ALBERT

Description: Abstract 3415 Poster Board III-303 High dose chemotherapy and SCT is an accepted treatment option for patients with relapsed lymphoid malignancies. Relapse remains a significant issue for patients with advanced disease. Predicting effective disease control with improved safety, we investigated the administration of intravenous (i.v.) busulfan (Bu) combined with melphalan (Mel) in patients with lymphoid malignancies undergoing ASCT. Patients and Methods Bu130 mg/m2 was infused daily for 4 days, either as a fixed dose per BSA (n=20), or to target an average daily AUC of 5,000 uMol-min ± 12% determined by a test dose of i.v. Bu at 32 mg/m2 given 48 hours prior to the high dose regimen (n=82), followed by a rest day, followed by two daily Mel doses at 70mg/m2. Stem cells were infused the following day. Dilantin was given for seizure prophylaxis. Results 102 patients (38 F/64 M) with non-Hodgkin's lymphoma (n=12), Hodgkin's lymphoma (n=49) and multiple myeloma (n=41) with median age 44 years (range 19-66) have been enrolled to date. The median number of prior chemotherapy regimens was 3 (range 1-6). At time of study entry, 88% of patients were in relapse (sensitive relapse n=70, refractory relapse n=19) and 12% were in second remission. The median CD34+ cell dose infused was 5.2 × 106/kg (range 0.7-12.5). Median days to ANC ≥ 0.5 × 109/L and platelet count ≥ 20 × 109/L were 10 (range 8-44) and 9 (7-141), respectively. There was no grade IV or V toxicity. The most commonly observed toxicities were grade I or II nausea and vomiting (77%), mucositis (67%), and diarrhea (55%)., Reversible grade III liver enzyme abnormalities were observed in 4% of patients; one patient developed reversible VOD. With a median follow-up of 2.1 years (range 0.2-4.3), the cumulative incidence of treatment-related mortality (TRM) at 100 days, 1 year, and 2 years was 1.0%, 3.1%, and 4.3%, respectively. Among patients with non-Hodgkin's or Hodgkin's lymphoma, the overall response rate was 90%, with 1- and 2-year PFS rates of 63% and 58%, respectively; 1- and 2-year OS rates were 90% and 82% respectively (Figure 1). PFS was significantly better in patients with chemo-sensitive lymphoma, 61% vs. 42% at 2 years, p=.03. Among patients with multiple myeloma, the overall response rate was 58%, with 1- and 2-year PFS rates of 67% and 44%, respectively; 1- and 2-year OS rates were 90% and 82%, respectively. Survival rates were not significantly different between the chemo-sensitive and chemo-refractory multiple myeloma patients. Conclusion Intravenous busulfan-melphalan is well-tolerated, and the individualized PK-directed dosing of i.v. busulfan likely contributes to the low toxicity profile of this regimen. The high response rate and disease control in patients with advanced disease is encouraging, and should be explored in larger phase II studies. Disclosures Andersson: Otsuka Pharmaceuticals: Consultancy.

