Predictive Factors For An Achievement Of 6-Month Early Molecular Response In New CP CML Patients Treated With Imatinib

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 5160-5160
Author(s):  
Sung-Eun Lee ◽  
Soo Young Choi ◽  
Soo-Hyun Kim ◽  
Yun Jeong Oh ◽  
Jin-Eok Park ◽  
...  
Keyword(s):  
Predictive Factors ◽  
Prognostic Significance ◽  
Molecular Response ◽  
Molecular Responses ◽  
Log Reduction ◽  
Qrt Pcr ◽  
Level Data ◽  
Daily Dose ◽  
Univariate Analyses ◽  
Transcript Type

Abstract Background Recent studies have demonstrated that early molecular response (EMR) is predictive for long-term outcomes. However, the value of EMR has not been fully defined. Recently, European Leukemia Net (ELN) recommended that BCR-ABL1 ≤ 10%, and/or Ph+ <35% at 6 months of treatment was an optimal response. The aim of this study was to identify predictive factors for an achievement of 6-month EMR (BCR-ABL1 ≤ 1%) and to evaluate prognostic implications of 6-month EMR. Methods CP CML patients who were newly diagnosed and receiving 400mg IM once daily with no prior treatment were eligible for this study. Molecular responses were monitored using qRT-PCR assay with 3 month intervals, and then 6 month intervals after achieving major molecular response (MMR). All qRT-PCR tests were performed in a single laboratory (Cancer Research Institute, The Catholic University of Korea, Seoul, Korea). Pharmacokinetics data of IM, drug adherence, and dose intensity as well as baseline biological characteristics were included as variables affecting the achievement of 6-month EMR. Results A total of 102 patients (including 61 men and 41 women) were enrolled. One patient changed IM treatment to second-generation TKI due to less than complete hematologic response before 3 months. At the time between 3 and 6 months, 9 patient were discontinued permanently from IM treatment due to progression (n = 1), ELN failure (n = 3), and intolerance (n = 5). Ninety-two patients’ molecular responses were analyzed at 6 months. Day 29 trough IM level data were available from 99 patients and trough IM level data on the end of cycle 6 were available from 84 patients. Univariate analyses revealed that age of ≥ 40 years (P = 0.061), male sex (P = 0.042), b3a2 transcript type (P = 0.008), intermediate (P = 0.007) and high Sokal risk (P = 0.013), increased leukocyte count (P = 0.018), increased blast percentage (0.028), large splenic size (P = 0.020), and mean daily dose by 6 months of <350 mg/day (P = 0.004) were potential predictive factors for no achievement of 6-month EMR. Increased log reduction of BCR-ABL1 from baseline to 3 months (P <0.001) was associated with achievement of 6-month EMR. After adjusting for factors affecting relapse on univariate analyses, multivariate analyses showed that b2a2 transcript type (RR of 9.35, P = 0.013), increased log reduction of BCR-ABL1 from baseline to 3 months (RR of 9.58, P = 0.001), and mean daily dose by 6 months of ≥350 mg/day (RR of 13.10, P = 0.019) were independent factors for a achieving of 6-month EMR. In addition, patients with high Sokal risk had a lower 6-month EMR, compared with those with low Sokal risk (RR of 0.02, P= 0.035). In the current study, patients with BCR-ABL1 ≤1% at 6 months had a better MMR rates at 12 months (63% vs 10%, P<0.001), 3-year CI of CCyR (100% vs 76.1%, P<0.001) and MMR (100% vs 66.4%, P<0.001), EFS (78.9% vs 30.6%, P<0.001), and FFS (97.2% vs 68.7%, P<0.001). Patients with BCR-ABL1 >1% at 6 months showed a trend for lower 3-year PFS, compared with those who achieved ≤1% (100% vs 94.1%, P = 0.063). Conclusions In this study, we re-confirmed the prognostic significance of 6-month EMR and found that b2a2 transcript type, early decline of BCR-ABL1 transcript, mean daily dose by 6 months (≥350 mg/day), and Sokal risk were associated of the achievement of 6-month EMR. These predictive factors for 6-month EMR should be considered in the clinical decision of changing therapy at this time point. Further clinical investigations in a larger patient population with longer follow-up are needed. Disclosures: No relevant conflicts of interest to declare.

Plasma Imatinib Trough Level Is a Predictor For 3-Month Early Molecular Response In New CP CML Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2716-2716
Author(s):  
Sung-Eun Lee ◽  
Soo Young Choi ◽  
Soo-Hyun Kim ◽  
Yun Jeong Oh ◽  
Jin-Eok Park ◽  
...  
Keyword(s):  
Predictive Factors ◽  
Conflicts Of Interest ◽  
Trough Level ◽  
Plasma Concentrations ◽  
Prognostic Significance ◽  
Molecular Response ◽  
Spleen Size ◽  
Newly Diagnosed ◽  
Qrt Pcr ◽  
Univariate Analyses

