of 75 years and 61% over the age of 80 years. Baseline demographics and disease characteristics were well balanced between arms. At data cut-of, with a median follow-up time of 40 months (95%CI, 38.5 - 41.7), 79 (42%) and 16 (17%) patients in DR and Rd arms were still on treatment, respectively. Median treatment duration was 34.5 months (95%CI, 28.3 - 40.9) in arm DR and 14.3 months (95%CI, 10.8 - 20.6) in arm Rd. Overall best response rates were 92% in DR and 85% in Rd arms (p=0.025). Median PFS was 48.5 months (95%CI, 35,1-NR) in DR arm vs. 21.5 months (95%CI, 16.2-36.0) in Rd arm, HR 0.51 (95%CI, 0.37-0.71), log-rank p<0.0001 (Figure 1). PFS benefit was consistent across all subgroups defined by age, ECOG, Charlson, ISS, cytogenetics and creatinine clearance. Median OS was not reached in DR (95%CI, 53.4-NR) vs. 36.0 months in Rd, HR 0.46 (95%CI, 0.31-0.69), log-rank p=0.0001. At least one AE (grade ≥ 3) occurred in 88% and 77% of patients in DR and Rd arms, respectively. Patients in DR group had more grade ≥ 3 hematologic AE with neutropenia (DR 62%, Rd 33%) but similar grade ≥ 3 infections, with 18% in DR and 19% in Rd arms. Among patients with infections, 5% in DR and 7% in Rd had a pneumonia. Discontinuations due to AEs were similar in both arms (28% in DR and 34% in Rd). Baseline health-related quality of life (HRQoL) were well balanced between the 2 arms. The DR group had significantly shorter times to clinically meaningful improvement than Rd group in all QLQ-C30 domains. Conclusion. The IFM2017-03 trial is the first phase 3 study dedicated to frail patients. It shows a significant reduced risk of progression or death by 49% in DR (dexamethasone-sparing regimen) vs. Rd, with a favorable safety profile and an improved HRQoL.

Background. The current standard of care for non-transplant eligible (NTE) newly diagnosed multiple myeloma (NDMM) is the combination of anti-CD38 immunotherapy daratumumab to lenalidomide-dexamethasone (DRd) on the basis of the Maia study (Facon et al. NEJM). This regimen has considerably improved the survival objectives for the study and the patients, PFS and OS. Interestingly, the MRD sustained 10-5 negative rate of DRd in MAIA is lower than 15%, alluding to the hypothesis that DRd may be immunogenic more than profoundly debulking in its main MOAs. We and other have hypothesized that adding a proteasome inhibitor (PI) to antiCD38 IT +Rd combination would significantly increase the sustained MRD negativity rate and might improve even further survivals. Two phase 3 studies for registration investigate the role of adding antiCD38 IT to VRd (antiCD38VRd quadruplet-based combination versus VRd), questioning on the added value of antiCD38 to the old standard of care VRd. We believe it is of importance to study the added value of a PI to antiCD38 IT +Rd combination in comparison to antiCD38 IT +Rd (the optimal standard of care today in the NTE NDMM) to demonstrate the impact in debulking of the PI on top of the immunogenic effect with the study of the MRD negative rate. We therefore have conducted the present study of Isa-VRd compared to Isa-Rd (IFM2020-05/Benefit, (NCT04751877). Benefit has fully enrolled as of September 2022, and there has been no safety warnings from the safety committee with the prolonged use of bortezomib for 18 months on a weekly basis in combination to Isa-Rd. Study Design and Methods. 270 NTE NDMM patients, aged [65-79] years old and non-frail, were randomized 1:1 and assigned to either the anti-CD38 mAb isatuximab + Rd (Isa-Rd) or isatuximab + VRd (Isa-VRd lite). Stratification across arms was done according to high-risk MM, age cutoff of 75 years and study centers. Patients receive isatuximab IV 10 mg/kg on days 1, 8, 15, and 22 of cycle 1, days 1 and 15 from cycle 2 to 12 and day 1 from cycle 13 onward, 28-day cycles. Lenalidomide and dexamethasone were given orally as approved. Bortezomib was administered weekly and subcutaneously on days 1, 8, 15 at 1.3 mg/m² from cycle 1 to 12 and on days 1, 15 from cycle 13 to 18, and then stopped. All patients will discontinue dexamethasone after cycle 12. Patients will then continue receiving Isa-Rd until progression in both arms. The primary objective is to evaluate the MRD negativity rate at 10-5 at 18 months in both arms, sustained MRD being key secondary at [12-24] months. The study will be considered positive if the MRD negativity rate at 10-5 at 18 months is 30% in the Isa-VRd arm, and twice as much as Isa-Rd arm within the same time point. Key secondary objectives include the survival analysis (OS, PFS, EFS, TTNT), response rates, duration of response, and safety. Conclusion. The study is estimated to read out March 2024, 18 months after the last patient enrolls.

