ALBERT

Description: Abstract 634 FLT3, a transmembrane receptor tyrosine kinase constitutively activated via mutation in blasts of patients (pts) with AML, is an important therapeutic target. Blasts from approximately 25% of pts have a length or internal tandem duplication (ITD) mutation in the juxtamembrane region or tyrosine kinase domain (TKD1) of FLT3, which is associated with reduced disease-free survival and overall survival (OS), particularly in pts with normal cytogenetics. Blasts from 5–10% of pts have a point mutation (typically D835Y) in the tyrosine kinase domain (TKD); the effect of this mutation on prognosis is uncertain. Midostaurin (PKC412) is a multi-targeted kinase inhibitor with demonstrated clinical activity in FLT3-mutant (FLT3–mut) and FLT3-wild-type (FLT3–wt) AML (peripheral blood blast reduction in 70% and 30% of pts, respectively) but rarely produces complete remissions). Preclinical studies demonstrated synergy between FLT3 inhibitors and chemotherapy. We conducted a Phase 1b trial to investigate the feasibility of administering daunorubicin (60 mg/m2 IV, days 1–3) and cytarabine (100 mg/m2 IVCI, days 1–7) induction and high-dose cytarabine post-remission therapy (3 gm/m2 over 3h every 12h, days 1, 3, and 5 for 3 cycles) plus oral midostaurin at 100 mg or 50 mg each twice daily on days 8–21 (sequentially) or days 1–7, 15–21 (concomitantly) with all chemo cycles in newly diagnosed pts under age 61 with de novo AML. Whereas 100 mg of midostaurin plus induction chemotherapy was poorly tolerated due to nausea and vomiting, the 40 pts who received 50 mg of midostaurin orally twice daily ( 20 each on the sequential and concomitant schedules; 27 FLT3–wt; 13 FLT3–mut [9 with an ITD]), tolerated the combination well. Median midostaurin exposure was 133 days (range 21–975) for the FLT3–mut pts and 90 days (range 7–1016) for FLT3–wt pts. Maintenance therapy with midostaurin was allowed with investigator discretion and was received by 5 pts (3 FLT3–mut, 2 FLT–wt). The median ages for the FLT3–wt and FLT3–mut pts were 50 years (range 25–60) and 46 years (range 20–65), respectively. 77% of the FLT3–mut pts displayed normal, 15% adverse and 8% other intermediate cytogenetics compared with 18.5%, 26%, and 26%, respectively, for FLT3-wt (also 18.5% favorable; 11% unknown). Complete response occurred in 32/40 (80%) of all pts (20/27 [74%] of FLT3–wt patients, 12/13 [92%] of FLT3–mut pts). Patients were censored at the last date they were known to be alive with a median post treatment follow-up for FLT3-mut pts of 1059 days and 1086 days for FLT3-wt. Even accounting for their differing cytogenetics and ages, the OS of the FLT3–mut subgroup was expected to be inferior to that of the FLT3–wt subgroup. However, we report that the 1 and 2 year OS for the pts with FLT3–mut AML was 85% and 62%, respectively, and was comparable to that of the FLT3–wt subgroup (81% and 59%, respectively). Although based on small numbers and not stratified for type of FLT3 mutation (TKD, ITD, ITD length, location, or allelic ratio), these long-term results suggest that combination therapy with a FLT3 inhibitor and chemotherapy might be effective enough to obviate the perceived need for allogeneic stem cell transplantation for FLT3–mut AML pts in first complete remission. Moreover, these data support the rationale for the ongoing international phase 3 study of induction, post-remission intensification, and maintenance with midostaurin (50 mg po bid) or placebo. Disclosures: Stone: Novartis: Research Funding, ad hoc consultancy; Cephalon: ad hoc consultancy. Off Label Use: midostaurin with chemothereapy for AML. Paquette:Novartis: Honoraria, Research Funding, Speakers Bureau. Schiller:Novartis: Research Funding, Speakers Bureau; Millenium: Research Funding, Speakers Bureau; Genzyme: Research Funding; Vion: Research Funding; Centocor: Research Funding; Eli Lilly: Research Funding; Celgene: Research Funding. Schiffer:Novartis: Consultancy, Research Funding; Genzyme: Consultancy. Ehninger:Novartis: Honoraria, Research Funding. Cortes:Novartis: Research Funding; Bristol-Myers Squibb: Research Funding; Wyeth: Research Funding. Kantarjian:Novartis: Research Funding. DeAngelo:Bristol-Myers Squibb: Speakers Bureau; Celgene: Speakers Bureau; Enzon: Speakers Bureau; Novartis: Speakers Bureau. Huntsman-Labed:Novartis: Employment, Equity Ownership. Dutreix:Novartis: Employment, Equity Ownership. Rai:Novartis: Employment, Equity Ownership. Giles:Novartis: Research Funding; Merck: Research Funding; Bristol-Myers Squibb: Research Funding; Vion: Research Funding.

