Accelerated Phase Pts Research Articles

Incidence and outcomes of chronic myeloid leukemia (CML) patients (pts) treated with second-generation tyrosine kinase inhibitors (TKI) who develop other chromosomal abnormalities (OCA).

7090 Background: Development of OCA has been reported among pts receiving imatinib as initial therapy for CML. Little is known about OCA development in CML pts treated with frontline 2nd generation TKI (dasatinib, nilotinib). Methods: OCA is defined as cytogenetic abnormality in non-Philadelphia chromosome positive clones as pts respond to TKI. Among pts treated with frontline dasatinib (n=99) or nilotinib (n=117), on parallel prospective single-arm phase II protocols at MDACC, 30 OCA ptswere identified, chronic (n=25) or accelerated phase (AP) (n=5). Results: 11 (11%) pts treated with dasatinib and 19 (16%) with nilotinib developed OCA; median follow-up 30 mo (range 0-71). Difference in OCA incidence with dasatinib and nilotinib was not statistically significant. At start of therapy, median age (years) of OCA pts was 53 (41-71) with dasatinib and 52 (37-82) with nilotinib, compared to those pts without OCA: 48 (18-83) with dasatinib and 49 (17-87) with nilotinib. Most common OCA was abnormality of chromosome 7 with 6 occurrences in 5 pts (1 pt with both inv(7) and +7) (inversion (n=1), 2 different translocations (n=2), deletions (n=2), and additions (n=1)). No pts developed trisomy 8 (historically most common OCA in imatinib-treated pts). Median time to first OCA: 9 mo (range 3-58) for all pts (12 mo (range 3-58) for dasatinib group and 9 mo (3-48) for nilotinib group). OCA disappeared spontaneously in 25 pts during follow-up. Outcomes for OCA versus non-OCA group (Table). For AP pts: 3/6 (50%) in dasatinib group and 2/17 (12%) in nilotinib group developed OCA. None of the OCA pts has developed AML or MDS. Conclusions: OCA is observed in 10-15% of pts receiving initial therapy with 2nd generation TKI. At median follow-up of 30 mo, occurrence of OCA confers no adverse impact on outcomes when compared to non-OCA pts treated with 2nd generation TKI and has not resulted in other hematologic disorders. [Table: see text]

Phase 2 Study of Dasatinib in Chinese Patients (Pts) with Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) or Advanced Phase Who Are Resistant to or Intolerant of Imatinib (IM)

Abstract 4434 Background:CML has a lower incidence in China than in Western countries and appears to affect a younger population (Au, Int J Hematol 2009). In recent years, IM has become the first-line standard of care across Asia for pts with newly diagnosed CML. In a cohort of Chinese pts, >25% of evaluable pts in CP failed to achieve a CCyR with first-line IM, and response rates were significantly lower in pts with accelerated-phase (AP) or blast-phase (BP) CML (Wang, J Exp Clin Cancer Res 2010). Dasatinib is a highly potent second-generation BCR-ABL inhibitor that has established efficacy and safety in pts with CML or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) after prior imatinib therapy. Dasatinib is approved by various regulatory authorities worldwide for first-line treatment of Philadelphia chromosome-positive (Ph+) CML in CP. Limited efficacy and safety data are available for second-generation BCR-ABL inhibitors in Chinese pts with CML or Ph+ ALL after imatinib therapy. Methods:In an open-label, single-arm phase 2 study, Chinese pts aged ≥18 years with IM resistant/intolerant CML or Ph+ ALL received dasatinib 100 mg once daily (CP) or 70 mg twice daily for AP/BP or Ph+ ALL. Bone marrow cytogenetic evaluation was performed at months 3 and 6, then every 6 months in CP pts, and was optional for pts with AP/BP or Ph+ ALL. Primary study objectives were to assess rates of major cytogenetic response (MCyR) in CP pts and complete and overall hematologic response (CHR and OHR) in pts with AP/BP or Ph+ ALL. OHR was defined as CHR, no evidence of leukemia, or return to CP. Treatment continued until disease progression or intolerable toxicity. Results:Of 140 enrolled pts, 121 pts had received ≥1 dose of dasatinib and were evaluable (59 with CP, 25 with AP, 35 with BP, and 2 with Ph+ ALL). Of pts with CML-CP or AP/BP/Ph+ ALL, 52 (88%) and 53 (85%) were IM resistant, 4 (7%) and 5 (8%) were IM intolerant, and 3 (5%) and 4 (6%) were both IM resistant and intolerant. Median time from original CML diagnosis to first dasatinib dose was 46.3 months (CP) and 50.2 months (AP/BP/Ph+ ALL). More than half of pts had received prior interferon therapy. At last follow-up, dasatinib therapy had been discontinued by 7 pts (12%) with CP and 43 pts (69%) with AP/BP/Ph+ ALL, due to disease progression or loss of response in 2% and 35%, study drug toxicity in 2% and 11%, stem-cell transplant in 0% and 5%, death in 2% and 2%, and other reasons in 7% and 16%, respectively. After a minimum of 12 months follow-up, MCyR was achieved by 30 pts with CP (51%), 10 pts with AP (40%), and 8 pts with BP/Ph+ ALL (22%). In pts with CP, median time to MCyR was 12 weeks and no patient lost MCyR. Complete cytogenetic response was achieved by 25 pts with CP (44%), 7 pts with AP (28%), and 6 pts with BP/Ph+ ALL (16%). CHR was achieved by 54 pts with CP (92%), 13 pts with AP (52%), and 6 pts (16%) with BP/Ph+ ALL. In CP pts, most (51/54) who achieved CHR did so within 2 months. Median times to CHR were 16 and 12 weeks for pts with AP and BP/Ph+ ALL, respectively. After 12 months, 3 pts in CP, 2 pts in AP, and 1 pt in BP had lost their CHR. OHR was achieved by 23 and 13 pts (92% and 35%) with AP and BP/Ph+ ALL, respectively. In safety assessments (Table), grade 3/4 cytopenia was frequent but managed by dose interruption/reduction or supportive care, with 1 pt discontinued for cytopenia. Pleural effusion of any grade occurred in 15%, 20%, and 22% of pts with CP, AP, and BP/Ph+ ALL, respectively. Grade 3/4 pleural effusion occurred in 1 pt with CML-CP (2%) and 5 pts with AP/BP/Ph+ ALL (8%). Conclusions:The current study confirms the efficacy and safety of dasatinib in Chinese pts with CML or Ph+ ALL that is resistant or intolerant to IM. Results were consistent with data from global trial populations.Table:Drug-related nonhematologic AEs and hematologic AEs by disease stagePatients, n (%)CP (n=59)AP (n=25)BP/Ph+ ALL (n=37)Nonhematologic AEsAny grade31 (53)18 (72)30 (81)Grade 3/47 (12)12 (48)21 (57)AE types (any grade, ≥10% of any disease group)Pleural effusion9 (15)5 (20)8 (22)Lung infection1 (2)4 (16)5 (14)Pneumonia0 (0)3 (12)1 (3)Headache12 (20)3 (12)1 (3)Diarrhea4 (7)5 (20)3 (8)Pyrexia1 (2)2 (8)7 (19)Grade 3/4 hematologic AEsNeutropenia31 (53)22 (88)29 (78)Thrombocytopenia36 (61)20 (80)33 (89) Disclosures:No relevant conflicts of interest to declare.

