Subcutaneous Omacetaxine (OM) Treatment of Chronic Phase (CP) Chronic Myeloid Leukemia (CML) Patients Following Multiple Tyrosine Kinase Inhibitor (TKI) Failure

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2290-2290 ◽  
Author(s):  
Jorge E. Cortes ◽  
Meir Wetzler ◽  
Jeff Lipton ◽  
Franck E Nicolini ◽  
Michele Baccarani ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Adverse Events ◽  
Median Duration ◽  
Bone Marrow Failure ◽  
Single Agent ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Employment Equity ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 2290 Introduction: Multiple TKI failure is a growing problem in a subset of CML patients. Treatment with a third TKI after two have failed often yields poor results. New treatment options are needed for this patient population. OM is a first-in-class cetaxine with demonstrated activity as a single agent in CML. It inhibits the production of short-lived oncoproteins (such as Mcl-1) involved in cancer cell survival via a mechanism independent of Bcr-Abl binding. Several studies have suggested that OM has a favorable toxicity profile when given to patients with CML via the subcutaneous route. We explored OM efficacy and safety in a subset of patients who had received therapy with multiple prior approved TKI. Methods: We analyzed a subset of adult CML-CP patients who had received two or more TKI (imatinib, dasatinib, nilotinib), from a combined interim dataset of two prospective Phase 2 studies (CML-202, for patients with the T315I kinase domain mutation, and CML-203, for patients with failure to ≥2 TKI) utilizing OM in the treatment adult patients with all phases of CML who had failed TKI. TKI failure was defined as no complete hematologic response (CHR) by 12 weeks (wk), no cytogenetic response by 6 months (mo), no major cytogenetic response (MCyR) by 12 mo, loss of CHR or MCyR, or progressive leukocytosis. The focus of this analysis was to assess the CHR and MCyR response rates as well as the overall safety of OM in these patients. Adverse events presented are Grade 3/4 events that occurred in ≥ 5% of patients (regardless of causality). Results: A total of 73 of the 93 CML-CP patients from these two studies had received two or more TKI prior to OM treatment. Median time from initial CML diagnosis to first dose of OM was 74.4 months. Mutations of any kind were seen in 48% of the patients, whereas 29% had no identified mutation and 23% had no available data on mutation status. Sixty (82%) of these 73 patients achieved or maintained (twelve patients were in CHR at study entry) a CHR and 17 (23%) achieved a MCyR (9 complete and 8 partial). The median duration of MCyR was 4.4+ months (range 1.2–14.1+). Median overall survival for patients treated with OM after failure of 2 or more TKI has not yet been reached [95% Confidence Interval (CI) 22.9, NA months] (Figure 1). Eleven patients had a treatment—emergent adverse event leading to death, and two deaths were probably related to study drug. Median progression-free survival was 11.1 months (95% CI 6.5, 13.8 months). Median follow-up time was 7.5 months for all patients with twenty-five patients remaining on study at the time of this data cut. A total of 36 of the 93 CP patients from these two studies had been treated with three or more TKI; 27 (75.0%) achieved or maintained a CHR and 7 (19.4%) achieved a MCyR (4 complete and 3 partial) on OM treatment. The median duration of MCyR in this group was 4.0+ months (range 1.2–11.5+) at the time of data cut-off. The primary Grade 3/4 adverse events in patients who received OM after failure of 2 or more TKI were hematologic, including thrombocytopenia (64%), neutropenia (48%) and anemia (40%) most commonly, followed by febrile neutropenia (12%), bone marrow failure (12%), pancytopenia (7%) and febrile bone marrow aplasia (6%). These events were dosing schedule dependent. Clinical sequelae were uncommon and managed with transient treatment interruptions and dose adjustments. Grade 3/4 non-hematologic adverse events were infrequent, with only fatigue (6%) occurring ≥5% of patients. Conclusions: OM, through a mechanism of action independent of Bcr-Abl, may offer a clinically viable option for patients who have progressed on multiple TKI treatment. Disclosures: Off Label Use: The drug is currently in development and has an NDA submitted for use in TKI resistant CML. Cram: ChemGenex: Employment, Equity Ownership. Humphriss: ChemGenex: Employment, Equity Ownership. Benichou: ChemGenex: Consultancy, Equity Ownership. Craig: ChemGenex: Employment, Equity Ownership, Executive Management Level.

Change in Chronic Low-Grade Nonhematologic Adverse Events (AEs) and Quality of Life (QoL) in Adult Patients (pts) with Philadelphia Chromosome–Positive (Ph+) Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Switched From Imatinib (IM) to Nilotinib (NIL)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3782-3782 ◽  
Author(s):  
Jorge E. Cortes ◽  
Jeffrey H. Lipton ◽  
Carole B. Miller ◽  
Sikander Ailawadhi ◽  
Luke Akard ◽  
...  
Keyword(s):  
Adverse Events ◽  
Median Duration ◽  
Research Funding ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Low Grade ◽  
Molecular Response ◽  
Employment Equity ◽  
End Point ◽  
Equity Ownership

