Molecular and clinical features of myeloid neoplasms with somatic DDX41 mutations.

We screened 47 subjects with DDX41 variants among 1529 subjects with myeloid neoplasms. The most common germline variants included Splice c.935 + 4A>T, p.T360Ifs*33, p.V152G, p.S217Ifs*4, p.R311* and p.R369*. Except for the p.R369*, no other variants have been previously reported. Clinical covariates of subjects with simple DDX41 somatic variants and germline/somatic biallelic variants are similar. The two-year overall survival (OS) of subjects with DDX41 variants was 85%. Overall response rate to demethylation therapy in subjects with DDX41 variants was 69%. The response did not correlate with the presence of a germline variant.

A prognostic immune risk score for diffuse large B-cell lymphoma.

We constructed a prognostic score for persons with diffuse large B-cell lymphoma (DLBCL) based on infiltrating immune cells. Data of 956 consecutive subjects were retrieved from the Gene Expression Omnibus database and assigned to training (GSE10846, n = 305) or validation (GSE87371 n = 206 and GSE117556 n = 445 combined) cohorts. Proportions of non-lymphoma cells in the sample were inferred using the ESTIMATE algorithm. An immune risk score was constructed comprised of eight types of non-lymphoma immune cells calculated using the CIBERSORT algorithm. Five-year survival of subjects with an immune risk score ≤ 0·45 in the training cohort was better than that of subjects with a score > 0·45 (hazard ratio [HR] = 3·99; 95% confidence interval [CI] = 2·74, 5·82; P < 0·001). HR in the validation cohort was HR = 2·17 (1·47, 3·21; P < 0·001). Enrichment analyses indicated correlations with genes controlling immune-related biological processes and pathways. A nomogram comprised of the immune risk score and most covariates including age, lactate dehydrogenase concentration (LDH), lymphoma-type (germinal centre B cell [GCB] versus non-GCB), Eastern Cooperative Oncology Group performance status (ECOG-PS) and rituximab therapy had a C-statistic of 0·76 compared with C-statistics of 0·69 and 0·69 for the International Prognostic Index (IPI) and Revised International Prognostic Index (R-IPI). These data indicate the immune risk score is an accurate, independent survival predictor in persons with DLBCL.

Novel prognostic scoring system for autologous hematopoietic cell transplantation in multiple myeloma.

We studied 2,528 patients with upfront autologous haematopoietic cell transplantation (AHCT) for multiple myeloma (MM) from 2008-2017 to develop a prognostic model to predict outcomes. High-risk cytogenetics included t(4;14), t(14;16), t(14;20), del13q on karyotype, del17p, +1q or 1pdel. A Cox model identified factors prognostic of progression/relapse in a training subset (n = 1,246). A weighted score using these factors was assigned to a validation cohort (n = 774). Presence of high-risk cytogenetics [hazard ratio, (HR) 1·68 (1·3-2·17)] and pre-AHCT bone marrow plasma cells (BMPCs) ≥10% [1·68 (1·33-2·12)] were assigned 4 points each; albumin at diagnosis <3·5 g/dl [1·31 (1·07-1·61)] 2; standard risk cytogenetics 1, and no cytogenetics abnormality, BMPCs <10% at AHCT and albumin ≥3·5 g/dl at diagnosis 0 points each. A three-category system with low risk (0-3), intermediate risk (4-8) and high risk (9-10) showed 3-year progression-free survival in the low vs. intermediate vs. high risk of 58% (95% CI: 52-63) vs. 49% (95% CI: 43-56) vs. 31% (95% CI: 12-51), P < 0.001 respectively, and 3-year OS in low vs. intermediate vs. high risk of 88% (95% CI: 84-91) vs. 81% (95% CI: 76-86) vs. 64% (95% CI: 39-80); P < 0·001. Our prognostic scoring system can identify MM patients at risk for early relapse after AHCT.

Mutation topography and risk stratification for de novo acute myeloid leukaemia with normal cytogenetics and no nucleophosmin 1 (NPM1) mutation or Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD).

About 25% of patients with newly diagnosed acute myeloid leukaemia (AML) have normal cytogenetics and no nucleophosmin 1 (NPM1) mutation or Fms-like tyrosine kinase 3 internal tandem duplication (FLT3-ITD). The prognosis and best therapy for these patients is controversial. We evaluated 158 newly diagnosed adults with this genotype who achieved histological complete remission within two cycles of induction therapy and were assigned to two post-remission strategies with and without an allotransplant. Targeted regional sequencing at diagnosis was performed and data were used to estimate their prognosis, including relapse and survival. In multivariable analyses, having wild-type or mono-allelic mutated CCAAT/enhancer-binding protein alpha (CEBPA) [hazard ratio (HR) 2·39, 95% confidence interval (CI) 1·08-5·30; P = 0·032), mutated NRAS (HR 2·67, 95% CI 1·36-5·25; P = 0·004), mutated colony-stimulating factor 3 receptor (CSF3R) (HR 2·85, 95% CI 1·12-7·27; P = 0·028) and a positive measurable residual disease (MRD)-test after the second consolidation cycle (HR 2·88, 95% CI 1·32-6·30; P = 0·008) were independently correlated with higher cumulative incidence of relapse (CIR). These variables were also significantly associated with worse survival (HR 3·02, 95% CI 1·17-7·78, P = 0·022; HR 3·62, 95% CI 1·51-8·68, P = 0·004; HR 3·14, 95% CI 1·06-9·31, P = 0·039; HR 4·03, 95% CI 1·64-9·89, P = 0·002; respectively). Patients with ≥1 of these adverse-risk variables benefitted from a transplant, whereas the others did not. In conclusion, we identified variables associated with CIR and survival in patients with AML and normal cytogenetics without a NPM1 mutation or FLT3-ITD.

