Phase II Study Of Combination Of Hyper-CVAD With Ponatinib In Front Line Therapy Of Patients (pts) With Philadelphia Chromosome (Ph) Positive Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2663-2663
Author(s):  
Elias Jabbour ◽  
Hagop Kantarjian ◽  
Deborah A. Thomas ◽  
Farhad Ravandi ◽  
Jorge E. Cortes ◽  
...  
Keyword(s):  
Phase Ii ◽  
Cytogenetic Analysis ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
Cytogenetic Response ◽  
Banding Technique ◽  
High Dose ◽  
Cell Transplant ◽  
Platelet Recovery ◽  
Cd20 Expression

Abstract Background Combination of cytotoxic chemotherapy with imatinib or dasatinib 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. Clinical trials of ponatinib have demonstrated its high activity and limited toxicity in Ph+ leukemias. The complete cytogenetic response (CCyR) rate is 40% to 50% in patients failing 2-3 TKIs and in those with a T315I mutation. 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 imatinib or dasatinib. Methods In this phase II trial, 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. Rituximab was administered during the first 4 cycles in pts with CD20 expression ≥20%. 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 28 pts with untreated Ph+ ALL and 2 pts previously treated (1 with prior cycle of chemotherapy before Ph+/BCR-ABL status was known not in CR, and 1 post HCVAD-dasatinib in CR) have received a median of 6 cycles (1-8) of therapy; 10 pts are receiving maintenance in CR. Median age was 55 years (28–75). Median WBC at diagnosis was 3.55 x 109/L (1.6 -629 x 109/L). CD20 expression was reported positive in 11 pts (37%). 2 (7%) had concomitant CNS disease at diagnosis. All pts were in CR after cycle 1. 24 of the 26 pts (92%) with Ph+ metaphases (at least 20 metaphases analyzed) by cytogenetic analysis at baseline achieved a CCyR after 1 cycle; 1 had a minor cytogenetic response only and one had no cytogenetic analysis at CR, both of them achieved a CCyR after cycle 2; 4 had a diploid karyotype at the start of therapy (one in CCyR post previous chemotherapy and 3 diploid by standard G-banding technique and positive by FISH and PCR). To date, 26 pts (93%) have achieved a MMR, of whom 19 (70%) have achieved a CMR at a median of 10 weeks from initiation of treatment (2 -28). MRD assessment by flow cytometry is negative in 26 (90%) pts at a median of 3 weeks (3-14). 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 increase of LFT’s in 11 pts (37%), thrombotic events in 3 (10%, 1 renal vein thrombosis and 2 pulmonary emboli), myocardial infarction (MI) in 3 (10%, 1 unexplained, 1 with history of cardiomyopathy, and 1 in the context of sepsis ), skin rash in 3 (15%), and pancreatitis in 2 (7%). 11 pts (37%) had their dose reduced to 30 mg and 2 pts (10%) switched to dasatinib (n=1) or imatinib (n=1). With a median follow up of 7 months (1-20), 21 pts are alive and in CR; 1 pt died in CR from an unrelated cardiac event after being taken off therapy and placed on imatinib, 1 pt died from multiple organ failure post sepsis (C2D13), and 1 from non ST elevation MI (NSTEMI) post cycle 2 (C2D41). 6 pts have undergone an allogeneic stem cell transplant. The 1-year progression-free and overall survival rates were 100% and 88% respectively. Conclusion The combination of hyperCVAD with ponatinib is safe and highly effective in achieving molecular remissions in pts with Ph+ ALL. Disclosures: Jabbour: Ariad: Consultancy; Novartis: Consultancy; BMS: Consultancy; Pfizer: Consultancy. Ravandi:Sunesis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Research Funding; Teva: Consultancy, Honoraria; Pfizer: Honoraria; Merck: Research Funding; Bayer/Onyx: Consultancy, Honoraria; EMD Serono: Research Funding; Medimmune: Research Funding; Amgen: Consultancy, Honoraria; Seattle Genetics: Consultancy, Honoraria. Cortes:Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Consultancy, Research Funding; Novartis: Research Funding; BMS: Research Funding. Faderl:Sanofi-Aventis: Membership on an entity’s Board of Directors or advisory committees, Research Funding.

