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Patients with severe thalassemia commonly have a survival that is significantly shorter than that of the general population. Allogeneic hematopoietic stem cell transplantation (allo-SCT) is the only established treatment that is potentially curative, but it is limited by the availability of donors and the medical condition of the patient. To expand the donor pool to include haploidentical related donors, we introduced a program consisting of a pharmacologic pretransplant immune suppression phase (PTIS) and 2 courses of dexamethasone and fludarabine, followed by pretransplant conditioning with fludarabine-i.v. busulfan and post-transplant graft-versus-host disease (GVHD) prophylaxis with cyclophosphamide, tacrolimus, and mycophenolate mofetil. We transplanted 83 consecutive transfusion-dependent patients with thalassemia (median age, 12 years; range, 1 to 28 years) with a minimum follow-up of 6 months (median, 15 months; range, 7 to 53 months); the 3-year projected overall and event-free survival is over 96%, and there have been no secondary graft failures. Of the first 31 patients, we had 2 graft failures, both of them occurring in patients with extremely high titers of anti-donor-specific HLA antibodies (anti-DSAs), but after adjusting the PTIS to include bortezomib and rituximab for patients with high titers of anti-DSAs and using pharmacologic dose guidance for busulfan, we had no graft failures in the last 52 patients. Six (7%) of 83 patients developed severe GVHD. We conclude that this is a safe and efficacious approach to allogeneic SCT in thalassemia, yielding results comparable to those available for patients with fully matched donors.

We studied if the inclusion of early post–stem cell transplantation (SCT) minimal residual disease (MRD) assessments improved prognostication in patients with acute myeloid leukemia (AML). Two hundred sixty-nine AML patients in morphological complete remission (CR) who underwent a first SCT were included if they had evaluable pre-SCT MRD assessment by multiparametric flow cytometry. Post-SCT MRD assessments were performed at days +30, +100, and +180. The primary outcome was 1-year relapse incidence (RI). Of 269 patients in CR, 83 (30.8%) had detectable MRD pre-SCT. Post-SCT, during routine disease assessment time points, 9 of 241 evaluable patients (3.7%) at day +30, 6 of 191 evaluable patients (3.1%) at day +100, and 4 of 133 evaluable patients (3%) at day +180 were MRD positive while in CR. MRD positivity at day +30 predicted the highest risk of relapse at 1 year (group 1, 1-year RI 78%). Among MRD-negative patients at day +30, either adverse risk category by European Leukemia Net (ELN) or intermediate risk who were aged ≥60 years and/or pre-SCT MRD-positive represented the intermediate-risk group (group 2, 1-year RI 29%). The remaining patients represented the low-risk group (group 3, 1-year RI 5%). For patients in CR beyond day +30 post-SCT, detectable MRD at any time point predicted impending relapse within 2 months. Early post-SCT MRD assessment—combined with pre-SCT MRD assessment, ELN risk category, and age—improves risk stratification for relapse in AML patients post-transplant. Studies aimed at preventing impending relapse in this high-risk population are urgently needed.

In this study, we compared transplantation outcomes of allogeneic hematopoietic stem cell transplantation (HSCT) in patients with advanced myelodysplastic syndrome (MDS) who received a CD34+ cell-selected and those who received an unmodified allograft. This analysis initially included 181 patients, 60 who received a CD34+ cell-selected transplant and 121 who received an unmodified transplant. Owing to significant differences in disease characteristics, the analysis was limited to patients with

We investigated the long-term safety and disease control data obtained with i.v. busulfan (Bu) combined with clofarabine (Clo) in patients with acute lymphoblastic leukemia (ALL) undergoing allogeneic hematopoietic stem cell transplantation (HSCT). A total of 107 patients, median age 38 years (range, 19 to 64 years) received a matched sibling donor (n = 52) or matched unrelated donor (n = 55) transplant for ALL in first complete remission (n = 62), second complete remission (n = 28), or more advanced disease (n = 17). Nearly one-half of the patients had a high-risk cytogenetic profile as defined by the presence of t(9;22) (n = 34), t(4;11) (n = 4), or complex cytogenetics (n = 7). Clo 40 mg/m2 was given once daily, with each dose followed by pharmacokinetically dosed Bu infused over 3 hours daily for 4 days, followed by hematopoietic cell infusion after 2 days of rest. The Bu dose was based on the drug clearance as determined by a test Bu dose of 32 mg/m2. The target daily area under the curve was 5500 µmol/min for patients aged 59 years. With a median follow-up of 3.3 years among surviving patients (range, 1 to 5.8 years), the 2-year progression-free survival (PFS) for patients undergoing HSCT in first complete remission (CR1), second complete remission (CR2), or more advanced disease was 62%, 34%, and 35%, respectively. The regimen was well tolerated, with nonrelapse mortality (NRM) of 10% at 100 days and 31% at 2 years post-HSCT. The incidence of grade II-IV and III-IV acute graft-versus-host disease (GVHD) was 35% and 10%, respectively; 18% patients developed extensive chronic GVHD. The 2-year overall survival (OS) for patients undergoing HSCT in CR1, CR2, or more advanced disease was 70%, 57%, and 35%, respectively. Among 11 patients aged >59 years treated with reduced-dose Bu in CR1 (n = 7) or CR2 (n = 4), 4 remain alive and disease-free, with a median follow-up of 2.6 years (range, 2 to 4.7 years). Only the presence of minimal residual disease at the time of transplantation was associated with significantly worse PFS and OS in multivariate analysis. Our data indicate that the Clo-Bu combination provides effective disease control while maintaining a favorable safety profile. OS and NRM rates compare favorably with those for traditional myeloablative total body irradiation-based conditioning regimens.

Background We previously reported that conditioning with Bu-Mel results in significantly longer PFS compared to Mel alone in patients with newly diagnosed multiple myeloma ([NDMM] Lancet Haematol 2019). Here we report the outcomes of the high-risk patients (based on chromosomal abnormalities as defined by IMWG) enrolled in this trial. Methods The primary objective was to compare PFS in NDMM patients who undergo auto-HCT with Bu-Mel versus Mel conditioning. Transplant eligible patients were randomly assigned (1:1) to treatment. Patients in Bu-Mel arm received test dose Bu 32 mg/m2 followed by PK adjusted Bu to achieve a target AUC of 5000 microMol-minute (days -7 to -4) and Mel 70 mg/m2 on days -2 and -1. Patients in Mel arm received Mel 200 mg/m2 on day -2. Results Sixty-two patients (Bu-Mel, n=32; Mel, n=30) were identified. Median age at transplant was 61 yrs in the Bu-Mel and 60 yrs in the Mel arm. Sixteen (50%) and 18 (60%) patients were male in the Bu-Mel and the Mel arm, respectively. The R-ISS stage was I in 6 (22%), II in 17 (63%), and III in 4 (15%) of 27 patients in the Bu-Mel arm versus I in 8 (38%), II in 9 (43%), and III in 4 (19%) of 21 patients in the Mel arm, p=0.39. There was no significant difference in the HCT-CI score, induction therapy, response to induction, number of patients receiving maintenance therapy, and other patients, disease, or treatment characteristics between the two treatment groups. The median time to neutrophil engraftment (ANC ≥500) was 11 days and 12 days in the Bu-Mel and Mel arms, respectively, p=0.002. The median time to platelet engraftment (platelet count ≥20K without transfusion support) was 10 days and 12.5 days in the Bu-Mel and Mel arms, respectively, p Conclusion Conditioning therapy with Bu-Mel before auto-HCT yields significantly longer PFS in high-risk myeloma patients compared with Mel alone. Longer follow-up is needed to characterize any OS benefit.

