Efficacy and Safety of Generic Imatinib Compared to Glivec in Chronic Phase - Chronic Myeloid Leukemia-Single Center Retrospective Analysis

Introduction: Glivec, Imatinib (IM), first tyrosine kinase inhibitor (TKI) has proven its efficacy and safety in Chronic Myeloid Leukemia - Chronic Phase (CML CP) in a large number of trials. In developing country like India Generic Imatinib formulations have been used recently as a more cost effective treatment, data on efficacy and safety of these drugs is sparse. Aim: To analyse and compare safety profile, the overall survival (OS) and progression-free survival (PFS) data of CML-CP patients receiving Glivec/Generic IM as first line therapy Method: A single centre retrospective analysis done on CML-CP patients who initiated treatment with either Glivec or Generic IM between July 2012 and July 2019 at Hemato-oncology Care Centre (HOCC) Vadodara India. Total 109 newly diagnosed CML-CP received IM as 400mg daily dose, dose was adjusted if significant cytopenia observed or in paediatric patients. Response assessment was made as per NCCN CML Version 1 2019 guidelines.Molecular monitoring of patients was done through BCR-ABL1 RQPCR, reported on international scale. Major Molecular Response (MMR) was considered when the ratio on international scale was less than 0.1% level or ≥ 3-log reduction in BCR-ABL1 mRNA from the standardized baseline, while Deep Molecular Response-MR4 was considered when the ratio on international scale was less than 0.01%.OS was measured from starting date of IM until to the date of death from any cause while on therapy or last seen.PFS was measured from starting date of IM to transformation to AP or BC or deaths while on therapy. Survival curves were calculated by the Kaplan-Meier method and compared with the log-rank test. Cox regression with Backward Wald Method, Chi-square test and t-test is applied using SPSS software version 21.0. A p-value <0.05 is considered to be statistically significant. Results: A Total 109 patients were analysed, received Glivec (47)43% or Generic IM (62)56%. The mean (SD) age was 42.2 years (13.3 years) in Glivec and 47.5 years (14.9 years) in the Generic IM group (P=0.06). There was male preponderance in both groups (Glivec 55%, Generic IM 62 %). Sokal score stratification in Glivec and Generic groups, was respectively: low risk 43%/40%; intermediate risk 36%/48% and high risk 21%/11% (P=0.08). The median follow‐up period was 36 months (range, 9-84). MMR was 61% and 38% in Glivec and Generic IM respectively(p=0.02), MMR was achieved in 40%,04%,11%,06% of Glivec and 29%,2%,5%,2% of Generic IM group patients, at 1st,2nd,3rd,4th year of treatment respectively(P=0.15).Deep Molecular Response-MR4 was significantly higher 40% in Glivec vs 23% in Generic IM group (P=0.01). Nearly 35% of patients were lost to follow up, 28% and 40% in Glivec and Generic IM group respectively(p=0.27). Reasons for drop out were - cost constraints, noncompliance, lack of understanding, lack of transport. Dose limiting cytopenia was observed in initial 3 months of treatment in 12% and 23 % in Glivec and Generic IM group respectively(P=0.28).The most common non haematological side effects in Glivec and Generic groups were skin hyperpigmentation 19%,17%, abdominal discomfort 16 %,11% ,Facial Puffiness 9%,5%, respectively(P =0.73). In each group 4% patients progressed to AP, managed with second generation TKI in Generic IM group and with increasing dose of Glivec to 600mg daily in Glivec group. Total 5% patients progressed to BC and died, 3% in Glivec vs 2% in Generic IM group. The risk factors for progression to AP or BC were high Sokal score, poor molecular response and dose limiting cytopenia. OS and PFS at 36 months were similar in Glivec and Generic IM (93.6% vs. 96.8% P=0.834) and (89.4% vs. 91.9%, P=0.839) respectively. Conclusion: Both the groups have shown similar OS and PFS at 36 months of median follow up, there was also no difference in the safety profile, meeting Generic IM unmet needs in developing country. However in view of higher MMR and Deep molecular response-MR4 in Glivec group, need long term follow up to determine its impact on outcome especially in reference to treatment free remission. Figure Disclosures No relevant conflicts of interest to declare.

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Programme for Harmonization to the International Scale in Latin America for BCR-ABL1 quantification in CML patients: findings and recommendations

Clinical Chemistry and Laboratory Medicine (CCLM) ◽

10.1515/cclm-2019-1283 ◽

2020 ◽

Vol 58 (12) ◽

pp. 2025-2035

Author(s):

María Sol Ruiz ◽

María Belén Sánchez ◽

Yuly Masiel Vera Contreras ◽

Evangelina Agrielo ◽

Marta Alonso ◽

...

