BCR-ABLIS Expression at Diagnosis and After 3 or 6 Months of Treatment Predicts CML Response to IMATINIB Therapy.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3426-3426 ◽  
Author(s):  
Paolo Vigneri ◽  
Fabio Stagno ◽  
Stefania Stella ◽  
Alessandra Cupri ◽  
Michele Massimino ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Rapid Identification ◽  
Response To Therapy ◽  
Molecular Characteristics ◽  
Correlated Response ◽  
Molecular Responses ◽  
Transcript Levels ◽  
Optimal Response ◽  
Intention To Treat

Abstract Abstract 3426 Imatinib mesylate (IM) has shown remarkable efficacy for the treatment of Chronic Myeloid Leukemia (CML) patients (pts) in the chronic phase of the disease. However, while most individuals achieve an optimal response to conventional IM therapy, approximately 30% either fail IM or develop intolerance to the drug. Thus, there is a growing need for biological parameters predictive of IM response (at diagnosis or during the first months of therapy) in order to recognize pts with a more aggressive disease that should receive alternative treatments. We examined the outcomes of the first 193 CML pts accrued to the observational SCREEN (Sicily and Calabria CML REgional ENterprise) multicenter non-sponsored study, and analyzed the responses of this unselected population. Pts characteristics were as shown in Table 1. All subjects received IM 400 mg daily. Median follow-up was 26 months (range 3–60). Complete hematological (CHR), cytogenetic (CCyR) and major molecular responses (MMR) were rated according to the European Leukemia Net 2006 guidelines. Peripheral blood samples were used for BCR-ABL determination by quantitative real-time polymerase chain reaction according to the International standardized Scale (IS). To identify parameters predictive of IM response, pts were stratified according to clinical and molecular responses or BCR-ABL transcript levels at diagnosis and analyzed for their outcome on an intention to treat basis. At 12 months, cumulative incidences of CHRs, CCyRs and MMRs were 100%, 82% and 43%, respectively. At 24 months, incidences of CCyR and MMR increased to 87% and 67%. According to the ELN criteria, 121 pts (62%) achieved an optimal response; 36 pts (19%) had a suboptimal response; 32 pts (17%) failed IM because of either primary (20 pts) or secondary (12 pts) resistance. Only 4 pts (2%) were intolerant to IM. Kaplan-Meyer estimates for overall, progression-free, event-free and failure-free survival at 60 months were 99%, 96% 80% and 72%. When we clustered all subjects in optimal responders (ORs) and suboptimal/resistant (S/R) pts and correlated response to therapy with various molecular characteristics we found that the amount of BCR-ABLIS transcripts at diagnosis predicted response to IM. Indeed, the median amount of BCR-ABLIS at diagnosis displayed by patients that failed IM or achieved a suboptimal response was significantly higher (104.154IS) than that of patients obtaining an optimal response (53.478IS; p=0.000611). As WBC counts were not significantly different between ORs and S/R pts (p=0.2065), increased amounts of BCR-ABLIS transcripts were probably representative of the aggressiveness of the leukemic clone. We also observed that pts displaying >10% BCR-ABLIS after 3 or 6 months of IM had a significantly lower chance of achieving a CCyR compared to pts with BCR-ABLIS levels lower than 10% (p<0.001). IM is a highly effective and well-tolerated treatment for most chronic phase CML pts, producing high rates of CHR, CCyR and MMR. However, 35–40% of newly diagnosed CML pts will either fail IM or obtain a suboptimal response. High levels of BCR-ABLIS transcripts at diagnosis may allow the rapid identification of CML pts that are likely to fail IM or to achieve a suboptimal response. Furthermore, failing to achieve BCR-ABLIS transcript levels <10% after 3 or 6 months of IM treatment significantly reduces the probability of subsequently obtaining a CCyR. Table 1. Characterisitics of CML pts included in the SREEN study Age (median yrs) 54 (range 24–90) Sex (M/F) 108/85 WBC × 109/L (median) 64.8 (range 3.4–718.0) Hb (g/dL) 12.1 (range 7.5–17.0) PLT × 109/L (median) 330.0 (range 67.0–1690.0) Organomegaly % 58 Sokal risk stratification % 49 Low/36 Intermediate/15 High Ph+ % (diagnosis) 96 ACA % (diagnosis) 7 BCR-ABL transcript variants % 38 e13a2/53 e14a2/9 other BCR-ABLIS % (median at diagnosis) 58.641 Disclosures: No relevant conflicts of interest to declare.

