A Phase 3 Pilot Study of Continuous Imatinib Versus Pulsed Imatinib with or without G-CSF in Patients with Chronic Phase CML Who Have Achieved a Complete Cytogenetic Response to Imatinib.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 1033-1033 ◽  
Author(s):  
Nicholas Heaney ◽  
Mark Drummond ◽  
Jaspal Kaeda ◽  
Franck Nicolini ◽  
Richard Clark ◽  
...  
Keyword(s):  
Pilot Study ◽  
Disease Progression ◽  
Residual Disease ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Phase 3 ◽  
Significant Difference ◽  
Ifn Therapy

Abstract Imatinib mesylate (IM) induces complete cytogenetic responses (CCR) in the majority of patients with CML in chronic phase (CP). Despite this reduction in disease burden many patients continue to have detectable Bcr-Abl transcripts in peripheral blood. We believe that IM-resistant Ph+ haemopoietic stem cells (HSC) contribute to this residual disease. IM has been shown to selectively target proliferating CML HSC, while simultaneously exerting an antiproliferative effect on the quiescent population-causing accumulation. We have previously characterised these quiescent cells and shown that intermittent in-vitro exposure of Ph+HSC to exogenous G-CSF leads to a reduction in number of quiescent and total HSC in culture (Clin Can Res 2006, 12: 626). This randomised, multi-centre, pilot phase 3 study was established to determine the safety and efficacy of combining G-CSF with IM in patients with CP CML who had achieved CCR on IM. 45 patients were equally randomised between 3 arms: continuous IM (cIM); pulsed IM (pIM 3 weeks IM and 1 week no drug); and pIM-G-CSF (pIM-G 3 weeks IM and 1 week G-CSF). The dose of IM administered was the dose on which the patient had achieved CCR. Patients had a median age of 59y (25–76y) and had been diagnosed with CML for a median of 36m (8–171m). 21 patients had prior IFN therapy with 4 autografted. Hasford scores were 36% low, 46% Intermediate, and 18% high. At baseline 25 patients had a major molecular response (MMR cIM 7, pIM 8, pIM-G 10). Patients were assessed monthly for 1 year with clinical examination, routine blood tests and Bcr-Abl Q-RT-PCR. Significant cardiovascular events were seen in 2 patients - 1 patient died of myocardial infarction (pIM-G) and 1 survived a stroke (cIM). There was a trend to less IM-associated side effects (diarrhoea, muscle cramps) in the experimental arms, though bony pain was reported in pIM-G (5 patients). Statistical analysis (ANCOVA) was performed on Bcr-Abl readings taken during the trial and no significant difference was detectable between the 3 arms. Further endpoint analyses showed that 4 achieved MMR (4 cIM) 21 maintained MMR (6 cIM, 6 pIM, 9 pIM-G) and 7 showed disease progression with loss of MMR (1 cIM, 2 pIM, 1 pIM-G) and/or loss of CCR (2 pIM, 1 pIM-G). 4 patients were withdrawn as a result of disease progression (3 pIM, 1 pIM-G). In conclusion both experimental arms appeared safe and well tolerated. In this pilot study there was no clear difference in efficacy when either pIM or pIM-G was compared to cIM, despite the 25% effective dose reduction of IM in the experimental arms. The absence of a clear benefit means that this approach cannot be recommended as an alternative to standard IM dosing, however may be applicable to a selected group of patients who cannot tolerate standard daily dosing.

Comparable Distribution of Minimal Residual Diesease between CD34 Positive Hematopoietic Progenitors, CD34 Negative Cells and Total White Cells in Patients with Chronic Myeloid Leukemia (CML) in Molecular Response.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1985-1985
Author(s):  
Thoralf Lange ◽  
Thomas Thielsen ◽  
Sabine Leiblein ◽  
Ruediger Alt ◽  
Guido Zschau ◽  
...  
Keyword(s):  
Residual Disease ◽  
False Positive Rate ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Wilcoxon Test ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Cd34 Cells ◽  
Significant Difference ◽  
Minimal Residual

