Randomized study of imatinib for chronic myeloid leukemia: comparing standard dose escalation with aggressive escalation

AbstractIn 2007, we conducted a prospective randomized study to compare an aggressive dose escalation (group B, n = 123) with the standard dose escalation proposed by European LeukemiaNet (group A, n = 122). In group B, if patients did not achieve a complete cytogenetic response (CCyR) at 3 months or did not achieve a major molecular response (MR3) at 6 months, imatinib was increased to 600 mg. At 6 months CCyR was achieved in 69.4% and 78.7% of patients in groups A and B, respectively. The rate of MR3 at 12 months and 24 months were similar in group A (52.1% and 70.0%) and group B (58.7% and 68.3%). The cumulative incidence of withdrawal by failure without accelerated/blast phase was higher in group A than in group B (9.2% vs 2.5% at 24 months). At 3 and 6 months, the protocol called for the imatinib dose to increase to 600 mg in 90 patients (74.4%) in group B. Among the 42 patients who received increased dose according to the protocol, 25 (60.0%) achieved MR3 at 12 months, whereas only 14 (35.0%) of 40 patients who did not receive an increased dose achieved MR3 (P < .05). The number of patients who withdrew from this study was similar (group A, 20%; group B, 21%). The early aggressive dose escalation failed to produce a better molecular response at 12 months. However, for patients who tolerate imatinib well, but show inadequate response at an early time point, aggressive dose escalation may contribute to achieving a better outcome. This study was registered at http://www.umin.ac.jp/ctr/ as #R000000965.

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Phase III Randomized Study of Imatinib Therapy in Chronic Phase Chronic Myeloid Leukemia Comparing Standard Dose-Escalation with Progressive Dose-Escalation (JALSG CML207 study)

Blood ◽

10.1182/blood.v128.22.941.941 ◽

2016 ◽

Vol 128 (22) ◽

pp. 941-941

Author(s):

Koichi Miyamura ◽

Shigeki Ohtake ◽

Kazunori Ohnishi ◽

Noriko Usui ◽

Chiaki Nakaseko ◽

...

Keyword(s):

