Publications by authors named "Aleksandr Lazaryan"

71 Publications

Phase 2 multicenter trial of ofatumumab and prednisone as initial therapy of chronic graft-vs-host disease.

Blood Adv 2021 Oct 14. Epub 2021 Oct 14.

H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida, United States.

Standard initial therapy of chronic graft vs. host disease (cGVHD) with glucocorticoids results in suboptimal and transient responses in a significant number of patients. Safety and feasibility of anti-CD20 directed B-cell therapy with ofatumumab (1000 mg IV on days 0 and 14) and prednisone (1 mg/kg/day) was previously established in our phase I trial (n=12). We now report the mature results of the phase II expansion of the trial (n=38). The overall NIH severity of cGVHD was moderate (63%) or severe (37%) with 74% of all patients affected by the overlap subtype of cGVHD and 82% by prior acute cGVHD. The combined therapy was generally well tolerated, with some anticipated infusion reactions to ofatumumab, and common toxicities of glucocorticoids. Total B-cell depletion following therapy was profound, with marginal recovery within first 12 months from initial therapy. The observed 6 month clinician-reported and 2014 NIH-defined overall response rates (ORR=complete + partial response[CR/PR]) of 62.5% (1-sided lower 90% confidence interval=51.5%) were not superior to pre-specified historic benchmark of 60%. Post-hoc comparison of 6 month NIH response suggested benefit compared to more contemporaneous NIH-based benchmark of 48.6% with frontline sirolimus/prednisone (CTN 0801 trial). Baseline cGVHD features (organ involvement, severity, initial IS agents) were not significantly associated with 6-month ORR. The median time to initiation of second-line therapy was 5.4 months (range 0.9-15.1 months). Failure-free survival (FFS) was 64.2% (95% CI 46.5-77.4%) at 6 months and 53.1% (95% CI 35.8-67.7%) at 12 months, whereas FFS with CR/PR at 12 months of 33.5% exceeded a benchmark of 15% in post-hoc analysis, and was associated with greater success in steroid discontinuation by 24 months (odds ratio 8 (95% CI 1.21-52.7). This single-arm phase II trial demonstrated acceptable safety and potential efficacy of the upfront use of ofatumumab in combination with prednisone in cGVHD. This trial is registered at www.clinicaltrials.gov as NCT01680965.
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http://dx.doi.org/10.1182/bloodadvances.2021005552DOI Listing
October 2021

An adapted European LeukemiaNet genetic risk stratification for acute myeloid leukemia patients undergoing allogeneic hematopoietic cell transplant. A CIBMTR analysis.

Bone Marrow Transplant 2021 Sep 28. Epub 2021 Sep 28.

Division of Hematology/BMT, Mayo Clinic, Rochester, MN, USA.

Cytogenetic and molecular abnormalities are known to influence post-transplant outcomes in acute myeloid leukemia (AML) but data assessing the prognostic value of combined genetic models in the HCT setting are limited. We developed an adapted European LeukemiaNet (aELN) risk classification based on available genetic data reported to the Center for International Blood and Marrow Transplant Research, to predict post-transplant outcomes in 2289 adult AML patients transplanted in first remission, between 2013 and 2017. Patients were stratified according to aELN into three groups: favorable (Fav, N = 181), intermediate (IM, N = 1185), and adverse (Adv, N = 923). Univariate analysis demonstrated significant differences in 2-year overall survival (OS) (Fav: 67.7%, IM: 64.9% and Adv: 53.9%; p < 0.001); disease-free survival (DFS) (Fav: 57.8%, IM: 55.5% and Adv: 45.3; p < 0.001) and relapse (Fav: 28%, IM: 27.5% and Adv: 37.5%; p < 0.001). Multivariate analysis (MVA) revealed no differences in outcomes between the Fav and IM groups, thus they were combined. On MVA, patients in the Adv risk group had the highest risk of relapse (HR 1.47 p ≤ 0.001) and inferior DFS (HR 1.35 p < 0.001) and OS (HR 1.39 p < 0.001), even using myeloablative conditioning or in those without the pre-HCT measurable-residual disease. Novel approaches to mitigate relapse in this high-risk group are urgently needed.
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http://dx.doi.org/10.1038/s41409-021-01450-3DOI Listing
September 2021

Single-route CNS prophylaxis for aggressive non-Hodgkin lymphomas: real-world outcomes from 21 US academic institutions.

Blood 2021 Sep 27. Epub 2021 Sep 27.

University of Virginia, United States.

Prophylaxis is commonly used to prevent central nervous system (CNS) relapse in diffuse large B cell lymphoma, with no clear standard of care. We retrospectively evaluated 1162 adult patients across 21 US academic centers with DLBCL or similar histologies who received single-route CNS prophylaxis as part of frontline therapy between 2013-2019. Prophylaxis was administered intrathecally (IT) in 894 (77%) and using systemic high-dose methotrexate (HD-MTX) in 236 (20%); 32 patients (3%) switched route due to toxicity and were assessed separately. By CNS-International Prognostic Index (IPI), 18% were considered low-risk, 51% moderate, and 30% high. Double-hit lymphoma (DHL) was confirmed in 243 of 866 evaluable patients (21%). Sixty-four patients (5.7 %) had CNS relapse, after median 7.1 months from diagnosis, including 15 of 64 (23%) within the first 6 months. There was no significant difference in CNS relapse between IT and HD-MTX recipients (5.4 vs 6.8%, p=0.4), including after propensity score matching to account for differences between respective recipient groups. Weighting by CNS-IPI, expected versus observed CNS relapse rates were nearly identical (5.8 vs 5.7%). Testicular involvement was associated with high risk of CNS relapse (11.3%) despite most having lower CNS-IPI scores. DHL did not significantly predict for CNS relapse after single-route prophylaxis, including with adjustment for treatment regimen and other factors. This large study of CNS prophylaxis recipients with DLBCL found no significant difference in CNS relapse rates between routes of administration. Relapse rates among high-risk subgroups remain elevated and reconsideration of prophylaxis strategies in DLBCL is of critical need.
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http://dx.doi.org/10.1182/blood.2021012888DOI Listing
September 2021

Reply to A. Heine et al.

J Clin Oncol 2021 Oct 4;39(29):3308-3309. Epub 2021 Aug 4.

Aleksandr Lazaryan, MD, MPH, PhD, Moffitt Cancer Center, Tampa, FL and Stephanie J. Lee, MD, MPH, Fred Hutchinson Cancer Research Center, Seattle, WA.

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http://dx.doi.org/10.1200/JCO.21.01559DOI Listing
October 2021

Increased Infections and Delayed CD4 T Cell but Faster B Cell Immune Reconstitution after Post-Transplantation Cyclophosphamide Compared to Conventional GVHD Prophylaxis in Allogeneic Transplantation.

Transplant Cell Ther 2021 Jul 28. Epub 2021 Jul 28.

Blood and Marrow Transplant and Cellular Immunotherapy, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida.

