Patients with Chronic Phase CML in the IRIS Study Who Receive Imatinib Mesylate (IM) 2nd Line after Prior IFN/Ara-C Have Sustained Complete Cytogenetic and Major Molecular Response Rates Similar to 1st Line IM Patients.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2139-2139
Author(s):  
Jaspal Kaeda ◽  
Andreas Hochhaus ◽  
Jerald Radich ◽  
Susan Branford ◽  
Charlene So ◽  
...  
Keyword(s):  
Chronic Phase ◽  
Response Rates ◽  
Cytogenetic Response ◽  
Progression Rate ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Real Time Quantitative Pcr ◽  
Log Reduction ◽  
Advanced Phase

Abstract The IRIS study compared IM and interferon+cytarabine (IFN/Ara-C) in patients (pts) with newly diagnosed CML-CP (n=553 per arm). IFN/Ara-C pts. could cross over to IM if they satisfied predetermined criteria for disease, either resistance/refractoriness (=resistance), or intolerance of or reluctance to continue the combination (=lack of resistance). Pts who received IM 1st line or 2nd line who achieved a complete cytogenetic response (CCyR) had BCR-ABL transcript levels measured serially by real-time quantitative PCR (RQ-PCR). Results were expressed as log reduction in BCR-ABL/BCR from a standardized baseline value for untreated pts. Yearly rates of 3 log reduction (Major Molecular Response, MMR) from IM treatment starting date were estimated by multiplying the CCyR rate by the MMR rate in CCyR pts at each time point. Overall, of 553 pts who received 1st line IM 82% achieved CCyR, an estimated 69% during the 1st year (yr) of treatment. Of 359 pts who received 2nd line IM, 80% achieved CCyR, 62% during the 1st yr; rates were lower in pts with resistance than in those without resistance to prior IFN/Ara-C (75% vs 85% overall, p=0.025, 56% vs 68% within first yr, p<0.01). Best observed and estimated molecular responses for CCyR pts. are summarized in the table. The median follow-up for BCR-ABL evaluation on 1st line vs 2nd line IM was 45 and 35 months, respectively. Molecular response on 1st- and 2nd-line IM in the IRIS study 1st-line IM 2nd-line IM after IFN/Ara-C All pts N = 553 All pts N = 359 Resistance N =174 Lack of resistance N =185 CcyR 454 (82%) 288 (80%) 131 (75%) 157 (85%) Pts with CCyR during treatment and PCR sample(s) N = 401 N = 211 N = 98 N = 113 –≥3 log reduction (MMR) 323 (81%) 154 (73%) 63 (64%) 91 (81%) –≥ 4 log reduction 216 (54%) 92 (44%) 35 (36%) 57 (50%) Estimated % of all pts who achieve CCyR and MMR by – 1 yr 36 24 19 28 – 2 yr 59 38 29 45 – 4 yr 67 67 58 72 – 5 yr 85 82 78 84 Overall response rates were similar between 1st and 2nd line IM pts, although responses in 2nd line IM pts may have occurred more slowly. However, the number of RQ-PCR samples between 1 and 2 yrs of 2nd line IM was limited as samples were not obtained routinely between Jan 2003 and Aug 2004. In pts who achieved CCyR, the estimated 5-yr progression rate to advanced CML phase was 3% for 1st line IM and 4% for 2nd line IM; using the broader definition of progression (including events such as CML-unrelated deaths and loss of MCyR/CHR) the progression rates were 9% and 8% respectively. In both 1st and 2nd line IM pts with CCyR who also achieved MMR, only an estimated 1% progressed to advanced phase within 5 yrs; the estimated broadly defined event rates were 5% and 4% respectively. In summary, for 1st line IM patients with a RQ-PCR follow-up of up to 5 yrs, an estimated 85% achieved MMR at 5 yrs compared with 59% at 2 yrs. Cytogenetic and molecular response rates were similar for 1st line and 2nd line IM pts, primarily due to responses in pts who crossed over for reasons other than resistance or refractoriness. For IM pts the rate of progression to advanced CML phase at 5 yrs was low in those with CCyR and even lower in pts who also achieved MMR.