Effect of Nilotinib (NIL) on Molecular Response in Chronic Myelogenous Leukemia - Chronic Phase (CML-CP) Patients (pts) with a Suboptimal Molecular Response to Imatinib (IM)–ENABL Study Update

Effect of Nilotinib (NIL) on Molecular Response in Chronic Myelogenous Leukemia - Chronic Phase (CML-CP) Patients (pts) with a Suboptimal Molecular Response to Imatinib (IM)–ENABL Study Update

Nilotinib Responses and Tolerability Confirmed in North American Patients with Chronic Myeloid Leukemia (CML) From ENACT (Expanding Nilotinib Access in Clinical Trials).

Abstract 3295 Poster Board III-1 Background: Nilotinib is a potent and highly selective BCR-ABL kinase inhibitor, approved for the treatment of patients (pts) with Philadelphia chromosome-positive chronic myelogeneous leukemia (Ph+ CML) in chronic phase (CP) and accelerated phase (AP) who are resistant or intolerant to prior therapy, including imatinib. The open label, multicenter ENACT study was initiated as a global expanded access program to obtain additional safety information in CML pts in a clinical practice setting outside of a registration study. This report focuses on a subset of patients enrolled in North America. Methods: Adult patients with imatinib resistant or -;intolerant Ph+ CML-CP, AP or BC were admitted to the study. The definition of imatinib resistance and intolerance were the same as the pivotal phase II registration study and pts could have been previously treated with other TKIs in addition to imatinib. Patients with impaired cardiac function, concurrent severe medical conditions or taking prohibited medications were excluded. Pts received nilotinib 400 mg twice daily (BID). Dose escalation was not permitted. Pts who required dose reduction to 400 mg once daily due to toxicity were allowed to have a dose re-escalation to 400 mg BID after resolution of the adverse events (AEs), lack of response, or persistent disease at the investigator's discretion. Results: A total of 207 North American pts were enrolled in the ENACT study between 01/2006 and 10/2008, including 172 CP pts (83%), 15 AP pts (7%) and 20 BC pts (10%). The median age of all pts was 54 years; 53% were imatinib-resistant, 45% were imatinib-intolerant, and 1.4% were resistant/intolerant. The most common prior anti-neoplastic therapy (other than imatinib) was hydroxyurea (73% of CP pts, 87% of AP pts, and 90% of BC pts), followed by dasatinib (32% of CP pts, 40% of AP pts, and 30% of BC). At study completion, 100 pts (48%) were continuing on nilotinib and 107 pts (52 %) discontinued treatment; 29 (17%) CP pts, 7 (47%) AP pts, and 14 (70%) BC pts discontinued due to disease progression. There were a total of 7 (3.4%) deaths during the study. Patient disposition is summarized in Table 1. Median (range) duration of nilotinib exposure was 227 (1-807) days for CP pts, 78 (15-426) days for AP pts, and 73 (8-571) days for BC pts; median average dose intensity was 766, 785 and 766 mg/day, respectively. Thirty-five CP pts (20%), 3 AP pts (20%) and 6 BC pts (30%) had their dose reduced due to AE, while 75 CP pts (44%), 5 AP pts (33%), and 8 BC pts (40%) had their dose interrupted due to AE. Median duration of dose interruption due to AE was short (8 days for CP and BC pts and 3 days for AP pts). The most common grade 3/4 hematologic AEs suspected of being drug related were thrombocytopenia (12% of CP pts, 20% of AP pts, and 15% of BC pts) followed by neutropenia (9% of CP pts, 27% of AP pts, and 15% of BC pts). The most frequent non hematologic all grades AEs or lab abnormalities included rash, headache, nausea, fatigue and hyperbilirubinaemia, and all were slightly higher in North American patients compared with the overall ENACT population. No patients discontinued treatment due to pleural effusion and there was no incidence of QTcF prolongation > 500 msec. Overall, major cytogenetic responses (MCyR) rates were 49% in CP, 27% in AP and 20% in BC pts, while complete cytogenetic responses (CCyR) rates were 36% in CP, 7% in AP and 20% in BC pts. Conclusions: ENACT is the largest dataset from a single CML study of the available TKIs that further demonstrates that nilotinib is generally well tolerated in pretreated patients in all phases of CML. The safety profile in this study is similar to that observed the pivotal phase II registration study, as are the cytogenetic response rates, with a maintenance of high dose intensity. This data supports the use of nilotinib at 400 mg BID as the recommended dose in these CML populations. Disclosures: Powell: Novartis Pharmaceuticals: Research Funding. Khoury:BMS: Honoraria; Wyeth: Honoraria; Novartis Pharmaceuticals: Honoraria; Chemgenex: Honoraria; Genzyme: Honoraria. Rizzieri:Novartis Pharmaceuticals: Honoraria, Research Funding, Speakers Bureau. Williams:Novartis Pharmaceuticals: Employment. Turner:Novartis Pharmaceuticals: Research Funding, Speakers Bureau; BMS: Research Funding, Speakers Bureau; wyeth: Research Funding.

Efficacy of Nilotinib in Patients (Pts) with Newly Diagnosed, Previously Untreated Philadelphia Chromosome (Ph)-Positive Chronic Myelogenous Leukemia in Early Chronic Phase (CML-CP).

