ASCO 2009

Clinical, pharmacokinetic (PK), and pharmacodynamic findings from a phase I trial of an Eg5 inhibitor (AZD4877) in patients with refractory acute myeloid leukemia (AML).

Category: Developmental Therapeutics: Molecular Therapeutics
Sub-category: Cell Cycle Inhibitors
Meeting: 2009 ASCO Annual Meeting

Citation: J Clin Oncol 27:15s, 2009 (suppl; abstr 3580)

Abstract No: 3580

Author(s): G. Borthakur, S. Faderl, F. Ravandi, S. Padmanabhan, W. Stock, K. Wu, J. Li, G. Curt, M. Tallman, M. Minden; University of Texas M. D. Anderson Cancer Center, Houston, TX; University of Texas Health Science Center at San Antonio, San Antonio, TX; University of Chicago, Chicago, IL; AstraZeneca R&D Boston, Waltham, MD; AstraZeneca, Wilmington, DE; Northwestern University, Chicago, IL; Princess Margaret Hospital, Toronto, ON, Canada

Abstract:

Background: AZD4877 is a potent, specific inhibitor of Eg5 (kinesin spindle protein). The only known function of Eg5 is to separate the centromeres during mitosis. Eg5 inhibition is thus specific for dividing cells, resulting in monoastral mitotic spindles (monoasters) and apoptotic cell death. Preclinically, hematologic tumor cell lines were generally more sensitive to AZD4877 than those derived from solid tumors. Methods: AZD4877 was administered IV daily x 3 as induction for up to 2 cycles, followed by consolidation (daily x 2) for up to 4 cycles. Eligibility criteria were standard. Results: Cohorts of 3-6 patients (pts) were treated at doses of 2, 4, 7, 10, 13, 16, and 18 mg/day. To date, 24 evaluable pts have received 33 induction and 3 consolidation cycles of treatment. Monoasters were detected at all dose levels evaluated (2, 7, 10, 13, and 18 mg/day). The T1/2 of AZD4877 ranged from 26 to 42 hr; PK were linear and drug levels non-cumulative. Myelosuppression, the dose limiting toxicity (DLT) in solid tumor studies, was not considered a DLT in this trial. Mucositis was the DLT at 18 mg/day; with 1 pt developing Gr 3 palmar-plantar syndrome at this dose. Bone marrow biopsies were undertaken at screening and as clinically indicated. In pts with evaluable biopsies, marrow blasts decreased by 60-80% in 2 pts, and by 30-50% in 3 pts, with no response in 3 pts. Conclusions: Enrollment is ongoing at 16 mg, the likely Phase 2 dose. Preliminary results suggest possible clinical activity in AML. An expansion phase at the MTD is planned.

Treatment patterns of chronic myelogenous leukemia patients with suboptimal responses to imatinib.

Meeting: 2009 ASCO Annual Meeting

Citation: J Clin Oncol 27:15s, 2009 (suppl; abstr 7090)

Abstract No: 7090

Author(s): A. Guérin, A. Guo, D. Williams, A. P. Yu, E. Wu, D. Latremouille-Viau, M. Tsaneva, J. Signorovitch, J. D. Griffin; Analysis Group, Inc., Boston, MA, Canada; Novartis Pharmaceuticals Corporation, East Hanover, NJ; Analysis Group, Inc., Boston, MA; Dana-Farber Cancer Institute, Boston, MA

Abstract:

Background: Imatinib is the first-line therapy for Philadelphia chromosome-positive chronic myelogenous leukemia (CML). Patients with suboptimal responses may have the dose of imatinib escalated or may be switched to an alternative kinase inhibitor such as dasatinib. The aim of this study is to examine the real-world treatment patterns of imatinib and dasatinib in CML patients. Methods: Two large U.S. administrative claims databases from January 1999 to March 2008 were combined (MarketScan and Ingenix Impact) to extract de-identified information of patients diagnosed with CML (ICD-9 code: 205.1) who were initiated on imatinib. Patients were followed from the first observed imatinib prescription to the end of data availability. Patients who increased imatinib dose to >400 mg/day were defined as dose escalators, while patients who initiated on imatinib and further switched to dasatinib were considered as switchers. Rates of imatinib dose escalation and switching to dasatinib were estimated. Kaplan-Meier (KM) survival analyses were used to estimate the rate of imatinib discontinuation, defined as a lack of imatinib supply for at least 90 days. Among switchers, the rate of switching back to imatinib was also estimated using KM survival analysis. Results: Among the 5,159 CML patients initiated with imatinib, 1,144 patients either had dose escalation of imatinib (839) or were switched to dasatinib (305) during the study period. Of the 5,159 patients, 12.1% patients discontinued imatinib by the end of the first year, and 25.4% discontinued by the end of the third year. Among the 305 switchers, 115 (37.7%) had an imatinib dose increase prior to the switch, and 66 (21.6%) were escalated to 800 mg of imatinib before switching. 51 patients (16.7%) had used imatinib for <6 months before switching, and 17.1% switched back to imatinib within 6 months of dasatinib treatment. Conclusions: This study showed that great variability was observed in the real world treatment pattern of CML patients. Most CML patients who initiated on imatinib did not dose increase or switch during the study period. Of those who switched to dasatinib, most did not attempt to increase the dose before switching, and a sizeable portion of patients had to switch back to imatinib.

Adverse events associated with escalating imatinib versus switching to dasatinib in patients with chronic myelogenous leukemia.

Meeting: 2009 ASCO Annual Meeting

Citation: J Clin Oncol 27:15s, 2009 (suppl; abstr 7092)

Abstract No: 7092

Author(s): E. Wu, A. Guo, D. Williams, A. Guérin, A. P. Yu, D. Latremouille-Viau, M. Tsaneva, J. Signorovitch, J. D. Griffin, V. Bollou; Analysis Group, Inc., Boston, MA; Novartis Pharmaceuticals Corporation, East Hanover, NJ; Dana-Farber Cancer Institute, Boston, MA

Abstract:

Background: After initial therapy with imatinib, some chronic myelegenous leukemia (CML) patients may require dose escalation or switching to another BCR/ABL kinase inhibitor to achieve the desired response. This study compared adverse events associated with either escalation of imatinib or switching to dasatinib. Methods: Two large administrative claims databases were combined (MarketScan and Ingenix Impact) to extract deidentified information on 17,382 patients diagnosed with CML (ICD-9 code: 205.1) from January 1999 to March 2008. 474 patients (dose escalators) had their dose of imatinib increased at some point to >400 mg/day but were never given dasatinib, while 175 patients were switched to dasatinib with or without dose escalation of imatinib (switchers). Patients were followed from the index date to treatment discontinuation or end of eligibility. Cox proportional-hazard models were used to compare the risk of common adverse events (AEs) associated with escalation or switching to dasatinib, controlling for demographics, imatinib treatment patterns, and prior therapies at baseline. Patients with the studied AEs at baseline were excluded from analyses of the corresponding AEs. Results: Switchers experienced significantly higher risk of the following AEs than escalators: fluid retention (HR 3.22 p < 0.0001), pleural effusion (HR 4.90 p < 0.0001), thrombocytopenia (HR 3.25 p = 0.0044), neutropenia (HR 3.40 p = 0.0009), and some non-hematologic adverse events (HR 2.38 p < 0.0001), dyspnea (HR 4.02 p < 0.0001), constipation (HR 5.79 p = 0.0041), nausea and vomiting (HR 2.40 p = 0.0100), and congestive heart failure (HR 5.01 p < 0.0001). No statistically significant differences in risk of other common AEs associated with imatinib and dasatinib were identified. Conclusions: 15.4% of CML patients treated with ?400mg of imatinib initially either had dose escalation or switch to dasatinib. Significantly more AEs were associated to those who switched to dasatinib than those who dose escalated. Further study is warranted to examine the causality of the difference in these AEs.