Post-transplantation cyclophosphamide (PTCy) is being increasingly used for graft-versus-host disease (GVHD) prophylaxis after allogeneic hematopoietic cell transplantation (allo-HCT) across various donor types. However, immune reconstitution and infection incidence after PTCy-based versus conventional GVHD prophylaxis has not been well studied. We evaluated the infection density and immune reconstitution (ie, absolute CD4 T cell, CD8 T cell, natural killer cell, and B cell counts) at 3 months, 6 months, and 1 year post-HCT in 583 consecutive adult patients undergoing allo-HCT with myeloablative (n = 223) or reduced-intensity (n = 360) conditioning between 2012 and 2018. Haploidentical (haplo; n = 75) and 8/8 HLA-matched unrelated (MUD; n = 08) donor types were included. GVHD prophylaxis was PTCy-based in all haplo (n = 75) and in 38 MUD allo-HCT recipients, whereas tacrolimus/methotrexate (Tac/MTX) was used in 89 and Tac/Sirolimus (Tac/Sir) was used in 381 MUD allo-HCT recipients. Clinical outcomes, including infections, nonrelapse mortality (NRM), relapse, and overall survival (OS), were compared across the 4 treatment groups. The recovery of absolute total CD4 T-cell count was significantly lower in the haplo-PTCy and MUD-PTCy groups compared with the Tac/MTX and Tac/Sir groups throughout 1 year post-allo-HCT (P = .025). In contrast, CD19 B-cell counts at 6 months and thereafter were higher in the haplo-PTCy and MUD-PTCy groups compared with the Tac/MTX and Tac/Sir groups (P < .001). Total CD8 T cell and NK cell recovery was not significantly different among the groups. Infection density analysis showed a significantly higher frequency of total infections in the haplo-PTCy and MUD-PTCy groups compared with the Tac/MTX and Tac/Sir groups (5.0 and 5.0 vs 1.8 and 2.6 per 1000-person days; P < .01) within 1 year of allo-HCT. The cumulative incidence of cytomegalovirus reactivation/infection at 1 year post-allo-HCT was higher in the haplo-PTCy group (51%) compared with the MUD-PTCy (26%), Tac/MTX (26%), or Tac/Sir (13%) groups (P < .001). The incidence of BK, human herpesvirus 6, and other viruses were also higher in the PTCy-based groups. Overall, the treatment groups had similar 2 year NRM (P = .27) and OS (P = .78) outcomes. Our data show that PTCy-based GVHD prophylaxis is associated with delayed CD4 T cell but faster B cell immune reconstitution and a higher frequency of infections compared with conventional GVHD prophylaxis but has no impact on nonrelapse mortality or overall survival.
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http://dx.doi.org/10.1016/j.jtct.2021.07.023DOI Listing
July 2021

Belumosudil for Chronic Graft-versus-Host Disease (cGVHD) After 2 or More Prior Lines of Therapy: The ROCKstar Study.

Blood 2021 Jul 15. Epub 2021 Jul 15.

Kadmon Corporation, West Chicago, Illinois, United States.

Belumosudil, an investigational oral selective inhibitor of rho-associated coiled-coil-containing protein kinase-2 (ROCK2), reduces type 17 and follicular helper T cells via downregulation of signal transducer and activator of transcription 3 (STAT3) and enhances regulatory T cells via upregulation of signal transducer and activator of transcription 5 (STAT5). Belumosudil may effectively treat patients with cGVHD, a major cause of morbidity and late nonrelapse mortality after an allogeneic hematopoietic cell transplant. This phase 2, randomized, multicenter registration study evaluated belumosudil 200 mg QD (n=66) and 200 mg BID (n=66) in subjects with cGVHD who had received 2 to 5 prior lines of therapy. The primary end point was best overall response rate (ORR). Duration of response (DOR), changes in Lee Symptom Scale score, failure-free survival, corticosteroid dose reductions and overall survival were also evaluated. Overall median follow-up was 14 months. The best ORR (95% CI) of belumosudil 200 mg QD and 200 mg BID was 74% (62%-84%) and 77% (65%-87%), respectively, with high response rates observed in all subgroups. All affected organs demonstrated complete responses. The median DOR was 54 weeks; 44% of subjects have remained on therapy for ≥1 year. Symptom reduction with belumosudil 200 mg QD and 200 mg BID was reported in 59% and 62% of subjects, respectively. Adverse events (AEs) were consistent with those expected in patients with cGVHD receiving corticosteroids and other immunosuppressants. Sixteen subjects (12%) discontinued belumosudil due to possible drug-related AEs. Belumosudil, a promising therapy for cGVHD, was well tolerated with clinically meaningful responses. (Funded by Kadmon Corporation, LLC; ClinicalTrials.gov number, NCT03640481.).
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http://dx.doi.org/10.1182/blood.2021012021DOI Listing
July 2021

Patterns and Predictors of Failure in Recurrent or Refractory Large B-Cell Lymphomas After Chimeric Antigen Receptor T-Cell Therapy.

Int J Radiat Oncol Biol Phys 2021 Jul 6. Epub 2021 Jul 6.

Department of Blood and Marrow Transplant and Cellular Immunotherapy, H. Lee Moffitt Cancer Center & Research Institute, Tampa, Florida.

Purpose: Chimeric antigen receptor T-cell (CAR T) therapy is capable of eliciting durable responses in patients with relapsed/refractory (R/R) lymphomas. However, most treated patients relapse. Patterns of failure after CAR T have not been previously characterized, and may provide insights into the mechanisms of resistance guiding future treatment strategies.

Methods And Materials: This is a retrospective analysis of patients with R/R large B-cell lymphoma who were treated with anti-CD19 CAR T at a National Cancer Institute-designated Comprehensive Cancer Center between 2015 and 2019. Pre- and posttreatment positron emission/computed tomography scans were analyzed to assess the progression of existing (local failures) versus new, nonoverlapping lesions (de novo failures) and identify lesions at a high risk for progression.

Results: A total of 469 pretreatment lesions in 63 patients were identified. At a median follow-up of 12.6 months, 36 patients (57%) recurred. Most (n = 31; 86%) had a component of local failure, and 13 patients (36%) exhibited strictly local failures. Even when progressing, 84% of recurrent patients continued to have a subset of pretreatment lesions maintain positron emission/computed tomography resolution. Lesions at a high risk for local failure included those with a diameter ≥5 cm (odds ratio [OR], 2.34; 95% confidence interval [CI], 1.55-3.55; P < .001), maximum standardized uptake value ≥10 (OR, 2.08; 95% CI, 1.38-3.12; P < .001), or those that were extranodal (OR, 1.49; 95% CI, 1.10-2.04; P = .01). In the 69 patients eligible for survival analysis, those with any lesion ≥5 cm (n = 46; 67%) experienced inferior progression-free survival (hazard ratio, 2.41; 95% CI, 1.15-5.04; P = .02) and overall survival (hazard ratio, 3.36; 95% CI, 1.17-9.96; P = .02).