Description: FLT3 (fms-like tyrosine kinase) activating mutations, either an ITD (repeat of 3-〉100 amino acids in the juxtamembrane region) or a point mutation in the activation loop, occur in blasts from 30% of AML patients (pts). ITD mutations are associated with a relatively poor prognosis. PKC412 is a multi-targeted kinase inhibitor that has clinical activity in mutant (reduction in peripheral blasts in 70%) and wild type (reduction in peripheral blast in 30%) FLT3 AML, but rarely produces complete remissions (Stone et al, Blood 2005; Estey et al, ASH 2003). We conducted a phase Ib trial with DA (daunorubicin 60 mg/m2 d 1–3 and cytarabine 100 mg/m2/d by IVCI x 7d) induction and post-remission therapy (cytarabine 3 gm/m2/3h q 12h, d1,3, and 5 for 3 cycles) plus PKC412 at 100 mg bid po continuously beginning on day 8 (arm 1) or day 1 (arm 2) (n=15) or an amended schedule: day 8–21 (arm 1) or day 1–7, 15–21 (arm 2) (n=15) in previously untreated adult AML pts ≤ age 60. Results demonstrated safety, but poor tolerability due to nausea and vomiting (Giles, et al, ASH 2004). The study was then amended to include the same chemotherapy, but with 50 mg PKC412 po bid (previously shown to lead to plasma levels sufficient to inhibit FLT3) on day 8–21 (arm 1) or day 1–7, 15–21 (arm 2); tolerability improved to acceptable levels with no patients withdrawing due to nausea, vomiting, or diarrhea (Stone at al, ASH 2005). The study has completed accrual (40 pts enrolled after the PKC412 50 mg po bid amendment) with 38 pts (26 with wild type FLT3 (FLT3wt) blasts and 12 with mutated FLT3 (FLT3mut) blasts) evaluable for efficacy and 37 pts for safety. Complete response (CR) occurred in 27/38 (71%). The CR rate in FLT3wt pts was 18/26 (69%); 9/13 (69%) pts achieved CR in each of the arms. CR occurred in 11/12 (92%) FLT3mut pts. CR rate in FLT3mut pts was 7/7 (100%) in Arm 1 and, 4/5 (80%) in arm 2. 4/11 CR pts relapsed after 7, 7, 10 and 15 months; 7 pts remain in first CR for 3–15 months. No drug-related deaths were reported. One patient withdrew due to Grade 4 increase in alkaline phosphatase. The most common serious Grade 3–4 side effects reported to date include thrombocytopenia 6/19 (31.5%), anemia 5/19 (26%) and neutropenia 5/19 (26%) in pts on arm 1; thrombocytopenia 2/18 (11%), anemia 1/18 (5.5%) and neutropenia 2/18 (11%) in pts on arm 2. All Grade 3–4 events were transient and/or reversible. No Grade 3 or 4 nausea and vomiting occurred in either arm. In conclusion, PKC412 at 50 mg po bid can be given safely and tolerably in newly diagnosed adult AML pts ≤ 60 years old in combination with DA and high dose cytarabine. The CR rate and preliminary DFS in FLT3mut pts is encouraging. A phase III study of chemotherapy +/− PKC 412 at 50 mg po bid on d8–21 per cycle in newly diagnosed pts ages 18–60 with mutant FLT3 AML is planned.

