Major Cytogenetic Response Rate Research Articles

Dasatinib Dose-Optimization in Chronic Phase Chronic Myeloid Leukemia (CML-CP): Two-Year Data from CA180-034 Show Equivalent Long-Term Efficacy and Improved Safety with 100 Mg Once Daily Dose

Dasatinib (SPRYCEL®) is an effective BCR-ABL inhibitor and is 325-fold more potent than imatinib in vitro against unmutated BCR-ABL. CA180-034 is a randomized, phase III, open-label study in patients with CML-CP (N=670) who have resistance, suboptimal response, or intolerance to prior imatinib 400–800 mg/d. Patients were randomized using a 2×2 factorial design to one of four treatment arms: 100 mg once daily (QD), 70 mg twice daily (BID), 140 mg QD, or 50 mg BID. Time to and duration of response, progressionfree survival (PFS), and overall survival (OS) were estimated using Kaplan-Meier analysis. Earlier reports demonstrated that dasatinib 100 mg QD (the currently approved dose in CML-CP) maintains efficacy while significantly minimizing adverse events (AEs). This finding was supported by pharmacokinetic analyses, which have demonstrated a correlation between low dasatinib steady-state trough plasma concentration (achieved with 100 mg QD dosing) and less frequent key toxicities and fewer dose interruptions. With a minimum of 2 years of follow-up in all patients, dasatinib 100 mg QD treatment resulted in a MCyR rate of 63% and a CCyR rate of 50%, and rates were similar in the other 3 arms (MCyR: 61%–63%; CCyR 50%–54%) (Table). Rates were similar when 14 patients with Ph-negative BCR-ABL-positive disease were excluded. Among responding patients in the 100 mg QD arm, median time to MCyR was 12.4 weeks and to CCyR was 13.0 weeks, and after 24 months, 87% of patients had maintained their MCyR and 89% had maintained their CCyR, with similar results in other arms. The 24-month PFS rate with 100 mg QD was 80% (vs 75%–76% in other arms) and OS rate was 91% (vs 88%–94%). In all arms, high response rates were achieved in patients with or without a baseline BCR-ABL mutation (CCyR rates for 100 mg QD: 40% vs 54%, respectively). Dasatinib was well tolerated and the incidence of treatment-related AEs after a minimum of 2 years of follow-up was similar to rates after a minimum of 1 year. In the 100 mg QD arm, overall 2-year rates (vs 1 year) were 2% (vs 2%) for grade 3 pleural effusion (grade 4: 0%), 23% (vs 22%) for grade 3/4 thrombocytopenia, and 35% (vs 34%) for grade 3/4 neutropenia. Among the 4 treatment arms, significant differences were observed in the overall incidences of drug-related pleural effusions (all grades: p=0.049) and cytopenias (p=0.003 for grade 3/4 thrombocytopenia), with lowest rates observed for 100 mg QD. After a minimum of 2 years of 100 mg QD treatment, 12% of patients discontinued therapy following drug toxicity (vs 6% after 1 year), compared with 2-year rates of 16%–21% in other arms. Overall, 2-year data from CA180-034 extend previous findings and demonstrate that dasatinib dose optimization at 100 mg QD is associated with minimal incidence of key grade 3/4 toxicities in Year 2, and maintains long-term efficacy, in patients with CML-CP following resistance, suboptimal response, or intolerance to prior imatinib. Response duration and PFS with dasatinib 100 mg QD are similar to other dose schedules.Table100 mg QD70 mg BID140 mg QD50 mg BIDAll randomized patientsn=167n=168n=167n=168CHR (%)92888792MCyR (%)63616361Median time to MCyR (wks)12.412.312.312.3MCyR maintained at 24 mos (%)87886888CCyR (%)50545050Median time to CCyR (wks)13.012.913.812.9CCyR maintained at 24 mos (%)8985789324-month PFS (%)8076757624-month OS (%)91889490Excluding Ph(−) BCR-ABL(+)n=164n=163n=163n=166MCyR (%)63616361CCyR (%)49535050All treated patientsn=165n=167n=163n=167Pleural effusion (drug-related), grade 3/4 (%)2554Neutropenia, grade 3/4 (%)35454447Thrombocytopenia, grade 3/4 (%)23384136Dose interruption (%)62777972Dose reduction (%)39626246

Tasigna for Chronic and Accelerated Phase Philadelphia Chromosome–Positive Chronic Myelogenous Leukemia Resistant to or Intolerant of Imatinib

This Food and Drug Administration (FDA) approval report describes the data and analyses leading to the approval by the FDA of nilotinib (Tasigna, AMN-107; Novartis Pharmaceuticals Corporation), an inhibitor of Bcr-Abl tyrosine kinase, for the treatment of chronic-phase (CP) and accelerated-phase (AP) chronic myelogenous leukemia (CML) resistant to or intolerant of imatinib. The FDA approval of the efficacy and safety of nilotinib was based on the results of an ongoing single-arm, open-label, phase 2 clinical trial. The primary end point for CML-CP was unconfirmed major cytogenetic response. The efficacy end point for CML-AP was confirmed hematologic response. The major cytogenetic response rate in 232 evaluable CP patients was 40% (95% confidence interval, 33%, 46%). The hematologic response rate in 105 evaluable AP patients was 26% (95% confidence interval, 18%, 35%). The median duration of response has not been reached for both CML-CP and CML-AP responding patients. In CML-CP patients, the common serious drug-related adverse reactions were thrombocytopenia and neutropenia. In CML-AP patients, the common serious drug-related adverse reactions were thrombocytopenia, neutropenia, pneumonia, febrile neutropenia, leukopenia, intracranial hemorrhage, elevated lipase, and pyrexia. Nilotinib prolongs the QT interval and sudden deaths have been reported; these risks and appropriate risk minimization strategies are described in a boxed warning on the labeling. On October 29, 2007, the U.S. FDA granted accelerated approval to nilotinib (Tasigna) for use in the treatment of CP and AP Philadelphia chromosome positive CML in adult patients resistant to or intolerant of prior therapy that included imatinib.

