Phase II Study of Combination of Hypercvad with Ponatinib in Front Line Therapy of Patients (pts) with Philadelphia Chromosome (Ph) Positive Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2289-2289 ◽  
Author(s):  
Elias Jabbour ◽  
Hagop M. Kantarjian ◽  
Deborah A. Thomas ◽  
Koji Sasaki ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Median Time ◽  
Research Funding ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Philadelphia Chromosome ◽  
High Dose ◽  
Vascular Events ◽  
Platelet Recovery

Abstract Background: Combination of cytotoxic chemotherapy with tyrosine kinase inhibitors (TKIs) is effective in the treatment of Ph+ ALL. Ponatinib is a more potent BCR-ABL inhibitor. It also suppresses the T315I clones, a common cause of relapse in pts with Ph+ ALL. The combinations of chemotherapy and ponatinib may be associated with better response rates and higher likelihood of eradication of minimal residual disease (MRD) than those reported with other TKIs. Methods: Pts with newly diagnosed Ph+ ALL received 8 cycles of hyper-CVAD (fractionated cyclophosphamide, vincristine [VCR], doxorubicin, dexamethasone) alternating with high dose methotrexate (MTX) and cytarabine every 21 days. Ponatinib was given at 45 mg po daily for the first 14 days of cycle 1 then continuously for the subsequent 7 cycles. Pts in CR received maintenance with ponatinib 45 mg po daily and vincristine and prednisone monthly for 2 years followed by ponatinib indefinitely. MRD monitoring was conducted. Results: To date, 34 pts with untreated Ph+ ALL and 3 pts previously treated (1 previous course) have received a median of 6 cycles (2-8); 10 pts are receiving maintenance in CR. 3 pts have completed the 2 years of maintenance and they are receiving single agent TKI. Median WBC at diagnosis was 8 x 109/L (0.9 -629 x 109/L). CD20 expression was reported positive in 11 pts (30%). 3 (8%) had concomitant CNS disease at diagnosis. All pts were in CR after cycle 1. 30/32 pts (94%) with Ph+ metaphases by CG analysis at baseline achieved CCyR after 1 cycle; 1 had mCyR only and 1 had no CG analysis at CR, both of them achieved CCyR after cycle 2. To date, 35 pts (95%) achieved MMR and 26 (70%) CMR. The median time to MMR and CMR were 3 and 10 weeks, respectively. MRD is negative in 35/36 (97%) pts, in whom a sample was sent for assessment. 9 (24%) received an allogeneic stem cell transplantation (ASCT) after a median of 4 cycles (3-10). Median time to neutrophil and platelet recovery for cycle 1 was 18 and 23 days, and 16 and 22 days for subsequent cycles, respectively. Grade ≥ 3 toxicity included infections during induction in 18 pts (49%), increased LFT’s in 12 (32%), thrombotic events in 3 (8%), myocardial infarction (MI) in 3 (8%, 2 unexplained, 1 in the context of sepsis ), skin rash in 4 (11%), and pancreatitis in 6 (16%). With a median follow up of 18 months (9-31), 31 pts are alive, 6 died in CR. 1 pt died in CR from an unrelated cardiac event after being taken off therapy and placed on imatinib, 1 from MOF (C2D13), 1 from NSTEMI (C2D41), 1 from potential MI (C4D42), 1 from head injury sustained after a fall (C4D13), and 1 from sepsis post ASCT. At the last follow-up, 8 pts (19%) are alive post ASCT; 13 pts remain on ponatinib at the dose of 15 mg daily in 14 and 30 mg daily in 1; Of the other 9 alive patients, 7 were switched to dasatinib, two were switched to imatinib and nilotinib (one each); 1 was lost of follow-up. All but one pt who switched to dasatinib remained in CR; the latter relapsed after a first remission of 10 months; she is receiving salvage therapy in combination with dasatinib. The 1-year progression-free and overall survival rates were 96% and 86%, respectively. Conclusion: The combination of hyperCVAD with ponatinib is highly effective in pts with Ph+ ALL. Due to the vascular events observed, some pts switched to alternative TKI; in the remaining, ponatinib dose was modified to 30 mg daily during consolidation with subsequent reduction to 15 mg in pts in CMR. Disclosures Kantarjian: ARIAD: Research Funding; Pfizer: Research Funding; Amgen: Research Funding. Kadia:GSK: Research Funding; ARIAD: Honoraria.

Frontline Hyper-CVAD with Ponatinib for Patients (pts) with Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia: Results of a Phase II Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 2496-2496
Author(s):  
Koji Sasaki ◽  
Susan O'Brien ◽  
Farhad Ravandi ◽  
Deborah A Thomas ◽  
Haim G Moore ◽  
...  
Keyword(s):  
Overall Survival ◽  
Median Time ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Event Free Survival ◽  
Vascular Events ◽  
Free Survival ◽  
Philadelphia Chromosome Positive

