Early Versus Deferred Treatment With Combined Fludarabine, Cyclophosphamide and Rituximab (FCR) Improves Event-Free Survival In Patients With High-Risk Binet Stage A Chronic Lymphocytic Leukemia – First Results Of a Randomized German-French Cooperative Phase III Trial

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 524-524 ◽  
Author(s):  
Carmen D Schweighofer ◽  
Florence Cymbalista ◽  
Carolin Müller ◽  
Raymonde Busch ◽  
Raphael Porcher ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Early Stage ◽  
Phase Iii ◽  
Event Free Survival ◽  
Advisory Committees ◽  
Phase Iii Trial ◽  
Free Survival ◽  
Risk Patients ◽  
Binet Stage

Abstract Introduction Patients with asymptomatic early Rai or Binet stage chronic lymphocytic leukemia (CLL) do not benefit from mono-chemotherapy. Therefore, clinical observation without treatment (watch&wait; W&W) has been the gold standard for the management of these patients. Chemoimmunotherapy with FCR improves the outcome of patients with advanced CLL, but its efficacy in early stage disease has not been investigated. Several clinical and biological variables identify those patients who have a high risk of an aggressive disease course and who might benefit from early interventions. Consequently, this trial was conducted to test the value of FCR treatment in patients with early stage, high-risk CLL. Methods This report represents the endpoint and safety analysis of a randomized German-French cooperative phase III trial comparing the efficacy of early versus deferred FCR therapy in treatment-naïve Binet stage A CLL patients with a high risk of disease progression. Risk assessment was performed using 4 prognostic markers: Lymphocyte doubling time <12 months, serum thymidine kinase >10 U/L, an unmutated immunoglobulin heavy chain variable region gene (IGHV) status, and presence of unfavorable cytogenetics (del11q, del17p, trisomy 12) by fluorescence-in-situ hybridization. Presence of at least 2 versus less than 2 of these factors defined “high-risk” versus “low-risk” CLL. High-risk CLL patients were further randomized to receive either 6 cycles FCR (HR-FCR) or to be followed by a W&W strategy (HR-W&W). Patients with low-risk CLL were observed only (LR-W&W). Results Between 2005 and 2010, a total of 824 patients was enrolled, 423 patients in 69 centers of the German CLL Study Group and 401 patients in 25 centers of the French Cooperative Group on CLL. The diagnosis of CLL needed to be established no longer than 12 months prior to enrollment and patients were required to present with previously untreated stage Binet A CLL at the time of inclusion. Overall, 800 patients (97.1%) were stratified, 201 of them categorized as high-risk CLL (25.1%). There was no significant difference between high-risk patients from the two study groups regarding common baseline characteristics (e.g., age, sex, comorbidity, immunophenotype) and the distribution of risk factors used for stratification. 100 out of 201 high-risk patients were randomized to receive FCR therapy (HR-FCR), while 101 patients were allocated to the HR-W&W arm. 18 out of 100 patients (18%) withdrew consent for FCR therapy before treatment was started. 71 (86.6%) of 82 treated patients completed ≥4 cycles. The most common of 228 CTC grade III/IV adverse events reported within 12 months after treatment initiation were hematotoxicity (73.2% of patients) and infections (19.5% of patients). Three patients (3.7%) developed fatal CTC grade V infections (2 septic bacteremias, 1 of them with pulmonary aspergillosis; 1 encephalitis). Out of 79 patients available for response assessment until month 12 after treatment start, 76 showed a complete or partial remission (ORR 96.2%), 2 patients had stable disease (2.5%) and 1 patient had progressed (1.3%). After a median follow up of 46 months (range 0-88 months), HR-FCR patients demonstrated a significantly improved event-free survival (EFS) compared to HR-W&W patients (median EFS not reached versus 24.5 months, respectively, P<0.0001, Fig. 1). Overall survival was not significantly different between HR-FCR and HR-W&W with 181 high-risk patients (90%) being alive at last follow up. Both, HR-FCR and HR-W&W patients exhibited a significant shorter event-free and overall survival than LR-W&W patients, demonstrating an efficient prognostic segregation of patients by the risk assessment used for this trial (analysis based on the German LR-W&W cohort only, complete German-French LR-W&W data will be presented at the meeting). Conclusion This is the first randomized phase III trial investigating the efficacy of FCR chemoimmunotherapy in early stage CLL. So far, the study has revealed two major results: 1. A combination of clinical and biological factors can be used to identify early stage CLL patients who experience a rapid disease progression with unfavorable outcome, 2. FCR chemoimmunotherapy substantially improves event-free survival in early stage high-risk CLL. Disclosures: Langerbeins: Roche: travel grants Other. Cazin:roche: meeting invitation Other, Membership on an entity’s Board of Directors or advisory committees; GSK: meeting invitation, meeting invitation Other, Membership on an entity’s Board of Directors or advisory committees. Fischer:Mundipharma: Travel grants, Travel grants Other; Roche: Travel grants Other. Stilgenbauer:Roche: Consultancy, Research Funding, Travel grants Other; Mundipharma: Consultancy, Research Funding. Leblond:Roche : Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity’s Board of Directors or advisory committees; Mundipharma: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Speakers Bureau. Hallek:F. Hoffmann-La Roche: Consultancy, Honoraria, Research Funding.

