Use of First or Second Generation TKI for CML after Allogeneic Stem Cell Transplantation: a Study By the CMWP of the EBMT
Authors: Chalandon Yves , Iacobelli Simona , Hoek Jennifer , Koster Linda , Volin Liisa , Finke Jürgen , Cornelissen Jan J. , Yakoub-Agha Ibrahim , Craddock Charles , Aljurf Mahmoud , Nagler Arnon , Passweg Jakob , Meijer Ellen , Crawley Charles , Hunter Ann Elizabeth , Afanasyev Boris , Koenecke Christian , Schaap Nicolaas P.M. , De Groot Marco R , Schleuning Michael , Olavarria Eduardo , Kröger Nicolaus 
Published: October 2019

Abstract
Background: Patients (pts) relapsing with CML after allogeneic hematopoietic stem cell transplantation (alloHSCT) may be treated with tyrosine kinase inhibitors (TKI) and/or donor lymphocyte infusions (DLI). As nowadays the majority of CML patients would have received at least imatinib prior to transplantation, we were interested in analizing a) the type of TKI used after alloHSCT, b) the indication for TKI treatment, c) the outcome of this treatment and d) the temporal relationship with DLI if given.
Patients and methods: 435 pts received TKI after first allogeneic HSCT for CML for different reasons. Transplants had been performed in first chronic phase (CP1, n=194), accelerated phase (AP, n= 60) or for more advanced disease (blast crisis (BC)/> CP1, n=177) from HLA identical siblings (n=231) or unrelated donors (n=204) between 2000 and 2013. TKI given prior to transplant was imatinib (n=268), dasatinib (n=162), nilotinib (n=88), bosutinib (n=4) and ponatinib (n=7). Median age at transplant was 44 (18.5-68) years, 274 pts (63%) were male. TKI post alloHSCT were given between 2000 and 2015. 1st TKI given was either imatinib (n=223), dasatinib (n=131), nilotinib (n=67), bosutinib (n=2) or ponatinib (12). The indications for TKI therapy were the same as for transplantation (n=262), for relapse/progression/persistent disease (n=124), for prophylaxis/pre-emptive (n=32), planned (n=5), others (n=8) and missing (n=4).
Results: Median follow-up from start of TKI was 55 (1-171) months. The median time interval from transplant to TKI was 6 (0.2-165) months. It was longer for TKI given for relapse/progression with 15 (1-89) months and shorter for TKI given for prophylaxis/pre-emptive with 1.6 (0.2-43) months. It was longer for imatinib with 11 (0.2-121) months vs 3.8 (0.2-165) months for other TKI.
Imatinib as 1st TKI was mainly given for relapse/progression/persistent disease (48%) and the other TKI for the same reason as for transplantation (83%). 103/223 (46%) of pts with imatinib, 99/131 (76%) with dasatinib, 55/67 (82%) with nilotinib and 11/14 (79%) with bosutinib/ponatinib post-transplantation had been treated with imatinib prior to transplantation. In total, 196 (45%) patients received DLI after alloHSCT, of which 63/435 (14.5%) had DLI prior to TKI post-alloHSCT, 19/435 (4.4%) had DLI at the same time of TKI and 114/435 (26%) had DLI post-TKI.
Best response after TKI was complete molecular remission in 17.7%, cytogenetic remission in 4.4%, hematological remission in 20.2% and no response/progression/relapse in 57.7% of pts. 50% of pts treated with imatinib had a response (molecular/cytogenetic/hematological) vs 34% with nilotinib, 33% with dasatinib and 33% with bosutinib/ponatinib, p=0.014.
OS was 60% (55-65%) at 5 years. It was 66% (60-73%) with imatinib vs 51% (42-60%) with other TKI, p=0.0024. 5 years RFS was 47% (42-53%). It was 53% (46-60%) with imatinib vs 40% (32-48%) with other TKI, p=0.0102. 5 years RI was 25% (21-30%). It was 21% (16-27%) with imatinib vs 31% (24-38%) with other TKI, p=0.0454. 5 years NRM was 27% (23-32%). It was 26% (20-31%) with imatinib vs 29% (22-36%) with other TKI, p=0.365.
In multivariate analysis for OS, imatinib vs other TKI post-transplant did not show anymore an effect, HR 1.19 (0.85-1.67), p=0.317. Factors influencing OS were time from diagnosis to transplant, HR 1.01 (1.00-1.01), p=0.009, AP vs CP1, HR 1.80 (1.11-2.91), p=0.017 and BC/>CP1 vs CP1, HR 2.3 (1.58-3.33), p<0.0001.
In multivariate analysis for RFS as for OS, imatinib vs other TKI did not have an effect, HR 1.11 (0.83-1.48), p=0.496. Other factors having a tendency or influencing RFS were time from diagnosis to transplant, HR 1.00 (1.00-1.01), p=0.054, AP vs CP1, HR 1.52 (1.00-2.31), p=0.050 and BC/>CP1 vs CP1, HR 2.11 (1.55-2.88), p<0.001.
Conclusion: These data suggest that TKI after alloHSCT induce a response in about 42% of pts regardless of the type of TKI used and that time from diagnosis to transplantation as well as the phase of disease at transplant remain the main factors influencing the outcome of CML patients relapsing after alloHSCT.

Disclosures
Kröger: Riemser: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Neovii: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding.