ALBERT

Description: Our previous PALG study in 445 de novo AML patients has demonstrated that addition of cladribine to the standard daunorubicine-cytarabine (DA) remission induction regimen - DAC has a beneficial influence on both the CR rate after one induction cycle (p=0,0008) and on survival in patients older than 40 y (Leukemia2004,18:989–97, updated at 7 y: ASH 2006, Abstr.N#2003). The goal of this study was to evaluate the efficacy of original combination including another purine analogue fludarabine – DAF (daunorubicine 60 mg/m2/d iv, d 1–3; cytarabine (AraC) 200 mg/m2/d ci, d 1–7, and fludarabine 25 mg/m2 iv d 1–5) in untreated patients with AML, aged up to 60 y, based on head to head comparison with DAC - (DNR, AraC, Cladribine), and standard DA regimens. We evaluated earlier the DAF protocol in relapsed or refractory AML (PALG pilot study; Ann Hematol.2008, 87:361–7. Epub 2007 Dec 12); the tolerance was good, CR 44%, LFS 38%. Primary objectives of the presented trial were: complete remission rate (CR) and overall survival (OS); secondary objectives were: toxicity and leukemia-free survival (LFS). Additional analysis was planned for patients submitted to an early bone marrow allotransplantation (alloBMT) after CR. Patients achieving CR received two courses of subsequent intensive consolidation: HAM (HD AraC, mitoxantrone) HD AraC. Reduction of consolidation was accepted in patients treated with early alloBMT. In case of partial remission (PR) after the first induction course the same regimen was repeated. Patients with no remission (NR) or with PR after 2 induction courses were withdrawn from the study. Between 09.2004 and 05.2008, 673 adult untreated AML patients aged 18–60 y, median 47 y, sex: male 49,5%, female 50,5%, treated in 18 co-operating Polish Adult leukemia Group (PALG) centres were centrally randomised to either DAF (n=225), DAC (n=224) or DA (n=224) arm (1:1:1). PML/RAR alfa positive - FAB M3 cases were excluded. The study groups were well balanced in respect of age, sex, FAB subtype, and WBC. After a single induction course the CR rate for patients receiving DAC equalling 63% was significantly higher if compared with DA - 51% (p=0,01), whereas no significant differences were noted between DAC vs. DAF - 55% and DAF vs. DA subgroups. Also the entire CR rate of 68% in the DAC arm was higher in comparison with DA one - 57% (p=0,02). No significant differences were found between DAC vs. DAF - 60%, and DAF vs. DA. At median time of 24 months (longest observation time 3,5y) the OS rate equalled 51% for the DAC treated subgroup and was higher in comparison to the standard DA arm - 39% and the DAF arm - 36% (p=0,03). The leukemia free survival rates (LFS) in DAC, DA and DAF treated cohorts equalled 51%, 32% and 41% respectively (p=NS). The early death rates of 8–10%. were similar in the studied treatment subgroups. All patients developed WHO grade IV thrombocytopenia and agranulocytosis. The frequency and severity of infections, mucositis, vomiting, diarrhoea, alopecia, polyneuropathy as well as of cardiac, liver or kidney dysfunctions were comparable in particular arms. In conclusion, this randomised study proves that the addition of cladribine to the standard DA induction regimen (DAC) improves CR rate and the overall survival in adults with AML aged up to 60 y, without additional toxicity. This beneficial effect was not observed in patients treated using the DAF protocol with fludarabine added to the standard “DA 3+7” schedule

Description: Abstract 2138 In a previous study by the Polish Adult Leukemia Group (PALG 4–2002) we demonstrated that status of minimal residual disease (MRD) during induction-consolidation is the most important factor predicting long-term outcome of adult ALL (Br J Haematol 2008). In a new PALG 5–2007 protocol the treatment was intensified for patients with MRD level 〉0.1% of bone marrow cells and adjusted to age. Induction consisted of Epirubicine(4×), Vincristine(4×), Prednisone and PEG-asparaginase. Patients with complete remission (CR) but MRD 〉0.1% obtained additional 2nd phase of induction: AraC+Cyclophosphamide(Ctx) + 6MP. Consolidation consisted of 2 courses of Methotrexate(Mtx) + Etoposide + Dexamethasone and subsequent 2 cycles of Ctx + high dose AraC, asparaginase, intrathecal prophylaxis and CNS irradiation. Doses of Mtx were 500 mg/m2 for patients with MRD35y and 1500 mg/m2 for all remaining ones. For Ph+ ALL imatinib 600 mg/d was administered in parallel to chemotherapy. Patients with standard risk disease continued with 2 years maintenance while those with high-risk were referred for alloHSCT. High risk was defined as the presence of at least one of: initial WBC 〉30×10e9/L, age 〉35y, pro-B, early-T, mature-T, late CR, t(9;22), t(4;11) or MRD 〉0.1% at any time during induction-consolidation. Results of PALG 5–2007 protocol (N=108, median age 32y, range 16–55y) were compared to PALG 4–2002 (N=253, age 28y, range 16–55y), in which MRD status was not taken into account for treatment decisions. CR rate was 92% for PALG 5–2007 compared to 89% for PALG 4–2002. The probability of the overall survival at 36 months was 56% vs. 33% (p=0.02), while leukemia-free survival was 53% vs. 28% (p=0.04), respectively. The probability of relapse decreased from 54% in PALG 4–2002 to 16% in PALG 5–2007 (p=0.002). In a multivariate analysis adjusted to age, initial WBC and the presence of t(9;22) treatment according to PLAG 5–2007 protocol was associated with decreased risk of mortality (HR=0.57, p=0.02), relapse (HR=0.37, p=0.006) and treatment failure (HR=0.64, p=0.049). We conclude that individualized therapeutic approach with treatment intensity adjusted to MRD status and age may result in improved outcome of adults with ALL. *This multi-institutional study was supported by Polish Ministry of Sciences Grant NN-402366433 Disclosures: Off Label Use: Dasatinib as first line therapy in Ph ALL.

Description: Introduction: Panobinostat (PAN) is a potent pan-deacetylase inhibitor (pan-DACi) that targets key aberrations in multiple myeloma (MM) cell biology, including protein metabolism and epigenetics. In a randomized phase 3 clinical trial in patients (pts) with relapsed or relapsed and refractory MM (PANORAMA 1), the addition of PAN to bortezomib (BTZ) and dexamethasone (Dex; PAN-BTZ-Dex) led to a clinically relevant and statistically significant increase in progression-free survival (PFS) of ≈ 4 months compared to placebo plus BTZ and Dex (Pbo-BTZ-Dex). PAN-BTZ-Dex was associated with a higher rate of adverse events (AEs) compared to Pbo-BTZ-Dex; however, a comparable number of pts completed the full duration of treatment on both treatment arms. Thus, we sought to determine the effect of treatment duration on the safety and efficacy of PAN-BTZ-Dex. Methods: The PANORAMA 1 trial consisted of two treatment phases (TP1 and TP2) with a maximum of 12 cycles total. In TP1 (eight 3-wk cycles), pts were randomized to receive oral PAN (20 mg) or Pbo administered three times a wk for the first 2 wks, and intravenous BTZ (1.3 mg/m2) administered on days 1, 4, 8, and 11 with Dex (20 mg) administered orally on the days of and after BTZ. Pts demonstrating clinical benefit could proceed to TP2 (four 6-wk cycles), in which PAN was administered on a similar schedule but BTZ was administered once-wkly (days 1, 8, 22 and 29) with Dex administered on the days of and after BTZ. This analysis focused on safety and efficacy specifically associated with the two treatment phases. For efficacy outcomes (PFS and near complete response/complete