Chronic myeloid leukemia (CML) with e1a2 BCR-ABL fusion transcript type: Analysis of characteristics, outcomes, and prognostic significance.

Meeting: 2009 ASCO Annual Meeting

Citation: J Clin Oncol 27:15s, 2009 (suppl; abstr 7030)

Abstract No: 7030

Author(s): D. Verma, H. Kantarjian, D. Jones, G. Borthakur, G. Garcia-Manero, D. A. Thomas, S. Verstovsek, M. Rios, J. Cortes; M. D. Anderson Cancer Center, Houston, TX

Abstract:

Background: The most common BCR-ABL fusion transcripts in CML are e13a2 (b2a2) and e14a2 (b3a2). Rarely, other transcripts like e1a2 are seen. Currently, there is no published series of data on efficacy of imatinib or other tyrosine kinase inhibitors (TKIs) in CML with e1a2. Methods: We analyzed records of 1,292 CML patients treated with TKI at our institution between January 2000 and November 2008. Results: 14 CML patients with e1a2 transcripts were identified, 9 in chronic phase (CP), 1 in accelerated phase (AP), and 4 in blast phase (BP). Median age at diagnosis was 60 (range 28-86) years, median follow-up 39.5 (range 2-109) months. Of the 9 in CP, 3 received interferon and then imatinib after interferon failure, 6 received TKI as first-line therapy (5 imatinib, 1 nilotinib): 5 achieved CHR only, 1 CCyR, 1 MCyR, 1 PCyR, and 1 did not respond to imatinib. 5 patients (2 post-interferon failure - 1 in CHR, 1 in PCyR; 3 frontline imatinib - 1 in CHR, 1 in CCyR, 1 non-responder) progressed to advanced phases (3 myeloid BP, 1 lymphoid BP, 1 AP) at a median 48 (range 4-92) months after CML diagnosis; with only 1 alive and in CMR after allogeneic SCT. AP patient received various TKIs sequentially and achieved only CHR with disappearance of clonal evolution. BP patients received Hyper-CVAD+imatinib/dasatinib or idarubicin+Ara-C; 2 did not respond, 1 had CCyR lasting 12 months with Hyper-CVAD+Imatinib and 1 had CMR after allogeneic SCT lasting 2 months. In all 14 patients, cytogenetic responses lasted 1-9 months before being lost and none (except 2) achieved MMR or CMR on imatinib or other TKI therapy. Six patients (5 CP, 1 AP) were alive at a median 39 (range 2-85) months after initial diagnosis: 4 with CHR (2 on imatinib, 1 nilotinib, 1 bosutinib), 1 with MCyR on imatinib, and 1 with CMR after allogeneic SCT. Conclusions: CML with e1a2 BCR-ABL fusion transcripts is rare and is associated with an inferior outcome to therapy with TKI, with responses being usually short-lived. These patients need to be identified as high-risk patients and monitored closely for efficacy during therapy with TKI.

Dasatinib dose-optimization study in chronic phase chronic myeloid leukemia (CML-CP): Three-year follow-up with dasatinib 100 mg once daily and landmark analysis of cytogenetic response and progression-free survival (PFS).

Meeting: 2009 ASCO Annual Meeting

Citation: J Clin Oncol 27:15s, 2009 (suppl; abstr 7007)

Abstract No: 7007

Author(s): R. M. Stone, D. W. Kim, H. M. Kantarjian, P. Rousselot, A. Hochhaus, P. E. Dorlhiac-Llacer, J. Milone, Y. Matloub, A. Lambert, N. P. Shah; Dana-Farber Cancer Institute, Boston, MA; St Mary's Hospital, Catholic University of Korea, Seoul, Republic of Korea; M. D. Anderson Cancer Center, Houston, TX; Hôpital Mignot, Université de Versailles, Le Chesnay, France; Universität Heidelberg, Mannheim, Germany; Hospital das Clinicas da Universidade de Sao Paulo, Sao Paulo, Brazil; Instituto de Trasplante de Medula Osea, La Plata, Argentina; Bristol-Myers Squibb, Wallingford, CT; Bristol-Myers Squibb, Braine-l'Alleud, Belgium; University of California, San Francisco, San Francisco, CA

Abstract:

Background: The recommended dosing regimen of dasatinib for CML-CP is now 100 mg once daily (QD) (previously 70 mg twice daily [BID]), based upon a phase III dose-optimization study (CA180-034) that enrolled patients (pts) with CML-CP with resistance, intolerance, or suboptimal response to imatinib. While therapeutic milestones have been established for pts with CML-CP treated with imatinib, they have not been well established for pts treated with second-line TKIs. Methods: Pts were randomized using a 2 × 2 factorial design to one of four treatment arms: 100 mg QD (n = 167), 70 mg BID (n = 168), 140 mg QD (n = 167), or 50 mg BID (n = 168). Details of study design and endpoints have been described previously. Results: After a minimum of 24 months of follow-up, the 24-month PFS rate with 100 mg QD was 80% (vs. 75%-76% in other arms) and the overall survival rate was 91% (vs. 88%-94%). In all arms, high response rates were achieved in pts with or without a baseline BCR-ABL mutation. Dasatinib 100 mg QD was well tolerated and rates of key side effects showed only a minimal increment from 12 to 24 months. Among the four treatment arms, significant differences were observed in rates of drug-related pleural effusion (all grades: p = 0.049) and cytopenia (p = 0.003 for grade 3/4 thrombocytopenia), with lowest rates observed for 100 mg QD. Dasatinib 100 mg QD treatment resulted in the lowest rates of treatment interruption, reduction, and discontinuation. In addition to providing 36-month follow-up, the likelihood of achieving long-term endpoints based on cytogenetic status at 6, 12, and/or 18 months will be presented. Conclusions: Dasatinib 100 mg once daily remains the optimal dosing schedule for pts with CML-CP. The landmark analyses to be presented should provide useful information to clinicians treating imatinib-resistant, -suboptimally responding, or -intolerant CML-CP pts with dasatinib 100 mg once daily based on cytogenetic response at key intervals.