The Predictive Value of Early Molecular Response in Chronic Phase CML Patients Treated with Dasatinib First Line Therapy

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 785-785 ◽  
Author(s):  
David Marin ◽  
Corinne Hedgley ◽  
Richard E Clark ◽  
Jane F Apperley ◽  
Letizia Foroni ◽  
...  
Keyword(s):  
Peripheral Blood ◽  
Predictive Value ◽  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Transcript Level ◽  
Molecular Response ◽  
Costal Margin ◽  
Molecular Responses ◽  
Transcript Levels ◽  
International Scale

Abstract Abstract 785 We assessed the correlation between molecular response at 3 and 6 months of dasatinib 100mg daily treatment and subsequent cytogenetic and molecular responses in 150 newly-diagnosed chronic phase CML patients treated with front line dasatinib in the UK SPIRIT 2 study (imatinib vs dasatinib). The median age was 54 years (range 18.4–82.1); 90 patients were male. The Sokal risk distribution was: 39 low, 65 intermediate and 46 high. At diagnosis 26 patients had splenomegaly >10cm below the costal margin; median WBC and platelet count were 65.7 (2.2-428) and 404 (101-2,433). The median hemoglobin level was 11.0 g/dl (4.17-15.8). The median percentage of blasts and basophils in peripheral blood was 0.4% (0-13.5) and 3.6% (0-19.2) respectively. The dose of dasatinib was adjusted according to tolerance. BCR-ABL1 transcripts in the peripheral blood were analyzed at 12 week intervals using RQ-PCR. Results were expressed as percentage ratios relative to an ABL1 internal control and expressed on the international scale. Complete molecular response (CMR) was defined as two consecutive samples with no detectable transcripts (RQ-PCR negative) and ABL1 control >40,000 (the median ABL1 control in the CMR samples was 96,000). In addition, we also explored a less stringent definition of CMR, namely CMR4.5 which was recently defined by the EUTOS group as BCR-ABL1 ratio of 0.0032 on the international scale, consistent with a 4.5 log reduction in the transcript level, without necessarily being RQ-PCR negative. With a median follow up of 15 months (range 6–29) the 2 year cumulative incidences (CI) of CCyR, MMR, CMR4.5 and CMR were 84.5, 72.1, 24.1 and 5.6% respectively. The median BCR-ABL/ABL ratios at 3, 6, 12 and 24 months were 0.830%, 0.093%, 0.040% and 0.034% respectively. We investigated the predictive value of the BCR-ABL1 transcript levels at 3 (>10% vs ≤10% and >1% vs ≤1%) and 6 months (>1% vs ≤1%) of dasatinib therapy on the 2 years CI of cytogenetic and molecular responses. The 135 patients who at 3 months had a BCR-ABL1/ABL1 ratio ≤10% and the 81 patients who had a ratio ≤1% had a significantly better 2 year CI of CCyR (89.1% vs 50.2%, p=0.02 and 100% vs 84.7%, p=0.01), MMR (83.7% vs 14.2%, p=0.004 and 85.2% vs 54.3 p<0.001), CMR4.5 (25.0% vs 0%, p<0.18 and 37.6 v 3.3% p=0.001) but not CMR (6.7 vs 0%, p=0.51 and 7.1 vs 0% p=0.46). Similarly, the 109 patients who at 6 months had a transcript ratio ≤1% had a better 2 year CI of MMR (86.3 vs 13.9%, p<0.001), CMR4.5 (31.2 vs 0%, p=0.03) and CMR (14.3 vs 0%, p=0.04) than the remaining patients. We used a receiver operating characteristic (ROC) curve to identify the optimal cut-off in the transcript level at 3 and 6 months that would predict the probability of each outcome with maximal sensitivity and specificity. Table 1 shows the results of applying the optimal cutoffs for each outcome in the 3-month analysis. Then we investigated whether the various outcomes could be better predicted using the cut-offs defined at 3 or at 6 months (including both the 1 and 10% cut-offs and the newly identified cut-offs) by using a multivariate model. For each outcome the cut-off defined at 3 months shown in Table 1 was superior. No pre-therapy patient characteristics were an independent predictor for cytogenetic or molecular response.Table 1.CI of the various responses according to cut-offs identified in the ROC analysis.3 month BCR-ABL1/ABL1 ratio (%)n2 year CI (%)pCCyR10493.3p<0.001≤2.724675.9>2.72MMR7987.6p<0.001≤0.967152.7≥0.96CMR4.55649.7p<0.001≤0.378947.1>0.387CMR4220.1p=0.01≤0.241080>0.24 The key finding from this analysis is that patients who achieve a transcript level ≤10% after 3 months of dasatinib (135 of 150) have an 89.1% probability of eventually achieving CCyR, compared to 50.2% for patients with higher transcript levels (p=0.02). This preliminary observation may allow the identification of around 10% of dasatinib-treated patients for whom other forms of treatment might be considered although our conclusions require verification in further studies. The predictive power of RQ-PCR assessment can be greatly improved by identifying the optimal cut-offs for the specific outcomes, which is particularly important when predicting for the achievement of CMR. It remains uncertain whether these differences in response will translate into differences in survival and the SPIRIT 2 study continues to address this question. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Early Molecular Response in Chronic Myeloid Leukemia Patients Predicts Future Response Status