Conclusions: Most patients who recur after CAR T experience a component of local progression. Furthermore, lesions with high-risk features, particularly large size, were associated with inferior treatment efficacy and patient survival. Taken together, these observations suggest that lesion-specific resistance may contribute to CAR T treatment failure. Locally directed therapies to high-risk lesions, such as radiation therapy, may be a viable strategy to prevent CAR T failures in select patients.
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http://dx.doi.org/10.1016/j.ijrobp.2021.06.038DOI Listing
July 2021

National Institutes of Health Consensus Development Project on Criteria for Clinical Trials in Chronic Graft-versus-Host Disease: III. The 2020 Treatment of Chronic GVHD Report.

Transplant Cell Ther 2021 09 11;27(9):729-737. Epub 2021 Jun 11.

Clinical Division of Hematology, Medical University of Graz, Graz, Austria. Electronic address:

Positive results from recent clinical trials have significantly expanded current therapeutic options for patients with chronic graft-versus-host disease (GVHD). However, new insights into the associations between clinical characteristics of chronic GVHD, pathophysiologic mechanisms of disease, and the clinical and biological effects of novel therapeutic agents are required to allow for a more individualized approach to treatment. The current report is focused on setting research priorities and direction in the treatment of chronic GVHD. Detailed correlative scientific studies should be conducted in the context of clinical trials to evaluate associations between clinical outcomes and the biological effect of systemic therapeutics. For patients who require systemic therapy but not urgent initiation of glucocorticoids, clinical trials for initial systemic treatment of chronic GVHD should investigate novel agents as monotherapy without concurrently starting glucocorticoids, to avoid confounding biological, pathological, and clinical assessments. Clinical trials for treatment-refractory disease should specifically target patients with incomplete or suboptimal responses to most recent therapy who are early in their disease course. Close collaboration between academic medical centers, medical societies, and industry is needed to support an individualized, biology-based strategic approach to chronic GVHD therapy.
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http://dx.doi.org/10.1016/j.jtct.2021.05.004DOI Listing
September 2021

Outcomes of CD19 Chimeric Antigen Receptor T Cell Therapy in Patients with Gastrointestinal Tract Involvement of Large B Cell Lymphoma.

Transplant Cell Ther 2021 09 30;27(9):768.e1-768.e6. Epub 2021 May 30.

Department of Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, Florida; Department of Oncologic Sciences, University of South Florida Morsani College of Medicine, Tampa, Florida. Electronic address:

CD19-directed chimeric antigen receptor (CAR) T cell therapy with axicabtagene ciloleucel (axi-cel) or tisagenlecleucel (tisa-cel) is approved for the standard of care treatment of relapsed or refractory large B cell lymphoma (LBCL). Patients with LBCL involving the gastrointestinal (GI) tract are at risk of perforation after lymphoma-directed therapy. The outcomes of CAR T cell therapy in patients with GI involvement have not been reported previously. This study aimed to determine the safety and efficacy of CD19 CAR T cell therapy in patients with LBCL involvement of the GI tract. This was a single-center retrospective study of 130 consecutive patients treated with standard of care or expanded-access axi-cel or tisa-cel for LBCL. Twenty-four of these patients had radiologic involvement of the GI tract before CAR T infusion. Incidence rates of severe immune effector cell-mediated toxicities and clinical outcomes were compared between the GI involvement and non-GI involvement groups. Three of the 24 patients with GI tract involvement experienced perforation. One patient had a contained gastric perforation after leukapheresis while receiving bridging radiation therapy to the stomach. This patient was eventually able to proceed with lymphodepletion and product infusion. In the other 2 patients, GI tract perforation occurred at day +13 and day +35 after CAR T infusion. All 3 patients subsequently died while experiencing lymphoma progression. Upper GI bleeding occurred in 1 other patient in the context of progressive disease at 6 months after product infusion. The incidence rates of severe cytokine release syndrome and immune effector cell-associated neurotoxicity syndrome, length of hospital stay, and use of anti-IL-6 and steroids were similar in the 24 patients with GI tract involvement and the 106 patients without GI tract involvement. No significant between-group differences were seen in the best overall response rate, progression-free survival, or overall survival. Our data show that outcomes of patients with GI tract involvement before CAR T cell therapy are similar to those without GI involvement, and that durable remissions can be observed. However, patients with preexisting GI tract involvement are at risk of perforation from disease progression before and after CAR T cell infusion.
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http://dx.doi.org/10.1016/j.jtct.2021.05.018DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8403629PMC
September 2021

High incidence of thromboembolism in patients with chronic GVHD: association with severity of GVHD and donor-recipient ABO blood group.

Blood Cancer J 2021 05 18;11(5):96. Epub 2021 May 18.

Blood and Marrow Transplant Program, Department of Medicine, University of Minnesota, Minneapolis, MN, USA.

Chronic graft-versus-host disease (cGVHD) after allogeneic hematopoietic cell transplantation (HCT) is associated with systemic inflammation and endothelial dysfunction, increasing risk for thromboembolic events (TEE). In 145 adult recipients who developed cGVHD after a matched sibling or umbilical cord blood donor HCT from 2010 to 2018, 32(22%) developed at least 1 TEE event, and 14(10%) developed 2 TEE events. The 5-year cumulative incidence of TEE was 22% (95% CI, 15-29%) with a median time from cGVHD to TEE of 234 days (range, 12-2050). Median time to the development of LE DVT or PE was 107 (range, 12-1925) compared to 450 days (range, 158-1300) for UE DVT. Cumulative incidence of TEE was 9% (95% CI, 0-20%), 17% (95% CI, 9-25%), and 38% (95% CI, 22-55%) in those with mild, moderate, and severe GVHD, respectively. Higher risk for TEE was associated with cGVHD severity (hazard ratio [HR] 4.9, [95% CI, 1.1-22.0]; p = 0.03), non-O-donor to recipient ABO match compared to O-donor to O-recipient match (HR 2.7, [95% CI, 1.0-7.5]; p = 0.053), and personal history of coronary artery disease (HR 2.4, [95% CI, 1.1-5.3]; p = 0.03). TEE was not associated with 2-year non-relapse mortality or 5-year overall survival.
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http://dx.doi.org/10.1038/s41408-021-00488-2DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8131386PMC
May 2021

ROCK2 Inhibition With Belumosudil (KD025) for the Treatment of Chronic Graft-Versus-Host Disease.

J Clin Oncol 2021 06 20;39(17):1888-1898. Epub 2021 Apr 20.

Fred Hutchinson Cancer Research Center, Seattle, WA.

Purpose: The rho-associated coiled-coil-containing protein kinase-2 (ROCK2) signaling pathway regulates the Th17/regulatory T cells balance and controls profibrotic pathways. Selective ROCK2 inhibition with belumosudil (KD025) may offer a novel approach to the management of chronic graft-versus-host disease (cGVHD).

Patients And Methods: A phase IIa, open-label, dose-finding study of belumosudil enrolled 54 patients with cGVHD who had received one to three prior lines of therapy (LOTs). The primary end point was overall response rate (ORR).

