Contrary to tandem autologous transplant (auto-auto), autologous followed by reduced intensity conditioning allogenic transplantation (auto-allo) offers graft-versus-myeloma (GVM) effect but with ...higher toxicity. Trials comparing these two strategies relied on availability of HLA-matched sibling donors for arm allocation (biological randomization) and yielded conflicting results. A pooled analysis of multiple trials with extended follow up provides an opportunity to compare these strategies. We obtained individual patient data from participants of four trials comparing auto-auto vs. auto-allo after induction therapy. There were 899 patients in auto-auto and 439 in auto-allo. Median follow up of survivors was 118.5 months. Median overall survival (OS) was 78.0 months in auto-auto and 98.3 months in auto-allo (HR = 0.84, P = 0.02). OS was 36.4% vs. 44.1% at 10 years (P = 0.01) for auto-auto and auto-allo, respectively. Progression-free survival was also improved in auto-allo (HR = 0.84, P = 0.004). Risk of non-relapse mortality was higher in auto-allo (10 year 8.3% vs. 19.7%, P < 0.001), while risk of disease progression was higher in auto-auto (10 year 77.2% vs. 61.6%, P < 0.001). Median post relapse survival was 41.5 months in auto-auto and 62.3 months in auto-allo (HR = 0.71, P < 0.001). This supports the existence of durable GVM effect enhancing myeloma control with subsequent therapies.
Desmoplastic small round cell tumor of the peritoneum (DSRCTP) is a rare, frequently fatal tumor. This retrospective study, based on CIBMTR registry data, describes the largest reported cohort of ...DSRCTP patients who have undergone Auto-SCT. The probabilities of disease-free survival (DFS) at 1 year for patients in CR and not in CR were 75% (95% confidence interval: 48-94%) and 35% (15-59%), respectively. The probability of OS at 3 years was 57% (29-83%) and 28% (9-51%) for patients in CR and not in CR, respectively. Median survival for the entire cohort was 31 months (36 months and 21 months for those in CR and not in CR, respectively). Engraftment at 42 days was 97% (88-100%). Treatment-related mortality was low, with only one death in the first 100 days. Auto-SCT is a tolerable approach in patients with DSRCTP, with the greatest benefit seen in those patients who obtain CR. For those not in CR, the median OS in this series is greater than previously reported (21 months vs 17 months), suggesting Auto-SCT is useful in prolonging DFS and OS, even in patients with residual or persistent disease pre-transplant.
Posttransplant lymphoproliferative disorder (PTLD) is an Epstein-Barr virus-associated malignancy that occurs in the setting of pharmacologic immunosuppression after organ transplantation. With the ...increased use of organ transplantation and intensive immunosuppression, this disease is becoming more common. We explore reduction in immunosuppression as an initial therapy for PTLD.
We analyzed our organ transplant patient database to identify patients with biopsy-proven PTLD who were initially treated with reduction of their immunosuppressive medications with or without surgical resection of all known disease.
Forty-two adult patients were included in this study. Thirty patients were treated with reduction in immunosuppression alone. Twelve patients were treated with both reduction in immunosuppression and surgical resection of all known disease. Thirty-one of 42 patients (73.8%) achieved a complete remission. Of those patients who were treated with reduction in immunosuppression alone, 19 of 30 (63%) responded with a median time to documentation of response of 3.6 weeks. Multivariable analysis showed that elevated lactate dehydrogenase (LDH) ratio, organ dysfunction, and multi-organ involvement by PTLD were independent prognostic factors for lack of response to reduction in immunosuppression. In patients with none of these poor prognostic factors, 16 of 18 (89%) responded to reduction in immunosuppression in contrast to three of five (60%) with one risk factor and zero of seven (0%) with two to three factors present. The analysis also showed that increased age, elevated LDH ratio, severe organ dysfunction, presence of B symptoms (fever, night sweats, and weight loss), and multi-organ involvement by PTLD at the time of diagnosis are independent prognostic indicators for poor survival. With median follow-up of 147 weeks, 55% of patients are alive with 50% in complete remission.
Reduction in immunosuppression is an effective initial therapy for PTLD. Clinical prognostic factors may allow clinicians to identify which patients are likely to respond to reduction in immunosuppression.
Despite emergence of novel therapies to treat hematologic malignancies, allogeneic hematopoietic cell transplantation (allo-HCT) remains an essential treatment modality capable of curing these ...diseases. Allo-HCT has been also shown to be curative in benign hematologic disorders such as aplastic anemia, sickle cell disease, and thalassemia, among others. Recently, the American Society for Transplantation and Cellular Therapy (ASTCT) published standardized definitions for hematopoietic recovery, graft rejection, graft failure, poor graft function, and donor chimerism. To attempt broader international consensus, a panel of adult and pediatric physician transplant experts was assembled from European Society for Blood and Marrow Transplantation (EBMT), ASTCT, the Center for International Blood and Marrow Transplant Research (CIBMTR), and Asia-Pacific Blood and Marrow Transplantation (APBMT). Consensus was defined as ≥70% of voting members strongly agreeing or somewhat agreeing with a definition. With few exceptions, there was a consensus to endorse the prior ASTCT definitions. Importantly, we revised existing EBMT and CIBMTR data collection forms to align with these harmonized definitions that will facilitate research and international collaboration among transplant researchers and across transplant registries.
