IFN-γ (interferon-gamma) Genotype Predict Cytogenetic and Molecular Response to Imatinib Therapy in Chronic Myeloid Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2178-2178
Author(s):  
Dong Hwan Dennis Kim ◽  
Jee Hyun Kong ◽  
Silvia Park ◽  
Chul Won Jung ◽  
Lakshmi Sriharsha ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Signaling Pathway ◽  
Interferon Gamma ◽  
Myeloid Leukemia ◽  
Imatinib Therapy ◽  
Functional Study ◽  
Molecular Response ◽  
Interferon Signaling ◽  
Action Mechanism

Abstract Abstract 2178 Poster Board II-155 Purpose: Interferon therapy had served as a standard therapy before introduction of imatinib into the treatment of chronic myeloid leukemia (CML) although its action mechanism is yet fully elucidated. After introduction of imatinib therapy, it provides significant therapeutic benefit to CML patients, however its response varies person-by-person. Some patient responds quickly and maintain long-term response without development of resistance, while others do not respond well or lose their response quickly thus developing resistance to imatinib. One of interesting observation is that the patients previously treated with interferon could maintain long-term complete molecular response (CMR) even after withdrawal of imatinib therapy, suggesting interferon signaling pathway seemed to be associated with favorable response to imatinib therapy. Variable response to imatinib therapy in CML can be explained by inter-individual variation of candidate genes involved in the biologic activity of CML cells such as apoptosis or angiogenesis as well as drug transport/metabolism of imatinib in addition to Interferon gamma signaling pathway. Methods: In the current study, we investigated 80 single nucleotide polymorphism (SNP) markers involved in the pathways of apoptosis (n=31; BCL2, BAX, BCL2L2, BCL6, BCL2L11, BIRC5, CASP1, CASP3, CASP7,CASP8, CASP9, CASP10, FAS, FASL, APAF1, TNFR2, PDCD1, GZMB), angiogenesis (n=7; VEGFA, VEGFR2), myeloid cell growth (n=13; FLT2, CSF3, CSF2, JAK3, IL1A, IL1B, IL1R), xenobiotic metabolism (n=13; ABCB1, ABCG2, CYP3A5, HOCT1), WT1 signaling (n=7), interferon signaling (n=4; IFNG, IFNGR1, IFNGR2) and others (n=5; GNB3, ULK3, ORM, PTK2). Discovery cohort includes 244 patients treated at the Princess Margaret Hospital, Toronto, ON, Canada. The DNAs from peripheral blood samples were genotyped with MALDI-TOF based technique (Sequenom). The results were validated internally using a Bootstrap procedure, and externally in an independent validation cohort of 187 Korean CML patients treated at the Samsung Medical Center, Seoul, Korea or Chonnam National University Hwasun Hospital, Hwasun, Korea. Results: In a single marker analysis, several genotypes were found to be correlated with complete cytogenetic response (CCR; IFNG “p-value, 0.01”, FAS “0.03”, FASL “0.006”, CASP8 “0.04”, CASP10 “0.04”), major molecular response (MMR; IFNG “0.04”, FAS “0.05”, JAK3 “0.03”), loss of response (IFNG “0.02”, BIRC5 “0.02”), treatment failure (IFNG “0.07”), or dose escalation of imatinib (IFNG “0.03”, ABCG2 “0.02”, APAF1 “0.04”, CASP2, “0.03”). Bootstrap methods showed a good correlation of each genotype with clinical outcomes. External validation was performed in an independent cohort with 187 Korean CML patients, the IFNG genotype (rs2069705) was validated that is able to predict CCR (HR, 0.46; p=3×10-5) or MMR (HR, 0.51; p=7×10-5) in CML patients. Conclusions: The current study suggested that the interferon gamma genotype seemed to predict the response to imatinib therapy, proposing potential involvement of interferon-gamma signaling pathway in the action mechanism of imatinib therapy in CML. Further detailed study on IFNG genotype and functional study of interferon gamma phenotype will help us to reach a clear conclusion on the role of IFNG gene in the action mechanism of imatinib therapy in CML. Disclosures: No relevant conflicts of interest to declare.

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

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

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

scholarly journals European Treatment and Outcome Study (Eutos) Score Predicts Early Molecular Response to Imatinib Therapy in Chronic Phase Chronic Myeloid Leukemia Patients (Cp-Cml)

2014 ◽  
Vol 25 ◽  
pp. iv337
Author(s):  
K. Sudheer Reddy ◽  
M. Manickavasagam ◽  
V. Venkata Sampath ◽  
D. Barghavi ◽  
A. Vindhyavasini ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Imatinib Therapy ◽  
Molecular Response ◽  
Outcome Study ◽  
Eutos Score

