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Reduced intensity conditioning with fludarabine and low dose total body irradiation before allogeneic hematopoietic stem cell transplantation (HCT) was developed to treat older or medically infirm patients with advanced hematologic malignancies. Given the regimen's low toxicity, it lends itself to be an outpatient procedure. Nevertheless, some patients experienced adverse events, leading to hospitalization during the first 100 days after HCT. The current study analyzed data from 957 patients with hematological malignancies who received either related (n=441) or unrelated (n=516) HLA-matched HCT between 1997 and 2017 (10% of patients mismatched for 1 HLA antigen or allele), with a median follow-up of 7.1 (range, 0.3-19.9) years. Median age of related recipients was 55 (range 18-79) years and 60 years for unrelated recipients (range 18-77). HCT-CI≥ 2 was similar for both groups (68% and 74%, respectively). The objective of the study was to determine how many patients required hospitalizations, the reasons for the hospitalizations, and whether hospitalizations adversely affected non-relapse mortality (NRM) and overall HCT outcome. We found that 54% of patients were not hospitalized or only had an overnight hospital admission for PBSC infusion. The main reasons for hospital admission (36% of related, 56% of unrelated recipients) were infection and regimen-related toxicity (Figure 1). Most admissions occurred in the first 3 weeks after HCT (60%), and these were mainly for neutropenic fever and regimen-related toxicity. The 5-year risk of NRM was significantly higher among hospitalized patients (27%) than among those who were not hospitalized (14%, Figure 2). Of note, the cumulative incidence curves between the two patient groups continued separating throughout the first 5-years. Table 1 shows an HR for NRM of 1.69 (95%CI; P=0.001) with the first hospital admissions. The HR for NRM increased with each subsequent admission by 1.3 (P=0.003). Univariate analysis also showed higher NRM among unrelated compared to related recipients. Five-year relapse mortality among hospitalized and non-hospitalized patients was similar (26% and 28%, respectively). In conclusion, 54% of current patients lived at home or in apartments throughout the HCT course while 46% had at least one hospital admission. Even one hospital admission adversely affected long-term outcome by increasing the risk of NRM. The events connecting hospital admission and increased NRM are subjects of ongoing analyses.

Urinary cytokines after HCT: evidence for renal inflammation in the pathogenesis of proteinuria and kidney disease

Several studies have shown that allogeneic hematopoietic cell transplantation (HCT) in first complete remission (CR1) of AML reduces the risk of relapse and improves relapse-free survival in intermediate- and poor-risk AML.[1][1] Benefits in (overall) survival are less obvious.[1][1],[2][2] One

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

We evaluated the pharmacodynamic relationships between mycophenolic acid (MPA), the active metabolite of mycophenolate mofetil (MMF), and outcomes in 308 patients after nonmyeloablative hematopoietic cell transplantation. Patients were conditioned with total body irradiation ± fludarabine, received grafts from HLA-matched related (n = 132) or unrelated (n = 176) donors, and received postgrafting immunosuppression with MMF and a calcineurin inhibitor. Total and unbound MPA pharmacokinetics were determined to day 25; maximum a posteriori Bayesian estimators were used to estimate total MPA concentration at steady state (Css). Rejection occurred in 9 patients, 8 of whom had a total MPA Css less than 3 μg/mL. In patients receiving a related donor graft, MPA Css was not associated with clinical outcomes. In patients receiving an unrelated donor graft, low total MPA Css was associated with increased grades III to IV acute graft-versus-host disease and increased nonrelapse mortality but not with day 28 T cell chimerism, disease relapse, cytomegalovirus reactivation, or overall survival. We conclude that higher initial oral MMF doses and subsequent targeting of total MPA Css to greater than 2.96 μg/mL could lower grades III to IV acute graft-versus-host disease and nonrelapse mortality in patients receiving an unrelated donor graft.

Background: Although in vitro and in vivo experiments have suggested that mesenchymal stromal cells (MSC) may have important immunomodulatory functions in allogeneic hematopoietic cell transplantation (HCT), results from clinical studies have been inconsistent. In the current study we investigate the safety of dog leukocyte antigen (DLA) identical or third party unrelated MSC in DLA-identical HCT. Results: There were no differences between treatment groups in depth of granulocyte or platelet nadirs, time to granulocyte or platelet engraftment, rate of acute GVHD or rejection. All dogs tolerated the MSC infusion well, although 2 dogs treated with unrelated MSC were euthanized on day 9 due to complications unrelated to the MSC infusion. While no formation of ectopic tissue was observed, GFP positive signals in bone marrow, spleen or liver were detected at time of necropsy in 75% and 50% of dogs treated with DLA-identical or unrelated MSC, respectively. Discussion: Treatment with DLA-identical or unrelated MSC in high dose DLA-identical HCT is safe, and provides a large animal HCT model in which to investigate immunological mechanisms and optimal treatment strategies for future human trials. Methods: Fourteen dogs were treated with 920 cGy total body irradiation (TBI) followed by transplantation of marrow from DLA-identical littermates and immunosuppression with cyclosporine. Prior to infusion of marrow, dogs received infusions of DLA-identical MSC from the marrow donor (n = 4), unrelated MSC (n = 4), or culture medium (n = 6), within 1 h of TBI. MSC obtained from relevant donors were ex-vivo expanded and transduced with GFP-retrovirus before infusion.

Most patients with hematologic malignancies have received extensive chemotherapy before hematopoietic cell transplantation (HCT), resulting in neutropenia, lymphocytopenia, and use of antibiotics. Accordingly, patients have a wide range of neutrophil counts, lymphocyte counts, and previous antibiotic use. The minimal toxicity of the current conditioning regimen allowed us to ask whether peritransplantation neutrophil or lymphocyte levels influences the risks of acute graft-versus-host disease (GVHD) or relapse. We analyzed outcomes in 459 patients age 7-75 years (median, 57 years) who received conditioning with fludarabine and low-dose total body irradiation for HLA-matched HCT. We report 2 key findings. First, low neutrophil nadirs within the first 3 weeks post-HCT had significant associations with increased risks of acute GVHD and 5-year nonrelapse mortality, but showed no association with the risk of relapse. Second, high lymphocyte counts immediately before HCT had significant associations with reduced risks of relapse and overall mortality, but no association with the risks of GVHD or nonrelapse mortality. These findings suggest that the immunologic mechanisms involved in acute GVHD might differ from those that initiate graft-versus-tumor effects.

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.

This study attempted to characterize causes of treatment failure, identify associated prognostic factors, and develop shorter-term end points for trials testing investigational products or regimens for second-line systemic treatment of chronic graft-versus-host disease (GVHD). The study cohort (312 patients) received second-line systemic treatment of chronic GVHD. The primary end point was failure-free survival (FFS) defined by the absence of third-line treatment, nonrelapse mortality, and recurrent malignancy during second-line treatment. Treatment change was the major cause of treatment failure. FFS was 56% at 6 months after second-line treatment. Lower steroid doses at 6 months correlated with subsequent withdrawal of immunosuppressive treatment. Multivariate analysis showed that high-risk disease at transplantation, lower gastrointestinal involvement at second-line treatment, and severe NIH global score at second-line treatment were associated with increased risks of treatment failure. These three factors were used to define risk groups, and success rates at 6 months were calculated for each risk group either without or with various steroid dose limits at 6 months as an additional criterion of success. These success rates could be used as the basis for a clinically relevant and efficient shorter-term end point in clinical studies that evaluate agents for second-line systemic treatment of chronic 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.

Strategies to prevent active infection with certain double-stranded DNA (dsDNA) viruses after allogeneic hematopoietic cell transplantation (HCT) are limited by incomplete understanding of their epidemiology and clinical impact. We retrospectively tested weekly plasma samples from allogeneic HCT recipients at our center from 2007 to 2014. We used quantitative PCR to test for cytomegalovirus, BK polyomavirus, human herpesvirus 6B, HHV-6A, adenovirus, and Epstein-Barr virus between days 0 and 100 post-HCT. We evaluated risk factors for detection of multiple viruses and association of viruses with mortality through day 365 post-HCT with Cox models. Among 404 allogeneic HCT recipients, including 125 cord blood, 125 HLA-mismatched, and 154 HLA-matched HCTs, detection of multiple viruses was common through day 100: 90% had ≥1, 62% had ≥2, 28% had ≥3, and 5% had 4 or 5 viruses. Risk factors for detection of multiple viruses included cord blood or HLA-mismatched HCT, myeloablative conditioning, and acute graft-versus-host disease (P values < .01). Absolute lymphocyte count of

The 2005 NIH chronic graft-versus-host disease (cGVHD) organ severity is based on the assessment of current status regardless of whether abnormalities are due to GVHD. The score assignment does not require knowledge of past manifestations, attribution, or whether cGVHD is still active. The aim of this study is to describe confounding factors affecting organ scores in patients with cGVHD. The study included 189 consecutive cGVHD patients evaluated at our center in 2013. Providers completed the NIH 0–3 organ-specific scoring evaluation with two questions added for each organ to identify abnormalities that were 1) not attributed to cGVHD, or 2) attributed to cGVHD plus other causes. Abnormalities attributed to causes other than GVHD were recorded. Eighty (14%) abnormalities were not attributed to cGVHD in at least one organ, and 41 (7%) abnormalities were attributed to cGVHD plus other causes in at least one organ. A total of 436 (78%) abnormalities were attributed only to cGVHD. Abnormalities not attributed to cGVHD were observed most frequently in the lung, gastrointestinal tract and skin. Most common abnormalities included pre-transplant condition, sequelae from GVHD, deconditioning, infections and medications. Our results support the the 2014 NIH consensus recommendation to consider attribution when scoring organ abnormalities.