A phase II study of continuous infusion homoharringtonine and cytarabine in newly diagnosed patients with chronic myeloid leukemia: CALGB study 19804

Both homoharringtonine (HHT), an alkaloid derivative from the Chinese yew tree that inhibits protein synthesis, and low-dose cytarabine have independent activity in CML and have been used in combination after failure of interferon therapy. The CALGB performed a phase II trial of HHT (2.5 mg/m(2) per day) plus cytarabine (7.5 mg/m(2) per day), given together via continuous intravenous infusion for 7 days in previously untreated patients with Ph chromosome positive chronic phase CML. HHT/cytarabine cycles were repeated every 28 days if the blood counts were adequate. The primary endpoint was the major cytogenetic response rate after 9 months. Forty of the 44 enrolled patients required reduction in the infusion duration during at least one cycle. Myelosuppression was common; 66% developed neutrophil count <500/microl, but grade 3 infections occurred in only 7%. Thirty-six of 44 patients (82%) achieved a complete hematologic remission; the median duration has not been reached. Only 4 of the 23 patients (17%) having adequate cytogenetic response assessment achieved a major response within nine cycles. Although HHT/cytarabine was generally well tolerated, the cytogenetic response rate did not exceed the level previously seen in patients with interferon-refractory CML and was not nearly as high as associated with imatinib in newly diagnosed patients.

Successful Use of National Cancer Registry Data to Monitor the Effective Use of Imatinib for Treating Chronic Myeloid Leukaemia

Imatinib is a tyrosine kinase inhibitor, which selectively antagonises the BCR-ABL molecular pathway which causes chronic myeloid leukaemia (CML). Imatinib was first approved by the Scottish Medicines Consortium (SMC) in January 2002 with the recommendation that its use be audited. The cost of the drug has major financial implications for health resources. All imatinib usage since its first prescription in Scotland in September 2000 to July 2003 was audited through pharmacy records and through the Scotland Leukaemia Registry (SLR), an existing national registry of patients with CML. One hundred and four patients in Chronic Phase (CP), 36 in Accelerated Phase (AP) and five in Blast Phase (BP) received imatinib. The median duration of therapy was not reached for CFP 17 months for AFP and two months for BP patients. Major (complete) cytogenetic response rates were 74% (63%) and 38% (24%) respectively for CP and APR Overall survival for all CP patients from the start of imatinib therapy was 94% at one year, 91% at two years and 83% at three years. An audit of the effectiveness of the SLR as an auditing agency, showed complete registration in 95% of cases. We believe such data collection should be an important ongoing resource for assessing outcomes in a rare form of leukaemia but one which already has major implications for health economics and will continue to do so given the future development of dual tyrosine kinase inhibitors for imatinib resistant cases.

Dasatinib 2-year efficacy in patients with chronic-phase chronic myelogenous leukemia (CML-CP) with resistance or intolerance to imatinib (START-C)

7009 Background: Dasatinib is 325-fold more potent than imatinib and 16-fold more potent than nilotinib against BCR-ABL in vitro. Extended 2-year follow-up data are available for the START-C study, an international, 75-center, phase II study in patients (pts) with CML-CP resistant or intolerant to imatinib. Methods: Pts were required to be either imatinib-resistant or -intolerant. The starting dose was dasatinib 70 mg BID, with dose escalations (90 mg BID) or reductions (50 or 40 mg BID) allowed for lack of response or toxicity. The primary endpoint was major cytogenetic response rate (MCyR). Results: Median time from CML diagnosis at baseline was 61 mos (range 3- 251). Best response to prior imatinib therapy was complete hematologic response (CHR) in 82%, complete cytogenetic response (CCyR) in 19%, and MCyR in 37% of pts. After a minimum follow up of 24 mos (LPFV to database closure; n=387, 288 imatinib-resistant, 99 imatinib-intolerant), CHR was noted in 91% (95% CI 88–94%), MCyR in 62% (95% CI 57–67%), CCyR in 53% and major molecular response (MMR) in 47% of pts. Rates of MCyR were 55% for imatinib-resistant pts, and 63% for pts with baseline BCR-ABL mutations; responses were seen across all mutations except T315I. In imatinib-intolerant pts, the CCyR (n=99) rate and MMR (n=94 evaluable) rate were both 78%. MCyRs were durable, with 88% of pts maintaining response at 24 mos. Progression-free survival (PFS) at 24 mos was 80% (75% in imatinib-resistant and 94% in imatinib-intolerant pts). Overall survival at 24 mos was 94% (92% in imatinib -resistant and 100% in imatinib-intolerant pts). Grade 3–4 toxicities included thrombocytopenia (49%) and neutropenia (50%), pleural effusion (9%), dyspnea (6%), bleeding (4%), diarrhea (3%), and fatigue (3%). 3% of imatinib-intolerant pts developed similar grade 3–4 toxicities; all were able to continue treatment after dose reduction, demonstrating lack of cross intolerance. The appearance of new higher grade toxicity between 12 and 24 months was uncommon. Conclusions: Dasatinib is well-tolerated in pts with CML-CP and induces cytogenetic responses that are highly durable and result in a PFS of 80% at 24-mos. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Bristol-Myers Squibb Bristol-Myers Squibb, Novartis Bristol-Myers Squibb Bristol-Myers Squibb, Novartis Bristol-Myers Squibb, Novartis Bristol-Myers Squibb

