scholarly journals A Predictive Score for Outcomes of Tyrosine Kinase-Inhibitor Therapy in Persons with Chronic Myeloid Leukaemia Presenting in Accelerated Phase

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 636-636
Author(s):  
Sen Yang ◽  
Xiaoshuai Zhang ◽  
Xiaojun Huang ◽  
Robert Peter Gale ◽  
Qian Jiang
Keyword(s):  
Propensity Score ◽  
Tyrosine Kinase ◽  
Propensity Score Matching ◽  
Haemoglobin Concentration ◽  
Chronic Phase ◽  
Initial Therapy ◽  
Predictive Score ◽  
Molecular Response ◽  
Who Criteria ◽  
Md Anderson

Abstract Background Chronic myeloid leukaemia (CML) presenting in accelerated phase (AP) is uncommon and there are few data on predictive co-variates for outcomes of tyrosine kinase-inhibitor (TKI)-therapy. Moreover, it is unknown which outcomes of TKI-therapy in these persons correlate with European LeukemiaNet (ELN) definitions of warning and failure which were developed in people in chronic phase or whether imatinib and 2 nd generation tyrosine kinase-inhibitors (TKIs) are equally effective. Objective Identify co-variates correlated with outcomes of TKI-therapy in persons with CML presenting in AP diagnosed by MD Anderson or World Health Organization (WHO) criteria and develop a predictive score. Determine which outcomes correlate with ELN criteria of warning and failure. Compare outcomes of initial therapy with imatinib versus 2 nd-generation TKIs. Methods We interrogated data from 312 and 334 consecutive subjects with CML presenting in AP and receiving imatinib or a 2 nd-generation TKI as initial therapy. Diagnosis of AP was based on widely-accepted MD Anderson or WHO criteria. Demographic, clinical and laboratory co-variates significantly correlated with outcomes were analyzed in a Cox multi-variable regression model. Propensity score matching was done to compare outcomes of initial therapy with imatinib versus a 2 nd generation TKIs. Results In the cohort defined by MD Anderson criteria there were 197 males (63%) with a median age of 41 years (Interquartile Range [IQR], 30 - 54 years). 106 subjects (34%) had ≥ 1 co-morbidities. Median haemoglobin concentration was 99 g/L (range, 40-176 g/L), WBC concentration, 138 x 10E+9/L (range, 3-797 x10E+9/L), platelet concentration, 450 x 10E+9/L (range, 11-4094 x10E+9/L) and percentage blood or bone marrow blasts (whichever was higher), 4% (range, 0-27%). Non-mutually exclusive criteria for classifying subjects as AP included: (1) 15-29% blasts (n = 22, 7%); (2) blood basophils ≥ 20% (n = 184, 59%); (3) platelets < 100 × 10E+9/L unrelated to therapy (n = 31, 10%); (4) clonal evolution (n = 45, 