Long Term Molecular Response To Triple Therapy With High Doses Imatinib In Patients With Chronic Myeloid Leukemia

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5199-5199
Author(s):  
Jose Luis Lopez ◽  
Hector Joel Rico
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Adverse Events ◽  
Triple Therapy ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Hematological Toxicity ◽  
Molecular Response ◽  
Sokal Score

Abstract Introduction Imatinib 400 mg daily is considered the best initial therapy for patients with chronic myeloid leukemia (CML) in the chronic phase (CP). However, only minorities of patients have a complete molecular remission (CMR) Another agent has antileukemic activity against Bcr-Abl-positive cells like Ara-C and interferon, the association of this drugs and imatinib in CML was evaluated in several trials with an increase in molecular response. The aim of this study was to evaluate the major molecular response (MMR) at 12 months with triple treatment schedule, analyze the evolution of these patients and general and hematologic toxicity. Material and Methods Patients diagnosed with CML at the Hospital General de Zona #35 in Juarez, Mexico were included. Eligibility criteria were adults with diagnosis of CML chronic phase on triple regimen for at least 12 months: Pegylated interferon-α 2a 90mcgrs via subcutaneous / week for 4 weeks + PO imatinib 800 mgs a day for 30 days + 20 mgs/mt2 cytarabine from day 1 to 10 subcutaneus. Patients were stratified according to Sokal score at diagnosis. The molecular analysis was performed in Quest diagnostic laboratory by means of real-time quantitative polymerase-chain-reaction (RT-PCR) results are expressed as a percent ratio of BCR-ABL1 to ABL1 and further adjusted to the international scale (IS) since august 2012. Patients could have received previous treatment for CML, with the exception of bone marrow transplantation. All patients provided written informed consent. This study was conducted in accordance with the Declaration of Helsinki. Molecular and adverse events were assessed. An analysis of molecular response at 12 months was planned and follows up patients with MMR every year. A MMR was defined a Bcr-Abl 0.1% or less and complete molecular response (CMR) as undetectable. Hematological toxicity was assessed according WHO scale. Results 41 patients completed the first 12 months in therapy, with a mean age of 44.4 years (17 to 71) 51% male and 49% female, the median and ranges of hemoglobin levels, leukocyte and platelet counts at diagnosis were 10.2 g/dl (5.1-16.0), 209.000 μL3 (10,600 - 529.000) and 565.500 μL (130.000 to 4,272,000) respectively. The percentages of cases by Sokal risk group were 70.7% low, 24.4% intermediate and 4.9% high risk. The Median follow up time was 58 months (range 14 to 120). At 12 months the number of patients who were in MMR was 27 (65.9%) including 8 (19.5%) with no BCR-ABL detectable. Median duration of triple therapy exposure at first year was 24 Weeks (range 12 to 32) Responses by Sokal score were 62%, 70% and 100% for low, intermediate and high respectively. Adverse events occurred in 88% cases; 33% of patients has at least one adverse event (AE) 42% 2 EA and 28% 3 EA, the most important EA was gastrointestinal. (table 1) 43.9% of patients has Hematological toxicity III-IV Median follow up time of patients in RMM was 64 months (range16-120) 2 patients were no evaluable. Patients who have RMM at 12 months 50% achieve a CMR at last follow up, 33% continues in RMM and 17% loss molecular response. Patients with CMR 72% have undetectable bcr-abl, 14% have loss molecular response and 14% in MMR Conclusions In this group of patients MMR was achieved in a higher proportion of cases at 12 months of treatment which is important in the long-term prognosis. Side effects grade 3 and 4 hematologic and non-hematologic were significant in this series of cases appearing in 44 and 88% respectively, which requires close monitoring of patients. The combination of interferon α2a, cytarabine and high-dose imatinib induces a MMR of 66% at 12 months of treatment, a 28%, 56% and 16% in MMR, CMR and loss molecular response respectively at last follow up. Clinical files n =36 Disclosures: No relevant conflicts of interest to declare.

scholarly journals Long-Term Follow-up Results after Imatinib Discontinuation in Chronic Myeloid Leukemia Patients with Undetectable Minimal Residual Disease