Significant Reduction of BCR-ABL Transcripts after Switching to Imatinib Therapy in Patients with CML and Complete or Near-Complete Cytogenetic Responses to Interferon-Alpha (IFN).

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2142-2142
Author(s):  
Susan Branford ◽  
Timothy Hughes ◽  
Steven Stylian ◽  
Anthony P. Schwarer ◽  
Chris Arthur ◽  
...  
Keyword(s):  
Chronic Phase ◽  
Progression Free Survival ◽  
Cytogenetic Response ◽  
Primary Objective ◽  
Imatinib Therapy ◽  
Molecular Response ◽  
Log Reduction ◽  
Advanced Phase ◽  
Molecular Assessment

Abstract IFN confers a survival advantage for the minority of patients with CML who achieve a complete cytogenetic response. The 10-year survival rate was reported as 72%. In the IRIS trial only 3% of patients remained on IFN after randomization and 65% crossed-over to imatinib. Imatinib offered superior compliance and toxicity profiles and clear quality of life advantages. Furthermore, patients on first line imatinib with a major molecular response (MMR) by 12 months had a 100% progression free survival to advanced phase. An important clinical question of whether IFN-responsive patients can experience further improvements with imatinib has not been answered. We studied 23 chronic phase patients treated with IFN for a median of 4.5 years (r1.6–14.3) who had achieved a complete (n=15) or near-complete (n=8) cytogenetic response. IFN was ceased and 400mg imatinib commenced in a clinical trial with the primary objective of determining if switching to imatinib in IFN-responsive patients improves response when assessed at the molecular level. Molecular assessment was undertaken for the first 12 months of imatinib therapy by measurement of peripheral blood BCR-ABL levels by quantitative PCR at 3 month intervals. A subset of 10 patients had follow-up molecular assessment for 3.8 to 4.5 years after commencing imatinib. Prior to IFN cessation all patients had detectable BCR-ABL and 16 of 23 had not achieved a MMR, which is a 3 log reduction of BCR-ABL from a standardized baseline value for untreated patients. At a median of 3 months of imatinib (r3–12) these 16 patients achieved MMR. A significant reduction of BCR-ABL over the 12 month assessment was considered >50% and this occurred in 15 of these 16 patients (median 98.4% reduction, r94.4–99.8). In the sole patient without a significant reduction, BCR-ABL returned to the pre imatinib level after repeated dose interruptions of 93 days and decrease to 200mg imatinib due to thrombocytopenia. Of the 7 patients with a MMR prior to IFN cessation, all 7 maintained this level of response after switching to imatinib. Therefore, over the 12 month assessment all patients either achieved MMR (n=16) or maintained MMR (n=7). One patient withdrew consent after 83 days. The 10 patients with longer molecular follow-up of up to 4.5 years of imatinib all maintained MMR. The typical molecular response is illustrated in the figure, which plots the log reduction of BCR-ABL from the standardized baseline for 3 patients assessed at regular time-points before and after switching to imatinib. In conclusion, the data suggest that switching to imatinib leads to rapid and significant improvement in IFN-responsive patients in terms of achieving MMR, a response with established prognostic value with imatinib therapy. The study should help patients and their physicians make evidence-based decisions about the potential benefits and risks of switching to imatinib with prior response to IFN. Figure Figure

scholarly journals Initial treatment for patients with CML

Hematology ◽  
2009 ◽  
Vol 2009 (1) ◽  
pp. 453-460 ◽  
Author(s):  
John M. Goldman
Keyword(s):  
Initial Treatment ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Log Reduction ◽  
Advanced Phase

