Sustained Durability of Responses Plus High Rates of Cytogenetic Responses Result in Long-Term Benefit for Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia (CML-CP) Treated with Imatinib (IM) Therapy: Update from the IRIS Study.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 21-21 ◽  
Author(s):  
Francois Guilhot
Keyword(s):  
Blast Crisis ◽  
Chronic Phase ◽  
Transcript Level ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Major Molecular Response ◽  
First Line

IM has proven to be superior to IFN+Ara-C for newly diagnosed pts with CML-CP (O’Brien et al, NEJM, 2003). At 30-months of follow-up, 79% of pts randomized to IM remain on IM with 83% of them now treated for > 24 months. Therefore, this analysis is focused on first-line IM pts (n=553). Evaluation included complete hematologic response (CHR), major/complete cytogenetic response (MCyR/CCyR), major molecular response (≥3 log reduction in BCR-ABL/BCR vs. pooled diagnostic samples) time to progression (TTP) - defined as loss of CHR/MCyR or evolution to accelerated phase/blast crisis [AP/BC] or death, time to AP/BC, and overall survival. Median follow-up for first-line IM pts is 31.1. Summary of results are the following: 1st-line imatinib * 95% CI Best observed CHR/MCyR/CCyR (%) 95/87/79 Estimated major molecular response at 12 mos. (%) 40 Estimated cumulative MCyR % at 30 mos. 90 Estimated cumulative CCyR % at 30 mos. 82 Estimated % free of progression at 30 mos. 88 (85–91)* Estimated % free of AP/BC at 30 mos. 95 (93–97)* Estimated % survival at 30 mos. 95 (93–97)* The additional follow-up confirmed durable responses with first-line therapy while also demonstrating the effect of cytogenetic response on long-term outcomes. The estimated rate of confirmed responders remaining in response after achieving a CCyR at 30 months is >92%. Similarly, the estimated rate of patients still in response at 30 months after achieving either a MCyR or CHR is also >92% for both groups. Only 2% of pts with a confirmed loss of MCyR and 1% of the pts with a confirmed loss of CCyR subsequently progressed to AP/BC. Of these pts, 3 of 5 benefited from a dose increase to 600 or 800 mg of IM, while only 1 of 7 pts with a confirmed loss subsequently achieved a MCyR without a dose escalation. A total of 75 pts received a marrow transplant (BMT) after discontinuation from the study; 30 in the IM arm (2 after crossover from IFN) and 45 pts who were randomized to IFN (21 after crossover to IM). There was no difference in survival after BMT between pts who received first-line IM treatment (8 deaths, 1 after crossover) and pts who had received IFN+Ara–C (7 deaths) or IFN+Ara–C followed by IM (7 deaths) (p=0.78). The estimated survival at 12 months after BMT is 70%, 75%, and 68% respectively in the three groups. A landmark analysis showed that for 407 pts who achieved MCyR within 6 months, their estimated rate free of AP/BC at 30 months is 97% vs. 89% for the 124 pts who did not achieve this level of response at 6 months (p<0.001). Additionally, the estimated survival at 30 months for the same pts is 97% vs. 92% (p=0.0162). The achievement of a major molecular response at 12 months was also associated with improved progression-free survival. For patients who had achieved CCyR and a reduction in BCR-ABL transcript level ≥ 3 log at 12 months, the probability of remaining progression free was 100% at 30 months compared to 93% for such patients with reduction in BCR-ABL transcript level < 3 log and 82% for patients who were not in CCyR at 12 months (p<0.0001). These results will be further updated using a data cut-off of 31-July-04 to reflect additional 12-months of data (i.e., 42-month follow-up).

Long Term Follow up of Patients with CML in Chronic Phase Treated with First-Line Imatinib Suggests That Earlier Achievement of a Major Molecular Response Leads to Greater Stability of Response.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 2113-2113 ◽  
Author(s):  
Susan Branford ◽  
Rebecca Lawrence ◽  
Andrew Grigg ◽  
John Francis Seymour ◽  
Anthony Schwarer ◽  
...  
Keyword(s):  
Chronic Phase ◽  
Low Risk ◽  
Initial Slope ◽  
Molecular Response ◽  
Average Dose ◽  
Major Molecular Response ◽  
First Line ◽  
Significant Difference