Pretransplant Consolidation Is Not Beneficial for Adults with ALL Undergoing Myeloablative Allogeneic Transplantation.

Allogeneic hematopoietic cell transplantation (alloHCT) is curative for patients with acute lymphoblastic leukemia (ALL) who achieve complete remission (CR1) with chemotherapy. However, the benefit of consolidation chemotherapy remains uncertain in patients undergoing alloHCT. We compared clinical outcomes of 524 adult patients with ALL in CR1 who received ≥2 (n = 109), 1 (n = 93), or 0 cycles (n = 322) of consolidation before myeloablative alloHCT from 2008 to 2012. As expected, time to alloHCT was longer with increasing cycles of consolidation. Patients receiving ≥2, 1, or 0 cycles of consolidation had an adjusted 3-year cumulative incidence of relapse of 20%, 27%, and 22%; 1-year transplant-related mortality (TRM) of 16%, 18%, and 23%; adjusted 3-year leukemia-free survival (LFS) of 54%, 48%, and 47%; and 3-year overall survival (OS) of 63%, 59%, and 54% (all P values >.40). Multivariable analysis confirmed that consolidation was not prognostic for LFS (relative risk, 1.20, 95% confidence interval, .86 to 1.67; P = .28 for no consolidation; RR, 1.18, 95% confidence interval, .79 to 1.76; P = .41 for 1 cycle versus ≥2 cycles = reference). Similarly, consolidation was not associated with OS, relapse, TRM, or graft-versus-host disease. We conclude that consolidation chemotherapy does not appear to provide added benefit in adult ALL patients with available donors who undergo myeloablative alloHCT in CR1.

Dialog between mantle cell lymphoma cells and lymphoma-associated macrophages underlies ibrutinib resistance.

INTRODUCTION: Patients with mantle cell lymphoma (MCL) frequently develop resistance to ibrutinib. Lymphoma-associated macrophages (LAMs) may play a causal role in this resistance but remain underexplored in current literature. OBJECTIVES: To elucidate the role of LAMs in mediating ibrutinib resistance in MCL. METHODS: We investigated macrophage polarization through multiparameter flow cytometry (MPFC) using antibodies against CD206 and CD86 in blood and tissue samples from patients with MCL, both resistant and sensitive to ibrutinib. Subsequently, we developed an in vitro co-culture model utilizing MCL cell lines to identify cytokines associated with ibrutinib resistance and macrophage M2 polarization. The mechanisms underlying resistance were examined using MPFC, RNA sequencing, and Western blot analysis. Additionally, we assessed whether SB225002, a CXCR2 inhibitor, could reverse ibrutinib resistance through CCK-8 and caspase-3 assays, as well as in a mouse xenograft model involving an ibrutinib-resistant MCL cell line. RESULTS: In patients exhibiting ibrutinib resistance, the ratio of M2 to M1 LAMs was significantly higher compared to sensitive patients. In co-cultures of LAMs and MCL cells, the percentage of M2 macrophages, the IC50 value for ibrutinib, and the concentrations of IL-8 and CXCL5 were significantly elevated. Mechanistically, CXCL5 secreted by LAMs interacted with the CXCR2 on MCL cells, leading to the activation of the Akt, p38, and STAT3 signaling pathways in the presence of ibrutinib; this activity was diminished upon blockade of the CXCL5/CXCR2 axis. The combination of SB225002 and ibrutinib significantly enhanced MCL cell apoptosis, suppressed lymphoma growth in the xenograft model, and reprogrammed macrophage phenotype compared to treatment with ibrutinib alone. CONCLUSION: Our data indicate that M2-polarized LAMs are associated with ibrutinib resistance in a model of MCL, and that a CXCR2 inhibitor can reverse this resistance. These findings suggest a potential new therapeutic strategy.

Direct adjusted survival and cumulative incidence curves for observational studies.