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 in patients with imatinib-resistant or -intolerant chronic myelogenous leukemia in chronic phase (CML-CP): Updated phase II results

7010 Background: Nilotinib, a potent and highly selective BCR-ABL inhibitor, has been approved in both the US and Europe for the treatment of patients (pts) with CML-CP and accelerated phase CML (CML-AP) who are resistant or intolerant to prior therapy, including imatinib. Methods: This phase 2, open-label study was designed to evaluate the efficacy and safety of nilotinib in pts with Philadelphia chromosome-positive (Ph+) imatinib-resistant or -intolerant CML-CP. Nilotinib was administered at 400 mg twice daily (BID), with the possibility to dose escalate to 600 mg BID for inadequate responses. The primary endpoint was the rate of major cytogenetic response (MCyR). Results: Included in this analysis were 321 pts (71% imatinib-resistant; 29% imatinib-intolerant). 72% of pts received prior imatinib doses > 600 mg. Of the 206 pts who did not have complete hematological remission (CHR) at baseline, 158 (77%) achieved CHR during nilotinib therapy. Overall, MCyR was observed in 184 pts (57%); 41% had complete CyR. MCyR was observed in 125 (55%) of the 227 imatinib-resistant pts and in 59 (63%) of the 94 imatinib-intolerant pts. The median time to CHR and MCyR was 1.0 and 2.8 months, respectively. The majority of pts (84%) maintained MCyR for at least 18 months. At 18 months, the estimated overall survival rate was 91%. Treatment with nilotinib is ongoing in more than half of pts enrolled. The most frequent grade 3/4 laboratory abnormalities were thrombocytopenia (28%), neutropenia (30%), and asymptomatic serum lipase elevation (15%). Grade 3/4 non-hematologic AEs were rare and included rash, headache, and diarrhea. A low incidence of QT prolongation (QTcF > 500 msec, < 1%) was observed overall. The safety profile of nilotinib has not changed with increased follow up. There was minimal cross-intolerance between nilotinib and imatinib in pts intolerant to prior imatinib treatment. Conclusions: The present study confirms that nilotinib induces significant and durable responses in CML- CP pts with imatinib-resistance or -intolerance. Nilotinib is well tolerated, with minimal occurrence of grade 3/4 AEs and minimal cross-intolerance to imatinib, and is a valuable new treatment option for this pt population. Author Disclosure Employment or Leadership Consultant or Advisory Role Stock Ownership Honoraria Research Expert Testimony Other Remuneration Novartis Bristol-Myers Squibb, Novartis Bristol-Myers Squibb, Novartis Bristol-Myers Squibb, Innovive, Merck, Novartis, Wyeth

Dasatinib efficacy by dosing schedule across individual baseline BCR-ABL mutations in chronic phase chronic myelogenous leukemia (CML-CP) after imatinib failure

7014 Background: Dasatinib is 325-fold more potent than imatinib and 16-fold more potent than nilotinib against unmutated BCR- ABL in vitro and has demonstrated efficacy in CML-CP patients (pts) resistant or intolerant to imatinib. Dasatinib's current labeled dose of 100 mg once daily reflects findings of a randomized phase III dose optimization study showing similar efficacy and less-frequent key side effects compared with 3 other dosing schedules. Here, we analyze efficacy according to frequently occurring individual baseline BCR-ABL mutations in this study (CA180–034). Methods: The study design has been described previously. Pts were randomized using a 2x2 factorial design to 100 mg or 140 mg dasatinib per day and to a once-daily vs twice-daily schedule. Samples were tested for the presence of point mutations in BCR-ABL by direct sequencing. Results: 670 pts were randomized, of which 581 had a baseline mutation analysis and 1-year cytogenetic response data available. For the 100 mg QD, 70 mg BID, 140 mg QD, and 50 mg BID groups, the overall major cytogenetic response (MCyR) rates were 62%, 58%, 63%, and 56%, respectively (not significant). MCyR by individual baseline mutations observed in ≥15 pts is shown. Conclusions: Dasatinib 100 mg once daily leads to MCyR across individual baseline BCR-ABL mutations except T315I, including those occurring in the P-loop region, and the MCyR rate appears similar to the 3 other dosing schedules. MCyR, n/N (%) pts Mutation 100 mg QD N=147 70 mg BID N=146 140 mg QD N=139 50 mg BID N=149 M244V 3/6 1/5 4/7 2/2 G250E 3/5 3/10 3/9 2/7 E255K/V 1/3 2/2 1/2 2/8 Any P-loop (residues 248–256) 5/8 9/17 6/17 5/17 T315I 0/5 0/1 1/4 0/5 M351T 1/7 4/8 5/8 8/10 F359C/I/V 5/8 6/9 2/3 7/10 H396P/R 4/5 1/2 2/4 2/5 Any 26/49 (53) 21/46 (46) 29/51 (57) 26/61 (43) 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, Novartis Bristol-Myers Squibb, Innovive, Merck, Novartis, Wyeth