Keyword(s):

Latin America ◽

Myeloid Leukemia ◽

World Health ◽

Molecular Response ◽

Limit Of Quantification ◽

International Scale ◽

Deep Molecular Response ◽

Health Organization ◽

First Time

AbstractObjectivesThe quantitation of BCR-ABL1 mRNA is mandatory for chronic myeloid leukemia (CML) patients, and RT-qPCR is the most extensively used method in testing laboratories worldwide. Nevertheless, substantial variation in RT-qPCR results makes inter-laboratory comparability hard. To facilitate inter-laboratory comparative assessment, an international scale (IS) for BCR-ABL1 was proposed.MethodsThe laboratory-specific conversion factor (CF) to the IS can be derived from the World Health Organization (WHO) genetic reference panel; however, this material is limited to the manufacturers to produce and calibrate secondary reference reagents. Therefore, we developed secondary reference calibrators, as lyophilized cellular material, aligned to the IS. Our purpose was both to re-evaluate the CF in 18 previously harmonized laboratories and to propagate the IS to new laboratories.ResultsOur field trial including 30 laboratories across Latin America showed that, after correction of raw BCR-ABL1/ABL1 ratios using CF, the relative mean bias was significantly reduced. We also performed a follow-up of participating laboratories by annually revalidating the process; our results support the need for continuous revalidation of CFs. All participating laboratories also received a calibrator to determine the limit of quantification (LOQ); 90% of them could reproducibly detect BCR-ABL1, indicating that these laboratories can report a consistent deep molecular response. In addition, aiming to investigate the variability of BCR-ABL1 measurements across different RNA inputs, we calculated PCR efficiency for each individual assay by using different amounts of RNA.ConclusionsIn conclusion, for the first time in Latin America, we have successfully organized a harmonization platform for BCR-ABL1 measurement that could be of immediate clinical benefit for monitoring the molecular response of patients in low-resource regions.

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

Blood ◽

10.1182/blood.v122.21.1493.1493 ◽

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.

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Velocity of Early BCR-ABL Transcript Elimination As an Optimized Predictor of Deep Molecular Response in Chronic Myeloid Leukemia Patients in Chronic Phase on Treatment with Dasatinib

Blood ◽

10.1182/blood.v126.23.4052.4052 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4052-4052

Author(s):

Kazunori Murai ◽

Kohei Yamaguchi ◽

Shigeki Ito ◽

Tomoaki Akagi ◽

Kazuei Ogawa ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Roc Analysis ◽

Chronic Phase ◽

Molecular Response ◽

Similar Data ◽

Newly Diagnosed ◽

Efficacy And Safety ◽

Once Daily ◽

Deep Molecular Response

Abstract Background: 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 (IMIDAS PART2 study; UMIN000006358). Several groups reported that some of CML patients who achieved stable deep molecular response (DMR) level or deeper could stop Tyrosine Kinase Inhibitor (TKI) and approximately 40% of these patients could keep therapy free survival by cessation of TKI. Discontinuation of TKI has emerged as a new goal of treatment in CML. Achievement of DMR is necessary for discontinuation of TKI. The aim of the present study was to analyze the prognostic significance of (i) BCR-ABL transcript International Scale (BCR-ABL IS) levels, (ii) the halving time and (iii) velocity of BCR-ABL transcript elimination using an optimized cutoff according to receiver operating characteristic (ROC) analysis. Methods: Eighty newly diagnosed CML-CP patients were included in this study. Patients received dasatinib 100mg once daily. Treatment has continued until disease progression or unacceptable toxicity. Clinical efficacy and safety was partially reported in 55th ASH Meeting. We sought to investigate the impacts of above 3 parameters within the initial 1 or 3 months of therapy. Halving time was calculated by the method, described by Branford et al. Velocity of BCR-ABL transcript elimination at 1 or 3 months (V-BCR-ABL1m or 3m respectively) was calculated as BCR-ABL IS at 1 or 3 months (BCR-ABL IS1m or 3m respectively) divided by that at diagnosis. Results: One patient was withdrawal before administration of dasatinib. Seventy-nine patients administered dasatinib 100 mg once daily. The estimated MMR and DMR rates were 92.1 % (95%CI, 76.8-97.3 %) and 60.9% (95%CI; 42.3-73.4 %) by 12 months respectively. The patients who had already achieved DMR at 3 months were excluded from landmark analysis. The cut off values for prediction of DMR at 12 months were obtained by ROC analysis. Those of BCR-ABL IS1m and BCR-ABL IS3m were 11.7% and 0.284% respectively. Those of halving times on 0-1 month and 0-3months (halving time1m and 3m) were 17.8 and 13.6 days respectively. Those of V-BCR-ABL1m and V-BCR-ABL3m were 0.321 and 0.018 respectively. The estimated DMR at 12 months, 95% CI and probability (P), obtained by Kaplan-Myer analysis, were shown in Figure 1. Odd' ratio, obtained by Chi-square test, was shown in Table 1. The patients with less than 0.321 at V-BCR-ABL1m showed the highest DMR at 12 months (80%), the least probability (P=0.009) and the least odd' ratio (0.175). At 3 months, there were similar data in these parameters among BCR-ABL IS3m, halving time3m and V-BCR-ABL3m. Figure 1 showed the cumulative DMR rate according to the cutoff values in V-BCR-ABL1m and V-BCR-ABL3m. V-BCR-ABL1m 0.321 and V-BCR-ABL3m 0.018 separated best. Conclusion: These data strongly suggested that V-BCR-ABL1m,3m would be a significant landmark to predict DMR at 12 months as well as BCR-ABL IS1m,3m, halving time1m,3m. Among them, less than 0.321 in V-BCR-ABL1m was identified as an optimized predictive cutoff value of DMR at 12 months. Disclosures Ishida: Bristol-Myers Squibb: Honoraria.

