Introduction: The programmed death-1 (PD-1) immune checkpoint pathway regulates T-cell-mediated antitumor immune responses in solid tumors and hematologic malignancies. Nivolumab (Bristol-Myers ...Squibb, Ono Pharmaceutical) is a fully human IgG4 PD-1-blocking monoclonal antibody with demonstrated efficacy in a range of tumors. Results from an independent cohort of 23 pts with R/R cHL in a phase 1 study (CA209-039) showed that nivolumab was well tolerated and yielded an overall response rate (ORR) of 87% (Ansell et al, N Engl J Med, 2015). This raises important questions including the necessary duration of treatment, the relevance of the depth of response (complete response CR vs partial response PR), the duration of response, and the feasibility of retreatment. Here, we present the clinical course and post-treatment outcomes from extended follow-up of these pts to shed some light on these questions.
Methods: Pts with R/R cHL received nivolumab 3 mg/kg at weeks (wks) 1 and 4, and then every 2 wks for up to 2 years (yrs). Therapy was stopped earlier in pts with intolerance to treatment or progressive disease (PD) without evidence of clinical benefit. Pts who discontinued treatment due to toxicity were followed for up to 120 days after discontinuation; other pts were followed for 1 yr after discontinuation. Responding pts discontinued after confirmed CR or 16 wks after unconfirmed CR, or continued treatment for up to 2 yrs if they had PR or stable disease (SD). Pts who discontinued treatment with ongoing CR, PR, or SD could be retreated for confirmed PD occurring <1 yr after nivolumab discontinuation. Responses were evaluated using the Revised Response Criteria for Malignant Lymphoma (Cheson et al, J Clin Oncol, 2007). The primary endpoint was safety, and the key secondary endpoint was antitumor activity.
Results: A total of 23 pts with R/R cHL were treated. The median follow-up observation time is now 86 wks (range: 32-107 wks). Of 20 responders (14 PR, 6 CR), 10 have had durable responses per protocol assessment; their treatment durations and response characteristics are shown in Table 1. Responses were maintained in 2 pts (#5 and #6) after discontinuing nivolumab for >40 wks and in 1 pt (#7) after stopping due to toxicity. Eight pts with durable responses have received nivolumab for >1 yr, including 7 pts who have been in response for >1.5 yrs. One pt (#2) with an initial CR experienced a relapse 43 wks after treatment was discontinued, and achieved a second response (CR) after retreatment with nivolumab. Of the 10 remaining responders, 4 eventually progressed (time to progression TTP range: 21.4-92 wks), 1 discontinued treatment due to toxicity with no PD within the 120-day follow-up period, and 5 discontinued nivolumab to undergo stem cell transplant (SCT; 4 allogeneic, 1 autologous) after achieving remission. Time to CR for all responders ranged from 3-88 wks after starting nivolumab, including 2 pts with initial PRs that converted to CRs with continued treatment. All 5 pts who proceeded to SCT had responded to nivolumab within 16 wks of starting treatment (4 PR, 1 CR). Three pts had a best overall response of SD (1 discontinued due to toxicity without documented PD within the 120-day follow-up period; 2 subsequently discontinued for PD TTP: 15 and 15.3 wks, respectively). Overall, 3 pts discontinued nivolumab due to adverse events (AEs; Grade 2 peripheral neuropathy, Grade 3 myelodysplastic syndrome, Grade 3 pancreatitis). Grade 1 or 2 immune-related AEs (IR-AEs) occurred in 4 of 10 pts and resolved without treatment in 2 pts. The incidence of IR-AEs did not increase with time on treatment.
Conclusions: In pts with R/R cHL, nivolumab was well tolerated and produced a high ORR. Responses occurred within 16 wks of nivolumab initiation in 15 of 20 pts. Early responses to nivolumab allowed 5 pts to proceed to SCT and lasted ≥1 yr in 7 of 10 pts who did not pursue SCT. One pt achieved CR again after retreatment with nivolumab when relapse occurred within 1 yr of discontinuing treatment following an initial CR.
Table 1Treatment and Response Parameters for Pts with Durable Ongoing ResponsesPt #Best ResponseDuration of Response, wksTime to First Response, wksTime on Treatment, wks1PR90.73.696+2CR82.17.191+3PR73.17.682.4+4PR71.414.988+5CR71.13.124.96CR65.17.122.97PR55.915.370.98CR48.339879CR45.35582.910PR41.738.782.1++Still on treatment
Ansell:Bristol-Myers Squibb: Research Funding; Celldex: Research Funding. Armand:BMS: Research Funding; Infinity: Consultancy, Research Funding; Sequenta, Inc.: Research Funding; Merck: Consultancy, Research Funding. Timmerman:Valor Biotherapeutics: Research Funding; Janssen: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding. Shipp:BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Sanofi: Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead: Consultancy; Merck: Membership on an entity's Board of Directors or advisory committees. Bradley Garelik:Bristol-Myers Squibb: Employment. Zhu:Bristol-Myers Squibb: Employment. Lesokhin:Efranat: Consultancy; Genentech: Research Funding; Aduro: Consultancy; Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding.