Abstract A major molecular response (MMR) by 12 or 18 months (m) of standard dose imatinib for patients (pts) with newly diagnosed chronic phase CML is associated with a low risk of progression to accelerated phase or blast crisis. Phase II/III trials suggest that MMR may be achieved earlier with higher doses of imatinib. We determined whether the timing of MMR affects the long term stability of response with regard to the acquisition of BCR-ABL mutations and/or loss of MMR (collectively defined as an “event”) for pts with up to 8 years of follow up since commencing first-line imatinib. All pts treated with 400 to 600mg of first-line imatinib who were monitored regularly at our institution for BCR-ABL levels by real-time quantitative PCR and mutation analysis by direct sequencing were evaluated: 181 pts were followed for a median of 45m (range (r) 3–96m). The event rate was compared for pts dependent on the time to MMR (≤0.1% IS (international scale)) in 6m intervals to 18m of imatinib. The events for pts with undetectable BCR-ABL (complete molecular response, CMR) were also determined. Strict sensitivity criteria were used for CMR: undetectable BCR-ABL where the sensitivity of analysis indicated BCR-ABL was &lt;0.003% IS, (equivalent to at least 4.5 log below the standardized baseline) which was confirmed on a subsequent analysis. Loss of MMR was defined as a confirmed &gt;2 fold rise from nadir to a level &gt;0.1% IS in pts who maintained imatinib dose. 144/181 pts (80%) achieved MMR at a median of 12m (r 3–53m). Consistent with other studies, maintaining a higher dose of imatinib in the first 6m of therapy was associated with a significantly higher frequency of pts achieving MMR by 6m. 118 pts received an average dose of &lt;600mg in the first 6m and 18/118 (15%) achieved MMR by 6m, whereas 63 pts received an average dose of 600mg in the first 6m and 23/63 (37%) achieved MMR by 6m, P=0.002. Mutations were detected in 14/181 pts (8%) at a median of 9m (r 3–42m). An event occurred in 8 pts with MMR at a median of 36m (r12–57m) after commencing imatinib, including one patient who had achieved CMR. Mutations were found in 4 pts and 3/4 lost MMR. The remaining 4 lost MMR without a mutation. The one patient with a mutation who did not lose MMR had a 3-fold rise in BCR-ABL at the time of mutation detection and responded to a higher imatinib dose. The other pts with mutations had therapeutic intervention upon cytogenetic relapse (2) or loss of MMR (1). The 4 pts with loss of MMR and no mutation had accelerated phase (1), cytogenetic relapse (2) and one maintained CCR with 3m of follow up. The median fold rise in BCR-ABL upon loss of MMR was 26 (r 4–220). The probability of an event if MMR was achieved by a) 6m was 0% (n=41 evaluable pts), b) &gt;6 to 12m was 12% (n=40) and c) 12 to 18m was 19% (n=33). The median follow up since MMR was achieved was not significantly different for the groups: 49m (r 3–87m), 38m (r 6–87m), 40m (r 9–78m), respectively, P=0.5. The risk of an event for pts with MMR achieved by 6m was significantly lower than in pts with MMR achieved by &gt;6 to 18m, P=0.04. CMR occurred in 55 pts who were followed for a median of 24m (r 3–55m) after its attainment. Only 1 event occurred in these 55 pts, which was at 6m after CMR was achieved and 57m after commencing imatinib. This patient had maintained MMR for 45m but loss of a major cytogenetic response occurred 6m after loss of MMR. There was a significant difference in the probability of CMR by 60m of imatinib dependent on the time to MMR, P&lt;0.0001 (Figure). All pts failed to achieve CMR by 60m if not in MMR at 18m whereas the actuarial rate of CMR at 60m was 93% in those with MMR by 6m. The initial slope of BCR-ABL decline correlated strongly with the decline over the longer term. The mean time to CMR after attainment of MMR was significantly faster for pts with MMR by 6m compared to those with MMR at &gt;6 to 12m and &gt;12 to 18m: 24m vs 37m vs 42m, respectively, P=0.001. This suggests the rate of BCR-ABL reduction below the level of MMR was faster in pts with MMR by 6m, which may be clinically beneficial as none of these pts had a subsequent event. Based on these findings we propose that inducing earlier molecular responses with higher dose imatinib or more potent kinase inhibitors may lead to more durable and deeper responses. It remains possible however, that early molecular response reflects a more biologically favourable disease rather than being the direct cause of more durable response. Finally, CMR was associated with an extremely low risk of events, making it an appropriate next target of therapy after MMR is achieved. Figure Figure

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.

