Low-Dose Decitabine Vs Best Supportive Care In Older Patients With AML and Low Blast Counts: Results Of a Subgroup Analysis Of The Randomized Phase III Study 06011 Of The EORTC Leukemia Cooperative Group and German MDS Study Group

Abstract Introduction Decitabine has been approved for the treatment of myelodysplastic syndromes (MDS) in the United States and acute myeloid leukemia (AML) in older patients in Europe. The definitions of MDS and AML differ between the FAB and WHO classification, mainly with regards to patients with 20 to 30% blasts in blood or bone marrow having MDS according to the FAB classification (i.e. refractory anemia with excess blasts [RAEB] or RAEB in transformation), but AML according to the WHO. In the phase III trial 06011, we compared low-dose decitabine with best supportive care (BSC) in patients ≥60 years with MDS according to the FAB classification (Lübbert et al., J Clin Oncol. 2011;29:1987-96). Here, we examine trial 06011 for the efficacy and safety of decitabine in patients with AML according to WHO and low proliferation, i.e., blast counts of 20 to 30%. Patients and Methods Patients were randomly assigned to receive decitabine or BSC. Decitabine 15 mg/m2 was given intravenously over 4 hours every 8 hours for 3 consecutive days in 6-week cycles, with a maximum of 8 cycles. Results were evaluated every 2nd cycle. In case of complete remission (CR) at least 2 further courses were administered. Primary endpoint was overall survival (OS). Response rates (CR; PR, partial remission; HI, hematologic improvement; PD, progressive disease), progression-free survival (PFS; time from random assignment to PD, relapse or death), AML-free survival (AMLFS; time from random assignment to AML according to FAB [>30% bone marrow blasts] or death), and toxicity were secondary endpoints. Results Applying the WHO criteria to the 233 patients enrolled onto the trial, 164 had MDS and 50 had AML with blast counts of 20 to 30%. The remaining 19 patients were excluded from the present analyses. They comprised 14 patients with chronic myelomonocytic leukemia, 2 with AML and ≥40% blasts, and 3 with no blast counts available. Among the AML patients, 27 were in the decitabine and 23 in the BSC arm. In both arms, the median age was 70 years. Of the patients in the decitabine arm, 59% received 3 or more treatment cycles. Response rates in the decitabine and the BSC arm were as follows: CR, 11% vs 0%; PR, 11% vs 0%; HI, 11% vs 0%; and PD, 37% vs 74%. Compared with the patients receiving BSC, those receiving decitabine had longer PFS (P=0.008; Table 1). However, this did not translate into a significantly improved AMLFS or OS of the decitabine treated patients, although median OS was 9.8 months, compared to 5.9 months among patients receiving BSC only (Table 1). With regard to toxicity differences between the decitabine and BSC arms, grade 1-2 nausea was observed in 46% vs 14% and grade 3-4 febrile neutropenia in 19% vs 0%. Among the MDS patients, those receiving decitabine (n=78) had a longer PFS (P=0.07) but similar AMLFS and OS compared to the patients receiving BSC only (n=86; Table 1). The impact of decitabine on PFS, AMLFS and OS did not significantly differ between the AML and MDS patients (Table 1). Response rates among the MDS patients in the decitabine and BSC arms were as follows: CR, 14% vs 0%; PR, 4% vs 0%; HI, 18% vs 2%; and PD, 23% vs 66%. Conclusions Our data point to the clinically relevant efficacy of decitabine given in the 3-day schedule among patients with AML and low blast counts, particularly by delaying progression or relapse. No impact of decitabine, compared to BSC or low-dose cytarabine, on OS in older patients with AML and 20 to 30% marrow blasts (median, 8.0 vs 6.1 months) has been previously also reported by Kantarjian et al. (J Clin Oncol. 2012;30:2670-7). In that study, decitabine was given with 20 mg/m2/day on 5 days every 4 weeks; PFS was not presented. The prolonged PFS that we observe may be used for example as non-intensive bridge to allogeneic stem cell transplantation after reduced-toxicity conditioning. Due to the post-hoc nature of our analyses and the relatively small patient numbers, further studies appear warranted to fully establish the benefit of decitabine in AML patients with low blast counts. Disclosures: Rüter: Boehringer-Ingelheim: Employment. Platzbecker:Celgene: Honoraria, Research Funding; Novartis: Honoraria, Research Funding. Giagounidis:Celgene: Consultancy, Honoraria. Selleslag:Celgene: Consultancy; Novartis: Consultancy; Amgen: Consultancy. Baron:Genzyme: Honoraria.

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Maintenance Therapy with Low-Dose Subcutaneous 5-Azacitidine in Older Patients with AML in 1st Remission.

Blood ◽

10.1182/blood.v114.22.1029.1029 ◽

2009 ◽

Vol 114 (22) ◽

pp. 1029-1029

Author(s):

Jeffrey E Lancet ◽

Rami S. Komrokji ◽

HuiYi Lin ◽

Carlos M. de Castro ◽

David A. Rizzieri ◽

...