Description: Background Imatinib is effective in L-CP CML patients (Pts), but response duration is unknown. From 12/1999 to 05/2000, the Novartis study STI571A110 recruited 454 Pts with confirmed diagnosis of CP CML. Pts were hematologically (n=133) or cytogenetically resistant/refractory (n=160) or intolerant (n=161) to IFN. Median time since diagnosis was 34 months (m). Pts were evaluated for best major and complete cytogenetic response (MCyR and CCyR), time to progression to accelerated phase (AP) or blast crisis (BC), and overall survival (OS). This abstract includes data up to 56 m after the first patient and more than 48 m after last patient started treatment. Results: Median drug exposure as of 31-Jul-04 was 50 m. The initial daily dose was 400 mg. Dose increases after a median of 14 m were reported in 227 (50%) Pts. The table below summarizes discontinuation reasons, best responses observed and the estimated long-term outcomes at 48 m. n=454 (%) [95% Conf intervals] Still on Treatment 269 (59.3) Discontinued 185 (40.7) Progression/deaths from any cause 105 (23.1) AEs/toxicities 32 (7.0) BMT 5 (1.1) Withdrew consent/Lost/Admin. problems 43 (9.5) Pts achieving MCyR (includes CCyR) 301 (66.3) Pts achieving CCyR 248 (54.6) % Pts free of progression to AP/BC at 48 m (74.6) [70.4–78.9] OS at 48 m (82.4) [78.9–86.0] Median time to CCyR was 8.3 m [8.3–8.6 m]; 45 of the 248 Pts achieved CCyR after dose increase. The yearly risk of progression to AP/BC did not increase when considering all patients (7.8%, 6.0%, 7.2% and 7.1% within year 1,2,3,4 respectively). The corresponding risk rates for patients in MCyR at 3 m were 2.7%, 0.7%, 2.2%, 2.4%. Using the 3-m (and 12 m) landmark (n=446 or 421), Pts with CCyR, PCyR and minor CyR had an estimated OS at 48 m of 94(94)%, 93(94) %, 86(92) %, whereas Pts with only minimal CyR or no CyR had estimated 4-year OS of 85(78) % and 77(71) %, respectively. Among Pts who achieved MCyR and arrived to 48m of follow-up, 79% [74–84] maintain it; this value compares with 86% [80–92] for Pts with MCyR within 3 m. The following figure shows the duration of MCyR according to the time when MCyR was reached. Pts who had MCyR by the 3rd m did significantly better than the other groups (p= 0.02). However a MCyR obtained at a late time point (〉12 m) has a duration similar to the entire cohort. Half of the Pts who lost MCyR did not progress to AP while on study. Conclusion: Imatinib treatment for L-CP CML Pts failing IFN therapy is effective and produces durable cytogenetic responses and survival, with more than 80% Pts alive at 48 m and no evident increase in progression rate over time. Even Pts who failed to achieve any CyR reached OS of 71%. Obtaining a MCyR at 3–12 m resulted in 〉90% OS. Duration of MCyR was longer in Pts who responded within 3m, than in the other groups. The results will be updated for the meeting including 60-m data up to 31-July-05. Figure Figure

Description: Abstract 1111 Poster Board I-133 Dasatinib is a potent inhibitor of the BCR-ABL tyrosine kinase which is effective in the treatment of imatinib refractory CML. While hematologic toxicities of neutropenia and thrombocytopenia are well known, large granular lymphocytosis has been reported in only a small number of patients without prior allogeneic stem cell transplant treated with dasatinib for CML. During routine follow up of leukocyte counts in 15 consecutive patients (age range 27-77 years) treated with dasatinib, 4 patients (2 chronic-phase, 1 accelerated phase with clonal cytogenetic progression, 1 blast-phase) developed a lymphocytosis (〉 3800/mm3). Peripheral blood smear and peripheral blood flow cytometry revealed a population of large granular lymphocytes (LGLs) expressing CD3, CD8, CD57, and variable expression of CD56. Lymphocytosis was first noted between 1 and 9 months after initiation of dasatinib and has persisted in 3 of the patients with a median follow up of 33 months from the onset of lymphocytosis. Peak absolute lymphocyte count ranged from 5000/mm3 to 6900/mm3 and approximately 40 to 60% of the lymphocytes were LGLs by flow cytometry with the remainder being predominantly T lymphocytes. These 4 patients with LGL lymphocytosis have all have major molecular responses and the patient with blast-phase has remained in a complete cytogenetic remission with a major molecular response 