ABCG2 and SLC22A1 Expression Are Associated with Imatinib Response in Chronic Myeloid Leukemia

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1422-1422
Author(s):  
Douglas Vivona ◽  
Luciene Terezina Lima ◽  
Carolina Tosin Bueno ◽  
Rosario D C Hirata ◽  
Mario H Hirata ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Philadelphia Chromosome ◽  
Cytogenetic Response ◽  
Response To Treatment ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Primary Resistance ◽  
Secondary Resistance ◽  
Altered Expression ◽  
Complete Cytogenetic Response

Abstract Abstract 1422 Background: Imatinib Mesylate (IM) used in the treatment of CML, interacts with membrane efflux transporters such as ABCB1 and ABCG2, whereas the active uptake of IM into the cells is mediated by SLC22A1. The predictive value of these markers is still controversial. The altered expression of these genes could impact on intracellular concentration of IM and contribute to resistance. Aims: The aim of this study was to investigate ABCB1, ABCG2 and SLC22A1 gene expression as potential sources of resistance to imatinib in patients with CML Methods: One hundred and eighteen patients in chronic phase of CML, both genders with age range 18 to 80 were studied. All patients were initially treated with a standard dose of IM (400 mg/day) and divided in two groups according to response. The responder group comprised 70 patients who had a complete cytogenetic response within 18 months of treatment. The non-responder group comprised 48 patients who did not have a complete cytogenetic response with the initial dose (400 mg/day) of IM or who relapsed during treatment and were submitted to higher doses of 600 or 800 mg/day. Criteria of failed response to treatment were established by European LeukemiaNet. Patients with cytogenetic patterns other than the Philadelphia chromosome and patients with mutations in the BCR-ABL1 gene were excluded from this study. Major molecular response (MMR) was defined as a reduction of BCR-ABL1 transcripts levels to ≤ 0.1% in the peripheral blood standardized on the International scale. Complete molecular response (CMR) was defined as a reduction ≤ 0.032% BCR-ABL1 transcripts levels. Primary resistance and secondary resistance also were evaluated. Real-Time PCR was performed to evaluate the ABCB1, ABCG2 and SLC22A1 mRNA relative expression to control gene GAPDH. Results: Expression of ABCG2 in the non-responder group was higher than in the responder group (P=0.028). This result was influenced by patients with primary resistance (n= 34 p=0.029) but not secondary resistance (n=14 p=0.249) when compared with responders (n=70). ABCB1 and SLC22A1 expression were similar between responder and non-responder groups. Higher levels of SLC22A1 mRNA were found in patients who achieved MMR in the responder group (p=0.009). The elevated ABCG2 expression was also found in those who did not achieve MMR (p=0.027) when all patients were analyzed. None of studied genes was associated with CMR. Conclusions: The high expression of ABCG2 is related to primary resistance and SLC22A1 is positively associated with major molecular response to treatment with IM. Our data suggests that ABCG2 may be a mediator of IM resistance, whereas SLC22A1 could be a good predictor of response to IM therapy. Financing: Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP 2009/54184-0). Disclosures: No relevant conflicts of interest to declare.

Prognostic Significance of the Lost of a Major Molecular Response In Philadelphia Chromosome-Positive Chronic Myelogenous Leukemia (Ph+CML).

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3435-3435
Author(s):  
J. Valentin García-Gutiérrez ◽  
Pilar Herrera ◽  
Marta Jimenez-Rolando ◽  
María Tenorio ◽  
María Calbacho ◽  
...  
Keyword(s):  
Kinase Inhibitors ◽  
Conflicts Of Interest ◽  
Residual Disease ◽  
Prognostic Significance ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Molecular Response ◽  
Major Molecular Response