Abstract Objectives: Most patients with chronic phase CML attain a complete cytogenetic response (CCR) to imatinib (IM) but BCR-ABL remains detectable by RT-PCR, indicating persistence of residual disease. One small study (Bhatia et al. Blood101(12):4701–7, 2003) suggested that the levels of minimal residual disease (MRD) in CCR patients may be highest in the CD34+ cells but it is not clear whether the cohort under study was truly representative of patients with stable CCR. To address this question, we compared the level of MRD in total white cells (TWC), CD34-positive (CD34+), CD34-negative (CD34−) and CFU-GM colonies in patients with a molecular response (MR, defined as a BCR-ABL / ABL ratio below 0.12% as suggested by Paschka et al. Blood104 (11): #1013, 2004) to IM. Patients and Methods: Twenty-two bone marrow samples were obtained from 13 CML patients with CCR [7 male/6 female, median age 57 (range 23–68) years]. At IM start all patients were in chronic phase (8 newly diagnosed, 5 refractory or intolerant to interferon alpha). The median time on IM at the date of the first analysis was 39 (range 10–50) month, the median duration of CCR and MR was 32 (range 4–49) and 20 (range 0–36) month, respectively. The frequency of CD34+ cells in unmanipulated BM as determined by FACS was compared to 33 patients with newly diagnosed CML and 9 healthy individuals. CD34+ cells were selected over immunomagnetic columns. At least 100 CD34+, CD34− and TWC were analyzed for BCR-ABL by FISH (Vysis LSI BCR-ABL ES probe, lab specific false positive rate of < 2%). CD34+ cells were plated in triplicate at 104 cells/ml and CFU-GM were counted on day 14. Quantitative PCR (qPCR) was performed on CD34+, CD34-, TWC and pools of 10 CFU-GM colonies. PCR-negative samples with less than 1000 copies of the ABL gene / μl cDNA were excluded. Results: The median frequencies of CD34+ cells in patients with MR, newly diagnosed patients and healthy controls were 0.30 (range 0.10–1.56)%, 3.81 (range 0.04–17.77)% and 0.88 (range 0.46 to 1.47)%, respectively (p<0.0005, Kruskal-Wallis-Test). BCR-ABL was undetectable by interphase FISH in all three compartments. Eleven (50%) and 16 (72%) out of 22 samples derived from the CD34+ and CD34− cells contained sufficient c-DNA for PCR. No significant differences were observed between the levels of BCR-ABL mRNA in CD34+, CD34− and TWC [median 0.023 (range, 0.001 to 0.149)%, 0.020 (range 0,005– 0,134)% and 0.011 (range 0.0005 to 0.257)%], respectively (p= ns, Wilcoxon-test). In the patients with more than one sample analyzed, the distribution of MRD between the compartments did not change significantly over time. C-DNA from colonies was available for 14 patients (63%). Again, no significant difference in BCR-ABL mRNA in comparison to CD34+, CD34− and TWC was detected [median 0.001 (range 0,001 to 0.0425)%]. Conclusion: In CML with MR to IM CD34+ cells are consistently BCR-ABL-negative. Comparable levels of BCR-ABL mRNA residual disease are present in total white cells, CD34+, CD34- and CFU-GM colonies, suggesting that residual disease is not limited to immature cells.

Does Previous Interferon Use Have Negative Effect on Imatinib Response in Chronic Myeloid Leukemia (CML)? A Single Center Study.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4821-4821
Author(s):  
Mustafa Yenerel ◽  
Reyhan Diz-Kucukkaya ◽  
Naciye Demirel ◽  
Mesut Ayer ◽  
Selim Yavuz ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
First Line ◽  
Group I ◽  
Blastic Phase ◽  
Significant Difference ◽  
Group Ii ◽  
Ifn Treatment

Abstract Aim: Effectiveness of imatinib in CML was evaluated on a cohort of 104 patients with a median 29 months of observation time, recruited between 3/2002 and 2/2006. Patients and methods: 104 patients diagnosed as having CML between 1990–2006 were included in this study. Their median age was 44 years (19–77) and 55% of patients were male. Imatinib was used in a dose of 400mg/day for chronic phase and 600mg/day for accelerated and blastic phase. In chronic phase patients with no cytogenetic response in 1 year and in accelerated or blastic phase patients with no hematologic response in 3 months, doses were increased to 600mg/day and 800 mg/day respectively. Interferon (IFN) treatment had been used as α-IFN 5 MIU/m2 daily combined with or without monthly courses of cytosine arabinoside (Ara-C) 20 mg/m2 for 10 days in 50 patients before imatinib. Cytogenetic response (CR) was monitored on bone marrow metaphases collected at baseline, 3, 6, 9 and 12 months during the first year, and every 6 months thereafter. CR was quantified by 20 metaphases Ph in bone marrow: 0% as complete (CCR), 1–35% major as (MjCR) and &gt; 95% as imatinib failure. Molecular response followed by PCR in bone marrow samples. We stratified the patients according to previous IFN treatment in two groups. CML patients who were treated with imatinib as a first line therapy were analyzed as Group I. Other patients who were treated initially with IFN and ara-C and those were switched to imatinib because of intolerance or unresponsiveness were accepted as Group II. Results: Age, sex distribution and disease phases of both groups were quite similar. Therapy responses are summarized in Table 1. Hematological response (HR) was seen in 90,4 % of the patients (94/104) in median 54 days (11–149) for Group I and 41 days (15–193) for Group II. There wasn’t any difference according to the time elapsed for HR (p=0,79). Cytogenetic data were interesting in our patients. As a total result, CR were achieved in 77,8 % of the patients in median 5,1 months (84 days– 2,7 years). CR rate was significantly higher in Group I (p=0.019). When we compared two groups according to early cytogenetic response in first 6 months, Group I had also much better results (p=0.049). CCR were achieved 35,6 % of the patients (37/104) and there wasn’t any difference between the groups (p=0,25). Molecular response was achieved in 19,2% of the patients followed by PCR (19/87) and there was no significant difference (p=0,15). We conclude that imatinib is highly effective as a first line agent in CML patients. Advanced disease age probably is the most important factor for the lower response rates in the second group. But, the role of previous IFN therapy should also be questioned. As a summary, imatinib should be used in every CML patient without any delay in order to get higher and sooner CR. Tablo 1. Imatinib response of the 104 patients with CML. HR (p=0.89) CR (p=0.019) MjCR in 6 months(p=0.049) CCR(p=0.25) Mol. Response(p=0,15) Imatinibfailure (p=0.03) Imatinib Follow-up Group I 90,7% (49/54) 77,8% (42/54) 57,4% (31/54) 40,7% (22/54) 30% (12/40) 22,2% (12/54) 22,1 months (3,7 months -3,5 yrs) Group II 88% (44/50) 56% (28/50) 38% (19/50) 30% (15/50) 17% (8/47) 40% (20/50) 3 years (9months-5,1 yrs)