Abstract Background: Addition of tyrosine kinase inhibitors (TKIs) to chemotherapy improves outcome in Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). Ponatinib is a more potent BCR-ABL inhibitor, and covers the T315I clones. The combination of hyper-CVAD with ponatinib may contribute to better response rates and higher likelihood of eradication of minimal residual disease (MRD) than those reported with other TKIs. Methods: Pts with newly diagnosed Ph+ ALL received 8 cycles of hyper-CVAD alternating with high dose methotrexate and cytarabine every 21 days. Ponatinib was given at 45 mg/day for the first 14 days of cycle 1 then continuously for the subsequent 7 cycles. Pts in CR received maintenance with ponatinib 45 mg/day and vincristine and prednisone monthly for 2 years followed by ponatinib indefinitely. Results: From 11/2011 to 9/2013, 34 pts with untreated Ph+ ALL and 3 pts previously treated (2 pts not in CR were treated with one cycle of chemotherapy before the detection of BCR-ABL1; 1 pt in CCyR after 2 cycles of chemotherapy and dasatinib) have received a median of 6 cycles (2-8); 13 are receiving maintenance in CR; 9 underwent ASCT after a median of 4 cycles. Baseline pt characteristic and outcome are described in table 1. The overall CCyR, MMR, and CMR rates were 100%, 95%, and 78%, respectively. The median time to MMR and CMR were 3 (range, 2-14) and 11 (range, 2-96) weeks, respectively. The median time to MRD negativity was 3 weeks (range, 3-14). Median time to platelet and neutrophil recovery for cycle 1 was 22 and 18 days, respectively, and 22 and 16 days for subsequent cycles. Grade ≥ 3 toxicity included infections during induction (54%), increased liver functional tests (38%), thrombotic events (8%), myocardial infarction (14%), hypertension (16%), skin rash (22%), and pancreatitis (22%). With a median follow up of 26 months, 29 (78%) remain alive and in CR. Six pts died in CR: 1 pt died in CR from an unrelated cardiac event after being taken off therapy and placed on imatinib, 1 from MOF (C2D13), 1 from NSTEMI (C2D41; ponatinib 45 mg daily), 1 from potential MI (C4D42; ponatinib 30 mg daily), 1 from head injury sustained after a fall (C4D13), and 1 from sepsis post ASCT. Two (5%) in CMR relapsed with no identifiable T315I mutations after a median of 18 months. One of these pts achieved a second CR after blinatumomab and dasatinib therapy. To date, 13 pts are receiving maintenance therapy in CR. After the increased incidence of vascular toxicities was recognized, we offered our pts the option to switch TKIs or to reduce the dose of ponatinib to 30 mg and further decreased to 15 mg in pts in CMR. Thirteen pts remained on ponatinib at a dose of 15 mg daily in 12 and 30 mg daily in 1 (transcript levels of 0.04%). No further vascular events were observed in pts receiving lower doses of ponatinib. Nine pts elected to switch TKIs to dasatinib (n=7), nilotinib, or imatinib (1 each). One pt was lost to follow-up. Of 9 patients who underwent ASCT while in first CR (7 with MMR and 2 with CMR before transplantation), all but one are alive and disease-free after transplantation. There was no difference in OS by whether patients were censored or not at the time of ASCT. After transplantation, TKI therapy was resumed in all but one patient (1 imatinib, 4 dasatinib, 1 nilotinib, and 1 ponatinib). The 2-year event-free and overall survival rates are 81% and 80%, respectively (Figures 1). Conclusion: The combination of hyperCVAD with ponatinib is highly effective in pts with Ph+ ALL. Due to the vascular events observed, the ponatinib dose was modified to 30 mg daily during consolidation with subsequent reduction to 15 mg in pts in CMR without further episode of cardiovascular events. Table 1. Patient characteristic and outcome N(%); Median [range] N= 37 Age (yr) 51 [27-75] Age ≥50 20 (54%) Age ≥60 12 (32%) Performance status, No. (%)  0-1 31 (84)  2 6 (16)  WBC (x 109/L) 8 [1-630]  Presence of CNS disease, No. (%) 3 (8)  CD20 positivity, No. (%) 11 (30) Type of BCR-ABL1 transcript, No. (%)  p190 27 (73)  p210 10 (27) Cytogenetics abnormality, No. (%)  Diploid 5 (14)  Philadelphia-chromosome positive 32 (86) Baseline cardiovascular risk factors, No. (%)  Hypertension 18 (49)  Dyslipidemia 4 (11)  Coronary artery disease 4 (11)  Peripheral arterial disease 1 (3) Overall response, No. (%)  CR 36/36 (100)  CCyR 32/32 (100)  MMR 35/37 (95)  CMR 29/37 (78)  Flow negativity 35/36 (97)  Early death 0 Figure 1. a) Event-free survival, b) overall survival Figure 1. a) Event-free survival, b) overall survival Disclosures O'Brien: Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding. Cortes:Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BerGenBio AS: Research Funding; BMS: Consultancy, Research Funding; Teva: Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy. Pemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Chahoud:American Society of Hematology (ASH): Other: 2015 HONORS Award recipient. Wierda:Glaxo-Smith-Kline Inc.: Research Funding; Celgene Corp.: Consultancy.

Phase II Study of the Frontline Hyper-CVAD in Combination with Ponatinib for Patients with Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 757-757 ◽  
Author(s):  
Koji Sasaki ◽  
Elias J. Jabbour ◽  
Farhad Ravandi ◽  
Naval G. Daver ◽  
Naveen Pemmaraju ◽  
...  
Keyword(s):  
Myocardial Infarction ◽  
Median Time ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Advisory Board ◽  
Molecular Response ◽  
Rt Pcr ◽  
Vascular Events

Abstract Background: The combination of tyrosine kinase inhibitors (TKIs) with chemotherapy is highly effective in Philadelphia chromosome positive (Ph+) acute lymphoblastic leukemia (ALL). Ponatinib is a more potent BCR-ABL inhibitor, and is effective against the T315I clone which commonly causes disease recurrences. The combination of hyper-CVAD with ponatinib may produce better response rates and higher likelihood of eradication of minimal residual disease (MRD) as compared to that reported with other TKIs. Methods: Patients with newly diagnosed Ph+ ALL received 8 cycles of hyper-CVAD alternating with high dose methotrexate and cytarabine every 21 days. Ponatinib was given at 45 mg po daily for the first 14 days of cycle 1 then continuously for the subsequent 7 cycles. Patients in complete response (CR) received maintenance with ponatinib 45 mg daily and vincristine and prednisone monthly for 2 years followed by ponatinib indefinitely. After an increased incidence of vascular toxicities was recognized, patients were offered the option to switch TKIs or to continue with a reduced dose of ponatinib of 30 mg with further decrease to 15 mg in patients in CMR. The evaluation of MRD status was performed by multicolor flow cytometry (FCM), and reverse transcription polymerase chain reaction (RT-PCR). The objective of this study is to evaluate response rates, CR duration, and overall survival (OS), and to assess the safety of this regimen. Rituximab and intrathecal chemotherapy were given for the first 4 courses. Results: To date, 53 patients with untreated Ph+ ALL and 4 patients previously treated (2 patients in CR; 2 patients not in CR) have received a median of 6 cycles (2-8); 11 patients are receiving maintenance in CR; 10 patients underwent allogeneic stem cell transplantation (ASCT) after a median of 4 cycles. Baseline patient characteristics and outcomes are described in table 1. The overall complete cytogenetic response (CCyR), major molecular response (MMR), and complete molecular response (CMR) rates were 100%, 96%, and 79%, respectively. The median time to MMR and CMR were 3 weeks (range, 2-14) and 11 weeks (range, 2- 96), respectively. The median time to MRD negativity by 6-color flow cytometry (FCM) was 3 weeks (range, 3-14). Median time to platelet and neutrophil recovery for cycle 1 was 22 days (range, 17-35) and 18 days (range, 13-29), respectively, and 22 days (range, 0-35) and 16 days (range, 0-28) for subsequent cycles. Grade ≥ 3 toxicity included infections during induction (47%), increased liver function tests (34%), thrombotic events (8%), myocardial infarction (6%), hypertension (15%), skin rash (15%), and pancreatitis (19%). With a median follow up of 33 months (range, 2-51), 44 81(%) patients remain alive and in CR (41 in CR1, and 3 in CR2). Six patients died in CR: 1 patient died in CR from an unrelated cardiac event 4 months after being taken off therapy and placed on imatinib, 1 from multiple organ failure due to sepsis (C2D13), 1 from non-ST elevation myocardial infarction (C2D41; ponatinib 45 mg daily), 1 from potential myocardial infarction (C4D42; ponatinib 30 mg daily), 1 from head injury after a fall (C4D13), and 1 from sepsis post allogeneic stem cell transplantation. Of 44 patients alive at the last follow-up, 20 (46%) patients remained on ponatinib (15 mg daily in 15, and 30 mg daily in 5), 12 (27%) switched to another TKI (9 to dasatinib, 2 to nilotinib, and 1 to imatinib), 8 (18%) underwent ASCT, 3 (7%) relapsed, and 1 (2%) had positive MRD by FCM and RT-PCR. No further vascular events were observed in patients receiving lower doses of ponatinib. The 3-year CR duration and OS rates are 82% and 80%, respectively (Figures 1). Of 10 patients who underwent ASCT while in first CR, 8 patients are alive in CR, 1 died of sepsis in CR, and 1 relapsed and died of disease progression. Landmark analysis at 4 months by ASCT showed no difference in 3-year CR duration (no ASCT, 79%; ASCT, 88%; p=0.48), and 3-year OS (no ASCT, 92%; ASCT, 79%; p=0.31). Conclusion: The combination of hyperCVAD with ponatinib is highly effective in patients with Ph+ ALL. Due to the vascular events observed, the ponatinib dose was modified to 30 mg daily during consolidation with subsequent reduction to 15 mg in patients in CMR without further episode of cardiovascular events. Disclosures Jabbour: ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Pemmaraju:incyte: Consultancy, Honoraria, Research Funding; novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria; stemline: Consultancy, Honoraria, Research Funding; cellectis: Consultancy, Research Funding; affymetrix: Research Funding. DiNardo:Celgene: Research Funding; Agios: Other: advisory board, Research Funding; Abbvie: Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding. Konopleva:Cellectis: Research Funding; Calithera: Research Funding. Jain:BMS: Research Funding; Celgene: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Incyte: Research Funding; Novimmune: Consultancy, Honoraria; Servier: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; Abbvie: Research Funding; Infinity: Research Funding; Novartis: Consultancy, Honoraria; Genentech: Research Funding; Seattle Genetics: Research Funding. Wierda:Novartis: Research Funding; Abbvie: Research Funding; Acerta: Research Funding; Gilead: Research Funding; Genentech: Research Funding. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. O'Brien:Pharmacyclics, LLC, an AbbVie Company: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria.