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 4553-4553
Author(s):  
Ho-Young Yhim ◽  
Na Ri Lee ◽  
Eun-Kee Song ◽  
Chang-Yeol Yim ◽  
So Yeon Jeon ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Adverse Events ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Molecular Response ◽  
Front Line ◽  
Sokal Score ◽  
Minimal Residual

Abstract Introduction Imatinib (IM) is an effective treatment in patients with chronic phase chronic myeloid leukemia (CML-CP). In the previous report (Leukemia research, 2012;36:689-693), we demonstrated that IM could be discontinued in CML patients achieved undetectable minimal residual disease (UMRD) after the treatment of front-line IM therapy. These observations were confirmed by prospective STIM1 and TWISTER studies. However, in both studies, approximately half of patients were treated with front-line interferon therapy, which might be a confounding factor when considering the impact of prior interferon on treatment free remission (TFR) in the previous IM discontinuation studies. Thus, the aim of this study was to investigate the long-term outcomes of IM discontinuation in patients with CML-CP, who have treated with front-line IM therapy and achieved UMRD. Patients and methods We consecutively enrolled patients with CML-CP, discontinued IM therapy after achieving UMRD for at least 12 months in 2 Korean institutions from June 2009 to Jan 2013. Patients with a prior history of any other treatment (>1 months) for CML before IM administration were excluded. UMRD was defined by undetectable levels of BCR-ABL transcript by RQ-PCR with sensitivity of at least 0.0046%IS. After discontinuation, BCR-ABL/ABL ratio was monitored by RQ-PCR monthly during the first 6 months and every 3 months thereafter, and molecular relapse was defined by detectable levels of BCR-ABL transcript in two successive assays. Results Nineteen patients (8 male, 11 female) with a median age of 52 years (range, 29-78) were included. The reasons for discontinuing IM were shared decision between physicians and patients with long undetectable BCR-ABL transcript (n=9), chronic adverse events of IM (n=6), patient’s request (n=3), and wish for pregnancy (n=1). At initial diagnosis, the Sokal score was low to intermediate in 11 patients and high in 8 patients. All patients started IM at a dose of 400mg/day and median interval between IM initiation and UMRD was 21.5 months (range, 7.0-61.9). IM therapy was then maintained during a median of 34.8 months (range, 12.1-72.4). With a median follow-up of 52.1 months (range, 17.5-60.5), the overall probability of UMRD persistence at 4-year was 22.1% (95% CI, 11.6-32.6). Fourteen patients (73%) lost UMRD after a median of 4.0 months (range, 1.1-22.8). 12 patients relapsed within first 9 months and 2 late relapse were identified at 20.5 and 22.8 months, respectively. No patients included in this analysis were progressed to advanced stage CML or died. IM therapy was resumed in all patients with molecular relapse, but 2 patients were switched to dasatinib owing to chronic adverse events of IM. At the time of this analysis, all patients were still sensitive to IM and dasatinib therapy. 12 patients re-achieved UMRD and 2 patients maintained stable major molecular response. In univariate analysis for molecular relapse, high risk of Sokal score (P<0.001), ≥24 months of interval between IM initiation and UMRD (P=0.016), and <34.8 months of duration of IM therapy after UMRD achievement (P=0.029) were significantly associated with frequent molecular relapse. Conclusion This study represents that IM discontinuation in patients who have received front-line IM therapy and achieved UMRD would be feasible, as approximately one-fourth of these patients could enjoy long-term TFR. Moreover, no molecular relapse was observed after 2 year of IM discontinuation. Although the Sokal score, time to deep molecular response, and duration of IM therapy were suggested as clinical factors for predicting molecular relapse in this analysis, further studies would be necessary to confirm the results in this population. Disclosures No relevant conflicts of interest to declare.

scholarly journals Duration of Major Molecular Response and Discontinuation in Deep Molecular Response (MR4.5) Were Associated with Longer Treatment-Free Survival after Imatinib Discontinuation - Results from Two Prospective Brazilian Trials

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1655-1655
Author(s):  
Katia B Pagnano ◽  
Fernanda S Seguro ◽  
Eliana C Miranda ◽  
Ana Beatriz Pascoal Lopes ◽  
Andre Abdo ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Adverse Events ◽  
Myeloid Leukemia ◽  
Cox Regression ◽  
Chronic Phase ◽  
Molecular Response ◽  
Free Survival ◽  
Deep Molecular Response ◽  
Treatment Free Remission