Subcutaneous omacetaxine mepesuccinate in imatinib-resistant chronic myeloid leukemia (CML) patients (Pts) with the T315I mutation: Data from an ongoing phase II/III trial.

Meeting: 2009 ASCO Annual Meeting

Citation: J Clin Oncol 27:15s, 2009 (suppl; abstr 7008)

Abstract No: 7008

Author(s): J. E. Cortes, H. J. Khoury, S. Corm, F. Nicolini, T. Schenk, D. Jones, A. Hochhaus, A. R. Craig, E. Humphriss, H. Kantarjian, Omacetaxine 202 Study Group; UT M. D. Anderson Cancer Center, Houston, TX; Emory University, Atlanta, GA; CHU Lille, Lille, France; Hôpital Edouard Herriot, Lyon, France; Universtatsmedizin Mannheim, Mannheim, Germany; ChemGenex Pharmaceuticals, Menlo Park, CA

Abstract:

Background: Omacetaxine (OM), a first-in-class cetaxine shows clinical activity against Ph+ CML with a mechanism independent of tyrosine kinase inhibition. Currently available tyrosine kinase inhibitors (TKIs) have no activity against T315I. Methods: Adult Pts with T315I+ CML following TKI failure received OM induction at 1.25 mg/m2 subcutaneous (SC) twice daily (BID) for 14 days every 28 days followed by maintenance at 1.25 mg/m2 SC BID for 7 days every 28 days (maintenance after at least one induction cycle and achievement of hematologic response). Results: 66 pts (39 chronic [CP], 16 accelerated [AP] and 11 blast phase [BP]) have been enrolled. All had failed prior imatinib and 80% failed ?2 prior TKIs. Median age is 58 yrs. Median disease duration is 58 mos. OM is well tolerated with transient myelosuppression as the primary toxicity. Grade 3/4 non-hematologic events are diarrhea (2%) and fatigue (4%). Efficacy data are available for 44 Pts. In CP Pts, the median number of cycles is 4 (1-22) with 39% having received ? 6 cycles of therapy; 64% of Pts have had the T315I clone reduced to below detection limits; the 2-year progression free survival is 70%. Conclusions: Omacetaxine in T315I+ CML Pts results in de-selection of the T315I clone and induces hematologic and cytogenetic responses.

Hematologic and Cytogenetic Responses

Response; Median Duration Number (%); Median in Mos

CP N=25 AP N=11 BP N=8

Hematologic - Overall 20 (80) 4 (36) 1 (13)
CHR 20 (80);11.5+ 2 (18); 9.6+ -
RCP NA 2 (18); 2.0+ 1 (13);3.4

Cytogenetic - Overall 7 (28) 1 (9) -
Major 5 (20) - -
Complete 4 (16); 4.8+ - -
Partial 1 (4); 4.2 - -
Minor 2 (8); 4.0+ 1 (9); 2.3

Subcutaneous omacetaxine mepesuccinate in chronic myeloid leukemia (CML) patients resistant or intolerant to two or more tyrosine kinase inhibitors (TKIs): Data from an ongoing phase II trial.

Meeting: 2009 ASCO Annual Meeting

Citation: J Clin Oncol 27:15s, 2009 (suppl; abstr 7027)

Abstract No: 7027

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Author(s): M. Wetzler, A. Hellmann, J. Lipton, L. Roy, D. Jones, T. Schenk, A. Hochhaus, A. Benichou, H. Kantarjian, J. Cortes, Omacetaxine 203 Study Group; Roswell Park Cancer Institute, Buffalo, NY; Medical University of Gdansk, Gdansk, Poland; Princess Margaret Hospital, Toronto, ON, Canada; CHU Poitiers, Poitiers, France; UT M. D. Anderson Cancer Center, Houston, TX; Universitatsmedizin Manheim, Manheim, Germany; Universitatsmedizin Mannheim, Mannheim, Germany; ChemGenex Pharmaceuticals, Lyon, France

Abstract:

Background: Omacetaxine (OM), a first-in-class cetaxine, shows clinical activity against Ph+ CML with a mechanism of action independent to tyrosine kinase inhibition. Patients (Pts) who have failed multiple TKIs may benefit from an alternative therapy for CML. Methods: Pts include adult CML following resistance or intolerance to at least 2 TKIs. T315I+ Pts are enrolled in a separate trial. Pts receive OM induction at 1.25 mg/m2 subcutaneous (SC) BID for 14 days every 28 days followed by maintenance at 1.25 mg/m2 SC BID for 7 days every 28 days (maintenance after at least one induction cycle and achievement of hematologic response). Results: 60 pts (30 chronic phase [CP], 14 accelerated phase [AP], and 16 blast phase [BP] have been enrolled with 51% having failed at least 3 prior TKIs. Median age: 58 yrs; 50% male. Median disease duration: 74 months. At baseline, 38.5% of pts had Bcr-Abl mutations including 9.6% with compound mutations. The most frequently observed mutations were F317L (11.5%) and V299L (5.8%). OM is well tolerated with transient myelosuppression as the primary toxicity. Grade 3/4 non-hematologic events are rare with pyrexia occurring in 4.3% of patients. Efficacy data are available for 30 Pts: Conclusions: Omacetaxine in multi-TKI resistant or intolerant CML is well tolerated and has achieved hematologic and cytogenetic responses in these heavily pre-treated Pts.

Hematologic and Cytogenetic Responses
Response: Median Duration Number(%); Duration in Mos
CP N=12 AP N=9 BP N=9

Hematologic Overall 9 (75) 4 (44) 6 (67)
CHR 9 (75); 6.1+ 2 (22); 3.5+ -
RCP NA 2 (22); 4.5+ 6 (67); 5.0

Cytogenetic Overall 2 (17) 2 (22) -
Partial 1 (8); 2.9 1 (11); 0.2 -
Minor 1 (8); 5.5 - -
Minimal - 1 (11); 4.4 -

BCR-ABL truncation due to premature translation termination as a mechanism of resistance to kinase inhibitors.

