HLA-matched Sibling Bone Marrow Transplantation Research Articles

Choice of conditioning regimens for bone marrow transplantation in severe aplastic anemia

AbstractAllogeneic bone marrow transplantation (BMT) is curative therapy for the treatment of patients with severe aplastic anemia (SAA). However, several conditioning regimens can be used for BMT. We evaluated transplant conditioning regimens for BMT in SAA after HLA-matched sibling and unrelated donor BMT. For recipients of HLA-matched sibling donor transplantation (n = 955), fludarabine (Flu)/cyclophosphamide (Cy)/antithymocyte globulin (ATG) or Cy/ATG led to the best survival. The 5-year probabilities of survival with Flu/Cy/ATG, Cy/ATG, Cy ± Flu, and busulfan/Cy were 91%, 91%, 80%, and 84%, respectively (P = .001). For recipients of 8/8 and 7/8 HLA allele-matched unrelated donor transplantation (n = 409), there were no differences in survival between regimens. The 5-year probabilities of survival with Cy/ATG/total body irradiation 200 cGy, Flu/Cy/ATG/total body irradiation 200 cGy, Flu/Cy/ATG, and Cy/ATG were 77%, 80%, 75%, and 72%, respectively (P = .61). Rabbit-derived ATG compared with equine-derived ATG was associated with a lower risk of grade II to IV acute graft-versus-host disease (GVHD) (hazard ratio [HR], 0.39; P < .001) but not chronic GVHD. Independent of conditioning regimen, survival was lower in patients aged >30 years after HLA-matched sibling (HR, 2.74; P < .001) or unrelated donor (HR, 1.98; P = .001) transplantation. These data support Flu/Cy/ATG and Cy/ATG as optimal regimens for HLA-matched sibling BMT. Although survival after an unrelated donor BMT did not differ between regimens, use of rabbit-derived ATG may be preferred because of lower risks of acute GVHD.

Comparison of graft-versus-host disease-free, relapse-free survival according to a variety of graft sources: antithymocyte globulin and single cord blood provide favorable outcomes in some subgroups.

Graft-versus-host disease-free relapse-free survival, which is defined as the absence of grade III-IV acute graft-versus-host disease, systemically treated chronic graft-versus-host disease, relapse, and death, is a novel, meaningful composite end point for clinical trials. To characterize risk factors and differences in graft-versus-host disease-free relapse-free survival according to a variety of graft sources, we analyzed 23,302 patients with hematologic malignancy that had a first allogeneic transplantation from 2000 through 2013 using the Japanese national transplant registry database. The 1-year graft-versus-host disease-free relapse-free survival rate was 41% in all patients. The rate was higher after bone marrow transplantation than after peripheral blood stem cell transplantation due to the lower risks of III-IV acute and chronic graft-versus-host disease. The rate was highest after HLA-matched sibling bone marrow transplantation. The rate after single cord blood transplantation was comparable to that after HLA-matched unrelated bone marrow transplantation among patients aged 20 years or under, and was comparable or better than other alternative graft sources among patients aged 21 years or over, due to the low risk of chronic graft-versus-host disease. Other factors associated with better graft-versus-host disease-free relapse-free survival include female patients, antithymocyte globulin prophylaxis (for standard-risk disease), recent years of transplantation, sex combinations other than from a female donor to a male patient, the absence of prior autologous transplantation, myeloablative conditioning, negative cytomegalovirus serostatus, and tacrolimus-based prophylaxis. These results provide important information to guide the choice of graft sources and are benchmarks for future graft-versus-host disease prophylaxis studies.

Optimal Outcomes in Young Class 3 Patients With Thalassemia Undergoing HLA-Identical Sibling Bone Marrow Transplantation.

