Histamine Monitoring in Patients with CML during Treatment with Imatinib: Comparison to Monitoring by Cytogenetics and BCR/ABL.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4836-4836
Author(s):  
Hermine Agis ◽  
Susanne Herndlhofer ◽  
Hans Semper ◽  
Hendrati Pirc-Donoewenater ◽  
Oskar Haas ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Interferon Alpha ◽  
Kinase Inhibitor ◽  
Residual Disease ◽  
Clinical Importance ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Marrow Transplant ◽  
Blood Histamine

Abstract The tyrosine kinase inhibitor STI571=imatinib is highly effective in the treatment of chronic myeloid leukemia (CML). Although most patients (pts) show a complete cytogentic response (CCR) to this tyrosine kinase inhibitor, drug resistance may occur. Therefore, monitoring of minimal residual disease (MRD) during imatinib-therapy is of clinical importance. However, most MRD-parameters require special technology and equipment and are expensive. We found that histamine levels are highly upregulated at diagnosis in pts with CML (controls, n=39: median, 55.2 ng/ml, range, 19.1–108 ng/ml vs CML, n=44: median, 5,684.5 ng/ml, range, 181–47,816 ng/ml; p<0.0005) and correlate with the presence of basophils (R=0.87). To define the value of whole blood histamine as a marker of MRD in CML, histamine levels were determined serially by RIA before and during treatment with imatinib in 80 pts with CML (chronic phase, CP, n=70; accelerated phase, AP, n=10). Of the pts with CML-CP, 29 were previously untreated, whereas 41 pts had received interferon-alpha or a bone marrow transplant prior to imatinib. From the 10 pts with CML-AP, 3 had received previous interferon-alpha. Imatinib was given at a dose of 400 mg/day (CML-CP) or 600 mg/day (CML-AP and CP pts who did not respond adequately to 400 mg/day) orally. The rate of complete cytogenetic response (CCR) amounted to 77.6%, the rate of major cytogenetic response was 80%. Blood histamine levels decreased significantly in CML pts during treatment with imatinib, and returned to normal levels in all pts with CCR. In most pts, loss of CCR was accompanied or was preceded by a recurrent increase in histamine as well as an increase in BCR/ABL determined by light cycler-based real time PCR. The pts who did not enter CCR exhibited higher histamine levels and higher levels of BCR/ABL compared to those with continuous CCR (p<0.05). Unexpectedly, whereas the numbers of basophils were found to correlate well with histamine levels during therapy with imatinib (R=0.96), no correlation was found between histamine and Ph+ metaphases (R=0.34) or histamine and percentage of BCR/ABL (R=0.14), suggesting that basophil-histamine is an independent variable. Basophil-histamine should thus be considered as a simple and reliable additional marker to monitor MRD in pts with CML.

scholarly journals Successful nilotinib therapy in a CML affected patient with A380T, P407S and V468A mutations, and a previous suboptimal cytogenetic response to imatinib

2015 ◽  
Vol 4 (6S) ◽  
pp. 7-11
Author(s):  
Fabio Stagno ◽  
Alessandra Cupri ◽  
Stefania Stella ◽  
Michele Massimino ◽  
Silvia Rita Vitale ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Myeloid Leukemia ◽  
Prognostic Value ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Initial Response ◽  
Cytogenetic Response ◽  
Affected Patient

Imatinib mesylate (IM) has shown unprecedented effectiveness in the treatment of Chronic Myeloid Leukemia (CML) patients (pts) in the chronic phase of the disease. However, some pts fail to respond or lose their initial response to IM. The European LeukemiaNet (ELN) published recommendations designed to identify patients responding poorly to imatinib. Here we report a case of a suboptimal cytogenetic responder to IM who had a successful response to the second generation tyrosine kinase inhibitor nilotinib (NIL). According to the ELN criteria, CML pts on IM-therapy might show a suboptimal response either because of failure to achieve a CCyR by 12 months of therapy or because of lack of a MMR after 18 months. The prognostic value of these two types of responders might be very different.

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’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.

A Phase 1 Study of DCC-2036, a Novel Oral Inhibitor of BCR-ABL Kinase, in Patients with Philadelphia Chromosome Positive (Ph+) Leukemias Including Patients with T315I Mutation

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 601-601 ◽  
Author(s):  
Jorge E. Cortes ◽  
Moshe Talpaz ◽  
Hagop M Kantarjian ◽  
Hedy Smith ◽  
Dale Bixby ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Dose Level ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Cytogenetic Response ◽  
Lower Extremity Weakness ◽  
Hematologic Response ◽  
T315i Mutation ◽  
Dose Levels

