Kooperativer Bibliotheksverbund

In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 3276-3276

Abstract: Background: Thrombocytopenia in MDS occurs in ~50% of pts with low/int-1 MDS and is associated with reduced survival; few therapies are available for these thrombocytopenic MDS pts. In a randomized PBO-controlled study, 250 pts with MDS were randomized 2:1 to receive weekly romiplostim or PBO. In the original June 2011 analysis, romiplostim reduced clinically significant bleeding events (HR romiplostim vs. PBO 0.83, 95% CI: 0.66, 1.05, P = 0.13) and platelet transfusions (RR 0.77, 95% CI: 0.66, 0.88, P 〈 0.001), and increased IWG HI-P incidence (OR 15.6, 95% CI: 4.7, 51.8, P 〈 0.001). Increases in peripheral blast counts to 〉 10% were more frequent with romiplostim (25/167, 15%) than PBO (3/83, 3.7%), and in most cases resolved after discontinuation. Due to concerns of the safety data monitoring committee that the potential benefit seen in the reduction of bleeding did not outweigh the potential risk for disease progression to AML and that transient increases in blast cell counts might put pts at risk for diagnosis of and treatment for AML, treatment with study drug was discontinued in February 2011. Pts were then moved into the long-term follow-up (LTFU) portion of the study. Previously reported (Giagounidis et al, Cancer 2014) 58-week incidence of AML was romiplostim: 6.0% (10 pts), PBO: 4.9% (4 pts), HR 1.20 (95% CI: 0.38, 3.84). This report provides additional data on LTFU of these pts up to March 2014, with a particular emphasis on AML incidence. Methods: Eligible pts had IPSS low/int-1 MDS and platelets 1) ≤20x109/L or 2) ≤50x109/L with a history of bleeding, and were receiving only supportive care. Disease progression to AML was defined as 1) ≥20% blasts in the bone marrow or peripheral blood after 4 weeks following discontinuation of romiplostim, 2) pathology consistent with leukemia including chloroma or leukemia cutis, or 3) anti-leukemic treatment initiation. Results are presented by treatment group. Results: Of 250 pts in the study, 210 entered LTFU, and 83 of these pts remained on study as of March 2014; the median (Q1, Q3) follow-up was 27.5 (10.8, 41.2) months. Reasons for discontinuation during LTFU were similar in the romiplostim and PBO groups and included death, lost to follow-up, and withdrawal of consent. During the active study period or during LTFU, death was reported in 50.9% (N = 85) of pts in the romiplostim group and 48.2% (N = 40) of pts in the PBO group (HR romiplostim vs. PBO 1.04, 95% CI: 0.71, 1.52) (Figure); mortality rates were greater in those with int-1 vs. low IPSS status for both the PBO and romiplostim groups (Table 1). AML was reported in 11.9% (N = 20) of pts in the romiplostim group and 9.8% (N = 8) of pts in