Background Myeloablative conditioning can be given safely to older patients by simply administering busulfan over a longer period (fractionated busulfan regimen) than the standard four day regimen. (Popat et al Lancet Haematology 2018). Subsequently, we added post-transplant cyclophosphamide (PTCy) GVHD prophylaxis to our fractionated regimen with a hypothesis that it will reduce GVHD and improve outcomes. Herein, we report the results of our retrospective analysis comparing outcomes of patients with AML who received fractionated busulfan myeloablative conditioning and PTCy versus standard tacrolimus (Tac) and methotrexate (Mtx) GVHD prophylaxis. Methods Patients with AML between 18-70 years of age with adequate organ function and 8/8-HLA matched related or unrelated donor, who were treated on 4 consecutive protocols using fractionated busulfan were included in the analysis. All patients received two fixed doses of busulfan 80mg/m2 as outpatient either on days -13 and -12, or on days -20 and-13 followed by busulfan on day -6 to -3 dosed to achieve target area under the curve (AUC) of 20,000 mol/min for the whole course based on pharmacokinetic studies. Fludarabine ± cladribine were given on day -6 to -3. GVHD prophylaxis was PTCy 50mg/kg on days 3 and 4 and Tac ± mycophenolate mofetil in PTCy cohort (n=53), or standard Tac+ Mtx (n=53). Patients in both the cohorts were matched 1:1 by propensity score. Results Baseline characteristics were similar between the PTCy and Tac/Mtx cohorts. The median age was 60 (range, 18-70) and 58 (range, 24-70) years, respectively, (P=0.3). Forty-nine percent were in CR, and 30% had comorbidity index >3 in each arm. Similar proportion of patients had ELN adverse risk in both arms (43% vs 40%, respectively P=0.7). The median follow up was 19 months (range, 3-36) in the PTCy and 46 months (range, 14-73) in Tac/Mtx cohort. Overall survival at 2-year was 78% vs 58% (P=0.03), non-relapse mortality was 6% vs 13% (P=0.2), incidence of grade 3-4 acute GVHD at 1-year was 6% vs 19% (P=0.07) and chronic GVHD at 2-year was 10% vs 29% (P=0.03) [Table 1 and figure 1]. The median time to neutrophil engraftment was prolonged by 3 days (15 vs 12 days; P Conclusion As compared to Tac/Mtx, PTCy-based GVHD prophylaxis not only reduced severe acute GVHD and chronic GVHD, but also improved overall survival in AML patients up to the age of 70 years who received myeloablative fractionated busulfan conditioning. Prospective randomized trial is warranted to validate these findings.

Background Myeloablative conditioning (MA) reduces relapse as compared to reduced intensity (RIC), [Scott BL JCO 2017]. But it is avoided in older patients and those with comorbidities due to high non-relapse mortality (NRM), whose outcomes remain dismal. A CIBMTR study of AML patients ≥60 years (100% CR1) showed NRM of 32-34%, relapse rate of 33-37%, progression free survival (PFS) of 31-34% and overall survival (OS) of 34-36% at 2 years. [McClune. JCO 2010] A prospective trial in AML (≥60 years, 100% CR1) showed better 2-year PFS (42%) and OS (48%). [Devine. JCO 2015] Herein, we report the results of MA HCT using timed-sequential (TS) busulfan (Bu) in 71 AML patients up to age 73. Methods Patients received intravenous Bu in TS manner targeted to achieve an area under the curve of 16,000-20,000 μmol.min, with fludarabine (flu) 40 mg/m2 intravenously for four days. Results Median age was 64 years (range, 29-73). Donor was HLA matched unrelated (n=45, 63%) or related (n=26, 27%). Most received peripheral blood graft (n=46, 65%). Only 26% (n=18) had MRD-negative CR1/2 at HCT; others had MRD-positive CR1/2 (13%, n=9), primary induction failure (PIF; 45%, n=32) or relapsed disease (16%, n=11). Nearly half (47%) had the European LeukemiaNet (ELN) adverse risk disease. More than half (55%) had HCT-CI ≥ 3. Median follow-up was 40 months (range, 21-63). The cumulative incidences of grade II-IV and III-IV acute GVHD at day 100 were 39% (95% CI, 28-51%) and 10% (95% CI, 3-17%), respectively and extensive chronic GVHD at 1 year was 20% (95% CI, 10-29%). NRM was 6% (95% CI, 0-11%) at day 100 and 24% (95% CI, 14-34%) at 2 years. At 2 years, relapse was 28% (95% CI, 3-53%) in the CR/MRD-negative group vs 48% (95% CI, 34-62%) in others; progression-free survival (PFS) was 78% (95% CI, 61-99.6%) vs 25% (95% CI, 16-40%) and overall survival (OS) was 78% (95% CI, 61-99.6%) vs 33% (95% CI, 22-48%), respectively. [Fig 1a] Two year OS was was 67% (95% CI 51-87%) in the CR group, irrespective of MRD [Fig 1b]. In multivariate analysis (MVA) adjusted for covariates higher dose Bu vs lower dose [HR 0.39, 95% CI 0.18-0.85, p=0.02] was the only significant predictor of lower relapse risk. In MVA adjusted for age, Bu dose and ELN risk, not being in CR/MRD-negative state was the only predictor of significantly inferior PFS [HR 3.2, 95% CI, 1.3-8.2, p=0.01]. For OS, MVA adjusted for age, Bu dose and ELN risk, HCT-CI ≥3 [HR 1.98, 95% CI, 1-3.9, p=0.05] and not being in CR/MRD-negative state [HR, 2.7, 95% CI 0.98-7.2, p=0.05] were associated with higher mortality. Conclusion Our outcomes of MA HCT in an extremely high risk older population are promising especially in CR patients, whose outcomes approach that of younger patients. This was achieved by delivering Bu in TS manner which minimized toxicity and potentially increased efficacy. This approach warrants further investigation.

