Higher Leukemia Free Survival after Post-Induction Hematopoietic Cell Transplantation Compared to Consolidation Therapy in Patients >60 Years with Acute Myelogenous Leukemia (AML): Report from the AML 2004 East German Study Group (OSHO)

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 280-280 ◽  
Author(s):  
Dietger Niederwieser ◽  
Haifa Kathrin Al-Ali ◽  
Rainer Krahl ◽  
Christoph Kahl ◽  
Hans-Heinrich Wolf ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
High Risk ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Normal Karyotype ◽  
Mutation Status ◽  
Free Survival ◽  
Flt3 Mutation ◽  
Unrelated Donors ◽  
The Difference

Abstract Treatment of elderly patients with AML remains challenging. While increasing doses of induction and consolidation chemotherapy have failed to improve outcome, efforts to decrease relapse rates using the graft-versus-leukemia effect have shown promising results in phase II studies. In the present analysis of the prospective OSHO 2004 study we evaluated the effect of post-induction hematopoietic cell transplantation (HCT) in comparison to conventional consolidation chemotherapy (CT) on outcome in elderly patients with AML. The OSHO 2004 study is part of the German intergroup study. Upon achieving complete remission (CR) after induction, patients were assigned to CT or HCT depending on the availability of a matched related or unrelated donor. Unrelated, single antigen mismatched donors were accepted in high risk situations. By April 2014 from 817 eligible patients, 505 entered CR (62%) after one or two induction therapies. From the 452 patients who received consolidation in CR 1, 31 patients (7%) relapsed and 10 (2%) died of complications during consolidation. No further therapy for medical reasons was given to 73 patients, 206 patients received second consolidation with cytarabine (0.5 g/m2 i.v. bid d1, 3, 5) plus mitoxantrone (10 mg/m² d1-2) and 132 patients underwent HCT. Most frequent conditioning regimens for HCT were low dose TBI (83%) and treosulfan/fludarabine (12%). Most of the patients received HCT from unrelated (80%) donors and the majority received grafts from HLA-identical (78%) donors. Our analysis was restricted to the 315 patients <75 years receiving either CT or HCT. Probabilities for overall survival (OS) and leukemia free survival (LFS) were estimated according to the Kaplan-Meier method and differences tested by the log-rank test. Relapse incidence (RI) and non relapse mortality (NRM) were described by estimating the cumulative incidence and testing the differences using the Gray's test. Multivariate Cox regression models and competing risks regression models were used to identify independent prognostic variables for outcomes. The median age was 67 (60-74) and 65 (60-74) years in the CT and the HCT groups (p<0.0005), respectively. There were no differences between CT and HCT regarding gender, AML type (de novo, secondary or therapy related) and FLT3 mutation status. However more patients with mutated NPM1 were observed in the CT as compared to the HCT group (39% vs 28%; p=0.07) and more patients entered into remission after one induction in the CT as compared to the HCT group (89% vs. 81%; p=0.05). Low risk cytogenetics and normal karyotype were present more frequently in the CT than in the HCT arm (p<0.0005). The interval from CR to CT was 50 days and from CR to HCT 72 days (p<0.0005). Patients receiving related or unrelated matched/mismatched HCT had superior LFS than those receiving CT (32±5% vs. 13±4% at 8 years, respectively; p<0.0005). The difference was more distinct when only those patients with matched related or unrelated donors were compared to those receiving CT (36±6% vs. 13±4% at 8 years; p<0.0005). Similar figures were obtained for overall survival [OS, 35±5% matched/mismatched HCT vs. 24±4% for CT (p=0.18) and 41±6% for matched HCT patients vs. 24±4% for CT (p=0.09)]. RI was lower after HCT (40±5%) than after CT (79±5%; p<0.0001). In contrast, NRM was higher in HCT patients (28±7%) than in CT patients (9±11%; p<0.0001). Subpopulation analyses identified no difference in LFS and OS between matched related versus unrelated HCT. The difference in LFS between HCT and CT was highest in patients with normal karyotype, high risk cytogenetics and patients with non-monosomal karyotyp. Prognostic factors for LFS, OS, RI and NRM were analyzed in a multivariate analysis. Significant prognostic factors for LFS were cytogenetic risk (p=0.04), HCT (p=0.01) and FLT3 mutation status (p=0.07). OS was determined by cytogenetics p<0.01) with a trend for lower age (p=0.07) and HCT (p=0.14). Prognostic factors for RI were cytogenetics (p< 0.0006), FLT3 mutation status (p<0.03) and HCT (p<0.0005). NRM was influenced by HCT (p=0.002). Conclusions: HCT from related or unrelated donors improved LFS and OS in patients with AML over the age of 60 years and in particular in those with high risk cytogenetics or normal karyotype disease. The LFS of over 30% after 8 years achieved by HCT represents a marked improvement in the prognosis of patients with AML aged 60-75 years in CR1. Disclosures Al-Ali: Novartis: Consultancy, Honoraria, Research Funding; Celgene: Honoraria, Research Funding. Wolf:Bayer: Honoraria; Geo Pharma: Honoraria. Hochhaus:ARIAD Pharmaceuticals, Inc.: Research Funding. Maschmeyer:Celgene: Consultancy.

