Single Centre, Retrospective Analysis of Treatment Outcomes and Prognostic Factors in Blastic Phase Chronic Myeloid Leukemia (CML-BP) Following Systemic Therapy

Introduction: Despite the introduction of BCR-ABL1 tyrosine kinase inhibitors (TKI), the prognosis of blastic phase chronic myeloid leukemia (CML-BP) remains dismal. Due to its low incidence, prospective evaluation of outcomes of CML-BP following systemic treatment is challenging. Thus, we aimed to evaluate the outcomes of CML-BP following systemic therapy, and to analyze prognostic factors affecting treatment outcomes.

Methods: We retrospectively identified 55 patients with CML-BP per the European LeukaemiaNet 2013 criteria who treated at the Princess Margaret Cancer Centre in Toronto, Canada between 2000 and 2022. Patient and disease characteristics at the time of CML-BP diagnosis are presented in Table 1. Multiparametric flow cytometry data are described below, with percentages reflecting the proportion of positive antigen expression in evaluable patients. Treatment outcomes measured included: complete response (CR), leukaemia-free survival (LFS) and overall survival (OS). Prognostic factors evaluated include: age, transformation from chronic/accelerated phase (CP/AP), clonal evolution (CE), additional cytogenetic abnormalities (ACA), ABL1 KD mutation, extramedullary disease, blast immunophenotype, systemic treatment modality (intensive chemotherapy (IC) +/- TKI vs TKI monotherapy) and allogeneic haematopoietic stem cell transplantation (HCT).

Results: Among the 55 patients, the median age at time of CML-BP diagnosis was 45 years (17 - 68) and included 35 (64%) cases of CML in myeloid BP (MBP) and 20 (36%) cases of lymphoid BP (LBP). 40 (72%) patients had transformed from a previous CP/AP with a median time of 2.4 years (0.1 - 19.3) from initial diagnosis to transformation. Extramedullary disease was present in 18/53 (34%) patients.

The blast immunophenotype of MBP patients (n=31) was: CD34⁺ (84%), CD117⁺ (52%), HLA-DR⁺ (68%), CD13⁺ (87%), CD33⁺ (97%), MPO⁺ (40%), CD38⁺ (100%) and CD123⁺ (50%). Nine MBP patients (36%) had aberrant CD7 expression. Among 17 evaluable LBP patients, the immunophenotypic profile was: CD34⁺ (94%), HLA-DR⁺ (76%), CD19⁺ (94%), CD20⁺ (41%), CD10⁺ (94%), TdT (88%), CD38+ (100%) and CD7+ (18%). Nine patients (53%) had aberrant CD13 expression and five (29%) displayed aberrant CD33 expression.

At CML-BP diagnosis, 21/42 (50%) had an ACA, of which 11 (26%) patients had high risk ACA, defined as −7/7q, 11q23 or 3q26.2 aberrations, or complex karyotype. Among transformed patients, CE was present in 16/43 (37%) patients. In 18 patients evaluated with Sanger sequencing at time of BP transformation, 9 patients (50%) had an ABL1-KD mutation.

54/55 received systemic therapy: 31 (57%) intensive chemotherapy (IC) + TKI, 7 (13%) IC alone, and 16 (30%) TKI monotherapy. Two patients died before response assessment, one after IC and one after TKI monotherapy. Among 46 patients with available post-treatment bone marrow assessments, CR/CRi rates were similar in those treated with IC+ TKI (29/31; 94%), IC only (5/6; 83%) or TKI only (7/9; 78%). Overall, 40/54 (74%) patients proceeded to allogeneic HCT after achieving CR/CRi or second CP.

After a median follow-up of 39 months, the 3-year LFS and OS rates of all patients were 34.9% (20.7-49.6%) and 44.9% (95% CI, 30.4-58.4%), respectively. Patients with CML-LBP had a significantly higher OS compared to those with CML-MBP (p=0.0463), however, no significant difference in LFS was seen (p= 0.0913). Median duration of LFS and OS was 1.56 and 2.51 years, respectively.

The following variables were found to be independently prognostic for OS: Transformation from CP/AP (p=0.0489, HR 4.328 [1.007, 18.60]), CD117 expression at time of CML-BP (p=0.0291, HR 2.809 [1.111, 7.102]), and IC + TKI (vs TKI monotherapy) (p=0.0068, HR 0.268 [0.104, 0.689]). CE at BP, transformation from CP/AP and IC +TKI (vs TKI monotherapy) were prognostic for LFS by univariate analysis, however, none was identified as independent risk factors.

Conclusion The prognosis of CML-BP remains poor despite systemic therapy. Transformation from CP/AP, CD117 positivity at diagnosis of CML-BP and TKI monotherapy were identified as independent, adverse prognostic risk factors for OS. However, treatment with IC + TKI appeared to improve survival outcomes compared with TKI therapy alone. Therefore, combination therapy with IC + TKI should be considered the optimal strategy in treatment patients with CML-BP.

Yee:Janssen: Research Funding; Gilead: Research Funding; Geron: Research Funding; Astex: Research Funding; Forma Therapeutics: Research Funding; Bristol-Myers Squibb/Celgene: Consultancy; F. Hoffmann La Roche: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; Jazz: Consultancy, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Abbvie: Honoraria; Takeda: Consultancy; TaiHo: Consultancy; Shattuck Labs: Consultancy; Pfizer: Consultancy; Karyopharm: Research Funding; Treadwell: Research Funding; Astellas: Consultancy. Schimmer:Otsuka Pharmaceuticals: Consultancy, Honoraria; Jazz: Consultancy, Honoraria; Medivir AB: Research Funding; UHN: Patents & Royalties: the use of DNT cells to treat AML; BMS: Consultancy, Honoraria, Research Funding; Takeda Pharmaceuticals: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Astra Zeneca: Consultancy, Honoraria. Schuh:AbbVie: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Astellas: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Servier: Membership on an entity's Board of Directors or advisory committees; GlycoMimetics: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Phebra: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Teva Pharmaceutical Industries: Membership on an entity's Board of Directors or advisory committees. Richard-Carpentier:Pfizer: Consultancy, Other: Advisory Board Participation; BMS: Other: Advisory Board Participation; Astellas: Consultancy, Honoraria, Other: Advisory Board Participation; AbbVie: Consultancy, Honoraria, Other: Advisory Board Participation; Taiho: Other: Advisory Board Participation. Gupta:Constellation Pharmaceuticals, Inc., a MorphoSys Company: Consultancy, Honoraria; Roche: Other: Participation on a Data Safety or Advisory board; Novartis: Consultancy, Honoraria; BMS Celgene: Consultancy, Honoraria, Other: Participation on a Data Safety or Advisory board; Sierra Oncology: Consultancy; Pfizer: Consultancy, Other: Participation on a Data Safety or Advisory board; AbbVie: Consultancy, Other: Participation on a Data Safety or Advisory board. Kim:Sanofi: Consultancy, Honoraria; Merck: Consultancy; Paladin: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; BMS: Research Funding; Novartis: Consultancy, Honoraria, Research Funding.