scholarly journals Outcomes of Chronic Phase (CP) Chronic Myeloid Leukemia (CML) Patients (pts) Surviving More Than 5 Years (yrs) after Initial Therapy with TKIs

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 5442-5442
Author(s):  
Eran Tallis ◽  
Hagop M. Kantarjian ◽  
Catherine Kendall Major ◽  
Maria Vazquez ◽  
Gautam Borthakur ◽  
...  
Keyword(s):  
Research Funding ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Initial Therapy ◽  
Treatment Discontinuation ◽  
Molecular Response ◽  
Equal Distribution ◽  
Genetics Research

Abstract Background: The introduction of tyrosine kinase inhibitors (TKIs) as the first line of treatment for CP-CML changed the natural history of the disease. The life expectancy of CML pts is now approaching that of the general population, with more pts having the option to discontinue treatments after achieving deep molecular response (DMR). In this study we sought to explore long-term outcomes of CML survivors including late relapses, durability of response, comorbidities, and feasibility of treatment discontinuation. Methods: We performed a chart review of pts with CP CML treated at our institution with frontline TKIs who have survived at least 5 yrs from initiation of their treatment. Results: We analyzed 388 pts treated with frontline TKIs between the years 2000-2011: 57% started treatment with imatinib, 22% with nilotinib and 21% with dasatinib. We grouped pts into two cohorts: those who received only one TKI throughout the entire follow up period (n= 299; 77%) and those who changed TKIs due to relapse or toxicity (n=89; 23%). The median follow up duration was 12 yrs [5-19] for both groups. Median overall Survival (OS) for pts surviving at least 5 yrs was not reached for those remaining on one TKI whereas OS for those who changed TKIs was 151 mo (p=0.27). For those who changed therapy, there was an equal distribution of initial TKI (p=0.67). Seventy patients (18%) required a change in TKI more than 5 years after starting treatment. After 5 years of treatment best response was MR4.5 in 66%, major molecular response (MMR) in 20%, complete cytogenetic response (CCyR) in 8%, partial cytogenetic response (PCyR) in 1%, and complete hematologic response (CHR) in 3%. Nine patients had lost CHR (2%) and 4 had progressed to blast phase before the 5 yr mark. At last follow up, 77% of patients had achieved MR4.5, 12% MMR, 3% CCyR, 1% PCyR, and 4% CHR. Eleven patients lost CHR (3%) with 6 patients progressing into blastic phase. Ninety two percent of patients with MR4.5 at 5 years of treatment maintained their response, and 8% lost MR4.5: 6% to MMR, 1% to CCyR, and 1% to CHR. Sixty six percent of patients with MMR at 5 years of treatment improved their response to MR4.5, 21% maintained MMR and 13% lost response - 5% to CCyR, 5% to CHR, and 3% lost CHR. Fifty five percent of patients in CCyR at 5 years improved their response to MMR (35%) or MR4.5 (19%) while 26% of patients lost cytogenetic response. Out of the patients who improved their response, 29% did so after starting a new TKI. More patients who never changed TKI achieved MR4.5 compared to those who who changed TKIs at some point (70%) (p=0.0021). Treatment discontinuation was considered for pts who sustained MR4.5. Forty nine pts (13%) discontinued TKIs after a median time of 9 yrs [5-17]. Withdrawal symptoms were observed in 24% of pts and primarily included joint or muscle pain. After a median follow up of 2 yrs [0-7] after discontinuation, 90% of pts remained in MR4.5. Five pts (10%) lost MR4.5 after discontinuation: 4 (8%) remained in MMR and 1 (2%) lost MMR to CHR. All these patients resumed therapy except for one who has sustained MMR still with no treatment. Patient's comorbidities were evaluated at initiation of treatment, at 5 yrs of follow up and at last follow up. An increase in patients' comorbidities was more pronounced for HTN and cardiovascular disease reaching up to 47% and 37% of patients at last follow up vs 26% and 13% at baseline respectively. Depression and/or anxiety were seen in 7% of patients at baseline and increased to 20% of patients at last F/U. Secondary malignancies developed in 48 pts (12%), mainly prostate cancer in 11 pts, non-melanoma skin cancer in 10 pts and melanoma in 5 pts. GU and colon cancers were seen in 1% of pts. Conclusion: Survivors of CML have a generally favorable outcome. However late relapses may occur (14% in our series) often requiring a change in treatment. This underscores the need to continued monitoring beyond 5 years. Co-morbidities and second malignancies may also occur in many patients, underscoring the need for a holistic follow-up of these patients. Disclosures Bose: Celgene Corporation: Honoraria, Research Funding; Incyte Corporation: Honoraria, Research Funding; Blueprint Medicines Corporation: Research Funding; Constellation Pharmaceuticals: Research Funding; Astellas Pharmaceuticals: Research Funding; Pfizer, Inc.: Research Funding; CTI BioPharma: Research Funding. Ravandi:Sunesis: Honoraria; Astellas Pharmaceuticals: Consultancy, Honoraria; Orsenix: Honoraria; Abbvie: Research Funding; Macrogenix: Honoraria, Research Funding; Seattle Genetics: Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Abbvie: Research Funding; Xencor: Research Funding; Bristol-Myers Squibb: Research Funding; Macrogenix: Honoraria, Research Funding; Amgen: Honoraria, Research Funding, Speakers Bureau; Seattle Genetics: Research Funding; Astellas Pharmaceuticals: Consultancy, Honoraria; Bristol-Myers Squibb: Research Funding; Xencor: Research Funding; Orsenix: Honoraria; Jazz: Honoraria; Sunesis: Honoraria; Jazz: Honoraria. Kadia:BMS: Research Funding; Takeda: Consultancy; Pfizer: Consultancy, Research Funding; Novartis: Consultancy; Amgen: Consultancy, Research Funding; Abbvie: Consultancy; Pfizer: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Research Funding; Celgene: Research Funding; BMS: Research Funding; Abbvie: Consultancy; Takeda: Consultancy; Jazz: Consultancy, Research Funding; Novartis: Consultancy; Jazz: Consultancy, Research Funding. Wierda:Genentech: Research Funding; AbbVie, Inc: Research Funding. Pemmaraju:Affymetrix: Research Funding; stemline: Consultancy, Honoraria, Research Funding; cellectis: Research Funding; samus: Research Funding; abbvie: Research Funding; celgene: Consultancy, Honoraria; daiichi sankyo: Research Funding; plexxikon: Research Funding; novartis: Research Funding; SagerStrong Foundation: Research Funding. Daver:Kiromic: Research Funding; Novartis: Research Funding; Sunesis: Research Funding; BMS: Research Funding; Incyte: Research Funding; Pfizer: Research Funding; Novartis: Consultancy; Incyte: Consultancy; Karyopharm: Consultancy; ImmunoGen: Consultancy; Karyopharm: Research Funding; Otsuka: Consultancy; ARIAD: Research Funding; Alexion: Consultancy; Daiichi-Sankyo: Research Funding; Sunesis: Consultancy; Pfizer: Consultancy. DiNardo:Medimmune: Honoraria; Bayer: Honoraria; Karyopharm: Honoraria; Celgene: Honoraria; Abbvie: Honoraria; Agios: Consultancy. Konopleva:Stemline Therapeutics: Research Funding; Immunogen: Research Funding; cellectis: Research Funding; abbvie: Research Funding. Champlin:Otsuka: Research Funding; Sanofi: Research Funding. Jabbour:novartis: Research Funding. Cortes:novartis: Research Funding.

Clinical Significance of Deeper Molecular Responses with Four Modalities of Tyrosine Kinase Inhibitors As Frontline Therapy for Chronic Myeloid Leukemia

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 164-164 ◽  
Author(s):  
Lorenzo Falchi ◽  
Hagop M. Kantarjian ◽  
Alfonso Quintas-Cardama ◽  
Susan O'Brien ◽  
Elias J. Jabbour ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Clinical Significance ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Initial Therapy ◽  
Molecular Responses ◽  
Free Survival

Abstract Abstract 164 Background: The achievement of a major molecular remission (MMR) after imatinib therapy in pts with chronic myeloid leukemia (CML) in chronic phase (CP) predicts for decreased risk of events, but has little impact in overall survival (OS) among patients with complete cytogenetic response (CCyR). Deeper molecular responses (MR), including undetectable transcripts, are frequently sought in patients with CML treated with tyrosine kinase inhibitors (TKI), but the prognostic significance of these responses is not known. Objectives: To determine the long-term clinical significance of achieving deeper level of MR achieved after therapy with TKI for CML in CP. Methods: Pts were included in clinical trials for initial therapy for CML with one of the following modalities: imatinib 400mg/day (IM400), imatinib 800mg/day (IM800), nilotinib (NILO) and dasatinib (DASA). We defined the level of MR as MMR, MR4, MR4.5 and undetectable transcripts (UND), corresponding to an ABL/BCR-ABL ratio (International Scale) of ≤0.1%, ≤0.01%, ≤0.0032%, and undetectable transcripts (minimum sensitivity 4.5-log), respectively. Results: A total of 495 pts were treated: 83 pts with IM400, 204 with IM800, 106 with NILO and 102 with DASA. At presentation leukocyte counts were higher in the NILO group (41.5 vs 22.2, 27.5 and 27×109/L for IM400, IM800 and DASA pts). All other patient characteristics were equally distributed across the 4 treatment groups. After a median follow-up of 73 months (2 to 142), complete cytogenetic response (CCyR) was achieved in 88%. CCyR rates for IM400, IM800, NILO and DASA pts were 82%, 88%, 90% and 90%, respectively. Best level of MR for the entire population was: <MMR in 17% of pts, MMR in 13%, MR4 in 5%, MR4.5 in 19%, UND in 44%. In IM400 pts MR was <MMR in 28% of pts, MMR in 10%, MR4 in 8%, MR4.5 in 14%, UND in 40%. In IM800 pts MR was <MMR in 14% of pts, MMR in 8%, MR4 in 5%, MR4.5 in 19%, UND in 54%. In NILO pts MR was <MMR in 18% of pts, MMR in 20%, MR4 in 7%, MR4.5 in 22%, UND in 33%. In DASA pts MR was <MMR in 18% of pts, MMR in 18%, MR4 in 7%, MR4.5 in 23%, UND in 39%. There was a trend for earlier achievement of MR with NILO: median times to MMR, MR4, MR4.5 and UND were 12, 17.4, 17.9 and 25.1 months, respectively, for IM400 pts; 5.8, 8.7, 11.8 and 23.7 months, respectively, for IM800 pts; 5.7, 7, 8.3 and 16.4 months, respectively, for NILO pts; 5.7, 8.8, 17.4 and 27.2 months, respectively, for DASA pts. To analyze the relationship between the degree of MR and clinical outcome we excluded pts not achieving a CCyR as their best response since the clinical significance of CCyR is well known. For the remaining 438 pts, the depth of molecular remission was inversely correlated with the risk of losing CCyR (19%, 16%, 11%, 7%, 2% in pts with <MMR, MMR, MR4, MR4.5 and UND, respectively) or losing MMR (31%, 42%, 24%, 2%, respectively), as well as the risk of events (22%, 20%, 15%, 12%, 3%, respectively), transformation (3%, 5%, 0%, 1%, 0%, respectively), or death (25%, 11%, 8%, 6%, 4%, respectively). The 6-year OS for pts with <MMR, MMR, MR4, MR4.5 and UND is 74%, 84%, 95%, 96% and 99%, respectively (p<.0001); transformation-free survival (TFS) is 95%, 93%, 100%, 99% and 100%, respectively (p<.014); event-free survival (EFS) is 74%, 74%, 86%, 89% and 99%, respectively (p<.0001). To adjust for the lead-time to achieve deeper responses, we then calculated OS, TFS and EFS rates at 6 years according to the depth of molecular response at 18 or 24 months. Results are summarized in table 1. Conclusion: Most patients treated with TKI as initial therapy for early CP CML achieve a MR during the course of treatment. BCR-ABL transcripts become undetectable in a significant fraction of them. Achieving a MMR or better at 18 months or 24 months is associated with significantly superior 6-years OS, TFS and EFS. These result suggest that deeper molecular responses (MMR and beyond) are associated with clinical benefit, with a particularly good outcome for those achieving undetectable transcript levels. Disclosures: Off Label Use: Imatinib, dasatinib and nilotinib frontline for chronic phase chronic myeloid leukemia on clinical trial. Kantarjian:Bristol-Myers Squibb: Research Funding; Ariad: Research Funding; Pfizer: Research Funding; Novartis: Research Funding. Jabbour:Pfizer: Honoraria; Novartis: Honoraria; Bristol-Myers Squibb: Honoraria. Ravandi:Bristol-Myers-Squibb: Research Funding. Cortes:Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding.