44 months after initiation of dasatinib. The 11 other patients (6 chronic-phase, 2 accelerated-phase, 3 blast-phase) treated with dasatinib for CML have not developed lymphocytosis. These patients have been followed for a median of 25 months (range 3-50 months) although some were treated with dasatinib for a relatively short period of time because of poor response of their advanced CML. Review of the peripheral blood smears from 3 of the 6 chronic phase patients without lymphocytosis who remain on dasatinib treatment did not reveal any LGLs. All of these 6 patients have had complete, sustained cytogenetic responses. A persistent pleural effusion developed in the blast phase patient with lymphocytosis approximately 12 months after lymphocytosis developed; no significant side effects were noted in the other 3 patients although one remains thrombocytopenic. Pleural effusions developed in 2 of the 6 patients without lymphocytosis who remain on dasatinib treatment. Previous reports have suggested an increased incidence of “inflammatory” type side effects such as pleural effusions and pneumonitis in patients with dasatinib related LGL proliferation, although the small number of patients in this series precludes analysis of this association. In summary, LGL proliferation was detected in a minimum of 27% of dasatinib recipients and may be associated with a beneficial response. While the mechanism of LGL proliferation has not been fully explained, it has been suggested that dasatinib mediated inhibition of immunoregulatory kinases such as Src is permissive of LGL proliferation. Further evaluation of the frequency and clinical impact of this phenomenon in the large clinical trials of patients treated with dasatinib is warranted. Disclosures Schiffer: Bristol Myers: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: Background: MDSs are clonal hematopoietic stem cell malignancies characterized by cytopenias resulting from ineffective hematopoiesis. A phase 2 study of lenalidomide (MDS-002) demonstrated hematological improvement in patients with MDS without an associated deletion 5q cytogenetic abnormality (List AF, et al. Haematologica2006;91[suppl1]:379[abst 1032]). We now report multicenter results after 〉2 yrs follow-up. Methods: A total of 214 pts with transfusion-dependent anemia were categorized into the following IPSS MDS risk groups after central review of bone marrow morphology, karyotype, and peripheral blood findings: Low/Int-1 (168 [78%]); Int-2/High (8 [4%]); and unclassified (38 [18%]). Patients were unclassified for missing or inadequate marrow studies for central review (morphology [29] or cytogenetic [7]) or other diagnoses (AML [1], atypical CML [1]). Patients were evaluated for frequency and duration of red blood cell transfusion independence (RBC-TI) (IWG criteria), hemoglobin (Hgb) response, and safety. The starting dose of lenalidomide was 10 mg (daily or daily × 3 wks q28d cycle). Results: Overall, 56 (26%) of 214 enrolled patients achieved RBC-TI. Median time to RBC-TI was 5 wks, median duration of RBC-TI response was 41.0 wks (range, 8.0–136.4), and median Hgb increase achieved during RBC-TI was 3.2 g/dL (range, 1.0–9.8). An additional 36 patients experienced a ≥ 50% reduction in RBC transfusions (overall hematological improvement in 92 [43%] patients). Overall, 47 (22%) patients had an abnormal karyotype at baseline and 9 (19%) patients achieved a cytogenetic response (4 complete). The most common drug-related grade 3/4 adverse events (AEs) were neutropenia and thrombocytopenia (25% and 20%, respectively). Deep vein thrombosis occurred in only 2 (1%) patients. The duration of RBC-TI was ≥ 52 weeks in 21 (38%) patients. Among these 21 patients, 14 (67%) did not require a lenalidomide dose reduction during the first 52 weeks of treatment. Analyses of response variables will be presented. Dose-limiting neutropenia/thrombocytopenia was not reported after 52 weeks. The most commonly reported AEs after 52 weeks were mild-moderate diarrhea and fatigue (38% and 29%, respectively). Conclusion: Lenalidomide is an active, well-tolerated treatment in MDS patients with transfusion-dependent anemia that is not associated with a deletion 5q abnormality. The rate of erythroid hematologic improvement and duration of RBC-TI is encouraging and offers a possible alternative to cytokine therapy.