Long-Term Follow-up of Combined Hypercvad (hCVAD) Regimen with Dasatinib (Db) in the Front Line Therapy of Patients (pts) with Philadelphia Chromosome Positive (Ph+) Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1512-1512 ◽  
Author(s):  
Hun Ju Lee ◽  
Hagop M. Kantarjian ◽  
Deborah A. Thomas ◽  
Stefan Faderl ◽  
Charles Koller ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
High Dose ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Platelet Recovery

Abstract Abstract 1512 Background: The introduction of tyrosine Kinase Inhibitors (TKI) has significantly improved the outcome of patients (pts) with Ph+ ALL. Dasatinib (Db) is a second generation dual SRC/ABL TKI with greater potency compared to Imatinib in inhibiting BCR/ABL. Aim: To determine the outcome of pts with Ph+ ALL treated with hCVAD + Db. Method: Between 9/06 and 7/09, pts with newly diagnosed Ph+ ALL received Db 50mg oral (PO) twice daily (BID) or 100mg PO daily for the first 14 days of each of 8 cycles of alternating hCVAD, and high dose cytarabine and methotrexate. Pts in complete remission (CR) continued to receive maintenance Db 50mg PO BID or 100mg PO daily, as well as monthly prednisone and vincristine for 2 years, followed by Db indefinitely. From 8/09 protocol was amended and pts received 100mg Db for the first 14 days of cycle #1 and then 70mg daily continuously for the next 7 cycles, as well as 2 doses of rituximab 375 mg/m2 during each of the first 4 cycles. Maintenance was with Db, vincristine and prednisone. Results: Sixty-one pts with newly diagnosed Ph+ ALL have been treated to date. Median age was 56 years (yrs) (range (r), 22–80) and 41 (67%) pts were >50 yrs. The median follow up is 26.1 months (mo) (r, 4–58). Central nervous system (CNS) involvement was noted in 9 (14%) pts at diagnosis. Sixteen (26%) pts had Ph+ alone, 38 (62%) pts had Ph+ with additional abnormalities, and 7 (12%) pts were Ph negative, and BCR/ABL positive. Median white blood cell count (WBC) at diagnosis was 13.4 × 109/L (r: 0.4–658), and 22 (36%) pts had WBC >30 × 109/L at diagnosis. BCR/ABL transcript was identified in 60 (98.3%) pts at diagnosis, including e1a2 in 46 (76%) pts, b2a2 in 10 (17%) pts, b2a2+b3a2 in 2 (3%) pts, b3a2 and e1a3 in 1 (1.6%) pt each. One pt had a variant transcript that was not detectable with the standard primers. The median number of induction and maintenance cycles received were 6 cycles (r: 1–8) and 13.5 cycles (r: 1–24), respectively. Fifty seven (94%) pts achieved CR1 and 1 (1.5%) pts achieved CR with incomplete platelet recovery with first induction cycle of chemotherapy. Three (4.5%) pts died before response assessment could be performed due to infections. Thirty-nine (64%) pts received maintenance, 3 (5%) pts are currently receiving induction and 19 (31%) pts had no maintenance [9 pts received allogeneic stem cell transplant (ASCT) prior to maintenance, 10 pts had progression of disease]. To date, twelve (19%) pts have relapsed and Abl kinase domain mutations were analyzed in 7 pts; mutations were noted in 4 pts. These included T315I in 2 pts, and F359V and V299L in 1 pt each. CNS relapse occurred in 5 pts. Salvage (S1) regimens included [hCVAD + another TKI in 7 pts, single agent TKI in 2 pts, single agent monoclonal antibody in 1 pt, methotrexate, vincristine, asparginase, dexamethasone (MOAD) in 1pt, intrathecal cytarabine/methotrexate plus CNS radiation and Db in 1 pt]. Eight pts achieved CR2, 3 pts were refractory (2 pts with T315I and 1 pt with F359V) and one is still undergoing salvage treatment. Median DFS and OS after S1 were 5.3 mo (r: 0.7–17.3) and 6.7 mo (r: 0.6–24.4), respectively. ASCT was performed in 15 (24%) pts, including 10 pts in CR1 and 5 pts in CR2. Donors were related in 8 (53%) and unrelated in 7 (47%) transplants. Sixteen pts have died 11 (68%) pts from infectious complications, 2 (13%) pts from multi-organ failure, 1 (6%) pt with graft versus host disease, and 2 (13%) pts from unknown causes. Three-year disease free survival (DFS) and overall survival (OS) (n=61) were 49% and 62%, respectively. Conclusion: Db plus hCVAD is an effective regimen with durable responses in pts with newly diagnosed Ph+ ALL. Disclosures: Kantarjian: BMS: Research Funding. Jabbour:Pfizer: Honoraria; BMS: Honoraria; Novartis: Honoraria. Cortes:Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Ariad: Membership on an entity's Board of Directors or advisory committees, Research Funding; Chemgenex: Membership on an entity's Board of Directors or advisory committees, Research Funding. Ravandi:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria.