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.

CML Patients Outcome after TKI Discontinuation: A Single Institution Experience in the US

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 1923-1923 ◽  
Author(s):  
Kamal Chamoun ◽  
Hagop M. Kantarjian ◽  
Mary Beth Rios ◽  
Rita Assi ◽  
Guillermo Garcia-Manero ◽  
...  
Keyword(s):  
Adverse Events ◽  
Relapse Rate ◽  
Research Funding ◽  
Cytogenetic Response ◽  
Advisory Board ◽  
Treatment Discontinuation ◽  
Molecular Response ◽  
Single Institution ◽  
Complete Cytogenetic Response

Abstract Chronic myeloid leukemia (CML) patients who achieve a complete cytogenetic response (CCyR) with tyrosine kinase inhibitor (TKI) have an expected survival rate comparable to that of the general population. It is practice to continue TKI therapy indefinitely. However, this chronic therapy may impact patient's lives either by its associated adverse events, or its influence on real-life events (eg. pregnancy, financial burden). Therefore, treatment discontinuation has been increasingly sought. Discontinuation of therapy for patients with sustained MR4.5 has been associated with 30-50% sustained molecular response in previous studies. However, patients may sometimes choose to discontinue therapy for various reasons regardless of the response. We retrospectively analyzed the outcome of 95 patients with CML who discontinued TKI therapy at a single institution. Median age at diagnosis was 50 years (range 26 - 75), 56 (59%) were females. Median follow up from diagnosis to treatment discontinuation was 120 months. TKI was the initial therapy in 62 patients (41 imatinib, 7 nilotinib, 12 dasatinib, 1 bosutinib, 1 ponatinib) and interferon in 33 patients (34%). At time of discontinuation, 67 patients (71%) were receiving their first TKI (48 imatinib, 6 nilotinib, 12 dasatinib, 1 ponatinib) while 25 (26%) and 3 (3%) patients were receiving their second and third TKI respectively. All patients achieved complete cytogenetic response (CCyR) and major molecular response (MMR) in a median of 3 (range 2-93) and 9 months (range 2-132) respectively. MR4.5 was achieved in 92 (97%) patients at a median of 17 months. Three patients had MMR as their best response. Patients received TKI for a median of 104 months (range 8-203) before discontinuation. Fifty two patients (54%) discontinued therapy due to adverse events, 27 (28%) electively due to sustained MR4.5, 7 (7%) due to pregnancy, 6 (6%) for financial reasons and 3 (3%) due to the occurrence of a second cancer. At time of discontinuation all patients were in CCyR; 90 patients (95%) were in MR4.5 and 5 patients (5%) in MMR. The median MR4.5 duration before discontinuation was 75 months (range 1-178); 84 had a sustained MR4.5 for at least 2 years and 59 for at least 5 years. After a median follow-up from treatment discontinuation of 23 months (0 to 113 months), 38 (40%) patients have lost their response at a median of 4 months (range 1-34) after discontinuation; 10 patients lost response after 12 months from discontinuation. Among patients with MR4.5 at discontinuation, molecular relapse occurred in 33 patients (37%) at a median of 4 months (range 1-34; 8 after 12 months from discontinuation). All 5 patients with MMR at discontinuation loss their response at a median of 8 months (range 2-14). Patients receiving imatinib, dasatinib or nilotinib had a median TKI treatment duration of 117, 64 and 65 months before discontinuation, and lost their response at a rate of 33%, 56% and 46%, respectively. Relapse rate for patients with MR4.5 sustained >2 years was 32%, whereas those with <2 years it was 82%; a similar analysis with cutoff of 5 years yielded a relapse rate of 15% and 77%, respectively. Among patients with b3a2 with MR4.5 at discontinuation, 35% lost response, compared to 33% for those with b2a2 and 53% for those with both b3a2 and b2a2. Twenty four relapsing patients were eventually retreated; 21 re-gained the response they had at the time of discontinuation in a median of 4.5 months after resumption of therapy. At last follow up, 82 (86%) patients were in MR4.5, 4 (4%) in MMR, 5 (5%) in CCyR, 3 (3%) in PCyR and 1 (1%) in mCyR. This analysis shows that patients with less than MR4.5 at time of discontinuation have higher risk of relapse. The lower percentage of relapse seen in patients who had been on imatinib likely represents the longer period of treatment before discontinuation compared to the 2nd generation TKIs. Late relapses (e.g., beyond a year) occur in a subset of patients. Although the majority of patients who lose their response after discontinuation respond to retreatment, treatment discontinuation is still not recommended outside clinical trials. Disclosures Jain: Pfizer: Consultancy, Honoraria, Research Funding; Celgene: Research Funding; Genentech: Research Funding; Servier: Consultancy, Honoraria; Seattle Genetics: Research Funding; Abbvie: Research Funding; Infinity: Research Funding; ADC Therapeutics: Consultancy, Honoraria, Research Funding; Novimmune: Consultancy, Honoraria; Pharmacyclics: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; Incyte: Research Funding; BMS: Research Funding. Daver:BMS: Research Funding; Karyopharm: Honoraria, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Research Funding; Kiromic: Research Funding; Sunesis: Consultancy, Research Funding; Otsuka: Consultancy, Honoraria. Konopleva:Calithera: Research Funding; Cellectis: Research Funding. DiNardo:Abbvie: Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Novartis: Other: advisory board, Research Funding; Celgene: Research Funding; Agios: Other: advisory board, Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Cortes:ARIAD: Consultancy, Research Funding; Bristol-Myers Squib: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

