804 Dasatinib Combined with Interferon-α Achieves a Complete Cytogenetic Response (CCyR) and Major Molecular Response (MMR) in a Patient with Chronic Myelogenous Leukemia (CML) Harboring the T315I BCR-ABL1 Mutation

Abstract Dasatinib (SPRYCEL®) is 325-fold more potent than imatinib against BCR-ABL in vitro and binds to BCR-ABL in both the inactive and active, oncogenic conformations. Dasatinib has been shown to be an effective treatment option for patients with imatinib-resistant or -intolerant chronic-phase chronic myelogenous leukemia (CP-CML). Here we report the extended follow-up of START-C, a 75-center, international study of dasatinib in 387 patients with CP-CML with resistance (n=288) or intolerance (n=99) to imatinib. Recruitment took place from February to July 2005. Dasatinib was administered on a 70-mg BID regimen; dose escalation (90 mg BID) or reduction (50 or 40 mg BID) were allowed for lack of response or toxicity, respectively. Median time from diagnosis of CML was 61 mo (range 32–50). Prior therapy included interferon-α in 65% of patients and stem-cell transplantation in 10%; 55% had received prior imatinib doses >600 mg and 53% treatment with imatinib for >3 years. Best response to prior imatinib therapy was complete hematologic response (CHR) in 82%, and complete (CCyR) and partial cytogenetic response (PCyR) in 19% and 18%, respectively. With a median follow-up of 15.2 mo, CHR was attained in 91% of patients (95% CI 87–93%), major cytogenetic response (MCyR) in 59% (95% CI 54–64%) (52% imatinib-resistant, 80% imatinib-intolerant), and CCyR in 49% (40% imatinib-resistant; 75% imatinib-intolerant). For patients with no prior MCyR to imatinib, 42% achieved a MCyR with dasatinib. A MCyR rate of 59% was recorded for patients with baseline BCR-ABL mutations; responses were seen across all mutations with the exception of T315I. MCyRs were durable, with only 7 of the 230 patients who had achieved a MCyR with dasatinib losing this response. Major molecular response rate (ie, a BCR-ABL/ABL ratio of <0.1% according to the international scale by RQ-PCR) at 12 mo was 25%. Progression-free survival at 15 mo was 90% while overall survival was 96%. Dose interruptions were required for 87% of patients and dose reduction for 73%; the average daily dose administered was 101 mg (range 11–171). Reports of grade 3–4 thrombocytopenia and neutropenia were documented for 48% and 49% of patients, respectively. Non-hematologic toxicity consisted primarily of diarrhea (37%), headache (32%), fatigue (31%), and dyspnea (30%). Pleural effusion was experienced by 27% of patients; this was categorised as grade 1–2 in 21% and grade 3–4 in 6%. Dasatinib-induced cytogenetic responses remain durable in patients with CP-CML resistant or intolerant to imatinib. Updated analyses corresponding to a minimum follow-up of 2 years on all patients will be presented.

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Significance of Increasing Levels of Minimal Residual Disease in Patients With Philadelphia Chromosome–Positive Chronic Myelogenous Leukemia in Complete Cytogenetic Response

Journal of Clinical Oncology ◽

10.1200/jco.2008.18.6999 ◽

2009 ◽

Vol 27 (22) ◽

pp. 3659-3663 ◽

Cited By ~ 43

Author(s):

Hagop M. Kantarjian ◽

Jianqin Shan ◽

Daniel Jones ◽

Susan O'Brien ◽

Mary Beth Rios ◽

...