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

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 1493-1493
Author(s):  
Kohei Yamaguchi ◽  
Kazunori Murai ◽  
Shigeki Ito ◽  
Tomoaki Akagi ◽  
Kazuei Ogawa ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Efficacy And Safety ◽  
Major Molecular Response ◽  
Once Daily

Abstract Background Dasatinib is a second-generation BCR-ABL inhibitor that has a 325-fold higher potency than imatinib and a 16-fold higher potency than nilotinib in vitro. The previous report from the global DASISION trial showed dasatinib resulted in significantly higher and faster rates of complete cytogenetic response (CCyR) and major molecular response (MMR) compared with imatinib. We conducted a phase II study to evaluate the efficacy and safety of dasatinib in patients with newly diagnosed chronic-phase chronic myeloid leukemia (CML-CP) in Japan. Methods Eighty newly diagnosed CML-CP patients were include in this study. Patients received dasatinib 100mg once daily. Treatment was continued until disease progression or unacceptable toxicity. Primary end point was the rate of major molecular response (MMR) by 12 months. MMR defined as a BCR-ABL transcript level of 0.1% or lower on the International scale by means of a real-time quantitative reverse transcriptase-polymerase chain reaction (RT-PCR) in peripheral blood. Secondary end points were the rate of complete cytogenetic response (CCyR) by 12 months, the rate of MR4.5 (either (i) detectable disease with <0.0032% BCR-ABL1 IS or (ii) undetectable disease in cDNA with >32,000 ABL1 transcripts in the same volume of cDNA used to test for BCR-ABL1) by 12 months and adverse events of dasatinib (UMIN #000006358). Results Eighty newly diagnosed CML-CP patients were included in this study. All except one patient administered dasatinib 100 mg once daily. One patient was withdrawal before administration of dasatinib. So far, there were 71 patients with 6 months follow-up and 51 patients with 12 months follow-up. The estimated MMR rates were 69.5 % (95%CI, 58.7-80.3 %) by 6 months and 82.7% (95%CI, 73.0-92.4 %) by 12 months. The estimated MR4.5 rates were 27.1 % (95%CI, 16.7-37.5 %) by 6 months and 48.9% (95%CI, 36.0-61.7 %) by 12 months. Only 6 patients were withdrawal because of adverse event (5 patients) and ineffectiveness (1 patient). Conclusion Dasatinib treatment results in higher rates of molecular responses in newly diagnosed CML-CP patients in Japan. Dasatinib as the first-line agent might be acceptable for CML-CP patients because of better clinical efficacy and less toxicity. Disclosures: No relevant conflicts of interest to declare.

Long-term benefits of imatinib (IM) for patients newly diagnosed with chronic myelogenous leukemia in chronic phase (CML-CP): The 5-year update from the IRIS study

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6506-6506 ◽  
Author(s):  
B. J. Druker ◽  
F. Guilhot ◽  
S. O’Brien ◽  
R. A. Larson
Keyword(s):  
Blast Crisis ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Marrow Transplant ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Rate Of Progression ◽  
Presentation Methods

6506 Background: IM was proven to be superior to IFN+Ara-C for newly diagnosed patients (pts) with CML-CP (O’ Brien et al, NEJM 2003). 1,106 pts were randomized between June 2000 and Jan 2001 to either IM 400 mg or IFN+Ara-C with 553 pts to each treatment. This abstract is based on data collected up to 54 months after last patient had been recruited on IM. 60-months (5-year) data will be available for presentation. Methods: Evaluations included complete hematologic response (CHR), complete/partial cytogenetic response (CCyR/PCyR - defined as 0% / 1–35% Ph+ metaphases respectively), major cytogenetic response (MCyR=CCyR+ PCyR), major molecular response (MMR) - defined as ≥ 3 log reduction of BCR-ABL transcript levels from the standardized baseline, time to progression - defined as loss of CHR/MCyR, evolution to accelerated phase/blast crisis (AP/BC), or death due to any cause during treatment, and overall survival. Results: With a median follow-up of 54-months, 72% of the 553 randomized pts remain on initial IM treatment (5% of pts discontinued due to adverse events, 9.5% due to unsatisfactory therapeutic effect and 11% due to other reasons another 2.5% crossed over to IFN+Ara-C). Overall, the cumulative best response rates of CHR, MCyR and CCyR are 97%, 88% and 82%, respectively. The overall estimated survival was 90% (93% when censored at bone marrow transplant). An estimated 84% of pts have not progressed on treatment and 93% of pts were free from progression to AP/BC. The annual rate of progression to AP/BC of < 1% in the fourth year was lower than each of the first three years (1.5, 2.8, and 1.6%, respectively). Of the pts with MCyR at 12 months (n=436), an estimated 96% were free of progression to AP/BC at 54 months whereas it was only 81% for the 73 pts who did not achieve a MCyR at 12 months (p< 0.001). No patient with a MMR within 12 months progressed to AP/BC within 54 months. Conclusions: This analysis confirms the high rates and durability of responses to IM. Encouragingly, the rate of progression in the fourth year was lower than in each of the preceding three years. Results further demonstrate the beneficial effect of cytogenetic and molecular responses on long-term outcomes. [Table: see text]

