scholarly journals 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 ◽  
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.

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

2019 ◽  
Vol 3 (3) ◽  
pp. 312-319 ◽  
Author(s):  
Koichi Miyamura ◽  
Kazunori Ohnishi ◽  
Shigeki Ohtake ◽  
Noriko Usui ◽  
Chiaki Nakaseko ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Standard Dose ◽  
Randomized Study ◽  
Early Time ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Inadequate Response ◽  
Number Of Patients ◽  
Group A ◽  
Group B

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.

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 ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3775-3775 ◽  
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.

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 ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1052-1052 ◽  
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.

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 ◽  
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.

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.

EUTOS Score Is Not Predictive for Survival and Outcome in Patients (pts) with Chronic Myeloid Leukemia in Early Chronic Phase (CML-CP) Treated with Tyrosine Kinase Inhibitors (TKIs) At MD Anderson Cancer Center (MDACC),

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3769-3769
Author(s):  
Aziz Nazha ◽  
Elias Jabbour ◽  
Jorge E. Cortes ◽  
Susan O'Brien ◽  
Jenny Shan ◽  
...  
Keyword(s):  
Research Funding ◽  
Kinase Inhibitors ◽  
Standard Dose ◽  
Chronic Phase ◽  
Cancer Center ◽  
High Dose ◽  
Molecular Response ◽  
Phase Ii Trials ◽  
Free Survival ◽  
Eutos Score

Abstract Abstract 3769 Background: Until recently, prognosis of pts with CML treated with TKI was based on scores developed in the chemotherapy and interferon era. Hasford and colleagues [Blood. 2011;(118):686–692] have identified the EUTOS score, using the percentage of basophils and spleen size, as a significant tool to predict the probability of achieving 18-month complete cytogenetic response (CCyR) and progression-free survival in patients treated with imatinib. Aims: To validate the EUTOS score in an independent MDACC cohort of pts, with early CML-CP treated with standard-dose imatinib, high-dose imatinib, dasatinib, and nilotinib, and its ability to predict transformation-free survival (TFS), event-free survival (EFS) and overall survival (OS). Methods: 465 consecutive pts with newly diagnosed CML–CP (0 – 6 months from diagnosis to TKI treatment) were treated with imatinib 400 mg daily (n=71), imatinib 800 mg daily (n=208), and 2nd TKIs (n=186; dasatinib n=88, nilotinib n=98) in sequential phase II trials. Entry criteria were similar for all trials. EUTOS score = (7 x basophils %) + (4 x spleen cm BCM). A EUTOS score of >87 indicates high-risk and ≤87 low-risk. Results: 465 pts with CML-CP were assessed. Median age was 47 years (range, 15–85). Median time from diagnosis to TKI therapy was 1 month (range, 0 to 6). 319 (69%), 112 (24%), and 34 (7%) pts were in low, intermediate, and high-Sokal score category, respectively. Median basophils percentage at baseline was 3 (range, 0 to 19). Median splenomegaly size was 0 cm (range, 0 to 30). 118 pts (25%) received previous cytoreduction therapy. Median follow-up was 117 months (range, 16 to 130) for pts receiving standard-dose imatinib, 88 months (range, 4 to 118) for those receiving high-dose imatinib, and 30 months (range, 3 to 69) for those receiving 2nd TKI. The overall CCyR rates were 87%, 91%, and 95%, respectively. The 4-year EFS, TFS, and OS rates for the whole group were 84%, 94%, and 95%, respectively. Overall, of the 465 pts, 427 (92%) were in low EUTOS score category (Table 1). Pts with low EUTOS score had higher rates of CCyR at anytime compared to pts with high EUTOS score (93% versus 81%, p=0.02). This difference was mainly significant among pts receiving 2nd TKI (p=0.03) while it was not different among pts receiving imatinib (p=0.27). There was no difference in the rates of major molecular response (85% versus 81%, p=0.48) between pts with low and high EUTOS score. There was no difference in TFS, EFS, and OS rates between pts with low and high EUTOS score, overall and among specific therapy (Table 1). Conclusion: Eight percent of pts with CML-CP treated at MDACC are of high EUTOS score. In this population, the EUTOS score was not predictive for overall MMR, TFS, EFS, and OS. Disclosures: Cortes: BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding.

