Risk factors and outcomes of COVID-19 in adult patients with hematological malignancies: A single-center study showing lower than expected rates of hospitalization and mortality.

BACKGROUND: Studies addressing coronavirus disease 2019 (COVID-19) in patients with hematological malignancies have reported mortality rates of up to 40%; however, included predominantly hospitalized patients. METHODS: During the first year of the pandemic, we followed adult patients with hematological malignancies treated at a tertiary center in Jerusalem, Israel, who contracted COVID-19, with the aim of studying risk factors for adverse COVID-19-related outcomes. We used remote communication to track patients managed at home-isolation, and patient questioning to assess the source of COVID-19 infection, community versus nosocomial. RESULTS: Our series included 183 patients, median age was 62.5 years, 72% had at least one comorbidity and 39% were receiving active antineoplastic treatment. Hospitalization, critical COVID-19, and mortality rates were 32%, 12.6%, and 9.8%, respectively, remarkably lower than previously reported. Age, multiple comorbidities, and active antineoplastic treatment were significantly associated with hospitalization due to COVID-19. Treatment with monoclonal antibodies was strongly associated with both hospitalization and critical COVID-19. In older (≥60) patients not receiving active antineoplastic treatment, mortality, and severe COVID-19 rates were comparable to those of the general Israeli population. We did not detect patients that contracted COVID-19 within the Hematology Division. CONCLUSION: These findings are relevant for the future management of patients with hematological malignancies in COVID-19-affected regions.

From skepticism to openness: a qualitative narrative analysis of medical students' attitudes following an integrative medicine course.

OBJECTIVE: The present study aimed to explore attitudes of medical students following a course in integrative medicine (IM) focused on palliative and supportive cancer. METHOD: Attitudes to IM among pre-clerkship medical students were assessed following a 3-day required course, which included interviews with international experts in IM and "hands-on" workshops mentored by IM and non-IM healthcare professionals. Student reflections were analyzed qualitatively, and written narratives were examined thematically. RESULTS: Of 161 students, 102 (63.4%) provided post-course reflections. The main narrative themes included pre-course attitudes, attitude changes and influencing factors, and insights on implementing IM in clinical practice. Pre-course attitudes were predominantly skeptical, with post-course attitudes more open and non-judgmental, addressing research on IM effectiveness and safety. Students looked favorably on the implementation of IM in clinical practice and felt the course enhanced communication with patients. CONCLUSIONS: Student attitudes to IM shifted following the course, from a skeptical to a more non-judgmental and accepting approach. IM course may facilitate a better understanding of the limitations and risks of IM practices, particularly in the supportive cancer care setting, as well as implications regarding students' own resilience and professional growth.

Health-related quality of life in patients with relapsed or refractory multiple myeloma: treatment with daratumumab, lenalidomide, and dexamethasone in the phase 3 POLLUX trial.

In the phase 3 POLLUX trial, daratumumab in combination with lenalidomide and dexamethasone (D-Rd) significantly improved progression-free survival in patients with relapsed/refractory multiple myeloma (RRMM) compared with lenalidomide and dexamethasone (Rd) alone. Here, we present patient-reported outcomes (PROs) from POLLUX, assessed using the validated European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire Core 30-item (EORTC QLQ-C30) and the EuroQol 5-dimensional descriptive system (EQ-5D-5L) questionnaires. Changes from baseline are presented as least-squares mean changes with 95% confidence intervals (CIs) derived from a mixed-effects model. PRO assessment compliance rates were high and similar in both D-Rd and Rd groups through cycle 40 (week 156). In this on-treatment analysis, mean changes from baseline were significantly greater in EORTC QLQ-C30 global health status, physical functioning, and pain scores in the D-Rd group versus the Rd group at multiple time points; however, magnitude of changes was low, suggesting no meaningful impact on health-related quality of life (HRQoL). Subgroup results were similar to those in the overall population. In the POLLUX study, baseline HRQoL was maintained with prolonged D-Rd treatment. These findings complement the sustained and significant improvement in progression-free survival observed with D-Rd and supports its use in patients with RRMM. Clinical trial registration: NCT02076009.

Outcome of paraosseous extra-medullary disease in newly diagnosed multiple myeloma patients treated with new drugs.

