Early landmark analysis of imatinib treatment in CML chronic phase: Less than 10% BCR-ABL by FISH at 3 months associated with improved long-term clinical outcome

Abstract Cytogenetic clonal evolution (CE) - the presence of cytogenetic abnormalities in addition to the Ph chromosome in chronic myeloid leukemia (Ph+ CML) is a known poor prognostic factor associated with disease progression. Occurence of additional cytogenetic abnormalities in both Ph positive and Ph negative mitoses was also described in imatinib treated CML patients and was associated with occuring therapy resistance. The long - term significance is so far poorly understood. Objective. To monitor cytogenetic abnormalities in chronic phase CML patients on imatinib treatment, following long-term interferon alfa (IFN) or hydroxyurea treatment. To compare the haematological disease progression in patients with or without cytogenetic evolution Patients and methods: Cytogenetic evolution was analyzed in 57 patients (median age 56, range 18–73) treated with imatinib in chronic phase, following interferon resistance or intolerance. The duration of IFN application was 22 months (range 3 – 46 months), duration of imatinib treatment was 16 months (range 6 – 55 months). Cytogenetic abnormalities were detected by conventional cytogenetics - caryotype analysis and fluorescence in situ hybridisation (FISH). Results: Complete cytogenetic remission was accomplished in 55 of 57 pts (96%) on imatinib, significant or complete cytogenetic response was observed in 36 of 57 patients (66%). Cytogenetic evolution was observed in 11 patients (19%) treated with imatinib: in the Ph+ clone (9 cases) and in the Ph− clone (2 cases). Median duration of imatinib treatment before the CE identification was 16 months (range 7–36 months). The most common additional abnormality was trisomy 8 (8 pts), second Ph chromosome (4 pts), and del (17) (4 pts). In 5 cases we observed the simultaneous occurence of two different cytogenetic abnormalities. Haematological progression was observed in 7 of 11 patients (63%) following 2 – 22 months imatinib treatment (median 9 months). 5 pts (46%) exited. Six patients live 8–22 months from the detection of cytogenetic evolution. Secondary malignancy was diagnosed in 1 patient. In the group of patients without cytogenetic evolution haematological progression was observed only in 9 of 46 (19.5%) cases, 4 patients died (14.3%). Conclusion: The role of IM concerning the cytogenetic evolution occurence in CML patients is not so far clear, the suppression of the Ph+ clone could enhance the proliferation of resistant ones. In our group of patients CE was documented in 11 patients (19%), in both Ph+ and Ph− cells. Significantly higher was the risk of haematological progression. CML patients treated with imatinib should be regularly monitored with conventional cytogenetic techniques, not only to follow the decrease in the proportion of Ph-positive cells, but also to look for new especially Ph-negative clonal chromosomal abnormalities. A longer follow-up time and systematic monitoring of cytogenetics is needed to establish the prognostic impact of clonal evolution in CML patients treated with imatinib.

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Landmark Analysis of Imatinib Treatment in CML Chronic Phase: ES-FISH <10% Ph+ At 3 Months Associated with Better Cytogenetic Response and Improved Long-Term Event-Free Survival

Blood ◽

10.1182/blood.v118.21.1702.1702 ◽

2011 ◽

Vol 118 (21) ◽

pp. 1702-1702

Author(s):

Anne-Charlotte Ohm ◽

Gisela Barbany ◽

Ingrid Arvidsson ◽

Robert Hast ◽

Leif Stenke

Keyword(s):

