Kinetics Of Molecular Response Research Articles

Treatment-Free Remission in Chronic Phase Chronic Myeloid Leukemia Patients Treated with Nilotinib Front-Line, in Real-Life Conditions: Influence of Switching to Another TKI Prior to Cessation.

Nilotinib (NIL) as front-line therapy in newly diagnosed chronic phase (CP) CML patients (pts) is able to induce high rates of sustained deep molecular response and high possibilities of treatment-free remission (TFR). However, the identification of factors influencing successful TFR in this population remains imprecise. This observational study retrospectively analyzed TFR rates, outcome, and tried to identify factors related to successful TFR in in- and out-study 221 pts treated in this setting with NIL 600 mg, in "real-life" conditions. All pts with newly diagnosed adult CP-CML receiving NIL 300 mg BID alone front-line between 10/2007 and 06/2022, were eligible. Data were retrospectively collected according to the national regulations with pts' information. All pts were assessed and followed according to ELN recommendations 2006→2020 along treatment and to the recommendations of the Fi-LMC (D. Rea et al., Cancer 2018, i. e. 2 years of sustained MR4.5) in case of TFR. In this regard, a TKI was resumed if loss of MMR on one instance. BCR::ABL1 assessments were performed in the 2 reference laboratories, standardised, and expressed in % (IS) with ≥32,000 copies of ABL1 as control. The primary endpoints were the rate of successful TFR on NIL first-line. Secondary endpoints were the kinetics of molecular response, factors influencing outcome, survival, and safety of NIL. Two hundred and one patients were enrolled with 56% males with a median age at diagnosis of 50 (17.5-83) years, and 26% of them had cardiovascular risk factors at onset (tobacco abuse 10%, hypercholesterolemia 9.55%, diabetes 1.36%, none with history of cardiovascular events [CVE]). ELTS scores were high in 13%, intermediate in 30% and low in 53% of pts, unknown in 4% of pts. Twenty-six (12%) pts harboured additional chromosomal abnormalities (ACA) at diagnosis. The median follow-up after NIL initiation was 85.16 (5.72-174) months. After a median of 37.7 months, 119 pts (58%) were not on NIL anymore for toxicities, resistance or TFR. Sixty-eight (31%) pts obtained the TFR criteria and stopped NIL after a median of 66.7 (27-132) months. The median time between first MR4.5 datapoint and TFR was 39 (15.31-120) months. With a median follow-up of 20.3 (0.03-108) months after NIL cessation, the survival without MMR loss after NIL cessation (figure 1.) is 64.38% (95% CI: 53.35- 77.69). Interestingly, no CVE occurred after NIL cessation, as well as no blast crisis. Two patients died in TFR from competitive events (2 solid tumours). We went on comparing the TFR group vs the non-TFR group. The median age at TFR was 56 (30-87) years with no difference at CML diagnosis in terms of age (49 vs 50 years, p=0.096), ELTS (p=0.276), ACA (15% vs 11%, p=0.483) between the 2 groups. In contrast, there was a difference in favour of female vs male gender in the TFR group (56%) vs non-TFR group (39%, p=0.031), and the median time to reach MMR was shorter in the TFR group 5.04 vs 10.2 months, p<0.001; as well as the median time to reach MR4.5 in the TFR group 18.2 vs 36.1 months, p<0.001. We finally compared the successful vs the unsuccessful TFR pts requiring TKI-rechallenge, in univariate analysis and multivariate analyses. The univariate analysis identified pts that have switched to another TKI before TFR for whatever reasons was a risk factor for subsequent loss of MMR [HR: 3.09 (95% CI: 1.30-7.34), Cox p-value=0.011]. This was confirmed by the log-rank survival curves of TFR in patients with or without switch (figure 2., log-rank p=0.008). Surprisingly, neither the duration of NIL before TFR [HR: 0.98 (0.96-1.00), Cox p-value=0.072], nor the duration of MR4.5 prior to NIL cessation [HR: 0.98 (0.95-1.01), Cox p-value=0.15] were found to have an impact. Additionally, the prognostic scores did not influence TFR success on NIL. The multivariate analysis confirmed that switching to another TKI was an unfavourable risk factor for molecular relapse [HR: 2.87 (1.20-6.84), p-value=0.018], and that the lack of impact of the duration of MR4.5 [HR: 0.98 (0.95-1.01), Cox p-value=0.218] had no significant influence. NIL first-line is able to induce high rates of successful TFR in newly diagnosed CP CML patients and switching to another TKI for toxicity and/or resistance, prior to TFR, represents an unfavourable risk factor for the success of TKI cessation. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Long-Term Outcome of Chronic Phase Chronic Myeloid Leukemia Patients Treated with Nilotinib Front-Line