Meeting: 2009 ASCO Annual Meeting

Citation: J Clin Oncol 27:15s, 2009 (suppl; abstr 7028)

Abstract No: 7028

Author(s): C. Yeh, W. Ma, H. Kantarjian, Z. J. Zhang, J. Cortes, M. Albitar; Quest Diagnostics Nichols Institute, San Juan Capistrano, CA; M. D. Anderson Cancer Center, Houston, TX

Abstract:

Background: The major mechanism underlying imatinib resistance in patients with chronic myeloid leukemia (CML) is clonal expansion of leukemic cells with point mutations in the BCR-ABL tyrosine kinase. We describe three novel ABL premature termination mutations leading to BCR-ABL truncation in leukemia patients with multidrug (imatinib/nilotinib/dasatinib) resistance. Methods: Peripheral blood or bone marrow samples from drug-resistant CML patients were collected. Total nucleic acids were purified and subjected to two rounds of PCR analysis, with the first PCR designed to eliminate amplification of the wild-type, non-translocated ABL gene. Bi-directional sequencing was then performed. HL60 cells (a Ph-negative myeloid leukemia cell line) and peripheral blood of healthy subjects were used as negative controls; a human CML cell line (K562) was used as a positive control. Results: We identified an exon 7 deletion in three CML patients, a 4-nt insertion (908insCAGG) near the exon 5/6 junction in one CML case, and an exon 6 point mutation (997C>T) in one patient with acute lymphoblastic leukemia (ALL). These mutations all create premature stop codons and cause termination at residues 381, 315, and 333, respectively, leading to truncated proteins with only the first quarter of the kinase domain (P-loop) or lacking the C-terminus of ABL including the A-loop. Conclusions: These novel mutations, and the previously documented 35-nt insertion in exon 8, may constitute a new class of mutations that 1) cause truncation of the BCR-ABL kinase; (2) abolish the regulatory element in the ABL kinase domain and the downstream C-terminal region; and (3) confer significant drug resistance.

Nilotinib in chronic myeloid leukemia patients in chronic phase (CML-CP) with imatinib (IM) resistance or intolerance: Longer follow-up results of a phase II study.

Meeting: 2009 ASCO Annual Meeting

Citation: J Clin Oncol 27:15s, 2009 (suppl; abstr 7029)

Abstract No: 7029

Author(s): H. Kantarjian, F. Giles, K. Bhalla, J. Pinilla, R. A. Larson, N. Gattermann, O. G. Ottmann, N. J. Gallagher, M. Baccarani, P. leCoutre; University of Texas M. D. Anderson Cancer Center, Houston, TX; Institute for Drug Development, CTRC, San Antonio, TX; Medical College of Georgia Cancer Center, Augusta, GA; H. Lee Moffitt Cancer Center & Research Institute, Tampa, FL; University of Chicago, Chicago, IL; Heinrich-Heine University, Düsseldorf, Germany; University Hospital of Frankfurt, Frankfurt, Germany; Novartis Pharma AG, Basel, Switzerland; University of Bologna, Bologna, Italy; Charité - Humboldt-Universitat, Campus Virchow, Berlin, Germany

Abstract:

Background: Nilotinib is a potent and highly selective BCR-ABL inhibitor approved for the treatment of Ph+ CML patients (pts) in CP or accelerated phase who are resistant or intolerant to prior therapy including IM. This study evaluated the efficacy and safety of nilotinib (400 mg bid) in CML-CP pts resistant or intolerant to IM. Methods: Primary endpoint was major cytogenetic response (MCyR). Secondary endpoints included complete cytogenetic response (CCyR), complete hematological response (CHR), MCyR duration, overall survival (OS), and safety. Results: CML-CP pts (n = 321, 70% IM-resistant, 30% IM-intolerant with resistance) with a minimum follow-up of 19 months (mos) were evaluated; 72% were treated with ?600 mg/day IM prior to enrollment. Median duration of prior IM treatment was 32 (<1-94) mos. Median dose intensity of nilotinib (790 mg/day; range 151-1,110 mg/day) closely approximated the planned dose. Nilotinib led to rapid and durable CHR and MCyR. CHR was observed in 94% of pts. 59% achieved an MCyR (2.8 mos median time to MCyR; 56% in IM-resistant, and 65% in IM-intolerant pts), including 73% of pts with a baseline CHR and 44% achieved a CCyR (41% in IM-resistant; 51% in IM-intolerant pts). Responses were durable, with 78% pts maintaining MCyR at 24 mos. Estimated OS rate was 88% at 24 mos. Safety profile did not change with longer follow-up. Most frequent grade (gr) 3/4 biochemical laboratory abnormalities were elevated lipase (17%), hypophosphataemia (16%), hyperglycemia (12%), and total bilirubin (8%) which were transient and clinically asymptomatic. Gr 3/4 non-hematologic AEs were infrequent: rash, headache, and diarrhea occurred in 2% of pts. Most common gr 3/4 hematological laboratory abnormalities were neutropenia (31%), thrombocytopenia (31%), and anemia (10%). Brief dose interruptions were successful in management of most AEs. Pleural or pericardial effusions (gr 3/4) were uncommon (< 1%). Conclusions: These results demonstrate that nilotinib was highly effective, with rapid and durable responses in CML-CP pts failing prior therapy due to resistance or intolerance. Nilotinib was well tolerated with favorable risk/benefit.

Chronic myeloid leukemia (CML) with e1a2 BCR-ABL fusion transcript type: Analysis of characteristics, outcomes, and prognostic significance.

Meeting: 2009 ASCO Annual Meeting

Citation: J Clin Oncol 27:15s, 2009 (suppl; abstr 7030)

Abstract No: 7030

Author(s): D. Verma, H. Kantarjian, D. Jones, G. Borthakur, G. Garcia-Manero, D. A. Thomas, S. Verstovsek, M. Rios, J. Cortes; M. D. Anderson Cancer Center, Houston, TX

Abstract:

Inference of imatinib (IM) effects on leukemic stem cell (SC) compartment via mathematical modeling of IRIS treatment response data.

Meeting: 2009 ASCO Annual Meeting

Citation: J Clin Oncol 27:15s, 2009 (suppl; abstr 7056)

Abstract No: 7056

Author(s): D. Bottino, Y. Chia, A. Stein, A. Georgieva, J. Yu, J. Kahn, G. Helmlinger, T. Kalebic; Novartis Pharmaceuticals, East Hanover, NJ; University of Minnesota, Minneapolis, MN; Novartis Pharmaceuticals, Cambridge, MA; Novartis Pharmaceuticals, Florham Park, NJ

Abstract:

Background: Continuous treatment of chronic phase CML (CML-CP) patients with imatinib (IM) induces durable responses in majority of patients with a decreasing rate of relapse (Hochhaus et al, Blood. 2007;110). We present a mechanistic mathematical model which uses 6-year follow up data from the International Randomized Study of Interferon Versus STI571 (IRIS) trial (O'Brien et al, N Engl J Med. 2003;348:994) to explore IM effects on leukemic stem cells (SCs) across the patient population. Methods: The model approximates hemopoiesis as a 4-stage process in which only the first stage, corresponding to the SC compartment, is capable of self-renewal. Leukemic SCs, early and late progenitors were assumed to have higher self-renewal and expansion/differentiation rates than their normal counterparts. Model parameters describing the patient population distributions of leukemic/total SC ratio at diagnosis and sensitivity of leukemic cells to IM, were then fitted to individual cytogenetic and molecular response (CR/MR) data from 200 randomly selected newly-diagnosed CML-CP patients with 6-year follow-up. Results: Based on our analysis, successful characterization of the wide range of clinically observed treatment responses requires the inhibition of the leukemic SC compartment by IM. The median predicted inhibition of the leukemic SC proliferation rate was 79%. The model further predicted that after 6 years of IM treatment, 45% of patients would achieve a leukemic/total SC ratio below 0.1. Conclusions: We have developed a mathematical model of IM effects on CML-CP based on 6-year CR and MR data from the IRIS trial. In contrast to prior reports (Michor et al, Nature. 2005;435), our modeling predicts that IM reduces the leukemic SC compartment in most CML-CP patients, which could provide a mechanistic rationale for the decreasing rate of relapse observed in the study population.