Dose Escalation ◽

Research Funding ◽

Standard Dose ◽

Randomized Study ◽

Chronic Phase ◽

Cytogenetic Response ◽

High Dose ◽

Molecular Response ◽

Group A ◽

Group B

Abstract Imatinib mesylate (IM) given orally at a daily dose of 400 mg was the standard of care as initial therapy for patients with chronic myeloid leukemia (CML) in the chronic phase (CML-CP), before 2ndTKI era. Treatment guidelines by European Leukemia Net (ENL) propose dose escalation based on clinical assessments of disease response in 2006. Preclinical data and results of single-arm studies raised the suggestion that better results could be achieved with a higher dose. However, randomized study to compare high-dose IM (800 mg) with the standard dose (400 mg) as front-line in all CML high-risk patients did not support the extensive use of high-dose IM. To improve the results of CML therapy, another alternative strategy is a dose-escalation based on more aggressive clinical assessments of disease response in comparison with the standard ELN proposed. In 2007, we conducted a prospective randomized study to compare different dose escalation programs; the standard-dose escalation program proposed by ENL (Group A) and the aggressive dose escalation program (Group B) among newly diagnosed patients with CML-CP. The aggressive dose escalation program consisted of the following interventions. If the patients do not obtained a complete cytogenetic response at 3 months or do not reach a major molecular response (MR3, IS=0.1%), IM is increased from standard dose of 400mg daily to 600 mg daily. The primary endpoint is the rate of major molecular response at 12 months, which is a surrogate for long-term progression-free survival (PFS). It is also a surrogate for complete molecular response, which is pointed out recently to be the condition for treatment free survival. Total 248 patients entered to this study between June 16 2007 and June 15, 2011. Median age was 49 years old (range 15-69); 86 were female and 162 were male. Sokal score index was high-risk in 46 patients, intermediate-risk in 77 and low-risk in the remaining. White blood cell count at diagnosis was 43X10^9/L in median (10-881 in range). There was no significant difference between Group A (N=126) and Group B (N=127) according to these factors. Overall survival was 100%, 98% and 98% at 1, 2 and 3 years after treatment, respectively. Three patients developed blast crisis during 3 years (day 177, 272, 481) and all received hematopoietic stem cell transplantation (HSCT). Two other patients who had no cytogenetic response also received HSCT. Eleven patients (4.5%, Group A, N=8, Group B, N=3) failed to achieve complete hematological remission. The overall complete cytogenetic response (CCR) rate at 6 months after the treatment was better in Group B (89%) than in Group A (79%) with borderline significance (p=0.05, Fisher's exact test). However, the overall CCR rate at 12 months was 92% in both groups. At 12 months, MR3 was achieved in 61% and 64% of patients in Group A and Group B, respectively (p=0.69). Also, at 24 months, MR3 was achieved in 91% and 87% of patients in Group A and Group B, respectively. At 3 months, plans called for 8 and 45 patients to increase the dose of IM to 600 mg in Group A and B, respectively; however, only 4 and 27 patients followed the protocol. At 6 months, 10 and 55 patients were to increase the dose of IM to 600 mg in Group A and B, respectively; however, only 2 and 24 patients followed this protocol. The main reason was intolerance of IM. Among the patients who were to increase the dose at 3 and 6 months, 53% of those who could do according to the protocol achieved MR3 at 12 months, while only 16% of patients failed to increase (p=0.08). Eighty patients experienced drug discontinuation during 1 year. The incidence of discontinuation was 37% in Group B, whereas it was 29% in Group B (p=0.18). A substantial part of patients withdrew from this study; however, there was no difference between Groups (A 20%, B 21%). This is the first randomized study to compare two different dose escalation programs. The aggressive dose escalation program showed a better early cytogenetic response than the standard-dose escalation program, but, failed to evidence a better molecular response in a later period. Higher efficacy of high dose IM might be cancelled by the more frequently discontinuation of IM in this group. This study concluded that aggressive dose escalation is not recommended and careful management of drug dose according to patients' condition (residual leukemia, adverse effect, emotion) might be the best way for better outcome, which is applicable to new generation TKIs. Disclosures Miyamura: Nippon Shinyaku CO, LT: Honoraria; Pfizer Inc: Honoraria; Novartis Pharmaceutical: Honoraria; Alexion Pharmaceutical Inc: Honoraria. Usui:Bristol-Myers Squibb: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Novartis: Research Funding. Nakaseko:BMS: Honoraria, Research Funding; PFIZER: Honoraria, Research Funding; NOVARTIS: Honoraria. Fujita:Chugai Pharmaceutical Co.,LTD: Honoraria. Okumura:Novartis Pharma: Honoraria. Hatta:Novartis Pharma: Honoraria. Naoe:Astellas Pharma Inc.: Research Funding; Kyowa-Hakko Kirin Co.,Ltd.: Honoraria, Patents & Royalties, Research Funding; Celgene K.K.: Honoraria, Research Funding; Amgen Astellas BioPharma K.K.: Honoraria; Chugai Pharmaceutical Co.,LTD.: Honoraria, Patents & Royalties; TOYAMA CHEMICAL CO.,LTD.: Research Funding; Otsuka Pharmaceutical Co.,Ltd.: Honoraria, Research Funding; CMIC Co., Ltd.: Research Funding; Fujifilm Corporation: Honoraria, Patents & Royalties, Research Funding; Sumitomo Dainippon Pharma Co.,Ltd.: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria; Nippon Boehringer Ingelheim Co., Ltd.: Honoraria, Research Funding; Pfizer Inc.: Research Funding.

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Is Local Anesthetic Infiltration Prior to Intravenous Cannulation Beneficial to Patients?

Nepal Journal of Obstetrics and Gynaecology ◽

10.3126/njog.v8i1.8853 ◽

2013 ◽

Vol 8 (1) ◽

pp. 10-13

Author(s):

Babu Raja Shrestha ◽

U Shrestha ◽

A Shrestha ◽

A Rana

Keyword(s):