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.

Phase II Study of Combination of the Hypercvad Regimen with Dasatinib in the Front Line Therapy of Patients with Philadelphia Chromosome (Ph) Positive Acute Lymphoblastic Leukemia (ALL).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 837-837 ◽  
Author(s):  
Farhad Ravandi ◽  
Hagop M. Kantarjian ◽  
Deborah A. Thomas ◽  
Stefan Faderl ◽  
Dan Jones ◽  
...  
Keyword(s):  
Stem Cell ◽  
Phase Ii ◽  
Research Funding ◽  
Stem Cell Transplant ◽  
High Dose ◽  
Cell Transplant ◽  
Newly Diagnosed ◽  
Allogeneic Stem Cell Transplant ◽  
Median Response ◽  
Platelet Recovery

Abstract Abstract 837 Background: Combination therapy with cytotoxic chemotherapy and tyrosine kinase inhibitors has improved the outcome for patients with Ph+ ALL with durable remissions in some patients even without an allogeneic stem cell transplant. The dual Src and Abl inhibitor dasatinib has ∼325 times more potent in vitro kinase inhibition than imatinib against BCR-ABL with significant clinical activity in patients with imatinib-resistant lymphoid blast phase CML (CML-LB) and Ph+ ALL. Aim: To determine the efficacy and safety of combining chemotherapy with dasatinib for treating patients with Ph+ ALL. Methods: In this phase II trial, patients with newly diagnosed Ph+ ALL receive dasatinib 50 mg po bid (or 100 mg daily) for the first 14 days of each of 8 cycles of alternating hyperCVAD and high dose cytarabine and methotrexate. Patients in CR continue to receive maintenance dasatinib 50 mg po bid (or 100 mg daily) and vincristine and prednisone monthly for 2 years followed by dasatinib indefinitely. Results: We have enrolled in the study 34 patients with untreated Ph+ ALL and 7 patients with 1 prior cycle of chemotherapy (before Ph+/BCR-ABL+ status was known). Patients younger than 50 years old have received a median of 6 cycles (range 2-8) and patients 50 years and older have received a median of 6 cycles (range 1-8). 20 patients are receiving maintenance in CR and two have completed the entire treatment regimen. Median age is 51 years (range 21 – 79); 22 patients were older than 50 years, Median WBC at diagnosis was 13.6 × 109/L (range, 1-276 × 109/L). 12 patients had CNS involvement at presentation. All patients are evaluable for assessment of response to induction; 39 (95%) achieved CR after first cycle or were CR at start. Two patients died before response assessment from infections. Thirty-one of 39 (79%) evaluable patients achieved cytogenetic (CG) CR after 1 cycle; 4 had a major CG response (3 had 5% and one had 15% Ph+), 2 had insufficient metaphases, and 2 are unknown (no CG exam on day 21 marrow). To date, 22 patients (56%) have achieved complete molecular remission (CMR) and another 8 (21%) have achieved a major (but not complete) molecular response (MMR) at a median of 14 weeks from initiation of treatment (range 2 – 59 weeks). Minimal residual disease assessment by flow cytometry is negative in 35 (90%) patients at a median of 3 weeks (range, 2-18 weeks). The median time to neutrophil and platelet recovery for cycle 1 is 18 and 23 days and for subsequent cycles is 15 and 20 days. Grade 3 and 4 adverse events have included bleeding (GI, GU, soft tissue and subdural hematomas)(18), pleural effusions (9), pericardial effusion (1), reversible rise in creatinine (10), deep vein thromboses (6), pulmonary emboli (3), as well as diarrhea, infections, hypophosphatemia, hypokalemia, hypocalcemia, hyperglycemia, and elevated transaminases. With a median follow up of 13 months (range 1-33), 29 patients (71%) are alive and 27 (66%) are in CR; 4 patients died in CR; 1 from an unrelated cardiac event and 3 from infections. Three patients have undergone an allogeneic stem cell transplant. The median disease free survival is 48+ weeks (range,1 to 140+) and the median overall survival is 52+ weeks (range, 3 to 143+). Eight patients have relapsed with a median response duration of 51 weeks (range 23-73) and 6 of them have died. In 5 patients morphological relapse was preceded by flow and molecular relapse. Five relapsed patients had ABL mutations (3 T315I, 1 F359V, and 1 V299L). Conclusion: Combination of chemotherapy with dasatinib is effective in achieving long term remissions in patients with newly diagnosed Ph+ ALL. Disclosures: Ravandi: Bristol Myers Squibb: Honoraria, Research Funding. Kantarjian:Bristol Myers Squibb: Research Funding. Wierda:Genzyme: Research Funding; Genentech: Consultancy, Honoraria. Cortes:Bristol Myers Squibb: Research Funding. O'Brien:Bristol Myers Squibb: Research Funding.