ABVD Versus Escalated Beacopp in Advanced Stage Hodgkin's Lymphoma: Results from a Retrospective, Multicenter European Study

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1565-1565 ◽  
Author(s):  
Patrizia Mondello ◽  
Irene Dogliotti ◽  
Jan-Paul Bohn ◽  
Federica Cavallo ◽  
Simone Ferrero ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Advanced Stage ◽  
Advisory Committees ◽  
Free Survival ◽  
High Risk Patients ◽  
Risk Patients

Purpose: Hodgkin's lymphoma (HL) is a highly curable disease even in advanced-stage, with &gt;90% of long-term survivors. Currently, the standard of care is ABVD (doxorubicin, etoposide, vinblastine and dacarbazine), as it is less toxic and as effective as other more intensive chemotherapy regimens. Alternatively, BEACOPP (bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine and prednisone) has been proposed as front-line intensified regimen with a better initial disease control and prolonged time to relapse when compared to ABVD. However, this advantage is associated with higher rates of severe hematologic toxicity, treatment-related deaths, secondary neoplasms and infertility. To date, the debate regarding which regimen should be preferred as first line for advanced-stage HL is still ongoing. To shed some light on this open question we compared efficacy and safety of both regimens in clinical practice. Patients and Methods: From October 2009 to October 2018, patients with HL stage III-IV treated with either ABVD or BEACOPP escalated (BEACOPPesc) were retrospectively assessed in 7 European cancer centers. Results: A total of 372 consecutive patients were included in the study. One-hundred and ten patients were treated with BEACOPPesc and 262 with ABVD. The baseline characteristics of the two groups did not differ significantly, except for a higher rate of high-risk patients in the BEACOPPesc group in contrast to the ABVD one (47% vs 18%; p= 0.003). Complete response rate (CR) assessed by PET imaging at the end of the second cycle was 67% and 78% for the ABVD and BEACOPPesc group (p= 0.003), respectively. Thirteen patients of the ABVD group achieved stable disease (SD) and 6 had a progression disease (PD). On the other hand, 4 of the patients in the BEACOPPesc group progressed, another 2 interrupted therapy because life-threatening toxicity. At the end of the therapy, CR was 76% in the ABVD group and 85% in the BEACOPPesc group (p= 0.01). A total of 20% patients in the ABVD group and 14% patients in the BEACOPPesc group received consolidation radiotherapy on the mediastinal mass at the dose of 30Gy. After radiotherapy, the number of patients with CR increased to 79% and 87% in the two groups (p= 0.041), respectively. Thirty-nine patients (35%) in the BEACOPPesc group required dose reduction of chemotherapy due to toxicity compared to 12 patients (5%; p= &lt;0.001) in the ABVD group. Overall, the rate of severe toxicities was higher in the BEACOPPesc group in comparison with the ABVD cohort. In particular, there was a significant increased frequency of acute grade 3-4 hematologic adverse events (neutropenia 61% vs 24%; anemia 29% vs 4%; thrombocytopenia 29% vs 3%), febrile neutropenia (29% vs 3%), severe infections (18% vs 3%). Myeloid growth factors were administered to 85% and 59% of patients in the BEACOPPesc group compared to the ABVD group. Blood transfusions were required in 51% and 6% of patients in the BEACOPPesc group compared to the ABVD cohort. Progression during or shortly after treatment occurred in 5 patients in the BEACOPPesc group (4%) and in 16 patients in the ABVD group (6%; p= 0.62). Among the 96 patients who achieved a CR after BEACOPPesc and radiotherapy, 8 relapsed (8%), compared to 29 of 208 patients in the ABVD group (14%; p= 0.04). At a median follow-up period of 5 years, no statistical difference in progression free survival (PFS; p=0.11) and event-free survival (EFS; p=0.22) was observed between the BEACOPPesc and ABVD cohorts. Similarly, overall survival (OS) did not differ between the two groups (p=0.14). The baseline international prognostic score (IPS &lt;3 vs ≥ 3) significantly influenced the EFS with an advantage for the high-risk group treated with BEACOPPesc (Figure 1A; p=0.03), but not the PFS (Figure 1B; p=0.06) and OS (Figure 1C; p=0.14). During the follow-up period, in the BEACOPPesc group one patient developed myelodysplasia and one acute leukemia. Second solid tumors developed in one patient in the ABVD group (lung cancer) and one in BEACOPPesc group (breast cancer). Conclusion: We confirm that the ABVD regimen is an effective and less toxic therapeutic option for advanced-stage HL. Although BEACOPP results in better initial tumor control especially in high-risk patients, the long-term outcome remains similar between the two regimens. Disclosures Ferrero: EUSA Pharma: Membership on an entity's Board of Directors or advisory committees; Servier: Speakers Bureau; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Gilead: Speakers Bureau. Martinelli:BMS: Consultancy; Pfizer: Consultancy; ARIAD: Consultancy; Roche: Consultancy; Novartis: Consultancy. Willenbacher:European Commission: Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Myelom- und Lymphomselbsthilfe Österreich: Consultancy, Honoraria; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Gilead Science: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; IQVIA: Membership on an entity's Board of Directors or advisory committees; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; oncotyrol: Employment, Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Fujimoto: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Tirol Program: Research Funding; Abbvie: Consultancy, Honoraria; Sandoz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Prognostic Importance of Duration of MDS Prior to Randomization Between Decitabine (DAC) Vs. Best Supportive Care (BSC) In Elderly IPSS Intermediate-2 and High Risk MDS Patients: Results of the 06011 EORTC-GMDSSG Phase III Trial

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 4024-4024
Author(s):  
Michael Lubbert ◽  
Stefan Suciu ◽  
Uwe Platzbecker ◽  
Aristoteles A.N. Giagounidis ◽  
Dominik Selleslag ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Cox Regression ◽  
Phase Iii ◽  
Prognostic Impact ◽  
Advisory Committees ◽  
Phase Iii Trial ◽  
Response Predictors ◽  
Long Duration

