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)

Response and Outcomes to Nilotinib at 24 Months in Imatinib-Resistant Chronic Myeloid Leukemia Patients in Chronic Phase (CML-CP) and Accelerated Phase (CML-AP) with and without BCR-ABL Mutations.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1130-1130 ◽  
Author(s):  
Jerald P. Radich ◽  
Giovanni Martinelli ◽  
Andreas Hochhaus ◽  
Enrico Gottardi ◽  
Simona Soverini ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Advisory Committees ◽  
Imatinib Resistant

Abstract Abstract 1130 Poster Board I-152 Background Nilotinib is a selective and potent BCR-ABL inhibitor, with in vitro activity against most BCR-ABL mutants (excluding T315I) indicated for the treatment of patients with Philadelphia chromosome positive (Ph+) CML in CPor AP resistant or -intolerant to prior therapy, including imatinib. In a previous analysis of nilotinib in patients with BCR-ABL mutations, mutations occurring at three specific amino acid residues (E255K/V, Y253H, and F359C/V) were shown to be associated with less favorable response to nilotinib. The current analysis is based on mature data with a minimum follow-up of 24-months for all patients. Outcomes of patients at 24 months were analyzed by mutation type. Methods Imatinib-resistant CML-CP (n = 200) and CML-AP (n = 93) patients were subdivided into the following mutational subsets: no mutation, sensitive mutations (including mutations with unknown in vitro IC50). or E255K/V, Y253H, or F359C/V mutations at baseline. Patients with mutations of unknown in vitro sensitivity were classified as sensitive in this analysis based on a previous finding that patients with these mutations responded similarly to nilotinib as patients with sensitive mutation. Patients with baseline T315I mutations were excluded from this analysis. Patient groups were analyzed for kinetics and durability of cytogenetic and molecular response to nilotinib, as well as event-free survival (EFS), defined as loss of hematologic or cytogenetic response, progression to AP/BC, discontinuation due to disease progression, or death, and overall survival (OS). Results In CML-CP and -AP patients with no mutation, sensitive mutations, or E255K/V, Y253H, or F359C/V mutations, hematologic, cytogenetic and molecular responses are provided in the Table. Overall, patients with no mutations responded similarly to patients with sensitive mutations, whereas patients with E255K/V, Y253H, or F359C/V mutations had less favorable responses. This correlation was observed in both CML-CP and CML-AP patients, respectively. Median time to CCyR was 3.3 months (range, 1.0–26.7) for CML-CP patients with no mutations, and 5.6 months (range, 0.9–22.1) for patients with sensitive mutations. At 24 months, CCyR was maintained in 74% of CML-CP patients with no mutation and in 84% of patients with sensitive mutations. One patient with CML-CP and an E255K mutation achieved CCyR at 25 months and maintained until last assessment at 30 months. Median time to MMR was similar at 5.6 months (range, 0.9–25.8) for CML-CP patients with no mutations and 5.6 months (range, 2.7–22.1) for patients with sensitive mutations. No patient with a less sensitive mutation achieved MMR. Median EFS and 24-month estimated OS rate are provided in the Table. Conclusions Imatinib-resistant CML-CP and CML-AP patients treated with nilotinib therapy with BCR-ABL mutations (excluding E255K/V, Y253H, or F359C/V) achieved rapid and durable cytogenetic responses, and estimated EFS and OS at 24 months similar to that of patients with no mutations, respectively. Patients with E255K/V, Y253H, or F359C/V mutations had lower and less-durable responses and shorter EFS than patients with sensitive mutations. Alternative therapies may be considered for patients with these uncommon mutations (E255K/V, Y253H, and F359C/V). Disclosures Radich: Novartis: Consultancy, Honoraria, Research Funding. Hochhaus:Novartis: Research Funding. Branford:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Shou:Novartis: Employment. Haque:Novartis: Employment. Woodman:Novartis: Employment. Kantarjian:Novartis: Research Funding. Hughes:Bristol-Myers Squibb: Advisor, Honoraria, Research Funding; Novartis: Advisor, Honoraria, Research Funding. Kim:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Wyeth: Research Funding. Saglio:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau.