Abstract Background Recent studies have demonstrated that measurements of BCR-ABL1 transcript levels at 3 and 6 months were able to identify high-risk patients treated with IM. However, the value of early molecular response has not been fully defined. New European Leukemia Net (ELN) recommendations concluded that a single measurement of BCR-ABL1 transcripts level after 3 months of treatment is not sufficient to define failure necessitating a change of treatment. The aim of this study was to identify predictive factors for an achievement of 3-month EMR. For the purpose, we explored contributing factors including trough plasma concentrations of IM, precise IM dose schedule. Additionally, in the same population, prognostic implications of 3- month EMR were analyzed. Methods Between December 2009 and June 2012, 102 patients with newly diagnosed CP CML were enrolled. They started IM (400 mg/day) therapy without prior treatment except hydroxyurea or anagrelide and molecular responses were monitored using qRT-PCR assay with 3 month intervals, and then 6 month intervals after achieving major molecular response (MMR). All qRT-PCR tests were performed in a single laboratory (Cancer Research Institute, The Catholic University of Korea, Seoul, Korea). Measurements of IM plasma concentrations were performed on day 29. Results A total of 102 newly diagnosed CP CML patients (including 61 men and 41 women) were analyzed. With a median age of 41 years (range, 18-75 years), the distribution of low, intermediate and high Sokal risk scores were 42%, 42% and 16%, respectively. All patients, except one patient who showed less than complete hematologic response, were evaluable for molecular analyses at 3 months. Day 29 trough IM level data were available from 99 patients. The median trough concentrations of IM were 1,252 (range, 439-3,491) and cut-off IM levels for Q1 and Q4 quartiles were 958 and 1767 ng/mL on day 29, respectively. Univariate analyses revealed that age of ≥ 40 years (P = 0.046), high Sokal risk (P = 0.066), high Euro risk (P = 0.004), increased platelet count (P = 0.028), increased blast percentage (0.023), and large spleen size (P = 0.046) were potential predictive factors for no achievement of 3-month EMR. In addition, plasma IM trough level of ≤ Q1 quartile on day 29 was associated with no achievement of 3-month EMR. After adjusting for factors affecting achievement of 3-month EMR on univariate analyses, multivariate analyses showed that large spleen size (RR of 0.79, P = 0.030) was predictor for no achievement of 3-month EMR and patients in ≤ Q1 of plasma IM trough level on day 29 had a lower 3-month EMR, compared with those in Q2-4 (RR of 15.61, P = 0.005). To evaluate the prognostic value of 3-month EMR in our cohort, we analyzed CCyR at 6 months, MMR at 12 months, and the 3-year CI of CCyR, MMR, and UMRD. In addition, the 3-year EFS, FFS, and PFS were also assessed. In patients with BCR-ABL1 ≤10% at 3 months, significantly higher rates of CCyR at 6 months (79% vs 13%, P < 0.001) and MMR at 12 months (54% vs 10%, P = 0.014) were observed, compared with that of patients with BCR-ABL1 >10%. They also had significantly better 3-year CI of CCyR (100% vs 63.0%, P<0.001) and MMR (100% vs 30.4%, P = 0.001), EFS (62.2% vs 26.3%, P = 0.002), and FFS (89.6% vs 73.7%, P = 0.044). However, there were no significant differences in 3-year PFS. Conclusions This study analyzed various factors, such as baseline biological characteristics, adherence to IM, IM dose intensity, pharmacokinetics. It provides predictors for 3-month EMR and re-confirmed the prognostic significance of 3-month EMR. The considering of IM plasma concentrations for 3-month EMR should be needed in the clinical decision of changing therapy at this time point. Further clinical investigations in a larger patient population with longer follow-up are needed. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Early Prediction of Stable MR4.5 By Achievement of 2.8 Log Reduction in BCR-ABL1 qPCR Levels at 6 Months in Patients with Chronic Myeloid Leukemia Treated with Frontline Imatinib

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 3022-3022
Author(s):  
Aisling Nee ◽  
Jeffrey H. Lipton ◽  
Dennis Dong Hwan Kim
Keyword(s):  
Median Time ◽  
Research Funding ◽  
Multivariable Analysis ◽  
Imatinib Therapy ◽  
Molecular Response ◽  
Molecular Responses ◽  
Log Reduction ◽  
Disease Characteristics ◽  
Univariate Analyses ◽  
Tki Discontinuation

