Delayed Hematopoietic Recovery After Autologous Stem Cell Transplantation In Patients Receiving Arsenic Trioxide-Based Therapy For Acute Promyelocytic Leukemia
Authors: Mannis Gabriel N. , Damon Lloyd E , Ai Weiyun Z. , Andreadis Charalambos , Gaensler Karin ML , Gupta Neel K. , Kaplan Lawrence D. , Leavitt Andrew D. , Logan Aaron C. , Olin Rebecca L. , Sayre Peter H. , Smith Catherine C , Venstrom Jeffrey M , Martin Thomas G 
Published: October 2019

Introduction
Arsenic trioxide (ATO)-based therapy for acute promyelocytic leukemia (APL) is highly effective and has been incorporated into standard therapeutic algorithms for patients with newly diagnosed and relapsed disease. Therapy for patients with high-risk or relapsed APL also includes high-dose chemotherapy with autologous stem cell transplantation (autoSCT). Both treatments have independently been demonstrated to improve long-term disease-free survival; however, the use of ATO prior to autoSCT has not been well studied. We sought to determine whether use of ATO prior to autologous stem cell collection impacts hematopoietic recovery following autoSCT.

Methods
Clinical histories of 31 consecutive patients undergoing autoSCT for APL at our institution since 1994 were reviewed. Viable CD34-positive cell recovery from cryo-preserved autograft products was assessed by pre- and post-thaw 7-amino-actinomycin D (7-AAD) staining. Student's t-tests and chi-squared tests were used for statistical analyses.

Results
A total of 32 autoSCTs were performed in this population. Twenty-four transplants (75.0%) were performed for patients in first complete remission (CR1) versus 8 transplants (25.0%) for patients in second complete remission (CR2). Seven of the 32 transplants (21.8%) were performed for patients who received ATO therapy prior to autologous stem cell collection. One patient received ATO with initial induction and consolidation therapy, 1 patient received ATO with initial consolidation therapy only, and 5 patients received ATO with re-induction therapy for relapsed disease.
A significantly higher proportion of patients who received ATO were transplanted in CR2 (71.5% vs 12.0%, p<0.01). There were otherwise no significant differences in clinical characteristics or risk features between the ATO pre-treated and the ATO-naïve transplant recipients, including: median age at diagnosis (45 years vs 44 years, p=0.62), median age at transplant (46 years vs 45 years, p=0.36), white blood cell count >10,000/uL at presentation (28.6% vs 45.8%, p=0.42), mean CD34-positive cells collected (94.5 x106/kg vs 69.9x106/kg, p=0.35), or mean CD34-positive cells infused (41.4x106/kg vs 39.7x106/kg, p=0.90). Four cases (12.5%) of delayed hematopoietic recovery were identified, defined as requiring >16 days after stem cell infusion to recover an absolute neutrophil count (ANC) >1,000/uL. Three of 7 patients (43%) who received prior ATO had delayed hematopoietic recovery, compared with 1 of 24 patients (4.2%) not previously treated with ATO (p<0.01).
Compared to ATO-naïve patients, ATO-treated patients experienced significantly longer time to ANC recovery (mean 19.7 days vs 10.4 days, p<0.01; median 14 days vs 10 days). In addition, ATO-treated patients required significantly longer transplant hospitalizations (37.2 days vs 24.6 days, p<0.01). Platelet recovery, defined as a sustained platelet count >50,000/uL, was also significantly delayed in the ATO-treated group (198.8 days vs 36.5 days, p<0.01; median 81 vs 18 days). The only significant predictor of delayed hematopoietic recovery was prior treatment with ATO (75.0% vs 14.2%, p<0.01).
Of 7 assessable APL patient samples, the mean viable CD34-positive cell recovery was 39 +/- 25.1%. This was significantly lower than the viable CD34-recovery (71.3 +/- 27.3%, p=0.02) evaluated in a random selection of 11 other cryo-preserved autologous stem cell products from patients with lymphoma (n=2) and multiple myeloma (n=9). Samples from 2 ATO-treated APL patients who experienced delayed hematopoietic recovery exhibited viable CD34-positive cell recoveries of only 3% and 26%.

Conclusions
There is an association between ATO exposure and delayed hematopoietic recovery after autoSCT for APL, but a causal relationship is not yet established. Because of the increasing frequency with which ATO is being used in the front-line treatment of APL, larger studies are warranted to validate these findings and to determine the potential mechanism of delayed hematopoietic recovery after autoSCT. Lower-than-expected viable CD34-positive cell recovery from APL patients suggests a possible detrimental contribution of prior ATO exposure. Our institution is now prospectively examining pre- and post-thaw CD34-positive cell recovery, viability, and colony-forming assays prior to autoSCT in patients who have previously received ATO.

Disclosures:
No relevant conflicts of interest to declare.