Woolfrey, Ann E.

Abstract Comparative outcomes of allogeneic hematopoietic cell transplantation (HCT) for BCR-ABL1− myeloproliferative neoplasms (MPNs) in blast phase (MPN-BP) vs de novo acute myeloid leukemia (AML), and AML with prior myelodysplastic syndromes (MDSs; post-MDS AML), are unknown. Using the Center for International Blood and Marrow Transplant Research (CIBMTR) database, we compared HCT outcomes in 177 MPN-BP patients with 4749 patients with de novo AML, and 1104 patients with post-MDS AML, using multivariate regression analysis in 2 separate comparisons. In a multivariate Cox model, no difference in overall survival (OS) or relapse was observed in patients with MPN-BP vs de novo AML with active leukemia at HCT. Patients with MPN-BP in remission had inferior OS in comparison with de novo AML in remission (hazard ratio [HR], 1.40 [95% confidence interval [CI], 1.12-1.76]) due to higher relapse rate (HR, 2.18 [95% CI, 1.69-2.80]). MPN-BP patients had inferior OS (HR, 1.19 [95% CI, 1.00-1.43]) and increased relapse (HR, 1.60 [95% CI, 1.31-1.96]) compared with post-MDS AML. Poor-risk cytogenetics were associated with increased relapse in both comparisons. Peripheral blood grafts were associated with decreased relapse in MPN-BP and post-MDS AML (HR, 0.70 [95% CI, 0.57-0.86]). Nonrelapse mortality (NRM) was similar between MPN-BP vs de novo AML, and MPN-BP vs post-MDS AML. Total-body irradiation–based myeloablative conditioning was associated with higher NRM in both comparisons. Survival of MPN-BP after HCT is inferior to de novo AML in remission and post-MDS AML due to increased relapse. Relapse-prevention strategies are required to optimize HCT outcomes in MPN-BP.

Abstract Abstract 467 Background: While donor-recipient disparity at HLA loci is associated with greater risk for severe acute graft vs. host disease (GVHD) and inferior survival after unrelated donor allogeneic hematopoietic cell transplantation (HCT), the impact of amino acid substitution (AAS) at peptide binding pockets of the HLA molecule is incompletely understood. Methods: Adult and pediatric patients who received myeloablative or reduced intensity/non-myeloablative first unrelated bone marrow or peripheral blood stem cell transplantation for AML, ALL, CML or MDS between 1988 and 2009 were included. Donors and patients were fully high resolution matched for HLA-A, B, C, and DRB1 (8/8) or had single mismatch (7/8) at one HLA class I locus. Among 7/8 donor-recipient pairs, cases were categorized based on the presence or absence of the AAS of interest at positions 9, 77, 99, 116, or 156 of the class I molecule. In multivariable analysis accounting for patient, disease, and transplantation variables, we studied the independent impact of AAS at these residues on risk for grade III-IV acute GVHD, chronic GVHD, treatment-related mortality, primary malignancy relapse, and overall survival. We compared 7/8 donor-recipient pairs with AAS of interest to 7/8 pairs without these AAS in the primary analyses. Additionally, we performed this analysis restricted to each HLA class I locus. Results: Donor-recipient pairs were 8/8 matched (n=5282), 7/8 with AAS of interest (n=1713), or 7/8 without AAS of interest (n=318). In multivariable analysis, AAS at position 116 was associated with increased risk for grade III-IV acute GVHD (HR 1.21, 1.04–1.42, p=0.0165). No other significant association was detected between AAS studied and clinical outcomes. In multivariable analysis restricted to each class I HLA locus, we detected the following: Among 7/8 matched pairs with mismatch at HLA-C, AAS at position 116 was associated with increased risk for severe acute GVHD (HR 1.42, 1.13–1.79, p=0.0031) and inferior OS (HR 1.2, 1.01–1.41, p=0.0343). AAS at position 99 was associated with increased TRM (HR 1.37, 1.11–1.69, p=0.0037). Of 7/8 pairs with mismatch at HLA-B, AAS at position 9 was associated with increased chronic GVHD (HR 2.19, 1.31–3.66, p=0.0029). Specific amino acid substitution pairs with frequency > 30 were tested for association with HCT outcomes. None met the significance level of 0.00125, pre-specified for multiple comparisons. Conclusions: These results support the concept that AAS at key peptide-binding residues in the HLA class I molecule are associated with increased risk for severe acute GVHD and lower survival. Disclosures: No relevant conflicts of interest to declare.

