Quantitative Polymerase Chain Reaction (qPCR) at Diagnosis and Follow-Up of Patients with Chronic Myeloid Leukemia in Treatment with Imatinib.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4688-4688
Author(s):  
Teresa Vallespí ◽  
Mildred Borrego ◽  
Doulous Colomé ◽  
Ana Jaen ◽  
Maria Rozman ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Treatment Time ◽  
Quantitative Polymerase Chain Reaction ◽  
Chronic Phase ◽  
Logarithmic Scale ◽  
Base Line ◽  
Molecular Response ◽  
Before And After

Abstract Imatinib, a selective inhibitor of tyrosin-kinasa BCR/ABL fusion protein, produces high response rates in patients with chronic myeloid leukemia (CML) in the chronic phase. The behavior of the levels of the BCR/ABL transcript by qPCR technique was studied in 24 patients (13M/11F; median age: 49.6 years, range: 23–73), diagnosed of CML in chronic phase, before and after the treatment with imatinib (at the 0, 3, 7, 11 and 15 months). Eight patients had previously received interferon alpha or busulphan and 16 hidroxiurea. The amplification of BCR/ABL with the qPCR technique, according to protocol BIOMED-2, was carried out in samples of bone marrow (n = 23) and peripheral blood (n = 48). Results were calculated in relation to a control gene of the glucuronidasa (GUS) and expressed in logarithmic scale (log10). Median time from the diagnosis was of 28 months and median treatment time with imatinib was 14 months. The median reduction of BCR/ABL transcripts was 1,98 log after three months and decreased further (2,71 log) during follow-up. Both of them were significative when compare with base line levels (P <0.001). The reduction was greater in patients who received a dose ³ 400 mg/day (n=16) than those with 300 mg/day (n=8). Three patients reached a major molecular response (ratio BCR-ABL/GUS <0.005) up to 15 months of treatment. In conclusion: the determination of the BCR/ABL transcripts by qPCR contributes with valuable information about the effect of imatinib in patients with CML. The logarithmic reduction is higher in the beginning of the treatment and doses ³ 400 mg/day are associated with a greater reduction of the tumoral load. Figure Figure

scholarly journals Introduction of a Treatment Approach for Chronic Myeloid Leukemia and Pregnancy Considering Leukemic Burden and Pregnancy Terms

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 5144-5144 ◽  
Author(s):  
Ekaterina Chelysheva ◽  
Anna Turkina ◽  
Evgenia Polushkina ◽  
Roman G. Shmakov
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Ethical Issues ◽  
Complete Blood Count ◽  
Treatment Approach ◽  
Quantitative Polymerase Chain Reaction ◽  
Chronic Phase ◽  
Molecular Response ◽  
Newly Diagnosed