Phase II Study of Combination of hyperCVAD with Dasatinib in Frontline Therapy of Patients with Philadelphia Chromosome (Ph) Positive Acute Lymphoblastic Leukemia (ALL)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2921-2921 ◽  
Author(s):  
Farhad Ravandi ◽  
Deborah Thomas ◽  
Hagop Kantarjian ◽  
Stefan Faderl ◽  
Charles Koller ◽  
...  
Keyword(s):  
Stem Cell ◽  
Phase Ii ◽  
Stem Cell Transplant ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
High Dose ◽  
Molecular Response ◽  
Cell Transplant ◽  
Allogeneic Stem Cell Transplant ◽  
Platelet Recovery

Abstract Background: Combination of cytotoxic chemotherapy with imatinib has improved the outcome for patients with Ph+ ALL with durable remissions in some patients without an allogeneic stem cell transplant. The dual Src and Abl inhibitor dasatinib has significant clinical activity in patients with imatinib-resistant lymphoid blast phase CML and Ph+ ALL. Methods: In this phase II trial, patients with newly diagnosed Ph+ ALL receive dasatinib 50 mg po bid (or 100 mg daily) for the first 14 days of each of 8 cycles of alternating hyperCVAD and high dose cytarabine plus methotrexate. Patients (pts) in CR continue to receive maintenance dasatinib 50 mg po bid (or 100 mg daily) and vincristine and prednisone monthly for 2 years followed by dasatinib indefinitely. Minimal residual disease (MRD) monitoring is conducted and patients may receive early and late intensifications depending on their MRD status. Results: To date 22 pts with untreated Ph+ ALL and 6 pts with 1 prior cycle of chemotherapy (before Ph+/BCR-ABL+ status was known) have received a median of 6 cycles (range 1–8); 9 pts are receiving maintenance in CR. Median age is 52 years (range 21 – 79); 16 pts were older than 50 years. Median WBC at diagnosis was 20.5 ×109/L (range, 1.6 –275 × 109/L). 5 pts had CNS involvement at presentation. All pts are evaluable for assessment of response; 26 (93%) achieved CR after 1 cycle. Two pts died before response assessment from infections; in both pts, bone morrow exam on day 14 showed no detectable disease. Twenty one of 26 (81%) evaluable pts achieved cytogenetic (CG) CR after 1 cycle; 2 had a major CG response (5% and 15% Ph+), 2 had insufficient metaphases, and one is unknown (no CG exam on day 21 marrow); 1 pt developed a pseudodiploid clone. To date, 14 pts (50%) have achieved complete molecular remission (CMR) and 5 (18%) have achieved a major molecular response (MMR) at a median of 10 weeks from initiation of treatment (range 2 – 46 weeks). MRD assessment by flow cytometry is negative in 22 (85%) pts at a median of 3 weeks (range, 2–17 weeks). The median time to neutrophil and platelet recovery for cycle 1 is 18 and 23 days and for subsequent cycles is 15 and 20 days, respectively. Grade ≥3 toxicity has included 13 episodes of bleeding (8 GI, 2 GU, 1 soft tissue hematoma and 2 subdural hematomas), 3 episodes of pleural effusions, infections, diarrhea, hypophosphatemia, hypocalcemia, elevated transaminases, and reversible rise in creatinine unrelated to treatment. With a median follow up of 10 months (range, 2–21), 21 pts are alive and 18 are in CR; 2 died at induction, 3 pts died in CR; 1 from an unrelated cardiac event and 2 from infections. 5 pts have relapsed (response durations were 54, 48, 47, 32, and 22 weeks) and 2 of them have died. In 2 pts morphological relapse was preceded by flow and molecular relapse. Four relapsed pts developed new ABL mutations (3 T315I and 1 F359V). One patient has undergone an allogeneic stem cell transplant. Conclusions: The combination of hyperCVAD with dasatinib is effective in achieving molecular remissions in patients with Ph+ ALL. There is a high incidence of T315I ABL mutation among the relapsed patients.