Background Waldenström macroglobulinemia (WM) is a rare hematological malignancy characterized by the accumulation of IgM-secreting clonal lymphoma cells with a lymphoplasmacytic morphological differentiation. Recently, BTK inhibition has emerged as a promising therapeutic strategy in WM (Buske, JCO 2022; Tam, Blood 2020). However, in real life, a large part of patients(pts) continue to be treated by chemoimmunotherapy (Buske, Lancet Hematol2018) including bendamustine (B)-rituximab (R) in salvage (Tedeschi , Leukemia Lymphoma 2015) or first line MW (Treon, ASH2016). We have previously reported a series of 69 WM pts treated by BR (Laribi, BJH 2018) and demonstrated that this regimen is efficient. However, the follow-up was relatively short and some questions remained unresolved in terms of long-range response and second cancer occurrence. Here we report results of this series with a longer follow-up. Methods Sixty-nine symptomatic previously untreated pts with WM diagnostic criteria according to the second WM Workshop recommendations were enrolled in this retrospective multi-center study between January 2013 and December 2017 in 13 French centers. MYD88L265P and CXCR4 mutations were searched using qPCR and or next generation sequencing. Del(17p) and/or TP53 mutation were investigated in 34 pts. All pts received a BR regimen consisting of 375 mg/m2 of R on day 1 and 90 mg/m2 of B on days 1 and 2, repeated every 4 weeks, with a maximum of 6 cycles. Cumulative incidence of secondary malignancies and high-grade lymphomas were computed, considering death free of malignancies as a competing event. Event-free survival (EFS), time to next treatment (TNT), progression-free survival (PFS) and overall survival (OS) were plotted using the log rank test and Kaplan-Meier graphical comparison. Results Pts median age was 69 years old (yo; range 45-88) at WM diagnosis and 71 yo (range 46-88) at therapy initiation. MYD88 and CXCR4 mutations were present in 45/51 (88%) and 11/44 (25%) of pts, respectively. A complex karyotype was disclosed in 6/44 (14%) pts, and 1/34 (3%) had TP53 alteration. According to the IPSSMW score, 14 (22%) pts were low risk, 32(46%) intermediate, and 32 (46%) high risk. Using consensus response criteria, the overall response rate was 97% (very good partial response [VGPR] with negative immunofixation 19%, VGPR 37%, PR40%, MR 1%) and the major response rate was 96%. Cumulative incidence of VGPR or better was 47.8%, 53.6%, 55%, and 56% at 6, 12, 18, and 24 months, respectively. After a median observation time of 68.5 months (range 23.13-106) post BR, the median OS was not reached (83-NR) , and the median PFS was 82 months (75-NR). Median OS for pts with mutated or WT MYD88 was NR and 72.8 months, respectively (p=0.046). Median OS for pts with mutated or WT CXCR4 was 70.2 months and NR, respectively (p=0.64). Median OS related to disease or treatment was not reached, while median OS related to other causes was 106 months. Sixteen (23.2%) pts relapsed. Fourteen received second line therapy and 2 supportive care. Eight patients received ibrutinib, and 6 chemo-immunotherapy. TNT was 31.55 months (range 2.66-82.43). Median PFS after a second line of treatment (PFS2) was 45 (9.13-NR) or 21 months (range 9.13-NR), for pts receiving ibrutinib or not. Eleven pts developed a second cancer: 9 solid tumors (2 pancreatic, 2 gastric, 1colic, 1 pulmonary, 1 breast, 1 cutaneous), and 2 treatment-related myeloid neoplasms (TRMN). Median EFS, defined as occurrence of death, relapse or second cancer was 82 months (61-NR). The cumulative incidence of second cancer was 2.90%, 5.80%, 10.49%, and 17.6% at 12, 24, 48, and 96 months, respectively (figure 1). Univariate analyses on OS disclosed statistically significant differences for age at diagnosis (p=0.001), age at first therapy (p <0.001), IgM>70g/L (p: 0.018), complex karyotype (p=0.037), and high risk IPSSMW (p<0.01). In multivariate analysis, only IPSSMW remained statistically significant (p<0.001) (table1). Univariate analyses on PFS only singled out age at diagnosis (p=0.03) or at first therapy (p=0.049) as statistically significant. Mutated MYD88 or CXCR4 did not impact OS nor PFS. Conclusion This study demonstrates that the BR regimen is efficient in treatment naïve WM pts, yielding long-term responses. The occurrence of secondary cancers, including TRMN, should be closely monitored in these patients. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

