We hypothesized that IV Busulfan (Bu) dosing could be safely intensified through pharmacokinetic (PK-) dose guidance to minimize the inter-patient variability in systemic exposure (SE) associated with body-sized dosing, and this should improve outcome of AML/MDS patients undergoing allogeneic stem cell transplantation (allo-HSCT). To test this hypothesis, we treated 218 patients (median age 50.7 years, male/female 50/50%) with fludarabine (Flu) 40 mg/m2 once daily ×4, each dose followed by IV Bu, randomized to 130 mg/m2 (N=107) or PK-guided to average daily SE, AUC of 6,000 µM-min (N=111), stratified for remission-status, and allo-grafting from HLA-matched donors. Toxicity and graft vs. host disease (GvHD) rates in the groups were similar; the risk of relapse or treatment-related mortality remained higher in the fixed-dose group throughout the 80-month observation period. Further, PK-guidance yielded safer disease-control, leading to improved overall and progression-free survival, most prominently in MDS-patients and in AML-patients not in remission at allo-HSCT. We conclude that AML/MDS patients receiving pretransplant conditioning treatment with our 4-day regimen may benefit significantly from PK-guided Bu-dosing. This could be considered an alternative to fixed dose delivery since it provides the benefit of precise dose delivery to a predetermined SE without increasing risk(s) of serious toxicity and/or GvHD.

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7540 Background: Patients (pts.) with advanced CTCL have a poor prognosis. There has been limited experience with the use of allogeneic hematopoietic stem cell transplantation (HSCT) in these pts. We report the results of 11 pts. with advanced CTCL/Sezary syndrome who underwent allogeneic HSCT at our institution. Patients and Methods: All pts. signed informed consent. Median age at the time of HSCT was 50.5 years (range, 22–63). There were 8 F/3M. All were diagnosed with stage IV disease. The median number of prior treatment regimens was 5.5 (range, 3–11). Treatment regimens included PUVA, TSEB, ECP, topical therapy, retinoids, bexarotene, denileukin diftitox, and multiagent chemotherapy. Seven pts. had a PR to treatment administered prior to transplantation, 2 pts. were in CRu and 2 pts. had SD. The conditioning regimen was fludarabine (125 mg/m2), melphalan 140 mg/m2 in 8 pts., fludarabine (125 mg/m2), cyclophosphamide (3 g/m2) ± rituximab in 2 pts., and fludarabine (120 mg/m2), busulfan (11.2 mg/m2) in 1 pt. Patients who received unrelated or mismatched related stem cells also received ATG. GVHD prophylaxis was with tacrolimus/methotrexate in all patients. Results: Ten of 11 pts. engrafted with a median time to ANC >500 mm3 of 12 days (range, 8–14). One pt. died at 17 days post transplant without engraftment due to sepsis. One pt. developed autologous reconstitution and underwent a 2nd allogeneic HSCT procedure and remains in CR at 3 years post transplant. Of the remaining 9 pts., 7 achieved full donor chimerism and 2 pts. were mixed chimera. At the time of this report 4 of 11 pts. have died. Cause of death was sepsis in 2, fungal pneumonia in 1, and PD in 1 pt. Three pts. relapsed post transplant, all 3 were induced back in to a CR by tapering of immunosuppression (2) or DLI (1). Overall 7 pts. continue to be alive and remission with a median follow up of 2.9 years (range, 3 months to 4.4 years). Four of 7 pts. have cGVHD requiring treatment (Table). Conclusions: Allogeneic HSCT is an effective therapy for refractory CTCL/SS and merits further evaluation. [Table: see text] No significant financial relationships to disclose.

