Imatinib Alone (IA) Vs. Imatinib + Ara-C (IMAC): A Randomized Phase III Clinical Trial for the Treatment of Early Phase (EP) Chronic Myeloid Leukemia (CML) Ph+. Preliminary Report of Mexican Cooperative Leukemia Group (GRUMELA).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1015-1015
Author(s):  
Rafael Hurtado Monroy ◽  
Pablo Vargas-Viveros ◽  
Eduardo Cervera ◽  
Myrna Candelaria ◽  
Alvaro Aguayo ◽  
...  
Keyword(s):  
Median Time ◽  
Alkylating Agents ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
High Rate ◽  
Phase Iii ◽  
Preliminary Results ◽  
Hematologic Response ◽  
Complete Hematologic Response

Abstract Imatinib mesylate is the standard treatment for chronic phase CML. Imatinib combinations with interferon alpha or Ara-C has shown synergistic anti-proliferative effects. In an attempt to improve the rate of cytogenetic responses we compare the use of IA vs. IMAC as initial therapy in EP (< 12 months) Ph+ CML patients (pts). The study was conducted in 48 Ph+ CML pts recruited within 12 months from diagnosis with no treatment other than alkylating agents and were randomized to receive IA 400 mg/day (N= 23) or imatinib 400 mg/day plus Ara-C (subcutaneous injection) 10 mg/m2/BSA daily for 10 days monthly (N= 25). Median age for IA group is 44 years (18–75) and 38 years (20–57) for IMAC group. Median time from diagnosis of CML to inclusion was 8 months (1–12). Complete Hematologic Response (CHR) was achieved in 20 pts. (86.9%) for the IA group and in 24 patients (96%) of the IMAC group in a median time of 3 weeks (range: 1–6). With a median follow-up of 9 months (range 3–12 months) Cytogenetic Responses (CgR) in group IA were achieved in 69%: Major Cytogenetic Responses (MCgR) (Bcr/Abl 1–35%) assessed by Bone Marrow Fluorescence in situ Hybridization (FISH) (performed pretreatment and at month 3 and 6) were obtained in 11 pts (47.8%) and minor Cytogenetic Response (mCgR) (Bcr/Abl 36–90%) in 5 pts (21.7%). In the IMAC group Cytogenetic Responses were achieved in 92%: MCgR in 16 (64%) and mCgR in 7(28%). Toxicity grade III neutropenia was present in 2 pts (8.6%) of IA group and in 3 pts (12%) for the IMAC group and grade I –II nausea and edema were the most frequent adverse reactions for both groups in about 30 % of cases. Six pts (26.3%) from the IA group has no response compared with 2 (8%) from the IMAC group. Two patients from the IMAC group and 1 from IA were removed due to Cytogenetic Clonal Evolution and lost of CgR. From these preliminary results we suggest that CHR and Global Cytogenetic Response are higher in the IMAC group, meanwhile there is a lower CgR and high rate of Pts with no cytogenetic response (26.3 vs. 8%) in the IA group. It is too early to conclude definitive differences in the cytogenetic responses at this time, but it appears to be a trend to greater CgR rate for the IMAC group. Data collection and patient accrual are ongoing and results with a 18 months follow up will be presented. Preliminary Results Response Imatinib Alone Imatinib + Ara-C CHR: Complete Hematologic Response, MCgR: Major Cytogenetic Response, mCgR: Minor Cytogenetic Response, CCgR: Complete Cytogenetic Response. CHR 20/23 (89.9%) 24/25 (96%) MCgR 11 (47.8%) 16 (64%) mCgR 5 (21.7%) 7 (28%) CCgR 0 0

Dasatinib Time to and Durability of Major and Complete Cytogenetic Response (MCyR and CCyR) in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 450-450 ◽  
Author(s):  
Michele Baccarani ◽  
Gianantonio Rosti ◽  
Giuseppe Saglio ◽  
Jorge Cortes ◽  
Richard Stone ◽  
...  
Keyword(s):  
Median Time ◽  
Chronic Phase ◽  
Progression Free Survival ◽  
Cytogenetic Response ◽  
Phase Iii ◽  
Phase Ii Trials ◽  
Kaplan Meier ◽  
Imatinib Resistant ◽  
Complete Hematologic Response