response [nCR/CR] rate), pt groups were delineated by those who received treatment 〉 8 cycles (completed TP1, 24 weeks) and all 12 cycles (completed TP2, 48 weeks). Median PFS was calculated based on time averaged dose (cumulative dose in a time interval divided by the planned number of dosing days) of PAN received to determine the potential role of dose adjustments/interruptions on efficacy. PFS was analyzed by Kaplan-Meier estimates. A safety analysis was conducted of AEs for TP1/TP2 for pts who completed TP2. Due to interdependencies among outcomes, further investigations of these data are needed. Results: Among the pts enrolled in the PAN-BTZ-Dex arm (N = 387), 169 (44%) completed TP1 and 102 (26.4%) completed TP2. Overall, pts who received a longer duration of treatment with PAN-BTZ-Dex demonstrated a longer PFS (Figure). Median PFS for pts who received PAN-BTZ-Dex and completed TP1 was 14.65 months (95% CI, 12.94, 16.85) and 17.64 months (95% CI, 15.90, 20.07) for those who completed TP2. In addition, nCR/CR rate was 52.9% for pts who completed TP2. Overall, the rates of commonly observed grade 3/4 AEs (≥ 20%) in the PAN-BTZ-Dex arm were thrombocytopenia (TCP, 57.0%), diarrhea (25.5%), and asthenia/fatigue (23.9%). Safety analysis for pts who completed TP2 demonstrated the higher rate of AEs in TP1 vs TP2 (excluding AEs that continued from TP1). For pts in the PAN-BTZ-Dex arm who completed treatment (n = 102), the rates of grade 3/4 events in TP1 and TP2 for common AEs were TCP (47.1% and 5.9%), diarrhea (25.5% and 8.8%), and asthenia/fatigue (19.6% and 5.9%). For pts in the Pbo-BTZ-Dex arm who completed treatment (n = 102), the rates for TP1 and TP2 were TCP (10.8% and 1.0%), diarrhea (5.9% and 0%), and asthenia/fatigue (7.8% and 0%). About half the pts (218/387; 56.3%) in the PAN-BTZ-Dex arm did not enter TP2 (112/218; 51.4% discontinued to due AEs). Analysis of time averaged dose of safety set pts on the PAN-BTZ-Dex arm demonstrated a median PFS of 12.71 (95% CI, 10.58, 14.19) months for pts who received 〉15-20 mg of PAN and 10.90 months (95% CI, 8.08, 12.71) for 〉10-15 mg. Conclusions: These data highlight the PFS and nCR/CR rate among pts able to complete TP2 with PAN-BTZ-Dex. Furthermore, for pts who completed the entire treatment regimen, the incidence of new/worsening AEs in TP2 where BTZ was administered on a once weekly schedule was decreased. Pts who received a lower time averaged dose due to dose adjustments/interruption of PAN had a similar median PFS to pts who received a time averaged dose closer to the planned dose. Together, these data support the hypothesis that optimal management of AEs for pts receiving PAN-BTZ-Dex via dose adjustments including BTZ and/or concomitant medications, particularly earlier during their course of therapy, could increase treatment duration and maintain outcomes. Figure 1 Figure 1. Disclosures San Miguel: Millennium: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Onyx: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; MSD: Membership on an entity's Board of Directors or advisory committees. Jedrzejczak:Amgen, Novartis : Consultancy, Research Funding. Guenther:Novartis: Consultancy, Research Funding. Siritanaratkul:Novartis: Research Funding; Roche: Research Funding; Janssen: Research Funding. Schlossman:Millennium: Consultancy. Hou:Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees. Lonial:Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Onyx: Consultancy; Sanofi: Consultancy. Sopala:Novartis Pharma AG: Employment. Redhu:Novartis : Employment. Paul:Novartis: Employment. Corrado:Novartis Pharma AG: Employment. Binlich:Novartis Pharma SAS: Employment. Richardson:Takeda: Research Funding; Millennium: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees.

