Comparison of HLA-matched sibling and unrelated donor transplantation in adult patients with acquired severe aplastic anemia.

The recent improvements in the outcomes of severe aplastic anemia (SAA) patients who received allogeneic stem cell transplantation (SCT) from unrelated donors (URD) suggest the possibility of its alternative first-line treatment. To address this issue, results of adult SAA patients receiving allogeneic SCT were compared between the following three donor-type groups: 8/8-matched sibling (MSD; n = 153), 8/8 well-matched unrelated (WM-URD; n = 72), and 6-7/8 partially matched unrelated (PM-URD; n = 33). Proportion of patients who experienced immunosuppressive treatment failures was significantly higher in the URD groups than in the MSD group (P< 0.01). The incidences of graft failure and transplant-related mortality, and graft-vs.-host disease-free, failure-free survival rates of the MSD, WM-URD, and PM-URD groups were 14.6, 0, and 0% (P< 0.01); 6.1, 10.3, and 21.7% (P= 0.03); and 76.7, 55.5, and 51.5% (P< 0.01), respectively. The overall survival (OS) rate of the MSD group (93.9%) was higher than that of the PM-URD (78.3%; P < 0.01) group, but not to that of the WM-URD (86.2%; P= 0.18) group. Our study showed comparable OS between the MSD group and WM-URD group, which suggest that the URD-SCT can be used as a first-line treatment for adult SAA patients with WM-URD.

Outcomes of allogeneic stem cell transplantation in patients with paroxysmal nocturnal hemoglobinuria with or without aplastic anemia.

OBJECTIVE: The aim of this study was to evaluate the long-term outcomes of allogeneic stem cell transplantation (SCT) in patients with paroxysmal nocturnal hemoglobinuria (PNH) with or without aplastic anemia (AA). METHOD: A total of 33 patients with PNH clones who underwent allogeneic SCT were analyzed. RESULTS: After a median follow-up of 57 months (range, 6.0-151.3), the 5-year estimated overall survival rate was 87.9±5.7%. Four patients died of transplant-related mortality (TRM). With the exception of one patient with early TRM, 32 patients were engrafted. Two patients who had developed delayed GF received a second transplant and recovered. The cumulative incidences of acute graft-vs-host disease (GVHD) (≥grade II) and chronic GVHD (≥moderate) were 27.3±7.9% and 18.7±7.0%, respectively. Twenty-one patients receiving SCT with reduced-intensity conditioning (RIC) had available follow-up data for PNH cell population for the first 6 months post-transplant. Analysis of these data revealed that the PNH clones disappeared within approximately 2 months. CONCLUSION: RIC regimen was sufficient to eradicate PNH clones with sustained donor-type engraftment after allogeneic SCT. Therefore, application of allogeneic SCT with RIC should be considered in patients with PNH, in accordance with the severity of the underlying bone marrow failure.

Similar outcomes of peripheral blood stem cells vs. bone marrow for human leukocyte antigen-matched unrelated donor transplantation in adult patients with acute myeloid leukemia using risk-adapted graft-versus-host disease prophylaxis.

BACKGROUND: In unrelated donor allogeneic stem cell transplantation (URD-SCT), most studies reported that peripheral blood stem cells (PBSC) resulted in higher incidence of acute and/or chronic graft-versus-host disease (GVHD) without survival benefits compared with bone marrow (BM). To overcome these shortcomings of PBSC, we have used a risk-adapted GVHD prophylaxis for patients that received HLA-matched URD-SCT, which was adding low-dose rabbit antithymocyte globulin (Thymoglobulin(®) , 1.25 mg/kg for 2 d) to conditioning in the transplants with PBSC and not BM. METHODS: To determine whether this strategy is effective, we analyzed 115 adult patients with acute myeloid leukemia who received HLA-matched URD-SCT with PBSC (n = 70) or BM (n = 45) using our risk-adapted GVHD prophylaxis strategy. RESULTS: The PBSC group showed faster neutrophil (11 d vs. 13 d; P < 0.01) and platelet (12 d vs. 18 d; P < 0.01) engraftment compared with the BM group. No difference was observed in the incidence of acute GVHD grade II-IV at 100 d (54.3% vs. 64.4%; P = 0.38) and chronic GVHD at 4 yr (65.1% vs. 60.0%; P = 0.83). Other outcomes including the incidence of relapse (30.8% vs. 31.2%; P = 0.53), non-relapse mortality (13.5% vs. 6.9%; P = 0.24), disease-free survival (55.7% vs. 61.9%; P = 0.68), and overall survival (62.2% vs. 63.2%; P = 0.96) at 4 yr were not significantly different. CONCLUSION: Our risk-adapted GVHD prophylaxis strategy resulted in similar transplant outcomes including comparable incidence of GVHD between the PBSC and BM groups in HLA-matched URD-SCT.

Prognostic factors for outcomes of allogeneic stem cell transplantation in chronic phase chronic myeloid leukemia in the era of tyrosine kinase inhibitors.