Bone marrow transplantation (BMT) for class 3 patients with thalassemia is challenging due to high rates of graft rejection and transplant-related mortality. Since the first studies of BMT in the late 1980s, a number of conditioning regimens have been designed to improve outcomes, but with suboptimal results. Here we report the outcome of transplantation in class 3 patients using a modified protocol. Sixty-three patients between 5 and 16.7 years of age with class 3 thalassemia received HLA-matched sibling BMT following either the original protocol (26 patients) or the modified protocol (37 patients). Both regimens comprised preconditioning cytoreduction with hydroxyurea and azathioprine starting at -45 days pretransplant, and fludarabine from days -16 to -12. Conditioning was performed with busulfan and cyclophosphamide (original protocol) or with busulfan, thiotepa, and cyclophosphamide (modified protocol). The 2 groups showed similar patient demographics. At day 0, the degree of cytoreduction (lymphopenia, neuthropenia, and thrombocytopenia) achieved by the modified protocol was greater than the original protocol. The incidence of graft failure/rejection was significantly higher in the original group (15%; 95% confidence interval [95% CI], 5-32%) compared with the modified group (0%) (P = 0.014). The respective 5-year thalassemia-free survival rates were 73% (95% CI, 51-86%) and 92% (95% CI, 77-97%) (P = 0.047). Both groups showed similar incidences of grades II to IV acute graft-versus host disease. Modified protocol did not increase nonhematological toxicity or infectious complications. The modified treatment protocol effectively and safely prevented graft failure/rejection and significantly increased thalassemia-free survival of class 3 patients with thalassemia.

Graft-versus-Host Disease after HLA-Matched Sibling Bone Marrow or Peripheral Blood Stem Cell Transplantation: Comparison of North American Caucasian and Japanese Populations

The risk of acute graft-versus-host disease (GVHD) after HLA-matched sibling bone marrow transplantation (BMT) is lower in Japanese than in Caucasian patients. However, race may have differential effect on GVHD dependent on the graft source. North American Caucasian and Japanese patients receiving their first allogeneic BMT or peripheral blood stem cell transplantation from an HLA-matched sibling for leukemia were eligible. BMT was performed in 13% of the Caucasian patients and in 53% of the Japanese patients. On multivariate analysis, the interaction term between race and graft source was not significant in any of the models, indicating that graft source does not affect the impact of race on outcomes. The risk of grade III or IV acute GVHD was significantly lower in the Japanese patients compared with the Caucasian patients (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.57 to 0.96), which resulted in lower risk of nonrelapse mortality in the Japanese patients (HR, 0.69; 95% CI, 0.54 to 0.89). The risk of relapse was also lower in this group. The lower risks of nonrelapse mortality and relapse resulted in lower overall mortality rates among the Japanese patients. In conclusion, our data indicate that irrespective of graft source, the risk of severe acute GVHD is lower in Japanese patients, resulting in a lower risk of nonrelapse mortality.

Graft-versus-Host Disease after HLA-Matched Sibling Bone Marrow or Peripheral Blood Stem Cell Transplantation: Comparison of North American Caucasian and Japanese Populations

Graft-versus-Host Disease after HLA-Matched Sibling Bone Marrow or Peripheral Blood Stem Cell Transplantation: Comparison of North American Caucasian and Japanese Populations

Impact of Race on Graft-Versus-Host Disease Rates after HLA-Matched Sibling Bone Marrow or Peripheral Blood Hematopoietic Cell Transplantation: Comparison of North American Caucasian Versus Japanese Populations

s / Biol Blood Marrow Transplant 21 (2015) S30eS53 S35 grade 3-4 aGVHD post PBSC alloHCT was 14% and 10% in the Caucasians and Japanese, respectively (Figure 1B). In multivariate analysis, the interaction term between race and graft source was not significant in any of the models, indicating that the impact of race on outcomes does not differ according to graft source. The risk of grade 3-4 aGVHD was significantly lower in Japanese compared to Caucasians (HR 0.74, 95% CI 0.57-0.96), which resulted in lower risk of non-relapse mortality (NRM) in Japanese compared to Caucasian patients (HR 0.69, 95% CI 0.54-0.89). The risk of relapse was also lower in Japanese compared to Caucasian patients (HR 0.75, 95% CI 0.63-0.89). Lower risk of NRM and relapse resulted in lower overall mortality rates in Japanese compared to Caucasians (HR 0.70, 95% CI 0.59-0.83). The risk of grade 3-4 aGVHD was significantly higher in PBSC compared to BM alloHCT recipients (HR 1.63, 95% CI 1.202.20), which resulted in higher NRM (HR 1.31, 95% CI 1.041.65) in PBSC compared to BM alloHCT recipients. Conclusions: Irrespective of graft source, the risk of severe aGVHDwas lower in Japanese patients, which resulted in the lower risk of NRM. The risk of severe aGVHD was higher in the PBSC alloHCT recipients, which resulted in the higher risk of NRM.