Keyword(s):

Elderly Patients ◽

Maintenance Therapy ◽

Older Patients ◽

Research Funding ◽

Low Dose ◽

Disease Free Survival ◽

Free Survival ◽

Grade 3 ◽

Disease Free ◽

Risk Categories

Abstract Abstract 1029 Poster Board I-51 Background: Elderly patients with AML have a poor outcome, with low complete response (CR) rates and durations of CR that are typically less than 1 year, highlighting the need for more effective post-remission therapy. 5-azacitidine (AZA) is a nucleoside analogue/DNA methyltransferase inhibitor approved for use in all FAB subtypes and risk categories of myelodysplastic syndromes (MDS). In higher-risk patients with MDS, including those with AML (former RAEB-T subtype), AZA improves overall survival and delays the time to leukemia transformation. We undertook a phase 2 pilot study of low-dose subcutaneous (SC) AZA in older adult patients with AML in 1st CR or CR with incomplete platelet recovery (CRp) following standard induction therapy. Methods: Study objectives included the following: 1) determine the one year disease-free survival in elderly patients with acute myeloid leukemia (AML) in first CR/ CRp treated with low-dose SC AZA as post-remission therapy. 2) determine safety and tolerability of SC AZA administered in the post-remission setting. 3) investigate the relationship between bone marrow genomic promoter methylation with 1-year disease-free survival. Eligibility included age ≥ 60 with AML in 1st CR/ CRp following 1-2 cycles of induction chemotherapy and 1-2 cycles of consolidation therapy, ECOG PS 0-2, adequate end-organ function. AZA was administered subcutaneously on 1 of 2 different dosing schedules: A) 50 mg/m2/d x 5d (d 1-5), or B) 50 mg/m2/d x 7d (d 1-5, 8-9). Cycles were repeated every 4 weeks, and up to 12 cycles. Results: As of August 2009, 16 patients have been enrolled on the study and 15 are currently evaluable. Nine patients received dosing schedule A and 6 received schedule B. Median age was 69 years (range 62-81); M/F was 13/2; baseline cytogenetic risk categories at initial diagnoses: poor (6), intermediate (8), and unknown/not done (1). Two of 15 patients had a history of antecedent MDS. Nine of 15 patients (60%) required 2 cycles of induction chemotherapy to achieve CR/CRp. The median time from achievement of CR/CRp to AZA initiation was 13.6 weeks (range 7 – 21.9 weeks). To date, the median number of AZA cycles received was 4, ;5 patients have received ≥ 6 cycles, 2 of whom have received the 12 planned cycles and another who remains on-study after 11 cycles. Median duration of CR/CRp was 54.8 weeks (95% CI: 28.1-96.4 weeks) estimated using the Kaplan-Meier method. Only 2 of 15 (13%) patients developed grade 3-4 non-hematologic adverse events (colitis, headache). Six of 15 (40%) patients developed reversible grade 3-4 neutropenia or thrombocytopenia, but only 3 required dose reduction. No patients discontinued AZA due to toxicity, and there were no deaths that occurred on-study. Criteria for early stoppage, based upon toxicity, have not been reached. Methylation array analyses are ongoing. SC AZA administered as maintenance therapy in older patients with AML in 1st CR/CRp appears feasible and safe. Extended treatment was possible in a high proportion of patients, with encouraging early signs of durable remissions. Accrual to this trial is ongoing and updated results will be presented. Disclosures: Lancet: Celgene: Research Funding. Komrokji:Celgene: Research Funding, Speakers Bureau. de Castro:Celgene: Speakers Bureau. Rizzieri:Celgene: Research Funding, Speakers Bureau. List:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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Short Survival and High Rates of Transformation Prevail in Chronic Myelomonocytic Leukemia Despite Hypomethylating Agent Therapy.

Blood ◽

10.1182/blood.v120.21.2800.2800 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2800-2800

Author(s):

Emily J. Vannorsdall ◽

Vu H. Duong ◽

Xinyi Ng ◽

Dan P. Zandberg ◽

Michael L. Tidwell ◽

...

Keyword(s):