BACKGROUND Patients with acute myeloid leukemia (AML) without complete remission (CR) or in first relapse (Rel1) can have extended leukemia control and survival after allogeneic hematopoietic cell transplantation (HCT). For patients in Rel1 or primary induction failure (PIF), transplantation versus treatment to achieve a second CR (CR2) and subsequent HCT might yield similar outcomes, but available comparative data are scarce. METHODS Survival was analyzed in 4682 HCT recipients according to disease status: PIF (N = 1440), Rel1 (failing ≥1 reinduction; N = 1256), and CR2 (N = 1986). RESULTS Patient, disease, and transplantation characteristics were similar, except that patients in CR2 more often had performance scores of 90% to 100%, de novo AML, and longer CR1 duration. Adverse cytogenetics were more common in patients who experienced PIF. The 5-year survival rate adjusted for performance score, cytogenetic risk, and donor type for CR2 was 39% (95% confidence interval [CI], 37%-41%) compared with 18% (95% CI, 16%-20%) for HCT in Rel1 and 21% (95% CI, 19%-23%) in PIF (P < .0001). CONCLUSIONS Although survival is superior for patients who undergo HCT in CR2, transplantation for selected patients in Rel1 or PIF may still be valuable. These data can guide decision making about additional salvage therapy versus prompt HCT for patients not in CR, but they also highlight that AML is intrinsically more treatable in patients who have favorable-risk cytogenetics, those with longer CR1 duration, and younger patients with better performance status. Cancer 2017;123:2025–2034. © 2017 American Cancer Society.

Allogeneic hematopoietic cell transplantation (HCT) from siblings or unrelated donors (URD) during complete remission (CR) may improve leukemia-free survival (LFS) in FMS-like tyrosine kinase 3+ (FLT3+) acute myeloid leukemia (AML), which has poor prognosis because of high relapse rates. Umbilical cord blood (UCB) HCT outcomes are largely unknown in this population. We found that compared with sibling HCT, relapse risks were similar after UCB (n=126) (hazard ratio (HR) 0.86, P=0.54) and URD (n=91) (HR 0.81, P=0.43). UCB HCT was associated with statistically higher non-relapse mortality compared with sibling HCT (HR 2.32, P=0.02), but not vs URD (HR 1.72, P=0.07). All three cohorts had statistically nonsignificant 3-year LFS: 39% (95% confidence interval (CI): 30-47) after UCB, 43% (95% CI: 30-54) after sibling and 50% (95% CI: 40-60) after URD. Chronic graft-versus-host disease rates were significantly lower after UCB compared with either sibling (HR 0.59, P=0.03) or URD (HR 0.49, P=0.001). Adverse factors for LFS included high leukocyte count at diagnosis and HCT during CR2 (second CR). UCB is a suitable option for adults with FLT3+ AML in the absence of an human leukocyte antigen-matched sibling and its immediate availability may be particularly important for FLT3+ AML where early relapse is common, thus allowing HCT in CR1 (first CR) when outcomes are best.

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

Allogeneic hematopoietic cell transplantation (HCT) offers curative potential to a number of older patients with acute myeloid leukemia (AML) in their first complete remission. However, there are limited data in the literature concerning post-HCT outcomes for older patients in their second complete remission (CR2).The purpose of the current study was to retrospectively investigate within the Center for International Blood and Marrow Transplant Research database parameters influencing posttransplant outcomes for patients 60 years of age or older undergoing HCT for AML in CR2.In total, 196 patients from 78 centers were identified; the median age was 64 years (range, 60-78 years). Seventy-one percent had a Karnofsky performance status ≥ 90 at the time of HCT. Reduced-intensity conditioning regimens were used in 159 patients (81%). A univariate analysis demonstrated a 3-year overall survival (OS) rate of 42% (95% confidence interval [CI], 35%-49%), a leukemia-free survival rate of 37% (95% CI, 30%-44%), a cumulative incidence of nonrelapse mortality of 25% (95% CI, 19%-32%), and a cumulative incidence of relapse (CIR) of 38% (95% CI, 31%-45%). A multivariate analysis demonstrated that cytogenetic risk was the only independent risk factor for OS (P = .023) with a hazard ratio (HR) of 1.14 (95% CI, 0.59-2.19) for intermediate-risk cytogenetics and an HR of 2.32 (95% CI, 1.05-5.14) for unfavorable-risk cytogenetics. For CIR, cytogenetic risk was also the only independent prognostic factor (P = .01) with an HR of 1.10 (95% CI, 0.47-2.56) for intermediate-risk cytogenetics and an HR of 2.98 (95% CI, 1.11-8.00) for unfavorable-risk cytogenetics.Allogeneic HCT is a curative treatment option for older patients with AML in CR2, particularly for those with favorable or intermediate cytogenetic risk. Cancer 2017;123:2035-2042. © 2017 American Cancer Society.

Regionalization of specialized health services can deliver high-quality care but may have an adverse impact on access and outcomes because of distance from the regional centers. In the case of hematopoietic cell transplantation (HCT), the effect of increased distance between the transplantation center and the rural/urban residence is unclear because of conflicting results from the existing studies. We examined the association between distance from primary residence to the transplantation center and rural versus urban residence with clinical outcomes after allogeneic HCT in a large cohort of patients. Overall mortality (OM), nonrelapse mortality (NRM), and relapse in all patients and those who survived for 200 days after HCT were assessed in 2849 patients who received their first allogeneic HCT between 2000 and 2010 at Fred Hutchinson Cancer Research Center (FHCRC)/Seattle Cancer Care Alliance. Median distance from FHCRC was 263 miles (range, 0 to 2740 miles) and 83% of patients were urban residents. The association between distance and the hazard of OM varied according to conditioning intensity: myeloablative (MA) versus nonmyeloablative (NMA). Among MA patients, there was no evidence of an increased risk of mortality with increased distance, but for NMA patients, the results did show a suggestion of increased risk of mortality for some distances, although globally the difference was not statistically significant. In the subgroup of patients who survived 200 days, there was no evidence that the risks of OM, relapse, or NRM were increased with increasing distance. We did not find any association between longer distance from transplantation center and urban/rural residence and outcomes after MA HCT. In patients undergoing NMA transplantations, this relationship and how it is influenced by factors such as age, payers, and comorbidities needs to be further investigated.

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

Cytomegalovirus (CMV) surveillance and preemptive therapy is the most commonly used strategy for CMV disease prevention in hematopoietic cell transplantation recipients. In 2007, we introduced a CMV prevention strategy for patients at risk for CMV disease using quantitative PCR surveillance, with treatment thresholds determined by patient risk factors. Patients (N = 367) received preemptive therapy either at a plasma viral load of ≥500 copies/mL, at ≥100 copies/mL if receiving ≥1 mg/kg of prednisone or anti-T cell therapies, or if a ≥5-fold viral load increase from baseline was detected. Compared with patients before 2007 undergoing antigenemia-based surveillance (n = 690) with preemptive therapy initiated for any positive level, the risk-adapted PCR-based strategy resulted in similar use of antiviral agents, and similar risks of CMV disease, toxicity, and nonrelapse mortality in multivariable models. The cumulative incidence of CMV disease by day 100 was 5.2% in the PCR group compared with 5.8% in the antigenemia group (1 year: 9.1% PCR vs 9.6% antigenemia). Breakthrough CMV disease in the PCR group was predominantly in the gastrointestinal (GI) tract (15 of 19 cases; 79%). However, unlike CMV pneumonia, CMV GI disease was not associated with increased nonrelapse mortality (adjusted hazard ratio, 1.19; P = .70 [GI disease] vs 8.18; P

Clonal cytogenetic abnormalities are a major risk factor for relapse after hematopoietic cell transplantation (HCT) for myelodysplastic syndrome (MDS). We determined the impact of the recently established 5-group cytogenetic classification of MDS on outcome after HCT. Results were compared with the impact of the International Prognostic Scoring System (IPSS) 3 cytogenetic risk groups, and the additional effect of a monosomal karyotype was assessed. The study included data on 1007 patients, 1-75 years old (median 45 years), transplanted from related (n = 547) or unrelated (n = 460) donors. Various conditioning regimens were used, and marrow, peripheral blood, or cord blood served as stem cell source. Both IPSS and 5-group cytogenetic risk classifications were significantly associated with post-HCT relapse and mortality, but the 5-group classification discriminated more clearly among the lowest- and highest-risk patients. A monosomal karyotype tended to further increase the rates of relapse and mortality, even after considering the IPSS or 5-group classifications. In addition, the pathologic disease category correlated with both relapse and mortality. Mortality was also impacted by patient age, donor type, conditioning regimen, platelet count, and etiology of MDS. Although mortality declined significantly in recent years, novel strategies are needed to overcome the barrier of high-risk cytogenetics.