Heart Rate ◽

Local Anesthetic ◽

Randomized Study ◽

Cardiovascular Responses ◽

Control Group ◽

Venous Cannulation ◽

Number Of Patients ◽

Group A ◽

Group B ◽

Local Anesthetic Infiltration

Aims: Intravenous cannulation causes pain, anxiety and frustration in patients along with changes in hemodynamic parameters. Infiltration of local anesthetic lessens the pain of intravenous cannulation. This study was performed to compare cardiovascular responses and verbal rating pain scores in two groups with and without local anesthetic infiltration prior to venous cannulation. Methods: This was a randomized study conducted in 100 elective surgical patients, divided into two study groups with 50 patients in each: group A (Control) and group B (local anesthetic infiltration). Prior to venous cannulation in group B, 0.5 ml of 1% lidocaine was infiltrated at the procedure site at dorsum of the wrist. Patients in group A were cannulated directly without local anesthetic infiltration. The hemodynamic changes pre and post cannulation and verbal pain rating scores were recorded by blind observers in all patients. Results: Demographic values in two groups were similar. Increase in heart rate from baseline value was significant in control group (p < 0.05). Post cannulation heart rate, systolic and diastolic blood pressure were significantly higher in group A compared to group B for the first three minutes (p < 0.05). Amongst higher number of patients in group A, verbal rating pain score was significantly higher. Ninety-four percent of the patients in group B were pain free, comfortable and satisfied with the procedure. Conclusions: Intravenous cannulation can be made pain free with patient satisfaction and hemodynamic stability if carried out with prior local anesthetic infiltration. Nepal Journal of Obstetrics and Gynaecology / Vol 8 / No. 1 / Issue 15 / Jan- June, 2013 / 10-13 DOI: http://dx.doi.org/10.3126/njog.v8i1.8853

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Imatinib Dose Escalation Is Effective in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP).

Blood ◽

10.1182/blood.v110.11.1047.1047 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1047-1047

Author(s):

Hagop M. Kantarjian ◽

Brian J. Druker ◽

Francois Guilhot ◽

Jorge Cortes ◽

Stephen G. O’Brien ◽

...

Keyword(s):

Dose Escalation ◽

Randomized Study ◽

Chronic Phase ◽

Cytogenetic Response ◽

Separate Analysis ◽

Inadequate Response ◽

Durable Response ◽

Entire Cohort ◽

The Impact

Abstract Background: Imatinib mesylate (IM) 400 mg/d is the standard of care for newly diagnosed patients (pts) with CML-CP. Dose escalation to 600 or 800 mg IM has been shown to be beneficial in patients with either an inadequate response or disease progression while on standard therapy (Kantarjian et al Blood 2003). In the International Randomized study of Interferon versus STI571 (IRIS) trial, initiated in 2000, dose escalation was allowed for patients who did not achieve a complete hematologic response (CHR) by 3 months or a minor cytogenetic response (minCyR) by 12 months, lost a major cytogenetic response (MCyR) at any time, or progressed (including increase in WBC); no dose escalation in cases of loss of CCyR were specified. The impact of IM dose escalation for patients on IRIS is presented in this post-hoc analysis. Methods: Patients were evaluated for hematologic and cytogenetic responses, progression (to accelerated or blast phase) free survival (PFS), and overall survival (OS) following dose escalation. Patients were included if their dose was increased within −0.5 to 3 months following the respective landmark evaluation. Instances of dose escalation (to ≥600 mg/d) on the IM arm were reviewed and classified, where possible, based on either criteria established by IRIS protocol or the European LeukemiaNet recommendations Results: Of 551 patients receiving first line IM, 106 pts (19%) had dose escalation to 600–800 mg/d. Median time to dose escalation was 22 months (range:3–74 months; 25th–75th percentile: 13–45 months). After dose escalation the median imatinib dose delivered was 604 mg/d (range: 294–800 mg/d; 25th–75th percentile:600–739 mg/d) and remained on treatment for a median of 19.4 months based on current follow-up. Last recorded dose was ≥600mg/d in 85% of these patients. Dose increases in 39 patients were based on the IRIS protocol criteria. Responses among these patients included: 6 of 7 who had not achieved CHR at 3 months achieved a CHR with dose escalation, 2 of these patients subsequently achieved a CCyR. Of 8 patients who had not achieved a minCyR at 12 months, 4 improved to a CCyR, and of 18 patients who lost their MCyR, 9 subsequently re-achieved an MCyR within 12.5 months after dose escalation, of whom 3 also attained a CCyR by 30-months after dose escalation. The 6 patients who received dose escalations upon progression, had an OS of 83% at 2 years after dose escalation. At 36-months after dose escalation the 39 patients dose escalated per IRIS protocol criteria achieved an estimated PFS and OS of 81%. In a separate analysis of these 106 pts, dose escalations in 48 pts were retrospectively classified according to the ELN recommendations. At 36-months follow-up after dose escalation these 48 patients achieved a 90% PFS and 89% OS. For the entire cohort of 106 patients who were dose escalated, estimated PFS was 89% and OS was 84% at 36 months after dose escalation. Conclusion: Based on these data, IM dose escalation to 600 and/or 800 mg allows poorly responding patients to achieve a clinically important durable response or re-gain responses. These slower responding or progressing patients benefited from IM dose escalation and thus, the data support dose escalation for these patients.

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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 ◽

10.1182/blood.v114.22.3302.3302 ◽

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.