Abstract Introduction Tyrosine kinase inhibitor (TKI) therapy has dramatically improved the prognosis of CML, with life expectancy now approaching that of the general population. TKIs are, however, associated with impaired quality of life, toxicity and financial burden to the patient and economy. Treatment free remission (TFR) is achievable in approximately half of patients who attain a sustained deep molecular response (DMR), however, it is not yet fully elucidated how best to predict candidates for successful TFR attempt. It is even harder to predict which patients will achieve a sustained DMR for 2 years or longer, which is a pre-requisite for TKI discontinuation. If it were possible to identify the patients who will not achieve a sustained DMR with Imatinib, a TKI switch could be considered earlier in order to make them a candidate for TFR attempt. Aims We aimed to identify disease characteristics and molecular responses that can predict future achievement of Stable MR4.5 (defined as a reduction in BCR/ABL1 transcripts of 4.5 logs or deeper on repeated testing for 2 consecutive years) with frontline Imatinib. Patients and Methods We collected data on pre-TKI variables (baseline disease characteristics), post-TKI variables (molecular response at various timepoints) and outcomes in patients commencing frontline Imatinib in our institution from 1999 to 2014 (n=593). Statistical analysis was performed using EZR software. Univariate analysis was performed by cumulative incidence method considering competing events and Gray test. Cut-offs for continuous variables were determined by recursive partitioning (rpart). Multivariable analysis was performed using Fine-Gray model. Results With 8.9 years of median follow-up duration, the overall survival was 96.9% at 8 years. The median time to MR4.5 was 8.8 years. The rate of MR4.5 was 39.7% at 5 years and 48.3% at 8 years. The rate of Stable MR4.5 was 25.6% at 8 years. In the subset of patients achieving MR4.5, over 80% subsequently achieved Stable MR4.5 (82.4% at 8 years) (Fig. 1). The median time from achievement of first MR4.5 to Stable MR4.5 was 3.5 years. Univariate analyses of baseline variables (age, gender, disease phase, additional cytogenetic abnormalities and baseline blood counts) were performed, using rpart method to determine cut-offs for blood counts as follows: white cell count (WBC) ≥218x109/L, blast percentage ≥4%, hemoglobin (Hb) ≥88.5g/L and platelets ≥176x109/L. The only statistically significant pre-TKI variables on these analyses were WBC, blast percentage, Hb and platelet count. Univariate analyses of the following post-TKI variables were also performed: molecular response at 3, 6 and 12 months, time to complete cytogenetic response, major molecular response and MR4.5.Early molecular responses of ≥1 log reduction in transcripts at 3 months, ≥2 logs at 6 months and ≥3 logs at 12 months were tested. The following cut-offs for molecular response, as determined by rpart method, were also tested: ≥2.2 log reduction at 3 months, ≥2.8 logs at 6 months and ≥3 logs at 12 months.Univariate analysis showed statistical significance (p<0.0001) for all the post-TKI variables tested. Multivariable analyses of baseline blood counts and molecular response at 3 and 6 months were performed. The only variable that remained statistically significant was molecular response at 6 months using a cut-off of ≥2.8 log reduction in transcripts (HR 3.1, p<0.001) (Table 1). 44.4% of patients achieved ≥2.8 log reduction in transcripts at 6 months, with a rate of Stable MR4.5 at 8 years of 65.8%, compared to 17.2% for those with <2.8 log reduction at 6 months (Fig. 2). Conclusions In patients who achieved MR4.5, over 80% subsequently achieved Stable MR4.5, making them eligible for TKI discontinuation. In multivariable analysis, molecular response at 6 months was the only predictor for subsequent achievement of Stable MR4.5. Based on this data, a patient at high-risk of failing to attain Stable MR4.5 with Imatinib therapy can be identified if they fail to achieve a 2.8 log reduction or deeper within 6 months of Imatinib therapy. If a patient interested in TFR has a molecular response at 6 months of less than a 2.8 log reduction, then a switch in therapy to a second generation TKI may be considered. The optimal 6 month response to predict future Stable MR4.5 remains unclear, but our data suggest that a cut-off in transcripts of ≥ 2.8 log reduction may be a better predictor of future Stable MR4.5. Disclosures Lipton: ARIAD: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Kim:BMS: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy; Paladin: Consultancy.

Early Responses At 3 Months and 12 Months After Starting Imatinib As Predictive Factors For The Achievement Of Deep MR In Japanese CML Patients

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2744-2744
Author(s):  
Masayoshi Masuko ◽  
Tatsuo Furukawa ◽  
Tadashi Koike ◽  
Kazue Takai ◽  
Koichi Nagai ◽  
...  
Keyword(s):  
Overall Survival ◽  
Predictive Factors ◽  
Study Group ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Observation Study ◽  
Molecular Responses ◽  
Optimal Response ◽  
Prior Therapy ◽  
Significant Difference

Abstract Background and Purpose Imatinib therapy shows excellent efficacy for chronic myeloid leukemia (CML) patients. The five-year overall survival of chronic-phase CML patients treated with imatinib can be expected to reach over 90%. Now, the goal of therapy has become the achievement of therapy-free remission (TFR) for most patients. However, predictive markers for achieving deep molecular response (MR) or TFR are yet to be elucidated. The recently published European LeukemiaNet recommendations 2013, which are mostly based on Caucasian studies, show the importance of an early response at 3 months or 12 months after starting imatinib treatment to assess optimal response. Using the registry of our study group, we assessed whether early cytogenetic or molecular responses at 3 months and 12 months after starting imatinib are associated with the achievement of deep MR or long-term outcome in Japanese CML patients. Patients and Method We reviewed 135 CML patients in the registry of our study group. Imatinib was started between December 2001 and June 2008. We retrospectively analyzed 92 CML patients (35 patients with prior therapy before imatinib) who could be assessed for partial cytogenetic response (PCyR: Ph<35% or bcr/abl transcript <10%) at 3 months after starting imatinib treatment, and 81 patients (25 patients with prior therapy before imatinib) who could be assessed for major molecular response (MMR: bcr/abl transcript <10% or 300 copies/μg) at 12 months in our multicenter observation study group. The clinical data was reviewed in August 2010. We excluded patients who had been switched from imatinib to a second tyrosine kinase inhibitor (TKI) before August 2010. We compared overall survival and the cumulative achievement of deep MR (negative bcr/abl transcript by PCR or the TMA-HPA method) between patients with and without PCyR at 3 months, also between patients with and without MMR at 12 months. The probability of overall survival and the cumulative incidence of deep MR were calculated by the Kaplan-Meier method and compared by the log-rank statistic. Results Seventy-six out of 92 patients (82.6%) achieved PCyR at 3 months. Forty out of 81 patients (49.3%) achieved MMR at 12 months. The patients with PCyR at 3 months showed significantly better overall survival (p=0.004) and higher cumulative achievement of deep MR (p=0.009) than the patients without PCyR. Overall survival between the patients with and without MMR at 12 months did not show a significant difference (p=0.06). However, the patients with MMR at 12 months showed significantly higher cumulative achievement of deep MR (p<0.001) than the patients without MMR. Conclusion Early cytogenetic and molecular responses at 3 months and 12 months after starting imatinib are also predictive factors for good prognosis and the achievement of deep MR in a registry of Japanese patients. Our data confirm the criteria of optimal response in European LeukemiaNet recommendations 2013 was appropriated for Japanese CML patients in practical setting. Disclosures: No relevant conflicts of interest to declare.