Clinical Outcome of CML Patients with Philadelphia Chromosome Complex Variants.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4499-4499
Author(s):  
Santiago del Castillo ◽  
Regina Garcia Delgado ◽  
Laura Entrena ◽  
Agustin M Hernandez ◽  
Arturo Campos ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Philadelphia Chromosome ◽  
Genetic Material ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Current State ◽  
Worse Prognosis

Abstract Abstract 4499 INTRODUCTION: The presence of translocation between chromosomes 9 and 22 that characterizes the chronic myeloid leukemia (CML) is occasionally accompanied by more complex variations involving additional exchange of genetic material with other chromosomes. This variants of Philadelphia chromosome have no worse prognosis than those others with the common translocation. MATERIAL: Since 1997 we have diagnosed in our hospital 5 CML patients who didn't show any of these variants. Three women 17, 23 and 76 years old and two men of 36 and 65. All of them diagnosed in chronic phase. Risk stage at diagnosis by Sokal were 1 high, 1 intermediate and 3 low. By Hasford 2 were intermediate end 3 low. Philadelphia chromosome variants involve a third chromosome in 4 cases (translocations 2;9;22, 9;22;12, 9;22;9 and 6;9;22) and in one case involving four chromosomes (translocation 1;2;9;22). Three patients diagnosed before the imatinib approval started treatment with IFN and Ara-C and subsequently changed to Imatinib treatment. Two others started treatment with imatinib directly. RESULTS: All patients had a good outcome with treatment being the current state of 2 patients in complete molecular response (105 and 60 months of follow-up) and 2 patients in Major Molecular Response (146 and 143 months). The 5th patient, a 17 years old woman, has been treated for three months with Imatinib and showed complete haematological response at first month and major cytogenetic response at third month. It is striking in this last patient the fact that two years earlier had been referred for study of myeloid moderate leukocytosis (20,000 leukocytes with circulating myeloid progenitors without anemia, thrombocytosis, or splenomegaly). The patient didn't come to clinic when Bone Marrow Test was cited and two years later resumes the visit continuing with the same leukocytosis in peripheral blood and without splenomegaly unchanged despite not having received any treatment. CONCLUSION: Our experience confirm that this type of patients with complex translocation variants have no worse prognosis than normal translocation under imatinib treatment and suggests that may have a more benign clinical behavior. Disclosures: No relevant conflicts of interest to declare.

BCR-ABL RNA Levels at the Time of a Complete Cytogenetic Response (CCR) Predict the Duration of CCR in Imatinib-Treated Chronic Myeloid Leukemia Patients.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1098-1098
Author(s):  
Richard D. Press ◽  
Zac Love ◽  
Ashlie A. Tronnes ◽  
Gwen Kurilik ◽  
Michael J. Mauro ◽  
...  
Keyword(s):  
Chronic Phase ◽  
Cytogenetic Response ◽  
Imatinib Therapy ◽  
Log P ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Log Reduction ◽  
Complete Cytogenetic Response ◽  
Rna Levels