Abstract Abstract 3782 Background: A large number of Ph+ CML pts treated with IM experience mild to moderate AEs that can negatively impact QoL. A recent study (Efficace F et al. Ann Hematol. 2012) reported that pts and healthcare professionals ranked several AEs induced by BCR-ABL tyrosine kinase inhibitors (fatigue ranked first) in the top 10 issues that adversely impact QoL in pts. The primary objective of the ongoing ENRICH study is to evaluate improvement of IM-related chronic low-grade nonhematologic AEs at the end of cycle (EOC) 3 (ie, after 12 weeks) in CML-CP pts when switched from IM to NIL because of chronic low-grade AEs. This is a report on 45 evaluable pts who completed EOC 3 as of the data cut-off (6/1/2012). Methods: Pts were eligible if they were treated with IM 400 mg/d for ≥3 mo and had IM-related grade (G) 1/2 nonhematologic AEs persisting '2 mo or recurring ≥3 times and recurring despite best supportive care. The study planned to enroll 50 pts in the US and Canada. Pts received NIL 300 mg twice daily for 1 y (or longer if NIL was not yet commercially available for frontline treatment). Nonhematologic AEs were graded using the Common Terminology Criteria for Adverse Events (version 4.03; 6/14/2010) grading scale. Molecular response was monitored by a central PCR lab monthly for the first 3 mo and then every 3 mo on study. Pt-reported outcomes, measured by 2 QoL questions and the MD Anderson Symptom Inventory (MDASI)-CML, were administered at baseline, EOC 1, EOC 3, and then every 3 mo thereafter. Results: 52 pts were enrolled into the study; enrollment closed in January 2012. The median duration (range) of previous IM treatment (tx) was 24.7 mo (2.3–123.0 mo); median duration (range) of NIL tx was 11.9 mo (0.2–23.7 mo). At baseline 199 IM-related nonhematologic AEs were reported (141 G1; 58 G2). Data for 49 pts were available and included in the safety and molecular response analyses; 45 pts were included in the primary end point analysis since 4 withdrew consent prior to EOC 3. These 45 pts accounted for 183/199 of the baseline IM-related AEs (130 G1; 53 G2); 1 AE evaluation is missing at EOC 3. 130/182 AEs (71.4%) improved by EOC 3 (primary end point): 117 resolved (90, 19, 8 by mo 1, 2, 3, respectively) and 13 improved from G2 to G1 (Table). By EOC 3, 64.1% and 53.8% of pts (n = 39) reported an improvement in global QoL from baseline over the last 24 h and last 7 d, respectively. Mean reductions from baseline in MDASI-CML severity score and interference score, and therefore improvement in symptoms, were 1.1 (n = 40) and 1.4 (n = 39) at EOC 1, and 1.2 (n = 39) and 1.7 (n = 38) at EOC 3, respectively. At baseline, 31/49 (63.3%) pts had major molecular response (MMR, 3-log reduction of BCR-ABL1; ≤0.1% IS); 18 and 10 pts had 4-log (MR4; BCR-ABL1 ≤0.01% IS) and 4.5-log reductions (MR4.5; BCR-ABL1 ≤0.0032% IS) in BCR-ABL1, respectively. After switch to NIL, all pts with a baseline MMR maintained MMR and 14/17 remaining pts without baseline MMR achieved MMR. Deeper responses were reported for 16 pts who reached MR4 after the switch, and 14 reached MR4.5. 20 pts were dose-reduced for NIL-related AEs, 2 of whom did not restart study drug. The other 18 pts were dose-reescalated to the original dose when the AEs improved to G1 or resolved. 40 G3 AEs occurred in 19 pts; of these, 24 AEs were investigator-reported as suspected to be NIL-related (hypophosphatemia, hyperglycemia, hypokalemia, increased bilirubin, increased lipase, arthralgia, pleural effusion, acute pancreatitis, dehydration, bronchitis, pruritus, rash, erythematous rash, exfoliative rash, papular rash, abdominal pain, gastroenteritis, and joint pain). 1 G4 AE (cardiac arrest, NIL-suspected) was reported; the pt recovered from the event but was discontinued from the study. Most AEs were managed by brief dose interruption. 9 pts discontinued study (5 due to AEs; 4 withdrew consent). No QTcF prolongation >500 msec occurred. Conclusions: The majority of IM-related nonhematologic AEs improved within 3 mo after switching to NIL; nearly half of the AEs resolved by EOC 1. More than half of pts experienced improvement in QoL and symptom burden on NIL. In general, pts achieved deeper molecular responses on study and approximately a quarter of pts reached MR4.5 after the switch to nilotinib. Disclosures: Cortes: Bristol-Myers Squibb: Consultancy, Research Funding; Novartis Pharmaceuticals: Consultancy, Research Funding; Ariad Pharmaceuticals: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; ChemGenex Pharmaceuticals: Consultancy, Research Funding; Deciphera Pharmaceuticals: Research Funding. Lipton:Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding. Miller:Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding. Ailawadhi:Millennium Pharmaceuticals: Consultancy, Honoraria. Akard:Cellerant: Research Funding; ChemGenex: Research Funding; Millennium: Honoraria; Novartis: Honoraria, Research Funding; Celgene: Honoraria; Bristol Myers-Squibb: Honoraria; Pfizer: Research Funding. Pinilla-Ibarz:Novartis Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Ariad: Consultancy, Research Funding. Lin:Novartis Pharmaceuticals: Employment, Equity Ownership. Ericson:Novartis Pharmaceuticals Corp: Employment, Equity Ownership. Mauro:Novartis Pharmaceuticals: Consultancy, Honoraria.

A Sequential Two-Stage Dose Escalation Study Evaluating The Safety and Efficacy Of Eltrombopag In Thrombocytopenic Patients With Myelodysplastic Syndrome (MDS) Resistant To Hypomethylating Agents (HMA)

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2760-2760 ◽  
Author(s):  
Rami S Komrokji ◽  
Vu H. Duong ◽  
Ling Zhang ◽  
Ji-Hyun Lee ◽  
Eric Padron ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Adverse Events ◽  
Median Duration ◽  
Dose Escalation ◽  
Phase 1 ◽  
Single Agent ◽  
Primary Objective ◽  
Duration Of Treatment ◽  
Dose Escalation Study ◽  
Grade 3

Abstract Introduction Thrombocytopenia remains a critical management challenge for MDS pts. The outcome of MDS Pts after HMA failure is poor. Eltrombopag is an oral, small non-peptide thormbopoeitin (TPO) receptor agonist. It has biologically distinct effects in part to its binding site on the TPO receptor that is distinct from that for native TPO and other synthetic agonists. We conducted an investigator initiated study with eltrombopag in MDS pts with thrombocytopenia after HMA failure. Methods The study is a phase 1, dose escalation design. Pts are allocated to dose cohorts of 50, 100, 150, 200, 250 and 300mg/day. Each dose cohort includes 6 pts. Key eligibility criteria include confirmed diagnosis of MDS or acute myeloid leukemia (AML) with 20-30% myeloblasts. Pts must have at least one prior HMA treatment. The mean platelet count within a month of enrollment must be ≤ 50 X 109 /L. Key exclusions include splenic enlargement > 8 cm, bone marrow fibrosis ≥ grade 3, and prior TPO agonist use. The primary objective of the study is to determine the MTD. Dose-limiting toxicity (DLT) is defined as treatment related non-hematological grade 3-4 toxicity. If no DLTs were observed during the first 2 cycles of therapy, the next cohort of patients receives a higher dose of eltrombopag. Pts who did not receive treatment for 8 weeks were replaced for DLT assessment. The secondary endpoints include response, overall survival (OS) and leukemia free survival (LFS). Results Thirty-one pts were enrolled. Table-1 summarizes baseline characteristics. Most pts had higher risk MDS who were heavily pretreated. The median interval from MDS diagnosis was 28 months. Six pts were enrolled in cohort 1 (50 mg), 10 pts in cohort 2 (100 mg) (4 pts replaced (2 deaths unrelated to treatment, 1 infection, 1 progressive disease (PD)), 12 pts were enrolled in cohort 3 (150 mg) where 6 pts were replaced (5 PD and 1 infection), and to date, 3 pts are enrolled in cohort 4 (200 mg). No protocol defined DLT have been encountered to date. No grade 3 or 4 treatment related adverse events have been reported. The most common adverse events that were deemed possibly, or probably related to study drug included fatigue (n=9), diarrhea (n=6), night sweats (n=3), headache (n=3), numbness (n=3). There were 2 pts with grade 2 pneumonia and grade 3 fatigue, and 2 grade 2 diarrhea events. Seven pts (23%) developed leukocytosis on treatment and 13 pts (42%) experienced an increase in circulating myeloblasts at some point during study treatment. Three of 27 pts developed higher grade bone marrow myelofibrosis (change from grade 0-1 to grade 2-3), one of whom received the 50 mg dose and 2 pts on the150 mg dose. Eleven pts (35%) progressed to AML, 9 out of 11 patients who progressed had RAEB-2 or RAEB-t and 5 had poor risk cytogenetics. The median follow up duration is 23 months. The best response on study per IWG 2006 criteria include marrow CR (mCR) + Hematological improvement (HI) (6%, n=2), mCR (3%, n=1), HI (13%, n=4), stable disease (SD) (29%, n=9), PD (36%, n=11) and not evaluable for response (13%, n=4). The overall response rate (HI+) was 22% (7 out 31 pts) and 26% among pts evaluable for response (7 out of 27 pts). HI included 6 platelet responses and 1 erythroid response. Among 20 pts who were platelet transfusion dependent, 6 became transfusion independent (30%). The median duration of response was 3.3 months. The median duration of treatment is 2 months. The most common reasons for eltrombopag discontinuation were PD (48%) and infection (10%). Median OS was 5 months whereas median OS was 8 months among HI+ responders. The median LFS was 3.5 months. Conclusions Eltrombopag yielded modest responses in heavily treated higher risk MDS pts after HMA failure. Leukocytosis, increased circulating myeloblasts and myelofibrosis were observed in subsets of pts. Future development of eltrombopag as a single agent in MDS should be in lower risk MDS or in combination with HMA in higher risk MDS. Disclosures: Off Label Use: Use of eltrombopag in MDS.

