Results of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Advanced Chronic Myeloid Leukemia (CML) Patients (pts) Who Failed Tyrosine Kinase Inhibitors (TKIs) after Developing BCR-ABL Kinase Domain (KD) Mutations.
Authors: Jabbour Elias , Cortes Jorge , de Padua Silva Leandro , De Lima Marcos , Jones Dan , O’Brien Susan , Rondon Gabriela , Popat Uday , Giralt Sergio , Kantarjian Hagop , Champlin Richard 
Published: October 2019

Background: HSCT is curative for many pts with CML, and may be effective after imatinib failure. Resistance to TKI therapy is often associated with point mutations in the BCR-ABL KD.

Aims: We assessed the efficacy of HSCT in pts with CML post TKI therapy failure, and who had BCR-ABL KD sequencing.

Patients and methods: Fortyseven pts with CML (chronic phase [CP]=34, accelerated phase [AP]=9, blast phase [BP] =4) had KD sequencing. Patient and treatment-related characteristics are described in the table. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and minimethotrexate.

Results: Nineteen pts (40%) harbored 20 different KD mutations; one pt harbored 2 different mutations. P-loop mutations were detected in 9 (45%) pts; the most common mutations were E255K and T315I detected in 4 pts, each. Table 1 describes pts characteristics. Forty-five pts (96%) engrafted within 12 days (range, 5–20). Both patients with primary graft failure received cord blood transplantation. There was no significant early regimen-related toxicity. Acute (GVHD) was observed in 28 (62%) pts (Grade I in 13, Grade II/III in 12, Grade IV in 3). Chronic GVHD was observed in 21 (47%) pts (extensive in 9). Chimerism studies at day 30 post HSCT were 100% of donor type in 27 (60%) and mixed in 18 (40%). Forty-one pts (91%) responded: 31 achieved a major molecular remission (complete in 30) and 11(24%) achieved a complete cytogenetic response only. Three pts harboring E255K did not respond. After a median follow-up of 22 months (range, 5–53) from HSCT, 31 (66%) pts were alive; 16 patients died, 10 of disease progression, 3 of GVHD, two of uncontrollable infection, and one of unknown cause. Sixteen pts relapsed (8 of them with mutations) after a median of 8 months (range, 1–44) from HSCT. The estimated 2-year survival was 63%. Table 2 summarizes outcome by phase at HSCT and mutation status.

Conclusion: HSCT is an important salvage option for pts with or without BCR-ABL KD mutations who develop resistance to TKI therapy. Outcomes were primarily determined by disease stage, and pts with mutations were more likely to have advanced CML at transplant, suggesting that they should be allografted once the mutation is identified after TKI failure.

Table 1. Patients characteristics

Total N=47 Mutant BCR-ABL N=19 Non Mutant BCR-ABL N=28 Age (years ; range)) 43 (19–64) 43 (19–63) 43 (22–64) Median time from diagnosis to HSCT (mos, range) 54 (6–170) 75 (6–117) 43 (7–170) Best Response to imatinib CHR (%) 20 (43) 10 (53) 10 (36) MCyR (%) 17 (36) 6 (32) 11 (39) CCyR (%) 15 (32) 5 (26) 10 (36) Failure to 2nd TKI (%) 29 (62) 16 (84) 13 (46) Ablative regimen (%) 9 (19) 5 (26) 4 (14) Match related ASCT (%) 23 (49) 11 (58) 12 (43) Stage at ASCT CP (%) 16 (34) 4 (21) 12 (43) AP (%) 12 (26) 4 (21) 8 (28) BP (%) 9 (19) 6 (32) 3 (11) 2ndCP (%) 10 (21) 5 (26) 5 (18)

Table 2. Outcomes

N (%) Mutant BCR-ABL (N=19) Non Mutant BCR-BL (N=28) Stage @ ASCT CP 4 (21) Advanced phases* 15 (79) CP 12 (43) Advanced phases* 16 (57) *Accelerated, blastic, and second chronic phases. ASCT=allogeneic stem cell transplantation; MMR=major molecular response; CCyR=complete cytogenetic response; CR=complete response Best Response MMR 4 (100) 7 (46) 9 (75) 11 (61) CCyR _ 5 (33) 1 (8) 5 (30) Relapse 1 (25) 4 (27) 1 (10) 7 (44) Median (mos) 4 15 (3–45) 9 5 (3–20) Alive in CR 2 (50) 5 (33) 8 (80) 8 (50) Median (mos, range) 27+ (13+–40+) 19+ (9+–25+) 28+ (12+–53+) 21+ (6+–48+) Death in CR 1 (25) 3 (20) 1 (10) 1 (6)