Characteristics and Outcome of Patients (pts) with V299L BCR-ABL Kinase Domain (KD) Mutation After Therapy with Tyrosine Kinase Inhibitors (TKIs).

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3428-3428
Author(s):  
Elias Jabbour ◽  
Hagop M. Kantarjian ◽  
Dan Jones ◽  
Yin Cameron ◽  
Elizabeth Burton ◽  
...  
Keyword(s):  
Research Funding ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Experimental Models ◽  
Molecular Response ◽  
Primary Resistance ◽  
Secondary Resistance ◽  
Abl Kinase

Abstract Abstract 3428 Point mutations of the BCR-ABL KD are the most frequently identified mechanism of resistance in pts with CML who fail TKI. Experimental models of in vitro drug sensitivity have shown that specific mutations may develop after incubation with second generation TKIs, albeit at a decreased frequency compared with imatinib. Some of the mutations are novel and not previously described after imatinib failure; in some instances they did not confer resistance to imatinib. One of them, V299L was rarely encountered after imatinib therapy but was reported to emerge after dasatinib exposure in induced mutagenesis models causing resistance to dasatinib by impairing its binding. We assessed the incidence and pattern of development of V299L in pts with TKI-resistant CML at our institution, and the response following change of therapy. V299L mutation was detected in 15 pts with CML: 1 occurred among 186 pts assessed for mutations (0.05%) after imatinib failure (1% of all mutation detected), 9 among 69 of the 170 evaluable (i.e., had abl sequencing) pts (13%) who developed mutations on dasatinib, and 5 among 19 of the 72 evaluable pts (26%) who developed mutations on bosutinib (p<0.001); none of the 51 pts who developed mutations on nilotinib (among 125 tested) acquired V299L. Median age for pts with V299L was 56 years (range, 26–82 years). Eight pts were previously treated with interferon-alpha. One pt developed V299L after receiving imatinib for 26 months (mos). The median time to development of V299L was 14 mos (range, 1–30 mos) for those treated with dasatinib (7 received dasatinib after imatinib failure, 1 after imatinib and nilotinib failure; and 1 after failure of imatinib, INNO-406, and bosutinib), and 13 mos (range, 2–48 mos) for those treated with bosutinib (after imatinib failure in 1, and as 3rd TKI after imatinib and dasatinib failure). The best response to TKI immediately preceding V299L (1 imatinib, 9 dasatinib, 5 bosutinib) was complete hematologic response only in 6 (40%, 4 dasatinib, 2 bosutinib), minor cytogenetic response in 2 (13%; 1 imatinib, 1 dasatinib), complete cytogenetic response in 4 (27%; 3 dasatinib, 1 bosutinib); no response in 3 pts (20%; 1 dasatinib, 2 bosutinib). The median duration of response was 17 mos. V299L was associated with primary resistance in 4 pts, and secondary resistance in 9. Two pts on dasatinib therapy remained in CHR and minor cytogenetic response, respectively, 3 months after the mutation detection. At the time the mutation was detected, 5 pts were in chronic (CP), 7 in accelerated (AP), and 3 in blast phase (BP). 3 pts (1 CP, 1 AP, 1 BP) received nilotinib after V299L detection and 1 in CPresponded (major molecular response sustained for 40+ mos). One pt received INNO406 and did not respond. One pt in BP was refractory to allogeneic stem cell transplantation and acquired a T315I mutation. Two pts received homoharringtonine, did not respond, but had an eradication of the mutant clone. After a median follow-up of 23 mos (range, 3–48 mos), from the time V299L was detected, 8 died (4 CP and 4 BP). In conclusion, V299L occurs more frequently after dual Src/Bcr-Abl kinase inhibitors therapy, paralleling the findings of in vitro studies. TKIs showing in vitro activity against this mutation (e.g. nilotinib) may be good treatment options for pts with this mutation if treated in chronic phase, but more data is need to evaluate the long-term benefit of this approach. Disclosures: Jabbour: BMS: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Cortes:Novartis: Research Funding; BMS: Research Funding; Pfizer: Consultancy, Research Funding.