Disease Progression ◽

Early Treatment ◽

Chronic Phase ◽

Cytogenetic Response ◽

Similar Data ◽

Term Survival ◽

Expression Levels ◽

Landmark Analysis ◽

Landmark Analyses

Abstract Abstract 1702 The use of imatinib (ima) and other tyrosine kinase inhibitors (TKI) has dramatically improved the clinical outcome for patients (pts) with chronic myeloid leukemia in chronic phase (CMLcp). Although most pts respond well, there is a subpopulation that fails to reach internationally defined clinical treatment goals, as assessed by techniques such as cytogenetics (CG) and quantitative polymerase chain reaction (PCR). Pts with a poor initial treatment response appear to have an increased risk of subsequent disease progression to accelerated phase or blast crisis, which still constitute a serious medical challenge. It was recently shown that landmark analysis assessing PCR levels after 3 months (mo) of ima treatment was linked to major cytogenetic response (mCyR) at 12 mo and risk of long-term progression (Hanfstein ASH2010 abstract 360). Similar data based on fluorescence in-situ hybridization (FISH) landmark assessment of larger CMLcp pt groups are still lacking. We have followed a cohort of 45 newly diagnosed CMLcp pts, all initiated on ima (400mg qd), by sequentially assessing their treatment responses by CG, PCR and interphase ES-FISH and relating early BCR-ABL expression levels to subsequent clinical response. A complete cytogenetic response (CCyR) was observed in 56% of evaluable pts after 6 mo, 80% after 12 mo and 94% after 24 mo of treatment. Corresponding figures for major molecular response (MMR) were 9%, 47% and 71%, respectively. Early levels of BCR-ABL as assessed by FISH could predict subsequent response. Thus, of patients with FISH-pos ≤10% at 3 mo 95% achieved CCyR at 12 mo, while this response was noted in only 67% of pts with FISH-pos >10% at 3 mo (p=0.042; Fisher's exact test, n=37). Similarly, all evaluable pts with FISH-pos ≤10% at 3 mo were alive and event-free (EFS) at 36 mo, as compared to 67% EFS at 36 mo among pts with FISH-pos >10% at 3 mo (p=0.008, n=37). Performing similar landmark analyses with FISH ≤ or >10% at 6 and 12 mo also yielded significant differences regarding EFS at 36 mo (p=0.046 and p=0.003, respectively). Employing corresponding landmark analyses with PCR at 3 mo and 6 mo, no significant association to EFS at 36 mo could be detected. In conclusion, our landmark analysis data indicate that ES-FISH can be used effectively already after 3 mo of ima treatment in order to identify a patient cohort with inferior long-term survival and with a higher risk for disease progression. FISH can unlike CG, be efficiently performed on peripheral blood cells which facilitates its clinical use. In comparison to PCR earlier data have shown that FISH, although less sensitive, may be more reliable and reproducible at higher BCR-ABL expression levels, typically seen in the early treatment phase. This may explain the superior outcome of early landmark analysis using FISH, as compared to PCR, in our study. Expanded trials on larger CMLcp pt cohorts are warranted to further clarify the prognostic value, and possible impact on early treatment alterations, of early FISH analyses during TKI treatment. Disclosures: No relevant conflicts of interest to declare.

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Deletions of the Derivative Chromosome 9 Do Not Influence Response to Imatinib of Early Chronic Phase Chronic Myeloid Leukemia Patients (A GIMEMA Working Party Analysis).

Blood ◽

10.1182/blood.v108.11.2112.2112 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2112-2112 ◽

Cited By ~ 1

Author(s):

Fausto Castagnetti ◽

Giulia Marzocchi ◽

Simona Luatti ◽

Francesca Buontempo ◽

Carmen Baldazzi ◽

...

Keyword(s):