Description: Introduction: In the randomized placebo controlled phase 3 trial PANORAMA 1 the pan-deacetylase inhibitor (pan-DACi) panobinostat combined with bortezomib and dexamethasone (PAN-BTZ-Dex) led to a statistically significant and clinically relevant increase in progression free survival in patients (pts) with relapsed or relapsed and refractory multiple myeloma (Pbo-BTZ-Dex; 12.0 vs 8.1 months; hazard ratio 0.63, P

Description: Abstract 1334 Background A number of molecular aberrations have been described in acute myeloid leukemia (AML). They disturb normal haematopoiesis and are response for leukaemogenic mechanism and drug resistance. Therefore, they seem to be of prime importance for treatment outcome. FMS-like tyrosine kinase 3- internal tandem duplication (FLT3-ITD) and mixed-lineage leukemia gene-partial tandem duplication (MLL-PTD) are leukemia associated aberrations which confer worse prognosis. Downstream regulatory targets of FLT3-ITD and MLL-PTD are not well defined. The over-expression of ABC transport proteins that function as a membrane pump responsible for the efflux of a range of chemotherapeutic drugs are known mechanism behind multidrug drug resistance (MDR) in AML. The p-glycoprotein (Pgp)-product of MDR1 gene and multidrug resistant protein-1 (MRP-1), breast cancer resistance protein (BCRP) encoded by the relevant genes negatively influence the results of AML therapy. Aims The aim of this study was to analyze the expression of the MDR-1, MRP-1, BCRP messenger RNA (mRNA) in relation to the response to induction chemotherapy and relapse and with pretreatment laboratory and clinical characteristics such as age (

Description: Background: Bruton’s tyrosine kinase (BTK) is a critical signaling molecule in the B-cell receptor signaling pathway essential for B-cell development, survival, and function. Ibrutinib is a first-in-class, once-daily, oral covalent inhibitor of BTK approved for the treatment of patients with MCL who have received at least 1 prior therapy. Previous results of the international, multicenter, open-label phase 2 trial demonstrated the durability of responses and favorable safety profile of daily oral ibrutinib in relapsed or refractory MCL (Wang et al, NEJM 2013). Here, we present the updated safety and efficacy results of this phase 2 trial with a median follow-up of approximately 27 months. Methods: 115 relapsed or refractory MCL patients were enrolled, and 111 patients were treated. All patients provided informed consent. Patients received oral ibrutinib 560 mg once daily until disease progression or unacceptable toxicity. Patients were eligible to continue therapy into a long-term extension study if they had stable disease or better. Tumor response was assessed by investigators using the 2007 revised IWG criteria. Adverse events (AEs) were characterized by preferred terms using MedDRA version 16.1 and were evaluated over 6-month time intervals (1-6, 7-12, 13-18, 19-24, 〉24 months). Prevalence was based on the number of patients with an AE occurring during a given interval (either a new episode or an ongoing episode from the prior 6-month period continuing into the current interval). Results: Data are reported for 111 patients. Baseline characteristics included median age 68 years (range, 40-84), median 3 prior therapies (range, 1-5), prior bortezomib in 43%, prior autologous stem cell transplant in 11%, high-risk MIPI in 49%, and bulky disease (≥5 cm) in 39%. Median treatment duration was 8.3 months; 51 patients (46%) were treated for 〉1 year, and 29 (26%) who continued treatment and follow-up in the extension study were treated for 〉2 years. The most common treatment-emergent AEs (reported in 〉30% patients) included infection (78% all grade, 28% grade ≥3), diarrhea (54% all grade, 5% grade ≥3), bleeding (50.5% all grade, 6% grade ≥3), fatigue (49.5% all grade, 4.5% grade ≥3), nausea (33% all grade, 1% grade ≥3), and dyspnea (32% all grade, 