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Background: ENESTop, an ongoing, single-arm, phase 2 study (ClinicalTrials.gov, NCT01698905), is the first trial specifically evaluating treatment-free remission (TFR; ie, stopping tyrosine kinase ...inhibitor TKI treatment without a loss of response) in patients with chronic myeloid leukemia in chronic phase (CML-CP) who achieved a sustained deep molecular response after switching from imatinib (IM) to nilotinib (NIL). Of 126 patients in ENESTop who were eligible to stop NIL, 57.9% (95% CI, 48.8%-66.7%) maintained TFR at 48 weeks. Here we present results from a subgroup analysis based on reasons for switching from IM to NIL, categorized as intolerance, resistance, and physician preference.
Methods:Eligible patients were adults with CML-CP who received ≥ 3 years of total TKI therapy (> 4 weeks of IM, followed by ≥ 2 years of NIL) and achieved a sustained MR4.5 (BCR-ABL1 ≤ 0.0032% on the International Scale BCR-ABL1IS) on NIL therapy; patients with a documented MR4.5 at the time of switch from IM to NIL were not eligible. Enrolled patients continued NIL treatment in a 1-year consolidation phase, and those without confirmed loss of MR4.5 (ie, consecutive BCR-ABL1IS > 0.0032%) were eligible to stop NIL in the TFR phase. Patients with loss of major molecular response (MMR; ie, BCR-ABL1IS > 0.1%) or confirmed loss of MR4 (ie, consecutive BCR-ABL1IS > 0.01%) during the TFR phase reinitiated NIL treatment. The primary endpoint was the proportion of patients who maintained TFR (ie, no loss of MMR, confirmed loss of MR4, or treatment reinitiation) at 48 weeks after stopping NIL.
In this post hoc analysis, rates of TFR at 48 weeks after stopping NIL and a Kaplan-Meier (KM) analysis of treatment-free survival (TFS; defined as the time from the start of TFR to the earliest occurrence of any of the following: loss of MMR, confirmed loss of MR4, reinitiation of NIL due to any cause, progression to accelerated phase/blast crisis, death due to any cause) were evaluated in subgroups of patients who switched from IM to NIL due to intolerance, resistance, or physician preference. These categories were determined by grouping the reasons for switching from IM to NIL, as reported by the investigators, based on relatedness to safety (intolerance), loss of response/treatment failure (resistance), and the physician's clinical judgment (physician preference); individual reasons included within each category are presented in the Figure.
Results:A total of 125 patients who entered the TFR phase were included in this analysis; 1 patient who was found to have had atypical transcripts was excluded. Among these 125 patients, the reasons for switching to NIL were categorized as intolerance in 51 patients (40.8%), resistance in 30 patients (24.0%), and physician preference in 44 patients (35.2%). The proportion of patients who maintained TFR at 48 weeks after stopping NIL was generally similar across the 3 subgroups: 30 of 51 (58.8%; 95% CI, 44.2%-72.4%) in the intolerance subgroup, 16 of 30 (53.3%; 95% CI, 34.3%-71.7%) in the resistance subgroup, and 27 of 44 (61.4%; 95% CI, 45.5%-75.6%) in the physician preference subgroup. KM analysis of TFS showed that in all 3 subgroups, the majority of TFS events occurred within the first 24 weeks after stopping NIL (Figure). There were no notable differences in the kinetics of TFS events among subgroups. The KM-estimated median duration of TFS was not reached by the data cutoff date in all 3 subgroups.
Conclusion: Primary analysis from ENESTop showed that among patients with CML-CP who achieved a sustained MR4.5after switching from IM to NIL, 57.9% of those who stopped NIL maintained TFR at 48 weeks. In the present analysis, TFR was maintained at 48 weeks after stopping NIL by > 50% of patients in the intolerance, resistance, and physician preference subgroups, with generally similar results across subgroups. These findings suggest that the rate of successful TFR following second-line NIL does not differ based on the reasons for switching from IM to NIL.