Beneficial Effects of Cytogenetic and Molecular Response on Long-Term Outcome in Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Treated with Imatinib (IM): Update from the IRIS Study.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 166-166 ◽  
Author(s):  
Bengt Simonsson ◽  
Keyword(s):  
Blast Crisis ◽  
Chronic Phase ◽  
Risk Groups ◽  
Low Risk ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Long Term Outcome ◽  
Increased Risk

Abstract Background: IM was proven to be superior to IFN+Ara-C for newly diagnosed pts with CML-CP (O’Brien et al, NEJM 2003). At 42-months of follow-up, 75% of the 553 pts randomized to IM remain on treatment. Of the 553 pts randomized to IFN+Ara-C only 4% are still on IFN+Ara-C. This update analysis is focused on IM pts. Methods: Evaluation included complete hematologic response (CHR), major/complete cytogenetic response (MCyR/CCyR) - defined as 0-35% Ph+ and 0% Ph+ metaphases respectively, major molecular response (MMR) - defined as ≥3 log reduction of bcr-abl transcripts from the standardized baseline, time to progression - defined as loss of CHR/MCyR or evolution to accelerated phase/blast crisis (AP/BC) or death due to any cause, time to AP/BC - defined as evolution to AP/BC or death due to CML, and overall survival. Results: With an average duration of 38 months of IM treatment, the best observed rates of CHR, MCyR and CCyR are 96%, 88% and 81%, respectively. Although the majority of MCyRs were achieved within the first 3 to 9 months, some pts achieved a MCyR and some even a CCyR after more than one year of treatment (Figure 1). The estimated MMR rate at 12 months is 40%. Figure 1 - Observed CHR, MCyR and CCyR during treatment with IM Figure 1 -. Observed CHR, MCyR and CCyR during treatment with IM The estimated progression-free rate at 42 months is 84%; additionally 94% are estimated free of progression to AP/BC (97% of the pts with CCyR and 73% of the pts without CCyR during study, p<0.001). The risk of relapse remains low with no apparent increased risk over time. The yearly hazard for progression to AP/BC is about 2% in each of the 4 years. The overall estimated survival at 42 months is 91% (considering all deaths). The estimated survival was lowest in pts with high risk Sokal score (84%) as compared to 91% in the intermediate risk pts and 94% in the low risk pts (p<0.001). Similarly, the best observed CCyR in the high, intermediate, and low risk groups were 69%, 80% and 88% respectively (p=0.002). In the subset of pts with CCyR the estimated survival at 42 months was 92%, 93% and 97% in the high to low risk groups (p=0.30), indicating that once pts achieve a CCyR, their survival is not significantly different between the Sokal risk groups. Of the 509 pts who were still on treatment at 12 months and had achieved a MCyR by then (n=436), the rate without progression to AP/BC at 42 months was 97% whereas it was only 83% for the 73 pts who did not achieve a MCyR at 12 months (p<0.001). The estimated survival rates at 42 months were 95% and 83% in these two response groups, respectively (p<0.001). Furthermore, for pts who had achieved a MMR at 12 months, the probability of remaining free from progression to AP/BC was 100% at 42 months compared to 95% for pts in CCyR but not in MMR, and 91% for pts not in CCyR at 12 months (p=0.0013). Conclusions: The follow-up confirms the beneficial effect of cytogenetic and molecular responses on long-term outcomes with IM. These results will be further updated using data cut-off of 31-July 2005 to reflect additional 12-months of data (i.e., 54-month follow-up).

Outcomes by Cytogenetic and Molecular Response at 12 and 18 Months of Imatinib in Patients with Newly Diagnosed Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) in the IRIS Trial.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2138-2138
Author(s):  
Michele Baccarani ◽  
Francois Guilhot ◽  
Richard A. Larson ◽  
Stephen G. O’Brien ◽  
Brian J. Druker ◽  
...  
Keyword(s):  
Blast Crisis ◽  
Randomized Study ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Pcr Analysis ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Long Term Outcomes ◽  
Free Survival

