RAS/RAF landscape in monoclonal plasma cell conditions.

ABSTRACT: Multiple myeloma is characterized by a huge heterogeneity at the molecular level. The RAS/RAF pathway is the most frequently mutated, in ∼50% of the patients. However, these mutations are frequently subclonal, suggesting a secondary event. Because these genes are part of our routine next-generation sequencing panel, we analyzed >10 000 patients with different plasma cell disorders to describe the RAS/RAF landscape. In this large cohort of patients, almost 61% of the patients presented a RAS/RAF mutation at diagnosis or relapse, but much lower frequencies occurred in presymptomatic cases. Of note, the mutations were different from that observed in solid tumors (higher proportions of Q61 mutations). In 29 patients with 2 different mutations, we were able to perform single-cell sequencing, showing that in most cases, mutations occurred in different subclones, suggesting an ongoing mutational process. These findings suggest that the RAS/RAF pathway is not an attractive target, both on therapeutic and residual disease assessment points of view.

Pathophysiologic implications of elevated prevalence of hereditary alpha-tryptasemia in all mastocytosis subtypes.

BACKGROUND: Mastocytosis and monoclonal mast cell (MC) activation syndrome (MMAS) are heterogeneous conditions characterized by the accumulation of atypical MCs. Despite the recurrent involvement of KIT mutations, the pathophysiologic origin of mastocytosis and MMAS is unclear. Although hereditary α-tryptasemia (HαT, related to TPSAB1 gene duplication) is abnormally frequent in these diseases, it is not known whether the association is coincidental or causal. OBJECTIVE: We evaluated the prevalence of HαT in all mastocytosis subtypes and MMAS and assessed the pathophysiologic association with HαT. METHODS: Clinical data, laboratory data, KIT mutations, TPSAB1 duplication (assessed by droplet digital PCR), and HαT prevalence were retrospectively recorded for all patients with mastocytosis and MMAS registered in the French national referral center database and compared to a control cohort. To increase the power of our analysis for advanced systemic mastocytosis (advSM), we pooled our cohort with literature cases. RESULTS: We included 583 patients (27 with MMAS and 556 with mastocytosis). The prevalence of HαT in mastocytosis was 12.6%, significantly higher than in the general population (5.7%, P = .002) and lower than in MMAS (33.3%, P = .02). HαT+ patients were more likely to have anaphylactic reactions and less likely to have cutaneous lesions than HαT- patients (43.0% vs 24.4%, P = .006; 57.7% vs 75.6%, respectively, P = .006). In the pooled analysis, the prevalence of HαT was higher in advSM (11.5%) than in control cohorts (5.2%, P = .01). CONCLUSION: Here we confirm the increase incidence of anaphylaxis in HαT+ mastocytosis patients. The increased prevalence of HαT in all subtypes of systemic mastocytosis (including advSM) is suggestive of pathophysiologic involvement.

KIR3DL2 contributes to the typing of acute adult T-cell leukemia and is a potential therapeutic target.

Adult T-cell leukemia (ATL) is a lymphoid neoplasm caused by human T-cell leukemia virus type 1 (HTLV-1), which encodes the transcriptional activator Tax, which participates in the immortalization of infected T cells. ATL is classified into 4 subtypes: smoldering, chronic, acute, and lymphoma. We determined whether natural killer receptors (NKRs) were expressed in ATL. NKR expression (KIR2DL1/2DS1, KIR2DL2/2DL3/2DS2, KIR3DL2, NKG2A, NKG2C, and NKp46) was assessed in a discovery cohort of 21 ATL, and KIR3DL2 was then assessed in 71 patients with ATL. KIR3DL2 was the only NKR among those studied frequently expressed by acute-type vs lymphoma- and chronic/smoldering-type ATL (36 of 40, 4 of 16, and 1 of 15, respectively; P = .001), although acute- and lymphoma-type ATL had similar mutation profiles by targeted exome sequencing. The correlation of KIR3DL2 expression with promoter demethylation was determined by microarray-based DNA methylation profiling. To explore the role of HTLV-1, KIR3DL2 and TAX messenger RNA (mRNA) expression levels were assessed by PrimeFlow RNA in primary ATL and in CD4+ T cells infected with HTLV-1 in vitro. TAX mRNA and KIR3DL2 protein expressions were correlated on ATL cells. HTLV-1 infection triggered KIR3DL2 by CD4+ cells but Tax alone did not induce KIR3DL2 expression. Ex vivo, autologous, antibody-dependent cell cytotoxicity using lacutamab, a first-in-class anti-KIR3DL2 humanized antibody, selectively killed KIR3DL2+ primary ATL cells ex vivo. To conclude, KIR3DL2 expression is associated with acute-type ATL. Transcription of KIR3DL2 may be triggered by HTLV-1 infection and correlates with hypomethylation of the promoter. The benefit of targeting KIR3DL2 with lacutamab is being further explored in a randomized phase 2 study in peripheral T-cell lymphoma, including ATL (registered on https://clinicaltrials.gov as #NCT04984837).