Kinetic of chronic myeloid leukaemia (CML) prevalence in Northern France since the introduction of imatinib

7088 Background: We conducted a retrospective study in the Nord Pas de Calais (NPC) area of France (4 millions inhabitants) in order to assess the CML prevalence since the introduction of imatinib in 2000. Methods: We recorded from 1985 to 2006 all new CML cases living in the NPC confirmed either by cytogenetic or molecular tests. Age-standardized incidence rates were calculated on the basis of the standard world population (1990–2005 period). The raw prevalence rates were calculated year by year for the last ten years, considering the known pts diagnosed before 1985 and still alive and the possible geographic mobility of the pts. Results: 906 newly diagnosed pts were identified, corresponding to a mean age-standardized incidence rate of 0.84/100 000 person-year. Survival data were obtained for 865 (95.5%) of them. 145 pts (16%) underwent allogeneic SCT, 387 pts (42.7%) were treated with interferon (median 13.2 months, 0–157), and 416 pts (46%) were treated with imatinib (median 37.3 months, 0.1–90). In the cohort of early chronic phase CML patients treated by imatinib the rates of major and complete cytogenetic responses are respectively 75.3% (186/247) and 70.8% (175/247) and the overall 5 years survival is 82.3%. The annual CML prevalence rates (/100 000 inh.) from 1998 until 2007 are respectively (frequency of patients on imatinib (%) and mean daily dose (mg)) : 5.76 (NA-NA), 5.78 (NA-NA), 6.17 (NA-NA), 6.48 (20–448), 6.77 (15.1–449), 7.31 (50.3–410), 7.97 (62.3–403), 8.83 (67.7–421), 9.75 (65.5–416) and 10.42 (67.3–420). The mean annual increase of the prevalence is 4.1% during 1998–2002 and 9.3% during 2003–2007. Conclusions: The progression of CML prevalence in the NPC greatly accelerated after 2002, which was concomitant to a large imatinib use and may have a substantial medico-economic impact. The complete results of this unique epidemiological study will be presented at the ASCO meeting. 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

Favorable long-term follow-up results over 6 years for response, survival, and safety with imatinib mesylate therapy in chronic-phase chronic myeloid leukemia after failure of interferon-α treatment

AbstractImatinib mesylate, a targeted inhibitor of BCR-ABL tyrosine kinase, is the standard of care for chronic myeloid leukemia (CML). A phase 2 trial of imatinib in late chronic-phase (CP) CML after interferon-α (IFNα) failure enrolled 532 patients, 454 with a confirmed diagnosis of CP CML. Median time from diagnosis was 34 months; median duration of imatinib treatment was 65 months. Cumulative best rates of major cytogenetic response (MCyR) and complete cytogenetic response (CCyR) were 67% and 57%, respectively. At the 5-year landmark, 184 (41%) of the 454 patients are in CCyR. At more than 6 years, 199 (44%) of the 454 patients remain on imatinib. Most responses occurred within 12 months of starting imatinib; however, some patients achieved initial MCyR and CCyR more than 5 years after imatinib initiation. Estimated rates of freedom from progression to accelerated phase (AP) and blastic phase (BP) and overall survival at 6 years were 61% and 76%, respectively. Both freedom from progression to AP/BP and overall survival (OS) were associated with cytogenetic response level at 12 months. No increase in rates of serious adverse events was observed with continuous use of imatinib for up to 6.5 years, compared with earlier time points. Imatinib continues to be an effective and safe therapy for patients with CP CML after failure of IFN.

Sprycel for Chronic Myeloid Leukemia and Philadelphia Chromosome–Positive Acute Lymphoblastic Leukemia Resistant to or Intolerant of Imatinib Mesylate

On June 28, 2006, the U.S. Food and Drug Administration approved dasatinib (Sprycel; Bristol-Myers Squibb), a new small-molecule inhibitor of multiple tyrosine kinases, for the treatment of adults with chronic phase, accelerated phase, or myeloid or lymphoid blast phase chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+) ALL) with resistance or intolerance to prior therapy including imatinib. This summary reviews the database supporting this approval. Four single-arm multicenter studies supported the efficacy and safety of dasatinib. The primary efficacy end point in chronic phase CML was major cytogenetic response. The primary end point in accelerated phase, myeloid phase, and lymphoid blast phase CML, and Ph(+) ALL was major hematologic response. The four studies combined enrolled 445 patients. In patients with chronic phase CML, the major cytogenetic response rate was 45% with a complete cytogenetic response rate of 33%. Major hematologic response rates in patients with accelerated phase CML, myeloid CML, lymphoid blast CML, and Ph(+) ALL were 59%, 32%, 31%, and 42%, respectively. Median response durations in chronic phase, accelerated phase, and myeloid phase CML had not been reached. The median durations of major hematologic response were 3.7 months in lymphoid blast CML and 4.8 months in Ph(+) ALL. Common toxicities with dasatinib included myelosuppression, bleeding, and fluid retention. This report describes the Food and Drug Administration review supporting the approval of dasatinib for CML and Ph(+) ALL based on the rates and durability of cytogenetic and hematologic responses.