The randomized phase 3 DASISION trial in pts with newly diagnosed CML-CP has demonstrated the improved efficacy of dasatinib 100 mg once daily (QD) compared with imatinib 400 mg QD based on the ...primary endpoint: rate of confirmed complete cytogenetic response (CCyR) within 12 mo (NEJM 2010 362 2260). Several studies have demonstrated the impact of early responses on long-term progression-free survival (PFS) and overall survival (OS), and the European LeukemiaNet (ELN) has recently updated its definitions of response to reflect the importance of achieving specific BCR-ABL transcript levels at 3, 6, and 12 mo. The aims of this analysis were to provide an update on efficacy and safety at 4 yrs and to examine the predictive value of early molecular responses in DASISION.
Pts with newly diagnosed CML-CP (n=519) were randomly assigned to receive dasatinib 100 mg QD (n=259) or imatinib 400 mg QD (n=260). Methods were reported previously. The protocol defined progression as increasing white blood cell count, loss of complete hematologic response or major cytogenetic response, transformation to accelerated phase (AP) or blast phase (BP), or death.
After 4 yrs, 67% and 65% of pts in the dasatinib and imatinib arms, respectively, remain on study treatment. The proportions of pts achieving molecular responses by 4 yrs (dasatinib v imatinib) were: major molecular response (MMR; BCR-ABL ≤0.1%) 76% v 63%; MR4 (BCR-ABL ≤0.01%) 53% v 42%; and MR4.5 (BCR-ABL ≤0.0032%) 37% v 30%. The likelihood of achieving MMR at any time was 1.6-fold higher with dasatinib v imatinib (hazard ratio 95% CI, 1.6 1.3–1.9). In pts who achieved MMR, the median time to MMR was 9.2 v 15.0 mo (dasatinib v imatinib). Four-yr PFS rates were 90% in both arms, and OS rates were 93% (dasatinib) and 92% (imatinib). In an intent-to-treat analysis, fewer pts receiving dasatinib (n=12/259; 5%) v imatinib (n=18/260; 7%) transformed to AP/BP. More pts achieved 2013 ELN-defined optimal molecular responses at 3 mo (BCR-ABL ≤10%, 84% v 64%), 6 mo (BCR-ABL ≤1%, 69% v 49%), and 12 mo (BCR-ABL ≤0.1%, 46% v 30%) with dasatinib v imatinib. In a relative risk analysis, pts with BCR-ABL ≤10% at 3 mo (regardless of treatment) were more likely to achieve CCyR, MMR, and MR4.5 and were at a proportionally lower risk of transformation to AP/BP or death. In the dasatinib arm, BCR-ABL ≤10% v >10% at 3 mo was associated with better PFS (P=.0004, 92% v 67% at 4 yrs), better OS (P=.0092, 95% v 83% at 4 yrs), and reduced transformation to AP/BP (n=6/198 3% v n=5/37 14% at 4 yrs). In the imatinib arm, BCR-ABL ≤10% v >10% at 3 mo conferred similar advantages (PFS: P<.0001, 95% v 70%; OS: P=.0021, 96% v 84%; transformation: n=4/154 3% v n=13/85 15%). Regardless of treatment, relatively few pts with BCR-ABL >10% at 3 mo achieved an optimal response of ≤1% at 6 mo (Table). The subgroup of pts with ≤1% at 6 mo had no transformations or deaths, although the subgroup with >1–10% at 6 mo had 3 transformations and 4 deaths (imatinib arm only). Most drug-related adverse events occurred within the first yr of treatment, with no new safety signals observed through yr 4.
This 4-yr follow-up from the DASISION trial continues to support dasatinib 100 mg QD as first-line treatment for pts with newly diagnosed CML-CP, with more pts achieving ELN-defined optimal molecular responses and fewer transforming to AP/BP compared with imatinib. The achievement of BCR-ABL ≤10% at 3 mo, more common among pts treated with dasatinib v imatinib, was associated with better PFS and OS and reduced transformation to AP/BP in both arms.