Gene therapy for haemophilia A and B, from basic principles to clinical implementation: An illustrated review.

INTRODUCTION: With recent approval of the first two gene therapies for haemophilia A and B, educational materials about AAV-based gene therapy are needed by the haemophilia community for a better understanding of this novel therapeutic approach and helping healthcare providers and patients making personalized choices amongst an increasing array of therapeutic options. AIM: To provide a comprehensive summary of the whole process of AAV-based gene therapy from basic principles to clinical implementation through an illustrated review. METHODS: The authors, with expertise in and knowledge about gene therapy for haemophilia A and B, reviewed relevant articles from PubMed database and translated them into illustrations. RESULTS: The review is divided into eight illustrated sections providing an overview of gene therapy for haemophilia A and B from haemophilia basics and current treatment landscape, principles of the AAV-based liver-directed gene therapy, through exploring the efficacy and safety results of published phase III clinical trials, current and future challenges, to implementation in clinical practice, including the hub and spoke models and the patient journey. CONCLUSION: This illustrated review educates healthcare professionals on AAV-based gene therapy for haemophilia A and B enabling them to further educate their peers and their patients.

Histological characterization of liver involvement in systemic mastocytosis.

BACKGROUND AND AIMS: Systemic mastocytosis (SM) is characterized by the accumulation of atypical mast cells (MCs) in organs. Liver histology of SM has been marginally described and accurate histological classification is critical, given the consequences of aggressive SM diagnosis. We aimed to describe the histological features associated with liver SM using updated tools. METHODS: Using the database of the French Reference Centre for Mastocytosis, we retrospectively identified patients with a liver biopsy (LB) and a diagnosis of SM. All LB procedures were performed according to the local physician in charge and centrally reviewed by an expert pathologist. RESULTS: A total of 28 patients were included: 6 had indolent SM, 9 had aggressive SM, and 13 had SM with an associated hematologic neoplasm. Twenty-five (89%) patients presented hepatomegaly, and 19 (68%) had portal hypertension. The LB frequently showed slight sinusoid dilatation (82%). Fibrosis was observed in 3/6 indolent SM and in almost all advanced SM cases (21/22), but none of them showed cirrhosis. A high MC burden (>50 MCs/high-power field) was correlated with elevated blood alkaline phosphatase levels (p = .030). The presence of portal hypertension was associated with a higher mean fibrosis grade (1.6 vs. 0.8 in its absence; p = .026). In advanced SM, the presence of nodular regenerative hyperplasia (NRH) was associated with decreased overall survival (9.5 vs. 46.3 months, p = .002). CONCLUSIONS: MC infiltration induced polymorphic hepatic lesions and the degree of fibrosis is associated with portal hypertension. NRH identifies a poor prognosis subgroup of patients with advanced SM. Assessing liver histology can aid in SM prognostic evaluation.

Efficacy and safety of mammalian target of rapamycin inhibitors in systemic mastocytosis: A nationwide French pilot study.