Extramedullary disease is relatively frequent in multiple myeloma, but our knowledge on the subject is limited and mainly relies on small case series or single center experiences. Little is known regarding the role of new drugs in this setting. We performed a meta-analysis of eight trials focused on the description of extramedullary disease characteristics, clinical outcome, and response to new drugs. A total of 2,332 newly diagnosed myeloma patients have been included; 267 (11.4%) had extramedullary disease, defined as paraosseous in 243 (10.4%), extramedullary plasmocytoma in 12 (0.5%), and not classified in 12 (0.5%) patients. Median progression-free survival was 25.3 months and 25.2 in extramedullary disease and non-extramedullary disease patients, respectively. In multivariate analysis the presence of extramedullary disease did not impact on progression-free survival (hazard ratio 1.15, P=0.06), while other known prognostic factors retained their significance. Patients treated with immunomodulatory drugs, mainly lenalidomide, or proteasome inhibitors had similar progression-free survival and progression-free survival-2 regardless of extramedullary disease presence. Median overall survival was 63.5 months and 79.9 months (P=0.01) in extramedullary and non-extramedullary disease patients, respectively, and in multivariate analysis the presence of extramedullary disease was associated with a reduced overall survival (hazard ratio 1.41, P<0.001), in line with other prognostic factors. With the limits of the use of low sensitivity imaging techniques, that lead to an underestimation of extramedullary disease, we conclude that in patients treated with new drugs the detrimental effect of extramedullary disease at diagnosis is limited, that lenalidomide is effective as are proteasome inhibitors, and that these patients tend to acquire a more aggressive disease in later stages. (EUDRACT2005-004714-32, NCT01063179 NCT00551928, NCT01091831, NCT01093196, NCT01190787, NCT01346787, NCT01857115).

Parameters associated with sperm quality prior to chemotherapy in lymphoma patients.

Sperm quality in lymphoma patients may be reduced even prior to initiation of chemotherapy. The objective of this study was to examine the relationship between lymphoma prognostic factors and sperm quality prior to chemotherapy. A retrospective cohort study was conducted in a Hadassah Medical Center sperm bank and the Hematology department. The cohort included 101 Hodgkin's and 90 non-Hodgkin's lymphoma patients that underwent sperm cryopreservation before chemotherapy between 1998 and 2015. Known lymphoma prognostic factors were compared between patients with normal and impaired sperm parameters. The Prognostic Score Ratio (PSR), an index representing the number of negative lymphoma prognostic measures that found in a lymphoma patient, was additionally calculated and compared between the groups. Among the prognostic factors of lymphoma, the following factors were found to be associated with impaired sperm parameters-low albumin (p < 0.001) and haemoglobin (p < 0.001) levels, B symptoms (p = 0.021) and PSR (p < 0.001). Logistic regression showed significant association of albumin and haemoglobin with reduced sperm quality (OR = 2.7 and OR = 13.5, p < 0.05; respectively). To conclude, low albumin and haemoglobin levels are related to reduced sperm quality. The linkage between these prognostic factors and sperm quality may be related to a general inflammatory status.

Ibrutinib plus obinutuzumab versus chlorambucil plus obinutuzumab in first-line treatment of chronic lymphocytic leukaemia (iLLUMINATE): a multicentre, randomised, open-label, phase 3 trial.