For CML Patients in Chronic Phase Who Achieve a Cytogenetic Response to Imatinib the Finding of a BCR-ABL Mutation Predicts for Progression to Advanced Phase but It Has No Such Significance in Primary Resistance.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 323-323
Author(s):  
Hugues de Lavallade ◽  
Jamshid S. Khorashad ◽  
Dragana Milojkovic ◽  
Simon Wagner ◽  
Jaspal Kaeda ◽  
...  
Keyword(s):  
Adverse Effect ◽  
Genomic Instability ◽  
Direct Sequencing ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Primary Resistance ◽  
Secondary Resistance ◽  
Advanced Phase

Abstract We analysed outcome for 211 CML patients treated with imatinib in chronic phase (CP) (99 newly diagnosed and 112 late chronic phase) who were screened for BCR-ABL kinase domain (KD) mutations using direct sequencing regardless of the response status. When a mutation was found all available previous cDNA samples were analysed by pyrosequencing to establish the date of its first occurrence and subsequent kinetics. The median age of patients was 47.4 years. The Sokal risk score was ‘low’ in 57 patients, ‘intermediate’ in 82 and ‘high’ in 72. The median follow up from starting imatinib was 45 months (rage 6 to 89 months). A mutation was detected in 34 of the 211 patients (16%) at a median time of 27 months from starting imatinib. Twenty-two different mutations were identified, the most frequent being M244V (n=6) and F359V (n=3). When studied serially by pyrosequencing the size of the mutant subclone never exceeded 50% of total BCR-ABL transcripts in 8 patients, while in 17 patients it exceeded 90% on at least one occasion. 48 patients discontinued imatinib while still in CP and received either dasatinib, nilotinib or an allograft. The overall progression-free survival (absence of advanced phase) at 5 years was 73%. Major (MCyR) and complete (CCyR) cytogenetic responses were achieved by 153 and 123 patients respectively; 56 patients achieved major molecular response. 24% of the patient with up front cytogenetic resistance had a mutation while 40% of the patients with acquired cytogenetic resistance develop a mutation. In an-intention-to-treat analysis, patients harboring a mutant clone had a poorer PFS at 4 years (78% versus 57%, p=0.0014). The various mutations had no differential effects based on their known imatinib IC50. By multivariate analysis, factors associated with worse PFS were the presence of a KD mutation and failure to achieve CCyR (relative risks for PFS 2.6 and 8.7 respectively, p=0.002). Interestingly, the adverse effect of the presence of a KD mutation was restricted to the patients who achieved a MCyR (PFS 91% versus 62% at 5 years, p = 0.0006); it had no adverse impact on patients who failed to achieve a MCyR (PFS 42% and 49%, p=0.73). Similar results were found when the analysis was repeated according to the achievement of CCyR (data not shown). Surprisingly patients with a continuously low percentage (≤50%) of mutated vs wild type (>50%) clones fared worse than patients in whom the mutated clone became the predominant population (PFS 14% vs 69% respectively, p=0.0005). Comparable results were obtained when the patients were censored at the point of discontinuing imatinib, correcting for the effects of subsequent treatment, ie allografting (data not shown). The fact that the adverse effect of a mutation seems to be restricted to patients who had achieved cytogenetic response, the fact that mutations present at low level seemed to have a remarkable adverse effect and the fact that the in-vitro level of resistance to imatinib of the specific mutation did not affect the PFS could all be explained if the development of a mutation is only a reflection of the genomic instability of the disease that leads to secondary resistance to imatinib and eventually to transformation. Thus genomic instability may be less important in explaining primary resistance to imatinib and eventual transformation in patients with up-front resistance.