4.5% grade ≥3). In total, grade ≥3 AEs occurred in 81% of patients and serious AEs (SAEs) of any grade in 63%. Treatment discontinuation due to AEs was reported in 11% of patients. As shown in the Table, prevalence rates for infection, diarrhea, and bleeding events were highest for the first 6 months and gradually declined thereafter. One SAE of infection occurred beyond 24 months. No clinically significant changes were observed in immunoglobulin levels over time. No SAE of diarrhea occurred after 6 months of therapy. The prevalence of major bleeding remained stable, occurring at a rate of ≤9% during each interval. The investigator-assessed overall response rate was 67%, with complete response (CR) in 22.5%. Median time to response was 1.9 months, and median time to CR was 5.5 months. Median duration of response was 17.5 months (Figure). Among all treated patients, with an estimated median follow-up of 26.7 months, median progression-free survival (PFS) was 13 months, and median overall survival (OS) was 22.5 months. The 24-month Kaplan-Meier PFS and OS rates were 31.1% (95% CI, 22.3-40.4) and 47.3% (95% CI, 37.1-56.9), respectively. Conclusions: Results with a median 27-month follow-up demonstrate the durability of responses and sustained single-agent activity of continuous ibrutinib in relapsed or refractory MCL. Approximately one-third of patients remain progression free at 24 months. Ibrutinib continues to show a favorable risk-benefit profile over time, with a safety profile consistent with that reported previously; these data with additional follow-up time did not reveal an increase in unforeseen AEs. Table. Prevalence of select AEs by 6-month intervals Select AEs,n (%) 1-6 months(n = 111) 7-12 months(n = 72) 13-18 months(n = 51) 19-24 months(n = 41) 〉24 months (n = 22) All patients (N = 111) Any diarrhea Grade 3* SAE 49 (44) 5 (5) 1 (1) 21 (29) 0 0 15 (29) 0 0 8 (20) 1 (2) 0 6 (27) 0 0 60 (54) 6 (5) 1 (1) Any infection Grade ≥3 SAE 76 (69) 20 (18) 16 (14) 43 (60) 11 (15) 9 (13) 30 (59) 6 (12) 4 (8) 22(54) 5 (12) 5 (12) 9 (41) 1 (5) 1 (5) 87 (78) 31 (28) 23 (21) Any bleeding Major bleeding 46 (41) 6 (5) 17 (24) 1 (1) 17 (33) 3 (6) 14 (34) 2 (5) 5 (23) 2 (9) 56 (51) 10 (9) *No grade 4 or 5 diarrhea. Figure 1 Figure 1. Disclosures Wang: Pharmacyclics, Janssen: Honoraria, Research Funding. Rule:Pharmacyclics, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Martin:Janssen: Honoraria. Goy:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research funding for clinical trials through institution, Research funding for clinical trials through institution Other; Millennium: Membership on an entity's Board of Directors or advisory committees, Research funding for clinical trials through institution, Research funding for clinical trials through institution Other, Speakers Bureau; Pharmacyclics, JNJ: Membership on an entity's Board of Directors or advisory committees, Research funding for clinical trials through institution Other, Speakers Bureau. Auer:Gilead, Celgene: Honoraria. Kahl:Pharmacyclics: Research Funding. Advani:Celgene: Research Funding; Pharmacyclics: Research Funding; Janssen Pharmaceuticals: Research Funding; Genentech: Research Funding; Seattle Genetics, Inc.: Research Funding; Takeda International Pharmaceuticals Co.: Research Funding. Williams:Pharmacyclics, Janssen: Consultancy, Research Funding. Barrientos:Pharmacyclics: Membership on an entity's Board of Directors or advisory committees, Research Funding. Stilgenbauer:Pharmacyclics, Janssen: Honoraria, Research Funding. Dreyling:Pharmacyclics: Honoraria, Membership on an entity's Board of Directors or advisory committees. Jedrzejczak:Amgen, Novartis : Consultancy, Research Funding. Johnson:Janssen-Cilag: Consultancy, Honoraria, Research Funding. Zhang:MD Anderson: Employment. Baher:Pharmacyclics: Employment. Cheng:Pharmacyclics: Employment. Beaupre:Pharmacyclics: Employment. Blum:Janssen, Pharmacyclics : Research Funding.