Combination of the Hypercvad Regimen with Dasatinib in Patients with Relapsed Philadelphia Chromosome (Ph) Positive Acute Lymphoblastic Leukemia (ALL) or Lymphoid Blast Phase of Chronic Myeloid Leukemia (CML-LB)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2578-2578 ◽  
Author(s):  
Theresa Liu-Dumlao ◽  
Susan O'Brien ◽  
Jorge E. Cortes ◽  
Deborah A. Thomas ◽  
Stefan Faderl ◽  
...  
Keyword(s):  
Research Funding ◽  
Kinase Inhibitors ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
High Dose ◽  
Molecular Response ◽  
Cell Transplant ◽  
Imatinib Resistance ◽  
Platelet Recovery

Abstract Abstract 2578 Prognosis for patients (pts) with Ph+ ALL has improved significantly with the introduction of tyrosine kinase inhibitors (TKI). Dasatinib is ∼325 times more potent than imatinib, and has shown activity in pts with imatinib resistance or intolerance, both in CML and Ph+ ALL. From 9/2006, pts with relapsed Ph+ ALL or CML-LB received dasatinib 100 mg po daily for the first 14 days of each of 8 cycles of alternating hyperCVAD, and high-dose cytarabine with methotrexate. Patients in complete remission (CR) continued to receive maintenance with dasatinib 100 mg po daily, with vincristine and prednisone monthly for 2 years, followed by dasatinib indefinitely. All patients proceeded to an allogeneic stem cell transplant as soon as feasible. From 8/2009, dasatinib dose was modified to 100mg po daily for the first 14 days of the first cycle, then at 70mg po daily continuously. Pts also received Rituximab on Days 1 and 11 of each of the first 4 cycles of therapy. A total of 32 pts with relapsed Ph+ ALL (n=18) or CML-LB (n=14) have received a median of 3 cycles (range=1–8 cycles). Twenty-three pts were treated on the initial regimen and 9 pts on the modified version. Median age was 50 yrs (range 21–77). Median number of prior regimens was 1 (range=1–2): hyperCVAD plus imatinib (n=10, 3 had transplant in first CR), other combination chemotherapy (n=12), monotherapy with TKI other than dasatinib (n=8), and investigational agents (n=2). Median WBC at start of treatment was 9.8 × 109/L (range=0.3–295.5 × 109/L). Median bone marrow blast percentage was 72% (range 0–97%; 1 pt had solitary CNS relapse). Eight (25%) patients had CNS involvement. Pre-treatment ABL mutations noted in 9 pts included: T315I(n=4), Y253F(n=1), Y253H(n=4), F359V(n=1), E459K(n=1), E255K(n=1), F317L(n=3), M351T(n=1). The overall response rate was 94%, with 23 pts (72%) achieving CR, and 7(22%) CR with incomplete platelet recovery (CRp). One pt died during induction. One pt had progressive disease. Twenty-five pts (83%) achieved complete cytogenetic remission after one cycle of therapy. Overall, 13 pts (43%) achieved complete molecular response, and 10 pts (33%) major molecular response (i.e., BCR-ABL/ABL<0.1%). Nine patients proceeded to allogeneic transplantation (ALL n=2, CML-LB n=7); one previously transplanted patient with ALL received donor lymphocyte infusion. Grade 3/4 toxicities included bleeding (GI, GU, and subdural hematomas), pleural effusions, pericardial effusions, infections, diarrhea, hypophosphatemia, hypocalcemia, elevated transaminases, and hyperbilirubinemia. The median follow-up for pts with CML-LB is 85 wks (range=12–209 wks); 3-yr OS is 76% (median not reached); and, 82% remain in CR at 3 yrs [median CR duration (CRD) not reached]. For ALL pts, median follow-up was 139 wks (range=74–175 wks); 3-yr OS is 33% (median=42 wks); and, 30% remain in CR at 3 yrs (median CRD=38 wks). The outcomes were the same for pts with CML-LB who did or did not receive a transplant (3-yr OS 83% for both cohorts). Among pts with ALL, outcome was better for those who underwent transplant (2 of 2 alive at 3 yrs as opposed to 4 of 16 without transplant). Conclusion: The combination of HyperCVAD regimen with dasatinib is effective in patients with relapsed Ph+ ALL and CML-LB. Disclosures: Cortes: Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Jabbour:Novartis: Honoraria; Pfizer: Honoraria; BMS: Honoraria. Kantarjian:BMS: Research Funding. Ravandi:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria.

scholarly journals Ramp-up Treatment Strategy in Philadelphia Positive Acute Lymphoblastic Leukemia Is Associated with Deep Molecular Remissions and Favorable Outcomes

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 5120-5120
Author(s):  
Nabiel A. Mir ◽  
Charles Bodine ◽  
Denise Peker ◽  
Kimo Bachiashvili ◽  
Pankit Vachhani ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Fish Analysis ◽  
Intensive Chemotherapy ◽  
Advisory Committees