Differences in Haematological and Non Haematological Toxicity during Treatment with Imatinib in Early and Late Chronic Phase Chronic Myeloid Leukemia Patients

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 4281-4281
Author(s):  
Massimo Breccia ◽  
Roberto Latagliata ◽  
Laura Cannella ◽  
Ida Carmosino ◽  
Caterina Stefanizzi ◽  
...  
Keyword(s):  
Weight Gain ◽  
Side Effects ◽  
Adverse Events ◽  
Median Duration ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Hematological Toxicity ◽  
Severe Thrombocytopenia ◽  
Muscle Cramps ◽  
Grade 3

Abstract Imatinib is a relatively specific inhibitor of the BCR/ABL tyrosine kinase, effective in chronic myeloid leukaemia (CML). Aim of present study was to analyse the frequency and type of hematological and non hematological adverse events in our series of late and early chronic phase CML patients treated with imatinib and correlate the grade of hematological toxicity with the response obtained. Hematological adverse events were seen in 59 out of 150 (39%) late CP patients: 20 patients (34%) experienced toxicity grade 1, 25 (42%) had toxicity grade 2 and 14 (24%) had toxicity grade 3–4. Of 100 early CP patients, 26 (26%) experienced hematological adverse event: 42% had toxicity grade 1, 50% had toxicity grade 2 and 7% had toxicity grade 3–4. Statistical differences were detected between early and late CP patients for grade 1–2 and 3–4 toxicity. Median duration of toxicity in late CP patients was 20 days (range 4–41) for grade 1, 16 days (range 4–27) for grade 2 and 18 days (range 8–40) for grade 3–4. In early CP patients the median duration of toxicity was 10 days (range 4–21) for grade 1, 14 days (range 6–28) for grade 2 and of 10 days (range 7–15) for grade 3–4. We analysed the clinical features associated to a greater risk of myelosuppression and found that a lower haemoglobin level was significant in early CP patients while a history of cytopenia during IFN therapy and a longer time elapsing from diagnosis was significant in late CP patients. The occurrence of hematological toxicity in late CP patients was associated to the persistent lack of complete cytogenetic response, whereas this correlation was not apparent in early CP patients. We compared the incidence of non hematological adverse events occurring in late and in early CP patients and found that in these latter some side effects were more frequent, such as weight gain, periorbital oedema (p=0.02), muscle cramps (p=0.03), skin rashes (p=0.002), diarrhoea (p=0.01), weeping (p=0.001) and infections (p=0.001). In late CP patients compared to early CP patients, we found as significant the occurrence during therapy of bone pain (p=0.001) and of hemorrhagic symptoms (p=0.002) in the absence of severe thrombocytopenia. Grade 3–4 adverse events were recorded at rates below 4% and decreased over time: in late CP patients hemorrhages and muscle cramps were the most common side effects of grade 3–4, whereas in early CP patients the most frequent events were nausea, weight gain and cutaneous rash. Cardiac toxicity was observed in 3 out of 250 patients and cardiac events most frequently occurred in elderly patients with pre-existing conditions that predispose to fluid retention, with overall frequency of these events being 1%. In conclusion, we have observed that hematological and non-hematological side effects during imatinib therapy are different among late and early CP patients and that severe hematological toxicity may influence cytogenetic response.

Bosutinib as Third-Line Treatment for Chronic Phase Chronic Myeloid Leukemia Following Failure of Second-Line Therapy with Dasatinib or Nilotinib

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 892-892
Author(s):  
H. Jean Khoury ◽  
Dong-Wook Kim ◽  
Andrey Zaritskey ◽  
Carlo Gambacorti-Passerini ◽  
Andreas Hochhaus ◽  
...  
Keyword(s):  
Research Funding ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Employment Equity ◽  
Advisory Committees ◽  
Line Therapy ◽  
Third Line Therapy ◽  
Equity Ownership ◽  
Third Line ◽  
Grade 3

