Older Adults with Chronic Myelogenous Leukemia (CML), During the Tyrosine Kinase Inhibitor (TKI) Era, Can Be Successfully Treated with Reduced Intensity Conditioning (RIC) Hematopoietic Cell Transplant (HCT) Using Sibling or Unrelated Donors: A Center for International Blood and Marrow Transplant Research (CIBMTR) Analysis
Authors: Warlick Erica D , McClune Brian , Pedersen Tanya L. , Awn Kwang W , Antin Joseph H. , Cahn Jean-Yves , DeLima Marcos , Gupta Vikas , Marks David I , Bunjes Donald , DiPersio John F. , Devine Steven , Weisdorf Daniel J. 
Published: October 2019

Abstract
Abstract 494
The introduction of tyrosine kinase inhibitors (TKI) and advent of RIC and non-myeloablative (NMA) conditioning hematopoietic cell transplants (HCT) have changed and the therapeutic strategy for patients with CML. We analyzed the post HCT outcomes of CML patients aged 40 and older undergoing RIC/NMA HCT in 2001–2007. Detailed information regarding pre HCT TKI use or rationale for timing of transplant was not available; however, the analysis time period captures the entry of TKIs into clinical practice. Outcomes were compared between age cohorts of 40–49, 50–59, and ≥ 60 years. Overall survival (OS), Day +100 acute graft versus host disease (aGVHD) grades II-IV, chronic (cGVHD), transplant-related mortality (TRM), relapse, and disease-free survival (DFS) were analyzed with multivariate analysis testing the impact of age, gender, disease status at HCT (CP1vs. CP2/accelerated phase (AP) vs. blast phase (BP), sex match, HLA match, GVHD prophylaxis, and conditioning intensity (RIC versus NMA as described by Bacigalupo et all 2009) on outcomes. A total of 306 CML patients underwent HCT at 125 centers: 117 (38%) aged 40–49; 119 (39%) aged 50–59; and 70 (23%) aged ≥ 60. At HCT most patients in the 40–49 age cohort were in CP1 (72%), while only 44% of patients aged 50–59 and 31% aged ≤ 60 were in CP1. Interval from diagnosis to HCT for CP1 patients was similar across age groups with a large percentage of each age cohort undergoing HCT ≥ 2 years (32%, 40%, and 45%, respectively). Sibling donors were the stem cell source for 56% of those aged 40–49; older cohorts had a higher percentage of unrelated donors (58 and 60%, respectively). Primarily peripheral blood grafts (78%, 80% and 90%) and RIC (78%, 76% and 70%) were used across age groups, respectively. GVHD prophylaxis was similar. Three year OS and cGVHD, Day +100 grade II-IV acute GVHD, and 1 year TRM were similar in all age cohorts. Three year relapse incidence increased and DFS decreased with age. Importantly in analysis of CP1 patients only, relapse and DFS were similar in each age cohort.Table 1:Univariate AnalysisOutcomeAge 40–49 Probability (95% CI)Age 50–59 Probability (95% CI)Age ≥ 60 Probability (95% CI)P-valueEntire CohortOSA54% (44–64)52% (42–61)41% (30–54)0.26aGVHDB II-IV26% (18–34)32% (24–40)32% (21–43)0.53cGVHDA58% (47–68)51% (41–61)43% (33–55)0.19TRMC18% (11–26)20% (13–27)13% (6–22)0.43RelapseA36% (27–46)43% (34–52)66% (53–77)0.001DFSA35% (26–45)32% (24–41)16% (7–27)0.01CP1 OnlyRelapseA34% (23–46)42% (28–56)51% (29–72)0.40DFSA43% (31–55)36% (23–51)39% (19–61)0.81A=3 year; B=Day +100; C=1 year
Multivariate analysis confirmed the significant adverse impact of advanced CML (AP/CP2+ and BP) at HCT, NMA conditioning intensity, male gender, and older age on relapse and DFS. Overall survival was not impacted by age, but was significantly worse with advanced CML at HCT. (Table 2)Table 2:Multivariate AnalysisOutcomeRR95% CIP valueRelapse:Age:10.69–1.6420.000340–491.0641.441–3.60750–592.28≥60Disease Status:10.1319–0.9170.01CP11.3350.0036–1.403AP/CP2+2.823BPConditioning Intensity10.222–0.469<0.0001NMA0.323RICGender10.397–0.830.0032Male0.574FemaleOverall SurvivalAge:10.55–1.2260.4240–490.8210.683–1.61850–591.051≥60Disease Status:11.206–2.47<0.0001CP11.7263.199–10.0740.42AP/CP2+5.677BPGender:10.0189–0.4810.019Male0.671Female
These data indicate that HCT is safe in older patients with CML with equivalent acute and chronic GVHD, TRM, and OS across age cohorts. Relapse increased in patients receiving NMA conditioning and in those aged 60 and above; most of whom had advanced disease. However, for HCT during CP1 relapse risks and DFS were similar, regardless of age. Allogeneic HCT using RIC conditioning for older patients with CP1 CML can control relapse with acceptable toxicity and survival. Comparison of outcomes with second line TKI versus HCT are as yet unreported but these favorable findings indicate appropriate consideration of HCT for older patients with CML.

Disclosures:
Gupta: Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.