Biological significance of HLA locus matching in unrelated donor bone marrow transplantation.

We hypothesized that the compatibility of each HLA loci between donor and patient induced divergent transplant-related immunologic responses, which attributed to the individualized manifestation of clinical outcomes. Here, we analyzed 7898 Japanese pairs transplanted with T-cell-replete marrow from an unrelated donor with complete HLA allele typing data. Multivariable competing risk regression analyses were conducted to evaluate the relative risk (RR) of clinical outcomes after transplantation. A significant RR of HLA allele mismatch compared with match was seen with HLA-A, -B, -C, and -DPB1 for grade III-IV acute graft-versus-host disease (GVHD), and HLA-C for chronic GVHD. Of note, only HLA-C and HLA-DPB1 mismatch reduced leukemia relapse, and this graft-versus-leukemia effect of HLA-DPB1 was independent of chronic GVHD. HLA-DRB1 and HLA-DQB1 double (DRB1_DQB1) mismatch was revealed to be a significant RR for acute GVHD and mortality, whereas single mismatch was not. Thus, the number of HLA-A, -B, -C, -DPB1, and DRB1_DQB1 mismatches showed a clear-cut risk difference for acute GVHD, whereas the number of mismatches for HLA-A, -B, -C, and DRB1_DQB1 showed the same for mortality. In conclusion, we determined the biological response to HLA locus mismatch in transplant-related immunologic events, and provide a rationale for use of a personalized algorithm for unrelated donor selection.

Changes in the clinical impact of high-risk human leukocyte antigen allele mismatch combinations on the outcome of unrelated bone marrow transplantation.

Several high-risk HLA allele mismatch combinations (HR-MMs) for severe acute graft-versus-host disease (GVHD) have been identified by analyzing transplantation outcomes in Japanese unrelated hematopoietic stem cell transplant recipients. In this study, we analyzed the effects of HR-MMs in 3 transplantation time periods. We confirmed that the incidence of grade III to IV acute GVHD in the HR-MM group was significantly higher than that in the low-risk (LR) MM group (hazard ratio [HR], 2.74; P < .0001) in the early time period (1993 to 2001). However, the difference in the incidence of grade III to IV acute GVHD between the HR-MM and LR-MM groups was not statistically significant (HR, 1.06; P = .85 and HR, .40; P = .21, respectively) in the mid (2002 to 2007) and late (2008 to 2011) time periods. Similarly, survival in the HR-MM group was significantly inferior to that in the LR-MM group (HR, 1.46; P = .019) in the early time period, whereas the difference in survival between the 2 groups was not statistically significant in the mid and late time periods (HR, 1.06; P = .75 and HR, .82; P = .58, respectively). In conclusion, the adverse impact of HR-MM has become less significant over time. Unrelated transplantation with a single HR-MM could be a viable option in the absence of a matched unrelated donor or an unrelated donor with a single LR-MM.

[A phase III study of the efficacy and safety of meropenem in patients with febrile neutropenia].

Efficacy, safety and pharmacokinetics of meropenem (MEPM) were assessed when 1 g (40 mg/kg for some of the pediatric patients) t.i.d. was administered every 8hours to 101 adult and 6 pediatric patients with febrile neutropenia (FN) as diagnosed based on the Japanese guideline for FN treatment. The efficacy rate evaluated as antifebrile effect up to Day 4 of treatment was 40.0% (40/100) in adult and 66.7% (4/6) in pediatric patients. The antifebrile effect in adult patients was analyzed after stratifying them according to their neutrophil counts up to Day 4. Treatment with MEPM produced an antifebrile effect not only in patients with higher neutrophil counts (> or = 500/mm3) but also in those with lower counts (< 100/mm3), and the efficacy rate was comparable between the two groups: 38.2% in the < 100/mm3 group and 29.4 to 55.6% in the > or = 500/mm3 group. The bacteriological efficacy of MEPM evaluated as disappearance rate on Days 3 to 5 and Day 7 was both 100% (8/8 and 4/4, respectively). The time above minimal inhibitory concentration (% T > MIC) in the treatment interval was greater than 90% in 9 out of 10 patients for whom likely causative organism was isolated and identified after MEPM treatment or for whom causative organism emerging after treatment was isolated and identified. The incidence of adverse events was 93.1% in adult and 83.3% in pediatric patients. There were three deaths and one serious adverse event reported among the adult patients; however, all these cases were assessed as not related to the study medication. The incidence of adverse drug reactions was 45.5% and 66.7%, respectively. All the observed adverse drug reactions were mild or moderate in severity and none of them was severe. Adverse drug reactions which were unknown from the previous MEPM clinical studies and investigation of the results of clinical experience include 'chest discomfort', 'blood uric acid decreased', 'lymphocyte deformation', 'blood uric acid increased', 'abnormal funduscopy', 'hypesthesia' and 'hemorrhagic cystitis'. All these events were mild or moderate in severity and resolved without requiring any action or after providing symptomatic treatment. There was no unknown adverse drug reaction that resulted in treatment discontinuation. No nervous system disorders such as convulsion and impaired consciousness were reported. The results show that monotherapy of MEPM 1 g (or 40 mg/kg for some of the pediatric patients) t.i.d. every 8 hours was effective, and was also safe and well tolerated in adult and pediatric patients with FN. Therefore, MEPM monotherapy is expected to be useful as the initial treatment for Japanese patients with FN.