Description: The optimal post-remission therapy for patients in first complete remission (CR1) continues to be debated. Some centers choose to omit more intensive regimens, such as autologous or allogeneic transplantation, preferring to reserve these for treatment after relapse. Such strategies are mostly based on reports of treatment in second CR, but fail to account for the fact that most relapsed patients do not get into a second CR. The purpose of this retrospective study is to analyze the overall survival (OS) rate of AML patients from the date of first relapse. The data are based on the outcome of 2441 patients entered on 8 consecutive ECOG studies for newly diagnosed AML between 1983 and 1997. The studies included are E3483, PC486, E3993, E4995, E1490, E3997 and the two Intergroup studies E3489 and E2491 (INT0129). The data are arbitrarily divided among patients older or younger than 55 years, as this was the age used in most studies to distinguish between younger and older patients. Of 1699 patients ≤55 years, 1150 (68%) achieved CR1 and 402 (35%) relapsed. The median OS of these patients from first relapse was 6.4 months with a 5-year OS of 11%. If APL patients are excluded and the data are analyzed only by studies for young AML patients (less than age 55 or 60), the median OS from first relapse is 6.2 months with a 5-year OS of only 9%. In the US Intergroup Study (E3489) for patients ≤ 55 years, the median OS from first relapse after an allogeneic transplant, an autologous transplant or consolidation chemotherapy was 6.6, 5.2 and 8 months, respectively with a 5-year OS of 18%, 0% and 0%, respectively. The latter data, however, require cautious interpretation as the numbers in these subgroups are small. These data indicate that patients who relapse after standard initial AML therapy have a dismal OS from the time of relapse. Some die at relapse and only a minority achieve a second CR. Those refractory to reinduction therapy uniformly have a very poor prognosis. These data thus suggest that in planning post-remission therapies approaches most likely to lead to a prolonged leukemia-free survival should be offered rather than reserving such strategies following relapse. Survival from relapse. Survival from relapse AML (incl APL) n No in CR1 No relapsed (%) Median (months) 2-year survival 5-year survival 55 years ≤ 1699 1150 402 (35%) 6.4 18% 11% 〉55 years 742 362 237 (65%) 4.7 11% 6%

Description: Activating mutations in FLT3 (fms-like tyrosine kinase), either an ITD (repeat of 3–33 amino acids in the juxtamembrane region) or a point mutation in the activation loop, occur in blasts from 30% of AML patients, are associated with poor prognosis, and represent an attractive therapeutic target. PKC412 is a multi-targeted kinase inhibitor which has clinical activity in mutant (reduction in peripheral blasts in 70%) and wild type (reduction in peripheral blast in 30%) AML, but rarely produces remissions (Stone et al, Blood 2005; Estey et al, ASH 2003). We combined DA induction (daunorubicin 60 mg/m2 d 1–3 and cytarabine 100 mg/m2/d by IVCI x 7d) and post-remission therapy (cytarabine 3 gm/m2/3h q 12h, d1,3,5 for 3 cycles) plus PKC412 in previously untreated AML patients less than or equal to age 60 in a phase Ib trial. Results with the original dose schedules of PKC 412: 100 mg po bid from day 8 continuously (arm 1) or day 1 continuously (arm 2) (n=15) or an amended schedule: day 8–21 (arm 1) or day 1–7, 15–21 (arm 2) (n=15) demonstrated safety, but poor tolerability due to nausea and vomiting (Giles, et al, ASH 2004). We now report results with a new amendment in which pts receive the same chemo regimen plus PKC412 at a reduced dose of 50 mg po bid (previously has been shown that PKC at 50 mg bid produces plasma levels sufficient to inhibit FLT3) on day 8–21 (arm 1) or day 1–7, 15–21 (arm 2). None of the 19 pts treated to date have had drug-related death; the most common drug related toxicities during induction and consolidation cycles were nausea (53%), vomiting (47%), ALT increase (32%), AST increase (26%), diarrhea (26%) and rash (21%); all were transient and/or reversible. No Grade 3 or 4 nausea and vomiting