Cryptic Philadelphia Chromosome in Newly Diagnosed Chronic Phase CML (CML-CP): Clinical Characteristics and Treatment Outcome after Treatment with 5 TKI Modalities

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3082-3082
Author(s):  
Ahmad N. Ghorab ◽  
Hagop M. Kantarjian ◽  
Preetesh Jain ◽  
Courtney D DiNardo ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Research Funding ◽  
Clinical Characteristics ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Response Assessment ◽  
Initial Therapy ◽  
Advisory Board ◽  
Molecular Response ◽  
Blastic Phase

Abstract Background: The Philadelphia chromosome (Ph) is the hallmark of chronic myeloid leukemia (CML). However a few patients present without Ph by conventional G-banding but express the BCR/ABL1 rearrangement detectable by molecular FISH and/or PCR representing a cryptic Philadelphia chromosome (i.e., Ph-, BCR-ABL1+ CML). There is a paucity of data regarding the outcome this small but important subset of patients when treated with tyrosine kinase inhibitors (TKI). In this report, we report the clinical characteristics and treatment outcome of these patients. Methods: We reviewed the medical records of all 630 patients with CML in chronic phase treated at a single institution in consecutive or parallel clinical trials with TKI as initial therapy between 2000 and 2015. Nine patients with Ph-negative BCR-ABL1-positive disease were identified. We analyzed their clinical characteristics and clinical outcome. Results: Median age of this group of patients was 34 years (range, 23 to 69); only 1 patient was aged >50 years. This is in contrast to the median age of 53 years for patients with standard Ph-positive CML. Male to female ratio was 1.2. Baseline cytogenetic characteristics are shown in Table-1. Transcript type was e14a2 in 4, e13a2 in 4, and both in 2. Eight patients presented with low risk Sokal score and one with high-risk score. Four patients received initial therapy with imatinib (400 mg daily in 1, 800 mg daily in 3), 2 with dasatinib, 2 with nilotinib and one with ponatinib. The cumulative response is presented in Table-2. All patients achieved complete hematological response (CHR) within 3 months. Eight patients achieved complete cytogenetic response (CCyR), 6 of them within 6 months from start of therapy; 7 patients achieved MMR within 12 months from the start of therapy. MR4.5 was achieved in 7, and it has been sustained for at least 2 years in 5 patients; no patient has electively discontinued therapy. After a median follow-up of 79 months from start of therapy, 5 patients remain on their original TKI (including the 2 patients who started on imatinib 800 but currently receiving imatinib 400 due to dose reduction) with the molecular response at last follow-up being undetectable BCR-ABL1 in 4 and MMR in 1. One patient transformed to blastic phase. Median overall survival (OS) of these patients was not reached (two patients died from unrelated causes: one from a car accident, the other, who had transformed to blastic phase, received therapy with clofarabine, idarubicin, ara-C then imatinib followed by SCT, and died from a fall); the other 7 patients are alive 13, 11,7.8, 6.5, 5, 4, and 3.4 years from diagnosis. Conclusion: Ph-negative BCR-ABL1-positive CML presents at a younger age than the average CML population, and usually presents with low-risk disease. These patients respond well to therapy with TKI and have a very favorable long-term outcome. *One patient did not have molecular response assessment since he PCR testing was not routinely done before CCyR in 2001 when the patient had the 3 month response assessment. Disclosures Kantarjian: Bristol-Myers Squibb: Research Funding; ARIAD: Research Funding; Amgen: Research Funding; Pfizer Inc: Research Funding; Delta-Fly Pharma: Research Funding; Novartis: Research Funding. DiNardo:Abbvie: Research Funding; Novartis: Other: advisory board, Research Funding; Daiichi Sankyo: Other: advisory board, Research Funding; Celgene: Research Funding; Agios: Other: advisory board, Research Funding. Jabbour:ARIAD: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Novartis: Research Funding; BMS: Consultancy. Cortes:ARIAD: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding.

scholarly journals Results of Dasatinib Therapy in Patients With Early Chronic-Phase Chronic Myeloid Leukemia

2010 ◽  
Vol 28 (3) ◽  
pp. 398-404 ◽  
Author(s):  
Jorge E. Cortes ◽  
Dan Jones ◽  
Susan O'Brien ◽  
Elias Jabbour ◽  
Farhad Ravandi ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Initial Therapy ◽  
Molecular Response ◽  
Nonhematologic Toxicity ◽  
Significant Difference ◽  
Grade 3