The risk of venous thromboembolism (VTE) is higher in myeloma patients receiving immunomodulatory compounds. A VTE prophylaxis using low-molecular-weight heparin or aspirin is therefore proposed. Apixaban is an oral direct anti-Xa. Several studies have shown the efficacy and safety of apixaban in VTE prophylaxis compared to enoxaparin. The objective of this prospective phase 2 pilot study was to assess the risk of VTE and bleeding in patients with myeloma treated with immunomodulatory compounds lenalidomide (len) or thalidomide (thal), using apixaban in a preventive scheme. Myeloma patients requiring Melphalan-Prednisone-Thalidomide in the first line, or Lenalidomide-Dexamethasone in the relapse setting received apixaban, 2.5 mg x 2/day for 6 months. Venous (pulmonary embolism-PE, or symptomatic proximal or distal deep vein thrombosis-DVT, or all proximal asymptomatic events detected by systematic proximal bilateral compression ultrasound) or arterial thrombotic events, and bleeding events (ISTH 2005) were registered. One hundred and four patients were enrolled (mean age 69.8 ± 7.8 years), 11 in first line and 93 in relapse. Two venous thrombotic events were observed, for example, an asymptomatic proximal DVT and a symptomatic distal DVT, in the context of apixaban stopped 14 days before, due to lenalidomide-induced thrombocytopenia. No PE or arterial cardiovascular events were reported. Only one major and 11 CRNM hemorrhages were reported. These data must now be confirmed on a randomized large study.

Imatinib has transformed chronic myeloid leukemia (CML) prognosis with a survival rate of almost 83% at 10 years.1 The second and third generations of tyrosine-kinase inhibitors (TKIs) have enlarged the therapeutic possibilities. Dasatinib and nilotinib induce higher complete cytogenetic response and major molecular response (MMR)2 rates than imatinib as well as fewer progression to blastic phase.3 Bosutinib was first studied in resistance/intolerance to imatinib situations4 Ponatinib, the only third line TKI, has a BCR-ABL1 pan-inhibitor activity and is maintaining efficacy against T315I mutation5. However, TKIs are associated with side effects (SEs) and may impair patient observance. Actual practices about TKIs switches are based on the 2013 European Leukemia Net guidelines. However, few studies have considered the prognostic impact of TKIs switches in daily practice.6 The aim of our study was to analyze the number of switches on a global cohort of patients treated in first line with imatinib outside a clinical trial. In this retrospective multicentric study, the patient cohort was established using BCR-ABL1 transcript follow-up curves from a multi-center network, centralized in the molecular biology laboratory of Rennes University Hospital. Two cohorts were constituted, 1 comprising patients who experienced one or more switches during follow-up, and the other including patients maintaining imatinib therapy. Patients had to be aged 18 or over and received a first line therapy by imatinib, started between 2006 and 2014. Patients who underwent ASCTs were excluded, as well as pregnant patients during follow-up. All patients provided written informed consent. Overall survival (OS) of patients according to the existence of TKIs switches was analyzed, as well as survival based on MMR obtaining in first line. Besides, this study analyzed the incidence of SEs during the different TKIs lines. Groups were compared using Student test and Mann-Whitney Wilcoxon tests. For qualitative variable, groups were compared by χ2 and Fisher tests. OS was represented using a curve with Kaplan-Meier estimator and its 95% CI. Survival curves by group were compared by a log-rank test. In total 192 patients were included, 87 patients in the switch group and 105 in the no-switch group (Figure 1A). The median follow-up time was 5.1 years. It was 4.5 years (0.8-10.2) in the no-switch group and 5.2 years [0.8-9.4] in the switch group. Median age at diagnostic was 61 years [24-88]. Both groups were similar concerning Sokal score (P = .56). OS at 5 years was 95% and 93% at 7 years (Figure 1B). When comparing OS according to the existence of switches or not, no difference was found between the 2 groups, with an OS at 5 years of 96% in the switch group and 93% in the no-switch group (P = .166) (Figure 1C). Data analysis in first line setting showed that MMR rate was significantly