Autoimmunity due to RAG deficiency and estimated disease incidence in RAG1/2 mutations

Autoimmunity due to RAG deficiency and estimated disease incidence in RAG1/2 mutations

HLA-Matched Sibling Transplantation for Severe Aplastic Anemia: Impact of HLA DR15 Antigen Status on Engraftment, Graft-versus-Host Disease, and Overall Survival

The HLA class II DRB1 antigen DR15 (common alleles *1501, *1502) is an important marker in the pathobiology of severe aplastic anemia (SAA). We studied 1204 recipients of HLA-matched sibling bone marrow transplantation for SAA to determine whether HLA DR15 status (as determined by allele-level typing) affected hematopoietic recovery, graft-versus-host disease (GVHD), or overall survival (OS). In multivariate analysis, secondary graft failure rate at 2 years was lower in patients who were HLA DR15+ (hazard ratio = 0.46, P = .01). However, neutrophil recovery at day -28, platelet recovery at day -100, acute GVHD, chronic GVHD, and overall mortality were independent of DR15 status. The 5-year probabilities of OS, after adjusting for age, race, performance score, transplant-conditioning regimen, and year of transplantation, were 78% and 81% for patients who were HLA DR15+ and HLA DR15-, respectively (P = .35). In conclusion, DR15 status is associated with secondary graft failure after HLA-matched sibling bone marrow transplantation for SAA but has no significant impact on survival.

HLA-matched sibling bone marrow transplantation for β-thalassemia major

AbstractWe describe outcomes after human leukocyte antigen-matched sibling bone marrow transplantation (BMT) for 179 patients with β-thalassemia major. The median age at transplantation was 7 years and the median follow-up was 6 years. The distribution of Pesaro risk class I, II, and III categories was 2%, 42%, and 36%, respectively. The day 30 cumulative incidence of neutrophil recovery and day 100 platelet recovery were 90% and 86%, respectively. Seventeen patients had graft failure, which was fatal in 11. Six of 9 patients with graft failure are alive after a second transplantation. The day 100 probability of acute graft-versus-host disease and 5-year probability of chronic graft-versus-host disease was 38% and 13%, respectively. The 5-year probabilities of overall- and disease-free survival were 91% and 88%, respectively, for patients with Pesaro risk class II, and 64% and 62%, respectively, for Pesaro risk class III. In multivariate analysis, mortality risks were higher in patients 7 years of age and older and those with hepatomegaly before BMT. The leading causes of death were interstitial pneumonitis (n = 7), hemorrhage (n = 8), and veno-occlusive disease (n = 6). Proceeding to BMT in children younger than 7 years before development of end-organ damage, particularly in the liver, should improve results after BMT for β-thalassemia major.

Bone Marrow Transplantation From HLA-Identical Sibling for Thalassemia.