Bone Marrow ◽

Clinical Trials ◽

Research Funding ◽

Response Rates ◽

Chronic Myelomonocytic Leukemia ◽

World Health ◽

Free Survival ◽

Entire Cohort ◽

Myelomonocytic Leukemia

Abstract Abstract 2800 Background: Chronic myelomonocytic leukemia (CMML) is a clonal hematopoietic stem cell disorder categorized as a mixed myeloproliferative/myelodysplastic disorder in the World Health Organization classification system. Diagnostic criteria include a persistent peripheral blood monocytosis >1 × 109/L and bone marrow dysplasia. Our recent review of SEER Medicare data (ASH 2011 abstract 2784) demonstrated that CMML has a shorter overall survival (OS) and more frequent progression to acute myeloid leukemia (AML), compared to myelodysplastic syndromes (MDS). Due to the heterogeneity of this disease and its differences from MDS, efforts to identify prognostic factors have been ongoing. The MD Anderson prognostic score was previously validated, but was derived from patients treated prior to the availability of the hypomethylating agents (HMAs) azacitidine and decitabine. HMAs have now emerged as standard therapy, with reported response rates of 37–69%, but their impact on survival and AML transformation is unclear. The OS of CMML patients has been reported at 12–18 months and transformation rates have varied between 15–52%. We reviewed our own single-center experience with CMML over the past 12 years. Methods: We conducted a retrospective review of CMML patients evaluated at the University of Maryland Greenebaum Cancer Center between January 2000 and August 2012. Patient and disease characteristics, treatments, complications, progression to AML, and OS were recorded and analyzed. Descriptive statistics were used for baseline characteristics and Kaplan-Meier analysis was performed for all time-to-event data. Statistical analyses were performed using SPSS version 20.0. Results: We identified 35 patients with CMML, 71% were male and 71% white, with a median age of 69 (range 34–86) years; 75% had <10% bone marrow (BM) blasts and 68% had low-risk cytogenetic findings (normal karyotype or -Y). Most patients treated prior to 2005 received hydroxyurea and/or erythropoiesis-stimulating agents or were enrolled on clinical trials, while patients treated since 2005 received HMAs as primary therapy. The median OS of the entire cohort was 19.5 months, with 49% of patients progressing to AML with a median time to progression (TTP) of 16.9 months. Of the entire cohort, patients with <10% and ≥10% BM blasts had an estimated OS of 19.4 and 11.7 months respectively (p=.021). Patients with low-, intermediate-, and high-risk (complex karyotype, +8, or chromosome 7 abnormalities) cytogenetic findings had an estimated OS of 23.3, 16.5, and 12.0 months respectively (p<0.001). Twenty-two patients received HMAs. Their estimated OS was 16.5 months, compared to 23.0 months for patients who did not receive HMAs (p =.683); 50% of patients treated with HMAs had known progression to AML, with TTP varying from 3–28 months. AML-free-survival was 16 months in patients receiving HMAs, compared to 14 months in patients not treated with HMAs (p=0.960). The majority of patients receiving HMA therapy (63%) were treated with ≥ 6 cycles; 57% of these patients transformed to AML despite initial response, often in a sudden and unpredictable manner. Conclusions: Published trials using HMAs in CMML have been limited by small patient numbers, short median follow-up, and paucity of data on AML transformation. Our study had a median follow-up period of 41.1 months. We found a high rate of AML transformation and short OS even in patients who received HMAs. HMA treatment had no statistically significant impact on AML-free survival or OS. Although the results may be confounded by some selection bias, treatment with HMAs was largely based on the date of diagnosis rather than prognostic variables or performance status. Therefore, the favorable response rates previously reported with these agents, and also seen in our patients, do not appear to translate into an OS or AML-free-survival advantage. Our study underscores the continued need for novel agents and the need to prioritize clinical trials for this group of patients. Additionally, based on our data, early bone marrow transplantation should be strongly considered for CMML patients when feasible. Disclosures: Davidoff: Novartis: Research Funding; Celgene: Research Funding; GlaskoSmithKline: Research Funding. Baer:Novartis, Inc.: Research Funding; Celgene, Inc.: Research Funding.

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Low-Dose Decitabine Versus Best Supportive Care in Elderly Patients With Intermediate- or High-Risk Myelodysplastic Syndrome (MDS) Ineligible for Intensive Chemotherapy: Final Results of the Randomized Phase III Study of the European Organisation for Research and Treatment of Cancer Leukemia Group and the German MDS Study Group

Journal of Clinical Oncology ◽

10.1200/jco.2010.30.9245 ◽

2011 ◽

Vol 29 (15) ◽

pp. 1987-1996 ◽

Cited By ~ 322

Author(s):

Michael Lübbert ◽

Stefan Suciu ◽

Liliana Baila ◽

Björn Hans Rüter ◽

Uwe Platzbecker ◽

...

Keyword(s):

Myelodysplastic Syndrome ◽

Supportive Care ◽

Low Dose ◽

Progression Free Survival ◽

Best Supportive Care ◽

Phase Iii ◽

Intensive Chemotherapy ◽

Free Survival ◽

Patient Reported ◽

Grade 3

Purpose To compare low-dose decitabine to best supportive care (BSC) in higher-risk patients with myelodysplastic syndrome (MDS) age 60 years or older and ineligible for intensive chemotherapy. Patients and Methods Two-hundred thirty-three patients (median age, 70 years; range, 60 to 90 years) were enrolled; 53% had poor-risk cytogenetics, and the median MDS duration at random assignment was 3 months. Primary end point was overall survival (OS). Decitabine (15 mg/m2) was given intravenously over 4 hours three times a day for 3 days in 6-week cycles. Results OS prolongation with decitabine versus BSC was not statistically significant (median OS, 10.1 v 8.5 months, respectively; hazard ratio [HR], 0.88; 95% CI, 0.66 to 1.17; two-sided, log-rank P = .38). Progression-free survival (PFS), but not acute myeloid leukemia (AML) –free survival (AMLFS), was significantly prolonged with decitabine versus BSC (median PFS, 6.6 v 3.0 months, respectively; HR, 0.68; 95% CI, 0.52 to 0.88; P = .004; median AMLFS, 8.8 v 6.1 months, respectively; HR, 0.85; 95% CI, 0.64 to 1.12; P = .24). AML transformation was significantly (P = .036) reduced at 1 year (from 33% with BSC to 22% with decitabine). Multivariate analyses indicated that patients with short MDS duration had worse outcomes. Best responses with decitabine versus BSC, respectively, were as follows: complete response (13% v 0%), partial response (6% v 0%), hematologic improvement (15% v 2%), stable disease (14% v 22%), progressive disease (29% v 68%), hypoplasia (14% v 0%), and inevaluable (8% v 8%). Grade 3 to 4 febrile neutropenia occurred in 25% of patients on decitabine versus 7% of patients on BSC; grade 3 to 4 infections occurred in 57% and 52% of patients on decitabine and BSC, respectively. Decitabine treatment was associated with improvements in patient-reported quality-of-life (QOL) parameters. Conclusion Decitabine administered in 6-week cycles is active in older patients with higher-risk MDS, resulting in improvements of OS and AMLFS (nonsignificant), of PFS and AML transformation (significant), and of QOL. Short MDS duration was an independent adverse prognosticator.

