Maintenance therapy after second autologous hematopoietic cell transplantation for multiple myeloma. A CIBMTR analysis.

The role of maintenance therapy after high-dose chemotherapy and first autologous transplantation in multiple myeloma (MM) is well established. We explored the effect of maintenance therapy on outcomes after salvage second autologous hematopoietic cell transplant (AHCT2) using the Center for International Blood and Marrow Transplant Research registry. Outcomes of interest included non-relapse mortality (NRM), relapse/progression (REL), progression-free and overall survival (PFS, OS). Of 522 patients who underwent AHCT2 between 2010 and 2018, 342 received maintenance therapy and 180 did not. Maintenance regimens included lenalidomide (42%), pomalidomide (13%), and bortezomib (13%). Median follow up was 58 months in the maintenance group and 61.5 months in the no-maintenance group. Univariate analysis showed superior outcomes at 5 years in maintenance compared to the no-maintenance group: NRM 2 (0.7-3.9)% vs 9.9 (5.9-14.9)%, (p < 0.01), REL 70.2 (64.4-75.8)% vs 80.3 (73.6-86.3)% (p < 0.01), PFS 27.8 (22.4-33.5)% vs. 9.8 (5.5-15.2)% (p < 0.01), and OS 54 (47.5-60.5)% vs 30.9 (23.2-39.2)% (p < 0.01), respectively. Use of maintenance therapy retained its association with improved outcomes in multivariate analysis. There was no difference in second cancers in the two groups (p = 0.39). We conclude that maintenance after AHCT2 is associated with improved 5-year outcomes.

Toxicity and efficacy of chimeric antigen receptor T-cell therapy in patients with diffuse large B-cell lymphoma above the age of 70 years compared to younger patients - a matched control multicenter cohort study.

Data regarding efficacy and toxicity of chimeric antigen receptor T (CAR-T) cell therapy in the elderly, geriatric population are insufficient. In 2019, tisagenlecleucel and axicabtagene-ciloleucel were commercially approved for relapsed/refractory diffuse large B-cell lymphoma. From May 2019 onwards, 47 relapsed/refractory diffuse large Bcell lymphoma patients, ≥70 years underwent lymphopharesis in three Israeli centers. Elderly (n=41, mean age 76.2 years) and young (n=41, mean age 55.4 years) patients were matched based on ECOG performance status and lactose dehydrogenase levels. There were no differences in CD4/CD8 ratio (P=0.94), %CD4 naive (P=0.92), %CD8 naive (P=0.44) and exhaustion markers (both HLA-DR and PD-1) between CAR-T cell products in both cohorts. Forty-one elderly patients (87%) received CAR-T cell infusion. There were no differences in the incidence of grade ≥3 cytokine-release-syndrome (P=0.29), grade≥3 neurotoxicity (P=0.54), and duration of hospitalization (P=0.55) between elderly and younger patients. There was no difference in median D7-CAR-T cell expansion (P=0.145). Response rates were similar between the two groups (complete response 46% and partial response 17% in the elderly group, P=0.337). Non-relapse mortality at 1 and 3 months was 0 in both groups. With a median follow-up of 7 months (range, 1.3-17.2 months), 6- and 12-months progression-free and overall survival in elderly patients were 39% and 32%, and 74% and 69%, respectively. EORTC QLQ-C30 questionnaires, obtained at 1 month, showed worsening of disability and cancer-related-symptoms in elderly versus younger patients. We conclude that outcomes of CAR-T cell therapy are comparable between elderly, geriatric and younger patients, indicating that age as per se should not preclude CAR-T cell administration. Longer rehabilitation therapy is essential to improve disabilities and long-term symptoms.

Diarrheal Morbidity During Hematopoietic Cell Transplantation: The Diagnostic Yield of Stool Cultures.