Abstract 341▪▪This icon denotes an abstract that is clinically relevant. Background:Nilotinib, an oral tyrosine kinase inhibitor with increased selectivity against Bcr-Abl and approximately 30-fold more potent than imatinib, is effective in CML after imatinib failure. We initiated a phase II study to evaluate the efficacy of nilotinib as 1st line therapy in pts with newly diagnosed CML-CP. Aims:To investigate the efficacy and safety of nilotinib as first-line therapy for pts with CML-CP. Methods:The primary objective was to estimate the proportion of pts attaining major molecular response (MMR) at 12 months (mo). Pts with untreated CML-CP within 6 mo from diagnosis were eligible and received nilotinib 400 mg twice daily. A cohort of patients with previously untreated CML in accelerated phase (AP) was also included. Results:Sixty-five pts (61 CP, 4 AP) have been treated for a median of 17 mo (range 1 to 43). The median age was 46 years (range 19 to 86). Among 48 pts who were not in CHR at the start, 47 (98%) achieved CHR (one discontinued after 2 weeks without adverse events). Among 51 pts followed for at least 3 mo, 50 (98%) achieved a complete cytogenetic response (CCyR). MMR has been achieved in 32 (63%) pts, including 12 (24%) with a complete molecular response. The rate of CCyR at different time points (intention-to-treat) for pts in CP compares favorably to that observed in historical controls treated with imatinib 400 mg or 800 mg daily:Months on therapyPercent with CCyRNilotinibImatinib 400mgImatinib 800mg3903763696548512976589189367892493678830926789MMR was achieved by 55% at 12 mo and 53% at 24 mo (corresponding rates with imatinib 400 mg 34 and 55%, and with imatinib 800 mg 58% and 66%, respectively). Grade 3-4 hematologic toxicity (transient) included thrombocytopenia 11%, neutropenia 12%, and anemia 5%. Grade 3-4 non-hematologic adverse events (regardless of causality) included elevation of bilirubin in 8% and lipase in 6%, and non-neutropenic fever in 6%. 24 (37%) pts had transient treatment interruptions and 11 (17%) had dose reductions. The actual median dose is 800 mg daily. Ten pts have discontinued therapy: 4 pts for toxicity, 2 because of transformation to accelerated or blast phase, and 4 for other reasons. 24 mo EFS (event = loss of CHR, loss of MCyR, AP/BP, death, or off because of toxicity) is 90%. All patients are alive. Among pts in AP, 3 achieved CCyR (all of them sustained); one patient progressed to blast phase and died. Conclusion:Nilotinib 400 mg twice daily induces a CCyR in nearly all patients as early as 3 mo after the start of therapy and MMR in more than 50% at 12 months with a favorable toxicity profile. Disclosures:Cortes:BMS: Research Funding; Novartis: Research Funding; Wyeth: Research Funding. Off Label Use: Presentation will include use of nilotinib as initial therapy for CML, and indication for which nilotinib is not approved.. O'Brien:Novartis: Research Funding. Jones:Novartis: Research Funding, Speakers Bureau. Jabbour:Novartis: Speakers Bureau; BMS: Speakers Bureau. Borthakur:Novartis: Speakers Bureau. Kantarjian:Novartis: Research Funding; MGI Pharma (Eisai): Research Funding; Genzyme: Research Funding; BMS: Research Funding.

Lower Healthcare Resource Utilization Associated with Managing Nilotinib Related Adverse Events in Chronic Myeloid Leukemia (CML) Patients – Evidence From a Clinical Practice Setting Study.

Abstract 4285 BackgroundOnly few studies have characterized the healthcare burden associated with managing adverse events (AEs) in the second-line treatment of CML. Information on incidence of AEs and resource utilization in managing these events would be valuable treatment related attributes. Nilotinib is a potent and selective BCR-ABL kinase inhibitor that is approved for the treatment of Ph+ CML patients in Chronic Phase (CP) and Accelerated Phase (AP), who were intolerant or have failed previous imatinib treatment. Dasatinib is another approved second-line agent in the treatment of imatinib resistant or intolerant CML. Nilotinib and dasatinib have shown differences in their safety profiles in clinical trials. ObjectivesThis study compared the safety profile of nilotinib, observed in a large study of CML patients in a clinical practice setting from participating North American sites to product information of nilotinib and dasatinib, and also compare potential cost differences between the two settings. MethodsAdult patients with imatinib resistant or intolerant Ph+ CML in CP, AP, and blast crisis (BC) were recruited to participate in this phase IIIb, open label, multi-center ENACT (Expanding Nilotinib Access in Clinical Trials) study. Data obtained from the participating North America sites is presented here. Patients who previously failed dasatinib treatment were also allowed to participate. The primary objective of the ENACT study was to obtain additional safety information with nilotinib treatment in a clinical practice setting. Patients received nilotinib 400 mg twice daily (BID). Patients were not permitted to dose escalate. A comprehensive set of hematological and non-hematological adverse event information was obtained in the study. Follow-up treatment in managing the AE, either as dose reduction, dose interruption, or other treatment is also recorded. Incidence of adverse events reported in this study was compared to nilotinib and dasatinib product information. Healthcare resource utilization was estimated from a US health plan perspective by constructing six-month marginal cost increase in patients who received follow-up care for the management of adverse event. Cost data were obtained from MedStat market scan database that contained over 5,000 CML patients. Multivariate regression models and sensitivity analyses were conducted to derive the marginal cost estimates. ResultsA total of 207 patients (172 CP pts, 15 AP pts, and 20 BC pts) were enrolled in the study from several sites in North America between Jan 2006 – Oct 2008. The median age was 54 years. At study completion, 48% were continuing on study treatment, 25% discontinued treatment due to unsatisfactory therapeutic effect, 14% discontinued due to AEs, and 13% discontinued due to other reasons. Percentage of patients with grade 3/4 hematological AEs suspected of being study drug related in CP, AP were: thrombocytopenia (12%, 20%), neutropenia (9%, 27%) and anemia (1.2%, 13%). The most frequent non hematologic AEs (all grades) included rash, headache, nausea, and fatigue. Study patients requiring additional therapy for the reported hematological adverse events was less than 50% in most cases. Dose reductions and dose interruptions of greater than 5 days to manage AEs occurred in 2.3% and 32% patients, respectively, with median duration of dose interruption of 12 days in CP patients and 7 days in AP patients. Total medical costs associated with managing the adverse events, estimated from MedStat cost data, for both hematological and non-hematological AEs observed in this analysis based on patients receiving additional treatment were $6,314 for CML patients in CP and AP, over a six-month treatment period. Medical costs associated with managing hematological adverse events made up the majority of these costs. The estimated costs from this study were significantly lower compared to the estimated burden of the AEs in the product information for nilotinib or dasatinib ($9,730 and $12,372, respectively). ConclusionsNilotinib related adverse event costs observed in this large clinical practice setting study compare favorably to the estimated costs from product information from nilotinib and dasatinib. The analysis is comprehensive in estimating the healthcare costs by characterizing the incidence of the AEs, and managing of the AEs through dose reductions, dose interruption or follow-up care. Disclosures:Guerin:Novartis: Consultancy, I am working for Analysis Group Inc and Analysis Group Inc received funds from Novartis to conduct the analysis. Bollu:Novartis Oncology: Employment. Williams:Novartis Pharmaceuticals: Employment.

Long-Term Efficacy of Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) in Patients (pts) with Advanced Chronic Myeloid Leukemia (CML) Post Imatinib Failure.