Abstract Dasatinib (SPRYCEL®) is a potent BCR-ABL inhibitor that is 325-fold more potent than imatinib and 16-fold more potent than nilotinib in vitro against unmutated BCR-ABL. In this analysis, time to, duration, and rates of cytogenetic responses to dasatinib were determined using Kaplan-Meier analysis in patients recruited to phase II trials in imatinib-resistant or -intolerant CML-CP (START-C and -R), which have more than 2 years of follow-up. In both trials, patients received dasatinib at the previous dose of 70 mg twice daily (the approved dose in CML-CP is now 100 mg once daily following phase III dose optimization demonstrating improved tolerability). In START-C, imatinib-resistant and -intolerant patients were recruited, and separate analyses were performed for each group. In START-R, a randomized trial of dasatinib vs escalated-dose imatinib, only imatinib-resistant patients were recruited and patients from the dasatinib arm were analyzed prior to cross over. In all dasatinib trials, MCyRs and CCyRs were determined using conventional bone marrow cytogenetic assessment. Progression was defined as increasing white blood cell count, loss of complete hematologic response, loss of MCyR, transformation to accelerated or blast phase, or death. Among imatinib-resistant patients treated in START-C, a MCyR had been achieved at 3, 6, and 12 months by 29%, 40%, and 51%, and a CCyR had been achieved by 18%, 28%, and 39%, respectively (Table). At 24 months, MCyR and CCyR had been achieved by 55% and 44%, respectively. Among responding patients, median time to MCyR was 2.9 months and to CCyR was 5.5 months. In resistant patients who had achieved a MCyR, 94% and 84% had maintained this response 12 and 24 months after it had been initially achieved. For CCyR, 95% and 86% had maintained their response at 12 and 24 months, respectively. Progression-free survival (PFS) at 12 and 24 months for imatinib-resistant patients was 88% and 75%. In START-R, dasatinib response rates and durability were similar to those observed in the imatinib-resistant population of START-C, and median times to MCyR and CCyR were 2.8 and 4.1 months, respectively. Among imatinib-intolerant patients treated in START-C, MCyRs had been achieved at 3, 6, and 12 months by 62%, 74%, and 80%, and CCyRs by 44%, 65%, and 74%, respectively. Rates at 24 months had reached 82% for MCyR and 78% for CCyR. Median times to achieve MCyR and CCyR in the intolerant population were both 2.8 months. Among responding patients, 99% and 97% of intolerant patients were without loss of MCyR 12 and 24 months after responding, and 100% and 98% were without loss of CCyR, respectively. The 12- and 24-month PFS rates were 98% and 94%. In conclusion, dasatinib treatment results in high rates of durable MCyRs and CCyRs in patients with imatinib-resistant or -intolerant CML-CP, and responses are achieved rapidly in most patients. Table START-C START-R Overall (N=387) Resistant (n=288) Intolerant (n=99) Resistant (n=101) CCyR achieved (%) 3 months 25 18 44 22 6 months 37 28 65 29 9 months 44 34 73 35 12 months 48 39 74 37 18 months 51 42 78 43 24 months 53 44 78 44 Median time to CcyR (months) 3.2 5.5 2.8 4.1 Patients without loss of CCyR (%) 12 months 97 95 100 97 24 months 90 86 98 94 PFS (%) 12 months 91 88 98 91 24 months 80 75 94 86

Dasatinib Efficacy in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) and Pre-Existing BCR-ABL Mutations

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 449-449 ◽  
Author(s):  
Martin C Müller ◽  
Jorge Cortes ◽  
Dong-Wook Kim ◽  
Brian J. Druker ◽  
Philipp Erben ◽  
...  
Keyword(s):  
Amino Acids ◽  
Median Time ◽  
Chronic Phase ◽  
Response Rates ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Imatinib Resistant ◽  
Dasatinib Treatment

Abstract Dasatinib (SPRYCEL®) is an effective BCR-ABL inhibitor that is 325-fold more potent than imatinib and 16-fold more potent than nilotinib in vitro against unmutated BCR-ABL. Across a series of phase II and III trials, dasatinib has demonstrated durable efficacy in patients with CML following resistance, suboptimal response, or intolerance to imatinib. BCR-ABL mutations are an important cause of imatinib failure and suboptimal response. Here, the efficacy of dasatinib in patients with CML-CP who had baseline BCR-ABL mutations following imatinib treatment was analyzed using data from three trials (CA180-013, -017, and -034). Mutational assessment of the BCR-ABL kinase domain was performed using RT-PCR and direct sequencing of peripheral blood cell mRNA. Hematologic, cytogenetic, and molecular response rates were reported after ≥24 mos of follow-up. Duration of response, progression-free survival (PFS), and overall survival (OS; in 013/034) were calculated using Kaplan-Meier analysis, and rates were estimated at the 24-mo time point. Of 1,150 patients with CML-CP who received dasatinib, 1,043 had a baseline mutational assessment and were analyzed further. Of these, 402 patients (39%) had a BCR-ABL mutation, including 8% of 238 imatinib-intolerant and 48% of 805 imatinib-resistant patients. Excluding known polymorphisms, 64 different BCR-ABL mutations were detected affecting 49 amino acids, with G250 (n=61), M351 (n=54), M244 (n=46), F359 (n=42), H396 (n=37), Y253 (n=26), and E255 (n=25) most frequently affected. Dasatinib treatment in patients with or without a baseline BCR-ABL mutation, respectively, resulted in high rates of major cytogenetic response (MCyR; 56% vs 65%), complete cytogenetic response (CCyR; 44% vs 56%), major molecular response (MMR; 33% vs 45%); PFS (70% vs 83%), and OS (89% vs 94%) (Table). After 24 mos, CCyRs in patients with or without a BCR-ABL mutation had been maintained by 84% vs 85%, respectively, of those achieving this response. Among patients with mutations who received dasatinib 100 mg once daily, which has a more favorable clinical safety profile, efficacy and durability were similar (MCyR: 55%; CCyR: 41%; MMR: 36%; PFS: 73%; OS: 90%). In general, high response rates and durable responses were observed in patients with different mutation types, including highly imatinib-resistant mutations in amino acids L248, Y253, E255, F359, and H396. When responses were analyzed according to dasatinib cellular IC50 for individual BCR-ABL mutations, dasatinib efficacy was observed in 44 patients who had any of 5 imatinib-resistant mutations with a dasatinib cellular IC50 >3 nM (Q252H, E255K/V, V299L, and F317L, excluding T315I), including MCyR in 34%, CCyR in 25%, MMR in 18%, PFS in 48%, and OS in 81%. Among patients whose mutations had a dasatinib IC50 ≤3 nM (n=254) or unknown IC50 (n=83), responses and durability were comparable to patients with no BCR-ABL mutation. As expected, few patients with a T315I mutation (IC50 >200 nM; n=21) achieved a response. Among 70 patients with >1 mutation, a MCyR was achieved in 53% and a CCyR in 37%. Among patients with mutational analysis at last follow-up (n=162), 42 (26%) retained a BCR-ABL mutation (20 retained a mutation with IC50 >3 nM), 42 (26%) lost a mutation (5 lost a mutation with IC50 >3 nM), and 44 (27%) developed a new mutation (39 developed a mutation with IC50 >3 nM), with some patients counted in more than one category. Overall, this analysis demonstrates that dasatinib has broad efficacy against all BCR-ABL mutations except for T315l. For patients with BCR-ABL mutations, dasatinib treatment is associated with durable responses and favorable long-term outcomes. Table Analysis by dasatinib IC50 No BCR-ABL mutation BCR-ABL mutation BCR-ABL mutation treated with 100 mg QD >3 nM (excl. T315I) 3 nM* Unknown IC50** Some patients had >1 mutation. *Excluding patients with a concurrent mutation with dasatinib IC50 >3 nM. **Excluding patients with a concurrent mutation with known dasatinib IC50. Patients, n 641 402 49 44 254 83 Response rates (≥24 mos of follow-up), % CHR 93 90 90 82 94 96 MCyR 65 56 55 34 58 73 CCyR 56 44 41 25 47 54 MMR 45 33 36 18 34 43 Median time to MCyR, mos 2.8 2.9 2.8 5.7 2.9 2.8 Median time to CcyR, mos 3.0 5.3 3.0 5.7 5.4 3.4 24-mo PFS (95% CI), % 83 (79.8–86.5) 70 (65.3–75.2) 73 (60.1–86.3) 48 (31.2–64.7) 73 (66.6–78.9) 89 (82.3–96.3) 24-mo OS (95% CI), % 94 (91.4– 95.7) 89 (85.1– 92.1) 90 (81.2– 98.3) 81 (68.8– 93.8) 90 (85.8– 94.2) 96 (91.2–100)