15%); (5) ≥ 2 features (n = 30, 10%). Co-variates associated with failure-free survival (FFS) were haemoglobin concentration < 100 g/L (HR = 1.9; 95% Confidence Interval [CI], 1.1, 3.1; p = 0.014) and blasts > 4.5% (HR = 1.8 [1.1 - 2.9]; p = 0.013). Co-variates associated with progression-free survival (PFS) were platelets < 230 × 10E+9/L (HR = 3.3 [1.7, 6.5]; p < 0.001), blasts > 4.5% (HR = 2.4 [1.3, 4.6]; p = 0.007) and ≥ 1 co-morbidities (HR = 2.4 [1.2, 4.7]; p = 0.010). Co-variates associated with survival were haemoglobin concentration < 100 g/L (HR = 3.3 [1.1, 10.2]; p = 0.04), platelets < 230 × 10E+9/L (HR = 11.4 [3.9, 33.3]; p < 0.001) and ≥ 1 co-morbidities (HR = 6.7 [2.3, 19.5]; p < 0.001). Next, we divided subjects into 4 cohorts: (1) low-risk (no adverse co-variate; n = 49); (2) intermediate-1 risk (1 adverse co-variate; n = 116); (3) intermediate-2 risk (2 adverse co-variates; n = 92); and (4) high-risk (≥ 3 adverse co-variates; n = 47) with significant different probabilities of FFS, PFS and survival (all p-values < 0.001). Using the 2020 ELN criteria for w arning at 3 months was significantly-associated with worse FFS (HR = 3.1 [1.7, 5.7]; p < 0.001). Failure at 3 months was significantly associated with worse PFS (HR = 9.3 [4.3, 18.8]; p < 0.001) and survival (HR = 6.2 [2.0, 19.2]; p = 0.002). In propensity score matching analyses subjects receiving initial therapy with imatinib had lower probabilities of complete cytogenetic response (CCyR; HR = 1.3 [1.0, 1.8]; p = 0.079), major molecular response (MMR; HR = 1.2 [0.8, 1.7; p = 0.386) and molecular response 4.5 (.5; HR = 1.8 [1.1, 3.1]; p = 0.019). However, other endpoints including FFS, PFS and survival were similar for both interventions. Similar results in the subjects diagnosed as AP using the WHO criteria. Conclusions We identify co-variates associated with several outcomes of TKI-therapy in persons presenting in AP CML and used these to develop a prognostic score. We show the 2020 ELN criteria for warning and failure to TKI-therapy developed in persons in chronic phase also operate in subjects diagnosed in AP. Lastly, using propensity score matching we show that whilst some landmarks are achieved more rapidly in persons initially treated with a 2 nd generation TKI, FFS, PFS and survival are similar to those in persons initially treated with imatinib. Our data should help inform physicians treating person with CML presenting in AP. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Clinical or Sub-Clinical Pancreatitis (PA) Associated with Nilotinib (Nb) As Frontline for Chronic Myelogenous Leukemia (CML)