Abstract Abstract 3435 Background: Albeit of well-known, dramatic improvements, there remain some questions to be solved around Ph+CML in treatment with tyrosine kinase inhibitors (TKI). Among these, the significance of the amount of minimal residual disease (MRD) measured by RT-PCR. For instance, loss of a so-called major molecular response (MMR) is claimed to be a Òsuboptimal responseÓ and following the ELN recommendations, a change in treatment should be considered in these patients. Aims: To evaluate the relevance of a loss of MMR in patients with complete cytogenetic response (CCR). Study Group and Methods: We have analized 81 patients treated with imatinib for CML in chronic phase with a median follow up of 66 months. 36 patients started imatinib after interferon failure and 45 as front line therapy. Major Molecular Response (MMR; BCR-ABL/ABL ratio<0.1% IS) at any time was achieved by 63 patients. Results: 22 patients (34%) lost MMR (documented al least twice). The risk of losing MMR was higher in late MMR (>18 months) compared with those cases whose MMR came much earlier (<18 months): 70% vs 18% (p=. 000). We have found no correlation among the lost of MMR and classical prognostic factors (Sokal-Index, mutations at the TK domain or imatinib plasma levels). Of these 22 patients, 7 (32 %) recovered MMR later with no therapy changes, 8 (36%) experienced fluctuations in the BCR-ABL transcript-levels without losing CCR, 4 (19%) did not attain a MMR but remained in stable CRR, and 3 (13%) lost CCR. These regained MMR after being treated on second generation TKI. The results show how the stability of the early MMR is greater than late MMR (table1). Conclusions: In our experience, one third of the patients who lost MMR recovered it later on the same treatment. And only 13% went on to treatment failure. Perhaps some similar cases (after first losing MMR) should be closely monitored before a change in treatment. Also of note is, of course regarding only our experience, that the risk of a loss of MMR seems to be maximal in patients who achieve a late MMR. Disclosures: No relevant conflicts of interest to declare.

For CML Patients in Chronic Phase Who Achieve a Cytogenetic Response to Imatinib the Finding of a BCR-ABL Mutation Predicts for Progression to Advanced Phase but It Has No Such Significance in Primary Resistance.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 323-323
Author(s):  
Hugues de Lavallade ◽  
Jamshid S. Khorashad ◽  
Dragana Milojkovic ◽  
Simon Wagner ◽  
Jaspal Kaeda ◽  
...  
Keyword(s):  
Adverse Effect ◽  
Genomic Instability ◽  
Direct Sequencing ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Primary Resistance ◽  
Secondary Resistance ◽  
Advanced Phase

Abstract We analysed outcome for 211 CML patients treated with imatinib in chronic phase (CP) (99 newly diagnosed and 112 late chronic phase) who were screened for BCR-ABL kinase domain (KD) mutations using direct sequencing regardless of the response status. When a mutation was found all available previous cDNA samples were analysed by pyrosequencing to establish the date of its first occurrence and subsequent kinetics. The median age of patients was 47.4 years. The Sokal risk score was ‘low’ in 57 patients, ‘intermediate’ in 82 and ‘high’ in 72. The median follow up from starting imatinib was 45 months (rage 6 to 89 months). A mutation was detected in 34 of the 211 patients (16%) at a median time of 27 months from starting imatinib. Twenty-two different mutations were identified, the most frequent being M244V (n=6) and F359V (n=3). When studied serially by pyrosequencing the size of the mutant subclone never exceeded 50% of total BCR-ABL transcripts in 8 patients, while in 17 patients it exceeded 90% on at least one occasion. 48 patients discontinued imatinib while still in CP and received either dasatinib, nilotinib or an allograft. The overall progression-free survival (absence of advanced phase) at 5 years was 73%. Major (MCyR) and complete (CCyR) cytogenetic responses were achieved by 153 and 123 patients respectively; 56 patients achieved major molecular response. 24% of the patient with up front cytogenetic resistance had a mutation while 40% of the patients with acquired cytogenetic resistance develop a mutation. In an-intention-to-treat analysis, patients harboring a mutant clone had a poorer PFS at 4 years (78% versus 57%, p=0.0014). The various mutations had no differential effects based on their known imatinib IC50. By multivariate analysis, factors associated with worse PFS were the presence of a KD mutation and failure to achieve CCyR (relative risks for PFS 2.6 and 8.7 respectively, p=0.002). Interestingly, the adverse effect of the presence of a KD mutation was restricted to the patients who achieved a MCyR (PFS 91% versus 62% at 5 years, p = 0.0006); it had no adverse impact on patients who failed to achieve a MCyR (PFS 42% and 49%, p=0.73). Similar results were found when the analysis was repeated according to the achievement of CCyR (data not shown). Surprisingly patients with a continuously low percentage (≤50%) of mutated vs wild type (>50%) clones fared worse than patients in whom the mutated clone became the predominant population (PFS 14% vs 69% respectively, p=0.0005). Comparable results were obtained when the patients were censored at the point of discontinuing imatinib, correcting for the effects of subsequent treatment, ie allografting (data not shown). The fact that the adverse effect of a mutation seems to be restricted to patients who had achieved cytogenetic response, the fact that mutations present at low level seemed to have a remarkable adverse effect and the fact that the in-vitro level of resistance to imatinib of the specific mutation did not affect the PFS could all be explained if the development of a mutation is only a reflection of the genomic instability of the disease that leads to secondary resistance to imatinib and eventually to transformation. Thus genomic instability may be less important in explaining primary resistance to imatinib and eventual transformation in patients with up-front resistance.