Abstract Abstract 892 Bosutinib (SKI-606) is an orally available, dual Src/Abl tyrosine kinase inhibitor (TKI) with minimal inhibitory activity against PDGFR or c-kit. This open-label, phase 1/2 study evaluated the safety and efficacy of bosutinib as third-line therapy in patients with Philadelphia chromosome-positive (Ph+) chronic phase (CP) chronic myeloid leukemia (CML). Adults (aged ≥18 years) who had failed prior imatinib (IM) therapy and were resistant or intolerant to dasatinib (DAS; n = 35 and n = 51, respectively) or resistant to nilotinib (NIL; n = 28) received oral daily treatment with a starting dose of 500 mg bosutinib. Of the 118 patients enrolled, 46% were male, the median age was 56 years (range, 20–79 years), and the median time from CML diagnosis to start of bosutinib was 6.7 years (range, 0.6–19.2 years). The median daily dose of bosutinib was 446 mg (range, 140–563 mg). At week 24, 26% of patients achieved a major cytogenetic response (MCyR), including 13% with a complete cytogenetic response (CCyR; see Table). Cumulative response rates were 34% for MCyR and 22% for CCyR. The majority (81%) of patients who achieved a MCyR still retained their response as of the data snapshot date (median follow-up duration of 23 months). Comparable rates of response were observed across Bcr-Abl kinase domain mutations, except for the T315I mutation. The most frequently reported treatment-emergent adverse events (TEAEs; ≥20% of patients, all grades) were diarrhea (83%), nausea (45%), vomiting (36%), rash (26%), headache (25%), and fatigue (22%). The incidence of TEAEs was generally similar for DAS-resistant, DAS-intolerant, and NIL-resistant patients. Gastrointestinal events were predominantly grade 1/2, had an early onset, and usually subsided within the first 4 weeks of treatment. The only grade 3/4 TEAE reported in ≥5% of patients was diarrhea (8%). One grade 3 pleural effusion was observed in a patient with concomitant pneumonia and a history of recurrent pleural effusions on DAS. Grade 3/4 hematologic laboratory abnormalities included thrombocytopenia (23%), neutropenia (16%), and anemia (8%); all were usually transient. Other grade 3/4 laboratory abnormalities (≥5% of patients) included elevations of magnesium (12%), alanine transaminase (ALT; 7%), and lipase (5%). Grade 3/4 transaminase elevations were observed more frequently in NIL-resistant patients (ALT, 18% [grade 4, n = 1]; aspartate transaminase [AST], 11% [grade 4, n = 1]) compared with DAS-resistant/intolerant patients (ALT, 3–4%; AST, 0–3%). On-treatment QTcF interval prolongation was observed in 13 patients (11%), but was only grade 1/2 (≤500 msec) with a reported rate of arrhythmia of <1%. Adverse events led to treatment discontinuation in 27% of DAS-intolerant patients, 14% of DAS-resistant patients, and 11% of NIL-resistant patients; thrombocytopenia (4%), neutropenia (3%), and increased ALT (3%) were the only events resulting in discontinuation of >2 patients. In conclusion, bosutinib has an acceptable safety profile in patients with CP CML following failure of IM and DAS or NIL, with primarily low-grade and transient gastrointestinal TEAEs. Bosutinib also demonstrated clinical activity as a third-line therapy, with over one-third of patients achieving a MCyR. These results emphasize the therapeutic potential of bosutinib for CP CML patients with resistance or, particularly, intolerance to other second-generation TKI therapies. Table 1: Table. IM failure + DAS resistant IM failure + DAS intolerant IM failure + NIL resistant Total Cytogenetic response at week 24, n (%)     Evaluablea 26 29 15 70     MCyR 5 (19) 9 (31) 4 (27) 18 (26)       CCyR 2 (8) 5 (17) 2 (13) 9 (13) Cytogenetic response(cumulative), n (%)     Evaluableb 32 38 21 91     MCyR 10 (31) 14 (37) 7 (33) 31 (34)       CCyR 3 (9) 13 (34) 4 (19) 20 (22) Patients retaining MCyR at time of latest data snapshot, n (%) 7 (70) 11 (79) 7 (100) 25 (81) Median follow-up time (range), months 12 (3–47) 27 (0.3–43) 7 (1–42) 23 (0.3–47) Median duration of MCyR (range), weeks 24 (6–64) 68 (7–124) 18 (6–185) 37 (6–185) a Evaluable patients had baseline and week 24 cytogenetic assessments. Patients who had experienced early progression or death before having a post-baseline assessment were also evaluable. b Evaluable patients had baseline and post-baseline cytogenetic assessments. Patients who had experienced early progression or death before having a post-baseline assessment were also evaluable. Disclosures: Khoury: BMS, Novartis: Honoraria. Kim:BMS, Novartis, Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Gambacorti-Passerini:Pfizer Inc: Research Funding. Hochhaus:Novartis, BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer Inc: Research Funding. Dorlhiac-Llacer:Novartis: Research Funding; BMS: Research Funding; Pfizer Inc: Research Funding. Kelly:Pfizer Inc: Employment, Equity Ownership. Besson:Pfizer Inc: Employment, Equity Ownership. McMullan:Pfizer Inc: Employment, Equity Ownership. Kantarjian:Pfizer, Novartis, BMS: Research Funding; Novartis: Consultancy. Cortes:Pfizer Inc: Consultancy, Research Funding.

Efficacy and Tolerability of Nilotinib in Chronic Myeloid Leukemia Patients in Chronic Phase (CML-CP) Who Failed Prior Imatinib and Dasatinib Therapy: Updated Results of a Phase 2 Study

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3234-3234 ◽  
Author(s):  
Francis Giles ◽  
Philipp D. le Coutre ◽  
Kapil N. Bhalla ◽  
Gert J Ossenkoppele ◽  
Giuliana Alimena ◽  
...  
Keyword(s):  
Adverse Events ◽  
Disease Progression ◽  
Median Time ◽  
Median Duration ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Tolerability Profile ◽  
Heavily Pretreated ◽  
Grade 3

Abstract Background: Treatment options are limited for patients with Philadelphia chromosome-positive (Ph+) CML who are resistant or intolerant to both imatinib and dasatinib. Nilotinib is a potent and highly selective BCR-ABL kinase inhibitor approved for the treatment of Ph+ CML patients in chronic (CML-CP) or accelerated phase (CML-AP) who are resistant or intolerant to prior therapy including imatinib. Here we report the updated results evaluating the safety and efficacy of nilotinib in patients with CML-CP who were either resistant or intolerant to both imatinib and dasatinib therapy. Methods: Nilotinib was dosed at 400 mg twice daily with an option to dose escalate to 600 mg twice daily in patients with inadequate hematologic and/or cytogenetic responses or disease progression. Results: A total of 37 patients (median age 62 years) with CML-CP were included in the analysis. The median time since first diagnosis of CML was 86 months. The median duration of prior imatinib therapy was 40.6 months with 84% being imatinib-resistant and 16% imatinib-intolerant. The median duration of prior dasatinib therapy was 6.6 months, with the majority of patients (65%) being intolerant to dasatinib therapy and 32% of patients were dasatinib resistant. Approximately half (51%) of the patients discontinued dasatinib due to grade 3/4 laboratory abnormalities or adverse events (AEs) and 32% discontinued due to disease progression. The median duration of nilotinib exposure was 218 days (7.3 months; range 43–723 days) and 65% of patients remained on nilotinib at the time of data cut-off. In total, only 4 (11%) patients discontinued nilotinib due to AEs and 9 (24%) discontinued due to disease progression. For CML-CP patients without complete hematologic response (CHR) at baseline, 81% achieved CHR with nilotinib treatment. The median time to first CHR for patients with confirmed HR was 1 month. Major cytogenetic response (MCyR) was achieved in 38% of patients with median time to first MCyR being 1 month and median duration of MCyR being 9.7 months. Complete cytogenetic response (CCyR) was achieved in 18% of patients. Estimated 1-year overall survival was 97%. The most frequent drug-related non-hematologic AEs on nilotinib were rash (22%), nausea (16%), and pruritus (14%). Newly occurring or worsening grade 3/4 hematologic laboratory abnormalities included neutropenia (38%), thrombocytopenia (24%), and anemia (5%). Other common grade 3/4 biochemical laboratory abnormalities included elevated lipase (24%), hyperglycemia (11%), elevated alanine aminotransferase (8%), and hypophosphatemia (8%). Brief dose interruptions were sufficient to manage most adverse events. Conclusions: Nilotinib is highly active in heavily pretreated CML-CP patients who failed both prior imatinib and dasatinib therapy. Importantly, most patients in this study were previously intolerant to dasatinib, and discontinuation of nilotinib in this study was uncommon. These results support nilotinib’s significant efficacy and favorable tolerability profile demonstrated in earlier trials with nilotinib as second-line therapy for the treatment of CML-CP. The frequency of adverse events among these heavily pretreated patients is low and similar to patients who failed imatinib only.