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 4443-4443
Author(s):  
Mahran Shoukier ◽  
Hagop M. Kantarjian ◽  
Elias Jabbour ◽  
Alfonso Quintas-Cardama ◽  
Zeev Estrov ◽  
...  
Keyword(s):  
Risk Factors ◽  
Tyrosine Kinase ◽  
Research Funding ◽  
Chronic Phase ◽  
Initial Therapy ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Close Monitoring ◽  
Pancreatic Cell ◽  
Free Survival

Abstract Abstract 4443 Background: Nilotinib is now standard therapy in chronic phase (CP) CML, both as initial therapy and after imatinib failure. One of the adverse effects of nilotinib is the increase in serum amylase and/or lipase levels with or without clinical pancreatitis.The mechanism by which nilotinib increases serum pancreatic enzymes is not clear. Nilotinib is able to inhibit the non-receptor tyrosine kinase c-abl with high affinity. It is possible that c-abl inhibition might interfere with the molecular mechanisms regulating pancreatic cell death, inducing pancreatic damage. Nilotinib may release calcium from the intracellular acinar stores which regulate exocrine pancreatic secretion, or it may promote the accumulation of fatty acid inside the pancreatic acinar cells which disturbs exocytose. (JOP. J Pancreas (Online) 2010 May 5; 291–293). Purpose: To understand the frequency, risk factors and management strategy for patients who develop pancreatitis (clinical or subclinical) during nilotininb frontline therapy for CML. Method: We reviewed the records of 105 CML patients treated at our institution on a clinical trial from 7/2005 to 7/2011 with nilotinib 400 mg twice daily as initial therapy for CML in chronic phase. Results: The median age for the total population was 52 yrs (range, 17 to 89), and 63 were males (60%). Thirteen (12%) pts experienced pancreatitis at least once, most frequently asymptomatic (ie, grade 1). Pancreatitis episodes occurred 28 times (2 episodes were grade 3, 2 episodes were grade 4, 10 episodes were grade 2, and 14 episodes were grade 1). Thirteen episodes (47%) occurred at a dose of 200 mg daily, 4 (14%) at 400 mg daily, and 11 (39%) at 800 mg daily. In 3 instances total bilirubin was also elevated (2 grade 2 and 1 grade 4). One patient experienced recurrent elevations (16 episodes) of lipase and amylase despite dose reduction to 200mg once daily. Concurrent use of hydrochlorothiazide and moderate alcoholic intake were identified as risk factors associated with pancreatitis in the patient who experienced recurrent episodes. Diabetes was identified as a risk factor for pancreatitis in other 4 pts. Twenty four episodes (86%) were characterized by an elevation of lipase and amylase without any clinical symptoms. In four instances, patients experienced a moderate abdominal pain without other symptoms of pancreatitis. In 3 instances, imaging (ultrasound and/or CT scan) demonstrated normal pancreases. Management of pancreatitis included transient nilotinib interruption in most instances. In most patients, lipase and amylase values returned to normal within 14 days of stopping nilotinib. Three patients eventually required change from nilotinib to other tyrosine kinase inhibitors (TKI) (imatinib 2, dasatinib 1) without recurrence of pancreatitis. One of these pts switched to imatinib because of recurrent pancreatitis and the other 2 were switched because of nilotinib toxicities (liver and cardiac toxicity). At the time of pancreatitis episodes, 54% had achieved complete cytogenetic response (CCyR), and 8% complete molecular response (CMR). Rates of (CCyR) were 92% and 94% in patients who experienced and who did not experience pancreatitis, respectively. Rates of major molecular response (MMR) were 100%and 87% in patients who experienced and who did not experience pancreatitis, respectively. Rates of complete hematologic response (CHR) were 100% and 98% in patients who experienced and who did not experience pancreatitis, respectively. The 3-year event-free survival (EFS), treatment- free survival (TFS), and overall survival (OS) rates were 100% in patients who experienced and 93%, 97%, and 100% in patients who did not experience pancreatitis, respectively. Conclusion: Pancreatitis associated with nilotinib is most frequently grade 1 and 2 (asymptomatic enzyme elevation). Close monitoring and timely intervention may allow patients to continue therapy and achieve the desired clinical benefit. Rarely, pancreatitis may require treatment discontinuation. Disclosures: Cortes: BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Deciphera: Research Funding.

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 A propensity score matching analysis of dasatinib and nilotinib as a frontline therapy for patients with chronic myeloid leukemia in chronic phase

Cancer ◽  
2016 ◽  
Vol 122 (21) ◽  
pp. 3336-3343 ◽  
Author(s):  
Koichi Takahashi ◽  
Hagop M. Kantarjian ◽  
Yulong Yang ◽  
Koji Sasaki ◽  
Preetesh Jain ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Propensity Score ◽  
Propensity Score Matching ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Propensity Score Matching Analysis ◽  
Frontline Therapy

scholarly journals Clinical Importance of Drug Adherence during Tyrosine Kinase Inhibitor Therapy for Chronic Myelogenous Leukemia in Chronic Phase

2019 ◽  
Author(s):  
Yasuhiro Maeda ◽  
Atsushi Okamoto ◽  
Kenta Yamamoto ◽  
Go Eguchi ◽  
Yoshitaka Kanai
Keyword(s):  
Tyrosine Kinase ◽  
Second Generation ◽  
Adverse Drug Events ◽  
Kinase Inhibitor ◽  
Myeloproliferative Neoplasm ◽  
Clinical Importance ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Drug Adherence