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 5529-5529
Author(s):  
Irina Martynkevich ◽  
Vasily Shuvaev ◽  
Ekaterina Petrova ◽  
Lyubov Polushkina ◽  
Lyudmila Martynenko ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Molecular Response ◽  
Prognostic Impact ◽  
Long Term Outcome ◽  
Transcript Levels ◽  
Optimal Response

Abstract Objectives and background: The level of early MR is important for the optimization of therapy and making a decision to a switch to 2nd line therapy in patients (pts) who have not achieved an optimal response (OR). According to the recent recommendations at definition of OR on CML therapy, pts must have the level of BCR-ABL transcript gene at 10% or less and Ph-positive cells 35% or less at 3 months. But, in half of all cases of pts with BCR-ABL >10% at 3 months progression events happen between 3 and 6 months. The goal of our research was to investigate the prognostic impact of a large BCR-ABL transcript amount at 3 months on the subsequent response and the long-term outcome of CML pts treated frontline with IM. Methods: We have examined 185 pts, who have got IM from January 2010 up to the present. Molecular monitoring has been done regularly in all patients according to ELN recommendations. Median age was 49 years. All pts were in CP. BCR-ABL transcript levels were assessed by real-time quantitative PCR. Results: In our study 54% (100/185 cases) of pts achieved the optimal response with BCR-ABL transcript levels ≤10% at 3 months, 50,3% (93/185 cases) did it - with BCR-ABL transcript levels ≤1% at 6 months, and only 18% achieved the optimal response at 12 months. The comparative analysis has shown statistical differences in all characteristics in 2 groups of pts, who either achieved or not the optimal response at 3 months. Pts with BCR-ABL transcript levels ≤10% more often achieved CCgR at 6 months (g=0,0000), CCgR during all period (g=0,0004), MMR at 12 months (g=0,0000), MMR during all period (g=0,0012) and MR4 during all period (g=0,0000), pts had londer event-free (g=0,0432) and overall (g=0,0279) 4-year survival. Figure 1 Figure 1. In our center we have switched 6 patients to the 2nd TKI - those who didn't achieve the optimal response at 3 months. The switching showed the positive influence on loss level expression of BCR-ABL gene in 5 out of 6 patients. After that all patients achieved the optimal response in the future. For example, we had one patient with failure of IM at 3 months. We switched him the therapy to NI in 5 months after the diagnosis. As a result the patient achieved CCgR at 1,5 months, and the deep molecular response 4,5 log at 3 months. Conclusions: Early and deep responses to TKIs are predictive of long-term response and favorable survival outcomes. 3-month reduction in BCR-ABL transcript levels to >10% is a factor of bad effectiveness of TKI therapy and requires switching to the 2nd TKI. Timely switching to the 2nd TKIs allows us to achieve an optimal response in CML patients with level BCR-ABL >10% at 3 months. References: Timothy P. Hughes, Giuseppe Saglio, Hagop M. Kantarjian et al. Early molecular response predicts outcomes in patients with chronic myeloid leukemia in chronic phase treated with frontline nilotinib or imatinib. Blood, 27 February 2014 x Volume 123, Number 9. Disclosures No relevant conflicts of interest to declare.

Impact of Imatinib Dose Escalation in Chronic Myeloid Leukemia Patients in Chronic Phase with Sub-Optimal Response or Failure with Imatinib 400 Mg.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 3289-3289
Author(s):  
Katia BB Pagnano ◽  
Marcia T Delamain ◽  
Eliana C.M. Miranda ◽  
Vagner O Duarte ◽  
Brunna Eulálio Alves ◽  
...  
Keyword(s):  
Median Time ◽  
Dose Escalation ◽  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Dose Increase ◽  
Free Survival ◽  
Optimal Response ◽  
Hematological Response

