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A non-myeloablative regimen of fludarabine and 200 cGy total body irradiation combined with post-grafting immunosuppression with mycophenolate mofetil and a calcineurin inhibitor facilitates allogeneic hematopoietic cell transplantation from HLA-matched related or unrelated donors in older patients and/or those with comorbidities. However, outcomes of prior studies have been disappointing in patients with myelodysplastic syndromes or myeloproliferative neoplasms due to high incidences of progression or graft failure (together termed hematopoietic cell transplantation-failure). We hypothesized that escalating the total body irradiation dose may improve the outcomes and subsequently performed a phase II total body irradiation dose-escalation trial. Patients with median age 66 years were enrolled in two arms to receive non-myeloablative conditioning followed by hematopoietic cell transplantation with total body irradiation dose escalation for excessive hematopoietic cell transplantation-failure: Arm A: myeloproliferative neoplasm/myelodysplastic syndrome low risk (n=36); and Arm B: myelodysplastic syndrome high-risk/chronic myelomonocytic leukemia (n=41). Total body irradiation dose levels were: Level-1 (300 cGy), Level-2 (400 cGy), or Level-3 (450 cGy). Patients received intravenous fludarabine 30 mg/m2 for three days. Total body irradiation was administered on day 0 followed by infusion of peripheral blood stem cells from HLA-matched related (n=30) or unrelated (n=47) donors. Post-grafting immunosuppression with mycophenolate mofetil and cyclosporine was administered. The primary end point was day 200 hematopoietic cell transplant failure, with the objective of reducing the incidence to

Sinusoidal obstruction syndrome, also known as veno-occlusive disease (SOS/VOD), is a potentially life threatening complication that can develop after hematopoietic cell transplantation. Although SOS/VOD progressively resolves within a few weeks in most patients, the most severe forms result in multi-organ dysfunction and are associated with a high mortality rate ( > 80%). Therefore, careful attention must be paid to allow an early detection of SOS/VOD, particularly as drugs have now proven to be effective and licensed for its treatment. Unfortunately, current criteria lack sensitivity and specificity, making early identification and severity assessment of SOS/VOD difficult. The aim of this work is to propose a new definition for diagnosis, and a severity-grading system for SOS/VOD in adult patients, on behalf of the European Society for Blood and Marrow Transplantation., FM was supported by educational grants from the 'Association for Training, Education and Research in Hematology, Immunology and Transplantation' (ATERHIT, Nantes, France)

Background Prophylactic systemic antibiotics (PSA) during conditioning regimen-induced neutropenia after hematopoietic cell transplantation (HCT) reduce bacteremia but may disrupt the gut microbiota, potentially affecting viral immunity and risk for viral infections. Prior studies suggest a critical role of gut microbiota in the reconstitution of CMV-specific CD8+ T cells and in protection from respiratory viral infections after HCT (J Immunol 2007; 178: 5209; Blood 2018; 131:2978). To identify whether PSA is associated with differences in CMV infection outcomes after HCT, we conducted a post-hoc analysis of CMV infection in the only RCT of PSA exclusively performed in HCT recipients (Infection 1986; 14:115). In that trial, HCT patients received either PSA (ticarcillin/tobramycin/vancomycin or mezlocillin/ceftizoxime) or no systemic antibiotics during neutropenia (absolute neutrophil count Methods A post-hoc analysis was performed of a previously conducted RCT in the pre-antiviral era (1984–1986) at the Fred Hutch. Patients received unscreened blood products and were tested weekly by CMV culture in throat, and disease was evaluated by tissue biopsy or bronchoalveolar lavage. CMV disease was confirmed by chart review. We compared the cumulative incidence of CMV at any site, CMV throat shedding, and CMV disease between randomization groups by day 100 post-transplant, treating death as a competing risk. Overall survival was also compared using Kaplan–Meier method. Results 119 and 125 allograft recipients were randomized to PSA and no prophylaxis, respectively. Baseline characteristics in both groups were balanced. CMV infection at any site and CMV throat shedding were greater in the PSA group (Figures 1 and 2); CMV disease was numerically reduced in the no PSA group (Figure 3). Overall survival by day 100 was not different between the groups (Figure 4). Conclusion CMV infection risk appeared to be increased in recipients of PSA with a significant anaerobic spectrum. While current PSA regimens have narrower spectrum activity, these results provide the rationale to study if changes in gut microbiota play a role in CMV reactivation and adaptive immunity after HCT. Disclosures All authors: No reported disclosures.

Autologous hematopoietic stem cell transplantation (aHSCT) is a well-established treatment for malignancies such as multiple myeloma (MM) and lymphomas. Various changes in the field over the past decade, including the frequent use of tandem aHSCT in MM, the advent of novel therapies for the treatment of MM and lymphoma, and the addition of new stem cell mobilization techniques, have led to the need to reassess current stem cell mobilization strategies. Mobilization failures with traditional strategies are common and result in delays in treatment and increased cost and resource utilization. Recently, plerixafor-containing strategies have been shown to significantly reduce mobilization failure rates, but the ideal method to maximize stem cell yields and minimize costs associated with collection has not yet been determined. A panel of experts convened to discuss the currently available data on autologous hematopoietic stem cell mobilization and transplantation and to devise guidelines to optimize mobilization strategies. Herein is a summary of their discussion and consensus.

Bloodstream infection (BSI) to due vancomycin-resistant Enterococcus (VRE) is an important complication of hematologic malignancy. Determining when to use empiric anti-VRE antibiotic therapy in this population remains a clinical challenge.A single-center cohort representing 664 admissions for induction or hematopoietic stem-cell transplant (HSCT) from 2006 to 2014 was selected. We derived a prediction score using risk factors for VRE BSI and evaluated the model's predictive performance by calculating it for each of 16232 BSI at-risk inpatient days.VRE BSI incidence was 6.5% of admissions (2.7 VRE BSI per 1000 BSI at-risk days). Adjusted 1-year mortality and length of stay were significantly higher in patients with VRE BSI. VRE colonization (adjusted odds ratio [aOR] = 8.4; 95% confidence interval [CI] = 3.4-20.6; P.0001), renal insufficiency (aOR = 2.4; 95% CI = 1.0-5.8; P = .046), aminoglycoside use (aOR = 4.7; 95% CI = 2.2-9.8; P.0001), and antianaerobic antibiotic use (aOR = 2.8; 95% CI = 1.3-5.8; P = .007) correlated most closely with VRE BSI. A prediction model with optimal performance included these factors plus gastrointestinal disturbance, severe neutropenia, and prior beta-lactam antibiotic use. The score effectively risk-stratified patients (area under the receiver operating curve = 0.84; 95% CI = 0.79-0.89). At a threshold of ≥5 points, per day probability of VRE BSI was increased nearly 4-fold.This novel predictive score is based on risk factors reflecting a plausible pathophysiological model for VRE BSI in patients with hematological malignancy. Integrating VRE colonization status with risk factors for developing BSI is a promising method of guiding rational use of empiric anti-VRE antimicrobial therapy in patients with hematological malignancy. Validation of this novel predictive score is needed to confirm clinical utility.

The risks and benefits of adding fludarabine to a 2-Gy total body irradiation (TBI) nonmyeloablative regimen are unknown. For this reason, we conducted a prospective randomized trial comparing 2-Gy TBI alone, or in combination with 90 mg/m2 fludarabine (FLU/TBI), before transplantation of peripheral blood stem cells from HLA-matched related donors. Eighty-five patients with hematological malignancies were randomized to be conditioned with TBI alone (n = 44) or FLU/TBI (n = 41). All patients had initial engraftment. Two graft rejections were observed, both in the TBI group. Infection rates, nonrelapse mortality, and graft-versus-host disease (GVHD) were similar between groups. Three-year overall survival was lower in the TBI group (54% versus 65%; hazard ratio [HR], .57; P = .09), with higher incidences of relapse/progression (55% versus 40%; HR, .55; P = .06), relapse-related mortality (37% versus 28%; HR, .53; P = .09), and a lower progression-free survival (36% versus 53%; HR, .56; P = .05). Median donor T cell chimerism levels were significantly lower in the TBI group at days 28 (61% versus 90%; P

Purpose We designed a minimal-intensity conditioning regimen for allogeneic hematopoietic cell transplantation (HCT) in patients with advanced hematologic malignancies unable to tolerate high-intensity regimens because of age, serious comorbidities, or previous high-dose HCT. The regimen allows the purest assessment of graft-versus-tumor (GVT) effects apart from conditioning and graft-versus-host disease (GVHD) not augmented by regimen-related toxicities. Patients and Methods Patients received low-dose total-body irradiation ± fludarabine before HCT from HLA-matched related (n = 611) or unrelated (n = 481) donors, followed by mycophenolate mofetil and a calcineurin inhibitor to aid engraftment and control GVHD. Median patient age was 56 years (range, 7 to 75 years). Forty-five percent of patients had comorbidity scores of ≥ 3. Median follow-up time was 5 years (range, 0.6 to 12.7 years). Results Depending on disease risk, comorbidities, and GVHD, lasting remissions were seen in 45% to 75% of patients, and 5-year survival ranged from 25% to 60%. At 5 years, the nonrelapse mortality (NRM) rate was 24%, and the relapse mortality rate was 34.5%. Most NRM was a result of GVHD. The most significant factors associated with GVHD-associated NRM were serious comorbidities and grafts from unrelated donors. Most relapses occurred early while the immune system was compromised. GVT effects were comparable after unrelated and related grafts. Chronic GVHD, but not acute GVHD, further increased GVT effects. The potential benefit associated with chronic GVHD was outweighed by increased NRM. Conclusion Allogeneic HCT relying on GVT effects is feasible and results in cures of an appreciable number of malignancies. Improved results could come from methods that control progression of malignancy early after HCT and effectively prevent GVHD.

