scholarly journals Comparison of BCR-ABL1 quantification in peripheral blood and bone marrow using an International Scale-standardized assay for assessment of deep molecular response in chronic myeloid leukemia

2020 ◽  
Vol 58 (8) ◽  
pp. 1214-1222
Author(s):  
Georg Greiner ◽  
Franz Ratzinger ◽  
Michael Gurbisz ◽  
Nadine Witzeneder ◽  
Hossein Taghizadeh ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Myeloid Leukemia ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Quantitative Polymerase Chain Reaction ◽  
Molecular Response ◽  
International Scale

AbstractBackgroundMonitoring of molecular response (MR) using quantitative polymerase chain reaction (PCR) for BCR-ABL1 is a pivotal tool for guiding tyrosine kinase inhibitor therapy and the long-term follow-up of patients with chronic myeloid leukemia (CML). Results of MR monitoring are standardized according to the International Scale (IS), and specific time-dependent molecular milestones for definition of optimal response and treatment failure have been included in treatment recommendations. The common practice to use peripheral blood (PB) instead of bone marrow (BM) aspirate to monitor the MR monitoring in CML has been questioned. Some studies described differences between BCR-ABL1 levels in paired PB and BM specimens.MethodsWe examined 631 paired PB and BM samples from 283 CML patients in a retrospective single-center study using an IS normalized quantitative reverse transcription (qRT)-PCR assay for quantification of BCR-ABL1IS.ResultsA good overall concordance of BCR-ABL1IS results was found, a systematic tendency towards higher BCR-ABL1IS levels in PB was observed in samples of CML patients in a major MR. This difference was most pronounced in patients treated with imatinib for at least 1 year. Importantly, the difference resulted in a significantly lower rate of deep MR when BCR-ABL1IS was assessed in the PB compared to BM aspirates.ConclusionsIn summary, our data suggest that the classification of deep MR in patients with CML is more stringent in PB than in BM. Our study supports the current practice to primarily use PB for long-term molecular follow-up monitoring in CML.

Dasatinib Is Well-Tolerated and Efficacious in Imatinib-Intolerant Patients with Chronic-Phase Chronic Myeloid Leukemia (CP-CML).

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1128-1128 ◽  
Author(s):  
Hanna Jean Khoury ◽  
Michael J. Mauro ◽  
Yousif Matloub ◽  
Tai-Tsang Chen ◽  
Erkut Bahceci ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Median Duration ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Chronic Phase ◽  
Phase Iii ◽  
Hematologic Toxicity ◽  
Molecular Response