PurposeDasatinib is effective therapy for chronic myeloid leukemia (CML) after imatinib failure. In this study, we investigate the efficacy of dasatinib as initial therapy for patients with CML in early chronic phase.Patients and MethodsPatients with newly diagnosed CML in early chronic phase were randomly assigned to receive dasatinib 100 mg once daily or 50 mg twice daily as initial therapy.ResultsAmong 50 patients observed for at least 3 months, 49 patients (98%) achieved a complete cytogenetic response (CCyR), and 41 patients (82%) achieved a major molecular response (MMR). Responses occurred rapidly, with 94% of patients achieving CCyR by 6 months. There was no difference in response rate by treatment arm. The projected event-free survival rate at 24 months is 88%, and all patients are alive after a median follow-up time of 24 months. Grade ≥ 3 neutropenia and thrombocytopenia occurred in 21% and 10% of patients, respectively. Nonhematologic toxicity was usually grade 1 to 2. There was no significant difference in toxicity between the two arms, and the actual median dose at 12 months was 100 mg (range, 20 to 100 mg).ConclusionDasatinib is an effective agent for the initial management of CML in early chronic phase, producing high rates of CCyR and MMR.

scholarly journals Second Treatment Free Remission after Combination Therapy with Ruxolitinib Plus Tyrosine Kinase Inhibitors in Chronic Phase Chronic Myeloid Leukemia (CML)

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 2555-2555
Author(s):  
Kendra Sweet ◽  
Ehab L. Atallah ◽  
Jerry P. Radich ◽  
Mei-Jie Zhang ◽  
Eva Sahakian ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Molecular Response ◽  
Advisory Committees ◽  
Treatment Free Remission ◽  
One Year

Abstract Background: Discontinuation of tyrosine kinase inhibitors (TKIs) is feasible in a subset of CML patients who have maintained a deep molecular response for at least two years. Numerous discontinuation trials have been performed and consistently show approximately 50% of patients relapse after stopping TKIs. A recent study examining rates of treatment free remission (TFR) after a second attempt at stopping TKIs found, with a median follow up time of 38.3 months, 64.3% of patients had a molecular relapse (defined as a loss of major molecular response (MMR)). At 12, 24 and 36 months, TFR rates were 48%, 42% and 35%, respectively. These data suggest some patients with a history of molecular relapse upon TKI cessation could successfully stop treatment on a subsequent attempt, yet the majority will relapse a second time. 'Complete eradication' of CML remains elusive in most patients likely as a result of minimal residual disease (MRD), which is the result of BCR-ABL independent drug resistance. More specifically, CML cells that reside in sanctuary sites such as the bone marrow adhere to fibronectin and demonstrate cell adhesion mediated drug resistance (CAM-DR). The bone marrow microenvironment contains many cytokines and growth factors capable of inducing STAT3-Y705 phosphorylation via the JAK-STAT pathway leading to protection against TKI-induced cell death. Inhibiting JAK2 and TYK2 leads to complete inhibition of pSTAT3-Y705, thereby implicating the role of activation of JAK2 and TYK2 in STAT3-Y705 phosphorylation and resistance towards BCR-ABL TKI-induced cell death. A phase I clinical trial combined ruxolitinib, which inhibits JAK2 and TYK2, plus nilotinib in chronic phase (CP) CML patients and found that ruxolitinib 15mg PO BID was safe and well tolerated with 4/10 patients achieving undetectable BCR-ABL1 transcripts by PCR. Study Design and Methods: This single arm phase II study (NCT03610971) will enroll 41 subjects from the H Jean Khoury Cure CML Consortium. Eligible subjects must have a confirmed diagnosis of CP-CML and have previously attempted to discontinue TKI therapy per NCCN guidelines and had molecular recurrence, defined as loss of MMR, and were restarted on TKI. This trial combines ruxolitinib 15mg BID plus BCR-ABL TKI (imatinib, dasatinib, nilotinib or bosutinib) for 12 28-day cycles in the combination treatment phase (CTP). RQ-PCR to measure BCR-ABL transcripts will be checked at screening and every three months during the CTP. In the event that a subject experiences intolerance to a TKI, has confirmed loss of MMR, or loss of MR4.5 (&gt;0.0032% IS) on two central PCR results, or discontinues ruxolitinib, the subject will be removed from CTP and enter into long term follow-up (LTFU). CTP phase will be followed by further RQ-PCR screening for the concurrent TFR phase. At this time ruxolitinib will be discontinued and any subject who has met the criteria for the TFR phase will be enrolled. During the TFR phase, subjects will discontinue their TKI and be monitored off treatment with RQ-PCR checked monthly for the first year, every six weeks for year two, and every 12 weeks during year three. Upon molecular recurrence, defined as loss of MMR, TKIs will be restarted. The primary endpoint is the 12-month TFR rate subsequent to completion of 12 cycles of combination therapy; however, subjects will remain in the TFR phase for three years. Therefore, the total duration of the trial will be approximately five years (one year on CTP + three years in the TFR phase + one-year LTFU). Study statistical design was calculated to yield a one-sided type I error rate of 0.025 and power of 65% when the true one-year relapse rate is 35%. This study will additionally assess patient-reported outcomes in conjunction with RQ-PCR testing. PROMIS and other measures will be self-administered through REDCap. Correlative studies will include comparing changes in pSTAT3 in K562 and KU812 cell lines using plasma from CML patients being treated with TKIs plus ruxolitinib, using the plasma inhibitory assay technique. Changes in pSTAT3 and pSTAT5 will be correlated with clinical response and rate of TFR. Additional correlatives include multiparameter flow-based assessment of the T-cell compartment (activity/polarization) as well as natural killer cell fractions in CML patients at various time points (TKIs alone, TKIs plus ruxolitinib and during TFR). Thus far, 14 patients have been enrolled. Disclosures Sweet: Astellas: Consultancy, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AROG: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees; Bristol Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees. Atallah: Amgen: Consultancy; BMS: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Abbvie: Consultancy, Speakers Bureau. Radich: Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Genentech: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Thompson: Novartis/ Bristol-Myers Squibb: Research Funding. Mauro: Pfizer: Consultancy; Takeda: Consultancy; Bristol Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Sun Pharma / SPARC: Research Funding. Pinilla Ibarz: AbbVie, Janssen, AstraZeneca, Novartis, TG Therapeutics, Takeda: Consultancy, Other: Advisory; Sellas: Other: ), patents/royalties/other intellectual property; MEI, Sunesis: Research Funding; AbbVie, Janssen, AstraZeneca, Takeda: Speakers Bureau. OffLabel Disclosure: Ruxolitinib is being used off-label in chronic myeloid leukemia

