scholarly journals Humoral Immunity and Adverse Events after Vaccination Against COVID-19 By a Vector Based Vaccine Sputnik V in Patients with Chronic Myeloid Leukemia

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4599-4599
Author(s):  
Ekaterina Yu. Chelysheva ◽  
Anna Petrova ◽  
Oleg A. Shukhov ◽  
Margarita Gurianova ◽  
Anastasiya Bykova ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Adverse Events ◽  
Myeloid Leukemia ◽  
Reverse Correlation ◽  
Molecular Response ◽  
Elderly Persons ◽  
S Protein ◽  
Specific Antibodies ◽  
Test Systems ◽  
Antibody Levels

Abstract Introduction Data on the effectiveness and safety of new vaccines against COVID-19 in patients (pts) with hematological diseases are just beginning to accumulate. We planned to obtain such information for pts with chronic myeloid leukemia (CML) during vaccination. Objective. To evaluate the antibodies formation and adverse events (AEs) after vaccination against COVID-19 in pts with CML Materials and methods. All pts with CML diagnosis who applied to the National Research Center for Hematology (NRCH, Moscow, Russia) for outpatient or remote consultations were suggested to prospectively report the AEs after getting a vaccination against COVID-19 by the most frequently used vector-based vaccine GamCovidVac (Sputnik V). Two vaccine components with the interval of 21 days were given at the vaccination facilities, as prescribed. At least after 3 weeks after the 2 nd injection, pts were advised to perform a blood test for the specific antibodies against spike (S) protein of SARS-CoV-2. A semi-quantitative test detecting the SARS-CoV-2 S1 subunit (RBD) IgG antibodies by enzyme-linked immunoassay (ELISA) kit was used in the clinic. The results were considered positive with the cutoff index >1,1. The use of any other lab tests detecting antibodies to S protein of SARS-CoV-2 was acceptable as well. Results. In total, 66 pts with chronic phase of CML received a vaccination by Sputnik V in the 7 months period (from 18.12.2020 to 20.07.2021). Me age was 54 years (range 29 - 89 years), 34 (52%) were males. Median (Me) CML duration was 8 years (from the moment of diagnostics up to 20 years). Fifty one (77%) pt received TKI therapy and 15 (23%) were off-therapy at the time of vaccination, including 12 (18%) in a treatment-free remission and 3 (4,5%) pts in the process of diagnosis. Deep and major molecular response (MMR) was in 46 (70%) and 7 (11%) pts, respectively. Two (3%) pts had a molecular response MR2, 11 (17%) had no MR2. Eight (12%) pts had a history of COVID-19 manifestation prior to vaccination. Me time for testing for the antibodies was 27 days (range 5-77) after the 2 nd vaccine injection. The tests were done in 44 (67%) of pts and revealed positive by any of the test systems in 42 (95%) pts. ELISA test was used in 30 (45%) pts and was positive in 25 (83%) of 30 pts. Me cutoff index in the positive samples was 7,7 (range 1,1 - 12) and corresponded to the value observed in healthy people after vaccination (medical stuff, data not shown). In all 3 pts with the history COVID 19, the index of positivity was above the Me value (Fig. 1, 2). Other test systems were used in 14 (21%) pts, in all 14 (100%) the antibodies were found. In 3 of 5 patients with the cutoff index<1 the antibodies were detected by using other test systems, but all with a level slightly above the detection threshold. Me age of these 5 pts was 63 years (range 59- 70), Me time of analysis was 49 days (range 23-59) after 2 nd vaccine shot. All these pts were on treatment by tyrosine kinase inhibitors, 3 pts with MMR and deeper, 1 pt with MR2 and 1 pt without MR2. A weak reverse correlation of the antibody levels with the time after vaccination was noted ( r = - 0,39, p = 0,033). A very weak reverse correlation with age was observed ( r = - 0,28, p = 0,127) (Fig. 1, 2). No AEs after the vaccination were observed in 25 (38%) pts while 41 (62%) pts reported the AEs and 7 (10%) pts did not report their reactions. The AEs were as follows: local pain/discomfort in the injection site in 19 (29%) pts, weakness and/or drowsiness in 20 (30%), fever and/or chills in 16 (24%), other reactions in 8 (12%) including headache, heartbeat, lower back pain, pain in limbs, activation of herpes infection. Conclusion: The single center study revealed no unusual or unexpected AEs in CML pts after the vaccination against COVID-19 by Sputnik V vaccine. The proportion of CML pts with specific antibodies after was 95% which is close to the published results of the 3rd phase study. No significant correlation was found with age (r = -0,28, p = 0,127), however, the absence or very low antibody levels were detected in individual patients aged about 60-70 years. This data raise a question of a necessity for a non-specific protection (masks, respirators, distance etc) and probably considering additional vaccination in some elderly persons. The duration of a humoral response against COVID-19, protective antibody titer and connection with clinical outcomes in CML pts need further evaluation in parallel with a common population. Figure 1 Figure 1. Disclosures Chelysheva: Pfizer: Speakers Bureau; Pharmstandart: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; Novartis Pharma: Speakers Bureau. Petrova: Pfizer: Speakers Bureau; Novartis Pharma: Speakers Bureau. Gurianova: Pfizer: Speakers Bureau. Turkina: Pharmstandart: Speakers Bureau; Pfizer: Speakers Bureau; Novartis Pharma: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau.