We are investigating the use of an (211)At-labeled anti-CD45 monoclonal antibody (mAb) as a replacement of total body irradiation in conditioning regimens designed to decrease the toxicity of hematopoietic cell transplantation (HCT). As part of that investigation, dose-escalation studies were conducted in dogs using (211)At-labeled anticanine CD45 mAb, CA12.10C12, conjugated with a maleimido-closo-decaborate(2-) derivative, 4. Unacceptable renal toxicity was noted in the dogs receiving doses in the 0.27-0.62 mCi/kg range. This result was not anticipated, as no toxicity had been noted in prior biodistribution and toxicity studies conducted in mice. Studies were conducted to understand the cause of the renal toxicity and to find a way to circumvent it. A dog biodistribution study was conducted with (123)I-labeled CA12.10C12 that had been conjugated with 4. The biodistribution data showed that 10-fold higher kidney concentrations were obtained with the maleimido-conjugate than had been obtained in a previous biodistribution study with (123)I-labeled CA12.10C12 conjugated with an amine-reactive phenylisothiocyanato-CHX-A″ derivative. The difference in kidney concentrations observed in dogs for the two conjugation approaches led to an investigation of the reagents. SE-HPLC analyses showed that the purity of the CA12.10C12 conjugated via reduced disulfides was lower than that obtained with amine-reactive conjugation reagents, and nonreducing SDS-PAGE analyses indicated protein fragments were present in the disulfide reduced conjugate. Although we had previously prepared closo-decaborate(2-) derivatives with amine-reactive functional groups (e.g., 6 and 8), a new, easily synthesized, amine-reactive (phenylisothiocyanate) derivative, 10, was prepared for use in the current studies. A biodistribution was conducted with coadministered (125)I- and (211)At-labeled CA12.10C10 conjugated with 10. In that study, lower kidney concentrations were obtained for both radionuclides than had been obtained in the earlier study of the same antibody conjugated with 4 after reduction of disulfide bonds.

Allogeneic hematopoietic cell transplantation (HCT) is the only known treatment with curative potential for myelodysplastic syndrome, but relapse is a major cause of failure. We studied results in 289 patients transplanted between June 2004 and December 2013. Minimal identifiable disease (MID) markers pre-HCT were determined by multiparameter flow cytometry (MFC) and cytogenetics on marrow aspirates. The impact of MID on outcome after low- and high-intensity conditioning HCT was determined. Among 287 assessable patients, 68 (23.7%) had more than 5% marrow blasts at HCT; 219 patients were in morphologic remission but 154 (53.7%) were MID positive, whereas 65 (22.6%) were MID negative. The impact of MID on outcome was significantly different between patients who received low-intensity conditioning and patients who received a high-intensity regimen. The impact of conditioning intensity differed across the various MID categories. In particular, the risk of overall mortality was higher with low-intensity than with high-intensity regimens for patients who were positive for MID by cytogenetics regardless of positivity by MFC (HR, 1.67 if MFC positive/cytogenetics positive, HR, 7.23 if MFC negative/cytogenetics positive). On the other hand, patients who were MID negative by both MFC and cytogenetics had similar risks of mortality with low- and high-intensity regimens (HR, .99). The main factor responsible for mortality after low-intensity conditioning in MID-positive patients was relapse. The presence of MID should be considered when deciding on conditioning intensity because it identifies subgroups of patients who may benefit from high- or low-intensity conditioning.

BACKGROUND: Cytogenetics and multicolor flow cytometry (MFC) are useful tools for monitoring outcome of treatment in acute myeloid leukemia (AML). However, no data are available regarding the meaning of results when the 2 tests do not agree. METHODS: The authors of this report analyzed 1464 pairs of concurrent cytogenetics and flow results from 424 patients, before and after hematopoietic cell transplantation, and compared the prognostic impact of discordant and concordant results. RESULTS: Informative discordant results were observed in 22% of patients. Compared with patients who had double-negative test results, either positive result had a significant impact on overall survival and relapse-free survival. The hazard ratios with either positive cytogenetic results or positive MFC results pretransplantation were 3.1 (P = .009) and 2.5 (P = .0008), respectively, for reduced overall survival and 2.7 (P = .01) and 4.1 (P < .0001), respectively, for decreased recurrence-free survival. Similar findings were obtained post-transplantation. Molecular cytogenetics, ie, fluorescence in situ hybridization (FISH), added value to the evaluation of discordant cases. CONCLUSIONS: The detection of residual AML by either cytogenetics or flow cytometry in patients who underwent hematopoietic cell transplantation predicted early relapse and shortened survival. Cancer 2012;. © 2011 American Cancer Society.

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

The first series of patients with metastatic renal cell carcinoma (RCC) treated by non-myeloablative allogeneic hematopoietic cell transplantation (HCT) was reported in 2000 and demonstrated an allogeneic graft-versus-tumor (GVT) effect that encouraged further investigation of this approach. However, the past 10 years have also witnessed profound changes in the medical management of metastatic RCC with the introduction of targeted therapies directed against VEGF or mammalian target of rapamycin (mTOR) signaling pathways creating uncertainty about a continued role for allogeneic HCT in the treatment of RCC.A total of 21 published reports describing clinical outcomes for 398 patients with metastatic RCC treated by allogeneic HCT compiled herein provide a composite overview of the world wide experience for key efficacy and toxicity outcomes. Review of correlative studies that identify donor-derived T cells as mediators of RCC-specific GVT effects offers insight into both the potential as well as the technical barriers to the delivery of antigen-specific post-transplant cellular therapy or vaccination designed to augment the allogeneic GVT effect.The future development of non-myeloablative allogeneic HCT for metastatic RCC will require novel treatment protocols designed to augment and sustain post-transplant GVT effects against RCC to generate renewed enthusiasm for this approach.

Background Allogeneic hematopoietic cell transplantation is a potentially curative treatment for patients with acute lymphoblastic leukemia. However, the majority of older adults with acute lymphoblastic leukemia are not candidates for myeloablative conditioning regimens. A non-myeloablative preparative regimen is a reasonable treatment option for this group. We sought to determine the outcome of non-myeloablative conditioning and allogeneic transplantation in patients with high-risk acute lymphoblastic leukemia.Design and Methods Fifty-one patients (median age 56 years) underwent allogeneic hematopoietic cell transplantation from sibling or unrelated donors after fludarabine and 2 Gray total body irradiation. Twenty-five patients had Philadelphia chromosome-positive acute lymphoblastic leukemia. Eighteen of these patients received post-grafting imatinib.Results With a median follow-up of 43 months, the 3-year overall survival was 34%. The 3-year relapse/progression and non-relapse mortality rates were 40% and 28%, respectively. The cumulative incidences of grades II and III-IV acute graft-versus-host disease were 53% and 6%, respectively. The cumulative incidence of chronic graft-versus-host disease was 44%. Hematopoietic cell transplantation in first complete remission and post-grafting imatinib were associated with improved survival (P=0.005 and P=0.03, respectively). Three-year overall survival rates for patients with Philadelphia-negative acute lymphoblastic leukemia in first remission and beyond first remission were 52% and 8%, respectively. For patients with Philadelphia chromosome-positive acute lymphoblastic leukemia in first remission who received post-grafting imatinib, the 3-year overall survival rate was 62%; for the subgroup without evidence of minimal residual disease at transplantation, the overall survival was 73%.Conclusions For patients with high-risk acute lymphoblastic leukemia in first complete remission, non-myeloablative conditioning and allogeneic hematopoietic cell transplantation, with post-grafting imatinib for Philadelphia chromosome-positive disease, can result in favorable long-term survival. (Clinicaltrials.gov identifier: NCT0036738)

We analysed the results of haematopoietic cell transplantation (HCT) in 30 patients aged 60-78 (median 65) years, with primary myelofibrosis or myelofibrosis evolving from antecedent polycythaemia vera or essential thrombocythaemia. Donors were human leucocyte antigen (HLA)-identical siblings (N = 15) or unrelated individuals (N = 15). Various conditioning regimens were used, ranging from very low intensity (fludarabine plus 2 Gy total body irradiation) to high dose (busulfan plus cyclophosphamide). Stem cell sources were granulocyte colony-stimulating factor mobilized peripheral blood progenitor cells in 29 patients and marrow in one patient. Sustained engraftment was documented in 27 of 30 patients. Day -100 mortality was 13%. With a median follow-up of 22 (range 0·5 - 69) months, 3-year overall survival and progression-free survival were 45% and 40%, respectively. Currently, 13 patients are surviving. Seven patients died with disease progression at 0·5 -22 months, and 10 patients died from other causes at 1·5 -37.5 months after HCT. While the selection of older patients for transplantation was probably biased, the present results are encouraging. Motivated older patients with myelofibrosis without substantial comorbid conditions should be offered the option of allogeneic HCT.

