Major Cytogenetic Response Duration Research Articles

Predictors of Response Duration and Survival with Second-Line Bosutinib Therapy in Patients (pts) with Chronic Phase Chronic Myeloid Leukemia (CML) Resistant or Intolerant to Prior Imatinib

▪Bosutinib (BOS), a Src/Abl tyrosine kinase inhibitor (TKI), is approved for adults with Philadelphia chromosome-positive (Ph+) CML that is resistant/intolerant to prior therapy. In this retrospective analysis, baseline and on-treatment characteristics of chronic phase (CP) CML pts receiving second-line BOS following imatinib resistance (IM-R) or intolerance (IM-I) in an ongoing open-label, phase 1/2 study and a long-term extension study were examined to identify potential predictors of duration of major cytogenetic response (MCyR), overall survival (OS), and progression-free survival (PFS), using a backward-elimination multivariate Cox regression model.A total of 284 (IM-R, n=195; IM-I, n=89) pts who received BOS starting at 500 mg/d were included in this analysis. Median (range) age was 53 (18‒91) y; time from CML diagnosis was 3.7 (0.1‒15.1) y; treatment duration was 25.6 (0.2‒106.7) mo; follow-up duration was 53.7 (0.5‒106.8) mo. For the last enrolled patient, time from first BOS dose was ≥6 y.After ≥6 y of follow-up, median MCyR duration and OS were not yet reached. Kaplan-Meier estimated probability of maintaining MCyR at 6 y was 71%, OS rate was 83%, and cumulative incidence of on-treatment disease progression or death was 21%. Several factors were identified as predictive of MCyR duration, OS or PFS, including baseline Ph+ ratio ≥95% vs ≤35% and MCyR by week 12, which were significant predictors of all 3. Other significant predictors of decreased OS included: age ≥65, BOS-sensitive mutations vs no mutations and higher peripheral blood (PB) blasts at baseline (all P ≤0.031; Table). Other significant predictors of decreased PFS included: higher PB blasts and no dose reduction to 400 mg/d due to AEs (all P ≤0.025; Table). Prior IM response or resistance did not predict long-term outcomes, nor did any treatment-emergent adverse events examined except for abnormal liver function test (LFT), which was predictive of increased OS.In conclusion, pts with CP CML resistant/intolerant to IM treated with BOS were identified as having an increased risk of poorer outcomes if they had the following characteristics: baseline Ph+ ratio ≥95% vs ≤35%, higher PB blasts at baseline or no MCyR by week 12. Having a better understanding of factors that may be predictive of long-term patient outcomes with TKI therapies may aid healthcare providers in the future selection of optimal treatment regimens for pts with Ph+ CML. [Display omitted] DisclosuresCortes:ARIAD Pharmaceuticals Inc.: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Teva: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding. Brümmendorf:Ariad: Consultancy, Honoraria; Novartis: Consultancy, Honoraria, Research Funding; Pfizer: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Patent: Patents & Royalties: Patent on the use of imatinib and hypusination inhibitors. Kim:BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; ILYANG: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Schafhausen:ARIAD: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria; BMS: Consultancy, Honoraria; Novartis: Consultancy, Honoraria. Nadanaciva:Pfizer Inc: Employment. Bardy-Bouxin:Pfizer Inc: Employment. Shapiro:Pfizer Inc: Employment, Other: Stock Ownership. Leip:Pfizer Inc: Employment. Lipton:Ariad: Equity Ownership, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; BMS: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Gambacorti-Passerini:Pfizer: Consultancy, Research Funding; BMS: Consultancy.

Efficacy of Tyrosine Kinase Inhibitors in Third Line Therapy in Chronic Phase Chronic Myeloid Leukemia