Abstract Background : Imatinib induces a complete cytogenetic response (CCR) in the majority of patients with chronic phase CML. CCR is durable in the majority of patients, but relapse occurs in a subset. To determine the potential of quantitative RT-PCR (qPCR) of BCR-ABL to predict cytogenetic relapse, we serially monitored residual disease in 90 CML patients with an imatinib-induced CCR. Methods and patients : mRNA was prepared from total nucleated cells from blood or bone marrow, and cDNA was synthesized using random hexamer primers. Relative BCR-ABL expression was then measured by real-time fluorescent PCR normalized for G6PDH expression. This assay has a detection limit of 1 CML cell in 100,000 and an analytical precision of 6% (CV). At the start of imatinib therapy, 85% of patients were in chronic phase, at a median 9.5 months after diagnosis. Patients were treated with imatinib alone (64%) or in combination with interferon or cytarabine (32%). One patient each was treated with imatinib in combination with either the farnesyltransferase inhibitor tipifarnib, donor leukocytes (after allogeneic BMT), or an experimental heat shock protein (hsp70) vaccine. During the imatinib follow-up time of 28 months (median), disease monitoring occurred by cytogenetics and qPCR (median 6 samples per patient). The CCR was achieved after 9.7 months (median) of imatinib therapy. Results : At the time of first achieving CCR, BCR-ABL RNA levels had decreased by a median of 1.8 logs below the median baseline level. During further follow-up, 26 patients (29%) experienced cytogenetic relapse (defined as any Ph-positive metaphase cell) at a median 6.0 months after CCR and a median 20 months after starting imatinib. There was no difference in the imatinib treatment time, the time to achieve CCR, or the post-CCR follow-up period between the patients with and without subsequent cytogenetic progression. qPCR data at the time of first CCR were available for 78 patients, including 25 of 26 with a subsequent cytogenetic relapse. The reduction of BCR-ABL RNA at the time of first achieving CCR was significantly less in those patients with a subsequent cytogenetic relapse (median 1.4 log) compared to those with a sustained CCR (median 2.0 log) (P=0.002). In the 64 patients with a sustained CCR, the molecular response progressively improved over time to reach a median reduction of 4.0 log at 15 months after CCR. Of the 29 patients achieving at least a 2 log reduction of BCR-ABL RNA at the time of first reaching CCR, only 3 (10%) had a subsequent cytogenetic relapse. In comparison, 22 of 49 patients (45%) with a less than 2 log reduction at the time of achieving CCR had a subsequent cytogenetic relapse (odds ratio = 7.1; 95% CI 1.9–26). At the time of first achieving CCR, a reduction in BCR-ABL RNA of less than 2 logs thus had a diagnostic sensitivity of 88% and a diagnostic specificity of 49% for predicting subsequent cytogenetic relapse. Conclusions : We conclude that, in the majority of imatinib-treated CML patients reaching CCR, the level of BCR-ABL RNA at the time that the CCR is first achieved is a sensitive predictor of the durability of the CCR. The availability of a laboratory marker capable of stratifying the subsequent risk of disease progression (early in remission) will be useful in targeting additional (or alternative) therapies to those patients with the highest risk.

Patients with Chronic Phase CML in the IRIS Study Who Receive Imatinib Mesylate (IM) 2nd Line after Prior IFN/Ara-C Have Sustained Complete Cytogenetic and Major Molecular Response Rates Similar to 1st Line IM Patients.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2139-2139
Author(s):  
Jaspal Kaeda ◽  
Andreas Hochhaus ◽  
Jerald Radich ◽  
Susan Branford ◽  
Charlene So ◽  
...  
Keyword(s):  
Chronic Phase ◽  
Response Rates ◽  
Cytogenetic Response ◽  
Progression Rate ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Real Time Quantitative Pcr ◽  
Log Reduction ◽  
Advanced Phase

Abstract The IRIS study compared IM and interferon+cytarabine (IFN/Ara-C) in patients (pts) with newly diagnosed CML-CP (n=553 per arm). IFN/Ara-C pts. could cross over to IM if they satisfied predetermined criteria for disease, either resistance/refractoriness (=resistance), or intolerance of or reluctance to continue the combination (=lack of resistance). Pts who received IM 1st line or 2nd line who achieved a complete cytogenetic response (CCyR) had BCR-ABL transcript levels measured serially by real-time quantitative PCR (RQ-PCR). Results were expressed as log reduction in BCR-ABL/BCR from a standardized baseline value for untreated pts. Yearly rates of 3 log reduction (Major Molecular Response, MMR) from IM treatment starting date were estimated by multiplying the CCyR rate by the MMR rate in CCyR pts at each time point. Overall, of 553 pts who received 1st line IM 82% achieved CCyR, an estimated 69% during the 1st year (yr) of treatment. Of 359 pts who received 2nd line IM, 80% achieved CCyR, 62% during the 1st yr; rates were lower in pts with resistance than in those without resistance to prior IFN/Ara-C (75% vs 85% overall, p=0.025, 56% vs 68% within first yr, p<0.01). Best observed and estimated molecular responses for CCyR pts. are summarized in the table. The median follow-up for BCR-ABL evaluation on 1st line vs 2nd line IM was 45 and 35 months, respectively. Molecular response on 1st- and 2nd-line IM in the IRIS study 1st-line IM 2nd-line IM after IFN/Ara-C All pts N = 553 All pts N = 359 Resistance N =174 Lack of resistance N =185 CcyR 454 (82%) 288 (80%) 131 (75%) 157 (85%) Pts with CCyR during treatment and PCR sample(s) N = 401 N = 211 N = 98 N = 113 –≥3 log reduction (MMR) 323 (81%) 154 (73%) 63 (64%) 91 (81%) –≥ 4 log reduction 216 (54%) 92 (44%) 35 (36%) 57 (50%) Estimated % of all pts who achieve CCyR and MMR by – 1 yr 36 24 19 28 – 2 yr 59 38 29 45 – 4 yr 67 67 58 72 – 5 yr 85 82 78 84 Overall response rates were similar between 1st and 2nd line IM pts, although responses in 2nd line IM pts may have occurred more slowly. However, the number of RQ-PCR samples between 1 and 2 yrs of 2nd line IM was limited as samples were not obtained routinely between Jan 2003 and Aug 2004. In pts who achieved CCyR, the estimated 5-yr progression rate to advanced CML phase was 3% for 1st line IM and 4% for 2nd line IM; using the broader definition of progression (including events such as CML-unrelated deaths and loss of MCyR/CHR) the progression rates were 9% and 8% respectively. In both 1st and 2nd line IM pts with CCyR who also achieved MMR, only an estimated 1% progressed to advanced phase within 5 yrs; the estimated broadly defined event rates were 5% and 4% respectively. In summary, for 1st line IM patients with a RQ-PCR follow-up of up to 5 yrs, an estimated 85% achieved MMR at 5 yrs compared with 59% at 2 yrs. Cytogenetic and molecular response rates were similar for 1st line and 2nd line IM pts, primarily due to responses in pts who crossed over for reasons other than resistance or refractoriness. For IM pts the rate of progression to advanced CML phase at 5 yrs was low in those with CCyR and even lower in pts who also achieved MMR.