Chronic Phase ◽

Working Party ◽

Response Rates ◽

Chromosome 9 ◽

Fish Analysis ◽

Molecular Response ◽

Imatinib Treatment ◽

Derivative Chromosome ◽

Term Survival

Abstract Extensive submicroscopic deletions adjacent to the breakpoint on derivative chromosome 9 [der(9)] have been reported in a subset of Chronic Myeloyd Leukemia (CML) patients and have been associated with an adverse outcome with conventional drugs and α-interferon (α-IFN). Huntly et al (Blood.2003; 102.2205–12) reported 275 CML pts who were treated with imatinib in CP, suggesting that der(9) deletions were associated with lower response rates and a shorter time to progression. Different data were reported by Quintas-Cardama et al (Blood.2005; 105:2281–6), who did not find any difference related with der(9) deletions in other 320 patients treated with imatinib. In these 2 studies, some patients began imatinib in early CP (51 and 152, respectively) while many patients (224 and 168, respectively) were treated in late CP. To establish the relationship of der(9) deletions with the response to imatinib in early CP patients, we planned a prospective study involving 3 consecutive multicentric national studies of the GIMEMA (Gruppo Italiano Malattie Ematologiche dell’Adulto) CML Working Party. 421 CML patients in early chronic phase were enrolled between January, 2004 and January, 2006; Fluorescence in situ hybridization (FISH) analysis of bone marrow cells was performed using BCR/ABL extra-signal, D-FISH or dual-color dual-fusion probes. At diagnosis, 52 (12%) of them had der(9) deletion and 369 (88%) had not. The 2 groups, with/without deletions, were comparable (no difference in age, Sokal risk, imatinib dose). Median observation time is 12 months. At 3 months, the CHR rates in with/without deletions patients were 87%/92%. At 6 months, the complete cytogenetic response (0% Ph-pos; CCgR) rates were 80%/80%, with major molecular response (MMolR, defined as a Bcr-Abl/Abl x 100 ratio < 0.1%) rates of 52%/51%, respectively. At 12 months, CCgR rates were 89%/86% and MMolR 52%/61%. No difference is significant. We conclude that the presence of der(9) deletions at diagnosis do not constitute a negative factor for response to imatinib: the haematological, cytogenetic and molecular response rates resulted equal between the 2 groups of patients with and without der(9) deletions. This finding is relevant to the long term effect of imatinib treatment, since both the CCgR and the MMolR are important and established indicator of long term survival.

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Distinct Impact of Imatinib on Growth In Prepubertal and Pubertal Children with Chronic Myeloid Leukemia

Blood ◽

10.1182/blood.v116.21.2277.2277 ◽

2010 ◽

Vol 116 (21) ◽

pp. 2277-2277

Author(s):

Haruko Shima ◽

Mika Tokuyama ◽

Akihiko Tanizawa ◽

Chikako Tono ◽

Kazuko Hamamoto ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Adverse Effects ◽

Myeloid Leukemia ◽

Conflicts Of Interest ◽

Negative Impact ◽

Chronic Phase ◽

Imatinib Treatment ◽

Growth Impairment ◽

Clinical Records

Abstract Abstract 2277 Imatinib is now widely used for treating chronic-phase chronic myeloid leukemia (CML) in children as well as in adults, and long-term adverse effects of imatinib therapy in children are now gaining attention. One of its adverse effects is the negative impact on growth in children, suggested by 3 recently published case reports. However, the incidence or prospect of growth impairment resulting from imatinib treatment has not been fully elucidated. In this study, we retrospectively analyzed the clinical records of 48 children with chronic-phase CML who were treated with imatinib as a first-line therapy between 2001 and 2006. The median age at diagnosis was 9 years (2 to 15 years). Cumulative change in height while on imatinib was assessed using the height standard deviations score (height-SDS), the converted height data from age- and sex-adjusted Japanese norms. Our data indicated that growth impairment (decrease in height-SDS) was observed in 72.9% of the patients, with median maximum reduction in height-SDS of 0.61 during imatinib treatment. Growth impairment was noticeable in children who were prepubertal at the commencement of imatinib treatment, while only mild or no growth impairment (with no decrease of height-SDS) was observed in most patients who were pubertal at the commencement of imatinib treatment. Furthermore, in prepubertal children with growth impairment, growth velocity tended to recuperate concomitant with pubertal maturation, suggesting that imatinib has little impact on growth during puberty. To our knowledge, this is the first report to describe and compare the distinct inhibitory effect of imatinib on growth in prepubertal and pubertal children with CML. Although the introduction of imatinib was a breakthrough in CML therapy, the possibility of continuous remission after discontinuation of imatinib remains uncertain. Thus, the possibility of adverse effects of long-term exposure to imatinib has become a huge issue, especially when treating children. We consider that it is important to promote awareness of growth deceleration in children, especially in young children who started imatinib treatment before puberty and are inevitably going to be subject to prolonged exposure. Disclosures: No relevant conflicts of interest to declare.