Systemic mastocytosis (SM) corresponds to a rare and heterogeneous spectrum of diseases characterized by the accumulation of atypical mast cells (MCs). Advanced mastocytosis (Adv-SM) is associated with poor survival; in contrast, patients with non-advanced SM (non-Adv-SM) usually have a normal life expectancy but may experience poor quality of life. Despite recent therapeutic progress including tyrosine kinase inhibitors, new treatment options are needed for refractory and/or intolerant patients with both severely symptomatic and Adv-SM. In vitro, the mTOR pathway is activated in MCs from patients bearing the KIT D816V mutation. Furthermore, rapamycin induces the apoptosis of KIT D816V MCs selectively. In this nationwide study, we report the outcomes of patients diagnosed with SM and treated with a mammalian target of rapamycin inhibitor (imTOR) within the French National Reference Center for mastocytosis (CEREMAST). All patients registered were relapsing, treatment-refractory, or ineligible for other cytoreductive therapy. Non-Adv-SM patients received imTOR as a monotherapy (rapamycin/everolimus), and Adv-SM patients received imTOR as a monotherapy or in combination with cytarabine. The objective response rate (ORR) in non-Adv-SM was 60% (partial response in 40% and major response in 20%), including reductions in skin involvement, mediator release symptoms, and serum tryptase. In the Adv-SM group, the ORR was 20% (including one major response and one partial response, both in patients with a KIT D816V mutation), which enabled a successful bridge to allogeneic stem cell transplantation in one patient. Our results suggest that imTOR treatment has potential benefits in patients with SM harboring a KIT D816V mutation.

Real-world study of the efficacy and safety of belantamab mafodotin (GSK2857916) in relapsed or refractory multiple myeloma based on data from the nominative ATU in France: the IFM 2020-04 study.

Belantamab mafodotin (BM) is an anti-BCMA antibody-drug conjugate (GSK2857916) that represents an alternative option in multiple myeloma. We sought to assess the efficacy and safety of BM in a real-world setting in patients who benefited from an early access program. We conducted an observational, retrospective, multicenter study. Eligibility criteria were treatment of relapsed or refractory multiple myeloma (RRMM) in monotherapy in adult patients who have received at least three lines of therapy previously, including at least one immunomodulatory agent (IMiD), a proteasome inhibitor (PI) and an anti-CD38 monoclonal antibody, and whose disease progressed during the last treatment period. The primary endpoint of the study is to assess the overall survival (OS). Between November 2019 and December 2020, 106 patients were treated with BM; 97 were eligible for the efficacy evaluation and 104 for safety. The median age was 66 (range, 37-82) years. High-risk cytogenetics were identified in 40.9% of patients. Fifty-five (56.7%) patients were triple-class refractory and 11 (11.3%) were penta-class refractory. The median number of prior lines of treatment was five (range, 3-12). The median number of BM cycles administered was three (range, 1-22). The overall response rate at best response was 38.1% (37/97). The median OS was 9.3 months (95% confidence interval [CI]: 5.9-15.3), and median progression-free survival was 3.5 months (95% CI: 1.9-4.7). The median duration of response was 9 months (range, 4.65-10.4). Treatment was delayed for 55 (52.9%) patients including 36.5% for treatment-related toxicity. Ophthalmic adverse events, mainly grade ≤2, were the most common toxicity (48%). The occurrence of keratopathy was 37.5%. Overall, our data are concordant with the results from DREAMM-2 in terms of efficacy and safety on a non-biased population.

Matching-adjusted indirect comparison of bleeding outcomes in severe haemophilia A: Comparing valoctocogene roxaparvovec gene therapy, emicizumab prophylaxis, and FVIII replacement prophylaxis.

INTRODUCTION: Head-to-head evaluation of valoctocogene roxaparvovec, the first gene therapy approved for haemophilia A, with emicizumab is not available. Therefore, phase 3 trial data were indirectly compared. AIM: To compare bleeding rates in trials evaluating 6 × 1013  vg/kg valoctocogene roxaparvovec (GENEr8-1; NCT03370913), 1.5 mg/kg emicizumab dosed every week (HAVEN 3; NCT02847637), and FVIII prophylaxis (270-902) in participants with severe haemophilia A (FVIII ≤1 IU/dL). METHODS: Valoctocogene roxaparvovec versus emicizumab and FVIII prophylaxis as used in 270-902 versus emicizumab cross-trial comparisons were performed using matching-adjusted indirect comparison (MAIC). Individual participant data from GENEr8-1 and 270-902 were weighted to equalise aggregate participant baseline characteristics from HAVEN 3. After MAIC weighting, annualised bleeding rates (ABR) and proportions of participants without bleeds were compared for treated bleeds, all bleeds, treated joint bleeds, and treated spontaneous bleeds. RESULTS: After MAIC weighting, ABR for all bleeds was statistically significantly lower with valoctocogene roxaparvovec than emicizumab (rate ratio [95% CI], .55 [.33-.93]). Additionally, significantly higher proportions of participants had no treated joint bleeds (odds ratio [95% CI], 2.75 [1.20-6.31]) and no treated bleeds (3.25 [1.53-6.90]) with valoctocogene roxaparvovec versus emicizumab. When compared with the mainly standard half-life FVIII prophylaxis regimens in 270-902, mean ABRs (except for all bleeds) were significantly lower, and significantly higher proportions reported 0 bleeds for all outcomes with emicizumab. CONCLUSION: Valoctocogene roxaparvovec provided generally lower bleeding rates and higher probability of no bleeds, including treated joint bleeds, than emicizumab. Emicizumab was more effective than FVIII prophylaxis regimens used in 270-902.

