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)

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.

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

Blood ◽

10.1182/blood.v112.11.2921.2921 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2921-2921 ◽

Cited By ~ 5

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.

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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 ◽

10.1182/blood.v124.21.2289.2289 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2289-2289 ◽

Cited By ~ 1

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.

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Discontinuation of Tyrosine Kinase Inhibitors (TKIs) in Philadelphia Chromosome-Positive (Ph+) Acute Lymphoblastic Leukemia (ALL)

Blood ◽

10.1182/blood-2019-127499 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 3819-3819 ◽

Cited By ~ 2

Author(s):

Bachar Samra ◽

Hagop M. Kantarjian ◽

Koji Sasaki ◽

Marina Y Konopleva ◽

Rita Khouri ◽

...

Keyword(s):

Board Of Directors ◽

Median Duration ◽

Research Funding ◽

Kinase Inhibitors ◽

Lymphoblastic Leukemia ◽

Philadelphia Chromosome ◽

Cell Transplant ◽

Advisory Committees ◽

Tki Discontinuation

Background: Treatment of Ph+ ALL has significantly improved since the addition of TKIs to chemotherapy, with improvement in complete molecular remission (CMR) and overall survival (OS) rates. However, the optimal duration of TKI is not yet established and the common practice is to continue indefinitely unless allogeneic stem cell transplant (ASCT) is performed. In pediatric setting, when TKIs were discontinued after 2 years of maintenance, high rates of relapse were seen, fortunately salvaged with ASCT and other approaches (Slayton WB et al; JCO. 2018 and Schultz KR; Leukemia 2014). In chronic myeloid leukemia, patients (pts) who achieve deep and sustained molecular remissions on TKI may be able to stop therapy successfully. Herein, we reviewed outcome of pts with Ph+ ALL treated with chemotherapy + TKI without ASCT who later discontinued TKI mainly due to adverse events. Methods: We reviewed 240 pts treated at our institution on sequential protocols with Hyper-CVAD chemotherapy + TKI (dasatinib [n=100], ponatinib [n=84], or imatinib [n=56]) between 2001 and 2019. We identified 9 pts (4%) in whom TKI was discontinued, 4 (44.5%) post dasatinib therapy, 4 (44.5%) post imatinib therapy, and 1 (11%) post ponatinib. We analyzed their characteristics and outcomes including molecular relapse rates and treatment-free remission (TFR). Pts were closely monitored with monthly PCR for the first 3 months, then every other month for 3 months, then every 3 months thereafter. Molecular relapse was defined as the loss of MMR (PCR>0.1%) or positivity of PCR at two assessments within a 2-week period. TKI was resumed upon molecular relapse. TFR was defined from the date of TKI discontinuation to molecular relapse or last-follow-up. Kaplan-Meier method was used for survival analysis. Results: Baseline characteristics are summarized in table 1. The median follow up from the time of diagnosis was 138 months (range: 40-190). The median age at diagnosis was 60 years (range: 20-80). Transcript type was p190 BCR-ABL1 in 7 pts (78%). Median time to CMR was 3 months (range: 0.4-120). Median duration of TKI therapy prior to discontinuation was 70 months (range: 23-143). Median duration of CMR before TKI stop was 52 months (range: 22-141). Reasons for stopping TKI were side effects in 8/9 pts, and physician's choice in 1 pt (after completing 2+ years of maintenance). At