INTRODUCTION: Diarrhea affects a significant proportion of patients undergoing hematopoietic cell transplantation (HCT). We explored the diagnostic yield of stool cultures for enteric pathogens among patients undergoing HCT. METHODS: This is a single-center, retrospective study. Between 5/2007 and 4/2020, consecutive patients who underwent HCT were included if inpatient bacterial stool cultures were collected. Patient characteristics, results, and timing of stool cultures obtained during hospitalization were collected. RESULTS: A total of 1072 individuals underwent autologous (n = 603) and allogeneic (n = 469) HCT. Overall, 947 stool culture samples were obtained from 561 (52%) patients with diarrheal illness during hospitalization for HCT. Most (99%) samples were obtained beyond 3 days of admission, mainly (77%) during neutropenia. Overall, only four (0.42%) (autologous, n = 3; allogeneic, n = 1) patients had a positive stool culture and in all cases Campylobacter spp. were the pathogens identified. The number of stool cultures needed-to-test to diagnose one case of bacterial infection was 237. The cost of diagnosing one case of bacterial diarrhea was US $8770. Patients with a positive stool culture did not have discerning characteristics. CONCLUSIONS: In our experience, the yield of stool cultures for enteropathogens in patients undergoing HCT is extremely low and thus should be avoided in most cases.

Venetoclax and donor lymphocyte infusion for early relapsed acute myeloid leukemia after allogeneic hematopoietic cell transplantation. A retrospective multicenter trial.

Prognosis in patients with post allogeneic HCT-early relapse of acute myeloid leukemia (<6 months post HCT) is dismal and response to salvage treatment is < 20%. In addition, majority of patients at this early point are unable to withstand intensive salvage chemotherapy. We hypothesized that the combination of donor lymphocyte infusion (DLI) and venetoclax may result in increased response in this difficult to treat patient group. We retrospectively analyzed 22 patients from February 2017-December 2019, who were given the Venetoclax/DLI combination. Median age was 65 (43-75) years. There were no cases of tumor lysis syndrome. Microbiology documented infections occurred in 8 patients (36%). Majority were able to tolerate the protocol without admissions. Acute GVHD was observed in 4 (18%) patients and cGVHD was observed in 6 (27%) patients. Overall response was observed in 11 (50%) patients (CR, n = 4; CRi, n = 1; CRp, n = 4; MLFS n = 2). Median time to response was 28 (18-67) days and median cycles of venetoclax 2 [1-8] and duration of response were 135 (31-564) days. Median survival was 6.1 months (95% CI .73-11.4). Cox regression model for survival showed decreased WBC at relapse, GVHD and better performance status were associated with better survival. These results may endorse the hypothesis that enhancing alloreactivity combined with venetoclax is safe and efficacious and should be further investigated in prospective trials.

Consolidation Treatment for Primary Central Nervous System Lymphoma: Which Modality for Whom?

Primary central nervous system lymphoma is a rare aggressive disease that largely affects elderly patients and is associated with poor prognosis. The optimal treatment approach is not yet defined and it consists of induction and consolidation phases. The combination of high-dose (HD) methotrexate-based chemotherapy followed by whole-brain radiotherapy (WBRT) prolongs the median progression-free survival (PFS) and overall survival 2- to 3-fold as compared to WBRT alone but is associated with significant delayed neurotoxicity. Alternative strategies are being investigated in order to improve disease outcomes and spare patients the neurocognitive side effects. These include reduced-dose WBRT, non-myeloablative HD chemotherapy, or HD chemotherapy with autologous stem cell transplantation (HDC/ASCT). There are no randomized studies that compare all these consolidation regimens head to head but recently HDC/ASCT has been evaluated versus WBRT in prospective randomized studies. These studies proved that WBRT and HDC/ASCT yield similar 2-year PFS with preserved or improved cognitive function after HDC/ASCT. Yet, the proportion of patients treated with such intensive consolidation is low, both in real life and in specialized centers, leaving many unsettled issues. This review is appraising current dilemmas related to the choice of consolidating therapeutic modalities, their associated acute and delayed toxicity, and future prospects for alternative approaches in the elderly.

Obinutuzumab-related adverse events: A systematic review and meta-analysis.

