Cytopenias in Patients (pts) with Chronic Myelogenous Leukemia (CML) in Chronic Phase (CP) Treated with Dasatinib (SPRYCEL®): Clinical Features and Management, Including Outcome after Hematopoietic Growth Factor Therapy.

Abstract

Dasatinib (SPRYCEL®, formerly BMS-354825) is a potent inhibitor of BCR/ABL, SRC, and other kinases with activity in pts with CML in all phases after imatinib failure. Although well-tolerated, dasatinib is associated with cytopenias in some pts, which may be a reflection of rapid elimination of the BCR/ABL(+) clone. We analyzed 122 pts with CML in CP treated with dasatinib at our institution. Thirty-eight (31%) pts developed at least 1 episode of grade 2–4 neutropenia (NP) and/or thrombocytopenia (TP) while on dasatinib; in 35 (29%) this was grade 3–4. Median age of these 38 pts was 55 yrs (range, 19 to 81) and median time from CML diagnosis to dasatinib start was 57 mo (range, 0.5 to 207). Pts had received imatinib for a median of 41 mo (range, 1 to 68); other prior therapies included interferon-α in 23 (61%), homoharringtonine in 6 (16%), farnesyl transferase inhibitors in 4 (11%), and nilotinib and allogeneic stem cell transplantation in 2 (5%) each. Initial dasatinib dose was 70 mg twice daily in 18 (47%), 140 mg once daily in 1 (3%), 50 mg twice daily in 6 (16%), 100 mg once daily in 4 (10%), >140 mg daily in 3 (8%) and < 100 mg daily in 6 (16%). Dasatinib was administered for a median of 57 wks (range, 7 to 140). NP occurred in 29 (24%) pts: grade 2 in 6 (5%), grade 3 in 14 (11%), and grade 4 in 9 (7%). TP occurred in 33 (27%) pts: grade 2 in 8 (7%), grade 3 in 15 (12%), and grade 4 in 10 (8%). Concomitant grade 2–4 NP and TP was observed in 24 (20%) pts (grade 3–4 in 13, 11%). The median time to NP was 59 days (range, 2 to 149) and to TP 28 days (range, 11 to 368). Grade 2–4 NP or TP was recurrent in all but 3 (92%) pts. Grade 2–4 hematologic toxicity occurred within the first 3 mo of therapy in 8 (21%) pts, after 3 mo in 7 (18%), and both before and after 3 mo in 23 (61%). Dasatinib was interrupted at some point due to grade ≥3 NP or TP in 34 (28%) pts. Anemia was observed in 29 (76%) of the 38 pts with grade 2–4 NP or TP; it was grade ≥3 in 5 (13%). Seven pts received G-CSF 300 mcg daily 2–7 days/wk after a median of 59 days (range, 11 to 268) from dasatinib start. G-CSF dose was adjusted to keep an ANC >1.0x109/L. The median ANC at G-CSF start was 0.75x109/L (range, 0.3 to 0.9x109/L). All pts reached ANC >2.0x109/L after a median of 10 days. From dasatinib start to G-CSF start, pts had been off dasatinib a median of 40% of the total treatment time, compared to 24% after G-CSF start (p=0.07). The combination of dasatinib and G-CSF was well tolerated. Of the 7 pts who received G-CSF, 5 were subsequently evaluable for response, and 2 achieved a major cytogenetic response (<35% Ph-positive cells). Three pts with grade ≥3 TP received support with interleukin-11 (IL-11) 10 mcg/kg 3 times per week (in 2 pts while on dasatinib). None of these pts had required platelet transfusion. Two pts reached a platelet count >100x109/L 94 and 125 days after the start of IL-11, respectively, and 1 pt had persistent TP that led to permanent dasatinib discontinuation. Fifteen (39%) pts received EPO and 9 (60%) of them had increments of their Hb levels ≥2 g/dL. In conclusion, cytopenias occur in a significant proportion of pts with CML in CP treated with dasatinib. This complication can be readily managed and can be frequently overcome by using growth factor support, which may allow for a more continuous dasatinib administration.