Outcome of Patients with Chronic Myeloid Leukemia in Lymphoid Blast Crisis (CML-LBC) and Philadelphia Chromosome (Ph)-Positive Acute Lymphoblastic Leukemia (ALL) Treated with Hyper-CVAD and Dasatinib
Authors: Morita Kiyomi , Kantarjian Hagop M. , Ravandi Farhad , Sasaki Koji , Jain Nitin , Konopleva Marina , Short Nicholas J. , Takahashi Koichi , Khouri Rita , Nasnas Patrice , DiNardo Courtney D. , Kadia Tapan M. , Garcia-Manero Guillermo , Daver Naval , Montalban Bravo Guillermo , Issa Ghayas C. , Cortes Jorge E. , Jabbour Elias 
Published: November 2020

Introduction:
Dasatinib monotherapy has demonstrated clinical activity in CML-LBC, however with limited duration of response and median overall survival (OS) &lt;6 months (mos) (Cortes et al 2008 Leukemia). Outcome of Ph-positive ALL has dramatically improved with hyper-CVAD (HCVAD) in combination with tyrosine kinase inhibitors (TKIs, Ravandi et al Cancer 2015). The aim of this study is to report on the outcome of patients (pts) with CML-LBC who received HCVAD plus dasatinib (HCVAD+Dasa) therapy, and compare it with the outcome of pts with Ph-positive ALL who received the same therapy.
Methods:
We reviewed 81 pts (CML-LBC, N=19 and newly diagnosed Ph-positive ALL, N=62) who were treated with HCVAD+Dasa at our institution between 9/2006 and 3/2016. De novo CML-LBC cases without prior CML or relapsed CML-LBC cases were excluded. HCVAD+Dasa therapy consisted of 4 alternating cycles of HCVAD and high-dose methotrexate (MTX) / cytarabine (AraC) with 8 intrathecal injections of MTX/AraC. Dasa was administered 100mg daily on days 1-14 for course 1, and 70mg daily on courses 2 and onwards. The maintenance phase consisted of vincristine and steroids in addition to Dasa. Pts with CD20-positive disease received additional rituximab. Allogeneic stem cell transplant (allo-SCT) was offered at physician's discretion if matched donor was available. Complete cytogenetic remission (CCyR) was defined as the absence of Ph by karyotyping. Major molecular response (MMR) was defined as BCR-ABL1 transcripts &lt;0.1%, and complete molecular response (CMR) as the absence of BCR-ABL1 transcripts with a sensitivity of 0.01%. OS was calculated from the start date of treatment to the date of death, or last follow-up. Progression-free survival (PFS) was calculated from the start date of treatment to the date of disease progression, or last follow-up.
Results:
Among pts with CML-LBC, median age was 49 years (yrs) (range, 26-76). Initial CML diagnosis was as chronic phase (N=17, 89%), accelerated phase (N=1, 5%), or myeloid blast phase (N=1, 5%). Median time from initial CML diagnosis to LBC was 9.5 mos (range, 3-257). Seventeen (89%) pts were previously treated with TKIs (9 [47%] imatinib, 6 [32%] nilotinib, 1 [5%] imatinib and nilotinib, 1 [5%] imatinib and bosutinib), of which 7 (41%) were refractory to TKIs. The median duration of TKI therapy was 8.3 mos (range, 3.2-37). Two (11%) pts had not received any TKIs. One had undergone allo-SCT. At the time of CML-LBC, 9 (47%) pts were on imatinib, 7 (37%) with nilotinib, and 1 (5%) with bosutinib. At CML-LBC, 11 (58%) had abnormal karyotype, all with additional cytogenetic abnormalities (ACAs) in addition to Ph. ABL1 mutations were detected in 8 of 14 (57%) tested-pts, none with T315I. BCR-ABL1 transcript was p210 in all pts. In pts with Ph-positive ALL, 52 (84%) had abnormal karyotype, of which 10 (19%) had Ph only and 41 (79%) had Ph with ACAs. p210 and p190 were detected in 13 (21%) and 48 (77%) pts, respectively. Morphologic response (CR or CRi) rates were similar between pts with CML-LBC (90%) and Ph-positive ALL (96%), whereas pts with CML-LBC were less likely to obtain deeper molecular remission. CCyR was achieved in 94% vs 95% of pts with CML-LBC vs Ph-positive ALL, respectively (p = 1). MMR was achieved in 68% vs 95% of pts with CML-LBC vs Ph-positive ALL, respectively (p = 0.006). CMR was achieved in 53% vs 74% of pts with CML-LBC vs Ph-positive ALL, respectively (p = 0.093, Table 1). Nineteen pts received allo-SCT (CML-LBC, N=8 [42%]; Ph-positive ALL, N=11 [18%]). With a median follow-up of 133 mos (95% CI: 115-137), 20 (25%) pts relapsed and 50 (62%) died. Pts with CBL-LBC had similar survival outcome compared with pts with Ph-positive ALL (5-yr PFS 50% vs 44% [p = 0.75], 5-yr OS 61% vs 48% [p = 0.74], Figure 1). The 5-yr OS rates were 88 % and 37% for pts with CML-BC with or without allo-SCT (p = 0.019). In pts with Ph-positive ALL, there was no difference in outcome based on allo-SCT (p = 0.252, Figure 2). In pts with Ph-positive ALL, outcome was predicted by the achievement of CMR. The 5-yr OS rates were 63% and 25% (p = 0.002) for pts with CMR and MMR, respectively (Figure 3). By MVA, allo-SCT seemed to predict better OS in CML-LBC (HR 0.20, p = 0.057), whereas CMR predicted better OS in Ph-positive ALL (HR 0.37, p = 0.015) (Table 2).