▪Introduction. Overall survival (OS) of patients in chronic phase (CP) chronic myeloid leukemia (CML) dramatically increased in the era of tyrosine kinase inhibitors (TKI). Meanwhile nearly half of patients discontinue 1-st line Imatinib due to resistance or intolerance. Half of them subsequently failure treatment with second line TKI. It seems that 20-25% of CP CML patients need 3-d line therapy (TKI-3l). There are a few reports regarding durable outcome of TKI-3l.Materials and Methods. In our retrospective study 53 patients (20 male, 33 female) with CML CP treated either by Nilotinib 400 mg BID (n=18), Dasatinib 100 mg QD (n=33) or Bosutinib 500 mg QD (n=5) as TKI-3l were included. The median age at the time of diagnosis was 46 years (23-88 years). The main reason for previous TKIs discontinuation was resistance: 48/53 (91%) had failure of one and 42/53 (79%) patients had failure of both previous TKIs treatment. Median CML duration before TKI-3l was 55 months (2-314 months). Before TKI-3l mutation analysis was performed in 35 patients: 18 mutations were revealed in 16 (46%) patients including T315I mutation in 3 cases. At the moment of 3-d line TKIs therapy initiation, all patients were in CP and 43/53 (81%) had at least complete hematologic response (CHR), 8/53 (15%) patients had major cytogenetic response (MCyR) including 1 patient with complete cytogenetic response (CCyR).Results. At the time of analysis, the median duration of TKI-3l therapy was 21 months (1-67 months). No additional patients achieved CHR, but during observational time CHR was maintained nearly in all 40/43 (93%) patients with CHR at baseline. New cases of MCyR and CCyR were observed in 15/45(33%) and 11/52(21%) of patients, respectively. Median time to MCyR and CCyR was 3.4 (3-8) and 5.2 (3-13) months, respectively. Median duration of MCyR and CCyR was 9.3 (1-43) months and 4.5 (3-6) months, respectively. Patients with resistant mutations did not obtain any cytogenetic response. TKI-3l treatment was discontinued in 21 patients. Intolerance was the reason of treatment discontinuation in 5/53(10%) cases. Progression to accelerated or blastic phases during therapy or after discontinuation occurred in 8/53 (15%) patients. Median time to progression was 14.7 months (1-46 months). There were 13 deaths in overall group of 53 patients. Two-year OS in TKI-3l was 67%. All patients with MCyR were alive and preserved CP phase.Concluson: Our results showed that 20% of patients might obtain at least CCyR and benefit with TKIs as third line. Therefore, after two TKI lines patients, who are not eligible for allogeneic transplantation and without resistant mutations should be treated with one more line of TKI therapy. DisclosuresLomaia:Novartis: Consultancy. Zaritskey:University of Heidelberg: Research Funding; Novartis: Consultancy.

Dasatinib in Children and Adolescents With Relapsed or Refractory Leukemia: Results of the CA180-018 Phase I Dose-Escalation Study of the Innovative Therapies for Children With Cancer Consortium

Dasatinib is a potent BCR-ABL inhibitor with proven efficacy in adults with newly diagnosed chronic myeloid leukemia (CML) in chronic phase (CP) and in imatinib-resistant/intolerant disease. This phase I study of the Innovative Therapies for Children with Cancer Consortium assessed dasatinib safety and efficacy in pediatric patients. Escalating once-daily dasatinib doses (60 to 120 mg/m(2)) were administered to children (n = 58) with (i) imatinib-pretreated CML or Philadelphia chromosome (Ph)-positive acute lymhoblastic leukemia (ALL) and (ii) treatment-refractory Ph-negative ALL or acute myeloid leukemia (AML). Dasatinib safety and efficacy profiles compared favorably with those in adults. The most common drug-related nonhematologic adverse events were nausea (31%, all grades; 2%, grade 3 to 4), headache (22%, 3%), diarrhea (21%, 0%), and vomiting (17%, 2%). Of 17 patients with CML-CP, 14 (82%) achieved complete cytogenetic response (CCyR) and eight (47%) achieved major molecular response. After ≥ 24 months of follow-up, median complete hematologic response (CHR) and major cytogenetic response (MCyR) durations were not reached. Of 17 patients with advanced-phase CML or Ph-positive ALL, six (35%) achieved confirmed CHR and 11 (65%) achieved CCyR. Median MCyR duration was 4.6 months (95% CI, 2.1 to 17.4 months). No patient with Ph-negative ALL or AML responded. Dasatinib pediatric pharmacokinetic parameters were comparable with those in adult studies, showing rapid absorption (time to reach maximum concentration, 0.5 to 6.0 hours) and elimination (mean half-life, 3.0 to 4.4 hours). Dasatinib 60 mg/m(2) and 80 mg/m(2) once-daily dosing were selected for phase II studies in children with Ph-positive leukemias.

