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A retrospective analysis of 25 patients with a history of prostate cancer (PC) who subsequently underwent allogeneic hematopoietic cell transplantation (HCT) for treatment of a hematologic malignancy was performed. Median patient age was 66.7 years. Median duration from the diagnosis of PC to HCT was 4.2 years. Twenty-three patients had Gleason group 1 or 2 disease. Therapy included prostatectomy (n = 13) and external beam or brachytherapy (n = 9). Hematologic diagnoses included both myeloid (n = 15) and lymphoid neoplasms (n = 10). Twenty-four patients received either a nonmyeloablative or reduced intensity conditioning regimen. GVHD prophylaxis included a calcineurin inhibitor and mycophenolate mofetil ± sirolimus. Twenty patients had HLA-matched sibling or HLA-matched unrelated donors; five patients had HLA-mismatched donors. Eleven patients are alive, and 14 have died. Median survival was 2.5 years (range, .02-12.6 years). The major cause of death was hematologic relapse. Only one patient had evidence of recurrent PC, occurring 1.5 years posttransplant. In carefully selected patients with a prior history of PC, there was no evidence of rapid recurrence of the solid tumor (ST) after HCT. PC patients who are in remission from their ST or have control of their disease on therapy should be considered eligible for HCT.

To compare the outcome of allogeneic stem cell transplantation for myeloid malignancies in breast cancer survivors to a contemporaneous control group.Medical records of all patients with a history of breast cancer who received allogeneic stem cell transplants at a single, tertiary referral Comprehensive Cancer Center between 2002 and 2019 were reviewed. Transplant outcomes were compared to 289 control patients without a history of breast cancer from the same time period. Main outcomes included survival, disease-free survival, non-relapse mortality, relapse or progression of hematologic malignancy, and incidence of recurrent breast cancer after hematopoietic cell transplantation. Comparisons between women with a history of breast cancer and controls utilized propensity score weighting to balance patient characteristics.Forty women, ages 30-74 years, with a history of breast cancer received an allogeneic hematopoietic cell transplant for a hematologic malignancy between December 2002 and February 2019. Twelve of the 40 patients are alive with a median survival of 7.4 years (range, 1.9-16.8 years). None of the patients had evidence of recurrent breast cancer prior to death or date of last contact. In multivariable Cox models, all transplant outcomes were similar between the patients and the control group with hematopoietic cell transplant comorbidity score as the most important confounding factor for adjustment in these models.A history of treated breast cancer should not exclude patients from consideration for allogeneic hematopoietic cell transplantation.

This retrospective analysis of 2503 adult (age ≥20 years) allogeneic hematopoietic cell transplantation (HCT) recipients assessed the effect of body mass index (BMI) on transplantation outcomes. The median patient age was 51.7years. Patients with both nonmalignant and malignant diagnoses were included. Patients received either a myeloablative (52%) or a reduced-intensity (48%) conditioning regimen. Donors were either related (42%) or unrelated (58%). Cord blood recipients were excluded. Granulocyte colony-stimulating factor-mobilized peripheral blood cells were the stem cell source in 86% of transplantations. Graft-versus-host disease prophylaxis included at least 2 immunosuppressive agents, 1 of which was a calcineurin inhibitor. Patient groups were categorized as underweight, normal weight, overweight, obese, or very obese based on BMI. Endpoints included day +100 mortality, overall mortality, nonrelapse mortality (NRM), and relapse. Changes in nutritional status, based on laboratory parameters, were also examined. Underweight patients had significantly lower early and overall survival and greater NRM. Very obese patients had increased NRM, which was associated with the intensity of conditioning regimen. With long-term follow-up, increasing NRM was associated with both underweight and obese patients compared with normal-weight individuals. Changes in serum protein and albumin levels did not correlate with BMI. Although enteral nutrition is now recommended for some undernourished patients, the efficacy of enteral or parenteral nutrition has not been well studied. For obese patients, there are no guidelines regarding weight loss before transplantation, and acute weight loss in the pretransplantation period may be detrimental.

Central nervous system (CNS) relapse after allogeneic hematopoietic stem cell transplantation (HSCT) confers a poor prognosis in adult patients with acute lymphoblastic leukemia (ALL). Preventing CNS relapse after HSCT remains a therapeutic challenge, and criteria for post-HSCT CNS prophylaxis have not been addressed. In a 3-center retrospective analysis, we reviewed the data for 457 adult patients with ALL who received a first allogeneic HSCT in first or second complete remission (CR). All patients received CNS prophylaxis as part of their upfront therapy for ALL, but post-transplantation CNS prophylaxis practice varied by institution and was administered to 48% of the patients. Eighteen patients (4%) developed CNS relapse after HSCT (isolated CNS relapse, n = 8; combined bone marrow and CNS relapse, n = 10). Patients with a previous history of CNS involvement with leukemia had a significantly higher rate for CNS relapse (P = .002), and pretransplantation CNS involvement was the only risk factor for post-transplantation CNS relapse found in this study. We failed to find a significant effect of post-transplantation CNS prophylaxis to prevent relapse after transplantation. Furthermore, no benefit for post-transplantation CNS prophylaxis could be detected when a subgroup analysis of patients with (P = .10) and without previous CNS involvement (P = .52) was performed. Finally, we could not find any significant effect for intensity of the transplantation conditioning regimen on CNS relapse after HSCT. In conclusion, CNS relapse is an uncommon event after HSCT for patients with ALL in CR1 or CR2, but with higher risk among patients with CNS involvement before transplantation. Furthermore, neither the use of post-HSCT CNS prophylaxis nor the intensity of the HSCT conditioning regimen made a significant difference in the rate of post-HSCT CNS relapse.

The majority of patients in need of a hematopoietic-cell transplant do not have a matched related donor. Data are needed to inform the choice among various alternative donor-cell sources.In this retrospective analysis, we compared outcomes in 582 consecutive patients with acute leukemia or the myelodysplastic syndrome who received a first myeloablative hematopoietic-cell transplant from an unrelated cord-blood donor (140 patients), an HLA-matched unrelated donor (344), or an HLA-mismatched unrelated donor (98).The relative risks of death and relapse between the cord-blood group and the two other unrelated-donor groups appeared to vary according to the presence of minimal residual disease status before transplantation. Among patients with minimal residual disease, the risk of death was higher in the HLA-mismatched group than in the cord-blood group (hazard ratio, 2.92; 95% confidence interval [CI], 1.52 to 5.63; P=0.001); the risk was also higher in the HLA-matched group than in the cord-blood group but not significantly so (hazard ratio, 1.69; 95% CI, 0.94 to 3.02; P=0.08). Among patients without minimal residual disease, the hazard ratios were lower (hazard ratio in the HLA-mismatched group, 1.36; 95% CI, 0.76 to 2.46; P=0.30; hazard ratio in the HLA-matched group, 0.78; 95% CI, 0.48 to 1.28; P=0.33). The risk of relapse among patients with minimal residual disease was significantly higher in the two unrelated-donor groups than in the cord-blood group (hazard ratio in the HLA-mismatched group, 3.01; 95% CI, 1.22 to 7.38; P=0.02; hazard ratio in the HLA-matched group, 2.92; 95% CI, 1.34 to 6.35; P=0.007). Among patients without minimal residual disease, the magnitude of these associations was lower (hazard ratio in the HLA-mismatched group, 1.28; 95% CI, 0.51 to 3.25; P=0.60; hazard ratio in the HLA-matched group, 1.30; 95% CI, 0.65 to 2.58; P=0.46).Our data suggest that among patients with pretransplantation minimal residual disease, the probability of overall survival after receipt of a transplant from a cord-blood donor was at least as favorable as that after receipt of a transplant from an HLA-matched unrelated donor and was significantly higher than the probability after receipt of a transplant from an HLA-mismatched unrelated donor. Furthermore, the probability of relapse was lower in the cord-blood group than in either of the other groups.

Comparisons without hematopoietic cell transplantation (HCT) to myeloablative (MAC) or reduced-intensity HCT (RIC) for adults with acute lymphoblastic leukemia (ALL) in first minimal-residual-disease negative remission (MRD(Neg) CR1) are limited. Further, the importance of MRD(Neg) following salvage therapy (MRD(Neg) CR2+) is unknown. We evaluated 89 patients in MRD(Neg) CR1 after adult-inspired treatment: 33 received MAC (12 Philadelphia chromosome [Ph]+), 17 received RIC (13 Ph+), and 39 Deferred HCT (3 Ph+). Three-year overall survival (OS) estimates for MAC, RIC, and Deferred HCT were 71%, 69%, and 68%, while 3-year event-free survival (EFS) estimates were 65%, 54%, and 28%, respectively. Further, HCT in MRD(Neg) CR1 performed similarly to MRD(Neg) CR2+: 3-year OS estimates were 70% and 69%, and 3-year EFS estimates were 62% and 62%, respectively. In conclusion, adults with ALL in MRD(Neg) CR1 following adult-inspired therapy had similar OS with or without HCT, and HCT in MRD(Neg) CR2 + can yield long-term survival.