Abstract Long term data is now available from the International Randomized Study of Interferon vs. STI571 (IRIS). We performed landmark analyses for pts on imatinib (IM) at 12 and 18 months (mos) (n=509 and n=480 respectively) and stratified for CCyR (Ph+ 0%), PCyR (Ph+ >0–35%) or No MCyR (Ph+ >35%) at both timepoints. Progression-free survival (PFS) included all progressions to accelerated phase or blast crisis during treatment with IM, whereas event-free survival (EFS) also included any loss of MCyR/CHR, increase in WBC and CML-unrelated deaths on treatment as events. Overall survival (OS) considered all deaths including those after discontinuation of IM and irrespective of whether pts went on to transplant. Outcomes in IM pts by cytogenetic response at 12 and 18 mos Estimated long-term outcomes at 60 mos (%) CcyR CcyR EFS PFS OS by 30 mos (%) by 60 mos (%) 12 mos landmark CCyR N = 350 93 97 95 – – PCyR N = 86 78 93 90 57 64 No MCyR N = 73 61 81 80 21 36 18 mos landmark CCyR N = 358 96 99 97 – – PCyR N = 66 80 90 90 38 50 No MCyR N = 56 69 83 82 11 27 Although the level of cytogenetic response was predictive for long-term outcomes, PFS and OS were not statistically significantly different between 12-mos CCyR and PCyR. Note that 64% of PCyR pts and 36% of pts without MCyR at 12 mos subsequently achieved CCyR. Using the 18-mos landmark, 50% of PCyR pts and 27% of pts without MCyR achieved CCyR at a later time. Long-term outcomes were evaluated based on available BCR-ABL transcript levels in pts with CCyR. A 3-log reduction from standardized baseline value in untreated pts was defined as a major molecular response (MMR). No pts who achieved both CCyR and MMR at 12 or 18 mos progressed to AP/BC by 60 mos. Approximately 5% of pts with CCyR but no MMR at 12 mos (p=0.007) and only 2% of CCyR pts without MMR at 18 mos (p=0.11) subsequently progressed. Of approximately 25% of CCyR pts with available PCR analysis who did not achieve MMR at 18 mos, about half did achieve MMR at a later time and their estimated EFS rate at 60 mths was 91%. At 60 mos, 69% of patients randomized to IM remained on treatment. Achievement of CCyR and MMR by 12 and 18 mos after start of IM in newly diagnosed CML-CP are predictive for favorable long-term outcomes. About 50% of pts in PCyR or CCyR at these time points eventually achieve CCyR and MMR, respectively, on continued IM treatment. The ability to identify patients who may be late responders should be further studied.

scholarly journals Efficacy and Safety of Radotinib Compared with Imatinib in Newly Diagnosed Chronic Phase Chronic Myeloid Leukemia Patients: 12 Months Result of Phase 3 Clinical Trial

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 476-476 ◽  
Author(s):  
Jae-Yong Kwak ◽  
Hawk Kim ◽  
Jeong A Kim ◽  
Young Rok Do ◽  
Hyeoung Joon Kim ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Research Funding ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Phase 3 ◽  
Grade 3