Rituximab, the first anti-CD20 monoclonal antibody, has dramatically improved outcomes for patients with B-cell lymphoproliferative disorders. Obinutuzumab was developed to potentiate activity and overcome resistance to rituximab. Clinical data suggest that obinutuzumab is superior to rituximab in follicular lymphoma (FL) and chronic lymphocytic leukemia (CLL). Yet, it has increased toxicity. This systematic review and meta-analysis compiled all randomized controlled trials (RCTs) comparing obinutuzumab-based regimens with rituximab-based regimens to better assess their toxicity profile. Primary outcome was grade 3-4 infections; secondary outcomes included any adverse events (AE), grade 3-4 AE, drug discontinuation rate, and 3-years mortality. Relative risks (RRs) were estimated and pooled using a fixed-effect model, unless there was significant heterogeneity, in which case a random-effects model was used. Our comprehensive search yielded five RCTs conducted between 2009 and 2014, including 4247 patients. The trials included FL patients, CLL and diffuse large B cell lymphoma. Monoclonal antibodies were given with different chemotherapy regimens (in four trials) or as monotherapy (in one trial). The point estimate favored increase in both grade 3-4 infections rate (RR 1.17 [95% CI, 1.0-1.36]) and any AE rate (RR 1.05 [95% 1-1.1]) with obinutuzumab, although this was not statistically significant. There was a significantly increased rate of grade 3-4 AE (RR 1.15 [95% CI, 1.09-1.2]), as well as grade 3-4 toxicities including thrombocytopenia (RR 2.8 [95% CI, 1.92-4.06]), infusion related reactions (RR 2.8 [95% CI, 2.16-3.64]) and cardiac events (RR 1.65 [95% CI, 1.11-2.46]). There was no significant difference in grade 3-4 anemia and neutropenia nor in the 3-year mortality rate. The point estimate favored increase in discontinuation rate due to AE with obinutuzumab, although without statistical significance (RR 1.24 [95% CI, 1.0-1.54]). In conclusion, physicians need to weigh the clinical benefits of this agent against higher toxicity.

Sequential treatment with FLAG-IDA/treosulfan conditioning regimen for patients with active acute myeloid leukemia.

Sequential protocols combining salvage chemotherapy with reduced intensity conditioning (RIC) and allogeneic hematopoietic cell transplantation (alloHCT) for high-risk acute myeloid leukemia (AML) have been studied more than a decade. Purpose of this retrospective analysis was to evaluate the anti-leukemic efficacy and toxicity of FLAG-IDA protocol (fludarabine, cytarabine, and idarubicin) followed by treosulfan-based conditioning for patients with active AML. From January 2014 to November 2019, a total of 29 active AML patients [median age, 64 years (range, 23-73)] were treated. All patients completed protocol regimen and were transplanted. Five patients (17%) had grade 3-4 toxicities; therefore, treosulfan was substituted with total body irradiation (TBI) non-myeloablative conditioning. Six (20%) patients died within 30 post-transplant days, all from infectious complications. Out of 23 evaluable patients on day 30, 22 (96%) achieved complete hematologic remission with full donor chimerism. Non-relapse mortality (NRM) rates at 1 and 3 years were 22% and 49%, respectively. Median overall survival (OS) was 12 (95% CI, 4-20) months. OS and disease-free survival were 50% and 46% at 1 year and 28% and 17% at 2 years, respectively. Age, gender, disease burden, number of previous lines, and comorbidity score did not predict survival. Sequential strategy combining FLAG-IDA and treosulfan may offer a salvage option for few selected patients with active AML; however, high NRM presents a major obstacle to treatment success. Future efforts should focus on reducing NRM by moderating regimen intensity and by better selection of patients.

Efficacy of folinic acid rescue following MTX GVHD prophylaxis: results of a double-blind, randomized, controlled study.