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Nilotinib Versus High-Dose Imatinib in Early Chronic Phase CML Patients Who Have Suboptimal Molecular Responses to Standard-Dose Imatinib: Updated Data From RE-Nice Study

Blood ◽

10.1182/blood.v120.21.3775.3775 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3775-3775 ◽

Cited By ~ 1

Author(s):

Soo-Young Choi ◽

Sung-Eun Lee ◽

Soo-Hyun Kim ◽

Eun-Jung Jang ◽

Jin-hwa Lee ◽

...

Keyword(s):

Dose Escalation ◽

Standard Dose ◽

Chronic Phase ◽

Cytogenetic Response ◽

High Dose ◽

Molecular Response ◽

Long Term Outcomes ◽

First Line

Abstract Abstract 3775 Background. In chronic myeloid leukemia (CML), achievement of optimal responses by time point has improved long-term outcomes. In contrast, several clinical studies investigating the clinical implications of suboptimal response showed that patients with suboptimal responses tend to have poor long-term outcomes. In IRIS study, patients who achieved major molecular response (MMR) at 18 months had event-free survival (EFS) benefit, compared to those who achieved complete cytogenetic response (CCyR) without MMR. However, the best treatment for these patients is still not confirmed. By the previous studies, sustaining standard-dose of imatinib (IM) is expected to yield less than 20 percent of additive MMR. In this prospective study, we investigated whether switching to nilotinib (NIL) or high-dose IM may be more effective for patients with suboptimal molecular response to IM as first-line therapy. Methods. Early chronic phase (CP) CML patients who have achieved CCyR but no MMR after at least 18 months and up to 24 months (≤ 18 to ≥24 months) on first-line IM therapy at a daily dose of 400 mg were enrolled in this clinical trial, and informed consents were obtained from all patients. In NIL arm, patients received oral dose of 400 mg BID (800 mg/day) and in high-dose IM arm, patients received 800 mg/day administrated as 400 mg BID. Primary endpoint is to evaluate the cumulative MMR rates by 12 months, and secondary endpoints are to evaluate the cumulative MMR, MR4.0 and undetectable molecular residual disease (UMRD) rates during further 24 month follow-up. Safety profiles will also be assessed. Patients showing lack of response (lack of complete hematologic response (CHR) at 6 months, increasing WBC, no major cytogenetic response (MCyR) at 24 months), loss of response (loss of CHR or MCyR) or severe intolerance to treatment were allowed to crossover to the alternative treatment. Results. With a data cut-off date of 10 Jul 2012, a total of 43 patients were randomized into NIL arm (n = 22) or high-dose IM arm (n = 21). With a median follow-up of 15 months (range, 1–36), all patients have maintained CCyR without progression to advanced disease, and progressive decrease in BCR-ABL1 transcript levels was observed in all patients. Cumulative incidence (CI) of MMR by 12 months showed no significant difference between NIL arm and high-dose IM arm (37.8 ± 11.9% vs 34.8 ± 10.6%, P = 0.789). In NIL arm, 3 in 22 (14%) and 2 in 22 (9%) patients achieved MR4.0 and UMRD, respectively, and in high-dose IM arm, 1 in 21 (5%) patients achieved MR4.0. Overall, the patients treated with high-dose IM showed toxicities more frequently, such as fatigue, dyspnea and decreased phosphate. In addition, 10 patients in high-dose IM arm have cross-over to NIL treatment due to lack of response (n=9) and intolerance (n=1), and the median duration of NIL treatment was 14 months (range, 7–26 months). Among them, 5 (50%) patients have achieved MMR with a median NIL treatment duration of 12 months (range, 3–18). Conclusions. These results demonstrate that early switching to NIL or dose escalation of IM could be recommended, considering the results of standard dose of IM in suboptimal molecular responders. When the tolerability of treatment was considered for switching to NIL or high-dose IM, NIL may be preferred. Through further clinical investigation on a large patient population and longer period observation, the efficacy and safety of early intervention of suboptimal molecular response using NIL or dose escalation of IM will be needed. Updated data with longer follow-up duration will be presented in the meeting. Disclosures: No relevant conflicts of interest to declare.