Plain language summary of the MAIA study of daratumumab plus lenalidomide and dexamethasone for the treatment of people with newly diagnosed multiple myeloma.

WHAT IS THIS SUMMARY ABOUT?: This is a summary of a clinical trial called MAIA. The trial tested 2 combinations of cancer drugs (daratumumab plus lenalidomide and dexamethasone compared with lenalidomide and dexamethasone) in people with newly diagnosed multiple myeloma. None of the participants who took part in the study had been treated before or were eligible to receive stem-cell transplants. HOW WAS THE STUDY IN THIS SUMMARY CONDUCTED?: A total of 737 participants took part. Half of the participants took daratumumab plus lenalidomide and dexamethasone, while the other half of the participants took only lenalidomide and dexamethasone. Once participants started taking the drugs, the cancer was monitored for improvement (response to treatment), worsening (disease progression), or no change. Participants' blood and urine were tested for myeloma protein to measure response to the treatment. Participants were also monitored for side effects. WHAT WERE THE RESULTS OF THE STUDY?: After approximately 56 months of follow-up, more participants who took daratumumab plus lenalidomide and dexamethasone were alive and had decreased myeloma protein levels (indicating improvement of cancer) than participants who took only lenalidomide and dexamethasone. The most common side effects were abnormally low white and red blood cell counts and increased lung infections. WHAT DO THE RESULTS OF THE STUDY MEAN?: In the MAIA study, participants with multiple myeloma who took daratumumab plus lenalidomide and dexamethasone lived longer and had decreased myeloma protein levels than participants who took only lenalidomide and dexamethasone, indicating survival could be more likely with daratumumab added. Clinical Trial Registration: NCT02252172 (Phase 3 MAIA study).

Daratumumab plus Lenalidomide and Dexamethasone for Untreated Myeloma.

BACKGROUND: Lenalidomide plus dexamethasone is a standard treatment for patients with newly diagnosed multiple myeloma who are ineligible for autologous stem-cell transplantation. We sought to determine whether the addition of daratumumab would significantly reduce the risk of disease progression or death in this population. METHODS: We randomly assigned 737 patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation to receive daratumumab plus lenalidomide and dexamethasone (daratumumab group) or lenalidomide and dexamethasone alone (control group). Treatment was to continue until the occurrence of disease progression or unacceptable side effects. The primary end point was progression-free survival. RESULTS: At a median follow-up of 28.0 months, disease progression or death had occurred in 240 patients (97 of 368 patients [26.4%] in the daratumumab group and 143 of 369 patients [38.8%] in the control group). The estimated percentage of patients who were alive without disease progression at 30 months was 70.6% (95% confidence interval [CI], 65.0 to 75.4) in the daratumumab group and 55.6% (95% CI, 49.5 to 61.3) in the control group (hazard ratio for disease progression or death, 0.56; 95% CI, 0.43 to 0.73; P<0.001). The percentage of patients with a complete response or better was 47.6% in the daratumumab group and 24.9% in the control group (P<0.001). A total of 24.2% of the patients in the daratumumab group, as compared with 7.3% of the patients in the control group, had results below the threshold for minimal residual disease (1 tumor cell per 105 white cells) (P<0.001). The most common adverse events of grade 3 or 4 were neutropenia (50.0% in the daratumumab group vs. 35.3% in the control group), anemia (11.8% vs. 19.7%), lymphopenia (15.1% vs. 10.7%), and pneumonia (13.7% vs. 7.9%). CONCLUSIONS: Among patients with newly diagnosed multiple myeloma who were ineligible for autologous stem-cell transplantation, the risk of disease progression or death was significantly lower among those who received daratumumab plus lenalidomide and dexamethasone than among those who received lenalidomide and dexamethasone alone. A higher incidence of neutropenia and pneumonia was observed in the daratumumab group. (Funded by Janssen Research and Development; MAIA ClinicalTrials.gov number, NCT02252172.).