Introduction: The advent of Tyrosine Kinase Inhibitors (TKI) changed the treatment paradigm of Philadelphia chromosome Positive (Ph+) Acute Lymphoblastic Leukemia (ALL). Different treatment strategies exist including combinations of TKI with steroids or with intensive multi-agent chemotherapy regimens. We present here our institutional experience of a "ramp-up" strategy using dasatinib with steroids as induction followed by the combination of dasatinib plus the intensive chemotherapy schema of HyperCVAD alternating with HD MTX/cytarabine. Methods: We performed a retrospective review of the electronic medical records of adult patients (pts) treated in our institution for Ph+ ALL. We collected and analyzed data for pts with Ph+ ALL treated with dasatinib and steroids followed by dasatinib plus HyperCVAD alternating with HD-MTX/cytarabine. Results: We identified 25 pts that were treated with the ramp-up treatment approach between 2014-2019. The median age at diagnosis was 45 years old (range 21-65 years old). Fifty-two percent were women and 60% white. Diagnosis of Ph+ ALL was based on FISH analysis with karyotype being positive for the Ph+ chromosomal abnormality in 64% pts; 8% of pts had cryptic translocation and rest not available ( N/A). Sixty percent of pts had p190 Bcr/Abl transcript, 16% had p210 and 8% N/A (including 2 pts that Bcr/Abl transcript was undetectable despite morphological disease). The CD20 by multicolor flow cytometry (MFC) was positive in 16%, heterogenous in 20%, and low/negative in the rest (64%). Eighty-four percent of pts had a WBC less than 50K/cmm at diagnosis; median WBC was 17K/cmm (range 0.8 -131.4 K/cmm). All pts except one received induction with initial dose of 140 mg of dasatinib daily; 84% received prednisone and rest received dexamethasone followed by prednisone. For those pts on dasatinib 140 mg daily, only 2 required adjustment/brief interruption during induction. Eighty-four percent of pts achieved morphological CR, 8% CRp, and 8% had residual ALL post induction with dasatinib and steroids. Of the 23 pts achieving CR/CRp, 34% had minimal residual disease (MRD) by MFC, 26% by FISH analysis and 86% by PCR for Bcr/Abl transcript (21 evaluable pts). Median time from initiation of induction to response bone marrow assessment was 26 days (range 14 - 40 days;75% percentile 28 days). All 25 pts proceeded with HyperCVAD alternating with HD MTX/cytarabine, and the dose of dasatinib used was 70 mg daily (aside from 1 patient who received 100 mg daily). Median time from induction to initiation of HyperCVAD was 34 days (range 17-68 days). The median number of courses (HyperCVAD or HD MTX/cytarabine) for the 25 pts was 3. The 13 pts that ultimately went to transplant in CR1 had also a median of 3 courses. Sixty percent of pts ultimately underwent allo-HSCT. Median time to allo-HSCT from initiation of HyperCVAD was 106 days (range 66-294; 75% percentile 163 days). Overall, all pts achieved CR/CRp with 68% of pts (from the 22 evaluable for molecular remission) attaining also undetectable Bcr/Abl PCR (complete molecular response) as a best response. All pts with post-induction residual disease achieved CR with the dasatinib/intensive chemotherapy combination. Twenty percent of pts had morphological relapse; two pts were treated for non-morphological relapse. Median time to morphological relapse was 148 days from induction (range 106-796 days). The median follow-up was 20.4 months (range 1.5 -58.4; 75% percentile 36.8 months). At last follow up 72% of pts were alive; median OS (not censored for allo-HSCT) was not reached (figure 1). There were no deaths in the first 60 days. Conclusion: Induction therapy with dasatinib and steroids was overall well tolerated and was associated with a very favorable CR/CRp rate, with only a minority of pts requiring treatment adjustment. Subsequent consolidation with dasatinib and HyperCVAD alternating with HD-MTX/cytarabine (+/- allo-HSCT) led to deep remissions in 68% of the pts. Sixty percent of pts underwent allo-HSCT and the median OS was not reached and with no deaths in the first 60 days. Hence, induction therapy with dasatinib and steroids followed by dasatinib plus HyperCVAD alternating with HD-MTX/cytarabine can be considered for Philadelphia chromosome-positive ALL pts to achieve deep remissions with low early mortality. Disclosures Vachhani: AbbVie: Membership on an entity's Board of Directors or advisory committees; Agios: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Speakers Bureau; Daiichi Sankyo: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Costa:Fujimoto Pharmaceutical Corporation Japan: Other: Advisor; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding; Sanofi: Consultancy, Honoraria, Speakers Bureau; GSK: Consultancy, Honoraria, Research Funding; Abbvie: Consultancy; Karyopharm: Consultancy. Erba:Amgen, Celgene, Daiichi Sankyo, ImmunoGen, Incyte, Jazz Pharmaceuticals, Millennium, Novartis, Ono, Pfizer, Seattle Genetics, Sunesis: Consultancy; Celgene, Incyte, Novartis: Speakers Bureau; Agios, Amgen, Astellas Pharma, Daiichi Sankyo, ImmunoGen, Janssen, Jazz Pharmaceuticals, Juno, Millennium, Seattle Genetics: Research Funding. Papadantonakis:Agios: Consultancy, Honoraria.

Phase II Study of Combination of the HyperCVAD Regimen with Dasatinib in Patients with Philadelphia Chromosome (Ph) or BCR-ABL Positive Acute Lymphoblastic Leukemia (ALL) and Lymphoid Blast Phase Chronic Myeloid Leukemia (CML-LB).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2814-2814 ◽  
Author(s):  
Farhad Ravandi ◽  
Deborah Thomas ◽  
Hagop Kantarjian ◽  
Stefan Faderl ◽  
Charles Koller ◽  
...  
Keyword(s):  
Phase Ii ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Clinical Activity ◽  
High Dose ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Blast Phase ◽  
Platelet Recovery

Abstract Combination of cytotoxic chemotherapy with imatinib has improved the outcome for patients with Ph+ ALL and resulted in eradication of minimal residual disease and durable remissions without allogeneic stem cell transplant in some patients (Thomas D, Blood, 2004; Yanada M, JCO, 2006; Wassmann B, Blood, 2006; de Labarthe A, Blood, 2007). The dual Src and Abl inhibitor dasatinib has a significantly higher in vitro kinase inhibition against BCR-ABL and has demonstrated potent clinical activity in patients with imatinib-resistant lymphoid blast phase CML (CML-LB) and Ph+ ALL with over 50% complete cytogenetic responses (CG CR) in phase I and II trials but with median progression free survival of only 3 to 4 months. We are conducting a phase II trial in which patients with newly diagnosed or relapsed Ph+ ALL or CML-LB receive dasatinib 50 mg po bid for the first 14 days of each of 8 cycles of alternating hyperCVAD and high dose cytarabine and methotrexate. Patients in complete remission (CR) continue to receive maintenance dasatinib 50 mg po bid daily and vincristine and prednisone monthly for 2 years followed by dasatinib indefinitely. To date 15 newly diagnosed patients with Ph+ ALL (cohort I) and 4 patients with relapsed Ph+ ALL or CML-LB (cohort II) have received a median of 4 cycles (range 1 – 8); 4 patients are receiving maintenance in CR. Median age for cohort I is 55 years (range 23 – 79) and for cohort II, 43 years (range 26 – 69); 13 and 3 patients were older than 50 years, respectively. Median WBC at diagnosis for cohort I was 4.3 × 109/L (range, 0.8 – 203.4 x 109/L). Three patients had CNS involvement. Fourteen and 3 patients in the 2 cohorts are evaluable for response to induction; 2 are too early. Thirteen patients (93%) in cohort I and all evaluable patients in cohort II have achieved CR after the first cycle; 1 patient in cohort I died on day 20 from infections before response assessment; her bone marrow exam on day 14 showed no detectable disease. Ten of 11 (91%) patients in cohort I have achieved CG CR after 1 cycle; 3 are too early. Three of 4 patients in cohort II have achieved CG CR after 1 cycle; 1 had a new CG abnormality and 1 is too early. Six patients have achieved complete molecular remission after the first cycle with the lowest BCR-ABL/ABL in the other patients ranging from 0.01 to 1.91. Median time to neutrophil and platelet recovery for cohort I is 18 and 25 days and for cohort II 18.5 and 30.5 days. Grade 3 and 4 toxicity has included 7 episodes of GI bleeding as well as infections, diarrhea, hypophosphatemia, hypocalcemia, elevated transaminases, and acute renal failure unrelated to treatment. With a median follow up of 4 months (range, 0 – 10), 15 patients are alive and in CR; 1 died at induction, 1 died in CR from an unrelated cardiac event, and 2 are too early. No patient has relapsed and no patient has received an allogeneic transplant. We conclude that the combination of the hyperCVAD regimen with dasatinib is feasible and can achieve early molecular remissions in patients with Ph+ ALL and CML-LB.