Abstract 3361Poster Board III-249Allogeneic bone marrow transplantation (BMT) is curative treatment for β-Thalassemia major. The most extensive patient series have been reported by transplant teams in Italy. Outside these large groups, smaller, more limited series have reported variable results. Here we report the current experience of BMT for thalassemia outside Italy, and describe the characteristics and transplant outcomes in children after HLA-identical sibling BMT for thalassemia. Patients aged ≤20 years at BMT who received a myeloablative HLA-matched sibling BMT for thalassemia between 1995 and 2001 at 19 centers were eligible for the survey (n=179). Recipients of mobilized peripheral blood or umbilical cord blood stem cells, and reduced intensity transplant preparation were excluded as there were too few patients in each category for analysis. Also excluded were patients previously reported by the Italian centers. The median age at BMT was 7 years and the median follow-up of survivors was 6 years. Most recipients had high-risk features at BMT. The distribution of Lucarelli risk class I, II and III categories was 2%, 42%; and 36%, respectively. Data required to assign a risk category was not available for 20% of the study population. Before BMT, 85% had received ≥ 20 red blood cell transfusions. Of 87% who had a pre-BMT liver biopsy, 59% had portal fibrosis. There was hepatomegaly in 52% of patients and 94% had inadequate iron chelation therapy. All patients received busulfan and cyclophosphamide with or without anti-thymocyte globulin as the transplant conditioning regimen and almost all received cyclosporine-containing GVHD prophylaxis. The overall survival (OS) probabilities at 100 days and at 5 years were 85% and 80%, respectively. Seventeen patients (9.5%) had graft failure that was fatal in 11 cases. Six of 9 patients with graft failure survive after a successful second transplantation. Thirty-five patients (20%) died after BMT and the leading cause of death was interstitial pneumonitis in the current analysis. The probability of acute GVHD (grade II-IV) was 38% and the 5-year probability of chronic GVHD was 13%. Veno-occlusive disease (VOD) occurred frequently after BMT (n=58; 32% of patients) and 21 of the 35 (57%) patients who died after BMT had had a history VOD. A multivariate analysis showed that age at BMT ≥10 years (RR 2.16, 95% CI 1.1 – 4.23, p=0.025) and baseline hepatomegaly (RR 5.57, 95% CI 2.14 – 14.49, p<0.001) were associated with higher risk of mortality. The probabilities of disease-free survival (DFS) and OS are shown in the Table below. Younger patients without hepatomegaly fared the best and, older patients with hepatomegaly, the worst. This series confirms reports from large single center series that the results after HLA-matched sibling BMT for thalassemia major are optimized when performed in young children before the development of risk-factors for poor outcome. Pulmonary and hepatic complications were the leading cause of death in high-risk patients.5-year OS5-year DFSAge < 10 years without hepatomegaly96%93%Age < 10 years with hepatomegaly73%69%Age ≥ 10 years without hepatomegaly86%81%Age ≥ 10 years with hepatomegaly53%53% Disclosures:No relevant conflicts of interest to declare.

Risk Factors for Graft Failure and Mortality after HLA-Matched Sibling Donor Transplant for Severe Aplastic Anemia in Brazil.

Higher rates of graft failure observed after conventional cyclophosphamide (Cy) at 200mg/kg and HLA-matched sibling bone marrow transplant (BMT) for severe aplastic anemia (SAA) in South America prompted the use of a different conditioning regimen: busulfan (Bu) at 12 mg/kg plus Cy at 120 mg/kg. This change was instituted to provide greater immunosuppression for heavily transfused patients (>15 blood transfusion units pre-BMT). We report transplant outcomes in 269 SAA patients who received their HLA-matched BMT at a single center in Brazil between 1990 and 2003. Median age at transplant was 19 years (range 2 – 45). Median time from diagnosis to transplant was 3 months; 78% were transplanted ≤ 6 months from diagnosis, 11%, 7–24 months and 11% > 24 months. 128 patients received Cy alone, 2, Cy plus anti-thymocyte globulin and 139, Bu plus Cy. Eighty-one patients (62%) who received Cy conditioning also received ≤15 blood transfusion units and 49 (38%) received >15 blood transfusion units pre- BMT; all patients who received Bu plus Cy conditioning received >15 blood transfusion units. All patients received T-cell replete bone marrow grafts and almost all patients received cyclosporine and short course methotrexate for graft-versus-host disease prophylaxis. Median follow-up of surviving patients after Cy is 9 years and after Bu plus Cy, 6 years. This reflects the change in practice after 1994, when Bu plus Cy was favored for patients who received >15 blood transfusion units pre-BMT. Most patients achieved neutrophil recovery; the day-60 probabilities of recovery were 95% and 86% after Cy conditioning (≤15 and >15 blood transfusion units, respectively) and 92% after Bu plus Cy. Corresponding day-100 probabilities of platelet recovery were 95%, 86% and 87%. Thirty-nine patients subsequently lost their graft; failure rates were similar after Bu plus Cy and Cy conditioning in patients who received ≤15 blood transfusion units (13% vs. 17%; RR 0.97, p=0.924). Though failure rates were higher (10 of 42, 24%) after Cy conditioning in patients who received >15 blood transfusion units this did not attain statistical significance when compared to those who received Bu plus Cy (16 of 128, 13%, p=0.077). This may be explained by limited numbers of patients in the heavily transfused Cy group. Younger age (≤10 years) was the only factor that was associated with higher rates of secondary graft failure (RR 2.91, p=0.001). As expected, the 8-year probability of overall survival was highest (87%) after Cy conditioning in patients who received ≤15 blood transfusion units. Mortality rates were higher after Bu plus Cy conditioning (RR 3.18, p<0.001) and Cy conditioning in patients who received > 15 blood transfusion units (RR 4.66, p<0.001). The corresponding 8-year probabilities of overall survival were 67% and 51% (p=0.059). The data suggest secondary graft failure rates are similar after Bu plus Cy conditioning in patients who received >15 blood transfusion units compared to those who received Cy conditioning and fewer transfusions. Though survival rates are generally lower in patients who receive >15 blood transfusion units, the use of Bu plus Cy appears to confer a survival advantage. Patients with SAA should be referred for transplantation as soon as the diagnosis is confirmed to avoid excess blood transfusion pre-BMT.

