Abstract

Efficacy of conventional chemoimmunotherapy is limited in patients with Richter syndrome (RS) with anticipated median overall survival (OS) of less than 10months. Allogeneic hematopoietic cell transplantation (allo-HCT) is commonly offered as a consolidative treatment option in RS. To our knowledge, there are no randomized controlled studies that have compared allo-HCT against other therapies in RS; available allo-HCT data are limited to small case series from single-institution or registry studies. We performed a systematic review and meta-analysis to assess the totality of evidence regarding the efficacy (or lack thereof) of allo-HCT for RS. We extracted data on post-allograft outcomes related to benefits (overall response rate [ORR], complete remission [CR], OS, and progression-free survival [PFS]). For harms, data were extracted on non-relapse mortality (NRM) and relapse post-allografting. Our search strategy identified 240 studies, but only four studies (n=72 patients) met our inclusion criteria. Pooled ORR, CR, OS, and PFS rates were 79%, 33%, 49%, and 30%, respectively. Pooled NRM and relapse rates were 24% and 28%, respectively. Results of this systematic review and meta-analysis indicate that allo-HCT yields encouraging OS in RS, thus remaining a reasonable treatment option in fit patients whose disease demonstrates a chemosensitive response to pre-transplant salvage therapies. Novel strategies are certainly needed to reduce the risk of relapse to further improve outcomes in these patients.

Abstract

INTRODUCTION Waldenstrom macroglobulinemia (WM) is an IgM-producing lymphoproliferative disorder that remains incurable. Patients with high-risk disease have an overall survival (OS) of less than 3 years. Both autologous (AHCT) and allogeneic (allo-HCT) hematopoietic cell transplantation (HCT) are prescribed for treatment of WM despite a lack of randomized controlled studies. MATERIALS AND METHODS We performed a comprehensive literature search using PubMed/Medline and EMBASE on September 10, 2019. Data on clinical outcomes related to benefits and harms was extracted independently by 3 authors. Fifteen studies (8 AHCT [n = 278 patients], 7 allo-HCT [n = 311 patients]) were included in this systematic review/meta-analysis. RESULTS Pooled OS, progression-free survival (PFS), and nonrelapse mortality (NRM) rates post AHCT were 76% (95% confidence interval [CI], 65%-86%), 55% (95% CI, 42%-68%), and 4% (95% CI, 1%-7%), respectively. Pooled OS, PFS, and NRM rates post allografting were 57% (95% CI, 50%-65%), 49% (95% CI, 42%-56%), and 29% (95% CI, 23%-34%), respectively. OS and PFS rates were reported at 3 to 5 years, and NRM was reported at 1 year in most studies. Pooled ORR (at day 100) post AHCT and allo-HCT were 85% (95% CI, 72%-94%) and 81% (95% CI, 69%-91%), respectively. Pooled complete response rates post AHCT and allo-HCT were 22% (95% CI, 17%-28%) and 26% (95% CI, 7%-50%), respectively. Relapse rates post AHCT and allo-HCT were 42% (95% CI, 30%-55%) and 23% (95% CI, 18%-28%), respectively. CONCLUSIONS Our results show that both AHCT and allo-HCT are effective in the treatment of WM. A 2-fold lower relapse rate but a 7-fold higher NRM was noted for allo-HCT compared with AHCT. The role of transplant in WM needs to be addressed in the era of novel agents.

Abstract

INTRODUCTION Lenalidomide maintenance, commonly prescribed in the post-autologous transplantation (AHCT) setting for multiple myeloma (MM), is associated with development of secondary primary malignancies (SPM). Proteasome inhibitor maintenance (PIM) has also been evaluated in MM. We conduct a systematic review/meta-analysis to assess the efficacy of PIM in MM. METHODS Performing a comprehensive search of the medical literature using PubMed/Medline and EMBASE on September 11, 2019, we extracted data on clinical outcomes related to benefits (OS, PFS and depth of hematologic response [DOHR]) and harms (SPM and adverse events). 2144 references were identified; three studies were eligible for inclusion. RESULTS A total of 1,760 patients were included in the analysis; 507 patients received bortezomib and 395 received ixazomib maintenance. Control arms were either placebo (n=261) or thalidomide (n=358). PIM did not improve OS (HR 0.88, 95% CI 0.73-1.05, p=0.15) but improved PFS (HR 0.77, 95% CI 0.69-0.86, p= <0.00001) and DOHR (HR 0.88, 95% CI 0.79-0.98, p=0.02) compared to control. There were no significant differences between PIM and control regarding SPM (p=NS) and =grade 3 peripheral neuropathy (PN) (p=NS). CONCLUSIONS PIM following AHCT in MM improves PFS and DOHR without an increase in development of SPM or severe PN compared to placebo/thalidomide.