Abstract Background Using oftyrosine kinase inhibitors (TKIs) in women with chronic myeloid leukemia (CML) at pregnancy is risky due to possible teratogenecity. Absence of TKIs for whole pregnancy is risky for remission loss and disease progression. Particular situations may warrant TKI usage at pregnancy for potential benefits despite potential risks although no precise indications have been developed. Rareness of cases and ethical issues make significant difficulties in decision making. Aim To develop and evaluate the treatment approach for CML and pregnancy considering leukemic burden and pregnancy terms. Materials and methods During years 2011-2015 we monitored prospectively 29 cases of pregnancy in 28 women with CML chronic phase developing the treatment scheme step by step (picture 1). In 16 cases molecular response (MR) at pregnancy start was the following: MR4 in 8 cases (BCR-ABL <0,01%), MR3 in 5 cases (BCR-ABL<0,1% and >0,01%), MR2 in 3 cases (BCR-ABL<1% and >0,01%). In 13 cases leukemic burden at pregnancy start was high: 6 cases without complete hematologic remission (CHR) including 5 newly diagnosed, 7 cases with BCR-ABL>1% and CHR. All women insisted to keep pregnancy in spite of risks. We recommended 1) immediate discontinuation of TKIs if they were taken 2) monthly follow-up of complete blood count (CBC) and BCR-ABL level by reverse quantitative polymerase chain reaction (RQ-PCR) 3) careful evaluation for developmental defects 4)possibility of using TKIs in cases of high leukemic burden starting from 15th pregnancy week as comparatively safe late term when main organogenesis is completed and blood-placental barrier (BPB) exists knowing that TKIs have limited BPB crossing ability. High leukemic burden was considered BCR-ABL>1% as this level correlates with complete cytogenetic response (CCyR) absence and increased progression risk. The absence and/or loss of CHR was crucial to warrant TKIs. Alternative approaches including interferon, leukapheresis and staying without treatment were weighted in all cases. Dasatinib (DAS) was avoided due to multitargeted action, high fetal/maternal (F:M) concentrations and known possibility of hydrops fetalis. All patients were informed about possible risks at every stage of pregnancy. Results In 19 of 29 cases TKIs taken at conception were discontinued at 4th -10th week: imatinib (IM) in 17 and nilotinib (NIL) in 2. Evaluation for BCR-ABL level was done regularly but not monthly. Practically significant timepoints for BCR-ABL evaluation were pregnancy start, week 15th and pregnancy end. In 17 cases TKIs were reinitiated or started first: 4 newly diagnosed cases, 2 with CHR loss, 11 with BCR-ABL>1% (high level at pregnancy start or MR loss). The TKIs taken were IM in 14 cases (dose 400 mg), NIL in 3 (1-400 mg, 1-600 mg 1- 800mg). In 1 woman NIL was taken from week 10th due to CHR loss and resistance to IM. In 12 other cases no TKIs were reinitiated at pregnancy as 11 had BCR-ABL<1% till pregnancy end and for 1 newly diagnosed at 35th week CML woman treatment was postponed till delivery. In 24 cases TKIs were continued after delivery. Five women with MR3-MR4 at pregnancy end prolonged off-treatment period for breastfeeding being on regular PCR control. All 5 newly diagnosed women got an optimal response on IM. In 3 woman switch from IM to TKI2 was needed after delivery. The 29 pregnancy outcomes were: 27 deliveries (1 woman twice), 1 spontaneous abortion on week 5th (IM stopped from week 4th), 1 non-developing pregnancy terminated at week 20th (IM at conception, intrauterine infection, normal fetus). All newborns had no birth defects. Eight children were born preterm (weeks 31-37), 7 of them had been exposed to TKIs after week 15th. Further development was without deviations, median follow-up 23 months (range 1 -52), including 17 children exposed to TKIs at late terms. In 5 cases the F:M concentration ratio was studied for IM and NIL ranging from 0,12 to 0,3. Conclusion Treatment approach considering leukemic burden and pregnancy terms may help to avoid treatment interventions in favorable situations and warrantinterests of both mother and child when treatment initiation is necessary.This approach can expand chances for woman with CML to have children. Possible risks should be understood by patient and physician. Management of CML at pregnancy in case of huge leukemic mass remains a complicated task, pregnancy in CML should be safely planned at deep remission. Figure 1. Figure 1. Disclosures Chelysheva: Bristol Myers Squibb: Honoraria; Novartis Pharma: Consultancy, Honoraria. Turkina:Bristol Myers Squibb: Consultancy; Pfizer: Consultancy; Novartis Pharma: Consultancy.

scholarly journals Side-effects profile and outcomes of ponatinib in the treatment of chronic myeloid leukemia

2020 ◽  
Vol 4 (3) ◽  
pp. 530-538 ◽  
Author(s):  
Onyee Chan ◽  
Chetasi Talati ◽  
Leidy Isenalumhe ◽  
Samantha Shams ◽  
Lisa Nodzon ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Inverse Correlation ◽  
Cancer Center ◽  
Molecular Response ◽  
Starting Dose ◽  
Dose Dependent Fashion ◽  
Dose Dependent