Outcome of Patients with Chronic Myeloid Leukemia Who Recieved an Intermittent Imatinib Therapy.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1034-1034
Author(s):  
Hyun-Gyung Goh ◽  
Soo-Hyun Kim ◽  
Jeong Lee ◽  
Sae-Eun Jang ◽  
Wan-Seok Kim ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Oral Dose ◽  
Median Duration ◽  
Myeloid Leukemia ◽  
Cytogenetic Response ◽  
Imatinib Therapy ◽  
Intermittent Therapy ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
600Mg Daily

Abstract Diagnosis of chronic myeloid leukemia (CML) is based on detection of the BCR-ABL gene or Philadelphia chromosome, and the BCR-ABL tyrosine kinase inhibitor imatinib has been the standard therapy for CML patients. Although imatinib therapy is effective in CML, it is still unclear whether imatinib can be safely discontinued without relapse. This study was designed to investigate the outcome of 26 CML patients after discontinuation of imatinib and to determine whether intermittent imatinib therapy can be employed in CML patients. Between May 2001 and Jun 2007, 555 patients have been treated with imatinib in St Mary’s Hospital of the Catholic University of Korea, and 26 patients discontinued imatinib when they achieved either complete cytogenetic response (CCyR) or complete molecular response (CMR). These 26 patients were diagnosed as Philadelphia positive (Ph+) CML between November 1995 and May 2002, and 22 patients were in chronic phase (CP) and 4 patients were in accelerated phase (AP) at diagnosis. The median age was 35 years (22–56), and 12 patients (46%) were female and 14 (54%) were male. Among 26 patients, 7 received interferon prior to imatinib therapy and 7 underwent SCT. Five patients received both interferon and SCT before imatinib therapy, and the remaining 7 patients received the imatinib as a front line therapy. Imatinib was started at oral dose of 400mg and 600mg daily for patients in CP and AP, respectively, and when they achieved CCyR or CMR, imatinib was discontinued after informed consent of the patient. In case of cytogenetic or molecular relapse, patients in all phases were retreated with imatinib at 400mg daily. Bone marrow (BM) or peripheral blood (PB) samples were obtained at regular intervals from diagnosis for hematologic response (HR), cytogenetic response (CyR) and molecular response (MR) monitorings. Eleven patients discontinued imatinib when they achieved CCyR, and 15 patients discontinued imatinib after achieving CMR. After the median duration of 7 month (4–48) observation without imatinib therapy, hematologic, cytogenetic and molecular relapses occurred in 4, 7 and 10 patients, respectively, and imatinib at oral dose of 400mg daily was reintroduced to all patients except 2 who continued to remain in CMR after imatinib discontinuation. Except 1 patient who expired and 2 patients who are in persistent molecular remission, all of 23 patients are maintaining the best response achieved after imatinib resumption with a median duration of 38 months (16–58). In conclusion, although imatinib cannot be discontinued completely, intermittent therapy can be considered for the treatment of CML patients. Intermittent imatinib treatment should not be restricted to CP patients who achieve CMR, and AP patients or patients with CCyR also can be considered for intermittent imatinib treatment. We will continue the follow-up of the patients enrolled in this study, and long-term study of intermittent imatinib treatment with expanded pool of patients will enable us to determine the accurate consequences of discontinuation of imatinib and intermittent imatinib treatment.

Long Term Adherence to Imatinib Therapy Is the Critical Factor for Achieving Molecular Responses in Chronic Myeloid Leukemia Patients.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3290-3290 ◽  
Author(s):  
Alex Bazeos ◽  
Jamshid Khorashad ◽  
François-Xavier Mahon ◽  
Lina L Eliasson ◽  
Dragana Milojkovic ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Independent Predictor ◽  
Chronic Phase ◽  
Imatinib Therapy ◽  
Adherence Rate ◽  
Molecular Response ◽  
Molecular Responses ◽  
Adherence To Therapy