AbstractFor adult patients who present with chronic myeloid leukemia (CML) in chronic phase it is now generally agreed that initial treatment should start with the tyrosine kinase inhibitor (TKI) imatinib at 400 mg daily. Five years after starting imatinib about 60% of these patients will be in complete cytogenetic response (CCyR), still taking imatinib; an appreciable proportion of these will have achieved a major molecular response, defined as a 3-log reduction in the level of BCR-ABL1 transcripts in their blood. The patients in CCyR seem to have a very low risk of relapse to chronic phase or of progression to advanced phase. Other patients may be resistant to imatinib or may experience significant side effects that require change of therapy. The best method of monitoring responding patients is to enumerate Philadelphia chromosome–positive marrow metaphases at 3-month intervals until CCyR and to perform RQ-PCR for BCR-ABL1 transcripts at 3-month intervals after starting imatinib. The recommendations for defining “failure” and “sub-optimal response” proposed by the European LeukemiaNet in 2006 have proved to be a major contribution to assessing responses in individual patients and are now being updated. Patients who fail imatinib may respond to second-generation TKIs, but allogeneic stem cell transplantation still plays an important role for eligible patients who fare badly with TKIs. Patients who present in advanced phases of CML should be treated initially with TKI alone or with TKI in conjunction with cytotoxic drugs, but their overall prognosis is likely to be much inferior to that of those presenting in early chronic phase.

Dasatinib Efficacy in Patients with Chronic Myeloid Leukemia in Chronic Phase (CML-CP) and Pre-Existing BCR-ABL Mutations

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 449-449 ◽  
Author(s):  
Martin C Müller ◽  
Jorge Cortes ◽  
Dong-Wook Kim ◽  
Brian J. Druker ◽  
Philipp Erben ◽  
...  
Keyword(s):  
Amino Acids ◽  
Median Time ◽  
Chronic Phase ◽  
Response Rates ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Imatinib Resistant ◽  
Dasatinib Treatment

Abstract Dasatinib (SPRYCEL®) is an effective BCR-ABL inhibitor that is 325-fold more potent than imatinib and 16-fold more potent than nilotinib in vitro against unmutated BCR-ABL. Across a series of phase II and III trials, dasatinib has demonstrated durable efficacy in patients with CML following resistance, suboptimal response, or intolerance to imatinib. BCR-ABL mutations are an important cause of imatinib failure and suboptimal response. Here, the efficacy of dasatinib in patients with CML-CP who had baseline BCR-ABL mutations following imatinib treatment was analyzed using data from three trials (CA180-013, -017, and -034). Mutational assessment of the BCR-ABL kinase domain was performed using RT-PCR and direct sequencing of peripheral blood cell mRNA. Hematologic, cytogenetic, and molecular response rates were reported after ≥24 mos of follow-up. Duration of response, progression-free survival (PFS), and overall survival (OS; in 013/034) were calculated using Kaplan-Meier analysis, and rates were estimated at the 24-mo time point. Of 1,150 patients with CML-CP who received dasatinib, 1,043 had a baseline mutational assessment and were analyzed further. Of these, 402 patients (39%) had