Subcutaneous Omacetaxine in Chronic or Accelerated Chronic Myeloid Leukemia Resistant to Two or More Tyrosine-Kinase Inhibitors Including Imatinib,

Subcutaneous Omacetaxine in Chronic or Accelerated Chronic Myeloid Leukemia Resistant to Two or More Tyrosine-Kinase Inhibitors Including Imatinib,

Subcutaneous Omacetaxine (OM) Treatment of Chronic Phase (CP) Chronic Myeloid Leukemia (CML) Patients Following Multiple Tyrosine Kinase Inhibitor (TKI) Failure

AbstractAbstract 2290 Introduction:Multiple TKI failure is a growing problem in a subset of CML patients. Treatment with a third TKI after two have failed often yields poor results. New treatment options are needed for this patient population. OM is a first-in-class cetaxine with demonstrated activity as a single agent in CML. It inhibits the production of short-lived oncoproteins (such as Mcl-1) involved in cancer cell survival via a mechanism independent of Bcr-Abl binding. Several studies have suggested that OM has a favorable toxicity profile when given to patients with CML via the subcutaneous route. We explored OM efficacy and safety in a subset of patients who had received therapy with multiple prior approved TKI. Methods:We analyzed a subset of adult CML-CP patients who had received two or more TKI (imatinib, dasatinib, nilotinib), from a combined interim dataset of two prospective Phase 2 studies (CML-202, for patients with the T315I kinase domain mutation, and CML-203, for patients with failure to ≥2 TKI) utilizing OM in the treatment adult patients with all phases of CML who had failed TKI. TKI failure was defined as no complete hematologic response (CHR) by 12 weeks (wk), no cytogenetic response by 6 months (mo), no major cytogenetic response (MCyR) by 12 mo, loss of CHR or MCyR, or progressive leukocytosis. The focus of this analysis was to assess the CHR and MCyR response rates as well as the overall safety of OM in these patients. Adverse events presented are Grade 3/4 events that occurred in ≥ 5% of patients (regardless of causality). Results:A total of 73 of the 93 CML-CP patients from these two studies had received two or more TKI prior to OM treatment. Median time from initial CML diagnosis to first dose of OM was 74.4 months. Mutations of any kind were seen in 48% of the patients, whereas 29% had no identified mutation and 23% had no available data on mutation status. Sixty (82%) of these 73 patients achieved or maintained (twelve patients were in CHR at study entry) a CHR and 17 (23%) achieved a MCyR (9 complete and 8 partial). The median duration of MCyR was 4.4+ months (range 1.2–14.1+). Median overall survival for patients treated with OM after failure of 2 or more TKI has not yet been reached [95% Confidence Interval (CI) 22.9, NA months] (Figure 1). Eleven patients had a treatment—emergent adverse event leading to death, and two deaths were probably related to study drug. Median progression-free survival was 11.1 months (95% CI 6.5, 13.8 months). Median follow-up time was 7.5 months for all patients with twenty-five patients remaining on study at the time of this data cut. A total of 36 of the 93 CP patients from these two studies had been treated with three or more TKI; 27 (75.0%) achieved or maintained a CHR and 7 (19.4%) achieved a MCyR (4 complete and 3 partial) on OM treatment. The median duration of MCyR in this group was 4.0+ months (range 1.2–11.5+) at the time of data cut-off. The primary Grade 3/4 adverse events in patients who received OM after failure of 2 or more TKI were hematologic, including thrombocytopenia (64%), neutropenia (48%) and anemia (40%) most commonly, followed by febrile neutropenia (12%), bone marrow failure (12%), pancytopenia (7%) and febrile bone marrow aplasia (6%). These events were dosing schedule dependent. Clinical sequelae were uncommon and managed with transient treatment interruptions and dose adjustments. Grade 3/4 non-hematologic adverse events were infrequent, with only fatigue (6%) occurring ≥5% of patients. Conclusions:OM, through a mechanism of action independent of Bcr-Abl, may offer a clinically viable option for patients who have progressed on multiple TKI treatment. [Display omitted] Disclosures:Off Label Use: The drug is currently in development and has an NDA submitted for use in TKI resistant CML. Cram: ChemGenex: Employment, Equity Ownership. Humphriss: ChemGenex: Employment, Equity Ownership. Benichou: ChemGenex: Consultancy, Equity Ownership. Craig: ChemGenex: Employment, Equity Ownership, Executive Management Level.

Use of nilotinib to induce responses with 24-month (mo) minimum follow-up in patients (pts) with chronic myeloid leukemia in blast crisis (CML-BC) resistant to or intolerant of imatinib.