BACKGROUND: Both single-agent ibrutinib and chlorambucil plus obinutuzumab have shown superior efficacy to chlorambucil monotherapy and are standard first-line treatments in chronic lymphocytic leukaemia. We compared the efficacy of the combination of ibrutinib plus obinutuzumab with chlorambucil plus obinutuzumab in first-line chronic lymphocytic leukaemia or small lymphocytic lymphoma. METHODS: iLLUMINATE is a multicentre, randomised, open-label, phase 3 trial done at 74 academic and community hospitals in Australia, Canada, Israel, New Zealand, Russia, Turkey, the EU, and the USA in patients with previously untreated chronic lymphocytic leukaemia or small lymphocytic lymphoma, either aged 65 years or older or younger than 65 years with coexisting conditions. Patients were randomly assigned (1:1) using a blocked randomisation schedule, stratified by Eastern Cooperative Oncology Group performance status and cytogenetics, to receive ibrutinib plus obinutuzumab (oral ibrutinib [420 mg once daily continuously] combined with intravenous obinutuzumab [100 mg on day 1, 900 mg on day 2, 1000 mg on day 8, and 1000 mg on day 15 of cycle 1 and on day 1 of subsequent 28-day cycles, for a total of six cycles]) or chlorambucil plus obinutuzumab (oral chlorambucil [0·5 mg/kg bodyweight on days 1 and 15 of each 28-day cycle for six cycles] combined with the same obinutuzumab regimen). Allocation concealment was achieved using an interactive web response system. Patients and investigators were not masked to treatment assignment. The primary endpoint was progression-free survival assessed by a masked independent review committee in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of study treatment. This study is registered with ClinicalTrials.gov (NCT02264574), and patient enrolment is complete. FINDINGS: Between Oct 6, 2014, and Oct 12, 2015, 229 patients were enrolled and randomly assigned to receive ibrutinib plus obinutuzumab (n=113) or chlorambucil plus obinutuzumab (n=116). After a median follow-up of 31·3 months (IQR 29·4-33·2), median progression-free survival was significantly longer in the ibrutinib plus obinutuzumab group (median not reached [95% CI 33·6-non-estimable]) than in the chlorambucil plus obinutuzumab group (19·0 months [15·1-22·1]; hazard ratio 0·23; 95% CI 0·15-0·37; p<0·0001). Estimated 30-month progression-free survival was 79% (95% CI 70-85) in the ibrutinib plus obinutuzumab group and 31% (23-40) in the chlorambucil plus obinutuzumab group. The most common grade 3 or 4 adverse events in both groups were neutropenia and thrombocytopenia. Serious adverse events occurred in 65 (58%) of 113 patients treated with ibrutinib plus obinutuzumab and 40 (35%) of 115 patients treated with chlorambucil plus obinutuzumab. Ibrutinib or chlorambucil treatment-related deaths were reported in one (1%) of 113 patients in the ibrutinib plus obinutuzumab group (sudden death) and one (1%) of 115 patients in the chlorambucil plus obinutuzumab group (neuroendocrine carcinoma of the skin). INTERPRETATION: Ibrutinib plus obinutuzumab is an efficacious and safe chemotherapy-free combination treatment in previously untreated patients with chronic lymphocytic leukaemia or small lymphocytic lymphoma independent of high-risk features and provides an alternative first-line treatment option for these patients. FUNDING: Pharmacyclics LLC, an AbbVie Company, and Janssen Research and Development.

Daratumumab, Lenalidomide, and Dexamethasone for Multiple Myeloma.

BACKGROUND: Daratumumab showed promising efficacy alone and with lenalidomide and dexamethasone in a phase 1-2 study involving patients with relapsed or refractory multiple myeloma. METHODS: In this phase 3 trial, we randomly assigned 569 patients with multiple myeloma who had received one or more previous lines of therapy to receive lenalidomide and dexamethasone either alone (control group) or in combination with daratumumab (daratumumab group). The primary end point was progression-free survival. RESULTS: At a median follow-up of 13.5 months in a protocol-specified interim analysis, 169 events of disease progression or death were observed (in 53 of 286 patients [18.5%] in the daratumumab group vs. 116 of 283 [41.0%] in the control group; hazard ratio, 0.37; 95% confidence interval [CI], 0.27 to 0.52; P<0.001 by stratified log-rank test). The Kaplan-Meier rate of progression-free survival at 12 months was 83.2% (95% CI, 78.3 to 87.2) in the daratumumab group, as compared with 60.1% (95% CI, 54.0 to 65.7) in the control group. A significantly higher rate of overall response was observed in the daratumumab group than in the control group (92.9% vs. 76.4%, P<0.001), as was a higher rate of complete response or better (43.1% vs. 19.2%, P<0.001). In the daratumumab group, 22.4% of the patients had results below the threshold for minimal residual disease (1 tumor cell per 105 white cells), as compared with 4.6% of those in the control group (P<0.001); results below the threshold for minimal residual disease were associated with improved outcomes. The most common adverse events of grade 3 or 4 during treatment were neutropenia (in 51.9% of the patients in the daratumumab group vs. 37.0% of those in the control group), thrombocytopenia (in 12.7% vs. 13.5%), and anemia (in 12.4% vs. 19.6%). Daratumumab-associated infusion-related reactions occurred in 47.7% of the patients and were mostly of grade 1 or 2. CONCLUSIONS: The addition of daratumumab to lenalidomide and dexamethasone significantly lengthened progression-free survival among patients with relapsed or refractory multiple myeloma. Daratumumab was associated with infusion-related reactions and a higher rate of neutropenia than the control therapy. (Funded by Janssen Research and Development; POLLUX ClinicalTrials.gov number, NCT02076009 .).