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Hughes:Ariad: 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; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Australasian Leukaemia and Lymphoma Group (ALLG): Other: Chair of the CML/MPN Disease Group. Boquimpani:Novartis: Research Funding, Speakers Bureau; BMS: Speakers Bureau. Takahashi:Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; BMS: Honoraria. Shuvaev:Pfizer: Honoraria; BMS: Honoraria; Novartis pharma: Honoraria. Ailawadhi:Pharmacyclics: Consultancy; Novartis: Consultancy; Amgen Inc: Consultancy; Takeda Oncology: Consultancy. Lipton:Pfizer: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Ariad: Consultancy, Research Funding. Turkina:Pfizer: Honoraria; Novartis Pharma: Honoraria; BMS: Honoraria. Moiraghi:BMS: Speakers Bureau; NOVARTIS: Speakers Bureau. Nicolini:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria; Ariad pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees. Sacha:BMS: Consultancy, Honoraria, Speakers Bureau; Incyte: Consultancy, Honoraria, Speakers Bureau; Pfizer: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Speakers Bureau; Adamed: Consultancy, Honoraria. Kim:Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Research Funding, Speakers Bureau; ILYANG: Consultancy, Honoraria, Research Funding. Fellague-Chebra:Novartis: Employment. Acharya:Novartis Healthcare Pvt. Ltd.: Employment. Krunic:Novartis: Employment, Equity Ownership. Jin:Novartis: Employment, Equity Ownership. Mahon:BMS: Honoraria; PFIZER: Honoraria; NOVARTIS PHARMA: Honoraria, Research Funding; ARIAD: Honoraria.
Objective: To determine the prevalence of JAK2 V617F mutation and its clinical correlation in patients with chronic myeloproliferative disorders (CMD): polycythemia vera (PV), essential ...thrombocythemia (ET) and idiopathic myelofibrosis (IMF).
Materials and methods: Detection of JAK2 V617F mutation by allele specific-PCR.
Results: One hundred and three patients with CMD were included in the study. JAK2 V617F distribution was PV 40/45 (89%), ET 30/43 (69%), and IMF 7/15 (47%). In PV and ET patients only, 18 had thrombosis at diagnosis and 12 during follow-up (these were microvascular: 11, venous: 7 and arterial: 12); of these 28/70 (40%) were JAK2pos versus 2/18 (11%) JAK2neg; P=0·02. In a median of 4 years, two patients with PV JAK2pos evolved to myelofibrosis and one patient with PV presented in leukemic transformation (JAK2pos before and after transformation); six patients died: four patients with IMF and two patients with PV.
Conclusions: We found an association between JAK2 V617F and thrombotic events in patients with PV and ET.
Celotno besedilo
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DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
The landscape of chronic myeloid leukemia (CML) has radically changed since the introduction of tyrosine kinase inhibitor (TKI), imatinib (IM), now considered as standard therapy. Although excellent ...cytogenetic responses are obtained, minimal residual disease still persists in a proportion of patients (pts) when measured by serial molecular monitoring by quantitative real-time polymerase chain reaction (RQ-PCR) to measure BCR-ABL transcript levels (Baccarani M et al. Blood 2006; 108:1809–20). We monitored BCR-ABL transcript levels by RQ-PCR in 176 chronic phase (CP) –complete cytogenetic response (CCyR) CML pts treated with IM. Median follow-up from start of therapy with IM was 35 (6–80) months. Pts were recruited from 33 centers in Argentina and 2 in Uruguay. Median follow up from the first assessment at our Institution was 18 (6–32) months. Seventy nine patients (45%) had received interferon as 1st line prior to IM and 97/176 (55%) pts received imatinib as 1st line. Eighty eight percent (155/176) pts had received IM 400mg/d and 12% (21/176) 600–800mg at study initiation. Fifty four percent presented with low Sokal score at diagnosis. Peripheral blood samples were tested by RQPCR every 6 months. Major molecular response (MMR) was defined as BCR-ABL/ABL ratio of <0,1% on the Internationale Scale. Rise in transcript levels was immediately reconfirmed. Cytogenetic and mutational analyses were performed if rise in transcripts was confirmed. Overall, 48% had MMR at the initial evaluation (baseline), and this increased to 57% at last follow-up (month 18). No patient with MMR achievement lost CCyR. Only 5 pts lost CCyR, never having achieved MMR (p=0.01). All patients could be divided in 3 groups according to transcript level outcome: 61% decline (at least 1 log reduction of BCR-ABL/ABL ratio), 27% stable (no log variation), 13% rise (increasing 1 log of BCR-ABL/ABL ratio). Among 136 pts with follow up at month 18, we observed (Table 1):
Molecular Response At baselineDecline in transcript levels %(pts)Stable transcript levels %(pts)Rise in transcript levels %(pts)Total %(pts)CMR ≥ 4 log red <0,01%/U MMR ≥ 3 log red < 0,1% (N:60)20(12)63(38)17(10)44(60)No MMR > 0,1% (N:76)47(36)47(36)5(4)56(76)Total35 (48)55(74)10(14)100(136)CMR: complete molecular response, U: undetectable
From the group of pts with rise in transcript levels, 5 pts lost CCyR, none lost complete hematologic response. Overall, 5%(9/176) pts eventually changed therapy to a 2nd generation TKI: 5 pts with cytogenetic relapse and 4 pts with increase in transcript levels.