A retrospective analysis identified 161 consecutive adults with acute lymphoblastic leukemia who underwent allogeneic hematopoietic cell transplantation (HCT) with full-intensity (myeloablative) conditioning between 1998 and 2006. Median patient age was 36.1 years. Seventy-six patients were in first complete remission (CR1), and 85 were in second or greater CR or in relapse. Fifty-nine patients had Philadelphia chromosome–positive acute lymphoblastic leukemia. A total of 159 patients received chemotherapy plus total body irradiation for conditioning. Graft-versus-host disease prophylaxis included a calcineurin inhibitor plus methotrexate or mycophenolate mofetil. Sixty of the donors were related, and 101 were unrelated. A total of 110 patients received granulocyte-colony stimulating factor–stimulated peripheral blood, 47 received bone marrow, and 4 received cord blood as the stem cell source. Fifty-five patients relapsed at a median of 231 days after transplantation. The estimated 5-year probabilities of relapse-free survival, relapse, and nonrelapse mortality were 47%, 30%, and 29%, respectively. By multivariate analyses, transplantation while in CR1 was the most important predictor of successful transplantation. Pretransplantation evidence of minimal residual disease, especially as detected by flow cytometric analysis, was associated with both lower overall survival and lower relapse-free survival. Compared with a similar cohort of patients undergoing transplantation between 1990 and 1997, overall survival was similar for patients undergoing transplantation in CR1, with lower nonrelapse mortality being offset by higher rates of relapse in patients who underwent transplantation more recently.

Hematopoietic cell transplantation (HCT) offers potentially curative therapy for chronic myelomonocytic leukemia (CMML). We evaluated HCT outcomes in 85 patients with CMML, 1.0-69.1 (median 51.7) years of age, with follow-up extending to 19 years. CMML was considered de novo in 71 and secondary in 14 patients. Conditioning regimens were of various intensities. Thirty-eight patients had related (34 HLA identical), and 47 (39 HLA matched) unrelated donors. The source of stem cells was marrow in 32 and peripheral blood progenitor cells in 53 patients. Acute graft-versus-host disease (aGVHD) grades II-IV occurred in 72% and chronic GVHD (cGVHD) in 26% of patients. Relapse incidence was 27% at 10 years. Relapse correlated with increasing scores by the MD Anderson prognostic score (P = .01). The major causes of death were relapse and infections ±GVHD. Progression-free survival (PFS) was 38% at 10 years. Mortality was negatively correlated with pre-HCT hematocrit (P = .007), and increased with high-risk cytogenetics (P = .02), higher HCT Comorbidity Index (P = .0008), and increased age (P = .02). WHO classification did not statistically significantly affect outcome. Thus, a proportion of patients with CMML have lasting remissions following allogeneic HCT and appear to be cured of their disease.

In this prospective study 60 patients of median age 46 (range: 5-60 years), with acute myelogenous leukemia (AML; n = 44), acute lymphoblastic leukemia (ALL; n = 3), or myelodysplastic syndrome (MDS; n = 13) were conditioned for allogeneic hematopoietic cell transplantation with a treosulfan/fludarabine (Flu) combination. Most patients were considered at high risk for relapse or nonrelapse mortality (NRM). Patients received intravenous treosulfan, 12 g/m(2)/day (n = 5) or 14 g/m(2)/day (n = 55) on days -6 to -4, and Flu (30 mg/m(2)/day) on days -6 to -2, followed by infusion of marrow (n = 7) or peripheral blood stem cells (n = 53) from HLA-identical siblings (n = 30) or unrelated donors (n = 30). All patients engrafted. NRM was 5% at day 100, and 8% at 2 years. With a median follow-up of 22 months, the 2-year relapse-free survival (RFS) for all patients was 58% and 88% for patients without high-risk cytogenetics. The 2-year cumulative incidence of relapse was 33% (15% for patients with MDS, 34% for AML in first remission, 50% for AML or ALL beyond first remission and 63% for AML in refractory relapse). Thus, a treosulfan/Flu regimen was well tolerated and yielded encouraging survival and disease control with minimal NRM. Further trials are warranted to compare treosulfan/Flu to other widely used regimens, and to study the impact of using this regimen in more narrowly defined groups of patients.

We hypothesized that initial treatment of acute graft-versus-host disease (GVHD) with low-dose glucocorticoids (prednisone-equivalent dose of 1 mg/kg per day) instead of standard-dose glucocorticoids (prednisone-equivalent dose of 2 mg/kg per day) does not compromise major transplantation outcomes. We retrospectively analyzed outcomes among 733 patients who received transplants between 2000 and 2005 according to initial treatment with low-dose (n = 347) versus standard-dose (n = 386) systemic glucocorticoids. The mean cumulative prednisone-equivalent doses at day 100 after starting treatment were 44 and 87 mg/kg for patients given low-dose and standard-dose glucocorticoids, respectively. Adjusted outcomes between the groups given low-dose versus standard-dose glucocorticoids were not statistically significantly different: overall mortality (hazard ratio [HR], 1.10; 95% confidence interval [CI], 0.9-1.4), relapse (HR, 1.22; 95% CI, 0.9-1.7), nonrelapse mortality (HR, 1.06; 95% CI, 0.8-1.5). The small number of patients with grades III/IV acute GVHD at onset precluded definitive conclusions for this subgroup. In multivariate analysis, the risks of invasive fungal infections (HR, 0.59; 95% CI, 0.3-1.0) and the duration of hospitalization (odds ratio, 0.62; 95% CI, 0.4-0.9) were reduced in the low-dose prednisone group. We conclude that initial treatment with low-dose glucocorticoids for patients with grades I-II GVHD did not compromise disease control or mortality and was associated with decreased toxicity.

Lineage-specific chimerism studies are commonly obtained at several time points after nonmyeloablative hematopoietic cell transplantation to assess the tempo and degree of engraftment, and to monitor graft rejection. For patients who receive myeloablative transplants, the value of frequent chimerism analyses using sensitive molecular techniques is less certain. In this study, a retrospective analysis was performed to assess the transplant outcome of 89 adult patients with ALL who had chimerism studies of unfractionated BM cells or peripheral blood subsets performed approximately 80 days after transplantation. These patients received unmanipulated, myeloablative transplants using either HLA-identical or HLA-mismatched, related or unrelated donor stem cells. Incomplete donor engraftment was present only in the CD3+ peripheral blood T cells in a small percentage of patients. There was no correlation of mixed chimerism with transplant outcome. Routine 'day 80' chimerism studies in this group of patients who receive intensive, myeloablative conditioning regimens are not recommended.

We identified 19 persons with B-cell chronic lymphocytic leukemia (CLL) who received genetically identical twin blood cell or bone marrow transplants after high-dose conditioning. Ten are alive (eight disease-free) with a median follow-up of 89 months (range, 31-171 months); 5-year relapse rate was 50% (95% confidence interval (CI), 26-73%). Estimated 5-year survival and disease-free survival were 61% (95% CI, 37-82%) and 45% (95% CI, 23-68%). In two of four patients tested at 12 and 21 months by polymerase chain reaction no evidence of residual CLL was detected post-transplant. In one recipient who relapsed at 6 years, molecular studies showed a different CLL clone from that detected pretransplant. This clone was subsequently identified in the donor suggesting transfer of occult leukemia at the time of transplant. Genetically identical twin transplants can result in long-term disease-free survival and molecular remissions, these data suggest the potential for CLL control in the absence of allogeneic graft-versus-leukemia effect. The case of leukemia transfer indicates the need for careful evaluation of donors prior to graft collection.

A total of 104 patients, aged 18 to 70 years, with a diagnosis of chronic idiopathic myelofibrosis (CIMF), polycythemia vera (PV), or essential thrombocythemia (ET) with marrow fibrosis were transplanted from allogeneic (56 related and 45 unrelated) or syngeneic (n = 3) donors. Busulfan (BU) or total body irradiation (TBI)-based myeloablative conditioning regimens were used in 95 patients, and a nonmyeloablative regimen of fludarabine plus TBI was used in 9 patients. The source of stem cells was bone marrow in 43 patients and peripheral blood in 61 patients. A total of 63 patients were alive at a follow-up of 1.3–15.2 years (median, 5.3 years), for an estimated 7-year actuarial survival rate of 61%. Eleven patients had recurrent/persistent disease, of whom 8 died. Nonrelapse mortality was 34% at 5 years. Patients conditioned with targeted BU (plasma levels 800–900 ng/mL) plus cyclophosphamide (tBUCY) had a higher probability of survival (68%) than other patients. Dupriez score, platelet count, patient age, and comorbidity score were statistically significantly associated with mortality in univariate models. In a multivariable regression model, use of tBUCY (P = .03), high platelet count at transplantation (P = .01 for PV/ET; P = .39 for other diagnoses), younger patient age (P = .04), and decreased comorbidity score (P = .03) remained statistically significant for improved survival. Our findings show that hematopoietic cell transplantation offers potentially curative treatment for patients with ICMF, PV, or ET.