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.

Efficacy of Dasatinib in Patients with Chronic-Phase Chronic Myelogenous Leukemia with Resistance or Intolerance to Imatinib: 2-Year Follow-Up Data from START-C (CA180-013).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 734-734 ◽  
Author(s):  
Richard M. Stone ◽  
Hagop M. Kantarjian ◽  
Michele Baccarani ◽  
Jeffrey H. Lipton ◽  
Timothy Hughes ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Interferon Α ◽  
Hematologic Toxicity ◽  
Molecular Response ◽  
Imatinib Resistant ◽  
Grade 3

Abstract Dasatinib (SPRYCEL®) is 325-fold more potent than imatinib against BCR-ABL in vitro and binds to BCR-ABL in both the inactive and active, oncogenic conformations. Dasatinib has been shown to be an effective treatment option for patients with imatinib-resistant or -intolerant chronic-phase chronic myelogenous leukemia (CP-CML). Here we report the extended follow-up of START-C, a 75-center, international study of dasatinib in 387 patients with CP-CML with resistance (n=288) or intolerance (n=99) to imatinib. Recruitment took place from February to July 2005. Dasatinib was administered on a 70-mg BID regimen; dose escalation (90 mg BID) or reduction (50 or 40 mg BID) were allowed for lack of response or toxicity, respectively. Median time from diagnosis of CML was 61 mo (range 32–50). Prior therapy included interferon-α in 65% of patients and stem-cell transplantation in 10%; 55% had received prior imatinib doses >600 mg and 53% treatment with imatinib for >3 years. Best response to prior imatinib therapy was complete hematologic response (CHR) in 82%, and complete (CCyR) and partial cytogenetic response (PCyR) in 19% and 18%, respectively. With a median follow-up of 15.2 mo, CHR was attained in 91% of patients (95% CI 87–93%), major cytogenetic response (MCyR) in 59% (95% CI 54–64%) (52% imatinib-resistant, 80% imatinib-intolerant), and CCyR in 49% (40% imatinib-resistant; 75% imatinib-intolerant). For patients with no prior MCyR to imatinib, 42% achieved a MCyR with dasatinib. A MCyR rate of 59% was recorded for patients with baseline BCR-ABL mutations; responses were seen across all mutations with the exception of T315I. MCyRs were durable, with only 7 of the 230 patients who had achieved a MCyR with dasatinib losing this response. Major molecular response rate (ie, a BCR-ABL/ABL ratio of <0.1% according to the international scale by RQ-PCR) at 12 mo was 25%. Progression-free survival at 15 mo was 90% while overall survival was 96%. Dose interruptions were required for 87% of patients and dose reduction for 73%; the average daily dose administered was 101 mg (range 11–171). Reports of grade 3–4 thrombocytopenia and neutropenia were documented for 48% and 49% of patients, respectively. Non-hematologic toxicity consisted primarily of diarrhea (37%), headache (32%), fatigue (31%), and dyspnea (30%). Pleural effusion was experienced by 27% of patients; this was categorised as grade 1–2 in 21% and grade 3–4 in 6%. Dasatinib-induced cytogenetic responses remain durable in patients with CP-CML resistant or intolerant to imatinib. Updated analyses corresponding to a minimum follow-up of 2 years on all patients will be presented.

