Imatinib High Dose (800 mg): Results of a Phase II Trial of the GIMEMA (Gruppo Italiano Malattie Ematologiche Dell’Adulto) CML Working Party in Intermediate Sokal Risk Patients and Status-of-the-Art of an Ongoing Multinational, Prospective Randomized Trial of Imatinib Standard Dose (400 mg Daily) vs High Dose (800 mg Daily) in High Sokal Risk Patients.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4776-4776
Author(s):  
Gianantonio Rosti ◽  
Fausto Castagnetti ◽  
Marilina Amabile ◽  
Nicoletta Testoni ◽  
Angela Poerio ◽  
...  
Keyword(s):  
Phase Ii ◽  
Standard Dose ◽  
Chronic Phase ◽  
Working Party ◽  
Great Majority ◽  
Observation Time ◽  
Phase Iii ◽  
High Dose ◽  
Molecular Response ◽  
Risk Patients

Abstract Imatinib has become the treatment of choice for CML. The standard dose (SD) for CP CML is 400 mg daily: results are less favourable in pts at high or intermediate Sokal risk vs low Sokal risk ones. In intermediate Sokal risk, the IRIS trial (Hughes et al NEJM 349:15, 2003 ) reported at 12 mos a complete cytogenetic response (CCgR- 0% Ph-pos) rate of 67% and a major molecular response (MMolR) rate of 45%. Pre-clinical and clinical data suggest that high doses (HD - 800 mg daily) of ima may be more effective. The GIMEMA CML Working party is conducting a phase II, multi-istitutional prospective study (serial n. CML/021) to investigate the effects of imatinib HD in intermediate Sokal risk. Between Jan, 2004 and May, 2005, 25 centers enrolled 82 pts (80 eval); median age 56 yrs (26–79). Pts evaluable at 3,6 and 12 mos are 80, 77 and 65, respectively. The median observation time is 12 mos. At 3 and 6 mos, 83% and 97% of the pts reached a stable CHR. At 6 mos, 86% obtained a CCgR and 53% of CCgR pts a MMolR (Bcr-Abl/Abl × 100 ratio < 0.1%). At 12 mos, the CCgR rate was 90% and the MMolR rate was 57%. One patient progressed to accelerated/blastic phase. The compliance to HD treatment was good: at 3, 6 and 12 mos 55%, 52% and 52% of the pts received a median daily dose of imatinib > 600 mg. Non hematopoietic AEs accounted for the great majority of dose reductions. The results of this trial further indicate that imatinib HD induces higher and more rapid responses in intermediate Sokal risk CML pts in early chronic phase, being superior to the results obtained with SD (IRIS) and in the range of the MD Anderson results (Kantarjian et al Blood 2004 103:2873). A second project is reserved to high Sokal risk CML pts in early CP: a multinational group, within EuropeanLeukemianet CML WP, is conducting a phase III trial (1:1) of imatinib 400 mg vs 800 mg. By July 31, 2005, 141 patients have been enrolled: GIMEMA (88 pts), Nordic CML Study Group (Sweden, Denmark, Norway and Finland) (25 pts), Turkey (25 pts) and Israel (3 pt).

Imatinib 800 mg: Preliminary Results of a Phase II Trial of the GIMEMA CML Working Party in Intermediate Sokal Risk Patients and Status-of-the-Art of an Ongoing Multinational, Prospective Randomized Trial of Imatinib Standard Dose (400 mg Daily) vs High Dose (800 mg Daily) in High Sokal Risk Patients.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1098-1098
Author(s):  
Gianantonio Rosti ◽  
Giovanni Martinelli ◽  
Fausto Castagnetti ◽  
Nicoletta Testoni ◽  
Giorgina Specchia ◽  
...  
Keyword(s):  
High Risk ◽  
Randomized Trial ◽  
Phase Ii ◽  
Response Rate ◽  
Phase Ii Trial ◽  
Standard Dose ◽  
Phase Iii ◽  
High Dose ◽  
Molecular Response ◽  
Risk Patients