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Intraperitoneal Hydrocortisone plus Bupivacaine versus Bupivacaine alone for Pain Relief after Laparoscopic Cholecystectomy

Journal of Lumbini Medical College ◽

10.22502/jlmc.v3i2.71 ◽

2016 ◽

Vol 3 (2) ◽

pp. 41 ◽

Cited By ~ 1

Author(s):

Mahesh Sharma ◽

Kalpana Kharbuja ◽

Nil Raj Sharma

Keyword(s):

Laparoscopic Cholecystectomy ◽

Pain Relief ◽

Normal Saline ◽

Randomized Study ◽

Saline Group ◽

Normal Saline Group ◽

Analgesic Requirement ◽

Number Of Patients ◽

Group A ◽

Group B

Introduction: Laparoscopic cholecystectomy has been the gold standard in the treatment of gallstones since last decades. Beside several benefits of laparoscopic cholecystectomy compared with open surgery, postoperative pain is still a frequent melancholy. Hence, pain management is utmost regarding patients' comfort. The main objective of the study was to compare the effect of intraperitoneal hydrocortisone plus bupivacaine with bupivacaine alone on pain relief following laparoscopic cholecystectomy. Methods: A randomized study was conducted from December 2015 to August 2015 that included 100 patients aged 20 to 60 years of both genders who were found to have symptomatic gallstones and were scheduled for elective laparoscopic cholecystectomy at Lumbini Medical College. Patients randomly received 100 mg hydrocortisone plus 100 mg bupivacaine in 200 ml normal saline (group A) or 100 mg bupivacaine in 200 ml normal saline (group B) into the peritoneum. Post-operative abdominal and shoulder pain were evaluated using Visual Analog Score (VAS). The patients were also followed up for postoperative analgesic requirements, and recovery variables. Data were collected, tabulated and analyzed statistically using SPSS version 19. Results: Total number of patients in this study were 100. Age and gender among both groups were comparable. VAS scores for pain was significantly lower for group A as compared to group B at 0, 2, 4, 6, 12, and 24 hours. Time of oral intake in hrs for liquids and solids was statistically significant in Group A compared to Group B. Rescue analgesic requirement was also significantly low in Group A compared to Group B. Hospital stay in both group were comparable. Conclusion: Combination of hydrocortisone plus bupivacaine can relieve pain after laparoscopic cholecystectomy better compared to bupivacaine alone when administered intraperitoneally.

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IMATINIB IN CHRONIC MYELOID LEUKEMIA: AN OVERVIEW

Mediterranean Journal of Hematology and Infectious Diseases ◽

10.4084/mjhid.2014.007 ◽

2013 ◽

Vol 6 (1) ◽

pp. e2014007 ◽

Cited By ~ 31

Author(s):

Tomasz Sacha

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Standard Dose ◽

Randomized Study ◽

Leukemic Cell ◽

Cytogenetic Response ◽

Kinase Domain ◽

Molecular Response ◽

Newly Diagnosed ◽

One Year

Imatinib was the first signal transduction inhibitor (STI), used in a clinical setting. It prevents a BCR-ABL protein from exerting its role in the oncogenic pathway in chronic myeloid leukemia (CML). Imatinib directly inhibits the constitutive tyrosine kinase activity. Imatinib binds to BCR-ABL kinase domain by preventing the transfer of a phosphate group to tyrosine on the protein substrate and the subsequent activation of phosphorylated protein. As the result, the transmission of proliferative signals to the nucleus is blocked and leukemic cell apoptosis is induced. The FDA has approved imatinib as first-line treatment for newly diagnosed CML in December 2002 following an International Randomized Study (IRIS), initiated in June 2000, comparing imatinib at a single daily dose 400 mg to IFN alpha plus cytarabine in newly diagnosed patients with CML in CP. Results from this study show the outstanding effectiveness of imatinib and its superiority with respect to the rates of complete hematological response (CHR), major and complete cytogenetic response (MCyR, CCyR). Patients randomized to imatinib arm at 8 – year data cut off continue to have a durable hematologic and cytogenetic response, low progression rates to AP or BC, and remarkable survival outcomes. An overall survival (OS) rate is 85% for patients receiving imatinib (93% when only CML-related deaths and those prior to stem cell transplantation are considered). The results have been confirmed in the last years by several groups. According these cumulative results the rates of CCyR achieved after one year of therapy with imatinib at standard dose ranged from 49% to 77%, and the proportion of patients who achieved major molecular response (MMR) after one year ranged between 18% and 58%. Discontinuation of imatinib has been also tried in patients in MMR, a molecular relapse occurs in about one third of patients, generally within 6 months from imatinib cessation.

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Imatinib Mesylate Dose Escalation Improves Disease Response in Chronic-Phase Chronic Myeloid Leukaemia Patients after Cytogenetic or Molecular Suboptimal Responses to Standard Doses of Imatinib.