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Clinical Characteristics and Treatment Allocations in Patients with Myelodysplastic Syndromes and Monosomy 7: Results from an International Multicenter Study Suggest That Hypomethylating Agents Significantly Improve Overall- and AML-Free Survival in Patients Classified As Very High Risk By IPSS-R

Blood ◽

10.1182/blood.v124.21.4656.4656 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4656-4656 ◽

Cited By ~ 2

Author(s):

Julie Schanz ◽

Friederike Braulke ◽

Ghulam J. Mufti ◽

Elena Crisà ◽

Austin Kulasekararaj ◽

...

Keyword(s):

Bone Marrow ◽

High Risk ◽

Research Funding ◽

Risk Group ◽

Best Supportive Care ◽

High Risk Group ◽

Study Cohort ◽

Monosomy 7 ◽

Free Survival ◽

Very High

Abstract Introduction: Total (-7) or partial (7q-) monosomy 7 is the second frequent abnormality in MDS, occurring in around 12% of MDS/AML and up to 40% of therapy-associated MDS/AML. The present study was designed to analyze clinical features, prognosis and response to different therapeutic strategies in patients with -7 or del(7q) in a multicentric, retrospective cohort study. Patients and Methods: 471 patients with MDS/AML following MDS and monosomy 7 were registered and retrospectively analyzed. The median observation time was 3.6 years. Inclusion criteria were defined as follows: Morphologic diagnosis of MDS/AML following MDS, bone marrow blast count <=30% and presence of -7 or 7q- proved by chromosome banding analysis (CBA) or fluorescence in situ-hybridization (FISH). The data was coalesced from 8 centers in London (n=140; 29.7%), Duesseldorf, (n=120; 25.5%%), Goettingen (n=118; 25.1%), Cologne (n=38; 8.1%), Freiburg (n=29; 6.2%), Munich (n=13; 2.8%), Dresden (n=10; 2.1%) and Mannheim (n=3; 0.6%). The median age in the study cohort was 66 years, 63% of patients were males. MDS/AML was therapy-associated in 53 (11%). According to IPSS-R, 9 (1.9%) were assigned to the low risk group, 39 (8.3%) to the intermediate group, 81 (17.2%) to the high-risk group and 133 (28.2%) to the very high risk group. The treatment was classified as follows: Best supportive care (BSC), low-dose Chemotherapy (LDC), high-dose chemotherapy (HDC), hypomethylating agents (HMA; either 5-azacytidine or decitabine), and others (e.g. valproic acid, steroids, lenalidomide or thalidomide). Survival analyses were performed regarding overall- (OS) as well as AML-free survival (AFS) using the Kaplan-Meier method. Results: 147 patients (31.2%) showed 7q-, 313 (66.5%) -7 and 11 (2.3) patients showed both abnormalities at the first cytogenetic examination. The abnormality was detected by CBA±FISH in 440 (93.4%) and by FISH only in 31 (6.6%). In the latter cases, the CBA was either unsuccessful or showed a normal karyotype. In 182 (38.6%) patients, -7/del7q was detected as a single abnormality, 77 (16.3%) showed two abnormalities and 184 (39.1%) showed a complex karyotype involving -7/7q-. As previously described (Schanz et al., 2012), untreated patients with an isolated 7q- as compared to an isolated -7 show a better prognosis regarding OS (median: 4.0 vs. 0.7 years; p<0.01) as well as AFS (median not reached vs. 2.3 years; p=0.062). Median hemoglobin level in the study cohort was 9.3 g/dl, ANC 0.98*103/μl, platelet count 73*103/μl and the median number of bone marrow blasts was 8%. Regarding the treatment, a best supportive care regimen was chosen in 195 (41%) patients. The remaining 276 (58.6) patients received 1-5 sequential therapies (one therapy: 31.6%; more than 1 therapy: 27.0%). 81 patients received an allogeneic bone marrow transplantation (ATX). Within the group of patients treated with HMA at any time of their disease (n=167), 147 (31.2%) received 5-Azacytidine, 8 (1.7%) Decitabine and 12 (2.5%) patients were treated with both drugs. As the first line therapy, 122 patients (25.9%) received HMA, 50 (10.6%) HDC, 28 (5.9%) ATX, 28 (5.9%) 11 (2.3%) LDC, and 28 (5.9%) were treated with other therapies. Patients eligible for ATX showed a significantly better prognosis as compared to any other therapy strategy: The median OS in was 2.1 years as compared to 1.1 years in non-transplanted patients (p<0.01). In patients not eligible for ATX, treatment with HMA at any course of their disease as compared to a BSC strategy was associated with a better OS (1.4 vs. 0.8 years, p=0.014). By comparing HMA to any other therapy, the OS did not differ significantly (1.4 years in HMA vs. 1.1 years in any other, p n.s.). In patients classified as very high risk according to IPSS-R, the median OS was significantly prolonged in patients receiving HMA as compared to BSC (1.1 vs. 0.6 years, p<0.01). This was also observed for the risk of AML-transformation in this subgroup of patients: The median time to AML was 1.8 years in HMA-treated patients versus 0.6 years in BSC (p=0.012). Conclusions: To our knowledge, the study describes the largest patient cohort with MDS/AML and monosomy 7 published to date. Further data regarding the clinical characteristics of this subgroup of patients and the treatment regimes applied will be presented in detail. The study was supported by research funding from Celgene Figure 1 Figure 1. Figure 2 Figure 2. Disclosures Schanz: Celgene: Honoraria, Research Funding, Travel grants: Celgene, Novartis, Lilly Other. Götze:Celgene Corp, Novartis Pharma: Honoraria. Nolte:Celgene, Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding, Travel grants Other.