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.

Phase II study of combination of hyperCVAD with ponatinib in frontline therapy of patients (pts) with Philadelphia chromosome (Ph) positive acute lymphoblastic leukemia (ALL).

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 7024-7024 ◽  
Author(s):  
Elias Jabbour ◽  
Hagop M. Kantarjian ◽  
Deborah A. Thomas ◽  
Farhad Ravandi ◽  
Jorge E. Cortes ◽  
...  
Keyword(s):  
Phase Ii ◽  
Cytogenetic Analysis ◽  
Potent Inhibitor ◽  
Lymphoblastic Leukemia ◽  
Philadelphia Chromosome ◽  
Platelet Recovery ◽  
T315i Mutation ◽  
Grade 3 ◽  
Clinical Trial Information

7024 Background: Combination of chemotherapy with TKIs was evaluated and appears to be effective in Ph+-ALL. Ponatinib is a more potent inhibitor and suppresses the T315I clones, a common cause of relapse in pts with Ph+- ALL. Clinical trials of ponatinib have demonstrated its high activity and limited toxicity in pts with Ph+-leukemia failing 2-3 TKIs and in those with a T315I mutation. Combinations of chemotherapy regimens and ponatinib may be associated with better response rates and higher likelihood of eradication of MRD. Methods: In this phase II trial, pts with newly diagnosed Ph+ ALL receive ponatinib 45 mg po QD for the first 14 days of cycle 1 then continuously for the subsequent 7 cycles. Pts in CR receive maintenance with ponatinib 45 mg po QD and vincristine and prednisone monthly for 2 years followed by ponatinib indefinitely. MRD monitoring is conducted. Results: To date 20 pts with untreated Ph+ ALL have received a median of 6 cycles; 5 pts are receiving maintenance in CR. Median age is 49 years. Median WBC at diagnosis was 2.45 x 109/L. All pts were in CR after 1 cycle. 15 of the 17 pts (88%) known to be Ph+ by cytogenetic analysis at baseline achieved CCyR after 1 cycle; 1 had mCyR only and 1 had no cytogenetic analysis at CR, both of them achieved CCyR after cycles 2; 3 had a diploid karyotype at the start. To date, 17 pts (85%) have achieved MMR, of whom 11 (55%) have achieved CMR at a median of 10 weeks from initiation of treatment. MRD assessment by flow cytometry is negative in 18 (90%) pts at a median of 3 weeks. Median time to neutrophil and platelet recovery for cycle 1 was 18 and 22 days, and 16 and 22 days for subsequent cycles, respectively. Grade ≥3 toxicity included increase of LFT’s/hyperbilirubinemia in 8 pts, thrombosis in 3, skin rash in 2, pancreatitis in 1, and pericardial effusion in 1. With a median follow up of 6 months, 19 pts are alive and in CR; 1 pt died in CR from an unrelated cardiac event. 1 pt has undergone an allogeneic transplant. The 1-year PFS and OS rates were 100% and 95%, respectively. Conclusions: The combination of hyperCVAD with ponatinib is safe and highly effective in achieving molecular remissions in pts with Ph+ ALL. Clinical trial information: NCT01424982.