6510 Background: Nilotinib is a highly potent and selective BCR-ABL inhibitor with efficacy in pts with imatinib-resistant and -intolerant CML in chronic phase (CP) and accelerated phase (AP). Results from pts with CML-BC treated with nilotinib in the phase II 2101 trial are presented. Methods: Pts were treated with nilotinib 400 mg bid. Primary endpoint was confirmed hematologic response (HR). Results: 136 pts with imatinib-resistant (82%) or -intolerant (18%) CML-BC were treated with nilotinib and followed for a minimum of 24 mo. 105 pts had myeloid blast crisis (MBC) and 31 pts had lymphoid blast crisis (LBC). Baseline BCR-ABL mutations were detected in 30% of pts with MBC and 61% with LBC; T315I mutations were detected in 1% of pts with MBC and 7% with LBC. Clonal evolution was detected in 54% of all pts. Best prior response to imatinib was stable or progressive disease in 46%, with only 10% achieving prior complete HR (CHR) and 13% major cytogenetic response (MCyR). Nilotinib resulted in HR in 24% of pts with MBC and 19% with LBC. CHR occurred in 13% of pts with MBC and LBC. Responses were rapid and durable. For pts with MBC, median time to HR was 1 mo, and median duration of HR was 26 mo (range, 1.25-29.08); 60% of pts maintained HR at 24 mo. Median duration of HR was 3.6 mo for pts with LBC and no pt maintained HR at 24 mo. Nilotinib induced MCyR and CCyR in 38% and 30% of pts with MBC and 52% and 32% with LBC, respectively. In MBC pts, median time to MCyR was 1.8 mo, and median duration of MCyR was 11 mo (range, 0.03-29.08); 44% of pts maintained MCyR at 24 mo. Median duration of MCyR was 3.2 mo for pts with LBC and no pt maintained MCyR at 24 mo. Survival was 42% at 12 mo and 27% at 24 mo; 12 pts with MBC and 2 pts with LBC had transplants following nilotinib therapy. Nonhematologic adverse events were generally mild and manageable and similar to those observed in pts with CML-CP. Conclusions: Nilotinib is effective therapy in pts with imatinib-resistant or -intolerant CML-BC, generating rapid and durable responses for pts with MBC. Nilotinib exhibits a favorable safety profile in CML-BC patients. No new safety concerns were observed with 24 mo minimum follow-up. Author Disclosure Employment or Leadership Position Consultant or Advisory Role Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Bristol-Myers Squibb, Novartis Novartis Bristol-Myers Squibb, Novartis Bristol-Myers Squibb, Genzyme, Novartis

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

7029 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. [Table: see text]

Dasatinib 100 Mg Once Daily (QD) Maintains Long-Term Efficacy and Minimizes the Occurrence of Pleural Effusion: An Analysis of 24-Month Data in Patients with Resistance, Suboptimal Response, or Intolerance to Imatinib (CA180-034).

Dasatinib (SPRYCEL®) is a potent BCR-ABL inhibitor that is 325-fold more potent than imatinib and 16-fold more potent than nilotinib against unmutated BCR-ABL in vitro. Pleural effusion in patients during dasatinib treatment is well described and may have an immune-mediated mechanism, although this remains under investigation. CA180-034 was a 4-arm randomized, phase III, dose-optimization study in 670 patients (662 treated patients) with chronic myeloid leukemia in chronic phase and resistance, suboptimal response, or intolerance to prior imatinib. Previously, it was demonstrated that dasatinib 100 mg QD maintained efficacy and led to fewer key side effects compared with 3 other dosing schedules (140 mg QD, 50 or 70 mg twice daily [BID]), including significantly fewer pleural effusions. Here, the management and outcomes of 165 patients randomized to and treated with dasatinib 100 mg QD, with and without pleural effusion, were compared with the 497 patients treated on other dose schedules after a minimum follow-up of 24 mos on CA180-034. Pleural effusion was graded using standard CTCAE criteria. Overall rates of pleural effusion (all grades) at 12 vs 24 mos were 10% vs 14% for patients treated with dasatinib 100 mg QD, and 16% vs 23%, 21% vs 26%, 20% vs 25% for patients treated with 50 mg BID, 140 mg QD, or 70 mg BID, respectively. In patients receiving 100 mg QD, rates of pleural effusion by grade at 12 vs 24 mos were: grade 1, 2% vs 1%; grade 2, 6% vs 10%; and grade 3, 2% vs 2%; no grade 4 events were reported. The median time to development of pleural effusion (of any grade) was 10.3 mos for 100 mg QD compared with 9.5, 4.9, and 4.5 mos for 50 mg BID, 140 mg QD, and 70 mg BID, respectively. Management for pleural effusion included transient dose interruptions in 12 patients on the 100 mg QD arm and 71 patients on the other 3 arms combined. Dose reductions for pleural effusion occurred in 8 patients on the 100 mg QD arm and in 43 patients on the other 3 arms. Medical management of pleural effusion on the 100 mg QD arm vs the other 3 arms included use of diuretics in 13 patients vs 70 patients, corticosteroids in 6 patients vs 32 patients, and diuretics and/or corticosteroids in 14 patients vs 79 patients. Diagnostic and/or therapeutic thoracentesis was performed in 3 patients on the 100 mg QD arm vs 9 patients in the other 3 arms. The overall major cytogenetic response rate was 64% for 165 patients on the 100 mg QD arm, comprising 70% for those with a pleural effusion and 63% for those without; in the other treatment arms, rates ranged from 64 to 74% in those with a pleural effusion and from 59 to 61% in those without (Table). In the 100 mg QD arm, the 24-mo progression free survival rate was 78% in those with a pleural effusion and 80% in those without. In conclusion, pleural effusion is medically manageable; 24-mo data show that dasatinib 100 mg once daily minimizes the risk of pleural effusion and, both in patients with or without a pleural effusion, maintains long-term efficacy.Table: 24-month efficacy of dasatinib 100 mg QDWith pleural effusion (n=23)Without pleural effusion (n=142)Major Cytogenetic Response (MCyR) Rate70%63%MCyR Duration at 18 mo93%93%MCyR Duration at 24 mo70%90%Complete Cytogenetic Response (CCyR) Rate61%49%CCyR Duration at 18 mo93%95%CCyR Duration at 24 mo70%95%Progression Free Survival78%80%Overall Survival89%91%