Abstract Abstract 601 Background. DCC-2036 is a novel and potent tyrosine kinase inhibitor (TKI) which binds to a novel region called the switch pocket, thereby preventing BCR-ABL from adopting a conformationally active state. Efficacy against multiple imatinib-resistant BCR-ABL mutants has been demonstrated both in vitro and in vivo (Chan et al., Cancer Cell 2011;19:556). Importantly, DCC-2036 retains full potency against the T315I mutant in preclinical efficacy studies. Methods. This study was designed to find the maximal tolerated dose (MTD) of DCC-2036 when administered daily as a single-agent on a 28-day cycle. Eligible patients included adults with Ph+ CML/ALL who were refractory/intolerant to ≥2 TKI's or were T315I positive. Initially DCC-2036 capsules were administered orally once daily (QD) at increasing dose levels. Only 1 patient was enrolled in each of the lowest dose cohorts of 57mg QD and 114 mg QD. For higher doses, 3– 6 patients were enrolled into each ascending dose cohort with standard dose limiting toxicity (DLT) rules evaluating safety in cycle 1 to determine dose escalation. A transition from unformulated capsules (C) to formulated tablets (T) occurred after the 1200 mg QD dose level. Paired blood samples were obtained for PK and PD assessments. Results. 30 patients (16 males, 14 females; median age 59, range 31 – 80) with CML including 19 in Chronic (CP); 8 in Accelerated (AP) and 3 in Blast (BP) Phase were enrolled. Enrolled patients had received 1–6 prior CML treatments, and 11 patients had the T315I mutation. To date, a total of 212.5 (median 5.6; range 0.2 – 23.4) 28-day cycles were administered over 10 dose levels either as C (7 dose levels) or T (3 dose levels). The 7 C dose levels were studied first and included 57 mg QD through 1200 mg QD. Following transition to T, evaluation continued with 100 mg QD, 100 mg twice daily (BID), and 200 mg BID. Two reversible DLTs (Grade 3 peripheral neuropathy and Grade 4 lower extremity weakness) occurred during the initial treatment cycle at the 200 mg T BID dose level. Evaluation of 6 patients at the 150 mg T BID dose level determined that dose to be the MTD. Preliminary safety data show that other Grade (Gr) 3/4 adverse events (AEs) were Gr 3 slurred speech and Gr 3 eruptive nevi. Gr 1/2 AEs included dry mouth, constipation, diarrhea, paresthesias, and retinal vein occlusion. There was 1 case of Gr 2 pancreatitis that recurred on rechallenge in a patient with previous pancreatitis with nilotinib. Preliminary responses include one major molecular response in a CP patient with T315I mutation who started on capsules and transitioned to 100 mg T QD. There was one complete cytogenetic response in a CP patient at 100 mg T BID, and one partial cytogenetic response in a CP patient who started on capsules and transitioned to 100 mg T BID. One patient with AP CML and T315I mutation had a complete hematologic response at 450 mg C QD. Another patient with AP CML had a partial hematologic response after receiving 200 mg BID for 1 cycle and then downdosing to 100 mg T BID. Four out of 8 patients receiving 100 mg tablets and evaluable for efficacy (completed 3 cycles of treatment) had responses. PK results indicate dose-related, nonlinear increases in both peak plasma concentration (Cmax) and exposure (AUC). PD results reveal both acute and steady state post-treatment reductions in phospho-protein levels on Days 1 and 8. Marked reductions in pSTAT5 and pCRKL have been observed in subjects with both CP and AP and appear to be required for clinical response. Conclusion. The MTD of DCC-2036 tablets is 150 mg BID. Preliminary results suggest that DCC-2036 is well tolerated and has anti-leukemia activity in subjects with refractory CML and T315I positive disease. PD results are consistent with inhibition of BCR-ABL signaling in this first-in-man study of a switch pocket tyrosine kinase inhibitor. Disclosures: Cortes: Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; Chemgenex: Consultancy, Research Funding; Deciphera Pharmaceuticals: Research Funding. Bixby:Novartis: Speakers Bureau; Bristol Myers Squibb: Speakers Bureau; GlaxoSmithKline: Speakers Bureau. Rafferty:Deciphera Pharmaceuticals: Employment. Berger:Deciphera Pharmaceuticals: Employment. Wise:Deciphera Pharmaceuticals LLC: Employment. Rutkoski:Deciphera Pharmaceuticals: Employment. Smith:Deciphera Pharmaceuticals: Employment. Van Etten:Deciphera Pharmaceuticals: Consultancy, Research Funding.

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.