Ixazomib significantly prolongs progression-free survival in high-risk relapsed/refractory myeloma patients.

Certain cytogenetic abnormalities are known to adversely impact outcomes in patients with multiple myeloma (MM). The phase 3 TOURMALINE-MM1 study demonstrated a significant improvement in progression-free survival (PFS) with ixazomib-lenalidomide-dexamethasone (IRd) compared with placebo-lenalidomide-dexamethasone (placebo-Rd). This preplanned analysis assessed the efficacy and safety of IRd vs placebo-Rd according to cytogenetic risk, as assessed using fluorescence in situ hybridization. High-risk cytogenetic abnormalities were defined as del(17p), t(4;14), and/or t(14;16); additionally, patients were assessed for 1q21 amplification. Of 722 randomized patients, 552 had cytogenetic results; 137 (25%) had high-risk cytogenetic abnormalities and 172 (32%) had 1q21 amplification alone. PFS was improved with IRd vs placebo-Rd in both high-risk and standard-risk cytogenetics subgroups: in high-risk patients, the hazard ratio (HR) was 0.543 (95% confidence interval [CI], 0.321-0.918; P = .021), with median PFS of 21.4 vs 9.7 months; in standard-risk patients, HR was 0.640 (95% CI, 0.462-0.888; P = .007), with median PFS of 20.6 vs 15.6 months. This PFS benefit was consistent across subgroups with individual high-risk cytogenetic abnormalities, including patients with del(17p) (HR, 0.596; 95% CI, 0.286-1.243). PFS was also longer with IRd vs placebo-Rd in patients with 1q21 amplification (HR, 0.781; 95% CI, 0.492-1.240), and in the "expanded high-risk" group, defined as those with high-risk cytogenetic abnormalities and/or 1q21 amplification (HR, 0.664; 95% CI, 0.474-0.928). IRd demonstrated substantial benefit compared with placebo-Rd in relapsed and/or refractory MM (RRMM) patients with high-risk and standard-risk cytogenetics, and improves the poor PFS associated with high-risk cytogenetic abnormalities. This trial was registered at www.clinicaltrials.gov as #NCT01564537.

Evaluation of cerebrospinal clonal gene rearrangement in newly diagnosed non-Hodgkin's lymphoma patients.

Overt central nervous system (CNS) involvement in aggressive non-Hodgkin's lymphoma (NHL) is rare at diagnosis. Much effort is put to identify risk factors for occult CNS involvement, and the risk assessment of CNS relapse. Prophylactic treatment carries risk of adverse events and its efficacy is not clear. Detection of cerebrospinal fluid molecular gene rearrangement (GRR) as a method to detect occult disease has been studied in acute leukemia and primary CNS lymphoma. To date, the capacity of a positive GRR in newly diagnosed NHL patients to predict CNS relapse has not been addressed. We retrospectively studied the prognostic value of GRR in cerebrospinal fluid samples of 148 newly diagnosed patients with high grade NHL. We demonstrate that positive GRR at diagnosis does not affect PFS or OS and did not predict CNS relapse. However, although numbers were small, repeated positive samples (≥ 2) correlated with a higher risk for CNS relapse (p = 0.048), possibly stressing the need for an aggressive preventive approach.

[THE TIME HAS COME! COMPLEMENTARY MEDICINE IN MEDICAL TRAINING IN ISRAEL].

INTRODUCTION: The use of complementary and alternative medicine (CAM) has become increasingly popular in most Western countries. As a result, safety-related issues associated with these practices have become more apparent, including adverse effects and negative interactions with conventional medical therapies. The potential dangers associated with CAM are further exacerbated by the absence of high-quality clinical research on the subject; a lack of a basic understanding of the principles of CAM among physicians; and a reluctance of patients to disclose their use of CAM, including those modalities being used in parallel with conventional medical treatments. The increase in CAM use by their patients and the increased potential for harmful effects and interactions are central to the increasing interest among physicians and other healthcare professionals in learning more about CAM paradigms and practices of care. In light of this increasing interest in CAM, the majority of medical schools in the U.S. and Canada and a large number in Europe are providing their students with compulsory or elective courses on this subject. A similar process is taking place in Israel, with the Faculty of Medicine at the Hebrew University in Jerusalem having completed its first compulsory course in CAM at the Hadassah University Medical Center, Ein Karem. The increased use of CAM presents a number of challenges to the conventional medical profession. Medical schools can and should provide students with the knowledge and skills which will enable them to discuss CAM use with their patients, providing evidence-based guidance on the safe and effective use of these modalities.

Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma.

BACKGROUND: Lenalidomide plus dexamethasone is a reference treatment for relapsed multiple myeloma. The combination of the proteasome inhibitor carfilzomib with lenalidomide and dexamethasone has shown efficacy in a phase 1 and 2 study in relapsed multiple myeloma. METHODS: We randomly assigned 792 patients with relapsed multiple myeloma to carfilzomib with lenalidomide and dexamethasone (carfilzomib group) or lenalidomide and dexamethasone alone (control group). The primary end point was progression-free survival. RESULTS: Progression-free survival was significantly improved with carfilzomib (median, 26.3 months, vs. 17.6 months in the control group; hazard ratio for progression or death, 0.69; 95% confidence interval [CI], 0.57 to 0.83; P=0.0001). The median overall survival was not reached in either group at the interim analysis. The Kaplan-Meier 24-month overall survival rates were 73.3% and 65.0% in the carfilzomib and control groups, respectively (hazard ratio for death, 0.79; 95% CI, 0.63 to 0.99; P=0.04). The rates of overall response (partial response or better) were 87.1% and 66.7% in the carfilzomib and control groups, respectively (P<0.001; 31.8% and 9.3% of patients in the respective groups had a complete response or better; 14.1% and 4.3% had a stringent complete response). Adverse events of grade 3 or higher were reported in 83.7% and 80.7% of patients in the carfilzomib and control groups, respectively; 15.3% and 17.7% of patients discontinued treatment owing to adverse events. Patients in the carfilzomib group reported superior health-related quality of life. CONCLUSIONS: In patients with relapsed multiple myeloma, the addition of carfilzomib to lenalidomide and dexamethasone resulted in significantly improved progression-free survival at the interim analysis and had a favorable risk-benefit profile. (Funded by Onyx Pharmaceuticals; ClinicalTrials.gov number, NCT01080391.).

Carfilzomib significantly improves the progression-free survival of high-risk patients in multiple myeloma.

The presence of certain high-risk cytogenetic abnormalities, such as translocations (4;14) and (14;16) and deletion (17p), are known to have a negative impact on survival in multiple myeloma (MM). The phase 3 study ASPIRE (N = 792) demonstrated that progression-free survival (PFS) was significantly improved with carfilzomib, lenalidomide, and dexamethasone (KRd), compared with lenalidomide and dexamethasone (Rd) in relapsed MM. This preplanned subgroup analysis of ASPIRE was conducted to evaluate KRd vs Rd by baseline cytogenetics according to fluorescence in situ hybridization. Of 417 patients with known cytogenetic risk status, 100 patients (24%) were categorized with high-risk cytogenetics (KRd, n = 48; Rd, n = 52) and 317 (76%) were categorized with standard-risk cytogenetics (KRd, n = 147; Rd, n = 170). For patients with high-risk cytogenetics, treatment with KRd resulted in a median PFS of 23.1 months, a 9-month improvement relative to treatment with Rd. For patients with standard-risk cytogenetics, treatment with KRd led to a 10-month improvement in median PFS vs Rd. The overall response rates for KRd vs Rd were 79.2% vs 59.6% (high-risk cytogenetics) and 91.2% vs 73.5% (standard-risk cytogenetics); approximately fivefold as many patients with high- or standard-risk cytogenetics achieved a complete response or better with KRd vs Rd (29.2% vs 5.8% and 38.1% vs 6.5%, respectively). KRd improved but did not abrogate the poor prognosis associated with high-risk cytogenetics. This regimen had a favorable benefit-risk profile in patients with relapsed MM, irrespective of cytogenetic risk status, and should be considered a standard of care in these patients. This trial was registered at www.clinicaltrials.gov as #NCT01080391.

A phase II multicenter study of the anti-CD19 antibody drug conjugate coltuximab ravtansine (SAR3419) in patients with relapsed or refractory diffuse large B-cell lymphoma previously treated with rituximab-based immunotherapy.