the PBO group (HR 1.21, 95% CI: 0.53, 2.76). The proportions of pts who either died or developed AML were 52.7% (N = 88) in the romiplostim group and 48.2% (N = 40) in the PBO group (HR 1.10, 95% CI: 0.75, 1.60) (Figure). Fourteen of the 28 AML cases occurred in pts who were RAEB-1 at screening (none were RAEB-2) and 5 cases were diagnosed due to anti-AML treatment use alone (Table 2). In LTFU, the rate of pt-reported use of MDS therapy (e.g., azacitidine or cyclosporine) in the romiplostim group was 42.8% (N = 59, 95% CI: 34.4%, 51.5%) and 28.2% (N = 20, 95% CI: 18.1%, 40.1%) in the PBO group. Reported use of AML therapy (e.g., chemotherapy) occurred at a rate of 10.2% (N = 14) in the romiplostim group and 8.5% (N = 6) in the PBO group. Conclusion:Following the 2011 decision to stop study drug, results have been updated with more observational time on study. Specifically, the HRs for death or progression to AML (romiplostim vs. PBO) are 1.04 (95% CI: 0.71, 1.52) and 1.21 (95% CI: 0.53, 2.76), respectively, compared with 2013 HRs of 1.04 (95% CI: 0.70, 1.54) and 1.14 (95% CI: 0.49, 2.62), respectively. As LTFU continues, additional data will be evaluated. Safety concerns regarding risk of disease progression to AML are still being investigated. Table 1: Survival by Baseline IPSS n (%) RomiplostimN = 167 PBON = 83 Low 14/46 (30.4%) 3/23 (13.0%) 95% CI (%) 17.7, 45.8 2.8, 33.6 Int-1 71/121 (58.7%) 37/60 (61.7%) 95% CI (%) 49.4, 67.6 48.2, 73.9 Table 2: Progression to AML to Date Study-defined AML, n (%) RomiplostimN = 20 PBON = 8 TotalN = 28 Baseline WHO classification RAEB-1/2 11 (55%) 3 (37.5%) 14 (50%) Non-RAEB 9 (45%) 5 (62.5%) 14 (50%) AML diagnosis by Bone marrow/peripheral blast 〉 20% 17 (85%) 6 (75%) 23 (82.1%) Anti-AML therapy alone 3 (15%) 2 (25%) 5 (17.9%) Figure Figure 1 Figure 1. Disclosures Kantarjian: Amgen Inc.: Research Funding. Off Label Use: Romiplostim is indicated for the treatment of thrombocytopenia in patients with chronic immune thrombocytopenia (ITP) who have had an insufficient response to corticosteroids, immunoglobulins, or splenectomy. The use of romiplostim in myelodysplastic syndromes is under investigation.. Mufti:Amgen Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Fenaux:Amgen Inc.: Research Funding. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Membership on an entity's Board of Directors or advisory committees. Szer:Sandoz: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Platzbecker:Amgen Inc.: Honoraria. Kuendgen:Celgene: Research Funding. Gaidano:Amgen Inc.: Consultancy, Honoraria. Wiktor-Jedrzejczak:Amgen Inc.: Research Funding. Orejudos:Amgen Inc.: Consultancy. Lopez:Amgen Inc.: Employment, Equity Ownership. Giagounidis:Amgen Inc.: Consultancy, Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.3276.3276