Chronic myeloid leukemia (CML) is a myeloproliferative neoplasm constituting approximately 15% of newly diagnosed leukemia in adult patients. Development of tyrosine kinase inhibitors (TKIs) have dramatically improved outcomes in patients with chronic CML in chronic phase. However, adverse drug events (ADEs) associated with TKI therapy have influenced drug adherence, resulting in adverse clinical outcomes and a decline in the quality of life (QoL). In this study, we carried out a unique questionnaire survey to evaluate ADEs, which comprised 14 adverse events. We compared drug adherence rates between patients using imatinib and those who switched from imatinib to nilotinib, a second-generation TKI. Following the switch, the total number of ADEs decreased considerably in most cases. Simultaneously, better QoL was observed in the nilotinib group than in the imatinib group. Drug adherence was measured using Morisky&rsquo;s 9-item Medication Adherence Scale (MMAS). MMAS increased significantly after switching to nilotinib in all cases. Drug adherence is a critical factor for achieving molecular response in patients with CML. In fact, our results showed a strong inverse correlation between clinical outcome [international scale (IS)] and adherence (MMAS), with a stronger tendency in the nilotinib group than in the imatinib group. In conclusion, low occurrence of ADEs induced a high level of QoL and a good clinical response with second-generation TKI nilotinib treatment.

scholarly journals Nilotinib therapy in an imatinib intolerant chronic myeloid leukemia patient with pulmonary severe hypertension

2015 ◽  
Vol 4 (2S) ◽  
pp. 17-20
Author(s):  
Mario Annunziata
Keyword(s):  
Side Effects ◽  
Tyrosine Kinase ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Chronic Myeloid Leukemia Patient ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Cutaneous Rash

Imatinib mesylate is a tyrosine kinase inhibitor that has significant efficacy in the treatment of chronic myelogenous leukemia. In general, hematologic and extrahematologic side effects of imatinib therapy are mild to moderate, with the large majority of patients tolerating prolonged periods of therapy. However, a minority of patients are completely intolerant of therapy, while others are able to remain on therapy despite significant side effects. Here, we describe a chronic phase CML patient with pulmonary arterial hypertension, mechanical hearth valve, who experienced extrahematologic adverse event (persistent grade III cutaneous rash, despite two discontinuations of imatinib and using of steroid). Necessitating switch to one of new tyrosine kinase inhibitors, nilotinib, has resulted in complete cytogenetic response and major molecular response, after 3 and 6 months, respectively. No cross-intolerance with imatinib was observed during nilotinib therapy. Besides, this clinical case suggests that warfarin and nilotinib can be used concurrently without the risk of increased anticoagulant effect.

scholarly journals A Retrospective Analysis about Frequency of Monitoring in Italian Chronic Myeloid Leukemia Patients after Discontinuation

2020 ◽  
Vol 9 (11) ◽  
pp. 3692
Author(s):  
Matteo Dragani ◽  
Giovanna Rege Cambrin ◽  
Paola Berchialla ◽  
Irene Dogliotti ◽  
Gianantonio Rosti ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Molecular Response ◽  
Molecular Monitoring ◽  
Delay In Diagnosis ◽  
Number Of Patients

Successful discontinuation of tyrosine kinase inhibitors has been achieved in patients with chronic-phase chronic myeloid leukemia (CML). Careful molecular monitoring after discontinuation warrants safe and prompt resumption of therapy. We retrospectively evaluated how molecular monitoring has been conducted in Italy in a cohort of patients who discontinued tyrosine kinase inhibitor (TKI) treatment per clinical practice. The outcome of these patients has recently been reported—281 chronic-phase CML patients were included in this subanalysis. Median follow-up since discontinuation was 2 years. Overall, 2203 analyses were performed, 17.9% in the first three months and 38.4% in the first six months. Eighty-six patients lost major molecular response (MMR) in a mean time of 5.7 months—65 pts (75.6%) during the first six months. We evaluated the number of patients who would experience a delay in diagnosis of MMR loss if a three-month monitoring schedule was adopted. In the first 6 months, 19 pts (29.2%) would have a one-month delay, 26 (40%) a 2-month delay. Very few patients would experience a delay in the following months. A less intense frequency of monitoring, particularly after the first 6 months off treatment, would not have affected the success of treatment-free remission (TFR) nor put patients at risk of progression.