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Long-Term Follow-Up of CML Patients Treated with Autografting Followed by IFN-A and Imatinib for Relapsed Patients.

Blood ◽

10.1182/blood.v104.11.5217.5217 ◽

2004 ◽

Vol 104 (11) ◽

pp. 5217-5217

Author(s):

A.M. Carella ◽

Maria T. Corsetti ◽

Germana Beltrami ◽

Carlo Bodenizza ◽

Marina Cavaliere

Keyword(s):

Clinical Evidence ◽

Chronic Phase ◽

High Dose ◽

Imatinib Treatment ◽

Long Term Follow Up ◽

Previously Treated ◽

Cytogenetic Remission ◽

Group 1

Abstract Residual diploid hematopoietic progenitor cells (HPC) represent a quantitatively useful reservoir from a therapeutic standpoint, particularly early in the course of the disease. Clinical evidence for the persistence of diploid HPC in CML has been provided by the fact that Ph-negative cells are mobilized into the blood of patients treated with chemotherapy/G-CSF, IFN-a and, more recently, with Imatinib. In this report, we update our experience in 50 patients with early chronic phase not previously treated with IFN-a. All patients completed the mobilization protocol (ICE/mini-ICE) and diploid or prevalently diplod HPC were mobilized in peripheral blood after G-CSF. High-dose therapy consisted of Busulfan (4 mg/kg/d x 4 days) (44 patients) or TBI-containing regimen (6 patients). No patient died of the procedure. After engraftment, all patients were treated with IFN-a (3–5 MU/d three times weekly). The median follow-up of 50 patients is 77 months (range, 8 to 142 months). At present (July 31, 2004), 39 patients (78%) are alive at a median follow-up of 89 months (range, 43 –142) from autografting: 15/39 patients maintain major cytogenetic remission (MCyR) under IFN-a (1 patient received MUD in MCyR;) 23 patients (22 in CP and 1 in AP), who relapsed cytogenetically received Imatinib. Sixteen out of 23 pts on Imatinib achieved MCyR (2 patients) or complete cytogenetic remission (CCyR) (14 patients). Eleven out of 50 patients died at a median of 35 months (range, 8 to 106 months): 9 patients of blastic transformation (2 in the Imatinib group), 1 patient of fulminant hepatitis and 1 of cardiac arrest under Imatinib treatment. In conclusion, intensive treatment with autografting/IFN-a ± Imatinib was able to control the disease in 39/50 patients of whom 31 patients are still in major/complete cytogenetic remission.

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Time to Complete Cytogenetic Response (CCyR) Does Not Affect Long-Term Outcomes for Patients on Imatinib Therapy.

Blood ◽

10.1182/blood.v110.11.27.27 ◽

2007 ◽

Vol 110 (11) ◽

pp. 27-27 ◽

Cited By ~ 17

Author(s):

Francois Guilhot ◽

Richard A. Larson ◽

Stephen G. O’Brien ◽

Insa Gathmann ◽

Brian J. Druker

Keyword(s):