Abstract Abstract 1128 Poster Board I-150 Imatinib (IM), a tyrosine kinase inhibitor (TKI), has been the mainstay of treatment for chronic phase chronic myeloid leukemia (CP-CML). However, IM resistance and intolerance are of considerable clinical relevance. Dasatinib (DAS), a second-line TKI, is effective in the IM-intolerant patient population. The purpose of this study was to determine baseline factors that can affect DAS response and evaluate long term efficacy in this population. Intolerance to IM was defined as ≥ Grade 3 non-hematologic toxicity and/or Grade 4 hematologic toxicity lasting > 7 days. A total of 271 Ph+ CP-CML IM-intolerant patients who received DAS were pooled from two randomized trials (Phase II-trial, CA 180013 and Phase III trial, CA 180034). DAS doses were 50 mg BID (n=43), 70 mg BID (n=141), 100 mg QD (n=43) or 140 mg QD (n=44). At baseline, the median duration of disease for the IM-intolerant patients was 24 months (range: 0.9-182.5) and the median duration of IM therapy was 9 months (range: 0.03-69.06). Of these patients, 46 (17%) had hematologic toxicity and 228 (84.1%) had non-hematologic toxicity to IM. Seventy-nine (29%) patients had prior complete cytogenetic response (CCyR) on IM and 171 (63%) patients did not. The data for prior CyR to IM was not reported for 21 (7.7%) patients. Of the 79 patients who had achieved CCyR on IM, 30 patients had maintained CCyR and 49 patients had lost this response prior to start of DAS. Of the 171 patients who did not achieve CCyR on IM, 62 (36.3%) had been on IM for 3 12 months and 109 (63.7%) for < 12 months. At 2-year follow up of the 271 patients treated with DAS, 121 (44.6%) discontinued DAS (7.4% due to hematologic toxicity and 14% due to non-hematologic toxicity). Of the patients who were intolerant of IM due to hematologic toxicity (n=46), 10 (21.7%) discontinued DAS due to hematologic toxicity, and 3 (6.5%) due to other toxicities. Of the patients with non-hematologic IM-intolerance (n=228), 10 (4.4%) discontinued DAS due to hematologic toxicity, and 35 (15.4%) due to other toxicities. The median average daily dose of DAS was 99 mg/day in the population who achieved CCyR on DAS and 71.5 mg/day in the population who did not achieve CCyR on DAS. The probability of achieving CCyR on DAS was 43.5% in patients with hematologic IM-intolerance versus 78.9% with non-hematologic IM-intolerance. The CCyR, major molecular response (MMR), progression-free survival (PFS) and overall survival (OS) at 2-year follow up for the groups classified by their CCyR status at start of DAS or IM-intolerance status are summarized in Table 1. Conclusions DAS was well-tolerated and associated with high rates of CyR in IM-intolerant patients. Patients with a prior CCyR to IM and those who switched due to non-hematologic imatinib-intolerance had the highest rates of CCyR and MMR on DAS, while patients without CCyR after more than 12 months of IM therapy or IM-intolerance due to hematologic toxicity had the lowest rates of CCyR and MMR. Disclosures Khoury: BMS: Honoraria; Wyeth: Honoraria; Novartis Pharmaceuticals: Honoraria; Chemgenex: Honoraria; Genzyme: Honoraria. Mauro:Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding. Matloub:Bristol-Myers Squibb: Employment. Chen:Bristol-Myers Squibb: Employment. Bahceci:Bristol-Myers Squibb: Employment. Deininger:Novartis: Consultancy; Bristol-Myers Squibb: Consultancy; Calistoga: Research Funding; Genzyme: Research Funding.

Consistency Of RQ-PCR Analysis Results In Peripheral Blood and Bone Marrow Samples In Chronic Myeloid Leukemia Patients: Relevance From The Practical and Logistic Point Of View

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2592-2592
Author(s):  
Giovanna Rege-Cambrin ◽  
Carmen Fava ◽  
Enrico Gottardi ◽  
Filomena Daraio ◽  
Emilia Giugliano ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Myeloid Leukemia ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Wilcoxon Test ◽  
Molecular Response ◽  
Two Samples ◽  
The Mean