Allogeneic hematopoietic cell transplantation for plasma cell myeloma can lead to graft-vs-myeloma immunity and long-term survivorship, but limited efficacy and associated toxicities have prevented ...its widespread use. Cellular immunotherapies seek to induce more specific, reliable and potent antimyeloma immune responses with less treatment-related risk than is possible with allogeneic transplantation. Strategies under development include infusion of vaccine-primed and ex vivo expanded/costimulated autologous T cells after high-dose melphalan, genetic engineering of autologous T cells with receptors for myeloma-specific epitopes, administration of DC/plasma cell fusions and administration expanded marrow-infiltrating lymphocytes. In addition, novel immunomodulatory drugs such as inhibitors of the programmed death-1 T cell regulatory pathway may synergize with cellular immunotherapies.
Donor lymphocyte infusions (DLIs) induce potent graft versus tumor (GVT) effects for relapsed chronic myelogenous leukemia (CML) after allogeneic stem cell transplantation (SCT) but are disappointing ...for other diseases. Disease resistance can occur if donor T cells are not appropriately activated in vivo. Ex vivo T-cell activation might overcome disease-induced anergy and augment GVT activity. We performed a phase 1 trial of ex vivo–activated DLI (aDLI) for 18 patients with relapse after SCT. Activated donor T cells are produced through costimulation with anti-CD3– and anti-CD28–coated beads. Patients with aggressive malignancies received induction chemotherapy, and all patients received conventional DLI (median, 1.5 × 108 mononuclear cells/kg) followed 12 days later by aDLI. Activated DLI was dose escalated from 1 × 106 to 1 × 108 CD3+ cells per kilogram in 5 levels. Seven patients developed acute graft versus host disease (GVHD) (5 grade I-II, 2 grade III), and 4 developed chronic GVHD. Eight patients achieved complete remission, including 4 of 7 with acute lymphocytic leukemia (ALL), 2 of 4 with acute myelogenous leukemia (AML), 1 with chronic lymphocytic leukemia (CLL), and 1 of 2 with non-Hodgkin lymphoma (NHL). Four complete responders relapsed while 4 remain alive in remission a median 23 months after aDLI. Overall, 10 of 18 remain alive 11 to 53 months after aDLI. Adoptive transfer of costimulated activated allogeneic T cells is feasible, does not result in excessive GVHD, and may contribute to durable remissions in diseases where conventional DLI has been disappointing.
Lenalidomide is an active treatment for multiple myeloma (MM) and is increasingly used as part of the initial treatment of this disease. Recent reports have suggested decreases in the number of CD34+ ...cells collected and increases in the failure rate among patients whose initial therapy contained lenalidomide when mobilized with G-CSF alone. A retrospective data analysis of 364 patients with MM who underwent stem cell mobilization and attempted harvest at the Hospital of the University of Pennsylvania between January 2002 and December 2007 was performed. Forty-three of the patients received lenalidomide in their induction regimen, and were mobilized with either CY and G-CSF or G-CSF alone. The number of apheresis cycles and the failure rate were lower, whereas the mean number of collected stem cells was higher in patients who were mobilized with CY and G-CSF in comparison with G-CSF alone. This suggests that lenalidomide does not prevent the harvest of adequate numbers of CD34 cells for autologous stem cell transplant, but mobilization with G-CSF and CY may be required to obtain adequate numbers of stem cells. Finally, in our study, the number of lenalidomide cycles did not correlate with stem cell yield.
We conducted a retrospective analysis of 50 lymphoma patients (Hodgkin's disease and non-Hodgkin's lymphoma) who had an 18F-fluoro-deoxyglucose positron emission tomography (FDG-PET) scan after at ...least two cycles of salvage chemotherapy and before autologous stem cell transplantation (ASCT) at our institution. The patients were categorized into FDG-PET negative (N = 32) and positive (N = 18) groups. The median follow-up after ASCT was 19 months (range: 3-59). In the FDG-PET-negative group, the median progression-free survival (PFS) was 19 months (range: 2-59) with 15 (54%) patients without progression at 12 months after ASCT. The median overall survival (OS) for this group was not reached. In the FDG-PET-positive group, the median PFS was 5 months (range: 1-19) with only one (7%) patient without progression at 12 months after ASCT. The median OS was 19 months (range: 1-34). In the FDG-PET-negative group, chemotherapy-resistant patients by CT-based criteria had a comparable outcome to those with chemotherapy-sensitive disease. A positive FDG-PET scan after salvage chemotherapy and prior ASCT indicates an extremely poor chance of durable response after ASCT.
Nonmyeloablative allogeneic transplantation is an emerging therapy for hematologic and solid malignancies and potentially offers patients reduced transplant-related toxicity. Data regarding ...infectious complications of these protocols are limited, but early studies have demonstrated little infectious morbidity, particularly low rates of invasive fungal infections (IFIs). In the present study, 31 consecutive cases of nonmyeloablative transplantation were reviewed over a 2.5-year period, with a specific focus on infectious complications. Twenty-six patients (84%) had at least 1 significant infection during the year after transplantation, and infection-related mortality was 37%. Cytomegalovirus end-organ disease was diagnosed in 3 patients (10%). Ten patients (32%) were given the diagnosis of IFI; 7 (23%) met criteria for proven IFI. Fungal-related mortality was 80% within the group of patients with IFI and accounted for a significant portion of the overall mortality in the study. Severe graft-versus-host disease, high-dose corticosteroid use, recurrent neutropenia, and relapsed or refractory disease were factors associated with development of IFI.
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