Abstract Abstract 4024 Background: The hypomethylating agents 5-azacytidine (Vidaza) and 5-aza-2′-deoxycytidine (Decitabine, DAC) are active in different MDS subtypes. Compared to other response predictors to DAC, prior MDS duration has received only limited attention (1, 2), with conflicting results. Based on our finding that long duration of MDS prior to DAC treatment may be a novel factor linked to a better outcome (1), we now assess its value in the phase III trial 06011 (DAC versus BSC [3]). Immediate enrolment after diagnosis was allowed in that trial, median MDS duration prior to randomization thus only 3 months (mths). Methods: Comparison of progression-free (PFS), AML-free (AMLFS) and overall survival (OS) according to MDS duration >= vs. <3 mths in 233 patients (pts) with higher-risk MDS (median age 70 years) randomized to DAC (n=119) or BSC (n=114). Comparisons by long-rank test and multivariate analyses by Cox regression (Performance Status [PS], cytogenetics and IPSS high risk N/Y) were performed retrospectively: MDS duration had not yet been known as possible stratification factor at time of study initiation, and the trial thus not been powered to detect significant differences with regard to this discriminator. Results: A better prognosis of patients with MDS duration >=3 vs <3 mths was observed in DAC arm (B vs A) and BSC arm (D vs C). Conversely, DAC yielded better results than BSC in each MDS duration group: <3 mths (A vs C) and >=3 mths (B vs D). In both arms (n=233), Mult. indicated that MDS duration (>=3 vs <3 mths) adjusted for treatment, PS, cytogenetics and IPSS group was an independent prognostic factor regarding PFS (HR=0.75, 95%CI 0.58–0.99), AMLFS (HR=0.68, 95%CI 0.51–0.90), and OS (HR=0.75, 95%CI 0.56–0.99). The tests for interaction treatment × duration of MDS were not significant for 3 endpoints: PFS (p=0.38), AMLFS (p=0.90), OS (p=0.67). Conclusion: In intermediate-2 and high-risk MDS pts, long duration from MDS diagnosis to start of DAC or BSC appeared to be associated with a better outcome. This finding is in sharp contrast to the adverse prognostic impact of antecedent disease duration in patients who received intensive chemotherapy (4). It is supported by a similar analysis of pts with AML from MDS treated on the 00331 DAC phase II multicenter trial: those with longer MDS duration prior to DAC also had better outcome (5). Application of this discriminator in the evaluation also of other DAC schedules and MDS treatments therefore appears warranted. References: 1. Wijermans et al., Ann. Hematol. 84 (suppl. 1): 9–14, 2005 2. Kantarjian et al., Cancer 109:265-73, 2007 3. Wijermans et al., Blood 112 (suppl. 1): abs. 226, 2008 4. Estey et al., Blood 90:2969-77, 1997 5. Lübbert, Schmoor et al., abstract submitted, ASH 2010 Disclosures: Platzbecker: Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Salih:Pfizer: Research Funding. Muus:Celgene: Membership on an entity's Board of Directors or advisory committees; Alexion: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees.

Impact of the Timing of Complete Remission and Transplantation on Estimates of Event-Free Survival in Acute Myeloid Leukemia

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 214-214 ◽  
Author(s):  
Jun Yin ◽  
Betsy R. Laplant ◽  
Geoffrey L. Uy ◽  
Guido Marcucci ◽  
William Blum ◽  
...  
Keyword(s):  
Clinical Trials ◽  
Complete Remission ◽  
Board Of Directors ◽  
Phase Ii Study ◽  
Phase Iii ◽  
Event Free Survival ◽  
Advisory Committees ◽  
Free Survival ◽  
Phase Iii Study ◽  
Induction Failure

Abstract Background: Event free survival (EFS) is often used as an endpoint in AML clinical trials. EFS-based endpoints are controversial due to the lack of a consistent definition for the timing of complete remission (CR), and consideration of hematopoietic cell transplantation (HCT). Here, we examined the impact of the timing of achievement of CR and censoring for HCT in the estimation of the EFS, and assessed its robustness as an endpoint in AML. Methods: All prospective trials since 2003 using anthracycline and cytarabine chemotherapy for newly diagnosed patients (pts) with AML conducted through the Alliance for Clinical Trials in Oncology, and whose primary endpoint data has been reported, were included (5 trials total). Trial 1 - randomized phase III study in older AML pts (n=504, median age 69, 61% male); trial 2 - single-arm phase II study in older FLT3-mutated AML pts (n=54, median age 67, 56% male); trial 3 - randomized phase III study in younger AML pts (n=546, median age 48, 55% male); trial 4 - randomized phase III study in younger FLT3-mutated AML pts (n=717, median age 48, 45% male); and trial 5 - single arm phase II study in core-binding factor AML pts with no restriction on age (n=61, median age 51, 51% male). Induction failure was defined as one of: no CR by 60 days (Definition 1), no CR by the end of all protocol induction courses (Definition 2), or no CR by the end of all protocol treatment (Definition 3). CR was defined as <5% blasts in a cellular marrow with recovery of >1000 neutrophils/ul (>1500 neutrophils/ul for trial 1), >100,000 platelets/ul, and no red cell transfusion requirement. EFS was defined as the time from randomization / registration to the first evidence of induction failure using each of the 3 methods above, relapse, or death from any cause. Patients last known to be alive without relapse were censored at the date of last contact. Including the 3 induction failure definitions and consideration of censoring or no censoring for HCT, the Kaplan Meier estimates of EFS were computed for the six different definitions of EFS. Results: The number of deaths was respectively 464, 38, 307, 357, and 13 across the 5 trials, with a median follow-up of 99.7, 28.2, 60.1, 58.2, and 33.5 months on the alive patients, respectively. Not considering HCT, in trial 1, the median EFS ranged from 2.0 to 4.3 months (115% difference); in trial 2, the median EFS ranged from 6.9 to 8.3 months (20% difference); in trial 3, the median EFS ranged from 9.8 to11.2 months (14% difference); and in trial 4, the median EFS ranged from 5.5 to 9.7 months (76% difference). The median EFS was not achieved in trial 5; however the 1-year EFS estimates ranged from 78 to 83% (6% difference). Consistently across all trials, as expected, the EFS estimate using the 60-day induction failure yielded the shortest estimates, whereas the end-of-treatment induction failure yielded the longest estimates. Results were similar both with and without censoring at the time of HCT as the event of interest occurred prior to transplantation in most cases. Conclusions: Although relapse and death are firm endpoints, the determination of failure to achieve CR is not consistent across studies. While there is minimal impact of censoring at HCT on EFS estimates, the median EFS estimates differed considerably based on the timing of CR used to define induction failure, with the magnitude of difference being large enough in most cases (observed range: 14% to >100%) to lead to incorrect conclusions about efficacy in a single arm trial if the trial definition was not consistent with the definition used for the historical control. The timing of CR should be carefully examined in the historical control data used to guide the design of the next trial. Table. Table. Disclosures Uy: Glycomimetics: Consultancy; Boehringer Ingelheim: Consultancy. Stone:Celator: Consultancy; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy; Amgen: Consultancy; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy; Novartis: Consultancy; Jansen: Consultancy; Pfizer: Consultancy; ONO: Consultancy; Juno Therapeutics: Consultancy; Merck: Consultancy; Roche: Consultancy; Seattle Genetics: Consultancy; Sunesis Pharmaceuticals: Consultancy; Xenetic Biosciences: Consultancy.