Keyword(s):

Chronic Myelogenous Leukemia ◽

Kinase Inhibitors ◽

Residual Disease ◽

Quantitative Polymerase Chain Reaction ◽

Philadelphia Chromosome ◽

Cytogenetic Response ◽

Myelogenous Leukemia ◽

Therapeutic Interventions ◽

Molecular Response ◽

Complete Cytogenetic Response

Purpose The aim of this study was to evaluate the clinical relevance of increases in quantitative polymerase chain reaction (QPCR) levels in patients with chronic myelogenous leukemia (CML) who are in complete cytogenetic response (CGCR) on therapy. Patients with Philadelphia chromosome (Ph)–positive CML receiving tyrosine kinase inhibitors (TKIs) are frequently monitored for response by QPCR studies for minimal molecular disease. The clinical significance of increasing levels of QPCR in patients in CGCR is uncertain. Patients and Methods One hundred sixteen patients in durable CGCR, and on imatinib therapy for at least 18 months, had increases in QPCR levels (documented at least twice consecutively) as defined by literature reports. These were further analyzed by the achievement of major molecular response (MMR) defined as QPCR ≤ 0.05%, as well as by the degree of increase in QPCR. Results Only 11 (9.5%) of 116 patients with increases in QPCR had CML progression; 10 of them were among 44 patients (23%) who either lost a MMR or never had a MMR, and had more than 1 log increase of QPCR. Conclusion Most patients with increases in QPCR remain in CGCR. Patients who lose a MMR or never achieve a MMR, and have more than 1 log increase of QPCR, should be monitored more closely, and may be evaluated for mutations of BCR-ABL kinase domain and considered for investigational therapeutic interventions.

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Imatinib in Children with Newly Diagnosed Chronic Phase Chronic Myelogenous Leukemia (CP CML): AAML0123 COG Study.

Blood ◽

10.1182/blood.v108.11.2140.2140 ◽

2006 ◽

Vol 108 (11) ◽

pp. 2140-2140 ◽

Cited By ~ 3

Author(s):

Martin A. Champagne ◽

Cecilia Fu ◽

Myron Chang ◽

Linda Cooley ◽

Nyla A. Heerema ◽

...

Keyword(s):

Liver Toxicity ◽

White Cell Count ◽

Phase 1 ◽

Chronic Phase ◽

Cytogenetic Response ◽

Myelogenous Leukemia ◽

Molecular Response ◽

Newly Diagnosed ◽

Minor Response ◽

Complete Cytogenetic Response

Abstract Introduction. Our prior phase 1 study (P9973) established the safety profile and suggested efficacy of imatinib in children with CP CML at doses varying from 260–570 mg/m2. The purpose of this phase 2 study was to define the rates of response in children with previously untreated CP CML. Methods. Patients less than 22 years of age at study entry with newly diagnosed CP CML, with no prior therapy other than hydroxyurea, were eligible. Imatinib was administered orally at a dose of 340 mg/m2 daily, with courses defined as 28-day intervals. A hematological response (HR) was defined at the end of courses 1 and 2 as a reduction in the white-cell count to <10 x 109/L and in platelet count to <450 x 109/L, and was considered a complete response (CHR) when maintained for at least four weeks. Cytogenetic response is defined as follows, based on the absolute percent of Ph+ metaphase cells on marrow specimens: complete cytogenetic response (CCyR) 0% Ph+ cells; partial (PCyR)1–35%; minor 39–65%; minimal 66–95%; none 96–100%. Iterative cytogenetic analyses were performed every 3 months during therapy. Toxicities were reported prospectively using the NIH CTCv2.0 criteria. Results. 50 children (42% boys), with a median age of 11.8 years (range 2.3–19.1) completed more than one course of therapy and were evaluable for response. Median number of courses delivered was 22.5 (range 1–43), with a median follow-up of 795 days. 96% of the calculated dose was administered. Eleven patients experienced 14 non-hematological grade 2–4 adverse events, and one patient discontinued therapy because of toxicity. The HR and CHR rates were 78% and 12%, at the end of course 1, and 20% and 78%, respectively, at the end of course 2. Only one patient was reported as a hematologic non-responder at the end of course 2. At the end of the third course, 33 patients were evaluated for cytogenetic response. Twelve (36%) children were in CCyR; 10 (30%) in PCyR; 5 in minor response; 4 in minimal response; 2 with no cytogenetic response. Six patients did not have cytogenetic evaluation; while in 11 (33%) the study was not possible due to insufficient sampling. Overall, 33 (66%) CCyRs were documented, at a median time of 5.6 months (91% documented by 9 months). Only 1 patient achieved a CCyR after course 10. Thirty-three children were removed from protocol, of which 23 underwent stem cell transplantation. One patient progressed to blast phase while on therapy, while six additional patients had cytogenetic progression. Of the 3 remaining patients, two patients had difficulty with taking medications and one had grade 4 liver toxicity. At 1 year, the estimated event free and overall survivals are 96% and 98%, respectively. Conclusion. Imatinib is well tolerated in previously untreated children with CP CML and induces comparable rates of complete cytogenetic response to those observed in adults. Current evaluation of molecular response is being performed.