Conclusions:
Outcome of CML-LBC has improved with HCVAD+Dasa therapy, particularly in pts who received subsequent allo-SCT. Further improvement can be obtained by the use of novel TKI and targeted agents.

Disclosures
Kantarjian: Oxford Biomedical: Honoraria; Janssen: Honoraria; Delta Fly: Honoraria; BioAscend: Honoraria; Aptitute Health: Honoraria; Abbvie: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Jazz: Research Funding; Immunogen: Research Funding; Daiichi-Sankyo: Honoraria, Research Funding; BMS: Research Funding; Ascentage: Research Funding; Amgen: Honoraria, Research Funding; Adaptive biotechnologies: Honoraria; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; Pfizer: Honoraria, Research Funding. Ravandi:Macrogenics: Research Funding; Orsenix: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria; AstraZeneca: Consultancy, Honoraria; Xencor: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Research Funding; Astellas: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy, Honoraria, Research Funding. Sasaki:Novartis: Consultancy, Research Funding; Otsuka: Honoraria; Pfizer Japan: Consultancy; Daiichi Sankyo: Consultancy. Jain:AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Aprea Therapeutics: Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Cellectis: Research Funding; Genentech: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; TG Therapeutics: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Incyte: Research Funding; Verastem: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ADC Therapeutics: Research Funding; Fate Therapeutics: Research Funding; Precision Bioscienes: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Research Funding; Pfizer: Research Funding; Adaptive Biotechnologies: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; AstraZeneca: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BeiGene: Honoraria, Membership on an entity's Board of Directors or advisory committees. Konopleva:Ablynx: Research Funding; Ascentage: Research Funding; Cellectis: Research Funding; Calithera: Research Funding; Genentech: Consultancy, Research Funding; Amgen: Consultancy; Agios: Research Funding; AbbVie: Consultancy, Research Funding; Eli Lilly: Research Funding; Stemline Therapeutics: Consultancy, Research Funding; Forty-Seven: Consultancy, Research Funding; Sanofi: Research Funding; AstraZeneca: Research Funding; Rafael Pharmaceutical: Research Funding; Reata Pharmaceutical Inc.;: Patents & Royalties: patents and royalties with patent US 7,795,305 B2 on CDDO-compounds and combination therapies, licensed to Reata Pharmaceutical; Kisoji: Consultancy; F. Hoffmann La-Roche: Consultancy, Research Funding. Short:Astellas: Research Funding; Takeda Oncology: Consultancy, Honoraria, Research Funding; Amgen: Honoraria; AstraZeneca: Consultancy. DiNardo:Syros: Honoraria; MedImmune: Honoraria; AbbVie: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; ImmuneOnc: Honoraria; Jazz: Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Agios: Consultancy, Honoraria, Research Funding; Notable Labs: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy; Daiichi Sankyo: Consultancy, Honoraria, Research Funding; Takeda: Honoraria. Kadia:Abbvie: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Astellas: Research Funding; JAZZ: Honoraria, Research Funding; Genentech: Honoraria, Research Funding; Pulmotec: Research Funding; Incyte: Research Funding; Celgene: Research Funding; Cellenkos: Research Funding; Cyclacel: Research Funding; BMS: Honoraria, Research Funding; Astra Zeneca: Research Funding; Amgen: Research Funding; Ascentage: Research Funding; Novartis: Honoraria. Garcia-Manero:Merck: Research Funding; H3 Biomedicine: Research Funding; AbbVie: Honoraria, Research Funding; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Onconova: Research Funding; Acceleron Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Astex Pharmaceuticals: Consultancy, Honoraria, Research Funding; Amphivena Therapeutics: Research Funding; Helsinn Therapeutics: Consultancy, Honoraria, Research Funding; Jazz Pharmaceuticals: Consultancy; Novartis: Research Funding. Daver:Karyopharm: Research Funding; Servier: Research Funding; Genentech: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novimmune: Research Funding; Gilead: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Trovagene: Research Funding; Fate Therapeutics: Research Funding; ImmunoGen: Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Jazz: Consultancy, Membership on an entity's Board of Directors or advisory committees; Trillium: Consultancy, Membership on an entity's Board of Directors or advisory committees; Syndax: Consultancy, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; KITE: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Daiichi Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Issa:Celegene: Research Funding; Syndax: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees. Cortes:Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Sun Pharma: Research Funding; BioPath Holdings: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Telios: Research Funding; Astellas: Research Funding; Amphivena Therapeutics: Research Funding; Arog: Research Funding; BiolineRx: Consultancy, Research Funding; Merus: Research Funding; Immunogen: Research Funding; Jazz Pharmaceuticals: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; Bristol-Myers Squibb: Research Funding. Jabbour:Pfizer: Other: Advisory role, Research Funding; Adaptive Biotechnologies: Other: Advisory role, Research Funding; Takeda: Other: Advisory role, Research Funding; BMS: Other: Advisory role, Research Funding; Amgen: Other: Advisory role, Research Funding; AbbVie: Other: Advisory role, Research Funding; Genentech: Other: Advisory role, Research Funding.