Outcomes of Therapy Related Acute Lymphoblastic Leukemia in Adults after Allogeneic Stem Cell Transplantation - Twenty-Year Experience from a Tertiary Care Center
Authors: Nampoothiri RAM V , Law Arjun , Lam Wilson , Al-Shaibani Zeyad , Loach David , Chen Carol , Kim Dennis Dong Hwan , Michelis Fotios V. , Kumar Rajat , Mattsson Jonas , Lipton Jeffrey H. , Viswabandya Auro 
Published: November 2019

Introduction
Therapy related acute leukemias are late complications of treatment with mutagenic agents for both malignant and non-malignant disorders. The prevalence of therapy induced Acute lymphoblastic leukemia(t-ALL) is thought to be much less than that of t-AML/MDS, with our institute reporting a 6.9% prevalence of t-ALL among all patients of adult ALL. There is limited data on role of allogeneic hematopoietic stem cell transplantation (allo-HSCT) in t-ALL. Recent reports suggested comparable outcomes with de-novo ALL after allo-HSCT. We aim to report our 20-year experience of allo-HSCT in t-ALL.
Patients and Methods
We retrospectively reviewed all cases of t-ALL who underwent allo-HSCT at our centre from October 1998 to July 2019. Patients were analysed and compared for demographic features, prior malignancy and its treatment, latent period before ALL, clinical, cytogenetic and molecular characteristics of ALL, induction and consolidation treatment received, transplant details including donor details, conditioning regimens, GVHD prophylaxis as well as post-transplant complications (including transplant related mortality, occurrence and severity of acute and chronic GVHD, CMV and EBV reactivations), relapse rate, relapse free survival (RFS) and overall survival (OS). Predictors of survival were calculated by Cox-Regression Analysis.
Results
A total of 18 patients underwent allo-HSCT for t-ALL. M:F ratio was 1:1. Median age at allo-HSCT was 44 years (range 20-70 years). Baseline characteristics, prior malignancy and treatment received are summarized in Table 1. Median latent period from prior malignancy to diagnosis of ALL was 44.8 months (range 6-157 months). Complex cytogenetics was present in 16.7% patients (n=3) while 11q23 rearrangement (KMT2A-MLL) and t(9;22) rearrangement was seen in 33.3% (n=6) and 22.2% (n=4) patients respectively. Median time to allo-HSCT from diagnosis of t-ALL was 5 months. Stem cell donors were matched related, matched unrelated and haplo-identical in 27.8% (n=5), 55.6% (n=10), and 16.7% (n=3) patients, respectively. Conditioning regimen was myeloablative in 44.4% (n=8) patients and reduced intensity in 55.6% (n=10) patients. GVHD Prophylaxis used was ATG-CSA-PTCy in 50% (n=9) patients, CSA/MMF in 22.2% (n=4) patients, and other regimens in 27.8% (n=5) patients. Post HSCT CMV and EBV virus reactivation occurred in- 33.3% (n=6) and 47.1% (n=8) patients, respectively. Acute GVHD (any grade) occurred in 70.6% (n = 12) while chronic GVHD (any grade) occurred in 31.3% (n=5) patients. Transplant related mortality (Death before day 100) occurred in 27.8% (n=5) patients. Four (22.2%) patients relapsed. Median RFS was 4 months (Range 0.5-194 months) while median OS was 5.88 months (Range 0.5-194 months) (Figure 1a&b). One patient (5.5%) had relapse of their primary malignancy (CA Breast) 12 years after allo-HSCT. One year RFS and OS for all patients (excluding patients who have not completed one year of followup after HSCT but have not relapsed or died) was 43.8% and 46.7% respectively. None of the basic disease characteristics, treatment characteristics, or transplant or post-transplant parameters including donor type, conditioning received, GVHD prophylaxis used, occurrence of Acute or chronic GVHD etc. were significantly predictive of OS and RFS on Cox-Regression analysis, though the analysis is limited by the small sample size.
Conclusions
Therapy related ALL is an uncommon but increasingly recognized disease entity. Our outcomes of Allogeneic HSCT in t-ALL were comparable to that in de novo ALL as per previously reported literature. Multicenter studies on t-ALL with more patients and longer follow up duration may provide us with predictive factors of relapse and survival post allogeneic HSCT.

Disclosures
Michelis: CSL Behring: Other: Financial Support. Mattsson:Celgene: Honoraria; Therakos: Honoraria; Gilead: Honoraria.