Sustained Molecular Responses to Dasatanib (SPRYCEL®) in Patients with Philadelphia Chromosome-Positive (Ph(+)) Acute Lymphoblastic Leukemia (ALL) or Lymphoid Blast Phase (LyBP) Chronic Myeloid Leukemia after Imatinib (IM) Failure: A Single-Center Experience.
Authors: Chromik Joerg , Pfeifer Heike , Wunderle Lydia , Schoch Nadine , Wassmann Barbara , Brueck Patrick , Gollerkeri Ashwin , Hoelzer Dieter , Ottmann Oliver G. 
Published: October 2019

Abstract
Background: Dasatanib (SPRYCEL®, formerly BMS-354825) is a potent inhibitor of BCR-ABL and SRC kinases with significant clinical activity in pts. with CML or Ph(+)ALL who have failed IM. The association between patient characteristics and pretreatment disease features and subsequent response to dasatinib has not been established.
Patients and Methods: We evaluated the response of 34 consecutive pts. with Ph(+)ALL (n=30) or LyBP (n=4) who were enrolled at our center in two multicenter phase II studies of dasatinib in pts with Ph(+) lymphoid leukemias resistant to or intolerant of IM (CA180-015 and CA180-035). Dasatinib was given orally, at a starting dose of 70mg twice a day. Bone marrow (BM) was examined after 2 weeks and then monthly and included cytology, cytogenetics, quantitative PCR and BCR-ABL mutation analysis. Hematologic responses had to be maintained for at least 4 weeks. Thirty-two pts. (94%) were IM-resistant, 14 (41%) had undergone prior SCT, and 6 (18%) had failed prior therapy with nilotinib. Of 26 pts. evaluable at baseline, 18 had a complex karyotype in conjunction with either a single (n=12) or a double (n=6) Ph chromosome. BCR-ABL tyrosine kinase domain (TKD) mutations at baseline were observed in 17 of 29 eval. pts. (59%), 5 (17%) with T315I and 9 (31%) with p-loop mutations.
Results: Dasatinib induced a major hematologic response (MHR) in 48% of pts. (38% complete hematologic responses (CHR), 10% no evidence of leukemia: <5% BM blasts but incomplete PB recovery). Negative predictors of hematologic response were prior nilotinib failure (MHR: 0 of 7 pts, and presence of a T315I mutation (MHR: 0 of 5 pts.). Factors not associated with an inferior hematologic response or survival were p-loop mutations, complex karyotype, additional Ph chromosomes, prior SCT, >2nd relapse versus 1st relapse, BM blasts >80% or percentage of PB blasts. Clearance of PB blasts by day 7 was associated with an 82% MHR rate, no MHR was noted in pts. in whom PB blasts persisted after 14 days. BCR-ABL negativity by RT-PCR was achieved by 6 patients (18%) and was observed exclusively in patients who had undergone prior SCT. Thus, remission quality appears to be superior in pts with prior SCT, despite similar hematologic response rates. In addition, molecular responses were sustained only in the subgroup of patients (n=5) with wild-type BCR-ABL at study entry. Estimated median time to progression was 85 d in MHR pts. who remained PCR pos. and was not reached in the PCR neg. group. Severe adverse events (Grades 3+4) included pleural effusion (14,7%), thrombocytopenia (8,8%), neutropenic fever (8,8%), pulmonary hypertension with cor pulmonale (5,8%), gastrointestinal hemorrhage (5.8%), subdural hematomas (5.8%) and diarrhea (5,8%), indicating the need for close patient monitoring in this advanced disease population.
Conclusion: Dasatinib has significant activity in Ph(+)ALL pts who have failed prior therapy including IM. In this single-center experience of 34 pts, sustained molecular responses were observed only in the 5 pts previously transplanted who had no evidence of TKD mutations at the start of dasatinib treatment, suggesting that additional immunologic and non-mutational resistance mechanisms play an important role in determining the long-term response in pts with Ph(+)ALL.