Nilotinib

Nilotinib is an orally administered BCR-ABL tyrosine kinase inhibitor that has shown good clinical efficacy in imatinib-resistant or -intolerant, Philadelphia chromosome-positive, chronic myeloid leukaemia (CML) in a phase I/II trial. The phase I component of the trial established the dosage regimen used in the phase II part of the trial, which included several arms. Three of these arms, or phase II trials, evaluated nilotinib in each of the three phases of CML (chronic, accelerated or blast crisis).I n the phase II trial in patients with chronic-phase CML, major cytogenetic response (primary endpoint) was achieved in 48% of the 280 patients who received nilotinib and had a follow-up period of > or = 6 months. Major cytogenetic response rates did not differ between imatinib-resistant and -intolerant patients, and nilotinib was effective in patients with BCR-ABL mutations (except T315I). Haematologic response rate (primary endpoint) was 47% in the phase II trial with nilotinib in patients with accelerated-phase CML (n = 119). Complete haematologic response was achieved in 26% of patients and 21% had no evidence of leukaemia or returned to chronic-phase CML. Major cytogenetic response, an important secondary endpoint in the trial, occurred in 29% of patients. Data from the phase II trial in patients with CML in blast crisis (n = 135) also showed promising results, with 39% of patients achieving haematologic response with nilotinib. Adverse events reported with nilotinib have generally been of mild to moderate severity. Grade 3 or 4 neutropenia and thrombocytopenia were reported in 29% of patients each.

Dasatinib

Dasatinib is a small-molecule inhibitor of multiple tyrosine kinases, including BCR-ABL, SRC, c-KIT, ephrin A receptor and platelet-derived growth factor-beta receptor kinases, at nanomolar concentrations. In vitro, dasatinib is 325-fold more potent than imatinib against cells expressing wild-type BCR-ABL. The efficacy and tolerability of oral dasatinib has been established in the START phase II trials in adults with chronic myeloid leukemia (CML) or Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph-positive ALL) who were intolerant or resistant to imatinib, and optimal dasatinib dosage regimens were identified in phase III randomized trials. In patients with chronic phase CML, the major cytogenetic response rate in the START-C trial (median follow-up 15.2 months) was 59% with dasatinib, and in the randomized START-R trial (median follow-up 15 months), was greater with dasatinib than with high-dose imatinib (52% vs 33%). Major hematologic response rates with dasatinib were 63% in patients with accelerated phase CML (follow-up > or =9 months; START-A trial), 34% in patients with myeloid blast phase CML and 35% in those with lymphoid blast phase CML (follow-up > or =12 months; START-B and START-L trials), and 41% in patients with Ph-positive ALL (follow-up > or =12 months; START-L trial). Based on phase III results, a once-daily dasatinib regimen is considered optimal in chronic phase CML (starting dosage 100 mg once daily), while a twice-daily regimen continues to be recommended in accelerated phase, myeloid blast phase or lymphoid blast phase CML and Ph-positive ALL (starting dosage 70 mg twice daily). Adverse events were frequent in patients treated with dasatinib, but most were mild to moderate in severity. Grade 3/4 adverse events were uncommon and were clinically manageable.

Efficacy of Imatinib Mesylate Dose-Escalation in CML Patients Showing Suboptimal Response to Standard Dose.

Introduction: We report the results of our prospective single arm study performed to evaluate the efficacy of Imatinib mesylate (IMT) dose-escalation therapy and the influence of BCR/ABL mutational status on the treatment outcome.Methods: Patients with chronic phase(CP) chronic myelogenous leukemia (CML) who had not achieved a complete hematologic response (CHR) after 3 months, a major cytogenetic response (MCyR) after 6 months, nor a complete cytogenetic response (CCyR) after 6-12 months of standard IMT therapy (400mg per day) were included. Patients in accelerated phase (AP) or blast crisis (BC) who had failed to achieve CHR after 3 months of IMT (400 or 600mg per day) were also eligible. 600mg of IMT had been administered for patients with CP CML per day, and 600mg or 800mg for AP or BC CML for at least 12 months. For each patient, BCR/ABL gene mutation test was performed on 6 loci. Cytogenetic response (CyR) was evaluated with the percentage of bcr/abl positive cells in bone marrow aspirate by means of FISH per 6 months. Molecular responses (MR) were assessed per 3 months with a logarithmic decrease in BCR-ABL/ABL gene ratio (BA/A) of peripheral blood or bone marrow aspirate from a standardized median value of BA/A in 56 patients with newly diagnosed CML.Results: 77 patients were enrolled and 61 patients were assessable for the evaluation of MR. The median age was 50 years old (range: 20-70). Stages at the time of the enrollment were CP for 56, AP for 4, BC for 1 patient(s). The median time from the initiation of IMT therapy to dose-up was 20 months (range: 0-62). BCR/ABL gene mutational status could be obtained in 24 patients (wild:mutant=20:4). The median follow-up was 19.9 months (range: 6.5-24.3). For 34 patients whose 6th-month CyR is available, MCyR rate (MCyRR) was 26.5% and CCyR rate (CCyRR) was 23.5%. The 12th-month MCyRR was 61.1% and CCyRR was 50.0%. Patients with wild type showed a MCyRR of 20% and a CCyRR of 15% on the 12th month after dose-up, whereas no patient with mutant type showed a CCyR or a MCyR. CMR rate and MMR rate on the 12th-month were 16.7% and 26.7%. Among 20 patients with wild type, one patient achieved a 6th-month CMR, 2 patients MMR's, whereas no patient with mutant type could achieve a MMR during the entire treatment period. Hematologic and non-hematologic toxicities were tolerable.Conclusion: IMT dose-escalation could induce quite a number of durable CyR's and MR's without any serious toxicity in patients who had failed to achieve either a CHR or a CyR with a standard IMT therapy.