Our results confirm that molecular responses continue improving over time and a significant number of pts achieve undetectable transcript levels with continued imatinib therapy. Achievement of MMR is associated with sustained cytogenetic response. These results emphasize the validity and feasibility of molecular monitoring in all areas of the world.
This is the largest Latin American study of BCR-ABL mutations in chronic myeloid leukemia (CML) patients, resistant to imatinib (IM). In 195/467 (41%) patients, mutations were detected. The most ...frequent mutation was T315I (n = 31, 16%). Progression-free (PFS) and overall survival (OS) at 5 years were lower in patients with BCR-ABL mutations (43% vs. 65%, p = 0.07 and 47% vs. 72%, p = 0.03, respectively) and in those with the T315I mutation (p = 0.003 and p = 0.03). OS and PFS were superior in subgroup who switched to second generation inhibitors (SGIs) after IM failure (OS: 50% vs. 39% p = 0.01; PFS: 48% vs. 30% p = 0.02). BCR-ABL mutations conferred a significant poor prognosis in CML patients.
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Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Abstract Background Monitoring minimal residual disease (MRD) by real-time quantitative polymerase chain reaction (RT-PCR) in chronic myeloid leukemia (CML) patients is mandatory in the era of ...tyrosine kinase inhibitors. Achieving a major molecular response (MMR) at 12 and 18 months predicts a better progression and event-free survival. Patients and Methods The objective of this prospective, multicentric study was to evaluate MRD by standardized RT-PCR in 178 patients with chronic-phase CML who were treated with imatinib at different institutions in Argentina and Uruguay and to determine if achievement of a stable MMR ( BCR-ABL transcript levels < 0.1%) identifies a low-risk cytogenetic relapse group. The median age of the patients was 50 years, and 55% of them had received imatinib as first-line therapy. BCR-ABL transcript levels were measured after achievement of complete cytogenetic remission (CCyR) and at 6-month intervals. Results MMR was detected in 44% patients at the start of the study. This value increased to 79% at month 36 of evaluation. Complete molecular response (CMR) also increased from 24% to 52% of patients. Not achieving a stable MMR determined a higher risk of cytogenetic relapse (9% of MMR patients not achieving an MMR vs. 1% of patients who achieved MMR). Patients with sustained MMR had a significantly better cytogenetic relapse-free survival at 48 months (97% vs. 87%; P = .008) but showed no differences in overall survival. Patients who did not remain in CCyR changed treatment. Conclusions A stable MMR is a strong predictor for a durable CCyR. Standardized molecular monitoring could replace cytogenetic analysis once CCyR is obtained. These results emphasize the validity and feasibility of molecular monitoring in all standardized medical centers of the world.
Imatinib induces complete cytogenetic response (CCyR) in 82% of patients with CML in chronic phase. There is a subset of patients who either failed to achieve or lose hematological/CCyR. Kinase ...domain mutations have emerged as a potential cause for treatment failure.
Aims: In the current study we have investigated ABL kinase domain mutations, amplifications and quantification of BCR-ABL transcripts by Q-PCR in Imatinib resistant patients.