SERIES EDITORS' NOTE: Large randomized clinical trials testing the impact of subject-, disease- and transplant-related co-variates on outcomes amongst recipients of haematopoietic cell transplants are uncommon. For example, who is the best donor, which is the best pretransplant conditioning regimen or the best regimen to prevent or treat acute and/or chronic graft-versus-host disease. To answer these questions we often rely on analyses of data from large observational datasets such as those of the Center for International Blood and Marrow Transplant Research (CIBMTR) and the European Society for Blood and Marrow Transplantation (EBMT). Such analyses have proved extremely important in advancing the field. However, in contrast to randomized trials, we cannot be certain potentially important prognostic or predictive co-variates are balanced between cohorts selected for comparison from an observational dataset, a limitation which can lead to incorrect conclusions. In the typescript which follows the authours describe a method to adjust for known imbalances in co-variates and get a closer approximation of the truth. They give two examples, the impact of a new pretransplant conditioning regimen on disease-free survival (DFS) in subjects with Ewing sarcoma and the impact of donor-type on treatment-related mortality (TRM) and leukaemia relapse in subjects with acute leukaemia. Direct adjusted survival and cumulative incidence function (CIF) analyses are an important step forward. These analyses can be done using available statistical packages and we encourage readers to use them rather than reporting unadjusted analyses. Finally, we must emphasize direct adjustment can only be done for know prognostic or predictive co-variates, not unknown co-variates. Unknown co-variates will be balanced in randomized trials which is why we do them. So direct adjustment is an important step forward but not a perfect substitute for randomized trials. But any step forward is important. To quote Laozi: (A journey of a thousand miles begins with a single step).

Thalidomide plus prednisone with or without danazol therapy in myelofibrosis: a retrospective analysis of incidence and durability of anemia response.

Low-dose thalidomide and prednisone alone or combined are effective therapies in some persons with primary myelofibrosis (PMF) and anemia with or with RBC transfusion dependence. Danazol is also effective in some persons with PMF and anemia. Responses to these drugs are typically incomplete and not sustained. It is unclear whether adding danazol to thalidomide and prednisone would improve efficacy. We retrospectively compared the outcomes of 88 subjects with PMF and anemia receiving thalidomide and prednisone without (n = 46) or with danazol (n = 42). The primary end point was anemia response, which was 71% (95% confidence interval (CI), 57, 85%) in subjects receiving thalidomide/prednisone/danazol compared with 46% (32, 60%; P = 0.014) in those receiving thalidomide/prednisone. Response rates in subjects who were RBC transfusion dependent was also higher in the danazol cohort (61% (38, 84%)) vs. 25% (6, 44%); P = 0.024). Time to response was rapid (median, 2 months (range, 1-11 months)) and similar between the cohorts. Response duration was longer in the thalidomide/prednisone/danazol cohort (HR 2.18 (1.18-5.42); P = 0.019). Adverse effects were mild and similar between the cohorts. In conclusion, thalidomide/prednisone/danazol seems superior to thalidomide/prednisone in persons with PMF and anemia. Our conclusion requires confirmation in a randomized trial.

Improved Outcomes After Autologous Hematopoietic Cell Transplantation for Light Chain Amyloidosis: A Center for International Blood and Marrow Transplant Research Study.

PURPOSE: Autologous hematopoietic cell transplantation, or autotransplantation, is effective in light-chain amyloidosis (AL), but it is associated with a high risk of early mortality (EM). In a multicenter randomized comparison against oral chemotherapy, autotransplantation was associated with 24% EM. We analyzed trends in outcomes after autologous hematopoietic cell transplantation for AL in North America. PATIENTS AND METHODS: Between 1995 and 2012, 1,536 patients with AL who underwent autotransplantation at 134 centers were identified in the Center for International Blood and Marrow Transplant Research database. EM and overall survival (OS) were analyzed in three time cohorts: 1995 to 2000 (n = 140), 2001 to 2006 (n = 596), and 2007 to 2012 (n = 800). Hematologic and renal responses and factors associated with EM, relapse and/or progression, progression-free survival and OS were analyzed in more recent subgroups from 2001 to 2006 (n = 197) and from 2007 to 2012 (n = 157). RESULTS: Mortality at 30 and 100 days progressively declined over successive time periods from 11% and 20%, respectively, in 1995 to 2000 to 5% and 11%, respectively, in 2001 to 2006, and to 3% and 5%, respectively, in 2007 to 2012. Correspondingly, 5-year OS improved from 55% in 1995 to 2000 to 61% in 2001 to 2006 and to 77% in 2007 to 2012. Hematologic response to transplantation improved in the latest cohort. Renal response rate was 32%. Centers performing more than four AL transplantations per year had superior survival outcomes. In the multivariable analysis, cardiac AL was associated with high EM and inferior progression-free survival and OS. Autotransplantation in 2007 to 2012 and use of higher dosages of melphalan were associated with a lowered relapse risk. A Karnofsky score less than 80 and creatinine levels 2 mg/m(2) or greater were associated with worsened OS. CONCLUSION: Post-transplantation survival in AL has improved, with a dramatic reduction in early post-transplantation mortality and excellent 5-year survival. The risk-benefit ratio for autotransplantation has changed, and randomized comparison with nontransplantation approaches is again warranted.