The Combination of Interferon-Alpha with Imatinib in Early Chronic Phase Chronic Myeloid Leukemia Patients Induces a Significant Improvement of the Molecular Responses in the First Two Years of Treatment: Results From Three Studies From the GIMEMA CML Working Party.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2192-2192 ◽  
Author(s):  
Francesca Palandri ◽  
Fausto Castagnetti ◽  
Ilaria Iacobucci ◽  
Marilina Amabile ◽  
Gabriele Gugliotta ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Interferon Alpha ◽  
Prospective Studies ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Transcript Levels ◽  
Ifn Alpha ◽  
Number Of Patients

Abstract Abstract 2192 Poster Board II-169 Thanks to its striking effectiveness, imatinib (IM) is the current standard of therapy in chronic myeloid leukemia (CML). However, Interferon-alpha (IFN-alpha) has induced a low but reproducible curative effect in some CML patients, inducing durable remissions lasting even after therapy discontinuation. For this reason, the interest on the possible use of IFN-alpha in the treatment of CML is still substantial, and very recently some newer prospective studies from the French and the German Groups have proposed the re-introduction of IFN-alpha in the front-line treatment of early chronic phase CML (ECP-CML), in association with IM (Rousselot et al, Haematologica 2009;94:abs.1093; Hehlmann et al, Haematologica 2009;94:abs. 0478). We compared the response of 495 ECP-CML patients, enrolled into three different prospective studies promoted by the GIMEMA CML WP (419 treated with imatinib 400mg and 76 treated with imatinib 400mg plus IFN-alpha) (study protocols NCT00511121, NCT00514488 and NCT00511303). Cytogenetic analysis was performed by standard banding techniques and cytogenetic response was rated according to the European LeukemiaNet guidelines. Molecular response was assessed on peripheral blood cells by a standardized quantitative reverse-transcriptase polymerase chain reaction (RQ-PCR) method on an ABI PRISM 7700 Sequence Detector (Perkin Elmer, Faster City, CA). BCR-ABL transcript levels were expressed as a percentage according to the IS. Patients were equally distributed by Sokal risk in the two cohorts. Median follow-up was 43 mos (range, 12- 67) in the IM group and 54 mos (range, 11-63) in the IM+IFN-alpha group. Compliance to IM was excellent in both groups, with 90 to 95% of patients receiving IM 400 mg/daily throughout the follow-up. Conversely, the proportion of patients continuing IFN-alpha dropped from 41% at 12 mos to 18% at 18 mos, 13% at 24 mos, 3% at 36 mos; by the end of the fourth year, all patients were off IFN-alpha. The number of patients in CCgR was higher in the IM+IFN-alpha than in the IM group at 6 mos (60% vs 42%, p=0.002) but not from 12 mos on (Table 1). The number of patients in MMolR was higher in the IM+IFN-alpha than in the IM group at 6, 12 and 24 mos, but not later on (Table 2). Also the number of patients with undetectable Bcr-Abl transcript levels was higher in the IM+IFN-alpha group at 12 months (15% vs 5%, p=0.003) but not later on (19% vs 18% at 48 mos). These data support the preliminary analysis of the French SPIRIT group, reporting a higher rate of MMolR after initial treatment with IM and IFN-alpha as compared to IM alone. The loss of the difference from 24 mos on could be explained by the fact that almost all patients had discontinued IFN-alpha during the first two years, pointing out that the low compliance to the combination may limit its utility in practice. ACKNOWLEDGEMENT The Italian Association Against Leukemia-lymphoma and myeloma (BolognAIL), The Fondazione del Monte di Bologna e Ravenna, The Italian Ministery of Education (PRIN 2005, No. 20050 63732_003, and PRIN 2007, No 2007F7 AE7B_002), The University of Bologna, The European Union (European LeukemiaNet). Disclosures: Pane: Novartis: Research Funding; Ministero dell'Università/PRIN: Research Funding; Regione Campania: Research Funding; Ministero della Salute/Progetto integrato Oncologia: Research Funding. Saglio:Celgene: Honoraria; Novartis: Honoraria.

