A Schattenberg

The immune reactivity of allogeneic lymphocytes plays a major role in the control of leukemia after bone marrow transplantation. In patients with recurrent leukemia after marrow transplantation, chimerism and tolerance provide ideal conditions for adoptive immunotherapy with donor lymphocytes. We studied the effect of donor lymphocyte transfusions on acute and chronic leukemia in relapse after bone marrow transplantation. One hundred thirty-five patients with chronic myeloid leukemia (CML) (N = 84), acute myeloid leukemia (AML) (N = 23), acute lymphoblastic leukemia (ALL) (N = 22), myelodysplastic syndrome (MDS) (N = 5), and polycythemia vera with osteomyelofibrosis (PCV) (N = 1) were treated with transfusions of donor lymphocytes. Patients were monitored for response of leukemia, including in CML, the use of the polymerase chain reaction for bcr/abl mRNA transcripts and for the occurrence of graft-versus-host disease (GVHD) and myelosuppression. Complete remissions were induced by donor lymphocyte transfusions in 54 patients with CML (73%) and in the patient with PCV; complete remissions were also induced in five patients (29%) with AML and a patient with MDS. In contrast, ALL did not respond to adoptive immunotherapy with donor lymphocyte transfusions. Remissions were durable in patients treated for CML in chronic phase (probability of remission: 87% at 3 years). Lymphocyte transfusions were also given to 18 patients with ALL, AML, MDS, and transformed phase CML who were in remission after chemotherapy. These remissions were not durable. Fifty-two patients (41%) developed GVHD of grade 2 or more, and 41 patients (34%) showed signs of myelosuppression. Seventeen patients died without leukemia, 14 patients with GVHD and/or myelosuppression. Donor lymphocyte transfusions exert strong effects against myeloid forms of leukemia and induce durable remissions in CML.

IMPORTANCE: High-dose immunosuppressive therapy and autologous hematopoietic stem cell transplantation (HSCT) have shown efficacy in systemic sclerosis in phase 1 and small phase 2 trials. OBJECTIVE: To compare efficacy and safety of HSCT vs 12 successive monthly intravenous pulses of cyclophosphamide. DESIGN, SETTING, AND PARTICIPANTS: The Autologous Stem Cell Transplantation International Scleroderma (ASTIS) trial, a phase 3, multicenter, randomized (1:1), open-label, parallel-group, clinical trial conducted in 10 countries at 29 centers with access to a European Group for Blood and Marrow Transplantation-registered transplant facility. From March 2001 to October 2009, 156 patients with early diffuse cutaneous systemic sclerosis were recruited and followed up until October 31, 2013. INTERVENTIONS: HSCT vs intravenous pulse cyclophosphamide. MAIN OUTCOMES AND MEASURES: The primary end point was event-free survival, defined as time from randomization until the occurrence of death or persistent major organ failure. RESULTS: A total of 156 patients were randomly assigned to receive HSCT (n = 79) or cyclophosphamide (n = 77). During a median follow-up of 5.8 years, 53 events occurred: 22 in the HSCT group (19 deaths and 3 irreversible organ failures) and 31 in the control group (23 deaths and 8 irreversible organ failures). During the first year, there were more events in the HSCT group (13 events [16.5%], including 8 treatment-related deaths) than in the control group (8 events [10.4%], with no treatment-related deaths). At 2 years, 14 events (17.7%) had occurred cumulatively in the HSCT group vs 14 events (18.2%) in the control group; at 4 years, 15 events (19%) had occurred cumulatively in the HSCT group vs 20 events (26%) in the control group. Time-varying hazard ratios (modeled with treatment × time interaction) for event-free survival were 0.35 (95% CI, 0.16-0.74) at 2 years and 0.34 (95% CI, 0.16-0.74) at 4 years. CONCLUSIONS AND RELEVANCE: Among patients with early diffuse cutaneous systemic sclerosis, HSCT was associated with increased treatment-related mortality in the first year after treatment. However, HCST conferred a significant long-term event-free survival benefit. TRIAL REGISTRATION: isrctn.org Identifier: ISRCTN54371254.