Abstract Ponatinib is associated with cardiovascular adverse events (CAEs), and its frequency in the real world is limited. In this retrospective study, we examined the survival outcomes and associated toxicities in 78 consecutive ponatinib-treated patients with chronic myeloid leukemia (CML) at the Moffitt Cancer Center from January 2011 through December 2017. The most common non-CAE was thrombocytopenia (39.7%), occurring in a dose-dependent fashion. Eighteen patients (23.1%) experienced some form of CAE, with the most common being arrhythmia (9%) and hypertension (7.7%), whereas 3 patients experienced myocardial infarction (3.8%). Before 2014, most patients were started on ponatinib 45 mg daily. There was an inverse correlation between cardio-oncology referral and the number of CAEs (P = .0440); however, a lower ponatinib starting dose, more frequent dose reduction, and increased cardio-oncology referral all were likely to have contributed to the observed decrease in CAEs after 2014. The response rate and 5-year overall survival (OS) were higher than those observed in the Ponatinib Ph+ ALL and CML Evaluation (PACE) trial (major molecular response, 58.7% vs 40% and OS, 76% vs 73%; median follow-up of 32.5 months). Ponatinib-treated patients with chronic phase–CML did not show a significant improvement with allogeneic stem cell transplantation, whereas those with accelerated phase/blast phase–CML had a much better outcome (median OS of 32.9 months vs 9.2 months; P = .01). These results demonstrate that ponatinib is highly effective. Dose adjustments and increased awareness of the cardiotoxicities associated with ponatinib may help maximize its benefits.

High and Early Rates of Cytogenetic and Molecular Response with Nilotinib 800 Mg Daily as First Line Treatment of Ph-Positive Chronic Myeloid Leukemia in Chronic Phase: Results of a Phase 2 Trial of the GIMEMA CML Working Party

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 181-181 ◽  
Author(s):  
Gianantonio Rosti ◽  
Fausto Castagnetti ◽  
Angela Poerio ◽  
Massimo Breccia ◽  
Luciano Levato ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Working Party ◽  
Hematologic Toxicity ◽  
Molecular Response ◽  
Average Dose ◽  
Open Label ◽  
Grade Iii

Abstract Imatinib (IM) 400 mg daily is the standard treatment for chronic myeloid leukemia in early chronic phase (ECP): the results of the IRIS trial have shown a 72 months overall survival of 95%; EFS and PFS were 83% and 93%, respectively; the cumulative rate of complete cytogenetic response (CCgR) for the IM 400 mg arm was 25% at 3 months (at 6, 12, 18 and 60 months it was 51%, 69%, 76% and 87%, respectively). Nilotinib, a second generation TKI, has a higher binding affinity and selectivity for Abl with respect to IM, being 20 to 50 times more active in IM-sensitive cell lines and is highly effective in IM resistant patients, across every disease phase. To investigate the therapeutic efficacy and the safety of nilotinib 400 mg BID in untreated, ECP, Ph-pos CML patients, the italian GIMEMA CML Working Party is conducting an open-label, single stage, multicentric, phase II study trial (ClinicalTrials.gov. NCT00481052); all patients provided written informed consent. The primary endpoint is the CCgR rate at 1 year; the kinetic of molecular response is studied by Q-PCR baseline and after 1, 2, 3, 6, 9 and 12 months from treatment start. PATIENTS Seventy-three patients have been enrolled from 20 Centres between June, 2007 and February, 2008. The median age was 51 years (range 18–83), 45% low, 41% intermediate and 14% high Sokal risk. Median follow-up is currently 210 days (range 68–362). RESULTS All 73 patients and 48/73 (66%) completed 3 and 6 months on treatment, respectively. Response at 3 and 6 months (ITT): the CHR rate was 100% and 98%, the CCgR rate 78% and 96%, respectively. A MMR, defined as a BCR-ABL:ABL ratio &lt; 0.1% according to the International Scale, was achieved by 3% of all treated patients after 1 month on treatment, but this proportion rapidly increased to 22% after 2 months, 59% after 3 months and 74% after 6 months. One patient progressed at 6 months to accelerated-blastic phase with the T315I mutation. NILOTINIB DOSE AND COMPLIANCE No dose escalation was permitted in case of resistance; the median daily average dose was close to the intended dose, 789 mg (range 261 – 800); 34/73 patients (47%) interrupted nilotinib at least once, with a median duration of dose interruption of 15 days (range 2–98). The dose of nilotinib at the last visit was 400 mg BID for 52 patients (71%), 400 mg daily for 20 patients (27%) and 200 mg daily for 1 patient (1%). ADVERSE EVENTS: AEs (grade III/IV) were manageable with appropriate dose adaptations: hematologic toxicity was recorded so far in 4 pts (5% - only 1 event grade IV neutropenia); the most frequent biochemical laboratory abnormalities (grade III) were total bilirubin increase (15%), GOT/GPT increase (11%) and lipase increase (4%). Only 1 episode of grade IV lipase increase was recorded. It is noteworthy, considering the 48 cases with at least 6 months of follow-up, that the incidence of any grade II and III nonhematologic adverse event, decreased from 50% and 8% (first 3 months) to 23% and 6% (second trimester), respectively. ECG monitoring: in 16 patients (22%), transient and not clinically relevant ECG abnormalities have been recorded; 2 more patients (3%) revealed a transient and uneventful QTc prolongation (&gt;450 but &lt;499 msec). CONCLUSIONS: The results that have been achieved in these unselected patients and within a multicentric trial, strongly support the notion that in ECP Ph-pos CML patients both cytogenetic and molecular responses to nilotinib are substantially faster than the responses to IM. Acknowledgments: Work supported by European LeukemiaNet, COFIN, University of Bologna and BolognAIL.