Chronic phase chronic myeloid leukemia patients who failed interferon alpha and switched to imatinib: Long-term 9-year follow-up of 134 patients

2015 ◽  
Vol 90 (5) ◽  
pp. E95-E96
Author(s):  
Massimo Breccia ◽  
Roberto Latagliata ◽  
Matteo Molica ◽  
Gioia Colafigli ◽  
Marco Mancini ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Interferon Alpha ◽  
Myeloid Leukemia ◽  
Chronic Phase

Dasatinib Is Well-Tolerated and Efficacious in Imatinib-Intolerant Patients with Chronic-Phase Chronic Myeloid Leukemia (CP-CML).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1128-1128 ◽  
Author(s):  
Hanna Jean Khoury ◽  
Michael J. Mauro ◽  
Yousif Matloub ◽  
Tai-Tsang Chen ◽  
Erkut Bahceci ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Median Duration ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Phase Iii ◽  
Hematologic Toxicity ◽  
Molecular Response

Abstract Abstract 1128 Poster Board I-150 Imatinib (IM), a tyrosine kinase inhibitor (TKI), has been the mainstay of treatment for chronic phase chronic myeloid leukemia (CP-CML). However, IM resistance and intolerance are of considerable clinical relevance. Dasatinib (DAS), a second-line TKI, is effective in the IM-intolerant patient population. The purpose of this study was to determine baseline factors that can affect DAS response and evaluate long term efficacy in this population. Intolerance to IM was defined as ≥ Grade 3 non-hematologic toxicity and/or Grade 4 hematologic toxicity lasting > 7 days. A total of 271 Ph+ CP-CML IM-intolerant patients who received DAS were pooled from two randomized trials (Phase II-trial, CA 180013 and Phase III trial, CA 180034). DAS doses were 50 mg BID (n=43), 70 mg BID (n=141), 100 mg QD (n=43) or 140 mg QD (n=44). At baseline, the median duration of disease for the IM-intolerant patients was 24 months (range: 0.9-182.5) and the median duration of IM therapy was 9 months (range: 0.03-69.06). Of these patients, 46 (17%) had hematologic toxicity and 228 (84.1%) had non-hematologic toxicity to IM. Seventy-nine (29%) patients had prior complete cytogenetic response (CCyR) on IM and 171 (63%) patients did not. The data for prior CyR to IM was not reported for 21 (7.7%) patients. Of the 79 patients who had achieved CCyR on IM, 30 patients had maintained CCyR and 49 patients had lost this response prior to start of DAS. Of the 171 patients who did not achieve CCyR on IM, 62 (36.3%) had been on IM for 3 12 months and 109 (63.7%) for < 12 months. At 2-year follow up of the 271 patients treated with DAS, 121 (44.6%) discontinued DAS (7.4% due to hematologic toxicity and 14% due to non-hematologic toxicity). Of the patients who were intolerant of IM due to hematologic toxicity (n=46), 10 (21.7%) discontinued DAS due to hematologic toxicity, and 3 (6.5%) due to other toxicities. Of the patients with non-hematologic IM-intolerance (n=228), 10 (4.4%) discontinued DAS due to hematologic toxicity, and 35 (15.4%) due to other toxicities. The median average daily dose of DAS was 99 mg/day in the population who achieved CCyR on DAS and 71.5 mg/day in the population who did not achieve CCyR on DAS. The probability of achieving CCyR on DAS was 43.5% in patients with hematologic IM-intolerance versus 78.9% with non-hematologic IM-intolerance. The CCyR, major molecular response (MMR), progression-free survival (PFS) and overall survival (OS) at 2-year follow up for the groups classified by their CCyR status at start of DAS or IM-intolerance status are summarized in Table 1. Conclusions DAS was well-tolerated and associated with high rates of CyR in IM-intolerant patients. Patients with a prior CCyR to IM and those who switched due to non-hematologic imatinib-intolerance had the highest rates of CCyR and MMR on DAS, while patients without CCyR after more than 12 months of IM therapy or IM-intolerance due to hematologic toxicity had the lowest rates of CCyR and MMR. Disclosures Khoury: BMS: Honoraria; Wyeth: Honoraria; Novartis Pharmaceuticals: Honoraria; Chemgenex: Honoraria; Genzyme: Honoraria. Mauro:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding. Matloub:Bristol-Myers Squibb: Employment. Chen:Bristol-Myers Squibb: Employment. Bahceci:Bristol-Myers Squibb: Employment. Deininger:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Calistoga: Research Funding; Genzyme: Research Funding.