Abstract Background Consensus has been achieved that standardized molecular quantitative analysis (RQ-PCR) on peripheral blood (PB) is a suitable method for monitoring residual disease in chronic myeloid leukemia (CML). However, BM is still obtained at specific timepoints, and in a number of cases, only bone marrow (BM) sample collected for cytogenetic analysis is available. Being one of the laboratory involved in the standardization process of molecular monitoring for CML patients, we decided to perform a comparative analysis of BM and PB samples in order to evaluate the consistency of the results. Methods Between March 2009 and January 2013, 230 consecutive RQ-PCR tests to assess BCR-ABL transcript levels from simultaneously collected PB and BM samples were performed (for a total of 460 analysis) on 77 patients affected by Ph+ CML in chronic phase treated in our center. All samples were analyzed in the same laboratory following international guidelines (Cross N, Leukemia 2012) and results were expressed according to the International Scale; ABL1 was used as control gene. Time from blood-drawn to processing was within 3-4 hours. Results Among the 230 pairs, 3 were considered as not evaluable because of inadequate material; for the purpose of this study, the remaining 227 pairs were considered as “evaluable”. 204 pairs were classified as “fit” when both BM and PB ABL amplification resulted in more than 10.000 copies; 23 pairs were considered unfit for ABL1 <10.000 in either one of the two samples (21) or both (2). The mean number of ABL1 copies in all evaluable samples was 35.639 for BM (SD 21.465) and 30.958 for PB samples (SD 18.696). Correlation analysis was performed on the whole population and in 4 subgroups: No Complete Cytogenetic Response (CCyR, 22%), CCyR without Major Molecular Response (MMR), (21.6%), CCyR with MMR (excluding patients with MR4 or better,19.8%), and CCyR with MR4 – MR4.5 (32,6%). Cytogenetic response was not available in 9 BM samples (4%), not included in the subgroup analysis. Spearman correlation of BCR/ABL ratio values between PB versus BM paired samples resulted in a statistically significant correlation in all groups, both for evaluable and fit pairs. Correlation was stronger in samples that were not in MMR or better (table 1 and figure 1). The Wilcoxon test showed that the mean difference of BCR/ABL values between paired PB and BM samples was not significantly different from zero (in evaluable and fit pairs by considering the whole population). Concordance was further analyzed by the K test which resulted in a coefficient equal to 0.627, corresponding to a notable degree of concordance. For patients in CCyR, agreement on classification of response (MMR, MR4, MR4.5) between paired PB and BM samples was observed in 125/168 evaluable pairs; 22 out of the 43 evaluable cases of disagreement were due to technical failures (in 10 BM and 12 PB samples). In 14 of the remaining 21 cases, PB was more sensitive. Conclusions In a single center experience of molecular analysis, BCR/ABL ratio was highly consistent in BM and PB samples. In less than 10% of the cases a single test did not reach the required sensitivity of 10.000 ABL copies and the double testing allowed to obtain a valid result. This may be especially valuable in evaluating an early response (i.e. at 3 months), when the amount of disease has prognostic relevance. The analysis will be expanded to include samples coming from different centers to evaluate a possible role of timing and transport on data consistency. Disclosures: Saglio: Novartis: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria; Celgene: Consultancy, Honoraria.

scholarly journals Concomitant essential thrombocythemia with JAK2 V617F mutation in a patient with chronic myeloid leukemia with major molecular response with imatinib and long-term follow-up

2016 ◽  
Vol 12 (1) ◽  
pp. 485-487 ◽  
Author(s):  
KATIA BORGIA BARBOSA PAGNANO ◽  
MÁRCIA TORRESAN DELAMAIN ◽  
MARIANA MUNARI MAGNUS ◽  
JOSÉ VASSALLO ◽  
CARMINO ANTONIO DE SOUZA ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Essential Thrombocythemia ◽  
Myeloid Leukemia ◽  
Jak2 V617f ◽  
Jak2 V617f Mutation ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Long Term Follow Up

scholarly journals Impact of Proteomic Profile of Peripheral Blood and Bone Marrow Sera on Molecular Response in Patients with Chronic Myeloid Leukemia: Preliminary Data

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5515-5515
Author(s):  
Nicola Sgherza ◽  
Vito Garrisi ◽  
Giacoma De Tullio ◽  
Simona Serratì ◽  
Angela Iacobazzi ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Myeloid Leukemia ◽  
Preliminary Data ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Differentially Expressed ◽  
Molecular Response ◽  
Proteomic Profile ◽  
Group A ◽  
Group B