Nilotinib in Chronic Myeloid Leukemia Patients in Chronic Phase (CMLCP) with Imatinib Resistance or Intolerance: 2-Year Follow-up Results of a Phase 2 Study.

Background: Nilotinib is a potent and highly selective BCR-ABL kinase inhibitor approved for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia patients in chronic (CML-CP) or accelerated phase (CML-AP) who are resistant or intolerant to prior therapy including imatinib.Methods: This open-label, single-arm, phase 2 study was designed to evaluate the efficacy and safety of nilotinib in CML-CP patients resistant or intolerant to imatinib. Imatinib intolerant patients with prior major cytogenetic response (MCyR) on imatinib were not eligible for this trial. Nilotinib was dosed at 400 mg twice daily with the option of dose escalation to 600 mg twice daily if responses were inadequate. Rate of MCyR was the primary endpoint. Secondary endpoints included complete cytogenetic response (CCyR), complete hematological response (CHR), duration of MCyR, survival, and safety.Results: A total of 321 CML-CP patients (71% imatinib-resistant; 29% imatinib-intolerant) were evaluated. Most patients were heavily pretreated with 72% having received more than 600 mg/day of imatinib prior to study entry. Furthermore, imatinib-intolerant patients could not have achieved prior MCyR on imatinib therapy. Median duration of prior imatinib treatment was 33 months (range 0.3–95 months). Dose reductions (25%) and discontinuations (15%) due to adverse events were infrequent on nilotinib therapy and median dose intensity (788 mg/day; range 151–1112 mg/day) closely approximated the planned dose. Median duration of exposure was 465 days (15.5 months). Overall, nilotinib therapy resulted in rapid and durable hematologic and cytogenetic responses. Of all imatinib-resistant and –intolerant patients, 58% achieved MCyR (1 month median time to MCyR), with 72% of patients having a baseline CHR achieving MCyR. The MCyR rate was 63% in imatinibintolerant and 56% in imatinib-resistant patients, respectively. Overall, 42% of patients achieved a CCyR (50% in imatinib-intolerant and 39% in imatinib-resistant patients, respectively). Responses were durable, with 84% of patients maintaining their MCyR at 18 months. Estimated overall survival (OS) rates at 12 and 18 months were 95% and 91%, respectively. Nearly half of all patients (47%) were still receiving nilotinib at the time of cut-off for data analysis. Longer follow-up has not significantly changed the safety profile of nilotinib. The most frequently reported grade 3/4 biochemical laboratory abnormalities were elevated lipase (16%), hypophosphatemia (15%), hyperglycemia (12%), and elevated total bilirubin (7%). Overall, biochemical laboratory abnormalities were transient and clinically asymptomatic. Grade 3/4 non-hematologic adverse events were infrequent with rash, headache, and diarrhea occurring in only 2% of patients. No pleural or pericardial effusions were documented during nilotinib therapy. The most common grade 3/4 hematological laboratory abnormalities included neutropenia (30%), thrombocytopenia (28%), and anemia (10%). Overall, QTcF changes greater than 60 milliseconds from baseline were infrequent, occurring in only 8 patients (2.5%), and QTcF prolongation >500 milliseconds was uncommon (<1%), occurring in only 3 patients. Brief dose interruptions were sufficient to manage most adverse events.Conclusions: Nilotinib is highly effective and produces rapid and durable responses in CML-CP patients who failed prior therapy including imatinib due to resistance or intolerance and is an important treatment option for this patient population. Nilotinib is well tolerated with minimal occurrence of grade 3/4 adverse events; safety profile has not changed with longer follow-up.