The aim of this study was to estimate the prognostic factors for the outcomes of chronic myeloid leukemia (CML) patients receiving allogeneic stem cell transplantation (SCT) in chronic phase (CP) in the era of tyrosine kinase inhibitors (TKIs). Ninety-seven patients who underwent allogeneic SCT in CP were analyzed. Forty-seven were TKI-naïve at the time of transplant, and 50 received TKI(s) treatment before transplantation. After a median follow-up of 115.8 months, the 4-year overall survival and event-free survival were 80.4 and 58.8%, respectively. Multivariate analysis showed that there were no differences in survival outcomes based on prior TKI therapy. Older age was a prognostic factor for higher treatment-related mortality (TRM), and the type of graft source and younger age were associated with relapse, but prior TKI therapy and disease status at the time of transplant were not associated with either TRM or relapse. Additionally, a major molecular response at 1 month and an MR(4.5) at 3 months were important predictors of favorable long-term outcomes. This study demonstrates the prognostic factors for the outcomes of allogeneic SCT in CP CML and shows that survival outcomes were not affected by the administration of long-term multi-TKI treatment prior to transplantation.

The efficacy of rabbit antithymocyte globulin with cyclosporine in comparison to horse antithymocyte globulin as a first-line treatment in adult patients with severe aplastic anemia: a single-center retrospective study.

Antithymocyte globulin (ATG) is the drug of choice for immunosuppressive therapy (IST) in patients with severe aplastic anemia (SAA) ineligible for allogeneic stem cell transplantation. Recently, rabbit ATG with cyclosporine A has been used as a first-line IST regimen in patients with SAA because of unavailability of horse ATG. We retrospectively analyzed adult SAA patients who were treated with horse ATG (n=46) or rabbit ATG (n=53) between Feb 2001 and May 2010 to compare hematologic response and survival. Overall response rates at 3, 6, 12, and 18 months were similar in both the horse and rabbit ATG groups: 28.3 versus 35.8 % (P=0.421), 39.1 versus 45.3 % (P=0.537), 45.7 versus 49.1 % (P=0.735), and 47.8 versus 50.9 % (P=0.757), respectively. The complete response (CR) rate at 6 months in the horse ATG was significantly superior in comparison with the rabbit ATG (13.0 versus 1.9 %, P=0.031). But CR rates became similar in both groups after 6 months: 17.4 versus 11.3 % (P=0.387) at 12 months and 21.7 versus 22.6 % (P=0.914) at 18 months. Lymphocyte depletion after ATG was more profound and protracted in the rabbit ATG group compared to the horse ATG group. Overall survival (P=0.460) and failure-free survival (P=0.911) were not significantly different between the two groups. Our retrospective study demonstrated that the efficacy of first-line IST with rabbit ATG is similar to that with horse ATG. However, the time from treatment to CR was longer with rabbit ATG than with horse ATG, partly due to more profound and protracted lymphocyte depletion.

Improvement in hematopoiesis after iron chelation therapy with deferasirox in patients with aplastic anemia.

Iron overload due to regular transfusions of packed red cells can cause multiple organ damage. Iron chelation therapy (ICT) is important in patients with aplastic anemia (AA) who require blood transfusions as supportive management. With the introduction of the oral iron chelator deferasirox, ICT has become more widely available and feasible. We studied 4 adult AA patients who had transfusion-induced iron overload and showed hematological improvement after ICT with oral deferasirox. Following deferasirox treatment, hemoglobin increased and serum ferritin levels decreased, and the patients subsequently became transfusion independent. Our experience raises the possibility of the potential benefit of ICT on hematopoiesis. Further long-term studies in larger patient cohorts are needed to clarify the effect of the restoration of hematopoiesis after iron chelation therapy.

Survival benefits from reduced-intensity conditioning in allogeneic stem cell transplantation for young lower-risk MDS patients without significant comorbidities.

OBJECTIVE: The aim of this study was to determine the optimum conditioning intensity for allogeneic stem cell transplantation (SCT) in young (age ≤50), lower-risk (INT-1 by IPSS) Myelodysplastic syndrome (MDS) patients without significant comorbidities (hematopoietic cell transplantation-comorbidity index score ≤3). METHODS: Transplant outcomes from 46 consecutive patients were retrospectively analyzed according to the conditioning intensity: reduced-intensity conditioning (RIC; n = 14), intensified RIC by adding low-dose total body irradiation (iRIC; n = 15), and myeloablative conditioning (MAC; n = 17). RESULTS: After a median follow-up of 73.7 months, RIC had a better 4-yr overall survival (OS) (92.9%) compared with the iRIC (64.2%) or MAC (70.6%). Multivariate analysis showed that RIC was associated with improved OS compared with the MAC [relative risk (RR) of 0.08, P = 0.022] because of a lower transplant-related mortality (TRM) (RR, 0.08, P = 0.035). iRIC failed to show survival benefits over the MAC (RR of 0.77, P = 0.689) because of similarly high TRM (RR of 0.41, P = 0.480). Cumulative incidence of acute and chronic graft-versus-host disease (GVHD) after RIC was higher, but GVHD-specific survival was significantly better (RIC 100% vs. iRIC 45.7% vs. MAC, P = 0.018). Relapse rate was not different among the three groups, but in the RIC group, azacitidine was available and useful for inducing remission in two patients. CONCLUSION: This study shows that RIC improved OS by directly lowering TRM and indirectly giving an additional chance for relapsed MDS in the era of hypomethylating treatment. RIC-SCT should be considered for relative healthy lower-risk MDS patients.