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Imatinib mesylate therapy in newly diagnosed patients with Philadelphia chromosome–positive chronic myelogenous leukemia: high incidence of early complete and major cytogenetic responses

Blood ◽

10.1182/blood-2002-02-0545 ◽

2003 ◽

Vol 101 (1) ◽

pp. 97-100 ◽

Cited By ~ 114

Author(s):

Hagop M. Kantarjian ◽

Jorge E. Cortes ◽

Susan O'Brien ◽

Francis Giles ◽

Guillermo Garcia-Manero ◽

...

Keyword(s):

Imatinib Mesylate ◽

Chronic Myelogenous Leukemia ◽

Quantitative Polymerase Chain Reaction ◽

Philadelphia Chromosome ◽

Chronic Phase ◽

Cytogenetic Response ◽

Myelogenous Leukemia ◽

Interferon Α ◽

Combination Regimens ◽

Philadelphia Chromosome Positive

Abstract Fifty patients with Philadelphia chromosome–positive (Ph+) chronic myelogenous leukemia (CML) in early chronic phase received imatinib mesylate, 400 mg orally daily. After a median follow-up of 9 months, 49 patients (98%) achieved a complete hematologic response and 45 patients (90%) achieved a major cytogenetic response, complete in 36 patients (72%). Compared with similar patients who received interferon-α with or without hydroxyurea or other interferon-α combination regimens, those receiving imatinib mesylate had higher incidences of complete and major (Ph < 35%) cytogenetic responses at 3 months (34% and 74% versus 1%-4% and 9%-24%, respectively), 6 months (52% and 80% versus 3%-7% and 11%-28%, respectively), and 9 months (60% and 77% versus 5%-11% and 14%-30%, respectively; P < .001). Competitive quantitative polymerase chain reaction (QPCR) studies at 9 months showed a median QPCR value (ratio of BCR-ABL/ABL transcripts × 100) of 0.59% overall and of 0.24% (range, 0.001%-29.5%) for complete cytogenetic response.

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Sustained Molecular Responses with Interferon α2a Maintenance Therapy after Imatinib Plus IFN Induction Treatment for Chronic Phase Chronic Myelogenous Leukemia.

Blood ◽

10.1182/blood.v110.11.28.28 ◽

2007 ◽

Vol 110 (11) ◽

pp. 28-28 ◽

Cited By ~ 2

Author(s):

Andreas Hochhaus ◽

Andreas Neubauer ◽

Martin C. Mueller ◽

Simone Napieralski ◽

Philipp Erben ◽

...

Keyword(s):