Clinical Outcome of CML Patients with Philadelphia Chromosome Complex Variants.

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4499-4499
Author(s):  
Santiago del Castillo ◽  
Regina Garcia Delgado ◽  
Laura Entrena ◽  
Agustin M Hernandez ◽  
Arturo Campos ◽  
...  
Keyword(s):  
Conflicts Of Interest ◽  
Philadelphia Chromosome ◽  
Genetic Material ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Imatinib Treatment ◽  
Current State ◽  
Worse Prognosis

Abstract Abstract 4499 INTRODUCTION: The presence of translocation between chromosomes 9 and 22 that characterizes the chronic myeloid leukemia (CML) is occasionally accompanied by more complex variations involving additional exchange of genetic material with other chromosomes. This variants of Philadelphia chromosome have no worse prognosis than those others with the common translocation. MATERIAL: Since 1997 we have diagnosed in our hospital 5 CML patients who didn't show any of these variants. Three women 17, 23 and 76 years old and two men of 36 and 65. All of them diagnosed in chronic phase. Risk stage at diagnosis by Sokal were 1 high, 1 intermediate and 3 low. By Hasford 2 were intermediate end 3 low. Philadelphia chromosome variants involve a third chromosome in 4 cases (translocations 2;9;22, 9;22;12, 9;22;9 and 6;9;22) and in one case involving four chromosomes (translocation 1;2;9;22). Three patients diagnosed before the imatinib approval started treatment with IFN and Ara-C and subsequently changed to Imatinib treatment. Two others started treatment with imatinib directly. RESULTS: All patients had a good outcome with treatment being the current state of 2 patients in complete molecular response (105 and 60 months of follow-up) and 2 patients in Major Molecular Response (146 and 143 months). The 5th patient, a 17 years old woman, has been treated for three months with Imatinib and showed complete haematological response at first month and major cytogenetic response at third month. It is striking in this last patient the fact that two years earlier had been referred for study of myeloid moderate leukocytosis (20,000 leukocytes with circulating myeloid progenitors without anemia, thrombocytosis, or splenomegaly). The patient didn't come to clinic when Bone Marrow Test was cited and two years later resumes the visit continuing with the same leukocytosis in peripheral blood and without splenomegaly unchanged despite not having received any treatment. CONCLUSION: Our experience confirm that this type of patients with complex translocation variants have no worse prognosis than normal translocation under imatinib treatment and suggests that may have a more benign clinical behavior. Disclosures: No relevant conflicts of interest to declare.