Genetic variants of human granzyme B predict transplant outcomes after HLA matched unrelated bone marrow transplantation for myeloid malignancies.

Serine protease granzyme B plays important roles in infections, autoimmunity, transplant rejection, and antitumor immunity. A triple-mutated granzyme B variant that encodes three amino substitutions (Q48R, P88A, and Y245H) has been reported to have altered biological functions. In the polymorphism rs8192917 (2364A>G), the A and G alleles represent wild type QPY and RAH mutant variants, respectively. In this study, we analyzed the impact of granzyme B polymorphisms on transplant outcomes in recipients undergoing unrelated HLA-fully matched T-cell-replete bone marrow transplantation (BMT) through the Japan Donor Marrow Program. The granzyme B genotypes were retrospectively analyzed in a cohort of 613 pairs of recipients with hematological malignancies and their unrelated donors. In patients with myeloid malignancies consisting of acute myeloid leukemia and myelodysplastic syndrome, the donor G/G or A/G genotype was associated with improved overall survival (OS; adjusted hazard ratio [HR], 0.60; 95% confidence interval [CI], 0.41-0.89; P = 0.01) as well as transplant related mortality (TRM; adjusted HR, 0.48; 95% CI, 0.27-0.86, P = 0.01). The recipient G/G or A/G genotype was associated with a better OS (adjusted HR, 0.68; 95% CI, 0.47-0.99; P = 0.05) and a trend toward a reduced TRM (adjusted HR, 0.61; 95% CI, 0.35-1.06; P = 0.08). Granzyme B polymorphism did not have any effect on the transplant outcomes in patients with lymphoid malignancies consisting of acute lymphoid leukemia and malignant lymphoma. These data suggest that there is an association between the granzyme B genotype and better clinical outcomes in patients with myeloid malignancies after unrelated BMT.

Unrelated bone marrow transplantation induced long-term remission in a patient with life-threatening Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis.

We present a case of life-threatening Epstein-Barr virus (EBV)-associated hemophagocytic lymphohistiocytosis (HLH) with severe hepatitis that was successfully treated by allogeneic stem cell transplantation from an unrelated donor. A 26-year-old woman was admitted to hospital with a high fever and liver dysfunction. Laboratory tests, including bone marrow aspiration, revealed severe HLH that occurred after EBV infection. High-dose methylprednisolone and etoposide therapy did not control the disease. We could control the HLH, but the EBV viremia continued following the CHOPE (cyclophosphamide, doxorubicin, vincristine, prednisone, and etoposide) chemotherapy regimen. Therefore, the patient underwent allogeneic bone marrow transplantation from an HLA-matched, unrelated donor. The patient has remained in good condition without disease recurrence for 2 years after bone marrow transplantation. Although there is no consensus regarding allogeneic stem cell transplantation for EBV-HLH, it is the treatment of choice for aggressive EBV-HLH when the patient is refractory to intensive chemotherapy.

Peripheral blood stem cell versus bone marrow transplantation from HLA-identical sibling donors in patients with leukemia: a propensity score-based comparison from the Japan Society for Hematopoietic Stem Cell Transplantation registry.