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.

scholarly journals Induction with Bortezomib and Dexamethasone (BD) Followed By Risk Adapted High Dose Melphalan and Autologous Stem Cell Transplantation and BD Consolidation in Patients with AL Amyloidosis: A Phase II Feasibility Study

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3178-3178 ◽  
Author(s):  
Heather Landau ◽  
Nicole Montanez ◽  
Alexandra Cowan ◽  
Hoover Elizabeth ◽  
Carlos Flombaum ◽  
...  
Keyword(s):  
Stem Cell ◽  
Phase Ii ◽  
Research Funding ◽  
Treatment Initiation ◽  
High Dose ◽  
Al Amyloidosis ◽  
Cell Transplant ◽  
Weekly Schedule ◽  
Newly Diagnosed ◽  
Critical Determinant

Abstract Background: The depth and durability of hematologic response is a critical determinant of outcome in patients (pts) with light chain (AL) amyloidosis. Complete hematologic remissions (CR) following risk-adapted melphalan and stem cell transplant (RA-SCT) in pts with AL amyloidosis is associated with organ improvement and extended overall survival (OS). We have previously shown that using bortezomib and dexamethasone (BD) as consolidation following RA-SCT is associated with deeper hematologic responses and favorable outcomes. We have conducted a prospective phase II trial using BD as induction followed by RA-SCT and BD consolidation to determine the safety and hematologic and organ response rates of this treatment program for newly diagnosed, transplant-eligible pts with AL amyloidosis. Methods: Untreated pts with AL amyloidosis received 1-3 cycles of BD (B 1.3mg/m2, IV/SC, and D 40mg, IV/PO, days 1, 4, 8, 11). BD was discontinued before 3 cycles in patients who achieved CR. Pts were then assigned melphalan 100, 140 or 200mg/m2 based on age, renal function and cardiac involvement; Starting 3 months following RA-SCT, pts received six cycles of BD (B 1.3mg/m2, IV/SC and D 20mg, IV/PO days 1, 8, 15, 22) every 12 weeks as consolidation. Hematologic responses were assessed using International Society of Amyloidosis criteria (Palladini et al. JCO 2012) and organ responses using updated criteria (Palladini et al. Blood 2014), after induction, 3 months post RA-SCT, and at 12 and 24 months from treatment initiation. Patients with New York Heart Association Class III/IV heart failure, ECOG > 2 or > grade 2 neuropathy were ineligible. Results: Twenty pts, 70% male, with a median age of 60.1 years with renal (55%), cardiac (65%), liver/GI (15%) or nervous system (15%) involvement received BD induction and 18 patients have been transplanted. Two pts with cardiac disease died during BD induction (10% TRM); 85% of pts are alive with a median follow up of 28 mo. By intent to treat, 60% and 70% of patients achieved at least a very good partial response (>VGPR) following BD induction and RA-SCT, respectively. Overall, 95% of patients achieved hematologic responses (>PR) including 35% CR. Cardiac and renal responses were seen in 75% (N=8) and 60% (N=10) of evaluable pts at 1 year following treatment initiation. Most common grade >3 adverse events included GI (40%), Renal (30%), infectious (10%), and cardiovascular (10%); Grade 2 or higher neuropathy was seen in 40% of pts and warranted discontinuation of BD consolidation in 35% of pts. Conclusion: In newly diagnosed AL amyloidosis pts, BD induction followed by RA-SCT was safe and rapidly and effectively induced responses resulting in organ improvement. There was 10% TRM during BD induction and no deaths during transplant supporting the notion that early mortality in newly diagnosed AL pts is independent of treatment received. The high incidence of neuropathy may be related to the administration of BD on a twice weekly schedule and rendered some pts ineligible for post-transplant therapy. Whether transplant-eligible pts will ultimately derive more benefit from proteasome inhibitor induction versus consolidation is worthy of further study. Disclosures Landau: Spectrum Pharmaceuticals: Honoraria; Janssen: Consultancy; Janssen: Consultancy; Prothena: Consultancy, Honoraria; Takeda: Research Funding; Onyx: Honoraria, Research Funding. Landgren:Celgene: Honoraria; International Myeloma Foundation: Research Funding; BMJ Publishing: Consultancy; Onyx: Research Funding; Onyx: Consultancy; BMJ Publishing: Honoraria; Celgene: Consultancy; Bristol-Myers Squibb: Consultancy; Medscape: Consultancy; Medscape: Honoraria; Bristol-Myers Squibb: Honoraria; Onyx: Honoraria. Giralt:TAKEDA: Consultancy, Honoraria, Research Funding; JAZZ: Consultancy, Honoraria, Research Funding, Speakers Bureau; AMGEN: Consultancy, Research Funding; SANOFI: Consultancy, Honoraria, Research Funding; CELGENE: Consultancy, Honoraria, Research Funding. Hassoun:Novartis: Consultancy; Takeda: Research Funding; Celgene: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees.