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

Computational and Mathematical Methods in Medicine ◽

10.1155/2021/3110622 ◽

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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Duration of Major Molecular Response and Discontinuation in Deep Molecular Response (MR4.5) Were Associated with Longer Treatment-Free Survival after Imatinib Discontinuation - Results from Two Prospective Brazilian Trials

Blood ◽

10.1182/blood-2019-125368 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1655-1655

Author(s):

Katia B Pagnano ◽

Fernanda S Seguro ◽

Eliana C Miranda ◽

Ana Beatriz Pascoal Lopes ◽

Andre Abdo ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Adverse Events ◽

Myeloid Leukemia ◽

Cox Regression ◽

Chronic Phase ◽

Molecular Response ◽

Free Survival ◽

Deep Molecular Response ◽

Treatment Free Remission

Several trials have demonstrated the feasibility of discontinuation of tyrosine kinase inhibitors (TKI) treatment in chronic myeloid leukemia (CML) patients (pts) with deep molecular response. Aims: to report the results of two Brazilian imatinib (IM) discontinuation trials and to evaluate factors impacting in treatment-free remission (TFR) and treatment-free survival (TFS) after IM discontinuation. Methods:Between September 2016 and January 2019, 60 CML pts were included in two ongoing phase II, single arm, prospective Brazilian discontinuation trials: Pilot Study of Discontinuation in Patients With Chronic Myeloid Leukemia With Deep Molecular Response - Evaluation of Pioglitazone in Treatment-free Remission (TFR) (EDI-PIO UNICAMP)(NCT02852486)and Imatinib Discontinuation in Patients With Chronic Myeloid Leukemia Chronic Phase With Sustained MR4log(USP) (NCT03239886). Inclusion criteria: age >18 years, chronic phase, minimum of 3 years of IM therapy, deep molecular response for ≥ 2 years (confirmed by 4 tests in the last 2 years, defined as MR4.0 in USP trial and MR4.5 in EDI-PIO). Patients participating in EDI-PIO trial used pioglitazone 30 mg/day plus IM for 3 months before IM discontinuation (n=30). After discontinuation, pts were monitored by quantitative RQ-PCR monthly in the first year, every 2 months in the second year and every 3 months in the third year. Criteria for IM re-initiation: loss of MMR (in one test), loss of cytogenetic response, loss of hematologic response, disease progression or confirmed loss of MR4.0 (this criteria used only in EDI-PIO trial). TFR was calculated from the date of discontinuation until first event (loss of MMR; IM reintroduction; death any cause or last follow-up); TFS was calculated from the date of IM discontinuation until reintroduction or last follow-up (censoring deaths not related to CML). Adverse events after IM discontinuation were reported according to CTCAE. Results:Data cut-off for analysis was February 2019. In the 1stanalysis 48 pts who discontinued IM in MR4.5 were analyzed. Patient's characteristics from EDIPIO (n=30) and USP (n=18) trials were: 57% vs. 67% male, median age of 55 (29-77) and 56 (33-95) years (29-95) at discontinuation; 16% and 33% had used previously Interferon; median duration of IM treatment of 10 (3-16) vs. 10 (5-15) years; median duration of MMR 95 (30-149) vs. 93 (57-130) months; MR4.0 was 90 (26-135) vs. 89 (30-123) months; and MR4.5 was 76 (23-135) vs. 75 (30-102) months; none variable had statistical difference.One patient died in MMR due to cardiac failure. TFR was 61% (95% CI 47-75) at 20 months. Sixteen (33%) out 48 re-initiated IM (2 with confirmed loss of MR4.0 and 14 with loss of MMR) in a median time of 20 (1-26) months. All relapsed pts recovered MMR after IM reintroduction, in a median time of 2 months (0-4). There was no transformation to advanced phases. No serious adverse events were reported during pioglitazone treatment. In the Cox regression the duration of MMR was associated with a longer TFR HR: 0.96 (beta-) (CI 95%:0.94-0.99, P= 0.006). Gender, age at diagnosis, age at discontinuation, treatment with pioglitazone, Sokal and EUTOS scores, BCR-ABL transcripts type, duration of IM therapy, duration of MR4.0 and MR4.5 and previous use of Interferon did not affect TFR.In the second analysis all 60 pts were included. TFS was 56% and was higher in pts who discontinued IM in sustained MR4.5 vs. MR4.0 (63% vs. 33%, P=0.04)(Figure). The independent factors for TFR in the multivariate analysis by Cox-regression were the duration of MMR [HR: 0.97 (beta-), 95%CI: 0.95-0.98, P=0.001] and intermediate/high risk Sokal [HR 3.14 95%CI: 1.08-9.11, P= 0.035]. Twenty-four out of 60 pts (40%) re-initiated IM (2 with confirmed loss of MR4.0 and 22 with loss of MMR).Adverse events occurred in 38 (63%) pts, 30% attributed to withdrawal syndrome. Some pts presented more than one event. Grade 1-2: arthralgia or muscular pain (17), hyperglycemia (4), hypertriglyceridemia (2), polycythemia (2), hypertension (3), and others (11). Four pts had grade 3-4 event: arthralgia (1), death for cardiac failure (1), abortion and hypertriglyceridemia (1). Conclusions:both trials demonstrated the feasibility and safety of IM discontinuation in pts in sustained deep molecular response. The duration of MMR was associated with a higher TFR and TFS rate. Imatinib discontinuation was more successful in pts in stable MR4.5. Figure Disclosures Pagnano: Pint Pharma: Consultancy; Abbvie: Consultancy; Sandoz: Consultancy. Delamain:Novartis: Honoraria.