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 116, No. 21 ( 2010-11-19), p. 2138-2138

Abstract: 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 MRD 〈 0.1%, aged 〉 35y 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.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V116.21.2138.2138

Language: English

Publisher: American Society of Hematology

Publication Date: 2010

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 128, No. 22 ( 2016-12-02), p. 2000-2000

Abstract: Background: Thrombocytopenia occurs in ~50% of patients with low/int-1 risk myelodysplastic syndrome (MDS) and is associated with reduced survival. In a placebo (PBO)-controlled study, 250 patients with MDS were randomized 2:1 to receive weekly romiplostim or PBO. In the original June 2011 analysis, romiplostim reduced clinically significant bleeding events [hazard ratio (HR) romiplostim vs PBO 0.83, 95% CI: 0.66−1.05, P = 0.13] and platelet transfusions (relative risk 0.77, 95% CI: 0.66−0.88, P 〈 0.001) and increased IWG hematologic improvement platelets (HI-P) incidence (odds ratio 15.6, 95% CI: 4.7−51.8, P 〈 0.001). Peripheral blast count increases 〉 10% were more frequent with romiplostim (25/167, 15%) than PBO (3/83, 3.6%) and resolved after discontinuation in most cases. In February 2011, the DMC recommended that treatment with study drug be discontinued as the potential benefit seen in the reduction of bleeding did not outweigh the potential risk for disease progression to AML, and that transient increases in blast cell counts might put patients at risk for diagnosis of and treatment for AML. Patients were moved into long-term follow-up (LTFU). Previously reported (Giagounidis et al, Cancer 2014) 58-week incidence of AML was 6.0% (N = 10) for romiplostim and 4.9% for PBO (N = 4); HR 1.20 (95% CI: 0.38−3.84). This report provides final 5-year LTFU data. Methods: Eligible patients were receiving only supportive care and had IPSS low/int-1 risk MDS and platelets 1) ≤20 × 109/L or 2) ≤50 × 109/L with a history of bleeding. Disease progression to AML was defined as 1) ≥20% blasts in bone marrow or peripheral blood after 4 weeks following discontinuation of romiplostim; 2) pathology consistent with leukemia; or 3) antileukemic treatment. Results are presented by treatment group. Results: At baseline, median (Q1, Q3) age was 70 (61, 77) years, the majority (59%) of patients were male; 27.6% were IPSS low risk and 72.4% were int-1 risk. WHO classifications were RCMD: 67.6%, RAEB-1: 13.2%, MDS-U: 11.2%, RA: 4.4%, RCMD-RS: 2.4%, RARS: 0.8%, and RAEB-2: 0.4%. Of 250 patients in the study, 210 entered LTFU and 66 completed the 5 years of LTFU; median (Q1, Q3) follow-up was 27.5 (10.8, 58.7) months. Reasons for discontinuation (death, lost to follow-up, and consent withdrawal) during LTFU were similar in both groups. During the active study period and LTFU, death was reported in 93 (55.7%) patients in the romiplostim group and 45 (54.2%) patients in the PBO group (HR romiplostim vs PBO 1.03, 95% CI: 0.72−1.47) (Figure); mortality rates were greater in those with IPSS int-1 vs low risk for both groups (Table). AML was reported in 20 (11.9%) patients in the romiplostim group and 9 (11.0%) patients in the PBO group (HR 1.06, 95% CI: 0.48−2.33). The proportions of patients who either died or developed AML were 56.9% (N = 95) in the romiplostim group and 55.4% (N = 46) in the PBO group (HR for AML-free survival 1.04, 95% CI: 0.73−1.48) (Figure). Nearly half (N = 14, 48%) of the 29 AML cases occurred in patients who were RAEB-1 at screening (none RAEB-2), and 6 cases were diagnosed because of anti-AML treatment use alone (Table). In LTFU, patient-reported use of MDS therapy (eg, azacitidine or cyclosporine) was 42.8% (N = 59, 95% CI: 34.4%−51.5%) in the romiplostim group and 31.4% (N = 22, 95% CI: 20.9%−43.6%) in the PBO group. AML therapy (eg, chemotherapy) was used in 14 (10.2%) patients in the romiplostim group and 7 (10.0%) patients in the PBO group. Conclusions: Following the decision in 2011 to stop study drug secondary to increased AML rates at that time and transient blasts increases, final 5-year LTFU HRs (romiplostim vs placebo) for death or progression to AML, respectively, are 1.03 (95% CI: 0.72−1.47) and 1.06 (95% CI: 0.48−2.33). In conclusion, romiplostim reduced bleeding events and platelet transfusions, with no increase in AML incidence or impact on survival. Disclosures Kantarjian: Amgen Inc.: Research Funding. Fenaux:Amgen Inc.: Research Funding. Sekeres:Celgene: Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Membership on an entity's Board of Directors or advisory committees; Millenium/Takeda: Membership on an entity's Board of Directors or advisory committees. Szer:Alexion: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Alexion Australia: Consultancy, Honoraria; Amgen Inc.: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Shire: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pfizer: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Platzbecker:Celgene Corporation: Honoraria, Research Funding; TEVA Pharmaceutical Industries: Honoraria, Research Funding; Janssen-Cilag: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Kuendgen:Celgene: Research Funding. Gaidano:Morphosys: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; GlaxoSmithKline: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen Inc.: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees. Wiktor-Jedrzejczak:Angelini: Consultancy; Novartis: Consultancy, Research Funding; Celgene: Consultancy; Janssen-Cilag: Consultancy; Novartis: Consultancy, Research Funding; BMS: Research Funding; Sandoz: Consultancy; Amgen Inc.: Research Funding. Carpenter:Amgen Inc.: Employment, Equity Ownership. Mehta:Amgen Inc.: Employment, Equity Ownership. Franklin:Amgen Inc.: Employment, Equity Ownership. Giagounidis:Amgen Inc.: Consultancy, Honoraria.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V128.22.2000.2000

Language: English

Publisher: American Society of Hematology

Publication Date: 2016

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 120, No. 21 ( 2012-11-16), p. 1334-1334