Allogeneic hematopoietic stem cell transplantation represents a curative treatment approach for a large range of hematologic malignancies. Traditionally, high-dose radiochemotherapy as preparative regimen has been thought to be necessary for successful allogeneic stem cell transplantation. However, high-dose conditioning often results in considerable medullary and extramedullary toxicity, contributing to high rates of treatment-related mortality. This limits the use of this procedure to patients below 60 years of age without significant comorbidities. Since the peak incidence of most hematological malignancies is beyond the 5th decade of life, the majority of patients are not eligible for high-dose treatment. During the last 15 years, several dose-reduced or even non-myeloablative conditioning regimens have been developed, offering a curative treatment option for these patients. This review summarizes the history of reduced-intensity conditioning (RIC) transplantations, depicts the differences among regimens, highlights significant patient factors, and describes the impact on selected hematological malignancies.

Extracorporeal photopheresis (ECP) and the purine analog pentostatin exert potent immunomodulatory effects but have not been evaluated for their ability to enhance engraftment of hematopoietic stem cells. We evaluated in a canine model of dog leukocyte antigen (DLA)-identical hematopoietic cell transplantation (HCT) whether ECP in combination with pentostatin could enhance engraftment using a nonmyeloablative regimen consisting of 100 cGy total body irradiation (TBI) and postgrafting immunosuppression with mycophenolate mofetil (MMF) and cyclosporine (CSP). We have shown previously that with 100 cGy TBI alone as conditioning, all of six dogs rejected their graft 2–12 weeks after HCT. With the addition of pentostatin to 100 cGy TBI, 6 of 10 dogs rejected their graft. We now tested the additional use of ECP alone (n=2) or ECP plus 3–6 doses of pentostatin (n=7) before 100 cGy TBI and HCT. Eight out of 9 dogs rejected their grafts within 6–11 weeks after HCT. Compared to data without ECP, we failed to demonstrate a positive impact of the use of either ECP or pentostatin for prevention of rejection.

Background: There is limited data comparing the outcomes of the two most common (FM or FB) RIC regimens in AML. Previous smaller retrospective studies suggest increased non-relapse mortality (NRM) but decreased relapse with FM based RIC with a variable effect on overall survival as compared to FB. Methods: AML patients aged ≥18 years who had their 1st allo HCT using FM or FB (iv Bu only) RIC between 2001-2015 who had data reported to CIBMTR were studied. Patients with cord blood or identical twin donors, TBI as a part of conditioning, GVHD prophylaxis with T cell depletion/CD34 selection or post HCT Cyclophosphamide were excluded. Primary endpoint was overall survival (OS), and secondary endpoints included non-relapse mortality (NRM), relapse, leukemia free survival (LFS) and acute and chronic GVHD. Cox proportional hazards multivariable regression was used to compare the two RIC regimens while adjusting for significant patient, disease and transplant related factors. Major subgroup analysis included patients in CR pre-HCT. Results: 622 patients received FB and 791 had FM RIC. Median age of the FM group was 59 years, range (18 to 76) and median age of FB group was 61 years, range (18- 77). Compared to FB RIC regimen, FM group had more patients with active disease (36% vs 18%), with mismatched donors (24% vs 15%), with bone marrow grafts (19% vs 9%), HCT before 2005 (29% vs 12%) and without ATG/alemtuzumab (58 % vs 48%); but fewer patients in CR1 (46% vs 62%) and matched sibling donor grafts (21% vs 30%). There was significantly increased NRM in the FM vs FB within 3 mo post HCT (hazard ratio (HR)=3.85 (95% confidence intervals [CI] 2.46-6.03), but not beyond 3 mo FM vs FB , HR= 1.14 (95% CI 0.88-1.47). There was significantly decreased relapse for FM vs FB, (HR=0.65 (0.55-0.76), p Conclusion: The current study of this large CIBMTR AML transplant cohort has showed that in these two most common RIC regimens for allogeneic HCT, long-term survival with FM was similar to FB. While the FM regimen showed higher early NRM, it was associated with lower risks of relapse. Further analysis to evaluate FB and FM regimens in relationship to comorbidities, comprehensive geriatric assessments, and presence of minimal residual disease is warranted to better define the relative efficacy of these two RIC regimens in AML. Disclosures Weisdorf: Pharmacyclics: Consultancy; Seattle Genetics: Consultancy; SL Behring: Consultancy; FATE: Consultancy; Equillium: Consultancy.

Although HCT offers the best potential for cure for patients with high risk leukemia and MDS, the procedure may not be an option for all patients due to the toxicity of the conditioning regimen. Reduced-intensity conditioning (RIC) allo-HCT regimens are associated with lower non-relapse mortality (NRM), but patients receiving these regimens have a higher risk of relapse. Radioimmunotherapy (RIT) can potentially deliver high doses of targeted radiation while minimizing toxicity to normal tissue. When combined with RIC allo-HCT, RIT may improve responses without increasing toxicity associated with myeloablative conditioning. We evaluated the safety and efficacy of yttrium 90 (90Y)-anti-CD45 antibody (MAb; BC8) followed by a standard RIC regimen with fludarabine (Flu) and 2 Gy total body irradiation (TBI) as a means of developing an improved HCT strategy for high-risk acute leukemia or MDS patients. We used CD45 as a target due to its ubiquitous expression on hematopoietic stem cells including the leukemic blasts. We used the high-energy (2.2 MeVmax) beta-emitter 90Y, which has a relatively short half-life (2.7 days) to eliminate targeted malignant cells. This phase I dose-escalation trial (NCT01300572) was designed to estimate the safety, feasibility and maximum tolerated dose (MTD) of 90Y-BC8-DOTA MAb when combined with Flu and 2 Gy TBI followed by HLA‐matched, related or unrelated allo-HCT for patients with high-risk leukemia or MDS. The MTD was defined as the radiation absorbed dose delivered by 90Y-BC8-DOTA MAb associated with a true dose-limiting toxicity (DLT) rate of 25%, where a DLT is defined as Bearman grade III/IV regimen-related toxicity. Doses of 90Y were escalated in increments of 2 Gy depending on the occurrence of DLT. Inclusion required patients to have advanced leukemia or high-risk MDS (defined as primary refractory or relapsed AML/ALL, secondary AML, MDS expressed as RAEB or CMML). To determine the dose of 90Y-BC8-DOTA, patients first underwent a biodistribution step using a trace-labeled infusion of 111Indium (111In)-BC8-DOTA followed by gamma-camera imaging. On pre-HCT day -12, patients received 90Y-BC8-DOTA at a prescribed radiation dose calculated from the trace-labeled 111In-BC8-DOTA biodistribution, followed by Flu (30 mg/m2/day) on days -4 to -2. TBI (2 Gy) was administered on day 0, prior to G-CSF mobilized donor PBSC infusion. GVHD prophylaxis consisted of mycophenolate mofetil and cyclosporine. Fifteen patients, median age of 62 (range 37-76), were treated (10 with advanced AML, 5 with high-risk MDS). At time of HCT, 9 patients had refractory active disease while 6 were in remission with minimal residual disease (Table 1). The patients received 22.8 to 151.2 mCi of 90Y, delivering an average of 10.5 Gy to marrow, 70 Gy to spleen, and 17 Gy to liver. Although a maximum dose of 28 Gy was delivered to the liver, no DLT was observed. Therefore, the MTD could not be estimated. Treatment led to complete remission in 13 patients (87%), 2 patients had persistent disease after HCT. All patients engrafted with a median donor-derived CD3 and CD33 chimerism both 100% by day 28 after HCT. Ten patients (67%) developed grade II-IV acute GVHD (grade II: n=7; III: n=2; IV: n=1). Five patients (33%) developed chronic GVHD. Six patients relapsed, 5 of whom subsequently died due to progression of disease. The median time to relapse among these 6 patients was 59 days (range, 6- 351 days). One patient died from stage IV steroid-refractory GVHD. One patient died in remission from acute renal failure at 7 months after HCT. Eight patients (53%) are surviving with a median follow-up of 1.8 (range, 0.9-5.9) years. Estimated overall survival at one and two years were 66% and 46%, respectively, with progression-free survival estimated to be 46% at each of these time points. The 1-year estimate of relapse was 41% (Fig. 1). The inclusion of 90Y-BC8-DOTA into a RIC allo-HCT regimen is feasible, tolerable and no DLTs were observed. The efficacy of this approach is promising considering the high-risk leukemia/MDS patients with active disease enrolled. Current studies are evaluating the use of an alpha emitter, astatine-211, which is short-lived (t ½ = 7.2 hours) and provides high-energy radiation, conjugated to anti-CD45 MAb BC8 as part of an HCT conditioning regimen for patients with advanced AML, ALL, or high-risk MDS, in place of 90Y with the goal of continuing to improve outcomes using RIT for allo-HCT (NCT03128034). Disclosures Orozco: Actinium Pharmaceuticals: Research Funding. Green:Juno Therapeutics: Patents & Royalties, Research Funding. Gopal:Incyte: Consultancy; Pfizer: Research Funding; Gilead: Consultancy, Research Funding; Teva: Research Funding; Aptevo: Consultancy; Merck: Research Funding; Janssen: Consultancy, Research Funding; Spectrum: Research Funding; Takeda: Research Funding; BMS: Research Funding; Seattle Genetics: Consultancy, Research Funding; Brim: Consultancy; Asana: Consultancy. Pagel:Pharmacyclics, an AbbVie Company: Consultancy; Gilead: Consultancy.