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.

scholarly journals Very long-term follow-up results of imatinib mesylate therapy in chronic phase chronic myeloid leukemia after failure of interferon alpha therapy

Cancer ◽  
2012 ◽  
Vol 118 (12) ◽  
pp. 3116-3122 ◽  
Author(s):  
Hagop Kantarjian ◽  
Susan O'Brien ◽  
Guillermo Garcia-Manero ◽  
Stefan Faderl ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Imatinib Mesylate ◽  
Interferon Alpha ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Interferon Alpha Therapy ◽  
Long Term Follow Up ◽  
Alpha Therapy

Bosutinib Versus Imatinib in Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia – BELA Trial: 24-Month Follow-up

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 455-455 ◽  
Author(s):  
Jorge E Cortes ◽  
Anish Maru ◽  
Carmino Antonio Antonio De Souza ◽  
François Guilhot ◽  
Ladan Duvillie ◽  
...  
Keyword(s):  
Overall Survival ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Primary Reason ◽  
Newly Diagnosed ◽  
Function Test ◽  
Grade 3

Abstract Abstract 455 Introduction: Bosutinib (SKI-606) is an orally active, dual competitive inhibitor of the Src and Abl tyrosine kinases. The phase 3 BELA study compared bosutinib with imatinib in patients (pts) with newly diagnosed chronic phase (CP) chronic myeloid leukemia (CML). Methods: Pts were randomized 1:1 to open-label oral bosutinib 500 mg/d (n = 250) or imatinib 400 mg/d (n = 252) and stratified by Sokal score risk group (low, medium, high) and geographical region. The primary efficacy endpoint was complete cytogenetic response (CCyR) at 12 mo in the intent-to-treat population. Key secondary and exploratory efficacy endpoints included major molecular response (MMR) at 12 mo, time to CCyR and MMR, duration of CCyR and MMR, time to and incidence of transformation to accelerated/blast phase (AP/BP) CML, event-free survival (EFS), and overall survival. Safety analyses included all treated pts. Results: The median treatment duration was 19.3 mo for bosutinib and 19.5 mo for imatinib; 67% and 74% of pts, respectively, are still receiving therapy. The primary reason for discontinuation of bosutinib was toxicity (23%), while the primary reason for discontinuation of imatinib was disease progression (13%). Rates of CCyR and MMR are shown in the table. The rate of cumulative CCyR by 18 mo was 79% in both arms, and the cumulative rate of MMR by 18 mo was 55% in the bosutinib arm versus 45% in the imatinib arm. Median time to CCyR was faster for bosutinib versus imatinib (12.7 vs 24.6 wk); median time to MMR was also faster for bosutinib versus imatinib (36.9 vs 72.3 wk). Transformation to AP/BP CML while on treatment occurred in 4 (2%) pts on bosutinib and 13 (5%) pts on imatinib. On-study deaths from any cause occurred in 6 (2%) pts receiving bosutinib versus 13 (5%) pts receiving imatinib, and included 5 (2%) and 9 (4%) pts, respectively, who died due to CML progression. Median on-treatment EFS and overall survival were not yet reached for either arm. At 18 mo, the Kaplan-Meier estimates of EFS were 95% for bosutinib versus 91% for imatinib, and the estimates of overall survival were 99% versus 95%, respectively. Bosutinib was associated with higher incidences compared with imatinib of gastrointestinal events (diarrhea [69% vs 22%, respectively], vomiting [32% vs 14%], pyrexia [18% vs 10%], and abdominal pain [13% vs 7%]). In contrast, bosutinib was associated with lower incidences of edema (peripheral edema [4% vs 11%] and periorbital edema [1% vs 14%]) and musculoskeletal events (myalgia [5% vs 11%], muscle cramps [4% vs 22%], and bone pain [4% vs 10%]). Fewer pts on bosutinib experienced grade 3/4 laboratory abnormalities of neutropenia (11% vs 24% with imatinib), while the incidences of grade 3/4 anemia and thrombocytopenia were similar between treatment arms (8% with anemia and 14% with thrombocytopenia). Grade 3/4 liver function test abnormalities occurred more frequently with bosutinib versus imatinib (increased alanine aminotransferase [23% vs 4%] and aspartate aminotransferase [12% vs 3%]). Although common with bosutinib, gastrointestinal events and liver function test abnormalities were typically transient, managed with dose modifications, and not life threatening. Conclusions: The study did not meet the primary endpoint (CCyR at 12 mo); early discontinuation of bosutinib due to adverse events may have contributed to this observed lack of difference. However, bosutinib did result in a higher rate of MMR at 12 mo, faster times to MMR and CCyR, fewer events of transformation to AP/BP CML, and fewer overall and CML-related deaths compared with imatinib, suggesting superiority of bosutinib in pts with newly diagnosed CP CML. In addition, the 18-mo estimates for both EFS and OS currently favor bosutinib. Bosutinib and imatinib were each associated with acceptable but distinct toxicity profiles. Based on these results, bosutinib may offer a new therapeutic option for pts with newly diagnosed CP CML. Minimum of 24 mo of follow-up will be presented for all pts. Disclosures: Cortes: Pfizer Inc: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Guilhot:CHU de Poitiers: Employment; Pfizer Inc: Consultancy; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria. Duvillie:Pfizer Inc: Employment. Powell:Pfizer Inc: Employment, Equity Ownership. Countouriotis:Pfizer Inc: Employment. Gambacorti-Passerini:Pfizer Inc: Honoraria, Research Funding; BMS: Research Funding; Novartis: Honoraria; Biodiversity: Honoraria.