Overall Survival ◽

Blast Crisis ◽

Chronic Phase ◽

Cytogenetic Response ◽

Imatinib Therapy ◽

Imatinib Treatment ◽

Long Term Outcomes ◽

Term Survival ◽

Significant Difference

Abstract Background: Results from the International Randomized Study of Interferon and STI571 (IRIS) trial showed that achievement of a CCyR is prognostically relevant for long-term survival in patients (pts) with chronic myeloid leukemia in chronic phase (CML-CP). With the advent of next generation tyrosine kinase inhibitors (TKIs), there is a need to understand factors that may influence long term outcomes. Here we analyze whether time to achievement of a CCyR affects long term outcomes. Methods: The relationship between time to CCyR and long-term outcomes was examined for 551 imatinib-treated patients with newly diagnosed CML-CP at the 6-year follow up of the IRIS trial. As evaluations included non-responders, landmark analyses were conducted in which only pts who were treated for ≥1 year were included (n=509). Patients were stratified according to time to achieving a CCyR as follows: ≤6 months (n=265), >6≤12 months (n=99), >12≤18 months (n=34), >18 months (n=49), or no CCyR during imatinib treatment (n=62). In each category patients were assessed for duration of cytogenetic response, event free survival (EFS; any event while on study), freedom from progression to accelerated phase (AP) or blast crisis (BC), and overall survival (OS). Results: In the 447 patients who were treated for at least 1 year and achieved a CCyR (<1% Ph+) during therapy, the durability of major cytogenetic response (1%–35% Ph+) did not differ significantly regardless of when CCyR was achieved (P=0.76). For the overall population, estimated 6-year rates were 88% for OS, 83% for EFS, and 93% for freedom from progression to AP/BC. No statistically significant difference was observed between the responders when categorized according to time to response. However, patients who did not achieve a CCyR had significantly worse outcomes than those who achieved CCyR (P<0.001). Estimated 6-year OS rates were 94%, 95%, 91% and 98% for patients who first achieved a CCyR within 6, 12, 18 months and after 18 months, respectively (P=0.55 for overall comparison of the response categories), compared with 63% for pts without CCyR during imatinib therapy. Estimated EFS rates at 6 years were 93%, 90%, 87% and 89% (P=0.58) and 33% for patients who do not achieve a CCyR, respectively. At 6 years the estimated rates of freedom from progression to AP/BC were 97%, 97%, 97% and 98% (P=0.98), respectively, but only 63% for pts who do not achieve a CCyR. Overall Survival by Time to CCyR. Conclusion: Long-term outcomes on imatinib for patients in CML-CP are independent of time to achieve CCyR. Therefore, achievement of a “late” CCyR does not increase the potential for progression or portend a worse overall survival for patients treated with imatinib. Figure Figure

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Survival Outcome of Imatinib Mono Therapy in Chronic Phase Chronic Myeloid Leukemia - a Single Center Experience in Belorus

Blood ◽

10.1182/blood.v128.22.5452.5452 ◽

2016 ◽

Vol 128 (22) ◽

pp. 5452-5452

Author(s):

Janna Kozich ◽

Elza Lomaia ◽

Andrey Zaritskey

Keyword(s):