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3106 Background Allogeneic stem cell transplantation (SCT) is potentially curative for patients with CML who fail tyrosine kinase inhibitor (TKIs) treatment but remain in chronic phase (CP). In addition, TKI may ‘downstage’ advanced disease, creating a window of opportunity for SCT in second CP (CP2). Sequential therapy, as proposed by Champlin et al (ASH 2009), using a reduced intensity preparative regimen, followed by low dose donor lymphocyte infusion (DLI) is well tolerated and associated with prolonged disease control, especially for patients in CP1. There is preclinical and clinical evidence that hypomethylating agents have immunomodulatory effects when given after SCT (de Lima, Cancer 2010). We then hypothesized that low dose 5-azacitidine (AZA) given early after SCT will induce a more rapid and durable molecular complete remission (molCR). Patients and Methods Objective: To increase the frequency of achievement of molCR following reduced intenstity allogeneic SCT. Eligibility: CML in CP who had failed to respond to treatment with one or more TKI. Patients received a preparative regimen of fludarabine 40 mg/m2 × 4 days, busulfan 130 mg/m2 × 2 days, and thymoglobulin 2.5 mg/kg daily × 3 days followed by allogeneic SCT from an HLA matched related or unrelated donor. Graft-versus-host disease (GVHD) prophylaxis was tacrolimus and mini-methotrexate (5 mg/m2 on SCT days 1, 3 and 6 and 11). Those not in molCR 30 days after SCT receive AZA 32 mg/m2 every 28 days for four cycles starting on day +35. Patients were required to have engraftment and initial hematologic recovery, stable organ function and no active GVHD to start AZA treatment. Patients were treated between 2/09 - 9/10, and those with at least 6 months of follow-up are presented here. Results 15 patients were entered on study. Eight patients received AZA for a median of 4 cycles. Seven patients did not receive AZA: two were in molCR post transplant, 2 had hematologically progressive disease, 2 were cytopenic, which precluded AZA and 1 patient declined. AZA was administered outpatient with minimal, reversible toxicity: grade I/II/III thrombocytopenia (37.5%), grade I nausea (25%) and grade I fatigue (25%). Grade II-IV acute GVHD occurred in 10 pts. Four AZA patients subsquently received DLI (1 × 107 CD3 cells/Kg) and 75% (3 of 4) converted to MolCR and cytogenetic CR. 7 of the 8 patients that received AZA achieved a MolCR with median follow-up of 12.6 months (range, 3.4–24), compared with MolCR of 57% for those that didn't receive AZA. (Figure 1: cumulative incidence of MolCR) (Table 1). Thirteen patients are alive with a median of 25 months of follow-up (Figure 2) and two died of CML. One patient with overt relapse of chronic phase CML received a second transplant and is alive in MolCR. Conclusion Azacitidine is well tolerated post nonmyeloablative SCT and may contribute to achieveent of molCR. Larger number of patients and longer follow-up are necessary to define the efficacy of this intervention. Disclosures: De Lima: Celgene: Research Funding. Off Label Use: azacitidine used post transplant.

BACKGROUND: Both autologous and allogeneic stem cell transplantation (SCT) are potentially curative treatment options for patients with hematologic malignancies. Due to a high risk of regimen-related toxicity, only patients with satisfactory organ-system function are considered eligible for this treatment. A low left ventricular ejection fraction (LVEF) of ≤ 45% is considered to be a major risk factor for post-transplant cardiac toxicity and non-relapse mortality (NRM). However, many patients with advanced hematologic malignancies and low LVEF can potentially benefit from this therapy. To address this issue, we studied the incidence of cardiac toxicity and NRM in 89 patients with low LVEF undergoing SCT. METHODS: We performed a retrospective analysis on 89 patients with impaired cardiac function, who underwent an autologous (33 patients) or allogeneic (56 patients) SCT between January 2000 and February 2006 at our institution. Pre-transplant evaluation included bidimensional echocardiogram and an electrocardiogram. Cardiac toxicity was defined as congestive heart failure (CHF), atrial/ventricular arrhythmia or acute myocardial ischemia. In the allogeneic group, 22 patients received a myeloablative (16 busulfan-based, 6 TBI-based), while 34 patients received a fludarabine-based reduced-intensity preparative regimen. Twenty-three patients (41%) received allo SCT from an unrelated donor. The majority of patients in the autologous group received BEAM (with rituximab or IL-2) based regimen (24 patients) and 6 patients received high dose melphalan. RESULTS: 57% of the allogeneic transplants were for acute leukemia. 76% of autologous transplant recipients had Hodgkin’s or non-Hodgkin’s lymphoma. Baseline LVEF, within 30 days prior to SCT, ranged from 20 to 45%. After a minimum of 6-month follow up, cardiac toxicity was seen in 6 patients in the auto SCT group and 6 patients in the allo SCT group (13%). In 9 of the 12 patients toxicity occurred within 60 days of SCT. Major causes of cardiac toxicity were CHF in 6 patients (7%) and atrial fibrillation in 5 patients (6%). Two patients had both CHF and AF. There were no documented episodes of acute myocardial ischemia. Median time to develop a cardiac event was 23 days from SCT (range, 9–200 days). Cumulative incidence of NRM at 100 days was 15% (95% CI 9–24). Only 1 death was directly attributable to a cardiac cause. These results are comparable to SCT performed in patients with normal LVEF. On univariate analysis age > 60 years at the time of SCT and history of smoking were significant predictors for development of cardiac toxicity after SCT. Prior history of smoking remained significant on multivariate analysis (HR 5.7, 95% CI 1.2–29, P=0.03). LVEF, type of transplant or the underlying disease did not emerge as significant predictors of post-transplant cardiac toxicity or NRM. Median survival was worse in patients who developed cardiac complications after SCT (median survival 108 days versus 889 days respectively). CONCLUSIONS: Both allogeneic and autologous SCT are feasible in patients with hematologic malignancies and low LVEF. A prospective study with stratification for cardiac risk factors is warranted in patients with low LVEF.