Bosutinib As Therapy for Chronic Phase Chronic Myeloid Leukemia Following Failure with Imatinib Plus Dasatinib and/or Nilotinib: 24-Month Minimum Follow-up Update

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3785-3785 ◽  
Author(s):  
H. Jean Khoury ◽  
Carlo Gambacorti-Passerini ◽  
Hagop M. Kantarjian ◽  
Dong-Wook Kim ◽  
David Marin ◽  
...  
Keyword(s):  
Pleural Effusion ◽  
Chronic Myeloid Leukemia ◽  
Disease Progression ◽  
Median Time ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Grade 3

Abstract Abstract 3785 Bosutinib (BOS) is an orally active, dual Src/Abl tyrosine kinase inhibitor (TKI). This open-label, phase 1/2 study evaluated BOS in patients (pts) with chronic phase chronic myeloid leukemia (CP CML) following TKI failure. A total of 119 pts aged ≥18 y with prior imatinib (IM) failure plus dasatinib (DAS) resistance (n = 38), DAS intolerance (n = 50), nilotinib (NIL) resistance (n = 27), NIL intolerance (n = 1), or failure of DAS and NIL (n = 3) received BOS starting at 500 mg/d. Median age was 56 y (range, 20–79 y); 45% of pts were male; median time from CML diagnosis was 6.5 y (range, 0.6–18.3 y). Median BOS duration was 8.6 mo (range, 0.2–60.8 mo); 24% of pts are still on treatment. Dose escalation to BOS 600 mg/d occurred in 19% of pts. Time from last pt's first dose to data cutoff was 25 mo (median follow-up duration of 31.4 mo [range, 0.3–66.0 mo]). A confirmed complete hematologic response (CHR) was attained/maintained by 73% of evaluable pts (Table). The Kaplan-Meier (KM) probability of maintaining a CHR at 2 y was 67%. A major cytogenetic response (MCyR) was attained/maintained by 41%, including 32% with a complete cytogenetic response (CCyR). Among evaluable pts without a baseline CCyR, 36% (n = 37/102) achieved a MCyR, including 28 (28%) with a CCyR. The KM probability of maintaining a MCyR at 2 y was 71%. Of 86 pts with baseline mutation status, 40 (47%) pts had 19 unique Bcr-Abl kinase domain mutations, including 7 (8%) pts with T315I. Responses were seen across mutations (75% CHR, 43% MCyR excluding T315I), including those conferring resistance to other TKIs; responses in pts with T315I were low (29% CHR; 14% MCyR). Nine of 37 pts evaluated at baseline and treatment discontinuation had ≥1 new mutation (V299L, n = 4; L248V, n = 2; T315I, n = 2; F359C, n = 1; G250E, n = 1); 8 of 9 pts had discontinued BOS due to disease progression or lack of efficacy. On-treatment transformation to accelerated phase CML occurred in 5 (4%) pts after 16 to 428 d on study; no pt transformed to blast phase CML. KM-estimated on-treatment progression-free survival (PFS) at 2 y was 75%; KM-estimated overall survival (OS) at 2 y was 84% (Table). There were 23 (19%) deaths on study, with 6 deaths occurring ≤30 d after the last BOS dose. Most deaths were due to disease progression (n = 10 [8%]) or an adverse event (AE; n = 10 [8%]; including 1 treatment-related death due to gastrointestinal bleeding). Three deaths were due to unknown cause ≥509 d after the last BOS dose. Non-hematologic treatment-emergent AEs (TEAEs) seen in ≥20% of pts (all grades; grade 3/4) included diarrhea (82%; 8%), nausea (49%; 1%), vomiting (40%; 1%), rash (27%; 3%), headache (26%; 3%), fatigue (24%; 1%), and abdominal pain (20%; 1%). The incidence of individual TEAEs was generally similar across groups regardless of prior TKI exposure. Diarrhea TEAEs were predominantly grade 1/2, first reported early during treatment (median time to first event of 1.5 d [range, 1–210 d]), and transient (median event duration of 2 d [range, 1–524 d]). The incidence of pleural effusion was highest among DAS-intolerant pts (n = 11 [22%], including 3 pts with grade 3 events); for 9 of 11 pts pleural effusion had been indicated as a reason for intolerance to prior DAS. Grade 3/4 laboratory abnormalities reported in ≥10% of pts included thrombocytopenia (25%), neutropenia (19%), lymphopenia (17%), and hypermagnesemia (12%). Dose reductions and interruptions were used to manage AEs in 50% and 66% of pts. A total of 32 (27%) pts discontinued treatment due to an AE, most commonly hematologic events. In conclusion, BOS therapy continues to demonstrate durable efficacy and manageable toxicity after follow-up of ≥24 mo in CP CML following resistance