Nilotinib in chronic myeloid leukemia patients in accelerated phase (CML-AP) with imatinib (IM) resistance or intolerance: Longer follow-up results of a phase II study.

Meeting: 2009 ASCO Annual Meeting

Citation: J Clin Oncol 27:15s, 2009 (suppl; abstr 7057)

Abstract No: 7057

Author(s): P. D. Le Coutre, F. Giles, A. Hochhaus, J. F. Apperley, G. Ossenkoppele, A. Haque, N. J. Gallagher, M. Baccarani, J. Cortes, H. Kantarjian; Charité - Humboldt-Universitat, Campus Virchow, Berlin, Germany; The Institute for Drug Development, CenterC, San Antonio, TX; Universitätsmedizin Mannheim University Heidelberg, Mannheim, Germany; Hammersmith Hospital, Imperial College, London, United Kingdom; VU University Medical Center, Amsterdam, Netherlands; Novartis, Florham Park, NJ; Novartis Pharma AG, Basel, Switzerland; University of Bologna, Bologna, Italy; M. D. Anderson Cancer Center, Houston, TX

Abstract:

Background: Nilotinib is a potent and highly selective BCR-ABL inhibitor approved for the treatment of Ph+ CML patients (pts) in chronic phase or AP who are resistant or intolerant to prior therapy including IM. This study evaluated the efficacy and safety of nilotinib (400 mg bid) in CML-AP pts resistant or intolerant to IM. Methods: Primary endpoint was confirmed hematologic response (HR). Secondary endpoints included major cytogenetic response (MCyR), time to progression, overall survival (OS), and safety. Results: 137 CML-AP pts (80% IM-resistant; 20% IM-intolerant with resistance) with minimum follow-up of 11 months (mos) (median age, 57 years; median duration of prior IM treatment, 28 mos) were included. IM-intolerant pts were also IM-resistant and without MCyR at study entry. 79% pts had prior IM ?600 mg/day. Median dose intensity of nilotinib was 775 mg/day and median duration of exposure was 272 days. 56% had confirmed HR and 31% had complete hematologic response (CHR). 30% of IM-resistant and 37% of IM-intolerant pts achieved CHR. Responses were rapid, with a median time to first HR of 1 mo. HRs were durable at 24 mos with 54% of pts maintaining their response. MCyR was achieved in 32% of pts (30% in IM-resistant, 41% in IM-intolerant) and complete cytogenetic response in 20% of pts (18% in IM-resistant, 30% in IM-intolerant). Cytogenetic responses were also durable with 70% of pts maintaining MCyR at 24 mos; 83% of pts maintained CCyR at 12 mos. Estimated OS at 24 mos was 67%. Only 9% of pts discontinued therapy due to drug-related adverse events (AE). The most frequently reported grade 3/4 laboratory abnormalities were thrombocytopenia (41%), neutropenia (42%), anemia (25%), elevated serum lipase (18%), and hypophosphatemia (14%). The rates of grade 3/4 myelosuppression were low, predictable, and easily managed with median onset of 14 to 29 days and median duration of 8 to 26 days. Grade 3/4 non-hematologic AEs were rare (< 1%) and included nausea, fatigue, and diarrhea. Conclusions: These long-term follow-up results confirm that nilotinib induces rapid and durable responses in CML-AP pts who failed prior IM due to intolerance or resistance, with a favorable risk/benefit.

A phase III study exploring various doses of imatinib (IM) or IM in combination for newly diagnosed chronic phase (CP) chronic myeloid leukemia (CML) patients (pts): Results of an interim analysis of the SPIRIT trial of French CML group.

Meeting: 2009 ASCO Annual Meeting

Citation: J Clin Oncol 27:15s, 2009 (suppl; abstr 7058)

Abstract No: 7058

Author(s): F. E. Nicolini, F. X. Mahon, J. Guilhot, A. Buzyn, M. Tulliez, C. Berthou, B. Christian, D. Guyotat, C. Preudhomme, F. Guilhot; Hôpital Edouard Herriot, Lyon, France; Fi-LMC, Poitiers, France; CHU de Poitiers, CIC 802 INSERM, Poitiers, France

Abstract:

Background: IM 400 mg daily is the front-line treatment of CP CML, but provides only 50% major molecular responses (MMR) at 18 months (Mo). We designed a phase III randomized multicenter open-label prospective trial comparing IM 400 mg/d (n=159) with 3 experimental arms: IM 600 mg/d (n=160), IM 400 mg/d + s/c cytarabine (Ara-C), (20 mg/m2/d, d15-28 of 28-day cycles) (n=158) and IM 400 mg/d + s/c Peg-IFN2a (90 µg/wk) (n=159). Pts were allocated at a 1.1.1.1 ratio, stratified by Sokal risk groups. Molecular assessments were centralized and blinded. An interim analysis of 636 pts was planned based on an IS BCR-ABL/ABL ratio <0.01% (Optimal Molecular Response, OMR) at 1 year (?=0.85%, ?=10%). Results: 636 pts were recruited between 9/2003 and 10/2007, median age ) yrs, 62% males, median follow-up for alive pts ) Mo. At 3 Mo, 88% of pts achieved complete hematologic response. Complete cytogenetic response (CCyR), MMR and OMR rates are presented (Table). MMR rates at 6 and 12 Mo were higher for IM-PegIFN as compared to IM-400 (p<10-3). At 18 Mo the cumulative OMR rates were 22% (IM-400), 28% (IM-600), 25% (IM-Ara-c), 43% (IM-PegIFN). Grade 3/4 neutropenia and/or thrombocytopenia occurred during the first year in 8% IM-400, 14% IM-600, 41% IM-Ara-C and 40% IM-PegIFN arms respectively. Grade 3/4 non-hematological toxicities occurred in 19% IM-400 (edemas, muscle cramps), 30% IM-600, 27% IM-Ara-C (diarrhea) and 31% IM-PegIFN pts (skin rashes, asthenia). Within the first 12 Mo, discontinuation of experimental treatment occurred in 8% IM-600, 39% Ara-C and 45% PegIFN pts. Conclusions: Although a significant number of pts reduced or stopped PegIFN within the first year, significant improvements in molecular response rates were observed in the IM-Peg IFN arm and may translate into survival benefit.

