CD34+ Selection Avoids Methotrexate and Reduces the Severity of Oral Mucositis in TBI-Based Allogeneic Stem Cell Transplantation

Abstract

▪Oral Mucositis (OM) is a frequent and debilitating complication of standard myeloablative T-replete allogeneic stem cell transplantation (allo-SCT), often requiring narcotic analgesia, total parenteral nutrition (TPN) and prolonged hospitalization. The incidence of World Health Organization (WHO) grade 3-4 OM after total body irradiation (TBI) based myeloablative conditioning can exceed 50% when methotrexate is used for graft versus host disease (GVHD) prophylaxis. Ex vivo T cell depleted (TCD) allo-SCT is known to be associated with improved GVHD-free survival. However its impact on early transplant outcomes, particularly the incidence of OM has not been described. We conducted a single institution retrospective analysis of the severity and incidence of OM and its related outcomes in 105 consecutive recipients of ex vivo T cell depleted (TCD) allo-SCT from their 6/6 matched sibling donors between 2006 to 2014. All subjects received a fully myeloablative conditioning regimen consisting of fludarabine (25mg/m2/day) from day -8 thru day -4, age-adapted fractionated TBI from day -7 thru day -4 followed by cyclophosphamide (60 mg/kg/day) on day -3 and day -2. TBI was delivered in 8 fractions at a total dose of 1200cGy with lung shielding to 600cGy for subjects <age 55 years and 400-600cGy for subjects ≥age 55 years (21% of subjects). None of the subjects received palifermin or intravenous methotrexate. On day 0, subjects received a G-CSF mobilized peripheral blood stem cell product selected for CD34+ progenitors using the Miltenyi CliniMACS system along with a T- lymphocyte dose of 5 to 50 x10e4 CD3+/kg (resulting in a 3-4 log TCD graft). Low dose cyclosporine until day 21 was the only GVHD prophylaxis. OM was graded by WHO and Bearman toxicity scales until day +21. All subjects achieved successful primary engraftment with a median time to neutrophil engraftment of 12 days (range 9-25 days) and a median length of stay (LOS) of 28.5 days. The incidence of WHO grade 2-4 and 3-4 OM were 46.7% and 34.3%, respectively, with a median severity of 0.5. By the Bearman toxicity scale, the incidence of grade 1, 2 and ≥3 OM were 53.3%, 15.2% and 0% respectively, with a median grade of 1. OM grading was strongly correlated between the WHO and Bearman toxicity scales (r= 0.69, p <0.0001). The severity of Grade 3-4 OM (WHO) mucositis was even lower in subjects who received 400-600cGy versus 1200 cGy TBI for conditioning (4.5% versus 42.1%, p<0.001). 62 subjects (59.1%) required at least intermittent narcotic analgesia (median duration of 6 days; range: 0 - 21 days) but only 16 (15.2%) of these subjects required continuous infusion of narcotic analgesics (median duration of 0 days; range: 0 - 11 days). Thirty six subjects (34.3%) required TPN support for a median duration of 9 days (range 1 -21 days). There were significant correlations between the severity of mucositis and the requirement for intravenous narcotic medications (r= 0.29, p =0.003) and the LOS (r= 0.24, p = 0.01). These findings extend the known benefits of TCD allo-SCT to an improvement in the quality of life to the early transplant phase. In conclusion, CD34+ selected allo-SCT is associated with significant reductions in the incidence and severity of OM, duration of narcotic analgesia and TPN use after TBI-based myeloablative conditioning compared to historical controls. The magnitude of the benefit is at least comparable to published reports of the impact of palifermin in standard T-replete transplantation. DisclosuresNo relevant conflicts of interest to declare.