Elevated lactate dehydrogenase is an adverse predictor of outcome in HLA-matched sibling bone marrow transplant for acute myelogenous leukemia

Prognostic factors for survival following allogeneic BMT for AML include age, disease status and cytogenetic risk classification. Lactate dehydrogenase (LDH) levels have not been studied as a potential risk factor. We reviewed our experience with BMT for AML and included LDH at the time of admission in an analysis of prognostic factors for survival. We found that LDH >330 U/l (1.5 times the upper limit of normal at our institution), older age, active disease, peripheral stem cell graft and male-to-male transplant were significant adverse predictors of survival. After accounting for LDH, other factors such as disease status and cytogenetics were not significantly associated with the outcome of BMT. All but one patient with an LDH >330 U/l had active disease. However, when patients in CR were excluded, LDH >330 U/l remained a significant adverse predictor of overall survival (hazard ratio 2.70, 95% confidence interval 1.41-5.16, P=0.003). We conclude that LDH is an important adverse risk factor for survival and should be included in future studies of risk performed on larger patient cohorts.

60: A high lactate dehydrogenase (LDH) level predicts for shorter survival following HLA-matched sibling bone marrow transplant (BMT) for patients with acute myelogenous leukemia (AML)

Historically, the most important adverse risk factors for survival after BMT for AML are Active disease (ActDis), poor-risk cytogenetics, and older age. High serum LDH at the time of diagnosis is an adverse risk factor for survival for AML in the absence of BMT, but has not been explored as a risk factor in setting of BMT. We performed a multivariable analysis of these and other potential risk factors for overall and progression-free survival. From August 1992 to July 2005, we treated 87 patients with AML, who also had informative cytogenetic studies from the time of diagnosis, with high-dose busulfan-containing preparative regimens and an HLA-matched sibling BMT.

Lactate Dehydrogenase (LDH) Level Predicts the Outcome of Patients with Acute Myelogenous Leukemia (AML) Following HLA-Matched Sibling Bone Marrow Transplant (BMT).