Results: The median time from cGVHD diagnosis to enrollment was 20 months. Seventy-eight percent of patients had severe cGVHD, 50% had ≥ 4 organs involved, 73% had cGVHD refractory to their last LOT, and 50% had received ≥ 3 prior LOTs. With an overall median follow-up of 29 months, the ORR (95% CI) with belumosudil 200 mg once daily, 200 mg twice daily, and 400 mg once daily was 65% (38% to 86%), 69% (41% to 89%), and 62% (38% to 82%), respectively. Responses were clinically meaningful, with a median duration of response of 35 weeks, and were associated with quality-of-life improvements and corticosteroid (CS) dose reductions. CS treatment was discontinued in 19% of patients. The failure-free survival rate was 76% (62% to 85%) and 47% (33% to 60%) at 6 and 12 months, respectively. The 2-year overall survival rate was 82% (69% to 90%). Belumosudil was well-tolerated, with low rates of cytopenia. There were no unexpected adverse events and no apparent increased risk of infection, including cytomegalovirus infection and reactivation.

Conclusion: Belumosudil treatment resulted in a high ORR and overall survival rate and demonstrated quality-of-life improvements, CS dose reductions, and limited toxicity. Data from the study indicated that belumosudil may prove to be an effective therapy for patients with treatment-refractory cGVHD.
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http://dx.doi.org/10.1200/JCO.20.02754DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8189612PMC
June 2021

Impact of Total Body Irradiation-Based Myeloablative Conditioning Regimens in Patients with Acute Lymphoblastic Leukemia Undergoing Allogeneic Hematopoietic Stem Cell Transplantation: Systematic Review and Meta-Analysis.

Transplant Cell Ther 2021 07 30;27(7):620.e1-620.e9. Epub 2021 Mar 30.

Department of Internal Medicine, Morsani College of Medicine, University of South Florida, Tampa, Florida.

Allogeneic hematopoietic cell transplantation (allo-HCT) is a curative treatment option for patients with acute lymphoblastic leukemia (ALL). Both total body irradiation (TBI)-based and chemotherapy only-based myeloablative transplantation conditioning regimens have been applied, but the optimal regimen remains unclear. We performed a systematic review to assess the efficacy of TBI-based versus chemotherapy only-based myeloablative conditioning regimens. We searched PubMed, Embase, and Cochrane databases and meeting abstracts for all studies comparing TBI-based and chemotherapy only-based conditioning regimens in patients who underwent allo-HCT for ALL. Two authors independently reviewed all studies for inclusion and extracted data related to overall survival (OS), progression-free survival (PFS), nonrelapse mortality (NRM), relapse, and acute and chronic graft-versus-host disease (GVHD). Eight studies were included in the final analysis. The overall methodological quality of the included studies was optimal. TBI-based regimens showed evidence of benefit compared with chemotherapy only-based conditioning regimens in terms of relapse (relative risk [RR], 0.82; 95% confidence interval [CI], 0.72 to 0.94; 6 studies, 5091 patients), OS (hazard ratio [HR], 0.76; 95% CI, 0.64 to 0.89; 7 studies, 4727 patients), and PFS (HR, 0.74; 95% CI, 0.63 to 0.85; 7 studies, 4727 patients). The TBI-based regimen did not increase the likelihood of grade II-IV acute GVHD (RR, 1.12; 95% CI, 0.92 to 1.36; 5 studies, 4996 patients) or chronic GVHD (RR, 1.10; 95% CI, 1.00 to 1.21; 5 studies, 4490 patients), or NRM (RR, 0.94; 95% CI, 0.69 to 1.28; 6 studies, 4522 patients). However, TBI-based regimens were associated with an increased risk of grade III-IV acute GVHD (RR, 1.29; 95% CI, 1.01 to 1.63; 3 studies, 3675 patients). A subgroup comparison of patients age ≥16 years showed similar results. This systematic review represents evidence supporting the use of TBI-based conditioning regimen in patients undergoing allo-HCT for ALL who are candidates for myeloablative conditioning, as it offers better OS, PFS, and less relapse with acceptable NRM.
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http://dx.doi.org/10.1016/j.jtct.2021.03.026DOI Listing
July 2021

ELN 2017 Genetic Risk Stratification Predicts Survival of Acute Myeloid Leukemia Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation.

Transplant Cell Ther 2021 03 2;27(3):256.e1-256.e7. Epub 2021 Feb 2.

Blood and Marrow Transplantation and Cellular Immunotherapy, H. Lee Moffitt Cancer Center and Research Institute, Tampa, Florida. Electronic address:

European LeukemiaNet (ELN) 2017 risk stratification by genetics is prognostic of outcomes in patients with acute myeloid leukemia (AML). However, the prognostic impact of the 2017 ELN genetic risk stratification after allogeneic hematopoietic cell transplantation (alloHCT) is not well established. We examined the effect of 2017 ELN genetic risk stratification on alloHCT outcomes of AML. We included 500 adult (≥18 years) AML patients in first (n = 370) or second (n = 130) complete remission receiving alloHCT from 2005 to 2016. Patients were classified into favorable (12%), intermediate (57%), and adverse (32%) 2017 ELN risk groups. The Cox proportional hazard model was used to conduct the multivariable analyses of leukemia-free survival (LFS) and overall survival (OS). Relapse and nonrelapse mortality were analyzed by the Fine-Gray regression model. OS at 2 years was 72% in the favorable versus 60% in the intermediate versus 45% in the adverse risk groups (P < .001). In multivariable analyses, the 2017 ELN classifier was an independent predictor of OS after alloHCT with significantly higher overall mortality in the intermediate (hazard ratio [HR] = 1.68, 95% confidence interval [CI], 1.06-2.68; P = .03) and adverse (HR = 2.50, 95% CI, 1.54-4.06; P < .001) risk groups compared to the favorable risk group. Similarly, LFS was worse in the intermediate (HR = 1.63, 95%, CI 1.06-2.53; P = .03) and adverse (HR 2.23, 95% CI, 1.41-3.54; P < .001) risk groups while relapse was higher in the adverse risk group (HR = 2.36, 95% CI, 1.28-4.35; P = .006) as compared to the favorable risk group. These data highlight the prognostic impact of the 2017 ELN genetic risk stratification on the survival of AML patients after alloHCT. Patients in the adverse risk group had the highest risk of relapse and worst survival. Thus the 2017 ELN prognostic system can help identify AML patients who may benefit from clinical trials offering relapse mitigation strategies to improve transplant outcomes.
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http://dx.doi.org/10.1016/j.jtct.2020.12.021DOI Listing
March 2021

Incidence and Management of Effusions Before and After CD19-Directed Chimeric Antigen Receptor (CAR) T Cell Therapy in Large B Cell Lymphoma.

Transplant Cell Ther 2021 03 27;27(3):242.e1-242.e6. Epub 2020 Dec 27.