Cortes:Ariad: Consultancy, Grant to institution Other, Honoraria; BMS: Grant to institution, Grant to institution Other; Novartis: Grant to institution, Grant to institution Other; Pfizer: Consultancy, Grant to institution, Grant to institution Other, Honoraria; Teva: Consultancy, Grant to institution Other, Honoraria; Tragara: Membership on an entity's Board of Directors or advisory committees; Ambit: Grants/grants pending for institution Other; Astellas: Grants/grants pending for institution, Grants/grants pending for institution Other; Incyte: Grants/grants pending for institution, Grants/grants pending for institution Other; Arog: Grants/grants pending for institution Other; Celgene: Grants/grants pending for institution, Grants/grants pending for institution Other; sanofi: Grants/grants pending for institution, Grants/grants pending for institution Other. Hochhaus:BMS: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Ariad: Research Funding; MSD: Research Funding. Kim:BMS: Consultancy, Grant/grants pending for institution; travel support to meetings for study/other purposes Other, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Consultancy, Grants/grants pending for institution, Grants/grants pending for institution Other, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; ARIAD: Grants/grants pending for institution, Grants/grants pending for institution Other; ILYANG: Grants/grants pending for institution, Grants/grants pending for institution Other, Speakers Bureau. Shah:BMS: Consultancy, Grants/grants pending to institution for costs related to clinical research Other; Ariad: Consultancy, Grants/grants pending to institution for costs related to clinical research, Grants/grants pending to institution for costs related to clinical research Other. Rowlings:Newcastle Mater Hospital: Clinical trial support and travel to investigator's meeting paid to institution Other. Nakamae:Novartis: Consultancy, Grants/grants pending Other, Speakers Bureau; BMS: Consultancy, Grants/grants pending; travel/accomodations/meeting expenses unrelated to activities listed, Grants/grants pending; travel/accomodations/meeting expenses unrelated to activities listed Other, Speakers Bureau. Bradley-Garelik:BMS: Employment. Mohamed:BMS: Employment, Stock/stock options; travel/accommodations/meeting expenses unrelated to activities listed Other. Saglio:Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria; ARIAD: Consultancy, Honoraria; Celgene: Consultancy, Honoraria.
Abstract only
6504
Background: In the phase 3 DASISION trial of dasatinib v IM in patients (pts) with newly diagnosed CML-CP, dasatinib had higher 12-month rates of complete cytogenetic response ...(CCyR) and major molecular response (MMR) (Kantarjian, NEJM 2010;362:2260). By 12 months confirmed CCyR (cCCyR) rates for dasatinib v IM were 77% v 66%, P=0.001, meeting the primary endpoint. Methods: Pts were randomized to receive dasatinib 100 mg once daily (QD; n=259) or IM 400 mg QD (n=260). Results: Minimum 24-month follow-up (median 26.6 months) is reported here. 24-month molecular response rates were higher for dasatinib v IM: MMR (BCR-ABL ≤0.1%) 64% v 46%, P<0.0001; MR
4
(BCR-ABL ≤0.01%) 29% v 19%, P=0.0053; MR
4.5
(BCR-ABL ≤0.0032%) 17% v 8%, P=0.0032. MMR rates were higher for dasatinib in all Hasford risk groups (high 73% v 56%; intermediate 61% v 50%; low 73% v 56%). Of pts who achieved MMR at 12 months, on dasatinib v IM, 97% v 92% had maintained their MMR at 24 months, respectively. Pts receiving dasatinib v IM had faster responses; median time to CCyR and MMR was 3.2 v 6.0 and 15 v 36 months, respectively. In an intent-to-treat analysis, fewer pts receiving dasatinib (n=9; 3.5%) transformed to accelerated/blast phase v IM (n=15; 5.8%) on study or during follow-up after discontinuation. 24-month overall and progression-free survival were similar for dasatinib v IM: 95.4% v 95.2% and 93.7% v 92.1% (follow-up is ongoing). Few additional adverse events (AEs) were reported between 12 and 24 months in both arms, with grade 3/4 nonhematologic AE rates ≤1%. In each arm, 10 pts had a BCR-ABL mutation detected at time of discontinuation. For dasatinib v IM, 23% v 25% discontinued treatment for drug-related AEs (7% v 5%), progression (5% v 7%), failure (3% v 4%), unrelated AEs (2% v <1%), death (2% v <1%), and other (4% v 8%). Few pts discontinued between 12 and 24 months for dasatinib (n=19; 7%) and IM (n=16; 6%). Conclusions: Updated data with minimum 36-month follow-up will be presented, including mutation analyses in pts who discontinued, progressed, or had suboptimal response. Pts receiving dasatinib had a lower transformation rate and higher molecular responses v pts receiving IM, supporting the use of dasatinib in newly diagnosed CML-CP.