Donor Type, Chronic Gvhd Subtype , and the Severity of Chronic Gvhd at the Time of Initiation of Chronic Gvhd Treatment Affect Failure-Free Survival in the Patients with Chronic Gvhd

Blood ◽  
2015 ◽  
Vol 126 (23) ◽  
pp. 3139-3139
Author(s):  
Jieun Uhm ◽  
Elizabeth Shin ◽  
Marc Poch Martell ◽  
Fotios V. Michelis ◽  
Auro Viswabandya ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Prognostic Factors ◽  
High Risk ◽  
Research Funding ◽  
Chronic Gvhd ◽  
Overlap Syndrome ◽  
Unrelated Donor ◽  
Free Survival ◽  
Unrelated Donors ◽  
Severe Grade

Abstract Introduction: Chronic graft versus host disease (cGVHD) is one of the major complications after allogeneic hematopoietic cell transplantation (allo-HCT). Several prognostic factors have been proposed to predict the outcomes of cGVHD including progressive type onset, extensive skin involvement, thrombocytopenia and NIH global score (NIH GS). Most studies have been focusing on the factors at the diagnosis of cGVHD without consideration of baseline characteristics prior to allo-HCT. We attempted to evaluate the prognostic factors for the outcomes of cGVHD treatment including the characteristics at the start of cGVHD treatment as well as prior to HCT. Method: We retrospectively reviewed 668 consecutive patients who underwent allo-HCT between 2004 and 2012 at the Princess Margaret Cancer Centre, Toronto, Canada, among whom 277 patients diagnosed as cGVHD and received systemic corticosteroids as a frontline cGVHD therapy. Chronic GVHD was classified and graded using the NIH consensus criteria. We evaluated non-relapse mortality (NRM), relapse and failure-free survival (FFS). FFS was defined as time to a switch in systemic therapy, NRM or relapse. The Kaplan-Meier method was used for FFS. The cumulative incidences of NRM, relapse and the treatment switch (TS) were calculated considering competing risks. Multivariate analysis was performed using the Cox proportional hazard regression model for FFS. Results: With a median follow-up duration of 26 months, the median time from HCT to cGVHD treatment was 183 days (range, 61-828). 102 patients (36.8%) were classified as classical cGVHD and 175 (63.2%) as overlap syndrome. At the start of cGVHD treatment 25 patients (9.0%) had mild cGVHD by the NIH GS, 189 (68.2%) moderate and 63 (22.7%) severe. Median age at allo-HCT was 51 year-old (range, 19-70). 162 patients (58.5%) were males and 65 (23.5%) patients were gender match of female donor to male recipient. 257 patients (92.8%) received peripheral blood stem cells (PBSC).175 grafts (63.2%) were from matched sibling donors (MSD). 180 patients (65%) received myeloablative conditioning. GVHD prophylaxis was calcineurin inhibitor (CNI) and methotrexate (n=82, 29.6%), CNI and mycophenolate mofetil (n=141, 50.9%), CNI and T-cell depletion (n=37, 13.5%) or others (n=17, 6.1%). The median FFS was 255 days (95% CI, 218-321). The severity of cGVHD, NIH GS correlated with FFS: median FFS was 164 days in severe vs 238 days in moderate vs 304 days in mild (p=0.001). The overlap syndrome was associated with a shorter FFS than classical cGVHD (223 vs 329 days, p=0.015). Patients receiving MSD graft showed longer FFS (329 days) than unrelated donor (196 days; p=0.004). The cumulative incidence of TS was 47.7% at 1 year. The NRM was 7.1% and relapse rate was 6.8% at 1 year. The MSD was associated with a lower 1-year NRM than the unrelated donors (4.2% vs 12.3%, p=0.003) while no difference between 2 groups for TS (p=0.731) or relapse at 1 year (p=0.565). Patients with overlap syndrome had higher NRM at 1 year than with classical cGVHD (10.0% vs 2.2%, p=0.009), but no differences in TS or relapse at 1 year (p=0.167 and p=0.138). Chronic GVHD severity by NIH GS showed a significant correlation with TS (28% in mild, 51.9% in moderate, and 43.8% in severe grade at 1 year, p=0.02) and NRM (4% in mild, 3.6% in moderate, and 19.1% in severe grade at 1 year, p<0.001), but with relapse (p=0.784). Multivariate analysis for FFS confirmed that the use of unrelated donor showed a worse FFS (hazard ratio (HR) 1.660, p=0.001). FFS was also associated with the severity of cGVHD, NCC GS (mild vs moderate vs severe; HR 1 vs 2.1 vs 2.9, p=0.002) and the cGVHD subtype (classical vs overlap, HR 1 vs 1.39, p=0.028). We then assigned score 0 for NIH GS mild, 1 for moderate, and 2 for severe; for NIH subtype, score 0 for classical and 1 for overlap; for donor types, score 0 for MSD and 1 for unrelated donors. After summation of the scores, we regrouped them into low (score 0, n=11, 3.9%), intermediate (score 1-2, n=168, 60.6%), and high risk groups (score 3-4, n=98, 35.3%). The risk stratification model correlated nicely with FFS (FFS duration, 1977 days in low vs 341 days in intermediate, and 150 days in high risk group, p<0.001). Conclusion: the use of unrelated donor, overlap subtype of chronic GVHD and severe grade of chronic GVHD at the time of initiation of chronic GVHD treatment affect adversely on failure-free survival. Disclosures Kim: Novartis Pharmaceuticals: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding.