Abstract Abstract 3289 Poster Board III-1 Imatinib dose escalation has been used in sub-optimal response and therapeutic failure to imatinib in conventional doses. The aim of this study was to evaluate the efficacy of imatinib dose increase in CML patients in CP who did not achieve the best response to imatinib 400 mg QID. Patients and methods: All CML patients in CP treated in our institution with imatinib 400mg between March 2002 and December 2008 were evaluated. Imatinib was escalated to 600–800mg in cases with sub-optimal response or failure, according to Leukemia Net or IRIS Trial criteria. All survival curves were calculated from date of dose increase: overall survival (OS) until death or last follow-up, event free survival (EFS) until loss of complete hematological response (CHR) or major cytogenetic response (MCyR), progression to accelerated phase (AP) or blast crisis (BC) or death from any cause. Transformation free survival (TFS) was calculated from dose increase until progression to AP, BC or death. Results: 137 patients in CP were treated with imatinib 400 mg. Dose was escalated in 55 (40%) patients due to loss or failure to achieve CRH (13 = 24%); progression to BC (2 = 3.5%); no CCR (11 = 20%); loss of RCC (5 = 9%); CCR without major molecular response (MMR) after 18 months of imatinib (24 = 43.5%). Males: 37, females 18 cases. Median age: 44 (16–74) years. Twenty-eight patients (49%) were treated with imatinib as first line therapy and 51% had used IFN previously. Median time between diagnosis and imatinib start was 4.5 (0–94) months. Responses: 94% achieved CHR; 58% CCR and 34% MMR. After dose increase, 31 (56%) responded: 58% of the patients with previous sub-optimal molecular response achieved MMR. Among those who benefited from dose increase, only 3 cases lost the response: one with hematological resistance and two with cytogenetic resistance (2 lost CCR and one CHR). Seven out of 16 patients who increased dose due to cytogenetic failure (loss of response, failure and sub-optimal response) achieved response: one had partial cytogenetic response (PCyR) and 6 CCR. Five patients with hematological failure presented response: CHR (2), CCR (1), PCyR (1) and MMR (1). Patients with BC (2 cases) did not respond to dose escalation. TFS was 89% and 67% in 2 and 5 years, respectively. EFS was 71% and 64% in 2 and 5 years respectively. When stratified by the type of failure, EFS was 100%, 49% and 34% in the group with molecular sub-optimal response with median time of 22 (4–41) months, cytogenetic 17 (1.2–42) and hematological failure 7.7 (0.2–57), respectively (P<0.03). Conclusions: imatinib dose escalation was successful in molecular sub-optimal response. However, the patients who do not achieve MMR might be candidates to second line treatment. Patients who did not achieve cytogenetic or hematological response did worse with imatinib dose escalation. Disclosures: No relevant conflicts of interest to declare.

Biphenotypic Blast Phase (B-BP) of Chronic Myeloid Leukemia (CML): A Single Institution Experience

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 1687-1687
Author(s):  
Hady Ghanem ◽  
Hagop M. Kantarjian ◽  
Elias Jabbour ◽  
Lakshmikanth Katragadda ◽  
Jorge E. Cortes ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Kinase Inhibitor ◽  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Median Number ◽  
Cancer Center ◽  
Molecular Characteristics ◽  
Blast Phase ◽  
Extramedullary Disease

Abstract Abstract 1687 Approximately two thirds of patients with CML BP exhibit a myeloid phenotype, and one third a lymphoid phenotype. In rare occasions, patients exhibit a mixed phenotype. Biphenotypic blast phase (Bi-BP) are rare and generally portend a very unfavorable prognosis. To evaluate the incidence and outcome of Bi-BP, we reviewed 1143 patients with CML BP diagnosed and treated at M.D. Anderson Cancer Center between November 1973 and February 2012. Only Bi-BP with both myeloid and B-lymphoid differentiation was included in this analysis. Twelve (1%) patients had Bi-BP. At presentation, the median age was 62 years (range, 29–81), WBC count 12×109/L (range, 6–214), hemoglobin 10 g/dL (range, 7–14), platelet count 94×109/L (range, 41–531), peripheral blood blasts 30% (range, 0–83), and bone marrow blasts 66% (range, 0–91). Five (42%) patients had extramedullary disease involving the central nervous system (CNS; n=2), lymph nodes (n=2), and CNS, orbit and skin without bone marrow disease (n=1) (Table 1). The median time from diagnosis to transformation was 15 months (range, 0–58). Six patients expressed a b2a2 BCR-ABL1 transcript (p210), whereas 4 patients expressed b3a2 (p210) and in 2 patients such information was not available. Three patients presented initially with BP and 9 evolved to BP from chronic phase (CP). Out those 9, 6 had failed imatinib, 3 interferon, 1 dasatinib, 1 ara-C and 1 hydroxyurea prior to transformation. Median number of treatments prior to BP was 1 (range, 1 to 3). Initial therapy for Bi-BP was hyper-CVAD in 2 patients, one of them achieving complete cytogenetic remission (CCyR); hyper-CVAD and dasatinib in 1 patient, achieving a marrow CR; idarubicin, ara-C, and imatinib followed by allogeneic stem cell transplantation in 1 patient, with no response; idarubicin, ara-C, vincristine and dexamethasone in 1 patient, achieving CCyR; troxicitabine in 1 patient, achieving CCyR; combination of decitabine and imatinib in 1 patient, achieving CCyR; azacitidine and valproic acid in 1 patient with no response; and imatinib with homoharrangtonine in 1 patient with no response. Overall, 5 patients responded, to a variety of chemotherapy regimens that included a tyrosine kinase inhibitor in 2 of them. Median duration of response was 7 months (range, 1–55). One patient died during induction chemotherapy. A total of 5 patients received subsequent therapy: TKI in 3 patients and allogeneic SCT in 2 patients. Three patients developed BCR-ABL1 gene mutations: Y253H (n=1), T315I (n=1), and F317L & V299L (n=1). At last follow up, 10 patients were dead (5 due to progression) and 2 were lost to follow up. In conclusion, Bi-BP is a rare entity, which frequently exhibits an aggressive course, extramedullary disease, and high resistance to conventional chemotherapy. Therapy requires the use of chemotherapy in combination with a TKI. Nevertheless, responses are short-lived and patients should be offered allogeneic SCT or novel investigational approaches. Table 1. Summary of patients' clinical and molecular characteristics, response to treatments and outcomes Disclosures: No relevant conflicts of interest to declare.