Abstract only
TPS9594
Background: Dasatinib is a BCR-ABL inhibitor approved for treatment in adult patients (pts) with newly diagnosed Ph+ CML-CP; CML resistant/intolerant to prior therapy, including ...imatinib; and Ph+ acute lymphoblastic leukemia (ALL). There are no established dasatinib treatment regimens for children/adolescents with relapsed/refractory leukemia, but pediatric trials are underway. A phase I dose-escalation study of dasatinib in pediatric pts with refractory solid tumors (n=28) and imatinib-refractory, Ph+ leukemia (n=11) reported a maximum tolerated dose of 85 mg/m
2
twice daily in solid-tumor pts and at least a partial cytogenetic response (CyR) in all evaluable CML pts (n=9) (Aplenc, J Clin Oncol 2011). Preliminary results from a phase I dose-escalation study in pediatric pts with subtypes of relapsed/refractory
leukemia (NCT00306202) indicate that dasatinib was well tolerated up to 120 mg/m
2
(Zwaan, Blood 2010 abstr 2265). Further study of dasatinib in pediatric pts is warranted. Methods: To evaluate the safety and efficacy of dasatinib monotherapy in children/adolescents with newly diagnosed CML-CP or Ph+ leukemias resistant/intolerant to imatinib, a phase II nonrandomized, global study of dasatinib in pts birth to <18 y is ongoing (NCT00777036): Cohort 1 (C1), Ph+ CML-CP pts resistant/intolerant to imatinib; Cohort 2 (C2), Ph+ ALL, accelerated or blast phase CML pts resistant/intolerant to or relapsed after imatinib therapy; or Cohort 3 (C3), newly diagnosed, treatment-naïve Ph+ CML-CP pts. Treatments are once daily with dasatinib 60 mg/m
2
(C1/C3) or 80 mg/m
2
(C2) for ≥24 months. Primary endpoints are major CyR (C1), complete hematologic response (C2), and complete CyR (C3). Secondary endpoints include safety, tolerability, best response, time to/duration of response, survival, and molecular response rates. BCR-ABL mutations are evaluated. First patient first visit was March 2009; estimated trial completion is September 2016. As of January 2012, 63 pts (n=27 aged <12 y; n=36 aged ≥12 y) have been treated in C1/C2 (n=41) and C3 (n=22). Enrollment is ongoing at 79 sites.
Abstract 2295
During first-line BCR-ABL inhibitor therapy for CML-CP, concomitant medication use is associated with worse adherence to CML therapy, which may detrimentally affect efficacy (St ...Charles, ASH 2009; Marin, J Clin Oncol 2010). Medications may include adjuvants to anti-CML therapy or treatments for comorbid conditions. Depending on posology, the number of medications may affect BCR-ABL inhibitor efficacy and safety. Dasatinib is a BCR-ABL inhibitor 325-fold more potent than imatinib at inhibiting BCR-ABL in vitro and is taken once daily (QD) at any time of day with or without food. Medications that prolong QTc, or increase or decrease dasatinib levels (CYP3A4 substrates/inhibitors/inducers, PPIs and H2 antagonists) should be avoided. In the phase 3 DASISION trial, first-line dasatinib 100 mg QD had superior efficacy vs imatinib 400 mg QD in pts with newly diagnosed CML-CP, including significantly higher complete cytogenetic response (CCyR) and major molecular response (MMR) rates. Here, efficacy and safety of dasatinib (and imatinib) by number and type of baseline medications were analyzed.
519 pts with newly diagnosed CML-CP were randomized to dasatinib 100 mg QD (n=259) or imatinib 400 mg QD (n=260) arms. Exclusion criteria included prior interferon or systemic anti-CML therapy (except anagrelide, hydroxyurea, or ≤28 days of imatinib), and baseline pleural effusion, cardiovascular disease, or bleeding disorder unrelated to CML. Efficacy and safety were assessed using rates of CCyR/MMR or drug-related adverse events (AE), respectively. Baseline medications were defined as any additional medication taken prior to initiating study therapy, as reported by individual investigators.