Nilotinib Efficacy According to Baseline BCR-ABL Mutations in Patients with Imatinib-Resistant Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3216-3216 ◽  
Author(s):  
Andreas Hochhaus ◽  
Dong-Wook Kim ◽  
Giovanni Martinelli ◽  
Timothy P. Hughes ◽  
Simona Soverini ◽  
...  
Keyword(s):  
Clonal Selection ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Response Rates ◽  
Cytogenetic Response ◽  
Kinase Domain ◽  
Molecular Response ◽  
Abl Kinase ◽  
Imatinib Resistant

Abstract Resistance or intolerance to imatinib in CML-CP occurs in ~20–30% of cases. The most frequent cause of resistance is clonal selection of cells harboring BCR-ABL kinase domain mutations. Nilotinib is a rationally designed, selective and potent BCR-ABL inhibitor with activity against most BCR-ABL mutants (not T315I) indicated for the treatment of Ph+ CML patients (pts) in chronic (CP) or accelerated phase (AP) resistant or intolerant to prior therapy including imatinib. This subanalysis of a phase II study of nilotinib in imatinib-resistant CML-CP pts assessed the occurrence of BCR-ABL mutations at baseline and during nilotinib treatment and their impact on treatment outcome after 12 months of nilotinib therapy. Of 321 CML-CP pts, 281 (88%) had baseline mutation data available, 114/281 (41%) had detectable BCR-ABL mutations prior to nilotinib therapy. The frequency of mutations at baseline was 55% among imatinib-resistant pts (n=192) and 10% among imatinib-intolerant pts (n=89). 23% of imatinib-resistant pts had mutations that were sensitive to nilotinib in vitro (IC50 ≤150 nM). These 12 different mutations (n=44) spread across the entire BCR-ABL kinase domain including P-loop, A-loop, and other regions. 14% of imatinib-resistant pts had 3 mutations that were less sensitive to nilotinib in vitro (IC50 &gt;150 nM; Y253H, E255K/V, and F359C/V) and another 15% had a total of 16 mutations with unknown sensitivity to nilotinib. In imatinib-resistant pts lacking baseline mutations, after 12 months of therapy, major cytogenetic response (MCyR) was achieved in 60%, complete cytogenetic response (CCyR) in 40%, and major molecular response (MMR) in 28% of pts. In pts with detectable mutations, 51% achieved MCyR, 32% CCyR, and 20% MMR. Cytogenetic response rates in pts harboring mutations sensitive to nilotinib (MCyR 59%; CCyR 41%) or mutations with unknown sensitivity to nilotinib (MCyR 63%; CCyR 50%;) were comparable to those for pts without baseline mutations (MCyR 60%; CCyR 40%). Pts with mutations less sensitive to nilotinib in vitro had less favorable response after 12 months of therapy (23% MCyR). Pts with baseline mutations had a higher rate of disease progression during nilotinib treatment compared to pts without baseline mutations (46% vs. 26%). Different rates of progression were also observed with different mutations: 34% (15/44) of pts with mutations sensitive to nilotinib vs. 69% (18/26) with mutations less sensitive to nilotinib progressed. Mutations most frequently associated with progression were E255K/V (6/7) and F359C/V (9/11). Progression was defined as any of the following: investigator’s evaluation as progression, development of CML-AP or blast crisis, loss of CHR, loss of MCyR. During nilotinib therapy, 48/281 (17%) pts had newly detectable mutations, which were more frequent in pts with baseline mutations than in pts without baseline mutations (29% vs. 9%, respectively). The majority of pts without baseline mutations also did not have newly detectable mutation at the time of progression (n=14/18) suggesting that pts without baseline mutations are less likely to progress due to newly detectable mutations. In the 63 pts who progressed, 29% had no detectable mutation at progression, suggesting the involvement of alternative mechanisms of resistance in these pts. Overall, nilotinib treatment results in significant cytogenetic responses in pts with imatinib-resistant CML-CP with or without BCR-ABL mutations. The majority of imatinib-resistant pts with detectable BCR-ABL mutations at baseline also responded to nilotinib. Pts with BCR-ABL mutations sensitive and with unknown sensitivity to nilotinib in vitro achieved significant response rates with nilotinib therapy, comparable to those for pts without baseline mutations.