or intolerance to multiple TKIs, with a majority of pts maintaining response at 2 y and few new transformations, deaths, TEAEs, or discontinuations due to AEs since the prior report ∼1 y earlier (Blood 2012;119:4303–12). n (%) IM + DAS-R IM + DAS-I IM + NIL-R IM + DAS ± NILa Total Evaluableb 37 49 25 4 115     CHR 23 (62) 39 (80) 19 (76) 3 (75) 84 (73) Evaluableb 36 44 26 4 110     MCyR 12 (33) 21 (48) 10 (39) 2 (50) 45 (41)     CCyR 7 (19) 19 (43) 7 (27) 2 (50) 35 (32) Treated 38 50 27 4 119     PFS at 2 yc 70% 81% 79% 38% 75%     OS at 2 yc 77% 85% 92% 75% 84% R, resistant; I, intolerant. a Includes 3 pts with prior exposure to all 3 TKIs and 1 NIL-I pt. KM rates may be unreliable due to the small number of pts in this cohort. b Received ≥1 dose of BOS and had a valid baseline response assessment. c Based on KM estimates Disclosures: Gambacorti-Passerini: Pfizer Inc: Consultancy, Research Funding; Novartis, Bristol Myer Squibb: Consultancy. Kantarjian:Pfizer: Research Funding. Kim:BMS, Novartis, Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Marin:Novartis: Research Funding; BMS: Research Funding. Dorlhiac-Llacer:Novartis, Bristol Myer Squibb, Pfizer: Research Funding. Bullorsky:Novartis, BMS: Consultancy, Speakers Bureau. Leip:Pfizer Inc: Employment. Kelly:Pfizer Inc: Employment, Equity Ownership. Turnbull:Pfizer Inc, l3/Inventiv Clinical Solutions: Employment. Besson:Pfizer Inc: Employment. Cortes:Novartis, Bristol Myers Squibb, Pfizer, Ariad, Chemgenex: Consultancy, Research Funding.

Nilotinib in chronic myeloid leukemia patients in accelerated phase (CML-AP) with imatinib (IM) resistance or intolerance: Longer follow-up results of a phase II study

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 7057-7057
Author(s):  
P. D. Le Coutre ◽  
F. Giles ◽  
A. Hochhaus ◽  
J. F. Apperley ◽  
G. Ossenkoppele ◽  
...  
Keyword(s):  
Median Duration ◽  
Elevated Serum ◽  
Chronic Phase ◽  
Dose Intensity ◽  
Cytogenetic Response ◽  
Serum Lipase ◽  
Prior Therapy ◽  
Hematologic Response ◽  
Grade 3

7057 Background: Nilotinib is a potent and highly selective BCR-ABL inhibitor approved for the treatment of Ph+ CML patients (pts) in chronic phase or AP who are resistant or intolerant to prior therapy including IM. This study evaluated the efficacy and safety of nilotinib (400 mg bid) in CML-AP pts resistant or intolerant to IM. Methods: Primary endpoint was confirmed hematologic response (HR). Secondary endpoints included major cytogenetic response (MCyR), time to progression, overall survival (OS), and safety. Results: 137 CML-AP pts (80% IM-resistant; 20% IM-intolerant with resistance) with minimum follow-up of 11 months (mos) (median age, 57 years; median duration of prior IM treatment, 28 mos) were included. IM-intolerant pts were also IM-resistant and without MCyR at study entry. 79% pts had prior IM ≥600 mg/day. Median dose intensity of nilotinib was 775 mg/day and median duration of exposure was 272 days. 56% had confirmed HR and 31% had complete hematologic response (CHR). 30% of IM-resistant and 37% of IM-intolerant pts achieved CHR. Responses were rapid, with a median time to first HR of 1 mo. HRs were durable at 24 mos with 54% of pts maintaining their response. MCyR was achieved in 32% of pts (30% in IM-resistant, 41% in IM-intolerant) and complete cytogenetic response in 20% of pts (18% in IM-resistant, 30% in IM-intolerant). Cytogenetic responses were also durable with 70% of pts maintaining MCyR at 24 mos; 83% of pts maintained CCyR at 12 mos. Estimated OS at 24 mos was 67%. Only 9% of pts discontinued therapy due to drug-related adverse events (AE). The most frequently reported grade 3/4 laboratory abnormalities were thrombocytopenia (41%), neutropenia (42%), anemia (25%), elevated serum lipase (18%), and hypophosphatemia (14%). The rates of grade 3/4 myelosuppression were low, predictable, and easily managed with median onset of 14 to 29 days and median duration of 8 to 26 days. Grade 3/4 non-hematologic AEs were rare (< 1%) and included nausea, fatigue, and diarrhea. Conclusions: These long-term follow-up results confirm that nilotinib induces rapid and durable responses in CML-AP pts who failed prior IM due to intolerance or resistance, with a favorable risk/benefit. [Table: see text]