189/259 pts (73%) in the dasatinib arm and 194/260 pts (75%) in the imatinib arm were receiving ≥1 baseline medication (median 2, range 1–7). Medications taken by ≥5% of pts were prophylactic allopurinol therapy for tumor lysis syndrome (51%); alimentary tract or metabolism therapies, eg, antacids or PPIs (33%: omeprazole 6%, famotidine <1%); nervous system therapies, eg, NSAIDs or other analgesics (22%); cardiovascular therapies, eg, calcium channel blockers, loop diuretics, β blockers, and ACE inhibitors (21%); agents for blood or blood-forming organs, eg, folic acid or statins (15%); systemic antibiotics/antifungals/vaccines (7%); and respiratory system therapies, eg, antihistamines or inhaled steroids (7%). 12-month CCyR and MMR rates were unaffected by the number of baseline medications. Pts in the dasatinib arm receiving 0, 1–3, or ≥4 medications (27%, 56%, and 17%, respectively) had CCyR rates of 79%, 85%, and 87% and MMR rates of 43%, 49%, and 42%, respectively. Pts in the imatinib arm receiving 0, 1–3, or ≥4 medications had CCyR rates of 76%, 70%, and 71% and MMR rates of 35%, 26%, and 23%, respectively. In pts receiving baseline medications, safety was similar irrespective of the number received. Respective grade 3/4 thrombocytopenia rates for pts receiving 0, 1–3, or ≥4 medications were 28%, 17%, and 13% in the dasatinib arm and 9%, 9%, and 17% in the imatinib arm; grade 3/4 neutropenia rates were 29%, 13%, and 31% in the dasatinib arm and 31%, 18%, and 11% in the imatinib arm. Nonhematologic AEs of any grade occurring in ≥10% of pts receiving dasatinib and 0, 1–3, or ≥4 medications, respectively, were diarrhea in 17% vs 19% vs 13% (13% vs 19% vs 17% with imatinib), nausea/vomiting in 12% vs 9% vs 18% (25% vs 23% vs 23% with imatinib), arthralgia/myalgia in 12% vs 10% vs 11% (28% vs 13% vs 14% with imatinib), rash in 6% vs 12% vs 18% (19% vs 16% vs 20% with imatinib), fluid retention in 9% vs 23% vs 24% (41% vs 44% vs 37% with imatinib), pleural effusion in 1% vs 13% vs 13% (0% with imatinib) and superficial edema in 7% vs 8% vs 16% (25% vs 41% vs 31% with imatinib). Efficacy and safety patterns were generally comparable in pts receiving various baseline medication categories. Additional analyses of on-study medication characteristics and effects on efficacy or safety will be presented.
Although occurrence of pleural effusion and fluid retention appeared higher in patients receiving ≥1 medication with dasatinib, overall, the number of medications administered at baseline in the DASISION trial did not appear to affect efficacy or safety of dasatinib (or imatinib) in pts with newly diagnosed CML-CP.
Guilhot: Bristol-Myers Squibb: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Off Label Use: This abstract discusses the use of first-line dasatininb in CML-CP. Kantarjian: Bristol-Myers Squibb: Research Funding; Novartis: Consultancy, Research Funding; Wyeth: Research Funding. Shah: Bristol-Myers Squibb: Consultancy; Novartis: Consultancy; Ariad: Consultancy. Hochhaus: Bristol-Myers Squibb: Consultancy, Research Funding; Novartis: Consultancy, Research Funding. Bradley-Garelik: Bristol-Myers Squibb: Employment. Dejardin: Bristol-Myers Squibb: Employment, Equity Ownership. Cortes: Bristol-Myers Squibb: Research Funding.
Abstract 2282
The Phase 3 DASISION trial comparing dasatinib 100 mg once daily with imatinib 400 mg once daily as initial treatment in patients (pts) with newly diagnosed CML-CP has demonstrated ...superior efficacy and favorable safety of dasatinib after a minimum of 12 months of follow-up (Kantarjian, H, et al. N Engl J Med 2010;362:2260). While fluid retention was more frequent with imatinib than with dasatinib, pleural effusion was seen only with dasatinib. Here, we provide a detailed analysis of pts experiencing pleural effusion, a clinically relevant adverse drug reaction.
519 pts with newly diagnosed, treatment-naive CML-CP (median disease duration of 1 month) were randomly assigned to either dasatinib 100 mg once daily (259 pts) or imatinib 400 mg one daily (260 pts). Key endpoints included complete cytogenetic response (CCyR), major molecular response (MMR) and safety. All pts were assessed by chest x-ray at baseline and at 6 months after randomization, or more frequently, if indicated clinically. Pts with pleural effusion at baseline were excluded. Pleural effusion was graded according to CTCAE version 3 (grade 1, asymptomatic; grade 2, symptomatic, up to 2 therapeutic thoracenteses; grade 3, symptomatic requiring supplemental oxygen, < 2 therapeutic thoracenteses; grade 4, life-threatening, hemodynamic instability).