Abstract Abstract 3290 Poster Board III-1 There is a great variability in the degree of molecular responses achieved by chronic myeloid leukemia (CML) patients treated with imatinib. These different levels of molecular response could reflect different degrees of adherence to therapy. We measured the adherence to imatinib therapy in 87 consecutive CML chronic phase patients who had received imatinib 400 mg day as first line therapy for a median of 59.7 months before enrolment (range 25–104) and therefore all them were in complete cytogenetic response. Adherence levels were monitored during a 3-month period using microelectronic monitoring devices (MEMS) and were related to levels of molecular response. MEMS consist of an electronic device fitted in the cap of a normal looking medication bottle that automatically records each time the bottle is opened. MEMS are considered as the ‘gold standard' for measuring adherence. We also measured the imatinib plasma level, the presence of TKD mutations and the following prognostic factors measured at diagnosis: hOCT1 transcripts level, polymorphism 1236C>T in ABCB1, Sokal risk group, hemoglobin, leukocytes , BCR-ABL1 transcript type and BCR1-ABL1 ratio and demographic data. The study protocol was approved by the Research Ethics Committee and patients gave written informed consent to participate. The median adherence rate was 97.6% (range 22.6–103.8%). In 23 (26.4%) patients adherence was ≤90% (median 76%) and in 12 (13.8%) ≤80% (median 63%). We found a strong association between adherence rate (≤90% or >90%) and the 6-year probability of major molecular response (MMR) (28.4% vs 94.5%, p<0.0001) and complete molecular response (CMR) (0% vs 43.8%, p=0.002) (Fig 1). Multivariate analysis identified adherence (RR=11.7, p=0.001) and expression of the molecular transporter hOCT1, (RR=1.79, p=0.038) as the only independent predictors for MMR. Adherence was the sole independent predictor for CMR. No molecular responses were observed when the adherence was ≤20% (p=0.0001). In patients whose imatinib dose had been increased (n=32) the adherence was poor (median 86.4%). Adherence was the only independent predictor for failure to achieve a 3-log transcript reduction (RR=17.66, p=0.006) in this subgroup of patients. Patients with CML vary greatly in their response, as demonstrated originally by Sokal et al. in 1984, and the same variation is seen in patients treated with imatinib in the modern era. The basis for this variation is unknown but it has been attributed to the intrinsic biological heterogeneity of the leukemia. In contrast we show here that adherence to therapy is the major factor determining the degree of response that a CML patient treated with imatinib will achieve. Disclosures: Mahon: Novartis: Consultancy, Research Funding. Apperley:Novartis: Consultancy, Honoraria. Rezvani:Novartis: Consultancy, Honoraria, Research Funding. Marin:Novartis: Consultancy, Research Funding.

scholarly journals Concomitant essential thrombocythemia with JAK2 V617F mutation in a patient with chronic myeloid leukemia with major molecular response with imatinib and long-term follow-up

2016 ◽  
Vol 12 (1) ◽  
pp. 485-487 ◽  
Author(s):  
KATIA BORGIA BARBOSA PAGNANO ◽  
MÁRCIA TORRESAN DELAMAIN ◽  
MARIANA MUNARI MAGNUS ◽  
JOSÉ VASSALLO ◽  
CARMINO ANTONIO DE SOUZA ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Essential Thrombocythemia ◽  
Myeloid Leukemia ◽  
Jak2 V617f ◽  
Jak2 V617f Mutation ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Long Term Follow Up

scholarly journals The IFNG (IFN-γ) Genotype Predicts Cytogenetic and Molecular Response to Imatinib Therapy in Chronic Myeloid Leukemia

2010 ◽  
Vol 16 (21) ◽  
pp. 5339-5350 ◽  
Author(s):  
Dong Hwan (Dennis) Kim ◽  
Jee Hyun Kong ◽  
Ji Young Byeun ◽  
Chul Won Jung ◽  
Wei Xu ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Imatinib Therapy ◽  
Molecular Response ◽  
Ifn Γ

scholarly journals The HIGH BCR-ABL1 GENE PERCENTAGE AT TIME OF PRESENTATION: A TOOL TO PREDICT FAILURE IN ACHIEVING EARLY MOLECULAR RESPONSE IN CHRONIC MYELOID LEUKEMIA (CML): A TERTIARY CARE CENTER EXPERIENCE

2021 ◽  
Vol 71 (Suppl-1) ◽  
pp. S71-75
Author(s):  
Amjad Khan ◽  
Riaz Ahmed ◽  
Sarah Fatimah ◽  
Muhammad Nadeem ◽  
Shama Iqbal ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Imatinib Therapy ◽  
Military Hospital ◽  
Molecular Response ◽  
Number Of Patients

Objective: To determine the relationship of baseline quantitative BCR ABL1 gene percentage and therapeutic response i.e. Early Molecular Response (EMR) at 3 months with first generation Tyrosine kinase inhibitors (Imatinib) in patients with Chronic Myeloid Leukemia (CML) in chronic phase (CP). Study Design: Prospective observational study. Place and Duration of Study: Combined Military Hospital, Rawalpindi, Pakistan, and Armed Forces Institute of Pathology Rawalpindi, Pakistan from Oct 2017 to Oct 2019. Methodology: One hundred and seventy patients, 18 years of age or older with newly diagnosed Chronic Myeloid Leukemia (CML) in chronic phase (CP) with quantitative baseline BCR-ABL (IS) transcript were included in the study. All enrolled patients were placed on Imatinib therapy (400 mg/day) and Reverse transcription polymerase chain reaction (RT-PCR) for BCR ABL transcript was repeated at 3 months to document EMR (BCR-ABL (IS) <10%). Patients who were in accelerated/blast phase, or already taking any Tyrosine Kinase Inhibitors (TKI) or chemotherapy were excluded from the study. Results: In our study 101 (59.4%) patients achieved early molecular response. Out of these 80 (70.8%) patients with BCR-ABL<50% at baseline value showed early molecular response. However, only 21 (36.8%) with BCRABL >50% at baseline achieved early molecular response (p-value <0.001). Conclusion: A significant number of patients achieved early molecular response with Imatinib therapy that had BCR ABL below 50%, however those with baseline BCR ABL >50%, the rate of EMR was comparatively lower.

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