Clinical Characteristics and Outcome of Patients (pts) with V299L BCRABL Kinase Domain (KD) Mutation after Therapy with Tyrosine Kinase Inhibitors (TKIs).

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 1105-1105
Author(s):  
Elias Jabbour ◽  
Hagop M. Kantarjian ◽  
Dan Jones ◽  
Elizabeth Burton ◽  
Jorge Cortes
Keyword(s):  
Kinase Inhibitors ◽  
Mutation Detection ◽  
Lymphoblastic Leukemia ◽  
Point Mutations ◽  
Cytogenetic Response ◽  
Experimental Models ◽  
Molecular Response ◽  
Primary Resistance ◽  
Secondary Resistance

Abstract Background. Point mutations of the BCR-ABL KD are the most frequently identified mechanism of resistance in pts with CML and Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL) who fail TKI. Experimental models of in vitro drug sensitivity have shown that specific mutations may develop after incubation with second generation TKIs, albeit at a decreased frequency compared with imatinib. Some of the mutations are novel and not previously described after imatinib failure; in some instances they did not confer resistance to imatinib. One of them, V299L was rarely encountered after imatinib therapy but was reported to emerge after dasatinib exposure in induced mutagenesis models causing resistance to dasatinib by impairing its binding. Aims. We assessed the incidence and pattern of development of V299L in pts with TKI-resistant CML and Ph+ ALL at our institution, and the response following change of therapy. Results. V299L mutation was detected in 14 pts (12 CML, 2 Ph+ ALL): 1 occurred among 186 pts assessed for mutations (0.05%) after imatinib failure (1% of all mutation detected), 9 among 47 pts (19%) who developed mutations on dasatinib therapy, and 4 among 18 pts (22%) who developed mutations on bosutinib therapy (p&lt;0.001); none of the 49 pts who developed mutations on nilotinib therapy acquired V299L. Median age was 55 years (range, 26–82 years). Seven pts were previously treated with interferon-alpha. One pt developed V299L after receiving imatinib for 26 months (mos). Nine pts developed V299L after being on dasatinib for a median of 14 mos (range, 1–30 mos); 7 received dasatinib after imatinib failure, 1 after imatinib and nilotinib failure; and 1 after failure of imatinib, INNO-406, and bosutinib. In 4 pts V299L appeared after receiving bosutinib as 3rd TKI after imatinib and dasatinib failure, for a median of 5 mos (range, 2–8 mos). None of the 11 evaluable pts treated with 2nd generation TKIs had V299L at start of therapy. The best response to TKI immediately preceding V299L (1 imatinib, 9 dasatinib, 4 bosutinib) was complete hematologic response only in 5 (36%, 4 dasatinib, 1 bosutinib), minor cytogenetic response in 2 (14%; 1 imatinib, 1 dasatinib), complete cytogenetic response in 4 (29%; 3 dasatinib, 1 bosutinib); no response in 3 pts (1 dasatinib, 2 bosutinib). The median duration of response was 14 mos. V299L was associated with primary resistance in 3 pts, and secondary resistance in 9. Two pts on dasatinib therapy remained in CHR and minor cytogenetic response, respectively, 3 months after the mutation detection. At the time the mutation was detected, 4 pts were in chronic (CP), 7 in accelerated (AP), 1 in blast phase (BP), and 2 with Ph+ ALL. 3 pts (1 CP, 1 AP, 1 BP) received nilotinib after V299L detection and 1 responded (major molecular response sustained for 16+ mos). One pt received INNO406 and did not respond. One pt with Ph+ ALL was refractory to allogeneic stem cell transplantation and acquired a T315I mutation. Two pts received homoharringtonine, did not respond, but had an eradication of the mutant clone. After a median follow-up of 8 mos (range, 3–29 mos), from the time V299L was detected, 4 died (1 CP, 1 BP, 2 ALL). The estimated 2-year survival from mutation detection was 74%. Conclusion. V299L occurs more frequently after dual Src/Bcr-Abl kinase inhibitors therapy, paralleling the findings of in vitro studies. TKIs showing in vitro activity against this mutation (e.g. nilotinib) may be good treatment options for pts with this mutation.