After a minimum follow-up of 12 months with median treatment duration of 14.3 months (range, 0.3–25.8), 26 (10%, median age, 60 years) of the 258 dasatinib-treated pts (median age, 46 years) experienced pleural effusion. Of the pts with pleural effusion, 6 (23%) had low, 17 (65%) had intermediate and 3 (12%) had high Hasford risk scores. There were no grade 3 or 4 pleural effusion events. All events were grade 1(2%) or grade 2 (8%). Most events (n = 22, 85%) occurred more than 8 weeks after the start of study drug. In pts who had a pleural effusion, the median time to the event was 28 weeks (range, 4–88). Lymphocytosis (defined as peripheral blood lymphocyte count > 3.6 × 109/L) was noted in 11 (42%) of the 26 pts with pleural effusion, as compared to 46 (20%) of 232 pts with no pleural effusion. Pleural effusion was managed by dose modification and/or medical intervention. Therapy was interrupted in 19 pts, and the dose of dasatinib was reduced in 8 pts (4 pts, to 80 mg; 1 pt, to 70 mg; 3 pts, to 50 mg). Twelve pts received diuretics, 7 received corticosteroids, and only 1 pt underwent therapeutic thoracentesis. Only 3 pts (1.2%) discontinued therapy due to pleural effusion (grade 2). Eleven pts who continued dasatinib had resolution of their pleural effusion. Five pts had recurrent effusions. Of the 26 pts with pleural effusion, 24 (92%) achieved a CCyR and 17 (65%) achieved a MMR by 12 months of treatment; the corresponding CCyR and MMR rates in the total pt population were 83% and 46%, respectively Seven of the 8 pts with pleural effusion who reduced their dose achieved CCyR and MMR.
In pts with newly diagnosed CML-CP treated with dasatinib as initial therapy, pleural effusion was mild to moderate in severity, and was manageable with dose interruption and/reduction and/or a short course of diuretics and/or corticosteroids. The occurrence of pleural effusion and management interventions did not negatively affect the achievement of CCyR or MMR. These findings are in line with data reported previously for second-line dasatinib in CML pts resistant or intolerant to imatinib (Porkka, K, et al. Cancer 2010;116:377). Furthermore, pleural effusion and peripheral lymphocytosis may be indicative of immune-mediated antitumor activity of dasatinib.
Porkka: BMS, Novartis: Consultancy, Honoraria, Research Funding. Baccarani: Novartis, Bristol-Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hochhaus: Brostol-Myers Squibb, Novartis: Consultancy, Research Funding. Kantarjian: BMS, Pfizer and Novartis: Research Funding; Novartis: Consultancy. Mustjoki: BMS, Novartis: Honoraria. Bradley-Garelik: Bristol-Myers Squibb: Employment, Equity Ownership. Zhu: Bristol-Myers Squibb: Employment. Cortes: Brostol-Myers Squibb, Novartis and Wyeth: Consultancy, Honoraria.
Abstract 206
Dasatinib is 325-fold more potent than imatinib in vitro against unmutated BCR-ABL, and is an established second-line treatment for patients (pts) with CML-CP who are resistant, ...intolerant or have a suboptimal response to imatinib. The Phase 3 DASISION study compares dasatinib with imatinib as initial treatment for pts with newly diagnosed CML-CP. After a minimum of 12 months (mos) of follow-up, dasatinib 100 mg once daily demonstrated significantly higher and faster rates of complete cytogenetic response (CCyR) and major molecular response (MMR) compared to imatinib 400 mg once daily (Kantarjian, H, et al. N Engl J Med 2010;362:2260). Eighteen-mo follow-up data are presented here.
519 pts with newly diagnosed CML-CP (median disease duration of 1 mo) stratified by Hasford risk were randomized to either dasatinib 100 mg once daily (n=259), or imatinib 400 mg once daily (n=260). The study design and endpoints have been described previously. All analyses were based on intention-to-treat pts.