Introduction: Survival rates continue to improve after allogeneic HCT (Gooley et al, NEJM, 2013). Population-based studies also indicate overall improvement in survival of older (60-80 years old) AML patients (pts) (Bower, Blood Cancer Journal, 2016). Yet, only a small minority (6%-8%) of them receive HCT (Medeiros, Ann Hematol. 2015). Given these potentially incongruent findings and the changing face of survival in AML, we designed the first prospective multi-center longitudinal study dating from first presentation of adults with AML to be treated at one of 13 different referral centers that provide both AML treatment and HCT. We compared survival according to whether or not pts received HCT at later time points. Methods: We enrolled 695 pts (Table 1). Data on demographics, AML status, cytogenetic risks per European Leukemia Network (ELN), and response; age; comorbidities per the HCT-comorbidity index (CI); function including activities of daily living (ADL); frailty; geriatric assessment including cognition; QOL including the Functional Assessment of Cancer Therapy-Bone Marrow Transplant Scale (FACT-BMT), Euro-QOL 5-Dimension scale, ENRICHD Social Support Instrument, Social Activity Log, and Patient Health Questionnaire 9-item Depression Scale (PHQ-9) were collected at enrollment and at 1, 3, 6, 9, 12, 18, and 24 months thereafter. We used time-dependent Cox regression analyses to identify baseline and time-dependent risk factors associated with mortality in the overall population. The factors identified as significantly associated with mortality (p Results: Median follow-up was 16.8 months (range 0.1-52.4). In the initial multivariate analyses, the following were identified as significantly associated with an increased risk of mortality (Table 2): HCT-CI scores ≥5 (p Survival after HCT was 58% at 2-years. Initial unadjusted analyses showed significantly lower risks of mortality in association with receiving allogeneic HCT (p=0.0003). These findings were similar in pts with intermediate (p=0.0005) or unfavorable (p However, in the adjusted models, the advantage of HCT in reducing mortality rates was lost both in the overall population (p=0.21, see figure) as well as in the other groups (p>0.54, 0.40, and 0.51, respectively, Table 3). Formal tests of interactions (Table 3) showed no statistically compelling evidence that the association of HCT and mortality varies with respect to the timing of mortality or to the underlying ELN risk. Conclusions: In a prospective observational study, adjusting for key AML-specific and pt-specific variables negated the observed benefit of HCT over non-HCT therapies in reducing mortality rates among AML pts. Our results might reflect 1) improvement in supportive care and non-HCT therapies, 2) a relatively high non-relapse mortality early after HCT and the need for longer follow-up to demonstrate an adjusted benefit of HCT, and 3) the high selectivity of the transplant eligibility process, as we accounted here for variables that are often ignored in "genetic assignment" randomized studies (i.e. comorbidities and function). New randomized trials are needed; however, these trials have to be more inclusive of vulnerable pts and measure pt-specific variables. Trials focusing on reducing burden of comorbidities, frailty and poor function are needed alongside trials to treat AML with or without HCT. Disclosures Gerds: Celgene: Consultancy; Apexx Oncology: Consultancy; CTI Biopharma: Consultancy; Incyte: Consultancy. Shami:JSK Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Baston Biologics Company: Membership on an entity's Board of Directors or advisory committees; Lone Star Biotherapies: Equity Ownership; Pfizer: Consultancy. Rizzieri:Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Arog: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Wang:Amgen: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Novartis: Speakers Bureau; Novartis: Speakers Bureau; Amgen: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Faderl:Jazz Pharmaceuticals: Employment, Equity Ownership. Koprivnikar:Alexion: Consultancy, Speakers Bureau; Amgen: Speakers Bureau; Otsuka: Consultancy. Sekeres:Opsona: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees. Becker:GlycoMimetics: Research Funding.

Background: Patients with acute myeloid leukemia (AML) admitted to the ICU have high in-hospital mortality, ranging from 40-70% (Halpern A, JAMA Oncology, 2017, 3; 374 and Thakkar SG, Cancer, 2008, 112; 2233). A model that considers AML-specific as well as ICU-specific variables could be of great value to identify critically ill patients likely to survive beyond hospital discharge and would help providers frame goals of care discussions. The AML Composite Model (AML-CM) was recently developed to predict early as well as late mortality after diagnosis of AML (Sorror ML, JAMA Oncology, 2017, 3:1675). The AML-CM incorporates AML cytogenetic risk, age, and comorbidity burden. It is unknown whether the AML-CM scores calculated at diagnosis of AML could add prognostic value to variables collected at the time of admission to ICU. To this end, we investigated the predictive value of AML-CM scores at diagnosis in addition to other risk factors including traditional ICU markers of illness severity collected from the time of ICU admission for prediction of 90-day mortality in patients with AML. Methods: This is a retrospective study of 218 patients with AML admitted to an ICU at one of two affiliated referral hospitals at any time during or after the initiation of chemotherapy between 2008 and 2017. We used factors from three time points: 1) initial diagnosis: sex, race, and AML-CM; 2) time of ICU admission: age, presence of relapsed or refractory disease, history of hematopoietic stem cell transplant (HCT), presence of neutropenia with ANC Results: The final study population was 217 patients, because one patient was lost to follow-up. The median age at ICU admission was 59 (range 19-83), 58% were male, and 79% were white. Mortality was 52% at 90 days. The median AML-CM was 7 (interquartile range 5-10), with 54% having AML-CM ≥7, and 46% having AML-CM The results of the univariate and multivariable analyses are listed in Table 1. The following variables were independently associated with 90-day mortality in the multivariate analysis: AML-CM ≥ 7 was associated with 3.6 times the odds of dying (95% CI 1.9-6.8, p=0.0001); IMV, 4.8 times the odds of dying (95% CI 2.2-10.5, p The AUC of the multivariable model which combined the 5 variables with statistically significant association on univariate analysis was 0.77. Based on results above, we calculated 90-day mortality rates among patients with 0 (n=39), 1 (n=84), 2 (n=75), and 3-4 (n=19) of the following factors: AML-CM ≥7, history of HCT, relapsed or resistant/refractory disease at ICU admission, and use of IMV (figure 1). Mortality rates at 90 days were 10%, 48%, 68%, and 95%, respectively. Conclusions: We identified 4 risk factors that show promise in predicting 90-day mortality after ICU admission in patients with AML: the AML-CM from time of diagnosis, history of HCT prior to ICU admission, disease status at ICU admission, and use of invasive mechanical ventilation within 24 hours of admission. Collectively, these factors can provide strong rationale to consider futility of ICU care among those with 3-4 risk factors, who represent ~9% of the population and have an extremely high risk of mortality at 90 days. Further, patients with 1-2 risk factors (73% of population) could be good candidates for early palliative care consult coincident with ICU admission given relatively high mortality risk within 90 days. Disclosures Becker: GlycoMimetics: Research Funding.