High-sensitivity detection of M351T, F317L, and F311C BCR-ABL kinase domain mutation in chronic myeloid leukemia patients treated with novel tyrosine kinase inhibitors (TKIs) imatinib and dasatinib

Meeting: 2009 ASCO Annual Meeting

Citation: J Clin Oncol 27:15s, 2009 (suppl; abstr 7061)

Abstract No: 7061

Author(s): A. R. Mir, S. Sazawal, A. Saxena, R. Saxena; All India Institute of Medical Sciences, New Delhi, India; MAMC , New Delhi, India

Abstract:

Objectives: (1) To study the detection of M351T, F317L, and F311C ABL kinase domain mutation in CML patients treated with TKIs (imatinib and dasatinib). (2) To evaluate the effect of imatinib dose esculation in the CML patients carrying M351T mutations. Methods: One hundred CML patients were treated with imatinib at 400 mg/day from 2 to 4 years .They were diagnosed by RT-PCR for BCR-ABL transcripts. Early screening for the M351T, F317L, and F311C mutations was performed by allele specific-oligonucleotide-PCR (ASO-PCR). Results: We evaluated 100 CML patients for kinase domain mutation by ASO-PCR after three years of imatinib initiation. Patients were categorized into three groups. Group A All 100 CML patients were treated with imatinib at conventional dose of 400 mg/day and were screened for M351T mutation after three years of imatinib initiation. (40%) 40/100 were positive for M351T mutation consequently 20/40 were treated with high dose imatinib at 600 to 800 or 1,000 mg/day. After 11 months of dose escalation, 15/20 lost M351T mutation but remaining five who resist M351T mutation, developed a more fatal mutation called gate keeper mutation T315I. 2/5 died, three progressed to advanced disease. Group B All 100 CML patients were screened for F311C mutation after three years of imatinib initiation and (10%) 10/100 were positive. After 10 months, 4/10 developed a more fatal mutation in 315 and consequently 2/4 died and one progressed to advanced disease. Group C It included 12 imatinib-resistant CML patients treated with dasatinib at 70 to 100 mg/day. At the initiation of dasatinib, no one was positive for F317L and T315I mutation. After 10 months of dasatinib treatment, all were screened for F317L/ T315I mutation by ASO-PCR, 4/12 were positive for F317L mutation and no one was positive for T315I mutation. After 6 months of mutation detection 2/4 progressed to blast crisis, and 1/4 died. Conclusions: ASO-PCR proved to be a very economical, sensitive, and rapid technique for detection of KD mutations M351T, F317L, and F311C ABL mutation and is more sensitive than mutation detection by sequencing. The detection of M351T, F317L, and F311C -ABL mutation at any stage has prognostic significance.

Effect of nilotinib on the pharmacokinetics and pharmacodynamics of warfarin.

Meeting: 2009 ASCO Annual Meeting

Citation: J Clin Oncol 27:15s, 2009 (suppl; abstr 7063)

Abstract No: 7063

Author(s): O. Yin, N. J. Gallagher, D. Fischer, L. Zhao, W. Zhou, G. Golor, H. Schran; Novartis Pharmaceuticals Corporation, Florham Park, NJ; Novartis Pharma AG, Basel, Switzerland; Novartis Pharmaceuticals Corporation, East Hanover, NJ; Parexel International GmbH, Berlin, Germany

Abstract:

Background: Nilotinib, a highly selective and potent BCR-ABL tyrosine kinase inhibitor, is approved for the treatment of CML-CP and CML-AP in patients resistant or intolerant to prior therapy including imatinib. Nilotinib has shown competitive inhibition of CYP2C9 in vitro, but its effect on CYP2C9 activity in human is unknown. This study evaluated the effects of nilotinib on the pharmacokinetics (PK) and pharmacodynamics (PD) of warfarin, a sensitive CYP2C9 substrate, in healthy subjects. Methods: Twenty-four subjects (6F, 18M, age 21-65 years) were enrolled to receive a single oral 25 mg warfarin with either 800 mg nilotinib or matching placebo (administered 30 minutes after consumption of a high-fat meal) in a cross-over design. Serial blood samples were collected post-dose for determining nilotinib, S- and R-warfarin concentrations. Prothrombin time (PT) and international normalized ratio (INR) were determined as PD measures for warfarin. CYP2C9 genotyping was performed in all subjects using TaqMan assay. Results: Sixteen subjects were identified as CYP2C9 extensive metabolizers (EM) and 8 as intermediate metabolizers (IM), but none was poor metabolizer. PK parameters of S- and R-warfarin were found to be similar between two treatments (warfarin + nilotinib versus warfarin alone) for both EM and IM groups. The geometric mean ratios (90% CIs) for the Cmax and AUC0-? of S-warfarin in all subjects were 0.98 (0.95-1.02) and 1.03 (0.99-1.07), respectively, and for R-warfarin were 1.00 (0.96-1.04) and 1.02 (0.99-1.06) respectively. Mean ratios for the maximum value and AUC of PT were 1.00 (0.96-1.04) and 1.00 (0.98-1.02), respectively, and for INR were 1.00 (0.97-1.01) and 1.00 (0.99-1.01), respectively. Nilotinib Cmax was 1872±560 ng/mL, which is comparable to the mean steady-state Cmax in CML and GIST patients receiving 400 mg BID doses. Adverse effects observed following either treatment were generally consistent with the known safety profiles of both drugs, and there were no new safety issues observed. Conclusion: The study results demonstrate a lack of effect of nilotinib on the PK and PD of warfarin, suggesting nilotinib does not inhibit CYP2C9 activity in human subjects. These findings suggest that warfarin can be used with nilotinib concurrently without the risk of bleeding.

Monitoring chronic myeloid leukemia (CML) response to tyrosine kinase inhibitors (TKI) and homoharringtonine (HHT) using peripheral blood (PB) fluorescence in situ hybridization (FISH) and quantitative RT-PCR (Q-PCR): Are bone marrow biopsies still needed?

