Hypercvad Plus Imatinib or Dasatinib for Patients with Lymphoid Blastic Phase of Chronic Myeloid Leukemia

Chronic Myeloid Leukemia (CML) may progress at advanced phase at the rate of 1–1.5% per year. Blastic phase (BP) CML (defined by a bone marrow blast count >30%) can show lymphoid features in up to 20–30% of cases. With the use of single agent imatinib or dasatinib, median overall survival (OS) ranges between 7 and 11 months. Combination therapy may offer an improved outcome. We analyzed the outcome of patients (pts) with lymphoid BP-CML treated with hyperfractionated cyclophosphamide, vincristine, adriamycin, dexamethasone (HCVAD) plus imatinib or dasatinib.

32 pts with lymphoid BP-CML were treated at MD Anderson with HCVAD plus imatinib or dasatinib between 2000 and 2011. The starting dose of imatinib was 400 mg (2 pts), 600 mg (20 pts) and 800 mg (1 pt). The starting dose of dasatinib was 50 mg (1 pt), 100 mg (7 pts) and 140 mg (1 pt). Survival curves were calculated using Kaplan-Meier estimates and were compared using the log-rank test.

the median age was 48 (22–74) and 72% were male. Four (12%) pts had a de novo diagnosis, 21 (66%) were previously treated with a tyrosine kinase inhibitor (TKI) for chronic phase (CP) and 3 (9%) for BP. At diagnosis, median WBC was 23.4 (1.1–165.4) x10⁹/L, hemoglobin 10.6 (6.3–16.4) g/dL, platelets 51 (6–526) x10⁹/L, blasts 33 (0–91)%, basophils 0 (0–2)%, creatinine 1 (0.6–1.5) mg/dL, albumin 3.8 (2–4.7) g/dL, bilirubin 0.5 (0.2–3.4) mg/dL, alanine aminotransferase 34 (12–446) IU/L; on bone marrow, median blasts were 78 (26–97)%, basophils 0 (0–4)% and additional chromosomal aberrations (ACA) were found in 15/24 (62%) pts, affecting mostly chromosome (chr) 7 (60%), chr9 (40%), chr8 (33%) and chr1 (27%). Before BP diagnosis, median Philadelphia (Ph) positivity by FISH was 67% (0–96); 6/14 (43%) pts showed a Ph mutation (Y253H, T315I, Q252H, F317L, E255K, M244V) at time of progression to BP. Median time from CML diagnosis to BP was 18 (2–33) months, with no significant differences according to previous Ph FISH positivity or CML therapies. Imatinib was added to HCVAD in 23 pts and Dasatinib in 9. Complete Remission (CR) was obtained in 27 (84%) of them (78% with imatinib, 100% with dasatinib). Twenty-three of 27 (87%) CR were achieved after 1^stcycle of induction. Early mortality (i.e., within 60 days) occurred in 3 pts. Patients received a median of 4 (1–8) cycles of HCVAD. At the time of CR, median BCR-ABL transcript levels were 1.7 (0–100). The levels decreased to a median of 0.01 (0–100) after 3–4 cycles of therapy; 7/27 (26%) pts achieved negative values of BCR-ABL transcripts after a median of 2 (1–4) months. Three (43%) of 7 pts who achieved complete molecular remission relapsed. MRD by flow cytometry became negative in 15/17 (88%) pts: 14 after induction, 1 after 2 months. Six (40%) of the pts with negative flow cytometry for MRD relapsed. Thirteen pts received SCT in remission: 4 relapsed and died after SCT. Median Progression Free Survival (PFS) was not reached and was longer among SCT recipients (p=0.03) and patients who had a negative flow cytometry at the time of CR (p<0.001). OS was 17 (7–27) months and was longer in patients with no more than 1 line of treatment for CP of CML, with ACA (p=0.01) and among SCT recipients (p<0.001). Among patients who had a CR, OS was longer if flow cytometry was negative at the time of CR (p=0.02) and if BCR-ABL transcript levels were < 1.7% (p=0.01) at the time of CR or <0.025% as best result (p=0.03).

HCVAD plus imatinib or dasatinib is an effective regimen for pts with lymphoid BP CML, particularly when followed by SCT. ACA and less than 1 treatment for CML are positive prognostic factors. Better results are observed if negative flow cytometry and low levels of BCR-ABL transcripts are achieved with therapy.

Ravandi:BMS: Honoraria, Research Funding.