We retrospectively analyzed the results of 707 adult patients who underwent myeloablative peripheral blood stem cell transplantation (PBSCT) (n = 365) and myeloablative bone marrow transplantation (BMT) (n = 342) for leukemia from HLA-identical sibling donors between 2000 and 2005 using the propensity score method. The results were obtained from the Japan Society for Hematopoietic Cell Transplantation registry. Multivariate Cox analysis showed that PBSCT was associated with lower overall survival (OS) in standard-risk patients [adjusted hazard ratio (aHR) = 1.83; 95% confidence interval (CI) 1.04-3.23; P = 0.036], but not in high-risk patients (aHR = 1.11; 95% CI 0.76-1.61; P = 0.599). Hematopoietic recovery was significantly faster after PBSCT. The risk of acquiring grade III-IV acute graft-versus-host disease (GVHD) (aHR = 2.23; P = 0.040) and extensive chronic GVHD (aHR = 1.93; P = 0.001) were significantly higher after PBSCT. PBSCT was associated with higher non-relapse mortality in standard-risk patients (aHR = 2.30; 95% CI 1.08-4.88; P = 0.030), but not in high-risk patients (aHR = 1.29; 95% CI 0.65-2.54; P = 0.468). Relapse after transplantation did not differ between PBSCT and BMT either in standard-risk group or in high-risk group (aHR = 1.17; 95% CI 0.55-2.52; P = 0.684 and aHR = 0.81; 95% CI 0.52-1.28; P = 0.370, respectively). In this retrospective analysis, OS was significantly lower after PBSCT in standard-risk patients, but not in high-risk patients. PBSCT was associated with significant risks of grade III-IV acute GVHD and extensive chronic GVHD.

Outcome of allogeneic bone marrow transplantation from unrelated donors for adult Philadelphia chromosome-negative acute lymphocytic leukemia in first complete-remission.

The indication of allogeneic stem cell transplantation (allo-SCT) for Philadelphia chromosome-negative acute lymphocytic leukemia [Ph(-) ALL] from unrelated donors is not established. To assess its potency of unrelated patients in first complete-remission (CR1) transplanted from unrelated donors and the potential prognostic factors affecting the probability of survival, we retrospectively analyzed a total of 41 adult Ph(-) ALL patients in CR1 who underwent unrelated bone marrow transplantation at 6 transplantation centers of the Nagoya Blood and Marrow Transplantation Group between 1993 and 2006. The median age of the 41 patients was 28 years (range, 18-51 years). HLA was matched in 33 transplants, with mismatches in 8 (HLA-A allele mismatch:1, HLA-DR serological mismatch: 2, HLA-DRB1 mismatch: 5). Leukemia-free survival (LFS) at 3 and 6 years from allo-SCT was 60.3 and 47.7%, respectively. LFS at 5 years was 62.1% for those transplanted from HLA-matched donors. LFS was significantly lower with HLA-mismatched donors due to higher transplantation-related mortality. Relapse was observed in 3 patients. Our study suggested that unrelated allo-SCT could improve LFS of patients with a potential graft-versus-leukemia effect. Unrelated allo-SCT for Ph(-) ALL patients in CR1 could be more beneficial by reducing TRM, such as selecting a HLA-matched donor.

Insomnia and depression during protective isolation in patients with hematological disorders.

OBJECTIVE: Patients treated in a protective isolation unit (PIU) often experience loneliness and increased feelings of seclusion, leading to elevated levels of distress, but the relationship between psychiatric distress and environmental factors is unclear. Therefore, we retrospectively compared the impact of environmental factors on insomnia and depression between patients in the PIU and those in a standard ward (SW). METHODS: Subjects were 246 patients with hematological disorders hospitalized in Meitetsu Hospital between April 1, 2007 and July 31, 2008 (62 PIU patients and 184 SW patients). We assessed insomnia and depression, as well as concomitant corticosteroid (CS) administration, stem cell transplantation (SCT) therapy, and complications resulting from these therapies. Details of medical history and patient information were retrospectively extracted from patients' charts, medical records and the electronic laboratory database at the hospital. RESULTS: Patients in the PIU tended to be complicated by insomnia or depression more than those in the SW, but the stay in the PIU was not significantly related to the incidence of insomnia or depression. Our findings indicated that use of CS was a risk factor for insomnia. The prevalence of depression was higher in patients with therapeutic complications. All PIU patients with depression also received SCT. CONCLUSION: Our findings suggest an increased potential for insomnia after administration of CS and depression in cases with complications after SCT, which is important to keep in mind for patients with hematological disorders.