Abstract Higher bone marrow cell dose has been associated with improved survival after allogeneic BMT. Although PBSC provides higher cell dose, it also provides a higher number of T cells which increases the risk of GVHD and may negatively impact the outcome in pediatric patients. A prospective multi-center trial was conducted to evaluate the safety and feasibility of G-CSF primed bone marrow in children receiving HLA-identical sibling bone marrow transplantation (BMT). Thirty eight children at 9 different centers, 17 female and 21 male with a median age of 9.8 years (range 0.8–17) were enrolled between May 2003 and May 2005. Fifteen patients had high risk diseases (ALL ≥CR2=4, AML≥ CR2/refractory=5, Advanced MDS=3, JMML=1, NHL=2) and 23 had standard risk disease (SAA=6, Red Cell Aplasia=1, Sickle cell disease=1, CML-CP=2, AML CR1=9, ALL CR1=2, MDS-RA=2). Five patients had undergone a prior allogeneic transplant. All patients received myeloablative preparative regimens (Cy/TBI±VP-16=12, BU/Cy±other=20 and Cy/ATG=6) and 32 (84%) received CSP/FK506 with MTX as GVHD prophylaxis. Donors were HLA identical siblings except for one who was syngeneic. Donors with median age of 9.2 y (range 1.1–22) received 5 mcg/kg/day of GCSF SQ for 5 consecutive days. Bone marrow was collected on the fifth day with a median volume of 14.5 cc/kg (range 5.2–25). No donor experienced any complications related to G-CSF administration or harvest, up to the time of last follow-up at one month after the harvest. The absolute CD34 cell count at the day of the harvest was measured in 28 patients and it was significantly higher in bone marrow compared to peripheral blood, median of 50/μl (8–247) vs 513/μl (116–156) respectively (p <0.0001). Median nucleated and CD 34 cells infused was 8.4x108/kg (range 2.4–60.9) and 8.7x106/kg (range 2–27.6) respectively. No G-CSF was administered post transplant. All patients had neutrophil engraftment at a median of 19 days (13–28), and all but one patient with early post-transplant relapse had platelet engraftment at a median of 20 days (9–44). Thirteen patients (35%) developed grade 2 GVHD and 4 of 34 evaluable patients (12%) developed chronic GVHD (3 limited and 1 extensive). There was no transplant related mortality. Among 30 patients with malignant disorders 9 (30%) relapsed (6 with high risk and 3 with standard risk disease). The EFS and OS of patients with standard disease at 1 year is 84% (95% CI 68–100%) and 95% (95% CI 87–100) respectively. With a median follow up of 1 year the estimated EFS and OS of all patients at one year is 76% (CI 62–93) and 92% (95% CI 83–100) respectively. We conclude that G-CSF primed bone marrow from pediatric donors is safe and can result in high NC and CD34 cell dose that facilitate engraftment after myeloablative BMT without a discernable increase in the risk of GVHD. A prospective randomized trial comparing G-CSF primed bone marrow to unstimulated marrow is planned.