a BCR-ABL mutation, including 8% of 238 imatinib-intolerant and 48% of 805 imatinib-resistant patients. Excluding known polymorphisms, 64 different BCR-ABL mutations were detected affecting 49 amino acids, with G250 (n=61), M351 (n=54), M244 (n=46), F359 (n=42), H396 (n=37), Y253 (n=26), and E255 (n=25) most frequently affected. Dasatinib treatment in patients with or without a baseline BCR-ABL mutation, respectively, resulted in high rates of major cytogenetic response (MCyR; 56% vs 65%), complete cytogenetic response (CCyR; 44% vs 56%), major molecular response (MMR; 33% vs 45%); PFS (70% vs 83%), and OS (89% vs 94%) (Table). After 24 mos, CCyRs in patients with or without a BCR-ABL mutation had been maintained by 84% vs 85%, respectively, of those achieving this response. Among patients with mutations who received dasatinib 100 mg once daily, which has a more favorable clinical safety profile, efficacy and durability were similar (MCyR: 55%; CCyR: 41%; MMR: 36%; PFS: 73%; OS: 90%). In general, high response rates and durable responses were observed in patients with different mutation types, including highly imatinib-resistant mutations in amino acids L248, Y253, E255, F359, and H396. When responses were analyzed according to dasatinib cellular IC50 for individual BCR-ABL mutations, dasatinib efficacy was observed in 44 patients who had any of 5 imatinib-resistant mutations with a dasatinib cellular IC50 &gt;3 nM (Q252H, E255K/V, V299L, and F317L, excluding T315I), including MCyR in 34%, CCyR in 25%, MMR in 18%, PFS in 48%, and OS in 81%. Among patients whose mutations had a dasatinib IC50 ≤3 nM (n=254) or unknown IC50 (n=83), responses and durability were comparable to patients with no BCR-ABL mutation. As expected, few patients with a T315I mutation (IC50 &gt;200 nM; n=21) achieved a response. Among 70 patients with &gt;1 mutation, a MCyR was achieved in 53% and a CCyR in 37%. Among patients with mutational analysis at last follow-up (n=162), 42 (26%) retained a BCR-ABL mutation (20 retained a mutation with IC50 &gt;3 nM), 42 (26%) lost a mutation (5 lost a mutation with IC50 &gt;3 nM), and 44 (27%) developed a new mutation (39 developed a mutation with IC50 &gt;3 nM), with some patients counted in more than one category. Overall, this analysis demonstrates that dasatinib has broad efficacy against all BCR-ABL mutations except for T315l. For patients with BCR-ABL mutations, dasatinib treatment is associated with durable responses and favorable long-term outcomes. Table Analysis by dasatinib IC50 No BCR-ABL mutation BCR-ABL mutation BCR-ABL mutation treated with 100 mg QD &gt;3 nM (excl. T315I) 3 nM* Unknown IC50** Some patients had &gt;1 mutation. *Excluding patients with a concurrent mutation with dasatinib IC50 &gt;3 nM. **Excluding patients with a concurrent mutation with known dasatinib IC50. Patients, n 641 402 49 44 254 83 Response rates (≥24 mos of follow-up), % CHR 93 90 90 82 94 96 MCyR 65 56 55 34 58 73 CCyR 56 44 41 25 47 54 MMR 45 33 36 18 34 43 Median time to MCyR, mos 2.8 2.9 2.8 5.7 2.9 2.8 Median time to CcyR, mos 3.0 5.3 3.0 5.7 5.4 3.4 24-mo PFS (95% CI), % 83 (79.8–86.5) 70 (65.3–75.2) 73 (60.1–86.3) 48 (31.2–64.7) 73 (66.6–78.9) 89 (82.3–96.3) 24-mo OS (95% CI), % 94 (91.4– 95.7) 89 (85.1– 92.1) 90 (81.2– 98.3) 81 (68.8– 93.8) 90 (85.8– 94.2) 96 (91.2–100)