scholarly journals The Omission of High-Dose Cytarabine during Consolidation Therapy of Ph-Positive ALL Patients Treated with Nilotinib and Low-Intensity Chemotherapy Results in an Increased Risk of Relapses Despite Non-Inferior Levels of Late BCR-ABL1 MRD Response. First Results of the Randomized Graaph-2014 Study

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 512-512
Author(s):  
Philippe Rousselot ◽  
Yves Chalandon ◽  
Sylvie Chevret ◽  
Jean-Michel Cayuela ◽  
Francoise Huguet ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Board Of Directors ◽  
Primary Endpoint ◽  
Research Funding ◽  
Lymphoblastic Leukemia ◽  
High Dose ◽  
Cell Transplant ◽  
Advisory Committees ◽  
High Dose Cytarabine ◽  
To Receive

Abstract On behalf of the GRAALL group. Introduction. Tyrosine kinase inhibitors (TKIs) have dramatically improved the outcome of patients diagnosed with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). In a previous randomized trial (GRAAPH-2005; Chalandon Y., Blood 2015), our group demonstrated that anthracycline and cyclophosphamide could be safely omitted during the first Hyper-CVAD chemotherapy cycle when combined to imatinib. In the present GRAAPH-2014 trial, we investigated whether the use of nilotinib, a 2 nd generation TKI, would allow further decreasing chemotherapy intensity through the omission of high-dose cytarabine (HD-AraC) during consolidation cycles 2 and 4. Methods. From March 2016, patients aged 18-60 years old were randomized frontline to receive 4 cycles (1=3, 2=4) of chemotherapy combined with continuous nilotinib 400 mg bid. Cycle 1 and 3 were similar in both arms, identical to the less-intensive first cycle of the previous GRAAPH-2005 trial with weekly vincristine and dexamethasone and nilotinib instead of imatinib. Cycle 2 and 4 differed between control arm A (MTX 1 g/sqm over 24h, HD-AraC 3 g/sqm/12h for 2 days) and experimental arm B (MTX 1 g/sqm over 24h only). Marrow minimal residual disease (MRD) was assessed by both BCR-ABL1 and IG-TCR qPCR after each cycle (MRD1-4). Patients in complete remission (CR) after cycle 4 were eligible to receive allogeneic stem cell transplant (alloSCT). Non allografted patients had the option to receive autologous SCT (autoSCT) if a major molecular response (MMolR) (MRD4 BCR-ABL1 &lt;0.1%) was achieved. AlloSCT and autoSCT were followed by a 2-year imatinib maintenance. The randomization was stratified on age (≤40y, &gt;40y) and BCR-ABL1 breakpoint region (M/m-bcr). MMolR rate at MRD4 was the primary endpoint of this non-inferiority study, with a margin set at 0.15. In February 2019, the study DSMB decided to stop the randomizations after an unplanned analysis demonstrating a significant excess of relapse in arm B (without HD-AraC). An intention-to-treat analysis is provided. All patients gave informed consent. The study is registered at EudraCT under the number: 2014-002146-44. Results. A total of 156 patients were randomized (77 in arm A, and 79 in arm B). Median age was 47.1 years old (range 18.1-59.9). One-hundred and ten patients had the m-bcr (70.5%) and 46 (29.5%) the M-bcr. An IKZF1 intragenic deletion was found in 87/153 (56.9%). Median follow-up was 2.8 years (95%CI 