Response and Outcomes to Nilotinib at 24 Months in Imatinib-Resistant Chronic Myeloid Leukemia Patients in Chronic Phase (CML-CP) and Accelerated Phase (CML-AP) with and without BCR-ABL Mutations.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1130-1130 ◽  
Author(s):  
Jerald P. Radich ◽  
Giovanni Martinelli ◽  
Andreas Hochhaus ◽  
Enrico Gottardi ◽  
Simona Soverini ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Median Time ◽  
Research Funding ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Advisory Committees ◽  
Imatinib Resistant

Abstract Abstract 1130 Poster Board I-152 Background Nilotinib is a selective and potent BCR-ABL inhibitor, with in vitro activity against most BCR-ABL mutants (excluding T315I) indicated for the treatment of patients with Philadelphia chromosome positive (Ph+) CML in CPor AP resistant or -intolerant to prior therapy, including imatinib. In a previous analysis of nilotinib in patients with BCR-ABL mutations, mutations occurring at three specific amino acid residues (E255K/V, Y253H, and F359C/V) were shown to be associated with less favorable response to nilotinib. The current analysis is based on mature data with a minimum follow-up of 24-months for all patients. Outcomes of patients at 24 months were analyzed by mutation type. Methods Imatinib-resistant CML-CP (n = 200) and CML-AP (n = 93) patients were subdivided into the following mutational subsets: no mutation, sensitive mutations (including mutations with unknown in vitro IC50). or E255K/V, Y253H, or F359C/V mutations at baseline. Patients with mutations of unknown in vitro sensitivity were classified as sensitive in this analysis based on a previous finding that patients with these mutations responded similarly to nilotinib as patients with sensitive mutation. Patients with baseline T315I mutations were excluded from this analysis. Patient groups were analyzed for kinetics and durability of cytogenetic and molecular response to nilotinib, as well as event-free survival (EFS), defined as loss of hematologic or cytogenetic response, progression to AP/BC, discontinuation due to disease progression, or death, and overall survival (OS). Results In CML-CP and -AP patients with no mutation, sensitive mutations, or E255K/V, Y253H, or F359C/V mutations, hematologic, cytogenetic and molecular responses are provided in the Table. Overall, patients with no mutations responded similarly to patients with sensitive mutations, whereas patients with E255K/V, Y253H, or F359C/V mutations had less favorable responses. This correlation was observed in both CML-CP and CML-AP patients, respectively. Median time to CCyR was 3.3 months (range, 1.0–26.7) for CML-CP patients with no mutations, and 5.6 months (range, 0.9–22.1) for patients with sensitive mutations. At 24 months, CCyR was maintained in 74% of CML-CP patients with no mutation and in 84% of patients with sensitive mutations. One patient with CML-CP and an E255K mutation achieved CCyR at 25 months and maintained until last assessment at 30 months. Median time to MMR was similar at 5.6 months (range, 0.9–25.8) for CML-CP patients with no mutations and 5.6 months (range, 2.7–22.1) for patients with sensitive mutations. No patient with a less sensitive mutation achieved MMR. Median EFS and 24-month estimated OS rate are provided in the Table. Conclusions Imatinib-resistant CML-CP and CML-AP patients treated with nilotinib therapy with BCR-ABL mutations (excluding E255K/V, Y253H, or F359C/V) achieved rapid and durable cytogenetic responses, and estimated EFS and OS at 24 months similar to that of patients with no mutations, respectively. Patients with E255K/V, Y253H, or F359C/V mutations had lower and less-durable responses and shorter EFS than patients with sensitive mutations. Alternative therapies may be considered for patients with these uncommon mutations (E255K/V, Y253H, and F359C/V). Disclosures Radich: Novartis: Consultancy, Honoraria, Research Funding. Hochhaus:Novartis: Research Funding. Branford:Novartis Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Shou:Novartis: Employment. Haque:Novartis: Employment. Woodman:Novartis: Employment. Kantarjian:Novartis: Research Funding. Hughes:Bristol-Myers Squibb: Advisor, Honoraria, Research Funding; Novartis: Advisor, Honoraria, Research Funding. Kim:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Wyeth: Research Funding. Saglio:Novartis: Consultancy, Speakers Bureau; BMS: Consultancy, Speakers Bureau.

Switching patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP) with residual disease on long-term imatinib (IM) to nilotinib (NIL): ENESTcmr 24-mo follow-up.

2013 ◽  
Vol 31 (15_suppl) ◽  
pp. 7053-7053
Author(s):  
Nelson Spector ◽  
Brian Leber ◽  
Jeffrey Howard Lipton ◽  
Carmino De Souza ◽  
Beatriz Moiraghi ◽  
...  
Keyword(s):  
Residual Disease ◽  
Blast Crisis ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Molecular Responses ◽  
The Difference ◽  
Treatment Free Remission