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.

BCR-ABL RNA Levels at the Time of a Complete Cytogenetic Response (CCR) Predict the Duration of CCR in Imatinib-Treated Chronic Myeloid Leukemia Patients.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1098-1098
Author(s):  
Richard D. Press ◽  
Zac Love ◽  
Ashlie A. Tronnes ◽  
Gwen Kurilik ◽  
Michael J. Mauro ◽  
...  
Keyword(s):  
Chronic Phase ◽  
Cytogenetic Response ◽  
Imatinib Therapy ◽  
Log P ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Log Reduction ◽  
Complete Cytogenetic Response ◽  
Rna Levels

Abstract Background : Imatinib induces a complete cytogenetic response (CCR) in the majority of patients with chronic phase CML. CCR is durable in the majority of patients, but relapse occurs in a subset. To determine the potential of quantitative RT-PCR (qPCR) of BCR-ABL to predict cytogenetic relapse, we serially monitored residual disease in 90 CML patients with an imatinib-induced CCR. Methods and patients : mRNA was prepared from total nucleated cells from blood or bone marrow, and cDNA was synthesized using random hexamer primers. Relative BCR-ABL expression was then measured by real-time fluorescent PCR normalized for G6PDH expression. This assay has a detection limit of 1 CML cell in 100,000 and an analytical precision of 6% (CV). At the start of imatinib therapy, 85% of patients were in chronic phase, at a median 9.5 months after diagnosis. Patients were treated with imatinib alone (64%) or in combination with interferon or cytarabine (32%). One patient each was treated with imatinib in combination with either the farnesyltransferase inhibitor tipifarnib, donor leukocytes (after allogeneic BMT), or an experimental heat shock protein (hsp70) vaccine. During the imatinib follow-up time of 28 months (median), disease monitoring occurred by cytogenetics and qPCR (median 6 samples per patient). The CCR was achieved after 9.7 months (median) of imatinib therapy. Results : At the time of first achieving CCR, BCR-ABL RNA levels had decreased by a median of 1.8 logs below the median baseline level. During further follow-up, 26 patients (29%) experienced cytogenetic relapse (defined as any Ph-positive metaphase cell) at a median 6.0 months after CCR and a median 20 months after starting imatinib. There was no difference in the imatinib treatment time, the time to achieve CCR, or the post-CCR follow-up period between the patients with and without subsequent cytogenetic progression. qPCR data at the time of first CCR were available for 78 patients, including 25 of 26 with a subsequent cytogenetic relapse. The reduction of BCR-ABL RNA at the time of first achieving CCR was significantly less in those patients with a subsequent cytogenetic relapse (median 1.4 log) compared to those with a sustained CCR (median 2.0 log) (P=0.002). In the 64 patients with a sustained CCR, the molecular response progressively improved over time to reach a median reduction of 4.0 log at 15 months after CCR. Of the 29 patients achieving at least a 2 log reduction of BCR-ABL RNA at the time of first reaching CCR, only 3 (10%) had a subsequent cytogenetic relapse. In comparison, 22 of 49 patients (45%) with a less than 2 log reduction at the time of achieving CCR had a subsequent cytogenetic relapse (odds ratio = 7.1; 95% CI 1.9–26). At the time of first achieving CCR, a reduction in BCR-ABL RNA of less than 2 logs thus had a diagnostic sensitivity of 88% and a diagnostic specificity of 49% for predicting subsequent cytogenetic relapse. Conclusions : We conclude that, in the majority of imatinib-treated CML patients reaching CCR, the level of BCR-ABL RNA at the time that the CCR is first achieved is a sensitive predictor of the durability of the CCR. The availability of a laboratory marker capable of stratifying the subsequent risk of disease progression (early in remission) will be useful in targeting additional (or alternative) therapies to those patients with the highest risk.

scholarly journals Nilotinib for the frontline treatment of Ph+ chronic myeloid leukemia

Blood ◽  
2009 ◽  
Vol 114 (24) ◽  
pp. 4933-4938 ◽  
Author(s):  
Gianantonio Rosti ◽  
Francesca Palandri ◽  
Fausto Castagnetti ◽  
Massimo Breccia ◽  
Luciano Levato ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
First Year ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Phase 2 Study ◽  
Frontline Treatment

AbstractNilotinib has a higher binding affinity and selectivity for BCR-ABL with respect to imatinib and is an effective treatment of chronic myeloid leukemia (CML) after imatinib failure. In a phase 2 study, 73 early chronic-phase, untreated, Ph+ CML patients, received nilotinib at a dose of 400 mg twice daily. The primary endpoint was the complete cytogenetic response (CCgR) rate at 1 year. With a median follow-up of 15 months, the CCgR rate at 1 year was 96%, and the major molecular response rate 85%. Responses were rapid, with 78% CCgR and 52% major molecular response at 3 months. During the first year, the treatment was interrupted at least once in 38 patients (52%). The mean daily dose ranged between 600 and 800 mg in 74% of patients, 400 and 599 mg in 18% of patients, and was less than 400 mg in 8% of patients. Dose interruptions were mainly due to nonhematologic and biochemical side effects. Myelosuppression was irrelevant. One patient progressed to blastic crisis after 6 months; one went off-treatment for lipase increase grade 4 (no pancreatitis). Nilotinib is safe and very active in early chronic-phase CML. These data support a role for nilotinib for the frontline treatment of CML. This study was registered at ClinicalTrials.gov as NCT00481052.

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).

Clinical Significance of Molecular Monitoring in Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) with Imatinib Therapy.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 272-272 ◽  
Author(s):  
Jorge Cortes ◽  
Moshe Talpaz ◽  
Susan O’Brien ◽  
Dan Jones ◽  
Raja Luthra ◽  
...  
Keyword(s):  
Clinical Significance ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Molecular Responses ◽  
Transcript Levels ◽  
Log Reduction ◽  
Cytogenetic Remission ◽  
Complete Molecular Response

