Prognostic Factors in Treatment of Chronic Myeloid Leukemia with Tyrosine Kinase Inhibitors- Single Center Experience.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 2210-2210 ◽  
Author(s):  
Kajetana Foryciarz ◽  
Tomasz Sacha ◽  
Izabela Florek ◽  
Sylwia Czekalska ◽  
Magdalena Zawada ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Prognostic Factors ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Population Based ◽  
Molecular Response ◽  
First Line

Abstract Abstract 2210 Poster Board II-187 Background: Imatinib mesylate (IM), a targeted inhibitor of the BCR-ABL tyrosine kinase, is widely used to treat chronic myeloid leukemia (CML). However, considerable number of patients fails to achieve or loose complete cytogenetic response (CCyR) or major molecular response (MMR). The mechanisms of failure in the majority of cases are unknown. Identification of patients who may subsequently fail to respond to imatinib would provide a considerable aid to clinical management. Few long-term retrospective population-based data on the outcome of these patients are available. Aims: To identify prognostic factors that can predict failure of treatment with tyrosine kinase inhibitors (TKI), and to optimise CML therapy after first line TKI failure. Patients and methods: The retrospective population-based analysis included 138 patients (68 females, 70 males, median age 47 yrs) in early chronic phase (ECP) (n=63), late chronic phase (LCP) (n=60) or accelerated phase (AP) (n=15) of CML. All enrolled patients were treated with IM 400mg/day for CP or 600 mg/day for AP as a first line TKI. Patients were monitored for cytogenetic and molecular response every 6 and 3 months respectively using conventional cytogenetic on bone marrow and quantitative PCR (RQ-PCR) on peripheral blood. Results of RQ-PCR were expressed as a ratio of BCR-ABL/ABL% [IS]. Definitions of CCyR, MMR as well as CP and AP were consistent with European LeukemiaNet recommendations. The analyzed factors included: time to complete hematologic remission (CHR), time to CCyR, time to MMR and additional cytogenetic abnormalities in Ph positive cells [ACA Ph(+)] during first line IM treatment and % of CCyR and MMR during second line TKI treatment. To estimate probability of CCyR and MMR cumulative incidence analysis was used. Cytogenetic and molecular progression free survival (PFS) was estimated by Kaplan-Meier analysis. Results: Probability of CCyR for the analyzed group was 55%, 60% and 62% after 12, 18 and 24 months of treatment with IM respectively. Probability of cytogenetic PFS was 92%, 83%, 81% and 76% in 12, 18, 24 and 36 months respectively. There was observed statistically significant correlation between probability of achievement of CCyR, MMR and the following: time to CHR, time to imatinib introduction, phase of the disease and ACA Ph(+). No correlation between probability of CCyR, MMR and age, sex, Sokal and Hasford risk factors was observed. 1) Early CHR in up to 8 weeks after diagnosis (dx) predicted CCyR and MMR achievement irrespective of treatment schedule to CHR (p<0,0001) (Fig 1.). 2) Early IM introduction up to 4 months since dx increased probability of CCyR and MMR in 12 and 18 months respectively (p<0,0001). 3) Patients in LCP were significantly less likely to obtain CCyR and MMR comparing to ECP and results in this group were similar to AP patients (p=0,0004) (Fig. 2). 4) Early CCyR up to 6 months after starting IM increased probability of MMR (p<0,0001). 5) ACA Ph(+) were confirmed as an adverse prognostic factor regarding to achieving (p=0,005) and maintaining (p=0,01) of CCyR. 6) Treatment with higher dose of IM predicted better outcome when ACA Ph(+) at diagnosis and/or at least 10% of blasts in bone marrow or peripheral blood at dx were considered as AP criteria. 7) Among patients after IM failure those treated with 2G TKI were more likely to achieve and maintain CCyR (52%) than those with escalation of IM (24%) (p=0,02). Conclusions: These data suggest need of 1) therapy intensification from the very moment of diagnosis, 2) early achievement of CHR, 3) early IM introduction (<4 months from dx in analysed population), 4) the precise defining of AP with rigid criteria may result in better outcome. 5) Relative risk (Sokal and Hasford) relationship with treatment results seems to be not sufficient when IM is introduced after a long time since diagnosis. 5) Treatment switch to 2G TKI but not imatinib escalation after first line IM treatment failure is proposed to be an optimal treatment standard. Disclosures: Foryciarz: Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Sacha:Novartis: Consultancy, Honoraria, Research Funding; BMS: Consultancy, Honoraria, Research Funding. Florek:BMS: Research Funding; Novartis: Research Funding. Czekalska:BMS: Research Funding; Novartis: Research Funding. Zawada:Novartis: Research Funding; BMS: Research Funding. Skotnicki:Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau.