Efficacy and Tolerability of Nilotinib in Chronic Myeloid Leukemia Patients in Chronic Phase (CML-CP) Who Failed Prior Imatinib and Dasatinib Therapy: Updated Results of a Phase 2 Study

Background: Treatment options are limited for patients with Philadelphia chromosome-positive (Ph+) CML who are resistant or intolerant to both imatinib and dasatinib. Nilotinib is a potent and highly selective BCR-ABL kinase inhibitor approved for the treatment of Ph+ CML patients in chronic (CML-CP) or accelerated phase (CML-AP) who are resistant or intolerant to prior therapy including imatinib. Here we report the updated results evaluating the safety and efficacy of nilotinib in patients with CML-CP who were either resistant or intolerant to both imatinib and dasatinib therapy.Methods: Nilotinib was dosed at 400 mg twice daily with an option to dose escalate to 600 mg twice daily in patients with inadequate hematologic and/or cytogenetic responses or disease progression.Results: A total of 37 patients (median age 62 years) with CML-CP were included in the analysis. The median time since first diagnosis of CML was 86 months. The median duration of prior imatinib therapy was 40.6 months with 84% being imatinib-resistant and 16% imatinib-intolerant. The median duration of prior dasatinib therapy was 6.6 months, with the majority of patients (65%) being intolerant to dasatinib therapy and 32% of patients were dasatinib resistant. Approximately half (51%) of the patients discontinued dasatinib due to grade 3/4 laboratory abnormalities or adverse events (AEs) and 32% discontinued due to disease progression. The median duration of nilotinib exposure was 218 days (7.3 months; range 43–723 days) and 65% of patients remained on nilotinib at the time of data cut-off. In total, only 4 (11%) patients discontinued nilotinib due to AEs and 9 (24%) discontinued due to disease progression. For CML-CP patients without complete hematologic response (CHR) at baseline, 81% achieved CHR with nilotinib treatment. The median time to first CHR for patients with confirmed HR was 1 month. Major cytogenetic response (MCyR) was achieved in 38% of patients with median time to first MCyR being 1 month and median duration of MCyR being 9.7 months. Complete cytogenetic response (CCyR) was achieved in 18% of patients. Estimated 1-year overall survival was 97%. The most frequent drug-related non-hematologic AEs on nilotinib were rash (22%), nausea (16%), and pruritus (14%). Newly occurring or worsening grade 3/4 hematologic laboratory abnormalities included neutropenia (38%), thrombocytopenia (24%), and anemia (5%). Other common grade 3/4 biochemical laboratory abnormalities included elevated lipase (24%), hyperglycemia (11%), elevated alanine aminotransferase (8%), and hypophosphatemia (8%). Brief dose interruptions were sufficient to manage most adverse events.Conclusions: Nilotinib is highly active in heavily pretreated CML-CP patients who failed both prior imatinib and dasatinib therapy. Importantly, most patients in this study were previously intolerant to dasatinib, and discontinuation of nilotinib in this study was uncommon. These results support nilotinib's significant efficacy and favorable tolerability profile demonstrated in earlier trials with nilotinib as second-line therapy for the treatment of CML-CP. The frequency of adverse events among these heavily pretreated patients is low and similar to patients who failed imatinib only.