Abstract Most patients (pts) with CML in chronic phase treated with imatinib achieve a major cytogenetic (CG) remission, and increasing numbers of pts are achieving molecular responses. To determine the clinical significance of molecular responses in these pts, we analyzed the results of quantitative PCR monitoring among 280 pts with CML in CP who achieved a complete CG remission with imatinib therapy (117 after IFN-α failure, 163 previously untreated). Pts have been followed for a median of 31.2 mo (range, 3 to 52 mo). The median BCR-ABL/ABL ratio before the start of therapy was 37.43 (range, 0.004 to 170.53). A major molecular response (i.e., BCR-ABL/ABL ratio <0.05%) was achieved in 174 (62%) pts, and transcripts became undetectable (i.e., complete molecular response) in 95 (34%). Median time to major molecular responses was 10 mos (range, 2.8 to 46 mos) and for complete 16.7 mos (range, 3 to 48 mos) but responses have occurred as late as 48 mos with no evidence of a time after which responses do not improve any more. In a multivariate analysis, clinical characteristics associated with an increased probability of achieving a major molecular response were early chronic phase previously untreated (p=.03), no splenomegaly (p=.03), and ≤90% Ph-positive metapahases at the start of therapy (p=0.05). Only 9 of 166 (5%) patients who achieved a major molecular response and have had subsequent cytogenetic analysis have lost their cytogenetic response, compared to 25 of 68 (37%) of those who did not achieve this response (p<0.0001). Only 3 of 82 (4%) with complete molecular response have lost their cytogenetic response. Patients achieving a major molecular response 12 mos after the start of therapy have a significantly better complete cytogenetic remission duration than those not achieving this response at this time point, and similar but not statistically significant trends can be detected with earlier responses (at 3 and 6 mos). Pts with more than a 1-log-reduction in transcript levels after 3 mos of therapy have a 90% probability of achieving a 3-log reduction at 24 mos, compared to 55% for those with ≤1-log decrease (p=0.0002). We then evaluated the significance of an increasing trend in transcript levels. None of the 44 pts with an increase of <0.05 has lost the complete CG remission, compared to 6 of 33 (18%) with an absolute increase of 0.05 to 1, and 5 of 11 (45%) with an increase of >1.0 (p=0.0001). The probability of cytogenetic relapse is particularly high for patients who never achieved a major molecular remission. We conclude that achieving a major molecular response, particularly within the first year of therapy with imatinib, is predictive of a durable cytogenetic remission and should be the goal of therapy with imatinib. Increasing transcript levels after achieving a complete CG response predict for a relapse in patients who did not achieve a major molecular response.

BCR-ABL Levels Continue To Decrease up to 42 Months after Commencement of Standard Dose Imatinib in Patients with Newly Diagnosed Chronic Phase CML Who Achieve a Major Molecular Response.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 274-274 ◽  
Author(s):  
Susan Branford ◽  
Z. Rudzki ◽  
A. Grigg ◽  
J. F. Seymour ◽  
K. Taylor ◽  
...  
Keyword(s):  
Cell Mass ◽  
Chronic Phase ◽  
Imatinib Therapy ◽  
Rapid Progression ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Major Molecular Response ◽  
Log Reduction ◽  
Number Of Patients