Active disease (ActDis), poor-risk cytogenetics, and older age have historically been considered the most important adverse risk factors for survival after BMT for AML. We performed a multivariable analysis of these and other potential risk factors for overall and progression-free survival. From August 1992 to July 2005, we treated 87 patients with AML, who also had informative cytogenetic studies, with high-dose busulfan-containing preparative regimens and an HLA-matched sibling BMT. The median age was 43 years (range 19 to 62). The median LDH level at the time of BMT was 204 U/L (range 93–1555 U/L; normal 100–220 U/L). Forty-one patients were in either first (n= 30) or second complete remission (n=11; CR). 46 patients with ActDis were treated. The 87 patients were then classified according to the SWOG/ECOG (Blood 96:4075, 2000), MRC (Blood 92:2322, 1998), and CALGB (Blood 100:4325, 2002) cytogenetic classification systems. With a median follow-up of 56.0 months (range 4.5–107.8 months), the median relapse-free survival is 13.5 months for patients in CR1 and 4.1 months for patients in CR2. The relapse-free survival of patients with ActDis was 5.5 months. A Cox proportional hazards analysis that included gender, age, LDH, disease status, cytogenetic risk group, preparative regimen, source of stem cells, and CMV status was performed for overall and relapse-free survival. Significant risk factors for shorter survival in univariate analysis included male gender, LDH >330 U/L (but not LDH >220 U/L or per 100 U/L increase), and peripheral stem cells as a source of hematopoietic reconstitution (n = 7). Surprisingly, a male donor to a male recipient was also an adverse risk factor (p<0.001). However, in multivariable analysis, only LDH >330 U/L (p=0.002), source of stem cells (p=0.019), and male donor to male recipient (p<0.001) remained as significant adverse risk factors. In fact, patients with ActDis and an LDH ≤ 330 U/L had similar survival to patients treated in remission, while patients with ActDis and LDH > 330 U/L had significantly worse survival as shown below. We conclude that high LDH (>1.5X upper limit of normal) is a significant adverse risk factor for survival after BMT for AML and predicts outcome better than more traditional risk factors such as age, disease status, and cytogenetic risk profile. [Display omitted]

Cytogenetic Classification Systems and Overall Survival Following Bone Marrow Transplant (BMT) for Acute Myelogenous Leukemia (AML).

Risk-adapted therapy for AML in first complete remission generally calls for allogeneic BMT for patients with poor risk cytogenetics. However, poor risk cytogenetics is defined differently in commonly-applied classification schemes. We hypothesized that differences in cytogenetic classification might result in differences in survival after BMT. From September 1991 to December 2003, we treated 47 patients with AML in first complete remission with high-dose busulfan-containing preparative regimens and an HLA-matched sibling BMT. The median age was 42 years (range 18 to 60). At the time of diagnosis, 35 patients had either a normal karyotype or at least one clonal abnormality. Cytogenetic analysis was unavailable for the other 12 patients. The 47 patients were then classified according to the SWOG/ECOG (Blood 96:4075, 2000), MRC (Blood 92:2322, 1998), or CALGB (Blood 100:4325, 2002) cytogenetic classification systems and analyzed for overall survival. With a median follow-up of 4.9 years, 3 year overall survival for various cytogenetic risk groups are displayed in the table:SWOG/ECOGCALGBMRCIntermediate risk69%63%74%Poor risk43%42%18%Unknown risk45%52%45%Concordance indices were 0.58 for CALGB, 0.60 for SWOG, and 0.66 for MRC, demonstrating a slight superiority of the MRC system. Consistent with reports of large, prospective randomized trials of BMT for AML in first remission, patients with poor risk cytogenetics have worse overall survival compared to patients with intermediate risk cytogenetics. Overall survival appears to be different for patients classified as poor risk by MRC criteria. Larger, prospective studies are needed to confirm this observation, but our results suggest that standardized, international cytogenetic risk criteria are needed to develop risk-adapted strategies for the treatment of AML.

Use of infliximab/daclizumab combination for the treatment of acute and chronic graft versus host disease of the liver and gut

We report the use of Infliximab/Daclizumab combination for the treatment of acute and chronic graft versus host disease (GVHD) of the liver and gut in two children who failed standard GVHD therapy. Infliximab was given at a dose of 10 mg/kg weekly × 4 and Daclizumab 1 mg/kg days 1, 4, 8, 15, 22. Patient #1 (Pt) developed grade 2 chronic GVHD of the liver a year after his third allogeneic HLA-matched sibling bone marrow transplant (BMT) for relapsed juvenile myelomonocytic leukemia. Despite immunosuppressive therapy with FK506, mycophenolate mofetil and prednisone 2 mg/kg/dose, liver enzymes failed to normalize. Within 1 week of initiation of therapy with Infliximab/Daclizumab, liver enzymes and bilirubin normalized. Pt #2 developed acute GVHD of the liver and gut grade 3 day +37 after allogeneic-HLA matched sibling BMT for Philadelphia positive acute lymphoblastic leukemia. Pt did not show clinical response despite the addition of prednisone 2 mg/kg/dose to his immunosuppressive regimen. Resolution of acute GVHD was observed within two weeks of initiation of Infliximab/Daclizumab. Both patients tolerated the regimen well with no toxicities and were off immunosuppression 8 and 11 months respectively from the initiation of therapy for GVHD. We conclude that the combination of Infliximab/Daclizumab seems to be effective in the treatment of acute and chronic GVHD of the liver and gut. Future prospective studies in a larger cohort of patients are needed to confirm this observation.