scholarly journals Efficacy and Safety of Radotinib Compared with Imatinib in Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia Patients: 12 Months Result of Phase 3 Clinical Trial

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 476-476 ◽  
Author(s):  
Jae-Yong Kwak ◽  
Hawk Kim ◽  
Jeong A Kim ◽  
Young Rok Do ◽  
Hyeoung Joon Kim ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Research Funding ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Phase 3 ◽  
Grade 3

Abstract Background Radotinib is a second generation BCR-ABL1 tyrosine kinase inhibitor (TKI) developed by IL-YANG Pharm. Co., Ltd (Seoul, South Korea) and approved by the Korea FDA for the treatment of chronic phase chronic myeloid leukemia (CML-CP) patients who have failed prior TKIs. We conducted the randomized, open-label, phase 3 study to assess the efficacy and safety of radotinib, as compared with imatinib, for the first-line treatment of newly diagnosed CML-CP. Methods Based on baseline demographics and Sokal risk score, 241 patients were randomized 1:1:1 to radotinib 300 mg twice daily (bid) (n=79), radotinib 400 mg bid (n=81), or imatinib 400 mg once daily (qd) (n=81). The primary endpoint was the rate of major molecular response (MMR) by 12 months and molecular response was assessed by RQ-PCR at baseline and every 3 months. Secondary endpoints were the rate of complete cytogenetic response (CCyR), MR4.5 by 12 months, and the rate of progression to accelerate phase or blast crisis. Results All three study groups were well balanced with baseline age, gender, race and Sokal risk score. With minimum follow-up of 12 months, the proportions of patients receiving a study drug were 86.3% (69/79) in radotinib 300 mg bid group, 71.6% (58/81) in radotinib 400 mg bid group, and 81.5% (66/81) in imatinib 400 mg qd group. By 12 months, rates of MMR were significantly higher in patients receiving radotinib 300 mg bid (51.9%, P = .0044) and radotinib 400 mg bid (45.7%, P = .0342) compared with imatinib (29.6%). The median time to MMR among responders were shorter on radotinib 300 mg bid (5.7 months) and radotinib 400 mg bid (5.6 months) than imatinib group (8.2 months). The MR4.5 rates by 12 months were also higher for both radotinib 300 mg bid (15.2%) and 400 mg bid (13.6%) compared to imatinib (8.6%). The CCyR rates by 12 months were also higher for radotinib 300 mg bid (91.1%, P = .0120) compared with imatinib (76.5%). There was no progression to accelerated phase or blast crisis in all groups by 12 months. Discontinuation due to adverse events (AEs) or laboratory abnormalities occurred in 7 (8.8%), 16 (19.8%), and 5 (6.2%) patients for radotinib 300 mg bid, radotinib 400 mg bid and imatinib, respectively. Grade 3/4 thrombocytopenia occurred in 16.5% of patients receiving radotinib 300 mg bid, in 13.6% for radotinib 400 mg bid, and in 19.8% receiving imatinib. And grade 3/4 neutropenia occurred in 19.0%, 23.5%, and 29.6% for radotinib 300 mg bid, 400 mg bid and imatinib, respectively. The most common any grade non-laboratory AEs were skin rash (35.4% and 33.3%), nausea/vomiting (22.8% and 23.5%), headache (19.0% and 30.9%), and pruritus (19.0% and 30.0%) in radotinib 300 mg bid and radotinib 400 mg bid, respectively; AEs in the imatinib group were edema (34.6%), myalgia (28.4%), nausea/vomiting (27.2%), and skin rash (22.2%). Overall, grade 3/4 non-laboratory AEs were uncommon in all groups. Conclusions With minimum 12 months follow-up, radotinib demonstrated significantly higher and faster rates of CCyR and MMR than imatinib in patients with newly diagnosed CML-CP. The safety profiles of the radotinib and imatinib were different, and most AEs were manageable with optimal dose reduction. The results of this trial support that radotinib can be one of the standard of care in newly diagnosed CML-CP. Table. Baseline Characteristics, Molecular and Cytogenetic Response Rates Radotinib 300mg BID Radotinib 400mg BID Imatinib 400mg QD (N=79) (N=81) (N=81) Age, median (range), years 45 (20-75) 43 (18-84) 45 (18-83) Gender, n (%) Male 52 (65.8) 47 (58.0) 52 (64.2) Female 27 (34.2) 34 (42.0) 29 (35.8) Sokal risk, n (%) Low 21 (26.6) 22 (27.2) 22 (27.2) Intermediate 38 (48.1) 38 (46.9) 39 (48.2) High 20 (25.3) 21 (25.9) 20 (24.7) MMR by 12 months, % 51.9 45.7 29.6 P = .0044 P = .0342 Cumulative Incidence of MMR by 12 months¢Ó, % 57.0 58.0 35.0 P = .0040 P = .0037 MR4.5 by 12 months, % 15.2 13.6 8.6 CCyR by 12 months, % 91.1 81.5 76.5 ¢Ó Kaplan-Meier estimates of MMR Disclosures Kim: IL-YANG Pharm. Co. Ltd: Research Funding. Kim:Alexion Pharmaceuticals: Research Funding. Chung:Alexion Pharmaceuticals: Research Funding. Choi:Alexion Pharmaceuticals: Research Funding.