the time of TKI stop, 8 pts were in CMR, and 1 pt with low positive transcript level (0.01%). Median follow-up post TKI discontinuation was 37 months (range: 9-75). None of the pts had morphological relapse. Three pts (33%) had molecular relapse within a median of 6 months (range: 0.8-13.2 months). All 3 resumed TKI therapy: 2 of them regained MMR after a median of 4 months (range: 4.0-4.6 months); third pt continues to respond; the BCR-ABL1 transcripts down from 17.68% to 0.36% after 7 months (Table 2). Six pts remain alive and 3 pts died of disease-unrelated causes. The median TFR was not reached; 3-y TFR was 65% (Figure 1). Though the number of pts was only 9, the duration of CMR had a tendency of successful TFR (P=0.062; HR, 0.09; [95% CI, 0.009-1.119] with duration of CMR for 2 years, and P=0.137; HR, 0.15; [95% CI, 0.01-1.80] with duration of CMR for 3 years, as a binomial variable). The median duration of CMR in pts who relapsed and who did not relapse was 22 months (range, 0-39.9) and 58 months (range, 30.9-140.6), respectively (P= 0.096). Conclusions: Our anecdotal experience reflects the feasibility of stopping TKI in a subset of pts with Ph+ ALL and sustained molecular remissions. Longer follow up and validation of these findings on a larger cohort are highly needed before attempting to discontinue TKI. Disclosures Kantarjian: Astex: Research Funding; Ariad: Research Funding; Jazz Pharma: Research Funding; AbbVie: Honoraria, Research Funding; Cyclacel: Research Funding; Immunogen: Research Funding; Actinium: Honoraria, Membership on an entity's Board of Directors or advisory committees; BMS: Research Funding; Takeda: Honoraria; Agios: Honoraria, Research Funding; Novartis: Research Funding; Amgen: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding. Sasaki:Otsuka: Honoraria; Pfizer: Consultancy. Konopleva:Ascentage: Research Funding; Reata Pharmaceuticals: Equity Ownership, Patents & Royalties; Agios: Research Funding; Ablynx: Research Funding; Cellectis: Research Funding; Amgen: Consultancy, Honoraria; F. Hoffman La-Roche: Consultancy, Honoraria, Research Funding; Calithera: Research Funding; Stemline Therapeutics: Consultancy, Honoraria, Research Funding; Forty-Seven: Consultancy, Honoraria; Eli Lilly: Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Kisoji: Consultancy, Honoraria; Astra Zeneca: Research Funding; Genentech: Honoraria, Research Funding. O'Brien:Acerta: Research Funding; AbbVie: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Sunesis: Consultancy, Research Funding; Janssen: Consultancy, Honoraria; Kite: Research Funding; GlaxoSmithKline: Consultancy; Gilead: Consultancy, Research Funding; Eisai: Consultancy; Celgene: Consultancy; Astellas: Consultancy; Aptose Biosciences, Inc: Consultancy; Amgen: Consultancy; Alexion: Consultancy; TG Therapeutics: Consultancy, Research Funding; Vaniam Group LLC: Consultancy; Verastem: Consultancy; Regeneron: Research Funding; Pharmacyclics LLC, an AbbVie Company: Consultancy, Research Funding. Kadia:Pfizer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Jazz: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Research Funding; Bioline RX: Research Funding; BMS: Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Genentech: Membership on an entity's Board of Directors or advisory committees; Pharmacyclics: Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding. Jabbour:Takeda: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Adaptive: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; AbbVie: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Cyclacel LTD: Research Funding.