Pegylated Interferon-Alpha 2a in Combination with Nilotinib As First-Line Therapy in Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia (Nilopeg trial). Four-Year Follow-up Results

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 1578-1578 ◽  
Author(s):  
Franck E. Nicolini ◽  
Gabriel Etienne ◽  
Viviane Dubruille ◽  
Lydia Roy ◽  
Françoise Huguet ◽  
...  
Keyword(s):  
Board Of Directors ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Chronic Phase ◽  
Pegylated Interferon ◽  
Molecular Response ◽  
Advisory Committees ◽  
Molecular Responses ◽  
Log Reduction

Abstract Background & aims In the Nilopeg trial (EudraCT 2010-019786-28), we have previously demonstrated that the combination of nilotinib (Tasigna® Novartis), a second generation inihibitor (TKI2), combined to pegylated interferon-alpha 2a (Peg-IFN, Pegasys®, Roche) in de novo chronic phase chronic myeloid leukemia (CP-CML) patients is able to induce high rates of molecular responses with an acceptable additional toxicity (F. E. Nicolini et al. Lancet Haematology 2015) within 24 months of follow-up. We report here the ≥4-year follow-up of such patients for toxicity and efficacy. Methods In a phase 2 study, newly diagnosed CP-CML patients were assigned to a priming strategy by Peg-IFN (± HU) for a month at 90 mg/wk, prior to a combination of nilotinib 300 mg BID + Peg-IFN 45 micro.g/wk for ≥ 1 year, maximum 2 years. After 2 years nilotinib was continued alone. The primary endpoint was the rate of confirmed molecular response 4.5 (MR4.5) by 1 year. Molecular assessments were centralised for all patients and expressed as BCR-ABLIS in % for 2 years and then performed in each center [all expressed in % on the international scale (IS)]. All data presented here are in intention-to-treat. Events were defined as death, progression to AP or BC, failure on nilotinib or nilotinib treatment discontinuation for any cause excluding treatment-free remission (TFR). Results Fourty-two patients were enrolled in this trial (one withdrawn its consent prior to treatment initiation), and the median follow-up is now 50.7 (47.8-52.8) months. Sokal and Euro scores were high for 12% and 2%, intermediate for 49% and 55% and low for 39% and 43% of the patients respectively. The median age at treatment initiation was 53 (23-85) years, 2 patients had a masked Philadelphia chromosome, 3 a variant form, and 1 additional chromosomal abnormalities, all patients had "major" BCR-ABL1 transcripts. The rates of Complete Cytogenetic Responses (CCyR) at "6", and "12" months of combination (i. e. at 5 and 11 months of TKI2) were 71%, and 100% respectively. Eighty seven percent of patients had a BCR-ABLIS ≤10% at M3 (i. e. after 2 months TKI). The rates of molecular responses respectively at 12, 24, 36 and 48 months were 76%, 78%, 83%, 73% for MMR, 51%, 58.5%, 66%, 58.5% for 4 log reduction (MR4), 17%, 34%, 34%, 44% for 4.5 log reduction (MR4.5), 12%, 32%, 29%, 41.5% for ≥5 log reduction (MR5), shown as cumulative incidence curves for MR4.5 in figure 1. The median doses of Peg-IFN delivered to the patients during the first year were 45 (0-45) micro.g/wk, and for nilotinib 600 (300-600) mg daily. Interestingly, logistic regression analysis adjusted on MR4.5 responses showed a significant relationship with the mean doses of Peg-IFN delivered to the patients at 12 months (p=0.003, OR = 1.09 [1.03-1.16]), 24 months (p=0.005, OR = 1.08 [1.02-1.14]) and 48 months (p=0.024, OR = 1.09 [1.01-1.17], but not with the mean doses of nilotinib [p=0.84, OR = 0.99 [0.99-1.01], p=0.087, OR = 1 [0.99-1.01], and p=0.88, OR = 1 [0.99-1.01] respectively. Eight patients (19.5%) were in TFR for a median of 6.8 (0.5-9.5) months after 2-year consecutive MR4.5, and none lost MMR yet at last follow-up. One patient died of progression (unmutated myeloid blast crisis at M6, who relapsed after unrelated allogeneic stem cell transplantation). There was no additional grade 3-4 hematologic or biochemical toxicities occurring after 24 months. At last follow-up 10 patients switched for another TKI (2 for dasatinib, 5 for imatinib, and 3 for imatinib followed by dasatinib), for unsufficient cytogenetic or molecular response (2 patients) or for toxicity (7 patients). Overall, 4 patients presented some cardio-vascular events 3 coronary stenoses, one brain stroke). Conclusion Despite additional initial toxicities Peg-IFN priming strategy, followed by the combination of nilotinib and Peg-IFN during the first year induces very high rates of durable deep molecular responses (MR4 and MR4.5) at later time-points, offering TFR for number of patients. To date, no emerging severe adverse events occurred. However, to confirm these promising results, a randomised phase III study testing nilotinib versus nilotinib + Peg-IFN is absolutely warranted and in progress. Figure 1. Cumulative incidence of MR4.5 Figure 1. Cumulative incidence of MR4.5 Disclosures Nicolini: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ariad Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Etienne:ARIAD: Consultancy, Honoraria, Speakers Bureau; Novartis: Consultancy, Honoraria, Other: Congress Travel/Accomodations, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau. Roy:BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Huguet:Novartis: Consultancy, Research Funding; BMS: Consultancy, Speakers Bureau; ARIAD: Consultancy, Speakers Bureau; PFIZER: Consultancy, Speakers Bureau. Legros:ARIAD: Speakers Bureau; BMS: Speakers Bureau; Novartis: Research Funding, Speakers Bureau. Giraudier:Novartis: Speakers Bureau. Coiteux:BMS: Speakers Bureau; ARIAD: Speakers Bureau; Novartis: Speakers Bureau. Guerci-Bresler:ARIAD: Speakers Bureau; BMS: Speakers Bureau; Novartis: Speakers Bureau; PFIZER: Speakers Bureau. Rea:Pfizer: Honoraria; Ariad: Honoraria; Novartis: Honoraria; Bristol-Myers Squibb: Honoraria. Amé:BMS: Speakers Bureau; Novartis: Speakers Bureau. Cony-Makhoul:Novartis: Consultancy, Honoraria, Speakers Bureau; BMS: Consultancy, Honoraria, Speakers Bureau. Gardembas:Novartis: Speakers Bureau. Hermet:Novartis: Speakers Bureau; BMS: Speakers Bureau. Rousselot:Pfizer: Consultancy; BMS: Consultancy, Speakers Bureau; Novartis: Speakers Bureau. Mahon:ARIAD: Consultancy; Bristol-Myers Squibb: Consultancy, Honoraria; Pfizer: Consultancy; Novartis: Consultancy, Honoraria.