Department of Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, Florida; Department of Oncologic Sciences, Morsani College of Medicine, University of South Florida, Tampa, Florida. Electronic address:

In patients with lymphoma, third-space fluid accumulations may develop or worsen during cytokine release syndrome (CRS) associated with chimeric antigen receptor (CAR) T cell therapy. Pre-existing symptomatic pleural effusions were excluded by the ZUMA-1 trial of axicabtagene ciloleucel for large B cell lymphoma (LBCL) and variants. The incidence and management of effusions during CAR T cell therapy for LBCL are unknown. We performed a single-center retrospective study evaluating 148 patients receiving CD19-directed CAR T cell therapy for LBCL between May 2015 and September 2019. We retrospectively identified patients who had radiographic pleural, pericardial, or peritoneal effusions that were present prior to the time of CAR T infusion (pre-CAR T) or that newly developed during the first 30 days after CAR T-cell infusion (post-CAR T). Of 148 patients, 19 patients had a pre-CAR T effusion, 17 patients without pre-existing effusion developed a new infusion after CAR T, and 112 patients had no effusions. Comparing pre-CAR T effusions to new effusions post-CAR T, pre-CAR T effusions were more often malignant (84% versus 12%), persistent beyond 30 days (95% versus 18%), and required interventional drainage after CAR T infusion (79% versus 0%). Compared to patients with no effusion, patients with pre-CAR T therapy effusions had a higher frequency of high-risk baseline characteristics, such as bulky disease and high International Prognostic Index. Similarly, patients with pre-CAR T therapy effusions had a higher rate of toxicity with grade 3 or higher CRS occurring in 32% of patients. On multivariate analysis adjusting for age, Eastern Cooperative Oncology Group status, bulky disease, albumin, and lactate dehydrogenase, a pre-CAR T therapy effusion was associated with reduced overall survival (hazard ratio, 2.34; 95% confidence interval, 1.09 to 5.03; P = .03). Moreover, there was higher non-relapse mortality (11% versus 1%; P = .005). Post-CAR T effusions were not associated with significant difference in survival. Effusions commonly complicate CAR T cell therapy for lymphoma. Malignant effusions that occur prior to CAR T therapy are frequently persistent and require therapeutic intervention, and patients have a higher rate of toxicity and death. Effusions that newly occur after CAR T therapy can generally be managed medically and tend not to persist.
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http://dx.doi.org/10.1016/j.jtct.2020.12.025DOI Listing
March 2021

Impact of infused CD34+ stem cell dosing for allogeneic peripheral blood stem cell transplantation with post-transplant cyclophosphamide.

Bone Marrow Transplant 2021 07 3;56(7):1683-1690. Epub 2021 Mar 3.

Department of Bone Marrow Transplant and Cellular Immunotherapy, H. Lee Moffitt Cancer Center, Tampa, FL, USA.

Higher infused total nucleated cell dose (TNC) in allogeneic bone marrow transplant (BMT) with post-transplant cyclophosphamide (PTCy) is associated with improved overall survival. As many centers prefer peripheral blood stem cell grafts (PBSCT) with PTCy, the effect of cell dose on outcomes with this platform also requires elucidation. We retrospectively evaluated 144 consecutive adult patients who received allogeneic T-cell replete PBSCT with PTCy-based graft-versus-host disease (GVHD) prophylaxis for a hematologic malignancy from 2012-2018. The infused CD34+ cell dose was stratified into low (<5 × 10/kg), intermediate (5-10 × 10/kg) and high (>10 × 10/kg) dose level groups. In multivariate analysis, the low CD34+ cell dose group had worse non-relapse mortality (HR = 4.51, 95% CI: 1.92-10.58, p < 0.001), progression- free survival (HR = 4.11, 95% CI: 2.07-8.15, p < 0.001), and overall survival (HR = 4.06, 95% CI: 2.00-8.25, p ≤ 0.001) compared to the intermediate group. Clinical outcomes between the intermediate and high CD34+ cell dose groups were similar. TNC and CD3+ cell dose had no significant impacts on outcomes. These findings suggest that, in patients receiving allogeneic PBSCT with PTCy, infused CD34+ cell doses >5 × 10 cells/kg may result in improved survival. Thus, this study supports targeting a CD34+ cell dose of >5 × 10 cells/kg for allogeneic PBSCT with PTCy.
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http://dx.doi.org/10.1038/s41409-021-01219-8DOI Listing
July 2021

Acute patient-reported outcomes in B-cell malignancies treated with axicabtagene ciloleucel.

Cancer Med 2021 03 28;10(6):1936-1943. Epub 2021 Feb 28.

Moffitt Cancer Center, Department of Health Outcomes and Behavior, Tampa, FL, USA.

Chimeric antigen receptor T-cell therapy with axicabtagene ciloleucel (axi-cel) has considerably improved survival in adults with relapsed/refractory large B-cell lymphoma. This study reports patient-reported outcomes (PROs) such as quality of life (QOL) and toxicity in the first 90 days after treatment. Hematologic cancer patients treated with axi-cel (N = 103, mean age = 61, 39% female) completed SF-36 or PROMIS-29 QOL questionnaires prior to treatment and 90 days after. PRO-Common Terminology Criteria for Adverse Events toxicity items were completed by patients at baseline and 14, 30, 60, and 90 days after treatment. Mixed models examined change in PROs over time. From preinfusion to 90 days later, patients reported improvements in physical functioning, pain, and fatigue (ps < 0.01), but worsening of anxiety (p = 0.02). Patient-reported toxicities worsened by day 14 with improvement thereafter. The five most severe symptoms at day 14 included fatigue, decreased appetite, dry mouth, diarrhea frequency, and problems with concentration. Results indicate improvement in some domains of QOL over time with transient patient-reported toxicities.
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http://dx.doi.org/10.1002/cam4.3664DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7957158PMC
March 2021

A phase 2 trial of GVHD prophylaxis with PTCy, sirolimus, and MMF after peripheral blood haploidentical transplantation.

Blood Adv 2021 03;5(5):1154-1163

Blood and Marrow Transplant and Cellular Immunotherapy, and.

The introduction of posttransplant cyclophosphamide (PTCy) made performing allogeneic hematopoietic cell transplantation (HCT) from HLA haplotype-incompatible donors possible. In a setting of PTCy and tacrolimus/mycophenolate mofetil (MMF) as a graft-versus-host disease (GVHD) prophylaxis, a peripheral blood (PB) graft source as compared with bone marrow reduces the relapse rate but increases acute GVHD (aGVHD) and chronic GVHD (cGVHD). This phase 2 trial assessed sirolimus and MMF efficacy following PTCy as a GVHD prophylaxis after PB haploidentical HCT (haplo-HCT). With 32 evaluable patients (≥18 years) enrolled, this study had 90% power to demonstrate a reduction in 100-day grade II-IV aGVHD to 20% from the historical benchmark of 40% after haplo-HCT using PTCy/tacrolimus/MMF. At a median follow-up of 16.1 months, the primary end point of the trial was met with a day-100 grade II-IV aGVHD cumulative incidence of 18.8% (95% confidence interval [CI], 7.5% to 34.0%). There were no graft-failure events and the 1-year probability of National Institutes of Health (NIH) moderate/severe cGVHD was 18.8% (95% CI, 7.4% to 34.0%), nonrelapse mortality was 18.8% (95% CI, 7.4% to 34.0%), relapse was 22.2% (95% CI, 9.6% to 38.2%), disease-free survival was 59.0% (95% CI, 44.1% to 79.0%), GVHD-free relapse-free survival was 49.6% (95% CI, 34.9% to 70.5%), and overall survival was 71.7% (95% CI, 57.7% to 89.2%) for the entire cohort. These data demonstrate that GVHD prophylaxis with sirolimus/MMF following PTCy effectively prevents grade II-IV aGVHD after PB haplo-HCT, warranting prospective comparison of sirolimus vs tacrolimus in combination with MMF following PTCy as GVHD prophylaxis after PB HCT. This trial was registered at www.clinicaltrials.gov as #NCT03018223.
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http://dx.doi.org/10.1182/bloodadvances.2020003779DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7948297PMC
March 2021

New is forgotten old: IMiDs against chronic GVHD.