Abstract BACKGROUND. Chronic Myeloid Leukemia (CML) is a myeloproliferative neoplasm characterized by an aberrant protein (BCR–ABL) which is a constitutively active tyrosine kinase. According to the latest ELN recommendations for the management of CML, molecular response (MR) is best assessed according to the International Scale (IS) as the ratio of BCR-ABL1 transcripts to ABL1 transcripts, or other internationally recognized control transcripts. It is expressed and reported as BCR-ABL1% on a log scale where 10%, 1%, 0.1%, 0.01%, 0.0032%, and 0.001% correspond to a decrease of respectively 1 (MR1), 2 (MR2), 3 (MR3), 4 (MR4), 4.5 (MR4.5) logs below the standard baseline that was used in the IRIS study. Recent advances in the proteomic field have allowed us to better understand the biology of several cancer types and/or discover new candidate biomarkers, but very few data are available in CML. AIMS. The purpose of this study was to evaluate a possible correlation between depth of MR and proteomic profile in sera samples obtained from the peripheral blood and bone marrow of CML patients. PATIENTS AND METHODS Samples were consecutively and prospectively obtained from 20 CML patients observed between January and June 2014 at the Hematology Unit of the National Cancer Research Centre “Istituto Tumori Giovanni Paolo II” in Bari, Italy. Each individual involved in the study signed an informed consent form authorizing the Institute to utilize their biological tissues for research purposes. All patients at diagnosis displayed the classic t(9;22) Ph chromosome according to standard cytogenetics. The BCR/ABL transcript at RT-PCR was b3a2 in 13 patients and b2a2 in 7 patients. Peripheral blood and bone marrow samples were centrifuged within 30 minutes of sample taking. Serum specimens were immediately collected and frozen at −80°C. Twenty sera from peripheral blood were sampled from 5 patients in MR1 response, four in MR2, eight in MR3, two in MR4 and 1 patient at diagnosis; for eleven patients serum from bone marrow was also available; in particular 2 were sampled from patients in MR1, 3 in MR2, 4 in MR3, 1 in MR4 and 1 at diagnosis. Patients were grouped in two cohorts: the first comprised those with lower molecular response to MR3 (group A: 10 patients) and the second greater than or equal to MR3 (group B: 10 patients). The association of proteomic profile with molecular response was performed using the SELDI ToF Mass Spectrometry platform. Each specimen was spotted on an IMAC30 metal affinity protein-chip, prepared according to the manufacturer's instructions, and analyzed in duplicate. RESULTS Fourteen differentially expressed peaks were highlighted when comparing peripheral sera from group A and group B, but none was statistically significant. When comparing 11 available serum samples from the bone marrow of groups A (6) and B (5), four peaks (m/z 10629, m/z 3889, m/z 7772, m/z 7987) were reported as differentially expressed in a statistically significant way (p<0.05). Focusing the differential expression analysis in peripheral sera only on MR1 patients (including one patient at diagnosis) versus MR4 patients, one peak at m/z 11092 was identified as significantly and differentially expressed (p < 0.05) (Figure 1). Similarly, comparing bone marrow sera only from MR1 and MR4 patients respectively, 32 peaks were differentially expressed. Once again the peak at m/z 11092 resulted under expressed in MR1 patients, and interestingly the single patient at diagnosis had the lowest value. No statistical differences were evidenced when comparing peripheral blood and bone marrow sera obtained from b3a2 and b2a2 patients. CONCLUSIONS These preliminary data suggest that an over-expression of m/z 11092 in serum obtained from peripheral blood and bone marrow could be associated with a deeper molecular response; further investigations are needed on a larger number of patients in order to confirm or refute our results and, to definitively characterize the peak at m/z 11092. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

scholarly journals Generic Imatinib in Chronic Myeloid Leukemia: Survival of the Cheapest

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 630-630 ◽  
Author(s):  
Danthala Madhav
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Adverse Events ◽  
Imatinib Mesylate ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Quantitative Polymerase Chain Reaction ◽  
Comparable Efficacy ◽  
Molecular Response ◽  
Free Survival

