Background: Reduced intensity conditioning (RIC) for hematopoietic cell transplant (HCT) are better tolerated than myeloablative conditioning regimens and permit HCT in patients with advanced age. However, RIC is associated with increased risk of disease relapse. The addition of targeted marrow irradiation (TMI) to RIC may permit intensification and increased disease control without additional toxicity. We conducted a phase I dose escalation trial of TMI in combination with fludarabine and busulfan (flu/bu) RIC for high-risk hematologic malignancy patients. Methods: Eligible patients were 18 years or older, diagnosed with high-risk hematologic malignancies and candidates for an allogeneic HCT with available matched related (MRD) or unrelated donor (MUD). Eligible subjects were not candidates to receive myeloablative conditioning. TMI, 1.5 Gy was given twice daily on days T-10 through T-7. Dose escalation was done by increasing the number of fractions; dose levels included 1.5 Gy (n = 3), 3 Gy (n = 4), 4.5 Gy (n = 3) and 6 Gy (n = 2); fludarabine, 30 mg/m2/day, was given on T-6 through T-2 and busulfan was given on days T-5 and T-4 with a daily dose of 4800 microM⋅minute. Results: 9 subjects were enrolled, median age was 66 years (range 25-74), baseline diagnoses included acute myeloid leukemia (n = 3), myelodysplastic syndrome (n = 2), myeloproliferative disorder, non-Hodgkin lymphoma, multiple myeloma and T prolymphocytic leukemia (all n = 1). Median number of prior treatments was 3 (range 1-10). Median Charlson comorbidity index (CCMI) was 4 (range 1-7) and Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) was 1 (range 1-5). Stem cell source was a MUD in all cases. Neutrophil and platelet engraftment occurred at a median of 15 (range 11-17) and 24 (range 15-11) days, respectively. The maximum tolerated dose (MTD) of TMI was 4.5 Gy, with 2 subjects experiencing grade IV mucositis at the 6 Gy dose level. Grade 3 hyperbilirubinemia was observed in both subjects treated at the 6 Gy dose level, secondary to hepatic veno-occlusive disease and to severe sepsis and hypotension. Three subjects presented grade II-III acute GVDH. At a median follow up of 6 months, six patients have died; Kaplan Meier estimate of overall survival was 60%, with relapse free survival of 50%; the incidence of non-relapse mortality was 11%. Conclusions: The combination of TMI with flu/bu conditioning prior to transplant is feasible in a population of high-risk hematologic malignancy patients, with a MTD of 4.5 Gy. Mucositis and reversible hepatotoxicity are the dose limiting toxicities of this combination. Careful patient selection and monitoring may allow use of TMI plus flu/bu conditioning in patients at high risk of toxicity and relapse after transplant. Future studies are aimed at investigating whether further dose escalation of TMI is feasible in younger, fitter HCT patients.

Introduction: Secondary engraftment failure after hematopoietic stem cell transplant (HSCT) is characterized by pancytopenia and 1-year mortality reported to reach as high as 75% (1) secondary to infectious and bleeding complications. It is frequently associated with treatment of CMV reactivation. Reinfusion of a second graft from the original donor is the preferred treatment but carries the risk of graft versus host disease (GVHD) given high T lymphocyte graft content. The CliniMACS® CD34 reagent system permits in vitro selection and enrichment of CD34+ cells from heterogeneous hematologic cell populations and is used for T cell depletion of HSCT. We report the results of a pilot study of infusion of CD34+ selected stem cell boost for treatment of post-transplant secondary engraftment failure.