Background Post transplant cyclophosphamide (PTCy), tacrolimus, and MMF GvHD prophylaxis makes transplantation from haploidentical donors feasible without T cell depletion. In matched donor transplant recipients, cumulative incidences of grades II-IV acute, grades III-IV acute, and chronic GVHD were 51%, 15%, and 14%, respectively when single agent PTCy was used (Kanakry et al JCO 2014 32:3497-3505). However; as a single agent it was inferior to tacrolimus and methotrexate in another study (Alousi etal BBMT 2015, 906-912). We therefore hypothesized that addition of tacrolimus to PTCy may be needed to prevent severe acute GVHD and improve transplant outcomes. Methods All patients with AML undergoing first allogeneic transplant from matched sibling or at least 9/10 matched unrelated donor between 1/1/2011 to 4/30/2018 were eligible for this retrospective study if they received a melphalan or timed sequential busulfan (course AUC 20,000 umol/min) based conditioning regimen. GVHD prophylaxis consisted of tacrolimus and methotrexate 5mg/m2 on day 1, 3, 6, and 11 in the Tac/MTX cohort (n=140); and cyclophosphamide 50mg/kg given on days 3 and 4 and tacrolimus in the PTCy cohort (n=76). Results Patient characteristics were similar in both cohorts except that patients in PTCy cohort were younger with a median age of 59 years versus 63.5 years (P Outcomes and results of univariate analysis are summarized in Table1. Conclusion Tacrolimus and PostCy based GVHD prophylaxis reduces severe GVHD and improves survival.

Background The cell of origin (COO) classification has been shown to predict survival outcomes in de-novo diffuse large B-cell lymphoma (DLBCL), however, it is unclear if this holds true following high-dose chemotherapy and autologous stem cell transplantation (auto-SCT) in relapsed DLBCL patients. The current analysis aims to compare survival outcomes based on COO classification in relapsed DLBCL patients who received auto-HCT. Methods This retrospective study includes relapsed/refractory DLBCL patients, aged 18 and above, who received auto-HCT with standard of care conditioning from January 2007 to December 2016 at our institution. Hans algorithm using CD10, BCL6 and MUM1 markers was performed to classify patients as per COO into the GCB and non-GCB types. Kaplan Meier method was used to estimate progression free survival (PFS) and overall survival (OS). Results A total of 122 DLBCL (71 GCB, 51 non-GCB) patients were analyzed. Detailed patient characteristics are provided in Table 1. Except for GCB cohort being older (64 vs. 58 years, p 70 (HR=2.9, p=0.03) and IPI score 0 (HR=0.3, p=0.005) were significant variables in predicting PFS. After adjusting for these variables, no significant differences were seen in PFS between two groups. The median OS has not yet been reached in both groups therefore a difference in OS cannot be analyzed. Conclusion Our results suggest that cell of origin is not prognostic for patients with relapsed/refractory DLBCL treated with high dose chemotherapy followed by auto-SCT.

More active high-dose regimens are needed for refractory/poor-risk relapsed lymphomas. We previously developed a regimen of infusional gemcitabine/busulfan/melphalan, exploiting the synergistic interaction. Its encouraging activity in refractory lymphomas led us to further enhance its use as a platform for epigenetic modulation. We previously observed increased cytotoxicity in refractory lymphoma cell lines when the histone deacetylase inhibitor vorinostat was added to gemcitabine/busulfan/melphalan, which prompted us to clinically study this four-drug combination. Patients ages 12 to 65 with refractory diffuse large B cell lymphoma (DLCL), Hodgkin (HL), or T lymphoma were eligible. Vorinostat was given at 200 mg/day to 1000 mg/day (days -8 to -3). Gemcitabine was infused continuously at 10 mg/m(2)/minute over 4.5 hours (days -8 and -3). Busulfan dosing targeted 4000 μM-minute/day (days -8 to -5). Melphalan was infused at 60 mg/m(2)/day (days -3 and -2). Patients with CD20(+) tumors received rituximab (375 mg/m(2), days +1 and +8). We enrolled 78 patients: 52 DLCL, 20 HL, and 6 T lymphoma; median age 44 years (range, 15 to 65); median 3 prior chemotherapy lines (range, 2 to 7); and 48% of patients had positron emission tomography-positive tumors at high-dose chemotherapy (29% unresponsive). The vorinostat dose was safely escalated up to 1000 mg/day, with no treatment-related deaths. Toxicities included mucositis and dermatitis. Neutrophils and platelets engrafted promptly. At median follow-up of 25 (range, 16 to 41) months, event-free and overall survival were 61.5% and 73%, respectively (DLCL) and 45% and 80%, respectively (HL). In conclusion, vorinostat/gemcitabine/busulfan/melphalan is safe and highly active in refractory/poor-risk relapsed lymphomas, warranting further evaluation. This trial was registered at ClinicalTrials.gov (NCI-2011-02891).

Chimerism testing after allogeneic hematopoietic stem cell transplantation (allo-HSCT) in patients with acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) represents a promising tool for predicting disease relapse, although its precise role in this setting remains unclear. We investigated the predictive value of T lymphocyte chimerism analysis at 90 to 120 days after allo-HSCT in 378 patients with AML/MDS who underwent busulfan/fludarabine-based myeloablative preparative regimens. Of 265 (70%) patients with available T lymphocyte chimerism data, 43% of patients in first or second complete remission (CR1/CR2) at the time of transplantation had complete (100%) donor T lymphocytes at day +90 to +120 compared with 60% of patients in the non-CR1/CR2 cohort (P = .005). In CR1/CR2 patients, donor T lymphocyte chimerism ≤ 85% at day +90 to +120 was associated with a higher frequency of 3-year disease progression (29%; 95% confidence interval [CI], 18% to 46% versus 15%; 95% CI, 9% to 23%; hazard ratio [HR], 2.1; P = .04). However, in the more advanced, non-CR1/CR2 cohort, mixed T lymphocyte chimerism was not associated with relapse (37%; 95% CI, 20% to 66% versus 34%; 95% CI, 25% to 47%; HR, 1.3; P = .60). These findings demonstrate that early T lymphocyte chimerism testing at day +90 to +120 is a useful approach for predicting AML/MDS disease recurrence in patients in CR1/CR2 at the time of transplantation.

We evaluated the prognostic significance of a modified European LeukemiaNet (ELN) classification for patients with acute myelogenous leukemia (AML) undergoing hematopoietic stem cell transplantation (HSCT) while in first complete remission (CR1). We analyzed 464 AML patients with matched related (n = 211, 45.5%), matched unrelated (n = 176, 37.9%), and mismatched donors (n = 77, 16.6%). Patients were classified into 4 modified ELN risk groups (favorable, intermediate-I, intermediate-II, and adverse) separately for 354 patients age < 60 years and 110 patients age ≥ 60 years. In this modified version of ELN classification, patients with normal cytogenetic were classified by FLT3-ITD mutational status: favorable risk if FLT3-ITDwild and intermediate-I if FLT3-ITDmut. The best outcomes occurred in the ELN favorable and intermediate-II groups in younger AML patients and in the favorable and intermediate-I groups in older AML patients. Older AML patients had worse transplant outcomes within each modified ELN risk group except intermediate-I when compared with younger patients; leukemia-free survival at 3 years was 67.8% versus 49.8% in favorable, 53.4% versus 50.7% in intermediate-I, 65.7% versus 20.2% in intermediate-II, and 44.6% versus 23.8% in adverse group younger and older patients, respectively. Among lesion-specific abnormalities, del5q/−5 and abnl(17p) had the worse transplant outcomes, with 3-year leukemia-free survival rates of 18.4% and 20% in younger CR1 patients. In conclusion, the modified ELN prognostic classification developed for chemotherapy outcomes also identifies prognostic groups for HSCT, which is useful for a selection of patients for post-transplant strategies to improve outcomes.