Abstract BMT CTN 0201 was a randomized study of unrelated donor bone marrow (BM) vs. peripheral blood (PB) (N=551) in hematopoietic cell transplantation (HCT) for hematologic malignancies. The primary analysis after 2 years of follow up showed similar survival, disease-free survival and treatment-related mortality between the graft types. There was a higher rate of graft failure with bone marrow (9% vs. 3%, p=0.002) and a higher rate of chronic GVHD with peripheral blood (53% vs. 41%, p=0.01). (Anasetti et al, NEJM 2012) Patient reported outcomes (PROs) were collected from patients > 16 years old at enrollment and 0.5, 1, 2 and 5 years after transplantation with the Functional Assessment of Cancer Therapies - Bone Marrow Transplant (FACT-BMT), Mental Health Inventory (MHI), and Lee chronic graft-versus-host disease (cGVHD) symptom scale. At 5 years, 102 BM and 93 PB participants were alive and eligible for the quality of life (QOL) study. Clinically meaningful differences (changes in scores that are noticeable to patients) were considered 0.5 x standard deviation of the total population based on the distribution method. Results: Data as of 5/25/15 were analyzed. 70% completed the pre-randomization assessment, and 74-78% of adult survivors completed the 5 year assessment. Age < 30 at transplant and high risk disease were associated with missing 5 year data, but not graft source. Response rates at 0.5, 1 and 2 years were 28-43% of survivors. There are no differences in any of the primary QOL scores in the first two years after HCT using univariate comparisons, although missing data severely limit conclusions during this period. At 5 years, the FACT-Trial Outcome Index (TOI), the MHI Psychological Well-Being, and the cGVHD symptom scale scores are all significantly better for BM patients, although only the latter two are still significant after adjustment for multiple testing (p<0.0125 because of 4 primary QOL variables). Results were similar when tested in multivariate models adjusting for baseline patient-reported scores and also imputing missing values based on patient characteristics (Table). Of the 7 chronic GVHD subscales, symptoms in the eye, lung, and energy were significantly better with BM (p<0.01). A diagnosis of cGVHD was highly associated with patient-reported cGVHD symptoms but not with QOL or psychological status. Inclusion of extensive cGVHD in the multivariate models did not change the significance of PRO differences suggesting that differences in cGVHD incidence do not explain the PRO findings. With a median follow up of 73 months for survivors, no difference in survival between PB and BM is observed (p=0.84, Figure). Conclusion: At 5 years after transplant, recipients of unrelated donor BM have better psychological well-being and less burdensome chronic GVHD symptoms than recipients of PB. Survival rates are similar. Table. Comparisons of primary QOL variables at 5 years, adjusted for QOL values at baseline and missing data using inverse probability weighting using significant clinical characteristics. QOL scale Bone marrow (n=102) Peripheral blood (n=93) P value Clinically significant difference* Difference between BM and PB (95% CI) FACT-BMT TOI, mean +/- SE (higher scores better) 76.7 +/- 1.6 (n=79) 70.5 +/- 1.9 (n=69) 0.014 8.5 6.2 (1.3-11.1) MHI - Psychological well-being, mean +/- SE (higher scores better) 78.9 +/- 1.7 (n=80) 72.2 +/- 1.9 (n=72) 0.011 8.4 6.7 (1.6-11.8) MHI-Psychological Distress, mean +/- SE (lower scores better) 16.0 +/- 1.3 (n=80) 19.0 +/- 1.5 (n=71) 0.128 6.5 -3.0 (-6.8,0.9) Chronic GVHD symptoms, mean +/- SE (lower scores better) 13.1 +/- 1.5 (n=80) 19.3 +/- 1.6 (n=72) 0.004 7.1 -6.3 (-10.5, -2.0) SE, standard error *0.5 x STD Figure 1. Figure 1. Disclosures Lee: Bristol-Myers Squibb: Consultancy; Kadmon: Consultancy. Maziarz:Athersys: Consultancy, Patents & Royalties, Research Funding; Novartis: Consultancy.

Abstract Allogeneic hematopoietic cell transplantation (allo-HCT) is a potentially curative treatment of chronic myeloid leukemia (CML). Optimal conditioning intensity for allo-HCT for CML in the era of tyrosine kinase inhibitors (TKIs) is unknown. Using the Center for International Blood and Marrow Transplant Research database, we sought to determine whether reduced-intensity/nonmyeloablative conditioning (RIC) allo-HCT and myeloablative conditioning (MAC) result in similar outcomes in CML patients. We evaluated 1395 CML allo-HCT recipients between the ages of 18 and 60 years. The disease status at transplant was divided into the following categories: chronic phase 1, chronic phase 2 or greater, and accelerated phase. Patients in blast phase at transplant and alternative donor transplants were excluded. The primary outcome was overall survival (OS) after allo-HCT. MAC (n = 1204) and RIC allo-HCT recipients (n = 191) from 2007 to 2014 were included. Patient, disease, and transplantation characteristics were similar, with a few exceptions. Multivariable analysis showed no significant difference in OS between MAC and RIC groups. In addition, leukemia-free survival and nonrelapse mortality did not differ significantly between the 2 groups. Compared with MAC, the RIC group had a higher risk of early relapse after allo-HCT (hazard ratio [HR], 1.85; P = .001). The cumulative incidence of chronic graft-versus-host disease (cGVHD) was lower with RIC than with MAC (HR, 0.77; P = .02). RIC provides similar survival and lower cGVHD compared with MAC and therefore may be a reasonable alternative to MAC for CML patients in the TKI era.