Results of Imatinib Therapy In Patients with Early and Late Chronic-Phase Chronic Myeloid Leukemia In a South Brazilian Cohort.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4487-4487
Author(s):  
Marcelo Capra ◽  
Mariza Shaan ◽  
Katia Fassina ◽  
Mario Sérgio Fernandes ◽  
Marco Antônio Schilling ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Second Line Therapy ◽  
Line Therapy ◽  
Sokal Score ◽  
Hasford Score

Abstract Abstract 4487 Background: Imatinib treatment for Chronic Myeloid Leukemia (CML) was first introduced in Brazil in 2001, initially used as second line therapy for patients resistant or intolerant to interferon (IFN). In 2008 imatinib was adopted as front-line therapy for chronic-phase (CP-CML) and clinical experience is improving since then, but little is known about the result of its introduction in our clinical practice. Aims: To evaluate the impact of imatinib treatment in the outcomes of a cohort of CP-CML and the prognostic significance of Sokal and Hasford scores and late-onset treatment. Methods: We conducted a retrospective study in a cohort of patients with CP-CML from a south Brazilian database. All patients received imatinib 400mg as first or second-line therapy. Patient evaluation and response criteria followed the European LeukemiaNet. The outcomes were response to treatment, event-free survival (EFS) and overall survival (OS). Results: We analyzed data from 185 pts with CP-CML diagnosed since 1990. The median age at diagnosis was 48 years (4 – 85). The median time from diagnosis to imatinib was 7 months (0 – 178) and 29% of pts had more than 12 months lapse. Prior therapy with IFN was used in 70% pts. All pts had a minimum follow-up of 12 months. At baseline, 57 pts (31%) were in complete hematological response (CHR) due to the use of previous treatment. Of the 127 pts not in CHR at baseline, 98% achieved CHR early during imatinib treatment. 177 pts had cytogenetic evaluation during treatment and 9 pts were in complete cytogenetic response (CCyR) due to the use of previous IFN. Of the 168 pts not in CCyR at baseline, 86,4% achieved a major cytogenetic response (MCyR) during imatinib treatment (84% had a CCyR and 2,4% had a partial cytogenetic response). The rate of pts achieving MCyR any point during treatment differed significantly in the low, intermediate and high risk Sokal score groups (97%, 81% and 78% respectively, P=0,04), but not in the Hasford score groups (90%, 85% and 72%, P=0,22). Minor cytogenetic response was seen in 3,6% of pts, minimal cytogenetic response in 6% and 9,5% had no cytogenetic response. The median time to a MCyR was 9 months, with 62% of pts achieving MCyR at 12 months. The rate of pts achieving MCyR in 12 months differed significantly between pts who start imatinib before 12 months from diagnosis (68%) and those late treated (47%, P=0,02). Evaluation of minimal residual disease at the molecular level was available for 155 pts: 25,5% of pts had a complete molecular response (CMR), 43% had a major molecular response (MMR) and 2 pts were in MMR at baseline due to previous IFN. The projected EFS and OS rates at 4 years were, respectively, 68% and 92% after a median follow-up time of 4 years. The rate of EFS differed significantly in the low, intermediate and high risk Sokal score groups (80%, 66% and 52% respectively, P=0,04), but not in the Hasford score groups (78%, 62% and 44%, P=0,09). During treatment with imatinib, 120 pts (65%) had a register of any grade hematologic adverse event (21% being grades 3 or 4) and 165 pts (90%) had a register of any grade nonhematologic adverse event (9,3% being grades 3 or 4). Of the 185 pts who received treatment, 134 (72%) continue to receive imatinib and 51 (28%) discontinued treatment. The reasons for discontinuation were: 11 (6%) pts had drug-related adverse events (3 [1,6%] hematologic and 8 [4,3%] nonhematologic), 17 (9,2%) had disease progression (5 [2,7%] loss of CHR, 10 [5,4%] loss of CCyR, 2 [1%] had progression to accelerate or blastic phase), 22 (11,9%) had treatment failure (3 [1,6%] had no CHR, 13 [7%] had no CCyR and 6 [3,2%] had no MMR), 1 pt (0,5%) discontinued due to comorbidity. For the 51 (100%) pts that discontinued imatinib, 31 (61%) switched to dasatinib, 17 (33%) to nilotinib, 1 (2%) to hydroxyurea, 1 (2%) to other treatment and 1 (2%) remained without treatment. Sixteen pts (8,6%) died during imatinib treatment or during long-term follow-up after discontinuation of imatinib. Conclusions: In our population of CP-CML pts treated with imatinib, a majority of patients achieved complete cytogenetic and major molecular responses, with a prolonged of OS and EFS and good safety profile. Sokal score showed better prognosis prediction than Hasford. Early onset of imatinib therapy led to better outcomes and justifies imatinib as front-line treatment of our patients. Disclosures: No relevant conflicts of interest to declare.