Durable Responses with the JAK1/ JAK2 Inhibitor, INCB018424, In Patients with Polycythemia Vera (PV) and Essential Thrombocythemia (ET) Refractory or Intolerant to Hydroxyurea (HU)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 313-313 ◽  
Author(s):  
Srdan Verstovsek ◽  
Francesco Passamonti ◽  
Alessandro Rambaldi ◽  
Giovanni Barosi ◽  
Peter J. Rosen ◽  
...  
Keyword(s):  
Median Duration ◽  
The United States ◽  
Study Medication ◽  
Employment Equity ◽  
Allele Burden ◽  
Platelet Counts ◽  
Upper Limit ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 313 Background: While advanced PV and ET patients at high thrombotic risk are managed primarily with HU, patients who are intolerant or refractory to HU have limited therapeutic options. Identification of a dominant gain-of-function mutation in the JAK2 kinase, V617F, in myeloproliferative neoplasms (MPNs), including PV and ET, provided a key rationale for the development of a molecularly targeted therapy for these diseases. Long term follow-up data from an ongoing trial of INCB018424, a selective JAK 1/ JAK 2 inhibitor, in PV and ET patients refractory or intolerant to HU are presented. Methods: Study 18424-256 is an uncontrolled open-label Phase 2 study being conducted at 6 sites in the United States and Italy. An initial 8-week run-in evaluation established 10-mg and 25-mg twice daily as starting doses for expansion cohorts in PV and ET, respectively; dose adjustments for safety and efficacy are allowed so that each subject is titrated to their most appropriate dose. For PV, response is defined based on Hct control in the absence of phlebotomy, improvement or elimination of palpable splenomegaly when present, and normalization of leukocytosis and thrombocytosis. For ET, response is defined based on improvement or normalization of WBC and platelet counts and, when present, elimination of palpable splenomegaly. PV results (n=34; median 108 months from diagnosis): After a median follow-up of 15 months (range 8–21), 97% of enrolled subjects achieved Hct control to <45% in the absence of phlebotomy, and all continued to maintain phlebotomy-independence at the time of last follow-up visit. Splenomegaly was present in 74% of subjects at entry: 59% of those achieved ≥ 50% reduction in palpable spleen length, or the spleen became non-palpable with all maintaining spleen response at the time of the last follow-up visit. Leukocytosis > 15×109/L was present in 47% of subjects and improved (≤ 15×109/L) or normalized (≤ upper limit of normal) in 88% and 63%, respectively. Thrombocytosis > 600×109/L was present in 38% of subjects and improved (≤ 600×109/L) or normalized (≤ upper limit of normal) in 92% and 69%, respectively. 59% of subjects achieved phlebotomy independence, resolution of splenomegaly and normalization of leukocytosis and thrombocytosis. 6 patients discontinued therapy (3 due to AEs, 2 withdrew consent, 1 for no response). Grade 3 AEs potentially related to study medication included thrombocytopenia (2 patients), neutropenia (1), renal tumor (1), asthenia (1), viral infection (1), and atrial flutter (1). No Grade 4 drug-related AEs have occurred. ET results (n=39; median 84 months from diagnosis): After a median follow-up of 15 months (range 4–21), 49% of enrolled subjects normalized platelet counts to ≤ upper limit of normal after a median of 0.5 months and for a median duration of 3.5 months. 82% maintained platelet counts < 600×109/L, for a median duration of 9.8 months. Of 14 patients with baseline platelet counts > 1000×109/L, 13 have experienced > 50% reduction. 88% maintained normal WBC (median duration 14.5 months). Palpable spleens resolved in 3 of 4 subjects; 1 reduced >50% from baseline. 49% of subjects achieved normalization of WBC and platelet counts in the presence of non-palpable splenomegaly. 9 patients discontinued therapy (4 due to AEs, 2 withdrew consent, 3 for no response). Grade 3 AEs potentially related to study medication included leukopenia (2 patients), GI disorder (1), and peripheral neuropathy (1). No Grade 4 drug-related AEs have occurred. Both patient groups demonstrated reductions in patient-reported symptom scores for pruritus, night sweats, and bone pain. Of 26 PV patients reporting pruritus at baseline (median score of 6 on a 10-point scale), 24 reported scores of 0 after a median duration of 1 month and for a median duration of 7 months. 42% of PV and 56% of ET patients had at least a 20% decrease in JAK2V617F allele burden; 6% of PV and 12% of ET had >50% decrease. Clinical responses were unrelated to the presence/absence of JAK2V617F mutation at entry or to the allele burden changes following treatment. Conclusions: Rapid and durable clinical benefits (normalization of hematological parameters, resolution of splenomegaly and alleviation of symptoms) have been demonstrated in advanced PV and ET patients with >1 year of follow-up. In this study, INCB018424 continues to be a well tolerated, effective therapy in patients with PV and ET refractory or intolerant to hydroxyurea. Disclosures: Verstovsek: Incyte Corporation: Research Funding. Levy:Incyte Corporation: Employment, Equity Ownership. Bradley:Incyte Corporation: Employment. Garrett:Incyte Corporation: Employment. Vaddi:Incyte corporation: Employment. Huber:Incyte Corporation: Employment, Equity Ownership. Schacter:Pfizer Corporation: Employment. Vannucchi:Novartis: Membership on an entity's Board of Directors or advisory committees.