Introduction: Acute myeloid leukemia (AML) is most frequently diagnosed in older patients (pts), whose median survival is less than 1 year. Allogeneic hematopoietic cell transplantation (HCT) is a potentially curative treatment. However, older pts often have significant comorbidities and other geriatric health problems, and the effect of these on the probability of receiving HCT is unknown. To this end, we designed a prospective, multi-center, longitudinal, observational study dating from first presentation of adult pts with AML to be treated at one of 13 different referral centers that provide both AML treatment and HCT. We examined the effects of different variables (see methods) on the probability to 1) survive long enough to receive HCT and 2) to receive HCT if such survival occurred. Methods: We enrolled 695 pts (Table 1). Data on demographics, AML status, cytogenetic risks per European Leukemia Network (ELN), and response; age; comorbidities per the HCT-comorbidity index (CI); function including instrumental activities of daily living (IADL) and activities of daily living (ADL); frailty including walk test; geriatric assessment (GA) including cognition; Karnofsky performance status (KPS); QOL including the Functional Assessment of Cancer Therapy-Bone Marrow Transplant Scale (FACT-BMT), Euro-QOL 5-Dimension scale (EQ-5D), ENRICHD Social Support Instrument, Social Activity Log, and Patient Health Questionnaire 9-item Depression Scale (PHQ-9) were collected at enrollment and at 1, 3, 6, 9, 12, 18, and 24 months thereafter. High-risk myelodysplastic syndromes (MDS) receiving AML-like therapy were included. We used competing risk Cox regression analyses, treating HCT as the event of interest and death without HCT as a competing risk, with staggered entry (left truncation) at time of consent. Associations between variables were assessed both at enrollment and over time. Results: The overall rate of HCT at 9 months after enrollment was 43% (Figure 1) and 92% of pts who received HCT did so by the 9 month mark. In multivariate analyses, death without HCT (Table 2) was associated with augmented HCT-CI scores ≥5 (HR:2.11, p Among survivors (Table 3), low likelihood to receive HCT was associated with age ≥70 years (HR:0.40, p=0.0001), low ELN risk (HR:0.28, p Conclusions: In a prospective, observational, multi-center study, increasing age, comorbidity burden, ELN risk, low-intensity initial AML induction regimen, depression, and functional dependence increase risks of early mortality without HCT. In those who survived long enough to potentially receive HCT, age up to 69 years and/or multiple comorbidities were not found to be barriers to HCT, likely reflecting the widespread use of reduced-intensity conditioning regimens. However, the independent sharp decline in receipt of HCT in pts aged 70-80 years suggests continued bias, although pts in this age group have been shown to derive similar benefit from HCT as younger pts. Use of objective comorbidity and GA tools rather than age per se to decide on HCT is encouraged. The adverse impact of impairments in psychological health and function on survival and of impairments of cognition, geriatric health, and performance status on receipt of HCT emphasize the need for interventions that target these health limitations in conjunction with AML treatment to improve outcomes. Finally, the benefit of intensive vs. less-intensive induction therapies should be addressed with a randomized trial. Disclosures Gerds: Celgene: Consultancy; Apexx Oncology: Consultancy; Incyte: Consultancy; CTI Biopharma: Consultancy. Shami:Lone Star Biotherapies: Equity Ownership; Baston Biologics Company: Membership on an entity's Board of Directors or advisory committees; JSK Therapeutics: Employment, Equity Ownership, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy. Rizzieri:Arog: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teva: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Incyte: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees. Wang:Novartis: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy; Jazz: Speakers Bureau; Novartis: Speakers Bureau; Amgen: Consultancy; Jazz: Speakers Bureau; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees. Faderl:Jazz Pharmaceuticals: Employment, Equity Ownership. Koprivnikar:Amgen: Speakers Bureau; Otsuka: Consultancy; Alexion: Consultancy, Speakers Bureau. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees; Opsona: Membership on an entity's Board of Directors or advisory committees. Becker:GlycoMimetics: Research Funding.

INTRODUCTION: Emerging data indicate myeloid-derived suppressor cells (MDSCs) adversely impact outcomes of patients with a variety of malignancies. However, it is less clear how MDSCs affect acute myeloid leukemia (AML) disease biology or the response of AML patients to treatment. Here, we studied a cohort of people with AML undergoing hematopoietic cell transplantation (HCT) in first complete remission (CR1) to examine the relationship between the monocytic subtype of MDSCs (M-MDSCs), pre-transplant measurable residual disease (MRD) status, and outcome after HCT. PATIENTS AND METHODS: Adults ≥18 years of age were included if they underwent first allogeneic HCT with myeloablative or nonmyeloablative conditioning for AML in CR1 from April 2006 until October 2014. Prospective MRD testing in bone marrow aspirates was performed routinely via 10-color multiparameter flow cytometry (MFC) as part of the pre-transplant work-up. Pre-transplant MFC data were used retrospectively to quantify M-MDSCs as the proportion of monocytes (identified by side scatter properties and CD14 positivity) with low or negative expression of HLA-DR. M-MDSC frequency was then expressed as a percentage of the total number of viable cells in the sample. Available combinations of antigens measured by MFC did not allow for the identification of other MDSC subsets (e.g. granulocytic MDSCs). RESULTS: We identified 349 adults undergoing allogeneic HCT for AML in CR1 for whom pre-transplant MRD testing was performed and for whom follow-up data were available. Of these, 8 had to be excluded because of insufficient MFC events available for identification of M-MDSCs. In the remaining 341 patients, M-MDSC frequency ranged from The median follow-up time after HCT among all survivors was 5.8 (range, 2.0-11.4) years. The time was slightly longer for survivors with lower compared to those with higher M-MDSC frequency (6.1 [range 2.6-11.4] vs. 5.1 [range 2.0-11.3] years; p=0.0076). Stratified by the median M-MDSC frequency, the 3-year estimates of overall survival were similar for patients with lower and higher pre-HCT M-MDSCs (58.2% [95% confidence interval 50.4-65.2%] vs. 57.6% [49.8-64.7%]), as were 3-year estimates for relapse free survival (53.5% [45.7-60.7%] vs. 48.3% [40.6-55.6%]), 3-year estimates of the cumulative incidence of relapse (31.8% [24.9-38.8%] vs. 34.6% [27.6-41.8%]), and 3-year estimates of non-relapse mortality (14.7% [9.9-20.5%] vs. 17.0% [11.8-23.0%]). Analyses restricted to the subset of patients undergoing myeloablative (MA) conditioning or those undergoing MA conditioning in MRDneg remission showed qualitatively similar results. CONCLUSIONS: In the largest study to date examining the role of M-MDSCs in AML, we found no convincing evidence for a prognostic role of these cells for adults undergoing allografting in CR1. Disclosures Walter: Actinium Pharmaceuticals, Inc.: Other: Clinical trial support, Research Funding; Amgen Inc.: Other: Clinical trial support, Research Funding; Amphivena Therapeutics: Consultancy, Equity Ownership, Other: Clinical trial support, Research Funding; Aptevo Therapeutic: Consultancy, Other: Clinical trial support, Research Funding; Covagen AG: Consultancy, Other: Clinical trial support, Research Funding; Seattle Genetics, Inc.: Consultancy, Other: Clinical trial support, Research Funding; Boehringer Ingelheim Pharma GmbH & Co. KG: Consultancy; Pfizer: Consultancy.

Introduction: The preferred post-remission therapy for older patients (pts) with AML remains uncertain. We compared outcomes for older AML pts in CR1 receiving HCT reported to the CIBMTR to older AML pts achieving CR1 on National Clinical Trials Network induction and non-HCT consolidation therapy (CT) trials. Methods: This study focused on pts 60-75 years of age treated between 2004 to 2013. CT pts (n=211) underwent induction and consolidation on Alliance for Clinical Trials in Oncology, ECOG-ACRIN or SWOG clinical trials for initial therapy for newly diagnosed AML; the CIBMTR provided data for HCT pts (n=431). CT patients received at least one cycle of CT on study and were excluded if HCT occurred at any time. Time to event started at CR1 and pts entered at CT or HCT, respectively, using left-truncation to account for differential entry times. Results: For the CT cohort, first consolidation included standard therapy (e.g., cytarabine or a hypomethylating agent) and additional study drug (e.g., bortezomib, dasatinib, sorafenib, and Zosuquidar, gemtuzumab) or tipifarnib alone. Among HCT pts, the donor was a HLA-matched sibling or unrelated donor (URD) in 66% and the others were partially HLA-matched/mismatched URD (10%) or cord blood (24%). HCT pts were younger and more frequently had high-risk AML (high WBC, secondary AML and unfavorable cytogenetics) (Table). The median time from CR1 to HCT and CT was 3.2 and 0.5 months, respectively. Allogeneic HCT showed worse overall survival (OS) (HR=1.52, p=0.02) prior to 9 months and better OS thereafter (HR= 0.53, p Conclusions. Allogeneic HCT led to heightened early risks from TRM, but resulted in superior long-term survival in older AML pts receiving HCT relative to CT by reducing relapse. Efforts to attenuate early TRM after allogeneic HCT may further improve HCT outcomes for older pts. Disclosures Ustun: novartis: Speakers Bureau. Attar:Agios: Employment, Equity Ownership. Larson:Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BristolMyers Squibb: Consultancy, Research Funding; Ariad/Takeda: Consultancy, Research Funding. Roboz:Roche/Genentech: Consultancy; Eisai: Consultancy; Cellectis: Research Funding; Aphivena Therapeutics: Consultancy; Sandoz: Consultancy; Janssen Pharmaceuticals: Consultancy; Otsuka: Consultancy; Jazz Pharmaceuticals: Consultancy; Sandoz: Consultancy; AbbVie: Consultancy; Celltrion: Consultancy; Cellectis: Research Funding; Eisai: Consultancy; Astex Pharmaceuticals: Consultancy; Argenx: Consultancy; Pfizer: Consultancy; Celgene Corporation: Consultancy; Novartis: Consultancy; Jazz Pharmaceuticals: Consultancy; Bayer: Consultancy; Bayer: Consultancy; Roche/Genentech: Consultancy; Orsenix: Consultancy; Astex Pharmaceuticals: Consultancy; Celgene Corporation: Consultancy; Daiichi Sankyo: Consultancy; Pfizer: Consultancy; Janssen Pharmaceuticals: Consultancy; Otsuka: Consultancy; Orsenix: Consultancy; Daiichi Sankyo: Consultancy; Celltrion: Consultancy; Novartis: Consultancy; Aphivena Therapeutics: Consultancy; Argenx: Consultancy; AbbVie: Consultancy. Uy:GlycoMimetics: Consultancy; Curis: Consultancy. Stone:Fujifilm: Consultancy; Ono: Consultancy; Orsenix: Consultancy; Otsuka: Consultancy; Agios: Consultancy, Research Funding; AbbVie: Consultancy; Argenx: Other: Data and Safety Monitoring Board; Celgene: Consultancy, Other: Data and Safety Monitoring Board, Steering Committee; Arog: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Jazz: Consultancy; Astellas: Consultancy; Merck: Consultancy; Pfizer: Consultancy; Sumitomo: Consultancy; Amgen: Consultancy; Cornerstone: Consultancy. Foran:Agios: Research Funding; Xencor, Inc.: Research Funding. Weisdorf:Seattle Genetics: Consultancy; Equillium: Consultancy; FATE: Consultancy; SL Behring: Consultancy; Pharmacyclics: Consultancy.