Several trials have demonstrated the feasibility of discontinuation of tyrosine kinase inhibitors (TKI) treatment in chronic myeloid leukemia (CML) patients (pts) with deep molecular response. Aims: to report the results of two Brazilian imatinib (IM) discontinuation trials and to evaluate factors impacting in treatment-free remission (TFR) and treatment-free survival (TFS) after IM discontinuation. Methods:Between September 2016 and January 2019, 60 CML pts were included in two ongoing phase II, single arm, prospective Brazilian discontinuation trials: Pilot Study of Discontinuation in Patients With Chronic Myeloid Leukemia With Deep Molecular Response - Evaluation of Pioglitazone in Treatment-free Remission (TFR) (EDI-PIO UNICAMP)(NCT02852486)and Imatinib Discontinuation in Patients With Chronic Myeloid Leukemia Chronic Phase With Sustained MR4log(USP) (NCT03239886). Inclusion criteria: age >18 years, chronic phase, minimum of 3 years of IM therapy, deep molecular response for ≥ 2 years (confirmed by 4 tests in the last 2 years, defined as MR4.0 in USP trial and MR4.5 in EDI-PIO). Patients participating in EDI-PIO trial used pioglitazone 30 mg/day plus IM for 3 months before IM discontinuation (n=30). After discontinuation, pts were monitored by quantitative RQ-PCR monthly in the first year, every 2 months in the second year and every 3 months in the third year. Criteria for IM re-initiation: loss of MMR (in one test), loss of cytogenetic response, loss of hematologic response, disease progression or confirmed loss of MR4.0 (this criteria used only in EDI-PIO trial). TFR was calculated from the date of discontinuation until first event (loss of MMR; IM reintroduction; death any cause or last follow-up); TFS was calculated from the date of IM discontinuation until reintroduction or last follow-up (censoring deaths not related to CML). Adverse events after IM discontinuation were reported according to CTCAE. Results:Data cut-off for analysis was February 2019. In the 1stanalysis 48 pts who discontinued IM in MR4.5 were analyzed. Patient's characteristics from EDIPIO (n=30) and USP (n=18) trials were: 57% vs. 67% male, median age of 55 (29-77) and 56 (33-95) years (29-95) at discontinuation; 16% and 33% had used previously Interferon; median duration of IM treatment of 10 (3-16) vs. 10 (5-15) years; median duration of MMR 95 (30-149) vs. 93 (57-130) months; MR4.0 was 90 (26-135) vs. 89 (30-123) months; and MR4.5 was 76 (23-135) vs. 75 (30-102) months; none variable had statistical difference.One patient died in MMR due to cardiac failure. TFR was 61% (95% CI 47-75) at 20 months. Sixteen (33%) out 48 re-initiated IM (2 with confirmed loss of MR4.0 and 14 with loss of MMR) in a median time of 20 (1-26) months. All relapsed pts recovered MMR after IM reintroduction, in a median time of 2 months (0-4). There was no transformation to advanced phases. No serious adverse events were reported during pioglitazone treatment. In the Cox regression the duration of MMR was associated with a longer TFR HR: 0.96 (beta-) (CI 95%:0.94-0.99, P= 0.006). Gender, age at diagnosis, age at discontinuation, treatment with pioglitazone, Sokal and EUTOS scores, BCR-ABL transcripts type, duration of IM therapy, duration of MR4.0 and MR4.5 and previous use of Interferon did not affect TFR.In the second analysis all 60 pts were included. TFS was 56% and was higher in pts who discontinued IM in sustained MR4.5 vs. MR4.0 (63% vs. 33%, P=0.04)(Figure). The independent factors for TFR in the multivariate analysis by Cox-regression were the duration of MMR [HR: 0.97 (beta-), 95%CI: 0.95-0.98, P=0.001] and intermediate/high risk Sokal [HR 3.14 95%CI: 1.08-9.11, P= 0.035]. Twenty-four out of 60 pts (40%) re-initiated IM (2 with confirmed loss of MR4.0 and 22 with loss of MMR).Adverse events occurred in 38 (63%) pts, 30% attributed to withdrawal syndrome. Some pts presented more than one event. Grade 1-2: arthralgia or muscular pain (17), hyperglycemia (4), hypertriglyceridemia (2), polycythemia (2), hypertension (3), and others (11). Four pts had grade 3-4 event: arthralgia (1), death for cardiac failure (1), abortion and hypertriglyceridemia (1). Conclusions:both trials demonstrated the feasibility and safety of IM discontinuation in pts in sustained deep molecular response. The duration of MMR was associated with a higher TFR and TFS rate. Imatinib discontinuation was more successful in pts in stable MR4.5. Figure Disclosures Pagnano: Pint Pharma: Consultancy; Abbvie: Consultancy; Sandoz: Consultancy. Delamain:Novartis: Honoraria.