Abstract Introduction: The patent expiration of Imatinib mesylate (Glivec, ®Novaritis) on February 1, 2016, has brought the focus back on generic versions of the drug, and an opportunity to provide a safe and cost effective alternative. India has witnessed a mushrooming of home grown pharmaceutical companies, that have drawn on Darwinian theory to promote the concept of "survival of the cheapest", in pursuit of a deeper penetrance into the cash strapped population. The launch of Veenat (®NATCO pharma) at a fraction of the price of the innovator drug is a case in point. Objectives: To determine the molecular and cytogenetic responses, survival endpoints (event free survival (EFS), failure free survival (FFS), transformation free survival (TFS), overall survival (OS), and safety of innovator and generic brands of imatinib. Materials and Methods: In this retrospective analysis, data from 1,812 patients with chronic myeloid leukemia (CML) treated with frontline Imatinib mesylate (Innovator/Generic) at a single institution between 2008 and 2014 is included. Of these 1,812 patients, 445 were excluded due to inadequate data and follow up. Thus, data from 1,193 patients who were treated with Glivec (®Novartis), and 174 patients with Veenat (®NATCO) was available. Observations: A higher percentage of patients in the generic arm compared to the innovator arm, were in accelerated phase (9.7% vs 6.7%) and blast crisis (7.4% vs 3.7%), respectively.After a median follow up of 1,347 days, 805 (67.4%) patients achieved complete cytogenetic response (CCgR), 259 (21.7%) achieved major molecular response (MR3), and 205 (17.1%) achieved 4 log reduction in BCR ABL transcripts (MR4) in the innovator arm. After a median follow up of 1,220 days, 112 (64.3%), 24 (13.7%), and 42(24.1%) patients achieved a CCgR, MR3 and MR4 respectively, in the generic arm.Follow up assessments using real-time quantitative polymerase chain reaction (q-PCR) and/ or cytogenetic tests were not available in 230 (19.2%) and 40 (22.9%) patients, in the innovator and generic groups respectively, despite inclusion in a sponsorship program.Adherence to treatment was poor in 192 (16%) and 30 (17.2%) patients in the innovator and generic arms respectively. Results: In a fairly homogenous population of lower economic strata, on a free drug access program, the prime factors influencing adherence were low educational level, assumptions of "cure", recent bereavement, stigma of cancer diagnosis and repeated hospital visits. Transformation to accelerated/blast phase occurred in 7.7% and 7.4% of patients in the innovator and generic arms respectively. Testing for BCR-ABL1 mutations was done in 31 (17.8%) patients in the generic arm and 132(11%) patients in the innovator arm, after failure of treatment or suboptimal response. Mutations were identified in 14 (8%) patients in the generic arm and 52 (4.3%) patients in the innovator arm.The most common subsequent treatments chosen were, dose escalation (249 [20.8%] vs 30 [17.2%]), Nilotinib (26 [2.1%] vs 8 [4.5%]), Dasatinib (11 [0.9%] vs 9 [5.1%]) and hydroxyurea (11 [0.9%] and 4 [2.2%]) in the innovator and generic arms respectively. There was no difference in EFS (p=0.46), FFS (p=0.16), TFS (p=0.9), or OS (p=0.13) between the two groups. The frequency of reported grade 1, or 2 non-hematological adverse events which included musculoskeletal pain, muscle cramps, and peripheral edema, and hematological adverse events was comparable between the study groups. However, the incidence of grade 3 skin rash was higher in the generic group (2.8%) in comparison to the innovator group (0.2%). Conclusion: The findings of the present study showed comparable efficacy and safety of the generic and innovator versions of imatinib in the treatment of patients with chronic myeloid leukemia. Disclosures No relevant conflicts of interest to declare.

scholarly journals Increased Expression of TIGIT/CD57 in Peripheral Blood/Bone Marrow NK Cells in Patients with Chronic Myeloid Leukemia

2020 ◽  
Vol 2020 ◽  
pp. 1-8
Author(s):  
Danlin Yao ◽  
Ling Xu ◽  
Lian Liu ◽  
Xiangbo Zeng ◽  
Juan Zhong ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Myeloid Leukemia ◽  
Nk Cells ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Replicative Senescence ◽  
Cell Function ◽  
De Novo ◽  
Nk Cell ◽  
Molecular Response