Fifty-six patients, 10 to 66 years of age, with idiopathic myelofibrosis (IMF) or end-stage polycythemia vera or essential thrombocythemia received allogeneic hematopoietic cell transplants from related (n = 36) or unrelated (n = 20) donors. Forty-four patients were prepared with busulfan plus cyclophosphamide and 12 with total body irradiation plus chemotherapy. The source of stem cells was marrow in 33 and peripheral blood in 23 patients. All but 3 patients achieved engraftment. While 50 patients showed complete donor chimerism, 3 patients were found to be mixed chimeras at 26, 48, and 86 months after transplantation, respectively. Two patients died from relapse/progressive disease, and 18 died from other causes. There are 36 patients surviving at 0.5 to 11.6 (median, 2.8) years, for a 3-year Kaplan-Meier estimate of 58% (CI, 43%-73%). Dupriez score, cytogenetic abnormalities, and degree of marrow fibrosis were the most significant risk factors for posttransplantation mortality. Patients conditioned with a regimen of busulfan targeted to plasma levels of 800 to 900 ng/mL plus cyclophosphamide had a higher probability of survival (76% [CI, 62%-91%]) than other patients. Results with unrelated donors were comparable with those with HLA-identical sibling transplants. Thus, allogeneic hematopoietic cell transplantation offers long-term relapse-free survival for patients with myelofibrosis.

Psoralen plus ultraviolet A irradiation (PUVA) has immunomodulatory effects and is used to treat a variety of immune-mediated dermatologic diseases. We administered PUVA to 103 patients for treatment of steroid-resistant acute graft-versus-host disease (GVHD) of the skin. Twenty-nine patients had related donors (12 HLA-mismatched) and 74 had unrelated donors (23 HLA-mismatched). The median onset of GVHD was day 13 after transplantation, and the median onset of PUVA treatment was day 46. PUVA was administered as secondary therapy for 86 patients and tertiary therapy or greater for 17 patients. The median number of treatments was 16, and the mean cumulative exposure was 41 J/cm2. PUVA was generally well tolerated with 8 patients discontinuing therapy because of toxicity. At the start of PUVA treatment, 48 patients had rash affecting >50% of their body surface area (BSA), and 91 had rash involving >25% BSA. Of 65 patients who were evaluated after 6 weeks of PUVA treatment, 11 still had rash involving >50% BSA, 24 had rash involving >25% BSA, and 24 had no rash. The mean daily dose of prednisone at the start of PUVA therapy was 1.6 mg/kg compared to 0.7 mg/kg after 6 weeks of therapy. Fifty-nine patients (57%) did not require additional therapy for skin GVHD after starting PUVA. Ninety-two percent of patients developed chronic GVHD. Fifty-three patients (51%) remain alive at 129-1883 days after transplantation. These results suggest that PUVA can be an effective therapy for steroid-resistant acute GVHD of the skin. Biol Blood Marrow Transplant 2002;8(4):206-12.

Acute lymphoblastic leukemia (ALL) is the most common indication for transplantation of marrow from unrelated donors in children. We analyzed results of this procedure in children with ALL treated according to a standard protocol to determine risk factors for outcome. From January 1987 to 1999, 88 consecutively seen patients with ALL who were younger than 18 years received a marrow transplant from an HLA-matched (n = 56) or partly matched (n = 32) unrelated donor during first complete remission (CR1; n = 10), second remission (CR2; n = 34), third remission (CR3; n = 10), or relapse (n = 34). Patients received cyclophosphamide and fractionated total-body irradiation as conditioning treatment and were given methotrexate and cyclosporine for graft-versus-host disease (GVHD) prophylaxis. Three-year rates of leukemia-free survival (LFS) according to phase of disease were 70% for CR1, 46% for CR2, 20% for CR3, and 9% for relapse (P

Background. In a pilot trial we evaluated the toxicity and efficacy of sirolimus (rapamycin) as second-line therapy for the treatment of acute graft-versus-host disease (GVHD) in 21 patients (1-46 years of age) after allogeneic hematopoietic stem cell transplantation (HSCT). Methods. All patients were treated with methylprednisolone at 2 mg/kg/day, but failed to respond satisfactorily. Sirolimus was started 19-78 (median 37) days after HSCT when 10 patients had grade III and 11 had grade IV GVHD. The first four patients received a loading dose (15 mg/m 2 ) of oral sirolimus on day 1 followed by 5 mg/m 2 /day for 13 days. The next 17 patients received either 5 (n=7) or 4 (n=10) mg/m 2 /day for 14 days without a loading dose. Eleven patients completed the 14-day sirolimus course. Five patients were treated for 9-13 days, two for 6 days, and three for 1-3 days. Results. Sirolimus was discontinued early in 10 patients because of lack of improvement in GVHD (n=5), myelosuppression (n=2), seizure (n=2), and attending physician preference (n=1). The most common and significant adverse events were thrombocytopenia (n=7) and neutropenia (n=4). Other side effects included increased blood triglycerides (n=8) and cholesterol (n=3). Five patients had evidence of a hemolytic uremic syndrome concurrently with or after sirolimus treatment. Eighteen of the 21 patients received 6 or more doses of sirolimus and 12 responded, 5 with complete and 7 with partial responses. Six of the 12 responders (28% of all patients enrolled) and 1 nonresponder are currently alive at 400-907 days after HSCT, 3 with chronic GVHD. Fourteen of the 21 patients (66%) died 40-263 days after transplant. Conclusion. These data suggest that sirolimus has activity in the treatment of steroid-refractory acute GVHD. However, there was considerable toxicity and further dose optimization studies seem warranted.

Patients with a lymphohematopoietic malignancy considered to be at high risk for posttransplant relapse were enrolled in a study to compare the use of cyclosporine (CSP) as a single agent with a combination of methylprednisolone (MP) and CSP for graft-versus-host disease (GVHD) prophylaxis after marrow transplantation from an HLA-identical sibling donor. Sixty patients were randomized to receive CSP only and 62 were randomized to receive CSP plus MP. Daily CSP was started on day −1 (5 mg/kg/d intravenously) and administered at gradually reduced doses until day 180. MP was started on day 7 at 0.5 mg/kg/d, increased to 1.0 mg/kg/d on day 15, started on a taper schedule on day 29, and discontinued on day 72. All 104 evaluable patients (surviving ≥28 days) had sustained engraftment. The incidence rates of grades II-IV acute GVHD were 73% and 60% for patients receiving CSP and CSP plus MP, respectively (P = .01). No difference was seen for grades III-IV GVHD. However, chronic GVHD occurred somewhat more frequently in patients receiving CSP plus MP (44%) than in patients receiving only CSP (21%; P = .02). The incidence of de novo chronic GVHD was marginally higher in patients receiving CSP plus MP (P = .08). No significant differences in the risk of infections were observed. There was a suggestion that the risk of relapse was lower in patients receiving CSP plus MP (P = .10) and, although the overall survival in the two groups was not different (P = .44), there was a slight advantage in favor of CSP plus MP-treated patients for relapse-free survival (P = .07). These results suggest that prophylactic MP, when combined with CSP, has only limited efficacy in acute GVHD prevention and may increase the probability of chronic GVHD.

Nine patients with Fanconi anaemia (FA) were conditioned for HLA-identical sibling bone marrow transplant (BMT) with reduced dose of cyclophosphamide (Cy) without radiation or antithymocyte globulin (ATG). The total dose of Cy was 140 mg/kg (n=2) or 120 mg/kg (n=7). The median patient age was 8 years (range 4–19). Graft-versus-host disease (GVHD) prophylaxis was with methotrexate and cyclosporine (n=8) or cyclosporine alone (n=1). All patients had sustained engraftment and two developed grade ≥II acute GVHD. Cy toxicity included grade ≥2 mucositis seen in all evaluable patients and haemorrhagic cystitis in two patients. The Kaplan-Meier survival estimate is 89% with a median follow-up of 285 d (range 56–528). For the purpose of comparison, this report also reviews and updates long-term follow-up data on 32 previously reported FA patients conditioned with 140–200 mg Cy/kg without radiation. The lowest dose of Cy (without radiation or ATG) after which HLA-identical sibling marrow transplant can be successfully performed in FA patients has yet to be determined, but it appears that uniform and sustained engraftment can be achieved with a Cy dose of as low as 120 mg/kg.