Description: Rozrolimupab, a recombinant mixture of 25 fully human RhD-specific monoclonal antibodies, represents a new class of recombinant human antibody mixtures. In a phase 1 or 2 dose escalation study, RhD+ patients (61 subjects) with primary immune thrombocytopenia received a single intravenous dose of rozrolimupab ranging from 75 to 300 μg/kg. The primary outcome was the occurrence of adverse events. The principal secondary outcome was the effect on platelet levels 7 days after the treatment. The most common adverse events were headache and pyrexia, mostly mild, and reported in 20% and 13% of the patients, respectively, without dose relationship. Rozrolimupab caused an expected transient reduction of hemoglobin concentration in the majority of the patients. At the dose of 300 μg/kg platelet responses, defined as platelet count ≥ 30 × 109/L and an increase in platelet count by 〉 20 × 109/L from baseline were observed after 72 hours and persisted for at least 7 days in 8 of 13 patients (62%). Platelet responses were observed within 24 hours in 23% of patients and lasted for a median of 14 days. Rozrolimupab was well tolerated and elicited rapid platelet responses in patients with immune thrombocytopenia and may be a useful alternative to plasma-derived products. This trial is registered at www.clinicaltrials.gov as #NCT00718692.

Description: Abstract 1067 Elderly patients with acute myeloid leukemia are heterogenous group with poor outcome. All age, biological status and co-morbidities limit applicability of intensive chemotherapy. The PALG elaborated original system allowing stratification of patients aged 〉60 years to three groups with different therapeutic approach. Altogether 537 patients with newly diagnosed AML and median age 70 years (range 60–93) were classified as 1) ‘fit’ (n=163): age 60–79y, ECOG 0–2, proper liver and kidney function, without comorbidities, 2) ‘unfit’ (n=210): age 〉60 years, ECOG 0–2, normal liver and kidney function, comorbidities allowed, 3) ‘frail’ (n=164): ECOG 3–4. According to PALG 1/2005 protocol ‘fit’ patients were treated similarly as younger adults with daunorubicin (DNR, 3 days) + cytarabine (AraC, 7 days) +/− cladribine, followed by DNR + AraC consolidation and maintenance. ‘Unfit’ patients received either two courses of AraC+DNR (2+5) or AraC (5 days) + thioguanine + methotrexate, followed by manitenance. ‘Frail’ patients were considered for palliative cytoreduction and supportive care. Results: Complete remission (CR) rate was 35% for ‘fit’, 22% for ‘unfit’ and 0% for ‘frail’ patients. Median survival in the respective groups equaled 39 weeks, 26 w., and 14 w., while the probability of survival at 1 year was 39%, 27% and 10%. The rate of early (up to 8 weeks) mortality was 31%, 24% and 31%, respectively. In the Cox model the only factor independently affecting the risk of overall mortality in both ‘fit’ and x‘unfit’ group was serum LDH above upper quartile (HR=2, p=0.005 for ‘fit’, HR=1.65, p=0.006 for ‘unfit’). Among ‘frail’ patients the risk of mortality was increased in patients with performance status ECOG〉2 (HR=1.85, p=0.0008), initial WBC 〉8.5×10e9/L (HR=1.65, p=0.006), and bone marrow blasts 〉58% (HR=1.8, p=0.001). We conclude that the proposed stratification system is feasible for elderly AML patients and represets a model for further developments of individualized therapeutic approaches. Survival of patients in whom remission induction therapy may be applied depends on initial tumor burden as reflected by high serum LDH level. The outcome of patients referred for palliative treatment depends additionally on initial performance status. In contrast, neither age nor karyotype were found to independently affect outcome in this study. Disclosures: No relevant conflicts of interest to declare.

Description: Key Points Ibrutinib demonstrates durable responses and sustained single-agent activity in relapsed or refractory MCL at median 26.7-month follow-up. Ibrutinib shows a favorable benefit-risk profile over time, with a manageable safety profile.