Reduced-intensity conditioning (RIC) regimens in cord blood transplant (CBT) are increasingly utilized for older patients and those with comorbidities. However, the optimal conditioning regimen has not yet been established and remains a significant challenge of this therapeutic approach. Antithymocyte globulin (ATG) has been incorporated into conditioning regimens in order to decrease the risk of graft failure; however, use of ATG is often associated with infusion reactions and risk of post-transplant complications. We report the results of a non-ATG-containing RIC regimen, where patients received 2 Gy TBI unless they were considered to be at higher risk of graft failure, in which case they received 3 Gy of TBI. Thirty patients underwent CBT using this protocol for high-risk hematological malignancies. There was only one case of secondary and no cases of primary graft failure. At 1 year, estimates of non-relapse mortality, OS and PFS were 29%, 53% and 45%, respectively. The cumulative incidences of grade III-IV acute and chronic GVHD were 14% and 18%, respectively. In summary, the results of this study demonstrate that this non-ATG-containing conditioning regimen provides a low incidence of graft failure without increasing regimen-related toxicity.

The association between pre–hematopoietic stem cell transplantation (HSCT) vancomycin-resistant Enterococcus (VRE) colonization, HSCT-associated VRE bacteremia, and HSCT mortality is disputed. We studied 161 consecutive patients with acute leukemia who underwent HSCT at our hospital between 2006 and 2014, of whom 109 also received leukemia induction/consolidation on our unit. All inpatients had weekly VRE stool surveillance. Pre-HSCT colonization was not associated with increases in HSCT mortality but did identify a subgroup of HSCT recipients with a higher risk for VRE bacteremia and possibly bacteremia from other organisms. The major risk factor for pre-HSCT colonization was the number of hospital inpatient days between initial admission for leukemia and HSCT. One-third of evaluable patients colonized before HSCT were VRE-culture negative on admission for HSCT; these patients had an increased risk for subsequent VRE stool surveillance positivity but not VRE bacteremia. Molecular typing of VRE isolates obtained before and after HSCT showed that VRE strains frequently change. Postengraftment VRE bacteremia was associated with a much higher mortality than pre-engraftment VRE bacteremia. Pre-engraftment bacteremia from any organism was associated with an alternative donor and resulted in an increase in hospital length of stay and cost. Mortality was similar for pre-engraftment VRE bacteremia and pre-engraftment bacteremia due to other organisms, but mortality associated with post-engraftment VRE bacteremia was higher and largely explained by associated severe graft-versus-host disease and relapsed leukemia. These data emphasize the importance of distinguishing between VRE colonization before HSCT and at HSCT, between pre-engraftment and postengraftment VRE bacteremia, and between VRE bacteremia and bacteremia from other organisms.

HLA-mismatched grafts are a viable alternative source for patients without HLA-matched donors receiving ablative hematopoietic cell transplantation (HCT), although their use in reduced intensity conditioning (RIC) or nonmyeloablative (NMA) conditioning HCT has been not well established. Here, we extended HCT to recipients of HLA class I-mismatched grafts to investigate whether NMA conditioning can establish stable donor engraftment. Fifty-nine patients were conditioned with fludarabine (Flu) 90 mg/m(2) and 2 Gy total body irradiation (TBI), followed by immunosuppression with cyclosporine (CsA) 5.0 mg/kg twice a day and mycophenolate mofetil (MMF) 15 mg/kg 3 times a day for transplantation of granulocyte colony-stimulating factor (G-CSF)-mobilized peripheral blood stem cells (PBSCs) from related (n = 5) or unrelated donors (n = 54) with 1 antigen +/- 1 allele HLA class I mismatch or 2 HLA class I allele mismatches. Sustained donor engraftment was observed in 95% of the evaluable patients. The incidence of grade II-IV acute and extensive chronic graft-versus-host disease (aGVHD, cGVHD) was 69% and 41%, respectively. The cumulative probability of nonrelapse mortality (NRM) was 47% at 2 years. Two-year overall and progression-free survival (OS, PFS) was 29% and 28%, respectively. NMA conditioning with Flu and low-dose TBI, followed by HCT using HLA class I-mismatched donors leads to successful engraftment and long-term survival; however, the high incidence of aGVHD and NRM needs to be addressed by alternate GVHD prophylaxis regimens.

Purpose A nonmyeloablative (NMA) regimen of fludarabine and 200cGy TBI combined with post-grafting immunosuppression with mycophenolate mofetil (MMF) and a calcineurin inhibitor allows for allogeneic hematopoietic cell transplantation (HCT) from HLA-matched related or unrelated donors in older patients and those with comorbidities affected by myelodysplastic syndrome (MDS) or myeloproliferative neoplasms (MPN). Results of phase I/II studies in patients with chronic myelomonocytic leukemia (CMML) or MDS/MPN have been disappointing, however, due to high incidences of relapse or graft failure (together termed HCT-failure). We hypothesized that escalating the TBI dose may decrease relapse and ensure engraftment. We performed a phase I/II TBI dose-escalation trial and compared the rates of HCT-failure. Methods This was a study conducted at three transplant centers. Patients ages 50-75 or Patients with MDS/MPN could not have received myelosuppressive chemotherapy; patients with CMML who had progressed could have received myelosuppressive chemotherapy before HCT to reduce marrow blasts to less than 5%. Patients were enrolled in groups of 6; dose escalation rules were imposed for HCT failure >20% before day 200 on Arms A and B. Stopping rules were imposed for nonrelapse mortality (NRM) at day 200 of >25% in Arm A and >35% in Arm B. The TBI dose levels were: Level 1: 300cGyLevel 2: 400cGyLevel 3: 450cGy All patients received fludarabine 30/m2/day IV x3 days on days -4 to -2. TBI was administered on day 0 followed by infusion of G-CSF mobilized PBSC from HLA-matched related (n=30) or unrelated (n=47) donors. Post-grafting immunosuppression with MMF and cyclosporine was administered. The primary endpoint was a decrease in the incidence of day200 HCT-failure to Results The study enrolled 77 patients with 36 patients in Arm A and 41 patients in Arm B. Median follow-up is 56.3 months among surviving patients. The primary endpoint (Figure 1) was reached on Arm A at dose level 1 (300cGy TBI) with a cumulative incidence of day200 HCT-failure of 11%. The primary endpoint was not reached in Arm B at dose levels 1 and 2, with dose escalation being triggered at 12 and 5 patients respectively. The endpoint was reached on dose level 3 (450cGy) with a cumulative incidence of day200 HCT-failure of 9%. See Table 2 and Figures 2-5 for OS, PFS, RI and NRM. Cumulative incidence of grades III-IV acute graft-versus-host (aGvHD) by day100 was 17% in Arm A, 12% in Arm B for dose levels 1-2, and 9% in Arm B for dose level 3. Chronic graft-versus-host (cGvHD) cumulative incidence at 1year was 44% in Arm A, 35% in Arm B for dose levels 1-2 and 29% in Arm B for dose level 3. Regarding chimerism analysis, no statistically significant differences were seen among the different arms (Figure 6). Summary and Conclusions In Group A (MPN / low-risk MDS), increasing the TBI dose from 200cGy to 300cGy reduced the day200 HCT-failure rate from 31% in previous trials to 11%. As a result, the OS and PFS was 61% and 58%, respectively, at 2 years. Similarly, for Group B (high-risk MDS / CMML), the day200 HCT-failure rate was reduced from 58% in previous trials to 9% when 450cGy was used. This resulted in an OS and PFS of 37% and 33%, respectively, at 2 years. TBI doses of 300cGy and 400cGy were insufficient to reduce HCT-failure in this high risk group. In conclusion, increasing the TBI dose can lead to a higher success rate in this setting of nonmyeloablative conditioning by reducing both relapse and rejection. Further studies are necessary to decrease nonrelapse mortality, especially among patients affected by high-risk disease. Current trials using targeted radioimmunotherapy are currently being investigated towards this end. Disclosures Flowers: Pharmacyclics: Consultancy. Maloney: Kite Pharmaceuticals: Other: Advisory board; Celgene: Other: Advisory board; Juno Theraapeutics: Other: Advisory board, Patents & Royalties, Research Funding; Roche/Genetech: Other: Advisory board.