Pomalidomide (POM) with Low-Dose Dexamethasone (LoDEX) in Patients with Relapsed and Refractory Multiple Myeloma (RRMM): Impact of Renal Function on Patient Outcomes

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4072-4072 ◽  
Author(s):  
David S. Siegel ◽  
Paul G. Richardson ◽  
Rachid Baz ◽  
Min Chen ◽  
Mohamed Zaki ◽  
...  
Keyword(s):  
Renal Function ◽  
Adverse Events ◽  
Safety Data ◽  
Parent Drug ◽  
Advisory Board ◽  
Investigational Drug ◽  
Employment Equity ◽  
Baseline Serum ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 4072 Background: One of the most common end-organ damage in pts with MM is renal insufficiency (RI). Patients (pts) presenting with severe RI generally have a poor outcome. However, those pts who correct their renal function achieve outcomes comparable to those of pts with normal renal function (Chanan Khan, Clin Cancer Res 2012;18:2145-63). POM is extensively metabolized and renally eliminated, with <5% eliminated as the parent drug. POM is approximately 30% protein-bound. The characteristics of POM suggest that exposure to parent drug would not be substantively affected by the degree of renal function. MM-002 is a multicenter phase 1/2 study randomizing heavily-pretreated RRMM pts to receive POM alone or POM+LoDEX (Richardson PG, et al. Blood 2011;118:abs 634). In this post hoc analysis of pts who received POM+LoDEX, safety data are analyzed according to the degree of renal function to determine whether renal function alters the safety profile of POM therapy. Methods: Eligible pts with MM who had received ≥2 prior therapies were randomized to treatment with either POM+LoDEX (POM, 4 mg/day for days 1–21 of a 28-day cycle; LoDEX, 40 mg/week) or POM alone. Pts with baseline serum creatinine >3.0 mg/dL were excluded from the study. At progression, pts receiving POM alone could receive POM+LoDEX at investigator's discretion. Pts were retrospectively categorized into three groups based on calculated baseline creatinine clearance (CrCl) by the Cockcroft-Gault formula: CrCl >60 mL/min; CrCl 45–60 mL/min; CrCl <45 mL/min. Treatment-emergent adverse events (TEAEs) were defined as any AE occurring or worsening after first treatment with study medication and within 30 days after end of treatment. All pts received aspirin, 81 to 100 mg/day, or another form of thromboprophylaxis. Results: A total of 113 pts received POM+LoDEX; the median age of these pts was 64 years (range 34–88). Median number of prior therapies was 5 (range 2–13). The majority of pts were male (62/113, 54.9%) and had an ECOG status score of 0 (32/113, 28.3%), or 1 (68/113, 60.2%). Seventy pts had CrCl >60 mL/min, 14 had CrCl 45–60 mL/min, and 26 had CrCl <45 mL/min. Only 5 pts had CrCl ≤30. The average daily dose of POM (4 mg) and the relative dose intensity (0.9) were similar across the three renal groups. Median time to first POM dose reduction by renal group was 49.5 days (d), 71.0 d, and 32.5 d respectively; treatment duration was 5.5 months (mos), 5.0 mos, and 3.4 mos, in pts with CrCl >60 mL/min, CrCl 45–60 mL/min, and CrCl <45 mL/min, respectively. Grade 3/4 TEAEs occurring in ≥10% of pts are presented in the Table. Grade 3/4 neutropenia was observed in 40% of pts with CrCl >60 mL/min, 21% of pts with CrCl 45–60 mL/min, and 54% of pts with CrCl <45 mL/min. Grade 3/4 anemia and thrombocytopenia were observed in 19%, 21%, 35% and 20%, 14%, and 15%, respectively for pts with CrCl >60 mL/min, CrCl 45–60 mL/min, and CrCl <45 mL/min. Frequently observed non-hematological grade 3/4 AEs included pneumonia and fatigue which was observed in 24%, 21%, 19% and 14%, 29%, and 8% of pts, respectively for pts with CrCl >60 mL/min, CrCl 45–60 mL/min, and CrCl <45 mL/min. Conclusions: Adverse events observed with POM, given at 4 mg/day on days 1–21 of each 28-day cycle in combination with LoDEX, were generally comparable regardless to baseline renal function, however these data are confounded by low pt numbers. A prospective study (MM-008) investigating POM in MM pts with different degrees of renal impairment is ongoing. Disclosures: Siegel: Onyx: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Millennium Pharma: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau; Celgene: Advisory Board Other, Honoraria, Speakers Bureau; Merck: Advisory Board, Advisory Board Other, Honoraria, Speakers Bureau. Off Label Use: Pomalidomide is an investigational drug and is not approved for the treatment of patients with any condition. Richardson:Celgene, Millennium, Johnson & Johnson: Advisory Board Other. Baz:Celgene, Millennium, Bristol Myers Squibb, Novartis: Research Funding. Chen:Celgene: Employment, Equity Ownership. Zaki:Celgene: Employment, Equity Ownership. Anderson:Acetylon, Oncopep: Scientific Founder, Scientific Founder Other; Celgene, Millennium, BMS, Onyx: Membership on an entity's Board of Directors or advisory committees.

A Phase II Multicenter Study of the Histone Deacetylase Inhibitor (HDACi) Abexinostat (PCI-24781) in Relapsed/Refractory Follicular Lymphoma (FL) and Mantle Cell Lymphoma (MCL)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 55-55 ◽  
Author(s):  
Andrew M. Evens ◽  
Julie M Vose ◽  
Wael Harb ◽  
Leo I. Gordon ◽  
Robert Langdon ◽  
...  
Keyword(s):  
Phase I ◽  
Phase Ii ◽  
Safety Profile ◽  
Tumor Size ◽  
Phase Ii Study ◽  
Cell Lymphoma ◽  
Single Agent ◽  
Employment Equity ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 55 Background: Abexinostat (PCI-24781) is a novel oral pan-HDACi that has previously demonstrated potent preclinical activity in lymphoma cell lines and animal models (Evens et al, Clin Ca Res 2009) as well as a tolerable safety profile in phase I solid tumor clinical studies (Undevia et al, ASCO 2008). In a phase I single-agent clinical trial in patients (pts) with multiply relapsed/refractory lymphoma and leukemia, anti-tumor activity was noted in FL and MCL; 4/4 FL pts showed durable clinical benefit with median time on treatment of >8 months; 1 of 2 MCL pts had a complete remission (CR) and remains on treatment for >3 years. Based on these encouraging single-agent abexinostat data, a phase II extension study was completed in relapsed/refractory FL and MCL. Methods: The primary objective of this phase II study was objective response rate (ORR, complete [CR] and partial remission [PR]), while reduction in tumor size (CR + PR + stable disease) and safety were also examined. Abexinostat was given orally twice daily at 45mg/m2 on a 4-week cycle for 7 days/week every other week, which is the previously established dose and schedule identified in the phase I study. For pharmacodynamic correlative analyses, tubulin and histone acetylation were measured in peripheral blood mononuclear cells (PBMCs) at pre-dose and 4 hours after the first dose of abexinostat. Results: A total of 30 pts were enrolled (n=16 FL and n=14 MCL pts) of which 25 were response-evaluable. The median age was 67 years (36–81) and the median prior therapies were 3 (1–5), 77% of which were rituximab-containing and one-third (33%) had undergone prior autologous stem cell transplant (31% FL, 36% MCL). The ORR in all pts was 48% (12/25). A reduction in tumor size was observed in 86% (12/14) of FL pts, while the ORR in FL was 64% (9/14); the FL intent-to-treat ORR was 56%. With a median follow-up of 10.3 months (1.2–20.9), the progression-free probability was 86% in FL pts. Furthermore, the median duration of response (DOR) in FL pts has not been reached, as 5 responders remain on study. Notably, 4 FL pts were on treatment for over 16 months. Among MCL pts, reduction in tumor size was noted in 27% (3/11), while the ORR was similar at 27% (3/11). The median progression-free survival (PFS) in MCL pts was 4 months (1–12), while the DOR in the 3 responding patients were 2+, 3, and 6+ months. Therapy was overall well tolerated. The most common treatment-related adverse events (AEs) of any grade (> 20% incidence) include: nausea (60%), fatigue (57%), diarrhea (50%), thrombocytopenia (37%), vomiting (30%), anemia (27%), decreased appetite (23%), dysgeusia (20%) and neutropenia (20%). The most common grade 3/4 related AEs (> 5% incidence) were thrombocytopenia (17%), neutropenia (13%), fatigue (13%), and anemia (7%). There were no deaths reported on the study. Pharmacodynamic analyses revealed that a majority of pts had increased tubulin acetylation in PBMCs, however this finding did not correlate with response or toxicity. Conclusion: In this phase II study, the novel pan-HDACi, abexinostat, was clinically active and overall well tolerated in relapsed/refractory B-cell lymphoma. The safety profile was consistent with this class of agents with <20% of subjects experiencing grade 3/4 cytopenias (during the course of prolonged treatments). Moreover, there was significant clinical activity noted in FL with an ORR of 64%, which included several durable responses in this multiply-relapsed pt population. Further examination of single-agent abexinostat in FL is warranted. Disclosures: Off Label Use: PCI24781 is not FDA approved; it is an investigational agent. Plasencia:Pharmacyclics: Employment, Equity Ownership. Sirisawad:Pharmacyclics: Employment, Equity Ownership. Yue:Pharmacyclics: Employment, Equity Ownership. Luan:Pharmacyclics: Employment, Equity Ownership. Siek:Pharmacyclics: Employment, Equity Ownership. Zhou:Pharmacyclics: Consultancy. Balasubramanian:Pharmacyclics: Employment, Equity Ownership.