This report updates the results of marrow transplantation at the Fred Hutchinson Cancer Research Center for patients with severe aplastic anemia whose donors were HLA-nonidentical relatives. Between 1970 and 1993, 40 patients received transplants for severe aplastic anemia from related donors other than HLA genotypically matched siblings. Nine patients (group 1) were conditioned with cyclophosphamide (Cy) at 50 mg/kg for 4 doses and received marrow from phenotypically HLA-matched relatives. With the exception of one accidental death, all patients are alive and disease free 3-18 years after transplantation. Thirty-one patients received marrow from HLA-mismatched relatives who differed by one or more loci. Fifteen of these patients (group 2) received Cy at 50 mg/kg for 4 doses without total body irradiation (TBI) and none survived. Because of failure to sustain engraftment in 9 of 14 evaluable patients in group 2, the regimen for HLA-mismatched patients was changed in 1984 to include Cy at 60 mg/kg for 2 doses and TBI was added at 1200 cGy to increase immunosuppression (group 3). Sixteen patients in group 3 received marrow grafts after failure to respond to immunosuppressive therapy. Eight of the 16 patients in group 3 remain alive without disease between 1.5 and 11.3 years after transplantation. In conclusion, transplants from phenotypically HLA-identical related donors can be carried after Cy alone and results are comparable to those observed with genotypically HLA-identical siblings. Transplants from related donors mismatched for one or more HLA loci require a more intensive conditioning regimen, for example, one containing TBI, to achieve sustained engraftment.

From 1990 to 1993 we performed a prospective study of busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg) in 30 patients with refractory anemia (RA) undergoing related (n = 17) or unrelated (n = 13) donor marrow transplantation. Nineteen patients survive disease free (63% 3-year actuarial disease-free survival [DFS]) and no patient relapsed. These results were compared to those of 38 historical controls with RA treated with cyclophosphamide and total body irradiation, of whom 22 are disease-free survivors and 1 relapsed. After correcting for significant variables between the two treatment groups, we found no statistically significant difference in outcome based on preparative regimen. Combining data from these 68 patients plus 2 additional patients with RA treated before 1993 with busulfan and cyclophosphamide, we identified four variables independently associated with improved survival: younger age, shorter disease duration, lower neutrophil count pretransplant, and lower hematocrit pretransplant. We also found that 15 patients 40 to 55 years of age had a 46% 3-year actuarial DFS and 26 patients receiving unrelated or mismatched related donor marrow had a 50% 3-year actuarial DFS. We conclude that there does not appear to be any significant difference in outcome based on preparative regimen in this patient population. In addition, allogeneic bone marrow transplantation may be a reasonable approach to therapy of RA early after diagnosis. However, whether early intervention with transplantation prolongs survival over that expected without transplantation cannot be ascertained with certainty from available data.

The purpose of this investigation was to define the maximum tolerated dose (MTD) of unshielded total body irradiation (TBI) delivered from dual {sup 60}C sources at an exposure rate of 0.08 Gy/min and given in thrice daily fractions of 1.2 Gy in patients with advanced lymphoid malignancies. Forty-four patients with a median age of 28 (range 6-48) years were entered into a Phase I/II study. All patients received cyclophosphamide (Cy), 120 mg/kg administered over 2 days before TBI. Marrow from human leukocyte antigen (HLA) identical siblings was infused following the last dose of TBI. An escalation-deescalation schema designed to not exceed an incidence of 25% of Grade 3-4 regimen-related toxicities (RRTs) was used. The first dose level tested was 13.2 Gy followed by 14.4 Gy. None of the four patients at the dose level of 13.2 Gy developed Grade 3-4 RRT. Two of the first eight patients receiving 14.4 Gy developed Grade 3-4 RRT, establishing this as the MTD. An additional 32 patients were evaluated at the 14.4 Gy level to confirm these initial observations. Of 40 patients receiving 14.4 Gy, 13 (32.5%) developed Grade 3-4 RRTs; 46% in adults and 12% in children. The primary dose limiting toxicity wasmore » Grade 3-4 hepatic toxicity, which occurred in 12.5% of patients. Noninfectious Grade 3-4 interstitial pneumonia syndrome occurred in 5% of patients. The actuarial probabilities of event-free survival, relapse, and nonrelapse mortality at 2 years were 0.10, 0.81, and 0.47, respectively, for patients who received 14.4 Gy of TBI. The outcome for patients receiving 14.4 Gy of TBI was not different from previous studies of other CY and TBI regimens in patients with advanced lymphoid malignancies. These data showed that the incidence of Grade 3-4 RRTs in adults was greater than the 25% maximum set as the goal of this study, suggesting that 13.2 Gy is a more appropriate dose of TBI for adults, while 14.4 Gy is an appropriate dose for children. 36 refs., 1 fig., 3 tabs.« less

The pharmacokinetics, safety, and efficacy in marrow transplantation of FK506-based immunosuppression for graft-versus-host disease (GVHD) prophylaxis was evaluated in an open label pilot study of 18 patients. Patients more than 12 years of age (median, 35 years; range, 15 to 50 years) with advanced hematologic malignancies receiving HLA-matched sibling marrow grafts were randomized to receive FK506 alone, FK506 and methotrexate (MTX), or FK506 and methyl-prednisolone. Of 17 evaluable patients, all had evidence of sustained marrow engraftment. The median time to an absolute neutrophil count of greater than 500/microL was 15 days for patients receiving FK506 alone or FK506 plus methylprednisolone and 23 days for FK506 plus short MTX. Pharmacokinetic studies did not show any significant difference in clearance of FK506 when administered alone or in combination with methylprednisolone or MTX. The mean bioavailability after oral administration in these same three groups was 0.49 +/- 0.1, 0.27 +/- 0.12, and 0.16 +/- 0.08, respectively (P = .003). The decrease in bioavailability may have resulted from an exacerbation of radiation-induced gastroenteritis by MTX. The most significant adverse effect associated with the administration of FK506 was nephrotoxicity, which occurred in 14 of 18 patients (78%). The mean glomerular filtration rate, determined by clearance of (99MTc)DTPA, decreased to 56% (+/- 18%) of the pretransplant baseline level by week 8 (P = .002). Eight of 18 patients (44%) developed grades II-IV acute GVHD, predominantly of the skin and gastrointestinal tract. The actuarial probability of transplant-related mortality during the first 100 days was 24%. The actuarial probability of 1-year disease-free survival was 39%. In conclusion, although bioavailability of FK506 may be affected in patients receiving MTX, this study suggests that FK506 may have a role in the management of patients after allogeneic marrow transplantation.

A prospective randomized study was conducted comparing two conditioning regimens for the treatment of patients with chronic myeloid leukemia in chronic phase by marrow transplantation from HLA identical siblings. Sixty-nine patients received 60 mg/kg of cyclophosphamide on each of 2 successive days followed by 6 fractions of total body irradiation each of 2.0 Gy (CY-TBI), and 73 patients received 16 mg/kg of busulfan delivered over 4 days followed by 60 mg/kg CY on each of 2 successive days (BU-CY). There was no significant difference between the CY-TBI and the BU-CY groups in the 3-year probabilities of survival (0.80 for both), relapse (0.13 for both), or event-free survival (CY-TBI, 0.68; BU-CY, 0.71) or in speed of engraftment or incidence of venocclusive disease of the liver. The 4-year probabilities of survival and event- free survival for patients transplanted within 1 year of diagnosis were 0.86 and 0.72, respectively, for each group. Significantly more patients in the CY-TBI group experienced major creatinine elevations. There was significantly more acute graft-versus-host disease in the CY- TBI group. Fever days, positive blood cultures, hospitalizations, and inpatient hospital days were significantly more common in the CY-TBI group than in the BU-CY group. In conclusion, the BU-CY regimen was better tolerated than, and associated with survival and relapse probabilities that compare favorably with, the CY-TBI regimen.

Humanized anti-Tac is a genetically engineered human IgG1 monoclonal antibody specific for Tac, the alpha subunit of the interleukin-2 (IL- 2) receptor, and blocks IL-2-dependent activation of human T lymphocytes. The safety, pharmacokinetics, and immunosuppressive activity of humanized anti-Tac were evaluated in 20 patients who developed acute graft-versus-host disease (GVHD) after allogeneic marrow transplantation. Patients had developed acute GVHD at 5 to 26 (median, 14) days after transplantation and had failed to respond to primary therapy with glucocorticoids. Sequential groups of 4 patients each received a single 1-hour infusion of antibody in escalating doses of 0.5, 1.0, or 1.5 mg/kg; 8 additional patients were then treated with 1.5 mg/kg. A second infusion of antibody was administered after 11 to 48 (median, 16) days in 8 patients who had transient improvement of GVHD after the first infusion. Acute side effects, limited to chills in 1 patient and diaphoresis in another, were observed during or shortly after the antibody infusion. Overall improvement of acute GVHD occurred in 8 patients, 6 of whom were treated with a single antibody infusion and 2 with two infusions. Four responses were complete and 4 were partial. Three additional patients had improvement in one organ but progression in another. Responses occurred in 9 of 16 cases with skin disease, 3 of 15 with liver disease, and 6 of 12 with gastrointestinal disease. Two patients survive at 529 and 645 days after antibody treatment. Two patients died after relapse of leukemia. Sixteen patients died of infection or organ failure between 5 and 211 (median, 55) days. The terminal elimination half-life of the antibody was 44 to 363 hours, with a harmonic mean of 79, 88, and 94 hours, respectively, for the three doses studied. Absolute peripheral blood T-lymphocyte counts remained unchanged during the 56 days after infusion of the antibody. A fraction of circulating T cells expressed the alpha chain of the IL-2 receptor that, in some patients, was bound by antibody in vivo up to 28 days after treatment. No patient developed a measurable antibody response to humanized anti-Tac. Humanized anti-Tac has a long half-life after intravenous injection in humans, superior to any rodent monoclonal antibody specific for human T cells, and does not appear to induce antibody formation in recipients of marrow transplants. Improvement of steroid-refractory GVHD in 40% of patients after only one or two antibody infusions indicates that humanized anti-Tac is immunosuppressive.