higher in the no-switch group with 91% against 28% (P < .0001), but reaching or not MMR in first line had no impact on OS (P = .168). Loss of MMR was seen in first line in the 2 groups with 42% in the switch group versus 3% in the other group (P < .0001). Median time to MMR in first line was 12 months in both groups. The main reason for switching to second line were SEs (46%) followed by absence of MMR (43%) and then by the loss of MMR (11%). Mutations rarely occurred with 5 cases in the switch group and 1 in the no-switch group. No mutations were detected during the subsequent lines. Distribution in second line was as follows: 70 patients were treated with dasatinib (81%), 16 patients with nilotinib (18%) and 1 patient with bosutinib (1%). Global MMR rate in second line was 67%, ie, 63% with dasatinib and 88% with nilotinib (P = .11): median time to MMR was 5 months [1-45] with dasatinib and 4 months [2-12] with nilotinib. The reasons for switching to third line were as follow: loss of MMR (n = 5, 16%), toxicity (n = 25, 78%), and primary resistance (n = 2, 6%). SE reported in first line with imatinib concerned 83% of patients, with 81% in the switch group and 85% in the no-switch group. Grade 3/4 toxicity affected 26% of patients exclusively in the switch group. Cutaneous toxicity was more frequently observed in the switch group, 25% versus 14% in the no-switch group (P = 0.05). Significantly more hepatic SEs were also reported in the switch group, 12% compared with 2% (P = 0.006), including 80% of grade 3/4 in the switch group. Conversely, fluid retention was more often described in the no-switch group, 42% versus 24% (P = .01). In second line, overall toxicity was similarly observed among patients treated either with dasatinib or nilotinib. Liver toxicity was reported in 4 patients (25%) with nilotinib, and pleural effusion in 17 (28%) patients with dasatinib. Cardiovascular event was documented in 4 patients treated with nilotinib. In third line, 21 patients out of 39 experienced grade 1 or 2 toxicity (54%). We must point out that few mutations were observed in this study as these analyses were seldom undertaken, mainly for patients showing insufficient molecular response. Therapy observance was not systematically documented in the patient's file, and TKI blood dosages rarely performed. Among patients not reaching MMR, we detected 5 mutations (F359I, F359C, L387F, H396R, and Q346R). In our study of 192 patients, the 93% OS rate at 7 years looks identical to that observed in the literature.2 We report that TKI switches are very common in real life affecting up to 45% of patients treated with imatinib in first line. Previous studies also reported switches in this setting, ranging from 12% up to 46%.1,2 Reasons for these switches were SEs accounting for 46% of switches to second line, a lower figure than previously described in a French series of 60 patients with up to 65% of switches for intolerance. When considering dasatinib and nilotinib related toxicities, results were similar to that generally reported. We must underline that the reasons for the switch remain hazardous in real practice, based on physician appraisal and patient's singularity, and do not always rely on objective criteria. To conclude, switching patients treated in first line with imatinib does not affect OS, and further studies should address the reasons of these switches in prospective trials. We thank the BREHAT network for its contribution. The authors declare that they have no conflict of interest with the contents of this article. All authors read and approved the final version of the article. Designed the study: Norwood, Lamy, Escoffre-Barbe Performed statistical analysis: Le Pabic Performed molecular analysis: Pastoret, Fest, Boulland Performed cytogenetic analysis: Henry Data collection, data analysis, data interpretation, article preparation, writing and completion and final approval of article: Norwood, Luycx, Le Coz, Moreau, Trebouet, Niault, Launay, Allangba, Bareau, Doncker, Grulois, Jacomy, Le Dû, Lamy, Escoffre-Barbe TL and MEB report grants from Novartis, BMS during the conduct of the study. The other authors declined any conflict of interest.

The British Journal of Haematology publishes original research papers in clinical, laboratory and experimental haematology. The Journal also features annotations, reviews, short reports, images in haematology and Letters to the Editor.