The Average Baseline BCR-ABL Levels Are Significantly Higher in Patients with Resistance to Dasatinib As First-Line Treatment for Early Chronic Phase Chronic Myeloid Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4436-4436
Author(s):  
Cristian Tomasetti ◽  
Hagop M. Kantarjian ◽  
Ritesh Ramchandani ◽  
Elias Jabbour ◽  
Alfonso Quintás-Cardama ◽  
...  
Keyword(s):  
Drug Resistance ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Leukemic Cells ◽  
Cancer Center ◽  
First Line ◽  
Number Of Patients ◽  
Significant Difference

Abstract Abstract 4436 Background: The development of drug resistance remains a problem for some chronic myeloid leukemia (CML) patients treated with tyrosine kinase. Point mutations are the main mechanism behind drug resistance, and they can occur prior to therapy. Thus, there may be a positive correlation between the baseline BCR-ABL levels and the occurrence of drug resistance. Methods: We define a “relapse/no-response” as a BCR-ABL/ABL transcript ratio of >10% (international scale) at 6 months or later during continuous dasatinib treatment. Statistical analysis is performed an all early chronic phase CML treated with dasatinib as first-line therapy (n=102) in a prospective clinical trial at the M.D. Anderson Cancer Center. The probability of having drug resistant leukemic cells already present at diagnosis is also estimated. Results: Seven of the 90 (7.8%) evaluable patients had a “relapse/no-response”. The mean (median) BCR-ABL/ABL transcript ratio at baseline for the “relapse/no-response” group was 23.3% (20.7%), while for the rest of the patients was 14.1% (9.9%), a statistically significant difference. The incidence rates of “relapse/no-response” for patients with a BCR-ABL/ABL transcript ratio at baseline equal to or larger than 20% was 13.8%, versus 7.8% overall for the entire dataset. Our estimates suggest that if the therapy were to be started on average one month earlier, the probability of a “relapse/no-response” would decrease from 7.8% to 6.9%. Conclusions: The BCR-ABL transcript levels at baseline are significantly higher for those patients later incurring in a “relapse/no-response”. Moreover, our estimates suggest that starting the treatment as soon as possible after diagnosis may be critical for reducing the number of patients developing drug resistance. Disclosures: Kantarjian: Novartis: Research Funding; Pfizer: Research Funding; Ariad: Research Funding; Bristol-Myers Squibb: Research Funding. Jabbour:Pfizer: Honoraria; Novartis: Honoraria; BMS: Honoraria. Cortes:Novartis: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding.

scholarly journals Outcomes of Chronic Phase Chronic Myeloid Leukemia Patients Following Tyrosine Kinase Inhibitors Dose-Reductions

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3093-3093
Author(s):  
Jee Hyun Kong ◽  
Hanna Jean Khoury ◽  
Elliott F. Winton ◽  
Leonard T. Heffner ◽  
Manila Gaddh ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Board Of Directors ◽  
Dose Reduction ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Advisory Committees ◽  
Society Research