scholarly journals Differential gene expression analysis of dasatinib-induced colitis in a patient with chronic myeloid leukemia followed for 3 years: a case report

2021 ◽  
Vol 21 (1) ◽  
Author(s):  
Naoki Oshima ◽  
Yoshiyuki Mishima ◽  
Kotaro Shibagaki ◽  
Kousaku Kawashima ◽  
Norihisa Ishimura ◽  
...  
Keyword(s):  
Gene Expression ◽  
Chronic Myeloid Leukemia ◽  
Adverse Events ◽  
Differential Gene Expression ◽  
Myeloid Leukemia ◽  
Colonic Mucosa ◽  
Kinase Inhibitor ◽  
Molecular Response ◽  
Multikinase Inhibitor ◽  
Differential Gene

Abstract Background Dasatinib is a second-generation tyrosine kinase inhibitor (TKI) developed for treatment of patients with chronic myeloid leukemia (CML). The drug has been shown to act as a potent multikinase inhibitor by blocking not only the BCR-ABL1 gene sequence but also the SRC kinase family, though unexpected adverse events such as pleural effusion have recently been reported in patients undergoing treatment with dasatinib. Hemorrhagic colitis is a unique gastrointestinal adverse events associated with dasatinib and its pathogenesis remains poorly understood. Case presentation We report here a case of dasatinib-induced asymptomatic colitis in a patient with CML, who showed no exacerbation in careful observations and maintained deep molecular response (DMR) during a 3-year period. In addition, we performed transcriptome analysis of inflamed colonic mucosa specimens to clarify the possible mechanism of colitis that develops in association with dasatinib administration. Our results demonstrated that differential gene expression, especially lymphocyte-associated genes and chemokines, is substantially involved in inflammation of colonic mucosa in affected patients. Conclusion Dasatinib induces immune-mediated colitis following lymphocyte infiltration.

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 Outcomes and Side Effect Profile of Ponatinib in Treatment of Chronic Myeloid Leukemia (CML): A Retrospective Single-Center Experience

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 4259-4259 ◽  
Author(s):  
Onyee Chan ◽  
Chetasi Talati ◽  
Leidy Isenalumhe ◽  
Michael Fradley ◽  
Samantha Shams ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Adverse Events ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Small Sample ◽  
Categorical Variables ◽  
Routine Practice ◽  
Molecular Response ◽  
The Impact ◽  
Dose Dependent

