Clonal Hematopoiesis and Cardiovascular Disease in Patients With Multiple Myeloma Undergoing Hematopoietic Cell Transplant.

Importance: There is a paucity of information on the association between clonal hematopoiesis of indeterminate potential (CHIP) and cardiovascular disease (CVD) in patients with cancer, including those with multiple myeloma (MM) undergoing hematopoietic cell transplant (HCT), a population at high risk of developing CVD after HCT. Objective: To examine the association between CHIP and CVD in patients with MM and to describe modifiers of CVD risk among those with CHIP. Design, Setting, and Participants: This was a retrospective cohort study of patients with MM who underwent HCT between 2010 and 2016 at City of Hope Comprehensive Cancer Center in Duarte, California, and had pre-HCT mobilized peripheral blood stem cell (PBSC) products cryopreserved and accessible for CHIP analyses. The study team performed targeted panel DNA sequencing to detect the presence of CHIP (variant allele frequency 2% or more). Main Outcomes and Measures: The primary end point was the 5-year cumulative incidence and risk for developing de novo CVD (heart failure, coronary artery disease, or stroke) after HCT. Results: Of 1036 consecutive patients with MM (580 male [56%]; median age, 60.0 years) who underwent a first autologous HCT, 201 patients had at least 1 CHIP variant (19.4%) and 35 patients had 2 or more variants (3.4%). The 5-year incidence of CVD was significantly higher in patients with CHIP (21.1% vs 8.4%; P < .001) compared with those without CHIP; the 5-year incidence among those with 2 or more variants was 25.6%. In the multivariable model, CHIP was associated with increased risk of CVD (hazard ratio [HR], 2.72; 95% CI, 1.70-4.39), as well as of individual outcomes of interest, including heart failure (HR, 4.02; 95% CI, 2.32-6.98), coronary artery disease (HR, 2.22; 95% CI, 1.06-4.63), and stroke (HR, 3.02; 95% CI, 1.07-8.52). Patients who had both CHIP and preexisting hypertension or dyslipidemia were at nearly 7-fold and 4-fold increased risk of CVD, respectively (reference: no CHIP, no hypertension, or dyslipidemia). Conclusion and Relevance: CHIP was significantly and independently associated with risk of CVD in patients with MM undergoing HCT and may serve as a novel biologically plausible biomarker for CVD in this cohort. Patients with MM and both CHIP and cardiovascular risk factors had an exceptionally high risk of CVD. Additional studies are warranted to determine if cardiovascular preventive measures can reduce CHIP-associated CVD risk.

Bendamustine lymphodepletion is a well-tolerated alternative to fludarabine and cyclophosphamide lymphodepletion for axicabtagene ciloleucel therapy for aggressive B-cell lymphoma.

Fludarabine/cyclophosphamide (Flu/Cy) is established for lymphodepletion (LD) prior to standard-of-care CAR T-cell therapy for lymphoma. There is ongoing need to test alternative LD regimens to preserve efficacy, improve safety, and address challenges including the recent national fludarabine shortage. We retrospectively evaluated outcomes among patients with relapsed/refractory aggressive B-cell lymphoma who received bendamustine (n = 27) or Flu/Cy (n = 42) LD before axicabtagene ciloleucel (axi-cel) at our institution. The median change in absolute lymphocyte count from pre-LD to time of axi-cel infusion was -0.6×109 /L in bendamustine cohort and -0.7×109 /L in Flu/Cy cohort. The best overall response/complete response rates were 77.8% (95% CI: 57.7%-91.4%)/48.1% (95% CI: 28.7%-68.1%) among bendamustine cohort and 81.0% (95% CI: 65.9%-91.4%)/50.0% (95% CI: 34.2%-65.8%) among Flu/Cy cohort. Six-month progression-free survival were 43.8% (95% CI: 24.7%-61.3%) and 55.6% (95% CI: 39.0%-69.3%) in bendamustine and Flu/Cy cohorts, while 6-month overall survival were 81.5% (95% CI: 61.1%-91.8%) and 90.4% (95% CI: 76.4%-96.3%), respectively. Relative to Flu/Cy-treated patients, bendamustine-treated patients did not show an increase in hazards associated with experiencing progression/relapse/death (aHR:1.4 [95% CI: 0.7-2.8]; p = .32) or death (aHR:1.6 [95% CI: 0.5-5.6]; p = .46), after adjusting for baseline number of prior therapies and refractory disease. Any grade/grade ≥3 CRS were observed in 89%/3.7% and 86%/4.8% among bendamustine and Flu/Cy cohorts, while any grade ICANS/grade ≥3 ICANS were observed in 30%/19% and 55%/31% respectively. While more Flu/Cy-treated patients experienced grade ≥3 neutropenia compared with bendamustine-treated patients (100% vs. 68%), grade ≥3 infectious complications were comparable (24% vs. 19% respectively). More patients received bendamustine LD and axi-cel as outpatient than Flu/Cy cohort, without increased toxicities and with shorter median inpatient stays. In conclusion, we observed comparable efficacy and lower any grade ICANS among patients receiving bendamustine relative to Flu/Cy LD, followed by axi-cel.

Long-term Outcome of Allogeneic Hematopoietic Stem Cell Transplantation From Unrelated Donor Using Tacrolimus/Sirolimus-based GvHD Prophylaxis: Impact of HLA Mismatch.