Abstract

BACKGROUND Evidence about the impact of marital status before hematopoietic cell transplantation (hct) on outcomes after hct is conflicting. METHODS We identified patients 40 years of age and older within the Center for International Blood and Marrow Transplant Research registry who underwent hct between January 2008 and December 2015. Marital status before hct was declared as one of: married or living with a partner, single (never married), separated or divorced, and widowed. We performed a multivariable analysis to determine the association of marital status with outcomes after hct. RESULTS We identified 10,226 allogeneic and 5714 autologous hct cases with, respectively, a median follow-up of 37 months (range: 1-102 months) and 40 months (range: 1-106 months). No association between marital status and overall survival was observed in either the allogeneic (p = 0.58) or autologous (p = 0.17) setting. However, marital status was associated with grades 2-4 acute graft-versus-host disease (gvhd), p < 0.001, and chronic gvhd, p = 0.04. The risk of grades 2-4 acute gvhd was increased in separated compared with married patients [hazard ratio (hr): 1.13; 95% confidence interval (ci): 1.03 to 1.24], and single patients had a reduced risk of grades 2-4 acute gvhd (hr: 0.87; 95% ci: 0.77 to 0.98). The risk of chronic gvhd was lower in widowed compared with married patients (hr: 0.82; 95% ci: 0.67 to 0.99). CONCLUSIONS Overall survival after hct is not influenced by marital status, but associations were evident between marital status and grades 2-4 acute and chronic gvhd. To better appreciate the effects of marital status and social support, future research should consider using validated scales to measure social support and patient and caregiver reports of caregiver commitment, and to assess health-related quality of life together with health care utilization.

Abstract

INTRODUCTION HTLV-1 associated adult T cell leukemia/lymphoma (ATLL) is an aggressive malignant disorder associated with the Human T-cell Lymphotropic Virus Type-1 (HTLV1). Intensive conventional chemotherapy regimens and autologous hematopoietic cell transplantation (auto-HCT) have failed to improve outcomes in ATLL. Allogeneic HCT (allo-HCT) is commonly offered as front-line consolidation despite lack of randomized controlled studies (RCT). METHODS We performed a comprehensive search of the medical literature using PubMed/Medline, EMBASE and Cochrane reviews on September 10, 2018. We extracted data on clinical outcomes related to benefits (complete response [CR], overall [OS] and progression-free [PFS] survival) and harms (relapse and non-relapse mortality [NRM]), independently by two authors. Our search strategy identified a total of 801 references. Nineteen studies (n= 2446 patients) were included in the systematic review; however, only 18 studies (n=1767 patients) were included in the meta-analysis. RESULTS Reduced intensity conditioning (RIC) regimens were more commonly prescribed (52%). Bone marrow (50%) and peripheral blood (40%) were more frequently used as stem cell source. The pooled post-allografting CR, OS, and PFS rates were 73% (95%CI=57-87%), 40 % (95%CI=33-46%), and 37% (95%CI=27-48%), respectively. Pooled relapse and NRM rates were 36% (95%CI=28-43%) and 29% (95%CI=21-37%), respectively. The heterogeneity among the included studies was generally high. CONCLUSIONS These results support the use of allo-HCT as an effective treatment for patients with ATLL, yielding pooled OS rates of 40%, but relapse still occurs in over one-third of cases. Future studies should evaluate strategies to help reduce relapse in patients with ATLL undergoing allo-HCT.