scholarly journals Primary Plasma Cell Leukemia Outcomes Remain Dismal Despite Novel Agents and Hematopoietic Cell Transplantation

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 266-266
Author(s):  
Sagar Patel ◽  
Saulius K. Girnius ◽  
Binod Dhakal ◽  
Lohith Gowda ◽  
Raphael Fraser ◽  
...  
Keyword(s):  
High Risk ◽  
Board Of Directors ◽  
Plasma Cell ◽  
Research Funding ◽  
Hematopoietic Cell Transplantation ◽  
Disease Status ◽  
Cell Leukemia ◽  
Advisory Committees ◽  
Primary Plasma Cell Leukemia ◽  
Equity Ownership

Background Primary plasma cell leukemia (pPCL) is a rare plasma cell neoplasm with a high mortality rate. There have been improvements in multiple myeloma (MM) outcomes with novel induction agents and use of hematopoietic cell transplantation (HCT) with maintenance, but similar progress has not been reported for pPCL. We examined the outcomes of pPCL patients receiving novel agents with autologous (autoHCT) or allogeneic (alloHCT) approaches as reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) in the modern era. Methods From 2008 to 2015, 348 pPCL pts underwent HCT (N = 277 - autoHCT and 71 - alloHCT) with 45% and 48% having research level data available, respectively. Cumulative incidences of non-relapse mortality (NRM) and relapse/progression (REL), and probability of progression-free survival (PFS) and overall survival (OS) were calculated. Cox multivariate regression was used to model survival after autoHCT only. Median follow-up in autoHCT and alloHCT was 48 and 60 months, respectively. Results AutoHCT Cohort Median age was 60 years and 93% received HCT within 12 months of diagnosis with 76% after a single line of induction (Table 1). 35% had high risk cytogenetics. 23% received bortezomib, doxorubicin, cisplatin, cyclophosphamide, and etoposide (VDPACE). Moreover, 40% received bortezomib (BTZ) and immunomodulatory drug (IMIID)-based triplets. Disease status at HCT was VGPR or better in 47%. 27% received maintenance therapy. At 4 years post-HCT, NRM was 7% (4-11%), REL 76% (69-82%), PFS 17% (13-23%), and OS 28% (22-35%) (Figures 1A, 2A, 2B). Disease status ≥VGPR at HCT and Karnofsky Performance Score &gt;90 significantly predicted superior OS in multivariate analysis. AlloHCT Cohort Median age was 53 years and 89% received HCT within 12 months of diagnosis (Table 1). 61% received a single alloHCT, while 39% used auto-alloHCT tandem approach. 42% had high-risk cytogenetics. 61% received total body irradiation with 44% receiving myeloablative conditioning. Use of VDPACE was higher at 41% in this cohort. VGPR status at HCT was similar (48%), while maintenance was used less often (12%). Grade II-IV acute GVHD occurred in 30% and chronic GVHD in 45%. At four years post-HCT, NRM was 12% (5-21%), REL 69% (56-81%), PFS 19% (10-31%), and OS 31% (19-44%) (Figures 1A, 1B, 2A, 2B). There were no differences in outcomes based on type of HCT. A comparison of post-HCT outcomes of CIBMTR pPCL patients from 1995 to 2006 showed that PFS and OS outcomes are inferior despite lower NRM in this modern cohort (Mahindra et al. Leukemia. 