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

CELSG CML 11 “ISTAHIT” Phase III Study – Planned Interim Analysis: High Doses of Imatinib Mesylate (800mg/day) Significantly Improve Rates of Major and Complete Cytogenetic Remissions (MCR, CCR) in Pretreated Ph+/BCR-ABL+ CML Patients in Chronic Phase.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1112-1112 ◽  
Author(s):  
Andreas L. Petzer ◽  
Dominik Wolf ◽  
Dominic Fong ◽  
Thomas Lion ◽  
Irina Dyagil ◽  
...  
Keyword(s):  
Dose Reduction ◽  
Interim Analysis ◽  
Standard Dose ◽  
Statistical Significance ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Phase Iii ◽  
High Dose ◽  
Clear Trend ◽  
Phase Iii Study

Abstract We have recently reported results from the first planned interim analysis of a multicenter, randomised, 2-arm - phase III study comparing imatinib standard dose (400 mg/day; arm A) with imatinib high dose (HD) induction (800 mg/day; HD arm B) followed by imatinib standard dose maintenance (400 mg/day) in pretreated Ph+/BCRABL+ CML patients in chronic phase (CP; Blood,110,1048a). The first planned interim analysis was performed after 50% of the patients had been treated for 12 months (mo) since randomisation. A total of 227 patients were randomized. Pretreatments included hydroxyurea (96%), interferon (72%), busulfan (17%) and “others” (26%; mainly AraC +/− combinations). Although rates of complete haematological responses did not differ significantly between the 2 arms at 3, 6 and 12 mo, significantly more patients achieved a major (MCR) and a complete cytogenetic response (CCR) at 3 mo (MCR: 21% arm A, 37% arm B, p=0.01; CCR: 6% arm A, 25% arm B, p&lt;0.001) and 6 mo (MCR: 34% arm A, 54% arm B, p=0.009; CCR: 20% arm A, 44% arm B, p&lt;0.001). At 12 mo, following dose reduction of imatinib to 400 mg/d for “maintenance” at mo 6 in the HD arm B, the rates of MCR (the primary endpoint of the study) were comparabel (59% arm A, 57% arm B). Nevertheless, there was still a clear trend to higher rates of CCR (37% arm A, 48% arm B) in the HD arm B, 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% arm A, 14% arm B; leukopenia: 24% arm A, 46% arm B; thrombocytopenia: 15% arm A, 39% arm B; p≤0.02). Updated results reveal, that the cumulative median doses of imatinib were 400 mg (arm A) and 767 mg (arm B), respectively. The median days of dose interruptions during the first 6 mo were not significantly different (12.5 days arm A, 13 days arm B; p=0.78). Nevertheless, significantly more patients (65.1%) remained on the initial 400mg dose of imatinib in arm A as compared to the initial 800mg dose in the HD arm B (45.6%; p=0.009). 35% of the patients that had to be dose reduced in arm B were reduced to 600mg/day, 63% to 400mg and 2% to 300mg. The cumulative rates of MCR in patients with no dose reduction/interruption were higher in the HD arm B (71%) compared to arm A (59%, p=0.232). Moreover, the cumulative rates of CCR were significantly better for patients with no dose reduction/interruption in the HD arm B (61%) compared to the patients with no dose reduction/interruption in arm A (36%, p=0.014). In addition, in the HD arm B the cumulative rates of CCR were significantly better for patients with no dose reduction/interruption (61%) compared to patients in the HD arm B with an interruption and/or dose reduction (34.9%; p=0.017). Conclusions: These updated phase III data not only support the concept of more rapid and higher rates of cytogenetic remissions (MCR, CCR) when higher doses of imatinib are applied, they also suggested that patients that are capable to tolerate continous high dose imatinib may have a better outcome.

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 &lt; 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 &gt; 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).

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.

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.