Oral Selinexor-Dexamethasone for Triple-Class Refractory Multiple Myeloma.

BACKGROUND: Selinexor, a selective inhibitor of nuclear export compound that blocks exportin 1 (XPO1) and forces nuclear accumulation and activation of tumor suppressor proteins, inhibits nuclear factor κB, and reduces oncoprotein messenger RNA translation, is a potential novel treatment for myeloma that is refractory to current therapeutic options. METHODS: We administered oral selinexor (80 mg) plus dexamethasone (20 mg) twice weekly to patients with myeloma who had previous exposure to bortezomib, carfilzomib, lenalidomide, pomalidomide, daratumumab, and an alkylating agent and had disease refractory to at least one proteasome inhibitor, one immunomodulatory agent, and daratumumab (triple-class refractory). The primary end point was overall response, defined as a partial response or better, with response assessed by an independent review committee. Clinical benefit, defined as a minimal response or better, was a secondary end point. RESULTS: A total of 122 patients in the United States and Europe were included in the modified intention-to-treat population (primary analysis), and 123 were included in the safety population. The median age was 65 years, and the median number of previous regimens was 7; a total of 53% of the patients had high-risk cytogenetic abnormalities. A partial response or better was observed in 26% of patients (95% confidence interval, 19 to 35), including two stringent complete responses; 39% of patients had a minimal response or better. The median duration of response was 4.4 months, median progression-free survival was 3.7 months, and median overall survival was 8.6 months. Fatigue, nausea, and decreased appetite were common and were typically grade 1 or 2 (grade 3 events were noted in up to 25% of patients, and no grade 4 events were reported). Thrombocytopenia occurred in 73% of the patients (grade 3 in 25% and grade 4 in 33%). Thrombocytopenia led to bleeding events of grade 3 or higher in 6 patients. CONCLUSIONS: Selinexor-dexamethasone resulted in objective treatment responses in patients with myeloma refractory to currently available therapies. (Funded by Karyopharm Therapeutics; STORM ClinicalTrials.gov number, NCT02336815.).

A prospective phase 2 trial of daratumumab in patients with previously treated systemic light-chain amyloidosis.

Daratumumab is a human monoclonal antibody targeting CD38, an antigen uniformly expressed by plasma cells in multiple myeloma and light-chain amyloidosis (AL). We report the results of a prospective multicenter phase 2 study of daratumumab monotherapy in AL (NCT02816476). Forty previously treated AL patients with a difference between involved and uninvolved free light chains (dFLC) >50 mg/L were included in 15 centers between September of 2016 and April of 2018. Patients received 6 28-day cycles of IV daratumumab, every week for cycles 1 and 2 and every 2 weeks for cycles 3 through 6. Median age was 69 years (range, 45-83). Twenty-six patients had ≥2 organs involved, with heart in 24 and kidney in 26. Median time from diagnosis to enrollment was 23 months (interquartile range, 4-122), with a median of 3 prior therapies (range, 1-5). At data cutoff (September of 2019), all patients discontinued therapy; 33 received the planned 6 cycles. Overall, 22 patients had hematological response, and 19 patients (47.5%) achieved very good partial response (dFLC <40 mg/L) or better. Median time to hematological response was 1 week. Patients with no response after 4 doses were unlikely to respond further. Renal and cardiac responses occurred in 8 and 7 patients, respectively. Daratumumab was well tolerated, with no unexpected adverse events. With a median follow-up of 26 months, the 2-year overall survival rate was 74% (95% confidence interval, 62-81). Daratumumab monotherapy is associated with deep and rapid hematological responses in previously treated AL patients, with a good safety profile. Further studies of daratumumab in combination regimens are warranted.

Emicizumab does not interfere with the activated clotting time.