BACKGROUNDPatients with FMS like tyrosine kinase 3 (FLT3)‐mutated acute myeloid leukemia (AML) have a poor prognosis and are referred for early allogeneic hematopoietic stem cell transplantation (HCT).METHODSData from the Center for International Blood and Marrow Transplant Research (CIBMTR) were used to evaluate 511 adult patients with de novo AML who underwent HCT during 2008 through 2011 to determine whether FLT3 mutations had an impact on HCT outcomes.RESULTSIn total, 158 patients (31%) had FLT3 mutations. Univariate and multivariate analyses revealed an increased risk of relapse at 3 years in the FLT3 mutated group compared with the wild‐type (WT) group (38% [95% confidence interval (CI), 30%‐45%] vs 28% [95% CI, 24%‐33%]; P = .04; relative risk, 1.60 [95% CI, 1.15‐2.22]; P = .0048). However, FLT3 mutation status was not significantly associated with nonrelapse mortality, leukemia‐free survival, or overall survival. Although more patients in the FLT3 mutated group died from relapsed primary disease compared with those in the WT group (60% vs 46%), the 3‐year overall survival rate was comparable for the 2 groups (mutated group: 49%; 95% CI, 40%‐57%; WT group: 55%, 95% CI, 50%‐60%; P = .20).CONCLUSIONSThe current data indicate that FLT3 mutation status did not adversely impact overall survival after HCT, and about 50% of patients with this mutation who underwent HCT were long‐term survivors. Cancer 2016;122:3005‐3014. © 2016 American Cancer Society.

Key PointsAmino acid substitution at peptide-binding residues of the HLA class I molecule is associated with graft-versus-host disease and mortality. Avoidance of donor-recipient combinations that result in amino acid substitution at peptide-binding residues may improve transplant outcomes.

AbstractImatinib mesylate (IM, Gleevec) has largely supplanted allogeneic hematopoietic cell transplantation (HCT) as first line therapy for chronic myeloid leukemia (CML). Nevertheless, many people with CML eventually undergo HCT, raising the question of whether prior IM therapy impacts HCT success. Data from the Center for International Blood and Marrow Transplant Research on 409 subjects treated with IM before HCT (IM+) and 900 subjects who did not receive IM before HCT (IM−) were analyzed. Among patients in first chronic phase, IM therapy before HCT was associated with better survival but no statistically significant differences in treatment-related mortality, relapse, and leukemia-free survival. Better HLA-matched donors, use of bone marrow, and transplantation within one year of diagnosis were also associated with better survival. A matched-pairs analysis was performed and confirmed a higher survival rate among first chronic phase patients receiving IM. Among patients transplanted with advanced CML, use of IM before HCT was not associated with treatment-related mortality, relapse, leukemia-free survival, or survival. Acute graft-versus-host disease rates were similar between IM+ and IM− groups regardless of leukemia phase. These results should be reassuring to patients receiving IM before HCT.

A prospective multicenter trial was conducted to evaluate the safety and feasibility of granulocyte colony-stimulating factor (G-CSF)–primed bone marrow (G-BM) in children receiving allogeneic bone marrow transplantation (BMT). A total of 42 children with a median age of 9.8 years (range, 0.8-17 years) were enrolled. Donors with median age of 9.2 years (range, 1.1-22 years) received 5 μg/kg per day of subcutaneous G-CSF for 5 consecutive days. BM was harvested on the fifth day. No donor experienced complications related to G-CSF administration or marrow har-vest. Median nucleated (NC) and CD34 cells infused was 6.7 × 108/kg (range, 2.4-18.5 × 108/kg) and 7.4 × 106/kg (range, 2-27.6 × 106/kg), respectively. Neutrophil and platelet engraftment was at a median of 19 days (range, 13-28 days) and 20 days (range, 9-44 days), respectively. A total of 13 (32%) patients developed grade 2 graft-versus-host disease (GVHD), and 5 (13%) of 40 evaluable patients developed chronic GVHD (3 limited and 2 extensive). Higher cell dose was not associated with increased risk of acute or chronic GVHD. Overall survival and event-free survival at 2 years were 81% and 69%, respectively. Collection of G-BM from pediatric donors is safe, and can result in high NC and CD34 cell doses that facilitate engraftment after myeloablative BMT without a discernable increase in the risk of GVHD.