Two Years Follow-up Results of Graspall/Graall-SA2–2008 Study: L-Asparaginase-Loaded Red Blood Cell Combined with Standard EWALL Chemotherapy in Older Patients with Newly Diagnosed Philadelphia Chromosome-Negative Acute Lymphoblastic Leukemia (Ph-ALL)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1473-1473 ◽  
Author(s):  
Mathilde Hunault-Berger ◽  
Thibaut Leguay ◽  
Françoise Huguet ◽  
Stéphane Leprêtre ◽  
Eric Deconinck ◽  
...  
Keyword(s):  
Red Blood Cells ◽  
Blood Cells ◽  
Older Patients ◽  
Residual Disease ◽  
Remission Rate ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
High Dose ◽  
Newly Diagnosed

Abstract Abstract 1473 Introduction: L-asparaginase-loaded red blood cells (GRASPA®) has been shown to be a new available option for combining L-asparaginase with standard chemotherapy in different ALL population, including older patients with the disease. Tolerability and preliminary results of efficacy of GRASPA® in GRASPALL/GRAALL-SA2–2008 study have already been presented. We report below the 2-year follow-up efficacy results of this study. Methods: GRASPALL/GRAALL-SA2–2008 study aimed at determining optimal dose of GRASPA® that could be combined with standard EWALL chemotherapy backbone in patients aged >55y with newly diagnosed Ph-ALL. It was an open label Phase II dose escalation study. Primary endpoint combined tolerance and efficacy (asparagine depletion ≥7 days). Three doses of L-Asparaginase-Loaded Red Blood Cells (50, 100 and 150 IU/kg), infused twice during induction cycles, were investigated. EWALL backbone consisted of dexamethasone prephase followed by induction-1 (dexamethasone d1–2/8–11, vincristine d1,8, and idarubicine d1–2/8–9) and induction-2 (cyclophosphamide d15–17 and cytarabine d16–19/23–26). Consolidation consisted of 6 monthly alternating cycles with methotrexate (d1) / E.coli asparaginase (d2) and high-dose cytarabine (d1, 3, 5). Maintenance included mercaptopurine, methotrexate and vincristine/dexamethasone pulses for 2 years. Hematological and molecular Ig/TCR minimal residual disease (MRD) response rates, survival were secondary endpoints. Results: Between March 2009 and October 2010, 30 patients were recruited in 20 centres in France by the GRAALL network. The 50, 100 and 150 dose levels included 3, 13 and 14 patients, respectively. Median age was 67 years (range 59–77). No differences in baseline characteristics were observed across the 3 dose level groups. The tolerability with L-Asparaginase-related side effects is reported below: Overall L-asp expected adverse events tended to be lower in the 100 UI/kg group. Regarding the efficacy and benefit/risk, asparagines depletion, remission rate, EFS and OS are reported below: Three patients received the dose of 50 UI/kg but this dose was insufficient to reach a 7-day asparagine depletion. Survival analysis showed that the dose of 100IU/kg was associated with median OS of 15.6 months an absolute value that compared favorably with historical controls: 8,8 mo (Rousselot et al. Drugs Aging,2011) and 10,5 mo (Hunault et al. Haematologica,2011) Conclusion: GRASPA® at a dose of 100 UI/kg appears to be a safe and active manner to introduce L-asparaginase during initial induction chemotherapy of older patients with Ph- ALL with a sustained asparagine depletion and a good efficacy/safety profile. Disclosures: Godfrin: ERYTECH Pharma: COO Other.

The Prognostic Value of Minimal Residual Disease (MRD) after Salvage Therapy in Patients (Pts) with Relapsed or Refractory (R/R) B-Cell Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3771-3771
Author(s):  
Musa Yilmaz ◽  
Hagop M. Kantarjian ◽  
Farhad Ravandi ◽  
Jeffrey L. Jorgensen ◽  
Sa Wang ◽  
...  
Keyword(s):  
B Cell ◽  
Salvage Therapy ◽  
Research Funding ◽  
Clinical Characteristics ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Inotuzumab Ozogamicin ◽  
Color Flow ◽  
Platelet Recovery