BCR/ABL Transcript At 3 Months Predicts Long-Term Outcomes Following Second Generation Tyrosine Kinase Inhibitor Therapy in the Patients with CML in Chronic Phase Who Failed Imatinib.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2777-2777
Author(s):  
Dennis Dong Hwan Kim ◽  
Hong Gi Lee ◽  
Suzanne Kamel-Reid ◽  
Jeffrey H. Lipton
Keyword(s):  
Tyrosine Kinase ◽  
Treatment Failure ◽  
Tyrosine Kinase Inhibitor ◽  
Second Generation ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Transcript Level ◽  
Molecular Response ◽  
Long Term Outcomes

Abstract Abstract 2777 Background: The BCR/ABL transcript level at 3 months can predict long-term outcomes following frontline therapy with Imatinib or Dasatinib in chronic myeloid leukemia (CML) patients. However, data is lacking with second generation tyrosine kinase inhibitor (2GTKI) therapy after Imatinib failure. Methods: A total of 112 patients with CML in chronic phase (CP) receiving 2GTKI after Imatinib failure were reviewed. Treatment outcomes including complete cytogenetic (CCyR), major molecular (MMR) and molecular response 4.5 (MR4.5), treatment failure, progression-free (PFS) and overall survival (OS) were compared according to BCR/ABL transcript levels at 3 or 6 months, divided into <1%IS, 1–10%IS and °Ã10%IS. Results: Using cut off of 1%IS and 10%IS BCR/ABL transcript level, 70 patients (65%) showed <1%IS of BCR/ABL transcript level at 3 months, 16 patients (15%) between 1 and 10%IS, and 21 patients (20%), °Ã10%IS at 3 months. BCR/ABL transcript level at 3 months showed better correlation with OS (p<0.001) than that at 6 months (p=0.147). Better OS was also observed in the patients achieving <1%IS (100%) and 1–10%IS (100%) than those with °Ã10%IS at 3 months (70.6%, p<0.001). Those with <1%IS exhibited the best CCyR (100% at 12 months), MMR (93.1±3.2% at 18 months) and MR4.5 (80.2±6.3% at 3 years); those with 1–10%IS, intermediate (56.4±15.5% CCyR at 12 months; 22.1±14.1% MMR at 18 months; 10.0±9.5% MR4.5 at 3 years); and those with °Ã10%IS, the lowest CCyR (16.7±11.2% at 12 months), MMR (6.2±6.1% at 18 months) and MR4.5 rates (0%). Especially, in the subgroup of Imatinib resistant patients (n=59), none of them achieved MR4.5 if BCR/ABL transcript level is above 1% at 3 months (i.e. those with 1–10%IS or °Ã10%IS). Multivariate analysis confirmed strong correlation of BCR/ABL transcript level at 3 months with CCyR (HR 0.019), MMR (HR 0.047), MR4.5 (HR 0.057), treatment failure (HR 12.264), PFS (HR 7.754) and OS (HR 15.115). The group with <1%IS at 3 months maintained significantly lower BCR/ABL transcript level compared to other 2 groups. Conclusion: The BCR/ABL transcript level at 3 months is the most relevant surrogate for outcomes following 2GTKI therapy after Imatinib failure. Disclosures: No relevant conflicts of interest to declare.

Molecular Response to Tyrosine Kinase Inhibitors (TKIs) for Chronic Myeloid Leukemia (CML), the Experience At Tawam Hospital, Abudhabi, UAE

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4458-4458
Author(s):  
Arif Alam ◽  
Sabir Hussain ◽  
Amar Lal ◽  
Donna Lee ◽  
Jorgen Kristensen
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Molecular Technique ◽  
Molecular Response ◽  
Female Ratio