scholarly journals Outcomes of Tandem Hematopoietic Stem Cell Autologous Transplant in High-Risk Myeloma Patients: A Single-Center Experience

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4901-4901
Author(s):  
Shona Philip ◽  
Selay Lam ◽  
Chai Wye Phua ◽  
Martha L Louzada ◽  
Anargyros Xenocostas ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Partial Response ◽  
Maintenance Therapy ◽  
Board Of Directors ◽  
Progression Free Survival ◽  
Single Center ◽  
Advisory Committees ◽  
Free Survival ◽  
Risk Patients

Abstract Introduction: Studies have demonstrated that multiple myeloma (MM) is a clinically, genetically complex and heterogeneous disease. Cytogenetic alterations identify high-risk patients in MM and are associated with a poor prognosis. They include at least one of the following at diagnosis: t(4;14), t(14;16), t(14;20), del(17p), 1q amp and 1q amp + del(1p). Autologous stem cell transplantation (ASCT) and the development of novel agents have considerably increased the median survival of MM patients. Patients with high-risk cytogenetics are associated with worse survival, and studies have shown improvement in progression-free survival with tandem ASCT when compared to single ASCT. Methods: This is a retrospective single-center study evaluating MM patients with high-risk cytogenetics at our center who have undergone a tandem autologous transplant from January 1, 2017, to December 31, 2020. Primary objective was overall response rates (ORR) and relapse rates. Secondary objectives looked at progression-free survival (PFS), overall survival (OS) using the Kaplan-Meier method. Results: From January 1, 2017, to December 31, 2020, 25 high-risk patients underwent tandem ASCT. Key patient characteristics are shown in table 1. Translocation (4:14) was seen in 8/25 (32%) patients; t(14:16) in 5/25 (20%) patients; del17p in 7/25 (28%), 1q amp in 8/25 (32%) patients, del1p + 1q amp in 5/25 (20%) patients. In terms of double hit and triple hit disease, 9/25 (36%) patients had two high risk changes and 3/25 (12%) with had three high risk changes. ISS staging wise, 5/25 (20%) patients were ISS stage I, 5/25 (20%) patients ISS stage 2 and 9/25 (36%) patients were ISS stage 3. The most common induction regimen consisted of cyclophosphamide, bortezomib, and dexamethasone (CyBorD). One patient each transitioned to daratumumab, lenalidomide and dexamethasone and PAD/CVD due to poor response. Maintenance therapy was given to 21/25 (84%) tandem ASCT patients with 5 (20%) patients receiving lenalidomide, 4 (16%) patients receiving proteasome inhibitor and 12 (48%) patients received dual maintenance. In terms of response, we recorded CR (complete response) vs VGPR (very good partial response) vs PR (partial response) after induction, 2-3 months after ASCT #1, 2-3 months after ASCT #2, 12 months after ASCT #2, and 12 months after maintenance. Following induction, 16 patients had achieved VGPR, and 9 of patients had achieved PR. After ASCT #1, 5 (55.5%) PR patients deepened their response to a VGPR. 1-3 months post ASCT #2, 3 (33.3%) PR patients deepened to a VGPR, and 2 (12.5%) VGPR patients achieved CR. 12 months after ASCT #2, 2 of the previous VGPR patients (12.5%) achieved CR, and 1 PR (11.1%) patient achieved VGPR. At the median follow-up time of 60 months, 44% of patients had relapsed. 1 patient relapsed within 1-3 months post ASCT#1. Nine other patients relapsed post ASCT #2 and maintenance except one patient who relapsed at time of ASCT #2. Univariable analysis identified hemoglobin as a statistically significant association with risk of progression or death. All patients who received any maintenance after tandem transplant were progression-free at 60 months (p&lt;0.001). Conclusion: In our retrospective study, results suggest that tandem ASCT allows for deepening of responses. Together with maintenance therapy, this contributes to the durability of further PFS prolongation in high-risk MM patients. Figure 1 Figure 1. Disclosures Lam: Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; AbbVie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Servier: Honoraria, Membership on an entity's Board of Directors or advisory committees; Hoffmann-La Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Meyers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Beigene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: 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; SeaGen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria, Membership on an entity's Board of Directors or advisory committees; Johnson & Johnson: Honoraria, Membership on an entity's Board of Directors or advisory committees. Phua: Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Honoraria; NovoNordisk: Honoraria, Membership on an entity's Board of Directors or advisory committees; AstraZeneca: Honoraria; Amgen: Honoraria. Louzada: Amgen: Honoraria; Pfizer: Honoraria; Celgene: Honoraria; Janssen: Honoraria.

Intensified CHOP with Rituximab for Intermediate or High-Risk Non-Hodgkin’s Lymphoma: Interim Analysis of a Randomized Phase III Trial in Elderly Patients by the Dutch HOVON and Nordic Lymphoma Groups.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 16-16 ◽  
Author(s):  
Pieter Sonneveld ◽  
Wim van Putten ◽  
Harald Holte ◽  
Douwe Biesma ◽  
Marinus van Marwijk-Kooy ◽  
...  
Keyword(s):  
High Risk ◽  
Elderly Patients ◽  
Incomplete Data ◽  
Interim Analysis ◽  
Cell Lymphoma ◽  
Phase Iii ◽  
Event Free Survival ◽  
Phase Iii Trial ◽  
Free Survival ◽  
Significant Difference