Efficacy and Tolerability of Bosutinib and Imatinib in Older Versus Younger Patients with Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia–BELA Trial

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4442-4442 ◽  
Author(s):  
Carlo Gambacorti-Passerini ◽  
Tim H Brümmendorf ◽  
Dong-Wook Kim ◽  
Irina Dyagil ◽  
Hagop M Kantarjian ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Age Groups ◽  
Chronic Phase ◽  
Newly Diagnosed ◽  
Employment Equity ◽  
Kaplan Meier ◽  
Equity Ownership ◽  
Grade 3

Abstract Abstract 4442 Bosutinib (BOS) is an orally active, dual Src/Abl kinase inhibitor with activity and manageable toxicity in the phase 3 BELA trial of patients (pts) with newly diagnosed (≤6 mo) chronic phase (CP) chronic myeloid leukemia (CML). The current analysis of the BELA trial summarizes the activity and tolerability of BOS 500 mg/d and imatinib (IM) 400 mg/d among older (≥65 y; BOS n = 30; IM n = 27) versus younger pts (<65 y; BOS n = 220; IM n = 225). Sokal risk scores were balanced between treatment arms but, as expected, higher among older pts (4% low; 72% intermediate; 25% high) versus younger pts (39% low; 44% intermediate; 17% high). Minimum follow-up duration was 24 mo. BOS was discontinued by 37% of pts (57% older vs 35% younger; P = 0.023); difference between age groups was primarily due to adverse events (AEs; 39% vs 22%; most commonly increased alanine aminotransferase [ALT]). IM was discontinued by 27% of pts (35% older vs 28% younger; P= 0.496); disease progression was the primary reason. In the intent-to-treat population, cumulative rate of complete cytogenetic response (CCyR) by 24 mo in older/younger pts was 70%/80% on BOS and 78%/80% on IM. Median time to CCyR was 24.0 wk for older versus 12.7 wk for younger pts on BOS and 24.4 wk versus 24.7 wk on IM; in younger pts CCyR was achieved significantly faster on BOS versus IM (P<0.001). Among older/younger pts with a CCyR, 57%/79% on BOS and 76%/85% on IM were still on treatment and retained their CCyR as of the data cutoff. Cumulative rates of major molecular response (MMR) by 24 mo in older/younger pts were 53%/60% on BOS and 48%/49% on IM. Median time to MMR was 48.1 wk for older versus 48.0 wk for younger pts on BOS and 60.6 wk versus 84.1 wks on IM; for younger pts MMR was achieved significantly faster on BOS versus IM (P<0.001). Among older/younger pts with a MMR, 63%/84% on BOS and 92%/89% on IM were still on treatment and retained their MMR as of the data cutoff. Kaplan-Meier event-free survival in older/younger pts at 2 y was 100%/91% on BOS and 81%/88% on IM. Kaplan-Meier on-treatment transformation to accelerated/blast phase CML by 2 y was 0% for older and 2% (4 transformations) for younger pts on BOS (4 total), and 9% (2 transformations) for older and 5% (11 transformations) for younger pts on IM (13 total). Kaplan-Meier overall survival in older/younger pts at 2 y was 100%/97% on BOS and 92%/95% on IM. The majority of deaths were due to disease progression (BOS, n = 6; IM, n = 10); few deaths due to AEs on BOS (n = 1) or IM (n = 2) were reported, none treatment related. BOS was associated with higher rates of gastrointestinal TEAEs, elevated ALT and aspartate aminotransferase (AST), and pyrexia; IM was associated with higher rates of musculoskeletal TEAEs and edema (Table). Rates of common TEAEs were generally similar or higher among older pts. Pleural/pericardial effusion occurred in 6 (21%) older pts (3/6 with treatment-related events; median event duration, 36.5 d) versus 5 (2%) younger pts (all with treatment-related events) on BOS, and in no IM pts. Overall grade 3/4 TEAEs were more frequent among older pts on both BOS and IM, as was dose modification (Table). Grade 3/4 lab abnormalities of elevated ALT (BOS, 18% older/24% younger; IM, 4% each) and AST (BOS, 7%/12%; IM, 4% each) were more frequent with BOS versus IM, but similar between age groups. Grade 3/4 lab abnormalities of neutropenia were more frequent with IM (23% older/22% younger) versus BOS (11% each) regardless of age; grade 3/4 anemia (6%-14%) and thrombocytopenia (14%-23%) were generally similar regardless of age or treatment arm. In conclusion, BOS demonstrated activity in both older and younger pts with newly diagnosed CP CML. Although the frequency of certain toxicities as well as treatment discontinuations due to TEAEs was higher among older pts, the toxicity profile of BOS remained manageable and distinct from that of IM regardless of age. Event, % BOS IM ≥65 y (n = 28) <65 y (n = 220) ≥65 y (n = 26) <65 y (n = 225) Non-hematologic TEAEsa     Diarrhea 86 68 46 22     Rash 36 22 27 18     Nausea 36 32 31 37     Vomiting 32 32 19 15     Dyspnea 32 5 12 3     Pyrexia 29 17 4 13     Elevated ALT 29 32 15 8     Elevated AST 25 27 15 8     Elevated lipase 25 12 19 10     Headache 21 12 8 12     Asthenia 21 5 4 7     Dyspepsia 14 6 23 5     Muscle spasms 14 3 35 21     Periorbital edema 7 <1 35 12 Any grade 3/4 TEAE 89 65 73 56 Dose reduction due to AE 64 40 42 18 Dose interruption due to AE 89 63 69 42 Treatment discontinuation due to AE 39 22 8 9 All treated pts were included in the safety analyses. a Includes TEAEs reported for ≥20% of older or younger pts. Disclosures: Gambacorti-Passerini: Pfizer Inc: Consultancy, Research Funding; Novartis, Bristol Myer Squibb: Consultancy. Brümmendorf:Bristol Myer Squibb: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; Patent on the use of imatinib and hypusination: Patents & Royalties. Kim:BMS, Novartis, Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Kantarjian:Pfizer Inc: Research Funding. Pavlov:Pfizer Inc: Employment, Equity Ownership. Gogat:Pfizer Inc: Employment, Equity Ownership. Duvillie:Pfizer Inc: Employment. Shapiro:Pfizer Inc: Employment, Equity Ownership. Cortes:Novartis, Bristol Myers Squibb, Pfizer, Ariad, Chemgenex: Consultancy, Research Funding.