Abstract The dose of 400mg per day of imatinib is currently considered standard therapy for patients with newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CP). The IRIS trial demonstrated superior response rates in imatinib treated patients compared to interferon alfa, and evaluated molecular response up to 24 months of imatinib therapy in patients who achieved a complete cytogenetic response (CCR). Those patients with a major molecular response (MMR, ≥3 log reduction of BCR-ABL) by 12 months had 100% progression free survival at 24 months. However, very few patients had undetectable BCR-ABL levels. In the current study, we monitored the molecular response for a median of 42 months (25th to 75th percentile 39–45 months) in all patients enrolled in the IRIS trial in Australia and New Zealand who commenced imatinib as their first-line therapy (n=28 patients). We aimed to determine if the BCR-ABL levels continued to decrease and whether additional patients achieve a MMR with a longer follow up. BCR-ABL transcript levels were monitored by real-time quantitative PCR at 3 to 6 month intervals. A CCR (approximately equivalent to a greater than 2-log reduction of BCR-ABL) was achieved in 24 of the 28 patients (85%). The table demonstrates that while the frequency of achieving a MMR increased between 12 and 42 months, most of the improvement occurred between 12 and 24 months. Conversely, from 24 to 42 months the number of patients achieving a ≥4-log reduction increased significantly (P<0.001) and the median BCR-ABL levels reduced (P=0.005). Thirteen patients had a MMR by 12 months and all had a 4 log reduction at 42 months. The median log reduction from 12 to 42 months in these patients was 1.2 logs (range 0.6 to 1.8 logs). Months on Imatinib (n=patients remaining on trial) Median BCR-ABL log reduction of all patients % of all patients who achieved MMR (≥3 log reduction) % of all patients who achieved ≥4 log reduction 12 (n=26) 3.0 46 4 18 (n=26) 3.2 64 4 24 (n=26) 3.4 68 7 30 (n=26) 3.6 68 25 36 (n=25) 3.9 71 32 42 (n=24) 4.2 71 54 Undetectable BCR-ABL transcripts in our assay represent a greater than 4 to 4.5 log reduction, depending on the quality of the RNA. Ten patients had undetectable BCR-ABL on at least 1 occasion, however only 4 patients (14%) had consistently undetectable levels for more than 6 months including their last sampling timepoints (ranging from 3 to 14 consecutive analyses). Of the 4 patients without a CCR all had disease progression and in 1 patient a BCR-ABL mutation was detected, followed by rapid progression to blast crisis. Only 1 other patient had a detectable mutation. A MMR was achieved in this patient prior to detection of the mutation. The MMR was subsequently lost, as was the CCR. In conclusion, with a follow up of 42 months of imatinib therapy the incidence of achieving MMR does not appear to increase significantly after 24 months. However, among patients achieving MMR by 12 months the BCR-ABL levels continued to decline significantly, suggesting that the leukemic cell mass is still decreasing even after 3.5 years of imatinib therapy. Nevertheless very few patients have persistently undetectable BCR-ABL.

Switch to nilotinib versus continued imatinib in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) with detectable BCR-ABL after 2 or more years on imatinib: ENESTcmr 12-month (mo) follow-up.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 6505-6505
Author(s):  
Jeffrey Howard Lipton ◽  
Timothy P. Hughes ◽  
Brian Leber ◽  
Carmino De Souza ◽  
Pedro E Dorlhiac-Llacer ◽  
...  
Keyword(s):  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Molecular Responses ◽  
Log Reduction ◽  
To Receive ◽  
Tki Discontinuation ◽  
Minimal Evidence

6505^ Background: Nilotinib induced significantly faster and deeper molecular responses vs imatinib in the ENESTnd trial. Achieving these deeper molecular responses may increase patient eligibility for future TKI discontinuation studies. Methods: CML-CP pts (N = 207) who achieved a complete cytogenetic response but were still BCR-ABL positive by RQ-PCR after ≥ 24 mo on imatinib were randomized 1:1 to receive nilotinib 400 mg BID (n = 104) or to continue their imatinib dose (400 or 600 mg QD [n = 103]). The primary endpoint was confirmed CMR (undetectable BCR-ABL by RQ-PCR with a sample sensitivity of ≥ 4.5 logs in 2 consecutive samples). Other endpoints included molecular responses (MMR ≤ 0.1%IS, MR4 ≤ 0.01%IS, and MR4.5 ≤ 0.0032%IS) and BCR-ABL ratio over time. Results: Rate of confirmed CMR was higher in the nilotinib arm vs imatinib by 12 mo (12.5% vs 5.8%) (Table). Rate of CMR (undetectable BCR-ABL in at least 1 sample) by 12 mo was significantly higher on nilotinib vs imatinib (23.1% vs 10.7%; P = .02). Rates of MMR, MR4, MR4.5, and CMR were also superior in pts switched to nilotinib, and these pts had significantly shorter times to achieve these responses. Imatinib-treated pts had minimal evidence of improvement in molecular response vs a median 0.5-log reduction in BCR-ABL by 12 mo for the nilotinib cohort. With 12-mo follow-up, 84% of pts remained on nilotinib and 96% on imatinib. The nilotinib safety profile was consistent with prior studies. Both drugs were well tolerated. Conclusions: Twice as many pts achieved deeper molecular responses after switching to nilotinib vs staying on imatinib. [Table: see text]

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