Abstract Background Radotinib is a second generation BCR-ABL1 tyrosine kinase inhibitor (TKI) developed by IL-YANG Pharm. Co., Ltd (Seoul, South Korea) and approved by the Korea FDA for the treatment of chronic phase chronic myeloid leukemia (CML-CP) patients who have failed prior TKIs. We conducted the randomized, open-label, phase 3 study to assess the efficacy and safety of radotinib, as compared with imatinib, for the first-line treatment of newly diagnosed CML-CP. Methods Based on baseline demographics and Sokal risk score, 241 patients were randomized 1:1:1 to radotinib 300 mg twice daily (bid) (n=79), radotinib 400 mg bid (n=81), or imatinib 400 mg once daily (qd) (n=81). The primary endpoint was the rate of major molecular response (MMR) by 12 months and molecular response was assessed by RQ-PCR at baseline and every 3 months. Secondary endpoints were the rate of complete cytogenetic response (CCyR), MR4.5 by 12 months, and the rate of progression to accelerate phase or blast crisis. Results All three study groups were well balanced with baseline age, gender, race and Sokal risk score. With minimum follow-up of 12 months, the proportions of patients receiving a study drug were 86.3% (69/79) in radotinib 300 mg bid group, 71.6% (58/81) in radotinib 400 mg bid group, and 81.5% (66/81) in imatinib 400 mg qd group. By 12 months, rates of MMR were significantly higher in patients receiving radotinib 300 mg bid (51.9%, P = .0044) and radotinib 400 mg bid (45.7%, P = .0342) compared with imatinib (29.6%). The median time to MMR among responders were shorter on radotinib 300 mg bid (5.7 months) and radotinib 400 mg bid (5.6 months) than imatinib group (8.2 months). The MR4.5 rates by 12 months were also higher for both radotinib 300 mg bid (15.2%) and 400 mg bid (13.6%) compared to imatinib (8.6%). The CCyR rates by 12 months were also higher for radotinib 300 mg bid (91.1%, P = .0120) compared with imatinib (76.5%). There was no progression to accelerated phase or blast crisis in all groups by 12 months. Discontinuation due to adverse events (AEs) or laboratory abnormalities occurred in 7 (8.8%), 16 (19.8%), and 5 (6.2%) patients for radotinib 300 mg bid, radotinib 400 mg bid and imatinib, respectively. Grade 3/4 thrombocytopenia occurred in 16.5% of patients receiving radotinib 300 mg bid, in 13.6% for radotinib 400 mg bid, and in 19.8% receiving imatinib. And grade 3/4 neutropenia occurred in 19.0%, 23.5%, and 29.6% for radotinib 300 mg bid, 400 mg bid and imatinib, respectively. The most common any grade non-laboratory AEs were skin rash (35.4% and 33.3%), nausea/vomiting (22.8% and 23.5%), headache (19.0% and 30.9%), and pruritus (19.0% and 30.0%) in radotinib 300 mg bid and radotinib 400 mg bid, respectively; AEs in the imatinib group were edema (34.6%), myalgia (28.4%), nausea/vomiting (27.2%), and skin rash (22.2%). Overall, grade 3/4 non-laboratory AEs were uncommon in all groups. Conclusions With minimum 12 months follow-up, radotinib demonstrated significantly higher and faster rates of CCyR and MMR than imatinib in patients with newly diagnosed CML-CP. The safety profiles of the radotinib and imatinib were different, and most AEs were manageable with optimal dose reduction. The results of this trial support that radotinib can be one of the standard of care in newly diagnosed CML-CP. Table. Baseline Characteristics, Molecular and Cytogenetic Response Rates Radotinib 300mg BID Radotinib 400mg BID Imatinib 400mg QD (N=79) (N=81) (N=81) Age, median (range), years 45 (20-75) 43 (18-84) 45 (18-83) Gender, n (%) Male 52 (65.8) 47 (58.0) 52 (64.2) Female 27 (34.2) 34 (42.0) 29 (35.8) Sokal risk, n (%) Low 21 (26.6) 22 (27.2) 22 (27.2) Intermediate 38 (48.1) 38 (46.9) 39 (48.2) High 20 (25.3) 21 (25.9) 20 (24.7) MMR by 12 months, % 51.9 45.7 29.6 P = .0044 P = .0342 Cumulative Incidence of MMR by 12 months¢Ó, % 57.0 58.0 35.0 P = .0040 P = .0037 MR4.5 by 12 months, % 15.2 13.6 8.6 CCyR by 12 months, % 91.1 81.5 76.5 ¢Ó Kaplan-Meier estimates of MMR Disclosures Kim: IL-YANG Pharm. Co. Ltd: Research Funding. Kim:Alexion Pharmaceuticals: Research Funding. Chung:Alexion Pharmaceuticals: Research Funding. Choi:Alexion Pharmaceuticals: Research Funding.

scholarly journals NOVEL-1st: Interim Analysis of a Non-Interventional, Multi-Center Observational Study to Assess the Safety and Efficacy of Nilotinib in Newly Diagnosed Patients with Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia in Chronic Phase (CML-CP) in Taiwan

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3019-3019
Author(s):  
Hwang Wen-Li ◽  
Shao-Min Han ◽  
Shyuann-Yuh Lin ◽  
Ming-Chih Chang ◽  
Li-Yuan Bai ◽  
...  
Keyword(s):  
Clinical Response ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Molecular Response ◽  
The Novel ◽  
Newly Diagnosed ◽  
First Line ◽  
Log Reduction