scholarly journals Is the Sokal or EUTOS long-term survival (ELTS) score a better predictor of responses and outcomes in persons with chronic myeloid leukemia receiving tyrosine-kinase inhibitors?

Leukemia ◽  
2021 ◽  
Author(s):  
Xiao-Shuai Zhang ◽  
Robert Peter Gale ◽  
Xiao-Jun Huang ◽  
Qian Jiang
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Molecular Response ◽  
Intermediate Risk ◽  
Term Survival ◽  
Long Term Survival ◽  
Sokal Score

AbstractData from 1661 consecutive subjects with chronic-phase chronic myeloid leukemia (CML) receiving initial imatinib (n = 1379) or a 2nd-generation tyrosine-kinase inhibitor (2G-TKI; n = 282) were interrogated to determine whether the Sokal or European Treatment and Outcome Study for CML (EUTOS) long-term survival (ELTS) scores were more accurate responses and outcome predictors. Both scores predicted probabilities of achieving complete cytogenetic response (CCyR), major molecular response (MMR), failure- and progression-free survivals (FFS, PFS), and survival in all subjects and those receiving imatinib therapy. However, the ELTS score was a better predictor of MR4, MR4.5, and CML-related survival than the Sokal score. In subjects receiving 2G-TKI therapy, only the ELTS score accurately predicted probabilities of CCyR, MMR, MR4, FFS, and PFS. In the propensity score matching, subjects classified as intermediate risk by the ELTS score receiving a 2G-TKI had better responses (p < 0.001~0.061), FFS (p = 0.002), and PFS (p = 0.03) but not survival. Our data suggest better overall prediction accuracy for the ELTS score compared with the Sokal score in CML patients, especially those receiving 2G-TKIs. People identified as intermediate risk by the ELTS score may benefit more from initial 2G-TKI therapy in achieving surrogate endpoints but not survival, especially when a briefer interval to stopping TKI therapy is the therapy objective.

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.

Efficacy of Frontline Nilotinib Therapy in Patients (Pts) with Newly Diagnosed Philadelphia Chromosome (Ph)-Positive Chronic Myeloid Leukemia in Early Chronic Phase (CML-CP)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 454-454 ◽  
Author(s):  
Alfonso Quintás-Cardama ◽  
Hagop M Kantarjian ◽  
Rajyalakshmi Luthra ◽  
Susan o'Brien ◽  
Elias Jabbour ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Adverse Events ◽  
Myeloid Leukemia ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Grade 3 ◽  
Elevated Transaminases