Abstract: 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 ( 〈 60, ≥60 years), disease status (de novo/secondary), cytogenetics, FLT3-ITD and MLL-PTD mutational status, white blood cell count (WBC) and the type of AML according to the French-American-British (FAB) classification. Moreover, the influence of MDR genes on disease free survival (DFS) and overall survival (OS) were estimated. Methods A total of 185 adult consequent patients (88 females and 97 males) at a median age of 53,1 years (range 18,5–86,6 years) with newly diagnosed, previously untreated AML, as well as 40 healthy donors were included in this study. DNA and RNA were extracted from mononuclear cells of bone marrow (147 patients) or peripheral blood (38 patients) samples collected after approval from the ethics committee and informed consent from the patients. FLT3-ITD and MLL-PTD were detected with PCR method. The RQ-PCR method was performed for the assessment of expression of the MDR-1, MRP-1, BCRP and LRP mRNA and the results were presented as coefficients calculated with an intermediate method according to Pfaffl's rule. The relative expression ratio of a target gene was calculated based on efficiency and the Ct deviation of the healthy donor′s sample versus the patient′s sample, and expressed in comparison to a reference gene: Results In univariate analysis, the high expression of MDR-1 mRNA ( 〉 0,13) was associated with outcome of induction therapy (p=0,06) and of BCRP mRNA ( 〉 1,14) with high relapse rate (RR) (p=0,013). We found that high expression of MDR-1 ( 〉 0,13), MRP-1 mRNA ( 〉 0,84) and BCRP mRNA ( 〉 1,14) significantly influence DFS (p=0,059, 0,032 and 0,009, respectively) and OS (0,048, 0,014 and 0,059, respectively). Interestingly, high BCRP mRNA expression ( 〉 1,14) proved to be an independent prognostic factor for RR (p=0,01) and DFS (p=0,002) in the multivariate analysis. FLT3-ITD and MLL-PTD were detected in 53 (29%) and 44 (25%), respectively. Interestingly, we found correlation between expression of MDR1, MRP1 and BCRP mRNA and FLT3-ITD and MLL-PTD mutational status in presented group of patients. The expression of MDR-1 mRNA was significantly higher in patients no harboring FLT3-ITD mutation (0,20 vs. 0,05, p= 0,0001) and ≥60 years old (0,30 vs. 0,10, p= 0,007). The higher expression of MRP-1 mRNA was found in patients with FLT3-ITD mutation (0,96 vs. 0,70, p= 0,002) and the expression of BCRP mRNA was significantly higher in patients with MLL-PTD (0,61 vs 0,38, p=0,03). Conclusions The combined analysis of MDR genes allowed different classes of AML to be identified, with distinct clinico-biological features. The high expression of MDR genes correlates with worse treatment outcome of patients with AML. It seems that especially BCRP is associated with clinical resistant disease in AML and influence the RR and DFS. Our study also shows that MDR gene expression in AML patients should be considered together with leukemia associated aberrations. The interesting correlation found between expression of MDR1, MRP1 and BCRP mRNA and FLT3-ITD and MLL-PTD in AML patients needs further investigation to determine its clinical value and made final conclusions. Disclosures: No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V120.21.1334.1334