Description: CBT is frequently complicated by delayed and failed engraftment when compared to other sources of hematopoietic stem cell support. Strategies to improve engraftment include double CBT and ex-vivo expansion. We are comparing these approaches in a randomized, prospective fashion. Patients (N=71) were randomized to receive either two unmanipulated (UNM) CB units (N=36) or one UNM unit and one unit which was EXP ex-vivo (N=35). The majority of CB units were 4/6 HLA matches. Methods: Diagnoses were AML/MDS (N=25; 35%), ALL(N=17; 24%), NHL(N=10; 14%), HD(N=7; 10%), CML (N=5; 7%), and CLL(N=7; 10%). Patients (Table 1) had primarily advanced disease, with a median of 3 (1–8) prior regimens including autotransplants in 22%. Preparative regimens included ATG and either myeloablative fludarabine plus dose-adjusted busulfan (N=13; myeloid diseases), or melphalan and thiotepa (N=28); patients not eligible for high-dose therapy received non-myeloablative fludarabine plus cyclophosphamide and 200 Gy TBI (=27) or melphalan (n=3). GVHD prophylaxis was tacrolimus plus either 3 doses of 5 mg/m2 methotrexate or MMF (table 1). Ex-vivo expansion: the smallest unit was CD133-selected using the CliniMACS device (day −14). The T cell-containing CD133-negative fraction was frozen. The CD133+ fraction was cultured for 14 days in media containing SCF, G-CSF and TPO. On day 0, the 2nd UNM unit was infused, followed by the CD133-negative and the EXP fractions. Results. Infused median total nucleated cells (TNC)×107/Kg was 3.5 and 3.6, and median CD34×105/Kg was 1.8 and 1.1, respectively for EXP and UNM pts. Median TNC fold-expansion was 23 (0.44–275) and for CD34+ cells, 2.3 (0–957). The median ex-vivo fold expansion of patients that engrafted platelets was higher than patients that did not engraft (23 (range, 0.4–275) versus 9.3 (range, 1.1–63), P=0.4). Patients that received EXP cells and a reduced-intensity regimen engrafted neutrophils in a median of 7 days (range, 4–15 days; n=14) versus 14 days (range, 5–32 days; n=12) in the UNM arm (P=0.05). Thirty-four patients are alive (48%) with a median follow up of 11.3 mo (range, 2–49 months). Twenty-four patients have relapsed (34%). Chimerism analysis showed that ultimately one CB unit dominated in all patients, on both the UNM and EXP arms of the trial. For the EXP arm the majority of patients had evidence of expanded CB chimerism posttransplant ranging from 7–82%. In half of those patients, the expanded CB unit predominated over the unmanipulated unit for 2–12 months posttransplant (52–87%), followed by gradual predominance of the unmanipulated CB unit by 14 months in all patients. Conclusion: Conclusion: EXP CBT was safe. The range of fold-expansion was highly variable. Accrual continues and we are focusing on strategies which improve CB expansion. Expanded Unmanipulated P Complete remission at UCBT 41% 59% 0.09 Median weight 85 (20–168) 76 (15–144) 0.18 Median age 43 (4–70) 38.1 (2–73) 0.4 Ablative preparative regimen 47% 68% 0.09 GVHD prophylaxis with methotrexate 32% 30% NS Time to ANC500 (median/95%CI) 14 days (4–32) 17 (5–45) 0.2 Proportion engrafting ANC500 80% 86% NS Time to PLT20K (median/95%CI) 34 (4–70) 34 (27–134) NS Proportion engrafting PLT 69% 55% 0.2 1-year survival 60% (40–75) 46% (27–63) 0.2 2-year survival 55% 20% 0.1 aGVHD gd II–IV/III–IV 43%/7% 43%/17% NS C.Incid. cGVHD 45% (28–78) 25% (15–65) 0.1 C.Incid.: cumulative incidence

Description: The use of reduced intensity conditioning has resulted in a significantly lower incidence of severe acute GVHD (aGVHD) compared with myeloablative conditioning. It is not known if reduced toxicity myeloablative conditioning has a similar impact. To answer this question, we evaluated the incidence of acute and chronic GVHD in a homogeneous group of AML/MDS patients treated with Fludarabine (Flu) and IV Busulfan (IVBu) between April 2001 and August 2005 at MD Anderson Cancer Center. METHODS: Retrospective analysis of all 195 consecutive AML/MDS patients (pts) who received conditioning with IVBu (130 mg/m2 for 4 days) and Flu (40 mg/m2 for 4 days) and allogeneic stem cell transplantation (ASCT). The cumulative incidence of GVHD was estimated considering disease progression or death in the absence of GVHD as competing risks. Cox’s proportional hazards regression analysis was used to compare the rates of GVHD. RESULTS: Median age at the time of transplantation was 46 years (12–65) with 4 pts being younger than 18 years. 