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Results of Imatinib Therapy In Patients with Early and Late Chronic-Phase Chronic Myeloid Leukemia In a South Brazilian Cohort.

Blood ◽

10.1182/blood.v116.21.4487.4487 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4487-4487

Author(s):

Marcelo Capra ◽

Mariza Shaan ◽

Katia Fassina ◽

Mario Sérgio Fernandes ◽

Marco Antônio Schilling ◽

...

Keyword(s):

Myeloid Leukemia ◽

Chronic Phase ◽

Cytogenetic Response ◽

Molecular Response ◽

Imatinib Treatment ◽

Second Line Therapy ◽

Line Therapy ◽

Sokal Score ◽

Hasford Score

Abstract Abstract 4487 Background: Imatinib treatment for Chronic Myeloid Leukemia (CML) was first introduced in Brazil in 2001, initially used as second line therapy for patients resistant or intolerant to interferon (IFN). In 2008 imatinib was adopted as front-line therapy for chronic-phase (CP-CML) and clinical experience is improving since then, but little is known about the result of its introduction in our clinical practice. Aims: To evaluate the impact of imatinib treatment in the outcomes of a cohort of CP-CML and the prognostic significance of Sokal and Hasford scores and late-onset treatment. Methods: We conducted a retrospective study in a cohort of patients with CP-CML from a south Brazilian database. All patients received imatinib 400mg as first or second-line therapy. Patient evaluation and response criteria followed the European LeukemiaNet. The outcomes were response to treatment, event-free survival (EFS) and overall survival (OS). Results: We analyzed data from 185 pts with CP-CML diagnosed since 1990. The median age at diagnosis was 48 years (4 – 85). The median time from diagnosis to imatinib was 7 months (0 – 178) and 29% of pts had more than 12 months lapse. Prior therapy with IFN was used in 70% pts. All pts had a minimum follow-up of 12 months. At baseline, 57 pts (31%) were in complete hematological response (CHR) due to the use of previous treatment. Of the 127 pts not in CHR at baseline, 98% achieved CHR early during imatinib treatment. 177 pts had cytogenetic evaluation during treatment and 9 pts were in complete cytogenetic response (CCyR) due to the use of previous IFN. Of the 168 pts not in CCyR at baseline, 86,4% achieved a major cytogenetic response (MCyR) during imatinib treatment (84% had a CCyR and 2,4% had a partial cytogenetic response). The rate of pts achieving MCyR any point during treatment differed significantly in the low, intermediate and high risk Sokal score groups (97%, 81% and 78% respectively, P=0,04), but not in the Hasford score groups (90%, 85% and 72%, P=0,22). Minor cytogenetic response was seen in 3,6% of pts, minimal cytogenetic response in 6% and 9,5% had no cytogenetic response. The median time to a MCyR was 9 months, with 62% of pts achieving MCyR at 12 months. The rate of pts achieving MCyR in 12 months differed significantly between pts who start imatinib before 12 months from diagnosis (68%) and those late treated (47%, P=0,02). Evaluation of minimal residual disease at the molecular level was available for 155 pts: 25,5% of pts had a complete molecular response (CMR), 43% had a major molecular response (MMR) and 2 pts were in MMR at baseline due to previous IFN. The projected EFS and OS rates at 4 years were, respectively, 68% and 92% after a median follow-up time of 4 years. The rate of EFS differed significantly in the low, intermediate and high risk Sokal score groups (80%, 66% and 52% respectively, P=0,04), but not in the Hasford score groups (78%, 62% and 44%, P=0,09). During treatment with imatinib, 120 pts (65%) had a register of any grade hematologic adverse event (21% being grades 3 or 4) and 165 pts (90%) had a register of any grade nonhematologic adverse event (9,3% being grades 3 or 4). Of the 185 pts who received treatment, 134 (72%) continue to receive imatinib and 51 (28%) discontinued treatment. The reasons for discontinuation were: 11 (6%) pts had drug-related adverse events (3 [1,6%] hematologic and 8 [4,3%] nonhematologic), 17 (9,2%) had disease progression (5 [2,7%] loss of CHR, 10 [5,4%] loss of CCyR, 2 [1%] had progression to accelerate or blastic phase), 22 (11,9%) had treatment failure (3 [1,6%] had no CHR, 13 [7%] had no CCyR and 6 [3,2%] had no MMR), 1 pt (0,5%) discontinued due to comorbidity. For the 51 (100%) pts that discontinued imatinib, 31 (61%) switched to dasatinib, 17 (33%) to nilotinib, 1 (2%) to hydroxyurea, 1 (2%) to other treatment and 1 (2%) remained without treatment. Sixteen pts (8,6%) died during imatinib treatment or during long-term follow-up after discontinuation of imatinib. Conclusions: In our population of CP-CML pts treated with imatinib, a majority of patients achieved complete cytogenetic and major molecular responses, with a prolonged of OS and EFS and good safety profile. Sokal score showed better prognosis prediction than Hasford. Early onset of imatinib therapy led to better outcomes and justifies imatinib as front-line treatment of our patients. Disclosures: No relevant conflicts of interest to declare.