Median treatment duration at the present analysis was 18 mos for each drug, with 81% of pts in the dasatinib arm and 80% in the imatinib arm still remaining on study drug. Median dose intensity was 99 mg/d for dasatinib and 400 mg/d for imatinib. Efficacy and safety results in the present analysis were consistent with those reported previously after 12 mos of follow-up. The rate of confirmed CCyR (cCCyR, CCyR on consecutive analyses at least 1 mo apart) by 18 mos continued to be higher for dasatinib than for imatinib (78% vs 70%); P=0.0366). Based on time-in-cCCyR (a measure of durability) analysis involving all randomized pts, dasatinib-treated pts were 28% less likely to experience a progression event (as defined by European LeukemiaNet 2006) after achieving a cCCyR or never achieving a cCCyR compared to those on imatinib. The MMR rate at any time was superior for dasatinib compared to imatinib (57% vs 41%, P=0.0002). Based on time-to-response analysis, pts on dasatinib were 1.84-fold more likely to achieve a MMR than those on imatinib (HR=1.84, P <0.0001). Rates of cCCyR in dasatinib-treated pts with low, intermediate and high risk were 92, 71 and 73%, respectively. The corresponding rates in the imatinib arm were 72, 71 and 64%. Rates of MMR in dasatinib-treated pts with low, intermediate and high risk were 63, 56 and 51%, respectively. The corresponding rates in the imatinib arm were 48, 40 and 30%. A BCR-ABL transcript level of ≤ 0.0032% was achieved in 13% dasatinib-treated and 7% imatinib-treated pts. Rates of progression-free survival at 18 mos were 94.9% for dasatinib and 93.7% for imatinib; the corresponding overall survival rates were 96.0% and 97.9%, respectively. Six pts (2.3%) in the dasatinib arm and 11 (4.3%) in the imatinib arm discontinued due to treatment failure as defined by 2006 European LeukemiaNet criteria. Six pts (2.3%) on dasatinib and 9 (3.5%) on imatinib had a transformation to accelerated or blast phase. Discontinuation of treatment due to drug-related adverse events (AEs) was infrequent for both dasatinib (6%) and imatinib (4%). Non-hematologic AEs (all grades) in ≥10% of pts (dasatinib vs imatinib) were fluid retention (23% vs 43%), diarrhea (18% vs 19%), nausea (9% vs 21%), vomiting (5% vs 10%), muscle inflammation (4% vs 19%), myalgia (6% vs 12%), musculoskeletal pain (12% vs 16%), fatigue (8% vs 11%) and rash (11% vs 17%). While superficial edema was less frequent with dasatinib than with imatinib (10% vs 36%), pleural effusion was seen only with dasatinib (12% vs 0%: grade 1, 2%; grade 2, 9%; grade 3, <1%), and did not impact the efficacy. Non-hematologic grade 3/4 AEs were infrequent in either arm (≤1%). Grade 3/4 cytopenias (dasatinib vs imatinib) were anemia (11% vs 7%), neutropenia (22% vs 20%) and thrombocytopenia (19% vs 10%). Two pts (0.8%) on dasatinib and 3 (1.2%) on imatinib had grade 3/4 bleeding. Cytopenia was the reason for discontinuation in 6 pts on the dasatinib arm (2.3%) and 3 on the imatinib arm (1.2%).
After 18 mos of follow-up, dasatinib 100 mg once daily continues to demonstrate superior efficacy compared to imatinib. Dasatinib also continues to be generally well tolerated. These results support the potential use of dasatinib as initial treatment for pts with newly diagnosed CML-CP.
Shah:Bristol-Myers Squibb, Novartis and Ariad: Membership on an entity's Board of Directors or advisory committees. Kantarjian:BMS, Pfizer and Novartis: Research Funding; Novartis: Consultancy. Hochhaus:Novartis, Bristol-Myers Squibb: Consultancy, Research Funding. Cortes:Brostol-Myers Squibb, Novartis and Wyeth: Honoraria. Bradley-Garelik:Bristol-Myers Squibb: Employment, Equity Ownership. Zhu:Bristol-Myers Squibb: Employment. Baccarani:Novartis, Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.
Abstract 2286
BCR-ABL kinase inhibitors dasatinib, nilotinib and imatinib have become the therapeutic mainstay for patients (pts) with CML-CP. It has been suggested that baseline comorbid conditions ...be considered in choosing BCR-ABL inhibitors as second-line treatment for pts with CML post-imatinib failure. Cardiovascular (CV) disease is an important comorbid condition in some pts with CML-CP (median age, ∼ 60 years) and can play a critical role in treatment decisions. The DASISION trial is a large Phase 3 study comparing dasatinib with imatinib as initial treatment in pts with newly diagnosed CML-CP and has demonstrated superior efficacy of dasatinib after a minimum of 12 months (mos) of follow-up (Kantarjian, H, et al. N Engl J Med 2010;362:2260-70). We assessed if baseline CV conditions impacted the efficacy and safety of these agents when used as initial treatment for CML-CP.