Retrospective Application of European LeukemiaNet Provisional Criteria for Second-Generation TKI Chronic Myeloid Leukemia

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2270-2270
Author(s):  
Massimo Breccia ◽  
Roberto Latagliata ◽  
Fabio Stagno ◽  
Antonella Gozzini ◽  
Elisabetta Abruzzese ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Second Generation ◽  
Conflicts Of Interest ◽  
Acquired Resistance ◽  
Chronic Phase ◽  
Primary Resistance ◽  
Free Survival ◽  
Optimal Response ◽  
Monitoring Response

Abstract Abstract 2270 An update of the European LeukemiaNet criteria for monitoring response of chronic myeloid leukemia patients was recently published and provisional criteria to evaluate patients during second generation TKI therapy after resistance to imatinib were proposed. In our study we retrospectively tested these criteria in a large series of CML patients resistant to imatinib further treated with second generation TKIs with the aim to analyze the outcome of suboptimal response and failure patients compared to those with optimal response and to validate the provisional criteria for monitoring response. One hundred twenty-seven CML patients resistant to imatinib were collected from 6 different Italian hematologic centers. There were 66 males and 61 females, median age 54 years (range 25–80). Twenty-seven patients were in late chronic phase after IFN resistance. Ninety-seven patients received second-generation TKI after acquired resistance, whereas 30 patients had primary resistance. We found that at different time points (3, 6 and 12 months), patients classified as failure showed significantly worse 2-year overall survival (OS), progression-free survival (PFS) and event-free survival (EFS) than sub-optimal and optimal response patients. At 3 months, “failure” patients, had an OS of 83% compared to 86% of sub-optimal and 97% of optimal response patients (p=0.001); PFS was 77% for failure patients compared to 92% and 99% for sub-optimal and optimal response patients, respectively (p=0.001), whereas EFS was 41% for failure vs 59% for sub-optimal (p=0.001) and 85% and optimal response patients, respectively (sub-optimal vs optimal p<0.001). At 6 months, OS was 82%, 88% and 99% for failure, sub-optimal and optimal response patients (p=0.05), respectively; PFS was 82% for failure compared to 94% and 99% for sub-optimal and optimal response patients, respectively (p=0.001); EFS was 47% vs 69% for failure and sub-optimal response (p=0.001) and 86% for optimal response patients (sub-optimal vs optimal, p<0.001). At 12 months again OS was 84% for failure patients compared to 95% and 99% for sub-optimal and optimal response patients (p=0.04); PFS was 86%, 95% and 99% for failure, sub-optimal and optimal response patients, respectively (p=0.001) and EFS was 48% for failure, 67% for sub-optimal response patients (p=0.002) and 89% for optimal response patients (sub-optimal vs optimal, p<0.001). We found that ELN provisional criteria identified at any times worse EFS for sub-optimal response patients, similar to that of failure patients, and failure criteria at 3 months identified patients who had worse PFS and EFS. ELN provisional criteria for second-generation TKIs treated patients appear to clearly predict outcome and can be useful to identify patients at high risk of progression. Disclosures: No relevant conflicts of interest to declare.