Rationale Phase I/II studies of autologous hematopoietic stem cell transplantation (HSCT) for multiple sclerosis (MS) were initiated, based on results of experimental transplantation in animal models of multiple sclerosis and clinical observations in patients treated concomitantly for malignant disease. Patients Eighty-five patients with progressive MS were treated with autologous HSCT in 20 centers and reported to the autoimmune disease working party of the European Group for Blood and Marrow Transplantation (EBMT). 52 (61 %) were female, median age was 39 [20-58] years. The median interval from diagnosis to transplant was 7 [1-26] years. Patients suffered from severe disease with a median EDSS score of 6.5 [4.5-8.5]. Active disease prior to transplant was documented in 79 of 82 evaluable cases. Results The stem cell source was bone marrow in 6 and peripheral blood in 79, and stem cells were mobilized into peripheral blood using either cyclophosphamide combined with growth factors or growth factors alone. Three patients experienced transient neurological complications during the mobilization phase. The high dose regimen included combination chemotherapy, with or without anti-lymphocyte antibodies or, with or without, total body irradiation. The stem cell transplants were purged of lymphocytes in 52 patients. Median follow-up was 16 [3-59] months. There were 7 deaths, 5 due to toxicity and infectious complications, 2 with neurological deterioration. The risk of death of any cause at 3 years was 10 (±7)% (95 % confidence interval). Neurological deterioration during transplant was observed in 22 patients; this was transient in most but was associated with MS progression in 6 patients. Neurological improvement by ≥ 1 point in the EDSS score was seen in 18 (21 %) patients. Confirmed progression-free survival was 74 (±12)% at 3 years being 66 (±23)% in patients with primary progressive MS but higher in patients with secondary progressive or relapsing-remitting MS, 78 (±13)%; p = 0.59. The probability of confirmed disease progression was 20 (±11)%. MRI data were available in 78 patients before transplant showing disease activity (gadolinium enhancing, new or enlarging lesions) in 33 %. Posttransplant MRI showed activity at any time in 5/61 (8 %) evaluable cases. Conclusion Autologous HSCT suggest positive early results in the management of progressive MS and is feasible. These multicentre data suggest an association with significant mortality risks especially in some patient groups and are being utilised in the planning of future trials to reduce transplant related mortality.

In this multicenter, randomized study, cytomegalovirus (CMV)-seropositive patients who received an allogeneic bone marrow transplant were provided high-dose intravenous acyclovir (500 mg/m(2) q8h) from the day of transplantation until engraftment. The patients were then randomly assigned to receive either oral valacyclovir, 2 g q.i.d. (n=83), or intravenous ganciclovir, 5 mg/kg q12h for 1 week, then 6 mg/kg once daily for 5 days per week (n=85), until day 100 after transplantation. CMV infection occurred in 12% of the patients who received valacyclovir and in 19% of the patients who received ganciclovir (hazard ratio [HR], 1.042; 95% confidence interval [CI], 0.391-2.778; P=.934). CMV disease developed in only 2 patients who received valacyclovir and in 1 patient who received ganciclovir (HR, 1.943; 95% CI, 0.176-21.44; P=.588). Oral valacyclovir can be an effective alternative to intravenous ganciclovir for prophylaxis of CMV disease after bone marrow transplantation.

The study is a randomized phase II trial investigating graft-versus-host disease prophylaxis after non-myeloablative (90 mg/m(2) fludarabine and 2 Gy total body irradiation) human leukocyte antigen matched unrelated donor transplantation. Patients were randomized as follows: arm 1 - tacrolimus 180 days and mycophenolate mofetil 95 days (n=69); arm 2 - tacrolimus 150 days and mycophenolate mofetil 180 days (n=71); arm 3 - tacrolimus 150 days, mycophenolate mofetil 180 days and sirolimus 80 days (n=68). All patients had sustained engraftment. Grade II-IV acute graft-versus-host disease rates in the 3 arms were 64%, 48% and 47% at Day 150, respectively (arm 3 vs. arm 1 (hazard ratio 0.62; P=0.04). Owing to the decreased incidence of acute graft-versus-host disease, systemic steroid use was lower at Day 150 in arm 3 (32% vs. 55% in arm 1 and 49% in arm 2; overall P=0.009 by hazard ratio analysis). The Day 150 incidence of cytomegalovirus reactivation was lower in arm 3 (arm 1, 54%; arm 2, 47%; arm 3, 22%; overall P=0.002 by hazard ratio analysis). Non-relapse mortality was comparable in the three arms at two years (arm 1, 26%; arm 2, 23%; arm 3, 18%). Toxicity rates and other outcome measures were similar between the three arms. The addition of sirolimus to tacrolimus and mycophenolate mofetil is safe and associated with lower incidence of acute graft-versus-host disease and cytomegalovirus reactivation. (clinicaltrials.gov identifier: 00105001).

Background: Nonmyeloablative conditioning with 2-Gy TBI alone or in combination with fludarabine (FLU/TBI) and HLA-matched related donor peripheral blood allografts followed by cyclosporine (CSP) and mycophenolate mofetil (MMF) for the prophylaxis of graft-versus-host disease (GVHD) is an effective therapy for many hematologic malignancies with reliable engraftment and moderate toxicity. The major causes of non-relapse mortality (NRM) are the development of acute and chronic GVHD. Several studies have demonstrated that tacrolimus may offer advantages compared with CSP for the prevention of GVHD in patients treated with myeloablative conditioning. The combination of tacrolimus and MMF, which has been used for GVHD prophylaxis after myeloablative hematopoietic cell transplantation (HCT), was well tolerated with low toxicity. Pilot data suggested an improved and perhaps superior GVHD prophylaxis with tacrolimus/MMF compared to our extensive historical experience using CSP/MMF with nonmyeloablative HCT. The purpose of this study is to evaluate the incidence of grade III-IV and II-IV acute GVHD, extensive chronic GVHD, along with the rate of NRM, relapse/progression, and overall survival after nonmyeloablative conditioning and post-grafting immunosuppression with tacrolimus and MMF. Methods: In a phase II multicenter clinical trial we evaluated the effect of post grafting immunosuppression with tacrolimus and MMF for the prophylaxis of GVHD following nonmyeloablative conditioning with 2-Gy TBI alone or in combination with 90mg/m2 FLU (FLU/TBI) for patients with hematologic malignancies. Patients at low risk of graft rejection (preceding autologous HCT within 6 months) received TBI alone (n=50) while the remaining patients received FLU/TBI conditioning (n=100). Tacrolimus was administered orally (0.06 mg/kg, Q12 hr) from days -3 to +56 and in the absence of GVHD tapered off by day +180. Tacrolimus was targeted to 15-20 ng/ml for the first 28 days and 10-20 ng/ml subsequently while on full dose. MMF was given orally (15 mg/kg, Q12 hr) from day 0 until day 27. Results: 150 patients were enrolled from 2004 to 2013 and received peripheral blood stem cells (median doses of 8.1×106 CD34+ cells/kg and 3.5×108 CD3+ cells/kg) from HLA-matched related donors. Diagnosis at transplant included AML (n=42), ALL (n=6), CLL (n=2), MDS/MPD (n=12), NHL (n=25), HL (n=8), and MM (n=55). Median patient age was 56 (range 19-74) years. Sixty-one percent of patients had an HCT comorbidity index (HCT-CI) score of greater than 2. Five percent of patients had failed a prior autologous HCT in FLU/TBI group. Median follow-up was 5.2 years. One graft failure was observed in the FLU/TBI group and no patients rejected their graft. The early NRM at day 100 was 1%. The cumulative incidences of grade II-IV and grade III-IV acute GVHD at 120 days were 26% (FLU/TBI 25%; TBI 28%) and 4% (FLU/TBI 2%; TBI 8%), respectively. Only one patient developed grade IV acute GVHD. Forty-eight percent of patients had chronic GVHD by 5 years (FLU/TBI 44%; TBI 54%). Five-year NRM was low at 12%. The overall cumulative incidence of relapse/progression at 5 years was 52%. Five-year overall and progression-free survivals were 51% and 37%, respectively. Conclusions: Post-grafting immunosuppression and GVHD prophylaxis with tacrolimus/MMF resulted in a low risk of acute and chronic GVHD, which compares favorably with our experience in a concurrent trial using CSP/MMF with FLU/TBI conditioning (46% grades II-IV acute and 72% chronic GVHD with CSP/MMF, respectively; BBMT, 2013, 19: 1340-1347). Furthermore, we recently reported that the active metabolite of MMF (MPA) concentration at steady state (MPA Css) was lower in patients who received concomitant CSP than patients receiving tacrolimus. Low total MPA Css was associated with an increased risk of severe acute GVHD following nonmyeloablative HCT (BBMT 2013, 19: 1159-1166). Together these data warrant consideration of a randomized phase III trial to investigate the role of tacrolimus/MMF versus CSP/MMF in nonmyeloablative HCT. Figure 1. Cumulative incidences of grade II to IV acute GVHD (A) and chronic GVHD (B) Figure 1. Cumulative incidences of grade II to IV acute GVHD (A) and chronic GVHD (B) Disclosures Maloney: Seattle Genetics: Honoraria; Juno Therapeutics: Research Funding; Janssen Scientific Affairs: Honoraria; Roche/Genentech: Honoraria.