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Bortezomib, Lenalidomide and Low-Dose Dexamethasone (VRD) Versus Lenalidomide and Low-Dose Dexamethasone (Ld) for Newly-Diagnosed Multiple Myeloma- a Randomized Phase III Study

Blood ◽

10.1182/blood.v130.suppl_1.906.906 ◽

2017 ◽

Vol 130 (Suppl_1) ◽

pp. 906-906

Author(s):

Anjali Mookerjee ◽

Ritu Gupta ◽

Shivali Jasrotia ◽

Ranjit Sahoo ◽

Rakesh Kumar ◽

...

Keyword(s):

Multiple Myeloma ◽

Low Dose ◽

Progression Free Survival ◽

Response Rates ◽

Phase Iii ◽

Stage Iii ◽

Newly Diagnosed ◽

Free Survival ◽

Median Progression Free Survival ◽

Grade 3

Abstract Background: In this prospective study, we compared VRD with Ld as induction therapy for newly-diagnosed Multiple myeloma patients. The primary objective of this study is to compare the progression-free survival in the 2 arms. Methods: Between September 2014 and Oct 2016, 144 patients have been recruited and randomly assigned to receive 4 cycles of either Bortezomib 1.3 mg/m2 SC on days 1, 8, 15 and 22 with Lenalidomide 15mg/day from day 1 to 14 (Arm A) or Lenalidomide 25 mg/day from day 1 to 21 (Arm B). Patients in both arms received oral dexamethasone 40 mg on days 1,8,15 and 22. Both treatment regimens were 28-day cycles. All patients received 75 mg aspirin daily, acyclovir prophylaxis and monthly zoledronic acid. Response assessment was done at the end of the 4th cycle using the International Myeloma Working Group (IMWG) uniform response criteria. The study was approved by the Institute Ethics Committee (Ref IEC/NP-264/01-08-2014, RP-7/2014). Results: These are the results from an analysis of 143 patients (arm A-74, arm B-69). Baseline characteristics of patients were similar in both arms with respect to age, gender, ISS and DS stage, immunoglobulin subtype and serum LDH. Patients' median age is 56 years (range 31-70) in arm A and 52 years (range 28-69) in arm B. Gender M/F: Arm A 54/20 and 43/26 in arm B. ISS stage III 51 (68.9%) arm A vs 44 (63.8%) arm B. Serum LDH raised to >250 u/L was observed in 25 (44.6%) vs 31 (52.5%) in arms A and B, p=0.4. Revised staging including ISS and serum LDH at baseline: stage III 47 (81%) and 37 (65%) in arms A and B respectively. 14 (18.9%) and 19 (27.5%) of patients had light chain myeloma in arms A and B respectively. Overall response rates (sCR+CR+VGPR+PR) is 78.4% vs 73.9% in arms A and B respectively, p=0.6; sCR + CR 21 (28.4%) and 21 (30.4%) respectively, p=0.86. Median follow-up 17.1 months (range 1 to 33). Median overall survival (OS) is 30.2 months (95% CI 28.2 to 32.2) and 28.6 months (95%CI 26 to 31.3) in arms A and B respectively, p=0.3. Median progression-free survival (PFS) was 27.8 months (95%CI 25.4 to 30.2) and 28 months (95%CI 24.6 to 31.4) respectively, p=0.3. Estimated one-year OS is 88% vs 85% in arms A and B, and PFS 83% vs 72%, respectively. Grade 3 anemia occurred in one patient in arm B, and grade 3 deep vein thromboses in one patient in arm A. One patient in arm A developed grade 4 myelosuppression leading to therapy change at the end of the first cycle. Conclusion: In this analysis - response rates and median progression-free survival are similar in both arms. Disclosures No relevant conflicts of interest to declare.

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Radiographic progression-free survival as a surrogate endpoint of overall survival in men with metastatic castrate-resistant prostate cancer.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.5057 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. 5057-5057

Author(s):

Susan Halabi ◽

Akash Roy ◽

Qian Yang ◽

Wanling Xie ◽

William Kevin Kelly ◽

...

Keyword(s):

Prostate Cancer ◽

Radiographic Progression ◽

Progression Free Survival ◽

Surrogate Endpoint ◽

Phase Iii ◽

Random Assignment ◽

Moderate Correlation ◽

Free Survival ◽

Castrate Resistant Prostate Cancer ◽

Castrate Resistant

5057 Background: Radiographic progression-free survival (rPFS) is commonly used as a co-primary endpoint in randomized clinical trials in men with metastatic castrate-resistant prostate cancer (mCRPC). However, rPFS has not been established as a valid surrogate endpoint of overall survival (OS) in men with mCRPC. Here, we hypothesized that rPFS is a reliable surrogate for OS in mCRPC. We also explored whether PFS is a valid surrogate endpoint of OS at the aggregate trial level. Methods: We performed a systematic search of the literature encompassing the period January 2004-December 2020 using PubMed and clinical trials.gov to identify completed phase III trials in mCRPC post-docetaxel. Eligible trials had to be randomized phase III therapeutic trials that reported OS, PFS or rPFS. OS was measured from the date of random assignment to date of death from any cause or date of last follow-up. rPFS was defined as the time from random assignment to date of disease progression on CT and/or Tc bone scan per trial definition or death from any cause, whichever occurred first. PFS included PSA progression as a component of the composite endpoint. Trial level surrogacy was evaluated by fitting linear regression on the treatment effect of rPFS (or PFS) and OS (in other words, the weighted linear regression of the log(hazard ratio) of OS on the log(hazard ratio) of rPFS). It was pre-specified that rPFS would be considered a valid surrogate for OS if R² was 0·7 or higher. Results: We identified 33 in men with mCRPC post docetaxel approval. We assessed the association between PFS and OS in 29,456 patients from 30 trials. Overall, a moderate correlation was observed at the trial level between OS and PFS ( R2 = 0.46, 95 %CI = 0.20-0.68) in these trials. In 18 trials with 16,818 mCRPC patients where rPFS was considered as a key endpoint, a moderate correlation between the treatment effects on rPFS and OS was observed at the trial level ( R2= 0.65, 95% CI = 0.23-0.87). Conclusions: This meta-analysis demonstrates moderate correlation between treatment effects of rPFS and OS in patients with mCRPC. However, rPFS did not meet the pre-specified surrogacy threshold of 0.7. Clinical trial information: several.