45% of pts (n=93) were females and 47% (n=92) were in complete remission at the time of transplant. 55% (n=107) received a graft from a matched related donor (MRD), 38% (n=74) from a matched unrelated donor (MUD), and 7% (n=14) from a 1 Ag mismatched related or unrelated donor. Stem cell source was peripheral blood in 85% of recipients of a MRD graft and bone marrow in 88% of recipients of a MUD graft. The median number of CD34+ cells infused was 4.6 x 106/Kg (range 1.1–8.9) and 3.8 x106/Kg (range 0.2–13) in the two groups respectively. GVHD prophylaxis consisted of tacrolimus and mini-methotrexate. In addition, 29/74 recipients of a MUD graft received varying doses of pentostatin on a phase I/II clinical trial. Evaluation of GVHD was limited to pts who received a graft from a MRD or MUD and engrafted (n=179/181). With a median follow-up among survivors of 48 months (range 16–80), 100 day actuarial survival was similar in recipients of a MRD (96%) and MUD (93%) graft (p=0.3). A total of 50 pts (28%) developed grade II-IV and 15 pts (8%) grade III-IV aGVHD within 100 days after ASCT. Donor type was the most significant predictor of the incidence of grade II-IV aGVHD with a cumulative incidence of 18% (95% CI: 12–27) in recipients of a MRD graft and 38% (95% CI: 29–51) in recipients of a MUD graft (HR=0.4, p=0.001). Similarly the rate of grade III-IV aGVHD was significantly lower in recipients of a MRD graft (4% vs. 15%, HR=0.2, p=0.007). In contrast, donor type did not impact the incidence of chronic GVHD with a comparable cumulative incidence by 2 years in recipients of a MRD (53%, 95% CI: 44–63) and MUD graft (45%, 95% CI: 35–58), (HR=0.9, p=0.8). Similar results were observed when the comparison was restricted to de novo chronic GVHD (n=32). Use of peripheral blood stem cells was the only significant factor associated with a higher rate of chronic GVHD in recipients of a MRD graft (56% vs. 35%; HR=2.5, p=0.03). Female gender was associated with a significantly lower rate of chronic GVHD in recipients of a MUD graft (HR=0.4, p=0.006). There was no significant impact for age, percent donor chimerism at the time of engraftment, diagnosis (AML versus MDS), or donor/recipient CMV serostatus on the rate of grade II-IV aGVHD or chronic GVHD. CONCLUSION: The incidence of grade II-IV aGVHD is low following IVBuFlu conditioning and ASCT in AML/MDS patients. In this setting, donor type affects the incidence of acute but not chronic GVHD. Figure Figure

Description: Autologous SCT with Mel 200 mg/m2 conditioning is considered standard consolidation treatment for MM pts. However, Mel 200 results in response rates of 20–40%, with nearly all pts ultimately relapsing. A double alkylating regimen of IV Bu and Mel has been suggested as an effective and myeloablative pre-transplant conditioning regimen. The IV formulation of Bu has less pharmacokinetic variability, and results in less toxicity, specifically less hepatic and mucosal toxicity. Patients and Methods: The conditioning regimen consists of IV Bu 130 mg/m2 over 3 hr daily for 4 days, either as a fixed dose per BSA, or to target an average daily AUC of 5,000 μMol-min ± 12% determined by a test dose of IV Bu at 32 mg/m2 given 48 hours prior to the high dose regimen. After the four daily Bu doses, there is a rest day, followed by two daily doses of Mel at 70mg/m2. Stem cells are infused the following day. Dilantin is administered for seizure prophylaxis. Results: 25 pts (16 M/9 F) with median age 53 years (range 31–64) have been treated. Salmon-Durie stage at diagnosis was I (n=6), II (n=11), and III (n=8); B2M at diagnosis was available for 16 