Blood ◽

10.1182/blood.v110.11.1052.1052 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1052-1052 ◽

Cited By ~ 6

Author(s):

Delphine Rea ◽

Gabriel Etienne ◽

Selim Corm ◽

Pascale Cony-Makhoul ◽

Martine Gardembas ◽

...

Keyword(s):

Imatinib Mesylate ◽

Median Duration ◽

Dose Escalation ◽

Standard Dose ◽

Chronic Phase ◽

Cytogenetic Response ◽

High Dose ◽

Molecular Response ◽

Dose Increase

Abstract In chronic phase-chronic myeloid leukemia (CP-CML), a complete cytogenetic response (CCR) along with a major molecular response (MMR) on imatinib mesylate (IM) at 400mg/d represents a strong factor predicting survival. Suboptimal cytogenetic responders (minimal or minor CR (mCR) by 6 months or partial CR (pCR) by 12 months, ELN) have a probability of further achievement of CCR of only 50%. Suboptimal molecular responders (CCR without MMR by 18 months, ELN) have a decreased probability of remaining event-free survivors when compared to optimal responders. Since non-randomized trials suggest that high-dose IM at CML diagnosis produces high rates of optimal responses, dose escalation can be recommended for suboptimal responders to standard dose of IM, but this strategy has not been yet evaluated. Here, we present the results from a series of 24 CP-CML patients who experienced IM-dose escalation for cytogenetic or molecular suboptimal response to standard doses of IM. Suboptimal cytogenetic responders (n=10) included 9 males, median age was 51.3 years-old (27.7–64.2), all were in early CP. Sokal scores were low (n=5), int (n=2), high (n=2) and unknown (n=1). All patients were treated with IM frontline at 400mg/d (n=9) or 600mg/d (n=1) and 2 received PEGIFN associated with IM at 400mg/d (withdrawn after 3 months for intolerance in 1). Prior to dose escalation, 7 patients were in pCR at 12 months and 3 in mCR at 6 months. The search for BCR-ABL mutations was negative in 6 patients tested. IM was increased to 600mg/d (n=7) or 800mg/d (n=3) after a median time of 13.7 months (5.6–15.2) on initial IM treatment. Median follow-up from IM at standard and escalated doses were respectively 28 (16.1–79.1) and 14.9 months (2.2–73.5). Of 9 patients with cytogenetic evaluation, 100% obtained CCR after a median duration of high-dose IM of 6.2 months (2.4–12.6). Five patients (50%) achieved a MMR after a median duration of high-dose IM of 9.7 months (2.9–45). Only one patient treated with PEGIFN and IM increased to 600mg/d obtained a complete molecular response (CMR) 19.9 months after high-dose IM. Suboptimal molecular responders (n=14) included 11 males, median age was 38.2 years-old (20.9–63.2), 9 were in early CP and 5 in late CP. Six had previously received IFN for a median of 4 months (4–53). Sokal scores were low (n=5), int (n=5), high (n=3) and unknown (n=1). All patients had received IM at 400mg/d, for a median duration of 27.3 months (16.7–73.3). BCR-ABL mutations were detected in 2/8 patients tested (M244V and Q252R). IM was increased to 600mg/d (n=13) or to 800mg/d (n=1). Median BCR-ABL prior to dose increase was 0.79% (0.15–3.06). Median follow-up from standard and escalated doses of IM were respectively 45.2 (26.9–85.9) and 12.5 months (3.3–38.1). Six patients (43%) obtained a MMR after a median of 6.7 months (2–25.4) of high-dose IM, including 1 with the M244V mutation. None achieved a CMR. To conclude, IM-dose escalation is beneficial to suboptimal cytogenetic responders with a rate of achievement of CCR and MMR of respectively 100 and 50%. Regarding molecular suboptimal responders, the rate of MMR after dose increase in only 43% and other strategies should be considered.

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Nilotinib Or High-Dose Imatinib Compared With Standard-Dose Imatinib In Early Chronic Phase CML Patients Who Have Suboptimal Molecular Responses To Standard-Dose Imatinib: Including Updated Data From RE-Nice Study

Blood ◽

10.1182/blood.v122.21.1499.1499 ◽

2013 ◽

Vol 122 (21) ◽

pp. 1499-1499

Author(s):

Soo-Young Choi ◽

Sung-Eun Lee ◽

Yun Jeong Oh ◽

Soo-Hyun Kim ◽

Richard C. Woodman ◽

...