Graft rejection has been a problem after marrow grafts for patients with aplastic anemia who were conditioned with cyclophosphamide (CY). Rejection lessened when patients were given the marrow donor“s peripheral blood buffy-coat cells in addition to the marrow, but this result was achieved at the price of more chronic graft-versus-host disease (GVHD). Results with second transplants suggested that CY alternating with antithymocyte globulin (ATG) was more immunosuppressive than CY alone. Therefore, the current study explored CY and ATG without buffy-coat cell transfusions in 39 patients with aplastic anemia given marrow transplants from HLA-identical family members (siblings in 38 cases, father in 1 case). We hoped both to minimize the risks of graft rejection and of chronic GVHD and to improve survival. Patients were 2 to 52 years of age (median, 24.5); 87% had received previous transfusions, and 41% had therapy with immunosuppressive agents before transplant. They were administered four daily doses of CY (total, 200 mg/kg) alternating with three doses of ATG (total, 90 mg/kg) followed by an HLA-identical marrow graft. Methotrexate and cyclosporine were administered to prevent GVHD. Two patients rejected their grafts (5%), and both were successfully retransplanted. Acute (grade 2 or 3) GVHD occurred in 15% and chronic GVHD in 34% of patients. The actuarial survival rate at 3 years was 92%, which compares favorably to the 72% survival rate in 39 historical patients who were matched with current patients for age and risk factors for rejection and GVHD. CY/ATG is a well-tolerated and effective conditioning program for marrow grafting in aplastic anemia that, when combined with GVHD prevention by methotrexate/cyclosporine, results in excellent survival.

High-dose chemoradiotherapy followed by marrow transplantation from an HLA-matched sibling donor is curative for patients with acute leukemia. Autologous marrow transplantation has been used with success for some patients without such a sibling. Alternatively, the option of performing a transplant from an HLA-matched unrelated donor has been made possible by the recent development of large registries of HLA- typed volunteers. The purpose of this study was to compare the outcomes for patients with advanced leukemia treated by unrelated or autologous marrow transplantation. Forty-three patients with acute myeloid or lymphoid leukemia were transplanted from a closely HLA-matched unrelated donor. Results were compared with those of a disease-, disease-stage-, and age-matched cohort of 77 patients treated with autologous marrow transplantation at the same institution during the same period. Myeloid reconstitution with peripheral granulocyte counts greater than 10(9)/L was achieved in 93% of unrelated recipients and 70% of autologous recipients at a median of 24 and 36 days after transplantation, respectively (P = .0001). The cumulative proportions of patients discharged alive (79% v 77%) and times from transplant to first hospital discharge (35 v 34 days) were not different between unrelated and autologous recipients (P = .65). For patients transplanted in complete remission, relapse occurred after transplantation in 27% of the unrelated and in 55% of the autologous recipients (P = .08). For patients transplanted in relapse, the corresponding posttransplant relapse rates were 48% and 63%, respectively (P = .72). Forty percent of unrelated recipients and 28% of autologous recipients died in remission. Leukemia-free survivals were 33% for unrelated and 25% for autologous recipients transplanted in remission (P = .45), and 12% for unrelated and 5% for autologous recipients transplanted in relapse (P = .75). Unrelated donor transplants appear no less effective than autologous transplants to achieve long-term survival and may be more effective in eradicating leukemia in patients who have failed conventional chemotherapy. Further studies are warranted to assess the relative effectiveness of unrelated and autologous transplantation performed earlier in the course of the disease.

Summary. Four patients with Diamond-Blackfan syndrome (congenital hypoplastic anaemia) whose disease was resistant to corticosteroid treatment and who were red blood cell transfusion-dependent, were given marrow grafts from allogeneic human-leucocyte-antigen (HLA)-identical siblings. The patients were conditioned with regimens including cyclophosphamide and busulfan. Three of four patients had sustained and complete marrow engraftment. One patient showed early signs of haematopoietic recovery but died on day 35 of pulmonary toxicity. The three surviving patients are well with normal haematopoiesis and Karnofsky performance scores of 100%, 3·0, 7·4 and 10·6 years after transplantation. Congenital hypoplastic anaemia can be treated successfully by allogeneic marrow grafts.

PURPOSE This study compares outcomes of autologous bone marrow transplantation (ABMT) in patients with acute myeloid leukemia (AML) in untreated first relapse (REL1) or in second complete remission (REM2). PATIENTS AND METHODS Forty-seven patients with AML in REL1 (n = 21) or in REM2 (n = 26) were treated with busulfan (BU) and cyclophosphamide (CY) with or without total-body irradiation (TBI) followed by ABMT. All REL1 patients and four REM2 patients had marrow stored during first remission (REM1). Twenty-seven had marrow stored with and 20 without treatment in vitro with 4-hydroperoxycyclophosphamide (4-HC). Eighteen patients received BU and CY and 29 received BU, CY, and TBI. REL1 patients relapsed within a median of 9 months (range, 2 to 26) after marrow harvest and were transplanted a median of 30 days (range, 9 to 87) from detection of relapse. RESULTS With a median follow-up of 2.1 years (range, 0.4 to 5.3), 19 patients survive in remission (10 of 21 in REL1; nine of 26 in REM2). The actuarial probabilities of relapse-free survival at 2 years for patients transplanted in REL1 and REM2 were 45% +/- 22% and 32% +/- 18%, respectively (P = .33). The corresponding probabilities of relapse were 30% +/- 26% and 44% +/- 23%, respectively (P = .45). No conclusions could be drawn about the benefits of adding TBI to BU plus CY. There were no significant differences in neutrophil or platelet recovery or in posttransplant probabilities of relapse and nonrelapse mortality between patients who received marrow treated or not treated with 4-HC. CONCLUSION These results suggest that ABMT may produce long-term leukemia-free survival in approximately one third of patients with AML in REL1 or in REM2. There is no apparent clinical advantage in attempting to obtain second remissions in relapsed patients before ABMT if marrow has been cryopreserved during REM1. Although a strategy of transplantation in REL1 has advantages for the patient, such an approach involves the storage of marrow, which may not be used, and is impractical without the coordinated support of the treating physician, the patient, and the marrow transplant center.

Previous studies of risk factors for acute graft-versus-host disease (GVHD) involved patients receiving predominantly single-agent prophylaxis. Therefore, a retrospective analysis was performed on 446 patients, from a single institution, who received transplants of marrow from HLA-identical siblings and the combination of cyclosporine (CSP) and methotrexate (MTX) to determine risk factors for acute GVHD associated with this more effective form of GVHD prophylaxis. The incidences of Grades II-IV and Grades III-IV (severe) acute GVHD were 35% and 16%, respectively. Increased clinical grades of acute GVHD in patients without advanced malignant disease were associated with a decreased survival. In a multivariate Cox regression analysis, risk factors associated with the onset of Grades II-IV acute GVHD were sex mismatch and donor parity (P = .001), increased dose of total body irradiation (TBI) (P = .001), and reduction to less than 80% of the scheduled dose of MTX (P = .02) or CSP (P = .02). The multivariate analysis indicated a relative risk of 1.37 for acute GVHD in a group defined as having advanced malignant disease at transplant; however, this difference failed to reach conventional levels of statistical significance (P = .07). Reduction of MTX and CSP occurred in up to 36% and 44% of patients, respectively, primarily because of renal or hepatic dysfunction. The periods of increased risk for the onset of acute GVHD were up to 1 week after a reduction of MTX and 2 weeks after a reduction in CSP. When only patients who developed Grades II-IV acute GVHD were considered, the more severe acute GVHD of Grades III-IV was associated with increased patient age of 40 years or greater (P = .05) and dose reductions of CSP (P = .008). Serologic status of patient and donor for cytomegalovirus (CMV), HLA antigens in the A and B loci, and isolation in a laminar air flow room during marrow transplantation, all previously identified as risk factors for acute GVHD, were not confirmed as risk factors in this study population. The toxicity of MTX and CSP and the development of acute GVHD from inadequate immunosuppression because of dose reduction warrants further trials with potentially less toxic immunosuppressive agents. Risk factors for acute GVHD should be considered in clinical management and in the design of clinical trials.