Introduction Multiple myeloma (MM) is considered incurable but patients achieving minimal-residual disease (MRD) negative status following treatment have significantly better overall and progression-free survival. MM is highly heterogeneous both between and within patients, limiting the curative potential of novel agents targeting specific pathways. However all MM is highly sensitive to radiation. The α-emitter astatine-211 (211At) deposits a very large amount of energy (~100 keV/μm) within a few cell diameters (50-90 μm) resulting in irreparable double strand DNA breaks, making 211At, targeted to MM cells, particularly suited to eliminating MRD. CD38 is expressed on malignant plasma cells regardless of mutational status, and CD38 monoclonal antibodies (mAbs) constitute a proven targeted therapy for MM but do not alone eradicate disease. We proposed that 211At conjugated to an anti-CD38 mAb could effectively eliminate MM MRD, and tested this hypothesis in cellular and murine models. Methods We conjugated the anti-CD38 mAb OKT10 and an isotype matched control mAb, BHV1, to the amine-reactive labeling agent B10-NCS and labeled the final constructs with 211At. To assess in vitro cell binding we incubated each labeled construct with CD38+ cell lines, washed, and then measured cell pellet radioactivity in a gamma counter. To assess cytotoxicity we incubated CD38+ and CD38- cell lines with unlabeled or 211At-labeled OKT10-B10 for 60 hrs, then assayed viability. NOD.Cg-Rag1tm1MomIl2rgtm1Wjl/SzJ (NRG) mice bearing H929luc or OPM-2luc MM xenografts were generated by subcutaneous (SQ) flank injection of 107 cells 7 days prior to treatment. MRD was modeled by intravenous (IV) injection of 2.5 - 5 x 105 cells 5 days prior to treatment. Radioimmunotherapy (RIT) was administered by IV injection of 7.5 - 45 µCi of 211At-OKT10-B10 or 211At-BHV1-B10. For biodistribution studies (n = 5/group) mouse tissues were harvested 24 hrs post RIT and measured in a gamma counter. For therapy studies (n = 8-10/group), all mice received syngeneic bone marrow transplant 3 days post RIT. Disease progression was assessed by tumor dimensions, luminescence imaging and survival. Results 211At-CD38 mAb selectively bound and killed CD38+ but not CD38- MM cells in vitro. In vivo, biodistribution experiments demonstrated that 211At-CD38 RIT delivered 2.4 times more radiation to MM xenografts than did control 211At-BHV1 RIT (p = 0.007), and delivered significantly higher dose to tumor than to healthy tissues including lung (p = 0.04) and kidney (p = 0.015). In murine therapy studies, 211At-CD38 RIT at 15 - 45 µCi at least doubled median survival relative to untreated controls in each of two MM SQ xenograft models (p < 0.003). However, no mice in these models achieved complete remission and all eventually died of disease. In contrast, therapy studies using MRD models showed that 30 µCi 211At-CD38 RIT eliminated detectable disease in 80% of mice at day 21, compared to 20% of mice receiving nontargeted 211At RIT and 0% of untreated mice. At day 130, 50% of the 30 µCi 211At-CD38-RIT mice remained alive and disease-free, while all nontargeted and untreated mice died before day 85 (Fig. 1, survival of 30 µCi > 15 µCi 211At-CD38-RIT [p = 0.016] and all other groups [p < 0.0007]). The impact of therapy on body weight as well as hematopoietic, liver and kidney function was mild and returned to normal within 32 days of treatment. Conclusions The efficacy of CD38 targeted 211At appears to be a function of disease distribution and malignant plasma cell access, as compellingly demonstrated by our models. Bulky tumor geometry reduces mAb penetration. In contrast, the isolated cells and small tumor clusters that define MRD are readily accessible to mAbs, creating optimal conditions for α-emitter cell kill. In an era of highly potent MM therapy, preventing relapse remains frustratingly rare. Our approach is both agnostic to high-risk cytogenetic features and offers the potential to eliminate all residual MM cell clones. These encouraging findings will be explored in a clinical trial of 211At-CD38 RIT. Disclosures Orozco: Actinium Pharmaceuticals: Research Funding. Jones:Juno Therapeutics, a Celgene Company: Employment, Equity Ownership. Till:Mustang Bio: Patents & Royalties, Research Funding. Gopal:Teva: Research Funding; Spectrum: Research Funding; Janssen: Consultancy, Research Funding; BMS: Research Funding; Incyte: Consultancy; Gilead: Consultancy, Research Funding; Seattle Genetics: Consultancy, Research Funding; Brim: Consultancy; Pfizer: Research Funding; Aptevo: Consultancy; Takeda: Research Funding; Merck: Research Funding; Asana: Consultancy. Green:Juno Therapeutics: Patents & Royalties, Research Funding.

We retrospectively analyzed outcomes among 1206 patients with hematologic malignancies who had hematopoietic cell transplantation (HCT) from HLA-identical siblings (n = 630) or HLA-matched unrelated donors (n = 576) at a single institution between 2001 and 2007 for a correlation between recipient statin use and risk of graft-versus-host disease (GVHD). Among recipients with cyclosporine-based postgrafting immunosuppression (n = 821), statin use at the time of transplant (6%) was associated with a decreased risk of extensive chronic GVHD (cGVHD) (multivariate hazard ratio [HR], 0.62; 95% confidence interval [CI], 0.4-1.0; P = .05) and an increased risk of recurrent malignancy (HR, 1.75; 95% CI, 1.0-3.0; P = .04). Recipient statin use, however, had no apparent impact on the risks of cGVHD and recurrent malignancy among recipients given tacrolimus-based immunosuppression (n = 385; 8% statin treated). Risks of acute GVHD, nonrelapse mortality, and overall mortality were not significantly affected by recipient statin use. Hence, recipient statin treatment at the time of allogeneic HCT may decrease the risk of cGVHD in patients with cyclosporine-based immunosuppression, but at the expense of a compromised graft-versus-tumor effect.

Background. Posttransplant cyclophosphamide has been shown to control graft-versus-host disease and facilitate engraftment in the major histocompatibility complex-haploidentical transplant setting. Here, we hypothesized that methotrexate (MTX) could be used in a similar fashion. In patients with genetic diseases, the use of MTX rather than an alkylating agent such as cyclophosphamide would be preferable due to its reduced risk of promoting secondary malignancies. Method. Using our standard conditioning regimen consisting of a specific anti-CD44 mAb (S5) and 200 cGy total body irradiation followed by postgrafting immunosuppression with cyclosporine and mycophenolate mofetil as a control group, we compared outcomes with experimental animals receiving the same regimen with the addition of a single, large dose of posttransplant MTX on day +3 (50–400 mg/m2). Results. Adding MTX at all dose levels did not abrogate initial engraftment and controlled graft-versus-host disease in most cases. Dogs receiving MTX at the first dose level (50 mg/m2) improved time to rejection compared with controls (P=0.03) but did not decrease overall rates of rejection (P=0.56). However, increasing the dose of MTX beyond 50 mg/m2 seemed to have detrimental effects in both average (P=0.04) and peak (P=0.002) donor chimerism. Increasing the dose of MTX also promoted more profound lymphopenia. Finally, delaying cyclosporine and mycophenolate mofetil until after MTX administration did not seem to significantly improve engraftment kinetics. Conclusion. Adding high-dose MTX seemed to benefit the duration of donor chimerism at the lowest dose studied, but there was no benefit when escalating MTX doses to toxicity.

A nonmyeloablative conditioning regimen consisting of fludarabine (FLU) and 2 Gy TBI has been used extensively and with substantial engraftment success without promoting excessive nonrelapse mortality in medically infirm patients requiring hematopoietic cell transplantation. In this paper, we studied this same low-toxicity regimen as a means of promoting engraftment of unrelated donor hematopoietic cell transplantation in patients with Fanconi anemia (FA). All patients tolerated the regimen well with no mucositis or other severe toxicities. Of six patients transplanted, five achieved stable mixed or full donor chimerism. Acute and chronic GVHD occurred in four and three patients, respectively. Three patients are alive and well at a median of 45.9 (range, 20.9-68.1) months after transplant. In summary, this FLU-based regimen facilitates stable engraftment of unrelated PBSCs, but is associated with significant chronic GVHD.