Abstract BACKGROUND: Ponatinib is a third generation tyrosine kinase inhibitor (TKI) used to treat resistant chronic myeloid leukemia (CML). It has been associated with cardiovascular adverse events (CAEs); most specifically hypertension and arterial thrombotic events. Most CAEs are dose-dependent. The frequency of CAEs in the real-world setting has not been previously described. In this study, we describe the survival outcomes and associated toxicities in ponatinib-treated patients at Moffitt Cancer Center (MCC). METHODS: A retrospective review of CML patients treated with ponatinib at MCC between years 2011 and 2017 was performed to identify patients treated with ponatinib. Demographics, disease-specific variables and clinical outcomes were collected in accordance with the Institutional Board Review approved protocol. Frequency of adverse events on ponatinib were categorized. Pearson's chi-square test for independence was used to determine significance for categorical variables. Kaplan-Meier analysis with log-rank test was performed to estimate overall survival (OS). RESULTS: A total of 78 patients (38 females/40 males) treated with ponatinib with median age of 42.5 (range 14-70) years were included in the analysis. At the time of ponatinib initiation, 51 patients were in chronic phase (CP), 9 in accelerated phase (AP), and 18 in blast phase (BP). Ponatinib was 3rd or 4th line therapy in 65% of CP patients, with a mean starting dose of 39.65 mg per day. Dose reduction occurred in 64.7% of patients with CP and the mean duration of ponatinib was 14.6 months. The most common non-cardiovascular adverse events (NCAEs) were thrombocytopenia (39.7%), abdominal pain (33.3%), anemia (28.2%), elevated lipase (28.3%), and rash (26.9%) in a dose-dependent fashion. Most common new onset CAEs included arrhythmia (9%) and hypertension (7.7%). Three patients (3.8%) experienced a myocardial infarction, and two of these had significant cardiovascular risk factors at baseline. No other arterial thrombotic events were reported. A total of 18 patients (23.1%) experienced some form of CAE. Prior to 2014, more patients were placed on 45 mg ponatinib and more CAEs occurred during that time. After 2014, there is an increased awareness of potential cardiotoxicity associated with ponatinib and referral to cardio-oncology (CO) became a routine practice in our institution. Figure 1 summarizes the cardiac safety profile of ponatinib and frequency of CO referral. Ponatinib 45 mg and CAEs are not independent (X2 (1, N = 82) = 7.68, p < 0.05), but this correlation was lost when testing CAEs against patients who were on ponatinib 45 mg and either referred to CO or on cardiac protective medications (X2 (1, N = 82) = 3.55, p > 0.05) suggesting CAEs become independent of ponatinib dosing when cardioprotective measures are put in place. In patients with CP-CML, 69.6% achieved a complete cytogenetic response (CCyR) and 58.7% had a major molecular response (MMR). Patients with AP and BP achieved CCyR in 37.5% and 68.8%, respectively. Among the BP patients who achieved at least CCyR (n = 11), 81.1% of the patients had received TKI with chemotherapy at the time of BP. Five-year median OS of the entire cohort was 63%. With a median follow up of 32.5 months, the median OS from ponatinib initiation was not reached (NR) in CP with allogeneic stem cell transplantation (allo-SCT) (n = 17) or without allo-SCT (n = 34); was 32.9 months in AP with allo-SCT (n = 4), NR in AP without allo-SCT (n = 5); and NR in BP with allo-SCT (n = 6), and 5.45 months in BP without allo-SCT (n = 12) (p < 0.0001). CONCLUSIONS: In our series, the incidence of new arterial thrombotic events and hypertension appears lower than reported in the PACE trial. The incidence of CAEs declined after 2014 when early dose reductions became standard practice and early referrals to cardio-oncology increased. Non-CAEs and outcomes were similar to previous reports. Limitations of this analysis include its retrospective nature and small sample size. Future studies analyzing the impact of specific interventions on mitigating cardiovascular events are needed. Disclosures Sweet: BMS: Honoraria; Novartis: Consultancy, Honoraria, Speakers Bureau; Celgene: Honoraria, Speakers Bureau; Astellas: Consultancy; Agios: Consultancy; BMS: Honoraria; Agios: Consultancy; Astellas: Consultancy; Phizer: Consultancy; Jazz: Speakers Bureau; Phizer: Consultancy; Celgene: Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Jazz: Speakers Bureau.