Sixty-eight patients with moderate (n = 15) or severe (n = 53) aplastic anemia were entered into a prospective, randomized, two-arm treatment study comparing antihuman thymocyte globulin (ATG), lower-dose methylprednisolone (LDM) and oxymetholone to ATG, higher-dose methylprednisolone (HDM), and oxymetholone. There were no differences between the two groups when comparing age, sex, etiology of aplasia, disease duration, severity of aplasia, or pretherapy granulocyte counts. Side effects of LDM and HDM were similar. Of the 64 patients evaluable for response to therapy, 12 of 33 (36%) who received LDM had complete, partial, or minimal responses compared with 15 of 31 patients (48%) who received HDM (P = .33). Actuarial survival at 4 years is 43% for patients in the LDM group and 47% for patients in the HDM group (P = .99). Causes of death included hemorrhage, infection, evolution to acute leukemia, and complications of subsequent bone marrow transplantation. Long-term complications included paroxysmal nocturnal hemoglobinuria (n = 3), evolution to myelodysplasia or acute leukemia (n = 6), and recurrent aplasia (n = 6). We were unable to show a significant difference in toxicity, response rate, or survival for patients treated with ATG, oxymetholone, and LDM compared with patients who received ATG, oxymetholone, and HDM.

Thirty-six patients with advanced hematologic malignancy were entered into a Phase I study designed to define the maximum tolerated dose of unshielded total body irradiation delivered from dual 60 Cobalt sources at an exposure rate of 8 cGy/min and given in fractions twice daily for total doses ranging from 12 Gy to 17 Gy. All patients received cyclophosphamide, 120 mg/kg administered over 2 days before total body irradiation. Allogeneic marrow was infused from HLA-identical siblings (n = 29) or one locus HLA incompatible family members (n = 3); three patients received cryopreserved autologous marrow and one patient received syngeneic marrow. The maximum tolerated dose of total body irradiation given as 2 Gy fractions twice a day was 16 Gy. One of eight patients receiving 12 Gy, none of four receiving 14 Gy, three of 20 receiving 16 Gy, and two of four receiving 17 Gy developed severe (Grade 3–4) regimen-related toxicity. The primary dose limiting toxicity was pneumonitis, followed by veno-occlusive disease of the liver, renal impairment, and mucositis. Five patients (14%) are alive, four disease-free 798–1522 days posttransplant. Twenty (56%) relapsed posttransplant. Further investigation of regimens containing 16 Gy of hyperfractionated total body irradiation is warranted to assess anti-tumor efficacy.

A randomized trial of 12.0 Gy versus 15.75 Gy of total body irradiation (TBI) was performed in patients with acute myeloid leukemia undergoing allogeneic marrow transplantation while in first complete remission. All patients received 120 mg/kg cyclophosphamide followed by TBI and marrow from HLA-identical siblings. Cyclosporine and methotrexate were used for prophylaxis against acute graft-versus-host disease (GVHD). Thirty-four patients received 2.0-Gy fractions of irradiation daily for 6 days and 37 received 2.25-Gy fractions daily for 7 days. The 3-year actuarial probabilities for relapse-free survival were 0.58 for the patients who received 12.0 Gy and 0.59 for those who received 15.75 Gy. The 3-year probabilities of relapse were 0.35 for the 12.0 Gy group and 0.12 for the 15.75 Gy group (P = .06). The 3-year probabilities of transplant-related mortality were 0.12 and 0.32, respectively (P = .04). The probability of moderate to severe acute GVHD was 0.21 for the 12.0 Gy group and 0.48 for the 15.75 Gy group (P = .02). Patients exposed to the higher irradiation dose received less immunoprophylaxis against, and had a higher incidence of, acute GVHD. The increased dose of TBI significantly reduced the probability of relapse but did not improve survival because of increased mortality from causes other than relapse.

One hundred forty-seven consecutive patients with leukemia, myelodysplastic syndrome, or aplastic anemia were treated by marrow grafts from genotypically HLA-identical siblings (n = 122) or HLA- haploidentical family members (n = 25). Haploidentical recipients differed from their donors for no more than one HLA locus on the nonshared haplotype. All were given postgrafting immunosuppression with a combination of methotrexate and cyclosporine. In a randomized study we explored whether prednisone administered from day 0 through 35 along with methotrexate/cyclosporine could improve prevention of acute graft- versus-host disease (GVHD). The GVHD incidence in patients not given prednisone was comparable with that previously reported with methotrexate/cyclosporine. Unexpectedly, significant increases in acute and also chronic GVHD were seen in HLA-identical recipients administered prednisone, but not in the small number of patients administered HLA-nonidentical grafts. However, the resultant increase in transplant-related mortality in patients administered prednisone was offset by an increase in leukemic relapse in patients not administered prednisone, presumably related to the absence of a graft-versus- leukemia effect. Therefore, overall disease-free survival of the two groups of patients was comparable, with slightly more than 50% of the patients being alive at more than 2 years after transplantation. We speculated that prednisone adversely affected GVHD prophylaxis, interfering with methotrexate's cell cycle-dependent suppression of donor lymphocyte proliferation in response to host antigens. In a pilot study we explored whether beginning prednisone on day 15, after completion of methotrexate administration, would avoid this adverse effect. The GVHD incidence in patients administered methotrexate/cyclosporine along with “late” prednisone was comparable with that in patients not administered prednisone. We conclude that methotrexate/cyclosporine is effective in decreasing the incidence of grade II through IV GVHD, and that the addition of prednisone to this regimen is not beneficial in recipients of HLA-identical marrow grafts.

A murine IgG1 antibody specific for the IL-2-binding site on the human lymphocyte IL-2 receptor beta chain (CD25) was evaluated in 11 patients who developed acute graft-versus-host disease following allogeneic marrow transplantation. All patients had received cyclosporine and methotrexate for prophylaxis of GVHD, either alone (4 cases), or in combination with antithymocyte globulin (4 cases) or with prednisone (3 cases). Patients had developed GVHD at 7-53 days (median 12) after transplantation and had failed treatment with corticosteroids for 3-44 days (median 19). Residual GVHD was of grade II severity in 4 patients, grade III in 5 patients, and grade IV in 2 patients. Sequential patients received monoclonal antibody in escalating doses from 0.1 mg/kg/day to 1.0 mg/kg/day for 7 days. Side effects were fever, respiratory distress, hypertension, hypotension, and chills occurring in 11 of 72 (14%) antibody infusions. Trough antibody levels greater than 6 micrograms/ml were achieved in patients treated with 0.5 or 1.0 mg/kg/day. Four of eight evaluable patients had an IgM antibody response, and one had an IgG response to the murine immunoglobulin. Clinical response of GVHD was evaluated in 10 patients who received the entire course of the antibody treatment. Among 7 patients treated within 40 days from transplantation, one patient had a complete response in the skin as the only involved organ, and 3 patients had a partial response, 2 in the skin and one in the gastrointestinal tract. No responses were achieved with liver disease at anytime or in any organ in patients treated beyond 40 days after transplantation. Since administration of this antibody was well tolerated and some efficacy was observed in patients with acute GVHD treated early after transplantation, there is a rationale for testing this antibody as an agent for prophylaxis of GVHD.

Autoimmune phenomena may be detected in patients with aplastic anemia. In the etiology of aplastic anemia, it is not known whether these processes are primary factors (causative), perpetuating factors (following other causative factors), or merely epiphenomena. Response to immunosuppressive therapy would suggest a causative or perpetuating role for autoimmunity in development of this disease. We have reviewed trials of immunosuppressive therapy, including the use of antilymphocyte globulin, cyclophosphamide, high-dose corticosteroids, cyclosporine, and apheresis, as well as combinations of these agents, for treatment of aplastic anemia. Responses occur in 40-70% of patients who receive various preparations of antilymphocyte globulin. Responses to other immunosuppressive regimens have been less frequent. Responses to all immunosuppressive regimens are usually incomplete, and late complications, such as relapse, paroxymal noctural hemoglobinuria, or leukemia, are being reported with increasing frequency. For all treatments, potential mechanisms of action other than immune suppression are possible. HLA-matched sibling-donor bone marrow transplantation is the treatment of choice for children with severe aplastic anemia. For children without a matched sibling, antilymphocyte globulin is the best current therapy. No treatment has been shown to alter the long-term course of mild aplastic anemia. Other immunosuppressive agents and transplant regimens should be considered experimental. The therapeutic value of these modalities can only be established by well-monitored trials performed at centers with special clinical and laboratory expertise.