Preliminary Results From a Phase III Trial of Imatinib Versus Imatinib in Combination with Cytarabine in Patients with First Chronic Phase Myeloid Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 2758-2758 ◽  
Author(s):  
Noortje Thielen ◽  
Bronno van der Holt ◽  
Jan J Cornelissen ◽  
Rianne Ammerlaan ◽  
Pieter Sonneveld ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Phase Iii ◽  
High Dose ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Phase Iii Trial ◽  
Free Survival ◽  
Dasatinib Treatment

Abstract Abstract 2758 Background Imatinib (IM) is considered the first line therapy for newly diagnosed chronic myeloid leukemia (CML). Despite the increased overall survival and event free survival attained with IM, patients with unsatisfactory responses due to IM resistance still pose a considerable challenge. Addition of cytarabine to IM has shown synergistic anti-proliferative effects in in-vitro studies as well as in clinical trials. We conducted a prospective, multicenter, phase III trial (HOVON 78) comparing high dose IM or high dose IM combined with 2 successive cycles of standard-dose cytarabine in newly diagnosed CML patients. At the time our study was set out, high dose IM (600 or 800 mg) showed significantly higher molecular response rates than 400 mg in a HOVON dose escalation study (HOVON 51) of the combination of IM and cytarabine. Patients and methods This study started in June 2006, but was closed prematurely in April 2010 because of declining inclusion most probably due to excellent evolving results of IM monotherapy and the introduction of second generation tyrosine kinase inhibitors. Newly diagnosed CML patients between the age of 18 and 65 years in first chronic phase ≤ 2 months were randomized between IM monotherapy 800 mg daily (arm A) or IM 800 mg combined with 2 successive cycles of daily cytarabine 200 mg/m2 in 1–2 hours infusion for 7 days (arm B), followed by IM monotherapy. The first cycle of cytarabine was given as soon as possible, preferably within 14–28 days from the start of IM, whereas the second cycle was started after hematopoietic recovery (i.e. platelets > 100×109/l and WBC > 2.0×109/l). Response to treatment was assessed by hematological, cytogenetic and molecular analyses at regular intervals and was scored according to the ELN criteria. Reasons for going off protocol treatment were progression, excessive toxicity or intolerance of treatment, intercurrent death, no compliance of the patient or major protocol violation. The primary endpoint was the achievement of a major molecular response (MMR) at 12 months, and was compared between the 2 treatment arms using logistic regression. Secondary endpoints were progression free survival, overall survival and toxicity. The analyses were done according to the intention to treat principle, and were based on data available as of August 8, 2011. In order to detect with 80% power an improvement in 12-months' MMR from 60% to 75% (2-sided significance level alpha=0.05), 330 patients were required. Results One hundred and ten eligible patients from 19 Dutch and 2 Belgian centers were enrolled, 55 in each arm. One patient in arm B withdrew consent. The median age of the patients was 45 years (range, 17–65). Sokal risk scores were equally divided between the two groups, but arm A contained more patients with high Euro risk score (24 vs 7%, p = 0.03). Median follow up is 31 months (range, 0–57). So far, 34 patients went off protocol treatment; 16 in arm A and 18 in arm B. Reasons for going off protocol were progression to accelerated phase, blast crisis or progression from major molecular response (3 and 1 patients in arm A and arm B, respectively), excessive toxicity (7 vs 11), and other (6 vs 6). Nine patients in arm B only received one cycle of cytarabine. Cytarabine dose was reduced in one patient only in the first cycle. Although the molecular response data of 4 patients are not yet available, the proportion of patients who achieved a MMR at 12 months was similar between the two treatment arms; 51% in arm A and 47% in arm B (OR = 0.82, 95% CI 0.38–1.76, p = 0.60; adjusted for Sokal score), PFS at 48 months was 91% in both treatment arms (p = 0.80). OS at 48 months was 100% in arm A and 92% in arm B. Three patients died. One patient in arm A died of conduction abnormality, 49 months after start of therapy. This patient had switched to dasatinib treatment because of IM resistance. Two patients in arm B died, both having progressed to blast crisis. One died at 39 months due to aspergillus infection after allogenic stem cell transplantation, and one patient on dasatinib treatment died at 9 months due to an intracerebral bleeding. Forty SAEs occurred in 29 patients, 7 (in 6 patients) in arm A and 33 (23 patients) in arm B (p<0.001). The most common toxicities were pain, constitutional symptoms and gastro-intestinal complaints. Conclusion IM in combination with cytarabine is not superior compared to IM alone in achieving MMR at 12 months. Patients receiving combination therapy had significantly more toxicity. Disclosures: Janssen: Novartis: Consultancy. Ossenkoppele:Novartis: Consultancy.

scholarly journals Efficacy of Nilotinib Vs High-Dose Imatinib Vs Sustaining Standard-Dose Imatinib in Early Chronic Phase CML Patients Who Have Suboptimal Molecular Response to Frontline Imatinib