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Long Term Molecular Response To Triple Therapy With High Doses Imatinib In Patients With Chronic Myeloid Leukemia

Blood ◽

10.1182/blood.v122.21.5199.5199 ◽

2013 ◽

Vol 122 (21) ◽

pp. 5199-5199

Author(s):

Jose Luis Lopez ◽

Hector Joel Rico

Keyword(s):

Chronic Myeloid Leukemia ◽

Adverse Events ◽

Triple Therapy ◽

Myeloid Leukemia ◽

Chronic Phase ◽

Hematological Toxicity ◽

Molecular Response ◽

Sokal Score

Abstract Introduction Imatinib 400 mg daily is considered the best initial therapy for patients with chronic myeloid leukemia (CML) in the chronic phase (CP). However, only minorities of patients have a complete molecular remission (CMR) Another agent has antileukemic activity against Bcr-Abl-positive cells like Ara-C and interferon, the association of this drugs and imatinib in CML was evaluated in several trials with an increase in molecular response. The aim of this study was to evaluate the major molecular response (MMR) at 12 months with triple treatment schedule, analyze the evolution of these patients and general and hematologic toxicity. Material and Methods Patients diagnosed with CML at the Hospital General de Zona #35 in Juarez, Mexico were included. Eligibility criteria were adults with diagnosis of CML chronic phase on triple regimen for at least 12 months: Pegylated interferon-α 2a 90mcgrs via subcutaneous / week for 4 weeks + PO imatinib 800 mgs a day for 30 days + 20 mgs/mt2 cytarabine from day 1 to 10 subcutaneus. Patients were stratified according to Sokal score at diagnosis. The molecular analysis was performed in Quest diagnostic laboratory by means of real-time quantitative polymerase-chain-reaction (RT-PCR) results are expressed as a percent ratio of BCR-ABL1 to ABL1 and further adjusted to the international scale (IS) since august 2012. Patients could have received previous treatment for CML, with the exception of bone marrow transplantation. All patients provided written informed consent. This study was conducted in accordance with the Declaration of Helsinki. Molecular and adverse events were assessed. An analysis of molecular response at 12 months was planned and follows up patients with MMR every year. A MMR was defined a Bcr-Abl 0.1% or less and complete molecular response (CMR) as undetectable. Hematological toxicity was assessed according WHO scale. Results 41 patients completed the first 12 months in therapy, with a mean age of 44.4 years (17 to 71) 51% male and 49% female, the median and ranges of hemoglobin levels, leukocyte and platelet counts at diagnosis were 10.2 g/dl (5.1-16.0), 209.000 μL3 (10,600 - 529.000) and 565.500 μL (130.000 to 4,272,000) respectively. The percentages of cases by Sokal risk group were 70.7% low, 24.4% intermediate and 4.9% high risk. The Median follow up time was 58 months (range 14 to 120). At 12 months the number of patients who were in MMR was 27 (65.9%) including 8 (19.5%) with no BCR-ABL detectable. Median duration of triple therapy exposure at first year was 24 Weeks (range 12 to 32) Responses by Sokal score were 62%, 70% and 100% for low, intermediate and high respectively. Adverse events occurred in 88% cases; 33% of patients has at least one adverse event (AE) 42% 2 EA and 28% 3 EA, the most important EA was gastrointestinal. (table 1) 43.9% of patients has Hematological toxicity III-IV Median follow up time of patients in RMM was 64 months (range16-120) 2 patients were no evaluable. Patients who have RMM at 12 months 50% achieve a CMR at last follow up, 33% continues in RMM and 17% loss molecular response. Patients with CMR 72% have undetectable bcr-abl, 14% have loss molecular response and 14% in MMR Conclusions In this group of patients MMR was achieved in a higher proportion of cases at 12 months of treatment which is important in the long-term prognosis. Side effects grade 3 and 4 hematologic and non-hematologic were significant in this series of cases appearing in 44 and 88% respectively, which requires close monitoring of patients. The combination of interferon α2a, cytarabine and high-dose imatinib induces a MMR of 66% at 12 months of treatment, a 28%, 56% and 16% in MMR, CMR and loss molecular response respectively at last follow up. Clinical files n =36 Disclosures: No relevant conflicts of interest to declare.