Allogeneic HSCT is a potentially curative treatment for pts with CML, and is effective after imatinib failure. We assessed the long-term results of HSCT in 92 consecutive pts with CML that had failed imatinib. Herein are the results of this review. Preparative regimens were reduced-intensity intravenous (IV) busulfan (Bu)-fludarabine (Flu) in 40 pts, IV Bu-cyclophosphamide in 39, Flu-melphalan in 6, and total body irradiation (TBI) based regimens in 7. Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus and mini-methotrexate 5 mg/m2. Donors were matched related in 49 (53%) and matched unrelated in 43 (47%). Prior to HSCT, 43 (47%) pts received imatinib therapy after interferon failure and 49 (53%) as frontline therapy. At the start of imatinib therapy, 48 (52%) pts were in chronic phase (CP), 23 (25%) in accelerated phase (AP), and 21 (23%) in blastic phase (BP). Median time on imatinib before HSCT was 15 months (range, 2–50). Best response to standard-dose imatinib was complete cytogenetic response (CCyR) in 32 (35%), partial (PCyR) in 10 (11%), minor (mCyR) in 10(11%), and complete hematologic response (CHR) in 25 (27%). Median age at HSCT was 43 years (range, 14–69). At HSCT, 30 pts were in CP (33%), 27 in AP (29%), 17 in BP (18%), and 18 in second CP (20%). Pts were followed for a median of 48 months (range 4–93) from HSCT. All but 2 pts engrafted within a median of 12 days (range, 5–20). Acute GVHD was observed in 42 (46%) pts (Grade I in 15, Grade II/III in 19, Grade IV in 8). Chronic GVHD was observed in 35 pts (extensive in 20). Chimerism studies at day 30 post HSCT were available in 81 pts and were 100% of donor type in 61 (75%) and mixed in 20 (25%). Seventy-nine pts (86%) responded (100% for pts in CP, 93% for pts in AP, 94% for pts in 2nd CP, 41% for pts in BP). Sixty-three pts achieved a major molecular response (MMR), complete (CMR) in 60; 16 achieved a CCyR only. Of the 30 pts in CP that responded, 2 (7%; both achieved a CMR) relapsed, 9 and 24 months post HSCT. Of the 25 pts in AP who responded, 8 (32%: 6 CMR, 2 CCyR) relapsed after a median of 13 months (range, 2–51) post HSCT. Of the 17 pts in 2nd CP who responded, 6 (35%; 2 CMR, 4 CCyR) relapsed. Of the 7 pts in BP who responded, 4 (57%; 4 CMR) relapsed after a median of 16 months (range, 3–45) post HSCT. At the last follow-up, 49 (53%) pts were alive and 43 (47%) died. Causes of death included progressive disease in 29, GVHD in 6, infections in 5, diffuse alveolar hemorrhage in 2, and unknown cause in 1. One and 2-year survival rates were 65% and 54%. The median survival for pts in BP, 2nd CP, and AP were, 4, 14, and 72 months, respectively. The median survival for pts in CP has not been reached. The estimated 1- and 4-year survival by disease stage is as follows : BP, 24% and 12%; 2nd CP, 67% and 49%; AP, 67% and 62%; CP 87% and 74%, respectively.In conclusion, HSCT remains an effective salvage strategy post imatinib failure, and disease stage at HSCT remains the stronger prognostic factor.Response to allogeneic HSCT (MMR, major molecular response; CMR, complete molecular response; CCyR, complete cytogenetic response)CPAP2nd CPBPN30271817MMR (%)83706741CMR (%)77676741CCyR (%)100939541Relapse rate (%)7323557Median survival (mos)NR721441- and 4-year survival (%)87 & 7467 & 6267 & 4924 & 12

Molecular Predictive Markers in Dose Escalation Treatment for Suboptimal Responders to Standard Dose Imatinib in CML

Introduction Imatinib mesylate (IMT) dose escalation has been proposed as a therapeutic option in patients (Pts) with chronic myeloid leukemia (CML) who failed to achieve optimal response with standard dose IMT. We report the results of prospective multi-center single arm phase ¥≥study evaluating efficacy of escalated dose IMT. We intended to identify patterns of molecular change using serial quantitative RT-PCR and its relationship with clinical outcome. We also planned to find predictive markers for outcome with array comparative genomic hybridization (aCGH) and epigenetic study of bcr gene in addition to BCR/ABL mutation.Patient and methods Pts in chronic phase (CP) CML who failed to achieve optimal response by European LeukemiaNET with adequate organ function were enrolled. Pts in accelerated phase (AP) or blast crisis (BC) who failed to achieve complete hematologic response after 3 months of IMT were also eligible. CP Pts received 600mg daily, while Pts in AP or BC received 600 or 800mg IMT daily. Pts received IMT for at least 12 months or until the appearance of a progressive disease, intolerable toxicity. Along with cytogenetic response (CyR), molecular response (MR) was assessed with BCR-ABL/ABL gene ratio of peripheral blood or bone marrow aspirate. Baseline BCR/ABL gene mutation test was performed using Matrix-assisted laser desorption/ionization time of flight mass spectrometry. Genome-wide screening for regions of genetic gains and losses with baseline blood samples was performed for 38 Pts using aCGH. Methylation status of 4 CpG sites in bcr gene promoter region was tested for 40 Pts and average methylation level was used for analysis. Blood samples at baseline and 6 months after dose escalation were tested. 29 optimal responders to standard dose IMT and 38 healthy donors were also tested for bcr methylation status for additional comparison.Results 71 Pts (median age 49.0 years, M:F=50:21) received escalated dose IMT. Median time to treatment failure (TTTFx) was 18.0 months and toxicities were manageable. 44 and 52 Pts were evaluable for FISH at 6 months and 1 year, where 16 and 17 Pts showed complete CyR (CCyR) respectively. For 61 Pts with serial MR data, TTTFx was longer in Pts who achieved molecular reduction of more than 50% within 6 months (Molecular early responder: MER) than who didn't (p<0.001). MER's achieved CCyR more frequently at 6 months and 12 months (p=0.010, <0.001 respectively). Of 24 Pts who had mutational status data, 4 had mutation. They experienced TFx within 12 months and all failed to achieve CCyR. aCGH revealed significant copy number (CN) gain in chromosome 16p11.2 in MER's compared to non-MER's (p=0.034). Tendency for increased CN in 22q11.23 and decreased CN in 17q12 was observed in MER's without reaching statistical significance (p=0.072 and 0.070 respectively). 4 candidate genes within the above regions – GSTT1, SULTA1A, PYCARD, TADAZL – were evaluated for CN variation. GSTT1 CN loss was more frequently observed in MER's (p=0.035). GSTT1 CN loss also predicted the longer TTTFx without reaching statistical significance (p=0.086). In epigenetic study, Pts in PCyR at the time of study enrollment had increased baseline bcr methylation compared to Pts in less than PCyR (p<0.001). Pts who had increased amount of bcr methylation at 6 months compared to baseline had longer TTTFx compared to who did not (p=0.012). Baseline bcr methylation amount of study Pts was lower when compared to that of optimal responders and healthy donors (p=0.001 and p<0.001 respectively). bcr methylation decreased with increased duration of standard dose IMT both in study Pts and optimal responders (p=0.042 and 0.004 respectively), although the pattern of decrease was different between the two groups (p<0.001). In multivariate analysis baseline bcr methylation status was the only variable related to TTTFx (p=0.047).Conclusion Escalated dose IMT is a reasonable option for CML Pts showing less than optimal response to standard IMT. MER after escalated dose IMT is a useful early predictive marker for long term response. Mutational status of BCR-ABL at baseline is possibly important for response. Chromosome 16p11.2, 22q11.23 and 17q12 are potential locations related to IMT response and GSTT1 CN loss may be a genetic change affecting clinical outcome. bcr methylation status is an epigenetic marker associated with IMT response, where decreased bcr methylation status is related to poor IMT response.