INTRODUCTION: The activated clotting time (ACT) is a useful marker of unfractionated heparin (UFH) activity during cardiopulmonary bypass (CPB) or cardiac catheterization. Emicizumab, recently approved for bleeding prevention in haemophilia A patients, acts like FVIII but does not need prior activation; it therefore shortens coagulation times in assays using intrinsic pathway activators and so is expected to shorten the ACT. AIM: To evaluated emicizumab's impact on heparin-induced ACT (Hemochron®) prolongation. METHODS: We measured the high-range (HR) ACT in citrated blood samples from healthy donors (HDs) (n = 9), CPB patients (n = 3) and emicizumab-treated patients (n = 5) after spiking with UFH and/or emicizumab. The low range (LR) ACT was also measured in spiked-samples from HDs and emicizumab-treated patients. RESULTS: In HDs, the median [interquartile range] baseline HR-ACTs were similar with and without emicizumab (129 [123-138] and 136 [115-141] s for 50 µg/ml, respectively); whatever the concentration of emicizumab (10 to 50 µg/ml), increasing the UFH concentration (1-5 UI/ml) prolonged the HR-ACT. In blood from patients undergoing CPB, the HR-ACT prolongation observed during this procedure was not masked by emicizumab at any concentration. Likewise, the addition of increasing concentrations of UFH to blood from emicizumab-treated patients induced a concentration-dependent prolongation of HR-ACT. Baseline LR-ACT were prolonged in emicizumab-treated patients but as for HR-ACT, emicizumab does not prevent heparin-induced prolongation of LR-ACT. CONCLUSION: Emicizumab does not interfere with UFH-induced ACT prolongation. The hemochron® ACT can be used to monitor UFH in patients receiving emicizumab during CPB or cardiac catheterization.

Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone alone in newly diagnosed multiple myeloma (MAIA): overall survival results from a randomised, open-label, phase 3 trial.

BACKGROUND: In the primary analysis of the phase 3 MAIA trial (median follow-up 28·0 months), a significant improvement in progression-free survival was observed with daratumumab plus lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in transplantation-ineligible patients with newly diagnosed multiple myeloma. Here, we report the updated efficacy and safety results from a prespecified interim analysis for overall survival. METHODS: MAIA is an ongoing, multicentre, randomised, open-label, phase 3 trial that enrolled patients at 176 hospitals in 14 countries across North America, Europe, the Middle East, and the Asia-Pacific region. Eligible patients were aged 18 years or older, had newly diagnosed multiple myeloma, had an Eastern Cooperative Oncology Group performance status score of 0-2, and were ineligible for high-dose chemotherapy with autologous stem-cell transplantation because of their age (≥65 years) or comorbidities. Patients were randomly assigned (1:1) using randomly permuted blocks (block size 4) by an interactive web response system to receive 28-day cycles of intravenous daratumumab (16 mg/kg, once per week during cycles 1-2, once every 2 weeks in cycles 3-6, and once every 4 weeks thereafter) plus oral lenalidomide (25 mg on days 1-21 of each cycle) and oral dexamethasone (40 mg on days 1, 8, 15, and 22 of each cycle; daratumumab group) or lenalidomide and dexamethasone alone (control group). Randomisation was stratified by International Staging System disease stage, geographical region, and age. Neither patients nor investigators were masked to treatment assignment. The primary endpoint was progression-free survival, which was centrally assessed, and a secondary endpoint was overall survival (both assessed in the intention-to-treat population). The safety population included patients who received at least one dose of the study treatment. The results presented here are from a prespecified interim analysis for overall survival, for which the prespecified stopping boundary was p=0·0414. This trial is registered with ClinicalTrials.gov, NCT02252172. FINDINGS: Between March 18, 2015, and Jan 15, 2017, 952 patients were assessed for eligibility, of whom 737 patients were enrolled and randomly assigned to the daratumumab group (n=368) or the control group (n=369). At a median follow-up of 56·2 months (IQR 52·7-59·9), median progression-free survival was not reached (95% CI 54·8-not reached) in the daratumumab group versus 34·4 months (29·6-39·2) in the control group (hazard ratio [HR] 0·53 [95% CI 0·43-0·66]; p<0·0001). Median overall survival was not reached in either group (daratumumab group, 95% CI not reached-not reached; control group, 95% CI 55·7-not reached; HR 0·68 [95% CI 0·53-0·86]; p=0·0013). The most common (>15%) grade 3 or higher treatment-emergent adverse events were neutropenia (197 [54%] patients in the daratumumab group vs 135 [37%] patients in the control group), pneumonia (70 [19%] vs 39 [11%]), anaemia (61 [17%] vs 79 [22%]), and lymphopenia (60 [16%] vs 41 [11%]). Serious adverse events occurred in 281 (77%) patients in the daratumumab group and 257 (70%) patients in the control group. Treatment-related deaths occurred in 13 (4%) patients in the daratumumab group and ten (3%) patients in the control group. INTERPRETATION: Daratumumab plus lenalidomide and dexamethasone increased overall survival and progression-free survival in patients ineligible for stem-cell transplantation with newly diagnosed multiple myeloma. There were no new safety concerns. Our results support the frontline use of daratumumab plus lenalidomide and dexamethasone for patients with multiple myeloma who are ineligible for transplantation. FUNDING: Janssen Research & Development.