Meeting: 2009 ASCO Annual Meeting

Citation: J Clin Oncol 27:15s, 2009 (suppl; abstr 7064)

Abstract No: 7064

Author(s): H. J. Khoury, L. Lima, D. Saxe, K. P. Mann, M. Arellano, L. Heffner, L. Bernal-Mizrachi, M. McLemore, A. Langston, E. Winton; Emory University School of Medicine, Atlanta, GA; Winship Cancer Institute, Atlanta, GA

Abstract:

Background: The purpose of this study is to compare simultaneously obtained PB and bone marrow (BM) BCR-ABL FISH and Q-PCR to monitor response to TKI and HHT in CML. Methods: Between January 2005 and December 2008, 52 patients (pts) with chronic (n = 37, 80%), accelerated (n = 6, 7%), and blast phase (n = 9, 14%) CML had 112 simultaneous PB and BM FISH and Q-PCR before and/or after start of imatinib (IM, n = 27), dasatinib (n = 9), nilotinib (n = 1), bosutinib (n = 13), or HHT (n = 2) for newly diagnosed (n = 27), IM resistant (n = 20), or IM intolerant (n = 5) CML. 13 (26%) had chromosomal abnormalities in addition to the Philadelphia chromosome, and 10 (20%) had a detectable BCR-ABL mutation including the T315I in 2 pts. Results: 24 (46%) had simultaneous PB and BM FISH and/or Q-PCR measurements obtained at 1 time point, 9 (17%) at 2; 9 (17%) at 3; 10 (20%) at > 4 time points before and/or post-initiation of TKI or HHT. Excellent concordance was observed between PB and BM at all time points for both FISH (r = 0.96; p = 0.0003) and Q-PCR (r = 0.88; p= 0.0015). Correlation was not affected by the presence of additional chromosomal abnormalities, phase of the disease, treatment (TKI or HHT), or the number of prior therapies. Conclusions: FISH and Q-PCR are reliable methods to monitor CML response to TKI and HHT in patients with CML and may render the need for BM biopsy monitoring obsolete.

Does pre-imatinib (IM) fluorescence in situ hybridization (FISH) predict myelosuppression and outcomes in chronic myeloid leukemia (CML)?

Meeting: 2009 ASCO Annual Meeting

Citation: J Clin Oncol 27:15s, 2009 (suppl; abstr 7071)

Abstract No: 7071

Author(s): L. Lima, S. E. Assouline, D. Saxe, K. Mann, M. McLemore, L. Souza, M. Arellano, E. F. Winton, L. Bernal-Mizrachi, H. J. Khoury; Emory University School of Medicine, Atlanta, GA; McGill University, Montreal, QC, Canada

Abstract:
Background: IM-associated myelosuppression occurs in 4-40% of CML patients (pts) vs. 1-16% in GIST. Selective inhibition of predominantly Philadelphia chromosome (Ph+) driven hematopoiesis may explain development of myelosuppression. In the absence of clinically applicable methods to quantitate Ph+/Ph- progenitor ratio, we hypothesized that the pre-IM percentage of BCR-ABL+ cells measured by FISH predicts myelosuppression. Methods: FISH pre-IM was available in 58 CML pts with chronic phase (CP, n=52), or advanced phase (AP, accelerated =3, blast =3) at 2 institutions. Grade >3 myelosuppression occurred < 60 days from starting IM in 9 pts (400 mg/d=6, > 600 mg/d=3), leading to dose reduction (4), discontinuation (1) or continuation same dose IM despite myelosuppression (4). Cryopreserved marrow CD34+/CD38- cells from 14 pts with (7) or without (7) post-IM myelosuppression were sorted using flow cytometry and subjected to FISH analyses. Results: Median FISH was higher for myelosuppression (90%) vs. no myelosuppression (80%) pts (p= 0.03), and in AP vs. CP (97 % vs. 80%, p=0.003). Results of FISH on CD34+/CD38- cells will be reported. Table summarizes outcomes of CP pts. Median follow-up was 14 and 45 months for myelosuppression and no myelosuppression AP pts, respectively. Myelosuppression AP pts expired (CML=2, GVHD=1); 1 after complete hematologic (CHR) and minor cytogenetic response (CTGR), 1 after partial HR, and 1 resistant disease. All 3 pts without myelosuppression achieved CHR with major CTGR, and 2 had partial molecular response. 1 died from GVHD. Conclusions: Higher FISH pre-IM identifies a group of CML pts who develop myelosuppression and are less likely to respond to IM.

Imatinib mesylate experience of young patients with chronic myeloid leukemia in chronic phase—Care to cure.

Meeting: 2009 ASCO Annual Meeting

Citation: J Clin Oncol 27:15s, 2009 (suppl; abstr 7072)

Abstract No: 7072

Author(s): D. Biswajit, R. Rejiv, N. Manjunath, G. Prasad, S. Lakshmi, P. Devika, K. Geetha, T. G. Sagar; Cancer Institute (WIA), Chennai, India

Abstract:

Background: Chronic myeloid leukemia (CML) with introduction of imatinib has been transformed into a chronic illness. The options of treatment in a patient less than 35 years include imatinib or allogenic stem cell transplantation. Hence we studied this unique subset to look at the response rates, adverse effects, progression free survival, and overall survival with imatinib mesylate. Methods: 477 patients with Philadelphia positive CML in chronic phase were retrospectively analyzed from January 2002 to December 2007 at Cancer Institute (WIA), Chennai, India. Standard criteria were used for response evaluation and adverse effects. Results: A total of 248 young CML patients with age less than 35 years (51.9%) were diagnosed in chronic phase. The median age of study population was 27 years (4-35). The male to female ratio was 1.9: 1. Risk stratification was done using Sokal index and were classified into low (32.3%), intermediate (50.4%), and high (17.3%). All patients received imatinib 400 mg as the initial dose. Complete hematological remission (CHR) was seen in 96.7%.Cytogenetic (FISH) and molecular (RTPCR) monitoring was possible in 53.2% and 17.3%, respectively. 72% of the patients had major cytogenetic response. Major molecular response was seen in 34.8% while complete molecular response occurred in 23.2% of the patients. Primary and secondary imatinib failure was seen in 3.1% and 16.9%, respectively. 6.7% had grade 3 and grade 4 hematological toxicities. The other common non hematological toxicities included pedal edema (13.7%), hypo or hyper pigmentation (60.0%), hyalgia (14.5%), diarrhea (1.6%), and liver dysfunction (1.6%). None of the patients discontinued imatinib due to toxicities. The 3-year DFS and OS was 86.2% and 89.5%, respectively. Patients with male sex (p = 0.04), spleen > 8 cm (p = 0.02), high sokal index (p = 0.02), and loss of CHR (p < 0.001) were associated with poor outcome. Conclusions: Imatinib in young patients have an excellent tolerance and response. A small subset does not respond to therapy or develop resistance during treatment. Hence it is essential to identify these poor responders and to offer stem cell transplantation at the earliest.

Molecular responses with nilotinib 800 mg daily as first-line treatment of chronic myeloid leukemia in chronic phase: Results of a phase II trial of the GIMEMA CML WP.