Long-Term Outcome of Chronic Phase Chronic Myeloid Leukemia Patients Treated with Nilotinib Front-Line

An analysis of the kinetics of molecular response during the first trimester of treatment with nilotinib in newly diagnosed chronic myeloid leukemia patients in chronic phase

PurposeThis study was aimed to analyze the association of very early molecular response to nilotinib with the achievement of deep molecular response (MR4) at 18 months. We hypothesized that the BCR-ABL1 levels during the first 3 months of therapy, and the kinetics of their descent in this period, could be predictive of deep molecular response thereafter.MethodsThis substudy of the ENEST1st trial included 60 patients with chronic myeloid leukemia in chronic phase treated with front-line nilotinib, and BCR-ABL1IS levels were measured using GUS as the control gene. The analysis included seven time points during the first trimester of treatment (baseline and fortnightly thereafter).ResultsThe rates of MMR at 12 months, and of MR4 at 18 months (primary variable of the study), were 70 and 41%, respectively, similar to those obtained in the core study. BCR-ABL1IS ≤10% was achieved at 1, 1.5, 2 and 3 months in 50, 70, 83 and 93% of the patients, respectively. The observed shape of the BCR-ABL1IS descent was biphasic, with a faster slope during the first trimester and a median halving time (HT) of 11 days, the shortest reported in the literature. An HT ≤13 days was predictive of MMR at 12 months and MR4 at 18 months.ConclusionsThe association of a shorter HT with response provides a rationale for exploring very early kinetics patterns in all patients treated with potent TKIs such as nilotinib.

Kinetics of Molecular Response with Different Tyrosine Kinase Inhibitors (TKI) Used As Frontline Therapy in Chronic Myeloid Leukemia-Chronic Phase (CML CP),