were recorded. As of this report, 4 pts have completed the study, and 7 pts are still on study receiving consolidation after achieving CR. Causes of discontinuation include resistant disease (5), transplant after achieving CR (2), and non-drug related toxicity of sepsis and neutropenia (1). All 19 patients are evaluable for response: 9/12 (75%) achieved CR in Arm 1 and 5/7 (71%) achieved CR in Arm 2. Six out of six (100%) FLT3mut patients and 8/13 (62%) FLT3WT patients achieved CR. When a comparison of CR rate is made across all 49 patients in this study overall, there was a significant difference between the FLT3WT CR = 17/32 (53%), and FLT3mut CR=10/11 (91%) (p=0.033 by Fischers exact test). Median follow-up is short, 5 months (1–15). All ten FLT3mut patients that entered CR are alive with only one known relapse (at 15 months post-CR). Conclusions: PKC412 at 50 mg po bid can be given safely and tolerably in newly diagnosed ≤ 60 years old AML patients in combination with DA and high dose cytarabine. These combinations merit further study especially in patients with mutant FLT3 AML.

Description: Imatinib 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.

Description: Abstract 4532 Background Modern medical practice has benefitted significantly from the ability of practitioners and scientists to effectively present and debate their discoveries. Presentations at large subspecialty meetings have been an integral part of this process. The guidelines for abstract submissions to ASH and ASCO discourage repeated submission of the same or similar information. Methods We searched all submissions to the 2009 ASCO meeting involving hematologic malignancies (leukemia, lymphoma, MDS, myeloma and myeloproliferative disorders) and compared these with abstracts from the preceding 2008 ASH meeting to identify duplicate submissions. Duplicate abstracts were identified by correlating subject and author data through the online search engines of the respective organization's websites. Duplication was defined as the repetitive publication or presentation of data that did not seem to differ significantly in terms of content or clinical and scientific impact. The conflict of interest disclosures from the abstracts were examined to identify submissions utilizing pharmaceutical industry support, although such disclosures can be incomplete and it can be difficult to assess the precise role of the industry participants in the process. Hematopoietic stem cell transplant submissions were excluded from this analysis due to the low rate of duplication (3/32) ASCO transplant submissions were similar to those from ASH. Results 19% (47/250) of non-transplant hematologic malignancy ASCO abstracts had been previously presented at oral/poster sessions or published at the 2008 ASH meeting. 71 of the 250 submissions (28%) had authors from pharmaceutical companies while a total of 40% acknowledged research support from pharmaceutical companies (likely but not definitely always related to the content of the abstract). A significant fraction of the submitted and presented abstracts had major involvement with pharmaceutical companies as defined by authorship and/or research support (see table). The degree of pharmaceutical involvement was somewhat higher in the group of duplicate submissions. Conclusions A significant fraction of abstracts submitted to and presented at ASCO are very similar to work previously submitted to ASH. The titles of the abstracts are usually changed somewhat and the order of the authors is frequently shuffled. These findings are similar to a previous analysis of the 2006-ASH/2007-ASCO meetings done by one of the authors (CAS – unpublished data). There are many motivations for repeat presentation, including marketing or publicity opportunities for pharmaceutical companies as well as career advancement for academic investigators. Although arguments might be made that these meetings address different audiences, given the size limitations of the meeting agendas, duplicative presentations may potentially restrict other novel ideas from exposure and should be discouraged. Disclosures: No relevant conflicts of interest to declare.