7053^ Background: The 12-mo results of ENESTcmr demonstrated that switching pts on IM with sustained BCR-ABL positivity to NIL leads to faster, deeper molecular responses (MRs)vs remaining on IM. These deeper molecular responses (MR4.5 [BCR-ABL ≤ 0.0032%IS] or greater) are a prerequisite to enter most treatment-free remission studies. Here, we report 24-mo f/u of ENESTcmr. Methods: Philadelphia chromosome–positive CML-CP pts (N = 207) who achieved a complete cytogenetic response, but had detectable BCR-ABL transcripts after ≥ 2 y on IM, were randomized to receive NIL 400 mg twice daily (BID; n = 104) or continue their IM dose (400/600 mg once daily [QD]; n = 103). Results: By 24 mo, significantly more pts achieved confirmed undetectable BCR-ABL (by RQ-PCR with ≥ 4.5 log sensitivity in 2 consecutive samples) with a switch to NIL vs continuing IM (22.1% vs 8.7%; P = .0087). The increase in the rate of undetectable BCR-ABL from mo 12 to 24 was higher for pts on NIL vs IM (9.6 vs 2.9 percentage points). In pts without MR4.5 at baseline (BL), MR4.5 was achieved by 24 mo in 42.9% vs 20.8% of pts (NIL vs IM; P = .0006). In pts without major molecular response (MMR; ≤ 0.1%IS) at BL, MR4.5 was achieved by 24 mo in 29.2% vs 3.6% of pts (P = .016). No progressions to accelerated phase/blast crisis or deaths occurred on study since the 12-mo f/u. Event-free survival at 24 mo was 96.6% vs 92.8% in the NIL and IM arms, respectively. Discontinuations due to adverse events occurred in 11.5% and 2.9% of pts in the NIL and IM arms. The NIL safety profile was consistent with prior switch studies. Conclusions: By 24 mo, significantly more pts achieved deeper responses (MR4.5and undetectable BCR-ABL) with switch to NIL vs remaining on IM, and the difference between arms in these endpoints increased between 12 and 24 mo. Clinical trial information: NCT00760877. [Table: see text]

Towards Stopping Imatinib Therapy under the Umbrella of Interferone: Alpha-Interferone Improves Molecular Response in CML Patients with Imatinib Induced Complete Cytogenetic Remission: An Early Observation from a Study of Pegylated Interferone in the Set up of Minimal Residual Disease.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 4788-4788
Author(s):  
Izhar Hardan ◽  
Ninette Amariglio ◽  
Luba Trakhtenbrot ◽  
Avichai Shimoni ◽  
Maya Koren-Michowitz ◽  
...  
Keyword(s):  
Disease Progression ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Early Observation ◽  
Base Line ◽  
Molecular Response ◽  
Rt Pcr ◽  
Ifn Therapy ◽  
Set Up ◽  
Minimal Residual

Abstract The therapy with Imatinib mesylate (Ima) is related with a high rate of response in both newly diagnosed and previously treated CML patients (pt’s). However only 5% of treated pt’s achieve complete molecular remission (CMR) as defined by repeated negative nested PCR or RT-PCR studies, and discontinuation of therapy usually results in a rapid disease progression. The later phenomenon is related with the reduced activity of Ima on early Ph+ progenitor cells (LTCIC). Two recent reports suggests that, unlike the pt’s with less then CMR, in about half of the pt’s with CMR on Ima, discontinuation of therapy do not result in disease progression. Alpha interferone (IFN) was shown to be highly active in suppressing Ph+ LTCIC. Indeed, in patients achieving durable complete cytogenetic remissions (CCyR) with IFN, therapy can be discontinued. It was also shown that IFN therapy induces significantly higher response rate when applied in the set up of minimal residual disease (MRD, i.e. in CCyR after high dose chemotherapy), then at diagnosis. We therefore initiated a clinical trial that aims to suppress the Ph+ stem cells remaining active at the MRD set-up after Ima therapy, by the addition of IFN at that stage, to facilitate discontinuation of therapy in Ima responding pt’s. We report on an early observation in the first cohort of patients. Materials and methods. CML pt’s that achieved a durable CCyR (&gt; 1 year of negative classical cytogenetic and FISH studies) are eligible. After randomization, Pegylated alpha-2A interferone (Peg-IFN, Pegasys, Hoffmann - La Roche), 180 mcg/week, is added to therapy (basic Ima dose unchanged) in the study arm, and given for 12 months. Ima is discontinued after 9 months of Peg-IFN therapy following BM study that indicates maintained CCyR. Tight follow up of BM studies is than applied as it was shown that re-induction of response was feasible in all documented progressions caused by discontinuation of Ima. Pt’s on the control arm continue Ima therapy until progression. Results. To date, seven pt’s in the study arm completed 4 months of therapy. One patient chose to stop Peg-IFN therapy after two weeks due to side effects. He had a base line CMR that was unchanged in the 4 month’s study. The other six pt’s are 5 males and one female age 24 to 59 (median 36) years, with a disease duration of 34–98 (median 49) months. Five of the six failed (3) or lost response (2) to IFN therapy in the past. One patient underwent an autologous BMT which induced reversibility of resistance to IFN seven years ago. Two pt’s required dose reduction of Peg-IFN (to 90 mcg/week). All six pt’s continued their base line Ima dose. After 4 months of Peg-IFN therapy, four pt’s that started with a positive RT-PCR study (0.2%, 0.9%, 0.07% and 0.1%) achieved a CMR (zero bcr/abl transcripts in RT-PCR study). One patient reduced his MRD from 0.8% to 0.01%, and one patient kept a CMR that was documented prior to therapy. An updete of all pt’s completing 4 month of therapy in this study will be presented. Conclusions. The addition of Peg-IFN to CML patients with a durable Imatinib induced CCyR, improves molecular response and can induce CMR. This observation is an encouraging mile stone in the attempt of using IFN as a platform to facilitate discontinuation of Imatinib therapy in responding patients.