Abstract 3784▪▪This icon denotes a clinically relevant abstract Background:TKI are standard therapy for patients with CML CP. Imatinib was first established as frontline therapy and more recently dasatinib and nilotinib have shown improved rates and speed of response. Early molecular response has been associated with improved long-term outcome (Blood 2009; 113: 6315), thus the kinetics and rates of molecular response are important predictors of long-term outcome. Aim:To determine the kinetics and rates of molecular response with different TKIs used as initial therapy for patients with CML CP. Methods:We evaluated all pts treated with frontline TKIs (imatinib standard dose or high dose, dasatinib and nilotinib) in consecutive or parallel trials. Cytogenetic and molecular responses were assessed at least every 3 months for the first 12 months, then every 6 months, and were defined using the recommendations of European LeukemiaNet. Molecular responses were defined using international scale. Survival was calculated by the Kaplan-Meier method. Results:Of the 485 pts treated, 73 received imatinib 400mg; 208 imatinib 800mg; 99 dasatinib, and 105 nilotinib. Median age was 48 years (15–86) and median time from diagnosis to TKI therapy was 1 mo (1–13). The median follow-up for each group were 109 months (mo) with imatinib 400, 69 mo with imatinib 800, 30 with dasatinib and 25 mo with nilotinib. Nineteen pts with clonal evolution, but otherwise in CP, were included. Sokal risk score was high in 7%, intermediate in 24% and low in 69%. Cumulative rates of complete cytogenetic response (CCyR) were: imatinib 400mg 87%; imatinib 800mg 91%; dasatinib 96%; and nilotinib 94%. The rate of MMR with imatinib 400mg was 73%, with imatinib 800mg 87%, dasatinib 86%, and nilotinib 88%. Rates of CMR (BCR-ABL/ABL ≤0.0032% IS) were 51%, 71%, 61% and 62%. Median time to achieve MMR and CMR were: imatinib 400mg, 12 mo (3–60) and 18 mo (3–60); imatinib 800mg, 6 mo (3–60) and 9 mo (3–60); dasatinib, 6 mo (3–36) and 12 mo (3–54), and nilotinib 6 mo (3–48) and 6 mo (3–42). The median transcript levels at 3, 6, 12, 18, 24 and 36 mo by treatment arm are shown in table 1. The rates of MMR and CMR at 36 mo for imatinib 400mg were 58% and 34%. Corresponding rates for imatinib 800mg were 87% and 59%; for dasatinib 87% and 54%; and for nilotinib 90% and 63%. We then assessed the probability of achieving MMR and CMR at 12 mo according to the BCR-ABL/ABL levels at earlier timepoints. Two of 9 (22%) evaluable pts with transcript level >10 at 3 mo achieved a MMR at 12 mo but none achieved a CMR. In contrast, 31/52 (60%) evaluable pts with transcript level >1–10 at 3 mo, achieved a MMR at 12 mo and 4 (8%) achieved a CMR. Similarly, pts with level >0.1–1 at 3 mo, 72/129 (56%) evaluable pts achieved a MMR and 29 pts (22%) a CMR at 12 months. For each individual TKI, a similar trend was noted where a higher transcript level (>10; >1–10; >0.1–1) at 3 mo was associated with a decline in achieving a MMR and CMR at 12 mo (MMR- imatinib 400mg: 0%; 50%; 67%, imatinib 800mg: 0%; 62%; 80%, dasatinib: 33%; 67%; 71%, nilotinib: 100%; 50%, 88%, CMR-imatinib 400mg: 0%, imatinib 800mg: 0%; 8%; 10%, dasatinib:0%; 17%; 29%, nilotinib: 0%; 0%; 32%). The probability of transformation to AP/BP by transcript levels at 3 mo (>10; >1–10; >0.1–1, ≤0.1) was 0%, 3%, 2% and 1% for the overall population, with similar trends for the different therapies.Table 1Median transcript levels by treatment arm3 mo6 mo12 mo18 mo24 mo36 moImatinib 4000.20050.33600.03990.00840.00300.0079Imatinib 8000.18100.01830.00840.00490.00440.0027Dasatinib0.21500.03360.01400.00700.00320.0032Nilotinib0.16100.02100.01050.00320.00320.0032 Conclusion:New TKI provide a faster improvement in molecular response among pts with CML CP receiving TKI as initial therapy. Early responses are equally predictive of long-term outcome across all treatment options. Disclosures:Kantarjian:Novartis: Consultancy, Research Funding; BMS: Research Funding; Pfizer: Research Funding. Ravandi:Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Honoraria. Cortes:BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Ariad: Consultancy, Research Funding; ChemGenex: ChemGenex is now Cephalon, Inc., Consultancy, Research Funding; Deciphera: Research Funding.

Kinetics of Molecular Response among Newly Diagnosed Patients with PML-RARα+ Acute Promyelocytic Leukemia Treated with Arsenic Trioxide.

