Luciano J. Costa

Alternative donor transplantation after reduced intensity conditioning: Results of parallel phase 2 trials using partially HLA-mismatched related bone marrow or unrelated double umbilical cord blood grafts

The Blood and Marrow Transplant Clinical Trials Network conducted 2 parallel multicenter phase 2 trials for individuals with leukemia or lymphoma and no suitable related donor. Reduced intensity conditioning (RIC) was used with either unrelated double umbilical cord blood (dUCB) or HLA-haploidentical related donor bone marrow (Haplo-marrow) transplantation. For both trials, the transplantation conditioning regimen incorporated cyclophosphamide, fludarabine, and 200 cGy of total body irradiation. The 1-year probabilities of overall and progression-free survival were 54% and 46%, respectively, after dUCB transplantation (n = 50) and 62% and 48%, respectively, after Haplo-marrow transplantation (n = 50). The day +56 cumulative incidence of neutrophil recovery was 94% after dUCB and 96% after Haplo-marrow transplantation. The 100-day cumulative incidence of grade II-IV acute GVHD was 40% after dUCB and 32% after Haplo-marrow transplantation. The 1-year cumulative incidences of nonrelapse mortality and relapse after dUCB transplantation were 24% and 31%, respectively, with corresponding results of 7% and 45%, respectively, after Haplo-marrow transplantation. These multicenter studies confirm the utility of dUCB and Haplo-marrow as alternative donor sources and set the stage for a multicenter randomized clinical trial to assess the relative efficacy of these 2 strategies. The trials are registered at www.clinicaltrials.gov under NCT00864227 (BMT CTN 0604) and NCT00849147 (BMT CTN 0603).

Optimizing Autologous Stem Cell Mobilization Strategies to Improve Patient Outcomes: Consensus Guidelines and Recommendations

Autologous hematopoietic stem cell transplantation (aHSCT) is a well-established treatment for malignancies such as multiple myeloma (MM) and lymphomas. Various changes in the field over the past decade, including the frequent use of tandem aHSCT in MM, the advent of novel therapies for the treatment of MM and lymphoma, and the addition of new stem cell mobilization techniques, have led to the need to reassess current stem cell mobilization strategies. Mobilization failures with traditional strategies are common and result in delays in treatment and increased cost and resource utilization. Recently, plerixafor-containing strategies have been shown to significantly reduce mobilization failure rates, but the ideal method to maximize stem cell yields and minimize costs associated with collection has not yet been determined. A panel of experts convened to discuss the currently available data on autologous hematopoietic stem cell mobilization and transplantation and to devise guidelines to optimize mobilization strategies. Herein is a summary of their discussion and consensus.

Development and validation of a decision-making algorithm to guide the use of plerixafor for autologous hematopoietic stem cell mobilization

Plerixafor is an inhibitor of CXCR-4 (CXC chemokine receptor-4)/SDF (stromal cell-derived factor)-1 binding used in combination with granulocyte colony-stimulating factor (G-CSF) for mobilization of autologous peripheral blood hematopoietic stem cells (HSCs). We developed a data-generated, cost-saving decision-making algorithm that uses the CD34+ count in the peripheral blood on the fourth day of G-CSF administration (PB-CD34+), and the collection target (T-CD34+) to decide between continuing G-CSF only (G approach) or adding plerixafor to the mobilization regimen (G+P approach) aiming at the lowest cost. The G+P approach was more cost-effective with lower PB-CD34+. It was possible to determine, for each T-CD34+, the maximum PB-CD34+ for which the G+P approach is cost-effective, generating an algorithm for the use of plerixafor. We validated this algorithm in a cohort of 34 patients undergoing HSC mobilization. In all, 11 patients completed collection on the G approach and 23 patients on the G+P approach, with 91% of the patients completing collection within the predicted number of apheresis sessions. All patients who underwent transplantation engrafted with minimal differences in engraftment time between G and G+P approaches. This validated algorithm provides a potential cost-saving decision tool for the use of plerixafor in autologous HSC mobilization.