Safety and Efficacy of Subcutaneous (SC) Omacetaxine Mepesuccinate in Imatinib(IM)-Resistant Chronic Myeloid Leukemia (CML) Patients (pts) with the T315I Mutation – Results of An Ongoing Multicenter Phase II Study.

Background: Omacetaxine (homoharringtonine, HHT) shows clinical activity against Ph+ CML, with a mechanism of action independent of tyrosine kinase inhibition. Currently available tyrosine kinase inhibitors (TKIs) have not demonstrated activity in CML pts harboring the T315I BCR-ABL mutation.Study Goals: To evaluate the safety and efficacy of omacetaxine in pts with IM-resistant T315I+ Ph+ CML.Methods: Eligible pts include adult CML with confirmed T315I BCR-ABL mutation following imatinib failure after informed consent. Presence of T315I mutation is confirmed at one of 2 central reference labs. Induction schedule consists of 1.25 mg/m2 omacetaxine SC twice daily for 14 days every 28 days until complete hematologic response (CHR) or hematologic improvement (HI). Maintenance schedule may start after at least one induction cycle and after initial hematologic response. Maintenance treatment consists of 1.25 mg/m2 OMA SC twice daily for 7 days every 28 days, for up to 24 months.Study Results: To date, 50 pts have been enrolled, all having failed prior imatinib therapy, and 82% having failed 2 or more prior TKIs. Enrollment includes 26 pts in chronic phase (CP), 13 in accelerated phase (AP) and 11 in myeloid blast phase (BP). Median age: 58 yrs (19–84), 70% male. Mean baseline WBC values (/μl) were 11.51 (range 1.9–23.76) in CP, 18.88 (range 3.6– 78.2) in AP and 16.58 (range 2.4–51.5) in BP patients. Median disease duration is 58 months (range 5–285).Efficacy: Data are available for 30 pts: 15 CP, 10 AP and 6 BP pts. In CP pts, CHR has been achieved in 80% (12/15) with a median duration of response of 8 months (range 2.7 to 13.5+). Of these 12 pts achieving CHR, 11 pts continue on study with the remaining patient achieving complete cytogenetic response (CCyR) and being removed from treatment to receive allograft transplantation. The median time to hematologic response was 1.2 months (range 0.6 to 2.5). Overall cytogenetic response in CP pts is 20% (3/15) with 13% (2/15) achieving CCyR and 1 pt achieving a minimal cytogenetic reponse. Median duration of cytogenetic response is 9.1 months (range 7.1 to 9.2+) with one pt continuing in CCyR and the second patient receiving allograft as described above. In AP pts, overall hematologic response is 60% (6/10) with 5 of these patients remaining active in treatment. Two pts have achieved CHR, 3 returned to chronic phase and 1 showed HI. Median duration of response was 2.2 months (range 1 to 4.4+). Overall cytogenetic response rate in AP patients is 21% (3/14), with 2 pts achieving major cytogenetic response and 1 pt achieving minimal response. In BP patients, overall hematologic response rate is 33% (2/6) with 1 pt achieving CHR and 1 HI. Duration of response was 3.7 and 3.9 months respectively. The T315I mutated clone has been decreased below the limit of detection in 60% of evaluable patients.Safety: Data are available for 32 pts enrolled in all disease phases. The primary toxicity being myelosuppression which is reversible and managed by adjusting the number of dosing days received per cycle. Incidence of treatment emergent grade 3/4 events includes: thrombocytopenia 44%, neutropenia 34%, anemia 28%, febrile neutropenia 16%, and pancytopenia 9.4%. Injection site reactions have been mild with no grade 3–4 events reported. Four pts have died (3 BP, 1 AP) during the study period, all due to disease progression.Conclusions: Omacetaxine therapy in T315I mutated BCRABL+ IM-resistant CML is well tolerated and is producing durable CHRs and cytogenetic responses in these patients.

Nilotinib Is Associated with Minimal Cross Intolerance to Imatinib in Patients with Imatinib-Intolerant Philadelphia-Positive (Ph+) Chronic Myelogenous Leukemia (CML) in Either Chronic Phase (CP) or Accelerated Phase (AP).

Nilotinib, a highly selective BCR-ABL tyrosine kinase inhibitor that is 30-fold more potent than imatinib, represents an important treatment option for pts with imatinib-resistant or -intolerant Ph+CML. Reported are results from a phase II, open-label study evaluating the safety and efficacy of nilotinib in imatinib-resistant or -intolerant Ph+CML. Imatinib resistance was defined as treatment with imatinib ≥600 mg/d with disease progression (≥50% increase in WBCs, blasts, basophils, or platelets) or no hematologic response after 4 wks. Imatinib intolerance was defined as no prior MCyR and discontinuation of imatinib due to Grade 3/4 AE or persistent (>1 mo) or recurrent Grade 2 AE (recurred >3x) despite optimal supportive care. Nilotinib-imatinib cross-intolerance was defined as treatment with nilotinib and occurrence (regardless of causality) of Grade 3/4 of the same AE that led to discontinuation of imatinib therapy. Planned starting dose was nilotinib 400 mg BID but could be escalated to 600 mg BID for lack of response. Of 320 pts with CML-CP, 94 (29.4%) were enrolled for imatinib-intolerance for either nonhematologic and/or hematologic AEs, of these, 71 (76%) had Grade 3/4 AEs at study entry. Of 127 pts with CML-AP, 24 (18.9%) were enrolled for nonhematologic and/or hematologic imatinib-intolerance; of these, 16 (67%) had Grade 3/4 AEs at study entry. Some pts had >1 AE satisfying criteria for intolerance. Only 2/71 (3%) pts with nonhematologic imatinib-intolerance experienced a recurrence of similar Grade 3/4 AEs during nilotinib therapy. Of 37 pts with hematologic intolerance to imatinib, 19/37 (51%) did not develop Grade 3/4 or similar events during nilotinib therapy. Median duration of nilotinib exposure was 350.5 days in CML-CP and 141.5 days in CML-AP with median dose intensities of 725.8 mg/d and 768.8 mg/d, respectively. Only 1 pt (CML-AP) required a dose escalation to 600 mg BID. Although nilotinib and imatinib have some molecular similarities, these results support previous findings of minimal occurrence of cross-intolerance. These results also suggest important differences in safety profiles between imatinib and nilotinib. Thrombocytopenia appears to be the only intolerant AE that may recur with nilotinib. These results support nilotinib's excellent tolerability and indicate that it can be used effectively in both CML-CP and -AP pts with imatinib-intolerance.CML-CP Pts with Intolerance (N=94)CML-AP Pts with Intolerance (N=24)Intolerance AEsImatinib IntoleranceGrade 3/4 AE during NilotinibImatinib IntoleranceGrade 3/4 AE during NilotinibNon-hematologic562150Rash/Skin26050Fluid Retention17050GI16110Liver Toxicity10130 ALT4010 AST4100Myalgia/arthralgia9020Hematologic291683Thrombocytopenia241351Neutropenia8432Anemia2110

Expanding Nilotinib Access in Clinical Trials (ENACT) Study in Adult Patients (Pts) with Imatinib-Resistant or -Intolerant Chronic Myeloid Leukemia (CML) in Blast Crisis (BC), Accelerated Phase (AP), or Chronic Phase (CP): Preliminary Safety Analysis.