Dasatinib Is Well-Tolerated and Efficacious in Imatinib-Intolerant Patients with Chronic-Phase Chronic Myeloid Leukemia (CP-CML).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1128-1128 ◽  
Author(s):  
Hanna Jean Khoury ◽  
Michael J. Mauro ◽  
Yousif Matloub ◽  
Tai-Tsang Chen ◽  
Erkut Bahceci ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Median Duration ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Phase Iii ◽  
Hematologic Toxicity ◽  
Molecular Response

Abstract Abstract 1128 Poster Board I-150 Imatinib (IM), a tyrosine kinase inhibitor (TKI), has been the mainstay of treatment for chronic phase chronic myeloid leukemia (CP-CML). However, IM resistance and intolerance are of considerable clinical relevance. Dasatinib (DAS), a second-line TKI, is effective in the IM-intolerant patient population. The purpose of this study was to determine baseline factors that can affect DAS response and evaluate long term efficacy in this population. Intolerance to IM was defined as ≥ Grade 3 non-hematologic toxicity and/or Grade 4 hematologic toxicity lasting > 7 days. A total of 271 Ph+ CP-CML IM-intolerant patients who received DAS were pooled from two randomized trials (Phase II-trial, CA 180013 and Phase III trial, CA 180034). DAS doses were 50 mg BID (n=43), 70 mg BID (n=141), 100 mg QD (n=43) or 140 mg QD (n=44). At baseline, the median duration of disease for the IM-intolerant patients was 24 months (range: 0.9-182.5) and the median duration of IM therapy was 9 months (range: 0.03-69.06). Of these patients, 46 (17%) had hematologic toxicity and 228 (84.1%) had non-hematologic toxicity to IM. Seventy-nine (29%) patients had prior complete cytogenetic response (CCyR) on IM and 171 (63%) patients did not. The data for prior CyR to IM was not reported for 21 (7.7%) patients. Of the 79 patients who had achieved CCyR on IM, 30 patients had maintained CCyR and 49 patients had lost this response prior to start of DAS. Of the 171 patients who did not achieve CCyR on IM, 62 (36.3%) had been on IM for 3 12 months and 109 (63.7%) for < 12 months. At 2-year follow up of the 271 patients treated with DAS, 121 (44.6%) discontinued DAS (7.4% due to hematologic toxicity and 14% due to non-hematologic toxicity). Of the patients who were intolerant of IM due to hematologic toxicity (n=46), 10 (21.7%) discontinued DAS due to hematologic toxicity, and 3 (6.5%) due to other toxicities. Of the patients with non-hematologic IM-intolerance (n=228), 10 (4.4%) discontinued DAS due to hematologic toxicity, and 35 (15.4%) due to other toxicities. The median average daily dose of DAS was 99 mg/day in the population who achieved CCyR on DAS and 71.5 mg/day in the population who did not achieve CCyR on DAS. The probability of achieving CCyR on DAS was 43.5% in patients with hematologic IM-intolerance versus 78.9% with non-hematologic IM-intolerance. The CCyR, major molecular response (MMR), progression-free survival (PFS) and overall survival (OS) at 2-year follow up for the groups classified by their CCyR status at start of DAS or IM-intolerance status are summarized in Table 1. Conclusions DAS was well-tolerated and associated with high rates of CyR in IM-intolerant patients. Patients with a prior CCyR to IM and those who switched due to non-hematologic imatinib-intolerance had the highest rates of CCyR and MMR on DAS, while patients without CCyR after more than 12 months of IM therapy or IM-intolerance due to hematologic toxicity had the lowest rates of CCyR and MMR. Disclosures Khoury: BMS: Honoraria; Wyeth: Honoraria; Novartis Pharmaceuticals: Honoraria; Chemgenex: Honoraria; Genzyme: Honoraria. Mauro:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding. Matloub:Bristol-Myers Squibb: Employment. Chen:Bristol-Myers Squibb: Employment. Bahceci:Bristol-Myers Squibb: Employment. Deininger:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Calistoga: Research Funding; Genzyme: Research Funding.