scholarly journals Outcomes of Chronic Phase Chronic Myeloid Leukemia after Treatment with Multiple Tyrosine Kinase Inhibitors

2020 ◽  
Vol 9 (5) ◽  
pp. 1542
Author(s):  
Jee Hyun Kong ◽  
Elliott F. Winton ◽  
Leonard T. Heffner ◽  
Manila Gaddh ◽  
Brittany Hill ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitors ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Molecular Response ◽  
Line Treatment ◽  
First Line ◽  
Blastic Phase

We sought to evaluate the outcomes of chronic phase (CP) chronic myeloid leukemia (CML) in an era where five tyrosine kinase inhibitors (TKIs) are commercially available for the treatment of CML. Records of patients diagnosed with CP CML, treated with TKIs and referred to our center were reviewed. Between January 2005 and April 2016, 206 patients were followed for a median of 48.8 (1.4–190.1) months. A total of 76 (37%) patients received one TKI, 73 (35%) received two TKIs and 57 (28%) were exposed to >3 TKIs (3 TKIs, n = 33; 4 TKIs, n = 17; 5 TKIs, n = 7). Nineteen (9.2%) patients progressed to advanced phases of CML (accelerated phase, n = 6; myeloid blastic phase, n = 4; lymphoid blastic phase, n = 9). One third (n = 69) achieved complete molecular response (CMR) at first-line treatment. An additional 55 patients achieved CMR after second-line treatment. Twenty-five patients (12.1%) attempted TKI discontinuation and 14 (6.8%) stopped TKIs for a median of 6.3 months (range 1–53.4). The 10-year progression-free survival and overall survival (OS) rates were 81% and 87%, respectively. OS after 10-years, based on TKI exposure, was 100% (1 TKI), 82% (2 TKIs), 87% (3 TKIs), 75% (4 TKIs) and 55% (5 TKIs). The best OS was observed in patients tolerating and responding to first line TKI, but multiple TKIs led patients to gain treatment-free remission.

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 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.

Recurrent bone marrow aplasia secondary to nilotinib in a patient with chronic myeloid leukemia: A case report

2012 ◽  
Vol 18 (4) ◽  
pp. 440-444 ◽  
Author(s):  
Prathima Prodduturi ◽  
Anamarija M Perry ◽  
Patricia Aoun ◽  
Dennis D Weisenburger ◽  
Mojtaba Akhtari
Keyword(s):  
Bone Marrow ◽  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Kinase Inhibitors ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Bone Marrow Aplasia ◽  
Line Therapy ◽  
Grade 3

Nilotinib is a potent tyrosine kinase inhibitor of breakpoint cluster region-abelson (BCR-ABL), which has been approved as front-line therapy for newly diagnosed chronic myeloid leukemia in chronic phase and as second-line therapy after imatinib failure in chronic or accelerated phase chronic myeloid leukemia. Tyrosine kinase inhibitors have been associated with myelosuppression and grade 3 or grade 4 cytopenias are not uncommon in chronic myeloid leukemia patients treated with these drugs. There are a few reports of imatinib-associated bone marrow aplasia, but to our knowledge only one reported case of bone marrow aplasia associated with nilotinib. Herein, we report a 49-year-old male patient with chronic phase chronic myeloid leukemia, who developed severe bone marrow aplasia due to nilotinib. Possible mechanisms for this significant adverse drug reaction are discussed along with a review of literature.

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.