Patients and Methods: A total of 84 patients (pts) with CML treated with Imatinib were studied and 82 were evaluable. Sixty-one (74%) were in chronic phase (CP), eleven (14%) were in accelerated phase (AP), and ten (12%) were in blast crisis (BC).We analyzed the DNA from blood samples. Mutations were screened by conformation sensitive gel electrophoresis (CSGE). The amplification products displaying an abnormal pattern were sequenced using automatic system. The amplification of BCR-ABL rearrangement was studied in interphase nuclei using Vysis extra-signaling probe. Real time quantitative PCR (RQ-PCR) of BCR-ABL transcripts was performed in a subset of 44 patients to assess molecular response, using Light Cycler (Roche®), Syber Green Method.
Results: Eleven mutations from 82 evaluable patients were detected (13%). Seven were in p- loop: M244R (1), L247A (1), G250E (2), Q252H (1), E255K (2), and four in the Imatinib binding: T315I (3), H318L (1). Two patients had BCR-ABL amplifications with 4–6 signals in interphase nucleous and one of them showed extramedullary involvement in skin nodules. Five patients had clonal evolution with double Ph chromosome. Most of mutations were found in patients in late chronic phase (6/11: 54%). The detection occurred at a median of 49 months (range 12–154) after diagnosis. Eighty four percent of cases studied with RQ-PCR, had null molecular response (<1Log Reduction). Imatinib dose in patients with mutations had been escalated to 600–800 mg/day previously.
Conclusion: This is the first multicentric study in spanish-speaking South America. T315I was the most frequent mutation detected in our study and was associated with poor outcome. We found 13% of resistant cases with point mutations, all of them located in the p-loop or imatinib binding.This is an ongoing study and further recruitment is needed to confirm these findings. Early detection of mutations can have prognostic implication and allow therapeutic intervention such as dose escalation, combination therapy or second generation tyrosine kinase inhibitors.
Introduction: The evaluation of response to imatinib in CML patients (pts) as guide to clinical management is undergoing substantial changes of criteria. The degree of reduction of total leukemia ...cell mass by imatinib as measured by FISH and RQ-PCR studies, correlates with progression-free survival. Therapeutic decisions, as dose scalation, is mandatory in pts with rising level of bcr/abl transcripts.
Purpose: To determine the potential of RQ-PCR to predict the duration of response in pts in complete cytogenetic remission (CCyR).
Patients and Methods: A total of 160 CML pts in first chronic phase, in CCyR treated with imatinib 400mg daily were studied prospectively since November 2005 (147 pts from 30 hematology centers in Argentina and 13 pts from 2 centers in Uruguay). According to previous treatment they were divided in two groups: 83 pts (51%) received as first line treatment IFN/Cytarabine and 77 pts (49%) received imatinib as first line. According to Sokal Index, 72% were low risk, 19% intermediate risk and 9% high risk. At baseline all pts were first evaluated by FISH and RQ-PCR under EAC program protocol and recommendations of T.P. Hughes, et al (Blood 108:28–37, 2006). Only RQ-PCR is being performed at 6 and 18 months from the beginning of the study. The median duration since beginning with imatinib treatment was 28 months (range 6–58).
Results: At the time of first RQ-PCR evaluation, 93% had undetectable bcr/abl fusion gene by FISH and 7% had low level FISH positivity ( 0,1 – 5%). The distribution of the type of molecular responses (MR) in the 160 pts was: Complete (CMR)≥4 log red, U/<0.01% bcr-abl/c-abl : 23%; Major (MaMR) ≥ 3log red, <0,1%bcr-abl/c-abl : 17%; Minor (MiMR) >2 log red, 1–0,1 % bcr-abl/c-abl : 34%; MiMR < 2log red, 10–1% bcr-abl/c-abl : 15%; Nule (NuMR) <1 log red, > 10%bcr-abl/c-abl : 11%. Pts with Fish (+) showed association with MiMR. Thirty eight percent of pts with a follow-up between 6–24 months since the beginning of imatinib treatment achieved MaMR and CMR, similar rate as the observed in the group with > 24 months on imatinib (42%). Up to July 2006, 53 pts underwent a 2nd RQ-PCR evaluation at 6 months: 15% of pts improved molecular response, 68% maintained it while 17% showed worse response. The 87.5% of pts with decreasing bcr-abl transcripts level at 2nd evaluation corresponded to imatinib treatment as first line. The 78% of pts with rising levels at 2nd evaluation showed MiMR at beginning of this study. Up to now, no pts showed hematological relapse.