Dasatinib dose-optimization study in chronic phase chronic myeloid leukemia (CML-CP): Three-year follow-up with dasatinib 100 mg once daily and landmark analysis of cytogenetic response and progression-free survival (PFS)

2009 ◽  
Vol 27 (15_suppl) ◽  
pp. 7007-7007
Author(s):  
R. M. Stone ◽  
D. W. Kim ◽  
H. M. Kantarjian ◽  
P. Rousselot ◽  
A. Hochhaus ◽  
...  
Keyword(s):  
Chronic Phase ◽  
Progression Free Survival ◽  
Treatment Interruption ◽  
Cytogenetic Response ◽  
Phase Iii ◽  
Dose Optimization ◽  
Once Daily ◽  
Optimal Dosing ◽  
Optimization Study

7007 Background: The recommended dosing regimen of dasatinib for CML-CP is now 100 mg once daily (QD) (previously 70 mg twice daily [BID]), based upon a phase III dose-optimization study (CA180–034) that enrolled patients (pts) with CML-CP with resistance, intolerance, or suboptimal response to imatinib. While therapeutic milestones have been established for pts with CML-CP treated with imatinib, they have not been well established for pts treated with second-line TKIs. Methods: Pts were randomized using a 2 × 2 factorial design to one of four treatment arms: 100 mg QD (n = 167), 70 mg BID (n = 168), 140 mg QD (n = 167), or 50 mg BID (n = 168). Details of study design and endpoints have been described previously. Results: After a minimum of 24 months of follow-up, the 24-month PFS rate with 100 mg QD was 80% (vs. 75%-76% in other arms) and the overall survival rate was 91% (vs. 88%-94%). In all arms, high response rates were achieved in pts with or without a baseline BCR-ABL mutation. Dasatinib 100 mg QD was well tolerated and rates of key side effects showed only a minimal increment from 12 to 24 months. Among the four treatment arms, significant differences were observed in rates of drug-related pleural effusion (all grades: p = 0.049) and cytopenia (p = 0.003 for grade 3/4 thrombocytopenia), with lowest rates observed for 100 mg QD. Dasatinib 100 mg QD treatment resulted in the lowest rates of treatment interruption, reduction, and discontinuation. In addition to providing 36-month follow-up, the likelihood of achieving long-term endpoints based on cytogenetic status at 6, 12, and/or 18 months will be presented. Conclusions: Dasatinib 100 mg once daily remains the optimal dosing schedule for pts with CML-CP. The landmark analyses to be presented should provide useful information to clinicians treating imatinib-resistant, -suboptimally responding, or -intolerant CML-CP pts with dasatinib 100 mg once daily based on cytogenetic response at key intervals. [Table: see text]

Significance of Suboptimal Response to Imatinib, as Defined by the European LeukemiaNet, in Long-Term Outcome for Patients (Pts) with Chronic Phase (CP) Chronic Myeloid Leukemia (CML).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1932-1932 ◽  
Author(s):  
Yesid Alvarado ◽  
Hagop Kantarjian ◽  
Stefan Faderl ◽  
Jan Burger ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Chronic Phase ◽  
Cytogenetic Response ◽  
Term Outcome ◽  
Long Term Outcome ◽  
Complete Hematologic Response ◽  
Starting Dose ◽  
Prognostic Implications ◽  
Definition Of

Abstract The European LeukemiaNet recently published recommendations for evaluating response to imatinib among pts with CML. Criteria for failure and suboptimal responses were proposed. The significance of failure is accepted and constitutes grounds for change in treatment. The prognostic implications of having a suboptimal response are less clear making treatment decisions less clear in this setting. We analyzed the outcome of 281 pts treated with imatinib as frontline therapy for CML in CP: 73 at initial dose of 400mg daily and 208 at 800mg daily. Their median age was 48 yrs (range, 15 to 84 yrs) and their median follow-up 48 months (mo) (2–79 mo). After 3 mo of therapy none of the 273 evaluable pts met definition of suboptimal response according to the European LeukemiaNet, while 3 of 273 (1%) met definition for failure. At 6 mo 10/259 (4%) evaluable had suboptimal response and 9 (3%) failure. At 12 mo 19/246 (8%) had suboptimal and 14 (6%) failure, and at 18 mo 91/224 (41%) had suboptimal and 21 (9%) had failure. The probability of having a suboptimal response at 6 and 12 mo was significantly higher for pts treated with a starting dose of 400mg than those treated at 800mg: at 6 mo [12% suboptimal at 400mg vs 1% at 800mg (p=0.002)] and at 12 mo [17% and 4%, respectively (p&lt;0.001)]. The outcome at 24 months* by the response at specific times was as follows: Time Response % CCyR % MMR % Transf % Event CCyR=Complete cytogenetic remission, MMR=Major molecular remission, Transf=Transformation to accelerated or blast phase, Event=loss of complete hematologic response, loss of major cytogenetic response, transformation, or death 6 mo Optimal 91 60 2 6 Suboptimal 0 0 30 50 Failure 0 0 22 67 P .001 .001 .001 .001 12 mo Optimal 94 63 2 4 Suboptimal 56 25 0 16 Failure 0 0 21 57 P .001 .001 .001 .001 18 mo Optimal 98 85 0 1 Suboptimal 93 39 2 5 Failure 15 0 19 43 P .001 .001 .001 .001