Abstract Introduction: MRD positivity after induction/consolidation therapy in pts with de novo ALL has been shown to carry a very negative impact on outcome. However, the significance of MRD status in the salvage setting has not been extensively studied. Methods: We evaluated 130 pts with R/R B-cell ALL pts who received first (n=68), or second (n=62), salvage therapy between 2010 and 2015. Salvage therapies included single agent inotuzumab ozogamicin (INO; n=75), blinatumomab (n=20), or INO in combination with mini-hyper-CVD (n=35) [Jabbour E et al; EHA 2015]. Of the 130 pts treated, 78 (60%) responded and were assessed for MRD by six-color flow cytometry on marrow samples with a sensitivity of 0.01%. Morphologic responses were defined as follows, complete response (CR); disappearance of all disease with neutrophils ≥ 1.0 X 109/L, platelet > 100 X 109/L and blasts ≤ 5%, CRp; CR without platelet recovery, CRi; CR without platelet and/or neutrophil recovery. Results: The clinical characteristics of the 78 responding pts with R/R ALL are summarized in Table 1. Overall, MRD negativity was achieved at response in 41 pts (53%). Among the 41 pts who responded to single agent INO (12 CR, 26 CRp, 3CRi), 17 (41%) achieved a negative MRD status. Among the 11 pts who responded to blinatumomab (9 CR, 2Cri), 8 (73%) achieved a negative MRD status. Among the 26 pts who responded to INO in combination with mini-HCVD (21 CR, 4 CRp, 1CRi), 16 (62%) achieved a negative MRD status. Forty-four pts received allogeneic stem cell transplantation (ASCT): of those, 21 pts were MRD negative and 23 pts were MRD positive at the time of response. Median follow-up was 19 months (2-55). Overall, there was a trend for more durable morphologic responses in MRD negative pts compared with MRD positive pts: the median complete remission durations (CRD) were 17 months and 8 months, with a 2-year CRD rate of 47% and 28% respectively (Table 2). The median event-free survival (EFS) was 12 and 6 months, respectively; the 2-year EFS rates were 32% and 8%, respectively. Similarly, there was a trend for better overall survival (OS) with a median of 17 months and 9 months for pts with negative and positive MRD, respectively; the 2-year OS rates were 36% and 27%, respectively. No difference in outcome was reported whether pts were censored or not at the time of ASCT. Conclusion: In pts with R/R ALL, the achievement of negative MRD in addition to the morphologic response confers an improvement, although not statistically significant, in response duration and survival. Larger number of pts with longer follow-up is needed to validate these findings.Table 1.Clinical Characteristics of Pts (n=78)N (%)/Median [range]Age (years)38 [18-87]Sex (Male)50 (64)Performance Status1 [1-3]WBC (x 109/L)3 [0.3-38]% PB Blasts0 [0-83]% BM Blasts60 [8-97]CytogeneticsDiploid20 (26)t(9;22)4 (5)t(4;11)7 (9)Miscellaneous39 (50)Not done/ Insufficient metaphases8 (10)SalvageInotuzumab Ozogamicin41 (53)Blinatumomab11 (14)Inotuzumab Ozogamicin + mini-HCVD26 (33)Number of prior therapies1 prior therapy46 (59)2 prior therapies32 (41) Table 2. Response Rates and Survival by MRD Status MRD Negative (n=41) MRD Positive (n=37) p CR 24 18 n/a CRp 16 14 n/a CRi 1 5 n/a CRD, median (m) 17 8 0.63 2-year CRD rate (%) 47 28 EFS, median (m) 12 6 0.06 2-year EFS rate (%) 32 8 OS, median (m) 17 9 0.18 2-year OS rate (%) 36 27 Disclosures Cortes: Teva: Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BerGenBio AS: Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy. DiNardo:Novartis: Research Funding.

Is Less Chemotherapy Detrimental in Adults with Philadelphia Chromosome (Ph)-Positive Acute Lymphoblastic Leukemia (ALL) Treated with High-Dose Imatinib? Results of the Prospective Randomized Graaph-2005 Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 138-138 ◽  
Author(s):  
Yves Chalandon ◽  
Xavier Thomas ◽  
Sandrine Hayette ◽  
Jean-Michel Cayuela ◽  
Claire Abbal ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Surrogate Endpoint ◽  
Primary Objective ◽  
High Dose ◽  
No Donor ◽  
Related Mortality

Abstract Abstract 138 Aim: To compare a less intensive regimen based on high-dose imatinib (IM) to an intensive IM/HyperCVAD regimen in adults with Ph+ ALL, in terms of early response and outcome after stem cell transplantation (SCT). Methods: Patients aged 18–60 years with previously untreated Ph+ ALL not evolving from chronic myeloid leukemia were eligible if no contra-indication to chemotherapy and SCT (ClinicalTrials.gov ID, NCT00327678). After a steroid prephase allowing Ph and/or BCR-ABL diagnosis, cycle 1 differed between randomization arms. In arm A (IM-based), IM was given at 800 mg on day 1–28, combined with vincristine (2 mg, day 1, 8, 15, 22) and dexamethasone (40 mg, day 1–2, 8–9, 15–16, and 22–23) only. In arm B (IM/HyperCVAD), IM was given at 800 mg on day 1–14, combined with adriamycin (50 mg/m2, day 4), cyclophosphamide (300 mg/m2/12h, day 1, 2, 3), vincristine (2 mg, day 4 and 11), and dexamethasone (40 mg, day 1–4 and 11–14). All patients received a cycle 2 combining high-dose methotrexate (1 g/m2, day 1) and AraC (3 g/m2/12h, day 2 and 3) with IM at 800 mg on day 1–14, whatever their response. Four intrathecal infusions were given during this induction/consolidation period. Minimal residual disease (MRD) was centrally evaluated by quantitative RQ-PCR after cycle 1 (MRD1) and cycle 2 (MRD2). Major MRD response was defined as BCR-ABL/ABL ratio <0.1%. Then, all patients were to receive allogeneic SCT using related or unrelated matched donor stem cells or autologous SCT if no donor and a major MRD2 response. IM/chemotherapy maintenance was planned after autologous SCT. In the absence of SCT, patients received alternating cycles 1 (as in arm B) and cycles 2 followed by maintenance, like in the published IM/HyperCVAD regimen. The primary objective was non-inferiority of arm A in term of major MRD2 response. Secondary objectives were CR rate, SCT rate, treatment- and transplant-related mortality, relapse-free (RFS), event-free (EFS) and overall (OS) survival. Results: Among the 270 patients randomized between May 2006 and August 2011, 265 patients were evaluable for this analysis (133 arm A, 132 arm B; median age, 47 years; median follow-up, 40 months). Main patient characteristics were well-balanced between both arms. Due to higher induction mortality in arm B (9 versus 1 deaths; P=0.01), CR rate was higher in the less intensive arm A (98% versus 89% after cycle 1 and 98% versus 91% after cycle 2; P= 0.003 and 0.006, respectively). A total of 213 and 205 patients were evaluated for bone marrow MRD1 and MRD2. The rates of patients reaching major MRD response and undetectable MRD were 45% (44% arm A, 46% arm B; P=0.79) and 10% (in both arms) at MRD1 and 66% (68% arm A, 63.5% arm B; P=0.56) and 25% (28% arm A, 22% arm B; P=0.33) at MRD2, respectively. The non-inferiority primary endpoint was thus demonstrated (P= 0.002). Overall, EFS was estimated at 42% (95% CI, 35–49) and OS at 51% (95% CI, 44–57) at 3 years, with no difference between arm A and B (46% versus 38% and 53% versus 49%; P=0.25 and 0.61, respectively). Of the 251 CR patients, 157 (80 arm A, 77 arm B) and 34 (17 in both arms) received allogeneic and autologous SCT in first CR, respectively. Allogeneic transplant-related mortality was similar in both arms (31.5% versus 22% at 3 years; P=0.51). Of the 157 allografted patients, 133 had MRD2 evaluation and 89 had MRD2 <0.1%. In these patients, MRD2 did not significantly influence post-transplant RFS and OS, either when tested with the 0.1% cutoff or as a continuous log covariate. Of the 34 autografted patients, 31 had MRD2 evaluation and, according to the protocol, 28 had MRD2 <0.1%. When restricting the comparison to patients achieving major MRD2 response and with the current follow-up, a trend for better results was observed after autologous as compared to allogeneic SCT (RFS, 63% versus 49.5% and OS, 69% versus 58% at 3 years; P=0.35 and P=0.08, respectively). Conclusions: In adults, the use of TK inhibitors (TKI) has markedly improved the results of Ph+ ALL therapy, now close to those observed in Ph-negative ALL. We demonstrated here that chemotherapy intensity may be safely reduced when associated with high-dose IM. We will further explore this TKI-based strategy using nilotinib prior to SCT in our next GRAAPH-2013 trial. The trend towards a better outcome after autologous compared to allogeneic SCT observed in MRD responders validates MRD as an important early surrogate endpoint for treatment stratification and new drug investigation in this disease. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Blinatumomab Administered Concurrently with Oral Tyrosine Kinase Inhibitor Therapy Is a Well-Tolerated Consolidation Strategy and Eradicates Measurable Residual Disease in Adults with Philadelphia Chromosome Positive Acute Lymphoblastic Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 1414-1414 ◽  
Author(s):  
Amber C. King ◽  
Jeremy Pappacena ◽  
Martin S. Tallman ◽  
Jae H. Park ◽  
Mark Blaine Geyer
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Tyrosine Kinase ◽  
Research Funding ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Single Agent ◽  
Philadelphia Chromosome ◽  
Advisory Board ◽  
Molecular Response ◽  
Philadelphia Chromosome Positive