Chronic Myeloid Leukemia ◽

Clinical Outcome ◽

Median Time ◽

Survival Probability ◽

Myeloid Leukemia ◽

Chronic Phase ◽

First Line ◽

Term Survival ◽

Sokal Score

Abstract Introduction: Imatinib(IM) remains first-line treatment of choice in chronic myeloid leukemia (CML). Although nearly half of patients(pts) failure IM therapy, long-term survival is very high. It seems that this is due to the efficiency of subsequent treatment with new tyrosine kinase inhibitors (TKIs). We evaluate real long-term outcome of IM therapy when new TKIs are unavailable and mainly generic forms of IM are provided. Methods: All 63 pts (male-24, female-39) in chronic phase (CP) CML treated with IM in Gomel (Belorus) were included in the study. The pts never obtained new TKIs(not reimbursed) or allogeneic stem cell transplantation. Median age at the time of IM treatment start was 52 (range 18-71) years in whole group, 48 and 53years in men and in women respectively. IM was given within 3 months after diagnosis in 33 (52%) pts. Median CML duration before IM treatment for other group was 25,7 (range 4-136) months. The Sokal score distribution was low, intermediate and high in 54 (86%), 5 (8%) and 4(6%) cases respectively. Results: Median duration of IM therapy was 31 (2-135) months. It was 26 (range 5-83) and 37(range 2-135) months respectively in pts started IM within 3 months after CML or later. The reasons of IM discontinuation were toxicity(n=4) and resistance(n=15). During observational time 17(27%) pts progressed to accelerated (AP) or blastic phase (BP). Median time from IM to AP/BP was 9 (range 0,5-60) months. Pts with longer CML duration before IM were at higher risk for progression. Thus, median time from CML to IM started was 22 months and only 1 month in pts with and without progression to AP/BP. During observation 14 (22%) pts died. Progression was the main reason for death (n=12). Median time of ovecvrall survival was 31 (range 7-135) months. 5- and 8 year of (OS) probability for all pts were 78% and 60% respectively. 5-year survival probability was higher in pts started IM shortly after CML (see in figure 1). Complete cytogenetic response (CCyR) was obtained in 30(63%) of ots. Clinical outcome according to the time from CML to IM see in table 1. Only 1/30(3,3%) pt with and 13/32 (40%) pts without CCyR died during observation. The majority of pts had low Sokal score, so we couldn't analyze influence of Sokal scores on IM efficacy. IM therapy was discontinued in 18(30%) of pts. The reasons of IM discontinuation were toxicity(n=4) and resistance(n=15). 5 pts are still alive on interferon or different chemotherapy. The median time of observation after IM discontinuation was 2,5 (range 0,5-27) months. Conclusions: IM (mainly generics) therapy was effective in the most CP CML pts. Early onset of IM therapy and the achievement of CCyR were associated with an improved survival. When we compared the date on IM therapy to other clinical trials it seems that the cumulative rate of CCyR is lower in spite of the most pts were with low Sokal score. The study is nonrandomized retrospective, so it is impossible to claim that this is related to the use of IM generics. Meanwhile IM mono therapy as first line may provide low rate of AP/BC and high OS probability, although long-term clinical outcome definitely worse compared to studies, where new TKIs are available. To the best of our knowledge, this is the first, study of CML treatment by IM (generics) without second generation drugs. Table Clinical outcome on IM therapy in CP CML pts according to the time from CML to IM. Table. Clinical outcome on IM therapy in CP CML pts according to the time from CML to IM. Figure Survival probability in CP CML pts started IM within or outside 3 months after CML diagnosis Figure. Survival probability in CP CML pts started IM within or outside 3 months after CML diagnosis Disclosures Zaritskey: Janssen: Consultancy; Novartis: Consultancy.

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The Hasford Score Correlates with the Long-Term Molecular Response to Imatinib Treatment for Chronic Myeloid Leukemia Patients and May be Useful for Differentiating Low and Intermediate Risk Patients: A Single Institution Experience

Blood ◽

10.1182/blood.v124.21.3152.3152 ◽

2014 ◽

Vol 124 (21) ◽

pp. 3152-3152

Author(s):

Jaroslaw Dybko ◽

Ewa Medras ◽

Olga Haus ◽

Bozena Jazwiec ◽

Tomasz Wrobel ◽

...

Keyword(s):

