Clinical Outcomes of 2-Step Approach to Haploidentical Hematopoietic Stem Cell Transplantation (HSCT): Effects of CD34 Stem Cell Dose in the Setting of a Consistent T-Cell Dose

Abstract

Introduction:Haploidentical (HI) HSCT offers a curative option to patients (pts) who lack an HLA matched donor. In the 2-step approach, pts receive a relatively large, fixed T-cell dose (2 x 108/kg) followed 2 days later by cyclophosphamide (CY). CY eradicates only the alloreactive T-cells, thus inducing bidirectional tolerance. CD34-selected stem cells are then infused and are not exposed to CY. Unlike T-cell depleted approaches, the 2 step regimen allows for rapid immune recovery and lower infectious complications. Coupled with acceptable GVHD rates, this approach has been associated with low non-relapse mortality. Given the consistent T-cell dose utilized in all pts, we investigated the effects of the variable CD34 stem cells on clinical outcomes and immune recovery.Methods:We retrospectively analyzed data from 148 pts who underwent a 2-step approach to haploidentical peripheral blood HSCT at Thomas Jefferson University between February 2006 and February 2014. The myeloablative (MA) conditioning regimen consisted of 12 Gy of TBI administered over 4 days, while the reduced intensity conditioning (RIC) regimen consisted of fludarabine (30 mg/m2 D1-4) + cytarabine (2 gm/m2 D1-4)/or thiotepa (5 mg/kg D1-3) and a fraction of 2 Gy TBI (D6). Conditioning was followed by an infusion of 2 x 108 CD3+ cells/kg donor T cells (step 1). CY 60 mg/kg/d x 2 was given starting 2-3 days after the T cell infusion. A CD34 selected product was then infused (step 2). Tacrolimus and MMF were utilized for immune suppression. In a prior multivariate analysis in patients older than 60, we identified CD34 dose as affecting survival. Using recursive partitioning, a dose of 5.2 x106 was identified as the cutoff point demarcating differences in survival. This analysis compares differences in outcome in all patients who underwent the 2-step haploidentical HSCT regardless of age, using a cutoff CD34 dose of 5.2x106 to demarcate both groups.Results:Eighty-five pts received a CD34 dose < 5.2 x 106(low dose- LD) and 61 received a dose > 5.2 x 108 (high dose- HD). Pts characteristics are shown in the table. Median follow up was 19 months. HD group had a faster platelet recovery (p=0.007) and more rapid CD3/4 and CD3/8 recovery by day 30 (p=0.001). The incidence of grades II-IV GVHD was not statistically different between both groups (p= 0.76). Probability of overall survival (OS) at 5 years was 50% and 62% in the LD and HD groups, respectively (log-rank= 0.14) with relapsed disease being the major cause of death in both groups. OS was significantly better in the HD in a subset of patients above the age of 60 (n=57, log-rank= 0.032). The 5-year cumulative incidence of relapse related mortality and non-relapse related mortality were not statistically significant between both groups; RRM: LD= 27%, HD= 20% (p=0.45); NRM: LD= 24%, HD=17% (p=0.32).Conclusion:Based on a platform of identical T cell dosing, the higher CD34 stem cell dose group had more rapid platelet engraftment, earlier immune recovery and better overall survival in a subset of patients above the age of 60. There were no differences in GVHD rates between both groups, which favors the use of a higher CD34 stem cell dose in this approach.TableLower Dose (<5.2 x 106)Higher Dose (>5.2 x 106)Number8561Age (range)58 (19-74)52 (19-78)Sex (M/F)49/3636/25Median CD3/4 day 30 (cells/ uL)3471Median CD3/8 day 30 (cells/ uL)3057Median CD34 cells [x 106/kg] (range)3.52 (1.4-5.18)7.31 (5.3-10.6)Disease status at time of HSCTRemission (%)38 (45)24 (39)Active disease (%)47 (55)37 (61)DiseaseMyeloid Malignancy (%)58 (68)31 (51)ALL (%)11 (13)11 (18)NHL (%)11 (13)13 (21)Others (%)5 (6)6 (10)ConditioningMA (%)52 (61)34 (56)RIC (%)33 (39)27 (44)Outcomes:Median ANC recovery [days]1211Median Platelet recovery [days]1917aGVHD II-IV (%)33 (39)26 (43)aGVHD III-IV (%)8 (9.4)4 (6.5)cGVHD (%)14 (16)2 (3)Relapse (%)25 (29.4)14 (23)Deaths (%)41 (48)20 (33)Relapse2110Infection63Toxicity107GVHD40CMV Reactivation41 (48)25 (41) [Display omitted] [Display omitted] DisclosuresNo relevant conflicts of interest to declare.