Significant Discrepancy In Peripheral Blood Compared to Bone Marrow BCR-ABL Transcript Levels In Chronic Phase Chronic Myeloid Leukemia (CML)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4471-4471
Author(s):  
Jason N Berman ◽  
Wenda Greer ◽  
Ridas Juskevicius ◽  
Conrad V Fernandez ◽  
Mark Bernstein ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Chronic Myeloid Leukemia ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Health Centre ◽  
Chronic Phase ◽  
Transcript Level ◽  
Transcript Levels ◽  
Significant Difference

Abstract Abstract 4471 Chronic myeloid leukemia (CML) is associated with the reciprocal t(9;22)(q34;q11) translocation, which generates the BCR-ABL fusion oncogene and is the most common myeloproliferative disease affecting adults. The clinical outcome in this disease has been revolutionized with the use of imatinib mesylate (Gleevec), a targeted tyrosine kinase inhibitor, and molecular surveillance, with the development of quantitative PCR (qPCR) approaches to measure BCR-ABL transcript levels. A number of guidelines outlining follow-up strategies for patients with chronic phase CML on imatinib therapy have been established. Once a patient is stable, a typical recommendation includes peripheral blood (PB) monitoring by qPCR of BCR-ABL levels every 3–6 months to determine response or relapse, with consideration of annual bone marrow (BM) examinations to assess for cytogenetic evolution. At the Queen Elizabeth II Health Sciences Centre and IWK Health Centre in Halifax, Nova Scotia, 34 patients with chronic phase CML on imatinib were identified from 2006 to 2008, with 36 paired samples, where transcript levels were assessed in both PB and BM within one week of each other. In 24 of the cases, the BCR-ABL transcript levels in PB and BM were within 0.5 log values of each other. In the remaining 12 cases, BCR-ABL transcript levels differed by greater than 0.5 log. Three cases had higher BM levels, but surprisingly, 9 patients had a higher BCR-ABL transcript level in the PB. In all cases, BCR-ABL levels were assessed by Q-RT-PCR using the ABI7500 instrument and primers and probe designed to detect p210 and p190 breakpoints. Results were recorded as a ratio of %BCR-ABL to GAPDH that was amplified as an internal control. There was no significant difference in clinical, morphological or laboratory parameters between these patients and others who had comparable PB and BM BCR-ABL levels. These findings highlight the need to compare BCR-ABL transcript levels derived from the same tissue during longitudinal monitoring. Moreover, while potentially due to stochastic factors, the striking observation of higher PB BCR-ABL transcript levels raises the question of which tissue represents the most accurate source for monitoring of BCR-ABL transcript levels and whether there is value in confirming a significant change in PB transcript level with BM evaluation. The discrepant levels in PB and BM could not be attributed to technical issues; the timing of sample processing from collection and quality of mRNA were comparable and no variability was observed in GAPDH levels to account for the difference. Without a technical explanation, the mechanism underlying this phenomenon remains uncertain. We speculate that it may reflect CML stem cell geography with one possibility being that the CML niche may be located external to the BM. Further studies are needed to confirm these observations. If corroborated, then revision of surveillance approaches for chronic phase patients may be indicated. Disclosures: No relevant conflicts of interest to declare.

Rare Blast Phase (BP) Phenotypes of Chronic Myeloid Leukemia (CML)

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4434-4434
Author(s):  
Hady Ghanem ◽  
Hagop M. Kantarjian ◽  
Elias J. Jabbour ◽  
Jorge E. Cortes ◽  
Alfonso Quintás-Cardama
Keyword(s):  
T Cell ◽  
B Cell ◽  
Mediastinal Mass ◽  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Characteristics ◽  
Molecular Response ◽  
Cell Transplant ◽  
Muscle Involvement