Abstract High-risk Non-Hodgkin lymphoma (NHL) in elderly patients (&gt; 60 yrs) is associated with a relatively low complete response (CR) rate and a poor overall survival (OS). Previous studies have shown that addition of Rituximab to standard CHOP chemotherapy may improve CR and/or OS. A similar improvement has been shown for intensification of CHOP from 21 day intervals to 14 day intervals. The Dutch HOVON group and the Nordic lymphoma group have performed a multi-center, randomized phase III trial to compare 8 cycles of intensified CHOP (CHOP14) with the same regimen plus 6 administrations of Rituximab in previously untreated elderly patients with intermediate or high-risk NHL. Inclusion criteria were diffuse large B-cell lymphoma, mantle cell lymphoma or follicular lymphoma grade III; intermediate or high-risk NHL according to age adjusted IPI score; CD20-positive NHL; age 65 yrs or higher. The target number was 400 patients to be accrued in 5 years based on an expected increase in event-free survival with hazard ratio HR=0.70. Aplanned interim analysis was performed after inclusion of 250 patients, restricted to 211 patients included from 1st September 2001 to 1st October 2004. Forty patients had to be excluded because of lack of treatment and evaluation data, leaving 171 patients for the analysis. The median time off protocol treatment was 119 days (range 4–468 days). The median age was 73 years (range 62–88 years). There was no difference between the two treatment arms regarding histology, age, WHO classification of NHL, age-adjusted IPI score, Ann Arbor stage, WHO performance status and serum LDH. There was no significant difference of toxicity or CR between the two treatment arms. However, a highly significant difference was observed for event-free survival and overall survival in favor of the treatment arm with CHOP plus Rituximab. Based on this interim analysis, the randomization was halted and patients in the control arm were further treated with CHOP plus Rituximab. Since the outcome of the interim analysis could be biased due to incomplete data, a final decision to stop the trial awaits a new analysis which is planned for 26th August 2005 after collection of missing or incomplete data. If the new analysis confirms the results of the interim analysis, i.e. that Rituximab significantly improves the outcome of treatment in elderly patients with intermediate or high-risk NHL, even when an intensified CHOP regimen is used, the study will be closed and outcomes will be presented.

Early and Risk-Adapted Therapy with Fludarabine in High-Risk Binet Stage A CLL Patients Prolongs Progression Free Survival but Not Overall Survival: Results of the CLL1 Protocol of the German CLL Study Group (GCLLSG).

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2038-2038 ◽  
Author(s):  
Manuela A. Bergmann ◽  
Barbara F. Eichhorst ◽  
Raymonde Busch ◽  
Hartmut Doehner ◽  
Ursula Vehling-Kaiser ◽  
...  
Keyword(s):  
High Risk ◽  
Early Stage ◽  
Progression Free Survival ◽  
Absolute Lymphocyte Count ◽  
Observation Time ◽  
Phase Iii ◽  
Free Survival ◽  
Significant Difference ◽  
Binet Stage ◽  
Beta 2 Microglobulin

Abstract Background: Most patients (pts) with CLL present at early stages of their disease. This group is not homogenous with regard to its prognosis, and some pts show progression within 12 months after diagnosis. So far it is not clear if these pts benefit from early risk-adapted therapy. The CLL1 protocol, a randomized phase III trial of the GCLLSG, was conducted to assess if the early use of fludarabine prolongs progression free survival (PFS) in high risk (HR) CLL pts. High risk was defined by an elevated thymidine kinase (&gt;7 U/L) or beta-2-microglobulin (&gt;3,5 mg/L) and short lymphocyte doubling time (&lt;12 months) or diffuse bone marrow infiltration. Combining the biological and clinical factors, at least one parameter of each group needed to be positive to qualify for the high risk cohort. Patients: From 09/1997 to 12/2004 877 previously untreated Binet A pts were enrolled. 788 pts could be stratified, 471 pts (68,3%) to the low risk (LR), 218 pts (31,6%) to the HR cohort for disease progression. 99 pts were not eligible due to violation of inclusion/exclusion criteria. 104 pts (HRF) were randomized to treatment with fludarabine (fludarabine IV 25 mg/m2/d, day 1–5, every 28 days), 114 pts (HRWW) to “watch and wait”. 30 pts were not eligible for PFS and OS. Analyses on PFS and OS on 188 pts are presented here. Response was defined by NCI-WG criteria (Cheson et al., 1996), progression was defined by slightly modified NCI-WG criteria with regard to the early stage. Results: The median observation time was 45.3 months (95% CI, 3.2–96 mo) for HRF and 40.4 months (95% CI, 6.9–92 mo) for HRWW. The median age in the HRF arm was 61 vs. 62 yrs in the HRWW arm. The HRWW arm contained significantly more male pts (p=0.03). All other parameters used for risk stratification and other characteristics like age, performance state, comorbidity, B symptoms, absolute lymphocyte count, hemoglobine, platelets, lymphadenopathy, splenomegaly or hepatomegaly were not significantly different at time of randomization. Response to fludarabine could be evaluated in 70 pts. The overall response rate was 91%, 11 pts had complete remission (16%), 5 pts had nodular partial remission (PR) (7%), 48 pts (69%) had PR, 3 pts (4%) had stable disease and 3 pts (4%) had progressive disease. Main toxicities (grade 3 or grade 4 CTC) were leukocytopenia and infections. Infections were not significantly higher in the treatment arm (p=0.12). Dose reduction was necessary in 20% of pts due to toxicity. 20 deaths were reported in the HRF arm, 12 deaths were reported in the HRWW arm (p=0.47). Discussion: On an intent-to-treat analysis PFS was significantly longer in the HRF arm in comparison to the HRWW arm (24.2 vs. 15.9 mo, p=0.03). Though the median OS was not yet reached, no significant difference between both groups in OS was assessed (p= 0.47). Conclusion: CLL pts of Binet stage A but with risk features have a median time to progression of 15.9 months. Fludarabine prolongs the PFS, but not the OS in this group of patients.