Abstract

BACKGROUND The outcomes for patients with diffuse large B-cell lymphoma (DLBCL) with adverse clinical prognostic factors such as a high age-adjusted International Prognostic Index (aaIPI) are not optimal. In the current study, the authors performed a systematic review and meta-analysis to assess the totality of evidence pertaining to the efficacy of autologous hematopoietic stem cell transplantation (auto-HCT) consolidation for patients with DLBCL in first remission. METHODS The authors searched the Cochrane and MEDLINE/PubMed databases through December 1, 2018, for studies comparing conventional chemotherapy with rituximab (R-chemo) versus R-chemo and auto-HCT. Two authors independently reviewed all references for study inclusion and extracted data related to benefits (overall survival, progression-free survival, and response rates) and harms (treatment-related mortality and adverse events). RESULTS Four studies (1173 patients) met the inclusion criteria and were included in the current analysis. The median duration of follow-up ranged from 42 to 76 months. There was no difference noted with regard to the overall survival (hazard ratio, 1.01; 95% CI, 0.74-1.37), progression-free survival (hazard ratio, 0.77; 95% CI, 0.58-1.04), or response rates (risk ratio, 0.98; 95% CI, 0.92-1.04) between patients who received R-chemo and auto-HCT and those who received R-chemo alone. The risk of mortality and therapy failure was not found to be different when the analysis was limited to high aaIPI between the 2 groups. Although there was no difference noted with regard to the risk of treatment-related mortality, there was a significantly higher incidence of CTCAE grade 3 or 4 adverse events in patients who received R-chemo and auto-HCT compared with patients treated with R-chemo alone. CONCLUSIONS The findings from what to the authors' knowledge is the first meta-analysis performed in the rituximab era demonstrated no beneficial effect of upfront auto-HCT consolidation in patients with aggressive B-cell non-Hodgkin lymphoma, including high-risk clinical groups (high aaIPI).

Abstract

INTRODUCTION Mycosis Fungoides (MF) and Sezary Syndrome (SS) are the most common types of primary cutaneous T cell lymphomas (CTCL). The clinical presentation of MF is generally indolent whereas SS represents a more aggressive disease variant. Stage at diagnosis is the most important determinant of long-term survival outcome. Although most patients present with early stage disease, those who develop progressive disease or have an advance stage represent a therapeutic challenge due to lack of effective therapies. Allogeneic hematopoietic cell transplantation (allo-HCT) has been used as a potentially curative treatment modality with encouraging long-term outcomes. There remains however a lack of randomized controlled data and the published literature is limited to mostly retrospective studies. METHODS We performed a comprehensive search of the medical literature using PubMed/Medline, EMBASE and Cochrane reviews on September 13, 2018. We extracted data on clinical outcomes related to benefits (overall [OS] and progression-free [PFS] survival) and harms (relapse and non-relapse mortality [NRM]) independently by two authors. Our search strategy identified a total of 289 references. Five studies (n= 266 patients) were included in this systematic review and the meta-analysis. RESULTS Reduced intensity (RIC) and non-myeloablative (NMA) regimens were more commonly prescribed (76%). Mobilized peripheral blood stem cells (PBSC) were the preferred graft source (78%). The pooled OS and PFS rates were 59% (95%CI=50-69%) and 36% (95%CI=27-45%), respectively. Pooled relapse rate was 47% (95%CI=41-53%) and pooled NRM rate was 19% (95%CI=13-27%). CONCLUSIONS Results of this systematic review/meta-analysis show that allo-HCT yields encouraging OS and PFS rates; however; relapse remains a significant cause of allo-HCT failure. Novel strategies to further improve outcomes should focus on offering allo-HCT prior to development of resistant disease, and reducing relapse by incorporating post-transplant maintenance therapies.

Abstract

BACKGROUND Follow-up is integral for hematopoietic cell transplant (HCT) care to ensure surveillance and intervention for complications. We characterized the incidence of, and predictors for, being lost to follow-up. METHODS Two-year survivors of first allogeneic (10,367 adults and 3,865 children) or autologous (7,291 adults and 467 children) HCT for malignant/non-malignant disorders from 2002-2013 reported to the Center for International Blood and Marrow Transplant Research were selected. The cumulative incidence of being lost to follow-up (defined as having missed 2 consecutive follow-up reporting periods) was calculated. Marginal Cox models (adjusted for center effect) were fit to evaluate predictors. RESULTS The 10-year cumulative incidence of being lost to follow-up among adult allogeneic and autologous HCT survivors was 13% (95% CI, 12-14) and 15% (95% CI, 14-16), respectively. Among pediatric HCT survivors, estimates were 25% (95% CI, 24-27) and 24% (95% CI, 20-29), respectively. In adult allogeneic HCT survivors, younger age, non-malignant disease, public/no insurance (reference: private), living farther from the HCT center, and being unmarried were associated with being lost to follow-up. For adult autologous HCT survivors, older age and testicular/germ cell tumor (reference: non-Hodgkin lymphoma) were associated with greater risk of being lost to follow-up. Among pediatric allogeneic HCT survivors, older age, public/no insurance (reference: private), and non-malignant disease were associated with being lost to follow-up. Among pediatric autologous HCT survivors, older age was associated with greater risk of being lost to follow-up. CONCLUSION Follow-up focusing on minimizing attrition in high-risk groups is needed to ensure surveillance for late effects.