The Persistence of p190 BCR-ABL Transcripts Is Associated with Lower Probability of Molecular Response to Imatinib in Early and Late Chronic Phase CML Patients.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 3282-3282
Author(s):  
Anna Garuti ◽  
Adalberto Ibatici ◽  
Gabriella Cirmena ◽  
Maurizio Miglino ◽  
Riccardo Varaldo ◽  
...  
Keyword(s):  
Prognostic Significance ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Lower Probability ◽  
Molecular Response ◽  
Qrt Pcr ◽  
Complete Cytogenetic Response ◽  
Group 2 ◽  
Group 1

Abstract Background. It has been demonstrated that about 70% of patients with CML in chronic phase (CP) at diagnosis co-expressed p210 and p190 BCR/ABL transcripts, although at a much lower level (Blood1996;87:5213–17). In previous studies, the co-expression of p210 and p190 BCR-ABL transcripts at diagnosis was considered as indicative of higher tumor burden. However, the clinical relevance of p190 BCR-ABL mRNA monitoring in CML pts under Imatinib on bone marrow (BM) samples is not known. Materials and Methods. BM samples were obtained from 83 pts with CP-CML treated with Imatinib at a daily oral dose ranging between 300–500mg. These included 192 samples from 43 pts with late CP-CML (post-IFN failure) and 140 samples from 40 pts with early CP-CML who received Imatinib as first line therapy. Median follow-up was 18 (3–58) and 39 (12–58) months for early and late CP-CML, respectively. As part of a diagnostic work-up, BM samples from each patient were assessed for expression of both p210 and p190 BCR/ABL levels by real-time quantitative reverse transcription PCR (QRT-PCR) using a TAQ-Man system (ABI Prism 7700 Perkin Elmer) for BCR-ABL and ABL genes. The median number of BM assessment was 3 (2–6) for early CP-CML and 4 (2–10) for late CP-CML. A major molecular response (MMR) was defined as BCR-ABL/ABL ratios less than 0.05%. A specific nested RT-PCR screening was assessed for detection of p210 (b2a2, b3a2) and p190 (e1a2) BCR-ABL transcripts to confirm the negative data of p210 and p190 in QRT-PCR. Results. A MMR was obtained in 20 pts (50%) and 20 pts (46%) in early and late CP-CML respectively. However, early CP-CML pts showed a significantly greater reduction in p210 BCR-ABL levels compared to late CP-CML after 12 months of Imatinib therapy (p=0.006), indicating a different kinetic of molecular response. Co-expression of p210 and p190 BCR-ABL transcripts at diagnosis was 73% for early CP-CML, whereas it was not available for late CP-CML. To test whether the persistence of p190 BCR-ABL transcript was predictive of MMR, we divided CML pts in 2 groups, those with 0 or 1 p190 BCR-ABL positive samples (group 1) and those with 2 or more positive samples (group 2) during the follow-up. We found that CP-CML pts of the group 2 showed a significant lower probability to obtain MMR molecular response compared to pts of group 1 both for late and early CML patients respectively [17/24 (71%) vs 5/19 (26%) with p=0.0039)], [15/21 (71%) vs 6/18 (33%) with p=0.017)]. This correlation holds also for complete cytogenetic response (data not shown). Conclusions. In this study, approximately 50% of pts reached a MMR; half of them had undetectable values of p210 BCR-ABL transcripts. However, in a proportion of pts with complete cytogenetic response and low level of p210 BCR-ABL transcript, the expression of p190 is still detectable. The persistence of p190 signal despite the 2–3log fall in p210 BCR-ABL levels, may be of prognostic significance and may disclose unfolded concepts of biological relevance.