Improving outcomes among class 3 thalassemia patients receiving allogeneic hematopoietic stem cell transplantations (HSCT) remains a challenge. Before HSCT, patients who were ≥ 7 years old and had a liver size ≥ 5 cm constitute what the Center for International Blood and Marrow Transplant Research defined as a very high–risk subset of a conventional high-risk class 3 group (here referred to as class 3 HR). We performed HSCT in 98 patients with related and unrelated donor stem cells. Seventy-six of the patients with age < 10 years received the more conventional myeloablative conditioning (MAC) regimen (cyclophosphamide, busulfan, ± fludarabine); the remaining 22 patients with age ≥ 10 years and hepatomegaly (class 3 HR), and in several instances additional comorbidity problems, underwent HSCT with a novel reduced-toxicity conditioning (RTC) regimen (fludarabine and busulfan). We then compared the outcomes between these 2 groups (MAC versus RTC). Event-free survival (86% versus 90%) and overall survival (95% versus 90%) were not significantly different between the respective groups; however, there was a higher incidence of serious treatment-related complications in the MAC group, and although we experienced 6 graft failures in the MAC group (8%), there were none in the RTC group. Based on these results, we suggest that (1) class 3 HR thalassemia patients can safely receive HSCT with our novel RTC regimen and achieve the same excellent outcome as low/standard-risk thalassemia patients who received the standard MAC regimen, and further, (2) that this novel RTC approach should be tested in the low/standard-risk patient population.

Introduction The role of T-cell helper 1 cytokines, including TNF-α and IL-6, in the pathophysiology of acute graft-versus-host disease (aGVHD) is well established. Emerging data have also implicated IL-2, a marker of activated T-cells, in the GVHD reaction. 1 We hypothesized that pre-transplant IL-2 levels may correlate with the incidence of aGVHD. We tested our hypothesis in a cohort of 16 patients who received allogeneic stem cell transplantation (SCT) following fludarabine/busulfan based conditioning regimen and tacrolimus/methotrexate GVHD prophylaxis at our institution between 7/2012 and 1/2013. Methods TNF-α, IL-6, and IL-2 plasma levels were measured by ELISA day -13 (pre-SCT), day of SCT, days +7 and +14. Results Median age of patients was 61 years (range 47-70). The majority (62%) were treated for AML/MDS, and 81% had active disease at transplant. Median comorbidity index score was 3 (range 0-6). Donors were HLA-matched related (44%) or unrelated (56%), and peripheral blood was the stem cell source for all related donors and for 50% of unrelated donors. A quarter of the donor/recipient pairs were sex-mismatched (female donor to male recipient). The majority of donors (69%) were CMV seronegative, while 75% of recipients were CMV seropositive. Of 16 patients, 6 were diagnosed with grade II-IV aGVHD at a median of 28 days (range 18-83). Median follow-up was 24 months (range 3-64) in grade II-IV aGVHD-free patients. IL-2 levels (µg/mL) pre-SCT correlated with day of SCT, day +7, and day+14 levels. Median IL-2 was 0 (undetectable) pre-SCT (range 0-3.2) and on day of SCT (range 0-4.9). Patients with detectable (>0) IL-2 levels pre-SCT (n=5, median IL-2: 1.2, range 0.3-3.2) or on day of SCT (n=6, median IL-2: 2.6, range 0.2-4.9) were at high-risk of developing grade II-IV aGVHD. The incidence of grade II-IV aGVHD was 75% in patients (n=8) with detectable IL-2 levels pre-SCT and/or on the day of SCT (Figure). In contrast, none of the patients (n=8) who had undetectable IL-2 levels at both time points developed grade II-IV aGVHD (p=0.002). TNF-α and IL-6 levels (evaluated at the median) pre-SCT or on day of SCT were not associated with the incidence of grade II-IV aGVHD. Detectable pre-SCT IL2-were not correlated with ALC (K/µL) (median: 0.65 vs 0.87, p=0.6), but were correlated with longer duration since the last chemotherapy treatment (median 101 vs 47, p=0.02). Recipient age, disease status at SCT, CMV status, comorbidity index, and sex-mismatch did not correlate with pre-SCT IL-2 levels or with the incidence of grade II-IV aGVHD. Conclusion Our data suggest that elevated IL-2 before transplant may be associated with increased risk of aGVHD. Validation of these findings in larger datasets is warranted, as they may identify patients for trials of alternative GVHD prophylaxis.

Nodular lymphocyte-predominant Hodgkin lymphoma (NLPHL) is a distinct subtype of Hodgkin lymphoma that is characterized by unique clinical presentation, histological appearance, and indolent disease course. The recurrent nature of disease provides an opportunity to examine the role of stem cell transplantation in its management. We report here a single-center experience of 26 patients with relapsed NLPHL treated with high-dose chemotherapy and autologous stem cell transplantation between 1990 and 2008. With a median follow-up of 50 months (range, 2-138 months), the 5-year overall and event-free survival were 76% (SE 10%) and 69% (SE 10%), respectively. Our data suggest that high-dose chemotherapy and autologous transplantation should be considered as an option for patients with relapsed NLPHL.

This study was conducted to retrospectively compare the clinical outcomes after transplantation of T cell–depleted (TCD) and unmodified allografts in patients with acute myeloid leukemia (AML) in first complete remission (CR1). Patients received TCD grafts at Memorial Sloan-Kettering Cancer Center (MSKCC, N = 115) between 2001 and 2010 using the following preparative regimens: hyperfractionated total body irradiation (HFTBI)+thiotepa+fludarabine; HFTBI+thiotepa+cyclophosphamide; or i.v. busulfan+melphalan+fludarabine. TCD was performed by 1 of 2 immunomagnetic CD34+ cell selection methods for peripheral blood grafts or by soybean lectin agglutination followed by sheep red blood cell–rosette depletion for bone marrow grafts. No additional graft-versus-host disease (GVHD) prophylaxis was administered. Patients received unmodified grafts at M.D. Anderson Cancer Center (MDACC, N = 181) after conditioning with busulfan+fludarabine and GVHD prophylaxis with tacrolimus+mini-methotrexate. Patients with unrelated or human leukocyte antigen–mismatched donors received anti-thymocyte globulin (ATG) at both centers, with some recipients of matched related donor TCD transplants also receiving ATG, depending upon the preparative regimen. TCD graft recipients were more likely to be older, receive a mismatched transplant, and have peripheral blood used as the graft source. The incidences rates of grades 2 to 4 acute GVHD and chronic GVHD were significantly lower in the TCD graft group (5% versus 18%, and 13% versus 53%). Three-year relapse-free and overall survival rates were 58% and 57%, respectively, in recipients of TCD grafts, and 60% and 66% in recipients of unmodified grafts (P = not significant). Survival and relapse-free survival are similar after TCD and conventional transplants from related/unrelated donors in patients with AML in CR1, but TCD significantly reduces GVHD.