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Improved Leukemia-Free Survival after Post-Consolidation Treatment with Histamine Dihydrochloride and Interleukin-2 in AML: A Randomized Phase III Trial.

Blood ◽

10.1182/blood.v104.11.261.261 ◽

2004 ◽

Vol 104 (11) ◽

pp. 261-261 ◽

Cited By ~ 4

Author(s):

Mats Brune ◽

Sylvie Castaigne ◽

John Catalano ◽

Kurt Gehlsen ◽

Wolf-Karsten Hofmann ◽

...

Keyword(s):

Low Dose ◽

Interleukin 2 ◽

Phase Iii ◽

Rank Test ◽

Consolidation Therapy ◽

Histamine Dihydrochloride ◽

Free Survival ◽

Consolidation Treatment ◽

Log Rank Test ◽

Significant Difference

Abstract Background: Histamine dihydrochloride (HDC) potentiates immune-based therapies by protecting pivotal anti-neoplastic lymphocytes from phagocyte-induced suppression. Previous results in AML indicated that post-consolidation treatment with HDC and low-dose interleukin-2 (IL-2) is safe and feasible, and that the combination may prolong leukemia-free survival (LFS). Aims: The primary objective was to determine if post-consolidation treatment with IL-2 and HDC could improve LFS for AML pts in complete remission (CR). Secondary objectives included overall survival (OS), LFS in CR1 and CR>1 subgroups, and safety. Methods: This international, randomized, open-label, phase III study was conducted at 92 centers. From June 1998 to October 2000, 320 AML pts [148 females, 172 males, median age 57 (18–84) yrs] were enrolled in CR after completion of standard consolidation therapy. Pts were stratified by CR1 or CR>1 and randomized to either treatment (n=160) or no treatment (control, n=160) arms. The treatment was self-administered at home and included 10 cycles of low-dose IL-2 (aldesleukin, Chiron Corp) 18 000 U/kg, sc bid plus HDC (Maxim Pharmaceuticals) 0.5 mg sc bid. For cycles 1–3, each cycle comprised 3 wks of treatment and 3 wks of rest, whereas in cycles 4–10 the rest periods were 6 wks. The study arms were well balanced with respect to age, sex, karyotype-based risk, time from CR to inclusion and frequency of secondary leukemia. Pts were followed for relapse and survival using an identical assessment schedule until 3 yrs after last enrollment. All efficacy analyses were intent-to-treat. Results: The median follow-up of living pts was 46 months. For the primary endpoint, treatment with HDC/IL-2 increased LFS in the entire study population (CR1/CR>1, n=320, p=0.026 stratified log-rank test). There was no significant difference in OS (p=0.33). In the analysis of pre-stratified subgroups, one pt was excluded. For CR1 pts (n=262), HDC/IL-2 significantly improved LFS (p=0.011, log-rank test), with 3-year Kaplan-Meier estimates of 26% (control group) and 40% (treatment group). The difference in OS did not reach significance (p=0.16). For CR>1 pts (n=57), outcome was not affected by treatment. Side effects attributable to IL-2 included fever and local inflammatory reactions. HDC treatment induced symptoms of transient vasodilatation. Serious adverse events occurred in approximately 20% of pts in both groups. There were no treatment-related deaths. Conclusions: For AML pts in CR, post-consolidation therapy with HDC and IL-2 was safe and significantly improved LFS compared to standard of care. The benefit observed of HDC/IL-2 treatment appears to be explained by a reduction of relapses in CR1 pts.

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Low Dose Decitabine Versus Best Supportive Care in Elderly Patients with Intermediate or High Risk MDS Not Eligible for Intensive Chemotherapy: Final Results of the Randomized Phase III Study (06011) of the EORTC Leukemia and German MDS Study Groups

Blood ◽

10.1182/blood.v112.11.226.226 ◽

2008 ◽

Vol 112 (11) ◽

pp. 226-226 ◽

Cited By ~ 30

Author(s):

Pierre WijerMans ◽

Stefan Suciu ◽

Liliana Baila ◽

Uwe Platzbecker ◽

Aristoteles Giagounidis ◽

...