Abstract Introduction: Incorporation of ABL-targeted oral tyrosine kinase inhibitors (TKIs) to conventional chemotherapy regimens has improved outcomes for adult patients (pts) with (w/) Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL). However, the addition of chemotherapy to TKIs may increase rates of infectious complications, organ toxicity, hospitalization, and mortality. As a result, we and others have investigated novel chemotherapy-sparing approaches for pts w/ Ph+ ALL. The CD3/CD19-targeted bispecific T-cell engager blinatumomab (BLIN) has demonstrated single-agent activity in pts w/ B-ALL w/ minimal residual disease (MRD) or relapsed/refractory (R/R) ALL, including R/R Ph+ ALL (Martinelli et al., J Clin Oncol, 2017). In an effort to deepen responses, we have used BLIN concomitantly w/ commercially available TKIs as consolidation and re-induction therapy. Reported experience w/ BLIN+TKI is limited. Herein we describe the observed safety and efficacy of BLIN+TKI in pts w/ Ph+ ALL w/ varying disease burden at our institution. Methods: We reviewed electronic medical records of pts ≥ 18 years (yrs) old w/ previously treated Ph+ ALL receiving BLIN w/ concomitant, FDA-approved TKIs at Memorial Sloan Kettering Cancer Center (MSKCC) who began BLIN+TKI between March 2017 and April 2018. The primary objectives were to characterize the safety/toxicity profile and rates of MRD negativity by flow cytometry (FACS) and/or quantitative real-time PCR for BCR-ABL1 transcripts following consolidation (n=9) or re-induction (n=2) w/ BLIN+TKI. Results: Eleven pts (6F, 5M) were identified (Table 1). Median age at start of BLIN+TKI was 61.2 yrs (range, 27.7-76.9). Three pts had undergone prior allogeneic hematopoietic cell transplantation (alloHCT). No pt had baseline hepatic dysfunction, central nervous system (CNS) or extramedullary (EM) disease prior to BLIN+TKI. All pts had documented CD19 expression on blasts prior to treatment. Ponatinib (PON) was the most commonly used TKI (n=7) followed by dasatinib (DAS, n=3), and nilotinib (NIL, n=1); one pt taking BLIN+PON briefly received BLIN+DAS during cycle 1. All pts were admitted for initiation of BLIN+TKI. BLIN was started at 9 mcg/day IVCI w/ escalation to 28 mcg/day IVCI on day 8 (per recommended dosing for pts w/ R/R ALL) in 10 pts and at 28 mcg/day IVCI in one pt (per flat dosing schedule described by Gökbuget et al., Blood, 2018). All 7 pts w/ MRD by FACS (n=5) and/or BCR-ABL1 PCR (n=7) prior to BLIN+TKI exhibited MRD negativity by FACS following 1 cycle of BLIN+TKI; 6 of these 7 pts achieved complete molecular response (CMR) by PCR following 1 cycle (n=5) or 2 cycles (n=1) of BLIN+TKI. All 6 remain in ongoing CMR at 1.8-15.1 months after initial achievement of CMR. Neither of the 2 pts w/ morphologic disease responded to BLIN+TKI and ultimately succumbed to their disease. The 2 pts who began BLIN+TKI in CMR have both maintained continuous CMR. Three pts have proceeded to 1st (n=2) or 2nd (n=1) alloHCT post-BLIN+TKI, without documented, relevant toxicities attributable to prior blinatumomab exposure. Median event-free and overall survival were not reached in this small group of pts, w/ median follow-up of 7.7 months among survivors (range, 3.2-16.0 months). Three pts developed grade 1 cytokine release syndrome (CRS). Notably, 2 of these pts had morphologic ALL at time of BLIN+TKI; none of these events warranted interruption of therapy or corticosteroids. No pts developed neurologic toxicity. Five pts exhibited transient transaminitis during BLIN+TKI; none reached recommended parameters to discontinue BLIN. Of these 5 pts, 4 were on concurrent PON. One pt required dose attenuation of PON; hepatic enzymes otherwise normalized w/o intervention. Conclusions: Our small series suggests that BLIN+TKI may be a safe and effective consolidation strategy for pts w/ MRD+ Ph+ ALL to achieve or sustain CMR, creating a platform for alloHCT or other post-remission therapy. Observed rates of CRS were higher and neurologic toxicity appeared lower (none documented) than in other studies of BLIN in pts w/ MRD (Gökbuget et al., Blood, 2018). Higher risk of transaminitis was noted in pts receiving BLIN+PON and warrants further observation, particularly as 28 mcg/day IVCI flat dosing is increasingly used for pts w/ MRD. Earlier incorporation of BLIN+TKI into treatment paradigms for Ph+ ALL may limit toxicity while deepening response and maintaining CMR. Disclosures King: Genentech: Other: Advisory Board . Tallman:Daiichi-Sankyo: Other: Advisory board; Orsenix: Other: Advisory board; Cellerant: Research Funding; ADC Therapeutics: Research Funding; AbbVie: Research Funding; AROG: Research Funding; BioSight: Other: Advisory board. Park:Pfizer: Consultancy; Juno Therapeutics: Consultancy, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Consultancy; Novartis: Consultancy; Kite Pharma: Consultancy; Adaptive Biotechnologies: Consultancy; Shire: Consultancy. Geyer:Dava Oncology: Honoraria.

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