The Role of Early Cytogenetic Response in Patients with Chronic Myeloid Leukemia Treated with Imatinib and the Impact of Adherence and Comorbidities

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4423-4423
Author(s):  
Laura Fogliatto ◽  
Marcelo Capra ◽  
Mariza Shaan ◽  
Tito Vanelli Costa ◽  
Mayde Seadi Torriani ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Median Time ◽  
Myeloid Leukemia ◽  
Cytogenetic Response ◽  
Imatinib Therapy ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Major Molecular Response ◽  
Complete Cytogenetic Response

Abstract Abstract 4423 Background Treatment of chronic myeloid leukemia with imatinib leads to disease remission in a majority of patient, but in some patients (pts) controlling the disease remains a challenge. One of the proposed prognostic factors for identifying this subset of pts is the treatment response in the first months of therapy. Objectives We conducted a study to evaluate the importance of the early complete cytogenetic response (CCyR) and the factors associated with its achievement. Methods This is a retrospective study in a cohort of pts with chronic-phase chronic myeloid leukemia (CP-CML) enrolled in 14 Hematology centers in South Brazil. All pts received imatinib 400mg as first or second-line therapy. Early-imatinib treatment was considered when imatinib started before 12 months (mo) from diagnosis. Patient evaluation and response criteria followed the ELN recommendations. The ACE-27 (Adult Comorbidity Evaluation-27) is a 27 item comorbidity index for patients with cancer and assign weights from 1 to 3 based on the dysfunction grade of each condition (mild, moderate and severe, respectively). An ACE-27 score was applied to each patient. Imatinib suspensions were considered if superior to 20 days at any point during therapy. EFS was measured from the start of imatinib to the date of any of the following events while on therapy: death from any cause, loss of complete hematologic response, loss of complete cytogenetic response, discontinuation of therapy for toxicity or lack of efficacy, or progression to accelerated phase or blastic phase. Results We analyzed data from 450 pts with CP-CML diagnosed since 1990. The median age at diagnosis was 48 yr (4 – 85) and 55% were male. The median time from diagnosis to imatinib was 7 mo (0 – 178) and 71% pts were early-imatinib treated. Prior therapy with interferon was used in 60% pts. The median of follow-up was 47 mo. With 6 months of imatinib therapy, 198 pts (44%) achieved CCyR. In this group, the four year cumulative incidence of events was 33 (17%) and the EFS was 75,5%. 252 (56%) were not in CCyR at 6 months of therapy. In this group, a greater proportion of cumulative of events was observed: 86 (34%), and the EFS was 62,3%. This difference was significant (P=0,03; Figure 1). In this group of pts, 63% achieved CCyR after 6 months any time during follow up and the median time for CCyR in these pts was 17 months. The chance of achieving major molecular response (MMR) during follow up was 79% for the pts with CCyR at 6 months compared to 53% for the group with no CCyR at 6 months (P<0,001). Some factors were associated with reduced chance of CCyR at 6 months. In a multivariate analysis, the pts with late-onset imatinib treatment (more than 12 mo from diagnosis) had a CCyR rate of 31%, in contrast, the pts who started imatinib before 12 mo had a rate of 50% (P=0,02). The pts with good adherence to treatment had greater CCyR rate than those with poor adherence (interruption greater than 20 days), 51,4% and 35%, respectively (P=0,04). Comorbidity measured by ACE-27 score also influenced the CCyR rates at 6 months: 54% of score 0 (no comorbidity) patients achieved CCyR, compared to 30% of pts with score 1 (mild comorbidity), 33% of pts with score 2 (moderate) and 47% of pts with score 3 (severe) (P=0,009). The greater CCyR rate in the severe comorbidity group probably lacks significance due to the reduced number of pts in this group (22). Conclusions A great proportion of pts achieve CCyR after 6 months of imatinib therapy, nevertheless, the pts who achieve CCyR by 6 months of therapy have greater proportion of major molecular response and event-free survival. Imatinib therapy should be started as soon as possible and additional efforts must be taken to avoid nonadherence. Finally, special attention should be given to pts with comorbidities as their results tend to be worse. Disclosures: No relevant conflicts of interest to declare.