Conclusion: This is an on-going study in CML pts in CCyR, where 93% showed a negative FISH study, and 7% had low FISH positivity. By RQ-PCR, 40% of pts presented CMR or MaMR (≥3 log red). In 2nd RQ-PCR evaluation, 83% of pts improved or maintained the molecular response. Up to now all pts remain in hematological remission.
Background: Since the introduction of Imatinib (IM), the treatment of chronic myeloid leukemia (CML) experienced its most important change. As this drug became the first line for the treatment of ...CML, we learned that under-dosing was associated with a delay in achieving cytogenetic response and the development of acquired resistance. Last year we presented a case-control study that analyzed how compliance affects the cytogenetic response to Imatinib. This is an update of that data.
Materials and Methods: Twenty-four patients with newly diagnosed Ph (+) chronic phase CML (CP-CML) were included and followed for 24 months. Patients received 400mg of IM and were asked to note down all taken doses, and reasons for non-compliance. Follow up visits were scheduled every 28–30 days and prescriptions were filled in order to last for only 30 days. During each visit, the medication was counted and non-adherence reasons were determined. Adverse events were graded according to the CTC and modifications in the Imatinib dose were only allowed with related adverse events with a CTC score ≥3.
As a control group, we matched each case with a Phi + CP-CML patient from our data base of the same sex and similar age as the case patient. All control patients had to have complete information about dosing and response. They all received initial treatment with IM 400mg; thereafter, dose was adjusted according to each physician's criteria. Compliance was measured as: mg prescribed/mg taken during the study period.
Results: Twenty-four patients, 14 males median age 56 yo (range: 24–83), were included in the study. Three were lost to follow up, leaving only twenty-one for analysis of compliance. At the end of the first year, all patients had complete hematological response. Compliance during these 12 months was 96.1, which is clearly superior to the 80% reported in the setting of clinical trials. All patients had a complete hematological response, 89.9 achieved a major cytogenetic response (MCyR) and 87.4 a complete cytogenetic response (CCyR), compared to 60 of the control group with a MCyR (p=0.027) and 57.8 a CCyR (p=0.025). During the second year, four patients lost CCyR, three responded to an increase in IM dose and one progressed to an accelerated phase and died. Compliance fell slightly during this period to 90.86% which was reflected in 81.66% CCyR, which was still statistically higher than the 54% of major responses in the control group (p=0.033). In both groups, none of the patients not achieving MCyR at 12 months achieved MCyR at 24 months. Hematological toxicity was more frequently observed within the first 6 months of treatment and after the increase in dosage. Severity and incidence of adverse events were similar in both groups, and were the main reasons for interruption or reduction of IM dose in the control group. The only additional difference besides compliance between the two groups was the average IM dose prescribed during the duration of the study (cases group: 430mg – control group: 330mg).
Conclusions: Adherence to Imatinib is associated with an improvement in cytogenetic response that can be seen even at two years after the start of therapy. Since outcome and development of resistance seem to be associated with compliance to therapy, emphasis should be put on maintaining treatment at an adequate dose for as long as possible.
This is the largest Latin American study of BCR-ABL mutations in chronic myeloid leukemia (CML) patients, resistant to imatinib (IM). In 195/467 (41%) patients, mutations were detected. The most ...frequent mutation was T315I (n = 31, 16%). Progression-free (PFS) and overall survival (OS) at 5 years were lower in patients with BCR-ABL mutations (43% vs. 65%, p = 0.07 and 47% vs. 72%, p = 0.03, respectively) and in those with the T315I mutation (p = 0.003 and p = 0.03). OS and PFS were superior in subgroup who switched to second generation inhibitors (SGIs) after IM failure (OS: 50% vs. 39% p = 0.01; PFS: 48% vs. 30% p = 0.02). BCR-ABL mutations conferred a significant poor prognosis in CML patients.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
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