The use of methotrexate (MTX) for graft-versus-host disease (GVHD) prophylaxis is associated with increased rates of organ-specific toxicities. Despite limited data, the European Society for Blood and Marrow Transplantation-European LeukemiaNet working group recommend the use of folinic acid (FA) rescue to reduce MTX toxicity after allogeneic hematopoietic cell transplantation (allo-HCT). In a multicenter, double-blind, randomized, controlled trial, we explored whether FA rescue reduces MTX-induced toxicity. We enrolled patients undergoing allo-HCT with myeloablative conditioning with peripheral blood stem cell grafts, with GVHD prophylaxis consisting of cyclosporine and MTX. Patients were randomized to receive FA or placebo starting 24 hours after each MTX dose and continuing over 24 hours in 3 to 4 divided doses. The primary end point was the rate of grades 3 and 4 oral mucositis. After enrollment of 52 patients (FA, n = 28; placebo, n = 24), preplanned interim analysis revealed similar rates of grade 3 and 4 (46.6% vs 45.8%; P = .97) and grades 1 to 4 (83.3% vs 77.8%; P = .65) oral mucositis. With a median follow-up of 17 (range, 4.5-50) months, there was no difference in the rates of acute and chronic GVHD, disease relapse, nonrelapse mortality, and overall survival. These interim results did not support continuation of the study. We conclude that FA rescue after MTX GVHD prophylaxis does not decrease regimen-related toxicity or affect transplantation outcomes. This study was registered at clinicaltrials.gov as #NCT02506231.

Risk factors for mortality due to Acinetobacter baumannii bacteremia in patients with hematological malignancies - a retrospective study.

Carbapenem resistant Acinetobacter baumannii (CRAB) is a significant cause of hospital acquired bloodstream infections in patients with hematological malignancies. Data regarding outcomes in this group of patients are limited. We retrospectively analyzed mortality risk factors of hospitalized hematological patients with CRAB bacteremia in our center. Among 46 included patients, overall 7-day mortality was 72% (33/46). Risk factors for 7-day mortality in multivariate analysis were higher infection severity score (SOFA score) at presentation (OR 1.481, 95% CI 1.091-2.012, p = .012) while appropriate antibiotic therapy within 48 h was protective (OR 0.052, 95% CI 0.005-0.590, p = .017). Inappropriate antibiotic therapy within 24 h was not significantly associated with 7-day mortality nor was absolute neutrophil count. Thirty-day mortality was 96% (44/46). CRAB bacteremia in hematological patients is associated with extremely high mortality, regardless of therapy. Infection control measures and antimicrobial stewardship aiming to prevent this infection of dismal prognosis are of major importance.

Human herpes virus 6 reactivation following autologous hematopoietic cell transplantation - a single-center experience.

Data regarding presentation and management of human herpes virus 6 (HHV-6) reactivation among autologous hematopoietic cell transplantation (HCT) recipients are limited. We retrospectively reviewed medical charts of all autologous HCT patients tested for HHV-6 reactivation due to suspected clinical presentation between 1/2012 and 8/2017. Among 328 autologous HCT recipients, 44 patients were tested for HHV-6 reactivation. Thirty patients tested positive; 29 (97%) had sustained fever, six (20%) had rash and four (13%) had pneumonia. Median C-reactive protein was significantly lower in HHV-6 positive patients compared to negative patients (3.6 (range, 0.4-11) vs. 9.6 (range, 3.2-30) mg/dL, respectively, p = .004). Ganciclovir formulations were administrated in 29 (97%) patients with median time to fever resolution of one (range, 1-2) day. HHV-6 should be considered as an important cause of post engraftment fever in autologous HCT. Larger studies are warranted to evaluate incidence of HHV-6 reactivation and optimal treatment regimen.

Immune Mediated Cerebellar Ataxia: An Unknown Manifestation of Graft-versus-Host Disease.