NKG2D gene polymorphism has a significant impact on transplant outcomes after HLA-fully-matched unrelated bone marrow transplantation for standard risk hematologic malignancies.

BACKGROUND: NKG2D, an activating and co-stimulatory receptor expressed on natural killer cells and T cells, plays pivotal roles in immunity to microbial infections as well as in cancer immunosurveillance. This study examined the impact of donor and recipient polymorphisms in the NKG2D gene on the clinical outcomes of patients undergoing allogeneic T-cell-replete myeloablative bone marrow transplantation using an HLA-matched unrelated donor. DESIGN AND METHODS: The NKG2D polymorphism was retrospectively analyzed in a total 145 recipients with hematologic malignancies and their unrelated donors. The patients underwent transplantation following myeloablative conditioning; the recipients and donors were matched through the Japan Marrow Donor Program. RESULTS: In patients with standard-risk disease, the donor NKG2D-HNK1 haplotype, a haplotype expected to induce greater natural killer cell activity, was associated with significantly improved overall survival (adjusted hazard ratio, 0.44; 95% confidence interval, 0.23 to 0.85; p=0.01) as well as transplant related mortality (adjusted hazard ratio, 0.42; 95% confidence interval, 0.21 to 0.86; p=0.02), but had no impact on disease relapse or the development of grade II-IV acute graft-versus-host disease or chronic graft-versus-host disease. The NKG2D polymorphism did not significantly influence the transplant outcomes in patients with high-risk disease. CONCLUSIONS: These data suggest an association between the donor HNK1 haplotype and better clinical outcome among recipients, with standard-risk disease, of bone marrow transplants from HLA-matched unrelated donors.

Possible association between obesity and posttransplantation complications including infectious diseases and acute graft-versus-host disease.

Both obesity and malnutrition are considered risk factors for complications after bone marrow transplantation (BMT). To elucidate the impact of pretransplantation body mass index (BMI) on clinical outcome, we performed a retrospective cohort study with registration data from the Japan Marrow Donor Program (JMDP). Between January 1998 and December 2005, a total of 3935 patients received unrelated BMT through the JMDP; of these, 3827 patients for whom pretransplantation height and weight data were available were included in the study. Patients were stratified according to pretransplantation BMI values (low BMI: BMI < 18 kg/m(2), n = 295; normal BMI: 18 < or = BMI < 25 kg/m(2), n = 2906; overweight: 25 < or = BMI <30 kg/m(2), n = 565; obese: 30 kg/m(2) < or = BMI, n = 61). In a univariate analysis, pretransplantation BMI was associated with a significantly greater risk of grade II-IV acute graft-versus-host disease (GVHD; P = .03). Multivariate analysis showed that pretransplantation BMI tended to be associated with an increased risk of grade II-IV acute GVHD (P = .07). Obesity was associated with an increased risk of infection compared with normal BMI (odds ratio = 1.9; 95% confidence interval = 1.1 to 3.2; P = .02). Our findings demonstrate a correlation between pretransplantation BMI and posttransplantation complications. Although BMI depends strongly on multiple factors, the effect of obesity on clinical outcome should be evaluated in a prospective study.

Phase II study of tacrolimus and methotrexate for prophylaxis of acute graft-versus-host disease after HLA-A, B, and DRB1 genotypically mismatched unrelated bone marrow transplantation among Japanese patients.