Abstract The conventional treatment of chronic myeloid leukemia (CML) in early chronic phase (ECP) is imatinib 400 mg daily. The estimated rates of major (MCgR) and complete cytogenetic response (CCgR) at 42 months are 91% and 84%, respectively (IRIS Trial - F Guilhot, ASH 2004), with a survival free from accelerated and blastic phase of 84%. The rates of CCgR are significantly different according to Sokal score, being 91%, 84% and 69% for low, intermediate and high risk categories. Phase I and II trials of imatinib have clearly shown a dose-response effect; more importantly, a single center phase II trial of imatinib 800 mg in ECP showed significantly better results vs standard dose, in terms of CCgR (90% vs 74%) and of complete molecular response (28% vs 7% at 18 months) [H. Kantarjian et al, Blood 103 (8), 2004]. The GIMEMA (Gruppo Italiano Malattie Ematologiche dell’Adulto) CML WP is conducting a phase II trial of imatinib 800 mg in intermediate Sokal risk in ECP (trial CML/021). Overall, 89 pts (mean age 53 yrs) have been enrolled. Fourty-four patients completed 6 months of treatment: the complete hematological response rate is 100%; the MCgR and CCgR are 90% and 81%, respectively. The 6 months CCgR rate of this trial parallels the IRIS trial one in intermediate risk cases (84%), with a much shorter treatment period. The major molecular response rate at 6 months (RTQ-PCR as ratio BCR-ABL/ABL) is 56% (cut-off ≤ 0.12%) or 41% (cut-off ≤0.05%). The compliance to the treatment improved time by time, being 47% the patients receiving ≥ 80% of the scheduled dose between months 1–3 and 60% between months 4 - 6. A second project, exploring imatinib high dose, is reserved to high risk cases: a multinational working group, within the frame of Leukemianet CML WP, is conducting a phase III randomized trial (1:1) of imatinib 400 mg vs 800 mg in high Sokal risk in ECP. By July 31, 2005, 80 patients have been enrolled: GIMEMA CML WP (44 pts), Nordic Countries - Sweden, Denmark, Norway and Finland (25 pts), Turkey (10 pts) and Israel (1 pt).

Impact of Age in the Outcome of Patients with Chronic Myeloid Leukemia in Late Chronic Phase: Clinical and Molecular Results of a Phase II Study of the GIMEMA CML Working Party.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4805-4805
Author(s):  
Giovanni Martinelli ◽  
Francesca Palandri ◽  
Ilaria Iacobucci ◽  
Simona Bassi ◽  
Fausto Castagnetti ◽  
...  
Keyword(s):  
Phase Ii ◽  
Older Patients ◽  
Age Groups ◽  
Chronic Phase ◽  
Working Party ◽  
Progression Free Survival ◽  
Observation Time ◽  
Molecular Response ◽  
Term Outcome ◽  
Long Term Outcome

Abstract To assess the effect of age on response and compliance we performed a sub-analysis within a phase II trial of the GIMEMA CMLWorking Party (CML/002/STI571). Since the WHO cut-off age to define an older patient is 65 years, we identified: 226/284 (80%) younger patients (below 65 years) and 58/284 (20%) older patients (above 65 years) before starting imatinib. Responses (hematologic and cytogenetic) were lower in older age group but progression free survival and overall survival probabilities (median observation time 3 years) were the same. Moreover, among complete cytogenetic responders, no differences were found in the level of molecular response between the 2 age groups. As probably expected, older patients experienced more adverse events (AEs), both hematologic and non-hematologic: this worsen compliance, however, did not prevent a long term outcome similar to younger ones. CML

scholarly journals Results of high-dose imatinib mesylate in intermediate Sokal risk chronic myeloid leukemia patients in early chronic phase: a phase 2 trial of the GIMEMA CML Working Party

Blood ◽  
2009 ◽  
Vol 113 (15) ◽  
pp. 3428-3434 ◽  
Author(s):  
Fausto Castagnetti ◽  
Francesca Palandri ◽  
Marilina Amabile ◽  
Nicoletta Testoni ◽  
Simona Luatti ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Imatinib Mesylate ◽  
Myeloid Leukemia ◽  
Standard Dose ◽  
Prospective Trial ◽  
Chronic Phase ◽  
Working Party ◽  
Response Rates ◽  
High Dose ◽  
Molecular Response

AbstractImatinib mesylate has become the treatment of choice for chronic myeloid leukemia (CML): the standard dose for chronic- phase (CP) CML is 400 mg daily. Response rates are different according to Sokal score, being significantly lower in intermediate and high Sokal risk patients. Phase 1 and 2 trials have shown a dose-response effect and high-dose imatinib trials in early CP CML showed better results compared with standard dose. Our study is the first prospective trial planned to evaluate the efficacy and tolerability of high-dose imatinib in previously untreated intermediate Sokal risk CML patients. Seventy-eight patients were treated with 400 mg imatinib twice daily: complete cytogenetic response (CCgR) rates at 12 and 24 months were 88% and 91%; moreover, at 12 and 24 months 56% and 73% of CCgR patients achieved a major molecular response. The incidence of adverse events was slightly higher than reported by the most important standard-dose trials. With a median follow-up of 24 months, 3 patients progressed to advanced phase. In intermediate Sokal risk newly diagnosed CML patients, high-dose imatinib induced rapid and high response rates, apparently faster than those documented in the International Randomized Study of IFN and Imatinib for the same risk category. These clinical trials are registered at www.clinicaltrials.gov as no. NCT00510926.