The antitumor activity of NK cells in patients with chronic myeloid leukemia (CML) is inhibited by the leukemia microenvironment. Recent studies have identified that the expression of TIGIT, CD57, and KLRG1 is related to the function, maturation, and antitumor capabilities of NK cells. However, the characteristics of the expression of these genes in the peripheral blood (PB) and bone marrow (BM) from patients with CML remain unknown. In this study, we used multicolor flow cytometry to assay the quantity and phenotypic changes of NK cells in PB and BM from de novo CML (DN-CML) and CML patients acquiring molecular response (MR-CML). We found that the expression of TIGIT, which inhibits NK cell function, is increased on CD56+ and CD56dim NK cells in DN-CML PB compared with those in healthy individuals (HIs), and it is restored to normal in patients who achieve MR. We also found that the expression of CD57 on NK cells was approximately the same level in PB and BM from DN-CML patients, while decreased CD57 expression was found on CD56+ and CD56dim NK cells in HI BM compared with PB. Additionally, those two subsets were significantly increased in DN-CML BM compared to HI BM. The expression of CD57 correlates with replicative senescence and maturity for human NK cells; therefore, the increase in TIGIT on PB NK cells together with an increase in CD57 on BM NK cells may explain the subdued NK cell antileukemia capacity and proliferative ability in DN-CML patients. These results indicate that reversing the immune suppression of PB NK cells by blocking TIGIT while improving the proliferation of BM NK cells via targeting CD57 may be more effective in removing tumor cells.

Quantitative Polymerase Chain Reaction (qPCR) at Diagnosis and Follow-Up of Patients with Chronic Myeloid Leukemia in Treatment with Imatinib.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4688-4688
Author(s):  
Teresa Vallespí ◽  
Mildred Borrego ◽  
Doulous Colomé ◽  
Ana Jaen ◽  
Maria Rozman ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Treatment Time ◽  
Quantitative Polymerase Chain Reaction ◽  
Chronic Phase ◽  
Logarithmic Scale ◽  
Base Line ◽  
Molecular Response ◽  
Before And After

Abstract Imatinib, a selective inhibitor of tyrosin-kinasa BCR/ABL fusion protein, produces high response rates in patients with chronic myeloid leukemia (CML) in the chronic phase. The behavior of the levels of the BCR/ABL transcript by qPCR technique was studied in 24 patients (13M/11F; median age: 49.6 years, range: 23–73), diagnosed of CML in chronic phase, before and after the treatment with imatinib (at the 0, 3, 7, 11 and 15 months). Eight patients had previously received interferon alpha or busulphan and 16 hidroxiurea. The amplification of BCR/ABL with the qPCR technique, according to protocol BIOMED-2, was carried out in samples of bone marrow (n = 23) and peripheral blood (n = 48). Results were calculated in relation to a control gene of the glucuronidasa (GUS) and expressed in logarithmic scale (log10). Median time from the diagnosis was of 28 months and median treatment time with imatinib was 14 months. The median reduction of BCR/ABL transcripts was 1,98 log after three months and decreased further (2,71 log) during follow-up. Both of them were significative when compare with base line levels (P &lt;0.001). The reduction was greater in patients who received a dose ³ 400 mg/day (n=16) than those with 300 mg/day (n=8). Three patients reached a major molecular response (ratio BCR-ABL/GUS &lt;0.005) up to 15 months of treatment. In conclusion: the determination of the BCR/ABL transcripts by qPCR contributes with valuable information about the effect of imatinib in patients with CML. The logarithmic reduction is higher in the beginning of the treatment and doses ³ 400 mg/day are associated with a greater reduction of the tumoral load. Figure Figure

A New Computational Method to Predict Long-Term Minimal Residual Disease and Molecular Relapse after TKI-Cessation in CML

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3099-3099 ◽  
Author(s):  
Ingmar Glauche ◽  
Hendrik Liebscher ◽  
Christoph Baldow ◽  
Matthias Kuhn ◽  
Philipp Schulze ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Tyrosine Kinase ◽  
Tyrosine Kinase Inhibitor ◽  
Myeloid Leukemia ◽  
Research Funding ◽  
Kinase Inhibitor ◽  
Residual Disease ◽  
Molecular Response ◽  
Tki Treatment