Bone marrow transplantation from unrelated donors (UR-BMT) has been considered to be effective for patients with hematological malignancies who have no suitable related donor. However, disparities of HLA between a recipient and a donor increase the risk of severe acute graft-versus-host disease (GVHD). We evaluated GVHD prophylaxis using tacrolimus and methotrexate for HLA-A, B, or DRB1 genotypically mismatched UR-BMT. Fifty-five patients were enrolled in this study. The incidence of grade III to IV acute GVHD was 23.6% for all patients. No significant difference in the incidence of grade III to IV acute GVHD was observed between HLA-A or B 1 locus mismatch transplantation (18.8%) and HLA-DRB1 1 locus mismatch transplantation (16.7%) (P = 0.96). The incidence of chronic GVHD was 71.7%. Disease-free survival at 5 years was 53.2% for patients with standard risk disease and 24.5% for patients with high-risk disease. Patients with chronic GVHD exhibited better disease-free survival than those without chronic GVHD (53.2 vs. 30.9%, P = 0.011). Twenty patients (36.4%) had a relapse of leukemia and 14 of them died of recurrent leukemia. This study indicates tacrolimus and methotrexate can lower the risk of severe acute GVHD after HLA-A, B, or DRB1 genotypically 1 locus mismatched UR-BMT.

Impact of AB0-blood group incompatibility on the outcome of recipients of bone marrow transplants from unrelated donors in the Japan Marrow Donor Program.

BACKGROUND: Although the AB0 blood group is one of two major antigen systems of relevance for transplantation in humans, there are still conflicting data concerning the influence of AB0 incompatibility on transplant outcome. This study investigated the effect of AB0 incompatibility in recipients of bone marrow transplants from unrelated donors. DESIGN AND METHODS: We retrospectively analyzed data from 5,549 patients who underwent bone marrow transplantation from unrelated donors in the Japan Marrow Donor Program. RESULTS: Overall survival rates in the group with major and minor mismatches were significantly lower than the rate in the AB0-identical group (AB0-identical 63.0%; major mismatch, 56.9%; minor mismatch, 57.1% at 1 year). Treatment-related mortality was higher in the major and minor mismatch groups, but there was no significant difference in the rate of relapse. Cox proportional hazards modeling showed that both major and minor AB0 incompatibility were significant risk factors for transplant-related mortality, independently of disease, patients' age, and HLA incompatibility. Delayed engraftment of neutrophils, platelets, and erythrocytes was observed in transplants with major incompatibility. There was a high incidence of grade 3 and 4 acute graft-versus-host disease in the groups with major and minor mismatches, which was caused by a high incidence of stage 2 to 4 liver graft-versus-host disease. Interestingly, the risk of grade 2 to 4 graft-versus-host disease in the major mismatch group was higher in patients with early engraftment of erythrocytes. Among the patients receiving reduced-intensity conditioning, the transplant-related mortality was also increased in AB0-incompatible transplants. CONCLUSIONS: Major and minor AB0 incompatibility have specific effects on transplant-related mortality and acute graft-versus-host disease in recipients of bone marrow transplants from unrelated donors.

Hematopoietic stem cell transplantation for acute promyelocytic leukemia in second or third complete remission: a retrospective analysis in the Nagoya Blood and Marrow Transplantation Group.

Acute promyelocytic leukemia (APL) is the most curable subtype of acute myeloid leukemia. Second complete remission (CR2) can be easily achieved with several therapeutic options even after relapse. However, the optimal strategy to treat APL in CR2 is still controversial. We retrospectively compared the outcome of autologous (auto) and allogeneic (allo) hematopoietic stem cell transplantation (HSCT) for patients with APL in CR2 or CR3. Fifteen patients received auto and 13 received allo HSCT between 1999 and 2004 at eight hospitals belonging to the Nagoya Blood and Marrow Transplantation Group. Four-year disease-free survival (DFS) and overall survival (OS) for autografted patients were 68.9 and 75.8%, whereas those for allografted patients were 46.2 (P = 0.350) and 46.2% (P = 0.185), respectively. Three autografted patients and one allografted patient relapsed, and one autografted patient and five allografted patients died without leukemia relapse. Among 14 autografted patients who were evaluated for MRD with molecular analysis, relapse occurred in one with positive MRD (n = 2) and two with negative MRD (n = 12). These data suggest that auto HSCT is very effective for APL in CR2 or CR3, and may be preferable to allo HSCT for a portion of patients. Prospective studies are required to define the role of auto HSCT in the treatment of relapsed APL.

Chronic graft-versus-host disease after allogeneic bone marrow transplantation from an unrelated donor: incidence, risk factors and association with relapse. A report from the Japan Marrow Donor Program.