pts, median 2.8 (range 1.4–5.2). The median number of prior chemotherapy regimens was 2 (range 1–5). At time of study entry, 20 pts were in partial remission, and 5 had refractory disease. The median CD34+ cell dose infused was 5.00 × 106/kg (range 2.5–7.7). Median days to ANC ≥ 0.5 × 109/L and platelet count ≥ 20 × 109/L were 10 (range 8–13) and 9 (7–23), respectively. Eighteen pts had IV Bu delivered per test dose guidance, with a median first dose systemic Bu exposure of 4606 μMol-min (range 4008–5601), necessitating a secondary adjustment to achieve an average daily AUC of 5000 μMol-min +/−12% in 6 pts. Median Bu clearance was 94 ml/min/m2 (range 83–113). Seven pts received fixed dose Bu at 130 mg/m2. With median follow-up time of 3 months, 17 pts are evaluable for response based on EORTC consensus criteria that mandate a response maintained for at least 6 weeks (BJH1998, 102:1115): 1 complete response, 6 partial response, 1 minor response, 7 stable disease, and 2 progressive disease. The treatment was well tolerated, with grade II or III diarrhea (n=6), mucositis (n=7), and nausea (n=9) being the most common regimen-related toxicities. Transient ascites concurrent with chemotherapy administration in a pt with refractory disease and high tumor mass was the only noted possible hepatic toxicity. Carbon monoxide diffusion capacity (DLCO) was measured to evaluate for pulmonary toxicity in 16 pts. At 3 months post study, asymptomatic grade II and III pulmonary toxicity was noted in 2 and 1 pts, respectively; 1 pt was not evaluable due to concurrent pneumonia. No grade IV toxicities or deaths have been observed. Conclusion: Intravenous Bu-Mel is well tolerated, and individualized PK-directed dosing of IV Bu likely contributes to the low toxicity profile of this regimen. Although the final best response may be too early to evaluate, the preliminary response data in this group of poor prognosis MM pts suggest it is an effective conditioning regimen.

Description: Background and Rationale: Stem cell transplantation using alternative sources of stem cells from haploidentical relatives is an established therapy for high risk leukemia patients who lack a matched related or unrelated donor. Although efforts have been made to improve the engraftment rate in haploidentical stem cell transplantation, approximately 10–20% of these patients fail to achieve primary engraftment. The causes for this higher rate of graft failure are currently unknown. We hypothesized that anti-HLA antibodies directed against donor specific antigens (DSA) are a possible cause for graft failure in such patients. Materials and Methods: Twenty-two consecutive patients who received a T-cell depleted haploidentical graft at our institution after 9/2005 were evaluated prospectively for presence of DSA. The patients received a conditioning regimen consisting of fludarabine, melphalan and thiotepa previously described, and megadoses of CD34+ cells. The presence of antibodies against DSA was determined by testing the patients’ sera with a panel of fluorescent beads coated with single HLA antigen preparations using a Luminex™ platform; results were interpreted as fluorescence intensity (FI) against DSA mismatch. FI less then 500 was considered negative, while positive FI ranging 500–1500, 1500–3000 and 〉3000 were classified as weak, intermediate and strong, respectively. HLA A, B, C, DRB1, DRB3/4/5, DQB1 and DPB1 were typed by high resolution methods. Results: Of the 22 treated patients, 6 experienced primary graft failure (PGF). Five of these patients, all females with median age 39 years (range 26–50), were identified to have intermediate or strong FI anti DSA. The anti-HLA antibodies identified were directed against both HLA class I and II antigens, most commonly anti-HLA DRB1 (Table 1). After the first patient was identified to have graft failure in the presence of DSA, treatment with rituximab and plasma exchange was initiated in an attempt to decrease DSA titers and achieve engraftment. Subsequently, four patients were treated in this