Background Waldenstrom macroglobulinemia (WM) is a rare low-grade B-cell malignancy characterized by the infiltration of IgM-secreting lymphoplasmacytic cells in the bone marrow. There is no standard therapy for WM, but several drugs have been shown to be effective either alone or in combination. Bendamustine (B)-Rituximab (R) has been found to be effective in salvage (Tedeschi , Leukemia Lymphoma 2015) or first setting in MW (Treon, ASH2016). BR- regimen has however reported to be associated with an increase in secondary cancer and the development of secondary myelodysplastic syndrome (MDS) or acute myeloblastic leukemia (AML) in patients with previously treated non-Hodgkin lymphoma. Prolonged neutropenia after R-chemotherapy treatment of lymphoma or CLL has also been associated with an increase of MDS/AML, and a shorter interval between the occurrence of the two malignancies. However, this has not been evaluated in previously untreated WM, nor the possible relationship with secondary cytopenia to WM treatment. Methods Forty-four symptomatic previously untreated patients with WM based on the second WM Workshop recommendations for diagnostic criteria were enrolled in this retrospective multi-center study between January 2012 and January 2017 in ten French centers. MYD88L265P and CXCR4 mutations were searched using q PCR and or next generation sequencing. Del (17) p and/ or TP53 mutation were investigated for 22 patients. All patients received a BR regimen consisting of 375 mg/m2 of rituximab on day 1 and 90 mg/m2 of bendamustine on days 1 and 2, repeated every 4 weeks, with a maximum of 6 cycles. Long-term complications of BR, 6 months or more after treatment discontinuation were analyzed. PFS and OS were plotted using the log rank test and Kaplan-Meier comparison. Results The median age at WM diagnosis was 69 years old (range 45-88) and the median age at initiation of therapy was 70 years old (range 46-89). The MYD88L265Pmutation was present in 24/30 (80%) of the cases. CXCR4 mutations were observed in 2/14 cases, alteration of TP53 in 1/22 cases. The median time from diagnosis to therapy was 2 months (range 0-123 months). The median serum IgM level was 3,870mg/dl (range 650-12000). The criteria for initiating BR treatment were: anemia (54%), B-symptoms (45%), hyper viscosity (25%), adenopathy and/or splenomegaly (18%), thrombocytopenia (16%), neuropathy (11%), and amyloidosis (4%). According to the IPSSMW score, 22% of patients were low risk, 35% intermediate risk, and 43% high risk. Overall 82% of patients completed the planned 6 courses. Using consensus response criteria, the ORR was 95% (CR15%, VGPR 40% PR38% MR 2%) and the major response rate (CR+VGPR+PR) 93%. Toxicities attributed to BR led to dose reduction and/ or incomplete regimen of intended therapy in 18% of patients. Their median age was 78 years old. Toxicities were related to excessive or prolonged myelosuppression in 5 patients and infection in 3. Most of the adverse events were hematological and infectious toxic effects. Grade 3-4 neutropenia occurred in 4 (11%) cases and grade 3-4 thrombocytopenia in one (3%). Minor infections developed in eight cases: three cutaneous infections, two herpes zosters, one upper respiratory tract infection, one sinusitis, and one oral-herpes. Grade 3-4 pneumonia was observed in two cases and sepsis in one. Among 38 evaluable patients for toxicities after BR therapy, 16(42%) developed one or more long-lasting cytopenias: neutropenia (34%), anemia (10%), and thrombocytopenia (8%), all grade I and II. The median duration for prolonged neutropenia, anemia, and thrombocytopenia were 6 months (range: 6-24 months), 7.5 months (range: 6-9 months) and 12 months (6-30 months), respectively. After a median observation time of 27 months (range 5-51 months) after BR-regimen, the PFS and OS were 92% and 100%, respectively. Two patients relapsed at 24 and 45 months. One patient with a history of breast cancer prior to WM treatment relapsed from this solid tumor at 23 months. None of the patients developed aggressive lymphoma or secondary MDS/AML at the last follow-up. Conclusion The BR regimen is efficient in patients with previously untreated WM. In elderly patients, the dose of bendamustine needs to be lowered. Long-lasting cytopenia occurred in half of patients and resolved in most cases within one year after the end of treatment. Longer follow-up is needed to assess the long-term risks of BR treatment. Disclosures Laribi: MUNDIPHARMA: Research Funding; NOVARTIS: Honoraria, Research Funding; ROCHE: Research Funding; TEVA: Research Funding; HOSPIRA: Research Funding; AMGEN: Honoraria; TAKEDA: Honoraria, Research Funding. Leblond: SERVIER: Honoraria, Membership on an entity's Board of Directors or advisory committees; GILEAD: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; JANSSEN: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; BMS: Honoraria; ABBVIE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ROCHE: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; NOVARTIS: Honoraria, Membership on an entity's Board of Directors or advisory committees.