scholarly journals Generic Imatinib in Chronic Myeloid Leukemia: Survival of the Cheapest

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 630-630 ◽  
Author(s):  
Danthala Madhav
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Adverse Events ◽  
Imatinib Mesylate ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Quantitative Polymerase Chain Reaction ◽  
Comparable Efficacy ◽  
Molecular Response ◽  
Free Survival

Abstract Introduction: The patent expiration of Imatinib mesylate (Glivec, ®Novaritis) on February 1, 2016, has brought the focus back on generic versions of the drug, and an opportunity to provide a safe and cost effective alternative. India has witnessed a mushrooming of home grown pharmaceutical companies, that have drawn on Darwinian theory to promote the concept of "survival of the cheapest", in pursuit of a deeper penetrance into the cash strapped population. The launch of Veenat (®NATCO pharma) at a fraction of the price of the innovator drug is a case in point. Objectives: To determine the molecular and cytogenetic responses, survival endpoints (event free survival (EFS), failure free survival (FFS), transformation free survival (TFS), overall survival (OS), and safety of innovator and generic brands of imatinib. Materials and Methods: In this retrospective analysis, data from 1,812 patients with chronic myeloid leukemia (CML) treated with frontline Imatinib mesylate (Innovator/Generic) at a single institution between 2008 and 2014 is included. Of these 1,812 patients, 445 were excluded due to inadequate data and follow up. Thus, data from 1,193 patients who were treated with Glivec (®Novartis), and 174 patients with Veenat (®NATCO) was available. Observations: A higher percentage of patients in the generic arm compared to the innovator arm, were in accelerated phase (9.7% vs 6.7%) and blast crisis (7.4% vs 3.7%), respectively.After a median follow up of 1,347 days, 805 (67.4%) patients achieved complete cytogenetic response (CCgR), 259 (21.7%) achieved major molecular response (MR3), and 205 (17.1%) achieved 4 log reduction in BCR ABL transcripts (MR4) in the innovator arm. After a median follow up of 1,220 days, 112 (64.3%), 24 (13.7%), and 42(24.1%) patients achieved a CCgR, MR3 and MR4 respectively, in the generic arm.Follow up assessments using real-time quantitative polymerase chain reaction (q-PCR) and/ or cytogenetic tests were not available in 230 (19.2%) and 40 (22.9%) patients, in the innovator and generic groups respectively, despite inclusion in a sponsorship program.Adherence to treatment was poor in 192 (16%) and 30 (17.2%) patients in the innovator and generic arms respectively. Results: In a fairly homogenous population of lower economic strata, on a free drug access program, the prime factors influencing adherence were low educational level, assumptions of "cure", recent bereavement, stigma of cancer diagnosis and repeated hospital visits. Transformation to accelerated/blast phase occurred in 7.7% and 7.4% of patients in the innovator and generic arms respectively. Testing for BCR-ABL1 mutations was done in 31 (17.8%) patients in the generic arm and 132(11%) patients in the innovator arm, after failure of treatment or suboptimal response. Mutations were identified in 14 (8%) patients in the generic arm and 52 (4.3%) patients in the innovator arm.The most common subsequent treatments chosen were, dose escalation (249 [20.8%] vs 30 [17.2%]), Nilotinib (26 [2.1%] vs 8 [4.5%]), Dasatinib (11 [0.9%] vs 9 [5.1%]) and hydroxyurea (11 [0.9%] and 4 [2.2%]) in the innovator and generic arms respectively. There was no difference in EFS (p=0.46), FFS (p=0.16), TFS (p=0.9), or OS (p=0.13) between the two groups. The frequency of reported grade 1, or 2 non-hematological adverse events which included musculoskeletal pain, muscle cramps, and peripheral edema, and hematological adverse events was comparable between the study groups. However, the incidence of grade 3 skin rash was higher in the generic group (2.8%) in comparison to the innovator group (0.2%). Conclusion: The findings of the present study showed comparable efficacy and safety of the generic and innovator versions of imatinib in the treatment of patients with chronic myeloid leukemia. Disclosures No relevant conflicts of interest to declare.

