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

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.

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