Evaluation of Bone Marrowmmorphology in Addition to JAK2 Allele Burden Is Essential for Assessing Disease Status in Recombinant Interferon Alpha-Treated Polycythemia Vera Patients

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5471-5471
Author(s):  
Elizabeth Michelle Margolskee ◽  
Spencer Krichevsky ◽  
Attilio Orazi ◽  
Richard T. Silver
Keyword(s):  
Bone Marrow ◽  
Polycythemia Vera ◽  
Immunohistochemical Staining ◽  
Cell Mass ◽  
Prognostic Significance ◽  
Molecular Response ◽  
Recombinant Interferon ◽  
Molecular Responses ◽  
Allele Burden ◽  
Marrow Cellularity

Abstract Introduction Polycythemia vera (PV) is a myeloproliferative neoplasm (MPN) associated with the JAK2 V617F mutation. Recombinant interferon alfa-2b (rIFNα-2b) or pegylated rIFN2α (pegrIFNα-2a) treatment in PV is effective in inducing hematologic and molecular responses. Reduction in JAK2V617Fallele burden (%V617F) has been used increasingly as a surrogate marker of disease response to treatment and as a unique criterion for discontinuation of therapy. To date, no studies have evaluated the relationship between changes in %V617F and established indicators of disease activity such as bone marrow cellularity and degree of fibrosis. Having observed persistent marrow hypercellularity or progressive fibrosis in PV patients despite a significant reduction in %V617F, we therefore systematically examined the correlation of %V617F with marrow morphology. We also assessed immunohistochemical expression of pSTAT5 as a marker of JAK2 activation. Methods The diagnosis of PV was based on the WHO criteria which include presence of erythrocytosis and/or an increased Cr51 red cell mass, JAK2V617F mutation and typical bone marrow findings such as hypercellularity due to panmyelosis and megakaryocyte morphology consistent with PV. Patients with two marrow examinations and quantitative JAK2 levels measured at a median of 1.2 months from the biopsy date were eligible for inclusion. The JAK2V617Fallele burden in peripheral blood samples was determined by pyrosequencing. Clinical, hematologic and molecular responses were graded according to ELN criteria. Marrow fibrosis was scored according to the WHO three-tiered semi quantitative grading system. Immunohistochemical staining for p-STAT5 was performed on clot sections in a subset of patients. Results We identified 15 patients for inclusion. The median %V617F at the time of the initial biopsy was 62.2% (18.2-100%), which decreased to a median of 33% (0-93.7%) on subsequent evaluation (p=0.02). Patients were initially treated with peg rIFNα-2a 45-90 mcgm weekly (n=13) or rIFNα-2b (n=2), 1x106units thrice weekly, and gradually increased based upon response and tolerance. The median duration of treatment between biopsy was 4.2 years (0.8 - 6.6). All patients achieved either a complete (CHR) (n=8) or a partial (PHR) (n=7) hematologic response. Of these 15 patients, 3 achieved a complete molecular response (CMR), 4 a partial molecular response (PMR), and 8 patients no molecular response (NMR). We observed no correlation between clinical and molecular response: of the 8 patients who achieved CHR, 2 achieved a CMR and 6 did not. There was no correlation between clinical response and fibrosis or cellularity; of 8 patients who achieved CHR, 5 showed persistent/increased hypercellularity and 6 had persistent/increased fibrosis. We also found no correlation between marrow morphologic changes and molecular response. Of the 3 patients with CMR, all had persistent hypercellularity (range: 60-90%) and increased/persistent fibrosis. Among the 4 patients who achieved a PMR, 2 had increased cellularity and 2 decreased cellularity. All had increased or persistent fibrosis. Among the 8 patients with NMR, 2 had an increase in marrow cellularity, 2 no change, and 4 an insignificant decrease. Fibrosis increased in 2, was unchanged in 3, and decreased in 3. Thus, there were no significant correlations between changes in %V617F and cellularity (κ=0.02) and fibrosis (κ=0.04). Immunohistochemical staining for p-STAT5 expression in megakaryocyte nuclei showed no correlation between degree of positivity and %V617F. Conclusions Although we observed a statistically significant decrease in %V617F after treatment with rIFNα, there were no parallel changes in marrow morphology. In all patients with CMR, we observed persistent or worsening marrow disease, suggesting to us a need for continued therapy. In patients who achieved either CHR or PHR, we observed persistent hypercellularity and persistent/progressive fibrosis. Our results question the use of JAK2V617F allele burden as the sole criterion for discontinuation of rIFNα therapy. The prognostic significance of failing to attain a morphologic response in patients who have achieved a hematologic and/or molecular response remains unresolved. Resolution of these issues with longer follow-up is important, as premature discontinuation of rIFNα may allow the pathogenic mechanisms of the disease to progress unfettered. Disclosures Orazi: Novartis: Honoraria.

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.