A case report of the second de novo acute myeloid leukemia (AML) following allogeneic stem cell transplantation in a patient with the first AML.

Secondary leukemia occurring after hematopoietic stem cell transplantation (HSCT) for acute myeloid leukemia (AML) is rare. Secondary AML usually follows autologous and not allogeneic transplants. When a new leukemia develops in a patient successfully treated with an allogeneic HSCT, the possibility of a de novo or secondary leukemia from either the donor or recipient should be considered. We present a case initially diagnosed as de novo AML without a cytogenetic abnormality. The patient was successfully treated with an HLA-matched sibling allogeneic HSCT. However, more than six years later, AML developed again and was associated with new complex cytogenetic abnormalities. After a second HSCT, the patient has been followed without serious complications. Considering the allogeneic setting, the newly developed cytogenetic abnormalities, a relatively long latent period, and the good clinical course after the second allogeneic HSCT, this case might represent a second de novo AML following successful treatment of the first AML.

The activating killer cell immunoglobulin-like receptors as important determinants of acute graft-versus host disease in hematopoietic stem cell transplantation for acute myelogenous leukemia.

BACKGROUND: We investigated the influence of killer cell immunoglobulin-like receptor (KIR) genes, based on the genotypes of inhibitory or activating KIR, in stem cell recipients with acute myelogenous leukemia and their human leukocyte antigen-matched sibling donors on acute graft-versus host disease (GVHD) after hematopoietic stem cell transplantation. METHODS: We studied 53 consecutive donor-recipient pairs to determine the impact of KIR genotypes and their bidirectional KIR interactions. RESULTS: All activating KIR genes in donors were important factors for determining outcome in a manner distinctive for each gene studied. Specifically, the 2DS2 gene and the 2DS4*003 allele were closely correlated with acute GVHD. The 2DS1 gene was associated with a better long-term survival, even if present only in the donor and not the recipient. The 2DS3-2DS5 dual genes were more often involved in a variety of transplant-related complications. CONCLUSIONS: In conclusion, these factors may help predict transplant outcomes and aid in our understanding of immunogenetic specificity.

Successful interim therapy with imatinib prior to allogeneic stem cell transplantation in Philadelphia chromosome-positive acute myeloid leukemia.

OBJECTIVES: Imatinib (Glivec, STI571) has been successfully used in patients with chronic myelogenous leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome (Ph). We used imatinib interim therapy for four consecutive patients with newly diagnosed Ph+ acute myeloid leukemia (AML). We monitored the patient status for minimal residual disease by real-time quantitative polymerase chain reaction. METHODS AND RESULTS: Imatinib was administered on an interim schedule after each chemotherapy course. After the first imatinib cycle, all patients remained in sustained complete hematologic remission (CHR) with a decrease in the breakpoint cluster region of the Abelson oncogene locus transcript. All patients received a second imatinib cycle following consolidation and showed sustained CHR, including two cases with complete molecular remission. All cases underwent hematopoietic stem cell transplantation (HSCT) in favorable condition, and are still alive with a leukemia-free status at 6, 6, 9, and 25 months after HSCT. CONCLUSIONS: As a first-line interim therapy, imatinib appears to be a useful treatment strategy to provide a bridge to HSCT in patients with Ph+ AML. Further studies with a larger patient population and longer follow-up are needed for accurate assessment of the impact of imatinib on the long-term outcome of transplantation for patients with Ph+ AML.

The effect of first-line imatinib interim therapy on the outcome of allogeneic stem cell transplantation in adults with newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia.

Previously, we suggested that imatinib incorporation into conventional chemotherapy as an alternative (imatinib interim therapy) might be a useful strategy for bridging the time to allogeneic stem cell transplantation (SCT) for newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL). Here, we provide an updated report on this strategy in 29 patients. At the time of enrollment, 23 patients (79.3%) achieved complete remission (CR). After the first imatinib cycle, the median breakpoint cluster region-Abelson oncogene locus (BCR-ABL)/ABL ratios decreased by 0.77 log in 25 (86.2%) responders, and their BCR-ABL/ABL ratios decreased further by 0.34 log after the second imatinib cycle, which included 7 molecular CR. One patient (4.3%) relapsed during the imatinib therapy. The remaining 3 patients were primarily refractory to both imatinib and chemotherapy. Twenty-five (86.2%) of the 29 patients received transplants in first CR. With a median follow-up duration of 25 months after SCT, the 3-year estimated probabilities of relapse, nonrelapse mortality, disease-free survival, and overall survival were 3.8%, 18.7%, 78.1%, and 78.1%, respectively. In comparison to our historical control data, first-line imatinib interim therapy appears to provide a good quality of CR and a survival advantage for patients with Ph(+) ALL. Further long-term follow-up is needed to validate the results of this study.