A 24-year-old woman with advanced Hodgkin disease received the standard dosing protocol for busulfan/cyclophosphamide before allogeneic hematopoietic stem cell transplantation (HSCT)1 from a matched unrelated donor. The target area under the plasma concentration vs time curve (AUC) for busulfan was set at 950 μmol · L−1 · min−1, near the low end of the therapeutic interval of 900–1350 μmol · L−1 · min−1. The patient’s body mass index (BMI) was 45.5 kg/m2 (height, 170.2 cm; weight, 132.0 kg), so the dose was based on the patient’s ideal body weight. The patient received 2-hour intravenous infusions of busulfan every 6 h for 4 days (16 doses total). The patient was concurrently prescribed multiple medications, including an immunosuppressant, an antiviral, an antifungal, an antidepressant, an anxiolytic, a β-blocker, and a muscle relaxant, as well as antibiotics, warfarin, opioids, and antiepileptic drugs. After the first dose (51 mg Busulfex®; Otsuka Pharmaceutical), timed plasma samples were collected after infusion to determine the AUC. Pharmacokinetics (PK) analysis was performed, and the AUC was determined to be 642 μmol · L−1 · min−1. According to these results, the predicted busulfan dosage required to achieve the target AUC was 75 mg per dose for the remaining 14 scheduled doses. Because of the large change in dosage, additional PK monitoring of busulfan was performed after the fifth dose (day 2). The fifth dose was selected to allow time to reach a steady-state concentration (Css) after the dosage adjustment and to avoid challenges in interpretation due to possible circadian variation in busulfan concentrations (1). Samples for monitoring were collected at the same time of day as the first monitoring dose. The AUC after the fifth dose was 1342 μmol · L−1 · min−1. On the …

Purpose Allogeneic hematopoietic cell transplantation (HCT) after high-dose conditioning regimens imposes prohibitively high risks of morbidity and mortality for patients with high-risk acute myeloid leukemia (AML) who are older or have comorbid conditions. Here, we examined outcomes after nonmyeloablative allogeneic HCT in such patients. Patients and Methods Two hundred seventy-four patients (median age, 60 years) with de novo or secondary AML underwent allogeneic HCT from related (n = 118) or unrelated donors (n = 156) after conditioning with 2 Gy of total-body irradiation (TBI) with or without fludarabine. A calcineurin inhibitor and mycophenolate mofetil were used for postgrafting immunosuppression. Results With a median follow-up of 38 months in surviving patients, the estimated overall survival at 5 years was 33%. The estimated 5-year relapse/progression and nonrelapse mortality rates were 42% and 26%, respectively. The cumulative incidences of grades 2, 3, and 4 acute graft-versus-host disease (GVHD) were 38%, 9%, and 5%, respectively. The cumulative incidence of chronic GVHD at 5 years was 44%. Patients in first and second complete remission had better survival rates than patients with more advanced disease (37% and 34% v 18%, respectively). Patients with HLA-matched related or unrelated donors had similar survivals. Unfavorable cytogenetic risk status was associated with increased relapse and subsequent mortality. Chronic GVHD was associated with lower relapse risk. Conclusion Allogeneic HCT from related or unrelated donors after conditioning with low-dose TBI and fludarabine, relying almost exclusively on graft-versus-leukemia effects, can result in long-term remissions in older or medically infirm patients with AML.

We report the case of a 6.5-year-old male who received an unrelated orthotopic liver transplant for hepatic failure and encephalopathy following non-A-non-B hepatitis and subsequently developed severe aplastic anemia. For treatment of his aplastic anemia, he received a successful marrow transplant from his 9-year-old genotypically HLA- identical sister following conditioning with cyclophosphamide 200 mg/kg and anti-thymocyte globulin 90 mg/kg. Significant veno-occlusive disease of the liver and graft-versus-host disease did not occur. The patient remains alive without clinical chronic active hepatitis or need for blood product therapy. His hematocrit is 36%, white blood cell count 9.7 x 10(3)/mm3, and platelet count 1.7 x 10(5)/mm3 almost 2 years after marrow transplantation.

Autologous bone marrow transplantation (ABMT) for advanced hematologic malignancies is associated with high relapse rates. Interleukin-2 (IL- 2) and lymphokine-activated killer (LAK) cells represent a potentially non-cross-resistant therapeutic modality that might prevent or delay relapses if used early after ABMT at a time when the tumor burden is minimal. However, high-dose chemoradiotherapy and ABMT might increase patients' susceptibility to IL-2 toxicity, and might interfere with immunologic responses to IL-2 in vivo. Therefore, to determine safety, tolerance, and immunomodulatory effects of IL-2 therapy early after ABMT, IL-2 was administered by continuous intravenous infusion to 16 patients 14 to 91 days (median, 33) after ABMT for acute leukemia, lymphoma, or multiple myeloma. Patients were sequentially assigned to escalating IL-2 “induction” doses (0.3 to 4.5 x 10(6) U/m2/d, days 1 to 5), and all patients received a nonescalating IL-2 “maintenance” dose (0.3 x 10(6) U/m2/d, days 12 to 21). Most patients exhibited mild to moderate fever, nausea, diarrhea, and/or skin rash with IL-2 infusions. The maximum tolerated “induction” dose was 3.0 x 10(6) U/m2/d; dose- limiting toxicities were hypotension and thrombocytopenia. All toxicities reversed on stopping the IL-2 infusions, and all patients completed “maintenance.” Postinfusion lymphocytosis was exhibited by patients at all IL-2 dose levels. With the higher IL-2 doses, increased percentages of patients' PBMC expressed CD16 and CD56, with augmented lysis of K562 and Daudi, reflecting the induction of natural killer and circulating LAK effector activities. Increased LAK precursor activity was exhibited by patients at all IL-2 dose levels. Thus, the IL-2 therapy regimen was safely tolerated after ABMT, and pronounced immunomodulatory effects were observed with the higher IL-2 doses. These studies support the planned use of IL-2 and LAK cells after ABMT in an attempt to reduce relapses of advanced hematologic malignancies.

We compared the outcome of nonmyeloablative allogeneic hematopoietic cell transplantation (HCT) for patients with relapsed or refractory Hodgkin lymphoma (HL) based on donor cell source. Ninety patients with HL were treated with nonmyeloablative conditioning followed by HCT from HLA-matched related, n = 38, unrelated, n = 24, or HLA-haploidentical related, n = 28 donors. Patients were heavily pretreated with a median of 5 regimens and most patients had failed autologous HCT (92%) and local radiation therapy (83%). With a median follow-up of 25 months, 2-year overall survivals, progression-free survivals (OS)/(PFS), and incidences of relapsed/progressive disease were 53%, 23%, and 56% (HLA-matched related), 58%, 29%, and 63% (unrelated), and 58%, 51%, and 40% (HLA-haploidentical related), respectively. Nonrelapse mortality (NRM) was significantly lower for HLA-haploidentical related (P = .02) recipients compared to HLA-matched related recipients. There were also significantly decreased risks of relapse for HLA-haploidentical related recipients compared to HLA-matched related (P = .01) and unrelated (P = .03) recipients. The incidences of acute grades III-IV and extensive chronic graft-versus-host disease (aGVHD, cGVHD) were 16%/50% (HLA-matched related), 8%/63% (unrelated), and 11%/35% (HLA-haploidentical related). These data suggested that salvage allogeneic HCT using nonmyeloablative conditioning provided antitumor activity in patients with advanced HL; however, disease relapse/progression continued to be major problems. Importantly, alternative donor stem cell sources are a viable option.

The anti-cytomegalovirus (CMV) activity and safety of oral maribavir in CMV-seropositive allogeneic stem-cell transplant recipients were evaluated in a randomized, double-blind, placebo-controlled, dose-ranging study. After engraftment, 111 patients were randomized to receive CMV prophylaxis with maribavir (100 mg twice daily, 400 mg once daily, or 400 mg twice daily) or placebo. Within the first 100 days after transplantation, the incidence of CMV infection based on CMV pp65 antigenemia was lower in each of the respective maribavir groups (15%, P = .046; 19%, P = .116; 15%, P = .053) compared with placebo (39%). Similarly, the incidence of CMV infection based on plasma CMV DNA was lower in each of the respective maribavir groups (7%, P = .001; 11%, P = .007; 19%, P = .038) compared with placebo (46%). Anti-CMV therapy was also used less often in patients receiving each respective dose of maribavir (15%, P = .001; 30%, P = .051; 15%, P = .002) compared with placebo (57%). There were 3 cases of CMV disease in placebo patients but none in the maribavir patients. Adverse events, mostly taste disturbance, nausea, and vomiting, were more frequent with maribavir. Maribavir had no adverse effect on neutrophil or platelet counts. These results show that maribavir can reduce the incidence of CMV infection and, unlike ganciclovir, does not cause myelosuppression. This trial is registered at [www.ClinicalTrials.gov][1] as #[NCT00223925][2]. [1]: http://www.ClinicalTrials.gov [2]: /lookup/external-ref?link_type=CLINTRIALGOV&access_num=NCT00223925&atom=%2Fbloodjournal%2F111%2F11%2F5403.atom