Blood 2021 02;137(7):862-864

Moffitt Cancer Center.

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http://dx.doi.org/10.1182/blood.2020009282DOI Listing
February 2021

Tumor interferon signaling and suppressive myeloid cells are associated with CAR T-cell failure in large B-cell lymphoma.

Blood 2021 May;137(19):2621-2633

Department of Blood and Marrow Transplant and Cellular Immunotherapy.

Axicabtagene ciloleucel (axi-cel) is a chimeric antigen receptor (CAR) T-cell therapy for relapsed or refractory large B-cell lymphoma (LBCL). This study evaluated whether immune dysregulation, present before CAR T-cell therapy, was associated with treatment failure. Tumor expression of interferon (IFN) signaling, high blood levels of monocytic myeloid-derived suppressor cells (M-MDSCs), and high blood interleukin-6 and ferritin levels were each associated with a lack of durable response. Similar to other cancers, we found that in LBCL tumors, IFN signaling is associated with the expression of multiple checkpoint ligands, including programmed cell death-ligand 1, and these were higher in patients who lacked durable responses to CAR-T therapy. Moreover, tumor IFN signaling and blood M-MDSCs associated with decreased axi-cel expansion. Finally, patients with high tumor burden had higher immune dysregulation with increased serum inflammatory markers and tumor IFN signaling. These data support that immune dysregulation in LBCL promotes axi-cel resistance via multiple mechanistic programs: insufficient axi-cel expansion associated with both circulating M-MDSC and tumor IFN signaling, which also gives rise to expression of immune checkpoint ligands.
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http://dx.doi.org/10.1182/blood.2020007445DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8120145PMC
May 2021

Outcomes of chronic graft-versus-host disease following matched sibling donor versus umbilical cord blood transplant.

Bone Marrow Transplant 2021 06 8;56(6):1373-1380. Epub 2021 Jan 8.

Division of Hematology, Oncology and Transplantation, University of Minnesota, Minneapolis, MN, USA.

We compared chronic graft-versus-host disease (cGvHD) following umbilical cord blood (UCBT) and matched sibling donor peripheral blood transplant (MSD). 145 patients (2010-2017) with cGvHD after MSD (n = 104) and UCBT (n = 41) were included. Prior acute GvHD was less frequent in MSD (55% vs. 85%; p = 0.01). Severe cGvHD (32% vs. 15%, p = 0.01) and de-novo onset (45% vs. 15%, p < 0.01) were more frequent following MSD. Liver was more frequently involved in MSD recipients (38% vs. 6%); and GI in UCBT (33% vs. 63%), both p < 0.01. Overall response (CR + PR) was similar between both cohorts. 2-year CR was higher in UCBT (14% vs 33%, p = 0.02). Karnofsky score (KPS) ≥ 90 at cGvHD diagnosis was associated with higher odds of response (95%CI: 1.42-10, p < 0.01). The cumulative incidence of durable discontinuation of immune-suppressive therapy, failure-free survival (FFS) and NRM at 2-years were similar between cohorts. KPS < 90 (95%CI: 3.1-24.9, p < 0.01) and platelets <100 × 10e9/L (95%CI: 1.25-10, p = 0.01) were associated with higher risk of NRM. UCBT patients were more likely to have a prior acute GvHD, less severe cGvHD and more likely to attain CR. Despite differences, both cohorts had similar NRM and FFS. High-risk groups, including those with platelets <100 × 10e9/L and KPS < 90, need careful monitoring and intensified therapy.
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http://dx.doi.org/10.1038/s41409-020-01195-5DOI Listing
June 2021

Weight-based mycophenolate mofetil dosing predicts acute GVHD and relapse after allogeneic hematopoietic cell transplantation.

Eur J Haematol 2021 Feb 9;106(2):205-212. Epub 2020 Dec 9.

Division of Hematology, Oncology and Transplantation, Department of Medicine, University of Minnesota, Minneapolis, MN, USA.

Objectives: Higher MMF dose can reduce acute GVHD risk after allogeneic hematopoietic cell transplantation (HCT). We examined the effect of MMF dose, relative to patient actual body weight (mg/kg/day), on outcomes of 680 adults after HCT.

Methods: MMF was combined with cyclosporine (n = 599) or sirolimus (n = 81). We divided MMF dose/kg/day in quartiles.

Results: The median time to grade II-IV acute GVHD was 32 days. The incidence of grade II-IV acute GVHD at day 30 was 30% in 1st (<29), 20% in 2nd (29-34), 16% in 3rd (35-41), and 19% in 4th (≥42) quartile (P < .01). Corresponding relapse incidence at 1 year was 16%, 25%, 27%, and 31%, respectively (P = .01). In multivariate analysis, as compared to 1st quartile, higher dose of weight-based MMF reduced grade II-IV acute GVHD (HR = 0.64 for 2nd, HR = 0.48 for 3rd, and HR = 0.55 for 4th quartile), but increased the risk of relapse (HR = 1.63 for 2nd, HR = 1.75 for 3rd, and HR = 2.31 for 4th quartile).

Conclusions: Weight-based MMF dose had no significant impact on engraftment, chronic GVHD, or survival. These data suggest that higher weight-based MMF dose reduces the risk of acute GVHD at the expense of increased relapse and supports conducting prospective studies to optimize MMF dosing after HCT.
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http://dx.doi.org/10.1111/ejh.13537DOI Listing
February 2021

Specific Class I HLA Supertypes but Not HLA Zygosity or Expression Are Associated with Outcomes following HLA-Matched Allogeneic Hematopoietic Cell Transplant: HLA Supertypes Impact Allogeneic HCT Outcomes.

Transplant Cell Ther 2021 02 11;27(2):142.e1-142.e11. Epub 2020 Oct 11.