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

scholarly journals A phase II study of high-dose cisplatin and VP-16 in neuroblastoma: a report from the Société Française d'Oncologie Pédiatrique.

1987 ◽  
Vol 5 (6) ◽  
pp. 941-950 ◽  
Author(s):  
T Philip ◽  
R Ghalie ◽  
R Pinkerton ◽  
J M Zucker ◽  
J L Bernard ◽  
...  
Keyword(s):  
Hearing Loss ◽  
Phase Ii ◽  
Phase Ii Study ◽  
Bone Marrow Involvement ◽  
Stage Iv ◽  
Observation Time ◽  
Phase Iii ◽  
High Dose ◽  
Initial Stage ◽  
Duration Of Response

Forty-seven children or adolescents with initial stage IV (42 patients) or stage III (five) advanced neuroblastoma (12 were progressing after relapse and 35 had never reached complete remission [CR] after conventional therapy) were included in a phase II study of the combination of high-dose VP-16 (100 mg/m2/d X 5) and high-dose cisplatin (CDDP) (40 mg/m2/d X 5). Twenty patients had received prior CDDP therapy (total dose, 100 to 640 mg/m2; median, 320 mg/m2) and 38 of 47 had bone marrow involvement when included in the study. The overall response rate was 55%, with 22% CR. Duration of response was 5 to 18 months, with a median of 10 months. Eight patients are still disease free, with a median observation time of 13 months, but all had received additional therapy after two courses of this regimen. Gastrointestinal toxicity was frequent but tolerable. Myelosuppression was severe but of brief duration, ie, nadir of neutrophils was observed at day 15 with 95% of the patients recovering a normal count before day 28, and nadir of platelet count was at day 17 with only two severe and reversible episodes of bleeding. The overall incidence of sepsis was 8% (seven of 92 courses), with no death related to infection. No acute renal failure was observed after two courses, and only three of 47 children experienced a clear reduction of renal function. After two courses, only two children showed a hearing loss in the 1,000 to 2,000 Hz range, although hearing loss above the 2,000 Hz level was frequently encountered. It is concluded that high-dose VP-16 and CDDP is an effective regimen in advanced neuroblastoma with acceptable toxicity. Phase III studies are needed in previously untreated patients. J Clin Oncol 5:941-950.

scholarly journals Double-Blind, Randomized, Placebo-Controlled Phase II Dose-Finding Study To Evaluate High-Dose Rifampin for Tuberculous Meningitis

2018 ◽  
Vol 62 (12) ◽  
Author(s):  
S. Dian ◽  
V. Yunivita ◽  
A. R. Ganiem ◽  
T. Pramaesya ◽  
L. Chaidir ◽  
...  
Keyword(s):  
Adverse Events ◽  
Phase Ii ◽  
Tuberculous Meningitis ◽  
Standard Dose ◽  
Geometric Mean ◽  
Phase Iii ◽  
High Dose ◽  
Treatment Area ◽  
Double Blind ◽  
Time Curve

ABSTRACT High doses of rifampin may help patients with tuberculous meningitis (TBM) to survive. Pharmacokinetic pharmacodynamic evaluations suggested that rifampin doses higher than 13 mg/kg given intravenously or 20 mg/kg given orally (as previously studied) are warranted to maximize treatment response. In a double-blind, randomized, placebo-controlled phase II trial, we assigned 60 adult TBM patients in Bandung, Indonesia, to standard 450 mg, 900 mg, or 1,350 mg (10, 20, and 30 mg/kg) oral rifampin combined with other TB drugs for 30 days. The endpoints included pharmacokinetic measures, adverse events, and survival. A double and triple dose of oral rifampin led to 3- and 5-fold higher geometric mean total exposures in plasma in the critical early days (2 ± 1) of treatment (area under the concentration-time curve from 0 to 24 h [AUC0–24], 53.5 mg · h/liter versus 170.6 mg · h/liter and 293.5 mg · h/liter, respectively; P < 0.001), with proportional increases in cerebrospinal fluid (CSF) concentrations and without an increase in the incidence of grade 3 or 4 adverse events. The 6-month mortality was 7/20 (35%), 9/20 (45%), and 3/20 (15%) in the 10-, 20-, and 30-mg/kg groups, respectively (P = 0.12). A tripling of the standard dose caused a large increase in rifampin exposure in plasma and CSF and was safe. The survival benefit with this dose should now be evaluated in a larger phase III clinical trial. (This study has been registered at ClinicalTrials.gov under identifier NCT02169882.)