This phase II, single-arm, multicenter study examined the efficacy and safety of coltuximab ravtansine (an anti-CD19 antibody drug conjugate) in 61 patients with histologically documented (de novo or transformed) relapsed or refractory diffuse large B-cell lymphoma who had previously received rituximab-containing immuno-chemotherapy. Patients had received a median of 2.0 (range 0-9) prior treatment regimens for diffuse large B-cell lymphoma and almost half (45.9%) had bulky disease (≥1 lesion >5 cm) at trial entry. Patients received coltuximab ravtansine (55 mg/m2) in 4 weekly and 4 biweekly administrations until disease progression or unacceptable toxicity. Forty-one patients were eligible for inclusion in the per protocol population. Overall response rate (International Working Group criteria) in the per protocol population, the primary end point, was 18/41 [43.9%; 90% confidence interval (CI:) 30.6-57.9%]. Median duration of response, progression-free survival, and overall survival (all treated patients) were 4.7 (range 0.0-8.8) months, 4.4 (90%CI: 3.02-5.78) months, and 9.2 (90%CI: 6.57-12.09) months, respectively. Common non-hematologic adverse events included asthenia/fatigue (30%), nausea (23%), and diarrhea (20%). Grade 3-4 adverse events were reported in 23 patients (38%), the most frequent being hepatotoxicity (3%) and abdominal pain (3%). Eye disorders occurred in 15 patients (25%); all were grade 1-2 and none required a dose modification. Coltuximab ravtansine monotherapy was well tolerated and resulted in moderate clinical responses in pre-treated patients with relapsed/refractory diffuse large B-cell lymphoma. (Registered at: clinicaltrials.gov identifier: 01472887).

Presence of autoimmune disease affects not only risk but also survival in patients with B-cell non-Hodgkin lymphoma.

Although autoimmune diseases (AIDs) are known to predispose to non-Hodgkin lymphoma (NHL), their association with NHL prognosis has rarely been investigated. We examined associations between autoimmunity and B-cell NHL onset by comparing AID history (determined by self-report and medication review and supplemented by chart review where possible) among 435 adult B-NHL patients in Hadassah-Hebrew University Medical Center, diagnosed 2009-2014, and 414 age-and-sex frequency-matched controls. We examined AIDs as a whole, B- and T-cell-mediated AIDs, and autoimmune thyroid diseases. Among cases, we used Kaplan-Meier and Cox regression models to assess the association of AID with overall survival and relapse-free survival, adjusting for prognostically important patient and disease characteristics such as Ki67% staining, International Prognostic Index, rituximab treatment, and histological subgroup. Autoimmune diseases were associated with B-NHL (odds ratio [OR] = 1.95; 95% confidence interval (CI), 1.31-2.92), especially AIDs mediated by B-cell activation (OR = 5.20; CI, 1.90-14.3), which were particularly associated with marginal zone lymphoma (OR = 19.3; CI, 4.59-80.9). We found that time to relapse for all B-NHL patients with AIDs was significantly shorter (mean of 49.21 mo [±3.22]) than among patients without AID (mean of 59.74 mo [±1.62]), adjusted hazard ratio [HRadj ] = 1.69 (CI, 1.03-2.79). Specifically, in patients with diffuse large B-cell lymphoma, of whom 91.8% had received rituximab, a history of B-cell-mediated AIDs was associated with shorter relapse-free survival and overall survival, HRadj  = 8.34 (CI, 3.01-23.1) and HRadj  = 3.83 (CI, 1.20-12.3), respectively. Beyond confirming the well-known association between AIDs and B-NHL, we found that AID is an adverse prognostic factor in B-cell lymphoma, associated with a shortened time to relapse, suggesting that there are specific therapeutic challenges in the subgroup of patients suffering from both these diseases. Further work is required to address mechanisms of resistance to standard treatment in the setting of AID-associated B-NHL. In the era of immunotherapy, these findings have particular relevance.

Daratumumab resistance is frequent in advanced-stage multiple myeloma patients irrespective of CD38 expression and is related to dismal prognosis.