scholarly journals Impact of Baseline BCR-ABL Mutations on Response to Nilotinib in Patients With Chronic Myeloid Leukemia in Chronic Phase

2009 ◽  
Vol 27 (25) ◽  
pp. 4204-4210 ◽  
Author(s):  
Timothy Hughes ◽  
Giuseppe Saglio ◽  
Susan Branford ◽  
Simona Soverini ◽  
Dong-Wook Kim ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Phase Ii ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Imatinib Resistance ◽  
Mutational Status ◽  
Imatinib Resistant

Purpose Nilotinib is a second-generation tyrosine kinase inhibitor indicated for the treatment of patients with chronic myeloid leukemia (CML) in chronic phase (CP; CML-CP) and accelerated phase (AP; CML-AP) who are resistant to or intolerant of prior imatinib therapy. In this subanalysis of a phase II study of nilotinib in patients with imatinib-resistant or imatinib-intolerant CML-CP, the occurrence and impact of baseline and newly detectable BCR-ABL mutations were assessed. Patients and Methods Baseline mutation data were assessed in 281 (88%) of 321 patients with CML-CP in the phase II nilotinib registration trial. Results Among imatinib-resistant patients, the frequency of mutations at baseline was 55%. After 12 months of therapy, major cytogenetic response (MCyR) was achieved in 60%, complete cytogenetic response (CCyR) in 40%, and major molecular response (MMR) in 29% of patients without baseline mutations versus 49% (P = .145), 32% (P = .285), and 22% (P = .366), respectively, of patients with mutations. Responses in patients who harbored mutations with high in vitro sensitivity to nilotinib (50% inhibitory concentration [IC50] ≤ 150 nM) or mutations with unknown nilotinib sensitivity were equivalent to those responses for patients without mutations (not significant). Patients with mutations that were less sensitive to nilotinib in vitro (IC50 > 150 nM; Y253H, E255V/K, F359V/C) had less favorable responses, as 13%, 43%, and 9% of patients with each of these mutations, respectively, achieved MCyR; none achieved CCyR. Conclusion For most patients with imatinib resistance and with mutations, nilotinib offers a substantial probability of response. However, mutational status at baseline may influence response. Less sensitive mutations that occurred at three residues defined in this study, as well as the T315I mutation, may be associated with less favorable responses to nilotinib.

Lymphoid Foci in Bone Marrow of Patients with Chronic Myeloid Leukaemia Treated with Imatinib.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2008-2008 ◽  
Author(s):  
Marion M. Roberts ◽  
David M. Ross ◽  
Timothy P. Hughes ◽  
Luen Bik To
Keyword(s):  
Bone Marrow ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Response To Treatment ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Log Reduction ◽  
First Line Therapy ◽  
T Lymphocyte Proliferation

Imatinib treatment of CML is successful but long term. In spite of reported inhibition of T lymphocyte proliferation and activation, we noticed multiple lymphoid foci occurring in BM trephines from CML patients on Imatinib. Method: Patients with chronic phase CML were monitored with BM biopsies (generally 3 monthly) for 1 to 4 years on Imatinib (34 patients) and for 1.5 to 12 years on Interferon (22 patients). Three hundred and thirty-one trephine biopsies were assessed for the occurrence of lymphoid foci. Selected trephines with foci on recut sections were examined by immunocytochemistry with CD3 and CD20, and available aspirates were tested by flow cytometry and PCR for evidence of monoclonality. Results: Lymphoid foci in bone marrow trephines of patients with CML chronic phase occurred more frequently in Imatinib-treated patients (28/34 patients; 82%) than in Interferon-treated patients (9/22 patients; 41%) (p =0.001). Of 175 trephine biopsies from Imatinib-treated patients 68 (39%) contained lymphoid foci, compared to 18 of 156 (12%) trephines from Interferon-treated patients (p= 0.001). In 13/34 Imatinib-treated patients the BM trephine was positive on only one occasion, with 15/34 having multiple positive biopsies. In comparison BM trephine biopsies from random patients with various diagnoses have been described to have lymphoid foci in 3% of cases (Thiele et al, J Clin Pathology 1999,52,294). The majority of foci were interstitial but there were occasional paratrabecular foci. There was no difference between the incidence of foci in Imatinib-treated patients who had previously been treated with Interferon (11/14) and those who had Imatinib as first-line therapy (17/20). Lymphocyte numbers in BM aspirates were above normal in 32/175 aspirates and not coincident with the presence of foci in the corresponding trephines. Foci in the trephines examined by immunocytochemistry showed that the foci were a mixture of CD3 and CD20 positive cells. Flow cytometric immunophenotyping of available BM aspirates of patients with lymphoid foci showed no monoclonality, apart from 1 patient who developed monoclonal Non-Hodgkins lymphoma confined to the bone marrow during treatment with Imatinib. Only 2 patients had foci present at diagnosis of CML and one of these Imatinib-treated patients was the one who later developed NHL. Response to treatment as assessed by cytogenetic response could not be correlated with the development of lymphoid foci in the BM during treatment, as all Imatinib treated patients achieved complete cytogenetic remission. However patients with multiple positive trephine biopsies showed a trend (p=0.095) towards better molecular response as measured by a greater than 4 log reduction in BCR/ABL (8/14) than those with no lymphoid foci (1/6). Conclusion: Lymphoid foci occur frequently in the BM trephines of Imatinib- treated chronic phase CML patients; more commonly than in Interferon-treated CML patients. Both these patient groups have a higher number of lymphoid foci than is reported in random BM biopsies. This finding seems in contradiction to in vitro findings of Inatimib suppression of lymphocytic activation and proliferation. The occurrence of multiple foci suggests that the BM trephines and aspirates should continue to be monitored in Imatinib-treated patients. This early data also suggests that there may be a correlation of molecular response to Imatinib with the development of multiple lymphoid foci in the bone marrow.