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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 ◽

10.1182/blood.v118.21.1512.1512 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1512-1512 ◽

Cited By ~ 1

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.

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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 ◽

10.1182/blood.v110.11.2814.2814 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2814-2814 ◽

Cited By ~ 4

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.

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Combination of the hyperCVAD Regimen with Dasatinib Is Effective in Patients with Relapsed Philadelphia Chromosome (Ph) Positive Acute Lymphoblastic Leukemia (ALL) and Lymphoid Blast Phase Chronic Meyloid Leukemia (CML-LB)

Blood ◽

10.1182/blood.v112.11.2919.2919 ◽

2008 ◽

Vol 112 (11) ◽

pp. 2919-2919 ◽

Cited By ~ 3

Author(s):

Elias Jabbour ◽

Susan O’Brien ◽

Deborah A. Thomas ◽

Stefan Faderl ◽

Charles Asa Koller ◽

...

Keyword(s):

Kinase Inhibitor ◽

Lymphoblastic Leukemia ◽

Philadelphia Chromosome ◽

Clinical Activity ◽

High Dose ◽

Molecular Response ◽

Blast Phase ◽

Median Response ◽

Platelet Recovery ◽

Abl Kinase

Abstract The dual Src and Abl inhibitor dasatinib is ~325 times more potent in vitro against BCR-ABL kinase activity and has significant clinical activity in patients with imatinibresistant lymphoid blast phase CML (CML-LB) and Ph+ ALL. In this study, patients with relapsed Ph+ ALL or CML-LB received 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 continued to receive dasatinib 50 mg po bid (or 100 mg daily) and vincristine and prednisone monthly for 2 years followed by dasatinib indefinitely. To date 14 patients with relapsed Ph+ ALL or CML-LB have received a median of 3 cycles (range 1–8); 1 patient in complete remission (CR) is receiving maintenance therapy. Median age was 43 years (range 21–69); 4 (29%) patients were older than 50 years. Median WBC at start of treatment was 6.8 × 109/L (range, 0.4 – 27.2 × 109/L). Median blast percentage was 45% (range 0–96%) Three patients had CNS involvement. Median number of previous therapies was 1 (range, 1–4) including hyperCVAD and imatinib, tyrosine kinase inhibitor monotherapy, investigational agents and transplantation. All patients were evaluable for response. 10 patients (71%) achieved CR and 4 patients (29%) achieved CR with incomplete platelet recovery (CRp). Twelve of 14 (86%) patients achieved a major cytogenetic response, complete in 11, 1 (7%) had insufficient metaphases, and 1 (7%) had no response. Overall, 9 (64%) patients had achieved a major molecular response, complete in 5. Median time to neutrophil and platelet recovery during the first course was 18 and 22 days and 18 and 26 days, respectively after subsequent courses. Four patients relapsed after median response duration of 19 weeks (range, 9–38); two of them had acquired ABL kinase domain mutations: One patient lost his baseline mutation, Y253H, and acquired T315I and E450G; the second lost his 3 baseline mutations, Y253H, F359V, and E459K, and acquired T315I.Two patients received an allogeneic transplantation and one patient received a donor lymphocyte infusion. Grade 3 and 4 toxicities included 7 episodes of bleeding (4 GI, 1 GU, and 2 subdural hematomas), 4 episodes of pleural effusions, 2 episodes of pericardial effusions, infections, diarrhea, hypophosphatemia, hypocalcemia, elevated transaminases, and hyperbilirubinemia. With a median follow up of 6 months (range, 1–13 months), 9 patients are alive; 7 in CR/CRp. Two patients died after disease relapse, 1 died post transplant and 2 died in CR/CRp from infections. In conclusion, the hyperCVAD regimen with dasatinib is feasible and effective in patients with relapsed Phpositive ALL and CML-LB.

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Detection of MRD may predict the outcome of patients with Philadelphia chromosome–positive ALL treated with tyrosine kinase inhibitors plus chemotherapy

Blood ◽

10.1182/blood-2012-11-466482 ◽

2013 ◽

Vol 122 (7) ◽

pp. 1214-1221 ◽

Cited By ~ 131

Author(s):

Farhad Ravandi ◽

Jeffrey L. Jorgensen ◽

Deborah A. Thomas ◽

Susan O’Brien ◽

Rebecca Garris ◽

...

Keyword(s):