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

Allogeneic hematopoietic cell transplantation (HCT) after nonmyeloablative conditioning for hematologic malignancies depends on graft-versus-tumor effects for eradication of cancer. Here, we estimated relapse risks according to disease characteristics. Between 1997 and 2006, 834 consecutive patients (median age, 55 years; range, 5-74 years) received related (n = 498) or unrelated (n = 336) HCT after 2 Gy total body irradiation alone (n = 171) or combined with fludarabine (90 mg/m2; n = 663). Relapse rates per patient year (PY) at risk, corrected for follow-up and competing nonrelapse mortality, were calculated for 29 different diseases and stages. The overall relapse rate per PY was 0.36. Patients with chronic lymphocytic leukemia (CLL) and multiple myeloma (MM) in remission (CR), low-grade or mantle cell non-Hodgkin lymphoma (NHL) (CR + partial remission [PR]), and high-grade NHL-CR had the lowest rates (0.00-0.24; low risk). In contrast, patients with advanced myeloid and lymphoid malignancies had rates of more than 0.52 (high risk). Patients with lymphoproliferative diseases not in CR (except Hodgkin lymphoma and high-grade NHL) and myeloid malignancies in CR had rates of 0.26-0.37 (standard risk). In conclusion, patients with low-grade lymphoproliferative disorders experienced the lowest relapse rates, whereas patients with advanced myeloid and lymphoid malignancies had high relapse rates after nonmyeloablative HCT. The latter might benefit from cytoreductive treatment before HCT.

A number of studies have suggested that prior chemotherapy correlates negatively with the efficiency of hematopoietic stem cell mobilization. However, little data exist with regard to the relative effects of the specific chemotherapeutic drug classes. We retrospectively reviewed the records of 201 consecutive patients with nonmyeloid malignancies undergoing CD34+ cell mobilization with chemotherapy+granulocyte colony-stimulating factor (G-CSF). The number of prior chemotherapy courses correlated negatively with the peripheral CD34+ cell concentration (pCD34) on the first day of collection (P

We evaluated the results of high-dose chemotherapy and autologous hematopoietic stem cell transplantation in patients with diffuse aggressive non-Hodgkin lymphoma (NHL) in first relapse (Rel 1) or second complete remission (CR 2). Data were evaluated from the Autologous Blood and Marrow Transplant Registry on 429 patients with diffuse aggressive NHL who underwent transplantation in Rel 1 or CR 2. Transplantations were performed between 1989 and 1996 and were reported to the Autologous Blood and Marrow Transplant Registry by 93 centers in North and South America. The probability of 3-year survival was 44% (95% confidence interval [CI], 33%–55%). The probability at 3 years of progression-free survival was 31% (95% CI, 27%–36%). Patients who underwent transplantation in CR 2 had a 3-year probability of progression-free survival of 38% (95% CI, 30%–46%) compared with 28% (95% CI, 22%–33%) for those who were not in remission at the time of transplantation (P < .001). In multivariate analysis, chemotherapy resistance, increased lactic dehydrogenase at diagnosis, an interval of

Relapse is the major cause of treatment failure after allogeneic transplantation of children with juvenile myelomonocytic leukemia (JMML), and the role of post-transplant immunomodulation is poorly understood. We report a 12-month-old child with JMML relapsed after unrelated marrow transplantation who received cytoreduction followed by donor lymphocyte infusion (DLI) with improvement, and after addition of interferon-alpha (IFN) achieved complete donor chimerism. He was weaned from IFN and has maintained complete remission for 19 months. This is the first published report of a patient with non-monosomy-7 JMML responding to post-transplant immunomodulation and suggests a role for DLI plus IFN in these patients.

Patients with neutropenia and persistent fever are often treated empirically with amphotericin B or liposomal amphotericin B to prevent invasive fungal infections. Antifungal triazoles offer a potentially safer and effective alternative.In a randomized, international, multicenter trial, we compared voriconazole, a new second-generation triazole, with liposomal amphotericin B for empirical antifungal therapy.A total of 837 patients (415 assigned to voriconazole and 422 to liposomal amphotericin B) were evaluated for success of treatment. The overall success rates were 26.0 percent with voriconazole and 30.6 percent with liposomal amphotericin B (95 percent confidence interval for the difference, -10.6 to 1.6 percentage points); these rates were independent of the administration of antifungal prophylaxis or the use of colony-stimulating factors. There were fewer documented breakthrough fungal infections in patients treated with voriconazole than in those treated with liposomal amphotericin B (8 [1.9 percent] vs. 21 [5.0 percent], P=0.02). The voriconazole group had fewer cases of severe infusion-related reactions (P0.01) and of nephrotoxicity (P0.001). The incidence of hepatotoxicity was similar in the two groups. Patients receiving voriconazole had more episodes of transient visual changes than those receiving liposomal amphotericin B (22 percent vs. 1 percent, P0.001) and more hallucinations (4.3 percent vs. 0.5 percent, P0.001). Parenteral voriconazole was changed to the oral formulation in 22 percent of the voriconazole group, with a reduction in the mean duration of hospitalization by one day in all patients (P=0.17) but by two days in patients at high risk (P=0.03).Voriconazole is a suitable alternative to amphotericin B preparations for empirical antifungal therapy in patients with neutropenia and persistent fever.

Background While delayed or failed engraftment following reduced intensity conditioning (RIC) umbilical cord blood transplant (UCBT) now occurs less frequently than initially reported, it continues to be higher than in the conventional donor setting. It has been shown that patients who have had a prior autologous transplant or who have received chemotherapy within 4 months of UCBT have an increased incidence of sustained donor engraftment compared with those without this prior therapy (98% vs 64%) (Barker et al ASH abstract 2003). The standard measure of engraftment following UCBT is neutrophil recovery to > 500 x 3 days. However, there has recently been established a possible correlation between time to neutrophil engraftment and early full donor chimerism after UCBT (Avery S et al BMT 2012). Herein, we conducted an RIC UCBT trial in which patients were assigned to one of two treatment regimens based on their risk of graft failure. In addition to evaluating sustained donor engraftment characterized by time to neutrophil recovery, we also sought to assess the achievement of full donor chimerism at Day +28 post-transplant in patients pre-determined to be high versus low risk of graft failure. Methods Forty-eight patients median age 59 years (range 25 - 73) and comorbidity index = 3 (range 0 - 8) with high risk hematologic malignancies received an RIC regimen containing cyclophosphamide 50mg/kg on Day -6, fludarabine 40mg/m2 Day -6 to -2 (dose reduced to 35mg/m2 for creatinine clearance < 70), and either 200 cGy TBI (Arm 1 = low risk of graft failure) or 300 cGy TBI (Arm 2 = high risk of graft failure) on Day -1. High risk for graft failure was defined as “receiving < 2 cycles of multiagent chemotherapy or no multiagent chemotherapy within the 3 months prior to UCBT.” Low risk for graft failure was defined as “having received a prior autologous transplant within 12 months or ≥ 2 cycles of multiagent chemotherapy with at least one cycle of therapy within the 3 months prior to UCBT.” Patients on both arms received GVHD prophylaxis with cyclosporine from Day -1 to Day +180 and mycopheolate mofeteil 1 gram every 8 hours until Day +40. Forty-seven of 48 patients received 2 UCB units (one patient received a single UCB) with a median TNC/kg of 4.05 x 107 and a post-thaw median CD34+cells/kg of 1.75 x 105. UCB grafts (98%) were 1-2 HLA antigen mismatched with the recipient. Twenty-six patients were assigned to Arm 1 and 22 patients were assigned to Arm 2. Bone marrow and peripheral blood chimerism assessment were performed at approximately Day +28 and Day +80. The blood was flow sorted in the clinical hematopathology lab into defined lineage subsets. Wilcoxon rank-sum test was used to compare the 2 groups. Results All evaluable patients engrafted (n = 46). Patients on Arm 1 achieved neutrophil recovery (ANC > 500 x 3 days) at a median of 12 days (range 6 - 38) versus 23 days (range 7- 46) in patients on Arm 2 (p = 0.01). Day +28 chimerism values were evaluable for 23 patients on Arm 1 and 20 patients on Arm 2. Median chimerism in the CD3+ compartment was 100% (57 - 100) and 100% (0 - 100) on Arm 1 and Arm 2 respectively (p = 0.58). Median chimerism in the CD33+compartment was 98% (15 - 100) and 100% (44-100) on Arm 1 and Arm 2 respectively (p =0.26). Median chimerism in the bone marrow was 98% (15 - 100) and 100% (4 - 100) on Arm 1 and Arm 2 respectively (p = 0.84). This was maintained at Day +80. Acute graft versus host disease (GVHD) grades II - IV was seen in 84% (n = 21) and 68% (n = 15) of patients on Arm 1 and 2 respectively with 5% and 12% grade III-IV GVHD in the respective arms. Chronic GVHD was seen in 40% of patients on Arm 1 (8 mild, 2 moderate) and 23% on Arm 2 (3 mild, 1 moderate, 1 severe). Overall survival at 1 year in Arm 1 was 43% (95% CI: 22-62%) and Arm 2 was 46% (95% CI: 20-69%). Conclusions The goal of this RIC UCBT study was to assess engraftment rates by neutrophil recovery and Day +28 chimerism in patients at low versus high risk of graft rejection. Although time to neutrophil recovery was significantly faster in patients with low risk of graft failure, patients at high risk of rejection achieved a similar incidence of full donor chimerism at Day +28 as those with low risk of graft rejection. Using Day +28 chimerism as a measure of engraftment, patients deemed high risk of graft failure achieved early engraftment with UCBT following an RIC conditioning regimen containing 300cGy TBI. Disclosures: No relevant conflicts of interest to declare.