Keyword(s):

High Risk ◽

Supportive Care ◽

Disease Progression ◽

Low Dose ◽

Phase Iii ◽

Intensive Chemotherapy ◽

Free Survival ◽

Phase Iii Study ◽

The Difference ◽

Grade 3

Abstract Introduction: In 2002 the EORTC and the German MDS Study Group initiated a randomized phase III study comparing low dose Decitabine to supportive care in patients (pts) of 60 years or older with primary or secondary MDS or CMML. MDS patients with either 11–20% BM blasts or ≤ 10% blasts and poor cytogenetics could be included. Pts with a BM blast count between 21–30% without signs of disease progression for at least one month were also candidates for the study. Methods: Patients were centrally randomized; stratification factors were cytogenetics risk group, IPSS, MDS (primary vs secondary) and study centre, The treatment schedule was 15 mg/m2 Decitabine i.v. over 4 hours every 8 hours for the first 3 three consecutive days, of every 6 week-cycle, for a maximum of 8 cycles. Results were evaluated every 2nd cycle. When a complete remission was reached at least another 2 courses were given. The primary endpoint of the study was Overall Survival. AML free survival, Progression Free Survival (PFS), response rate, toxicity and QoL were secondary endpoints. A total of 185 deaths were required to detect a hazard ratio (HR) of 0.66 (alpha=5%, beta=20%). Intent-to-treat analysis was used. Results: Between 10.2002 and 5.2007 a total of 233 pts (149 male and 84 female) were recruited from 40 centres. The median age was 70 (60–90 years); RAEB-t was diagnosed in 32% of the pts. Most pts had an IPSS Intermediate-2 (55%) or high risk (38%). Poor risk cytogenetics was found in 46% of the patients. Prior therapy for MDS (not being intensive chemotherapy) was given in 20% of pts. The randomized groups were well balanced regarding stratification factors, age and FAB classification. The median follow up was 2.5 years. Time to Off Study was 180 (Decitabine) vs 112 days (SC arm). The median number of cycles given to the patients was 4 with 40%getting no more than 2 cycles. In a significant number of pts, subsequent treatment, consisting of transplant (10%) or induction chemotherapy (11%), was given. The distribution of best response in Decitabine vs SC arm was CR (13% vs 0%), PR (6% vs 0%), HI (15% vs 2%), SD (14% vs 22%), PD (29% vs 68%), hypoplasia (14% vs 0%), inevaluable (8% vs 8%). The 18 pts on Decitabine with a HI showed the following responses: 3-lineage (n=7), 2-lineage (n=5) and 1-lineage (n=6). The median time to response (CR/PR/HI) was 0.32 yrs and the response duration was 0.72 years. Median OS was 0.84 (Decitabine) vs 0.71 years (SC arm), estimated HR was 0.88, 95% CI 0.66–1.17, p=0.38 (logrank 2-sided). The PFS was significantly (p=0.004) longer in Decitabine vs SC arm: median was 0.55 vs 0.25 years, HR=0.68 (95% CI 0.52–0.88). Time to AML or Death was not significantly improved (p=0.24): median was 0.73 vs 0.51 years (HR=0.85, 95% CI 0.64–1.12). Toxicity. The toxicity was mainly cytopenia related toxicity that was either disease related or hematotoxicity; CTC grade 3–4 febrile neutropenia was 26% (Decitabine) vs 7% (SC arm) and Grade 3–4 infection was 59% vs 47%. Differences in non hematologic toxicities were mainly gastrointestinal: grade 1–2 nausea (28% vs 16%) and grade 1–2 vomiting (16% vs 9%). During the study period, 29 (Decitabine) vs 25 (SC arm) patients died: due to either progression to MDS/AML (7 vs 20), toxicity (9 vs 0), progression and/or toxicity (10 vs 1), other reasons (3 vs 4). Conclusions. Decitabine was found to be an effective drug in these high risk MDS patients with a overall RR of 34%, (similar to earlier studies), leading to a significant PFS improvement as compared to SC arm. The difference Decitabine vs SC arm regarding time to AML or Death was not significant. Due to shorter treatment duration (not being continued beyond 8 cycles) and maybe also due to subsequent treatments administered after disease progression, the difference regarding OS was lower (HR=0.88) and not statistically significant.

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Clofarabine Plus Low-Dose Cytarabine Induction Followed by Consolidation with Clofarabine Plus Low-Dose Cytarabine Alternating with Decitabine as Frontline Therapy for Patients (pts) with Acute Myeloid Leukemia (AML) ≥ 60 Years (yrs).

Blood ◽

10.1182/blood.v114.22.2058.2058 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2058-2058

Author(s):

Sameer A Parikh ◽

Hagop Kantarjian ◽

Guillermo Garcia-Manero ◽

Elias Jabbour ◽

Tapan Kadia ◽

...

Keyword(s):