Neurologic complications of allogeneic hematopoietic cell transplantation (allo-HCT) include infections, cerebrovascular events, therapy-induced neurotoxicity, recurrent malignancies, and neurologic manifestations of graft-versus-host disease (GVHD). Anti-glutamic acid decarboxylase (GAD) antibody-associated cerebellar ataxia is a well-established disorder of autoimmune origin, but there are no reports in the literature of its occurrence following allo-HCT. We describe a middle-aged woman with chronic GVHD after allo-HCT who presented with a rapidly progressive cerebellar syndrome. Thorough investigation revealed only cerebellar atrophy on brain imaging and positive anti-GAD65 antibodies in serum and cerebrospinal fluid suggesting the diagnosis of anti-GAD antibody-associated cerebellar ataxia. Despite prompt treatment with high-dose corticosteroids, intravenous immunoglobulins, and rituximab, the patient's condition rapidly deteriorated, and she died 4 months later. This case suggests that anti-GAD antibody-associated cerebellar ataxia may be a rare manifestation of chronic GVHD.

Hypomethylating Agents-associated Infections-Systematic Review and Meta-analysis of Randomized Controlled Trials.

BACKGROUND: The reported data regarding the effects of hypomethylating agents (HMAs) on the risk of infections seem to be poorly documented and heterogeneous. We conducted a systematic review and meta-analysis of all randomized controlled trials comparing HMA-containing regimens with any other regimen administered to patients with myeloid neoplasms. MATERIALS AND METHODS: A comprehensive search was conducted until February 2018. Two reviewers appraised the quality of the trials and the extracted data. The primary outcome was grade 3/4 infections. The secondary outcomes included febrile neutropenia, fever of unknown origin, grade 3/4 neutropenia, infection-related mortality, and all-cause mortality. The relative risks (RRs) and 95% confidence intervals (CIs) were estimated and pooled. A fixed-effect model was used to pool the data unless significant heterogeneity was present, in which case a random-effects model was used. RESULTS: We identified 9 trials reported from 2002 to 2016 and randomizing 2184 patients. HMAs were associated with an increase in grade 3/4 infections compared with the comparator (RR, 1.30; 95% CI, 1.02-1.66). This was true for the subgroup of patients aged >60 years (RR, 1.19; 95% CI, 1.01-1.39). In addition, HMAs resulted in an increase in the rate of fever of unknown origin and neutropenia (RR, 1.48; 95% CI, 1.15-1.92; RR, 1.48; 95% CI, 1.22-1.78, respectively). Although no difference was found in the incidence of fatal infections (RR, 1.44; 95% CI, 0.72 to 2.89), treatment with HMA reduced the incidence of all-cause mortality (RR, 0.74; 95% CI, 0.66-0.88). CONCLUSION: Treatment with HMAs was associated with an increase in the grade 3/4 infection rate.

Thalassemia Major and Intermedia in Patients Older than 35 Years: A Single Center Experience.

BACKGROUND: During the past decades, beta thalassemia major (TM) and beta thalassemia intermedia (TI) have transformed from a universally fatal disease at a young age into a chronic disease. This advancement is attributed to improved chelation therapy as well as enhanced management strategies, with focused attention on disease and treatment-related complications. OBJECTIVES: To describe characteristics of adults with thalassemia as well as treatment modalities, disease and treatment-related complications, and socioeconomic information of the patients. METHODS: We preformed a retrospective analysis of 14 adult patients > 35 years of age with TM and TI who were treated at our institute, a single center specializing in the care of adult thalassemia patients living in Israel, between the years 2006 and 2016. RESULTS: The median age of patients was 37 years and most patients were transfusion-dependent. The median number of chelation therapeutic lines was three, and 85.7% of patients were treated at one point by combination chelation therapy. Most patients suffered from at least some form of endocrine dysfunction (n=12), and four patients developed overt heart failure. Of the patients, 85% had completed at least a high school education, 78% were employed, and 64.2% were married. CONCLUSIONS: Prolonged survival of thalassemia patients in recent years has been accompanied by a new set of challenges for both the patients and the treating staff. Further research is warranted to improve both medical management and the socioeconomic well-being of this unique group of adult thalassemia patients.