Abstract 1943 Reduced intensity conditioning (RIC) regimens in umbilical cord blood transplant (UCBT) are increasingly utilized for older patients (pts) and those with comorbidities. However, the optimal conditioning regimen has not yet been established and remains a significant challenge of this therapeutic approach. Incorporation of ATG into the conditioning regimen is thought to decrease the incidence of graft rejection, but it is associated with high incidence of infusion associated reactions and serum sickness, delayed T cell recovery, increased infections and higher risk of EBV post-transplant lymphoproliferative disorder (PTLD). We report the results of a non-ATG containing RIC regimen, in which ATG is replaced with a higher dose of TBI in pts considered to be at higher risk of graft failure. All pts received fludarabine (40mg/m2/day) from day −6 to day −2 and cyclophosphamide (50mg/kg) on day −6. Pts who had received a previous autologous transplant within 12 months or ≥ 2 cycles of multiagent chemotherapy with at least one cycle of therapy within the 3 months previous to UCBT received a single fraction of 200cGy TBI on day −1. All other pts were considered at higher risk of graft rejection and received a single fraction of 300cGy of TBI on day −1. GVHD prophylaxis began on day −3 and consisted of cyclosporine A (CSA) and mycophenolate mofetyl (MMF). CSA was continued until at least day +100 and then tapered 10% per week starting on day +101 and discontinued no sooner than 6 months post-transplant. The duration of MMF was prolonged, with initiation of a taper on day+40 post transplant and then in the absence of GVHD, tapered by 12% per week and discontinued after day + 96. Thirty pts underwent double UCBT at 3 transplant centers using this protocol between February 2006 and January 2011. Median age and weight of the pts were 60 (range, 24–73) years and 78 (range, 55–141) kg, respectively. Disease status included AML-CR1 (n=11) and CR2 (n=5), ALL-CR2 (n=1) and refractory ALL (n=2), biphenotypic leukemia in 1st CR (n=1), MDS (n=1), relapsed/ refractory Hodgkin lymphoma (n=3), transformed DLBCL (n=1), primary PTCL (n=1) and very high grade B cell lymphoblastic lymphoma in 2nd CR (n=1). Nine pts (30%) had failed prior hematopoietic cell transplantation (HCT), of which 5 were auto, 3 were allo and 1 both auto and allo transplant. All pts received 2 cord blood units to achieve the required cryopreserved cell dose of 3.0×107 TNC/kg. The median cell doses infused were 4.92 × 107 (range, 3.12–8.3) TNC/kg and 0.26×106 (range, 0.02–2.85) CD34+ cells/kg. Among the 60 infused units, HLA matching was 6/6 in 3% (n=1), 5/6 in 30% (n=9) and 4/6 in 67% (n=20) of the pts. Twenty-two pts (73%) received 2GY and 8 (27%) received 3Gy of TBI. The median number of prior treatments and comorbidity score were 3 (range, 0–8) and 3 (range, 1–8), respectively. The median follow up was 183 days (range, 132 to 1303 days). Neutrophils engraftment occurred in all pts at a median of 13 (range, 6 to 40) days and platelet (PLT) engraftment (>50×109/L ) occurred at a median of 32 (range, 23 to 42) days, respectively. There was only one case of secondary graft rejection and no cases of primary graft rejection. The cumulative incidence of acute GVHD grade II-IV and III-IV were 60% and 24%, respectively; the cumulative incidence of chronic GVHD was 18%. Day 100 NRM was 17%. At one year, NRM, OS and PFS were 29%, 53% and 45%, respectively. Causes of death included relapse (n=6), multi-organ failure (n=2), sepsis (n=1), diffuse alveolar hemorrhage (n=1), necrotizing hemorrhagic meningitis (n=1), leukoencephalopathy (n=1) and intracranial bleed (n=1). There were no cases of CMV disease or PTLD. On multivariate analysis, only neutrophil and platelet engraftment were associated with mortality, with hazard ratios of 0.07 (95%, CI 0.009–0.61), p=0.01) and 0.11 (95%, CI 0.03–0.41, p=0.0009), respectively. Other variables, such as age, number of previous regimens, presence of minimal residual disease prior to transplant, dose of TBI (3Gy vs 2Gy), high-risk disease, comorbidity score and acute GVHD grade II-IV were not statistically significantly associated with poorer survival. In summary, results of this study to date demonstrate that this non-ATG containing conditioning regimen, with intensified immunosuppression and increased dose of TBI, provides a low incidence of graft rejection without increasing toxicity or the incidence of chronic GVHD. Disclosures: No relevant conflicts of interest to declare.

Context A minimally toxic nonmyeloablative regimen was developed for allogeneic hematopoietic cell transplantation (HCT) to treat patients with advanced hematologic malignancies who are older or have comorbid conditions. Objective To describe outcomes of patients 60 years or older after receiving minimally toxic nonmyeloablative allogeneic HCT. Design, Setting, and Participants From 1998 to 2008, 372 patients aged 60 to 75 years were enrolled in prospective clinical HCT trials at 18 collaborating institutions using conditioning with low-dose total body irradiation alone or combined with fludarabine, 90 mg/m 2 , before related (n = 184) or unrelated (n = 188) donor transplants. Postgrafting immunosuppression included mycophenolate mofetil and a calcineurin inhibitor. Main Outcome Measures Overall and progression-free survival were estimated by Kaplan-Meier method. Cumulative incidence estimates were calculated for acute and chronic graft-vs-host disease, toxicities, achievement of full donor chimerism, complete remission, relapse, and nonrelapse mortality. Hazard ratios (HRs) were estimated from Cox regression models. Results Overall, 5-year cumulative incidences of nonrelapse mortality and relapse were 27% (95% CI, 22%-32%) and 41% (95% CI, 36%-46%), respectively, leading to 5-year overall and progression-free survival of 35% (95% CI, 30%-40%) and 32% (95% CI, 27%-37%), respectively. These outcomes were not statistically significantly different when stratified by age groups. Furthermore, increasing age was not associated with increases in acute or chronic graft-vs-host disease or organ toxicities. In multivariate models, HCT-specific comorbidity index scores of 1 to 2 (HR, 1.58 [95% CI, 1.08-2.31]) and 3 or greater (HR, 1.97 [95% CI, 1.38-2.80]) were associated with worse survival compared with an HCT-specific comorbidity index score of 0 (P = .003 overall). Similarly, standard relapse risk (HR, 1.67 [95% CI, 1.10-2.54]) and high relapse risk (HR, 2.22 [95% CI, 1.43-3.43]) were associated with worse survival compared with low relapse risk (P Conclusion Among patients aged 60 to 75 years treated with nonmyeloablative allogeneic HCT, 5-year overall and progression-free survivals were 35% and 32%, respectively.

Abstract 3450 Objective: Allogeneic hematopoietic cell transplantation (HCT) following a variety of reduced-intensity conditioning regimens has been reported to produce encouraging results in patients with AML. In these studies disease relapse was the main cause of treatment failure, with 2–4 year relapse rates ranging between 32–61% resulting in overall survivals of 28–45% at 2–4 years. Our goal here was to examine whether pre-HCT variables could identify patients at high risk for relapse following nonmyeloablative allogeneic HCT, who thus would become candidates for additional interventions to reduce the risk of AML relapse. Methods: The data were derived from 274 consecutive Seattle Consortium patients (median age: 60 years) with de novo or secondary AML who underwent allogeneic HCT from related or unrelated donors after conditioning with 2 Gy total body irradiation (TBI) with or without fludarabine (90 mg/m2) as recently reported (Gyurkocza et al., JCO 2010 Jun 10;28(17):2859–2867). Cox regression was used to perform multivariate analysis of risk factors for relapse in a subset of 231 patients in morphologic leukemia-free state (defined as less than 5% marrow blasts) with (n=134) or without (n=97) peripheral blood cell count recovery (defined as platelets > 100,000/ml and neutrophils > 1,000/ml) at the time of HCT. In this multivariate model, AML beyond 1st complete remission (CR1), unfavorable cytogenetics (according to SWOG criteria), incomplete peripheral blood cell count recovery before HCT, and shorter time between diagnosis and HCT were associated with statistically significantly higher risk of relapse (Table 1). From this multivariate model we developed a relapse risk score that summarizes the contribution of multiple risk factors by assigning weights based on the relative magnitude of the log hazard ratios associated with the principal risk factors. From a starting score of 0, points were added or subtracted based on the following factors: 2nd CR: +1 point; 3rd or later CR: +2 points; unfavorable cytogenetics: +1 point; absence of pre-HCT peripheral blood cell count recovery: +0.5 points; time from diagnosis to HCT > 18 months, -2 points (Table 2). Patients were then stratified into 2 relapse risk groups according to whether the total risk score was ≤0 (low-risk) or >0 (high-risk). Results: Stratification of patients according to the proposed Relapse Risk Score resulted in a clear separation of the two risk groups, with 5-year relapse rates of 50% and 17% in the high- and low-risk groups, respectively (Figure 1A). Five-year overall survival rates were 26% and 50% in the high- and low-risk groups, respectively (Figure 1B). Conclusion: Our Relapse Risk Score may be a useful tool to identify patients with AML at high risk for relapse, who could potentially benefit from additional interventions to reduce the risk of relapse following allogeneic HCT. We are currently attempting validation in an independent cohort of patients with AML to make this Risk Score more generalizable. Relapse/Progression (A) and Overall Survival (B) rates stratified by Relapse Risk Score. Disclosures: Off Label Use: Off label usage of fludarabine, cyclosporine, tacrolimus and mycophenolate mofetil is discussed.