Abstract Abstract 454 Efficacy of Frontline Nilotinib Therapy in Patients (Pts) with Newly Diagnosed Philadelphia Chromosome (Ph)-Positive Chronic Myeloid Leukemia in Early Chronic Phase (CML-CP) Alfonso Quintás-Cardama, Hagop Kantarjian, Raja Luthra, Susan O'Brien, Elias Jabbour, Gautam Borthakur, Farhad Ravandi, Guillermo Garcia-Manero, Stefan Faderl, Marina Konopleva, William Wierda, Elizabeth Burton, Jorge Cortes 1MD Anderson Cancer Center, University of Texas, Houston, TX Background: In 2005, we initiated a phase II study of nilotinib as 1st line therapy in pts with newly diagnosed CML-CP to investigate the efficacy and safety of nilotinib as frontline therapy for pts with CML-CP. Methods: The primary objective was to estimate the proportion of pts attaining major molecular response (MMR) at 12 months (mo). Pts with untreated CML-CP within 6 mo from diagnosis were eligible and received nilotinib 400 mg twice daily. Results: 100 pts (41% female) have received for a median of 24 mo (range 1 to 72mos). Median age was 49 years (range 17–86). Median WBC, PB blasts, PB basophils, hemoglobin, and platelet count was 42.6, 0%, 2.5%, 12.3, 307, respectively. Five pts (5%) had a variant Philadelphia chromosome and 1 (1%) had deletion of derivative chromosome 9. Seventy-two (72%), 20 (20%), and 8 (8%) pts had low, intermediate, and high Sokal risk score. Among the 102 CP pts who were not in CHR at the start, 100 (98%) achieved CHR (one discontinued after 2 weeks without adverse events). Among 73 CP pts followed for at least 12 mo, 69 (95%) achieved a complete cytogenetic response (CCyR). MMR at 18 mo has been achieved in 51 (89%) pts, including 30 (52%) with a complete molecular response (CMR)(Table 1). The median time to achieve CCyR, MMR was 6 mo each. Grade 3–4 thrombocytopenia, neutropenia, and anemia occurred in 9%, 12%, and 6% pts. The most frequent non-hematologic toxicities were rash (62%), pain (57%), and elevated transaminases (45%) and bilirubin (42%). However, grade 3–4 non-hematologic adverse events (possible, probable or suspected relationship only) were rare, including: pain and increased bilirubin (4% each), elevated lipase, fatigue, and elevated transaminases (2% each), and hyperglycemia (1%). One (1%) pt experienced QTc prolongation (grade 2; QTc prolonged from 444msec to 483msec), not associated with arrhythmias and resolved after a brief treatment interruption. Forty-five (45%) pts had transient treatment interruptions (median days off-nilotinib 7 [range 1–68]) and 27 (27%) had dose reductions. Of the patients that were dose reduced, their current or last known dose was either 200mg daily (n=7), 200mg twice daily (n=14), or 400mg daily (n=6). Nineteen (19%) pts terminated nilotinib therapy due to toxicity (n=7), personal reasons or loss to follow-up (n=7), loss of MCyR (n=2), progression to BP (n=2), or death (n=1). Of the pts who discontinued therapy, 3 were tested for BCR-ABL1 mutations; 2 were found to have mutations (F359C and Y253H). The 48 mo probability of EFS (event= loss of CHR, loss of MCyR, AP/BP, or death) is 88%. The annual rate of events during the first 48 mo of follow-up was 4%, 0%, 2%, 5%, and 0% and the rate of transformation 2%, 0%, 0%, and 0%, respectively. The best response achieved on nilotinib by the 2 pts that transformed to BP was CCyR and PCyR, respectively. The overall survival at 48 mos is 96%. One pt died due to stroke, unrelated to nilotinib. No other vascular events have been observed to date. Conclusion: Nilotinib 400 mg twice daily induces CCyR in 78% of pts as early as 3 mo and MMR in 86% at 12 mo after the start of therapy, with very low rates of progression to AP/BP and a mild toxicity profile. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Long-term outcomes with frontline nilotinib versus imatinib in newly diagnosed chronic myeloid leukemia in chronic phase: ENESTnd 10-year analysis

Leukemia ◽  
2021 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Timothy P. Hughes ◽  
Richard A. Larson ◽  
Dong-Wook Kim ◽  
Surapol Issaragrisil ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Survival Rates ◽  
Chronic Phase ◽  
Individual Treatment ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Long Term Outcomes ◽  
Treatment Free Remission

AbstractIn the ENESTnd study, with ≥10 years follow-up in patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase, nilotinib demonstrated higher cumulative molecular response rates, lower rates of disease progression and CML-related death, and increased eligibility for treatment-free remission (TFR). Cumulative 10-year rates of MMR and MR4.5 were higher with nilotinib (300 mg twice daily [BID], 77.7% and 61.0%, respectively; 400 mg BID, 79.7% and 61.2%, respectively) than with imatinib (400 mg once daily [QD], 62.5% and 39.2%, respectively). Cumulative rates of TFR eligibility at 10 years were higher with nilotinib (300 mg BID, 48.6%; 400 mg BID, 47.3%) vs imatinib (29.7%). Estimated 10-year overall survival rates in nilotinib and imatinib arms were 87.6%, 90.3%, and 88.3%, respectively. Overall frequency of adverse events was similar with nilotinib and imatinib. By 10 years, higher cumulative rates of cardiovascular events were reported with nilotinib (300 mg BID, 16.5%; 400 mg BID, 23.5%) vs imatinib (3.6%), including in Framingham low-risk patients. Overall efficacy and safety results support the use of nilotinib 300 mg BID as frontline therapy for optimal long-term outcomes, especially in patients aiming for TFR. The benefit-risk profile in context of individual treatment goals should be carefully assessed.