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.

Long-Term Significance of Achieving a Major Cytogenetic Response (MCyR) without a Complete Hematologic Response (CHR) among Patients (pts) with Chronic Myeloid Leukemia (CML) in Advanced Phase Treated with Second Generation Tyrosine Kinase Inhibitors (TKI).

The BCR-ABL TKI, dasatinib (D) and nilotinib (N), are effective in Philadelphia chromosome-positive (Ph+) leukemias, including all stages of imatinib-resistant CML and Ph+ ALL. For both dasatinib and nilotinib, the reported rates of MCyR are higher than the rates of CHR; that is, some pts achieve MCyR but may have cytopenias that make their hematologic response less than a CHR; this has been attributed to myelosuppression induced by TKI. At present it is not known whether pts with MCyR who do not have CHR have a similar outcome as those with a CHR. We studied 135 pts with accelerated (AP; n=84) or blast phase (BP; n=47) CML or Ph+ ALL (n=4) treated with D (59) or N (76) for imatinib resistance, to see whether the presence of cytopenias at the time of best response affected the prognosis. The median age was 55 yrs (range, 15 to 98) and 62 were female. 56 (41%) had bcr/abl mutations at the start of therapy. Overall 36 pts (27%) achieved MCyR. All the 36 pts who achieved a MCyR after treatment with N or D had received imatinib for an average time of 34 mos (range 4–78) and 24/36 pts had obtained a MCyR under imatinib. They started the new TKI 66 mos after first diagnosis (12–336). 2-yr survival rates for pts that achieved MCyR was 72% compared to 35% for those without MCyR (p<0.001). There was a trend for an inferior survival for those not having a concomitant CHR at the time of MCyR compared to those with CHR (2-yr survival 58% vs 82%; p=0.11). The rates of CHR and MCyR were 68% and 29%, respectively in AP; 32% and 21% in BP, and 50% and 50% in Ph+ ALL. Among pts in AP, 17/24 (70%) who achieved a MCyR, had a CHR at the time of best cytogenetic response; 6 of these 17 (35%) pts eventually failed (lost response or transformed), compared to 3/7 (43%) of those with no CHR at the time of MCyR (p=0.28). The results are similar when analyzing separately pts treated with N or D. 2-yr survival was 88% and 66% for those with and without concomitant CHR (p=0.29). Among the 10 pts in BP that achieved a MCyR, 5 had a CHR at the time of best cytogenetic response. Three (60%) of these pts eventually failed (lost response), compared to 4 failures among the 5 pts with no CHR at the time of MCyR (p=1.0). Survival rates at 2 yrs were 60% and 40% for those with and without concomitant CHR (p=0.29). Among the 2 patients with ALL that achieved MCyR, one had comcomitant CHR (treated with N) and the other did not have CHR (D); both of them failed. Of the 18 pts who failed after having achieved an MCyR, 7 had a mutation before starting treatment with a 2nd TKI (A433T, G250E, E355G, E459K, M244V, M315T, F317L), and 6 developed a new mutation after treatment (F317L, F311I, Y253H, G476C, E255K, H359V). Five of them occurred in pts with a concomitant CHR and 1 without a CHR. These results suggest that achievement of MCyR with residual cytopenias (ie, without a concomitant CHR) may not have the same favorable outcome as that of MCyR with concomitant CHR. Whether this is related to pt- or disease-related characteristics remains to be determined.

Lower Dose of Imatinib Provides Outcomes Similar to the Standard Dose Imatinib in Japanese Patients with Early Chronic-Phase CML: The Interim Analyses of JALSG CML202 Study.