Major Molecular Responses to Dasatinib (BMS-354825) Are Observed in Imatinib-Resistant Late Stage Chronic and Advanced CML Patients: Impact and Fate of Imatinib-Resistant Clones in Dasatinib-Treated Patients.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 437-437 ◽  
Author(s):  
Susan Branford ◽  
Timothy Hughes ◽  
John Nicoll ◽  
Ron Paquette ◽  
Eric Bleickardt ◽  
...  
Keyword(s):  
Molecular Analysis ◽  
Direct Sequencing ◽  
Blast Crisis ◽  
Chronic Phase ◽  
Molecular Response ◽  
Imatinib Resistance ◽  
Molecular Responses ◽  
Log Reduction ◽  
Imatinib Resistant

Abstract Acquired imatinib-resistance in Ph-positive leukemia is frequently associated with mutations in the BCR-ABL kinase domain. Dasatinib is more potent than imatinib for inhibiting BCR-ABL activity and has preclinical efficacy against imatinib resistant mutations tested so far, except for T315I. We report the molecular analysis of imatinib resistant/intolerant patients treated at UCLA in a Phase I dose escalation trial of dasatinib. We sought to determine whether patients achieve significant reductions in the BCR-ABL level as measured by quantitative PCR (RQ-PCR); the effect of dasatinib on mutant BCR-ABL clones in-vivo; and the contribution of mutations to progression. Patients with accelerated phase or blast crisis CML, or Ph+ALL (AP/BC, n=14) were treated for a median of 5 months (range 1 to 11) and late (median disease duration 8 years) chronic phase CML patients (CP, n=19) for a median of 12 months (range 3 to 21). Patients were tested 2 to 17 times by RQ-PCR (267 analyses) and direct sequencing (167 analyses). Prior to commencing dasatinib, mutations were detected in resistant patients only (8 AP/BC and 15 CP). For our molecular analysis a ≥2-log reduction of BCR-ABL below the standardized baseline was considered significant. This level approximates to a complete cytogenetic response. A 3-log reduction defines a major molecular response (MMR), which is associated with a high progression free survival in imatinib treated patients. Overall, 6 of 14 (43%) AP/BC and 7 of 19 (37%) CP patients achieved ≥2-log reductions (MMR in 4 (29%) and 4 (21%) patients respectively). The response was maintained in 2 of 6 AP/BC and 6 of 7 CP patients achieving ≥2 log reductions. The table classifies the molecular response according to the detection of a baseline mutation. Molecular response ≥2 log BCR-ABL reduction intolerant and no baseline mutant resistant and no baseline mutant resistant and baseline mutant CP 2/3 (67%) 1/1 (100%) 4/15 (27%) AP/BC 1/1 (100%) 3/5 (60%) 2/8 (25%) Overall 3/4 (75%) 4/6 (67%) 6/23 (26%) Mutations were detected at last analysis in all 23 patients with baseline mutations. The sensitivity of the direct sequencing technique is approximately 20%. The same mutation that was present at baseline was present in 21 patients and 5 of these patients had an additional mutation. The remaining 2 patients had different mutations, one being F317I (CP). This mutation has not been reported in imatinib resistant patients to our knowledge. Mutations were present in all patients who progressed (1 CP, 7 AP/BC). Six of these patients had T315I that was detected at baseline (3) or evolved during therapy (3). T315I evolved in 3 other patients who have not progressed (1CP, 2 AP/BC). Overall, the T315I mutation evolved in 6 patients and was accompanied by significant rises in BCR-ABL in all patients of 2.5 to 185-fold. In conclusion 39% of all patients achieved significant molecular responses, with major molecular responses in 24% overall. The majority of CP patients maintained the molecular response. Baseline mutations remained detectable in almost all patients including those with significant BCR-ABL reductions. The mutation that became detectable most frequently during dasatinib therapy was T315I and non-mutation relapse was rare. A focus of future trials may be on managing the remaining resistant mutations.

An MMR Control RNA for Reliable Monitoring of BCR-ABL Transcripts in Treated CML Patients.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2939-2939
Author(s):  
Julie Toplin ◽  
Courtney Fuller ◽  
Linda Fletcher ◽  
Stephane Wong ◽  
Peter Maslak ◽  
...  
Keyword(s):  
Cell Line ◽  
Conversion Factor ◽  
Prognostic Significance ◽  
Progression Free Survival ◽  
Gene Transcript ◽  
Molecular Response ◽  
Stability Studies ◽  
Control Gene ◽  
Qrt Pcr ◽  
International Scale

