Updated Outcomes during the Pandemic: Relationship between CD34and CD3 Cell Doses, One-Year Graft-Versus-Relapse-Free-Survival, Graft-Versus-Host Disease, and Overall Survival in Haploidentical Hematopoietic Stem Cell Transplantation Using Post Transplant Cytoxan: A Single Center Experience

Background:

Haploidentical hematopoietic cell transplantation (haplo-HCT) has emerged as a popular alternative to traditional HLA-matched hematopoietic cell transplant. The major advancement of haplo-HCT has increased donor availability to many patients in need, therefore investigating the factors that may affect outcomes is necessary to improve overall survival and reduce transplant-related mortality. Data regarding optimal dose of CD34 cells, CD3 cells and CD34/CD3 ratio used during haplo-HCT to ensure favorable outcomes with post-transplant cyclophosphamide (PTCy) is lacking. Previously we have reported improved outcomes using CD34 cells limited to 7x10^6 cells/kg or less. In this report we are presenting an updated analysis including outcomes related to CD34/CD3 ratio used during haplo-HCT.

Methods:

We retrospectively analyzed adult patients at USC Norris Cancer Hospital who received haplo-HCT from 2014 to 2020. The primary endpoint assessed was 1-year GVHD-free/relapse-free survival (GRFS). Secondary endpoints included overall survival (OS), 1-year transplant related mortality (TRM) and incidence of acute and chronic GVHD. Kaplan Meier survival curves and log-rank tests were used to evaluate 1-year GRFS and OS with CD34 cell dose ≥ 7x10^6 cells/kg and < 7x10^6 cells/kg; CD3 cell dose < 2.5x10^8 cells/kg and ≥ 2.5x10^8 cells/kg; and CD34/CD3 ratio <2, 2-3, >3-5 and >5.

Results:

103 adult haplo-HCT recipients were reviewed with 55.3% male and 44.7% female. The age range was 21-71 years old (median = 51), and a majority of patients were Hispanic (62%). The most common underlying hematologic disorders included AML (40.8%), ALL (34.1%), and MDS/MPN (13.6 %). 41.7% patients with leukemia were in CR1, 55% were CR2/CR3 and 78% were MRD negative by flow cytometry prior to transplant. 73% received myeloablative conditioning and 83.5% received peripheral blood stem cells.

Median CD34 dose, CD3 dose and CD34/CD3 ratio were 6.1 x10^6cells/kg, 2.27 x10^8 cells/kg and 3.2 respectively. Median time to recovery of neutrophil, platelets, and lymphocyte was 17, 24, and 124 days respectively. Incidence of 1-year GRFS was 43.7%. 1-year TRM was 13.6% and rate of aGVHD and cGVHD was 42.7% (n = 44) and 35.9% (n = 37) respectively.

There was no difference in 1-year GRFS and OS when multiple dose levels of CD34 cells and CD3 cells were compared. Although when dichotomized, a CD34 cell dose of ≥ 7x10^6 cells/kg compared to < 7x10^6 cells/kg showed higher dose had significant improvement in 1- year overall survival (p-value=0.01) but no statistical difference in 1 year GRFS (p value=0.24).

CD3 cell dose < 2.5 x 10^8 cells/kg trended towards worse 1-Year GRFS compared to ≥ 2.5 x 10^8 cells/kg (43.9% compared to 58.6%; p-value 0.075), similarly CD3 dose of < 2.5x10^8 cells/kg showed a lower 1-year OS compared to > 2.5x10^8 cells/kg but was not statistically significant (78.7% compared to 89.4%; p-value 0.092). 1-year GRFS and OS did not show statistical difference at CD34:CD3 ratios of < 2, 2-3, 3-5 and > 5, although on cox regression analysis the HR for 1-year GRFS was 2.92 (95% CI 1.21-7.05) in patients with CD34:CD3 > 5 as compared to reference of < 2 (p-value 0.017). Multivariate regression also showed CD3 cell doses of 2-3x10^8 cells/kg and >3 x 10^8 cells/kg were associated with worse 1-year GRFS with HR of 0.43 and 0.40 and p-value of 0.041 and 0.048 respectively when compared to reference of < 1x10^8 CD3 cells/kg.

Discussion:

Our results demonstrate 43.7% survived 1 year compared with reports of 24-35%. The OS was significantly better in the CD34 dose > 7x10^6 cells/kg. CD3 <2.5x10^8 cells/kg showed a trend towards lower 1-year GRFS and OS, which was not statistically significant. On multivariate analysis CD3 dose of > 2x10^8 cells/kg was associated with inferior 1-year GRFS. Conversely, higher CD34/CD3 ratio >5 was associated with increased 1-year GRFS. Thus, our findings indicate that along with improvement in OS by using >7x10^6 CD34 cells/kg, lower CD 3 cell dose <2x10^8 cells/kg and higher CD34/CD3 ratio > 5 can improve 1-year GRFS in patients receiving haplo-HCT.

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