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Evaluation of the Imatinib Treatment of Patients with Chronic Myeloid Leukemia (CML). a Retrospective Study from Algerian Working Group on CML (GAT-LMC)

Blood ◽

10.1182/blood.v128.22.5454.5454 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5454-5454

Author(s):

K Djouadi ◽

A Bouchakour ◽

S Taoussi ◽

MT Abad ◽

Z Ouchenane ◽

...

Keyword(s):

Overall Survival ◽

Myeloid Leukemia ◽

Chronic Phase ◽

Progression Free Survival ◽

Molecular Response ◽

Imatinib Treatment ◽

Free Survival ◽

Sokal Score ◽

Eutos Score

Abstract Introduction: The advent of anti-tyrosine kinase has revolutionized the treatment of chronic myeloid leukemia. Indeed, from 2000, the IMATINIB has become internationally the gold standard of treatment for CML chronic phase, while the allogeneic bone marrow transplant was previously, the 1st intention choice, when an HLA-matched donor is available. The aim of this study is to evaluate the efficiency and the toxicity of a treatment with Imatinib(copy), drug used in Algeria to treat patients with a CML chronic phase. The main objective is to evaluate the overall survival and the progression-free survival to these patients. Materials and methods: This is a longitudinal study, National, multicenter, retrospective, which included Algerian patients with chronic phase CML and treated with Imatinib between January 2007 and December 2013. A technical form was established and distributed to different hematology services nationwide, to collect and analysis the following data: Patient's general characteristics, disease circumstances of discovery, clinical and para-clinical examinations at diagnosis (blood count, blood smear, bone marrow aspiration, karyotype, molecular biology, Sokal prognostic classification score and Eutos score). The treatment: Imatinib 400 mg / d, a therapeutic assessment is made according to the ELN recommendations adapted to our conditions and capabilities in Algeria: The complete hematologic response (CHR) at 03 months and molecular response and / or cytogenetic and / or Fish at 03, 06.12, 18.24 months and more according to capabilities. At 03mois and / or 6 months we search a bcr / abl rate <10%. At 12 months we research a major molecular response (MMR), defined by a bcr / abl ratio lower than 0, 1% according to the ELN. A ratio between 0.1 to 1% is considered a good response according to GAT-LMC (the CML study Algerian group) so the Imatinib treatment is continued. The median follow-up of patients in December 2014 is 48 months (12-84 months). Overall survival and progression-free survival are determined by using the Kaplan-Meier method. The descriptive analysis of the quantitative variables by calculating averages, medians and the qualitative variables, by using percentages and 95% confidence interval. The Chi2 test is used to compare between two variables. Results: From 1024 collated sheets, 1007 are assessable; the median age of patients was 45.7 years (06-87 years), it's about 516 men and 491 women with a sex ratio M / F 1.05. The Diagnosis of CML is done by cytogenetic examination in 337 patients (33%), by Fish 214 patients (21%) and by molecular biology in 401 patients (39%). The prognostic classification (PC), according to the Sokal score, found a low risk in 18.7%, 55.5% as intermediate and a high risk in 25.8%. The Eutos score is less than 87 in 97% and more than 87 in 03%. A CHR at 03mois was found in 907 patients (90.1%). There is no correlation between the RHC at 03 months and the SOKAL PC (p = 0.23), by cons we found a significant correlation with the Eutos score (p <10-3). Molecular assessment at 03 and 06 months is performed in 222 patients and a bcr / abl ratio <10% was found in 66.5%. A molecular evaluation at 12 months showed an MMR in 55.4%. Cytogenetic evaluation (FISH) has found a 28.6% CCyR at 3 months, 45% at 6 months, 64.2% at 12 months (IRIS = 68%), 75.7% at 18 months (IRIS = 76.2%) and 85% at 24 months. Overall survival was 84% at 08 years and it is significantly correlated to Sokal score (p <10-6). A failure to TRT was found in 11.5% of the cases and a 10, 1% relapse rate, related to non-adherence to TRT in 50% of the cases and a lack of monitoring by a regular molecular control in the other half of the cases. Event-free survival at 08 years was 76%. A good clinical and biological tolerance is noted in 90% of the cases. Only 8% of patients were switched to a 2nd generation TKIs because of intolerance. A non-adherence to TRT was found in 14.4%. Conclusion: Imatinib, used in Algeria, is a very interesting molecule both efficiency side and tolerance level. However, we must ensure a molecular monitoring for a patients optimal follow up, and an adequate patient education for a better adherence. Disclosures No relevant conflicts of interest to declare.