Abstract Background The selective tyrosine kinase inhibitor (TKI) nilotinib has been approved for the treatment of adult patients with newly diagnosed Philadelphia chromosome positive chronic myeloid leukemia in chronic phase (Ph+ CML-CP) globally, including Taiwan. The NOVEL-1st study was conducted to examine the long-term safety and efficacy of nilotinib in this group of patients in routine clinical practice in Taiwan. Methods The NOVEL-1st study was a non-interventional, multi-center study. A total of 129 patients with newly diagnosed and previously untreated Ph+ CML-CP were enrolled from 11 centers across Taiwan between January 2013 and June 2016. The follow-up period was 36 months. The primary objective was to collect long-term safety data on nilotinib. Secondary objectives were to evaluate the efficacy of nilotinib by clinical response, disease progression, and survival. Results The median age of the enrolled patients was 49.7 (20.2-89.6) years of whom 58.3% were males. The median duration from CML diagnosis to study enrolment was 25.5 days. Of the 129 enrolled patients, 59 (45.7%) had completed the study, 29 (22.5%) had withdrawn from the study and other patients are still under follow up. The most common reasons included adverse events (AE) (n = 8), discontinuing nilotinib (n = 6), and death (n = 4). All 129 patients were included in the safety analysis, while 122 patients in whom molecular response data were collected were included in the efficacy assessment. At the time of data cut-off, a total of 1,278 AEs were reported by 120 (93.0%) patients, of which 140 (11.0%) AEs in 41 (34.2%) patients were serious and 499 (39.0%) AEs in 40 (33.3%) patients were drug-related. Non-hematological and hematological AEs were consistent with other reports, with no new safety signal detected. Common hematological AEs (incidence ≥ 10 %) included thrombocytopenia (29.5%), anemia (19.4%), and leukopenia (14.0%). Frequent non-hematological AEs (incidence ≥ 10 %) included rash (21.7%), upper respiratory tract infection (19.4%), pruritus (18.6%), cough (17.1%), constipation (14.7%), diarrhea (12.4%), increased alanine aminotransferase (11.6%), increased bilirubin (10.1%), and insomnia (10.1%). Compared to previous studies, we observed lower rates of cardio- or cerebrovascular events (1.6%), fluid retention (2.3%), and hyperglycemia (2.3%) of all grades, but a higher rate of hepatotoxicity (20.9%) was seen in the study population. Five (3.9%) patients expired during the study of whom 2 were due to CML progression. The efficacy outcomes were comparable to other first-line studies of nilotinib. From 3 to 36 months, the rates of clinical response increased over time, from 67.4% to 91.5% for complete hematological response (CHR), 45.0% to 86.0% for complete cytogenetic response (CCyR), 15.5% to 79.1% for major molecular response (MMR), 3.9% to 56.6% for MR4.0 (BCR-ABL ≥ 4 log reduction), and 2.3% to 38.8% for MR4.5 (BCR-ABL ≥ 4.5 log reduction). The median time to CHR, CCyR, MMR, and MR4.0 were 4, 5, 9, and 25 months, respectively (not reached for MR4.5). Early molecular response (EMR), defined as BCR-ABL ≤ 10% at Month 3, was seen in 88.7% of patients. MR4.0 and MR4.5 were significantly higher for patients with deeper EMR, confirming an association between early and long-term deep molecular response. To date, the median OS and PFS were not reached as death and disease progression were only observed in 5 and 2 patients, respectively. Conclusions The initial results of NOVEL-1st were comparable to other published first-line studies of nilotinib and demonstrated that nilotinib as a first-line treatment for Ph+ CML-CP patients was well-tolerated and efficacious in the real-world setting. Clinical response was observed as early as 3 months. Early molecular response is a potential predictor of long-term clinical outcome. The final analysis will be conducted when all patients have completed the study. Disclosures No relevant conflicts of interest to declare.

IRIS 6-Year Follow-Up: Sustained Survival and Declining Annual Rate of Transformation in Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Treated with Imatinib.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 25-25 ◽  
Author(s):  
Andreas Hochhaus ◽  
Brian J. Druker ◽  
Richard A. Larson ◽  
Stephen G. O’Brien ◽  
Insa Gathmann ◽  
...  
Keyword(s):  
Adverse Events ◽  
Blast Crisis ◽  
Randomized Study ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Continuous Treatment ◽  
Annual Rate ◽  
Interferon Α