To reduce the incidence of graft-versus-host disease (GVHD), we added Thymoglobulin (THY) to dose-adjusted oral busulfan plus cyclophosphamide (targeted BUCY). The starting dose of THY was 4.5 mg/kg given over days −3, −2, and −1, escalated in steps of 1.5 mg/kg in cohorts of 15 evaluable patients. Escalation was dependent on acute GVHD incidence and Epstein-Barr virus reactivation. Fifty-six patients with myelodysplastic syndrome and other myeloid disorders underwent transplantation with peripheral blood progenitor cells from related (n = 30) or unrelated (n = 26) donors. All but 2 patients achieved engraftment, and 56% survived in remission beyond 1 year. The incidence of acute GVHD was 50%, and that of chronic GVHD was 34%. The highest THY dose was 6.0 mg/kg, a dose at which 1 patient experienced Epstein-Barr virus reactivation. Nine patients did not receive the prescribed THY dose. Results were comparable for related and unrelated transplants and for patients given 4.5 or 6.0 mg/kg THY. Among 27 myelodysplastic syndrome patients (14 with related and 13 with unrelated donors) who underwent transplantation concurrently with targeted BUCY without THY, the incidence of acute and chronic GVHD was 82%. Thus, THY 4.5 to 6.0 mg/kg seemed beneficial for GVHD prevention in BUCY-conditioned patients who underwent transplantation with peripheral blood progenitor cells, although relapse-free survival did not differ significantly from that in comparable historical controls not given THY.

A total of 109 patients (aged 6-66 years; median, 46 years) with myelodysplastic syndrome (MDS) were treated with busulfan (BU) targeted to plasma concentrations of 800 to 900 ng/mL plus cyclophosphamide (CY), 2 × 60 mg/kg, and hemopoietic stem cell (HSC) transplantation from related (n = 45) or unrelated donors (n = 64). At the time of transplantation, 69 patients had less than 5% myeloblasts in the marrow, and 40 patients had more advanced disease. All but 2 evaluable patients had engraftment. The Kaplan-Meier estimates of 3-year relapse-free survival (RFS) were 56% for related and 59% for unrelated recipients. The cumulative incidences of relapse were 16% for related and 11% for unrelated recipients. Nonrelapse mortality (NRM) at 100 days (3 years) was 12% (28%) for related and 13% (30%) for unrelated recipients. The only factor significant for RFS was the etiology of MDS (de novo better than treatment related;P = .03). Factors significantly correlated with relapse were advanced French-American-British classification (P = .002) and International Prognostic Scoring System score (P = .009), poor-risk cytogenetics (P = .03), and treatment-related etiology (P = .03). None of the factors examined was statistically significant for NRM. Patient age and donor type had no significant impact on outcome. RFS tended to be superior in patients receiving transplants with peripheral blood rather than marrow stem cells. Thus, a targeted BUCY regimen provided effective transplant conditioning for patients with MDS receiving transplants from HLA-identical siblings or alternative donors. Although there was still considerable nonrelapse morbidity and mortality, the present regimen was used successfully even in patients older than 60 years of age.

Advanced mycosis fungoides (MF) is incurable with conventional treatments. High-dose chemoradiotherapy with autologous bone marrow transplantation has induced remissions in a small number of patients with MF, but this modality is limited by a high relapse rate. We report induction of complete remission in a 37-year-old woman with rapidly progressive stage IV MF with allogeneic stem cell transplantation (Allo SCT). She remains in continuous complete remission 2 years after transplant. Allo SCT for MF is theoretically attractive, because there is no contamination of the graft by malignant cells, and because of the possibility of graft-versus-tumor effect. Although the results in this patient are encouraging, more patients and longer follow-up are needed to define the usefulness of Allo SCT in the treatment of MF.

Between 1980 and 1999, 25 patients with chronic lymphocytic leukemia (CLL) received related donor hematopoietic stem cell transplants. Median patient age was 46.6 years. Preparative regimens included busulfan (BU) plus cyclophosphamide (CY), CY plus TBI, and etoposide, CY plus TBI. Twenty-one donors were HLA-identical siblings, one was a DR mismatched sibling, and three were identical twins. Bone marrow was the source of hematopoietic stem cells in 22 cases and G-CSF stimulated peripheral blood in three cases. Most patients received methotrexate and cyclosporine for GVHD prophylaxis. Fourteen patients developed grades 2-4 acute GVHD and 10 developed clinical extensive chronic GVHD. Late clearance of CLL cells was associated with the development of chronic GVHD in one patient. Two patients had recurrent CLL. Nonrelapse mortality at day 100 was 57% for the seven patients conditioned with BU/CY and 17% for the 18 patients conditioned with TBI-containing regimens. Actuarial survival at 5 years for the 25 patients is 32%. All patients who received BU/CY died within 3 years of transplant. For the 14 patients transplanted since 1992 and who received TBI, actuarial 5-year survival is 56%. The maximum response of CLL to hematopoietic cell transplantation may be delayed, but long-term disease-free survival can be achieved.

Various infectious agents have been implicated in causing aplastic anemia (AA), either by direct lytic infection or by inducing a pathophysiologic host immune response.[1][1] But little attention has been given to cytomegalovirus (CMV), even though the myelosuppressive potential of this virus, in

Patients with a lymphohematopoietic malignancy considered to be at high risk for posttransplant relapse were enrolled in a study to compare the use of cyclosporine (CSP) as a single agent with a combination of methylprednisolone (MP) and CSP for graft-versus-host disease (GVHD) prophylaxis after marrow transplantation from an HLA-identical sibling donor. Sixty patients were randomized to receive CSP only and 62 were randomized to receive CSP plus MP. Daily CSP was started on day −1 (5 mg/kg/d intravenously) and administered at gradually reduced doses until day 180. MP was started on day 7 at 0.5 mg/kg/d, increased to 1.0 mg/kg/d on day 15, started on a taper schedule on day 29, and discontinued on day 72. All 104 evaluable patients (surviving ≥28 days) had sustained engraftment. The incidence rates of grades II-IV acute GVHD were 73% and 60% for patients receiving CSP and CSP plus MP, respectively (P = .01). No difference was seen for grades III-IV GVHD. However, chronic GVHD occurred somewhat more frequently in patients receiving CSP plus MP (44%) than in patients receiving only CSP (21%; P = .02). The incidence of de novo chronic GVHD was marginally higher in patients receiving CSP plus MP (P = .08). No significant differences in the risk of infections were observed. There was a suggestion that the risk of relapse was lower in patients receiving CSP plus MP (P = .10) and, although the overall survival in the two groups was not different (P = .44), there was a slight advantage in favor of CSP plus MP-treated patients for relapse-free survival (P = .07). These results suggest that prophylactic MP, when combined with CSP, has only limited efficacy in acute GVHD prevention and may increase the probability of chronic GVHD.

The influence of busulfan (BU) plasma concentration on outcome of transplantation from HLA identical family members for the treatment of chronic myelogenous leukemia (CML) was examined in 45 patients transplanted in chronic phase (CP) (n = 39) or accelerated phase (AP) (n = 6). All patients received the same regimen of BU, 16 mg/kg orally and cyclophosphamide (CY), 120 mg/kg intravenously. Plasma concentrations of BU at steady state (CSSBU) during the dosing interval were measured for each patient. The mean CSSBU was 917 ng/mL (range, 642 to 1,749; median, 917; standard deviation, 213). Of patients with CSSBU below the median, seven (five of 18 in CP and two of four in AP) developed persistent cytogenetic relapse and three of these patients died. There were no relapses in patients with CSSBU above the median. The difference in the cumulative incidence of relapse between the two groups was statistically significant (P = .0003). CSSBU was the only statistically significant determinant of relapse in univariable or multivariable analysis. The 3-year survival estimates were 0.82 and 0.64 for patients with CSSBU above and below the median (P = .33). There was no statistically significant association of CSSBU with survival or nonrelapse mortality, although the power to detect a difference in survival between 0.82 and 0.64 was only 0.24, similarly CSSBU above the median was not associated with an increased risk of severe regimen-related toxicity. We conclude that low BU plasma levels are associated with an increased risk of relapse.