scholarly journals Meta-Analysis of Gastrointestinal Adverse Events from Tyrosine Kinase Inhibitors for Chronic Myeloid Leukemia

Cancers ◽  
2021 ◽  
Vol 13 (7) ◽  
pp. 1643
Author(s):  
Prahathishree Mohanavelu ◽  
Mira Mutnick ◽  
Nidhi Mehra ◽  
Brandon White ◽  
Sparsh Kudrimoti ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Adverse Events ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Meta Analysis ◽  
Chronic Phase ◽  
Molecular Response ◽  
Gastrointestinal Adverse Events

Tyrosine kinase inhibitors (TKIs) are the frontline therapy for BCR-ABL (Ph+) chronic myeloid leukemia (CML). A systematic meta-analysis of 43 peer-reviewed studies with 10,769 CML patients compared the incidence of gastrointestinal adverse events (GI AEs) in a large heterogeneous CML population as a function of TKI type. Incidence and severity of nausea, vomiting, and diarrhea were assessed for imatinib, dasatinib, bosutinib, and nilotinib. Examination of combined TKI average GI AE incidence found diarrhea most prevalent (22.5%), followed by nausea (20.6%), and vomiting (12.9%). Other TKI GI AEs included constipation (9.2%), abdominal pain (7.6%), gastrointestinal hemorrhage (3.5%), and pancreatitis (2.2%). Mean GI AE incidence was significantly different between TKIs (p < 0.001): bosutinib (52.9%), imatinib (24.2%), dasatinib (20.4%), and nilotinib (9.1%). Diarrhea was the most prevalent GI AE with bosutinib (79.2%) and dasatinib (28.1%), whereas nausea was most prevalent with imatinib (33.0%) and nilotinib (13.2%). Incidence of grade 3 or 4 severe GI AEs was ≤3% except severe diarrhea with bosutinib (9.5%). Unsupervised clustering revealed treatment efficacy measured by the complete cytogenetic response, major molecular response, and overall survival is driven most by disease severity, not TKI type. For patients with chronic phase CML without resistance, optimal TKI selection should consider TKI AE profile, comorbidities, and lifestyle.

scholarly journals Efficacy and Tolerability after Unusually Low Doses of Dasatinib in Chronic Myeloid Leukemia Patients Intolerant to Standard-Dose Dasatinib Therapy

2010 ◽  
Vol 4 ◽  
pp. CMO.S6413 ◽  
Author(s):  
Mariana Serpa ◽  
Sabri S. Sanabani ◽  
Israel Bendit ◽  
Fernanda Seguro ◽  
Flávia Xavier ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Standard Dose ◽  
Chronic Phase ◽  
Patient Treatment ◽  
Hematological Toxicity ◽  
Drug Discontinuation ◽  
Once Daily ◽  
Starting Dose

We report our experience in 4 patients with chronic myeloid leukemia (CML) who had discontinued imatinib as a result of adverse events and had switched to dasatinib. The chronic phase ( n 2) and accelerated phase ( n 2) CML patients received dasatinib at starting dose of 100 and 140 mg once daily, respectively. Reappearance of hematological toxicity was observed in 3 patients and pancreatitis in one patient. Treatment was given at a lower dose and patients were followed. The median follow-up was 13 months and the median dose of dasatinib until achievement of complete cytogenetic remission (CCyR) was 60 mg daily (range = 20 to 120 mg). All four patients had achieved CCyR at a median of 4 months (range = 3 to 5 months) and among them, three had also achieved major molecular remission. We conclude that low-dose dasatinib therapy in intolerant patients appears safe and efficacious and may be tried before drug discontinuation.

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