ALLORESPONSES IN TOLERANT RECIPIENTS OF COMBINED KIDNEY/BONE MARROW TRANSPLANTATION WITH NON-MYELOABLATIVE CONDITIONING

P931 Introduction: We analyzed in vitro responses in 6 patients who received combined non-myeloablative HLA-matched sibling bone marrow (BM) and kidney transplantation (Tx) for the treatment of multiple myeloma (MM) with renal failure. Patients 3 - 6 were participants in an Immune Tolerance Network study. Methods: Mixed lymphocyte reaction (MLR), cell-mediated lymphocytotoxicity (CML), and limiting dilution assays (LDA) were performed. Donor chimerism was monitored by microsatellite analysis. T cell recovery was followed by flow cytometry. Results: In Patient 1, initial multilineage mixed chimerism declined to undetectable levels after Day 105. CyA was discontinued on Day 73 and the transplanted kidney has shown no evidence of rejection > 5.5 years. Early CD8 T cell recovery and strong anti-donor cytotoxic T lymphocyte (CTL) responses were seen in CML and LDA, without anti-donor MLR responses. The myeloma is in complete remission (CR) > 5.5 years. In Patient 2, initial mixed chimerism became undetectable after Day 123. CyA was discontinued on Day 77 and the kidney has shown no rejection > 3 years. Early recovery of anti-3rd party responses but not anti-donor responses were seen in MLR and CTL and helper T lymphocyte (HTL) LDA. Urinary light chain was reduced by 90% after Tx, but the myeloma later progressed. In Patient 3, multilineage mixed chimerism converted to donor full chimerism by Day 62. MMF was added to control mild chronic GvHD and CyA was discontinued on Day 379. The patient showed transient anti-donor responses in MLR and CTL-LDA prior to conversion to donor full chimerism, and high anti-host CTLp frequencies following conversion to donor full chimerism. The kidney has shown no rejection. The patient is in CR > 30 months. In Patient 4, initial mixed chimerism declined to undetectable levels by Day 71. CyA was discontinued on Day 60. The kidney has shown no rejection > 21 months. Early recovery of anti-3rd party responses but not anti-donor responses were seen in MLR and CTL and HTL-LDA. Urinary light chain persisted post-Tx. In Patient 5, multilineage mixed chimerism converted to donor full chimerism by Day 90. CyA was discontinued on Day 35. The patient showed transient anti-donor responses in HTL and CTL-LDA prior to conversion to donor full chimerism, and high anti-host CTLp frequencies following conversion to donor full chimerism. The kidney has shown no rejection. In Patient 6, initial mixed chimerism was observed, but became undetectable by Day 98. CyA was discontinued on Day 60. The kidney has shown no rejection > 3 months. No anti-donor responses were seen in MLR and CTL and HTL-LDA, but a high anti-host HTLp frequency was seen on POD70. Conclusions: Combined kidney/BMTx with non-myeloablative conditioning for MM patients is a promising strategy for successful induction of renal allograft tolerance and also provides potent anti-myeloma effects. Donor marrow rejection and anti-donor alloresponses can appear in patients despite maintenance of tolerance to donor kidneys.

Polymorphisms of transforming growth factor-beta1 and transforming growth factor-beta1 type II receptor genes are associated with acute graft-versus-host disease in children with HLA-matched sibling bone marrow transplantation.