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 1816-1816 ◽  
Author(s):  
Soo Young Choi ◽  
Sung-Eun Lee ◽  
Yun jeong Oh ◽  
Soo-Hyun Kim ◽  
Richard C. Woodman ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Standard Dose ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
High Dose ◽  
Molecular Response ◽  
Group 3 ◽  
Group 2 ◽  
Group 1

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 nilotinib (NIL) versus high-dose IM versus sustaining standard-dose IM for CCyR patients with suboptimal molecular response to frontline IM 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 divided into 3 treatment groups; NIL 400mg BID (800 mg/day; group 1) vs IM 400 mg BID (800 mg/day; group 2) vs IM 400mg QD (400mg/day; group 3). Group 1 and 2 patients were selected in RE-NICE multicenter study and group 3 patients were selected with the same inclusion criteria of RE-NICE. The efficacy endpoints are MMR rate by 12 months and MMR rate and undetectable molecular residual disease (UMRD) rates by 36 months. Safety profiles of each group were compared. 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 intolerance to treatment were allowed to switch to other treatment. Results. With a data cut-off date of 17 Jul 2014, a total of 83 patients were evaluated; 29 patients in NIL group (group 1), 29 patients in high-dose IM group (group 2) and 25 patients in standard-dose IM group (group 3). With a median follow-up of 36 months (range, 1-63), all patients in group 1 remained in nilotinib treatment, 17 patients in group 2 switched to NIL 400mg BID due to intolerance (n=4) and lack of response (no MMR; n=13). In group 3, with a median follow-up of 71 months (range, 6-132), 15 patients switched to other treatment due to intolerance (n=5) and lack of response (no MMR; n=10). Up to now, all patients in three groups have maintained CCyR without progression or resistance. 10 in 29 (35%), 8 in 29 (28%) and 5 in 25 (20%) patients achieved MMR by 12 months, and 20 in 29 (69%), 15 in 29 (51%) and 11 in 25 (44%) patients achieved MMR by 36 months in group 1, group 2 and group 3 respectively. Overall, 3 patients in group 1 (3/29, 10%) achieved confirmed UMRD. Overall 3 years probability of MMR was significantly higher in group 1 than the other two groups (67.8% vs 41.0% vs 40.4%, group 1, 2, 3 respectively, group 1 vs 2, P=0.089, group 1 vs 3, P=0.035, group 2 vs 3, P=0.614). Compare to other groups, the patients in group 2 showed higher toxicities, such as leukopenia, anemia, thrombocytopenia, edema, fatigue, dyspnea and hypophosphatemia. Conclusions. Nilotinib 400mg twice daily treatment showed better efficacy than high-dose or same standard-dose imatinib for the treatment of patients who have suboptimal molecular response to initial standard-dose imatinib. Additionally, a switch to nilotinib in suboptimal molecular responder to imatinib would also be preferable option in terms of tolerability. Updated data with longer follow-up duration will be presented in the meeting. Disclosures No relevant conflicts of interest to declare.

scholarly journals Efficacy of nilotinib in a young patient with high Sokal risk CML Ph+ in treatment failure after high dose imatinib

2015 ◽  
Vol 5 (5S) ◽  
pp. 7-14
Author(s):  
Sabina Russo ◽  
Giuseppa Penna ◽  
Arianna D’Angelo ◽  
Alessandro Allegra ◽  
Andrea Alonci ◽  
...  
Keyword(s):  
Treatment Failure ◽  
Standard Dose ◽  
Cytogenetic Response ◽  
High Dose ◽  
Molecular Response ◽  
Optimal Response ◽  
Mutational Screening ◽  
Therapeutic Choice ◽  
Lower Limits ◽  
Recent Evaluation

This article describes the case of a 44 year old man, at high-risk according to the Sokal Index, after CML Ph+ diagnosis, started imatinib at the standard dose (400 mg/day). Initially he reached optimal response, but at month 12, because of a loss of cytogenetic response, he was documented as a treatment failure. The mutational screening revealed no mutations and the blood level testing (BLT) showed values of ​​lower limits, therefore he increased imatinib to 800 mg/day. This therapeutic choice did not result in the achievement of an optimal response and the imatinib compliance was deteriorated. So, after nearly 12 months of treatment with high dose imatinib, we considered the treatment as a failure, and he switched to nilotinib, at the dose of 800 mg/day. After only 3 months of treatment, he reached complete cytogenetic response (CCyR) and major molecular response (MMolR), which the patient continues to maintain, as documented by the recent evaluation at month 30.

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