Abstract Abstract 4458 Chronic Myeloid Leukemia (CML) is a clonal myeloproliferative disorder characterized by the presence of a balanced reciprocal translocation involving the long arms of chromosomes 9 and 22. The fusion gene that is created by this translocation (BCR-ABL1) encodes for a constitutively active protein tyrosine kinase that is primarily responsible for the leukemic phenotype. Targeted therapy with Tyrosine Kinase Inhibitors (TKIs) has become the recommended first-line treatment for patients with CML. Monitoring of the CML is done with quantification of the BCR-ABL transcripts by RQ-PCR–based molecular technique. Twenty nine patients were diagnosed with CML in chronic phase between January 2009 till June 2012. The median age was 32 years (range 22–68 years). Male to female ratio was4.14:1. Three patients were lost from follow up after diagnosis and are excluded. Molecular response is available for 16 patients. Nine patients were treated with Imatinib 400 mg daily, four with Dasatinib 100 mg daily and three with Nilotinib 400 mg BID daily as upfront therapy. Twelve patients have achieved MMR/CMR (75 %) within 18months of starting therapy. Four patients have failed to achieve MMR by 24 months. All non responders were on Imatinib. Interestingly six (37.5%) patients achieved MMR/CMR within 9 months of starting TKIs. Of these only 1 was on Imatinib while the rest were on 2nd generation TKIs (Nilotinib 3 and Dasatinib 2). MMR report from Enestnd trial is 67–71% in favor of Nilotinib as compared to Imatinib 44%, while the Dasision trial reported a MMR of 44 % in favor of Dasatinib with faster rate to response. Our results mirror the results of these phase 3 randomized trial with MMR/CMR of 75 %. Until today there has been no case of progressive disease. Our data is limited but shows that the median age is much lower compared to Western countries, just reflecting differences in the age distribution of the population in the UAE with 80% being below the age of 65 years. Expatriates accounts for approximately 80% of the population in the UAE and many are temporary employed, having limited health care coverage, limited financial means as well as limited possibilities to attend regular follow-ups. This leads to compliance problems, loss from follow-up and suboptimal management and monitoring of their disease. Disclosures: Alam: BMS/Novartis: Consultancy, Honoraria. Hussain:BMS: Consultancy, Honoraria.

Predictive Value of 3-Month Early Molecular Response in New Chronic Phase Chronic Myeloid Leukemia Patients Treated with Radotinib

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 4053-4053
Author(s):  
Sung-Eun Lee ◽  
Soo Young Choi ◽  
Jae-Yong Kwak ◽  
Hawk Kim ◽  
Jeong-A Kim ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Predictive Value ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Molecular Response ◽  
Phase 3 ◽  
Qrt Pcr ◽  
Study Therapy