A randomized trial was performed to compare two regimens of total body irradiation in patients with chronic myeloid leukemia treated by allogeneic marrow transplantation while in the chronic phase. All patients received cyclophosphamide 120 mg/kg followed by total body irradiation and marrow from HLA-identical siblings. Cyclosporine and methotrexate were used for prophylaxis against acute graft-versus-host disease. Fifty-seven patients were randomized to receive 2.0 Gy fractions of irradiation daily for 6 days and 59 were randomized to receive 2.25 Gy fractions daily for 7 days. The probabilities of relapse at 4 years were 0.25 for the 12.0 Gy group and 0.00 for the 15.75 Gy group (P = .008). The actuarial probabilities of survival and relapse-free survival at 4 years were 0.60 and 0.58 among the patients who received 12.0 Gy compared with 0.66 and 0.66 for those who received 15.75 Gy. The 4-year probabilities of transplant-related mortality were 0.24 and 0.34 respectively (P = .13) while the probability of moderate to severe acute graft-versus-host disease was 0.33 for the 12.0 Gy group and 0.44 for the 15.75 Gy group (P = .15). The lower relapse probability in the patients receiving the higher dose of total body irradiation did not result in improved survival because mortality from causes other than relapse was increased.

Median ages of pts with most hematological malignancies are beyond 60 years. The advent of nonmyeloablative conditioning regimens has extended the use of allogeneic HCT to these older pts. Here, we retrospectively investigated outcomes among 280 pts aged ≥60 years, given HCT between 1998 and 2006. Results were broken down in 3 age groups 60–64 (n=166), 65–69 (n=90), and ≥70 (n=24) years old, respectively. Pts aged ≥70 years had less preceding chemotherapy, less often failed autologous HCT, more often had related grafts, and had higher comorbidity scores compared to pts in the other two age groups (table 1). Acute leukemias were more frequent and lymphoma/multiple myeloma were less frequent among pts aged ≥70 years old, resulting in higher risk for relapse (Table 1). After HCT, non-relapse mortality, relapse, and progression free survivals at 5-years for all pts were 26%, 41%, and 32% respectively. Five-year Kaplan Meier rate of overall survival was 35%, of those 12% vs. 23% were with vs. without chronic GVHD requiring immunosuppressive therapy, respectively. There were no statistically significant differences in outcomes among the three age groups except for more infections and days of hospitalization among pts aged 65–69 years compared to the other two age groups (Table 2). In multivariate analyses of risk factors, high HCT-comorbidity index (1–2 and ≥3) independently predicted higher NRM (HR: 2.84 and 3.0, respectively, p=0.01) and, not surprisingly, previously defined high relapse risk predicted relapse (HR: 2.17, p=0.06); both predicted worse OS (p=0.005 and p=0.0009, respectively) and PFS (p=0.01 and p=0.02, respectively). Pts given unrelated grafts did as well as recipients of related grafts. In conclusion, nonmyeloablative allogeneic HCT can be curative among pts older than 60 years with resolution of chronic GVHD among a majority of pts. Comorbidities and relapse risk rather than age should be used for benefit-risk assessment. Continued enrollment of elderly pts in prospective studies including unrelated donors is warranted. Table 1: Pt characteristics Age groups, years (60–64) (n=166) (65–69) (n=90) (70–74) (n=24) Median Interval from Dx to HCT, months 19 15 8 Median (range) # of prior regimens 3 (0–14) 3 (0–13) 2 (0–10) Median CD34+ cell number x 106/kg 6.7 6.7 6.5 Median CD3+ cell number x 108/kg 2.9 3.1 3.4 % Prior radiotherapy 18 11 13 Prior HCT Failed 19 12 4 Planned 8 6 4 Positive patient CMV sero-status 58 65 79 HLA-matched related 54 53 83 Donor HLA-matched unrelated 41 44 17 HLA-mismatched unrelated 5 3 0 Conditioning 2 Gy TBI 12 13 21 2 Gy TBI + FLU 88 87 79 HCT-CI scores 0 27 27 15 1–2 30 39 25 3–4 30 17 40 ≥5 13 17 20 Diagnoses Acute leukemia 35 47 62 Chronic leukemia 15 13 13 Lymphoma/myeloma 21 23 8 Myelodysplastic/myeloproliferative 16 16 17 Others 3 1 0 Disease status at HCT CR 46 41 38 PR 15 30 21 Refractory 28 21 33 Relapse 11 8 8 Relapse risk Low 19 17 8 Standard 48 51 38 High 33 32 54 Table 2: Outcomes per age groups HCT Outcomes Age groups, years P* (60–64) (n=166) (65–69) (n=90) (70–74) (n=24) FUO indicates fever of unknown origin *Test for trend μBased on hazard ratio analysis Bacterial 1.4 2.3 1.7 .0004 Rates of Infection episodes per person Viral 0.7 1.1 0.7 NS within 100 days FUO 0.3 0.4 0.1 NS Fungal 0.3 0.2 0.3 NS Median (range) days of hospitalization 1 (0–60) 4.5 (0–179) 0.5 (0–47) NS % Acute GVHD Grades II–IV 52 49 54 NSμ Grades III–IV 16 12 13 NSμ Chronic extensive GVHD 39 45 54 0.05μ NCI-CTC criteria grades III–IV non-hematological toxicities 42 57 50 NSμ Pts with Full donor chimerism at 1-year CD3/CD33/BM 68/ 84/ 80 66/ 83/ 77 67/ 79/ 71 NSμ CR at 2-years 40 47 63 NSμ 5-years Relapse/progression 38 46 46 NSμ 5-years NRM 28 22 29 NSμ 5-years OS 37 36 23 NSμ 5-years PFS 34 31 25 NSμ Patients alive and off all immunosuppression 24 25 5 NSμ

Use of HLA-mismatched unrelated donors after myeloablative conditioning is an effective treatment of blood disorders when HLA-matched donors are not available. However, the feasibility of HLA-mismatched HCT following nonmyeloablative conditioning is not well established. We previously demonstrated in over 1200 patients (pts) that a nonmyeloablative conditioning regimen consisting of 2 Gy TBI and fludarabine (90 mg/m2) followed by post-grafting immunosuppression with MMF/CSP was an effective approach for HCT from 10/10 HLA-matched donors. Here we report the results of a clinical trial aimed at determining whether stable hematopoietic grafts from HLA-class I mismatched donors could be safely established after nonmyeloablative conditioning. Pts were conditioned with fludarabine and 2 Gy TBI, followed by extended immunosuppression with CSP (day −3 to +180; tapered by +365) and MMF (tid days 0 to +100; tapered by +150). 46 pts ineligible for myeloablative conditioning were enrolled on this multi-institutional study through April/07. 36 unrelated and 3 related donor-recipient pairs were mismatched in both the HVG and GVH vectors. 43 unrelated pairs were mismatched for at least one antigen (AG) (15 at HLA-A, 5 at HLA-B, 22 at HLA-C) except one pt who had two allele mismatches (HLA-A and B). All 3 related pairs were mismatched for one HLA-A AG. 13 pts, in addition to the AG mismatch, had an allelic mismatch (3 at HLA-A, 4 at HLA-B, 6 at HLA-C). All pts were matched for HLA-DRB1 and HLA-DQB1 at the allele level. Diagnoses included NHL (n=17), HD (n=5), AML (n=11), ALL (n=5), CLL (n=3), MM (n=4) and MDS/AML (n=1). The median age of pts was 56 (range 13–69) years and median time from diagnosis to HCT was 32 (range 5–205) months. Disease status at time of HCT included CR (n=23), PR (n=11), stable disease (n=2), and refractory relapse (n=10). Before HCT, pts had received a median of 7 (range 2–15) courses of therapy. 43% had failed myeloablative HCT (autologous n=18; allogeneic n=2). All pts received G-CSF mobilized PBSC containing median doses of 7.3 ×106 CD34 and 2.4 × 108 CD3 cells /kg. 12 pts were not evaluable for the graft rejection outcome (3 early death, 7 mismatched in GVH vector only, 2 tandem auto-allo). The remaining pts showed median percentages of donor peripheral blood T cell, granulocyte and marrow chimerism of 100% at all time points (on days 28, 56, and 84). Two pts experienced graft rejection but had a successful 2nd HCT from the same or an alternative donor. 35 of the 46 pts developed acute GVHD (2 grade I, 21 grade II, 5 grade III, 7 grade IV) and 15 developed chronic GVHD. At 2 years, the cumulative probabilities of relapse/progression and non-relapse mortality were 30% and 45%, respectively. The 2 year Kaplan-Meier estimates of OS and PFS were 27% and 25%. This study demonstrates that nonmyeloablative conditioning using fludarabine and low-dose TBI can be successfully used for grafts from pts with HLA- class I mismatched donors.