Introduction Central nervous system (CNS) recurrence after allogeneic hematopoietic stem cell transplantation (HSCT) confers a poor prognosis in adult patients with acute lymphoblastic leukemia (ALL). Preventing CNS recurrence after HSCT remains a therapeutic challenge, and criteria for post-HSCT CNS prophylaxis have not been addressed. Our goal was to investigate the post-HSCT outcome of ALL patients and identify patient groups who may benefit from post-HSCT CNS prophylaxis. Methods In this two-center retrospective study, we studied all adult (age≥18) ALL patients who underwent HSCT at MD Anderson Cancer Center or Fred Hutchinson Cancer Research Center between 1997 and 2011. We included all adult ALL patients who were transplanted in the first or second complete remission (CR) and who received any prophylactic or therapeutic CNS therapy before HSCT. We assessed the cumulative incidence of systemic and CNS relapses in a competing risks framework with a competing risk of non-relapse death. Since data from second and subsequent relapses were not available, patients whose first relapse did not include CNS involvement were censored at the time of relapse. To analyze the association between post-HSCT CNS prophylactic therapy and CNS relapse, we used a landmark analysis, including only patients who had not relapsed or died by 3 months post HSCT. Results We included 415 adult ALL patients (239 in CR1 and 176 in CR2) who were transplanted with a myeloablative total body irradiation based (MA-TBI, n=252), myeloablative non-TBI based (MA-nonTBI, n= 130), or reduced intensity conditioning regimen (RIC, n=33). Median age at HSCT was 37 years (range 18-70; 59% male). Sixty seven patients (16%) had a history of pre-HSCT CNS involvement either at diagnosis or at time of first relapse, while 339 patients (81%) had no CNS disease at any time before HSCT. Overall 175 patients (42%) received CNS prophylaxis after HSCT. CNS prophylaxis included intrathecal methotrexate, cytarabine, or both agents. Two patients received prophylactic cerebrospinal radiotherapy. The median follow-up for the 189 surviving patients was 4.2 years. Sixteen patients (3.8% of all patients, 13.2% of all relapses) developed CNS relapse (11 isolated and 5 combined with marrow relapse) at a median of 231 days (range 38-1397) after HSCT. Seven of these patients had pre-HSCT CNS disease. The 4-year cumulative incidence of relapse after HSCT among all patients was 31.7% and 28.2% for patients with and without CNS prophylaxis after HSCT, respectively (P=0.51). The 4-year cumulative incidence of CNS relapse was 6% and 2.6% for patients with and without CNS prophylaxis after HSCT, respectively (P=0.16) (Figure 1). When the analysis was limited to the patients without prior CNS involvement, there was still no benefit to post-HSCT CNS prophylaxis (P=0.63). Patients with a prior history of CNS involvement with leukemia had a significantly higher rate for CNS relapse, 11.6% vs. 2.7% (P=0.003) (Figure 2). The 4-year rate of CNS relapse was not impacted by intensity of the HSCT conditioning regimen and was 3%, 4%, and 6.5% for RIC, MA-TBI, and MA-nonTBI, respectively. Conclusion CNS relapse is an uncommon event following HSCT for ALL in CR1 or CR2. Furthermore, neither the intensity of the HSCT conditioning regimen nor the routine use of post-HSCT CNS prophylaxis made a significant difference in the rate of post-HSCT CNS relapse in patients who had received CNS prophylaxis prior to HSCT. Not surprisingly, patients with a pre-HSCT history of CNS involvement had a significantly higher risk of CNS relapse after HSCT. Disclosures: No relevant conflicts of interest to declare.

This study evaluated the acute toxicity of trimetrexate (TMTX) used in combination with cyclosporine (CsA) for prevention of acute graft-versus-host disease (GVHD) in patients undergoing allogeneic marrow transplantation from HLA-mismatched, related donors. TMTX has a mechanism of action similar to that of methotrexate (MTX) ; however, unlike MTX, TMTX is not primarily dependent on renal excretion. Patients were conditioned for transplant with cyclophosphamide, anti-thymocyte globulin, and total body irradiation. TMTX, 10 mg/m 2 i.v., was administered on days 1, 3, 6, 11, 18, 25, 32, and 39 after transplant. CsA, 1.5 mg/kg i.v., was administered every 12 hr beginning on day -1. Eleven patients with hematologic malignancies or aplastic anemia (median age = 34 yr) received TMTX. Toxicity assessed included nausea, vomiting, fever, rash, time to myeloid and platelet engraftment, mucositis, and hepatic and renal dysfunction. Toxicity of TMTX was not different from that observed with MTX in a similar patient population. One patient died on day 16 before engraftment. The other 10 patients all engrafted and all developed acute GVHD at a median time of 11 days after transplant. The major manifestation of acute GVHD was in the skin, and all but one patient responded to primary therapy with corticosteroids. Seven patients have survived a median of 447 days after transplant. No significant toxicity from TMTX was observed. Further trials are warranted to define the role of TMTX in marrow transplantation.

Abstract 592 Relapse occurs in approximately 30% of patients with acute lymphoblastic leukemia (ALL) after allogeneic hematopoietic transplantation (allo-HCT), with relapse rate of more than 60% in high-risk patients. The outcome of relapsed patients is usually poor despite salvage therapies. To improve the outcome of ALL patients after HCT identification of markers to predict impending relapse is necessary. In this study we retrospectively evaluated the prognostic value of minimal residual disease (MRD) monitoring by seven-color multiparametric flow cytometry (MFC) in 159 patients with ALL, who underwent myeloablative allo-HCT in our center between April 2006 and March 2011. Sixty two patients were younger than 18 years at time of transplant, 90 patients were in CR1, 57 patients were in CR2, and 12 patients were in ≥CR3 at time of transplant. 133 patients had B-ALL, 24 patients had T-ALL, and 2 patients had biphenotypic leukemia. Among the B-ALL patients 34 patients had Ph+ disease. Seven-color MFC was performed on bone marrow aspirates before and after HCT. MRD was defined as a cell population showing deviation from normal antigen expression patterns compared with normal or regenerating marrow, with total blast count lower than 5%. Overt hematologic relapse was identified as total blast count ≥5%. 153 patients had pre-HCT flow data within 50 days before transplant. Among these patients MRD pre-HCT increased the risk of relapse (HR=3.17; 95% CI, 1.60–6.28; p=.002) and mortality (HR=2.39; 95% CI, 1.46–3.90, p=.0005) relative to the risk without MRD before HCT. These results were qualitatively unchanged after adjusting for the presence of abnormal cytogenetics or positive BCR-ABL by molecular testing. One year estimates of relapse for patients without and with MRD pre-HCT were 12% and 27%, respectively, and one year estimates of overall survival (OS) were 75% and 44% respectively. Three years estimated relapse were 16% and 33% and 3 years estimated OS were 68% and 40% for patients without and with MRD pre-HCT respectively (Figures 1, 2). 137 patients had “day-28” flow data, where MFC was done between day 17 and day 40 post-transplant. Among patients who had not relapsed by the time of their day-28 MFC, the risk of relapse was higher among patients with positive day-28 MFC compared to those with a negative day-28 MFC (HR=3.55; 95 CI,1.58–8.02; p=.002). Patients with MRD at day 28 were also at increased risk of subsequent mortality compared to those without MRD at day 28 (HR=2.47; 95% CI, 1.23–4.96; p=.01). These results were qualitatively unchanged after adjusting for the presence of abnormal cytogenetics. One year estimates of relapse for patients without and with MRD post-HCT were 15% and 39%, respectively, and 1-year estimates of OS were 76% and 41%, respectively. Three years estimated relapse were 19% and 45% and 3 years estimated OS were 70% and 33% for patients without and with MRD post-HCT, respectively. Modeling post-HCT flow values as a time-dependent covariate also showed an increased risk of relapse (HR=5.27; 95% CI, 2.16–12.87, p=.0003) and death (HR=3.21; 95% CI, 1.58–6.53, p=.001) among patients who had MRD compared to those who did not. These associations remained qualitatively the same after adjusting for presence of pre-HCT MRD (HR=6.04 for relapse; HR=3.53 for overall mortality). These data suggest that pre- or post-HCT MRD, as detected by seven-color MFC, is associated with increased risk of relapse and death after myeloablative HCT for ALL. Figure 1. Cumulative incidence of relapse after HCT based on MRD status before HCT Figure 1. Cumulative incidence of relapse after HCT based on MRD status before HCT Figure 2. Overall survival after HCT based on MRD status before HCT Figure 2. Overall survival after HCT based on MRD status before HCT Disclosures: No relevant conflicts of interest to declare.

Summary. Seventeen patients with aplastic anaemia were treated with recombinant human granulocyte-macrophage colony stimulating factor (rhGM-CSF) for 14 d. Nonrespond-ing patients were then treated with anti-human thymocyte globulin (ATG), methylprednisolone and oxymetholone. Side-effects of rhGM-CSF included fever, nausea and vomiting, diarrhoea, bone pain, headache and chills. Two patients had sustained trilineage haemopoietic recovery after receiving only rhGM-CSF. Of 11 patients who received immunosuppressive therapy, there was one complete response, two partial responses, one minimal response, and seven nonres-ponses. Actuarial survival at 2 years is 64%. Early administration of rhGM-CSF had no apparent effect on subsequent response to immunosuppressive therapy.

We treated 93 patients with myelodysplastic syndrome using cyclophosphamide and either total body irradiation (n = 88) or busulfan (n = 5) followed by marrow transplantation. Sixty-five marrow donors were genotypically HLA-identical siblings and 28 were other family members or unrelated donors. Before transplantation all patients had either severe neutropenia or thrombocytopenia or had greater than 5% blasts in the marrow or peripheral blood. The probabilities of disease- free survival, relapse, and non-relapse mortality at 4 years were 41%, 28%, and 43%, respectively. Multivariate analysis revealed that younger age and shorter disease duration were significantly associated with improved disease-free survival and decreased non-relapse mortality. Relapse was seen only in patients with excess blasts at the time of transplantation (51% at 4 years). Patients younger than age 40 and without excess blasts had a 4-year disease-free survival of 62%. This study confirms that allogeneic marrow transplantation can cure some patients with myelodysplasia. Because of the favorable outcome in younger patients without excess blasts, we recommend that transplantation be considered early for patients younger than age 40, before disease progression or development of life-threatening cytopenias. For older patients and those with excess blasts, changes in the transplant procedure will be necessary to improve outcome.