Second-line bosutinib (BOS) for patients (pts) with chronic phase (CP) chronic myeloid leukemia (CML): Final 10-year results of a phase 1/2 study.

2021 ◽  
Vol 39 (15_suppl) ◽  
pp. 7009-7009
Author(s):  
Carlo Gambacorti-Passerini ◽  
Tim H. Brümmendorf ◽  
Dong-Wook Kim ◽  
Yeow Tee Goh ◽  
Irina S Dyagil ◽  
...  
Keyword(s):  
Phase 1 ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Dose Intensity ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Second Line ◽  
Prior Therapy ◽  
Kaplan Meier ◽  
Imatinib Resistant

7009 Background: BOS is approved for Philadelphia chromosome (Ph)+ CML resistant/intolerant to prior therapy and newly diagnosed Ph+ CP CML. In a phase 1/2 study, second-line BOS showed durable efficacy and manageable toxicity in pts with imatinib-resistant (IM-R) or -intolerant (IM-I) Ph+ CP CML. Methods: This final efficacy and safety analysis of the phase 1/2 study and extension study was based on ≥10 y of follow-up (FU). Ph+ CP CML pts who received BOS starting at 500 mg/d after prior treatment (Tx) with imatinib only were included. Results: 19% of pts were on BOS at y 10, and 13% were still on BOS at study completion after ≥10 y; 19% completed ≥10 y of FU. Median duration of Tx and FU were 26 and 54 mo, respectively. Median (range) dose intensity was 436 (87–599) mg/d. The most common primary reasons for permanent Tx discontinuation were lack of efficacy (unsatisfactory response or disease progression; 27%) and adverse events (AEs; 26%). In pts with a valid baseline assessment, cumulative complete cytogenetic response (CCyR), major molecular response (MMR) and MR4 rates (95% CI), respectively, were 50% (43–56), 42% (35–49) and 37% (30–44) (IM-R: 48% [41–56], 46% [37–55] and 39% [31–48]; IM-I: 53% [41–64], 36% [25–48] and 33% [22–45]). Responses were durable, with estimated probabilities of maintaining CCyR, MMR and MR4 > 50% after ≥10 y (Table). At 10 y, cumulative incidence of on-Tx progression/death was 24% and Kaplan-Meier (K-M) overall survival 72% (Table); 55 deaths (IM-R: n = 41; IM-I: n = 14) occurred on study, none BOS-related. Any grade Tx-emergent AEs (TEAEs) in ≥40% of pts were diarrhea (86%), nausea (46%) and thrombocytopenia (42%). Pleural effusion, cardiac and vascular TEAEs occurred in 13%, 12% and 11% of pts, respectively. 28% of pts had AEs leading to permanent Tx discontinuation; most common (≥2% of pts) were thrombocytopenia (6%), neutropenia (2%) and alanine aminotransferase increased (2%). Conclusions: These 10-y data are consistent with prior results of durable efficacy and manageable toxicity with second-line BOS and support long-term BOS use in CP CML pts after imatinib failure. Clinical trial information: NCT00261846 and NCT01903733. [Table: see text]

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