Five hundred nineteen pts with newly diagnosed CML-CP (median disease duration of 1 mo) were randomized to either dasatinib 100 mg once daily (n = 259) or imatinib 400 mg once daily (n = 260). Complete cytogenetic response (CCyR), major molecular response (MMR) and drug-related adverse events (AEs) were analyzed in pts with CV conditions and in those without. Pts with myocardial infarction (MI) within 6 mos, uncontrolled angina within 3 mos, congestive heart failure (CHF) within 3 mos, congenital prolonged QT syndrome, QTc interval of > 450 msec or ventricular arrhythmias were excluded. Pts with CV conditions including hypertension, MI > 6 mos prior to the start of treatment, uncontrolled angina > 3 mos prior to the start of treatment, CHF > 3 mos prior to the start of treatment, unstable angina (UA), left ventricular (LV) dysfunction, coronary artery disease (CAD), peripheral artery disease (PAD), transient ischemic attack (TIA), stroke and QTc interval of ≤ 450 msec were not excluded.
Across the 2 treatment arms, there were 85 pts (16%) with ≥ 1 baseline CV condition, 42 of whom had ≥ 2. Of the 85 pts, 69 (35 dasatinib; 34 imatinib) reported having baseline hypertension and 16 (8 dasatinib; 8 imatinib) reported other baseline CV conditions (some pts reported more than 1 CV condition) including LV dysfunction (n = 6), CAD (including clinically documented CAD, prior MI and unstable angina; n = 15), PAD (n = 11), and cerebral artery disease (including prior stroke and TIA, n = 8). The distribution of CV conditions was balanced across the 2 treatment arms. Safety profiles of dasatinib and imatinib in pts with baseline CV conditions were generally similar to those in pts without (Table). Notably, fluid retention including superficial edema and pleural effusion appeared to have occurred more frequently in pts with baseline CV conditions compared to those without. Pleural effusions were all grade 1 or 2, and manageable by dose interruption and/or reduction. In both arms, the 12-mo rates of CCyR and MMR in pts with baseline CV comorbidities were similar to the corresponding rates in pts without (Table). Safety and efficacy profiles of pts with hypertension and pts with CV conditions other than hypertension were also generally similar to those in pts without any CV condition.
Although fluid retention and cardiac AEs were more common in patients with any baseline CV condition, overall these data show no substantial impact of baseline CV conditions on the general safety and efficacy of dasatinib or imatinib as initial treatment for CML-CP.
Saglio: Brostol-Myers Squibb and Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees. Hochhaus: Brostol-Myers Squibb and Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Cortes: Brostol-Myers Squibb, Novartis and Wyeth: Consultancy, Honoraria. Kantarjian: BMS, Pfizer and Novartis: Research Funding; Novartis: Consultancy. Baccarani: Brostol-Myers Squibb and Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees. Bradley-Garelik: Bristol-Myers Squibb: Employment, Equity Ownership. Dejardin: Bristol-Myers Squibb: Employment, Equity Ownership. Shah: Bristol-Myers Squibb, Novartis and Ariad: Membership on an entity's Board of Directors or advisory committees.
We report the 5-year analysis from the phase III Dasatinib Versus Imatinib Study in Treatment-Naïve Chronic Myeloid Leukemia Patients (DASISION) trial, evaluating long-term efficacy and safety ...outcomes of patients with chronic myeloid leukemia (CML) in chronic phase (CP) treated with dasatinib or imatinib.
Patients with newly diagnosed CML-CP were randomly assigned to receive dasatinib 100 mg once daily (n = 259) or imatinib 400 mg once daily (n = 260).
At the time of study closure, 61% and 63% of dasatinib- and imatinib-treated patients remained on initial therapy, respectively. Cumulative rates of major molecular response and molecular responses with a 4.0- or 4.5-log reduction in BCR-ABL1 transcripts from baseline by 5 years remained statistically significantly higher for dasatinib compared with imatinib. Rates for progression-free and overall survival at 5 years remained high and similar across treatment arms. In patients who achieved BCR-ABL1 ≤ 10% at 3 months (dasatinib, 84%; imatinib, 64%), improvements in progression-free and overall survival and lower rates of transformation to accelerated/blast phase were reported compared with patients with BCR-ABL1 greater than 10% at 3 months. Transformation to accelerated/blast phase occurred in 5% and 7% of patients in the dasatinib and imatinib arms, respectively. Fifteen dasatinib-treated and 19 imatinib-treated patients had BCR-ABL1 mutations identified at discontinuation. There were no new or unexpected adverse events identified in either treatment arm, and pleural effusion was the only drug-related, nonhematologic adverse event reported more frequently with dasatinib (28% v 0.8% with imatinib). First occurrences of pleural effusion were reported with dasatinib, with the highest incidence in year 1. Arterial ischemic events were uncommon in both treatment arms.
These final results from the DASISION trial continue to support dasatinib 100 mg once daily as a safe and effective first-line therapy for the long-term treatment of CML-CP.
PDF