Superior CMR-Rates with Tolerability-Adapted Imatinib 800 Mg Vs. 400 Mg Vs. 400 Mg + IFN In CML: The Randomized German CML-Study IV

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 357-357 ◽  
Author(s):  
Rüdiger Hehlmann ◽  
Susanne Jung-Munkwitz ◽  
Michael Lauseker ◽  
Martin C. Müller ◽  
Armin Leitner ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Research Funding ◽  
Randomized Study ◽  
Chronic Phase ◽  
High Dose ◽  
Molecular Response ◽  
Advisory Committees ◽  
Good Tolerability ◽  
First Choice ◽  
The Impact

Abstract Abstract 357 Treatment of CML with imatinib of 400 mg can be unsatisfactory. Treatment optimization is warranted. The German CML-Study group has therefore conducted a randomized study comparing imatinib 800 mg vs 400 mg vs 400 mg + IFN. A significantly faster achievement of MMR at 12 months has been observed with imatinib 800 mg in a tolerability adapted manner and MMR by 12 months has been found to translate into better overall survival. Since stable CMR has been associated with durable off-treatment remissions we sought to analyse the impact of tolerability-adapted imatinib 800 mg on CMR and survival. Standardized determinations of molecular response and evaluation of its impact on outcome are goals of CML-Study IV. CMR4 is defined as a BCR-ABL/ABL ratio of <0,01 on the International Scale. From July 2002 – April 30, 2009 1022 newly diagnosed patients with CML in chronic phase were randomized, 1012 were evaluable (338 with imatinib 800 mg, 324 with imatinib 400 mg, 350 with imatinib plus IFN). Median observation time was 40 months. The median average daily imatinib doses were 628 mg in the 800 mg arm and 400 mg in the 400 mg based arms. The actual median daily doses in the 800 mg arm per 3-months periods were: 555 mg, 737 mg, 613 mg, 600 mg, and 600 mg thereafter, reflecting the run–in period with imatinib 400 mg for 6 weeks in the first period and the adaptation to tolerability from the third 3-months period onwards. Median daily imatinib doses in the 400 mg arms were 400 mg throughout. Adaptation of imatinib dose in the 800 mg arm according to tolerability is reflected by similar higher-grade adverse events rates (WHO grades 3 and 4) with all treatments. Significantly higher remission rates were achieved with imatinib 800 mg by 12 months. The cumulative incidences of CCR by 12 months were 63% [95%CI:56.4-67.9] with imatinib 800 mg vs 50% [95%CI:43.0-54.5] with the two 400 mg arms. The cumulative incidences of MMR by 12 months were 54.8% [95%CI:48.7-59.7] with imatinib 800 mg vs 30.8% [95%CI:26.6-36.1] with imatinib 400 mg vs 34.7% [95%CI:29.0-39.2] with imatinib + IFN. The cumulative incidences of CMR4 compared with the MMR incidences over the first 36 months are shown in Table 1. Imatinib 800 mg shows superior CMR4 rates over the entire 36 months period, CMR4 is reached significantly faster with imatinib 800 mg as compared to the 400 mg arms. The CMR4 rates reach 56.8% by 36 months [95%CI:49.4-63.5] as compared to 45.5% with imatinib 400 mg [95%CI:38.7-51.0] and 40.5% with imatinib plus IFN [95%CI:34.6-46.3]. Most patients have stable CMR4 over the entire period. Time after start of treat-ment (months) Cumulative incidences MMR(%) CMR4 (%) IM400 n=306 D IM800 n=328 D IM400 +IFN n=336 IM400 n=306 D IM800 n=328 D IM400 +IFN n=336 6 8.6 9.5 18.1 9.7 8.4 3 0.7 3.7 1.3 2.4 12 30.8 24.0 54.8 20.1 34.7 7.5 12.3 19.8 7.4 12.4 18 50.3 18.1 68.4 14.3 54.1 21.2 12.2 33.4 9.8 23.6 24 63 13.0 76.0 13.2 62.8 30.7 12.3 43 13 30.0 36 79.3 2.3 81.6 10.9 70.7 45.5 11.3 56.8 16.3 40.5 In summary, superior CMR4 rates are achieved with high-dose imatinib adapted to good tolerability, and more patients in the tolerability-adapted 800 mg arm have stable CMR4 qualifying for treatment discontinuation as compared to the 400 mg based arms. With improved application imatinib remains first choice for early CML. Disclosures: Koschmieder: Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Membership on an entity's Board of Directors or advisory committees. Schnittger:MLL Munich Leukemia Laboratory: Employment, Equity Ownership. German CML-Study Group:Deutsche Krebshilfe: Research Funding; Novartis: Research Funding; Roche: Research Funding; BMBF: Research Funding; Essex: Research Funding.