Peripheral Blood Flow-Cytometry Chronic Myeloid Leukemia Stem Cells Detection and Quantification during Tyrosine Kinase Inhibitors Therapy

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 942-942 ◽  
Author(s):  
Monica Bocchia ◽  
Lara Aprile ◽  
Santina Sirianni ◽  
Elisabetta Abruzzese ◽  
Antonella Gozzini ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Kinase Inhibitors ◽  
Fish Analysis ◽  
Molecular Response ◽  
Line Treatment ◽  
First Line ◽  
Qrt Pcr ◽  
First Line Treatment

Abstract Introduction: In chronic myeloid leukemia (CML), tyrosine Kinase Inhibitors (TKIs) treatment is a potentially life-time therapy for the majority of patients (pts), as few of them, only after achieving a deep and stable molecular response, may discontinue TKIs without recurrence of disease. Available data suggest that relapse after TKIs discontinuation is due to the persistence of leukemic stem cells (LSCs) intrinsically resistant to TKIs. Survival of CML LSCs may be the consequence of activation of several pathways BCR-ABL1 independent. qRT-PCR, the most sensitive assay to monitor disease status in CML pts, may be inappropriate to quantify residual quiescent CML LSCs that are transcriptionally silent. Therefore, the possibility to easily quantify LSCs during TKIs treatment is a great opportunity to better understand the behavior of residual LSCs and potentially to identify those pts candidates to safely discontinue TKIs. Recently, Valent et al described that CD34+/CD38-/Lin- CML LSCs specifically co-express dipeptidylpeptidase IV (CD26) and that CD26 is a potential biomarker for the quantification and isolation of CML LSCs, in bone marrow samples of CML patients. Furthermore, Culen et al. quantified CD26+ LSCs bone marrow compartment in 31 CML patients at diagnosis and their number appears to correlate with response to TKIs treatment. In the present study we wanted to explore the feasibility, rate and potential implication of detecting CD26+ LSCs in peripheral blood (PB) from CML pts during TKI treatment. Methods: CML pts during first line treatment with any approved TKIs, referring to several Italian Hematology Centers, entered this non interventional cross sectional study after signing a proper informed consent. During a routine follow up visit, in which pts were checked for molecular response by standard PB qRT-PCR BCR-ABL1 analysis, additional 3 mls of PB were collected in EDTA and sent within 24 hours to Siena Hematology Lab to detect CD34+/CD38-/CD26+ LSCs by multicolor flow cytometry. After red blood cells lysis, cells were incubated with anti CD45 (BD Biosciences), CD34 (581), CD38 (HIT2), CD26 (M-A261) (BD Pharmigen). After washing, acquisition and analysis were performed by FACSCanto II (BD Biosciences, NR Nannini) using DIVA 8 software (BD, Biosciences). CD45+ cells acquired for each sample ranged from 500,000 to 1,000,000. Isotype controls were included in each staining. In 5 pts a FISH analysis of PB sorted CML LSCs population was also performed. Results: to validate our assay we first performed a FISH analysis of both PB sorted CD34+/CD38-/CD26+ and CD34+/CD38-/CD26- in 5 CML patients at 3-6 months after starting treatment, confirming Ph+ cells only in the CD26+ fraction. Afterward, we checked for circulating CML LSCs a total of 202 CML pts in first line treatment with TKIs for a median of 39 months (range 1-175). Type of TKI, length of treatment, molecular response and quantification of LSCs are summarized in Table 1. PB CML LSCs were detectable in 146/202 (72.3%) pts with a median number of CD26+ of 0,0165 cells/µL (range 0,0018-0,66). Kendall rank correlation coefficient used to analyze the relation between the measurable variables showed no correlation between BCR-ABL/ABLIS ratio (median 0,004 range 0-61) and number of residual LSCs (r 0.118 p=0.097). In 56/202 (27.7%) pts CD26+ LSCs were undetectable, yet we found no correlation with the concomitant degree of molecular response. Conclusions: this study represents the first attempt to measure in a large cohort of CML patients residual circulating LSCs during TKIs treatment. In our hands PB LSCs flow-cytometry assay appeared feasible, specific and sensitive and thus suitable for routine monitoring. As expected, the majority of CML patients, even in deep molecular response, still harbor residual LSCs and the number of PB CD26+ did not correlate with the number of BCR-ABL1 copies. This evidence suggests that the molecular response refers to transcriptionally active CML progenitor cells and not to quiescent, TKIs resistant, CML LSCs. Prospective studies evaluating the behavior of PB CML LSCs during different TKIs treatment, as well as studies monitoring PB CD26+ in CML pts that discontinued TKIs treatment are ongoing. Our goal is to rule out the impact, if any, of a "stem cell response" in addition to the standard molecular response in the management of CML patients mainly to identify those pts candidates for a safe TKI discontinuation. Disclosures Bocchia: Janssen: Honoraria; Novartis: Honoraria; Bristol-Myers Squibb: Honoraria. Aprile:Novartis: Honoraria. Castagnetti:Pfizer: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; ARIAD Pharmaceuticals: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Tiribelli:Ariad Pharmaceuticals: Consultancy, Speakers Bureau; Novartis: Consultancy, Speakers Bureau; Bristol-Myers Squibb: Consultancy, Speakers Bureau. Breccia:Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Honoraria; Celgene: Honoraria; Ariad: Honoraria; Pfizer: Honoraria. Rosti:Roche: Honoraria, Research Funding, Speakers Bureau; Incyte: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria, Research Funding, Speakers Bureau; BMS: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding, Speakers Bureau.