Results of Imatinib Dose Escalation After 36 Months of Follow-up in Chronic Myeloid Leukemia Patients with Failure or Sub-Optimal Response According to 2006 EuropeanLeukemia Net (ELN) Criteria.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3302-3302
Author(s):  
Massimo Breccia ◽  
Fabio Stagno ◽  
Roberto Latagliata ◽  
Paolo Vigneri ◽  
Laura Cannella ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Dose Escalation ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Standard Dose ◽  
Acquired Resistance ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response

Abstract Abstract 3302 Poster Board III-190 Introduction Imatinib mesylate (IM) given at a daily dose of 400 mg currently represents the gold standard of care for patients with chronic myeloid leukemia (CML) in chronic phase (CP). European LeukemiaNet (ELN) guidelines propose IM dose escalation to rescue those CML patients with either suboptimal response or drug resistance. We report on the long-term efficacy of IM dose escalation in 74 patients with CP-CML after suboptimal response or failure to IM conventional dose. Patients and methods Median age was 50 years (range 19-85), there were 52 males and 22 females. Thirteen patients were classified as hematologic failure (10 primary and 3 secondary), 57 patients as cytogenetic resistance (24 primary and 33 acquired). Three patients escalated the dose for cytogenetic suboptimal response and one patient for molecular suboptimal response at 18 months. Fifty-four received IM dose escalation from 400 to 600 mg and 20 patients from 400 to 800 mg. Results Overall, after a median follow-up of 36 months, 68/74 (91.8%) patients maintained or achieved a complete haematologic response (CHR); this was maintained in all patients who escalated the dose for cytogenetic failure or suboptimal response. A major cytogenetic response (MCyR) was achieved in 41 patients (72%) who escalated the dose for cytogenetic failure and in 6/13 (46%) patients who escalated imatinib for hematologic failure (p=0.002). Overall, complete cytogenetic responses (CCR) were achieved in 27 (37%) out of 74 CML patients: of the 13 hematologic failure patients, only 5 achieved CCyR: all patients had prior acquired resistance to imatinib. Of the 57 cytogenetic failure, 22 reached CCR: this response was obtained in 27% of the primary cytogenetic resistant, and in 50% of the acquired cytogenetic resistant patients (p=0.02). Three patients who escalated the dose for cytogenetic suboptimal response obtained CCR and complete molecular response (CMR), whereas one patient who escalated the dose for molecular suboptimal response at 18 months did not obtain CMR. Median time to cytogenetic response was 3.5 months. Cytogenetic responses occurred in 37/50 patients who escalated the dose to 600 mg and in 10/20 patients who escalated to 800 mg daily (p=0.234). CMR was obtained in 10 patients: in 7 patients who escalated the dose for cytogenetic failure and in 3 patients who escalated imatinib for suboptimal cytogenetic response. Estimated 2 year-progression free survival (PFS) and overall survival (OS) is 87% and 85% respectively. Sixteen patients (21.6%) experienced toxicities and had temporarily IM interruption. Conclusions Imatinib dose escalation can induce sustained responses in a subset of patients with cytogenetic resistance and a prior suboptimal cytogenetic response to standard-dose imatinib, whereas it appears less effective in haematologic failure patients or in molecular sub-optimal responders. The availability of second generation TKI should be taken into account in these letter categories of patients. 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.