Efficacy of Nilotinib in EARLY Chronic PHASE CML Patients WHO Have Suboptimal Cytogenetic or Molecular Response to Imatinib. A Multicentric Retrospective Study

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4454-4454
Author(s):  
Luigia Luciano ◽  
Elisa Seneca ◽  
Mario Annunziata ◽  
Luca Pezzullo ◽  
Paolo Danise ◽  
...  
Keyword(s):  
Retrospective Study ◽  
Second Generation ◽  
Conflicts Of Interest ◽  
Chronic Phase ◽  
Treatment Resistance ◽  
Progression Free Survival ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Free Survival

Abstract Abstract 4454 The CML-CP suboptimal responders rappresent an eterogenous group of patients in which it is possible either to obtain an optimal renponse or to experiment a failure. The Clinical data of MDACC, Hammersmith Hospital and GIMEMA group showed that patients with suboptimal response at 6 and 12 months have worse long term outcomes than patients with optimal responses, particularly if the suboptimal response occurs early in the treatment, suggesting an advantage for pts with early major molecular response, expecially for event free survival and progression free survival. Moreover, recently, the German group has shown the benefit of early major molecular response on overall survival too. So earlier use of nilotinib or dasatinib in suboptimal CP CML may be beneficial in two potential ways: by promoting an early response, thereby potentially improving prognosis; by avoiding the development of treatment resistance. The clinical challenge in this setting would be to accurately identify patients who are likely to fail treatment with TKIs. This retrospective analysis was designed to explore the efficacy of the early switch to Nilotinib in patients with suboptimal responses to imatinib (IM) according to ELN raccomandations. In this multicentric retrospective study, 15 CML-CP patients with suboptimal response to IM within 24 months from diagnosis were evaluated: 4pts with a low, 3 with intermedied and 5 with high Sokal score. The best response to IM was CCyR for 6 pts, PCyR for one pt and Complete Hematological Response for 5 pts. As for suboptimal responses, 5 pts were defined in suboptimal cytogenetic response: 2 pts at 12 months and 2 pts at 6 months; 6pts were 18 months suboptimal molecular responders and 1 pt had a loss of CCyR at 12 months. All patients were switched to Nilotinib 400 mg twice daily. Bone marrow was done at baseline in all pts and at 3,6,12 and 18 months in cytogenetic suboptimal pts, while the molecular analysis was performed on peripheral blood every three months in all other pts. 12 pts have been treated with Nilotinib for a median of 17,5 months (range 3–37), 9 patients for ≥ 12 months. Before switching to Nilotinib, pts were treated with IM 400 mg once daily apart for 2 patients who needed an adjustment dose to 300 mg and 600 mg for toxicity and suboptimal response, respectively. Among 6 pts with suboptimal CyR, 4 obtained CCyR, 3 at 3 months and one at 6 months; 2 pts had any response at the milestones timepoints and they switched to another therapy. All pts with molecular suboptimal response obtained MMR at 3 months apart for one, who showed MMR at 12 months. Nilotinib was well tolerated in all 12 pts; only one developed a moderate transaminase elevation. A brief drug intrerruption was sufficient to manage this adverse event. Our data confirm that second generation TKIs give deeper and earlier responses also in second line treatment, garantendo optimal PFS and OS. In our serie infact, Nilotinib treatment results in high and relatively quick cytogenetic and molecular response rate in CML –CP-pts with suboptimal response to IM. These results demonstrate that the early switch to Nilotinib could be raccomanded in suboptimal responders in order to improve the outcome of this kind of pts and strongly suggest the second generation TKI as first line therapy in CML patients. A larger patient population and a longer period of observation could allow to confirm these preliminary data. Disclosures: No relevant conflicts of interest to declare.