More active high-dose chemotherapy (HDC) regimens are needed for refractory Hodgkin's lymphoma (HL). We report a cohort analysis of 180 consecutive patients with primary refractory or poor-risk relapsed HL treated with busulfan-melphalan (Bu-Mel) (n = 39), gemcitabine-busulfan-melphalan (Gem-Bu-Mel) (n = 84), or BEAM (BCNU, etoposide, ara-C, melphalan; n = 57) between 2005 and 2010. Their pre-HDC positron emission tomography (PET) scans were interpreted prospectively. Despite more prevalent poor-risk features in the Gem-Bu-Mel cohort, such as PET-positive tumors at HDC, tumors growing at HDC, extranodal disease, or bulky tumors at prior relapse, this cohort had improved outcomes compared with the Bu-Mel and BEAM cohorts, with event-free survival (EFS) rates of 57%, 33%, and 39%, respectively (P = .01), at median follow-up of the whole population of 36 months (range, 3 to 72). Their respective overall survival (OS) rates were, respectively, 82%, 52%, and 59% (P = .04). Secondary acute myelogenous leukemia was seen in 5 patients after BEAM but was not seen in Gem-Bu-Mel and Bu-Mel cohorts (P = .004). Multivariate analyses showed independent adverse effects of an HDC regimen different from Gem-Bu-Mel (hazard ratio [HR] for EFS = 2.3, P = .0008; HR for OS = 2.7, P = .0005), positive PET at HDC (HR for EFS = 2.2, P = .004, HR for OS = 3.1, P = .0001), and >1 previous salvage line (HR for EFS = 1.9, P = .008, HR for OS = 1.8, P = .07). Gem-Bu-Mel improved outcomes in this cohort analysis of patients with refractory/poor-risk relapsed HL and merits evaluation in randomized phase III trials.

We investigated the safety and early disease control data for i.v. busulfan (Bu) in combination with clofarabine (Clo) in patients with acute lymphoblastic leukemia undergoing allogeneic hematopoietic stem cell transplantation (SCT). Fifty-one patients (median age, 36 years; range, 20-64 years) received a matched sibling (n = 24), syngeneic (n = 2), or matched unrelated donor transplant (n = 25) for acute lymphoblastic leukemia in first complete remission (n = 30), second complete remission (n = 13), or active disease (n = 8). More than one-half of the patients had a high-risk cytogenetic profile, as defined by the presence of t(9;22) (n = 17), t(4;11) (n = 3), or complex cytogenetics (n = 7). Clo 40 mg/m(2) was given once daily, with each dose followed by pharmacokinetically dosed Bu infused over 3 hours daily for 4 days, followed by hematopoietic SCT 2 days later. The Bu dose was based on drug clearance, as determined by the patient's response to a 32-mg/m(2) Bu test dose given 48 hours before the high-dose regimen. The target daily area under the receiver-operating characteristic curve was 5500 μM/min for patients age60 years and 4000 μM/min for those age ≥60 years. The regimen was well tolerated, with a 100-day nonrelapse mortality rate of 6%. With a median follow-up of 14 months among surviving patients (range, 6-28 months), the 1-year overall survival, disease-free survival, and nonrelapse mortality rates were 67% (95% confidence interval [CI], 55%-83%), 54% (95% CI, 41%-71%), and 32% (95% CI, 16%-45%), respectively. For patients undergoing SCT in first remission, these respective rates were 74%, 64%, and 25%. Our data indicate that the combination of Clo and Bu provides effective disease control while maintaining a favorable safety profile.

The introduction of tyrosine kinase inhibitors (TKI) has revolutionized therapy for patients with acute lymphoblastic leukemia (ALL) who have the Philadelphia (Ph) chromosome. A retrospective analysis was conducted on 102 adults and 11 children who received a first-matched related (n = 60), matched unrelated (n = 40), mismatched cord blood (n = 12), or haploidentical (n = 1) allogeneic hematopoietic stem cell transplantation (HSCT) for Ph-positive (Ph+) ALL in first complete remission (n = 71), second complete remission (n = 11), or with active disease (n = 31) between 1990 and 2009. Sixty-seven patients received TKI with upfront ALL therapy, and 32 patients received TKI maintenance following HSCT. With median follow-up of 5 years among survivors (range: 1.1-20.4 years), overall survival (OS) was significantly better for patients transplanted in first remission compared with HSCT in advanced disease: 43% versus 16%, P = .002. Disease stage and age at time of HSCT, the development of acute graft-versus-host disease (aGVHD), and decade of HSCT were found to significantly impact OS, progression-free survival (PFS), and nonrelapse mortality (NRM) in multivariate analyses. Allogeneic HSCT provides durable remission for patients with Ph+ ALL in first remission. Neither TKI use pre- nor post-HSCT were found to significantly impact transplant outcomes in univariate and multivariate analyses.

Complete remission (CR) is the gold standard for assessing outcomes following chemotherapy for acute myelogenous leukemia (AML). "CRp," a response criterion defined as fulfillment of all criteria for CR except platelet count recovery to ≥100 × 10(9)/L, is associated with inferior outcomes following chemotherapy. The prognostic importance of CRp before allogeneic stem cell transplantation (allo-SCT) remains unknown. We analyzed a cohort of AML (n = 334) and myelodysplastic syndrome (MDS; n = 10) patients to determine the prognostic significance of achieving CR versus CRp before allo-SCT. At time of transplantation, 266 patients were in CR (CR1 and ≥CR2) and 78 in CRp (CR1p and ≥CR2p). Median follow-up was 38 months (3-131 months). Overall survival, progression-free survival, and nonrelapse mortality (NRM) were most favorable in patients transplanted in CR (CR1 or ≥CR2) compared with CRp (CR1p or ≥CR2p). Achieving CR is therefore associated with improved posttransplantation outcomes compared with achieving CRp and is a significant prognostic factor that needs to be considered when evaluating AML/MDS patients for clinical trials and allo-SCT.

We retrospectively analyzed the outcomes of all acute myelogenous leukemia (AML) patients in first remission (n = 44; median age = 48 years; high-risk cytogenetics = 59%) who received unrelated donor hematopoietic cell transplantation (HCT) with myeloablative conditioning regimen of i.v. busulfan, fludarabine, and antithymocyte globulin (ATG) between January 2002 and November 2009 at our institution. Donor-recipient pairs were matched by high-resolution HLA-A, -B, -C, -DRB1, and -DQB1 typing (10/10 matches, n = 41; 9/10 matches, n = 3). With a median follow-up of 34 months, actuarial 3-year event-free survival (EFS) and overall survival (OS) is 70% and 78%, respectively. The 3-year EFS and OS in patients with and without poor risk cytogenetics is similar (63% versus 82%, P = 0.43 and 78% versus 82%, P = .89, respectively). The 3-year EFS and OS is also similar in patients above age 55 year versus patients age 55 year or younger (80% versus 67%, P = .47 and 80% versus 78%, P = .81, respectively). The 100-day and 3-year cumulative incidence of transplant-related mortality is 5% and 15%, respectively. Six patients have relapsed, and 3 of them are alive and in remission after salvage therapy, with a median follow-up of 23 months. These results indicate that the majority of AML patients eligible for this treatment can achieve long-term disease control.