Meeting: 2009 ASCO Annual Meeting

Citation: J Clin Oncol 27:15s, 2009 (suppl; abstr 7074)

Abstract No: 7074

Author(s): G. Martinelli, F. Castagnetti, A. Poerio, M. Breccia, F. Palandri, G. Alimena, F. Pane, G. Saglio, M. Baccarani, G. Rosti; Institute of Hematology L and A Seragnoli, Bologna, Italy; University of Rome – La Sapienza, Rome, Italy; CEINGE, University of Naples Federico II, Naples, Italy; Department of Clinical and Biological Science, Orbassano, Turin, Italy; Instituteof Hematology L and A Seragnoli, Bologna, Italy

Abstract:

Background: Nilotinib has a higher binding affinity and selectivity for Abl with respect to imatinib (IM). To investigate the efficacy and the safety of nilotinib 400 mg BID in untreated, early chronic phase (ECP) CML patients (pts), the GIMEMA CML WP is conducting a multicentric, phase II study trial (ClinicalTrials.gov NCT). Methods: 73 pts have been enrolled between June 2007 and February 2008. The median age was 51 years (range 18-83). Median follow-up is currently 210 days (range 68-362). Results: All 73 pts and 48/73 (66%) completed 3 and 6 months on treatment, respectively. Response at 3 and 6 months (ITT): CHR rate was 100% and 98%, CCgR rate 78% and 96%, respectively. A MMR was achieved by 3% after 1 month on treatment, but this proportion rapidly increased to 22% after 2 months, 59% after 3 months and 74% after 6 months. One patient progressed at 6 months to accelerated-blastic phase with the T315I mutation. The median daily average dose was close to the intended dose, 789 mg (range 261 - 800); 34/73 pts (47%) interrupted nilotinib at least once, with a median interruption of 15 days (range 2-98). The dose of nilotinib at the last visit was 400 mg BID for 52 pts (71%), 400 mg daily for 20 pts (27%), and 200 mg daily for 1 patient (1%). AEs (grade 3/4) were manageable with appropriate dose adaptations: hematologic toxicity was recorded so far in 4 pts (5%); the most frequent biochemical laboratory abnormalities (grade 3) were total bilirubin increase (15%), GOT/GPT increase (11%), and lipase increase (4%). Only 1 episode of grade 4 lipase increase was recorded. It is noteworthy, considering the 48 cases with at least 6 months of follow-up, that the incidence of any grade 2 and 3 non-hematologic adverse event, decreased from 50% and 8% (first 3 months) to 23% and 6% (second trimester), respectively. In 16 pts (22%), transient and not clinically relevant ECG abnormalities have been recorded; 2 more pts (3%) revealed a transient and uneventful QTc prolongation (>450 but <499 msec). Conclusions: In ECP Ph-pos CML pts both cytogenetic and molecular responses to nilotinib are substantially faster than the responses to IM.

Inadequate BCR-ABL monitoring in imatinib-treated patients with chronic myelogenous leukemia.

Meeting: 2009 ASCO Annual Meeting

Citation: J Clin Oncol 27:15s, 2009 (suppl; abstr 7077)

Abstract No: 7077

Author(s): E. Stanek, R. E. Aubert, C. Sanders, F. W. Frueh, J. Yao, R. S. Epstein; Medco Health Solutions, Inc., Franklin Lakes, NJ

Abstract:

Background: Recommendations for baseline and quarterly measurement of the BCR-ABL fusion transcript to monitor imatinib response in patients with chronic myelogenous leukemia (CML) were formally introduced in October 2006, and have been incorporated into nationally recognized treatment guidelines. Methods: To assess BCR-ABL testing rates, we conducted a retrospective cohort analysis using a >10 million-member health plan database comprised of integrated pharmacy and medical claims. The study cohort was defined as patients with an index imatinib pharmacy claim from July 1, 2006, to December 31, 2006, who had a CML diagnosis (ICD-9 205.1X; N = 504), and a minimum of 3 months continuous follow-up by claims history (N = 465). Over a period of up to four quarters from the index imatinib prescription date, BCR-ABL testing in each quarter was assessed by the presence of any of a set of 19 CPT-4 codes. BCR-ABL testing rates in each individual quarter and in consecutive quarters were measured. Results: The overall study cohort was 57% male; mean (±SD) age was 52±14 y/o, with 26% 19-44 y/o, 57% 45-64 y/o, and 15% ?65 y/o. Median duration of f/u was 559 days (interquartile range 302-628 days), and a cohort of 359 patients had 4 quarters of f/u. At least one BCR-ABL test was recorded in 60% of patients. The rate of first quarter BCR-ABL testing was 40%, and remained at 42%-43% in quarters 2 thru 4. Consecutive quarterly testing rates were 24% through the second quarter, 18% through the third quarter, and 14% through the fourth quarter. Conclusions: In this retrospective claims database analysis, only 14% of a large cohort of CML patients treated with imatinib had BCR-ABL testing recorded in each of 4 consecutive quarters. Inadequate compliance with recommended BCR-ABL testing can delay treatment decisions, and may be associated with poor clinical outcome.

Innovative phase I study of concomitant and consecutive treatment with dasatinib and MK-0457 in refractory Ph+ CML and ALL patients.

Sub-category: Leukemia

Meeting: 2009 ASCO Annual Meeting

Citation: J Clin Oncol 27:15s, 2009 (suppl; abstr 7080)

Abstract No: 7080

Author(s): C. Papayannidis, I. Iacobucci, S. Soverini, S. Paolini, D. Cilloni, F. Messa, F. Pane, E. Ottaviani, M. Baccarani, G. Martinelli; Department of Hematology/Oncology Seràgnoli - University of Bologna, Bologna, Italy; Department of Clinical and Biological Science, Orbassano, Turin, Italy; CEINGE Biotecnologie Avanzate, Naples, Italy

Abstract:

Background: MK-0457 is a pan-aurora kinase inhibitor with activity against wild-type and mutated BCR-ABL, including the T315I form, FLT3, and JAK-2. Methods: We conducted an innovative Phase I clinical study of sequential and concomitant treatment with dasatinib, previously administered for 3 months, and MK-0457. This combined activity suggests that MK-0457, in association with dasatinib, would suppress the emergence of T315I and other resistant clone, improving upon the response rate for dasatinib and the durability of response. The trial investigated two schedules of therapy: patients who achieved and maintained a major hematologic response (MHR) after 3 months of therapy with dasatinib (70 mg twice daily) received a 6-hour biweekly infusion of MK-0457 at 64 mg/m2/hr, whereas patients who failed to achieve a MHR received a 5-days continuous infusion of MK-0457 at 10 mg/m2/hr, every 4 weeks. Results: Two patients with Ph+ ALL and one patient with CML in myeloid blast crisis, previously unsuccessfully treated with imatinib, were enrolled. The first two patients, both in hematologic response after three months of treatment with dasatinib, subsequently received the 6-hour biweekly schedule, maintaining the hematological response. No hematological toxicity was described. The third patient, in progression disease, received the 5 days MK-0457 schedule. His peripheral blood count showed a severe pancytopenia, and his bad clinical conditions were compromised by a severe hemorrhagic pleural effusion. After one cycle of MK-0457, a complete recovery of the pulmonary disease and a complete hematologic response were obtained. Conclusions: The sequential and concomitant administration of dasatinib and MK-0457 represents a promising therapeutic strategy for refractory Ph+ CML and ALL.

Supported by: European LeukemiaNet, AIL, AIRC, FIRB 2006, Fondazione del Monte di Bologna e Ravenna, Merck Sharp & Dohme.

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