Renal Cell Carcinoma: New Developments in Molecular Biology and Potential for Targeted Therapies

Renal cell carcinoma (RCC) affects 38,000 individuals in the U.S. yearly. Seventy-five percent of cases are clear-cell carcinomas, and a majority is driven by dysfunction of the von Hippel-Lindau (VHL) gene. VHL loss of function and other non-VHL pathways leading to RCC share aberrant activation of the hypoxic response, such as upregulation of vascular endothelial growth factor (VEGF) and consequent neoangiogenesis. Metastatic RCC has been notoriously resistant to therapy. For decades, its treatment has been based on nephrectomy and limited use of toxic and often inefficient immunotherapy with interleukin-2 or interferon-alpha. However, new biologic agents are beginning to break the resistance barrier. Small-molecule multikinase inhibitors that target VEGF receptors (sunitinib and sorafenib) have a favorable toxicity profile and can prolong time to progression and preserve quality of life when used in newly diagnosed or previously treated patients. The anti-VEGF antibody bevacizumab enhances the response rate and prolongs disease control when added to interferon-alpha. Temsirolimus, a mammalian target of rapamycin inhibitor, prolongs the survival duration of patients with poor-risk disease. Despite three new drugs being approved for RCC in the past 2 years, responses are mostly partial and of limited duration. Multiple new drugs and drug combinations are undergoing clinical trials and will likely impact the treatment of RCC in future years. Compounds found to be active in the metastatic setting are now being tried in earlier stage disease in an attempt to improve curability. However, no method has yet been validated to predict patient response to these newer treatments.

Hematopoietic Cell Transplantation for Systemic Mature T-Cell Non-Hodgkin Lymphoma

PURPOSE To analyze outcomes of hematopoietic cell transplantation (HCT) in T-cell non-Hodgkin lymphoma. PATIENTS AND METHODS Outcomes of 241 patients (112 anaplastic large-cell lymphoma, 102 peripheral T-cell lymphoma not otherwise specified, 27 angioimmunoblastic T-cell lymphoma) undergoing autologous HCT (autoHCT; n = 115; median age, 43 years) or allogeneic HCT (alloHCT; n = 126; median age, 38 years) were analyzed. Primary outcomes were nonrelapse mortality (NRM), relapse/progression, progression-free survival (PFS), and overall survival (OS). Patient, disease, and HCT-related variables were analyzed in multivariate Cox proportional hazard models to determine association with outcomes. RESULTS AutoHCT recipients were more likely in first complete remission (CR1; 35% v 14%; P = .001) and with chemotherapy-sensitive disease (86% v 60%; P < .001), anaplastic large-cell histology (53% v 40%; P = .04), and two or fewer lines of prior therapy (65% v 44%; P < .001) compared with alloHCT recipients. Three-year PFS and OS of autoHCT recipients beyond CR1 were 42% and 53%, respectively. Among alloHCT recipients who received transplantations beyond CR1, 31% remained progression-free at 3 years, despite being more heavily pretreated and with more refractory disease. NRM was 3.5-fold higher (95% CI, 1.80 to 6.99; P < .001) for alloHCT. In multivariate analysis, chemotherapy sensitivity (hazard ratio [HR], 1.8; 95% CI, 1.16 to 2.87) and two or fewer lines of pretransplantation therapy (HR, 5.02; 95% CI, 2.15 to 11.72) were prognostic of survival. CONCLUSION These data describe the roles of autoHCT and alloHCT in T-cell non-Hodgkin lymphoma and suggest greater effectiveness earlier in the disease course, and limited utility in multiply relapsed disease. Notably, autoHCT at relapse may be a potential option for select patients, particularly those with anaplastic large-cell lymphoma histology.

Better leukemia-free and overall survival in AML in first remission following cyclophosphamide in combination with busulfan compared with TBI

Cyclophosphamide combined with total body irradiation (Cy/TBI) or busulfan (BuCy) are the most widely used myeloablative conditioning regimens for allotransplants. Recent data regarding their comparative effectiveness are lacking. We analyzed data from the Center for International Blood and Marrow Transplant Research for 1230 subjects receiving a first hematopoietic cell transplant from a human leukocyte antigen-matched sibling or from an unrelated donor during the years 2000 to 2006 for acute myeloid leukemia (AML) in first complete remission (CR) after conditioning with Cy/TBI or oral or intravenous (IV) BuCy. Multivariate analysis showed significantly less nonrelapse mortality (relative risk [RR] = 0.58; 95% confidence interval [CI]: 0.39-0.86; P = .007), and relapse after, but not before, 1 year posttransplant (RR = 0.23; 95% CI: 0.08-0.65; P = .006), and better leukemia-free survival (RR = 0.70; 95% CI: 0.55-0.88; P = .003) and survival (RR = 0.68; 95% CI: 0.52-0.88; P = .003) in persons receiving IV, but not oral, Bu compared with TBI. In combination with Cy, IV Bu is associated with superior outcomes compared with TBI in patients with AML in first CR.