fashion, two of which had a significant decrease in antibody titers and achieved engraftment. The remaining 2 patients experienced also PGF. All 3 patients who had PGF underwent a second transplant from the same donors. In one of these patients who experienced two graft losses, the DSA was strong before the first transplant decreased significantly a few days after transplantation and returned to the intermediate FI range before the second transplant. Overall, 4 of 6 (67%) haploidentical transplants performed in the in the presence of DSA, and 4 of 4 (100%) transplants performed in patients with moderate to high DSA titers failed to achieve engraftment. Rituximab and plasma exchange appeared to decrease the DSA in 2 of 4 patients with moderate titers, enough to allow engraftment (Table 1). No significant differences were found in the number of CD34+ cells infused, number of allele mismatched, and number of bone marrow blasts present at the time of transplant between the PGF and the control group. The fact that all patients with DSA were females prompted a review of the pregnancy history. The median number of pregnancies was 3 in the PGF group (N=5) as compared with 0 in the control group (N=6) (P=0.1). In addition, a review of the transfusion history to explain a possible alloimmunization at least in one patient without prior pregnancies, identified a median of 37 units (range 17–65) transfused in the PGF group (N=5) as compared with 15 the control group (range 4–38) (N=16) (P=0.007). Conclusion: Donor specific anti-HLA antibodies appear to play an important role in preventing engraftment in patients receiving a (T-cell depleted) haploidentical stem cell transplant. Figure 1. Relationship between HLA antibody titers and engraftment in 5 patients who received a total of eight haploidentical transplants at MDACC. Pt # AB type Initial titer R/PE Titer after R/PE/pre first SCT Engrafted Y/N Titer after first SCT/Pre second SCT Engrafted Y/N Legend: AB – antibody, R – rituximab, PE – plasma exchange, NT – not tested 1 A*3201 N/A N + + + N NT Y 2 A*0211 + + + Y + + N + + N B*391301 + + + + + + + + Cw*0702 + + + NT NT DRB1*0404 + + + 3 DRB1*0701 + + Y - Y N/A N/A DRB1*0701 + + + + + - 4 DRB4*0101 + + + Y + + + N - Y DQB1*0202 + + + + + + - DRB1*0401 + + +/− (borderline) 5 DRB4*0103 + + Y + Y N/A N/A DPB1*0401 + + + + + +

Description: Older age (e.g. 〉 55–60 yrs) is a commonly cited indication for reduced-intensity conditioning regimens (RIC) in the treatment of myeloid leukemias. These diseases, however, may benefit from the highest possible dose intensity that can be safely delivered. Here we analyze our experience treating patients (pts) older than 55 yrs. with intravenous (IV) busulfan (Bu)-based preparative regimens. Methods: Fifty-six pts older than age 55 yrs. with MDS (n=13), AML (n=33), or CML/myeloproliferative disorder (n=10) were transplanted from 6/1997 to 12/2004 on two consecutive protocols. Conditioning were IV fludarabine (Flu) 40 mg/m2 and IV Bu 130 mg/m2 over 3 hr (days -6 till -3) given once daily (BuFlu; n=36), and IV Bu 0.8 mg/kg over 2 hr every 6 hr for 16 doses (days -7 till -4), followed by Cyclophosphamide (Cy) 60 mg/kg on days -3 and -2 (IV BuCy2; n=20). Pts with an unrelated (UD) or mismatched donor received ATG. Graft-versus-host disease (GVHD) prophylaxis was based on tacrolimus and mini-methotrexate. Results: Median age was 58.4 yrs (55–66.8); 14 pts were older than 60 yrs. Most pts were not in complete remission (CR) at BMT (n=38, 68%, with similar distribution in pts older and younger than age 60). Donors were HLA-compatible siblings (SIBS) in 59% (n=33) and UD in 41% (n=23). UD were used in 5 pts 〉59 yrs (36%) and in 18 〈 60 yrs (43%). Stem cell source was bone marrow (n=23) or peripheral blood (n=33). All but one pt had documentation of donor cell engraftment. Median follow-up of surviving pts (June 2005) was 15 mos (range, 4–49; n=23). Grade II-IV acute (a) and chronic (c) GVHD rates were as follows (pts 59 yrs): 38% vs 64% and 45% vs 54%, respectively. 