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Generic Versus Branded Imatinib As Frontline Therapy in Chronic-Phase Chronic Myeloid Leukemia Patients in Italy: A Case-Control Study

Blood ◽

10.1182/blood-2019-131272 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5909-5909

Author(s):

Massimiliano Bonifacio ◽

Mario Tiribelli ◽

Gianni Binotto ◽

Maria Cristina Miggiano ◽

Marco Basso ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Board Of Directors ◽

Myeloid Leukemia ◽

Chronic Phase ◽

Molecular Response ◽

Efficacy And Safety ◽

Advisory Committees ◽

Historical Cohort ◽

Molecular Responses ◽

Sokal Score

Introduction. Imatinib is the most commonly used frontline drug in chronic phase (CP) chronic myeloid leukemia (CML) patients worldwide. In early 2017 a generic formulation of imatinib was introduced in Italy and uniformly replaced branded imatinib (Glivec®), upon requirement of regional health authorities. In the last years various groups reported on the efficacy and safety of generic imatinib with conflicting results, partly related to substandard pharmaceutical quality of some products used in developing countries. In a multicenter cohort of 294 patients treated in Italy with branded imatinib for at least 6 months and then switched to generic imatinib we observed that the majority of patients maintained or improved their molecular response. Here, we analyzed patients who received generic imatinib since diagnosis. Aims. To analyze the rates of molecular responses at 3, 6 and 12 months and of treatment discontinuation in CML patients treated frontline with generic imatinib, compared to a case-matched historical cohort of CML patients who received frontline branded imatinib at our institutions. Methods. We analyzed 31 newly diagnosed CP-CML patients consecutively enrolled in a prospective observational registry between January 2017 and July 2018, treated frontline with generic imatinib 400 mg/day (diverse manufacturers) and evaluable for all the ELN2013 molecular milestones (if not discontinued earlier). They were compared to a retrospective cohort of 31 patients, matched for age, gender, and Sokal risk, diagnosed between 2007 and 2014 and treated with branded imatinib 400 mg/day for at least 24 months before eventual switching to a generic formulation. Definitions of molecular responses were made according to the ELN2013 recommendations. Results. A total of 62 patients were included in the analysis: 31 patients (21 males and 10 females) treated with generic imatinib ("cases") and 31 treated with branded imatinib ("controls"). Median age at diagnosis of the cases was 68 years (range 33-89), Sokal score was low/intermediate/high in 8 (26%), 19 (61%) and 4 (13%) patients, respectively. The controls were matched for gender, age (+/- 4 years, median age 68, range 35-85) and Sokal score. As median follow-up time for the cases was 18.6 months (range 2.2-28.5), controls were censored at 24 months after imatinib start. Optimal molecular response at 3 months was attained in 23/30 (76.7%) cases and in 18/29 (62%) controls (p=0.35); one case died after 2 months of imatinib therapy for a CML-unrelated cause, while 2 controls were molecularly not evaluable. At 6 months, 17/29 (58.6%) cases and 17/30 (56.7%) controls achieved BCR/ABL transcript <1%, respectively (p=1). At 12 months, MMR was attained by 14/30 (46.7%) cases and by 13/29 (44.8%) controls (p=1). Twelve out of 31 patients (38.7%) permanently discontinued generic imatinib due to warning/failure response (n=6), intolerance (n=4) or death while on treatment at 2 and 13 months (meningoencephalitis of unknown origin and cardiovascular event, respectively). Among patients treated with branded imatinib, 12/31 (38.7%) stopped within the 24th month of therapy for resistance (n=8), intolerance (n=3) or death at 16 months (acute renal failure). No patient receiving generic imatinib progressed to advanced phase, while one control developed a blast crisis at 6 months of branded imatinib and deceased shortly after. Estimated overall survival at 24 months in cases and controls was 92.5% and 93.1%, respectively. Conclusions. Our preliminary data suggest an equivalent efficacy of generic imatinib compared to a matched population of historical patients treated with the originator drug in Italy. A continue pharmacovigilance by reporting efficacy and safety outcomes of generic drugs is needed to ensure an optimal management of CML patients. Disclosures Bonifacio: Novartis: Honoraria, Research Funding; Amgen: Honoraria; Incyte: Honoraria; Pfizer: Honoraria. Tiribelli:Pfizer: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Krampera:Novartis: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees.