Autologous or Reduced-Intensity Conditioning Allogeneic Hematopoietic Cell Transplantation for Chemotherapy-Sensitive Mantle-Cell Lymphoma: Analysis of Transplantation Timing and Modality

PURPOSE To examine the outcomes of patients with chemotherapy-sensitive mantle-cell lymphoma (MCL) following a first hematopoietic stem-cell transplantation (HCT), comparing outcomes with autologous (auto) versus reduced-intensity conditioning allogeneic (RIC allo) HCT and with transplantation applied at different times in the disease course. PATIENTS AND METHODS In all, 519 patients who received transplantations between 1996 and 2007 and were reported to the Center for International Blood and Marrow Transplant Research were analyzed. The early transplantation cohort was defined as those patients in first partial or complete remission with no more than two lines of chemotherapy. The late transplantation cohort was defined as all the remaining patients. RESULTS Auto-HCT and RIC allo-HCT resulted in similar overall survival from transplantation for both the early (at 5 years: 61% auto-HCT v 62% RIC allo-HCT; P = .951) and late cohorts (at 5 years: 44% auto-HCT v 31% RIC allo-HCT; P = .202). In both early and late transplantation cohorts, progression/relapse was lower and nonrelapse mortality was higher in the allo-HCT group. Overall survival and progression-free survival were highest in patients who underwent auto-HCT in first complete response. Multivariate analysis of survival from diagnosis identified a survival benefit favoring early HCT for both auto-HCT and RIC allo-HCT. CONCLUSION For patients with chemotherapy-sensitive MCL, the optimal timing for HCT is early in the disease course. Outcomes are particularly favorable for patients undergoing auto-HCT in first complete remission. For those unable to achieve complete remission after two lines of chemotherapy or those with relapsed disease, either auto-HCT or RIC allo-HCT may be effective, although the chance for long-term remission and survival is lower.

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

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

Peripheral Blood Progenitor Cell Mobilization for Autologous and Allogeneic Hematopoietic Cell Transplantation: Guidelines from the American Society for Blood and Marrow Transplantation

Peripheral blood progenitor cell mobilization practices vary significantly among institutions. Effective mobilization regimens include growth factor alone, chemotherapy and growth factor combined, and, more recently, incorporation of plerixafor with either approach. Many institutions have developed algorithms to improve stem cell mobilization success rates and cost-effectiveness. However, an optimal stem cell mobilization regimen has not been defined. Practical guidelines are needed to address important clinical questions, including which growth factor is optimal, what chemotherapy and dose is most effective, and when to initiate leukapheresis. We present recommendations, based on a comprehensive review of the literature, from the American Society of Blood and Marrow Transplantation.

Growth factor and patient-adapted use of plerixafor is superior to CY and growth factor for autologous hematopoietic stem cells mobilization

The ideal method to mobilize autologous hematopoietic stem cells (AHSCs) in patients with lymphoma or multiple myeloma remains to be determined. The use of plerixafor, added to growth factor, may overcome the limitations to the use of growth factor mobilization without chemotherapy. We developed and validated a cost-based decision-making algorithm that uses the CD34+ cell count in the peripheral blood on the fourth day of G-CSF administration and the target CD34+ cell count for the specific patient to decide on the use of plerixafor (MUSC algorithm). We compared this approach (MA cohort) with a historical cohort of patients undergoing mobilization with CY 2000 mg/m2 followed by G-CSF and GM-CSF (CY cohort). Fifty individuals are included in the MA cohort and 81 in the CY cohort. The mobilization failure rate was 2% in the MA cohort vs 22% in the CY cohort (P=0.01). Fewer patients in the MA cohort than in the CY cohort had infectious complications during mobilization requiring hospitalization (2 vs 30% P<0.01). There was significant shortening in the median number of days between starting mobilization and undergoing transplantation in the MA cohort (14 vs 43 days, P<0.01). In conclusion, growth factor and patient-adapted use of plerixafor provides safer hematopoietic stem cell mobilization and faster access to AHSC transplantation.