100-day treatment-related mortality (TRM) was 11% (due to graft rejection (n=1), toxicity (n=2); pulmonary hemorrhage with fungal pneumonia (n=1) and aGVHD (n=2). All early 100-day TRM pts were 〈 60 yrs. Overall, 17 pts relapsed and 33 pts have died. One-year TRM: 29%, n=16 (due to GVHD, n=7, infections, n=4; rejection, n=1; unknown causes, n=1; toxicity, n=2, bleeding, n=1). Only 2 pts 〉 59 yrs are alive, while the others died of cGVHD (n=5) and disease relapse (n=7). Conclusion: In this older population of predominantly relapsed pts with myeloid leukemias, major cause of treatment failure was not the preparative regimen employed, but GVHD and disease relapse. An association between intensity of the regimen, age and GVHD cannot be ruled out in this analysis. These results would suggest that age per se should not be used as the main reason for selecting a reduced intensity regimen in patients up to at least age 60 with myeloid leukemias. Figure Figure

Description: The HLA class II DP locus encode for both subunits of DPB1 heterodimers, which have low levels of expression on the cell surface of antigen presenting cells. We hypothesized that donor-recipient HLA-DP mismatch would lead to an increased incidence of acute (a) graft-versus-host disease (GVHD), and that 2 mismatches would likely be even more significant. Methods: We studied 84 consecutive patients (pts) with myeloid leukemias in complete remission (CR) transplanted from 01/02 to 02/06. Preparative regimens were ablative IV Busulfan-based (n=58) or Cy/TBI (n=2), and reduced intensity (Fludarabine (Flu)/Bu 130 mg/m2/2 doses plus Gleevec (n=8), and Flu/Melphalan 140 mg/m2 (n=16). Stem cell (SC) source was bone marrow (n=70) or peripheral blood (n=14). ATG was given in 78 cases. GVHD prophylaxis was tacrolimus and mini-methotrexate in all cases, with additional pentostatin in 31 pts. High-resolution typing was sequence-based for HLA-A, B, DRB1; SSP was used for DRB3/4/5, DQB1 and DPB1, and SBT/SSOP for HLA-C. A Cox proportional hazards regression model was used to study aGVHD-free and relapse-free (RFS) survival. Variables with a p-value 1st chronic phase (CP). Sixty-one pts were 10/10 HLA match (A, B, C, DRB1, DQB1), and 23 had one or more mismatches. All but one pt engrafted neutrophils at a median of 13 days. 33 pts (39%) and 13 pts (15%) developed grade II–IV and III–IV aGVHD, respectively. Chronic GVHD incidence was 51%. With a median follow-up of 18 mo. (range,1.3–52) 60 pts are alive; 40 pts have relapsed or died. Median survival has not been reached. Number of DP mismatches and incidence of aGVHD is shown in the table. The following covariates influenced aGVHD-free survival by MV analysis: Flu-based regimen (P=0.005; HR 0.25 (95%CI 0.1–0.66), reduced intensity regimens (p=0.02; HR 0.35 (95%CI 0.15–0.83) and presence of 2 DPB1 mismatches (p=0.02; HR 3.07 (95%CI 1.19–7.95). Presence of 1 DPB1 mismatch was not significantly associated with aGVHD. There was no statistically significant correlation between presence of 2 DP mismatches and RFS (P=0.17;HR 0.3 (95%CI 0.06–1.65);HR 0.75 for 1 mismatch) or with cGVHD. Actuarial 2-yr survival for 10/10 matched pts without DP mismatches (12/12) versus those with DP mismatches is 82% versus 71%(P=0.6). In the 10/10 matched group, GVHD was the cause of death only among recipients of 2 DP mismatches transplants (n=4). Conclusion: Mismatching at HLA-DPB1 may increase the risk of aGVHD following UDT. The role of DP in the development of GVHD and GVL effects merits future study. Incidence of acute GVHD 10 of 10 matches number of DP mismatches grade II–IV grade III–IV 0 8% 0% 1 23% 8% 2 45% 18% 〈 10 of 10 matches number of DP mismatches grade II–IV grade III–IV 0 45% 15% 1 82% 36% 2 80% 40%