Background: The dose of imatinib 400 mg is considered to be standard for chronic-phase chronic myeloid leukemia (CML) based on the IRIS study. However, the optimal dose of imatinib is not yet settled and the response of lower dose imatinib has not been investigated. Lower dose of imatinib might be enough in Asian patients since the results of PK in IRIS study showed weak correlation between imatinib trough level and body weight. We showed the results of the interim analysis of JALSG CML202 study and analyzed the efficacy of imatinib according to the mean daily dose level.Methods: The objectives of CML202 study are to determine the efficacy of imatinib monotherapy in patients with newly diagnosed chronic-phase CML, and to test whether combining imatinib with IFN or cytarabine ocfosfate overcome the resistance of imatinib and to estimate the frequency and severity of toxicities. Primary end point of imatinib monotherapy was overall survival, and that of combination therapy was cytogenetic response after 9 months. Newly diagnosed patients with chronic phase CML will receive imatinib at a dose of 400mg daily. At 9 months, if patients don't achieve major cytogenetic response (MCR), they were randomized to the combination therapies, imatinib plus conventional IFN or imatinib plus cytarabine ocfosfate.Results: From 2002 to 2006, 489 patients were enrolled to this study. On July 2007, 36 months median follow-up data were analyzed. Only 2 patients were enrolled to the combination therapy because a majority of patients achieved good response. 13 patients underwent HSCT. The estimated cumulative rates of complete hematologic response (CHR), MCR and complete cytogenetic response (CCR) were 97%, 97% and 91%, respectively. The estimated major molecular response (MMR) rate at 24 months was 55%. The estimated survival without AP/BC progression rate at 60 months was 94%. The overall estimated survival at 60 months was 94%. 95% of low risk patients achieved CCR significantly as compared with intermediate and high-risk patients according to Sokal risk. The mean daily dose of imatinib for the first 2 years was 400mg or more in 54% patients (400mg group), 300–399mg in 27% (300mg group), 200–299mg (200mg group) in 11%, and 100–199mg in 9% (100mg group), respectively. The cumulative rate of MCR and CCR at 60 months was 99% and 97% in 400mg group, 99% and 98% in 300mg group, 92% and 85% in 200mg group, and 81% and 48% in 100mg group, respectively (p=0.003 and p<0.0001). The cumulative rate of MMR at 18 months was 33% in 400mg group, 33% in 300mg group, 27% in 200mg group and 0% in 100mg group, respectively. The estimated rate of overall survival and progression-free survival at 60 months was 97% and 97% in 400mg group, 98% and 98% in 300mg group, 92% and 92% in 200mg group, and 87% and 87% in 100mg group, respectively (p=0.0002 and p=0.0009).Conclusion: The results of interim analyses of JALSG study were almost similar to those of IRIS study. However, the mean daily dose of imatinib was lower in our study than in IRIS study. The patients received imatinib 300mg showed outcomes similar to 400mg, suggesting that imatinib 300mg might be enough for Japanese patients. The comparative studies with PK measurement will ellucidate the optimal dose of imatinib.

Prognostic Significance of Prior Best Response to Imatinib in Patients (pts) with Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) Treated with Second Generation Tyrosine Kinase Inhibitors (TKIs).

Backgound. Imatinib mesylate therapy has significantly improved the prognosis of CML. A minority of pts in CP-CML are primary resistant to imatinib or develop resistance during treatment. Second generation TKIs such as dasatinib and nilotinib demonstrated efficacy in overcoming imatinib resistance, with high rates of hematologic and cytogenetic responses in CML post imatinib failure.Study Aims and Study Group. We assessed the impact of prior best response to imatinib on outcome of 120 pts in CP treated with new TKIs at our institution after imatinib failure: 75 (62%) received dasatinib and 45 (38%) recived nilotinib. Median age was 57 years (range, 21–83). The median duration of the disease was 67 months (range, 4–241). Pts have been followed for a median of 22 months (range, 1–44) from the start of 2nd generation TKIs.Results. Best response to imatinib was hematologic in 47 pts (40%) and cytogenetic in 60 (50%) (complete in 28, partial in 16, minor in 16). Five pts (4%) were primary refractory and 8 (6%) were intolerant. At the start of 2nd generation TKIs, 87 pts (73%) were in active CP with no complete hematologic response (CHR). Eighty-five (71%) harbored more than 90% Philadelphia-positive metaphases, and clonal evolution was noted in 28 pts (23%). Patients that had achieved a cytogenetic response at any time during their imatinib therapy had a better outcome than those who had only a hematologic response: CHR rates 98% vs 68%, p <0.001; major cytogenetic response (MCyR) rates 75% vs 26%, p<0.001; and complete cytogenetic response (CCyR) rates 68% vs 23%, p<0.001. This translated into an improved 12-month event-free survival (EFS) of 92% vs 68% (p<0.001) and a trend for better 12-month survival of 92% vs 89% (p=0.06) (Table1). Pts with CHR at the start of therapy with 2nd generation TKIs had higher rates of cytogenetic response than those not already in CHR (88% vs 64%; p=0.01). Low disease burden defined by Philadelphia-positive metaphases <90% was associated with higher rates of hematologic response (p=0.006), MCyR (p<0.001) and CCyR (p=0.003), with no impact on EFS. There was no difference in activity between the two 2nd generation TKIs with CHR rates of 89% and 80% (p=0.18), MCyR rates of 57% and 51% (p=0.57) and CCyR rates of 52% and 47% (p=0.71) for dasatinib and nilotinib, respectively.Conclusion. The probability of response to 2nd generation TKIs is highly dependent on prior response to imatinib and disease burden at the start of therapy.Table 1% CG response% 12-MonthBest response to imatinibN% CHRMajorCompleteEFSSurvivalNo CHR48040408080CHR326826236889Any CG response599875689292P-value<0.001<0.001<0.001<0.0010.06EFS=Event-free survival; CG=Cytogenetic; CHR=complete hematologic response

Better Molecular Response to Imatinib for Patients (pts) with Chronic Myeloid Leukemia (CML) in Chronic Phase (CP) Carrying the b3a2 Transcript Compared to b2a2.

