Srour, Samer A.

PURPOSE The likelihood of finding a human leukocyte antigen (HLA)–matched unrelated donor (MUD) for hematopoietic cell transplantation can be predicted using a donor search prognosis score. Patients without a MUD may use alternative donors (haploidentical related, mismatched unrelated, or umbilical cord blood). METHODS This multicenter biological assignment trial was conducted by the Blood and Marrow Transplant Clinical Trials Network (BMT CTN 1702). Eligibility criteria were broad to mirror clinical practice. The primary end point was 2-year survival from evaluability and compared between those Very Likely (>90%) and Very Unlikely (<10%) to find a MUD. All other patients, Less Likely to find a MUD, were enrolled in an observational arm. Transplant outcomes were compared for all three groups. RESULTS A total of 1,751 evaluable patients at 47 centers were Very Likely (54.7%), Less Likely (29.5%), and Very Unlikely (15.8%) to identify a MUD. Survival did not differ in univariate (hazard ratio [HR], 1.00 [95% CI, 0.82 to 1.21]; P = .98) or multivariate (HR, 1.07 [95% CI, 0.86 to 1.33]; P = .56) analyses between the Very Unlikely and Very Likely groups, measured through 2 years from the beginning of a search for a MUD or alternative donor. Of the transplanted patients (n = 1,179), MUD was used for 94% of the Very Likely, 38% of Less Likely, and 9% of Very Unlikely patients. Multivariate analyses showed no differences in relapse, treatment-related mortality, disease-free survival, and acute and chronic graft-versus-host diseases for the three search prognosis groups after transplantation. CONCLUSION Using a donor search prognosis strategy to prioritize an alternative donor for patients Very Unlikely to find a MUD resulted in survival and transplant outcomes that were not statistically different compared with those Very Likely to find a MUD.

Background: A donor search prognosis score based on HLA type and race/ethnicity can classify patients into 3 groups based on the likelihood of finding an HLA-matched (8/8) unrelated donor (MUD): Very Likely (44% of the population), Likely (41%) and Very Unlikely (15%). Previous studies showed that &gt;90% of Very Likely, 26% of Likely and &lt;10% of Very Unlikely patients used a MUD for their hematopoietic cell transplants (HCT), with the rest using other donor sources (mismatched unrelated donor, cord blood, or haploidentical relative). For some patients, prolonged efforts to identify a MUD might be futile and delay HCT, leading to increased morbidity, greater chance for relapse and disease resistance, and worse HCT outcomes. BMT CTN 1702 (NCT03904134) was the first national study to track the entire donor search identification process. Designed as a biologic assignment study, the goal was to estimate and compare overall survival between two arms: patients who are Very Likely to find a MUD versus those who are Very Unlikely to find a MUD. It tested whether provision of a donor search prognosis score to centers could prevent prolonged futile searches for the Very Unlikely group and improve their transplant rates and outcomes, compared to the Very Likely group. Methods: Eligible diagnoses included acute leukemia, myelodysplastic syndromes, lymphoma, acquired aplastic anemia and sickle cell disease. Patients could be consented at any time after diagnosis until an unrelated donor search was started. Consented patients became evaluable only after it was determined that no appropriate HLA-identical siblings were available. The primary endpoint was survival time after the patient was declared evaluable, regardless of whether HCT occurred, and was compared between the Very Unlikely and Very Likely groups. The target enrollment was 1732 evaluable patients. Because this was a biologic assignment trial and not a randomized trial, formal comparisons of overall survival between the Very Likely and Very Unlikely groups were done using a covariate-adjusted Cox proportional hazards model. The following covariates were a priori specified for adjustment in the model, according to the statistical analysis plan: sex, age, Karnofsky Performance Score (KPS), race/ethnicity, disease, disease status, and interval from consent to evaluability. Results: 1751 evaluable patients were enrolled at 47 centers: 44% female, median age 59.4 years (range 0.6-81.3 years), 73% were non-Hispanic White, 10% Hispanic White, 8% Black, 5% Asian/Native Hawaiian/Pacific Islander, 0.5% American Indian/Alaska Native. Among the evaluable patients, 1181 received a HCT, 827 died, and 924 are still alive with or without HCT, with a median of 25 months of follow up (range=6-54 months [mos], inter-quartile range [IQR]=25-34 mos). The distribution was: 958 Very Likely, 517 Less Likely, and 276 Very Unlikely. Individuals in the Very Unlikely group were younger and were less likely to be non-Hispanic White. The unadjusted cumulative incidences of undergoing HCT by 6 mos and 2 years [yrs], in the Very Unlikely group were 51% and 61% vs. 60% and 69% in the Very Likely Group; after adjustment, there was not a significant difference in the likelihood of undergoing HCT (Dehn et al, submitted). There was no difference in median time from evaluability to HCT: 3.4 mos Very Unlikely and 3.3 mos Very Likely. Unadjusted survival rates from the time of evaluability for the Very Unlikely and the Very Likely groups were: 6 mos (85% vs 84%), 1 yr (69% vs. 69%) and 2 yrs (55% vs. 56%). In the multivariate Cox model, there was no significant difference in the risk of death (HR = 1.07 for Very Unlikely vs. Very Likely, 95% confidence interval 0.86-1.33, p=0.56) adjusting for significant clinical covariates: age, KPS, disease status, and time from consent to evaluability were all significantly associated with overall survival. There was no significant center effect and no interaction between donor search prognosis group and clinical covariates. Conclusion: In this large multicenter BMT CTN study, using the donor selection strategy described, there was no difference in adjusted time to HCT or survival for patients Very Likely versus Very Unlikely to find an 8/8 MUD. These results suggest that patients Very Unlikely to identify a MUD should proceed to HCT using the best available alternative donor rather than delaying HCT to try to identify a MUD.