Outcomes of Patients with Chronic Phase CML Who Discontinued Ponatinib in the Frontline Setting

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1580-1580
Author(s):  
Preetesh Jain ◽  
Hagop M Kantarjian ◽  
Elias Jabbour ◽  
Zeev Estrov ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Clinical Trial ◽  
Median Time ◽  
Research Funding ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
The Other ◽  
Molecular Response ◽  
Vascular Events ◽  
Grade 3

Abstract Background: Ponatinib is a novel TKI efficacious in relapsed refractory patients (pts) with CML and in those with T315I mutation. Despite the achievement of deep early responses in most pts observed in the frontline setting, the concern for arterio-thrombotic events led to the discontinuation (DC) of ponatinib frontline clinical trial. In this study, we have assessed the outcomes after DC of ponatinib of pts in a clinical trial of frontline ponatinib in CML-CP. Methods: Fifty one pts with CML-CP were treated with frontline ponatinib in a single-arm, clinical trial between May 2012 and September 2013. Initial dose of ponatinib was 45 mg orally daily in 43 pts and, after amendment, 30 mg in 8 pts. All pts DC ponatinib therapy after June 2014 and were switched to another TKI. Patients were assessed for cause of DC, treatment received after ponatinib DC, response achieved/maintained on subsequent TKI, adverse events (AE) and survival after ponatinib DC. Survival was calculated from the time of ponatinib DC to the time of last follow up. Results: All 51 patients DC ponatinib: 38 per FDA recommendation and 13 due to AE. Median duration of ponatinib therapy was 13.2 months (range-2.1-25.4). At the time of DC, 47/51 (92%) pts were in complete cytogenetic response (CCyR) and 4 (8%) in partial cytogenetic response (PCyR); 1 pt DC before 3-mo evaluation. Forty (78%) pts were in MMR and 26 (51%) in molecular response 4.5-log (MR4.5). Thirty-six (70%) pts were switched to dasatinib, 7 (14%) to imatinib, and 4 (8%) each to nilotinib and bosutinib. After switching to another TKI, with a median of 13 months (range, 0.2 to 26.3) of follow-up, 2 pts have lost their cytogenetic response (both PCyR on ponatinib), 1 pt improved from PCyR to CCyR and one maintained PCyR; all 47 (92%) pts with CCyR on ponatinib maintained this response. Molecular responses improved in some pts: 6 improved from no MMR to MMR; 1 to MR4.5 (median time on ponatinib 4 months; median time on subsequent TKI 17 months); 11 from MMR to MR4.5 (median time on ponatinib 13 months; median time on subsequent TKI 17 months). One pt (treated with imatinib 400) lost MR4.5 to no MMR after 2 months. At last follow-up 37 pts (72%) had MR4.5 and 45 (90%) MMR. Two pts died after ponatinib DC. One pt was treated with imatinib 400 and developed grade-3 edema and recurrent lung cancer; the second was switched to dasatinib and had recurrent progressive peripheral arterial disease (PAD). Four pts had events (2 deaths, 1 secondary MDS with -7 and 1 pt lost major CyR). Median post ponatinib survival (Figure-1) and median post ponatinib event free survival (not shown) was not reached (1-year OS 98% and EFS 95%). Forty five pts continued on their first post-ponatinib TKIs, 5 required 2 post-ponatinib TKI and 1 pt received 3 different TKIs after DC. The most common cause for post-ponatinib TKI switch was toxicity (n=6). Of the 36 pts switched to dasatinib, 5 discontinued: 4 due to pleural effusion and 1 with acute renal failure. 29/36 pts (81%) were in MMR before switch and all maintained MMR; 4 pts achieved MMR after switch to dasatinib. Four pts developed grade 3-4 non hematological vascular AEs (3 among pts with such events while on ponatinib and 1 new vascular event within 3 months of ponatinib DC). Of the 4 pts switched to nilotinib, 1 DC within 3 months due to grade-3 pancreatitis and also developed grade-1 pulmonary hypertension with 1 month of discontinuing ponatinib. This pt was then switched to bosutinib. The other 3 pts maintained MMR and had no vascular events. Of the 4 pts switched to bosutinib, one developed MDS, one was switched back to ponatinib off protocol (patient's choice), 1 lost cytogenetic response and one DC therapy after 1 month and maintains MR4.5 (this pt had TIA while on ponatinib, developed cerebral infarct within 1 month post ponatinib). Seven pts switched to imatinib. One developed a new PAD within 3 months of ponatinib DC (history of MI while on ponatinib). The other 6 pts maintained MMR on imatinib. Overall, 15 pts who had aggravated hypertension on ponatinib were under control after DC of ponatinib. Conclusion: Treatment with 2nd generation TKIs and imatinib was effective and safe in pts who DC ponatinib, and most pts were able to maintain/improve the responses achieved on ponatinib. Ponatinib-associated hypertension was usually reversible after DC and most vascular events with subsequent TKIs occurred in patients with prior such events while on ponatinib. Figure 1. Post ponatinib survival in patients Figure 1. Post ponatinib survival in patients Disclosures Jabbour: pfizer: Research Funding; ariad: Research Funding; teva: Consultancy; teva: Research Funding; pfizer: Consultancy; bms: Consultancy; ariad: Consultancy. Estrov:incyte: Consultancy, Research Funding. Pemmaraju:Stemline: Research Funding; Incyte: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; LFB: Consultancy, Honoraria. Cortes:Pfizer: Consultancy, Research Funding; BerGenBio AS: Research Funding; Novartis: Consultancy, Research Funding; Teva: Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Ambit: Consultancy, Research Funding; Arog: Research Funding; Celator: Research Funding; Jenssen: Consultancy.