Arsenic trioxide (ATO) is an effective agent to induce molecular remission in patients with PML-RARα+ acute promelocytic leukemia (APL). ATO can induce molecular remission in majority of newly diagnosed and relapsed cases. However, there is limited data on the kinetics of this molecular response. From August 2006, fifteen consecutive newly diagnosed cases of APL treated with single agent ATO were serially monitored by real time PCR (RQ PCR) for PML-RARα expression. ATO was initially administered to induce remission for a maximum period of 60 days; this was followed by a 4 week interval and a consolidation course of ATO administered for 4 weeks. Subsequently after second 4 week interval, ATO was administered for 10 days / month for 6 months as a maintenance regimen. Peripheral blood RQ PCR was done at diagnosis, week 1, 2 and 4 and end of induction, onset of consolidation and at end of consolidation. RQ PCR was done using standard primers, probes, conditions and reagents as defined in the EAC program (Leukemia 2003; 17: 2318–2357). Abelson (ABL) gene was used as a control gene for normalization. The normalized copy number (NCN) was defined as ratio of PML-RARα/ABL expressed as a percentage. The median age of the patients was 29 years (range: 10 – 60). There were 8 (53%) males and 7 females. 5 (33.3%) belonged to the low risk (WBC < 5 x 109/L and Platelet count >20 x 109/Lt) as defined previously by our group for this regimen. 9 (60%) had the bcr1 isoform and the rest (n=6) had the bcr3 isoform. At diagnosis the median copy number was 5.27% (range: 1.47 – 54). A pattern of increased NCN was noted in the first two weeks in 9 (60%) patients (0.5 – 1.5 log increase) (Illustrated in Figure 1). It is possible that this could be related to the differentiation activity of ATO and the resulting hyperleucocytosis. However, this did not statistically correlate with the WBC count at the same time periods. All patients achieved complete molecular remission. 5 (33.3%) had undetectable levels of PML-RARα by the end of induction, 8 (53%) achieved this by onset of consolidation while 2 (13%) achieved this at the end of consolidation. None of these patients relapsed or died during the follow up period. There did not appear to be any correlation with the pattern of RQ PCR response and age, sex, risk status at diagnosis, bcr isoform and genetic polymorphisms among panel of genes known to be important for ATO biotransformation (GST A1, GST P1, GST M1, GST T1, MTHFR C677T, MTHFR A1298C). In comparison to reported data (Chomienne et al. Leukemia 2000; 14: 324–328) the kinetics and quality of molecular response following treatment with ATO is superior to that achieved with conventional ATRA based chemotherapy regimens. Kinetic data of molecular response in a large number of patients would help establish a molecular risk stratification strategy as early predictors of long term responses. [Display omitted]

Real-Time Detection of PML-RARA and RARA-PML Fusion Transcripts in High Risk Acute Promyelocytic Leukemia (APL) Treated with Arsenic Trioxide (ATO): Implications for Realization of Pre-Emptive Therapy for Molecular Relapse.

A key challenge in the management of APL is to improve upon survival rates now achieved with ATRA and anthracycline-based chemotherapy. One approach involves minimal residual disease (MRD) monitoring to identify patients otherwise destined to relapse, whose outcome may be improved by pre-emptive therapy. There is also scope for improvement through reduction in induction deaths and treatment-related mortality, with recent studies suggesting that molecularly targeted therapy involving ATO can achieve long term remissions with limited toxicity. However, such strategies are critically dependent upon optimized schedules for MRD detection to rapidly identify those patients needing additional treatment. Yet, there are limited data concerning assay sensitivity, optimal sample type or kinetics of relapse, that are fundamental to delivery of MRD-directed therapy. We determined expression levels of PML-RARA and reciprocal RARA-PML transcripts in diagnostic BM samples from 102 patients using real-time quantitative PCR (RQ-PCR). Normalized PML-RARA transcript levels varied by 3-logs, equating with marked inter-patient variability in maximal achievable sensitivities for MRD detection, ranging between 1 in 102 and 1 in 105 (med. 1 in 103.8). RARA-PML fusion transcripts were expressed in 68/102 (67%). Parallel detection of both transcripts increased sensitivity for MRD detection in 35/102 (34%); yet, the detection limit was still <1 in 104 in 49% due to the low level of fusion transcript expression. Serial MRD monitoring was undertaken in patients (n=32) treated with ATO for relapsed APL in UK and Eire since Nov 02: 22 in hematologic relapse (HR) and 10 treated pre-emptively in 1st molecular relapse (MR). RQ-PCR assessment prior to MR/HR showed a median increase in PML-RARA transcripts of 0.8 log/month (range 0.2–1.9). Analysis of paired BM and blood (PB) samples revealed that molecular conversion in BM invariably preceded that in PB; including a patient testing negative in PB despite a significant level of disease in BM (6% by FISH). Parallel use of the RARA-PML assay in evaluable patients increased rates of MRD detection, in some instances providing earlier warning of impending relapse. ATO was given using the conventional schedule (0.15mg/kg/d - Regimen A) or a regimen involving loading followed by intermittent dosing (0.3mg/kg/d x 5d, then 0.25mg/kg 2x/wk - Regimen B). No difference in kinetics of molecular response was observed; however amongst patients treated in HR, hyperleucocytosis was less common with Regimen B (peak WBC 5 vs 126 x 109/l, p=0.007), indicating that this schedule may favor apoptosis over differentiation and merits evaluation in newly diagnosed APL. OS from time of relapse was 60% at 3yrs; of 10 patients treated pre-emptively, 7 are in 2nd molecular CR at median of 23mo (7–40mo), 2 died in relapse, treatment is on-going in 1. This study highlights sample type, assay sensitivity (which demonstrates inter-patient and -sample variability) and kinetics of relapse as critical factors that need to be taken into account for the successful delivery of MRD-directed therapy, which is becoming increasingly pertinent to the management of other subsets of acute leukemia.