High-dose imatinib mesylate therapy in newly diagnosed Philadelphia chromosome–positive chronic phase chronic myeloid leukemia

Blood ◽  
2004 ◽  
Vol 103 (8) ◽  
pp. 2873-2878 ◽  
Author(s):  
Hagop Kantarjian ◽  
Moshe Talpaz ◽  
Susan O'Brien ◽  
Guillermo Garcia-Manero ◽  
Srdan Verstovsek ◽  
...  
Keyword(s):  
Imatinib Mesylate ◽  
Quantitative Polymerase Chain Reaction ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
High Dose ◽  
Molecular Response ◽  
Newly Diagnosed ◽  
Complete Cytogenetic Response

Abstract Imatinib mesylate (STI571) is effective in chronic phase chronic myelogenous leukemia (CML). However, most patients treated with 400 mg imatinib daily have variable levels of residual molecular disease. We treated 114 patients with newly diagnosed chronic phase CML with 400 mg imatinib twice daily. Overall, 109 patients (96%) had a major cytogenetic response (Philadelphia chromosome [Ph] &lt; 35%), and 103 (90%) had a complete response (Ph 0%). With a median follow-up of 15 months, no patient has progressed to accelerated or blastic phase. The estimated 2-year survival rate was 94%. By quantitative polymerase chain reaction (QPCR) studies, 71 (63%) of 112 patients showed BCR-ABL/ABL percentage ratios decrease to less than 0.05%, and 31 (28%) to undetectable levels. Compared with standard-dose imatinib, high-dose imatinib was associated with significantly better complete cytogenetic response (P = .0005), major molecular response (QPRC &lt; 0.05%; P = .00001), and complete molecular response (undetectable BCR-ABL; P = .001). High-dose imatinib was well tolerated but resulted in more frequent myelosuppression; 82% of patients continue to receive 600 mg or more of imatinib daily. In conclusion, high-dose imatinib induced higher rates of complete cytogenetic response and of molecular response in patients with newly diagnosed chronic phase CML. (Blood. 2004; 103:2873-2878)

scholarly journals Initial treatment for patients with CML

Hematology ◽  
2009 ◽  
Vol 2009 (1) ◽  
pp. 453-460 ◽  
Author(s):  
John M. Goldman
Keyword(s):  
Initial Treatment ◽  
Myeloid Leukemia ◽  
Kinase Inhibitor ◽  
Philadelphia Chromosome ◽  
Chronic Phase ◽  
Cytogenetic Response ◽  
Molecular Response ◽  
Major Molecular Response ◽  
Log Reduction ◽  
Advanced Phase

AbstractFor adult patients who present with chronic myeloid leukemia (CML) in chronic phase it is now generally agreed that initial treatment should start with the tyrosine kinase inhibitor (TKI) imatinib at 400 mg daily. Five years after starting imatinib about 60% of these patients will be in complete cytogenetic response (CCyR), still taking imatinib; an appreciable proportion of these will have achieved a major molecular response, defined as a 3-log reduction in the level of BCR-ABL1 transcripts in their blood. The patients in CCyR seem to have a very low risk of relapse to chronic phase or of progression to advanced phase. Other patients may be resistant to imatinib or may experience significant side effects that require change of therapy. The best method of monitoring responding patients is to enumerate Philadelphia chromosome–positive marrow metaphases at 3-month intervals until CCyR and to perform RQ-PCR for BCR-ABL1 transcripts at 3-month intervals after starting imatinib. The recommendations for defining “failure” and “sub-optimal response” proposed by the European LeukemiaNet in 2006 have proved to be a major contribution to assessing responses in individual patients and are now being updated. Patients who fail imatinib may respond to second-generation TKIs, but allogeneic stem cell transplantation still plays an important role for eligible patients who fare badly with TKIs. Patients who present in advanced phases of CML should be treated initially with TKI alone or with TKI in conjunction with cytotoxic drugs, but their overall prognosis is likely to be much inferior to that of those presenting in early chronic phase.

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