Chronic graft-versus-host disease (GVHD) remains the major cause of late morbidity and mortality after allogeneic stem cell transplantation. We retrospectively analysed 2937 patients who underwent bone marrow transplantation from an unrelated donor (UR-BMT) facilitated by the Japan Marrow Donor Program (JMDP) and survived beyond day 100 after transplantation. The cumulative incidence of chronic GVHD (limited + extensive) or extensive chronic GVHD at 5 years post-transplant was 45.8% and 28.2%, respectively. On multivariate analysis, seven variables predicting chronic GVHD were identified: recipient age over 20 years, donor age over 30 years, primary diagnosis of chronic myeloid leukaemia, human leucocyte antigen (HLA)-A or -B mismatch, total body irradiation-containing regimen, platelet count not having reached 50 x 10(9)/l by day 100, and prior acute GVHD. Among 2609 patients with haematological malignancy, overall survival was significantly higher in patients with limited chronic GVHD but lower in patients with extensive chronic GVHD compared with those without chronic GVHD. The cumulative incidence of relapse among patients with limited or extensive chronic GVHD was significantly lower than that among patients without chronic GVHD. Our results suggest that limited chronic GVHD provides a survival benefit to patients with haematological malignancies by reducing the risk of relapse without increasing the risk of death from chronic GVHD.

Effects of HLA allele and killer immunoglobulin-like receptor ligand matching on clinical outcome in leukemia patients undergoing transplantation with T-cell-replete marrow from an unrelated donor.

The responsible human leukocyte antigen (HLA) locus and the role of killer immunoglobulin-like receptor (KIR) ligand matching on transplantation outcome were simultaneously identified by multivariate analysis in 1790 patients with leukemia who underwent transplantation with T-cell-replete marrow from an unrelated donor (UR-BMT) through the Japan Marrow Donor Program. The graft-versus-leukemia (GVL) effect depended on leukemia cell type. HLA-C mismatch reduced the relapse rate in acute lymphoblastic leukemia (ALL) (hazard ratio [HR] = 0.47; P = .003), and HLA-DPB1 mismatch reduced it in chronic myeloid leukemia (CML) (HR = 0.35; P < .001). In contrast, KIR2DL ligand mismatch in the graft-versus-host (GVH) direction (KIR-L-MM-G) increased in ALL (HR = 2.55; P = .017). An increased rejection rate was observed in KIR2DL ligand mismatch in the host-versus-graft direction (HR = 4.39; P = .012). Acute GVH disease (GVHD) was increased not only in the mismatch of HLA-A, -B, -C, and -DPB1, but also in KIR-L-MM-G. As a whole, the mismatch of HLA-A, -B, and -DQB1 locus and KIR-L-MM-G resulted in increased mortality. In conclusion, not only the mismatch of HLA-C and -DPB1, but also KIR-L-MM-G affected leukemia relapse, which should be considered based on leukemia cell type. Furthermore, KIR-L-MM induced adverse effects on acute GVHD (aGVHD) and rejection, and brought no survival benefits to patients with T-cell-replete UR-BMT.

Long-term follow-up of 14 patients with philadelphia chromosome-positive acute lymphoblastic leukemia following autologous bone marrow transplantation in first complete remission.

We describe the clinical outcome of autologous bone marrow transplantation (ABMT) for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-ALL). Between 1985 and 2000, 14 patients in first complete remission underwent transplantation. In all cases, harvested marrow was purged with a cocktail of complement and monoclonal antibodies to common acute lymphoblastic leukemia antigen (CALLA). Eight patients died following BMT: 2 patients from interstitial pneumonia and 6 from disease recurrence. For the 6 surviving patients in continuous remission, the median follow-up period was 96 months. The probability of disease-free survival and the rate of relapse at 5 years were 41.7% and 51.4%, respectively. Minimal residual disease (MRD) was assayed quantitatively with patient-specific D-JH probes in 6 of 14 cases. A higher residual tumor burden at marrow harvest was associated with subsequent relapse. Efforts to reduce the MRD burden before harvesting stem cells should improve the clinical outcome of ABMT.

Low-dose cyclosporin A with short-term methotrexate for graft-versus-host disease prophylaxis in allogeneic bone marrow transplantation from human leukocyte antigen-identical siblings: a prospective phase II study in Japanese patients.