Background. Different types of BCR-ABL fusion mRNAs can be found in pts with CML due to different genomic breakpoints and alternative splicing. The two major forms join ABL exon 2 with exons 13 or 14 of BCR, resulting in two main transcripts, b2a2 and b3a2, respectively, that codify for a p210 protein present in the majority of CML patients. b3a2 is more frequent in newly diagnosed patients than the b2a2 transcript, and occasionally both transcripts may be present. The clinical significance of the specific transcript among CML pts treated with imatinib has not been clearly established, and some have suggested that b2a2 may be associated with better outcome. (Blood 2006 108: Abstract 4780) Genet.Mol. Res. 4(4): 803–811 ( 2005)Journal of Clinical Oncology , 2007 Vol 25, No 18S (June 20 Supplement), 2007: 7043.Purpose: To determine if there is a difference in outcome after imatinib therapy in CML pts according to their BCR-ABL transcript.Methods: We analyzed 480 pts with CP CML treated with imatinib, 251 receiving imatinib as frontline therapy and 229 after interferon (IFN) failure. Molecular response was evaluated using RT PCR every 3 months (mo).Results: The median follow-up was 62 mo (range 1–92 mo) Median age was 51 years (range 15–84). Overall, 187 of 480 (39%) pts expressed b2a2, 234 (49%) b3a2, 55 (11%) expressed both, and 4 (1%) expressed e1a2. The rates of major and complete cytogenetic response were similar for pts with b3a2 and b2a2, both in the newly diagnosed and the post-IFN failure: CCyR 91% for b3a2 and 89% for b2a2 in frontline, and 72% and 78%, respectively in the post-IFN failure group. However, among 433 pts evaluable for molecular response, transcript levels were significantly lower at 3, 6 and 12 months from start of therapy for pts with b3a2 compared to those with b2a2 (Table 1).Table 1Median BCR-ABL transcript levels over time by transcript type3 months6 months9 monthsoverallb2a21.82840.3180.1860.0464b3a20.51750.05530.03520.0033p-value0.001<0.001<0.001<0.001This resulted in a significantly higher probability of achieving a major molecular remission (MMR) and complete molecular remission (CMR; ie, undetectable transcript levels) for pts with the b3a2 transcript (Table 2).Table 2Molecular Response in patients Post IFN failure and patients newly treatedTranscriptNo.*MMR**(%)P valueCMR***(%)P valueNew Dx b2a210663592625New Dx b3a211588770.00854470.002Post IFN b2a26221341016Post IFN b3a29761630.00141420.001*Number of evaluable patients. Dx=DiagnosisThere was a trend for an improved transformation-free survival for pts with b3a2 compared to those with b2a2 (4-yr rates 98% vs 93%, respectively, p=0.08) and event-free survival (94% vs 87%, p=0.37). Although fewer pts co-expressed both transcript types, they behaved like the pts with b3a2.Conclusion: Pts with the b3a2 transcript have a better molecular response to imatinib that those with b2a2. This prognostic factor should be considered when evaluating response to therapy.

IRIS 6-Year Follow-Up: Sustained Survival and Declining Annual Rate of Transformation in Patients with Newly Diagnosed Chronic Myeloid Leukemia in Chronic Phase (CML-CP) Treated with Imatinib.

Background: The International Randomized study of Interferon versus STI571 (IRIS) study demonstrated that imatinib has superior safety and efficacy relative to interferon-α plus cytarabine (IFN+ara-C). Patients on the imatinib arm achieved an estimated 5-year OS of 89%. To monitor the long-term responses achieved by patients on imatinib, the 6-year follow-up of the IRIS patient population is summarized.Methods: 1106 patients were randomly assigned to either imatinib or IFN+ara-C and evaluated for hematologic and cytogenetic responses, event-free survival, progression to accelerated-phase (AP) or blast crisis (BC), overall survival (OS), and frequency of adverse events and discontinuations.Results: The downward trend in the risk of disease progression on imatinib has continued with a 0.4% event rate (including loss of response) and a 0% rate of transformation to AP/BC attained between years 5 and 6. Of 553 who were randomized to imatinib, 364 (65.8%) remain on study drug at 6 years: 14 (2.5%) crossed over to the IFN arm, and 175 (31.6%) pts have discontinued from imatinib study therapy for any reason. The following reasons were cited for discontinuation from the IRIS study: adverse events, 23 patients (4.2%); unsatisfactory therapeutic effect, 66 patients (11.9%); protocol violation, 15 patients (2.7%); withdrawal of consent, 32 patients (5.8%); administrative problems, 6 patients (1.1%); and 16 patients (2.9%) elected to undergo a stem cell transplantation (SCT). Death was the reason for discontinuation for 10 (1.8%) patients, and 7 patients (1.3%) were lost to follow-up. The best observed complete hematologic response rate among patients receiving first-line imatinib was 97%. The best observed major cytogenetic response (MCyR) and complete cytogenetic response (CCyR) rates were 89% and 83%, respectively, with 2 additional CCyR observed since the prior 5-year analysis. At the current 6-year follow-up, 325 patients are still in CCyR, another 24 had lost CCyR but regained it, 6 patients lost CCyR but remain in MCyR, and the remaining 9 patients never had a documented CCyR. Overall, an estimated 83% of patients were event-free, and 93% were free of progression to AP or BC at 6 years on imatinib study treatment, as patients were followed only for OS after discontinuation. After the second year on imatinib, the annual rate of events decreased every year, as did the annual relapse rate. Based on the current follow-up, a total of 66 (12%) patients have died (19 after SCT, 27 not due to CML). Estimated 6-year OS rate for all patients who received imatinib as initial therapy was 88%. When survival is censored at time of SCT for patients who proceeded to transplant, the estimated OS at 6 years is 91%. In an analysis of serious adverse events, no new safety issues were identified between the 5-year report and this analysis.Conclusions: The 6-year follow-up analysis of the IRIS population indicates that continuous treatment of chronic-phase CML with imatinib induces durable responses in a high percentage of patients with a decreasing rate of relapse and a favorable long-term safety profile.