T Lymphocytes ◽

Maintenance Therapy ◽

Chronic Myelogenous Leukemia ◽

Significant Proportion ◽

Chronic Phase ◽

Myelogenous Leukemia ◽

Induction Treatment ◽

Molecular Response ◽

Major Molecular Response ◽

Interferon Α2a

Abstract Most patients with chronic myelogenous leukemia (CML) relapse after discontinuation of imatinib (IM, Glivec®/Gleevec™). Thus, current recommendations suggest a lifelong IM therapy even in complete molecular responders. However, in view of potential long term adverse effects there is a concern of tyrosine kinase inhibition. Hence, strategies to circumvent permanent kinase inhibitor therapy would be of substantial clinical value. Interferon α (IFN), in contrast to IM, elicits an autologous antileukemic immune response to control CML, and stopping IFN in complete cytogenetic responders is not associated with relapse in a significant proportion of patients. We therefore sought to determine efficacy and tolerability of an IFN maintenance immunotherapy after IM/IFN induction in newly diagnosed chronic phase CML patients. Twenty patients (14 m, 6 f; median age 44.6, range 23.5–74.1 years) have been investigated. Hasford score revealed low (n=13), intermediate (n=6), and high risk (n=1) diseases. IM therapy had been administered for 2.4 yrs (0.2–4.9), combined with PEG-IFNα2a (Pegasys®, n=17) or IFNα2a (Roferon®, n=3). Maintenance therapy consisted of PEG-IFN (n=16) or IFN (n=4). Dose was adjusted according to response and tolerability and ranged between 135 μg PEG-IFN every three weeks to 180 μg PEG-IFN once weekly week, or alternatively between 2 to 5*3 Mill IU IFN/week. IM was stopped due to side effects (n=5) or after the patient’s individual request and informed consent (n=15). At the time of imatinib withdrawal, 19 patients were in complete cytogenetic remission and one patient did not show any cytogenetic response. Major molecular response was determined in peripheral blood leukocytes of 16 patients, including one patient with undetectable BCR-ABL transcripts. After a median observation time of 1.2 yrs (range 0.1–3.1), 15 patients showed major molecular response, seven of them were complete. Improvement of molecular response was observed in seven and a stable situation in ten patients. By 6 weekly assessments of BCR-ABL expression gradual molecular relapse was observed in three patients. All relapsing patients responded to readministration of IM. At the time of IM withdrawal and during IFN maintenance therapy myeloblastin (proteinase-3, PR3) mRNA expression was determined and compared to glucose-6-phosphate dehydrogenase transcripts as internal standard. During IFN monotherapy, median ratios PR3/G6PD increased from 0.06% (range, 0.02–3.5) to 0.14% (0.03–1.4; p=0.03). IFN response was associated with the detection of autoreactive PR3 specific T-lymphocytes during IFN maintenance therapy determined by a tetramer assay in 7/8 patients, suggesting that PR3-specific cytotoxic T lymphocytes contribute to the IFN-mediated antileukemic immunity. In conclusion, we report a high rate of improved or continuous molecular remissions in 17 of 20 patients (85%) on IFN monotherapy after prior induction with IM/IFN. This suggests a previously unrecognized beneficial role for IFN in the maintenance therapy after IM-mediated debulking and may impact future CML therapy.

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Imatinib as Front-Line Treatment in Chronic Myelogenous Leukemia: How Important is the Achievement of Complete Cytogenetic Response after 3 Months?

Blood ◽

10.1182/blood.v114.22.4271.4271 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4271-4271

Author(s):

Roberto Latagliata ◽

Massimo Breccia ◽

Ida Carmosino ◽

Federico Vozella ◽

Paola Volpicelli ◽

...

Keyword(s):