Chronic Myeloid Leukemia ◽

Myeloid Leukemia ◽

Chronic Phase ◽

Cytogenetic Response ◽

Molecular Response ◽

Imatinib Treatment ◽

Intermediate Risk ◽

Risk Patients ◽

Eutos Score

Abstract BACKGROUND: Since the beginning of the tyrosine-kinase inhibitor (TKI) era in the treatment of chronic myeloid leukemia (CML), there have been attempts to stratify patients for optimal management. An essential requirement for perfect stratification was the identification of factors capable of predicting long-term response [1]. The Sokal and Hasford scores were developed in the chemotherapy and interferon alfa eras, respectively [2]. The EUTOS score was found to predict probability of complete cytogenetic response (CCyR) within 18 months of Imatinib initiation and progression-free survival (PFS) for patients receiving Imatinib [3]. However, the usefulness of the EUTOS score in predicting survival and outcome in patients with early chronic phase CML treated with TKI was questioned [4]. The Hasford score failed to differentiate patients who achieved low and intermediate risk scores according to CCyR, MMR, and 5 years EFS [5] and in our study we found Hasford score correlated with the long-term molecular response. PATIENTS AND RESULTS: We analyzed a cohort of 88 patients (F/M:42/46, median age 51 (21-83)) receiving standard dose Imatinib treatment for first chronic phase of CML. As assessed by Hasford risk analysis, the group comprised 57 low risk and 31 intermediate risk patients. In the initial group of patients, there were 5 high risk patients who were excluded from the study. No additional chromosomal abnormalities were identified at diagnosis. All patients achieved complete cytogenetic response (CCyR) and major molecular response (MMR) at time points defined by the European Leukemia Net (ELN). Of these, 42 patients lost MMR in a median time of 47 months. Within this group we identified 20 low risk (LR) and 22 intermediate risk (IR) patients. There was a significant difference in maintenance of the MMR between IR and LR patients (p=0.03, Figure 1). This analysis revealed that all intermediate risk patients lost MMR after approximately 85 months of Imatinib treatment, while 62% of the low risk patients maintained MMR throughout this time frame. During analysis, all 42 patients were switched to second generation TKI. After 3 months of second generation TKI treatment, median bcr-abl transcript levels in the LR group were 0.01 (0.000-0.295) but in the IR group bcr-abl levels were 0.301 (0.000-44.5) (p=0.0006, Figure 2). CONCLUSIONS: As the Hasford metric was designed for assessing patients treated with interferon alpha, we found our results to be interesting, and to be relevant to the discussion on optimizing scoring systems in chronic myeloid leukemia patients. If the observed difference between low and intermediate risk patients in maintaining MMR on Imatinib is confirmed, IR patients will become candidates for different first line treatment. Despite clinical studies, the choice between Imatinib and second generation TKI as the first line treatment remains an issue. Our results (if confirmed) promise to directly impact treatment decisions affecting IR patients. References: 1. Breccia M, Alimena G. Bringing prognostic scores for chronic myeloid leukemia patients up to date. Expert Rev Hematol. 2011 Aug;4(4):373-5. 2. Hu B1, Savani BN. Impact of risk score calculations in choosing front-line tyrosine kinase inhibitors for patients with newly diagnosed chronic myeloid leukemia in the chronic phase. Eur J Haematol. 2014 Apr 26. 3. Hasford J1, Baccarani M, Hoffmann V, Guilhot J, Saussele S, Rosti G, Guilhot F, Porkka K, Ossenkoppele G, Lindoerfer D, Simonsson B, Pfirrmann M, Hehlmann R. Predicting complete cytogenetic response and subsequent progression-free survival in 2060 patients with CML on imatinib treatment: the EUTOS score. Blood. 2011 Jul 21;118(3):686-92 4. Jabbour E, Cortes J, Nazha A, O'Brien S, Quintas-Cardama A, Pierce S, Garcia-Manero G, Kantarjian H. EUTOS score is not predictive for survival and outcome in patients with early chronic phase chronic myeloid leukemia treated with tyrosine kinase inhibitors: a single institution experience. Blood. 2012 May 10;119(19):4524-6. 5. Yahng SA, Jang EJ, Choi SY, Oh YJ, Bang JH, Park JE, Jeon HL, Lee SE, Kim SH, Byun JY, Kim DW. Comparison of Sokal, Hasford and EUTOS Scores in Terms of Long-Term Treatment Outcome According to the Risks in Each Prognostic Model: A Single Center Data Analyzed in 255 Early Chronic Phase Chronic Myeloid Leukemia Patients Treated with Frontline Imatinib Mesylate. Blood 2012;120:Abstract 2794 Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

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Landmark Analyses of BCR-ABL Using ES-FISH Early After Start of Imatinib Treatment to Newly Diagnosed CMLcp Patients Predicts Longterm Clinical Outcome.