Recapturing Disease Response: A Phase II Study of High Dose Carfilzomib in Patients with Relapsed or Refractory Multiple Myeloma Who Have Progressed on Standard Dose Carfilzomib

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3051-3051 ◽  
Author(s):  
Ajai Chari ◽  
Hearn Jay Cho ◽  
Samir Parekh ◽  
Keren Osman ◽  
Talia Goldstein ◽  
...  
Keyword(s):  
Dose Escalation ◽  
Research Funding ◽  
Standard Dose ◽  
Randomized Study ◽  
Study Entry ◽  
Leg Pain ◽  
High Dose ◽  
Weekly Schedule ◽  
Disease Response ◽  
Grade 3

Abstract Background: Carfilzomib (CFZ) is FDA approved at 27 mg/m2 D1,2,8,9,15,16 (except 20 mg/m2 D1,2, of cycle 1) to be given over 10 minutes with an overall response rate (ORR) of 23.7% (Siegel 2012). When CFZ is given as a 30 minute infusion, the dose can be safely escalated to 56 mg/m2, presumably due to a lower Cmax, on a twice weekly schedule with a higher ORR of 55% (Papadopoulos 2014). Our hypothesis was that the disease response of patients who progressed on CFZ 27 mg/m2 could recaptured by dose escalation to 56 mg/m2. Methods: Inclusion criteria were progressive disease (PD) at time of study entry, refractory to CFZ 27 mg/m2 without any Grade 3/4 toxicities, > 2 lines of therapy (including bortezomib and an IMID), measurable disease, adequate heme parameters (ANC > 1.0, plt > 50k), and organ function (Cr Cl > 15, cardiac ejection fraction (EF) > 40%). CFZ was given at 56 mg/m2 Day 1,2,8,9,15,16 over 30 minutes with dexamethasone (dex) 8 mg and ondansetron 8mg premedication. EF was monitored every 2 cycles. Results: 13 patients received study treatment. The median age was 64.5 (50% greater than age 65 yo) with 4.5 median lines of treatment over 4 years from MM diagnosis. 5 (38%) were high molecular with risk gain of 1q21 by FISH and 3 with concurrent deletion of p53. Also 67, 58, 67, and 100% were refractory to each of the following respectively: lenalidomide, pomalidomide (pom), bortezomib, & CFZ. Prior to study entry, the median duration of time on CFZ 27 mg/m2 before PD was 136 days. All but 1 patient had been receiving dex 40 mg weekly and 3 had been receiving triplet therapy - 2 with concomitant pom and 1 with ibrutiinib (on a clinical trial). Of the 12 patients evaluable for efficacy, responses include 1 VGPR, 4 PRs, & 6 SDs, for an ORR of 42% and a median DOR of 6.5 mos. The median PFS was 3.5 mos. Interestingly, 2 of the 3 patients who progressed on CFZ based triplet regimens prior to study entry achieved a PR with CFZ dose escalation. Grade 3/4 toxicities (regardless of drug attribution) were primarily heme, with neutropenia (36%), thrombocytopenia (8%) and anemia (22%) respectively. Grade 3/4 nonheme AEs included 4 hypertension (HTN), 1 acute dyspnea, 1 ggt elevation, 1 back pain and 1 leg pain. When ggt was added on to screening labs for the patient with grade 4 ggt elevation prompting study discontinuation, it was noted to be elevated to grade 3 even at baseline. Of the 4 patients with Grade 3/4 HTN, 1 required dose CFZ modification but the remaining 3 were classified as grade 3 only due to the addition of an anti-HTN medications and did not require any CFZ dose modifications. HTN in one these 3 patients was also was in the setting of bone pain and PD. In the 4 patients with serial measurements of brain naturetic peptide (BNP), there were no changes. Similarly, EF was monitored on study for all patients and there were no decreases in EF or symptoms of CHF. Conclusions: Consistent with previous data, including from the Endeavor study, CFZ 56 mg/m2 is efficacious and well tolerated with manageable HTN. Even in this heavily pretreated population refractory to CFZ 27 mg/m2 and dex 40 mg weekly refractory and with high molecular risk features, dose escalation of CFZ to 56 mg/m2 with only dex 16 mg weekly was able to recapture disease response at ORR and PFS that have already surpassed the preplanned futility analysis. By avoiding early dose escalation of those that may be at risk for likely idiosyncratic side effects, both safety and lower cost may be maximized. These findings support enrollment to the ongoing SWOG S1304 randomized study comparing CFZ 27 and 56 mg/m2. Disclosures Chari: Array BioPharma: Consultancy, Research Funding; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium/Takeda: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Onyx: Consultancy, Research Funding. Osman:Millennium / Takeda: Research Funding. Catamero:Onyx: Other: Lecturer; Millennium/Takeda: Other: Lecturer; Celgene: Honoraria, Other: Lecturer. Verina:Celgene: Other: Lecturer. Jagannath:Novartis: Honoraria; Janssen: Honoraria; Merck: Honoraria; Celgene: Honoraria; Bristol Myers Squibb: Honoraria.