Nilotinib Efficacy According to Baseline BCR-ABL Mutations in Patients with Imatinib-Resistant Chronic Myeloid Leukemia in Chronic Phase (CML-CP)

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 3216-3216 ◽  
Author(s):  
Andreas Hochhaus ◽  
Dong-Wook Kim ◽  
Giovanni Martinelli ◽  
Timothy P. Hughes ◽  
Simona Soverini ◽  
...  
Keyword(s):  
Clonal Selection ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Response Rates ◽  
Cytogenetic Response ◽  
Kinase Domain ◽  
Molecular Response ◽  
Abl Kinase ◽  
Imatinib Resistant

Abstract Resistance or intolerance to imatinib in CML-CP occurs in ~20–30% of cases. The most frequent cause of resistance is clonal selection of cells harboring BCR-ABL kinase domain mutations. Nilotinib is a rationally designed, selective and potent BCR-ABL inhibitor with activity against most BCR-ABL mutants (not T315I) indicated for the treatment of Ph+ CML patients (pts) in chronic (CP) or accelerated phase (AP) resistant or intolerant to prior therapy including imatinib. This subanalysis of a phase II study of nilotinib in imatinib-resistant CML-CP pts assessed the occurrence of BCR-ABL mutations at baseline and during nilotinib treatment and their impact on treatment outcome after 12 months of nilotinib therapy. Of 321 CML-CP pts, 281 (88%) had baseline mutation data available, 114/281 (41%) had detectable BCR-ABL mutations prior to nilotinib therapy. The frequency of mutations at baseline was 55% among imatinib-resistant pts (n=192) and 10% among imatinib-intolerant pts (n=89). 23% of imatinib-resistant pts had mutations that were sensitive to nilotinib in vitro (IC50 ≤150 nM). These 12 different mutations (n=44) spread across the entire BCR-ABL kinase domain including P-loop, A-loop, and other regions. 14% of imatinib-resistant pts had 3 mutations that were less sensitive to nilotinib in vitro (IC50 &gt;150 nM; Y253H, E255K/V, and F359C/V) and another 15% had a total of 16 mutations with unknown sensitivity to nilotinib. In imatinib-resistant pts lacking baseline mutations, after 12 months of therapy, major cytogenetic response (MCyR) was achieved in 60%, complete cytogenetic response (CCyR) in 40%, and major molecular response (MMR) in 28% of pts. In pts with detectable mutations, 51% achieved MCyR, 32% CCyR, and 20% MMR. Cytogenetic response rates in pts harboring mutations sensitive to nilotinib (MCyR 59%; CCyR 41%) or mutations with unknown sensitivity to nilotinib (MCyR 63%; CCyR 50%;) were comparable to those for pts without baseline mutations (MCyR 60%; CCyR 40%). Pts with mutations less sensitive to nilotinib in vitro had less favorable response after 12 months of therapy (23% MCyR). Pts with baseline mutations had a higher rate of disease progression during nilotinib treatment compared to pts without baseline mutations (46% vs. 26%). Different rates of progression were also observed with different mutations: 34% (15/44) of pts with mutations sensitive to nilotinib vs. 69% (18/26) with mutations less sensitive to nilotinib progressed. Mutations most frequently associated with progression were E255K/V (6/7) and F359C/V (9/11). Progression was defined as any of the following: investigator’s evaluation as progression, development of CML-AP or blast crisis, loss of CHR, loss of MCyR. During nilotinib therapy, 48/281 (17%) pts had newly detectable mutations, which were more frequent in pts with baseline mutations than in pts without baseline mutations (29% vs. 9%, respectively). The majority of pts without baseline mutations also did not have newly detectable mutation at the time of progression (n=14/18) suggesting that pts without baseline mutations are less likely to progress due to newly detectable mutations. In the 63 pts who progressed, 29% had no detectable mutation at progression, suggesting the involvement of alternative mechanisms of resistance in these pts. Overall, nilotinib treatment results in significant cytogenetic responses in pts with imatinib-resistant CML-CP with or without BCR-ABL mutations. The majority of imatinib-resistant pts with detectable BCR-ABL mutations at baseline also responded to nilotinib. Pts with BCR-ABL mutations sensitive and with unknown sensitivity to nilotinib in vitro achieved significant response rates with nilotinib therapy, comparable to those for pts without baseline mutations.