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.

Patient (Pt)-Driven Discontinuation of Tyrosine Kinase Inhibitor Theray in Chronic Phase Chronic Myeloid Leukemia (CML) - Single Institution Experience

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3783-3783
Author(s):  
Ohad Benjamini ◽  
Hagop M. Kantarjian ◽  
Mary Beth Rios ◽  
Elias Jabbour ◽  
Susan O'Brien ◽  
...  
Keyword(s):  
Median Duration ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Transcript Level ◽  
Initial Therapy ◽  
Treatment Discontinuation ◽  
Molecular Response ◽  
Single Institution ◽  
Tki Discontinuation

Abstract Abstract 3783 Introduction: Some recent studies have reported on the outcome of CML pts who discontinued thyrosin kinase inhibitors (TKI) after achieving sustained undetectable bcr-abl transcript level. Most patients who stop TKI have experienced molecular relapse. Most patients respond after resuming TKIs regaining undetectable bcr-abl transcript levels. These series have prospectively planned treatment discontinuation and included only pts that have sustained complete molecular response (CMR) for at least 2 yrs. However, in many instances pts may want to discontinue TKIs not in CMR. Various reasons may lead patients to discontinue TKI treatment unexpectedly, among them severe adverse effects, pregnancy or economic constraints. This single institution experience reflects the heterogeneous nature of pt-driven TKI discontinuation. Aim: To characterize the outcome and profile of CML pts who chose to discontinue TKI therapy in a single center regardless of their initial response to TKI therapy. Methods: We retrospectively analyzed MDACC data on all patients with CML that were treated with TKIs in our institution and discontinued therapy. Results: A total of 26 patients with CML-CP managed at MDACC discontinued TKI between 2003 and 2012. The total median follow up time since diagnosis was more than 120 months (mos) (range, 45 mos to 304 mos). The median age at diagnosis was 48 yrs (range, 28–73); 15 pts were female. All pts had been diagnosed and treated in chronic phase. Interferon was initial therapy in 11 pts (42%) and 15 pts received TKI as initial therapy (4 received imatinib 400mg/day, 10 imatinib 600–800mg/day, and 1 bosutinib.) Of the 11 pts initially treated with IFN, 7 then received imatinib 400mg and 4 imatinib 800mg upon IFN failure. Pts treated frontline with TKI started therapy within a median of 0.8 mos from diagnosis (range 0 to 4) and those with previous interferon (n=11) after a median of 60 mos from diagnosis (31 to 164 mos). Before TKI discontinuation 21pts (81%) were receiving their first TKI and 5 (19%) were receiving 2nd (4) or 3rd line (1) TKI. Complete cytogenetic response (CCyR) had been achieved in all 26 pts at a median of 3.5 mos (3–93); Major molecular response (MMR) in all at a median of 9 mos (3–73) and CMR in 17 (65%) at a median of 22 mos (9–120). All patients discontinued therapy in CML-CP, all in CCyR, of them, 17 (65%) had undetectable transcripts, 2 (8%) had MR4.5, and 7 (27%) MMR. The median duration of CMR before TKI cessation was 62 mos, (0– 118). The median duration of total TKI therapy was 101 mos (3– 135). Fourteen pts (54%) discontinued TKI due to adverse events, 2 pts discontinued to become pregnant, 5 decided to stop after long CMR, and 5 pts discontinued for financial reasons. After TKI discontinuation patients were followed for a median of 11 mos (5–131). Among pts with CMR at discontinuation, molecular relapse occurred in 8 (47%) pts at a median of 4 mos (1–11) from discontinuation with median transcript level at relapse of 0.07 (IS) (range, 0.004–2.17). Six pts with initial INF therapy had CMR at time of TKI discontinuation, 50% of them relapsed. Among 7 pts who discontinued therapy in MMR, after a median follow-up from discontinuation of 21.6 months (range, 4.6–106), 4 remained at MMR, one has minor CyR and one CCyR without retreatment at last follow up after 78 and 105 months from TKI discontinuation, and one transformed to accelerated phase (AP). The 2 pts with MR4.5at discontinuation relapsed to MMR. Three pts had a transient molecular recurrence with spontaneous re-gain of CMR. Seven pts with relapse were treated again with TKI, 3 with nilotinib, 2 with dasatinib, and one each with imatinib and bosutinib (the later in AP). After a median of 13 months on therapy (range 4–52) all patients improved their response, 5 with CMR and 2 MMR (including the pt that had transformed to AP). There were no deaths or transformations to blastic phase of CML. At last follow up 14 (54%) pts were in CMR, 5 (19%) in MMR,5 (19%) in CCyR and 1 each in minor CyR and PCyR. Conclusion: Pt-driven TKI discontinuation in CML-CP leads to molecular relapse in nearly half of the pts who discontinue therapy in CMR. Some pts who discontinue in MMR may have sustained MMR. Treatment discontinuation should be considered experimental and cannot be recommended to pts as a standard approach. Disclosures: Ravandi: BMS: Honoraria, Research Funding.

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