Out of 690 allogeneic matched sibling donor transplants for multiple myeloma reported to the European Group for Blood and Marrow Transplantation (EBMT) registry, 334 were performed during the period 1983-93 (all with bone marrow) and 356 during 1994-98 [223 with bone marrow and 133 with peripheral blood stem cells (PBSCs)]. The median overall survival was 10 months for patients transplanted during the earlier time period and 50 months for patients transplanted with hone marrow during the later period. The use of PBSCs was associated with earlier engraftment but no significant survival benefit compared to bone marrow transplants during the same time period. The improvement in survival since 1994 with the result of a significant reduction in transplant-related mortality, which was 38%, 21% and 25% at 6 months and 46%, 30% and 37% at 2 years during the earlier period, and the later period with bone marrow and PBSCs respectively. Reasons for the reduced transplant-related mortality appeared to be fewer deaths owing to bacterial and fungal infections and interstitial pneumonitis, in turn a result of earlier transplantation and less prior chemotherapy. Better supportive treatment and more frequent use of cytokines may also play a role. The improvement in survival was not directly related to the increased use of PBSCs.

Donor leukocyte infusions (DLI) can induce sustained remissions in patients with acute and chronic myeloid leukemia who relapse after allogeneic bone marrow transplantation (allo-BMT). Also, in multiple myeloma (MM), incidental reports have indicated the existence of a graft-versus-myeloma effect (GVM) induced by allo-reactive T cells. We performed a retrospective study in a larger group of MM patients to characterize better the effect, prognostic factors, and toxicity of this new treatment modality. Thirteen patients with relapsed MM after allo-BMT were studied. Patients received a total of 29 DLI with T-cell doses ranging from 1 x 10(6)/kg to 33 x 10(7)/kg. Repetitive courses, sometimes with escalated cell doses, were undertaken in case of no response to or relapse after DLI. Eight of 13 patients responded: 4 patients achieved a partial remission and 4 patients achieved a complete remission. Dose escalation was effective in 3 patients. The time to response was median 6 weeks (range, 4 to 10 weeks). Major toxicities were secondary to acute and chronic graft-versus-host disease (GVHD), which occurred in 66% and 56% of all patients and in 87% and 85% of the responders, respectively. Two responding patients developed fatal BM aplasia. The only prognostic factors for response were a T-cell dose greater than 1 x 10(8)/kg and the occurrence of GVHD. Seven of nine patients developing acute GVHD responded, as compared with only 1 response in the 4 patients without GVHD and 6 of 7 patients with chronic GVHD responded, whereas no response was observed in the 5 patients without chronic GVHD. DLI are effective in a high percentage of patients with relapsed MM after allo-BMT, although it is associated with a high treatment-related toxicity. The dose of T cells used may be important in determining the GVM effect, with the highest probability of response after infusion of more than 1 x 10(8) T cells. Because the optimal individual dose may vary, patient-adapted therapy consisting of repeated infusions with escalating dose of donor leukocytes until maximum response is achieved may therefore be preferable.

PURPOSE: To determine the efficacy, toxicity, and long-term outcome and prognostic factors of donor lymphocyte infusions (DLI) in patients with relapsed multiple myeloma (MM) after allogeneic stem-cell transplantation (AlloSCT). MATERIALS AND METHODS: Twenty-seven patients received 52 DLI courses at a median of 30 months after the previous AlloSCT. Reinduction therapy was administered to 13 patients before DLI. RESULTS: Reinduction therapy was successful in eight of 13 patients. Fourteen patients (52%) responded to DLI, including six patients (22%) who achieved a complete remission (CR). Five patients responded after T-cell dose escalation in subsequent DLIs. Four patients experienced relapse or disease progression (three from partial response and one from CR). Five patients remain in remission more than 30 months after DLI. Major toxicity was acute and chronic graft-versus-host disease (GVHD), which was present in 55% and 26% of patients, respectively. Two patients died from bone marrow aplasia. Median overall survival of all patients was 18 months. Overall survival was 11 months for DLI-resistant patients and has not been reached for the responding patients. In two patients, sustained molecular remission was observed. The factors that were correlated with response to DLI were a T-cell dose of more than 1.10(8) cells/kg, response to reinduction therapy, and chemotherapy-sensitive disease before AlloSCT. CONCLUSION: These data confirm the potential and durable graft-versus-myeloma effect of DLI in patients with relapsed MM after AlloSCT. Future studies should be aimed at increasing response rates, especially in patients with chemoresistant disease, and reducing toxicity by limiting GVHD. Adjuvant DLI seems an attractive and promising approach for patients who do not achieve a molecular remission after AlloSCT.