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.

scholarly journals Nilotinib Vs Nilotinib Plus Pegylated Interferon α (Peg-IFN) Induction and Nilotinib or Peg-IFN Maintenance Therapy for Newly Diagnosed BCR-ABL1 Positive Chronic Myeloid Leukemia Patients in Chronic Phase (TIGER Study): The Addition of Peg-IFN Is Associated with Higher Rates of Deep Molecular Response

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 495-495 ◽  
Author(s):  
Andreas Hochhaus ◽  
Andreas Burchert ◽  
Susanne Saussele ◽  
Gabriela M Baerlocher ◽  
Tim H Brümmendorf ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Research Funding ◽  
Chronic Phase ◽  
Maintenance Phase ◽  
Pegylated Interferon ◽  
Induction Phase ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Pilot Phase ◽  
First Line

Introduction: The TIGER (CML V)-study* (NCT01657604) is a multicenter, randomized phase III trial to evaluate efficacy and tolerability of nilotinib (NIL) 2*300mg/d monotherapy vs NIL 2*300mg/d + pegylated interferon α2b (Peg-IFN) 30-50μg/week as first line therapy for chronic myeloid leukemia (CML) patients (pts) in chronic phase and discontinuation of therapy after Peg-IFN maintenance (Figure). Methods: In August 2012, recruitment started with a pilot phase, aiming to validate the recommended dose of Peg-IFN. 25 pilot phase patients were treated with the combination of NIL 2*300 mg daily and Peg-IFN (30-50μg/week according to tolerability and commenced after ≥6 weeks NIL monotherapy). During the main phase of the study, 692 newly diagnosed pts were randomized between NIL 2*300 mg/d and NIL/Peg-IFN combination according to the outcome of the pilot phase. Results: Within 5 years, a total of 717 pts (429 male; median age 51 years, range 18-85; 12.9% EUTOS high risk) were recruited from 109 sites in Germany, Switzerland, and the Czech Republic. 702 pts with typical BCR-ABL1 transcripts (97.9%) were eligible for molecular follow-up assessments according to the international scale (IS). Fifteen pts (2.1%) expressed atypical BCR-ABL1 transcripts. 692 pts were randomized after EUTOS risk stratification to receive NIL monotherapy (n=353) or NIL/PEG-IFN combination therapy (n=339). Median observation time since recruitment was 41 months. Up to now, 477 pts concluded the induction phase by achieving a confirmed major molecular response, MMR (BCR-ABL1 transcript levels ≤0.1% IS, which qualified for entering the maintenance phase of the study using NIL or Peg-IFN monotherapy. During the maintenance phase, 199 pts achieved or sustained MR4 (BCR-ABL1 ≤0.01% IS) for at least one year and then discontinued all therapy. While the rate of MMR at 12 and 18 mo - the first primary endpoint of the study - was not different between the treatment arms, adding Peg-IFN to upfront NIL significantly improved rates of MR4 and MR4.5, BCR-ABL1 ≤0.0032% IS) (Table). In competing risk analysis, median time to MMR was 5.7 vs 5.4 mo, to MR4 20.9 vs 12.5 mo, and to MR4.5 33.8 vs 23.2 mo for NIL vs NIL/Peg-IFN, respectively. After NIL discontinuation, during Peg-IFN maintenance therapy, rate of molecular recurrence (BCR-ABL1 &gt;1% IS) after 18 mo was 28%. From 199 pts