Abstract Background: The International Randomized study of Interferon versus STI571 (IRIS) study demonstrated that imatinib has superior safety and efficacy relative to interferon-α plus cytarabine (IFN+ara-C). Patients on the imatinib arm achieved an estimated 5-year OS of 89%. To monitor the long-term responses achieved by patients on imatinib, the 6-year follow-up of the IRIS patient population is summarized. Methods: 1106 patients were randomly assigned to either imatinib or IFN+ara-C and evaluated for hematologic and cytogenetic responses, event-free survival, progression to accelerated-phase (AP) or blast crisis (BC), overall survival (OS), and frequency of adverse events and discontinuations. Results: The downward trend in the risk of disease progression on imatinib has continued with a 0.4% event rate (including loss of response) and a 0% rate of transformation to AP/BC attained between years 5 and 6. Of 553 who were randomized to imatinib, 364 (65.8%) remain on study drug at 6 years: 14 (2.5%) crossed over to the IFN arm, and 175 (31.6%) pts have discontinued from imatinib study therapy for any reason. The following reasons were cited for discontinuation from the IRIS study: adverse events, 23 patients (4.2%); unsatisfactory therapeutic effect, 66 patients (11.9%); protocol violation, 15 patients (2.7%); withdrawal of consent, 32 patients (5.8%); administrative problems, 6 patients (1.1%); and 16 patients (2.9%) elected to undergo a stem cell transplantation (SCT). Death was the reason for discontinuation for 10 (1.8%) patients, and 7 patients (1.3%) were lost to follow-up. The best observed complete hematologic response rate among patients receiving first-line imatinib was 97%. The best observed major cytogenetic response (MCyR) and complete cytogenetic response (CCyR) rates were 89% and 83%, respectively, with 2 additional CCyR observed since the prior 5-year analysis. At the current 6-year follow-up, 325 patients are still in CCyR, another 24 had lost CCyR but regained it, 6 patients lost CCyR but remain in MCyR, and the remaining 9 patients never had a documented CCyR. Overall, an estimated 83% of patients were event-free, and 93% were free of progression to AP or BC at 6 years on imatinib study treatment, as patients were followed only for OS after discontinuation. After the second year on imatinib, the annual rate of events decreased every year, as did the annual relapse rate. Based on the current follow-up, a total of 66 (12%) patients have died (19 after SCT, 27 not due to CML). Estimated 6-year OS rate for all patients who received imatinib as initial therapy was 88%. When survival is censored at time of SCT for patients who proceeded to transplant, the estimated OS at 6 years is 91%. In an analysis of serious adverse events, no new safety issues were identified between the 5-year report and this analysis. Conclusions: The 6-year follow-up analysis of the IRIS population indicates that continuous treatment of chronic-phase CML with imatinib induces durable responses in a high percentage of patients with a decreasing rate of relapse and a favorable long-term safety profile.

Dasatinib versus imatinib (IM) in newly diagnosed chronic myeloid leukemia in chronic phase (CML-CP): DASISION 3-year follow-up.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 6504-6504 ◽  
Author(s):  
Andreas Hochhaus ◽  
Neil P. Shah ◽  
Jorge E. Cortes ◽  
Michele Baccarani ◽  
M. Brigid Bradley-Garelik ◽  
...  
Keyword(s):  
Chronic Phase ◽  
Progression Free Survival ◽  
Risk Groups ◽  
Cytogenetic Response ◽  
Transformation Rate ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Grade 3 ◽  
Intent To Treat

6504 Background: In the phase 3 DASISION trial of dasatinib v IM in patients (pts) with newly diagnosed CML-CP, dasatinib had higher 12-month rates of complete cytogenetic response (CCyR) and major molecular response (MMR) (Kantarjian, NEJM 2010;362:2260). By 12 months confirmed CCyR (cCCyR) rates for dasatinib v IM were 77% v 66%, P=0.001, meeting the primary endpoint. Methods: Pts were randomized to receive dasatinib 100 mg once daily (QD; n=259) or IM 400 mg QD (n=260). Results: Minimum 24-month follow-up (median 26.6 months) is reported here. 24-month molecular response rates were higher for dasatinib v IM: MMR (BCR-ABL ≤0.1%) 64% v 46%, P<0.0001; MR4 (BCR-ABL ≤0.01%) 29% v 19%, P=0.0053; MR4.5 (BCR-ABL ≤0.0032%) 17% v 8%, P=0.0032. MMR rates were higher for dasatinib in all Hasford risk groups (high 73% v 56%; intermediate 61% v 50%; low 73% v 56%). Of pts who achieved MMR at 12 months, on dasatinib v IM, 97% v 92% had maintained their MMR at 24 months, respectively. Pts receiving dasatinib v IM had faster responses; median time to CCyR and MMR was 3.2 v 6.0 and 15 v 36 months, respectively. In an intent-to-treat analysis, fewer pts receiving dasatinib (n=9; 3.5%) transformed to accelerated/blast phase v IM (n=15; 5.8%) on study or during follow-up after discontinuation. 24-month overall and progression-free survival were similar for dasatinib v IM: 95.4% v 95.2% and 93.7% v 92.1% (follow-up is ongoing). Few additional adverse events (AEs) were reported between 12 and 24 months in both arms, with grade 3/4 nonhematologic AE rates ≤1%. In each arm, 10 pts had a BCR-ABL mutation detected at time of discontinuation. For dasatinib v IM, 23% v 25% discontinued treatment for drug-related AEs (7% v 5%), progression (5% v 7%), failure (3% v 4%), unrelated AEs (2% v <1%), death (2% v <1%), and other (4% v 8%). Few pts discontinued between 12 and 24 months for dasatinib (n=19; 7%) and IM (n=16; 6%). Conclusions: Updated data with minimum 36-month follow-up will be presented, including mutation analyses in pts who discontinued, progressed, or had suboptimal response. Pts receiving dasatinib had a lower transformation rate and higher molecular responses v pts receiving IM, supporting the use of dasatinib in newly diagnosed CML-CP.

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