Abstract

Importance: Maintenance therapies are often considered as a therapeutic strategy in patients with lymphoma following autologous hematopoietic cell transplantation (auto-HCT) to mitigate the risk of disease relapse. With an evolving therapeutic landscape, where novel drugs are moving earlier in therapy lines, evidence relevant to contemporary practice is increasingly limited. The American Society for Blood and Marrow Transplantation (ASBMT), Center for International Blood and Marrow Transplant Research (CIBMTR), and European Society for Blood and Marrow Transplantation (EBMT) jointly convened an expert panel with diverse expertise and geographical representation to formulate consensus recommendations regarding the use of maintenance and/or consolidation therapies after auto-HCT in patients with lymphoma. Observations: The RAND-modified Delphi method was used to generate consensus statements where at least 75% vote in favor of a recommendation was considered as consensus. The process included 3 online surveys moderated by an independent methodological expert to ensure anonymity and an in-person meeting. The panel recommended restricting the histologic categories covered in this project to Hodgkin lymphoma (HL), mantle cell lymphoma (MCL), diffuse large B-cell lymphoma (DLBCL), and follicular lymphoma. On completion of the voting process, the panel generated 22 consensus statements regarding post auto-HCT maintenance and/or consolidation therapies. The grade A recommendations included endorsement of: (1) brentuximab vedotin (BV) maintenance and/or consolidation in BV-naive high-risk HL, (2) rituximab maintenance in MCL undergoing auto-HCT after first-line therapy, (3) rituximab maintenance in rituximab-naive FL, and (4) No post auto-HCT maintenance was recommended in DLBCL. The panel also developed consensus statements for important real-world clinical scenarios, where randomized data are lacking to guide clinical practice. Conclusions and Relevance: In the absence of contemporary evidence-based data, the panel found RAND-modified Delphi methodology effective in providing a rigorous framework for developing consensus recommendations for post auto-HCT maintenance and/or consolidation therapies in lymphoma.

Abstract

INTRODUCTION It is common practice to refer patients to transplantation centers for allogeneic hematopoietic cell transplantation (allo-HCT) for blastic plasmacytoid dendritic-cell neoplasm (BPDCN) despite lack of randomized controlled trials. We performed a systematic review to assess the totality of evidence pertaining to the efficacy of allo-HCT in BPDCN. METHODS We searched the Cochrane, PubMed, and Embase databases through January 5, 2018, for studies on allo-HCT for BPDCN. Two authors independently reviewed all references for inclusion and extracted data related to benefits (overall [OS] and progression-free/disease-free [PFS/DFS] survival) and harms (relapse and nonrelapse mortality) from included studies. When appropriate, data were pooled using random-effects model. RESULTS Four studies (128 patients) were included in analysis. Pooled OS rate was 50% (95% confidence interval [CI], 41-59) for all patients. Among patients who underwent allografting whose disease was in first complete remission (CR1), pooled OS and PFS/DFS rates were 67% (95% CI, 52-80) and 53% (95% CI, 29-76), respectively. For patients who underwent allografting in > CR1, pooled OS and PFS/DFS rates were 7% (95% CI, 0-32) for both outcomes. Relapse rates were higher when reduced-intensity regimens were used (40% [95% CI, 25-56] vs. 18% [95% CI, 7-31]). CONCLUSION This systematic review represents the best available evidence supporting allo-HCT in BPDCN, especially when offered in CR1. Use of myeloablative allo-HCT results in lower pooled relapse rates (18% vs. 40%). A prospective comparative study will be needed to determine the impact of intensity of the conditioning regimen on postallograft relapse.