2.6-3.1). All evaluable patients reached CR after a maximum of two cycles. Three patients died during cycle 1 (2 in arm A, 1 in arm B), and 2 during cycle 2 (1 per arm). Most patients received the 4 scheduled cycles (n=143, 91,7%). AlloSCT was performed in 91 patients (58.3%), whereas 41 patients received an autoSCT (26.3%) with no difference in allo/autoSCT rates between arms. A non-inferiority in late MRD response (MRD4) between the two arms was observed (primary endpoint). MMolR was reached in 55/75 (73.3%) and 61/78 (78.2%) of CR patients in arm A and B, respectively, with an estimated 95% CI of difference of -11% to +16% (-9.2% to +20.8% in the ITT analysis treating missing data as failures). At 3 years, overall survival (OS) was 86.0% in arm A versus 74.2% in arm B (p=.08, Figure A). Progression-free survival (PFS) was 79.6% in arm A versus 57.2% in arm B (p=.008, Figure B). Thirty-one patients experienced hematological relapse (8 in arm A and 23 in arm B). Twenty-height out of 31 relapsed patients were tested for the acquisition of BCR-ABL1 mutations, 20/28 (71%) had at least one mutation and 10/28 (36%) had a T315I mutation. At 3 years, the cumulative incidence of relapse (CIR) was 21.3%, significantly higher in arm B than in arm A (30.8% vs 10.6%, p=.007). When analyzing the CIR considering alloSCT as a competing event for relapse, a significant higher CIR was still observed in arm B as compared to arm A (Figure C). Conclusion. Four cycles of the combined administration of nilotinib and chemotherapy is very efficient for bridging younger adults with Ph-positive ALL to SCT. However, omitting HD-AraC is associated with a higher relapse incidence despite non-inferior levels of BCR-ABL1 MRD4. Figure 1 Figure 1. Disclosures Rousselot: Incyte, Pfizer: Consultancy, Research Funding. Chalandon: Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Gilead, Amgen, Jazz, Astra Zenec: Other: Travel EXpenses, Accomodation; Incyte: Speakers Bureau; Incyte, BMS, Pfizer, Abbie, MSD, Roche, Novartis, Amgen: Other: Advisory Board. Huguet: Novartis: Other: Advisor; Jazz Pharmaceuticals: Other: Advisor; Celgene: Other: Advisor; BMS: Other: Advisor; Amgen: Other: Advisor; Pfizer: Other: Advisor. Vincent: Takeda: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees. Vey: Amgen: Honoraria; BMS: Honoraria; BIOKINESIS: Consultancy, Research Funding; NOVARTIS: Consultancy, Honoraria, Research Funding; SERVIER: Consultancy; JAZZ PHARMACEUTICALS: Honoraria; JANSSEN: Consultancy. Raffoux: PFIZER: Consultancy; CELGENE/BMS: Consultancy; ASTELLAS: Consultancy; ABBVIE: Consultancy. Boissel: Amgen: Consultancy, Honoraria, Research Funding; CELGENE: Honoraria; Servier: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Incyte: Honoraria; SANOFI: Honoraria; PFIZER: Consultancy, Honoraria; JAZZ Pharma: Honoraria, Research Funding. Dombret: Amgen: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; Jazz Pharmaceuticals: Honoraria, Research Funding; Novartis: Research Funding; Pfizer: Honoraria, Research Funding; Servier: Research Funding; Abbvie: Honoraria; BMS-Celgene: Honoraria; Daiichi Sankyo: Honoraria. OffLabel Disclosure: Nilotinib as a therapy for PH-positive acute lymphoblastic leukemia