Kinase Inhibitors ◽

Residual Disease ◽

Lymphoblastic Leukemia ◽

Quantitative Polymerase Chain Reaction ◽

Philadelphia Chromosome ◽

Multiparameter Flow Cytometry ◽

Molecular Response ◽

Cell Transplant ◽

Treatment Intensification ◽

Philadelphia Chromosome Positive

Abstract From 2001 to 2011, 122 patients with newly diagnosed Philadelphia chromosome–positive acute lymphoblastic leukemia were treated with chemotherapy + imatinib (n = 54) or + dasatinib (n = 68). One hundred fifteen (94%) achieved complete remission (CR) including 101 patients who achieved it with only 1 induction course and had at least 1 minimal residual disease (MRD) assessment; 25 patients underwent an allogeneic stem cell transplant in first CR and were excluded, leaving 76 patients as the subject of this report. MRD monitoring by multiparameter flow cytometry (MFC) and real-time quantitative polymerase chain reaction (PCR) was performed at the end of induction and at ∼3-month intervals thereafter. Median age was 54 years (range, 21-84 years). There was no difference in survival by achievement of at least a major molecular response (MMR; BCR-ABL/ABL < 0.1%) at CR (P = .22). Patients achieving MMR at 3, 6, 9, and 12 months had a better survival (P = .02, .04, .05, and .01, respectively). Negative MFC at CR did not predict for improved survival (P = .2). At 3 and 12 months, negative MRD by MFC was associated with improved survival (P = .04 and .001). MRD monitoring by PCR and MFC identifies patients who benefit from treatment intensification in first CR.

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Discontinuation of Maintenance Tyrosine Kinase Inhibitors in Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia outside of Transplant

Acta Haematologica ◽

10.1159/000510112 ◽

2020 ◽

pp. 1-8

Author(s):

Bachar Samra ◽

Hagop M. Kantarjian ◽

Koji Sasaki ◽

Ahmad S. Alotaibi ◽

Marina Konopleva ◽

...

Keyword(s):

Acute Lymphoblastic Leukemia ◽

Tyrosine Kinase ◽

Tyrosine Kinase Inhibitors ◽

Median Duration ◽

Kinase Inhibitors ◽

Lymphoblastic Leukemia ◽

Philadelphia Chromosome ◽

Cell Transplant ◽

Tki Discontinuation

Background: The addition of tyrosine kinase inhibitors (TKIs) to chemotherapy has dramatically improved outcomes of patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL). When allogeneic hematopoietic stem cell transplant (HSCT) is performed, maintenance TKI is generally given for a fixed duration. However, the optimal duration of TKI outside of HSCT remains unknown, and the common practice is to continue indefinitely. Here, we report characteristics and outcomes of 9 patients treated with chemotherapy + TKI without HSCT and later discontinued TKI. Methods: Among 188 patients with Ph-positive ALL who did not undergo HSCT, 9 of them discontinued maintenance TKI mainly due to side effects. Patients were closely monitored with serial PCR testing for the BCR-ABL1 transcript. Major molecular response (MMR) was defined as BCR-ABL1 transcript ≤0.1% on the international scale for p210 transcripts and a 3-log reduction from baseline for p190 transcripts. Deep molecular remission (DMR) was defined as the absence of quantifiable BCR-ABL1 transcripts with a sensitivity of 0.01%. Molecular relapse was defined as loss of MMR. Treatment-free remission (TFR) was defined from time of TKI discontinuation to molecular relapse, last follow-up, or death from any cause. Results: At the time of TKI discontinuation, transcript level was undetected in 6 patients, <0.01% in 2 patients, and 0.01% in another patient. Prior to discontinuation, the median duration of TKI therapy and of DMR was 70 and 47 months, respectively. No morphological relapse occurred. Three patients (33%) had molecular relapse at a median of 6 months. All 3 resumed TKI therapy, and 2 of them regained DMR after a median of 13 months. After a median follow-up of 49 months, the median TFR was not reached, and the 4-year TFR rate was 65%. The median duration of DMR in patients with and without molecular relapse was 22 and 58 months, respectively (p = 0.096). Conclusion: TKI discontinuation outside of HSCT in Ph-positive ALL in the setting of compelling toxicity may be safe only among a highly selected group of patients with deep and prolonged DMR undergoing close and frequent monitoring. Validation of these findings in prospective clinical trials is highly needed.

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

Blood ◽

10.1182/blood.v128.22.757.757 ◽

2016 ◽

Vol 128 (22) ◽

pp. 757-757 ◽

Cited By ~ 2

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.

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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 ◽

10.1182/blood.v122.21.2663.2663 ◽

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.

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