Description: Introduction: Patients undergoing ASCT for CML are increasingly likely to have received a NTKI after failing imatinib mesylate. It is unknown whether the use of these NTKIs prior to ASCT increases transplant-related toxicity. Methods: We retrospectively analyzed the outcome of 12 patients with CML (1 in chronic phase, 6 in accelerated phase, and 5 in blastic phase) who received dasatinib (n=2), nilotinib (n=7), or both (n=3) prior to ASCT. Results: Median age was 41 years (range, 18–59 years). The median time on treatment was 134 days (range, 30–285 days), and the median time from the end of NTKI therapy to ASCT was 34 days (range, 7–130 days). Preparative regimen was ablative in 8 patients and non-ablative in 4. Stem cell source was a matched related donor in 7 patients, a matched unrelated donor in 3, a haplo-identical donor in 1, and unrelated cord blood in 1. All patients engrafted within 13 days. There was no significant early transplant-related toxicity: gastro-intestinal toxicities of grade 3 were encountered in 2 patients. One patient had secondary graft failure 6 months after the first ASCT that required a second ASCT. Acute graft-versus-host disease (GVHD) of grade 2 was observed in 7 patients (58%) and chronic GVHD in 6 (50%). Nine patients achieved a molecular response: four complete and five major (Q-PCR〈 0.05%). Three patients had disease progression by day 30 post ASCT. Two patients have relapsed after 6 and 18 months. After a median follow-up of 10 months (range, 3–22 months), 7 patients are alive in molecular response and 5 patients died, 4 of disease progression and one of extensive chronic GVHD. Conclusion: Previous treatment with NTKI did not increase transplant-related toxicity in this preliminary experience. Further follow-up and larger number of patients will be necessary to confirm these observations.

Description: Background: Reduced intensity allogeneic transplantation was developed to harness graft versus leukemia immune effect to treat older patients and patients with comorbidities who are not eligible for conventional myeloablative transplant. Limited but encouraging data are available on outcome of patients with myelofibrosis undergoing this therapy. We therefore sought to prospectively study the safety and efficacy of reduced intensity HCT in patients with myelofibrosis. Methods: Patients with intermediate or high risk MF were eligible if they had adequate organ function and at least 9/10 matched related or unrelated donor. Patients were conditioned with Fludarabine 40mg/m2 × 4 (days −5, −4, −3 −2) and Busulfan 130mg/m2 × 2 (day −3,−2). Thymoglobulin 2.5 mg/kg × 3 (day −3,−2 and −1) was additionally given to patients receiving unrelated donor graft. Tacrolimus and mini Methotrexate were used as graft versus host disease prophylaxis. All patients received standard supportive care. Results: Twelve consecutive patients with myelofibrosis were enrolled between 1/2006 and 7/2007. There were 6 males and 6 female with a median age of 59 (range 40–65). Four patients had primary MF, 3 post PV MF and 5 Post ET MF. Based on Lile criteria, 8 patients had intermediate risk disease and 4 had high risk disease. Eight patients had circulating blasts (1%-8%). Six patients had splenectomy prior to transplant; median spleen size was 15 cms (range 5–28cms) below the costal margin in the remaining 6 patients. Seven patients had mutated Jak 2. Median peripheral blood CD 34 count was 77/μl (range 2–3770/μl). Karyotype was abnormal in 6 patients and diploid in 6. Donors were siblings for 3 patients, matched unrelated for 6, and one antigen or allele mismatched unrelated for 3 patient. All but 1 patient received peripheral blood stem cells. All patients engrafted with a median time to neutrophil engraftment of 13 days (0–27) days) and a median time to platelet engraftment of 14 (0–74) days. Day 100 non relapse mortality was 0%. One patient developed grade 3 acute graft versus host disease (GVHD) and died. One patient developed limited chronic GVHD. All Jak 2 positive patients achieved molecular remission post transplant with negative JaK 2. Three patients relapsed: 2 in blast phase and 1 in chronic phase. With a median follow up of 177 (29–563) days, six month overall survival is 87%. Conclusion: RISCT induces molecular remission with very low non relapse mortality in older patients with myelofibrosis.