Although a combination of i.v. busulfan (Bu) and fludarabine (Flu) is a safe, reduced-toxicity conditioning program for acute myelogenous leukemia/myelodysplastic syndromes (AML/MDS), recurrent leukemia posttransplantation remains a problem. To enhance the conditioning regimen's antileukemic effect, we decided to supplant Flu with clofarabine (Clo), and assayed the interactions of these nucleoside analogs alone and in combination with Bu in Bu-resistant human cell lines in vitro. We found pronounced synergy between each nucleoside and the alkylator but even more enhanced cytotoxic synergy when the nucleoside analogs were combined prior to exposing the cells to Bu. We then designed a 4-arm clinical trial in patients with myeloid leukemia undergoing allogeneic stem cell transplantation (allo-SCT). Patients were adaptively randomized as follows: Arm I-Clo:Flu 10:30 mg/m(2), Arm II-20:20 mg/m(2), Arm III-30:10 mg/m(2), and Arm IV-single-agent Clo at 40 mg/m(2). The nucleoside analog(s) were/was infused over 1 hour once daily for 4 days, followed on each day by Bu, infused over 3 hours to a pharmacokinetically targeted daily area under the curve (AUC) of 6000 μMol-min ± 10%. Fifty-one patients have been enrolled with a minimum follow-up exceeding 100 days. There were 32 males and 19 females, with a median age of 45 years (range: 6-59). Nine patients had chronic myeloid leukemia (CML) (BC: 2, second AP: 3, and tyrosine-kinase inhibitor refractory first chronic phase [CP]: 4). Forty-two patients had AML: 14 were induction failures, 8 in first chemotherapy-refractory relapse, 7 in untreated relapse, 3 in second or subsequent relapse, 4 were in second complete remission (CR), and 3 in second CR without platelet recovery (CRp), 2 were in high-risk CR1. Finally, 1 patient was in first CRp. Graft-versus-host disease (GVHD) prophylaxis was tacrolimus and mini-methorexate (MTX), and those who had an unrelated or 1 antigen-mismatched donor received low-dose rabbit-ATG (Thymoglobulin™). All patients engrafted. Forty-one patients had active leukemia at the time of transplant, and 35 achieved CR (85%). Twenty of the 42 AML patients and 5 of 9 CML patients are alive with a projected median overall survival (OS) of 23 months. Marrow and blood (T cell) chimerism studies at day +100 revealed that both in the lower-dose Clo groups (groups 1+2) and the higher-dose Clo groups (groups 3+4), the patients had a median of 100% donor (T cell)-derived DNA. There has been no secondary graft failure. In the first 100 days, 1 patient died of pneumonia, and 1 of liver GVHD. We conclude that (1) Clo ± Flu with i.v. Bu as pretransplant conditioning is safe in high-risk myeloid leukemia patients; (2) clofarabine is sufficiently immunosuppressive to support allo-SCT in myeloid leukemia; and (3) the median OS of 23 months in this high-risk patient population is encouraging. Additional studies to evaluate the antileukemic efficacy of Clo ± Flu with i.v. Bu as pretransplant conditioning therapy are warranted.

From He Danamacoe Wom gery, Wom planta Ander Cance and M Unive Roche Progr New vices Cente New Colle of Bl Tamp Approved Octob Financial d *Task For Correspon FRCP Bosto Received N 2011 Am 1083-8791 doi:10.101 Generic Immunosuppressants in Hematopoietic Cell Transplantation Corey Cutler,* Aaron Kesselheim, Steven Gabardi, Borje S. Andersson, Paul Carpenter, Hanna J. Khoury, Mark Litzow, Scott D. Rowley, Scott Lanum, Helen Leather, Ya-Chen Tina Shih, Robert Peter Gale, John R. Wingard, Frederick R. Appelbaum, Claudio Anasetti

Anti-Tumor Necrosis Factor Alpha (TNF-alpha) therapy with infliximab has shown to be effective for patients with steroid-refractory acute graft-versus-host disease (aGVHD). An open-labeled, phase III trial was conducted to determine if the addition of infliximab to steroids could improve results for patients with newly diagnosed grade II-IV aGVHD. A total of 63 patients were randomized either to 2 mg/kg/day methylprednisolone (MP) or infliximab+ MP. Average age was 47 years (range: 20-70 years); 64% were male. Fifty-three percent and 51% of patients received a matched-sibling and/or bone marrow (BM) graft. Sixty-seven percent had grade II, 33% grade III-IV aGVHD; 62% had skin, 53% gastrointestinal (GI), and 7% had liver involvement. At days 7 and 28, the response rate for infliximab+ MP versus MP was 52% versus 78%, P=.03 and 62% versus 58%, P=.7, respectively. Cumulative incidences of GVHD-related mortality, nonrelapse mortality (NRM), and overall survival (OS) were not significantly different between the 2 groups (GVHD-related mortality: 38% versus 32%, P=.6; NRM: 52% versus 36%, P=.3; OS: 17% and 28%, P=.4 for infliximab+ MP versus MP, respectively). Patients with newly diagnosed aGVHD derive no benefit from the addition of anti-TNF-alpha therapy with infliximab when compared to corticosteroids alone.

Lenalidomide is an agent that has shown great activity in patients with multiple myeloma (MM). However, studies have suggested that this drug negatively affects subsequent stem cell collection. To investigate whether lenalidomide impairs stem cell mobilization and collection, we reviewed data for patients with MM who underwent mobilization with filgrastim. Predictors of mobilization failure were evaluated using logistic regression analysis. In 26 (9%) of 302 myeloma patients, stem cell mobilization failed. Mobilization failed in 25% of patients who had previously received lenalidomide, compared with 4% of patients who had not received lenalidomide (P < .001). In a multivariate analysis, prior lenalidomide use (odds ratio: 5.9; 95% confidence interval [CI]: 2.4-14.3) and mobilization more than 1 year after diagnosis (odds ratio: 4.6; 95% CI: 1.9-11.1) were significantly associated with failed mobilization. Twenty-one of 26 patients in whom mobilization with filgrastim failed underwent remobilization with chemotherapy and filgrastim; in 18 (86%) of these 21 patients, stem cells were successfully mobilized and collected. In patients with multiple myeloma, prior lenalidomide therapy is associated with failure of stem cell mobilization with filgrastim. Remobilization with chemotherapy and filgrastim is usually successful in these patients.