Background: Nilotinib is a novel, oral ATP-competitive inhibitor of BCR-ABL; it is significantly more potent (>30-fold) and selective than imatinib. ENACT is an ongoing multicenter, open-label, expanded-access study for pts with imatinib-resistant/intolerant CML in all phases. The primary objective is to evaluate the safety of nilotinib in these pts.Methods: Pts with imatinib-resistant or -intolerant CML-CP, -AP, or -BC, who received prior therapies including imatinib and dasatinib were eligible to receive nilotinib 400mg twice daily (BID). Dose escalation was not permitted. Pts who required dose reduction due to toxicity were allowed to have a dose re-escalation to 400mg BID after resolution of the adverse events (AE) to ≤Grade 1, lack of response, or persistent disease at the investigator's discretion.Results: To date, 1152 pts have been enrolled. Results for the first 587 pts enrolled between January 2006 and January 2007 are presented, 582 received nilotinib and are included for safety analysis (BC n=73, AP n=62, CP n=447): median time since CML diagnosis 52.8 (2.5–468.6) mos; 68.4% were imatinib-resistant and 31.4% were imatinib-intolerant; median duration of nilotinib exposure was 77 days (overall), 84 days for CP, 71 days for AP, and 48 days for BC. At data cutoff (January 31, 2007), 425(73%) pts were continuing on nilotinib, 10% for ≥6 mos. The main reason for discontinuation was unsatisfactory therapeutic effect (11% overall), which as expected was most frequent in BC pts (n=23, 32%). Discontinuations due to AEs occurred in 7% of pts but did not differ significantly among the CML phases: BC 9 (12%); AP 5 (8%); CP 29 (7%). Of the safety population (N=582), 536 (92%) had AEs reported in the database. The incidence and severity of hematologic AEs were higher in BC or AP. Nonhematologic AEs were overall mostly mild to moderate and included headache, rash, nausea, pyrexia, elevated lipase, vomiting, hyperbilirubinemia and myalgia. Among the 536 pts with AEs reported, 15 (2.8%) deaths occurred, most frequently in pts with BC (n=9, 12.5%), rather than AP (n=3, 5.1%) or CP (n=3, 0.7%). The most frequent causes of death in BC were intracranial hemorrhage (n=4), infectious complications (n=2), CML (n=2), or respiratory failure (n=1). Among pts in AP or CP, deaths were attributed to disease progression (n=2), infectious complications (n=2), CML (n=1), or respiratory failure (n=1).Conclusion: Preliminary analysis of this large expanded-access study further demonstrates that nilotinib is safe and well-tolerated in heavily pretreated pts with CML. Importantly, the occurrence of nonhematological AEs for CP, AP and BC pts enrolled in the study appear similar. Overall, both hematologic and nonhematologic AEs have been mild to moderate, and preliminary results from this safety study are consistent with previous published clinical experience with nilotinib phase I/II pivotal studies.

Response dynamics to nilotinib depend on the type of BCR-ABL mutations in patients with chronic myelogenous leukemia (CML) after imatinib failure

7024 Background: Nilotinib (AMN107) is an oral, aminopyrimidine-derivative, selective inhibitor of the BCR-ABL tyrosine kinase with improved potency and specificity compared with imatinib. In preclinical models, activity of nilotinib was also demonstrated in 32/33 imatinib- resistant mutant cell lines. We sought to explore the efficacy of nilotinib in vivo according to the type of preexisting BCR-ABL mutations associated with imatinib resistance. Methods: We have investigated peripheral blood samples from 101 chronic phase (CP) and 41 accelerated phase (AP) CML patients (pts) who had been enrolled in a phase II study investigating the efficacy and safety of 400mg nilotinib bid after imatinib failure. Screening for BCR-ABL mutations was performed by D-HPLC combined with DNA sequencing. The analysis covered amino acids 207–517 of the BCR-ABL tyrosine kinase domain. Results: Prior to nilotinib, 24 different BCR-ABL mutations involving 20 amino acids were detected affecting 44% CP and 61% AP pts. After 6 mo of therapy, complete hematologic response was achieved in 59%, major cytogenetic response (MCR) in 25% being complete (CCR) in 16% of pts with mutations vs 81%, 51% and 33% of pts without mutations, respectively. Response dynamics were associated with preclinical activity of nilotinib: MCR was reached in 10/18 pts with mutations associated with preclinical IC50 to nilotinib of &lt;100nM, 2/9 pts with IC50 of 100–1,000 nM, and 0/4 pts with mutation T315I demonstrating virtual resistance to imatinib and nilotinib. In AP pts, hematologic response was achieved in 56% and 31%, MCR in 24% vs 19%, and CCR in 24% vs 13% of pts with or without mutations, respectively. Conclusions: Nilotinib is efficacious in pts with BCR-ABL mutations, except T315I, as well as in patients with BCR-ABL-independent resistance. Time to response may depend on the individual type of the mutation and correlates with the IC50 to nilotinib. Thus, nilotinib may have an important therapeutic role in imatinib resistance as well as in frontline CML therapy to prevent emergence of resistant clones. [Table: see text]

Bcr-Abl and Wilms Tumor Gene (WT1) Kinetics in Nilotinib (AMN107) Treated CML Patients.

Background: In normal hemopoesis WT1 expression is restricted to early progenitors and is rapidly down-regulated in maturing blood cells. WT1 transcript quantification therefore may be an adjunct diagnostic method in CML patients (pts) that remain Bcr-Abl positive under treatment. Especially, in advanced CML pts WT1 transcript kinetics may precede a change in Bcr-Abl kinetics and may therefore be helpful to indicate early response to treatment. Nilotinib is a potent, highly selective, second generation Bcr-Abl inhibitor which in vitro is 30-fold more potent than imatinib and is currently studied in imatinib resistant or intolerant pts.Aim: The aim of this study was to compare kinetics of Bcr-Abl and WT1 transcripts in 33 CML pts with late chronic phase (CP) or advanced disease under treatment with nilotinib.Methods: All pts were treated as part of an ongoing phaseI/II clinical trial with nilotinib at a standard dose of 400 mg BID. 20 pts were in chronic phase (CP), 4 in accelerated phase (AP) and 9 in blast crisis (BC). Among the CP pts 4/20 were enrolled because of toxicity to prior imatinib treatment. WT1 and Bcr-Abl kinetics were expressed in relation to Abl expression. Data points were taken at baseline and every 4 weeks thereafter. Quantitative PCR was carried out by Taqman-analysis.Results: The median duration of nilotinib treatment was 8 months in CP pts, 4 in AP pts and 5.5 in BC pts. The follow up of all pts ranged between 3 and 13 months. All pts received imatinib prior to nilotinib and were Bcr-Abl positive at study entry. In CP samples WT1/Abl ratios (median:1.24x10−3) were 38 fold lower than Bcr-Abl/Abl (median:4.67x10−2) ratios at baseline (p≤0.014, t-test). However, in AP and BC pts no relevant difference of WT1/Abl and Bcr-Abl/Abl baseline levels were detectable. In BC patients a more rapid decline of WT1/Abl ratios compared to Bcr-Abl/Abl ratios was observed within the first four months of nilotinib therapy. In addition, in BC pts elevation of WT1 levels preceded hematologic relapses and was detectable earlier than elevation of Bcr-Abl/Abl ratios.Conclusions:In contrast to AP and BC pts in CP pts WT1/Abl ratios were significantly lower than Bcr-Abl/Abl ratios confirming the restriction of WT1 expression to early progenitors.In BC pts under nilotinib therapy WT1/Abl ratios may be an early marker of response as compared to Bcr-Abl/Abl ratios.A stable correlation of WT1/Abl and Bcr-Abl/Abl ratios was observed in AP pts under treatment.