scholarly journals High-Dose Imatinib in Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia: High Rates of Rapid Cytogenetic and Molecular Responses

2009 ◽  
Vol 27 (28) ◽  
pp. 4754-4759 ◽  
Author(s):  
Jorge E. Cortes ◽  
Hagop M. Kantarjian ◽  
Stuart L. Goldberg ◽  
Bayard L. Powell ◽  
Francis J. Giles ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Adverse Events ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Dose Intensity ◽  
Musculoskeletal Symptoms ◽  
High Dose ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Rapid Reduction

Purpose Long-term clinical outcome data have established imatinib 400 mg/d as standard front-line treatment for newly diagnosed patients with chronic myeloid leukemia (CML). Patients and Methods The Rationale and Insight for Gleevec High-Dose Therapy (RIGHT) trial is a multicenter study of imatinib 400 mg twice a day as initial therapy in 115 patients (70% Sokal low risk) with newly diagnosed CML in chronic phase who were observed for both molecular and cytogenetic responses for up to 18 months. Eighty-three patients (72%) completed the study, 10 patients (9%) discontinued the study because of adverse events, and six patients (5%) discontinued because of unsatisfactory therapeutic effect. Results Polymerase chain reaction analysis demonstrated rapid kinetics of major molecular response (MMR), with 48% of patients achieving MMR by 6 months, 54% by 12 months, and 63% by 18 months. Corresponding complete molecular response rates were 39%, 44%, and 55%, respectively. Median dose-intensity was 98%. Overall, 79% of patients who received at least 90% dose-intensity achieved MMR. The most frequent adverse events included myelosuppression, rash, fatigue, and musculoskeletal symptoms. Conclusion This study suggests that imatinib 400 mg twice a day results in more rapid reduction in tumor burden than imatinib 400 mg/d with minimal added toxicity.

scholarly journals Imatinib resistance: diagnostic and therapeutic choices

2015 ◽  
Vol 4 (2S) ◽  
pp. 21-25
Author(s):  
Marianna De Muro ◽  
Odoardo Maria Olimpieri ◽  
Rosa Greco ◽  
Lidia Altomare
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Plasma Level ◽  
Adverse Events ◽  
Myeloid Leukemia ◽  
Response To Therapy ◽  
Molecular Response ◽  
Dose Increase ◽  
Imatinib Resistance ◽  
Optimal Response ◽  
Complete Molecular Response

We report a case of a 42-year-old woman with t(9;22) positive chronic myeloid leukemia (CML) who developed a sub-optimal response to therapy with imatinib mesylate due to M351T mutation and low plasma level of imatinib. Dose increase of imatinib resulted in toxicity. She obtained a complete molecular response to therapy with nilotinib, without adverse events.

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.

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.

Five-Year Outcome of 215 Newly Diagnosed Chronic Myeloid Leukemia Patients Treated Frontline with Nilotinib-Based Regimens: A Gimema CML Working Party Analysis

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 3141-3141
Author(s):  
Gabriele Gugliotta ◽  
Fausto Castagnetti ◽  
Massimo Breccia ◽  
Luciano Levato ◽  
Giovanna Rege-Cambrin ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Adverse Events ◽  
Myeloid Leukemia ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Secondary Resistance ◽  
Long Term Outcome ◽  
Free Survival