CML and Imatinib Mesylate: Response Related to Karyotype.

Blood ◽  
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 &gt; 95% failure (F). Molecular response (MR): normal kariotype (Bcr/Abl negative and RT-PCR&lt;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)

Multicenter, Randomized, Phase III Study Comparing Imatinib (Glivec) Standard Dose (400 mg/d) with Imatinib High Dose Induction (800 mg/d) Followed by Imatinib Maintenance (400 mg/d) in Patients with Pretreated Ph+/BCR-ABL+ CML in Chronic Phase - Results from the First Planned Interim Analysis (CELSG-CML 11 ISTAHIT Study).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1048-1048
Author(s):  
Andreas L. Petzer ◽  
Dominik Wolf ◽  
Dominik Fong ◽  
Thomas Lion ◽  
Irina Dyagil ◽  
...  
Keyword(s):  
Interim Analysis ◽  
Standard Dose ◽  
Statistical Significance ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Phase Iii ◽  
High Dose ◽  
Molecular Response ◽  
Clear Trend ◽  
Phase Iii Trial

Abstract 227 patients with pretreated Ph+/BCR-ABL+ CML were randomized into this 2-arm phase III trial comparing standard dose Imatinib (400 mg/d; arm A) with high dose (HD) Imatinib (800 mg/d for 6 months) for induction followed by Imatinib 400 mg/d for maintenance (400 mg/d; arm B). The interim analysis presented here was performed on all patients after 50% of the patients had been treated for 12 months since randomisation. There were no significant differences between treatment arms regarding sex, age and different pretreatments. Rates of complete hematological responses did not differ significantly between both groups at 3, 6 and 12 months (82% arm A, 90% arm B). However, significantly* more patients achieved a major (MCR) and a complete cytogenetic response (CCR) at 3 months (MCR: 21% arm A, 37% arm B; CCR: 6% arm A, 25% arm B) and 6 months (MCR: 34% arm A, 54% arm B; CCR: 20% arm A, 44% arm B). Moreover, significantly* more patients achieved a major molecular response (MMR) at 6 months in the Imatinib HD arm B compared to arm A (20% vs 7%). At 12 months, following dose reduction of Imatinib to 400 mg/d for maintenance at month 6 in the HD arm B, the rates of MCR (the primary endpoint of the study) were comparable (57% arm A, 59% arm B). Nevertheless, there was still a clear trend to higher rates of CCR (37% arm A, 48% arm B) and MMR (16% arm A, 21% arm B) in the HD arm, but at the time of the interim analysis these values did not reach statistical significance. In contrast to non-hematological toxicities, grade 3/4 hematological toxicities were significantly* more common in the HD arm B [anemia: 2% (A), 12% (B); leukopenia: 23% (A), 41% (B), thrombopenia: 14% (A), 34% (B)]. In conclusion, this is the first randomized phase III trial demonstrating significantly* higher rates of MCR, CCR and MMR in chronic phase CML during therapy with HD Imatinib. *p<0.05

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