A phase II study of AMN107, a novel inhibitor of Bcr-Abl, administered to imatinib-resistant or intolerant patients (pts) with chronic myelogenous leukemia (CML) in accelerated phase (AP)

6531 Background: AMN107 is a potent, highly selective, aminopyrimidine inhibitor which in vitro is 30-fold more potent than imatinib and is active against 32/33 imatinib resistant Bcr-Abl mutations. Methods: This open-label study was designed to evaluate the safety and efficacy of AMN107 (400 mg bid) defined by hematologic/cytogenetic response (HR/CyR) rates in imatinib resistant or intolerant AP pts. Results: Preliminary data are presented for 22 pts (77% resistant and 23% intolerant to imatinib. Treatment is ongoing for 16 (73%) pts. Median age was 62 (43–76) yrs. Median duration of AMN107 exposure was 124 (3–207) days. Median time from AP diagnosis was 6 (0.2–56) mos. Three of 5 patients with data available had a Bcr-Abl mutation at baseline. HR occurred in 14 (64%) pts of which 10 (45%) were complete, 3 (14%) were marrow responses/no evidence of leukemia, and 1 return to chronic phase. CyR occurred in 6 pts (1 each complete, partial minor, and 3 minimal). All AE’s occurring in ≥10% pts were thrombocytopenia (8 [36%] pts; Gr 3/4, 6 [27%] pts), fatigue (7 [32%]), anemia, (6 [27%]; Gr 3/4, 4 [18%] pts) pruritus, muscle spasms (6 [27%] pts each), bone pain, cough, (5 pts [23%] each) rash (5 [23%] pts; Gr 3/4, 1 [5%] pt), neutropenia (4 [18%] pts, all Gr 3/4), diarrhea, headache, myalgia, pyrexia (4 [18%] pts each), abdominal pain, chills, constipation, dyspnea, nausea, extremity pain, and peripheral edema (3 [14%] pts each). Two 2 deaths occurred, 1 pt with thrombocytopenia had a CNS bleed and 1 pt had disease progression. Conclusions: These data suggest AMN107 is clinically active and has an acceptable safety profile when administered to pts with CML-AP. [Table: see text]

Frequency, Distribution and Prognostic Value of ABL Kinase Domain (KD) Mutations in Different Subsets of Philadelphia-Positive (Ph+) Patients (Pts) Resistant to Imatinib (IM) by the Gimema Working Party on CML.

Using denaturing-high performance liquid chromatography and sequencing, we screened for ABL KD mutations 319 IM-resistant Ph+ pts. Median time between diagnosis and IM start at 400–600 mg/d was 40 (0–160) months. Median duration of IM was 27 (9–62) months. Evaluable pts were 256/319 (80%). At the time of analysis, 178/256 (70%) pts were in chronic phase (CP)(36 previously untreated, 142 post-IFN failure), 16 (6%) pts were in accelerated phase (AP), 26 (10%) pts were in myeloid blast crisis (myBC), 36 (14%) were in lymphoid blast crisis (lyBC) or had Ph+ acute lymphoblastic leukemia (ALL). One hundred and forty-two pts had primary resistance to IM, 114 had acquired resistance. Ninety-eight mutations were found in 91/256 (36%) pts. In 6 pts (2 Ph+ ALL, 2myBC, 1 lyBC, 1 CP post-IFN failure) multiple mutations simultaneously occurred. Mutations mapped to 15 codons, the most frequent ones being E255K/V (15 pts), Y253F/H (12 pts), T315I (10 pts), M351T (10 pts), F359V/I (10 pts), M244V (9 pts), G250E (8 pts). Three novel amino acid substitutions (F311I; E355D; F359I) and a novel mutated codon (P296H) were detected; biochemical/structural characterization will be presented. Mutations were found in 36/178 (26%) CP pts (4/36 (11%) previously untreated, 32/142 (22%) post-IFN failure), 7/16 (44%) AP pts, 19/26 (73%) myBC pts and 29/36 (81%) lyBC/Ph+ ALL pts (CP vs. AP, p=.04; AP vs. BC, p=.01; CP vs. BC, p<.001). Mutations were associated in 41/142 (29%) pts with primary resistance (4/8 hematologic and 37/134 cytogenetic) and in 50/114 (44%) pts with acquired resistance (10/50 pts who lost CCgR, 16/32 pts who lost HR, 24/32 pts who progressed to AP/BC)(primary vs. acquired, p=.009). Thirty-nine out of 49 pts with P-loop or T315I mutations had already progressed to AP/BC at the time of mutation detection; 4 additional pts subsequently progressed. In contrast, only 17 of the 42 remaining pts with mutations had progressed or subsequently progressed (p<.001). In a subset of 93 IM-resistant CP pts who were homogeneously treated in the CML/002/STI571 trial, with a follow-up ranging between 10 and 51 months, presence of a mutation was significantly associated with greater likelihood of progression (Log-Rank p<.001) and shorter survival (Log-Rank p=.005). Pts carrying P-loop or T315I mutations showed a particularly poor outcome both in terms of time to progression (Log-Rank p=.003) and in terms of survival (Log-Rank p=.02). We conclude that: a) there is a significantly higher probability of mutations according to disease phase (Ph+ ALL and BC>AP>CP); b) there is a significantly higher probability of mutations in pts with acquired resistance vs. pts with primary resistance; c) mutations, and in particular those affecting P-loop or codon 315, are associated with a worse outcome. Supported by AIL, AIRC, Fondazione del Monte di Bologna e Ravenna.

Four Years of Follow-Up of 1027 Patients with Late Chronic Phase (L-CP), Accelerated Phase (AP), or Blast Crisis (BC) Chronic Myeloid Leukemia (CML) Treated with Imatinib in Three Large Phase II Trials.