8019 Background: The risk of venous thromboembolism (VTE) is higher in myeloma patients recieving IMiD* compounds (IMiD*: registered). A VTE prophylaxis using low-molecular-weight heparin or aspirin is proposed. Apixaban is an oral direct anti-Xa. Several studies have shown the efficiency and safety of apixaban in VTE prophylaxis compared to enoxaparin. The objective of this prospective pilot study was to assess the risk of VTE and bleeding in patients with myeloma treated with IMiD* compounds, using apixaban in a preventive scheme. Methods: Myeloma patients requiring Melphalan-Prednisone-Thalidomide in first line, or Lenalidomide-Dexamethasone in relapse, asymptomatic regarding VTE at inclusion, were enrolled between 2014 - 2016. All patients recieved apixaban, 2.5 mg x 2/day for 6 months, and were monthly monitored. Venous (pulmonary embolism – PE, or symptomatic proximal or distal deep vein thrombosis - DVT, or all proximal asymptomatic events detected by systematic proximal bilateral compression ultrasound) or arterial thrombotic events, and bleeding events (ISTH 2005) were registered. Based on meta-analysis of Carrier regarding VTE recurrence, and results from the ADOPT study in medical conditions regarding hemorrhages, < 13 symptomatic VTE events, < 3 severe and < 14 clinically relevant non major (CRNM) bleeding were expected on the treatment period. Results: 104 patients were enrolled (mean age 69.8 +/- 7.8yrs), 11 in first line, 93 in relapse. No PE or arterial cardiovascular events were reported. Two venous thrombotic events were registered, i.e an asymptomatic proximal DVT (patient in relapse) and a symptomatic distal DVT, although apixaban was stopped 14 days before, due to Lenalidomide-induced thrombopenia. Only one major and 11 CRNM hemorrhages were reported. Conclusions: Referring to the incidence of thromboembolic events in Carrier’s meta-analysis, and to hemorrhagic events in medical patients recieving apixaban in primary VTE prophylaxis, apixaban used in a preventive scheme seems to be efficient and safe in preventing VTE in myeloma patients treated with IMiD* compounds. Clinical trial information: NCT02066454.

Objective: The association between vasculitis and large granular lymphocyte (LGL) leukemia has rarely been reported or investigated. Thus, we assessed the clinical and biological phenotypes of LGL leukemia associated with vasculitis.Results: We studied a series of 11 patients displaying LGL leukemia associated with vasculitis (LAV). The mean age at diagnosis of LGL leukemia was 60.3 years; there were nine women and two men. The mean follow-up period was 45 months. The main LGL lineage was T-LGL (10 patients), and only one NK-LGL was identified. Clinical and biological features of T-LGL leukemia were compared with those from the 2009 French T-LGL registry. We did not find any relevant differences except that patients with LAV were predominantly female (p < 0.05). The most frequently observed vasculitis was cryoglobulinemia (n = 5). Three patients presented with cutaneous leukocytoclastic angiitis, two patients had ANCA-negative microscopic polyangiitis, and one patient had giant cell arteritis. The main clinical features involved the skin, e.g., purpura (91%), arthralgia (37%), peripheral neuritis (27%), and renal glomerulonephritis (18%). The most frequent histologic finding was leucocytoclastic vasculitis (54%). The rate of complete remission was high; i.e., 80%. A minority of patients had a vasculitis relapse (27%). Three patients (27%) died; one death was related to LGL leukemia (acute infection) and the two other deaths were related to vasculitis (both with heart failure).Conclusion: We conclude that vasculitis is overrepresented in the population of LGL patients, LAV predominantly affects women, vasculitis preferentially affects the small vessels, and LAV has high rate of complete response. (C) 2013 Elsevier Inc. All rights reserved.