Presence of Residual Disease Detected by Multidimensional Flow Cytometry Identifies Patients with AML At High Risk of Relapse – a Report From the Children's Oncology Group,

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 3545-3545 ◽  
Author(s):  
Michael R. Loken ◽  
Todd A. Alonzo ◽  
Laura Pardo ◽  
Robert B. Gerbing ◽  
Richard Aplenc ◽  
...  
Keyword(s):  
Flow Cytometry ◽  
High Risk ◽  
Residual Disease ◽  
Disease Free Survival ◽  
Phase Iii ◽  
Advisory Committees ◽  
Free Survival ◽  
Post Induction ◽  
Risk Patients ◽  
Disease Free

Abstract Abstract 3545 We previously demonstrated that presence of post induction residual disease detected by multidimensional flow cytometry (MDF) was associated with higher relapse risk and worse survival in a cohort of 225 children treated on AAML03p1. In this study we used a similar methodology in examining the post induction marrow specimens in patients treated on the COG AML phase III trial AAML0531. This study randomized 1022 children and young adults without Down Syndrome (DS) to an MRC based chemotherapy backbone with or without Gemtuzumab Ozogamicin (GO) in the first and fourth course of therapy. Of the 1022 eligible patients, 784 patients consented to participate in the correlative biology study and submitted marrow specimens by the end of first course for evaluation of disease status by MDF. Of these 784 marrow specimens, residual disease (RD) defined as ≥0.1% blasts by MDF was identified in 240 patients (31%). Prevalence of RD in patients in morphologic CR was 20% vs. 63% in those who failed to achieve a morphologic CR (37% of those who were not in morphologic CR had no RD by MDF). Presence of RD varied by risk groups, where those with favorable risk features (CBF AML) had an RD prevalence of 14%, high risk patients (-7, -5/del5q, high risk FLT3/ITD, course 1 blasts >15%) had an RD prevalence of 68% and the intermediate risk patients had an RD prevalence of 27%. Patients with RD who were in morphologic CR or PR at the end of the first course had disease-free survival (DFS) at 3 years of 34% vs. 60% in those without RD (p<0.0001). Corresponding overall survival (OS) at 3 years was 54% and 76% in those with and without RD, respectively (p<0.0001). We further evaluated the ability of post induction RD to predict outcome in specific risk categories. Of the 180 patients considered favorable risk by cytogenetic features who were in morphologic CR or PR at end of first course, 23 had RD by MDF (13%). Presence of RD in this favorable risk cohort was not associated with worse disease-free survival (DFS, p=0.54). Similar lack of prognostic significance was observed in patients considered high risk (p=0.38). In contrast to high and low risk patients, in 435 patients with no known risk features (intermediate risk) 118 patients had RD detected by MDF (27%). DFS at 3 years from end of first course in patients with RD was 33% vs. 55% for those without RD (p<0.0001). Corresponding OS at 3 years for those with and without RD was 51% and 70%, respectively (p<0.001). This study demonstrates the significance of early response to chemotherapy as measured by MDF in predicting clinical outcome in childhood AML. It also demonstrates that the presence of RD may not be predictive of outcome in those with high or low risk features. Multi-dimensional flow cytometry has been incorporated into the current COG phase III AML trial. Disclosures: Smith: Eisai: ; Archimedes Pharma: Membership on an entity's Board of Directors or advisory committees; Pfizer, Inc.: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics:.

Integrative Network Analysis of Newly Diagnosed Multiple Myeloma Identifies a Novel RNA-Seq Based High Riskgene Signature

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3285-3285
Author(s):  
Alessandro Lagana ◽  
Deepak Perumal ◽  
David Melnekoff ◽  
Ben Readhead ◽  
Brian Kidd ◽  
...  
Keyword(s):  
Overall Survival ◽  
High Risk ◽  
Board Of Directors ◽  
Research Funding ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Free Survival ◽  
Kaplan Meier ◽  
Risk Patients ◽  
Equity Ownership