Abstract Background. Nilotinib (NIL) is a potent and selective BCR-ABL inhibitor approved for the frontline treatment of chronic myeloid leukemia (CML) based on the results of the ENESTnd study. The sustained superiority of NIL vs. imatinib (IM) was confirmed after 5 years of follow-up (Hughes et al, abs. 677, EHA 2014). However, few data are available on patients (pts) treated frontline with NIL outside of Company-initiated trials. Objectives. To analyze the long-term outcome in a large, independent cohort of newly diagnosed CML pts treated frontline with NIL-based regimens. Methods. We analyzed 215 pts, enrolled in 2 multicenter phase II studies conducted by the GIMEMA CML WP (ClinicalTrials.gov. NCT00481052 and NCT00769327) or treated at the Bologna University Hospital, with NIL 300 mg or 400 mg BID as initial treatment; 123 pts received a sequential treatment with NIL and IM (NIL-IM), with a 3-months (mos) rotation period (all patients received NIL in the first 3 mos). The median age was 53 years (range 18–86). Ten out of 215 pts (5%) had a high EUTOS score. The median follow-up was 57 mos (range 36–81 mos). We assessed: the rates of Complete Cytogenetic Response (CCyR) and Major Molecular Response (MMR); the rates of optimal responders at each milestone according to ELN 2013 recommendations; the overall survival (OS; any death included), progression-free survival (PFS; progression to accelerated/blast phase [AP/BP] and deaths for any cause), failure-free survival (FFS; failures according to ELN 2013 recommendations and deaths for any cause), and event-free survival (EFS; events: failures, permanent discontinuation of NIL for any cause, including deaths). All analysis was made according to the intention-to-treat principle. Results. The cumulative rates of CCyR and MMR were 93% and 88%, respectively. At 3 mos, 82% of the pts were in Partial Cytogenetic Response and 90% had a BCR-ABL/ABL (IS) < 10%; at 6 mos, 86% were in CCyR and 83% had a BCR-ABL/ABL (IS) < 1%; at 12 mos, 72% were in MMR; all these pts were optimal responders according to ELN 2013 recommendations. Overall, 80 (37%) pts permanently discontinued NIL: 45 (21%) for adverse events or intolerance; 25 (12%) for failures; 7 (3%) while in stable MR4; 3 (1%) for other reasons. Cardiovascular adverse events (CVAE) were cause of permanent NIL discontinuation, after a median time of 37 mos, in 13 (6%) pts, and included 4 peripheral arterial occlusive diseases and 3 ischemic coronary diseases; only one pt died for CVAE. Nine (4.1%) pts progressed to AP/BP, 8/9 during the 1st year of therapy and one after 25 mos; all pts subsequently died (after a median of 13 mos, range 1-34 mos). NIL-resistant mutations were identified in 6 of these pts (4 T315I; 1 Y253H; 1 F359V); 7/9 progressions occurred in patients receiving NIL-IM. In addition, 6 pts were classified as failures at 3,6, or 12 mos according to ELN 2013 recommendations; afterwards, 10 pts developed a secondary resistance (3 loss of CHR, 3 loss of CCyR, and 4 confirmed loss of MMR). Overall, 17 (8%) pts died, in 7 cases for reasons unrelated to CML progression. The estimated 6-year OS, PFS, FFS, and EFS were 91%, 91%, 83%, and 59%, respectively. Conclusions. Our National experience showed that most pts treated frontline with NIL-based regimens were optimal responders according to ELN recommendations and that 91% of the patients were estimated to be alive and progression-free at 6 years. In particular, NIL alone was highly effective in the prevention of AP/BP. Considering that AP/BP had in most cases an early onset and an extremely poor prognosis, its prevention should be the priority of CML treatment, especially in the firsts 2-3 years. However, afterwards, the relatively high number of CVAE observed, suggests to focus, at least in selected patients, on strategies aimed at the prevention of CVAE (NIL dose reduction? switch to IM?). Acknowledgments. European LeukemiaNet, COFIN, Bologna University, BolognAIL Disclosures Gugliotta: Novartis: Consultancy; Bristol-Myers-Squibb: Consultancy. Castagnetti:Novartis: Consultancy; Bristol-Myers-Squibb: Consultancy. Breccia:novartis: Consultancy; BMS: Consultancy; Celgene: Consultancy. Abruzzese:Novartis: Consultancy. Martinelli:ARIAD: Consultancy; Pfizer: Consultancy; BMS: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau. Saglio:BMS: Consultancy, Fees for occasional speeches Other; Novartis: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; Pfizer: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; ARIAD: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other. Baccarani:Novartis, BMS, Pfizer, Ariad: Consultancy, Honoraria, Speakers Bureau. Rosti:Novartis: Consultancy; Bristol-Myers-Squibb: Consultancy; Ariad: Consultancy; Pfizer: Consultancy.

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.

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