Characteristics and Outcome of Patients (pts) with V299L BCR-ABL Kinase Domain (KD) Mutation After Therapy with Tyrosine Kinase Inhibitors (TKIs).

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3428-3428
Author(s):  
Elias Jabbour ◽  
Hagop M. Kantarjian ◽  
Dan Jones ◽  
Yin Cameron ◽  
Elizabeth Burton ◽  
...  
Keyword(s):  
Research Funding ◽  
Kinase Inhibitors ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Experimental Models ◽  
Molecular Response ◽  
Primary Resistance ◽  
Secondary Resistance ◽  
Abl Kinase

Abstract Abstract 3428 Point mutations of the BCR-ABL KD are the most frequently identified mechanism of resistance in pts with CML who fail TKI. Experimental models of in vitro drug sensitivity have shown that specific mutations may develop after incubation with second generation TKIs, albeit at a decreased frequency compared with imatinib. Some of the mutations are novel and not previously described after imatinib failure; in some instances they did not confer resistance to imatinib. One of them, V299L was rarely encountered after imatinib therapy but was reported to emerge after dasatinib exposure in induced mutagenesis models causing resistance to dasatinib by impairing its binding. We assessed the incidence and pattern of development of V299L in pts with TKI-resistant CML at our institution, and the response following change of therapy. V299L mutation was detected in 15 pts with CML: 1 occurred among 186 pts assessed for mutations (0.05%) after imatinib failure (1% of all mutation detected), 9 among 69 of the 170 evaluable (i.e., had abl sequencing) pts (13%) who developed mutations on dasatinib, and 5 among 19 of the 72 evaluable pts (26%) who developed mutations on bosutinib (p<0.001); none of the 51 pts who developed mutations on nilotinib (among 125 tested) acquired V299L. Median age for pts with V299L was 56 years (range, 26–82 years). Eight pts were previously treated with interferon-alpha. One pt developed V299L after receiving imatinib for 26 months (mos). The median time to development of V299L was 14 mos (range, 1–30 mos) for those treated with dasatinib (7 received dasatinib after imatinib failure, 1 after imatinib and nilotinib failure; and 1 after failure of imatinib, INNO-406, and bosutinib), and 13 mos (range, 2–48 mos) for those treated with bosutinib (after imatinib failure in 1, and as 3rd TKI after imatinib and dasatinib failure). The best response to TKI immediately preceding V299L (1 imatinib, 9 dasatinib, 5 bosutinib) was complete hematologic response only in 6 (40%, 4 dasatinib, 2 bosutinib), minor cytogenetic response in 2 (13%; 1 imatinib, 1 dasatinib), complete cytogenetic response in 4 (27%; 3 dasatinib, 1 bosutinib); no response in 3 pts (20%; 1 dasatinib, 2 bosutinib). The median duration of response was 17 mos. V299L was associated with primary resistance in 4 pts, and secondary resistance in 9. Two pts on dasatinib therapy remained in CHR and minor cytogenetic response, respectively, 3 months after the mutation detection. At the time the mutation was detected, 5 pts were in chronic (CP), 7 in accelerated (AP), and 3 in blast phase (BP). 3 pts (1 CP, 1 AP, 1 BP) received nilotinib after V299L detection and 1 in CPresponded (major molecular response sustained for 40+ mos). One pt received INNO406 and did not respond. One pt in BP was refractory to allogeneic stem cell transplantation and acquired a T315I mutation. Two pts received homoharringtonine, did not respond, but had an eradication of the mutant clone. After a median follow-up of 23 mos (range, 3–48 mos), from the time V299L was detected, 8 died (4 CP and 4 BP). In conclusion, V299L occurs more frequently after dual Src/Bcr-Abl kinase inhibitors therapy, paralleling the findings of in vitro studies. TKIs showing in vitro activity against this mutation (e.g. nilotinib) may be good treatment options for pts with this mutation if treated in chronic phase, but more data is need to evaluate the long-term benefit of this approach. Disclosures: Jabbour: BMS: Honoraria, Speakers Bureau; Novartis: Honoraria, Speakers Bureau. Cortes:Novartis: Research Funding; BMS: Research Funding; Pfizer: Consultancy, Research Funding.

Sign in / Sign up

Export Citation Format

Share Document