OBJECTIVE: Daratumumab is a promising new antimyeloma agent. We report a single center "real-world" series of multiple myeloma (MM) and amyloidosis (AL) patients treated with daratumumab. METHODS: Forty-one patients were included: 7 second-line MM, 30 heavily pretreated (median number of therapies of 5) advanced MM, and 4 with AL. RESULTS: Second-line patients and advanced AL showed high rate of durable overall responses. However, advanced MM patients had a dismal prognosis with an overall response rate (ORR) of 36%, and a short median progression-free and overall survival of 2.3 and 6.6 months, respectively. Responses were particularly poor in patients with extramedullary plasmacytomas. Neither the addition of another agent to daratumumab nor changing to the next line of therapy produced significant durable responses in this patient population. Flow cytometry analysis demonstrated that CD38 expression level was not predictive of response. We show that CD38 expression dynamics by a commercially available anti-CD38 antibody after daratumumab administration was hindered by competitive binding of daratumumab. CONCLUSIONS: Responses to daratumumab and combinations in patients with advanced MM, particularly with extramedullary disease, are low and short-lived, stressing the administration of this agent should be early in the course of the disease.

Modification of initial therapy in early and advanced Hodgkin lymphoma, based on interim PET/CT is beneficial: a prospective multicentre trial of 355 patients.

This multicentre study evaluated 5-year progression-free (PFS) and overall survival (OS) in early and advanced Hodgkin lymphoma (HL), where therapy was individualized based on initial prognostic factors and positron emission tomography-computed tomography performed after two cycles (PET-2). Between September 2006 and August 2013, 359 patients aged 18-60 years, were recruited in nine Israeli centres. Early-HL patients initially received ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) ×2. Depending on initial unfavourable prognostic features, PET-2-positive patients received additional ABVD followed by involved-site radiotherapy (ISRT). Patients with negative PET-2 and favourable disease received ISRT or ABVD ×2; those with unfavourable disease received ABVD ×2 with ISRT or, alternatively, ABVD ×4. Advanced-HL patients initially received ABVD ×2 or escalated BEACOPP (bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procarbazine, prednisone; EB) ×2 based on their international prognostic score (≤2 or ≥3). PET-2-negative patients further received ABVD ×4; PET-2-positive patients received EB ×4 and ISRT to residual masses. With a median follow-up of 55 (13-119) months, 5-year PFS was 91% and 69% for PET-2-negative and positive early-HL, respectively; 5-year OS was 100% and 95%, respectively. For advanced-HL, the PFS was 81% and 68%, respectively (P = 0·08); 5-year OS was 98% and 91%, respectively. PET-2 positivity is associated with inferior prognosis in early-HL, even with additional ABVD and ISRT. Advanced-HL patients benefit from therapy escalation following positive PET-2. EB can be safely de-escalated to ABVD in PET-2-negative patients.

Autologous transplantation and maintenance therapy in multiple myeloma.

BACKGROUND: This open-label, randomized, phase 3 study compared melphalan at a dose of 200 mg per square meter of body-surface area plus autologous stem-cell transplantation with melphalan-prednisone-lenalidomide (MPR) and compared lenalidomide maintenance therapy with no maintenance therapy in patients with newly diagnosed multiple myeloma. METHODS: We randomly assigned 273 patients 65 years of age or younger to high-dose melphalan plus stem-cell transplantation or MPR consolidation therapy after induction, and 251 patients to lenalidomide maintenance therapy or no maintenance therapy. The primary end point was progression-free survival. RESULTS: The median follow-up period was 51.2 months. Both progression-free and overall survival were significantly longer with high-dose melphalan plus stem-cell transplantation than with MPR (median progression-free survival, 43.0 months vs. 22.4 months; hazard ratio for progression or death, 0.44; 95% confidence interval [CI], 0.32 to 0.61; P<0.001; and 4-year overall survival, 81.6% vs. 65.3%; hazard ratio for death, 0.55; 95% CI, 0.32 to 0.93; P=0.02). Median progression-free survival was significantly longer with lenalidomide maintenance than with no maintenance (41.9 months vs. 21.6 months; hazard ratio for progression or death, 0.47; 95% CI, 0.33 to 0.65; P<0.001), but 3-year overall survival was not significantly prolonged (88.0% vs. 79.2%; hazard ratio for death, 0.64; 95% CI, 0.36 to 1.15; P=0.14). Grade 3 or 4 neutropenia was significantly more frequent with high-dose melphalan than with MPR (94.3% vs. 51.5%), as were gastrointestinal adverse events (18.4% vs. 0%) and infections (16.3% vs. 0.8%); neutropenia and dermatologic toxic effects were more frequent with lenalidomide maintenance than with no maintenance (23.3% vs. 0% and 4.3% vs. 0%, respectively). CONCLUSIONS: Consolidation therapy with high-dose melphalan plus stem-cell transplantation, as compared with MPR, significantly prolonged progression-free and overall survival among patients with multiple myeloma who were 65 years of age or younger. Lenalidomide maintenance, as compared with no maintenance, significantly prolonged progression-free survival. (Funded by Celgene; ClinicalTrials.gov number, NCT00551928.).