The development of intravenous busulfan (Bu) and its incorporation in the preparative regimens for allogeneic stem cell transplantation has changed transplantation for myelogenous malignancies. Bypassing the oral route to achieve 100% bioavailability translated into improved control over drug administration, with increased safety and reliability of generating therapeutic Bu levels, maximizing antileukemic efficacy. Bu-nucleoside analog-based conditioning chemotherapy, thus far represented by fludarabine (Flu), is becoming the conditioning chemotherapy regimen of choice for patients with acute myelogenous leukemia (AML) at many transplant centers. The use of busulfan Bu-based conditioning is extending rapidly also to hematopoietic stem cell transplantation (HSCT) for lymphoid malignancies, genetic diseases, and umbilical cord blood transplantation.

We postulated that fludarabine (Flu) instead of cyclophosphamide (Cy) combined with i.v. busulfan (Bu) as preconditioning for allogeneic hematopoietic stem cell transplantation (HSCT) would improve safety and retain antileukemic efficacy. Sixty-seven patients received BuCy2, and subsequently, 148 patients received Bu-Flu. We used a Bayesian method to compare outcomes between these nonrandomized patients. The groups had comparable pretreatment characteristics, except that Bu-Flu patients were older (46 versus 39 years, P < .01), more often had unrelated donors (47.3% versus 20.9%, P < .0003), and had shorter median follow-up (39.7 versus 74.6 months). To account for improved supportive care and other unidentified factors that may affect outcome (“period” effects), 78 acute myelogenous leukemia (AML) patients receiving Melphalan-Flu (MF), treated in parallel during this time (1997-2004) were used to estimate the period effect. The MF patients' outcomes worsened during this period. Therefore, the period effect is unlikely to explain the greatly improved outcome with Bu-Flu. Patients transplanted with Bu-Flu in the first complete remission (CR1) had a 3-year overall survival and event-free-survival (EFS) of 78% and 74%, respectively, whereas CR1 patients younger than age 41 had a 3-year EFS of 83%. These results support replacing BuCy ± ATG with Bu-Flu ± rabbit-antithymocyte globulin (ATG), and warrant a prospective comparison between allogeneic HSCT and conventional induction/consolidation chemotherapy for AML in CR1.

In pretransplantation therapy busulfan is typically given every 6 hours. We infused busulfan once daily at 130 mg/m2 for 4 days, performing pharmacokinetic analyses on plasma concentration-time data (n = 60 patients) on days 1, 3, and/or 4. Mean (percent coefficient of variation) maximum concentration, volume of distribution, half-life, and clearance were 3.6 microg/mL (13.8%), 22.6 L/m2 (20.2%), 2.73 hours (27.5%), and 109 mL/min/m2 (26%), respectively. The mean (percent coefficient of variation) and median daily areas under the curve were 4873 (21.8%) and 4871 microM x minute. Intrapatient variability in day-to-day estimated clearance was20%, without day-to-day drug accumulation. The pharmokinetic parameters were compared with those from 47 patients given intravenous busulfan at approximately 0.8 mg/kg (approximately 32 mg/m2) every 6 hours. We conclude that there is (1) a dose proportionality based on mean and median areas under the curve, (2) unchanged estimated clearance with a 4-fold increase in dose and a 2.5-fold difference in dosing rate, (3) negligible variability in dose-to-dose pharmacokinetics and negligible interdose accumulation with once-daily administration, and (4) no change in pharmokinetic parameter(s) with concomitant use of imidazole antifungals, oral contraceptives, or phenytoin. In summary, intravenous busulfan has highly predictable, linear pharmacokinetics from 32 mg/m2 (approximately 0.8 mg/kg) to 130 mg/m2 (approximately 3.2 mg/kg). Further, once-daily intravenous busulfan dosing is convenient, favoring its more widespread application.

Allogeneic progenitor cell transplantation is the only curative therapy for patients with refractory acute myelogenous leukemia or myelodysplastic syndromes. To identify prognostic factors in these patients, we performed a retrospective analysis of transplantation outcomes. Patients were selected if they had undergone an allogeneic transplantation between January 1988 and January 2002 and were not in remission or first untreated relapse at the time of transplantation. A total of 135 patients were identified. The median age was 49.5 years (range, 19-75 years). At the time of transplantation, 39.3% of patients had not responded to induction therapy, 37% had not responded to first salvage therapy, and 23.7% were beyond first salvage. Forty-one patients (30%) received unrelated donor progenitor cells. Eighty patients (59%) received either a reduced-intensity or a nonmyeloablative regimen. A total of 104 (77%) of 135 patients died, with a median survival time of 4.9 months (95% confidence interval, 3.9-6.6 months). The median progression-free survival was 2.9 months (95% confidence interval, 2.5-4.2 months). A Cox regression analysis showed that Karnofsky performance status, peripheral blood blasts, and tacrolimus exposure during the first 11 days after transplantation were predictive of survival. These data support the use of allogeneic transplantation for patients with relapsed or refractory acute myelogenous leukemia/myelodysplastic syndromes and suggest that optimal immune suppression early after transplantation is essential for long-term survival even in patients with refractory myeloid leukemias.

We investigated the pharmacokinetics (PK) of a recently approved intravenous busulfan (IVBU) formulation as a part of the preparative regimen in 20 children with advanced hematologic malignancies undergoing allogeneic hematopoietic stem cell transplantation. Seventeen patients received a thiotepa, IVBU, and cyclophosphamide-based regimen, and 3 patients received an IVBU and cyclophosphamide-based regimen. All patients received IVBU 0.8 mg/kg for the first 2 doses; thereafter, the IVBU dose was modified, if required, to achieve a final area under the concentration-time curve (AUC) at steady state of 1150 micromol/L/min per dose (range, 1000-1300 micromol/L/min per dose; SD +/-13%) based on the first-dose PK determination. PK studies were repeated on subsequent doses to verify the final AUC. Initial mean IVBU clearance and half-life were 3.96 mL/min/kg and 1.98 hours, respectively. Sixteen (80%) of the 20 patients received dose adjustments: 14 patients required dose escalations, and 2 required dose reductions. Overall, thirteen (72%) of 18 available sample sets at final follow-up PK analysis showed the IVBU exposure to be within the targeted range. IVBU PK was linear, and interpatient variability was much lower than that observed with oral busulfan. IVBU was well tolerated, and no case of hepatic veno-occlusive disease was encountered. Mild and transient hyperbilirubinemia was observed in 7 patients. Thirteen of the 20 patients were alive at a median follow-up of 651 days (range, 386-1555 days). We conclude that a standardized IVBU dose of 0.8 mg/kg in children does not always result in an AUC within the reference range defined in this study. Therapeutic drug monitoring with dose adjustment based on first-dose PK can optimize the systemic busulfan exposure for children undergoing allogeneic hematopoietic stem cell transplantation.