Sunitinib in Relapsed or Refractory Diffuse Large B Cell Lymphoma: Results of a Phase II Multi-Center Study of the NCIC Clinical Trials Group.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2729-2729
Author(s):  
Rena Buckstein ◽  
John Kuruvilla ◽  
Neil Chua ◽  
Christina Lee ◽  
David A Macdonald ◽  
...  
Keyword(s):  
B Cell ◽  
Phase Ii ◽  
Research Funding ◽  
Cell Lymphoma ◽  
B Cell Lymphoma ◽  
Hematological Toxicity ◽  
High Dose ◽  
Cell Transplant ◽  
Large B Cell Lymphoma ◽  
Large B Cell

Abstract Abstract 2729 Poster Board II-705 Background: There are limited effective treatment options for patients with diffuse large B cell lymphoma who relapse post autologous stem cell transplant or are transplant-ineligible. The detection of vascular endothelial growth factor (VEGF )A, B and C isoforms and their receptors on many large cell lymphoma samples suggests that the VEGF pathway is critically important and may contribute to disease progression. Sunitinib maleate, is an orally bioavailable inhibitor of VEGF receptor-1 (VEGFR-1), -2, and -3, PDGFR-α and β as well as KIT, FLT3, RET and CSF-1 (Chow, LQ JCO 2007). We tested the efficacy, safety and biomarker activity of sunitinib in patients with relapsed diffuse large B cell lymphoma in a multi-center prospective phase II study. Methods: Eligibility included age 18 or older, histologically confirmed relapsed or refractory diffuse large B-cell (DLBCL), primary mediastinal (PMBCL), or transformed indolent lymphoma, at least one and no more than 2 prior chemotherapy regimens (one anthracycline-containing). The primary endpoint was objective response defined by 1999 Cheson criteria. The secondary endpoints were progression-free and overall survival, toxicity and the effect of sunitinib on peripheral blood circulating endothelial cells (CECs) and their precursors (CEPs). Patients self administered sunitinib 37.5 mg po daily with no breaks in 4 week cycles for up to 1 year. CT imaging was performed every 2 cycles and CEC/CEP assays were done at baseline, day 1 of cycles 2, 3 then q 3 months thereafter. A Simon 2-stage design was used with at least 1 response needed after 15 evaluable patients to complete a planned accrual of 25 patients total. Results: Between Feb 2007 and September 2008 we enrolled 19 patients at 7 Canadian sites - 17 were eligible and are evaluable for toxicity and 15 are evaluable for response. The median age was 65 and patients were a median of 20.3 months(m) from diagnosis (range 5.8–132 m). Fourteen (82%) had a diagnosis of DLBCL, 10 (58%) had responded to their preceding line of chemotherapy - 5 (29%) had relapsed post high dose chemotherapy. The median number of cycles of sunitinib received was 2 (1–5) with only 5 patients remaining on drug for 3 or more cycles. Only 35% of patients received > 90% planned dose intensity with 14 patients missing doses and 5 undergoing dose reductions necessitated by toxicities. Hematological toxicity (grade 3 neutropenia in 5 pts, grades 3–4 thrombocytopenia in 6 pts) and was the most common reason for dose omission. Of the 15 evaluable pts, no objective responses were seen, and 9 achieved stable disease (median duration 3.4 m); and 6 had primary progressive disease. As a result, the study was closed at the end of the first stage. With limited serial sampling, there was no discernable relationship between the change in absolute or apoptotic CEC over time with clinical response as measured by best response or change in bi-dimensional measurements. Conclusions: Sunitinib 37.5 mg po daily showed no evidence of anti-tumour activity in relapsed/refractory large B cell lymphoma and is associated with greater than expected hematological toxicity. Disclosures: Buckstein: Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Off Label Use: It is being tested in NHL.

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