Department of Medicine, Adult Bone Marrow Transplantation Service, Memorial Sloan Kettering Cancer Center, New York, New York; Department of Medicine, Weill Cornell Medical College, New York, New York; Human Oncology & Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, New York. Electronic address:

Maximizing the probability of antigen presentation to T cells through diversity in HLAs can enhance immune responsiveness and translate into improved clinical outcomes, as evidenced by the association of heterozygosity and supertypes at HLA class I loci with improved survival in patients with advanced solid tumors treated with immune checkpoint inhibitors. We investigated the impact of HLA heterozygosity, supertypes, and surface expression on outcomes in adult and pediatric patients with acute myeloid leukemia (AML), myelodysplastic syndrome, acute lymphoblastic leukemia, and non-Hodgkin lymphoma who underwent 8/8 HLA-matched, T cell replete, unrelated, allogeneic hematopoietic cell transplant (HCT) from 2000 to 2015 using patient data reported to the Center for International Blood and Marrow Transplant Research. HLA class I heterozygosity and HLA expression were not associated with overall survival, relapse, transplant-related mortality (TRM), disease-free survival (DFS), and acute graft-versus-host disease following HCT. The HLA-B62 supertype was associated with decreased TRM in the entire patient cohort (hazard ratio [HR], 0.79; 95% CI, 0.69 to 0.90; P = .00053). The HLA-B27 supertype was associated with worse DFS in patients with AML (HR = 1.21; 95% CI, 1.10 to 1.32; P = .00005). These findings suggest that the survival benefit of HLA heterozygosity seen in solid tumor patients receiving immune checkpoint inhibitors does not extend to patients undergoing allogeneic HCT. Certain HLA supertypes, however, are associated with TRM and DFS, suggesting that similarities in peptide presentation between supertype members play a role in these outcomes. Beyond implications for prognosis following HCT, these findings support the further investigation of these HLA supertypes and the specific immune peptides important for transplant outcomes.
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http://dx.doi.org/10.1016/j.bbmt.2020.10.010DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8015676PMC
February 2021

High metabolic tumor volume is associated with decreased efficacy of axicabtagene ciloleucel in large B-cell lymphoma.

Blood Adv 2020 07;4(14):3268-3276

Department of Blood and Marrow Transplant and Cellular Immunotherapy, and.

High metabolic tumor volume (MTV) predicts worse outcomes in lymphoma treated with chemotherapy. However, it is unknown if this holds for patients treated with axicabtagene ciloleucel (axi-cel), an anti-CD19 targeted chimeric antigen receptor T-cell therapy. The primary objective of this retrospective study was to investigate the relationship between MTV and survival (overall survival [OS] and progression-free survival [PFS]) in patients with relapsed/refractory large B-cell lymphoma (LBCL) treated with axi-cel. Secondary objectives included finding the association of MTV with response rates and toxicity. The MTV values on baseline positron emission tomography of 96 patients were calculated via manual methodology using commercial software. Based on a median MTV cutoff value of 147.5 mL in the first cohort (n = 48), patients were divided into high and low MTV groups. Median follow-up for survivors was 24.98 months (range, 10.59-51.02 months). Patients with low MTV had significantly superior OS (hazard ratio [HR], 0.25; 95% confidence interval [CI], 0.10-0.66) and PFS (HR, 0.40; 95% CI, 0.18-0.89). Results were successfully validated in a second cohort of 48 patients with a median follow-up for survivors of 12.03 months (range, 0.89-25.74 months). Patients with low MTV were found to have superior OS (HR, 0.14; 95% CI, 0.05-0.42) and PFS (HR, 0.29; 95% CI, 0.12-0.69). In conclusion, baseline MTV is associated with OS and PFS in axi-cel recipients with LBCL.
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http://dx.doi.org/10.1182/bloodadvances.2020001900DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7391155PMC
July 2020

Immune reconstitution and associated infections following axicabtagene ciloleucel in relapsed or refractory large B-cell lymphoma.

Haematologica 2021 04 1;106(4):978-986. Epub 2021 Apr 1.

Dept. of Blood and Marrow Transplant and Cellular Immunotherapy, Moffitt Cancer Center, Tampa, USA.

CD19 CAR T-cell therapy with axicabtagene ciloleucel (axi-cel) for relapsed or refractory (R/R) large B cell lymphoma (LBCL) may lead to durable remissions, however, prolonged cytopenias and infections may occur. In this single center retrospective study of 85 patients, we characterized immune reconstitution and infections for patients remaining in remission after axi-cel for LBCL. Prolonged cytopenias (those occurring at or after day 30 following infusion) were common with >= grade 3 neutropenia seen in 21/70 (30-0%) patients at day 30 and persisting in 3/31 (9-7%) patients at 1 year. B cells were undetectable in 30/34 (88-2%) patients at day 30, but were detected in 11/19 (57-9%) at 1 year. Median IgG levels reached a nadir at day 180. By contrast, CD4 T cells decreased from baseline and were persistently low with a median CD4 count of 155 cells/μl at 1 year after axi-cel (n=19, range 33 - 269). In total, 23/85 (27-1%) patients received IVIG after axi-cel, and 34/85 (40-0%) received G-CSF. Infections in the first 30 days occurred in 31/85 (36-5%) patients, of which 11/85 (12-9%) required intravenous antibiotics or hospitalization ("severe") and were associated with cytokine release syndrome (CRS), neurotoxicity, tocilizumab use, corticosteroid use, and bridging therapy on univariate analyses. After day 30, 7 severe infections occurred, with no late deaths due to infection. Prolonged cytopenias are common following axi-cel therapy for LBCL and typically recover with time. Most patients experience profound and prolonged CD4 T cell immunosuppression without severe infection.
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http://dx.doi.org/10.3324/haematol.2019.238634DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8017820PMC
April 2021

Outcomes of rituximab-BEAM versus BEAM conditioning regimen in patients with diffuse large B cell lymphoma undergoing autologous transplantation.

Cancer 2020 05 12;126(10):2279-2287. Epub 2020 Feb 12.

Department of Laboratory Medicine, Karolinska Institutet, Stockholm, Sweden.

Background: Although rituximab-based high-dose therapy is frequently used in diffuse large B cell lymphoma (DLBCL) patients undergoing autologous hematopoietic cell transplantation (auto-HCT), data supporting the benefits are not available. Herein, we report the impact of rituximab-based conditioning on auto-HCT outcomes in patients who have DLBCL.

Methods: Using the Center for International Blood and Marrow Transplant Research (CIBMTR) registry, 862 adult DLBCL patients undergoing auto-HCT between 2003 and 2017 using BEAM (BCNU, etoposide, cytarabine, melphalan) conditioning regimen were included. All patients received frontline rituximab-containing chemoimmunotherapy and had chemosensitive disease pre-HCT. Early chemoimmunotherapy failure was defined as not achieving complete remission (CR) after frontline chemoimmunotherapy or relapse within 1 year of initial diagnosis. The primary outcome was overall survival (OS).

Results: The study cohort was divided into 2 groups: BEAM (n = 667) and R-BEAM (n = 195). On multivariate analysis, no significant difference was seen in OS (P = .83) or progression-free survival (PFS) (P = .61) across the 2 cohorts. No significant association between the use of rituximab and risk of relapse (P = .15) or nonrelapse mortality (P = .12) was observed. Variables independently associated with lower OS included older age at auto-HCT (P < .001), absence of CR at auto-HCT (P < .001) and early chemoimmunotherapy failure (P < .001). Older age (P < .0002) and non-CR pre-HCT (P < .0001) were also associated with inferior PFS. There was no significant difference in early infectious complications between the 2 cohorts.