Abstract Background: Recent studies have demonstrated that early molecular milestones were able to identify high-risk chronic myeloid leukemia patients treated with frontline imatinib (IM) and second generation tyrosine kinase inhibitors (2G TKIs) such as nilotinib and dasatinib. However, whether a single measurement of BCR-ABL1 transcripts level after 3 months of treatment is sufficient to define failure necessitating a change of treatment is not confirmed. Radotinib (RAD) is a 2G TKI for BCR-ABL1 tyrosine kinase, which was approved by the Korea FDA for the second-line therapy, and the phase 3 study comparing the efficacy and safety of RAD 300 and 400 mg twice daily and IM 400 mg once daily in patients with newly diagnosed CP CML was performed. The aim of this study was to identify the predictive value of 3-month molecular milestone for an achievement of major molecular response (MMR) by 12 months to RAD therapy. Additionally, in the same population, predictive factors for achieving MMR by 12 months were analyzed. Methods: Among 241 patients who were enrolled in the randomized, open-label, phase 3 study of RAD, 236 patients with available 3-month qRT-PCR on study therapy [RAD 300 mg twice (n = 79), RAD 400 mg twice (n = 79), IM 400 mg once (n = 78)] were evaluated. Molecular responses were monitored using a qRT-PCR assay in 3-month intervals by 12 months. All qRT-PCR were tested with at least 4.5-log sensitivity in the central laboratory (Cancer Research Institute, The Catholic University of Korea, Seoul, Korea) and MMR was defined as a BCR-ABL1 transcript level of 0.1% or lower on the international scale (IS). Results: 236 patients (including 149 men and 87 women) with available 3-month qRT-PCR on study therapy were evaluated. With a median age of 45 years (range, 18-84 years), the distribution of low, intermediate and high Sokal risk scores were 27%, 47% and 26%, respectively. At 3 months, BCR-ABL1 ≤10% [RAD 300 mg twice (n = 68), RAD 400 mg twice (n = 69), IM 400 mg once (n = 55)] and >10% [RAD 300 mg twice (n = 11), RAD 400 mg twice (n = 10), IM 400 mg once (n = 23)] were observed. In the IM 400 mg once group, patients with BCR-ABL1 ≤10% at 3 months showed a significant higher rate of MMR by 12 months compared with that of patients with BCR-ABL1 >10% (38.2% vs 13.0%, P = 0.028). In the RAD 300 and 400 mg twice group, an achievement of 3-month EMR was associated with a higher rate of MMR by 12 months [57.4% vs 18.2%, P = 0.016 (RAD 300 mg twice) and 50.7% vs 10.0%, P = 0.018 (RAD 400 mg twice)]. After adjusting for factors affecting achievement of MMR by 12 months on univariate analyses, multivariate analyses showed that b2a2 transcript type (RR of 0.46, P = 0.023), large spleen size (RR of 0.91, P = 0.001), and no achievement of 3-month EMR (RR of 0.24, P = 0.004) were predictor for not achieving MMR by 12 months. Significance of 3-month EMR for achieving MMR by 12 months was observed in the separated treatment groups: RR of 0.24, P = 0.037 in the IM 400 mg once group, RR of 0.17 P = 0.028 in the RAD 300 mg twice group, and RR of 0.11, P = 0.040 in the RAD 400 mg twice group. Conclusions: Our results suggest that 3-month EMR can play key roles for 12-month MMR achievement in CP CML patients treated with IM and RAD. In addition, some factors for achieving 12-month MMR were detected. To evaluate the long-term prognostic value of 3-month EMR, further clinical investigations in a larger patient population with longer follow-up are needed. Disclosures Kim: IL-YANG Pharm.Co.Ltd: Research Funding. Chung:Alexion Pharmaceuticals: Research Funding.

scholarly journals NCCN Task Force Report: Tyrosine Kinase Inhibitor Therapy Selection in the Management of Patients With Chronic Myelogenous Leukemia

2011 ◽  
Vol 9 (Suppl_2) ◽  
pp. S-1-S-25 ◽  
Author(s):  
Susan O'Brien ◽  
Ellin Berman ◽  
Joseph O. Moore ◽  
Javier Pinilla-Ibarz ◽  
Jerald P. Radich ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Chronic Myelogenous Leukemia ◽  
Task Force ◽  
Standard Dose ◽  
Relative Effectiveness ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Secondary Resistance ◽  
Task Force Report

The advent of imatinib has dramatically improved outcomes in patients with chronic myelogenous leukemia (CML). It has become the standard of care for all patients with newly diagnosed chronic-phase CML based on its successful induction of durable responses in most patients. However, its use is complicated by the development of resistance in some patients. Dose escalation might overcome this resistance if detected early. The second-generation tyrosine kinase inhibitors (TKIs) dasatinib and nilotinib provide effective therapeutic options for managing patients resistant or intolerant to imatinib. Recent studies have shown that dasatinib and nilotinib provide quicker and potentially better responses than standard-dose imatinib when used as a first-line treatment. The goal of therapy for patients with CML is the achievement of a complete cytogenetic response, and eventually a major molecular response, to prevent disease progression to accelerated or blast phase. Selecting the appropriate TKI depends on many factors, including disease phase, primary or secondary resistance to TKI, the agent's side effect profile and its relative effectiveness against BCR-ABL mutations, and the patient's tolerance to therapy. In October 2010, NCCN organized a task force consisting of a panel of experts from NCCN Member Institutions with expertise in the management of patients with CML to discuss these issues. This report provides recommendations regarding the selection of TKI therapy for the management of patients with CML based on the evaluation of available published clinical data and expert opinion among the task force members.

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