Language: English

Publisher: American Society of Hematology

Publication Date: 2012

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 2120-2120

Abstract: 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 〈 0.0001). Gastrointestinal (GI) toxicity, particularly diarrhea, a known class-effect of pan-DACi and BTZ, was the most common non-hematologic adverse event (AE) observed in both treatment arms, occurring at a higher incidence in the PAN-BTZ-Dex arm. Optimal management of GI toxicity, especially diarrhea-related AEs, in pts who receive PAN-BTZ-Dex could help maximize treatment outcomes. Here we present a detailed analysis of pts with diarrhea on the PANORAMA 1 study to inform strategies to reduce the effects of diarrhea and improve efficacy. Methods: The PANORAMA 1 trial included 12 cycles of treatment with two treatment phases (TP1: eight 3-week cycles; TP2: four 6-week cycles). In TP1, pts were randomized to receive oral PAN (20 mg) or Pbo administered thrice weekly for the first 2 weeks, with intravenous BTZ (1.3 mg/m2) administered on days 1, 4, 8, and 11 and Dex (20 mg) administered orally on the days of and after BTZ. In TP2 (for pts demonstrating clinical benefit), PAN or Pbo were administered similarly but BTZ was administered once-weekly (days 1, 8, 22 and 29) with Dex on the day of and after BTZ. For each cycle, prevalence and incidence for diarrhea AEs were determined; these were characterized by grade, improvement in grade, worsening of grade, and resolution of diarrhea. Results: In the PANORAMA 1 trial, a total of 260/381 (68.2%) pts treated with PAN-BTZ-Dex and 157/377 (41.6%) pts treated with Pbo-BTZ-Dex reported AEs of diarrhea; most were grade 1 or 2 (PAN-BTZ-Dex: 42.8% vs Pbo-BTZ-Dex: 33.7%). Grade 4 diarrhea was rare (PAN-BTZ-Dex: 1.3%; Pbo-BTZ-Dex: 0.5%). Dose adjustments/interruptions for diarrhea occurred in 26% on the PAN-BTZ-Dex arm and 9% on the Pbo-BTZ-Dex arm. Treatment discontinuation due to diarrhea occurred in 4.5% on the PAN-BTZ-Dex arm and 1.6% on the Pbo-BTZ-Dex arm. Serious AEs of diarrhea occurred in 11.3% on PAN-BTZ-Dex arm and 2.4% on Pbo-BTZ-Dex arm. There was no hemorrhagic diarrhea on the PAN-BTZ-Dex arm and in 1 pt in the Pbo-BTZ-Dex arm. In the majority of pts (56.2%) in the PAN-BTZ-Dex arm, diarrhea occurred for the first time in cycles 1-4 and was primarily grade 1/2; first onset occurred rarely in TP2 (Figure). Cumulative incidence of diarrhea on the PAN-BTZ-Dex arm plateaued by cycle 6 (61.9% by cycle 6; 68.2% overall). The cumulative number of pts with complete resolution of diarrhea (defined as resolved diarrhea that did not recur on treatment) increased over the course of the study. During treatment, 67.7% (258/381) in PAN-BTZ-Dex arm had either no diarrhea or complete resolution of their diarrhea. Analysis of diarrhea management by grade and treatment phase revealed that most pts received medication to manage the diarrhea. Antidiarrheal medications were administered to 70.8% (184/260) pts with diarrhea across all grades; loperamide was used most commonly. However, many pts with grade 1/2 diarrhea had no action taken in TP1: grade 1 - 58% (115/198); grade 2 - 26% (33/127), suggesting suboptimal management of diarrhea. Conclusions: These data demonstrate that diarrhea in pts who received PAN-BTZ-Dex occurs primarily in the first 1-4 cycles of treatment with cumulative incidence reaching a plateau around cycle 6. Majority of pts with diarrhea had complete resolution during treatment. Although diarrhea was commonly observed in pts who received PAN-BTZ-Dex in the PANORAMA 1 trial, it was manageable and seldom led to treatment discontinuation; however, some pts with grade 1/2 diarrhea did not receive proactive management. Optimal management of diarrhea with prompt intervention including antidiarrheal medication and dose holds/adjustments of BTZ and PAN at the first sign of loose stools may help to maintain pts on therapy and thus improve outcomes with PAN-BTZ-Dex. Future trials should seek to employ these strategies for pts who experience GI toxicity, and should consider subcutaneous administration of BTZ. In addition, studies using combinatorial agents with less overlapping GI toxicity with PAN may further improve safety in this setting. Figure 1 Figure 1. Disclosures 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. Dimopoulos:Celgene: Consultancy, Honoraria. 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. Moreau:Celgene: 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. Panneerselvam:Novartis: Employment, Equity Ownership. Redhu:Novartis: Employment. Corrado:Novartis Pharma AG: Employment. Binlich:Novartis Pharma SAS: Employment.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.2120.2120

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 4742-4742

Abstract: 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.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.4742.4742

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 112, No. 11 ( 2008-11-16), p. 133-133

Abstract: 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

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V112.11.133.133

Language: English

Publisher: American Society of Hematology

Publication Date: 2008

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 124, No. 21 ( 2014-12-06), p. 4453-4453

Abstract: 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.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V124.21.4453.4453

Language: English

Publisher: American Society of Hematology

Publication Date: 2014

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 126, No. 23 ( 2015-12-03), p. 4613-4613