Conclusion: In this large registry analysis of DLBCL patients undergoing auto-HCT, the addition of rituximab to the BEAM conditioning regimen had no impact on transplantation outcomes. Older age, absence of CR pre auto-HCT, and early chemoimmunotherapy failure were associated with inferior survival.
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http://dx.doi.org/10.1002/cncr.32752DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7190439PMC
May 2020

Cardiovascular Events Among Adults Treated With Chimeric Antigen Receptor T-Cells (CAR-T).

J Am Coll Cardiol 2019 12;74(25):3099-3108

Cardiovascular Imaging Research Center (CIRC), Department of Radiology and Division of Cardiology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts; Cardio-Oncology Program, Division of Cardiology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts. Electronic address:

Background: Chimeric antigen receptors redirect T cells (CAR-T) to target cancer cells. There are limited data characterizing cardiac toxicity and cardiovascular (CV) events among adults treated with CAR-T.

Objectives: The purpose of this study was to evaluate the possible cardiac toxicities of CAR-T.

Methods: The registry included 137 patients who received CAR-T. Covariates included the occurrence and grade of cytokine release syndrome (CRS) and the administration of tocilizumab for CRS. Cardiac toxicity was defined as a decrease in the left ventricular ejection fraction or an increase in serum troponin. Cardiovascular events were a composite of arrhythmias, decompensated heart failure, and CV death.

Results: The median age was 62 years (interquartile range [IQR]: 54 to 70 years), 67% were male, 88% had lymphoma, and 8% had myeloma. Approximately 50% were treated with commercial CAR-T (Yescarta or Kymriah), and the remainder received noncommercial products. CRS, occurring a median of 5 days (IQR: 2 to 7 days) after CAR-T, occurred in 59%, and 39% were grade ≥2. Tocilizumab was administered to 56 patients (41%) with CRS, at a median of 27 h (IQR: 16 to 48 h) after onset. An elevated troponin occurred in 29 of 53 tested patients (54%), and a decreased left ventricular ejection fraction in 8 of 29 (28%); each occurred only in patients with grade ≥2 CRS. There were 17 CV events (12%, 6 CV deaths, 6 decompensated heart failure, and 5 arrhythmias; median time to event of 21 days), all occurred with grade ≥2 CRS (31% patients with grade ≥2 CRS), and 95% of events occurred after an elevated troponin. The duration between CRS onset and tocilizumab administration was associated with CV events, where the risk increased 1.7-fold with each 12-h delay to tocilizumab.

Conclusions: Among adults, cardiac injury and CV events are common post-CAR-T. There was a graded relationship among CRS, elevated troponin, and CV events, and a shorter time from CRS onset to tocilizumab was associated with a lower rate of CV events.
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http://dx.doi.org/10.1016/j.jacc.2019.10.038DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6938409PMC
December 2019

Impact of cytogenetic abnormalities on outcomes of adult Philadelphia-negative acute lymphoblastic leukemia after allogeneic hematopoietic stem cell transplantation: a study by the Acute Leukemia Working Committee of the Center for International Blood and Marrow Transplant Research.

Haematologica 2020 05 26;105(5):1329-1338. Epub 2019 Sep 26.

Oncology Center, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia.

Cytogenetic risk stratification at diagnosis has long been one of the most useful tools to assess prognosis in acute lymphoblastic leukemia (ALL). To examine the prognostic impact of cytogenetic abnormalities on outcomes after allogeneic hematopoietic cell transplantation, we studied 1731 adults with Philadelphia-negative ALL in complete remission who underwent myeloablative or reduced intensity/non-myeloablative conditioning transplant from unrelated or matched sibling donors reported to the Center for International Blood and Marrow Transplant Research. A total of 632 patients had abnormal conventional metaphase cytogenetics. The leukemia-free survival and overall survival rates at 5 years after transplantation in patients with abnormal cytogenetics were 40% and 42%, respectively, which were similar to those in patients with a normal karyotype. Of the previously established cytogenetic risk classifications, modified Medical Research Council-Eastern Cooperative Oncology Group score was the only independent prognosticator of leukemia-free survival (=0.03). In the multivariable analysis, monosomy 7 predicted post-transplant relapse [hazard ratio (HR)=2.11; 95% confidence interval (95% CI): 1.04-4.27] and treatment failure (HR=1.97; 95% CI: 1.20-3.24). Complex karyotype was prognostic for relapse (HR=1.69; 95% CI: 1.06-2.69), whereas t(8;14) predicted treatment failure (HR=2.85; 95% CI: 1.35-6.02) and overall mortality (HR=3.03; 95% CI: 1.44-6.41). This large study suggested a novel transplant-specific cytogenetic scheme with adverse [monosomy 7, complex karyotype, del(7q), t(8;14), t(11;19), del(11q), tetraploidy/near triploidy], intermediate (normal karyotype and all other abnormalities), and favorable (high hyperdiploidy) risks to prognosticate leukemia-free survival (=0.02). Although some previously established high-risk Philadelphia-negative cytogenetic abnormalities in ALL can be overcome by transplantation, monosomy 7, complex karyotype, and t(8;14) continue to pose significant risks and yield inferior outcomes.
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http://dx.doi.org/10.3324/haematol.2019.220756DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7193485PMC
May 2020

Use of Chimeric Antigen Receptor T Cell Therapy in Clinical Practice for Relapsed/Refractory Aggressive B Cell Non-Hodgkin Lymphoma: An Expert Panel Opinion from the American Society for Transplantation and Cellular Therapy.

Biol Blood Marrow Transplant 2019 12 22;25(12):2305-2321. Epub 2019 Aug 22.

Lymphoma Program, Abramson Cancer Center at University of Pennsylvania, Philadelphia, Pennsylvania.

Axicabtagene ciloleucel (YESCARTA; Kite Pharma, a Gilead Company, Los Angeles CA) and tisagenlecleucel (KYMRIAH; Novartis Pharmaceuticals Corp., Basel, Switzerland) are two CD19-directed chimeric antigen receptor (CAR) T cell products currently approved by the US Food and Drug Administration; the European Medicines Agency; Health Canada; Ministry of Health, Labor and Welfare (Japan); and Therapeutic Goods Administration (Australia) for treatment of specific subtypes of relapsed/refractory aggressive B cell non-Hodgkin lymphoma (NHL). Although this approval has been transformative in the use of cellular immunotherapy in lymphoma, there are concerns regarding appropriate use of this novel therapy and of short- and long-term toxicities. To address these issues, representatives of the American Society of Transplantation and Cellular Therapy convened to recognize and address key issues surrounding the clinical application of CD19 CAR T cell therapy in B cell lymphomas, in collaboration with worldwide experts. The aim of this article is to provide consensus opinion from experts in the fields of hematopoietic cell transplantation, cellular immunotherapy, and lymphoma regarding key clinical questions pertinent to the use of CD19 CAR T cell products for the treatment of NHL. As the clinical practice using CAR T cells grows worldwide, we anticipate that this guidance will be relevant for hematology/oncology physicians who care for patients with lymphomas.
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http://dx.doi.org/10.1016/j.bbmt.2019.08.015DOI Listing
December 2019
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