Cost-Effectiveness Analysis (CEA) of Sequential Treatment with Tyrosine Kinase Inhibitors (TKIs) for Chronic Myelogenous Leukemia (CML)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2607-2607
Author(s):  
John Whalen ◽  
Ipek Stillman ◽  
Apoorva Ambavane ◽  
Eugene Felber ◽  
Dinara Makenbaeva ◽  
...  
Keyword(s):  
Research Funding ◽  
Lifetime Cost ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
High Dose ◽  
Employment Equity ◽  
Equity Ownership ◽  
Tki Treatment ◽  
Economic Analyses

Abstract Background: Imatinib has been approved for treatment of newly diagnosed CML since 2001. For patients failing imatinib, other treatment options such as dasatinib, nilotinib, bosutinib, and high-dose imatinib are recommended. Previous economic analyses assumed that patients are treated until progression, despite guidelines recommending changing treatments for non-responders. The objective was to perform a CEA of sequential treatment with 2nd line TKIs, from a commercial payer perspective in the United States (US). Methods: A Markov-cohort model was used to simulate lifetime treatment costs and health outcomes (discounted 3.0% per annum) for patients resistant or intolerant to 1st line imatinib. It compared six treatment sequences, starting from 2nd line (shown in the results table). The model included five health states: chronic phase 2nd line TKI, chronic phase 3rd line TKI, chronic phase no TKI, post-progression, and death. After 12 months of TKI treatment, patients without a major molecular or complete cytogenetic response (MMR or CCyR) moved to the next line of therapy (per NCCN guidelines). Patients could also move to the next treatment line if they lost MMR or CCyR, or discontinued due to drug-related toxicity. Data for response achievement, risks of progression, death, adverse events, and discontinuation were primarily based on data in published trials. Due to the lack of head-to-head studies for dasatinib vs. nilotinib in 2nd line, and a lack of time-to-response data for all three 2nd line treatments, MMR and CCyR rates were interpolated from available data points in 2nd line, while dasatinib and nilotinib rates were assumed to be equal in 3rd line. Dasatinib and imatinib progression, loss of response, and survival rates for 2nd line responders were assumed equal, due to data limitations. In each health state, patients accrued drug costs, resource use (related to monitoring, AE management, and disease management) costs and quality-adjusted life years (QALYs). Resource use, cost, and utility estimates were based on FDA labels, RedBook, Medicare and AHRQ Healthcare Cost Utilization Project data, and published economic analyses. Multi-way uncertainty analyses evaluated key contributors to uncertainty in the results, by testing various assumptions for probabilities of discontinuation, response, loss of response, progression, and survival. Results: The model predicts that 2nd line dasatinib provides increased survival (ΔLYs = ~0.4-2.6 years) and QALYs (ΔQALYs = ~0.4-2.8 years) in all patient groups when compared with 2nd line high-dose imatinib or nilotinib sequences. Also, 2nd line dasatinib was more costly (ΔLifetime Costs = ~$65,000 - $225,000) than high-dose imatinib and nilotinib, primarily due to longer survival and corresponding longer time on TKI treatment. In ±20% univariate sensitivity analyses, the model was most sensitive to 2nd line progression and survival estimates. Conclusions: This analysis suggests that dasatinib may be associated with increased life expectancy and quality of life when compared with high dose imatinib or nilotinib, among patients who are resistant or intolerant to 1st line imatinib, primarily based on higher cytogenetic response rates observed in studies of dasatinib. Other studies have shown improved quality of life for responders, and landmark analyses have shown improved survival for patients achieving cytogenetic response, but head-to-head clinical studies of sequential use of dasatinib and nilotinib are needed to confirm the model result. Based on the threshold of $150,000/QALY, dasatinib can be considered cost-effective in the US. Results Table: Sequence # Sequence 1 Sequence 2 Sequence 3 Sequence 4 Sequence 5 Sequence 6 1st line (not modeled – assumes 1st line imatinib for all sequences) 2nd line DAS NIL HDI DAS NIL HDI 3rd line NIL DAS NIL BOS BOS DAS Imatinib-resistant population LYs 7 6.5 4.5 7.3 6.8 4.5 QALYs 5.9 5.4 3.6 6.2 5.7 3.6 Lifetime Cost $497,391 $431,346 $270,308 $496,897 $431,084 $270,051 ICERs: DAS followed by NIL vs. NIL followed by DAS - $129,139 DAS followed by NIL vs. HDI followed by NIL - $96,356 Imatinib-intolerant population LYs 7.8 7.1 -- 8.1 7.4 -- QALYs 6.7 6.0 -- 7.0 6.3 -- Lifetime Cost $599,270 $509,456 -- $598,766 $509,174 -- ICERs: DAS followed by NIL vs. NIL followed by DAS - $125,800 BOS=bosutinib; DAS=dasatinib; HDI= high-dose imatinib; NIL=nilotinib; ICER=incremental cost-effectiveness ratio Disclosures Whalen: Evidera, Inc.: Consultancy, Employment; Bristol-Myers Squibb: Research Funding. Stillman:Evidera, Inc.: Consultancy, Employment; Bristol-Myers Squibb: Research Funding. Ambavane:Evidera, Inc.: Consultancy, Employment; Bristol-Myers Squibb: Research Funding. Felber:Bristol-Myers Squibb: Employment, Equity Ownership. Makenbaeva:Bristol-Myers Squibb: Employment, Equity Ownership. Bolinder:Bristol-Myers Squibb: Employment, Equity Ownership.

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