who discontinued all therapy, 63 experienced a molecular relapse (BCR-ABL1 &gt;0.1%). Relapse free survival by 18 mo after treatment discontinuation was 61% in the total cohort. By protocol, it is too early to assign relapse rates to the randomized treatment arm. Frequencies of adverse events after 24 mo of therapy were 90 and 92% (grade 1-5) and 36 and 42% (grade 3-5) for NIL vs NIL/Peg-IFN, respectively. Adverse events of special interest (all grades) were fatigue in 34.6 vs 40.4%, thrombocytopenia in 13.3 vs 18.9% and elevation of the alanin aminotransferase (ALAT) in 11.0 vs 18.9% of pts in the NIL vs NIL/Peg-IFN arms, respectively. Fifteen pts (2.1%) progressed to accelerated phase or blast crisis; 22 pts (3.1%) received an allogeneic stem cell transplantation, 10 of them after disease progression. In total, 22 pts (3.1%) died, 16 during the induction phase, 4 in the maintenance phase and 2 in treatment free remission. Four deaths were related to CML, 3 to vascular complications. Conclusions: This per protocol interim analysis demonstrates feasibility of the first-line treatment with NIL 2*300 mg/d combined with PEG-IFN 30-50 μg/week. Peg-IFN, when added upfront to NIL further increases the rates of MR4 and MR4.5, which may translate into higher rates oftreatment free remission. *The study is being conducted on behalf of the German CML Study Group, the Swiss Group for Clinical Cancer Research (SAKK) and the East German Study Group on Hematology and Oncology (OSHO). Disclosures Hochhaus: Pfizer: Research Funding; Novartis: Research Funding; BMS: Research Funding; Incyte: Research Funding; MSD: Research Funding. Burchert:Novartis: Research Funding. Saussele:Novartis: Honoraria, Research Funding; Incyte: Honoraria, Research Funding; BMS: Honoraria, Research Funding; Pfizer: Honoraria. Baerlocher:Novartis: Research Funding. Brümmendorf:Janssen: Consultancy; Ariad: Consultancy; University Hospital of the RWTH Aachen: Employment; Pfizer: Consultancy, Research Funding; Merck: Consultancy; Novartis: Consultancy, Research Funding. La Rosée:Novartis: Research Funding; Bristol-Myers-Squibb: Consultancy, Other: Travel support, Speakers Bureau. Heim:Novartis: Research Funding. Krause:Siemens: Research Funding; Takeda: Honoraria; MSD: Honoraria; Gilead: Other: travel; Celgene Corporation: Other: Travel. le Coutre:Bristol-Myers Squibb: Honoraria, Speakers Bureau; Incyte: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau; Pfizer: Honoraria, Speakers Bureau. Niederwieser:Daichii: Speakers Bureau; Cellectis: Consultancy. Lange:Novartis: Research Funding. Fabarius:Novartis: Research Funding. Hänel:Novartis: Honoraria; Amgen: Honoraria; Takeda: Other: advisory board; Celgene: Other: advisory board; Roche: Honoraria. Stegelmann:Novartis: Consultancy, Honoraria; Incyte: Consultancy, Honoraria. Mayer:AOP Orphan Pharmaceuticals AG: Research Funding. Hasford:Novartis: Research Funding. Hehlmann:Novartis: Research Funding. Ernst:Novartis: Research Funding. OffLabel Disclosure: Combination of Nilotinib and PEG-IFN alpha is being tested is off-label and being tested in the TIGER study.

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