Abstract Introduction Erlotinib is an epidermal growth factor receptor small-molecule inhibitor and is FDA approved for the treatment of lung and pancreatic cancers. In preclinical study, in vitro colony culture assays revealed that erlotinib at micro-molar concentrations effectively suppressed the growth and expansion of Polycythemia Vera (PV) hematopoietic progenitor cells while having little effect on normal cells. Several JAK inhibitors are being studied for the management of PV, one of which has been approved for the treatment of myelofibrosis (ruxolitinib). Aim To study the clinical effect of erlotinib in pts diagnosed with JAK2V617F + PV. Methods We conducted a single arm, prospective phase II study at the University of Oklahoma and the Oklahoma City VA hospitals in pts with WHO defined JAK-2 V617F positive PV from June 2010 to August 2012. Appropriate IRB approval was obtained in accordance with Hilsinki declaration. Pts had to be requiring phlebotomy. Toxicity was assessed by treating physicians using NCI version 4. Dose modification for erlotinib was done using label recommendations. Results Five Caucasian pts were enrolled (3 (60%) males, with median age at enrollment of 63 years, range 26-79). Pts had pretreatment median hemoglobin14.4 g/dL (10.4 -19.2 g/dL), median platelet count 511 x109 (424-681 x109), median white blood cell (WBC) 14.4 x109(7.8- 18.3 x109). Three pts had splenomegaly prior to treatment. Median number of prior pharmacologic treatments (hydroxyurea, anagralide or interferon) was 1, range 0-2. Pts were given erlotinib 150 mg orally daily for 16 weeks: responders (phlebotomy free or decrease in spleen size) were allowed to continue a total of 1 year of treatment, while non-responders were taken off the study. Three (60%) patients received therapy for 16 weeks and did not achieve hematological response or improvement in spleen size. Two (40%) pts were taken off the study after 2 doses secondary to severe toxicities (grade 3 colitis in 1 case, and grade 3 facial rash in 1case). No therapy continued beyond 16 weeks (due to toxicity or lack of response). All pts in the study developed rash (grade 1 – 3) and diarrhea (grade 1 – 2). Three pts developed mucositis (see Table 1). No death was observed during the study and follow up period (median follow up was 23 months, range 12-37 months). Study was closed due to lack of efficacy. Conclusions Despite in vitro efficacy of erlotinib as potent inhibitor of JAK-2 activity, erlotinib is not effective in pts with JAK-2 V617F positive PV with poor toxicity profile. Poor accrual was related to potential toxicity of erlotinib compared to alternative treatments in view of lack of clinical efficacy. Disclosures: No relevant conflicts of interest to declare.