Abstract Abstract 4434 Approximately 65% of patients (pts) with CML BP exhibit a myeloid phenotype, 30% a lymphoid, and 5% of cases exhibit other phenotypes. The vast majority of lymphoid BP cases are of B-cell origin. Other phenotypes of CML BP are very infrequent and poorly characterized. To evaluate the incidence and outcome of unusual BP phenotypes, we reviewed 1143 pts with CML BP diagnosed and treated at M.D. Anderson Cancer Center between November 1973 and February 2012. Thirteen (1%) pts had non-B-cell/non-myeloid CML BP: 8 pts with T-cell differentiation (T-BP) (including 4 pts with biphenotypic T-cell/myeloid), 2 pts with basophilic (B-BP), and 3 pts with megakaryoblastic phenotype (M-BP) (Table 1). Five pts presented initially in BP, whereas 7 other cases evolved to BP from chronic phase (CP) and 1 pt from accelerated phase (AP). The median time from diagnosis to transformation was 15.2 months (mos) (range, 0–103). The median age was 50 years (range, 21–74), median WBC count at presentation 40.2×109/L (range, 2.6–236), hemoglobin 10.7 g/dL (range, 7.1–13.6), platelet count 171×109/L (range, 17–383), peripheral blood blasts 9% (range, 0–100), and bone marrow blasts 20% (range, 0–88). Nine (69%) pts developed extramedullary disease: 4 with lymphadenopathy (LAN), 1 with LAN and mediastinal mass, 1 with pericardial tamponade and mediastinal mass, 1 with central nervous system disease, 1 with facial muscle involvement and 1 with splenomegaly, LAN, and granulocytic sarcoma of the breast. Four pts expressed a b2a2 BCR-ABL1 transcript (p210), whereas 3 pts expressed b3a2 (p210), 3 expressed e1a2 (p190), 2 expressed b2a2+b3a2 (p210), and 1 expressed an e13b2+e14a2 (p210) transcript at transformation that switched to e1a2 (p190) during dasatinib (DAS) therapy. Median number of treatments received prior to BP was 2 (range, 1 to 12): 6 pts received interferon (IFN), 5 imatinib (IMA), 3 allogenetic stem cell transplant (ASCT), 3 Ara-C, 1 DAS and 1 hyper-CVAD (HCVAD). Initial therapy consisted of HCVAD (n=4, combined with IMA 600 mg/d in 1 pt and with DAS 70 mg/d in 1 pt), VAD (n=1), nilotinib 400 mg twice daily (n=1), DAS 50 mg twice daily (n=1), troxicitabine (n=1), gemtuzumab (n=1), idarubicin (IDA) and ara-C (n=3; 1 with IMA 600 mg/d and 1 with IMA 400 mg/d), and ara-C (n=1). Four pts responded: 3 with chemotherapy and IMA, achieving a complete cytogenetic response (CCyR) that lasted 22, 26 and 79 mos, respectively; 1 pt achieved a major molecular response (MMR) after receiving gemtuzumab followed by haploidenticial SCT, lasting for 24 mos. Median duration of response was 25 mos (range, 22–79). Subsequent therapy consisted of a tyrosine kinase inhibitor (TKI) in 6 out of 13 pts. Two pts treated with DAS at 140 mg/d and 70 mg twice daily achieved a CCyR and 1 pt achieved MMR on DAS 140 mg/d. Of the 7 pts treated with DAS, 2 had BCR-ABL1 mutations: 1 carried K271R, Y232C/K271R, and M343Y/K271R prior to DAS, then acquired V299L and F317I on DAS, while the other pt carried Y264S prior to DAS, then developed V299L on DAS. After a median follow up of 4.2 years (range, 0.2 to 14.4), 4/13 (30%) pts are alive: 1 in MMR on IMA 400 mg/d, 1 in complete molecular response (CMR) on DAS 100 mg/d, 1 not in remission (non-compliance to DAS 140 mg/d), and 1 currently receiving HCVAD and DAS. By phenotype, 5/8 pts with T-BP responded to TKIs: 1 CMR, 1 CCyR, 1 MMR, 1 partial cytogenetic response (PCyR) and 1 hematologic response (HR); 2/3 pts with M-BP responded: 1 CCyR and 1 CHR. None of the B-BP pts responded. In conclusion, non-B-cell/non-myeloid CML BP occurs in 1% of pts with CML, frequently infiltrates extramedullary sites, and exhibits high resistance to conventional chemotherapy. Long-term responses can be achieved with ABL1 TKIs (preferably in combination with chemotherapy), which can be used as a bridge to allogeneic SCT. Table 1. Summary of pts clinical and molecular characteristics, response to treatments and outcomes by BP Phenotype Disclosures: No relevant conflicts of interest to declare.

Evaluation Of hOCT1expression In Patients With Chronic Myeloid Leukemia (CML) Treated With Imatinib In First Line

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4041-4041
Author(s):  
Cintia Do Couto Mascarenhas ◽  
Maria Helena Almeida ◽  
Eliana C M Miranda ◽  
Bruna Virgilio ◽  
Marcia Torresan Delamain ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Taqman Probe ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
First Line ◽  
Transcript Levels