Abstract Introduction: Major Molecular Response (MMR) is defined as a three-log reduction from a standardized baseline of BCR-ABL/control gene transcript ratio in CML patients at diagnosis. MMR has prognostic significance for progression-free survival for patients on Imatinib® therapy. Day-to-day monitoring of the MMR value in clinical laboratories is challenging due to the absence of a commercially available standardized MMR control RNA. To improve the reliability of BCR-ABL quantitation, MolecularMD has evaluated the feasibility of a single MMR control RNA valid for blood samples drawn in EDTA or PAXgene™ tubes. Material and Methods: Patient sample RNAs were interchanged between our laboratory and an International Randomized Interferon versus STI571 study (IRIS) laboratory, which had established an MMR value and international scale reporting. This exchange enabled our laboratory to establish an MMR value and reporting on an international scale using a validated conversion factor. A serial dilution of a BCR-ABL positive cell line into a human BCR-ABL negative cell line was prepared. These dilutions were tested in IRIS laboratories with established MMR value and international scale reporting and at our laboratory by QRT-PCR to determine the BCR-ABL/control gene ratio using respectively BCR and ABL control genes. We compared the BCR-ABL/ABL ratio in 104 paired PB CML patient samples drawn either in EDTA and PAXgene tubes and the BCR-ABL/BCR ratio in 32 patient samples. Stability studies were performed to evaluate the degradation of liquid and dried forms of the MMR RNA. Results: We established a conversion factor (CF) of 0.81 with an MMR value of 0.123%. Using this CF and MMR value, we created appropriate RNA dilutions that matched the MMR value using ABL as a control gene. Repeated analyzes of this MMR control RNA confirmed the accuracy of the sample with a median value of 0.124%, very close to the MMR value defined previously (0.123%). Stability studies demonstrated that the dried RNA samples could be stored several days at 37°C and freeze-thawed up-to 10 times without significant degradation. These RNA samples once reconstituted with water could also be used several times for BCR-ABL monitoring without any significant degradation. Comparison of BCR-ABL/ABL ratio between EDTA and PAXgene tubes revealed differences unlikely to have clinical impact on disease management suggesting that the MMR RNA created would be suitable under both EDTA and PAXgene extraction methodologies. Conclusions: We produced a stable MMR control RNA in large quantity for accurate monitoring of the MMR value. This MMR control RNA is now be tested in several laboratories to confirm the stability and reliability of this reagent. The MMR control RNA will be an important tool for standardizing MMR value in laboratories, and an integral part of a BCR-ABL QRT-PCR diagnostic kit.

Response to Imatinib in e13a2 Versus e14a2 BCR-ABL Fusion Transcripts in Chronic Myeloid Leukemia Saudi Patients

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5453-5453
Author(s):  
Wafa M. Elbjeirami ◽  
Amal S. Alabdulwahab ◽  
Hussein G. ELSayed ◽  
Nermeen Adel Abdelghaffer ◽  
Noha Elnagdi ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Clinical Outcome ◽  
Tyrosine Kinase ◽  
Myeloid Leukemia ◽  
Laboratory Data ◽  
Molecular Response ◽  
Fusion Transcripts ◽  
Log Reduction ◽  
Transcript Type

Abstract Background: Chronic myeloid leukemia (CML) is one of the predominant hematological malignancies in Saudi Arabia (SA). Different BCR-ABL fusion mRNAs occur immediately downstream of exon 2 or 3 of the M-bcr region and result in e13a2 or e14a2 fusion transcripts and the P210 BCR-ABL1 protein. To our knowledge, there is no published data addressing the frequency of BCR-ABL1 fusion transcripts among Saudi CML patients, and whether clinical outcome and gender have any correlation with BCR-ABL transcript type. Aims: First, to determine whether BCR-ABL transcript type, gender, and response to therapy have any correlation in Saudi CML patients presented at King Abdullah Medical City (KAMC) in Makkah, western region of SA. Second, to determine the frequency of BCR-ABL transcript variants, and compare it with the occurrence reported in other neighboring populations. Methods: Peripheral blood and bone marrow samples were analyzed by nested and multiplex RT-PCR to detect and quantify BCR-ABL transcripts from 72 evaluable Saudi CML patients seen at KAMC from January 2011 to present. Clinical and laboratory data were obtained from the medical charts of the patients. Results: From January 2011 to July 2016, 179 patients with newly or previously diagnosed chronic phase CML were referred to our institution and treated with imatinib mesylate as first-line therapy. However, results discussed herein were obtained from 72 evaluable patients for whom complete clinical charts and laboratory data were available. At diagnosis, the median age was 45 years (range 16-76), and there was nearly an equal number of males (N=35; 49%) versus females (N=37; 51%). These patients had high white blood cells (87.5%), high platelet counts (86%), and splenomegaly (61%). The follow up period ranged from 2 months to 66 months with a mean/median follow up of 1.83/1.7 year, respectively. At three months, 31 evaluable patients (54.4%) achieved early molecular response (EMR; 1 log reduction) of which 51.6% (N=16) were male, and 48.4% (N=15) were female. A major molecular response (MMR; 3-4 log reduction) in one year of treatment was obtained by 26 evaluable patients (36.1%) of which 53.8% (N=14) were male, and 46.2% (N=12) were female. Ten patients (18%) discontinued treatment with imatinib in the first year and were put on second line tyrosine kinase therapy (four for resistance and six for adverse events). Notably, six patients experienced disease progression and had tyrosine kinase domain mutation. We observed two deaths (2.8%), of which one involved E255K mutation. Out of 72 patients in the study, 48.6% (N=35) patients showed e13a2 fusion transcript, while 51.4% (N=37) patients showed e14a2 transcript. There was no significant differential transcript expression associated with gender as e13a2 expression was found in 42.9% (N=15) of females and 57.1% males (N=20). Similarly, expression of e14a2 was found in 59.5% females (N=22) and 40.5% males (N=15). Of the patients who achieved MMR in e13a2 expressing group, 33.3% (N=4) were female and 66.7% (N=8) were male. In e14a2 expressing patient group who achieved MMR, 57.1% (N=8) were female and 42.9% (N=6) were male. Conclusions: Our results compare favorably with those reported from the West and some Asian countries. There was no significant correlation between sex, type of BCR-ABL transcript and clinical outcome although we acknowledge that more data is needed in the future. These results further confirm lack of any predominance of the BCR-ABL isoforms e13a2 or e14a2 in Saudi CML patients under investigation, which is discordant with similar studies conducted in other groups of neighboring countries such as Sudan, Pakistan, and Iran. Disclosures No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document