In this study, we evaluated the influence of nonmyeloablative and ablative conditioning regimens on the occurrence of acute and chronic graft-versus-host disease (GVHD). One hundred thirty-seven patients undergoing matched-related sibling transplantations received the same GVHD prophylaxis. Myeloablative regimens included intravenous busulfan/cyclophosphamide (n = 45) and fludarabine/melphalan (n = 29). Patients in the nonmyeloablative group (n = 63) received fludarabine/idarubicin/cytarabine, cisplatin/fludarabine/idarubicin, and fludarabine/cyclophosphamide. The actuarial rate of grade II to IV acute GVHD was significantly higher (hazard ratio, 3.6; 95% confidence interval, 1.5–8.8) in patients receiving ablative regimens (36%) compared with the nonmyeloablative group (12%). The cumulative incidence of chronic GVHD was higher in the ablative group (40%) compared with the nonmyeloablative group (14%). The rates were comparable within the first 200 days and were significantly higher in the ablative group beyond day 200 (hazard ratio, 5.2; 95% confidence interval, 1.2–23.2). Nonrelapse and GVHD-related mortality were relatively low in both groups. The use of the described nonmyeloablative preparative regimens was associated with a reduced incidence of grade II to IV acute GVHD and chronic GVHD compared with the busulfan/cyclophosphamide and fludarabine/melphalan transplant regimens. It is interesting to note that nonrelapse mortality with nonmyeloablative regimens in older and more debilitated patients was low (14%) and comparable to that achieved with standard high-dose regimens in younger patients

This phase I/II dose-escalation study examined the safety and efficacy of recombinant human thrombopoietin (rhTPO) and granulocyte colony-stimulating factor (G-CSF) for postchemotherapy mobilization of peripheral blood progenitor cells (PBPCs) in patients with advanced breast cancer. Patients received cyclophosphamide, etoposide, and cisplatin (CVP) followed by G-CSF (6 microg/kg twice a day) and rhTPO (0.6, 1.2, 2.4, or 3.6 microg/kg as a single dose on day 5 or as 3 doses on days 5, 7, and 9 after chemotherapy). PBPCs were collected by daily leukapheresis when the postnadir white blood cell count reached > or = 2 x 10(9)/L; leukapheresis was continued until acquisition of a target dose of > or = 5 x 10(6) CD34+ cells/kg. Mobilized PBPCs were transplanted into patients after additional high-dose chemotherapy with cyclophosphamide, carmustine, and thiotepa (CBT). Comparisons were made with contemporaneously treated, nonrandomized, control patients who received the same chemotherapy regimens and G-CSF support but who did not receive rhTPO. Of 32 evaluable patients receiving rhTPO and G-CSF after CVP, 91% required only 1 leukapheresis to achieve a target PBPC graft; by contrast, only 69% of 36 of the control patients achieved the target graft with just 1 leukapheresis (P = .026). A median of 26.7 x 10(6) CD34 cells/kg per leukapheresis was obtained from the rhTPO-treated patients compared with 11.5 x 10(6) cells/kg per leukapheresis from the controls (P = .09). Higher rhTPO doses appeared to yield more CD34+ cells. When PBPCs were infused after high-dose CBT chemotherapy, the median times to return of an absolute neutrophil count of 0.5 x 10(9)/L and a platelet count of 20 x 10(9)/L were 15 and 16 days, respectively; these values did not differ from those in the control group (15 days for both neutrophil and platelets). No patient developed anti-TPO antibodies. These results indicate that rhTPO safely and effectively augments the number of PBPCs mobilized with chemotherapy and G-CSF and can reduce the required number of leukaphereses. Further studies are also warranted in patients who are likely to experience suboptimal PBPC mobilization when treated with currently available techniques.Biol Blood Marrow Transplant 2002;8(10):550-6.

Complete bioavailability of i.v. busulfan (Bu) provides dose assurance by reducing the interdose and interpatient variability in Bu systemic exposure (Bu-SE) associated with the oral formulation. We hypothesized that Bu-SE, represented by the area under the plasma concentration versus time curve (AUC), would correlate with treatment outcome after allogeneic hematopoietic stem cell transplantation (HSCT) for chronic myelogenous leukemia (CML). Therefore, we analyzed the risk of death, incidence of regimen-related toxicity, and incidence of acute GVHD (aGVHD) as functions of the per dose i.v. Bu AUC in 36 CML patients who received a HSCT from an HLA-matched family donor after the i.v. BuCy2 regimen. Per-dose Bu AUCs were calculated for each subject using data obtained for doses 1, 5, 9, and 13. Toxicity was evaluated using the modified National Cancer Institute criteria. Because no patient developed veno-occlusive disease, increased serum bilirubin was used to characterize hepatotoxicity. We found that the probabilities of developing gastrointestinal toxicity (P = .01), hepatotoxicity (P < .01), mucositis (P = .09), and aGVHD (P < .01) all increased with increasing AUC. Further, the risk of death was significantly lower for patients having a per-dose AUC between approximately 950 and 1520 microMol-min, whereas the risk increased sharply with either lower or higher AUC values. These data suggest that an optimal Bu therapeutic window, based on per-dose AUC, exists. Given the ability of i.v. Bu to provide a more consistent per-dose AUC, these results should be useful in designing future i.v.V Bu-based treatment protocols for stem cell transplantation.Biol Blood Marrow Transplant 2002;8(9):477-85.

One hundred patients of median age 34 years (range, 14-53) received bone marrow transplants from unrelated donors serologically matched for human leukocyte antigen HLA-A, HLA-B, and HLA-DR using tacrolimus and minimethotrexate for prevention of acute graft-versus-host disease (GVHD). Sixty-eight patient-donor pairs had allelic matches at HLA-DRB1 and HLA-DQB1, 20 pairs had a single mismatch at HLA-DRB1 or HLA-DQB1, and 12 were mismatched at both HLA-DRB1 and HLA-DQB1. Minimum follow-up time was 6 months. Grades 2 to 4 GVHD occurred in 43% of patients with matched donors, 69% with single allele-mismatched donors, and 71% with double allele-mismatched donors; grades 3 to 4 GVHD occurred in 22%, 43%, and 64%, respectively. On multivariate analysis, the relative risk of grades 2 to 4 GVHD was 2.2 (95% CI, 1.1-4.5; P = .03) with a single allele mismatch and 2.7 (95% CI, 1.2-6.0; P = .02) with a double allele mismatch. The relative risks of grades 3 to 4 GVHD were 3.0 (95% CI, 1.2-7.6; P = .02) and 5.0 (95% CI, 1.9-12.6; P = .001), respectively. Day 100 treatment-related mortality was also adversely affected by allelic mismatching, occurring in 21% of those with matched donors, 50% with single allele-mismatched donors, and 42% with double allele-mismatched donors (P = .02), but overall survival at day 180 did not differ significantly among the 3 groups. Tacrolimus does not abrogate the adverse impact of allele mismatching at HLA-DRB1 and HLA-DQB1 on the risk of moderate-to-severe acute GVHD.Biol Blood Marrow Transplant 2000;6(2A):190-7.

s / Biol Blood Marrow Transplant 21 (2015) S185eS205 S196 and low TRM and should be further investigated in prospective clinical trials.