Clinical Efficacy and Safety Of Dasatinib For Newly Diagnosed Chronic Myeloid Leukemia In Chronic Phase In Japan

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1493-1493
Author(s):  
Kohei Yamaguchi ◽  
Kazunori Murai ◽  
Shigeki Ito ◽  
Tomoaki Akagi ◽  
Kazuei Ogawa ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Efficacy And Safety ◽  
Major Molecular Response ◽  
Once Daily

Abstract Background Dasatinib is a second-generation BCR-ABL inhibitor that has a 325-fold higher potency than imatinib and a 16-fold higher potency than nilotinib in vitro. The previous report from the global DASISION trial showed dasatinib resulted in significantly higher and faster rates of complete cytogenetic response (CCyR) and major molecular response (MMR) compared with imatinib. We conducted a phase II study to evaluate the efficacy and safety of dasatinib in patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML-CP) in Japan. Methods Eighty newly diagnosed CML-CP patients were include in this study. Patients received dasatinib 100mg once daily. Treatment was continued until disease progression or unacceptable toxicity. Primary end point was the rate of major molecular response (MMR) by 12 months. MMR defined as a BCR-ABL transcript level of 0.1% or lower on the International scale by means of a real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) in peripheral blood. Secondary end points were the rate of complete cytogenetic response (CCyR) by 12 months, the rate of MR4.5 (either (i) detectable disease with <0.0032% BCR-ABL1 IS or (ii) undetectable disease in cDNA with >32,000 ABL1 transcripts in the same volume of cDNA used to test for BCR-ABL1) by 12 months and adverse events of dasatinib (UMIN #000006358). Results Eighty newly diagnosed CML-CP patients were included in this study. All except one patient administered dasatinib 100 mg once daily. One patient was withdrawal before administration of dasatinib. So far, there were 71 patients with 6 months follow-up and 51 patients with 12 months follow-up. The estimated MMR rates were 69.5 % (95%CI, 58.7-80.3 %) by 6 months and 82.7% (95%CI, 73.0-92.4 %) by 12 months. The estimated MR4.5 rates were 27.1 % (95%CI, 16.7-37.5 %) by 6 months and 48.9% (95%CI, 36.0-61.7 %) by 12 months. Only 6 patients were withdrawal because of adverse event (5 patients) and ineffectiveness (1 patient). Conclusion Dasatinib treatment results in higher rates of molecular responses in newly diagnosed CML-CP patients in Japan. Dasatinib as the first-line agent might be acceptable for CML-CP patients because of better clinical efficacy and less toxicity. Disclosures: No relevant conflicts of interest to declare.

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

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

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

Identification of a Rare e8a2 BCR-ABL Fusion Gene in Three Novel Chronic Myeloid Leukemia Patients Treated with Imatinib.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 4830-4830
Author(s):  
Jean-Michel Cayuela ◽  
Philippe Rousselot ◽  
Franck Nicolini ◽  
Daniel Espinouse ◽  
Christophe Ollagnier ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Fusion Gene ◽  
Chronic Phase ◽  
Fusion Transcript ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Minor Response ◽  
Worse Prognosis