Abstract Predicting minimal residual disease (MRD) levels in tyrosine kinase inhibitor (TKI)-treated chronic myeloid leukemia (CML) patients is of major clinical relevance. The reason is that residual leukemic (stem) cells are the source for both, potential relapses of the leukemicclone but also for its clonal evolution and, therefore, for the occurrence of resistance. The state-of-the art method for monitoring MRD in TKI-treated CML is the quantification of BCR-ABL levels in the peripheral blood (PB) by PCR. However, the question is whether BCR-ABL levels in the PB can be used as a reliable estimate for residual leukemic cells at the level of hematopoietic stem cells in the bone marrow (BM). Moreover, once the BCR-ABL levels have been reduced to undetectable levels, information on treatment kinetics is censored by the PCR detection limit. Clearly, BCR-ABL negativity in the PB suggests very low levels of residual disease also in the BM, but whether the MRD level remains at a constant level or decreases further cannot be read from the BCR-ABL negativity itself. Thus, also the prediction of a suitable time point for treatment cessation based on residual disease levels cannot be obtained from PCR monitoring in the PB and currently remains a heuristic decision. To overcome the current lack of a suitable biomarker for residual disease levels in the BM, we propose the application of a computational approach to quantitatively describe and predict long-term BCR-ABL levels. The underlying mathematical model has previously been validated by the comparison to more than 500 long-term BCR-ABL kinetics in the PB from different clinical trials under continuous TKI-treatment [1,2,3]. Here, we present results that show how this computational approach can be used to estimate MRD levels in the BM based on the measurements in the PB. Our results demonstrate that the mathematical model can quantitatively reproduce the cumulative incidence of the loss of deep and major molecular response in a population of patients, as published by Mahon et al. [4] and Rousselot et al. [5]. Furthermore, to demonstrate how the model can be used to predict the BCR-ABL levels and to estimate the molecular relapse probability of individual patients, we compare simulation results with more than 70 individual BCR-ABL-kinetics. For this analysis we use patient data from different clinical studies (e.g. EURO-SKI: NCT01596114, STIM(s): NCT00478985, NCT01343173) where TKI-treatment had been stopped after prolonged deep molecular response periods. Specifically, we propose to combine statistical (non-linear regression) and mechanistic (agent-based) modelling techniques, which allows us to quantify the reliability of model predictions by confidence regions based on the quality (i.e. number and variance) of the clinical measurements and on the particular kinetic response characteristics of individual patients. The proposed approach has the potential to support clinical decision making because it provides quantitative, patient-specific predictions of the treatment response together with a confidence measure, which allows to judge the amount of information that is provided by the theoretical prediction. References [1] Roeder et al. (2006) Dynamic modeling of imatinib-treated chronic myeloid leukemia: functional insights and clinical implications, Nat Med 12(10):1181-4 [2] Horn et al. (2013) Model-based decision rules reduce the risk of molecular relapse after cessation of tyrosine kinase inhibitor therapy in chronic myeloid leukemia, Blood 121(2):378-84. [3] Glauche et al. (2014) Model-Based Characterization of the Molecular Response Dynamics of Tyrosine Kinase Inhibitor (TKI)-Treated CML Patients a Comparison of Imatinib and Dasatinib First-Line Therapy, Blood 124:4562 [4] Mahon et al. (2010) Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol 11(11):1029-35 [5] Rousselot 
et al. (2014) Loss of major molecular response as a trigger for restarting TKI therapy in patients with CP- CML who have stopped Imatinib after durable undetectable disease, JCO 32(5):424-431 Disclosures Glauche: Bristol Meyer Squib: Research Funding. von Bubnoff:Amgen: Honoraria; Novartis: Honoraria, Research Funding; BMS: Honoraria. Saussele:ARIAD: Honoraria; Novartis: Honoraria, Other: Travel grants, Research Funding; Pfizer: Honoraria, Other: Travel grants; BMS: Honoraria, Other: Travel grants, Research Funding. Mustjoki:Bristol-Myers Squibb: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Ariad: Research Funding; Novartis: Honoraria, Research Funding. Guilhot:CELEGENE: Consultancy. Mahon:NOVARTIS PHARMA: Honoraria, Research Funding; BMS: Honoraria; PFIZER: Honoraria; ARIAD: Honoraria. Roeder:Bristol-Myers Squibb: Honoraria, Research Funding.