Chronic Myelogenous Leukemia ◽

Risk Score ◽

Cytogenetic Response ◽

Myelogenous Leukemia ◽

Imatinib Treatment ◽

Front Line ◽

Prognostic Role ◽

Complete Cytogenetic Response ◽

Pre Treatment

Abstract Abstract 4271 The achievement of Complete Cytogenetic Response (CCyR) (Ph+ cells 0%) with Imatinib treatment still remains the most important objective in Chronic Myelogenous Leukemia (CML) patients. According to The European Leukemia NET guidelines, CCyR should be achieved within the 12th month of treatment while at 3 months of treatment the goal should be complete haematological response. To address the prognostic role of the early achievement of CCyR, we revised 108 chronic phase CML patients [M/F 57/51, median age 54.9 years, interquartile range (IR) 40.8 – 68.1] treated with front-line Imatinib at our Institution from June 2002 to June 2008 who had evaluable karyotype after 3 months of treatment. At onset, median WBC and PLT counts were 78.4 × 109/l (IR 34.0 – 135.9) and 399 × 109/l (IR 282 – 585), respectively. Sokal risk score was low in 52 patients (48.1%), intermediate in 49 (45.4%) and high in 7 (6.5%); a short pre-treatment phase (< 3 months) with Hydroxyurea was administered to 94/108 patients (87%). After 3 months of Imatinib treatment, 84 patients (77.7%) achieved CCyR while 24 patients (22.3%) still presented Ph+ metaphases (median value 40%, IR 20 - 80) at cytogenetic analysis. At univariate analysis, factors with a negative prognostic impact on achievement of CCyR at 3 months were palpable spleen enlargement (p=0.002), WBC count at onset > 100.0 × 109/l (p=0.01) and pre-treatment with Hydroxyurea (p=0.032); on the contrary, sex, age, Sokal risk score and PLT value did not appear to affect early CCyR achievement. Among the 84 patients in CCyR after 3 months, there were 10 failures during follow-up (6 cytogenetic relapses, 2 molecular relapses and 2 evolution to blastic phase); among the 24 patients who did not achieve early CCyR, there were 12 failures during follow-up (9 primary resistances and 3 cytogenetic relapses). The difference in the incidence of failures during follow-up in the 2 groups was highly significant (p<0.001). In conclusion, the achievement of CCyR at 3 months seems unrelated to traditional prognostic factors (Sokal); furthermore, in our experience it appears to have an important prognostic role, as patients not achieving it showed a significantly higher rate of failures during the follow-up. Disclosures: No relevant conflicts of interest to declare.

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

Blood ◽

10.1182/blood.v118.21.1422.1422 ◽

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.

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Phase 1 study of polyethylene glycol formulation of interferon α-2B (Schering 54031) in Philadelphia chromosome–positive chronic myelogenous leukemia

Blood ◽

10.1182/blood.v98.6.1708 ◽

2001 ◽

Vol 98 (6) ◽

pp. 1708-1713 ◽

Cited By ~ 50

Author(s):

Moshe Talpaz ◽

Susan O'Brien ◽

Esther Rose ◽

Samir Gupta ◽

Jianqin Shan ◽

...

Keyword(s):

Polyethylene Glycol ◽

Chronic Myelogenous Leukemia ◽

Phase 1 ◽

Philadelphia Chromosome ◽

Cytogenetic Response ◽

Myelogenous Leukemia ◽

Interferon Α ◽

Phase 1 Study ◽

Severe Fatigue ◽

Complete Hematologic Response

Abstract Interferon α (IFN-α) therapy improves prognosis in Philadelphia chromosome (Ph)–positive chronic myelogenous leukemia (CML). Polyethylene glycol (PEG) attached to IFN-α prolongs its half-life and may offer better therapy. The aims of this phase 1 study were to define the maximal tolerated dose (MTD), dose-limiting toxicities (DLTs), and response with PEG IFN-α-2b. Twenty-seven adults with Ph+ CML in chronic or accelerated phases, in whom IFN-α treatment had failed, were studied. Patients had hematologic (9 patients) or cytogenetic resistance (12 patients) or intolerance to IFN-α (6 patients). PEG IFN-α-2b was given as a weekly subcutaneous injection starting at 0.75 μg/kg weekly and escalating to 1.5, 3, 4.5, 6, 7.5, and 9.0 μg/kg. The MTD was defined at 7.5 to 9 μg/kg; DLT included severe fatigue, neurotoxicity, liver function abnormalities, and myelosuppression. Longer administration of PEG IFN-α-2b resulted in chronic side effects not observed earlier, which defined the MTD and DLT. The proposed phase 2 dose of PEG IFN-α-2b was 6 μg/kg weekly. Among 19 patients with active disease, 7 (37%) achieved complete hematologic response (CHR); 2 (11%) had a cytogenetic response (complete). Among 8 patients treated in CHR, 7 (87%) improved cytogenetic response to complete (4 patients) or partial (3 patients). All 6 patients intolerant to IFN-α tolerated PEG IFN-α-2b; 4 improved their cytogenetic response. The results show that PEG IFN-α-2b is easier to deliver (once weekly), better tolerated, and perhaps more effective than IFN-α.

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