Abstract: Introduction Hemophagocytic lymphohistiocytosis (HLH) is a rare, life-threatening syndrome of extreme hyperinflammation. It does not self-limit and needs to be stopped by effective treatment. This reaction can be triggered by numerous factors, including infection, malignancy and autoimmune disease. HLH used to be diagnosed in children, but in last few years more and more adults with this syndrome are treated. This raising awareness enabled creating retrospective registry of adult HLH patients in Poland. Methods A multicenter retrospective analysis of adult (≥18 years) patients was performed. Inclusion criteria were based on the HLH-2004 protocol. Results Forty four adult (median age 34, range 18-80) patients from 13 clinical centers were reported. The gender ratio was balanced (M/F: 23/21). Patients fulfilled on the average 5.2 of HLH-2004 criteria. Due to the lack of possibility of sCD25 and NK activity testing in majority of centers only 6 criteria were actually evaluated. Also 6 patients with strong clinical suspicion (e.g. recurrent HLH) fulfilling 4 out of 6 available criteria were included. The most frequent triggering factor was malignancy (14/44) with lymphoma (T-cell 6/14, B-cell 4/14) being the most common. Infection-associated HLH was present in 13 patients, most of which was attributed to EBV (11/13; additionally CMV and B19 occurred). One patient suffered from both T-lymphoma and EBV infection. The most frequent autoimmune diseases identified were Still's disease (n=3) and systemic lupus erythematosus (n=2). In 11 patients clear triggering factor could not be identified. Three patients underwent liver transplantation. Baseline characteristics of all patients are shown in Table 1. Briefly, almost all patients presented with extreme hyperferritinemia, fever, splenomegaly. Other Important features are liver involvement and coagulopathy. Majority of patients were treated according to HLH-2004 protocol, except of patients with malignancy treated with disease-specific chemotherapy regimens (with emphasis on inclusion of etoposide if appropriate). None of the patients underwent stem cell transplantation (SCT) as HLH therapy; one patient had HLH triggered by EBV reactivation after alloSCT. Median survival was 66 days (Fig.1), 39% of patients survived with median observation of 21 months (3-98). Conclusions Heterogeneity of HLH syndrome was confirmed in Polish population, with malignancy and EBV infection being the most frequent triggering factors. Awareness of HLH in adults is raising, but it should be fostered as HLH is still underdiagnosed. Further studies are needed to deepen our knowledge about HLH in adults. Analysis of additional, newly diagnosed cases is ongoing and will be presented at the meeting. Table 1. Baseline patient characteristics Characteristic [unit] (n) % Median Range Fever (n=44) 97.7 Splenomegaly (n=44) 90.9 Hemophagocytosis (n=41) 70.7 Hyperferitinemia [µg/l] (n=44) 100 14280 846-126680 Hemoglobin [g/dl] (n=44) 8.3 6.1-13.9 Neutrophil count [G/l] (n=41) 1.1 0-173 Platelet count [G/l] (n=44) 43 4-349 Triglycerides [mg/dl] (n=38) 316 74-1559 Fibrinogen [mg/dl] (n=43) 166 30-901 PT [s] (n=30) 15.9 9-46.6 APTT [s] (n=39) 36 22-86.8 CRP [mg/l] (n=40) 40.1 0.4-373 LDH [U/l] (n=39) 970 195-13160 AST [U/l] (n=39) 150 16-16280 ALT [U/l] (n=40) 100 18-12390 Total Bilirubin [mg/dl] (n=37) 3.7 0.34-25.6 PT indicates Prothrombin Time; APTT, Activated Partial Thromboplastin Time; CRP, C-Reactive Protein; LDH, lactate dehydrogenase; AST, aspartate aminotransferase; ALT, alanine aminotransferase Disclosures Knopinska-Posluszny: Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Amgen: Speakers Bureau; Teva: Other: travel, accommodation, Speakers Bureau. Wiktor-Jedrzejczak:Amgen, Inc.: Research Funding; Onconova: Other: Advisory Board; Novartis: Research Funding; Pfizer: Other: Advisory Board; Roche: Other: Advisory Board, Research Funding; Jansen: Other: Advisory Board; Celgene: Other: Advisory Board.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V126.23.4613.4613

Language: English

Publisher: American Society of Hematology

Publication Date: 2015

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7

In: Blood, American Society of Hematology, Vol. 114, No. 22 ( 2009-11-20), p. 3309-3309