Poor outcome and high prevalence of invasive fungal infections in patients with adult T-cell leukemia/lymphoma exposed to zidovudine and interferon alfa.

Patients treated for adult T-Cell leukemia/lymphoma (ATL) have a poor prognosis and are prone to infectious complications which are poorly described. As the French reference center for ATL, we retrospectively analyzed 47 consecutive ATL (acute, n = 23; lymphoma, n = 14; chronic, n = 8; smoldering, n = 2) patients between 2006 and 2016 (median age 51 years, 96% Afro-Caribbean origin). The 3-year overall survival (OS) was 15.8%, 11.3%, and 85.7% for acute, lymphoma, and indolent (chronic and smoldering) forms respectively. Among aggressive subtypes, 20 patients received, as frontline therapy, high dose of zidovudine and interferon alfa (AZT-IFN⍺) resulting in an overall response rate (ORR) of 39% (complete response [CR] 33%) and 17 chemotherapy resulting of an ORR of 59% (CR 50%). Ninety-five infections occurred in 38 patients, most of whom had an acute subtype (n = 73/95; 77%). During their follow-up, patients receiving frontline chemotherapy or frontline AZT-IFNα developed infections in 74% (n = 14/19) and 89% (n = 24/27) of the cases respectively. Sixty-four (67%) of infections were microbiologically documented. Among them, invasive fungal infections (IFI, n = 11) included 2 Pneumocystis jirovecii pneumonia, 5 invasive aspergillosis, and 4 yeast fungemia. IFI exclusively occurred in patients with acute subtype mostly exposed to AZT-IFNα (n = 10/11) and experiencing prolonged (> 10 days) grade 4 neutropenia. Patients with aggressive subtype experiencing IFI had a lower OS than those who did not (median OS 5.4 months versus 18.4 months, p = 0.0048). ATL patients have a poor prognosis even in the modern era. Moreover, the high rate of infections impacts their management especially those exposed to AZT-IFNα.

Unique inflammatory signature in haemophilic arthropathy: miRNA changes due to interaction between blood and fibroblast-like synoviocytes.

In haemophilia, the recurrence of hemarthrosis leads to irreversible arthropathy termed haemophilic arthropathy (HA). However, HA is a unique form of arthropathy in which resident cells, such as fibroblast-like synoviocytes (FLS), come into direct contact with blood. Therefore, we hypothesized that FLS in HA could have a unique inflammatory signature as a consequence of their contact with blood. We demonstrated with ELISA and ELISPOT analyses that HA-FLS expressed a unique profile of cytokine secretion, which differed from that of non-HA-FLS, mainly consisting of cytokines involved in innate immunity. We showed that unstable cytokine mRNAs were involved in this process, especially through miRNA complexes as confirmed by DICER silencing. A miRNOME analysis revealed that 30 miRNAs were expressed differently between HA and non-HA-FLS, with most miRNAs involved in inflammatory control pathways or described in certain inflammatory diseases, such as rheumatoid arthritis or lupus. Analysis of transcriptomic networks, impacted by these miRNAs, revealed that protein processes and inflammatory pathways were particularly targeted in LPS-induced FLS, and in particular vascularization and osteoarticular modulation pathways in steady-state FLS. Our study demonstrates that the presence of blood in contact with FLS may induce durable miRNA changes that likely participate in HA pathophysiology.

Arsenic trioxide (As2O3) as a maintenance therapy for adult T cell leukemia/lymphoma.