A Cost-Utility Analysis of Nilotinib for CML Patients Who Have Become Resistant to Imatinib.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5175-5175
Author(s):  
H. Pilgrim ◽  
K. Jewitt ◽  
S. Ward
Keyword(s):  
Standard Dose ◽  
Chronic Phase ◽  
Cost Utility ◽  
Phase Iii ◽  
High Dose ◽  
Lifetime Horizon ◽  
Imatinib Resistant ◽  
Cost Effective Treatment ◽  
The Uk ◽  
The Cost

Abstract Background: New generation BCR-ABL tyrosine kinase inhibitors are promising treatments for CML patients who are imatinib resistant or intolerant. The objective of this study was to consider the cost-utility of nilotinib in comparison to ‘high dose’ (800 mg) imatinib (the current standard comparator in the UK) for chronic-phase CML patients resistant to standard dose 400 mg imatinib using a lifetime horizon. The analysis is based on a UK NHS perspective. Methods: A Markov model was developed using interim data from the phase II CAMN107A2101 registration study of nilotinib and data from the 39 patients who were dose-escalated, due to a sub-optimal response, to 800 mg imatinib within the IRIS phase III trial of imatinib versus interferon. Based on this evidence, the estimated 18-month survival has been extrapolated over a lifetime using parametric Weibull regression. Since the price of nilotinib in the UK was still to be determined at the time of preparation, the cost was assumed to be £106.94 per day, price parity with high dose imatinib. The costs and utilities associated with adverse events have been incorporated during the first six months following treatment. All costs and utilities were discounted at 3.5%. Results: Nilotinib is estimated to cost an additional £49K and generate an additional 2.18 Quality-Adjusted Life Year’s (QALYs) in comparison to high dose imatinib over a patient’s lifetime. Therefore, the incremental cost-utility of nilotinib versus high dose imatinib is expected to be approximately £22K per QALY gained. This result is subject to uncertainty around data extrapolation. However availability of longer term data from the ongoing nilotinib trial will allow validation at a later date. Conclusions: Our analysis suggests that nilotinib provides a clinically and cost-effective treatment (according to conventionally acceptable thresholds) for CML patients who have become imatinib resistant, in an indication where limited alternative treatment options exist.

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.

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.

High-dose imatinib mesylate treatment in patients (Pts) with untreated early chronic phase (CP) chronic myeloid leukemia (CML): 2.5-year follow-up

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6535-6535 ◽  
Author(s):  
E. Aoki ◽  
H. Kantarjian ◽  
S. O’Brien ◽  
M. Talpaz ◽  
F. Giles ◽  
...  
Keyword(s):  
Standard Dose ◽  
Chronic Phase ◽  
High Dose ◽  
Hematologic Toxicity ◽  
Molecular Response ◽  
Molecular Responses ◽  
Pre Treatment ◽  
Grade 3

6535 Background: The standard dose (SD) of imatinib for CP CML is currently 400 mg daily, but higher doses (HD) may be more effective. We conducted 2 consecutive trials using HD imatinib (i.e., 400mg twice daily) in previously untreated early CP CML pts. This is an updated analysis of the longer follow-up. Methods: A total of 175 previously untreated pts received HD imatinib. We compared the results with a previous study using SD imatinib (400mg/day) in untreated pts with early CP CML (N=50). Results: Cytogenetic and molecular responses were evaluable in 222 pts (N=49 at SD, 173 at HD) and 217 pts (N=46 at SD, 171 at HD), respectively. In HD group, Sokal risk classification was good in 69%, intermediate in 29%, and poor in 11% of pts. There were no differences in pre-treatment characteristics between two groups. The median age was 48 years in both groups. Median follow-up is 53 months for SD and 30 months for HD group. Patients treated with HD had a higher rate of complete cytogenetic responses (90% vs 78% with SD, p=0.03) and these occurred earlier, with 69% achieving this response after 6 months of therapy vs 45% with SD (p=0.001). The cumulative incidence of major molecular response was significantly better in HD group (p=0.03), and this response was also observed earlier in HD group: at 12 months 54% in HD and 24% in SD group had achieved this response (p=0.001). At 24 months, 19/70 (27%) evaluable pts with HD versus 3/31 (10%) of pts in SD group achieved complete molecular remission. Four pts (2%) in HD group and 4 pts (8%) in SD group have progressed to advanced phases (p=0.05). There was a trend in favor of the HD group for transformation-free-survival but it was not statistically significant (p=0.07). Overall survival is excellent in both groups (24 month survival, 99% with HD vs 98% with SD; p=0.24). Grade 3 or 4 hematologic toxicity was more frequent in HD group whereas extramedullary toxicity was similar in two groups. The median actual dose in HD group was 800 mg at 12 months, with 39% patients requiring dose reduction at some point. Conclusions: High-dose imatinib provides higher rates of complete cytogenetic responses and earlier molecular responses with some increase myelosupression. The long-term benefit of earlier responses remains to be demonstrated. [Table: see text]

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