Abstract Most patients with chronic myeloid leukemia (CML) express the BCR-ABL transcript with the b2a2 (e13a2) or b3a2 (e14a2) junctions corresponding to the major BCR gene breakpoint cluster region (M-BCR). We and others have reported that a small proportion of CML patients (1–2%), which have breakpoints that fall outside of the M-BCR, giving rise to shortened BCR-ABL transcripts (m-BCR, e6a2, b2a3, b3a3) or longer BCR-ABL transcripts (μ-BCR). The clinical and hematologic features of 8 additional patients with e8a2 BCR-ABL fusions transcripts have been recently reviewed (Demehri et al, Leukemia 2005) and, according to the authors, could be associated with thrombocytosis and a worse prognosis than common M-BCR transcripts. Here, we report three additional CML patients with an e8a2 BCR-ABL fusion transcript treated with imatinib and who achieved hematologic, cytogenetic remission. Molecular studies allowed us to quantify this rare BCR-ABL fusion mRNA. All the patients showed a major molecular response with a reduction of at least 3 logs compared to initial samples at a median follow-up of 34 months (range 30–39). None of the cases (patients #1, 2 and 3) described here showed thrombocytosis at diagnosis. The diagnosis of chronic phase CML was based on typical peripheral blood findings and cytogenetics. In all cases, standard karyotyping demonstrated a t(9;22)(q34;q11), but further molecular analysis revealed an atypical e8a2 BCR-ABL fusion gene. In case #1, FISH using the LSI-bcr/abl ES probe (Vysis) showed a typical M-BCR picture which was different with the case previously described. Multiplex RT-PCR for BCR-ABL and sequencing showed a fusion between BCR exon e8 and ABL exon a2, with a 55 base pair (bp) insert, which perfectly matched an inverted sequence from ABL intron Ib. Most of the patients with an e8a2 BCR-ABL fusion transcript previously described seem to be associated with a worse prognosis because none of them treated with interferon achieved even a minor response. Here, all the patients are alive, achieved complete cytogenetic and major molecular responses with a prolonged follow up, confirming thus the efficacy of imatinib mesylate in patients with rare BCR-ABL transcripts. Of note, in cases #2 and #3, the major molecular response was obtained after increasing the dosage of imatinib (400 to 600 mg/day), suggesting that those patients may require higher doses of imatinib to achieve proper molecular response. The aggressive clinical course of these leukemias could be shrouded by appropriate targeted therapy. A longer follow-up and the analysis of a large cohort of patients with e8a2 BCR-ABL fusions are necessary to analyse the clinical outcome of these patients. The study of these unusual transcripts is essential to gain more insights of their molecular pathological function and a more comprehensive survey of the different functions of the BCR-ABL chimeric protein.

scholarly journals Second-Generation Tyrosine Kinase Inhibitor Discontinuation in Chronic Myeloid Leukemia Patients with Stable Deep Molecular Response: A Systematic Review and a Meta-Analysis

2021 ◽  
Vol 2021 ◽  
pp. 1-9
Author(s):  
Qiongnan Di ◽  
Huiyang Deng ◽  
Yingxin Zhao ◽  
Bo-ya Li ◽  
Ling Qin
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Meta Analysis ◽  
Chronic Phase ◽  
Molecular Response ◽  
Weighted Mean ◽  
Deep Molecular Response ◽  
Tki Discontinuation

The treatment with 2nd-generation tyrosine kinase inhibitors (2G-TKIs), namely, dasatinib and nilotinib, has been reported to have faster and deeper responses in newly diagnosed chronic phase-chronic myeloid leukemia (CP-CML) patients as compared with imatinab. A number of studies on the discontinuation of 2G-TKIs have been conducted and recently published. A meta-analysis was conducted in this study to assess the rate of treatment-free remission (TFR) rate as well as the long-term safety of 2G-TKI discontinuation in CML patients with stable deep molecular response (DMR). 517 patients were recruited in 5 single-armed, prospective cohort studies. The overall weighted mean TFR rate at the follow-up of 12 months reached 57% (95% CI 51-64%; I 2 = 56.4 %). The weighted mean TFR rate at the 24-month follow-up was 53% (95% CI 47-60%; I 2 = 47.1 %). The loss of TFR was primarily concentrated in the first 12 months. 96.5% of patients, having restarted TKI therapy after a molecular relapse, achieved major molecular response (MMR) rapidly. There were four deaths at the two-year follow-up. As suggested from the results of the final study, 2G-TKI discontinuation in CML patients with stable DMR was reported to be feasible. Relapsed patients were retreated with 2G-TKI, and over 95% of patients could reach MMR. Almost no deaths occurred due to adverse events in two years after discontinuation, and more than half of the patients could maintain a TFR.

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