Molecular Responses in Newly Diagnosed Chronic Myelocytic Leukemia (CML) Patients Treated with 800 mg Imatinib Daily: An Update from the RIGHT Trial Study Group.

Recent long term clinical outcome data have now established 400 mg/d of imatinib as the first line treatment for newly diagnosed patients with CML. We report here the kinetics of molecular response in newly diagnosed CML patients initially treated with a higher dose of 800 mg daily of imatinib. The RIGHT trial is a multicenter study conducted in academic and community practices across the US using 800 mg daily of imatinib as initial therapy in patients with newly diagnosed CML. 115 patients, median age 50y (19y–81y), were followed for both molecular and cytogenetic responses for up to 18 mo. As of May 16, 2006, all patients on study had reached at least 12 mo of follow up, and 51 pt have reached 18 mo, with median follow up of 16 mo. Bone marrow for cytogenetics and PCR were done at baseline and 12 mo, and peripheral blood (PB) for PCR was obtained every 3 mo. As of June 27, 2006, 89 patients were still on study or reached the end of the study period. 10 patients came off study for adverse events and 10 patients withdrew consent. Within the first 12 months, 6 patients (5%) had documented progression of disease and 1/51 patients (1%) treated beyond 12 mo also progressed. One of the 7 patients who progressed showed a BCR-ABL mutation (E255V), while all other patients with mutation analysis had wild type BCR-ABL. PB sampling for PCR showed that the kinetics of major molecular response (MMR), defined as ≥3 log reduction in BCR-ABL/ABL, for these patients was rapid with 50/115 patients (44%) on treatment achieving a MMR by 6 mo. This differs from the previous IRIS study in which 400 mg daily of imatinib resulted in 21% MMR at the 6 mo time point. At 12 mo, MMR rate remained at 44% with 50/115 patients showing at least a 3 log reduction. There appeared to be a relationship between Dose Intensity (DI) and the kinetics of response. The 50 patients with a MMR at 12 mo had a median DI of 98.5% (39–100%). The 8 patients with slower response who failed to obtain both a 2 log reduction in BCR-ABL/ABL at 6 mo and MMR by 12 mo had a median DI of 79% (72–98). The median DI for the patients who progressed on study was 85%. Tolerability of the higher dose of imatinib did not differ significantly in this study for those over or under age 65. DI for the younger and older age groups was 98% (39–100%) and 91% (33–100%) respectively. No difference was noted in the types of AEs for either of the age groups. The most frequent AEs included myelosuppression, rash, fatigue, and musculoskeletal symptoms. 1/115 pt with previous cardiac history had Gr 4 CHF following a second myocardial infarct. We conclude that 800 mg of imatinib daily results in more rapid reduction in tumor burden than 400 mg daily. Tolerability of imatinib was sustainable in both older (>65y) and younger (<65y) pt and did not result in either a significantly greater rate of AEs or a different AE profile in older pt. Further follow up will be needed to determine if the rapid reduction in CML cells implied by the kinetic response to 800 mg imatinib will reduce later rates of progression over time.