BackgroundThis report updates the results of 3 large phase II studies of the orally available BCR-ABL tyrosine kinase inhibitor imatinib for patients (pts) in AP, BC and late chronic phase (L-CP) CML failing prior interferon therapy (Kantarjan et al, ASH 2003; Talpaz et al, ASH 2003).MethodsBetween August 1999 and June 2000, 1027 pts were enrolled in phase II trials for CML in L-CP (n=532), AP (n=235) or BC (n=260). Pts in L-CP were treated with 400 mg/day and pts in AP or BC with either 400 or 600 mg/day. Dose escalation up to 800 mg/d was allowed in the late-chronic phase study. Pts with a confirmed diagnosis of AP (n=181), BC (n=229) and late-chronic phase (n=454) were evaluated for efficacy. All pts were evaluated for safety. The median time from initial diagnosis to study entry was 32 months for L-CP pts.ResultsAs of 31-Jul-03, 5% patients with BC, 25% of CML-AP and 64% of L-CP patients still remain on treatment.At the recommended dose of 600 mg, an estimated 40% (AP) and 7% (BC) of patients remained progression-free at 36 months, and an estimated 55% (AP) and 14% (BC) patients were alive at 36 months after initiation of imatinib. The 3-year survival rates for pts with AP with a major cytogenetic response at 3 months were 85% vs. 52% for pts with no response (p<0.001). In L-CP patients with a median follow-up of 40 months, 65% of patients achieved a major cytogenetic response, which was complete in 52%. The cytogenetic responses were durable with an estimated 82% of the pts in continuos major cytogenetic response at 3 years. The estimated rates of progression-free survival and overall survival at 3 years were 80% and 88%. Pts with at least a minor cytogenetic response at 6 months ≤65% Ph+ cells) had an estimated 3-year survival rate of 96% vs. 86% for pts with a ( minimal response and 81% for pts with no cytogenetic response (p<0.001).ConclusionIn large phase II studies, continuous imatinib treatment is safe and has improved progression-free survival of patients at all stages of CML. Responses to imatinib are durable and are predictive of long-term outcomes. These results will be further updated at the meeting using a data base lock planned for 20-Sept-04 (using data collected up to 31-July-04, i.e. more than 4 years after the last pts enrollment).

Survival Advantage for Patients (pts) with Chronic Myeloid Leukemia (CML) in Accelerated Phase (AP) Treated with Imatinib.

When treated with imatinib, pts with CML in AP have a hematologic response rate of over 80%, and 25% achieve a major cytogenetic (CG) response. These results are superior to any other therapy available and have established imatinib as the standard of care for AP CML. However, a survival benefit was not defined in these single-arm studies. With longer follow-up of pts in AP treated with imatinib, we investigated whether imatinib therapy led to a survival advantage over other therapies that have been used for this disease. For this analysis, AP was defined as the presence of any of the following: blasts ≥15%, blasts + promyelocytes ≥30%, basophils ≥20%, platelets (plts) <100 x109/L unrelated to therapy, or clonal evolution. Since 1982, 395 pts with AP have been treated at MDACC: 177 (45%) with imatinib and 218 (55%) with other therapies including IFN-α-based therapy (n=102), homoharringtonine (n=36), decitabine (n=47), daunorubicin + ara −C (n=24), or others (n=9). The rate of complete hematologic response was 82% with imatinib and 38% with others (p < 0.0001), and major cytogenetic response was 48% and 13%, respectively (p <0.0001). The median follow-up is 41 months (mo) (range, 3 – 206): 38 mo (3 to 63) for the imatinib group and 82 mo (3 to 206) for the others. A total of 249 pts have died: 67 in the imatinib cohort and 182 in the control group. The median survival was 21 months for the control group, and has not been reached for the imatinib cohort (estimated rate 53% at 3 yrs). Clinical characteristics adversely affecting survival (p<0.05) included time from diagnosis to treatment >36 mo, splenomegaly, Hgb <10 g/dl, plts <100 x109/L, peripheral or marrow blasts ≥5%, marrow basophils >5%, blasts + promyelocytes >5%, clonal evolution, and treatment with imatinib. Pts treated with imatinib were older, but had fewer pts with splenomegaly, high blasts or clonal evolution than the control group. By multivariate analysis, the independent pre-treatment characteristics associated with survival (p<0.05) were splenomegaly, anemia, presence of peripheral blood blasts, and disease duration >1 yr. After adjusting for these differences in a multivariate analysis, treatment with imatinib was the most significant prognostic factor associated with improved survival (p<0.0001). We conclude that treatment with imatinib has changed the natural history of AP CML with an expected median survival in excess of 3 years.

Long-Term Incidence and Outcome of BCR-ABL Mutations in Patients (pts) with Chronic Myeloid Leukemia (CML) Treated with Imatinib Mesylate - P-Loop Mutations Are Not Associated with Worse Outcome.

Resistance to imatinib in CML may occur through mutations of the BCR-ABL kinase domain. We investigated the occurrence of mutations in 159 pts treated with imatinib by direct sequencing. Pts had been treated with imatinib for a median of 32 months (mo) (range, 4 to 60 mo). 52 mutations were identified in 49 (31%) pts: 3 pts had 2 different mutations; in 2 of them they appeared simultaneously. Mutations mapped to 23 different amino acid residues, with the most frequent locating to the P-loop (n=19; 39%), and the residues in imatinib binding pocket (n=12; 25%). The single most common mutations were G250E (n=8) and F317L (n=7). At the time imatinib was started, 34 pts (70%) were in chronic phase (CP) (13 previously untreated, 21 post-IFN failure), 14 (28%) in accelerated phase (AP), and 1 (2%) in lymphoid blast phase (BP). Three pts (2 AP, 1BP) had clonal evolution. Best response to imatinib for pts in CP was: cytogenetic (CG) response complete (CGCR) in 13 (38%), partial (CGPR) in 8 (24%), minor in 1 (3%), and hematologic response only in 12 (35%) (11 complete, 1 partial). For pts in AP, best response was: CGCR in 5 (36%), CGPR in 3 (21%), minor in 1 (7%), and hematologic only in 5 (36%). The pt in BP had achieved CGCR. At the time mutations occurred, 47 (96%) pts had lost their hematologic or cytogenetic response, and clonal evolution had occurred in 15 (68%) pts. Among pts who were initially treated in CP, 9 had transformed to AP and 3 to BP. Two pts treated in AP had progressed to BP. In 2 (4%) pts (1 CP, 1 AP) the mutation (F317L, F311I) was identified while in CGCR remission; both pts have remained in CG CR 2 and 4 mo, respectively after the mutations was identified. Five patients died (4 AP, 1 CP) after a median of 7 mo (1–20 mo) following the detection of mutations. Their mutations included F317L (n=2), M244V, F359V, H396R (1 each). Thus, after a median follow-up of 6 mo (range, 1–20 mo) from detection, only 1 of 19 pts with P-loop mutations has died versus 4 of 30 with non-P-loop mutations. The estimated 15-months survival rates were 95% and 83%, respectively (p=0.50). We conclude that 1) mutations occur frequently among pts with acquired resistance to imatinib; 2) in few instances they can be identified in pts in CGCR; and 3) P-loop mutations may not be associated with worse outcome compared to other mutations.