BACKGROUND: While tacrolimus and sirolimus (T/S)-based graft-versus-host disease (GvHD) prophylaxis has been effective in preventing acute GvHD post hematopoietic cell transplantation (HCT), its efficacy and long-term outcome in matched (MUD) and mismatched unrelated donor (mMUD) setting is not well defined. METHODS: Herein, we evaluated a consecutive case-series of 482 patients who underwent unrelated donor HCT (2005-2013) with T/S-based GvHD prophylaxis. RESULTS: With a median follow-up of 6.2 years (range = 2.4-11.3), the 5-year overall survival (OS) and relapse/progression-free survival were 47.5% (95% confidence interval [CI]: 43.0-52.0) and 43.6% (95% CI: 39.1-48.1), respectively; and the 5-year cumulative incidence of nonrelapse mortality (NRM) and relapse were 24.9%, and 31.5%, respectively. In this cohort, mMUD was associated with worse OS (39.0% versus 50.7% at 5 y; P = 0.034), primarily due to greater risk of NRM (33.5% versus 21.7%; P = 0.038). While rates of relapse, acute (II-IV or III-IV) or chronic GvHD (limited or extensive) were not different, death caused by chronic GvHD (20.8% versus 12.8%; P = 0.022) and infection (33.0% versus 18.1%; P < 0.01) were significantly greater in mMUD. In multivariable analysis, high-risk disease (hazard ratio [HR] = 2.21, 95% CI: 1.16-4.23; P < 0.01) and mMUD (HR = 1.55, 95% CI: 1.15-2.08; P = 0.004) were independent predictive factors for OS. CONCLUSIONS: T/S-based GvHD prophylaxis is an effective and acceptable GvHD prophylactic regimen. However, survival after mMUD remained poor, possibly related to the severity of chronic GvHD.

Iron chelators induce autophagic cell death in multiple myeloma cells.

We examined the antineoplastic effects of the iron chelators, deferasirox and deferoxamine in multiple myeloma cell lines as well as primary myeloma cells. These iron chelators showed marked antiproliferative activity as well as cytotoxicity toward myeloma cell lines and deferasirox was cytotoxic to bone marrow plasma cells from myeloma patients. We also demonstrate that autophagy induced by iron deprivation is the dominant mechanism that mediates the cytotoxicity of iron chelators in multiple myeloma. Exposure to iron chelators led to repression of mTOR signaling as evidenced by decreased phosphorylation of its target p70S6 kinase. Iron chelation, in particular with deferasirox has the potential to be readily translated to a clinical trial for multiple myeloma.

Allogeneic hematopoietic cell transplantation following reduced intensity conditioning for treatment of myelofibrosis.

This report describes our experience with reduced intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (HCT) using matched sibling and unrelated donors (MUDs) for treatment of myelofibrosis (MF). Nine patients with MF (median age, 54 years) were treated with RIC allogeneic HCT using MUDs for 7 of the 9 patients and sibling donors for 2 patients. By the Lille classification, 4 patients were characterized as having high risk, 4 as having intermediate risk, and 1 as having low risk. The RIC regimen consisted of fludarabine and a single dose of total body irradiation for the first patient and fludarabine/melphalan for the remaining 8 patients. Granulocyte colony-stimulating factor-primed peripheral blood stem cells (PBSCs) were used for all but 1 patient who received a total of 3 products because of graft failure, of which 2 were bone marrow cells and the third was PBSCs. Prophylaxis against graft-versus-host disease consisted of cyclosporin/mycophenolate with or without methotrexate. Seven patients were successfully engrafted with white blood cells, with an absolute neutrophil count > or =500 by a median of day +15 (range, 10-21 days). At the time of final fluorescence in situ hybridization and/or short tandem repeat analysis, 8 of 9 patients were chimeric, with 96%-100% donor cells and/or DNA. Five of the 9 patients were alive at the time of final contact, with a median follow-up of 32.2 months for the living patients. Overall survival probability at 1 year was 55.6% (95% confidence interval, 31.3%-77.4%). These results suggest that RIC MUD HCT using PBSCs can be an effective treatment for older patients with MF.

Does follicularity in large cell lymphoma predict outcome after autologous stem cell transplantation?

The purpose of this study was to evaluate whether follicular histology in large cell lymphoma influences treatment outcomes after autologous stem cell transplantation (ASCT). It remains an area of controversy whether the natural history of follicular large cell lymphoma (FLCL) is akin to diffuse large cell lymphoma (DLCL) with curative potential or is more similar to indolent follicular lymphomas with a pattern of late relapses after intensive chemotherapy. Although ASCT is a potentially curative treatment for patients with recurrent DLCL, the effectiveness of this approach in patients with FLCL is unclear. We undertook a retrospective analysis of 332 patients with large cell lymphoma who underwent ASCT at the City of Hope Comprehensive Cancer Center. With a median follow-up of 31 months, the projected 10-year overall survival and disease-free survival were similar between patients with FLCL and DLCL. Analysis of prognostic factors demonstrated that although age, chemotherapy refractoriness, and disease status at the time of ASCT were predictive of overall survival/disease-free survival, follicularity did not influence the outcome. Furthermore, the similar plateau in the survival curve for the DLCL and FLCL patients suggests that the behavior of FLCL is similar to that of DLCL and that FLCL is potentially curable with ASCT.