Dasatinib or high-dose imatinib for patients with chronic myelogenous leukemia chronic-phase (CML-CP) resistant to standard- dose imatinib: 2-year follow-up data from START-R

7012 Background: Resistance to imatinib is a well-recognized problem in CML-CP. Dasatinib is 325-fold more potent than imatinib against BCR-ABL in vitro is effective in imatinib-resistant CML patients. Prior to dasatinib, imatinib dose escalation to 800 mg/day was the primary option for resistance to standard-dose imatinib. Methods: In this global Phase II study, 150 patients (pts) with CML-CP resistant to imatinib 400–600 mg/d were randomized 2:1 to dasatinib 70 mg BID (n=101) or imatinib 800 mg/d (n=49). The primary endpoint of the study was major cytogenetic response (MCyR) at 12 wks. Crossover was permitted for confirmed progression, lack of MCyR at 12 wks, or intolerance despite dose reduction. MCyR rates at 12 weeks were 36% vs 29%; p=0.4025. Two-year follow-up is now presented. Results: With a minimum follow-up (LPFV to database closure) of 24 mos, MCyR rates were (53% vs 33%, p=0.017) for pts receiving dasatinib and high-dose imatinib, respectively; the difference being attributable to complete cytogenetic responses (44% dasatinib vs 18% imatinib, p=0.0025). Major molecular responses (MMR) were also more frequent with dasatinib (29% vs 12%, p=0.028). Duration of MCyR was greater with dasatinib; 90% of dasatinib pts maintained MCyR at 18 mos vs 74% of imatinib pts. Analysis of progression-free survival at 24 mos favored dasatinib (86% vs 65%, p=0.0012); results were consistent irrespective of the prior imatinib dose received (400 mg/d, p=0.0562; 600 mg/d, p=0.0033). Time to treatment failure also favored dasatinib (proportion of pts without failure at 24 mos: 59% vs 18% p<0.0001). Grade 3–4 non-hematologic toxicity was minimal for both treatment groups. Grade 3–4 cytopenia was more frequent with dasatinib. Discontinuation attributable to toxicity occurred in 22% of pts receiving dasatinib and 20% treated with imatinib. Conclusions: With an extended follow-up of 24 mos, the overall benefit-risk assessment favors dasatinib over high-dose imatinib in CML-CP pts with resistance to 400–600 mg imatinib. The current labelled dose of 100 mg QD was approved based on a subsequent Phase III dose optimization study which showed comparable efficacy with improved tolerability compared with 70 mg BID. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb Bristol-Myers Squibb, Novartis

Nilotinib Is Highly Active and Safe in Chronic Phase Chronic Myelogenous Leukemia (CML-CP) Patients with Imatinib-Resistance or Intolerance.

Background: Nilotinib is a novel, selective BCR-ABL inhibitor, designed to bind the ATP-binding site of BCR-ABL protein with higher affinity than imatinib. It is more potent than imatinib (IC50 <30 nM) against wild-type BCR-ABL and active against 32/33 imatinib-resistant BCR-ABL mutants.Methods: This open-label study was designed to evaluate the safety and efficacy of nilotinib in patients (pts) with Philadelphia (Ph+) imatinib-resistant or -intolerant CML-CP. Planned nilotinib dose was 400 mg twice daily (BID) with escalation to 600 mg BID for inadequate responses. The primary endpoint was the rate of major cytogenetic response (MCyR) determined on the conventional intent-to-treat patient population. Cytogenetic response (CyR) was assessed by bone marrow karyotyping; peripheral blood FISH was used if a marrow sample cannot be obtained.Results: This analysis includes data from 320 pts who received at least 6 months of nilotinib therapy (70.6% imatinib-resistant; 29.4% imatinib-intolerant). The median age was 58 years, the median duration of CML was 57.3 months, and 50.3% were males. Treatment with nilotinib is ongoing in 188 pts (58.8%) and 132 pts (41.3%) discontinued the treatment [51 (15.9%) for disease progression, 51 (15.9%) for adverse events (AE)]. The median duration of nilotinib exposure was 341 (1–624) days and the median average dose intensity was 792.1 mg/d (47.9–1111.6 mg/d). The dose was escalated to 600 mg BID in only 51 pts (15.9%). Complete hematological remission (CHR) at baseline was reported in 114 pts. Of the remaining 206 pts, 157 (76.2%) achieved CHR in 1 month. MCyR was observed in 180 pts (56.3%): 128/320 pts (40.0%) had complete cytogenetic response (CCyR). The median time to CHR and to first MCyR was 1.0 and 2.8 months, respectively. The median duration of MCyR has not been reached. Minor and Minimal CyR was seen in 22 (6.9%) and 42 (13.1%) patients respectively. The most frequent Grade 3/4 hematologic laboratory abnormalities included thrombocytopenia (27%), neutropenia (30%), anemia (9%), and asymptomatic serum lipase elevation (15%).Conclusion: The present study confirms nilotinib is an effective therapeutic option in CML-CP pts with imatinib-resistance or -intolerance, with an acceptable safety and tolerability profile. With longer follow up, cytogenetic response continues to increase and no change in safety profile has been observed on nilotinib therapy.