Abstract Abstract 5109 Background: Large granular leukemia (LGL) leukemia is derived from either T-cell or NK-cell lineages. Clinical presentation of LGL leukemia is dominated by recurrent infections associated with neutropenia, anemia, splenomegaly and auto-immune diseases. The association of vasculitis and LGL leukemia has been rarely reported and investigated. Objective: To improve knowledge about this association, we retrospectively describe the clinical and biological characteristics of patients, their response to therapy and their prognosis. Methods: We performed a retrospective study based on 229 patients included in the French national LGL proliferation registry and a national mailing survey to 1350 internists in order to collect medical characteristics of patients displaying both vasculitis and LGL leukemia. We retrospectively collected medical charts from 11 patients between September 1999 and February 2012. Medical history, hematologic laboratory tests and response to therapy were compiled at first presentation of LGL leukemia associated vasculitis (LAV) and at each visit. Results: At the time of diagnosis of LGL leukemia the mean age was 60. 3 years (range, 28–74 years). They were 9 women and two men. The mean of follow up was 45 months (range, 1–108). The main LGL lineage was T-LGL (10 patients, 91%) and only one NK-LGL was identified. Hematological laboratory findings revealed that 5 patients (45%) patients presented hyperlymphocytosis. The mean absolute circulating LGL count for the series was 1. 10 9/L (range, 0. 45–4. 59 x. 10 9/L). Three patient (27%) had neutropenia (<1. 5 x. 109/L), no one had thrombocytopenia. Anemia was detected in 4 patients (36%). The most frequently observed vasculitis was cryoglobulinemia (n=5). Three patients presented cutaneous vasculitis. Two patients had ANCA negative microscopic polyangiitis and one patient presented giant cell arteritis. Clinical features were dominated by skin localization e. g. purpura (91%), arthralgia (37%), peripheral neuritis (27%) and renal glomerulonephritis (18%). Leucocytoclastic vasculitis was histologically demonstrated in 6 cases. Ten vasculitis were treated: the most delivered treatment was the association of cyclophosphamide-corticosteroid (n=3), followed to methotrexate–corticoisteroid (n=2), chlorambucil-corticosteroid (n=2) and corticosteroid alone (n=2). One patient received azathioprine and corticosteroid. The complete remission rate was high 80% and a minority of them presented vasculitis relapse (27%). Three patients (27%) died: one related to LGL leukemia (acute infection) and the 2 others related to heart failure due to vasculitis. Conclusion: Association of LGL leukemia and vasculitis is rare but not fortuitous. Based on this retrospective analysis, it seems that LAV preferentially affect female patients, with a low LGL count. LAV present with frequent cutaneous involvement and have a good response to therapy. Pathophysiological link between LGL leukemia and vasculitis remains to be investigated. Disclosures: No relevant conflicts of interest to declare.

BACKGROUND:Large granular lymphocyte leukemia is a rare lymphoproliferative disorder associated with autoimmune diseases and impaired hematopoiesis. This study describes the clinical and biological characteristics of 229 patients with T-cell or NK-cell large granular lymphocyte leukemia. DESIGN AND METHODS:The diagnosis was based on a large granular lymphocyte expansion (> 0.5x10(9)/L) lasting more than 6 months. Monoclonal T-cell receptor gamma gene rearrangement was detected in all the cases of T-cell large granular lymphocyte leukemia. Patients with chronic NK-cell lymphocytosis had an indolent disease, while those with multiorgan large granular lymphocyte infiltration and an aggressive clinical disease were considered to have NK-cell large granular lymphocyte leukemia. RESULTS:The diagnosis of T-cell large granular lymphocyte leukemia was confirmed in 201 cases, chronic NK-cell lymphocytosis in 27 cases and NK-cell large granular lymphocyte leukemia in one case. Associated autoimmune diseases or other neoplasms were present in 74 and 32 cases, respectively. One hundred patients (44%) required treatment, mainly for neutropenia-associated infections (n=45), symptomatic autoimmune diseases (n =24), transfusion-dependant anemia (n=18), and other causes (n=13). Patients were treated with steroids (n= 33), methotrexate (n=62), cytoxan (n=32), or cyclosporine (n=24) either as first-, second-, third- or fourth-line therapy. The overall response rate at 3 months and complete response rate for the various treatments were as follows: steroids (12% and 3%), methotrexate (55% and 21%), cytoxan (66% and 47%), cyclosporine (21% and 4%), respectively. Four out of 13 patients responded to splenectomy. Eleven out of 15 patients responded to cytoxan after methotrexate treatment had failed. The mean number of treatments was 3.4 (range, 1-7). There were 15 large granular lymphocyte leukemia-related deaths. CONCLUSIONS:Patients with T-cell large granular lymphocyte leukemia and chronic NK-cell lymphocytosis have similar clinical and biological features and responses to treatment. First-line therapy with cytoxan should be tested in a prospective trial.