BACKGROUND: Adult T-cell leukemia-lymphoma (ATL) is an aggressive mature lymphoid proliferation associated with poor prognosis. Standard of care includes chemotherapy and/or the combination of zidovudine and interferon-alpha. However, most patients experience relapse less than 6 months after diagnosis. Allogeneic stem cell transplantation is the only curative treatment, but is only feasible in a minority of cases. We previously showed in a mouse model that Arsenic trioxide (As2O3) targets ATL leukemia initiating cells. RESULTS: As2O3 consolidation was given in 9 patients with ATL (lymphoma n = 4; acute n = 2; and indolent n = 3), who were in complete (n = 4) and partial (n = 3) remission, in stable (n = 1) and in progressive (n = 1) disease. Patients received up to 8 weeks of As2O3 at the dose of 0.15 mg/kg/day intravenously in combination with zidovudine and interferon-alpha. One patient in progression died rapidly. Of the remaining eight patients, three with indolent ATL subtype showed overall survivals of 48, 53 and 97 months, and duration of response to As2O3 of 22, 25 and 73 months. The other 5 patients with aggressive ATL subtype had median OS of 36 months and a median duration of response of 10 months. Side effects were mostly hematological and cutaneous (one grade 3) and reversible with dose reduction of AZT/IFN and/or As2O3 discontinuation. The virus integration analysis revealed the regression of the predominant malignant clone in one patient with a chronic subtype. CONCLUSION: These results suggest that consolidation with As2O3 could be an option for patients with ATL in response after induction therapy and who are not eligible for allogeneic stem cell transplantation.

NKp46 is a diagnostic biomarker and may be a therapeutic target in gastrointestinal T-cell lymphoproliferative diseases: a CELAC study.

OBJECTIVES: Primary GI T-cell lymphoproliferative diseases (T-LPD) are heterogeneous entities, which raise difficult diagnosis and therapeutic challenges. We have recently provided evidences that lymphomas complicating coeliac disease (CD) arise from innate-like lymphocytes, which may carry NK receptors (NKRs). DESIGN: NKRs expression was compared by flow cytometry in intraepithelial lymphocytes (IEL) from CD, type I or type II refractory CD (RCD). NKp46 was next assessed by immunohistochemistry in paraffin-embedded biopsies from 204 patients with CD, RCDI, RCDII or GI T-cell lymphomas and from a validation cohort of 61 patients. The cytotoxic properties of an anti-NKp46 monoclonal antibody conjugated to pyrrolobenzodiazepine (PBD) was tested ex vivo in human primary tumour cells isolated from fresh duodenal biopsies. RESULTS: NKp46 (but not CD94, NKG2A, NKG2C, NKG2D) was significantly more expressed by malignant RCDII IEL than by normal IEL in CD and RCDI. In paraffin biopsies, detection of >25 NKp46+ IEL per 100 epithelial cells discriminated RCDII from CD and RCDI. NKp46 was also detected in enteropathy-associated T-cell lymphomas (EATL, 24/29) and in monomorphic epitheliotropic intestinal T-cell lymphomas (MEITL, 4/4) but not in indolent T-LPD (0/15). Treatment with anti-NKp46-PBD could efficiently and selectively kill human NKp46+ primary IEL ex vivo. CONCLUSION: NKp46 is a novel biomarker useful for diagnosis and therapeutic stratification of GI T-LPD. Strong preclinical rationale identifies anti-NKp46-PBD as a promising therapy for RCDII, EATL and MEITL.

Daratumumab and dexamethasone is safe and effective for triple refractory myeloma patients: final results of the IFM 2014-04 (Etoile du Nord) trial.

Single agent daratumumab has shown clinical activity in relapsed, refractory multiple myeloma (RRMM). The Intergroupe Francophone du Myélome 2014-04 trial was designed to further investigate daratumumab in combination with dexamethasone in triple RRMM patients. Patients received daratumumab infusions in combination with weekly dexamethasone until disease progression or unacceptable toxicity. Fifty-seven patients were included in the trial and evaluable for response. The overall response rate and the clinical benefit rate were 33% (n = 19) and 48% (n = 27), respectively. Five (8·8%) patients achieved a very good partial response or better. The median time to response was 4 weeks. For responding patients, the median progression-free survival was 6·6 months, compared to 3·7 months (3·0-5·5) for those with a minimal or stable disease. The median overall survival (OS) for all patients was 16·7 months (11·2-24·0). For responding patients, the median OS was 23·23 months, whereas that of patients with progressive disease was 2·97 months. The incidence of infusion-related reactions was 37%; all cases were manageable and did not lead to dose reduction or permanent treatment discontinuation. These data demonstrate that treatment with daratumumab and dexamethasone results in a meaningful long-term benefit with an acceptable safety profile for patients with triple RRMM.