Abstract Introduction: Tyrosine kinase inhibitors (TKI) are overall well tolerated in chronic myeloid leukemia (CML) s, but more than 30% require dose reduction or change to another TKIs due to intolerance. Impact of TKI dose-reduction on outcomes in a "real world" setting is unknown, thus, we evaluated the characteristics and outcomes of chronic phase (CP)-CML patients who received doses of TKI lower than the label/FDA recommendation. Method: CP-CML with at least 12 months of follow-up, with ISBCR/ABL1 available after dose reduction were selected. Last TKI was defined as TKI which were taken at the last follow up visit or before disease progression to accelerated (AP) or blast phase (BP). FDA approved doses of imatinib (IM), dasatinib (DAS), nilotinib (NIL), bosutinib (BOS), and ponatinib (PON) were 400mg, 100mg, 600mg (300mg BID), 500mg, and 45mg, respectively . Results: Between January 2005 and April 2016, 173 CP-CML patients, started IM (75%), DAS (18%) NIL (5%) and PON, BOS on clinical trial in 2%. Overall Fifty-eight (33.5%) patients had TKI dose reduction. IM (n=15) dose was reduced to 75% (range, 25-75), DAS (n=15) to 50% (range, 20-80), NIL (n=15) to 50% (range, 13-67), BOS (n=15) to 80% (range, 40-80) and PON (n=15) to 33% (range, 33-67). Median age for patients that received dose-reduced TKI was 55 (range, 18-88), and 27% received > 3 prior TKIs. With a median follow up of 53.6 (range 13.4-183.7) months, only 1 progressed to AP, and none to BP. Overall 60% achieved MMR. Among 35 patients who achieved MMR before dose reduction, MMR was maintained in 25 (71.4%) for a median of 17.2 (2-97.9) months from dose-reduction. CMR was achieved in patients on a maintenance dose of IM, 100mg QD (n=8); DAS, 20mg QD (n=4); NIL 300mg QD (n=3) and BOS, 200mg QD (n=3). Conclusion: Similar to data reported from clinical trials, TKI dose reduction appears to be safe and associated with high response rates. This data confirms that the minimal effective dose for each TKI remains to be defined. Disclosures Heffner: Pharmacyclics: Research Funding; AbbVie: Research Funding; Millennium: Research Funding; Celgene: Research Funding. Jillella:Leukemia Lymphoma Society: Research Funding. Kota:Ariad Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Leukemia Lymphoma Society: Research Funding; Incyte: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees.

scholarly journals Imatinib Mesylate Is Safe and Effective in Maintaining Cytogenetic and Molecular Response Achieved with 1 Year Nilotinib First Line in Newly Diagnosed Chronic Myeloid Leukemia: Preliminary Results of a Prospective Clinical Trial

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5445-5445
Author(s):  
Nour Moukalled ◽  
Radwan Massoud ◽  
Rami Mahfouz ◽  
Jean Elcheikh ◽  
Ali Bazarbachi
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Molecular Response ◽  
First Line ◽  
Metabolic Complications ◽  
Number Of Patients ◽  
Long Term Treatment

Abstract Background: Achieving complete cytogenetic response (CCyR) at 12 months for patients with chronic phase chronic myeloid leukemia (CML) treated with imatinib as first line, is associated with significantly improved progression-free survival. Nilotinib has shown a faster and higher rate of CCyR and molecular response as compared to imatinib. However, nilotinib use is associated with diet restriction, higher financial costs, and its long-term use is incriminated in cardiovascular and metabolic complications. Methods: In this prospective single center trial, we evaluated the ability of imatinib to maintain a CCyR achieved after 12 months of first-line treatment with nilotinib. Inclusion criteria were adult patients with previously untreated Philadelphia -positive CML in chronic phase, with a WHO performance status ≤ 2. Patients received 1-year treatment with nilotinib (300mg twice daily) then were shifted to imatinib 400mg daily. Results: Eleven patients (5 females) were so far enrolled in the study, with a median age at diagnosis of 50 years (range 31-83). Patients were started on Nilotinib at a median of 29 days (range 2-32) from diagnosis. One patient had to discontinue nilotinib after 6 months and start dasatinib due to recurrent pancreatitis that resolved upon interruption of nilotinib. Eight patients completed one year of nilotinib, and were switched to Imatinib. The remaining 2 patients are currently on nilotinib as per protocol (less than 12 months since inclusion). Three patients on imatinib had to be switched back to nilotinib, because of imatinib intolerance (n=2; elevated liver transaminases and myositis) or because of loss of MMR (n=1). Therefore, at last follow up (median 64 months), 5 patients are on imatinib, 5 on nilotinib and 1 on dasatinib. All patients (100%) achieved complete hematological response (CHR) and CCyR at 3 and 18 months respectively, and maintained them thereafter. At 12 months, 6 out of 8 eligible patients achieved complete molecular response (CMR; n=3) or major molecular response (MMR; n=3). At 36 months, all eligible patients (n=7) were either in CMR (n=2) or in MMR (n=5). All patients who reached 4 years (n=6), 5 years (n=5) or 6 years (n=3) of follow up remained in either MMR or CMR. No patient developed long-term serious adverse event including cardiovascular or metabolic complications. Conclusion: These findings suggest that imatinib can maintain MMR achieved on short-term nilotinib therapy. This strategy is a potentially safe and effective long-term treatment approach, minimizing costs and cardiovascular and metabolic complications. This however, needs confirmation with a larger number of patients. Table. Table. Disclosures No relevant conflicts of interest to declare.

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