Efficacy of Dasatinib in Patients with Philadelphia-Chromosome-Positive Acute Lymphoblastic Leukemia Who Are Resistant or Intolerant to Imatinib: 2-Year Follow-Up Data from START-L (CA180-015).

Patients with Philadelphia-chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) generally have a rapid disease course and a poor overall prognosis that is compounded by resistance to imatinib. Dasatinib is a novel multi-targeted kinase inhibitor of BCR-ABL and SRC family kinases, with in vitro potency some 325-fold greater than imatinib against BCR-ABL and proven efficacy in this patient population. START-L is an open-label, international, multicenter study in which patients with imatinib-resistant or -intolerant Ph+ ALL enrolled from January through July 2005 were treated with dasatinib 70 mg BID. Dose escalation to 100 mg BID and reduction to 50 or 40 mg BID were allowed for inadequate response and toxicity, respectively. At the time of this update, all 46 treated patients (median age 48 years; 59% male) had a minimum follow-up of 12 mo. 96% of patients were imatinib-resistant; 46% had received doses of imatinib >600 mg/d, and 52% had received imatinib therapy for >12 mo. Median time from the initial Ph+ ALL diagnosis was 18 mo (range 3–163) and 37% had undergone prior stem-cell transplantation (SCT). BCR-ABL mutations were present at baseline in 78% of patients. The overall major hematologic response rate (MaHR) was 41% with a complete HR rate of 33%. Major cytogenetic response (MCyR) was achieved in 57% of patients with a complete CyR attained in all but one of these patients (54%). Response rates were consistent irrespective of pre-existing BCR-ABL mutations. The median duration of MCyR was 6.9 mo. Median overall survival (OS) was 8.0 mo and 22% of patients remained alive and progression-free after 1 year of treatment. Outcome was favorable for patients with prior SCT: median OS of 9.0 mo (5.8 mo for patients without prior SCT). As expected in these pre-treated patients, grade 3–4 cytopenias were significant with 78% of patients experiencing severe thrombocytopenia and neutropenia. Non-hematologic side-effects included diarrhea in 33% of patients (grade 3–4 in 9%), pleural effusion in 24% (grade 3–4 in 7%), nausea in 22% (no grade 3-4), and pyrexia in 22% (grade 3–4 in 2%). The dose of dasatinib was reduced in 30% of patients and interrupted in 43%; this was primarily attributable to non-hematologic toxicities. This resulted in a median of the average daily dose of 143 mg. Dasatinib continues to show impressive efficacy in this poor-prognosis patient population with Ph+ ALL after the failure of imatinib. Updated analyses corresponding to a minimum follow-up of 2 years will be presented.

A randomized study of interferon-α versus interferon-α and low-dose arabinosyl cytosine in chronic myeloid leukemia

Interferon-alpha (IFN-alpha) has significantly prolonged survival in chronic myeloid leukemia (CML), but some patients do not respond and many responses are not durable. To improve the results, IFN-alpha has been combined with other treatments, but so far only the association with low-dose arabinosyl cytosine (LDAC) has been shown to increase the response rate and to prolong survival. Here are reported the results of a study of 538 Philadelphia chromosome-positive CML patients who were assigned at random to treatment with IFN-alpha 2a alone or in combination with LDAC. The scheduled dose of IFN-alpha 2a was 5(6) IU/m(2)/d. The scheduled dose of AC was 40 mg/d for the first 10 days of each month of treatment. The efficacy endpoints were a complete hematologic response rate at 6 months (62% in the IFN-alpha-plus-LDAC arm versus 55% in the IFN-alpha arm; P =.11), major cytogenetic response (MCgR) rate at 24 months (28% versus 18%; P =.003), and overall survival (5-year survival, 68% versus 65%; P =.77). Treatment did not affect overall survival within different prognostic risk groups: low, intermediate, or high. Also the duration of MCgR was identical. The results of this study confirm the results of a similar French study only for the response rate, not for survival, suggesting that the relationship between cytogenetic response and survival may be extremely variable and that a meta-analysis of these and other studies of IFN-alpha versus IFN-alpha plus LDAC is required to settle the issue of the role of LDAC in the treatment of CML.