The Frequency of Detection of BCR-ABL Mutations in Imatinib Treated Patients with Chronic Phase CML Who Attain a Complete Cytogenetic Response (CCR) Does Not Diminish with Increasing Duration of CCR but the Associated Loss of Response Is Usually Gradual.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 271-271
Author(s):  
Susan Branford ◽  
Z. Rudzki ◽  
A. Grigg ◽  
J. Seymour ◽  
P. Browett ◽  
...  
Keyword(s):  
Early Stage ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Progression Free Survival ◽  
Cytogenetic Response ◽  
Free Survival ◽  
Loss Of Response ◽  
Gradual Loss ◽  
Complete Hematologic Response

Abstract The majority of patients with chronic phase (CP) CML treated with imatinib achieve a CCR, which is associated with a high progression-free survival (PFS). Nevertheless, BCR-ABL mutations have been observed in patients in ongoing CCR. We previously reported that virtually all patients with mutations develop evidence of resistance. The current analysis of 211 patients with CP CML aimed to determine the incidence of mutations in those who achieve CCR, assess whether the incidence varies with increasing duration of CCR, and evaluate the rate of loss of response in those who do develop mutations. BCR-ABL levels measured by quantitative RT-PCR at 1–6 month intervals were used to guide the frequency of mutation analysis. All patients were screened for mutations at least 6 monthly. Of the 211 patients, 159 (75%) achieved CCR after a median of 3 months (25th to 75th percentile 3–6 months), and were then followed for a median of 12 months after achieving CCR (25th to 75th percentile 6–28 months). Twelve patients lost CCR and this was associated with the development of a mutation in 8 (67%). The median time to loss of CCR was 3 months after the mutation was detected (range 1–10 months). Three of these 12 patients proceeded to transplant, and 9 received an increased imatinib dose (4 maintaining a major cytogenetic response (MCR); 3 re-establishing CCR). Only 1 of the 12 lost a complete hematologic response (CHR) (patient had 2 mutations) and none have progressed to blast crisis (BC) with a median follow-up of 9 months (range 6–38 months) including 3 patients with P-loop mutations, which have been associated with a poorer prognosis. As well as the 8 patients who lost CCR after a mutation was detected, mutations were detected in 3 patients who have maintained CCR; 2 had an increased imatinib dose. The detection of a mutation was associated with a rise in the BCR-ABL level in all patients with mutations. Of the 159 patients in CCR, mutations were detected in 11 of 25 (44%) with a &gt;2-fold rise in BCR-ABL whereas none of 131 patients with stable or decreasing BCR-ABL had a mutation detected (P&lt;0.0001). The probability of developing a mutation by 24 months after achieving CCR was 12% (95% CI 4–20%). The risk of developing a mutation did not vary with time during CCR, with 6.7% (95% CI 2.1–11.3%) during the first 12 months of CCR, and 6.0% (95% CI 0–12.8%) during the second 12 months (P=0.8). Patients who had a mutation detected while in CCR still had a favorable PFS (defined as sustained MCR/CHR and lack of evolution to accelerated phase/BC) of 90%, 15 months after the mutation was detected. Patients were censored at time of transplant. This relatively favorable outcome may be related to the rapid response in terms of dose intensification. In conclusion, BCR-ABL mutations may still be detected in patients with a low burden of CML and this risk does not appear to diminish up to 24 months in CCR. We observed a gradual loss of response in patients who did develop a mutation in CCR and none have yet progressed to BC. Thus we recommend that patients in CCR should be closely monitored with regular QPCR studies. Such a policy will usually identify patients with emerging resistance at an early stage and facilitate appropriate therapeutic intervention before disease progression.

Results of a Phase II Trial Testing Interferon Alpha 2b and Cytarabine in Children with Chronic Myelogenous Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1000-1000
Author(s):  
Frédéric Millot ◽  
Joelle Guilhot ◽  
Brigitte Nelken ◽  
Jean-Pierre Lamagnère ◽  
Thierry Leblanc ◽  
...  
Keyword(s):  
Children And Adolescents ◽  
Median Time ◽  
Progression Free Survival ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Hematologic Toxicity ◽  
Hematologic Response ◽  
Interferon Alpha 2B ◽  
Day Range ◽  
Complete Hematologic Response