The aim of this study was to determine whether the gene polymorphisms of Th1/Th2 and immunoregulatory cytokines were associated with aGVHD in Japanese children receiving allogeneic bone marrow transplantation (allo BMT). We investigated polymorphisms of genes encoding interleukin (IL)-4, IL-4 receptor (IL-4 R), IL-10, transforming growth factor (TGF)-beta1, TGF-beta1 type II receptor (TGF-beta1 RII), interferon (IFN)-gamma, IFN-gamma type 2 receptor (IFN-gamma R2), and IFN regulatory factor (IRF)-1. Sixty-seven patients were treated with allo BMT from HLA-identical siblings, and aGVHD was observed in 38. TGF-beta1 codon 10 leucine (Leu) /proline (Pro) polymorphism in donors was associated with the development of aGVHD. Patients having donors with the Pro allele had aGVHD more frequently than those without Pro allele (30/45 vs 8/20, odds ratio = 3.00; P = 0.04). TGF-beta1 RII 1167 C/T polymorphism in recipients was also associated with the development of aGVHD. The incidence was significantly higher in recipients with T allele than in those without T allele (21/27 vs 16/35, odds ratio = 4.16; P = 0.01). In conclusion, genetic backgrounds of TGF-beta1 and TGF-beta1 RII may be involved in the development of aGVHD in HLA-matched sibling BMT in Japanese children.

Prospective Trial of Chemotherapy and Donor Leukocyte Infusions for Relapse of Advanced Myeloid Malignancies After Allogeneic Stem-Cell Transplantation

Patients with advanced myeloid malignancies who experience relapse after allogeneic bone marrow transplantation (BMT) have a poor prognosis. Long-term survival after chemotherapy alone, second myeloablative transplant, or donor leukocyte infusions (DLIs) alone is unusual. DLIs may have minimal effectiveness in advanced disease because adequate cellular responses are not able to develop in the presence of bulky, fast-growing disease. A chemotherapy strategy was used to debulk disease before administration of granulocyte colony-stimulating factor (G-CSF)-primed DLIs. Sixty-five patients experiencing hematologic relapse of myeloid malignancy after HLA-matched sibling BMT were prospectively treated with cytarabine-based chemotherapy, then G-CSF-primed DLIs. No prophylactic immunosuppression was provided. Twenty-seven of 57 assessable patients experienced a complete response. Graft-versus-host disease (GVHD) was observed in 56% of the patients. Treatment-related mortality was 23%. Overall survival at 2 years for the entire cohort was 19%. Patients with a complete response were more likely to survive, with 1- and 2-year survival rates of 51% and 41%, respectively, with a median follow-up of more than 2 years. The 1-year survival for nonresponders was 5%. A posttransplant remission lasting more than 6 months before relapse was associated with a higher likelihood of response. GVHD was not required for durable remission. Salvage treatment with chemotherapy before DLI can help some patients with advanced myeloid relapse and is not dependent on GVHD. Patients with short remissions after BMT are unlikely to benefit from this approach, and the approach is associated with significant treatment-related mortality. Modifications of this approach or entirely different approaches will be required for most patients with this difficult clinical problem.

Prospective Trial of Chemotherapy and Donor Leukocyte Infusions for Relapse of Advanced Myeloid Malignancies After Allogeneic Stem-Cell Transplantation

PURPOSE: Patients with advanced myeloid malignancies who experience relapse after allogeneic bone marrow transplantation (BMT) have a poor prognosis. Long-term survival after chemotherapy alone, second myeloablative transplant, or donor leukocyte infusions (DLIs) alone is unusual. DLIs may have minimal effectiveness in advanced disease because adequate cellular responses are not able to develop in the presence of bulky, fast-growing disease. A chemotherapy strategy was used to debulk disease before administration of granulocyte colony-stimulating factor (G-CSF)–primed DLIs. PATIENTS AND METHODS: Sixty-five patients experiencing hematologic relapse of myeloid malignancy after HLA-matched sibling BMT were prospectively treated with cytarabine-based chemotherapy, then G-CSF–primed DLIs. No prophylactic immunosuppression was provided. RESULTS: Twenty-seven of 57 assessable patients experienced a complete response. Graft-versus-host disease (GVHD) was observed in 56% of the patients. Treatment-related mortalit...