AUTHORS
Omer Karrar, MD, Manuel M. Maroun, MD2, Hannah Goulart, MD3, Ghayas C. Issa, MD4, Fadi G. Haddad, MD5, Nitin Jain, MD6, Farhad Ravandi, MD7, Jayastu Senapati, MBBS, MD, DM8, Hussein Ali Abbas, MD, PhD9, Sherry Pierce, BSN, RN10, Sara Dellasala, BSc11, Elias Jabbour, MD12, Hagop Kantarjian, MD13, Nicholas Short, MD14
AFFILIATIONS
1 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
2 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
3 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
4 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
5 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
6 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
7 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
8 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
9 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
10 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
11 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
12 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
13 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
14 The University of Texas MD Anderson Cancer Center, Houston, Texas, United States
ABSTRACT
Background: Lymphoid blast phase chronic myeloid leukemia (CML-LBP) is a rare and aggressive manifestation of CML with poor long-term outcomes. Current consensus guidelines recommend acute lymphoblastic leukemia-directed therapy combined with a BCR::ABL1 tyrosine kinase inhibitor (TKI), followed by allogeneic hematopoietic stem cell transplantation (Allo-HSCT) in eligible patients (pts). However, the optimal treatment strategy, prognostic factors, and role of HSCT remain uncertain.
Methods: We retrospectively analyzed responses and survival outcomes of pts with newly diagnosed CML-LBP treated with TKI-based combination therapy at our institution. Only pts with B-cell immunophenotype were included. Pts were stratified as de novo (LBP as initial CML presentation) or transformed (progression from previously TKI-treated earlier phase CML); transformed pts were further stratified by duration of initial CML diagnosis (≤1 year [early transformed] vs. >1 year [late transformed]). We also evaluated predictors of long-term outcomes, including the role of allo-HSCT.
Results: 80 pts with newly diagnosed CML-LBP received TKI-based combination therapy between May 2001 and May 2025. The median age was 53 years (range, 23-82 years). 58 pts (73%) transformed from previously treated earlier phase CML, and 22 (28%) were de novo CML-LBP. 14 pts (18%) had extramedullary disease at CML-LBP diagnosis. 53% of tested pts (21/40) with transformed CML-LBP had ≥1 ABL1 KD mutation, including T315I in 3 (8%), F317L in 3 (8%), and E255K in 2 (6%). The first TKI received for CML-LBP was imatinib in 21 pts (26%), a 2nd generation TKI in 30 (38%), ponatinib in 28 (35%) and asciminib in 1 (1%). TKIs were given with intensive chemotherapy (IC) in 55 pts (69%), lower-intensity therapy (LIT) in 14 (18%), and chemotherapy-free regimens in 11 (14%; blinatumomab [n=10], inotuzumab ozogamicin [n=1]).
The overall response rate (ORR; CR/CRi/MLFS) was 81% (CR 71%, CRi 8%, MLFS 3%). The ORR was 52% with imatinib vs. 92% with a later-generation TKI (P<0.001). No differences in ORR were observed between pts with de novo vs. transformed CML-LBP nor in those who received IC, LIT or chemotherapy-free regimens. 95% of responders achieved flow MRD negativity, 79% achieved CCyR, 69% achieved MMR or better, 38% achieved CMR, and 82% of tested pts (9/11) achieved NGS IG/TR MRD negativity. Both the CCyR (84% vs. 50%; P=0.01) and MMR or better rates (75% vs. 40%; P=0.03) were higher with later-generation TKIs than imatinib.
With a median follow-up of 116.6 months, 26 of the 65 responders were bridged to allo-HSCT (33% of the overall cohort; 40% of responders). 22 of the responders (34%) died in remission (7 after HSCT and 15 in the absence of HSCT), and 15 of the responders (23%) subsequently relapsed (4 after HSCT and 11 in the absence of HSCT) after a median remission duration of 8.4 months (range, 1.6-39.8 months). The median RFS was 39.8 months (3-year RFS rate: 53%), and the median OS was 22.8 months (3-year OS rate: 45%).
On multivariate analysis, older age (HR 1.05, 95% CI, 1.02-1.09, P<0.001), late transformed CML-LBP (HR 2.13, 95% CI, 1.00-4.55, P=0.04), treatment with imatinib (HR 2.33, 95% CI, 1.01-5.26, P=0.04), p190 transcript (HR 5.56, 95% CI, 1.92-16.67, P=0.001) and failure to achieve CMR (HR 2.50, 95% CI, 1.03-6.25, P=0.04) were independently associated with inferior RFS. Older age (HR 1.05, 95% CI, 1.02-1.07, P<0.001), late transformed CML-LBP (HR 2.1, 95% CI, 1.09-4.04, P=0.03) and treatment with imatinib (HR 2.44, 95% CI, 1.25-4.76, P=0.008) were independently associated with inferior OS.
In a landmark analysis, the 3-year OS rates for responders who bridged directly to HSCT were 63% vs. 57% for those who did not (P=0.32); RFS also did not differ (P=0.25). Pts treated with later-generation TKIs had similar outcomes with or without HSCT (3-year OS rates: 69% vs. 62%, respectively; P=0.32). Among the 8 pts who achieved CMR and did not undergo HSCT, 1 pt relapsed (after 10.3 months of remission), and the 3-year RFS and OS rates were 88% and 83%, respectively.
Conclusion: TKI-based combination therapy produced high response rates and encouraging long-term outcomes in pts with newly diagnosed CML-LBP. Later-generation TKIs were associated with higher response rates and improved OS; better OS was also observed in younger pts and those with de novo or early transformed disease. Allo-HSCT did not improve OS, and pts who achieved CMR had excellent outcomes without HSCT.
DISCLOSURES
Omer Karrar, MD: No relevant conflicts of interest to declare.