International Journal of Laboratory HematologyVolume 32, Issue 4 p. 458-460 LETTER TO THE EDITOR Comparison of JAK2 V617F burden quantitation by two different quantitative-polymerase chain reaction methods H. Le Bars, H. Le Bars Département HITCSearch for more papers by this authorM.-L. Boulland, M.-L. Boulland Département HITCSearch for more papers by this authorB. Bareau, B. Bareau Service d'Hématologie CliniqueSearch for more papers by this authorB. Grosbois, B. Grosbois Département de Médecine Interne, CHU Rennes, FranceSearch for more papers by this authorM. Corolleur, M. Corolleur Département HITCSearch for more papers by this authorT. Lamy, T. Lamy Service d'Hématologie CliniqueSearch for more papers by this authorO. Fardel, O. Fardel Département HITC EA 4427 SeRAIC, Faculté de Pharmacie, Université de Rennes 1, FranceE-mail: [email protected]Search for more papers by this author H. Le Bars, H. Le Bars Département HITCSearch for more papers by this authorM.-L. Boulland, M.-L. Boulland Département HITCSearch for more papers by this authorB. Bareau, B. Bareau Service d'Hématologie CliniqueSearch for more papers by this authorB. Grosbois, B. Grosbois Département de Médecine Interne, CHU Rennes, FranceSearch for more papers by this authorM. Corolleur, M. Corolleur Département HITCSearch for more papers by this authorT. Lamy, T. Lamy Service d'Hématologie CliniqueSearch for more papers by this authorO. Fardel, O. Fardel Département HITC EA 4427 SeRAIC, Faculté de Pharmacie, Université de Rennes 1, FranceE-mail: [email protected]Search for more papers by this author First published: 24 June 2010 https://doi.org/10.1111/j.1751-553X.2010.01209.xRead the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL References James C., Ugo V., Casadevall N., Constantinescu S.N. & Vainchenker W. (2005) A JAK2 mutation in myeloproliferative disorders: pathogenesis and therapeutic and scientific prospects. Trends in Molecular Medecine 11, 546– 554. Jones A.V., Kreil S., Zoi K., Waghorn K., Curtis C., Zhang L., Score J., Seear R., Chase A.J., Grand F.H., White H., Zoi C., Loukopoulos D., Terpos E., Vervessou E.C., Schultheis B., Emig M., Ernst T., Lengfelder E., Hehlmann R., Hochhaus A., Oscier D., Silver R.T., Reiter A. & Cross N.C. (2005) Widespread occurrence of the JAK2 V617F mutation in chronic myeloproliferative disorders. Blood 106, 2162– 2168. Larsen T.S., Pallisgaard N., Moller M.B. & Hasselbalch H.C. (2007) The JAK2 V617F allele burden in essential thrombocythemia, polycythemia vera and primary myelofibrosis – impact on disease phenotype. European Journal of Haematology 79, 508– 515. Levine R.L. & Gilliland D.G. (2008) Myeloproliferative disorders. Blood 112, 2190– 2198. Lippert E., Girodon F., Hammond E., Jelinek J., Reading N.S., Fehse B., Hanlon K., Hermans M., Richard C., Swierczek S., Ugo V., Carillo S., Harrivel V., Marzac C., Pietra D., Sobas M., Mounier M., Migeon M., Ellard S., Kroger N., Herrmann R., Prchal J.T., Skoda R.C. & Hermouet S. (2009) Concordance of assays designed for the quantification of JAK2V617F: a multicenter study. Haematologica 94, 38– 45. Passamonti F. & Rumi E. (2009) Clinical relevance of JAK2 (V617F) mutant allele burden. Haematologica 94, 7– 10. Pemmaraju N., Moliterno A.R., Williams D.M., Rogers O. & Spivak J.L. (2007) The quantitative JAK2 V617F neutrophil allele burden does not correlate with thrombotic risk in essential thrombocytosis. Leukemia 21, 2210– 2212. Vannucchi A.M., Antonioli E., Guglielmelli P., Pardanani A. & Tefferi A. (2008) Clinical correlates of JAK2V617F presence or allele burden in myeloproliferative neoplasms: a critical reappraisal. Leukemia 22, 1299– 1307. Volume32, Issue4August 2010Pages 458-460 ReferencesRelatedInformation

Inorganic arsenic is a major environmental contaminant known to exert immunosuppressive effects. In this study, we report toxicity of AS(2)O(3), a trivalent inorganic form, toward isolated human hematopoietic CD34+ progenitor cells. Our results demonstrate that low concentrations of AS(2)O(3) (0-1-5 mu M) inhibit in vitro proliferation of CD34+ cells and their differentiation into various hematological cell lineages. These effects were associated with the induction of a necrotic process independent of caspases and likely related to mitochondrial damage. We conclude that As2O3 can impair in vitro human hematopoiesis by decreasing survival of CD34+ progenitor cells. (c) 2008 Wiley Periodicals, Inc.

Conclusion Rituximab appears to be a first line immunosuppressive therapy in acquired hemophilia, especially in post-partum hemophilia.