Abstract Introduction The majority of chronic myeloid leukemia (CML) patients (pts) in chronic phase (CP), present satisfactory response to imatinib treatment. However, 25-30% of these pts exhibit suboptimal response or treatment failure. The probability of achieving optimal response may be related with several factors. The human organic cation transporter 1 (hOCT1, SLC22A1), an influx transporter, is responsible for the uptake of imatinib into chronic myeloid leukemia (CML) cells The aim of this study was to analyze hOCT-1 levels at diagnosis of CML patients and correlate with cytogenetics and molecular responses. Methods hOCT-1 expression was evaluated in 58 newly diagnosed CML pts. Pts were treated with imatinib 400-600mg in first line. Samples were collected from peripheral blood at diagnosis and RNA was obtained from total leucocytes. For cDNA synthesis, 3 ug of RNA was used. hOCT-1 expression was evaluated by real-time PCR with TaqMan probe SLC22A1 (Applied Biosystems) and endogenous GAPDH control. The results were analyzed using 2-ΔΔCT. Cytogenetic analysis was performed at diagnosis, 3, 6, 12 and 18 months after starting therapy and then every 12-24 months thereafter if CCR was achieved. BCR-ABL transcripts were measured in peripheral blood at 3-month intervals using quantitative RT-PCR (RQ-PCR). Results were expressed as BCR-ABL/ABL ratio, with conversion to the international scale (IS). Major molecular response (MMR) was defined as a transcript level ≤ 0.1%. Results 58 CML pts, 60% male, median age of 46 years (19-87) were evaluated, 71% in chronic phase (CP), 21% in accelerated phase (AP) and 5% in blast crisis (BC). The mean and median of hOCT-1 transcript levels in the total group was 2.03 and 0.961 respectively (0.008–19.039) and CP pts was 1.86 and 1.00 (0.008-10.34).The median duration of imatinib treatment was 27 months (1-109) and 96.6% achieved complete hematological response, 79.3% complete cytogenetic response and 69% major or complete molecular response. The regression analysis showed correlation between higher transcript levels of hOCT-1 and BCR-ABL transcripts<10%) at 3 months analysis (p<0.0001). Albeit, there was no influence of the hOCT-1 transcript levels at diagnosis in the achievement of cytogenetic and molecular response at 24 months of treatment. Conclusions In this report, we found that high hOCT-1 expression was predictive of BCR-ABL transcripts<10% at 3 months, although we did not find correlation between hOCT-1 levels at diagnosis and the achievement of molecular response at 24 months, studies show that there is correlation between BCR-ABL log reduction in the first months of treatment and the achievement of molecular response. Disclosures: No relevant conflicts of interest to declare.

Nilotinib As Second or Third-Line Therapy for Myeloid Chronic Leukemia Chronic-Phase in Mexican Patients

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 5459-5459
Author(s):  
Manuel Ayala ◽  
Jacqueline Domínguez ◽  
Antonieta Chavez
Keyword(s):  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Response To Treatment ◽  
Long Term Results ◽  
Hematological Toxicity ◽  
Molecular Response ◽  
Second Line ◽  
Molecular Responses ◽  
Line Therapy ◽  
Imatinib Resistant

Abstract Background.- Nilotinib has 30-fold higher potency and increased selectivity against Bcr-Abl.Fast and deep responses can be achieved with nilotinib after failure to imatinib. In this study, we report the response rates and long-term results of using nilotinib after failure to imatinib or beyond. At the Specialty Hospital CMN "La Raza" nilotinibexperience launching this late 2006, has developed institutional experience. Objective.- To evaluate the cytogenetic and molecular response to treatment with nilotinib in the second line treatment of patients with CML-CP and its correlation with early molecular-response. Methods- During the experience with nilotinib as second-line therapy or beyond on CML-CP, 110 CML patients have been treated; established dose of nilotinib for all phase was 400 mg BID. Dose adjustments due toxicity were performed in accordance to previous publications, hematological and no hematological toxicity were scored in conformance to CTCAE v3. Patients were evaluated for hematologic, cytogenetic and molecular responses. Of all patients with CP-CML diagnosed treated with nilotinib, sixty-nine patients were included in the analysis, we selected those who had undergone a molecular evaluation at 3 months. In this study by BCR-ABL mutation status was analyzed. Twenty-seven percent (30 of 110) of the imatinib-resistant patients had BCR-ABL mutation(s) at baseline. One imatinib-resistant patients had the T315I mutation at baseline. The data from 69 patients with CP-CML were analyzed. Distribution of Sokal risk groups were as follows low-16/intermediate-14/high-57/NA-13%. Results.- Overall, 57 of the 69 patients (83%) of them had a transcript of ≤ 10% at 3 months. Forty-five out of 69 patients (65%) with transcript of ≤10% at 3 months achieved MMR at 12 months, while only 2 of 12 patients (17%) with ratio >10% had MMR, and 83% did not reach the MMR. The EFS by level of transcripts ≤10% at 3 months in 57 patients with 2 events was 96% while in >10% in 12 patients with 4 events was 67%, with an average estimate of time of EFS of 62 vs 43 months respectively. The EFS by MMR at 12 months in 32 patients without events was 100%, while without MMR in 37 patients with 6 events was 84% P=0.022. Nilotinib induced complete cytogenetic responses in 60 percent and 48% molecular responses in the 110 patients treated, 58% of which were major molecular responses, and deep molecular response 42%. To date, 96 of the treated patients remain alive (87%) and continue on treatment. Conclusions.- Nilotinib (Tasigna) is efficacy and well-tolerated treatment for patients with CML as second-line or beyond in our patients, The 48-month follow-up results show that nilotinib therapy continued to be effective, is comparable to diverse results of other international reports in developed countries. Disclosures No relevant conflicts of interest to declare.

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.

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