The JAK2V617F mutation in normal individuals takes place in differentiating cells.

The JAK2V617F mutation that results in a hyper-activation of the JAK2 kinase in the erythropoietin pathway is a molecular marker for myeloproliferative neoplasms. Using allele-specific Real-Time PCR, we detected the mutation in the blood of 17.3% (17/98) of normal donors; the mutant allele burden was, however, very low (<0.01% compared to >1% in polycythemia vera). It was much higher in differentiated blood cells in the peripheral blood than in undifferentiated CD34+ cells. Erythropoietin-stimulated differentiation of normal CD34+ cells in liquid culture increased the mutation frequency by 3.34-fold. When progenitors from 9 normal donors were grown in erythropoietin-stimulated semi-solid cultures, the mutation was found in 8.69% of the colonies, but only in <3% of the JAK2 alleles in each positive colony, suggesting that the mutation occurred only in a few cells per colony. In mouse erythroleukemia cells carrying human JAK2 DNA, wild-type or JAK2V617F, the frequencies of mutations from JAK2 wild-type to JAK2V617F and vice versa increased following erythroid differentiation. These results suggest that the mutation occurs and accumulates during differentiation. We hypothesize that genetic stability, which relies on DNA repair, is efficient in normal hematopoietic stem cells but is downgraded in differentiating cells, rendering them susceptible to mutations, including JAK2V617F.

Immune evasion by oncogenic proteins of acute myeloid leukemia.

PML-RARA and AML1-ETO are important oncogenic fusion proteins that play a central role in transformation to acute myeloid leukemia (AML). Whether these fusion proteins render the tumor cells with immune evasion properties is unknown. Here we show that both oncogenic proteins specifically downregulate the expression of CD48, a ligand of the natural killer (NK) cell activating receptor 2B4, thereby leading to decreased killing by NK cells. We demonstrate that this process is histone deacetylase (HDAC)-dependent, that it is mediated through the downregulation of CD48 messenger RNA, and that treatment with HDAC inhibitors (HDACi) restores the expression of CD48. Furthermore, by using chromatin immunoprecepitation (ChIP) experiments, we show that AML1-ETO directly interacts with CD48. Finally, we show that AML patients who are carrying these specific translocations have low expression of CD48.

Susceptibility loci associated with specific and shared subtypes of lymphoid malignancies.

The genetics of lymphoma susceptibility reflect the marked heterogeneity of diseases that comprise this broad phenotype. However, multiple subtypes of lymphoma are observed in some families, suggesting shared pathways of genetic predisposition to these pathologically distinct entities. Using a two-stage GWAS, we tested 530,583 SNPs in 944 cases of lymphoma, including 282 familial cases, and 4,044 public shared controls, followed by genotyping of 50 SNPs in 1,245 cases and 2,596 controls. A novel region on 11q12.1 showed association with combined lymphoma (LYM) subtypes. SNPs in this region included rs12289961 near LPXN, (P(LYM) = 3.89×10(-8), OR = 1.29) and rs948562 (P(LYM) = 5.85×10(-7), OR = 1.29). A SNP in a novel non-HLA region on 6p23 (rs707824, P(NHL) = 5.72×10(-7)) was suggestive of an association conferring susceptibility to lymphoma. Four SNPs, all in a previously reported HLA region, 6p21.32, showed genome-wide significant associations with follicular lymphoma. The most significant association with follicular lymphoma was for rs4530903 (P(FL) = 2.69×10(-12), OR = 1.93). Three novel SNPs near the HLA locus, rs9268853, rs2647046, and rs2621416, demonstrated additional variation contributing toward genetic susceptibility to FL associated with this region. Genes implicated by GWAS were also found to be cis-eQTLs in lymphoblastoid cell lines; candidate genes in these regions have been implicated in hematopoiesis and immune function. These results, showing novel susceptibility regions and allelic heterogeneity, point to the existence of pathways of susceptibility to both shared as well as specific subtypes of lymphoid malignancy.