Outcome of Relapsed Philadelphia Chromosome Positive Chronic Myeloid Leukemia (Ph+ CML) after Allogeneic Hematopoietic Cell Transplantation (HCT).
Authors: Heyn Simone , Krahl Rainer , Lange Thoralf , Eisfeld Ann-Kathrin , Niederwieser Dietger , Al-Ali Haifa K. 
Published: October 2019

Abstract
In the imatinib era, HCT is mainly offered to patients (pts) with advanced disease or imatinib resistance. In this analysis, relapse incidence (RI) and the long-term efficacy of imatinib and immunomodulation for relapse after HCT for Ph+ CML were evaluated.
Patients and Methods: From January 2000 to May 2006, 65 pts (38 m, 27 f; median age 41 (range 20–68) years) underwent HCT at the University of Leipzig. Median interval between diagnosis and HCT was 22 (2–264) months. Prior to HCT, 50 pts (77%) received imatinib for a median duration of 9 (range 1–54) months. Disease phase prior to imatinib was chronic phase (CP),n=25 (50%), accelerated phase (AP),n=18 (36%), blast phase (BP),n=7 (14%). HCT was performed because of resistance to imatinib, n=26 (BCR-ABL kinase domain (KD) mutations were found in 6 pts prior to HCT: F359V, G250E, Y253H, M315T, E255K, L248V. One patient had a K247R polymorphism), AP/BP prior to imatinib,n=14, or imatinib-intolerance/pts preference,n=10. HCT was performed in 15 (23%) pts (CP,n=12, AP,n=3) without prior imatinib. Conditioning consisted of 12 Gy TBI/cyclophosphamid 120 mg/kg in 44 (68%), and fludarabin 30 mg/m2/day for 3 days/2 Gy TBI in 21 (32%) pts. Donors were MRD, n=20; and MUD, n=45. After HCT, blood and marrow were examined at 3 months interval. A molecular relapse was diagnosed if two samples at least four weeks apart were BCR-ABL positive by reverse-transcriptase polymerase chain reaction (RT-PCR; sensitivity, approximately 1/106). In case of relapse, cyclosporine was tapered and withdrawn. Additionally, imatinib 400 mg/d was started. If a complete molecular remission (CMR) was achieved, imatinib was continued for another 12 months and then stopped.
Results: Engraftment occurred in 61 (94%) pts. OS and TRM at 5 years were 70%, and 23% respectively. At a median time of 7 months after HCT, 31/48 (65%) relapsed [molecular,n=18 (58%), cytogenetic,n=4 (13%), hematological,n=9 (29%)]. Type of conditioning, and donor type had no influence on RI which tended to be higher in pts with imatinib prior to HCT (p=0.03). Incidence of chronic GvHD in pts without and those with relapse was 65% and 13% respectively (p<0.001). RI tended to be higher in pts with imatinib resistance prior to HCT (77%) compared to imatinib sensitive CML (54%) (p=0.08). 6/7 pts with KD mutations relapsed after HCT. In 4 pts the same mutations were detected. All suffered from refractory relapse. Overall, CMR was achieved in 22/31 (71%) pts after a median treatment time of 5 months. 9/17 (53%) of imatinib resistant pts prior to HCT including two pts with KD mutations achieved CMR. After imatinib withdrawal, molecular relapse recurred in 11/22 (50%) pts after a median time of 3 months. Donor lymphocyte infusion was given and imatinib restarted. All pts achieved a sustained CMR. Overall, if chronic GvHD occurred at any time point (n=8), CMR was sustained even after imatinib withdrawal. In the remaining pts, imatinib therapy had to be continued indefinitely.
Conclusions: HCT can be curative even in pts with advanced CML or imatinib resistance. Some KD mutations could survive HCT and could be associated with refractory relapse. Nevertheless, relapse could be treated with imatinib. In the absence of GvHD, CMR after relapse under imatinib does not seem to be durable after imatinib withdrawal in most pts. RI was significantly less in pts with chronic GvHD which was also associated with sustained CMR after relapse even after imatinib withdrawal.