Abstract High-risk Multiple Myeloma (MM) is characterized by unresponsiveness to multiple therapies, rapid disease progression and short overall survival, and may be significantly different from relapsed MM, where aggressiveness is usually a result of drug-resistance associated to clonal selection. Several gene expression-based signatures have been proposed in the past years, however the identification of high-risk patients at diagnosis still represents a challenge. Next generation high-throughput sequencing technologies have enabled a deeper insight into cancer genomes and transcriptomes at an unprecedented level of detail. MMRF CoMMpass is a longitudinal, prospective observational study, started in 2011, that aims to collect and analyze sequencing and clinical data from >1,000 MM patients at initial diagnosis and at relapse. CoMMpass is a real world observational study and, as such, reflects the therapeutic heterogeneity seen across patient populations and provides a unique opportunity to correlate molecular profiles, genomic alterations and clinical characteristics of MM with treatment outcome. Here we present a network approach to identify high-risk myeloma patients developed using next generation sequencing data from 450 patients in the IA7 release of CoMMpass. We generated MMNet, an integrated network model of newly diagnosed myeloma based on RNA-seq, Whole-Exome (WXS) and Whole-Genome (WGS) data correlated with clinical outcomes. MMNet consisted of 37 modules of coexpressed genes, that were further characterized by functional enrichment analysis and correlation with clinical traits and genomic alterations, i.e. somatic mutations and copy number alterations inferred from WGS and WXS data. A total of 89 progression/death events have been reported for the cohort within the second year since the beginning of the study. Cox regression analysis identified a module of co-expressed genes whose over-expression was significantly correlated with early relapse (<2yr) (HR 1.75, 95%CI = 1.169-2.614, p=0.005). The module was also associated to stage III R-ISS, high clonality (>4 clones) and high mutational burden, as well as higher percentage of plasma cells in both bone marrow and peripheral blood, which are traits associated with high-risk disease. Module expression was also up regulated in patients with mutations in TP53 and MAX, 13q deletion and 1q amplification. We further narrowed down the signature to 286 genes (the MMNet-286 signature) strongly correlated with time to Event Free Survival (EFS) (r = -0.81, p = 0). This gene-set was significantly enriched for several pathways including Cell Cycle, DNA repair and Homologous Recombination (q < 0.01). Cox regression analysis showed that the two clusters induced by MMNet-286 discriminated between lower and higher risk patients with respect to EFS (HR = 2.22, 95% CI = 1.505-3.295, p = 4.007e-5) (Fig. 1). The prognostic value of MMNet-286 was confirmed on two independent datasets: Broyl-2010 (HR = 1.76, 95% CI = 1.182-2.642, p = 0.005) and Shaughnessy-2006 (HR = 2.65, 95% CI = 1.746-4.031, p = 2.03e-6) (Fig. 2 and 3). The Broyl-2010 dataset consisted of 275 samples from newly diagnosed myeloma patients included in the HOVON65/GMMG-HD4 trial (GSE19784). The Shaughnessy-2006 dataset consisted of 559 samples from newly diagnosed patients pre-TT2 and -TT3 treatments (GSE2658). Comparison of MMNet-286 with previous high risk signatures and disease classes revealed an overlap of five genes with the UAMS-70 signature, twelve genes with the EMC-92 signature and fifteen genes with the set of up-regulated genes in the UAMS PR class, for which the coexpression module was enriched. In Conclusion, our results demonstrate the advantages of employing integrated network models to identify prognostic features based on next generation sequencing data from large cohort of patients. Applications of the MMNet-286 signature include the generation of a prognostic assay (i.e. NanoString) for the identification of high-risk patients. Future work will aim at validation of the signature in larger cohorts from CoMMpass and other studies. Figure 1 Kaplan-Meier curves of event free survival in the MMRF cohort stratified by the MMNet-286 signature. Figure 1. Kaplan-Meier curves of event free survival in the MMRF cohort stratified by the MMNet-286 signature. Figure 2 Kaplan-Meier curves of overall survival in the Broyl cohort stratified by the MMNet-286 signature. Figure 2. Kaplan-Meier curves of overall survival in the Broyl cohort stratified by the MMNet-286 signature. Figure 3 Kaplan-Meier curves of overall survival in the Shaughnessy cohort stratified by the MMNet-286 signature. Figure 3. Kaplan-Meier curves of overall survival in the Shaughnessy cohort stratified by the MMNet-286 signature. Disclosures Chari: Novartis: Consultancy, Research Funding; Array Biopharma: Consultancy, Research Funding; Pharmacyclics: Research Funding; Amgen Inc.: Honoraria, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Consultancy, Research Funding. Cho:Genentech Roche: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Research Funding; Agenus, Inc.: Research Funding; Ludwig Institute for Cancer Research: Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Research Funding. Barlogie:Signal Genetics: Patents & Royalties. Dudley:GlaxoSmithKline: Consultancy; Janssen Pharmaceuticals, Inc.: Consultancy; Ayasdi, Inc.: Equity Ownership; Ecoeos, Inc.: Equity Ownership; NuMedii, Inc.: Equity Ownership; Ontomics, Inc.: Equity Ownership; AstraZeneca: Speakers Bureau; NuMedii, Inc.: Patents & Royalties; Personalis: Patents & Royalties.

scholarly journals Real-World Experience Using Letermovir for CMV Prophylaxis in High-Risk Allogeneic Hematopoietic Stem Cell Patients in the Setting of Using T-Cell Depletion As Gvhd Prophylaxis and the Impact on CMV Reactivation, 1-Year Overall Survival, and 1-Year Gvhd-Free-Relapse-Free Survival

Blood ◽  
2020 ◽  
Vol 136 (Supplement 1) ◽  
pp. 29-29
Author(s):  
Sami Dwabe ◽  
Mindy Hsiao ◽  
George Yaghmour
Keyword(s):  
T Cell ◽  
High Risk ◽  
Board Of Directors ◽  
Relapse Free Survival ◽  
Advisory Committees ◽  
Free Survival ◽  
High Risk Patients ◽  
Gvhd Prophylaxis ◽  
Risk Patients ◽  
Cmv Reactivation

Background: Cytomegalovirus (CMV) is a major cause of morbidity in allogeneic hematopoietic stem cell transplant (HSCT) patients. Marty et al. 2017 showed that letermovir is effective in preventing CMV reactivation in high-risk HSCT patients, though only 16% were haplo-identical. Recently, Karam et al. 2019 showed decreased rates of CMV reactivation in haplo-identical HSCT using letermovir in unselected high-risk patients. The effects of letermovir on other transplant-related outcomes including overall survival (OS), relapse free survival (RFS), and Graft-versus-host-disease (GVHD)-free-/relapse-free survival (GRFS), however, are not as well-known. With the increased use of post-transplant cyclophosphamide (PTCy) as GVHD prophylaxis in all transplant types, letermovir use may need to be broadened as those that are T-cell depleted are also at increased risk of CMV reactivation. Methods: We retrospectively analyzed adult patients at USC Norris Cancer Hospital (age ≥ 18) who received allo-HSCT from 2018 to 2020. Recipients who were CMV positive, received T-cell depleting therapies such as PTCy for GVHD prophylaxis and/or ATG in the conditioning regimen, and those who fulfilled the criteria in Marty et al. 2017 were categorized as high-risk. Patients were considered to have CMV reactivation if they had clinically significant serum CMV viremia or organ involvement by day+100. Letermovir was initiated on day+21 for high-risk patients. The primary end-point assessed was day+100 CMV reactivation. Secondary end-points included 1-year OS, 1-year RFS, 1-year transplant-related mortality (TRM), and 1-year GRFS, defined as grade 3-4 acute GVHD, systemic therapy-requiring chronic GVHD, relapse, or death in the 1-year post-HSCT period. Results: A total of 116 adult HSCT recipients were reviewed. 51% were male and 49% were female. The donor sources comprised of 27% match related, 28% match-unrelated, and 49% haplo-identical. Most common diseases included AML (38%), ALL (38%) and MDS (8%). 64% received myeloablative conditioning regimens while 36% received reduced intensity regimens. Furthermore, 92% of patients received peripheral blood with 8% receiving bone marrow. 70% of patients at time of transplant were in CR1 or had stable disease. 61% of patients received letermovir prophylaxis (n=71), all high-risk, and 39% did not (n=45). 13 high-risk patients did not receive letermovir due to insurance limitations and were included in the non-letermovir group. 85% (n =60) received T-cell depleting therapies in the letermovir group compared to 51% (n=23). 90% (n=64) were CMV positive in the letermovir group and 64% (n= 29) were positive in the non-letermovir group. Both groups were similar in regard to the incidence of GVHD. The only factors significantly associated with CMV reactivation were haplo-HSCT, CMV recipient positivity, use of PTCy as GVHD prophylaxis and/or ATG in conditioning regimen, risk status, and GVHD (p = 0.054, p = .017, p = 0.003, p = 0.050, and p = 0.024 respectively). In a subset analysis of all high-risk patients, CMV reactivation was 32% in the letermovir group and 69% in the non-letermovir group (p = 0.03). All other factors were not significantly associated with outcomes. CMV reactivation in the letermovir group was (32%) compared to the non-letermovir group (29%). 1-year OS, 1-year TRM, 1-year RFS, and 1-year GRFS were 85%, 13.2%, 87%, and 60% respectively in the letermovir group compared with 88%, 10%, 90%, and 56% in the non-letermovir group, though not statistically significant. Discussion: Our study confirms improved CMV reactivation outcomes with use of letermovir in high-risk patients. Furthermore, all end-points were similar between both groups, despite increased usage of myeloablative conditioning overall and more high-risk patients in the letermovir group, indicating improved 1-year OS, TRM, and GRFS compared with historical outcomes. Although the primary and secondary end-points were not statistically significant, it may be clinically meaningful, as our center has demonstrated similar outcomes amongst those who were high-risk and received letermovir and those who were low-risk and did not. This suggests broadened use of letermovir may be needed in the prevention of CMV reactivation and the improvement in overall outcomes. Further studies using letermovir in low risk patients may be necessary to investigate improved outcomes in the allo-HSCT setting. Disclosures Yaghmour: Jazz: Consultancy, Speakers Bureau; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Agios: Consultancy, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Astellas: Consultancy, Speakers Bureau; Alexion: Consultancy, Speakers Bureau.