Benefits of Early Switching From Imatinib to a Second-Generation Tyrosine Kinase Inhibitor Following 12 Month Complete Cytogenetic Response Failure: A Chart Review Analysis.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2792-2792
Author(s):  
Daniel J. DeAngelo ◽  
Lei Chen ◽  
Annie Guerin ◽  
Amy Styles ◽  
Clemence Aberki ◽  
...  
Keyword(s):  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Disease Progression ◽  
Research Funding ◽  
Index Date ◽  
Second Generation ◽  
Kinase Inhibitor ◽  
Cytogenetic Response ◽  
Analysis Group

Abstract Abstract 2792 Background: The National Comprehensive Cancer Network (NCCN) guidelines (version 1.2013) recommend that patients with chronic myelogenous leukemia in chronic phase (CML-CP) should be tested for cytogenetic response 12 months following imatinib initiation. Failure to achieve complete cytogenetic response (CCyR) at 12 months should result in either an increased dose of imatinib (up to 800mg) or a change to a second-generation tyrosine kinase inhibitor (TKI). This study observed patients who failed to achieve CCyR at 12 months following the initiation of imatinib and compared treatment response rates and disease progression between patients who switched to a second-generation TKI early versus patients who did not. Methods: An online chart abstraction form was used to survey US oncologists and hematologists. Physicians submitted de-identified information on up to 10 adult patients with CML-CP who initiated imatinib as first line therapy (between 01/01/2007 and 26/07/2010) and failed to achieve CCyR at 12 months (between 10–14 months). Patients either switched to a second-generation TKI within 3 months following CCyR failure (early-switchers), or remained on imatinib for ≥3 months following CCyR failure (non-switchers). Non-switchers may have later switched to a second-generation TKI. The index date was defined as the date of the 12-month CCyR failure. Detailed patient information was collected, including demographics, comorbidities, imatinib dosage, and hematologic and cytogenetic response prior to the index date. Cytogenetic response and disease progression was also collected after the index date. CCyR was defined as 0% Philadelphia chromosome positive (Ph+) cells on cytogenetic testing. The proportion of patients achieving CCyR by 6, 12, and 24 months was reported among patients who had ≥1 cytogenetic test during these periods. Documented CCyR was defined as CCyR achievement analyzed among all patients, if patients were not tested for CCyR following the index date they were considered not to have achieved CCyR. Time to first documented CCyR achievement and time to disease progression were both estimated using multivariate Cox proportional hazard ratios (HR), where exposure was calculated from the index date to the first documented CCyR achievement, or to the date of progression, respectively. Multivariate regression analyses controlled for age, sex, race, index year, Charlson comorbidity index, imatinib dose and hematological response prior to index date, percentage of Ph+ cells and CML disease duration at index date, number of days between CML diagnosis and imatinib initiation, and rise in transcript level and chromosome abnormalities in Ph+ cells reported prior to the index date. Results: The majority of the 108 surveyed physicians were from a private practice (72.2%) and a small/intermediate practice size (61.1%). Physicians provided information on 593 patients who failed to achieve CCyR at 12 months; 306 were early-switchers and 287 were non-switchers. Among the non-switchers, 78 later switched to a second-generation TKI, and 104 increased imatinib dose after the index date. Patient demographics and comorbidities were similar among early-switchers and non-switchers, however, results of the 12-month cytogenetic test revealed that early-switchers had a greater number of Ph+ positive cells (51. 5 ± 16.6) compared to non-switchers (47.2 ± 13.1, p=.002). The median follow-up time was 612.5 days (range = 91–1625) and 591 days (range = 365–1623), respectively. Among patients tested for cytogenetic response during the follow-up period (274 early-switchers and 252 non-switchers), 35% of early-switchers subsequently achieved CCyR, compared to 24 % of non-switchers (p=.006). Within 6 months after the index date, 4.7% of the early-switchers achieved CCyR vs. 0.4% of non-switchers; by 12 months, 20.1% vs. 12.3% achieved CCyR; and by 24 months, 33.6% vs. 21.8% achieved CCyR, respectively (all p<.016). After adjusting for confounding factors, early-switchers had an 80% greater documented CCyR achievement rate compared to that of non-switchers (HR=1.80; p=.002) and a progression rate that was 81% lower (3.8% vs.1.5%, HR=0.19, p=.034). Conclusion: Early switching from imatinib to a second-generation TKI following 12-month CCyR failure was associated with better cytogenetic response and a lower risk of progression. Disclosures: DeAngelo: Novartis: Consultancy. Off Label Use: Everolimus in AML. Chen:Novartis Oncology: Employment, Own stock in Novartis Other. Guerin:Analysis Group, Inc.: Consultancy, Employment, I am an employee of Analysis Group, Inc, which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding. Styles:Analysis Group, Inc.: Consultancy, Employment, Research Funding. Aberki:Analysis Group, Inc.: Consultancy, Employment, Research Funding. Giguere-Duval:Analysis Group, Inc.: Consultancy, Employment, Research Funding. Wu:Analysis Group, Inc.: Consultancy, Employment, I am an employee of Analysis Group, Inc, which has received consulting fees from Novartis Pharmaceuticals Other, Research Funding.

Sign in / Sign up

Export Citation Format

Share Document