Abstract Before the Imatinib era, a prospective phase II trial was conducted in 2000 to assess the efficacy and the tolerance a combination of interferon alpha 2b (IFN) and cytarabine in children and adolescents with chronic myelogenous leukemia in first chronic phase without a suitable HLA-identical donor. Children received daily IFN (5 million units/m2) and subcutaneous cytarabine (20 mg/m2) for monthly course of 10 days. Between September 2000 and March 2003, 14 children (10 males, 4 females) median age 12 years (range 2–16.5) were recruited from 12 french centres. Patients (pts) were evaluated for time to, rate of hematologic and cytogenetic responses, toxicity and progression free survival. The median duration of follow-up is 13 months (range 2–32 mo). Eight pts achieved a complete hematologic response after a median time of treatment of 3 months (range 0–4 mo) including a pt enrolled in complete hematologic response after 1 month of therapy with hydroxyurea. Three pts were not evaluable for the cytogenetic response (early discontinuation for toxicity, no achievement of complete hematologic response within 3 months of treatment, progression). The best cytogenetic response by 12 months was: major response in 7 pts including complete cytogenetic response in 2 pts, minor response in 3 pts and failure in 1 pt. The median time to major cytogenetic response was 7 months (range 3–12 mo). Thirteen pts discontinued treatment protocol with a median time of 11 months for the following reasons: absence of complete hematologic response at 3 months (2 pts), loss of hematologic response (2 pts), absence of major cytogenetic response at 12 months (1 pt ), loss of major cytogenetic response (2pts), progression (3 pts), adverse event (1pt), other (2 pts). Probability of progression free survival at 18 months was 66% (95% CI, 34–98%). No treatment-related death occurred. The most frequently reported drug-related events were fever, mucositis, neutropenia and thrombocytopenia. Grade 3 and 4 non hematologic toxicity (fever and mucositis) was observed in 4 pts and grade 3 and 4 hematologic toxicity (anemia, neutropenia and thrombocytopenia) in 7 pts. The median total dose of IFN and cytarabine administered was 3.7 million units/m2 /day (range 2.3–5.1) and 20 mg/m2 /day (range 11–23). The median duration of IFN therapy was 11 months (range1–117 mo). The median number of courses of cytarabine was 7 (range 1–37). The combination of IFN and cytarabine is a well tolerated therapy providing hematologic and cytogenetic responses in children and adolescents with CML. Rates of hematologic and cytogenetic responses compare favourably with results observed in adults. Results should be compared to these of imatinib in children and adolescents.

Characteristics and Outcome of Patients with Chronic Myeloid Leukemia (CML) and T315I Mutation Following Failure of Imatinib Mesylate Therapy.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1943-1943
Author(s):  
Elias Jabbour ◽  
Hagop Kantarjian ◽  
Dan Jones ◽  
Srdan Verstovsek ◽  
Alessandra Ferrajoli ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Cell Transplant ◽  
2Nd Generation ◽  
Hematologic Response ◽  
T315i Mutation

Abstract Background. T315I is an imatinib pocket binding mutation within the Bcr-Abl kinase domain that is highly resistant, both in vitro and in vivo, to imatinib and to 2nd generation tyrosine kinase inhibitors (TKIs). Several studies have suggested that patients with T315I have a poor outcome. Study Aims. The objectives of this study were to define the clinical characteristics of patients harboring the T315I mutation, and to assess their outcome after imatinib failure. Results. T315I was detected in 27 pts: 20 among a series of 186 pts assayed after imatinib failure (11% of all pts; 21% of all mutations detected) after a median of 37 months (mos) from start of imatinib, and 7 among 23 pts who developed new mutations after a median of 10 mos on therapy with a 2nd generation TKI. Median age was 52 years. Median time from diagnosis to T315I was 41 mos, and the median follow-up from the detection of mutation is 18 mos. At the time of T315I detection, 10 pts were in CP, 9 in AP, and 8 in BP. Fifteen pts (56%) had transformed to accelerated or blast phase at the time of T315I detection. Best response to TKI immediately preceding development of T315I (20 imatinib, 2 nilotinib, 2 dasatinib, 2 bosutinib, 1 INNO-406) was CHR in 13 (48%) and CyR in 9 (33%; complete in 6, partial in 1, minor in 2). The median duration of response was 44 mos. Except for the lack of response to a second TKI (p=0.001), there was no difference in pt characteristics between pts with or without T315I, other mutations, or no mutations. Among the 20 pts with T315I present prior to start of 2nd TKI, 5 responded, all hematologic (3 complete hematologic response -CHR-, 2 partial hematologic response -PHR-, 1 return to chronic phase); in contrast all 5 pts without T315I prior to 2nd TKI, responded (1 major molecular response -MMR-, 2 Minor cytogenetic response -CyR-, 1 CHR, 1 PHR); and among the 2 pts with unknown T315I status at start of 2nd TKI 1 had PHR and 1 complete cytogenetic response -CCyR-. Responses were usually transient but 3 pts had sustained responses for some time despite presence of T315I: 1 pt in AP harboring simultaneously F317L and G250E acquired a T315I mutation 5 mos after the start of nilotinib and achieved MMR that was sustained for 21 mos eventually lost to major CyR. A 2nd pt in AP treated with bosutinib acquired a T315I mutation 6 months after the start of bosutinib, but nonetheless achieved a minor CyR that has been sustained for more than 8 mos. A third patient with Y253H mutation developed T315I 1 mo after therapy with INNO-406 for CML AP; at the last follow-up, 4 months into therapy, he maintained a PHR. 4/14 pts (38%) treated with T315I-directed agents (aurora kinase inhibitors, homoharringtonine) responded. 4 pts received allogeneic stem cell transplant (ASCT) and 2 are alive: 1 in CMR 24+ months after ASCT and 1 in CCyR 9 months after ASCT, wit molecular relapse and recurrence of T315I. 11/27 pts with T315I (40%) died. Patients in CP had better outcome with 87% 2-year survival, compared to 45% in AP and 20% in BP. Survival of patients with T315I was similar to those with other mutations or without mutations (p=0.64). Conclusion. Altough T315I is a mutation highly resistant to conventional BCR-ABL TKI, occasional responses can be observed. Overall survival of patients with T315I mutations is mostly dependent on the stage of the disease.

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