Keyword(s):

Dose Escalation ◽

Advanced Disease ◽

Residual Disease ◽

Standard Dose ◽

Chronic Phase ◽

Cytogenetic Response ◽

High Dose ◽

Molecular Response ◽

First Line

Abstract Background In chronic myeloid leukemia (CML), achievement of optimal responses by time point has improved long-term outcomes. In IRIS study, patients who achieved major molecular response (MMR) at 18 months had event-free survival (EFS) benefit, compared to those who achieved complete cytogenetic response (CCyR) without MMR. However, the best treatment for these patients is still not confirmed. By the previous studies, sustaining standard-dose of imatinib (IM) is expected to yield less than 20 percent of additive MMR. In this study, we investigated the efficacy of switching to nilotinib (NIL) versus high-dose IM versus standard-dose IM for patients with suboptimal molecular response to IM as first-line therapy. Methods Early chronic phase (CP) CML patients who have achieved CCyR but no MMR after at least 18 months and up to 24 months ( 18 to 24 months) on first-line IM therapy at a daily dose of 400 mg were enrolled in RE-NICE study, and informed consents were obtained from all patients. In NIL arm, patients received 400 mg BID (800 mg/day) and in high-dose IM arm, patients received 800 mg/day administrated as 400 mg BID. Primary endpoint is to evaluate the cumulative MMR rates by 12 months, and secondary endpoints are to evaluate the cumulative MMR, MR4.0 and undetectable molecular residual disease (UMRD) rates during further 24 month follow-up. The efficacy of switching to NIL or high-dose IM were compared with that of the patients who maintained standard-dose of IM. Patients with standard-dose IM were selected with the same inclusion criteria and maintained standard-dose IM after enrollment period. To compare the efficacy among three groups, MMR rate, MR4.0 and undetectable molecular residual disease (UMRD) rates by 12 months were analyzed. Safety profiles also be assessed. Patients showing lack of response (lack of complete hematologic response (CHR) at 6 months, increasing WBC, no major cytogenetic response (MCyR) at 24 months), loss of response (loss of CHR or MCyR) or severe intolerance to treatment were allowed to crossover to the alternative treatment. Results With a data cut-off date of 15 Jul 2013, a total of 52 patients were randomized into NIL arm (n = 26) or high-dose IM arm (n = 26) and 16 patients were included in standard-dose IM group. With a median follow-up of 21 months (range, 1-36) in NIL arm and high-dose IM arm, all patients have maintained CCyR without progression to advanced disease, and progressive decrease in BCR-ABL1 transcript levels was observed in all patients. With a median follow-up of 12 months (range, 1-60), all patients in standard-dose IM group have maintained CCyR without progression to advanced disease. Cumulative incidence (CI) of MMR by 12 months showed no significant difference between NIL arm and high-dose IM arm (41.1% vs 28.8, P = 0.334). Only in NIL arm, 2 in 26 (8%) achieved confirmed MR4.0 and UMRD. By 12 months, 10 in 26 (39%), 7 in 26 (27%) and 3 in 16 (19%) patients achieved MMR, in NIL arm, high-dose IM arm and standard-dose IM group respectively. Overall, the patients treated with high-dose IM showed toxicities more frequently, such as leucopenia, anemia, Thrombocytopenia, edema, fatigue, dyspnea and decreased phosphate. In addition, 14 patients in high-dose IM arm have cross-over to NIL treatment due to lack of response (n=11) and intolerance (n=3), and the median duration of NIL treatment was 23 months (range, 2-36 months). Among them, 6 (43%) patients have achieved MMR with a median NIL treatment duration of 12 months (range, 0-18). Conclusions These results demonstrate that early switching to NIL or dose escalation of IM could be recommended, considering the results of standard dose of IM in suboptimal molecular responders. When the tolerability of treatment was considered for switching to NIL or high-dose IM, NIL may be preferred. Through further clinical investigation on a large patient population and longer period observation, the efficacy and safety of early intervention of suboptimal molecular response using NIL or dose escalation of IM will be needed. Updated data with longer follow-up duration will be presented in the meeting. Disclosures: No relevant conflicts of interest to declare.

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CML and Imatinib Mesylate: Response Related to Karyotype.

Blood ◽

10.1182/blood.v106.11.4866.4866 ◽

2005 ◽

Vol 106 (11) ◽

pp. 4866-4866

Author(s):

Araceli Rubio-Martinez ◽

Valle Recasens ◽

Maria D. Odero ◽

Daniel Rubio-Felix ◽

Maria J. Calasanz ◽

...