Induction Therapy ◽

Research Funding ◽

Low Dose ◽

Single Agent ◽

Disease Free Survival ◽

Response Rates ◽

High Response ◽

Multiple Drugs ◽

Low Dose Cytarabine

Abstract Abstract 2058 Poster Board II-35 Therapy of AML for elderly pts (≥ 60 yrs) remains challenging with low response rates, short durability of responses, and high toxicity rates following conventional therapy with standard-dose ara-C/anthracycline combinations. Clofarabine is a novel deoxyadenosine nucleoside analogue with single agent activity in frontline AML for older pts with ≥ 1 unfavorable prognostic factors. We have recently reported results of a randomized study suggesting higher response rates and comparable safety profile with the combination of clofarabine plus low-dose cytarabine over clofarabine alone. We have designed the current study of clofarabine plus low-dose cytarabine induction followed by consolidation with clofarabine plus low-dose cytarabine alternating with decitabine to maintain high response rates and improve disease-free survival based on the following hypotheses: 1) to extend duration of therapy by administering lower doses of the agents; and 2) to provide multiple drugs with different mechanisms of action to decrease risk of resistance. Pts were eligible if ≥ 60 yrs of age with newly diagnosed AML. Pts were excluded for ECOG PS > 2, creatinine > 1.5 mg/dL, cardiac ejection fraction < 40%, and prior therapy with clofarabine or decitabine. Induction therapy consisted of clofarabine 20mg/m2 i.v daily × 5 days plus cytarabine 20mg s.c. twice daily × 10 days in a laminar air flow room. Responding pts could receive up to 17 courses of consolidation therapy of clofarabine plus cytarabine (over 3 and 7 days, respectively) during consolidation courses 1-2, 6-8, 12-14) alternating with decitabine 20mg/m2 i.v. daily for 5 days during courses 3-5, 9-11, and 15-17. All pts received antibiotic prophylaxis with levofloxacin, valacyclovir and itraconazole (or equivalent). Forty pts have been enrolled with a median age of 70 yrs (range 60-80) of whom 22 (55%) had secondary AML (antecedent hematologic disorder in 11 pts). Two pts had received previous azacitidine for MDS. Fourteen pts (35%) had abnormal cytogenetics of whom 10 (25%) had monosomy 5, 7, or both. Four patients (10%) had a FLT3/ITD mutation. Of the 34 pts evaluable for response, 20 (59%) achieved CR and 2 (6%) CRp for an OR rate of 65%. Only 2 pts required 2 courses to CR. The OR rate for patients with diploid versus abnormal cytogenetics was 80% vs 50%; for pts with prior MDS versus no prior MDS 76% and 50%; and 75% for patients with FLT3 mutation. The median time to CR/CRp was 38 days (range 27-103). With a median follow up of 3.5 months (range 0.7-8.1), 2 pts relapsed (CR duration of 3.3 and 4.2 months, respectively); responses are ongoing in the remainder. Three pts (9%) died during induction therapy (one during re-induction) before a response could be established. The median number of consolidation cycles received by pts in CR was 3 (range 1-5). Most toxicities were ≤ grade 2 and included nausea/vomiting, diarrhea, rash, headache and mucositis. Six pts developed grade 3 elevations in serum transaminases which resolved at the end of induction therapy. Myelosuppression and neutropenic fever were common, but prolonged myelosuppression was rare. In conclusion, clofarabine plus low-dose cytarabine achieves high response rates with a manageable toxicity profile and low induction mortality in elderly pts with previously untreated AML. Time-to-event parameters will be provided with more extensive follow up. Disclosures: Off Label Use: Clofarabine and Decitabine in AML. Kantarjian:Genzyme: Consultancy, Research Funding. Faderl:Genzyme: Consultancy, Research Funding; Eisai: Research Funding, Speakers Bureau.

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Cladribine in Combination with Standard Daunorubicine and Cytarabine (DAC) as a Remission Induction Treatment Improves the Overall Survival in Untreated Adults with AML Aged < 60 y Contrary to Combination Including Fludarabine (DAF): A Multicenter, Randomized, Phase III PALG AML 1/2004 DAC/DAF/DA Study in 673 Patients-A Final Update.

Blood ◽

10.1182/blood.v114.22.2055.2055 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2055-2055

Author(s):

Jerzy Holowiecki ◽

Sebastian Grosicki ◽

Slawomira Kyrcz-Krzemien ◽

Kazimierz Kuliczkowski ◽

Aleksander B Skotnicki ◽

...

Keyword(s):

Overall Survival ◽

Research Funding ◽

Remission Rate ◽

Randomized Study ◽

Phase Iii ◽

Remission Induction ◽

Induction Treatment ◽

P Value ◽

Who Grade ◽

Free Survival

Abstract Abstract 2055 Poster Board II-32 This trial is a continuation of earlier Polish Adult Leukemia Group (PALG) studies on the use of purine analogues for therapy of AML patients (Leukemia 2004,18:989–97, updated at 7 y: ASH 2006, Abstr.N#2003, Ann Hematol. 2008, 87:361–7). The goal of the present study was to evaluate the efficacy of combination including 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 adult patients with AML, based on head to head comparison with DAC (DNR, AraC, Cladribine), and standard DA regimens (preliminary results: ASH 2008, abstr.#133). Primary end-points were: complete remission rate (CR) and overall survival (OS); secondary objectives were: toxicity and leukemia-free survival (LFS). Patients achieving CR received two courses of subsequent intensive consolidation: HAM (HD AraC, mitoxantrone) and 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 PALG centers were centrally randomized 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. The results are summarized in the table. Outcome DAC (n = 223) DAF (n = 219) DA (n = 210) P Value (DAC vs DA) P Value (DAC vs DAF) CR 68 59 56 .013 .08 CR after 1 cycle 62 55 50,5 .017 16 3-yr OS 46 30 31 02 .02 2-yr LFS 47 40 39 NS NS Both, the entire CR rate and the CR rate after a single induction course were significantly superior in the DAC arm if compared with DA and DAF subgroups. With a median follow-up of 34 months (the longest observation time 5y) the OS rate equaled 46% for the DAC treated subgroup and was higher in comparison to the standard DA arm and the DAF arm. There were no significant differences in the leukemia free survival rates. The early death rates of 8,5–11%. 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 updated results of randomized study prove that the incorporation 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. Disclosures: Robak: Celgene: Consultancy; Roche: Honoraria, Research Funding; Genmab: Research Funding; Cambridge Antibody Technology: Research Funding; GlaxoSmithKline: Honoraria. Warzocha:BMS: Consultancy, Honoraria; Celgene: Consultancy; Roche: Honoraria; Pfizer: Honoraria; Amgen: Honoraria.

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