High Dose Intensive Chemotherapy, as Is Standard in Childhood Leukemia, Is Feasible and Efficacious in Adult Patients with Acute Lymphoblastic Leukemia (ALL) up to the Age of 40: Results From the Dutch-Belgian HOVON-70 Study.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 323-323 ◽  
Author(s):  
A. W Rijneveld ◽  
B. van der Holt ◽  
S. M. G. J. Daenen ◽  
B. J. Biemond ◽  
A. A van de Loosdrecht ◽  
...  
Keyword(s):  
Stem Cell ◽  
High Risk ◽  
Treatment Regimen ◽  
Adult Patients ◽  
Phase Iii ◽  
Cell Phenotype ◽  
High Dose ◽  
Event Free Survival ◽  
Free Survival ◽  
Risk Patients

Abstract Abstract 323 Event-free survival (EFS) at 5 years in pediatric ALL is > 80% with dose intensive multi-agent chemotherapy. In contrast, adult ALL still has an unsatisfactory outcome, which may partly be due to less cumulative dosing of chemotherapeutic agents and less strict adherence to timing of successive cycles of chemotherapy. Given the earlier reported feasibility of pediatric schedules in adolescent patients, the HOVON group performed a prospective multicenter phase II trial to evaluate the feasibility and efficacy of an intensified treatment regimen in adult patients with newly diagnosed ALL aged 18–40 years. The treatment regimen was based on the French FRALLE-2000 protocol, including dose intensification for steroids, vincristine, L-asparaginase, and high dose methotrexate (MTX). Fifty-four patients, median age 26 years (range 17–39) were enrolled in 15 centres in the Netherlands and Belgium between December 2005 and August 2007. After a prednisolon prephase and a multidrug remission-induction (prednisolon, daunorubicin, vincristine, cyclophosphamide and L-asparaginase), patients received consolidation containing 5000 mg/m2 MTX twice, two intensifications with intensified L-asparaginase, interspersed by an interphase with again two times high dose MTX, and maintenance chemotherapy (oral MTX and 6-mercaptopurine (6-MP) with reinduction with vincristine and prednisolon) for two years. CNS prophylaxis with MTX was delivered intrathecally 18 times. Standard risk patients with an HLA-identical sibling stem cell donor proceeded to allogeneic stem cell transplantation (alloSCT) after the first intensification, high risk patients received alloSCT from either sibling or unrelated donors. Adherence to the treatment schedule was urged by defining a strict timetable. Feasibility was defined by completion of chemotherapeutic and alloSCT protocol treatment within this a pre-defined timeframe. Thirty-five patients (65%) had B-cell phenotype ALL, 17 (31%) had T-cell phenotype and 2 (4%) had biphenotypic leukemia. Moreover, 23 patients (43%) had high risk disease, of whom 9 patients with BCR-ABL positive ALL. In total 33 patients fully completed treatment as scheduled, including 18 alloSCT recipients. Complete remission (CR) was achieved in 91% (95% CI: 80–97). After a median follow-up of 26 months (range 15–36 months), 2-year event-free-survival (EFS) is 68% (95% CI: 53–78), 2-year disease free survival (DFS) 74% (95% CI: 59–84) and the 2-year overall survival (OS) 70% (95% CI: 55–81). Fifteen patients (28%) died, including 8 due to relapsed/refractory ALL, 3 due to infection, 3 due to toxicity and 1 due to graft versus host disease. CTC grade 4-5 toxicities (mainly liver/kidney function abnormalities and peripheral neuropathy) were observed in 15% during induction and 13% during consolidation. Severe infections (CTC grade 3-4) primarily occurred during induction (41%) and consolidation (39%). Failures were due to not reaching CR in 5 patients, early relapse in 2, severe extramedullary drug toxicity in 3, excessive delay in 7 and other reasons not otherwise specified (but most likely due to toxicity) in 4 patients. In conclusion, these data show that a dose-intensified chemotherapeutic regimen based on a pediatric schedule is safe and feasible in most adult ALL patients up to the age of 40, although a delay of subsequent cycles was frequently observed. Early efficacy data suggest a high CR rate and favourable DFS and OS. Based on this experience, a randomised phase III trial has recently been initiated. This trial was supported by the Dutch Cancer Foundation (CKTO 2005-08), EudraCT number 2005-000919-96 Disclosures: No relevant conflicts of interest to declare.

Sign in / Sign up

Export Citation Format

Share Document