Keyword(s):

Imatinib Mesylate ◽

Cytogenetic Study ◽

Specific Inhibitor ◽

Chronic Phase ◽

Cytogenetic Response ◽

Molecular Response ◽

Rt Pcr ◽

Group A ◽

Group B ◽

Mean Time

Abstract Background: Imatinib mesylate (STI571), as a specific inhibitor for tyrosine kinase product of oncoprotein Bcr/Abl. Efficacy of Imatinib is questioned when other cytogenetics abnormalities associated to t(9;22) are present. We describe our experience in CML patients treated with Imatinib in one centre, evaluating hematological (HR) and cytogenetic response (CR) related to kariotype. Patients and methods: 28 patients diagnosed as having CML, 1990–2005, Imatinib 400–800 mg/d, were stratified according to cytogenetic abnormalities: Group A: t(9;22) typical in 19 patients, Group B: patients with t(9;22) and different genomic rearrangement associated: 9. At diagnosis were classified in stages Kantarjian score and the cytogenetic study (kariotype, % metaphases Ph, FISH and PCR/RT-PCR in bone marrow (BM) and peripheral blood (PB)). HR was evaluated monthly and CR in BM every 3–6 months. In patient with complete cytogenetic response (CCR) we performed follow-up in PB by RT-PCR every 3 months and a cytogenetic study in BM once a year. Cytogenetic response (CR) was quantified by n° metaphases Ph in BM: 0% CCR, 1–35% partial (PCR), 36–95% minor (MCR) and > 95% failure (F). Molecular response (MR): normal kariotype (Bcr/Abl negative and RT-PCR<5 copies). Statistical analysis: Chi-cuadrado and Kaplan-Meier survival test. Results: 18 M /10 F (2 died by blast crisis), mean age 50 (range 30–72), Kantarjian score: A group (4: 2pts, 3: 5pts, 2: 5pts, 1: 7 pts). Mean time on therapy: 26.46 m (1–51 ). Previous therapy: α-interferon 7, α-interferon/pegilated 1, α-interferon/α-interferon+citarabine 3, α-interferon+citarabine 6. Imatinib as first line: 11. When Imatinib started: accelerated phase 3, chronic phase 23 and chronic phase post-blast crisis2. The results of therapy are in table I. We have not observed statistically significant differences (s.s.d) in MR (p=.577) and in OS (p=.581) between group A and B with the same doses. Two patients that had started therapy with Imatinib 800 mg/day (group A) reached MR three months later. In group B one patient 12 months after got MR surprisingly developed a ALL Ph’, he received chemotherapy plus Imatinib 800 mg/day and 6 months later he is in CCR. Conclusions: Three months after Imatinib therapy HR was 100% in both groups. One year undergoing therapy CR response was higher in A group (81% vs 50%). Nevertheless the n° of MR obtained in patients with complex karyotypes receiving Imatinib 400 mg/day has been high (33.3%) and without s.s.d.with those with classical translocation. Hematological and Cytogenetic response to Imatinib Months N.E.P. A Group (19) N.E.P. B Group (9) 1 19 HR : 100% 9 HR :78% 3 10 HR:100%. CR 7 (70%): 4CCR(2MR), 2PRC, 1MRC, 3F. 3 HR: 100%. CR 2 (67%): 2MCR, 1F 6 16 HR: 94%. CR: 12 (75%), 7CCR (3MR), 3PRC, 2MCR, 4F 6 HR: 86%. CR 4 (67%): 3CCR, 1MCR, 2F 12 16 HR: 94%. CR 13 (81%): 11CCR (6MR), 2PRC, 3 F 4 HR: 100%. CR 2 (50%): 2CCR (1MR), 2F 18 13 HR: 100%. CR 12 (92%): 10CCR (6MR), 2PRC, 1F 5 HR: 80%. CR 3(60%): 3CCR (2 MR), 2F 24 13 HR: 93%. CR 12 (92%): 10CCR (7MR), 2PRC, 1F 6 HR: 83%. CR : 4 (67%): 3CCR (3 MR*), 1PRC, 2F 36 4 HR: 100%. CR 3 (75%): 2CCR (1MR), 1PRC, 1F 5 HR: 60%. CR 2 (40%): 2CCR (2MR), 3F 48 2 HR: 100%. CR 1 (50%): 1 PRC,1F 0 MR:N 10 (52,6%). Mean time : 12 m (3–24 m). Imatinib : 488,88 mg/d, Months in MR : mean 15.8 (9–21m) 3 (33.3%). Mean time : 18 months (12–26 m). Imatinib : 400 mg/day. Months in MR : mean 18 (12–26 m)

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