Blood ◽

10.1182/blood.v114.22.4269.4269 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4269-4269

Author(s):

Lotta Ohm ◽

Robert Hast ◽

Ingrid Arvidsson ◽

Gisela Barbany ◽

Leif Stenke

Keyword(s):

Clinical Outcome ◽

Peripheral Blood ◽

Conflicts Of Interest ◽

Chronic Phase ◽

Molecular Response ◽

Imatinib Treatment ◽

Newly Diagnosed ◽

Control Gene ◽

First Line ◽

Molecular Responses

Abstract Abstract 4269 Background Imatinib (IMA) is recommended as first-line therapy for patients diagnosed with CML in chronic phase (CMLcp). Earlier studies, based particularly on the IRIS trial, have indicated that a favorable long-term clinical outcome to therapy is clearly associated with a reduction of the Ph-pos cell population and of BCR-ABL transcripts, as measured with cytogenetics and qPCR, respectively. We have investigated the response to IMA in a CMLcp cohort treated at our institution and assessed the prognostic value of early and repeated determinations BCR-ABL expression, using both ES-fluorescence in situ hybridization (FISH) and qPCR. Methods 45 pts with newly diagnosed CMLcp (24M/21F; median age 54 yrs, range 19-87; 5 with 9q del, 5 with variant translocations; Sokal scores 16 LR, 20 IR, 9 HR) were started on IMA (400mg qd) and hematologic, cytogenetic and molecular responses were followed at regular 3-mo intervals. Median IMA treatment time at follow-up was 29 mo (range 9-94). Regular cytogenetic karyotyping (CG) and interphase ES-FISH were performed on bone marrow cells (the latter method by scoring BCR-ABL in at least 500 cells on smear preparations, detection limit 20.2%) while qRT-PCR was performed on peripheral blood leukocyte samples with ABL as control gene. Major molecular response (MMR) was defined as the ratio BCR-ABL/control gene 20.1%. Results At diagnosis the pts displayed a median of 100% (range 67-100) Ph-pos metaphases by CG, while ES-FISH revealed BCR-ABL gene expression in a median of 86,2% (range 45,9-97,3) of cells. The response to IMA-treatment during the first 12 mo, displayed in Table I, included CCyR in 80%, MMR in 48% and reduction of FISH-detected BCR-ABL to <1% in 62% of analyzed pts. When first obtaining CCyR (negative CG), patients showed a median ES-FISH value of 0.27% (range 0 to 7.4%). Comparing pts who did vs. did not achieve CCyR at 12 mo (n= 36 vs. 9) FISH and PCR analyses at 3, 6 and 9 mo showed clear differences between the groups (Table II). At 24 months from start of IMA, 39 pts were evaluable for response and ‘events‘ (defined according to ELN as any of: death during study treatment, loss of CHR, loss of MCyR, progression to AP/BC or WBC>20). A total of 6 pts showed ‘event‘ (4 AP, 1 BC, 1 loss of CHR; 2 died). Table III provides landmark data related to FISH and PCR levels at 3 time points. Patients with a high remaining BCR-ABL expression were more likely to develop ‘events‘, as compared to those with low expression. Conclusion Our single centre data from an unselected CMLcp pat cohort on first-line IMA shows good clinical and molecular responses, well in line with results from the IRIS study. We propose that repeated, longitudinal interphase ES-FISH analyses may provide additional and important prognostic information regarding later targeted clinical endpoints. The method gives reliable information also early during the treatment, at higher disease penetration when PCR may be less reproducible, and can also be performed on peripheral blood samples. Disclosures: No relevant conflicts of interest to declare.

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