Cytomegalovirus (CMV) remains a major threat to recipients of allogeneic stem cell transplants (SCT). Potential toxicities of currently available anti-CMV agents complicate their use in this population. Maribavir (MBV) is an oral antiviral drug with a unique mechanism of action against CMV and a promising safety profile in early clinical studies. This randomized, double-blind, multicenter, dose-ranging study enrolled adult CMV-seropositive recipients of allogeneic SCT. After engraftment, patients were randomized to receive CMV prophylaxis with placebo or MBV at one of three doses for up to 12 weeks. CMV surveillance was performed weekly with both CMV pp65 antigenemia and plasma CMV DNA PCR assays. If CMV was detected, study drug was stopped and preemptive anti-CMV therapy started as per standard practice at each center. A total of 111 patients were enrolled (median age 47 years; 70% myeloablative SCT; 53% related donor). Incidence of CMV infection or disease in the first 100 days post-SCT are shown in the table. The safety profile of maribavir was favorable in this patient population; most adverse events occurred at similar rates in placebo and MBV groups. There was no adverse impact of MBV on neutrophil counts or other laboratory or ECG parameters. Consistent with prior clinical studies, the most notable events that appeared to be associated with MBV were mild-moderate taste disturbance, nausea, and diarrhea. In conclusion, maribavir prophylaxis reduced the rate of CMV infection compared to placebo, with a favorable safety profile in this complex patient population. Phase 3 studies of maribavir in stem cell and solid organ transplant recipients are being planned. Placebo MBV 100 mg BID MBV 400 mg QD MBV 400 mg BID N evaluable 28 27 27 26 p values represent comparison to placebo (stratified by myeloablative or nonmyeloablative SCT) CMV infection or disease based on: pp65 antigenemia 11 (39%) 4 (15%) 5 (19%) 4 (15%) p=0.046 p=0.116 p=0.053 plasma CMV DNA PCR 13 (46%) 2 (7%) 3 (11%) 5 (19%) p=0.001 p=0.007 p=0.038 Use of preemptive anti-CMV Rx 16 (57%) 4 (15%) 8 (30%) 4 (15%) p=0.001 p=0.051 p=0.002 CMV disease only 3 (11%) 0 0 0 p=0.089 p=0.084 p=0.091

Background: Eligibility for high dose chemotherapy and autologous stem cell rescue often includes adequate pulmonary function. While high dose melphalan has been noted to cause significant pulmonary toxicity in a small percentage of patients with adequate pulmonary function, there are little published data on risk factors and use in lung impaired patients. We retrospectively reviewed the charts of 50 patients with myeloma who received a fixed dose of melphalan (200 mg/m2) and who had pre-melphalan and at least one post-melphalan spirometry (FVC and FEV1) and diffusing capacity (DLco) measurement. Comparisons were made with Pearson correlations and one-way ANOVA. Patients receiving melphalan showed no significant differences in mean FVC (p=0.40), FEV1 (p=0.48) or hemoglobin corrected DLco (p=0.40) comparing baseline to 3-month and 1-year results with 1-way ANOVA. There was a consistent increase in mean FVC(L), FEV1(L) and DLco (ml CO/min/mmHg) from pre to 3 months post (3m) and to one-year post (1y): FVC: pre=3.89, 3m= 4.02, 1y=4.24; FEV1: pre=2.92, 3m=2.95, 1y=3.14; DLco: pre=24.3, 3m=25.1, 1y=26.5. However, individual changes in DLco showed a wide distribution. Therefore, we examined a number of potential risk factors for change in DLco at 3 months. No detrimental effects were discernable for age, gender, history of prior pulmonary disease including smoking, pre-melphalan lung function, the use of high dose cyclophosphamide in the mobilization regimen, amount of prior chemotherapy or chest radiation, disease stage or response, or renal function. CD34+ cell dose (p=0.017, r = −0.344) and immunoglobulin type (IgA worse than IgG) (p=0.029, r = 0.316) were correlated and were independent factors on regression analysis (p

Ninety-six patients with severe aplastic anemia who received a sex- mismatched, HLA-identical allogeneic sibling marrow transplant had sequential cytogenetic analyses performed to determine the incidence and implications of posttransplant mixed hematologic chimerism. Of the 96 patients, 56 (58.3%) became mixed chimeras with coexisting host and donor cells detected in peripheral blood or marrow 14 days or later after transplant, and 40 patients (41.7%) were complete chimeras with 100% donor-type hematopoietic cells. The incidence of mixed chimerism was independent of prior blood production transfusions and infusion of donor buffy coat. The rejection rate was significantly increased in the mixed chimeric group, particularly in patients not receiving buffy coat (14 of 36 rejecting), although overall, the majority (69.7%) retained their first graft. Rejection was seen almost exclusively in patients exposed to multiple transfusions before transplantation. If patients who reject their first graft are censored, the overall incidence of grades II through IV acute graft-v-host disease (GVHD) was significantly reduced in those with mixed chimerism. Transfused patients with mixed chimerism in particular were less likely to develop grades II through IV acute GVHD. The incidence of chronic GVHD was similar in the two groups and did not significantly influence survival. In this study, mixed chimerism persisted for up to 395 days posttransplant, either the first graft being rejected or, more commonly, hematopoiesis reverting to 100% donor-type cells. Mixed lymphohematopoietic chimerism may persist in patients with aplastic anemia who have received matched allogeneic marrow transplants for significant periods before hematopoiesis reverts to donor cell type.

Granulocyte and platelet recovery as well as platelet transfusion requirements following allogeneic marrow transplantation were analyzed in 67 patients with chronic myelogenous leukemia in the chronic phase. Twenty patients had splenectomy prior to transplantation. Forty-seven patients were transplanted without splenectomy, 21 of whom had splenic enlargement by physical examination. There were no differences in the proportion of patients with granulocyte recovery, but the recovery of peripheral granulocytes to levels of 200, 500 and 1,000/mm3 occurred more rapidly in the splenectomy group than in the no-splenectomy group. Patients with splenectomy received platelet transfusions for a mean of 10 (2–36) days as compared to 20 (3–82) days for patients without splenectomy (p < .001). Eighteen (90%) patients with splenectomy became platelet transfusion independent at a median of 16 (2–32) days after transplantation as compared to 40 (85%) patients without splenectomy who became transfusion independent at a median of 28 (15–86) days (p < .001). The proportion of patients achieving platelet levels of 50 and 100 × 103/mm3 did not differ between the two groups (p = .07), but patients in the splenectomy group achieved these levels more rapidly following transplant (p < .001). One of 17 evaluable patients in the splenectomy group and 31 of 46 in the no-splenectomy group became refractory to random platelets (p < .001) and required platelets from family members or unrelated completely or partially HLA matched donors. In the no-splenectomy group, splenic size did not affect the speed of granulocyte or platelet recovery or platelet transfusion requirements. There was no difference in the post-transplant survival of patients with or without splenectomy.

One hundred twelve patients with hematologic malignancies underwent marrow transplantation from HLA-matched sibling donors and were randomized to receive either prophylactic granulocyte transfusions (PG, 67 patients) or prophylactic systemic antibiotics (PSA, 45 patients) as prophylaxis against nosocomial infections. Patients were treated in conventional hospital rooms and studied until day 100 post-transplant. For the entire study period, 26 patients (39%) in the PG group developed septicemia compared to 15 patients (33%) in the PSA group. Twenty-eight patients (42%) in the PG group developed local major infections compared to 19 patients (42%) in the PSA group. Ten patients (15%) in the PG group developed viral interstitial pneumonitis compared to 6 patients (13%) in the PSA group. None of these differences were statistically significant. There was no difference in the incidence of bacterial or fungal infections or viral interstitial pneumonitis between the two groups during the granulocytopenic or post-engraftment period. There was no difference in the incidence and severity of graft-versus-host-disease (GVHD). Inability to carry out the prophylaxis was frequent in the PG group, with complications necessitating discontinuance of transfusion in 24% of the recipients and 13% of the donors. The use of PG as an infection prophylaxis modality in marrow transplantation is not supported by this study, as it is difficult to carry out and because PG did not show any advantage over the use of PSA in preventing nosocomial infections.