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Pioglitazone Did Not Affect PPAR-Γ, STAT5, HIF2α and CITED2 Gene Expression in Chronic Myeloid Leukemia Patients with Deep Molecular Response

Blood ◽

10.1182/blood-2019-128265 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 1637-1637 ◽

Cited By ~ 1

Author(s):

Ana Beatriz Pascoal Lopes ◽

Eliana C Miranda ◽

Valquíria Mariane Oliveira Póvoa ◽

Bruna Rocha Vergílio ◽

Graziele Cristina Pavan Furlin ◽

...

Keyword(s):

Gene Expression ◽

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Gene Expression Analysis ◽

Chronic Phase ◽

Molecular Response ◽

Ppar Γ ◽

Deep Molecular Response ◽

Treatment Free Remission

Preliminary reports demonstrated that pioglitazone, an antidiabetic drug that is agonist of peroxisome proliferator-activated receptor gamma (PPAR-γ) was able to reduce expression of STAT5 and its downstream targets HIF2α and CITED2, which are key guardians of the quiescence and stemness of chronic myeloid leukemia (CML) leukemia stem cells (LSCs). Leaving quiescence would turn the LSCs more sensitive to imatinib (IM) and cause an erosion of the LSCs. This was demonstrated in vitro and in vivo in CML patients that achieved complete molecular response after pioglitazone use. This was the rational for the design of EDI-PIO trial (Pilot Study of Imatinib Discontinuation in Patients with Chronic Myeloid Leukemia with Deep Molecular Response - Evaluation of Pioglitazone in Treatment-Free Remission) (NCT02852486). In this trial, pioglitazone was given in association with IM, with the aim to pull out the LSCs from the quiescence and sensitizing them to IM effect, increasing treatment-free remission (TFR) rates after treatment interruption. Aims: to evaluate PPAR-γ, STAT5, HIF2α and CITED2 gene expression before and after pioglitazone use in CML patients with criteria for IM discontinuation Patients and methods: EDI-PIO is a prospective, phase II trial. Inclusion criteria: CML in chronic phase, treated with IM for at least 3 years, with stable deep molecular response (MR4.5) for at least 2 years. Patients received pioglitazone 30 mg/day, orally, for 3 months before IM discontinuation. BCR-ABL levels were measured by real-time quantitative PCR monthly in the first year after discontinuation, every two months in the second year, and then every 3 months during the subsequent follow-up. Imatinib was reinitiated at molecular relapse (loss of major molecular response or confirmed loss of MR4.0). Total RNA was extracted from peripheral blood leukocytes, pre and post pioglitazone, and at 3 and 6 months after IM discontinuation. After cDNA synthesis, an aliquot was used for gene expression analysis by reverse transcriptase quantitative polymerase chain reaction (RT-qPCR), using specific primers for PPAR-γ, STAT5, HIF2α and CITED2. The relative gene expression was calculated using the equation, 2-ΔΔCT. GAPDH was used as control gene. Statistical analysis was performed using ANOVA. Treatment-free remission (TFR) was calculated from IM discontinuation until molecular relapse, reintroduction of IM by any cause, progression to advanced phases or death to any cause. Results: The study is closed for enrollment. Between June 2016 and January 2019, 32 chronic phase CML patients were recruited, of which 30 patients were included in gene expression analysis. Median age was 55 years at trial initiation; 56.7% were men, 50% low risk Sokal and the median time of IM treatment was 117 months (41-191). The median follow-up time was 20 months. TFR was 60% at 24 months. Eleven patients relapsed and IM was reintroduced, but none presented hematologic relapse or progression to advanced phases. There was no significant difference in STAT5, PPAR-γ, HIF2α and CITED2 expression pre and post pioglitazone, at 3 and 6 months after IM discontinuation. No difference was found in the comparison of the relapsed vs. non-relapsed group. Conclusions: pioglitazone did not affect STAT5, PPAR-γ, HIF2α and CITED2 gene expression in this group of pts with deep molecular response. The ACTIM trial demonstrated a reduction in STAT5 expression in bone marrow cells 6 months after pioglitazone exposure, but pioglitazone was given to pts with MMR, without MR4.0. There was no difference in gene expression in the groups with or without molecular relapse. TFR rates remains similar to those reported in other discontinuation trials. Disclosures Delamain: Novartis: Honoraria. Pagnano:Sandoz: Consultancy; Pint Pharma: Consultancy; Abbvie: Consultancy.

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