We hypothesized that reducing the dosage of prophylaxis for graft-versus-host disease (GVHD) would reduce the risk of relapse and toxicity after bone marrow transplantation (BMT) from human leukocyte antigen (HLA)-identical siblings. In a prospective phase II trial, 21 patients with leukemia and myelodysplastic syndrome underwent BMT from HLA-identical siblings and received GVHD prophylaxis consisting of low-dose (1.5 mg/kg per day) cyclosporin A (CSP) with short-term methotrexate (MTX) treatment. This low-dose group was compared with a group of retrospective control patients (n = 22) who received a standard CSP dosage (3.0 mg/kg per day) and MTX. One patient died of transplantation-related causes within 100 days. The regimen-related toxicity was quite tolerable. Although acute GVHD of grades II to III was more frequent in the low-dose group (47.6%) than in the control group (22.7%), the increase in acute GVHD did not significantly contribute to morbidity or mortality. There were no differences between the groups in the incidence and severity of chronic GVHD. The probabilities of relapse and survival of the groups were similar according to the risk for relapse at the time of transplantation. A prospective randomized study is required to determine whether low-dose or standard-dose CSP in combination with MTX is optimal for Japanese patients who undergo allogeneic BMT from HLA-identical siblings.

Myeloablative allogeneic hematopoietic stem cell transplantation for non-Hodgkin lymphoma: a nationwide survey in Japan.

We retrospectively surveyed the data of 233 patients who underwent myeloablative allogeneic hematopoietic stem cell transplantation (allo-HSCT) for non-Hodgkin lymphoma (NHL). Donors were HLA-matched relatives in 154 patients (66%) or unrelated volunteers in 60 (26%). Ninety patients (39%) were in complete remission. One hundred ninety-three (83%) received a total body irradiation (TBI)-based regimen, and 40 (17%) received a non-TBI-based regimen. Acute graft-versus-host disease (GVHD) occurred in 155 (67%) of the 233 evaluable patients; grade II to IV in 90 (39%), and grade III to IV in 37 (16%). Treatment-related mortality (TRM) was observed in 98 patients (42%), and 68% of them were related to GVHD. In a multivariate analysis, chemoresistance, prior autograft, and chronic GVHD were identified as adverse prognostic factors for TRM. Relapse or progression of lymphoma was observed in 21%. The 2-year overall survival rates of the patients with indolent (n = 38), aggressive (n = 111), and lymphoblastic lymphoma (n = 84) were 57%, 42%, and 41%, respectively. In a multivariate analysis, chemoresistance, prior autograft, and prior radiotherapy were identified as adverse prognostic factors for overall survival. Although myeloablative allo-HSCT represents an effective therapeutic option for patients with NHL, more work is still needed to decrease TRM and relapse.

Effect of conditioning regimen on the outcome of bone marrow transplantation from an unrelated donor.

Little information is available regarding the effect of the conditioning regimen on the outcome of bone marrow transplantation (BMT) from an unrelated donor. Therefore, we retrospectively compared the outcome after a cyclophosphamide/total body irradiation (Cy-TBI) regimen, an intensified Cy-TBI regimen (Cy-TBI+), a busulfan and cyclophosphamide (Bu-Cy) regimen, and a Bu-Cy regimen with total lymphoid irradiation (Bu-Cy-TLI). Clinical data of 1875 adult patients who underwent unmanipulated unrelated BMT for leukemia or myelodysplastic syndrome by using 1 of the 4 regimens between 1993 and 2002 were extracted from the database of the Japan Marrow Donor Program. The effect of the conditioning regimen was adjusted for other independent significant factors by multivariate analyses. The Cy-TBI regimen was significantly better than the Bu-Cy regimen with regard to the incidence of engraftment failure (odds ratio, 2.49; P = .046) and overall survival (relative risk [RR], 1.31; P = .050). The Bu-Cy-TLI regimen decreased relapse (RR, 0.13; P = .039) but increased nonrelapse mortality (RR, 1.89; P = .0061). The Cy-TBI+ regimen resulted in increased nonrelapse mortality (RR, 1.48; P = .0003) and inferior survival (RR, 1.45; P < .0001). The results of this retrospective study suggested that the Cy-TBI regimen was superior to other regimens in unrelated BMT.