Abstract: Abstract 3309 Poster Board III-197 Donor Lymphocyte Infusions (DLI) constitute a potent therapeutic option for treating relapse of chronic myelogenous leukemia (CML) after hematopoietic stem cell transplantation (SCT) inducing durable remissions in the majority of patients. A number of factors is known to influence the efficiency of DLI. A preliminary analysis of EBMT data had suggested that DLI efficiency might be inferior after peripheral blood stem cell transplantation (PBSCT) as compared to DLI following bone marrow transplantation (BMT) (Schmid et al. ASH, 2005). To control for a number of other factors that were not known at the time of the previous analysis, we repeated this analysis based on the results of 357 patients treated with DLI following PBSCT (N=108) and BMT (N=249). We limited the analysis to patients who relapsed after standard intensity conditioning SCT from HLA-identical family donors in first chronic phase of disease. The median age of patients was 39 years (range 18-60) with predominance of males (59%). 53% of patients with known data were CMV positive and in 44% of the patients there was a sex-mismatch with the stem cell donor. SCTs have been performed between 1994 and 2007 (median year: 1998) and the conditioning treatment included total body irradiation (TBI) in 68% and T cell depletion in 44% of patients. 92% of patients with known data achieved complete remission after SCT while grade II-IV acute GvHD occurred in 18% of patients and extensive chronic GvHD in 17% of patients. Median time to relapse was 17 months (range 0.6-129) and median time from SCT to first DLI infusion was 23 months (range 0.6-142). Looking at the patients with known data at the time of first DLI infusion, the relapse could be classified as molecular/cytogenetic in 63%, hematologic in 27% and transformed in 10% of patients. The median year of first DLI was 2000 ranging from 1995 to 2007. As the initial DLI infusion, 9% of patients received 〈 1×10e6, 62% 1.1-10×10e6 and 29% received 〉 10×10e6 CD3+ cells/kg. However, the comparative analysis of groups based on the stem cell source revealed that the group of patients transplanted with PBSCs included significantly more males (68 vs. 56%), were older (median age 42 vs. 39) and underwent more frequently T cell depletion at SCT (72 vs. 34%,). PBSCTs have been performed more recently (median year 1999 vs. 1997) and both duration of remission and time from SCT to first DLI were shorter after PBSCT (median duration: 12 vs. 21 months and 14 vs. 26 months respectively). The initial cell dose in patients from PBSCT arm was significantly lower than in BMT group (≤10×10e6 CD3+/kg in 89% vs. 65% of patients). Similarly to the previous study, we also observed a trend towards superior overall survival after DLI in BMT group compared to PBSCT group, especially in the early post-transplant period. The actuarial probability of survival at five years from DLI was 77% in PBSCT group and 79% in BMT group. However the differences were not statistically significant (p=0.77). The source of stem cells did not influence the occurrence of molecular/cytogenetic remissions after DLI (80% vs. 77%) grade II-IV acute GVHD (16% vs. 16%), chronic GVHD (23% vs. 30%) and myelosuppression (10% vs. 16%). In order to search for factors having impact on survival of analyzed patients, we performed both univariate and multivariate survival analyses. The univariate analysis revealed that interval from SCT to DLI longer than 2 years (p=0.001), date of DLI after 2000 (p=0.026) and molecular/cytogenetic stage of relapse at DLI (p 〈 0.001) were associated with favorable survival. Similarly, the multivariate Cox analysis identified interval between SCT and DLI (HR= 0.50, CI: 0.3-0.8; p=0.01 for after 2 years), date of DLI (HR=0.63, CI:0.4-1.0; p=0.07 for after 1999), and stage of relapse (HR=2.8, CI:1.2-6.5; p=0.02 for HemCR and HR=3.6, CI:1.8-7.0; p 〈 0.001 for missing data group), but not for stem cell source (HR=0.95, CI 0.56-1.6 ;p=0.86) as independent factors affecting survival. Based on our retrospective data from EBMT registry covering a period of 14 years of SCT and DLI, it seems that the PBSCT does not affect the efficiency of DLI compared to BMT. Therefore, keeping all limitations of a retrospective analysis in mind, it seems that differences in efficacy of DLI do not influence the decision whether PBSC or BM should be used as stem cell source for allogeneic SCT in CML in first chronic phase. Disclosures No relevant conflicts of interest to declare.

Type of Medium: Online Resource

ISSN: 0006-4971 , 1528-0020

URL: Article

DOI: 10.1182/blood.V114.22.3309.3309

Language: English

Publisher: American Society of Hematology

Publication Date: 2009

detail.hit.zdb_id: 1468538-3

detail.hit.zdb_id: 80069-7