Summary We retrospectively analyzed transfusion requirements within the first 100 d among allogeneic haematopoietic cell transplantation (HCT) recipients with haematological malignancies given either myeloablative (n = 1353) or nonmyeloablative conditioning (n = 503). We confirmed that myeloablative recipients required more platelet and red blood cell (RBC) transfusions than nonmyeloablative recipients (P

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.

The myeloproliferative neoplasms (MPNs) are a group of clonal disorders that arise from a pluripotent hematopoietic stem cell and are characterized by excess cellular proliferation. These disorders tend to be chronic in nature and can terminate over time into a bone marrow failure syndrome characterized by marrow fibrosis or transform into a leukemic phase. MPNs are predominantly diseases of the elderly and this is one reason why until very recently the standard treatment was supportive care. The only curative modality for these disorders is allogeneic hematopoietic cell transplantation. The introduction of reduced-intensity conditioning regimens now allows this life-saving therapy to be offered to elderly patients who were previously considered ineligible for high-dose conditioning owing to age or comorbidity. In this review, we will summarize the current strategies and future directions regarding the use of reduced-intensity conditioning regimens in the treatment of MPNs.

Hematopoietic cell transplantation (HCT) can be accomplished with grafts from alternative donors for patients lacking an HLA-matched related or unrelated donor. The optimal choice of an alternative donor stem cell source remains an open question and is influenced by several factors including chronic graft-versus-host disease (cGVHD). Chronic GVHD is a heterogeneous syndrome with major morbidity and adverse effects on quality of life (QoL) among long-term allogeneic HCT survivors. The aim of this study was to analyze the incidence of cGVHD and manifestations associated with severe morbidity and poor functional outcomes among recipients with alternative HCT donors. Methods: This retrospective study included adults who received a first alternative donor HCT for any diagnosis between 2006 and 2015 in Seattle and subsequently developed cGVHD. The alternative grafts included unrelated 4-6/6-HLA-matched single or double cord blood units (UCB), related HLA-haploidentical bone marrow or mobilized blood stem cells with post-transplant cyclophosphamide (R-HAPLO), and mobilized blood cells from unrelated donors with 1-allele mismatching at an HLA-A, B, C or DR locus at any HLA-typing resolution (1-mMUD). Endpoints were cumulative incidence frequencies (CI) of cGVHD and the CI of manifestations associated with severe morbidity (i.e., grade 2 or 3 keratoconjunctivitis sicca, scleroderma-like skin features, grade 2 or 3 myofasciitis, bronchiolitis obliterans, or esophageal stricture requiring dilation) and the CI of functional outcomes (i.e., return to work/school after the diagnosis of cGVHD, discontinuation of systemic immunosuppressive therapy, and change in KPS). We also compared the 2014 NIH overall severity of cGVHD at initial diagnosis, the incidence of new systemic immunosuppression after first-line therapy for cGVHD, non-relapse mortality and overall survival after cGVHD diagnosis. Results: Of 396 alternative donor HCT recipients, 129 developed cGVHD and were included in this study. Chronic GVHD developed in 29 of 163 UCB recipients (3-year CI, 18%), 21 of 88 R-HAPLO recipients (24%) and 79 of 145 1-mMUD recipients (55%) HCT (Fig. 1A). The median follow-up times after onset of cGVHD were 48 (range 4-121) months for UCB, 60 (range Conclusions: Compared to 1-mMUD group, UCB and R-HAPLO HCT recipients were less likely to develop cGVHD. Among those with cGVHD, UCB and R-HAPLO HCT recipients were less likely to develop manifestations of severe morbidity, had less protracted cGVHD (a shorter duration of systemic treatment), and higher likelihood of resuming work or school, suggesting better QoL compared to 1-mMUD HCT recipients. Our results will help better counsel patients about alternative HCT donors. A randomized study (NCT01597778) comparing UCB with R-HAPLO HCT is underway to determine which of these donors may be associated with superior outcomes. Disclosures Lee: Mallinckrodt: Honoraria; Amgen: Other: One-time advisory board member; Bristol-Myers-Squibb: Other: One-time advisory board member; Kadmon: Other: One-time advisory board member. Martin: Pfizer: Consultancy; Procter and Gamble: Equity Ownership; Incyte: Consultancy; Fresenius, Neovii: Research Funding. Cheng: Gilead Sciences, Inc.: Consultancy. Flowers: Pharmacyclics: Consultancy.

Introduction: Novel agents and autologous stem cell transplant (auto-SCT) have resulted in a survival benefit among patients with multiple myeloma (MM), but almost all ultimately relapse. Allogeneic transplant (allo-SCT) provides a tumor-free graft and graft-versus-myeloma (GVM) effect, but myeloablative conditioning regimens are associated with high rates of treatment-related mortality (TRM). In contrast, reduced intensity allo-SCT conditioning regimens are associated with lower TRM, but patients receiving these regimens tend to have a higher risk of relapse. Radioimmunotherapy (RIT) offers the potential to deliver high doses of targeted radiation while minimizing toxicity to normal tissue. When incorporated into reduced intensity allo-SCT, RIT may improve responses without the associated toxicity historically associated with myeloablative conditioning. We studied 90Yttrium conjugated to an IgG1 murine anti-CD45 monoclonal antibody (MAb) (BC8), in conjunction with a reduced intensity-conditioning regimen prior to allogeneic SCT. We used CD45 as a target due to its ubiquitous expression in hematopoietic stem cells. We used the high-energy (2.8 MeVmax) beta-emitter, 90Y to facilitate a bystander crossfire effect and eliminate malignant plasma cells. Methods: This is a single-arm, open label, dose-escalation, phase I trial designed to estimate the safety, feasibility and maximum tolerated dose (MTD) of 90Y-BC8-DOTA MAb when combined with fludarabine (flu) and low dose total body irradiation (TBI) followed by HLA-matched, related or unrelated allo-SCT for patients with high risk MM. Inclusion required patients to have at least one high risk MM-associated disease characteristic at diagnosis (del13 or hypodiploidy by conventional cytogenetics, t(4;14), t(14;16), del 17 by FISH, beta-2 microglobulin >3.5 mcg/mL, LDH >1.5 times upper limit of normal, plasma cell leukemia or progressive disease following primary therapy), and/or disease progression after auto-SCT. To determine the dose of 90Y-BC8-DOTA, patients first underwent a biodistribution step using a trace-labeled infusion of 111Indium-BC8-DOTA followed by gamma camera imaging and bone marrow biopsy. On pre-transplant day -12, patients received 90Y-BC8-DOTA at a dose calculated from the trace-labeled 111Indium-BC8-DOTA biodistribution, followed by Flu (30 mg/m2/day) on days -4 to -2. TBI (2 Gy) was administered on day 0, prior to growth factor mobilized donor peripheral blood stem cell infusion. GVHD prophylaxis consisted of mycophenolate mofetil and cyclosporine initiated on day 0 and day -3, respectively. The MTD was defined as the dose of 90Y-BC8-DOTA MAb associated with a true dose-limiting toxicity (DLT) rate of 25%, where a DLT is defined as Bearman grade III/IV regimen-related toxicity. Doses of 90Y were escalated in increments of 2 Gy depending on the occurrence of DLT. Results: A total of 15 patients were enrolled. Patient characteristics and outcomes are summarized in Table 1. One patient was withdrawn from the study prior to receiving the therapy dose after testing positive for human anti-mouse antibodies. The remaining 14 patients went on to receive 90Y-BC8-DOTA (0.5 mg/kg antibody) at escalating 90Y dose levels of 6 to 32 Gy to the liver, which is the normal critical organ. Six patients (43%) experienced grade 3-4 toxicity, predominantly GI and metabolic/electrolyte disturbances. No DLTs were observed. Because no DLTs were seen, the MTD could not be estimated. All patients achieved platelet and neutrophil engraftment, and 13 patients (93%) were >95% donor in the CD3, CD33 and CD56 compartments at day +28. Estimates of overall and progression-free survival at 2 years were 77% and 78%, respectively (Figure 1). Eleven patients who completed the study regimen are alive at 2.6 months to 4.1 years. Of these, 6 patients are in complete remission, 2 have persistent disease, and 3 have relapsed at 4 months, 6 months, and 3 years post-transplant. Three patients died: 2 due to progressive disease and 1 due to respiratory failure in the setting of liver GVHD. Conclusion: The inclusion of 90Y-BC8-DOTA into a reduced intensity allo-SCT conditioning regimen is feasible and no dose-limiting toxicities have been observed. The efficacy of this regimen is promising compared with historical control rates of conventional allo-SCT for MM and should be explored in a phase II trial. Disclosures Orozco: Actinium Pharmaceuticals: Other: Research Funding to Institution for sponsored Clinical Trials. Gopal: Seattle Genetics: Consultancy, Research Funding. Becker: GlycoMimetics, Inc.: Research Funding. Press: Roche: Honoraria, Research Funding; BMS: Honoraria; Bayer: Consultancy. Bensinger: Janssen: Membership on an entity's Board of Directors or advisory committees.