Long-Term Follow-Up of the French Stop Imatinib (STIM1) Study in Patients With Chronic Myeloid Leukemia

2017 ◽  
Vol 35 (3) ◽  
pp. 298-305 ◽  
Author(s):  
Gabriel Etienne ◽  
Joëlle Guilhot ◽  
Delphine Rea ◽  
Françoise Rigal-Huguet ◽  
Franck Nicolini ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Treatment Discontinuation ◽  
Molecular Response ◽  
Long Term Follow Up ◽  
Study Population ◽  
Analysis Point

Purpose Imatinib (IM) can safely be discontinued in patients with chronic myeloid leukemia (CML) who have had undetectable minimal residual disease (UMRD) for at least 2 years. We report the final results of the Stop Imatinib (STIM1) study with a long follow-up. Patients and Methods IM was prospectively discontinued in 100 patients with CML with UMRD sustained for at least 2 years. Molecular recurrence (MR) was defined as positivity of BCR-ABL transcript in a quantitative reverse transcriptase polymerase chain reaction assay confirmed by a second analysis point that indicated an increase of one log in relation to the first analysis point at two successive assessments or loss of major molecular response at one point. Results The median molecular follow-up after treatment discontinuation was 77 months (range, 9 to 95 months). Sixty-one patients lost UMRD after a median of 2.5 months (range, 1 to 22 months), and one patient died with UMRD at 10 months. Molecular recurrence-free survival was 43% (95% CI, 33% to 52%) at 6 months and 38% (95% CI, 29% to 47%) at 60 months. Treatment was restarted in 57 of 61 patients with MR, and 55 patients achieved a second UMRD with a median time of 4 months (range, 1 to 16 months). None of the patients experienced a CML progression. Analyses of the characteristics of the study population identified that the Sokal risk score and duration of IM treatment were significantly associated with the probability of MR. Conclusion With a median follow-up of more than 6 years after treatment discontinuation, the STIM1 study demonstrates that IM can safely be discontinued in patients with a sustained deep molecular response with no late MR.

scholarly journals An Atypical Initial Presentation of Chronic Myeloid Leukemia with Central Nervous System and Lymph Node Blast Crises

2016 ◽  
Vol 9 (2) ◽  
pp. 415-421 ◽  
Author(s):  
Khadega A. Abuelgasim ◽  
Saeed Alshieban ◽  
Nada A. Almubayi ◽  
Ayman Alhejazi ◽  
Abdulrahman R. Jazieh
Keyword(s):  
Central Nervous System ◽  
Bone Marrow ◽  
Nervous System ◽  
Chronic Myeloid Leukemia ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Single Agent ◽  
Chronic Phase ◽  
Current Evidence ◽  
Molecular Response

We describe the case of a young man with therapy-naive chronic myeloid leukemia who did not initially have any peripheral blood or bone marrow excess blasts but presented with extramedullary myeloid blast crises involving the central nervous system and multiple lymph nodes. Conventional cytogenetic tests were positive for t(9;22)(q34:q11) as well as for trisomy 8, 14 and 21 and del(16q). The patient’s peripheral blood and bone marrow were positive for the BCR-ABL oncogene when analyzed by fluorescence in situ hybridization and polymerase chain reaction. He achieved good clinical, radiological, cytogenetic and molecular response to acute myeloid leukemia induction chemotherapy combined with 16 doses of triple intrathecal chemotherapy and oral dasatinib (second-generation tyrosine kinase inhibitor) treatment. Due to his poor general condition, he was treated with 24 Gy of whole-brain radiation therapy, as allogeneic stem cell transplantation was not feasible. Although extramedullary CNS blast crises are usually associated with a very poor outcome, our patient remains in complete cytogenetic and molecular remission, on single-agent dasatinib, 4 years after the diagnosis with no current evidence of active extramedullary disease. This suggests that dasatinib has a role in controlling not only chronic-phase chronic myeloid leukemia, but also its CNS blast crisis.

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