2012). In addition, analysis of SEER (1995-2009) and CIBMTR databases showed that use of HCT increased from 12% (7-21%) in 1995 to 46% (34-64%) in 2009. Conclusion More newly diagnosed pPCL patients are receiving modern induction regimens translating into a higher proportion receiving HCT, but without significant further benefit post-HCT. Post-HCT relapse remains the biggest challenge and further survival in pPCL will likely need a combination of targeted and cell therapy approaches. This study provides a benchmark for future HCT studies for pPCL. Disclosures Girnius: Takeda: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Dhakal:Takeda: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Honoraria. Shah:University of California, San Francisco: Employment; Indapta Therapeutics: Equity Ownership; Genentech, Seattle Genetics, Oncopeptides, Karoypharm, Surface Oncology, Precision biosciences GSK, Nektar, Amgen, Indapta Therapeutics, Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene, Janssen, Bluebird Bio, Sutro Biopharma: Research Funding; Poseida: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Nkarta: Consultancy, Membership on an entity's Board of Directors or advisory committees; Kite: Consultancy, Membership on an entity's Board of Directors or advisory committees; Teneobio: Consultancy, Membership on an entity's Board of Directors or advisory committees. Qazilbash:Amgen: Consultancy, Other: Advisory Board; Bioclinical: Consultancy; Autolus: Consultancy; Genzyme: Other: Speaker. Kumar:Celgene: Consultancy, Research Funding; Takeda: Research Funding; Janssen: Consultancy, Research Funding. D'Souza:EDO-Mundapharma, Merck, Prothena, Sanofi, TeneoBio: Research Funding; Prothena: Consultancy; Pfizer, Imbrium, Akcea: Membership on an entity's Board of Directors or advisory committees. Hari:BMS: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Janssen: Consultancy, Honoraria; Kite: Consultancy, Honoraria; Amgen: Research Funding; Spectrum: Consultancy, Research Funding; Sanofi: Honoraria, Research Funding; Cell Vault: Equity Ownership; AbbVie: Consultancy, Honoraria.

scholarly journals BMT CTN 1803: Haploidentical Natural Killer Cells (CSTD002) to Prevent Post-Transplant Relapse in AML and MDS (NK-REALM)

Blood ◽  
2019 ◽  
Vol 134 (Supplement_1) ◽  
pp. 1955-1955
Author(s):  
Sumithira Vasu ◽  
Nelli Bejanyan ◽  
Steven Devine ◽  
Elizabeth Krakow ◽  
Elizabeth Krakow ◽  
...  
Keyword(s):  
High Risk ◽  
Nk Cells ◽  
Cumulative Incidence ◽  
Research Funding ◽  
Nk Cell ◽  
Ex Vivo ◽  
Marrow Transplant ◽  
Free Survival ◽  
Blood And Marrow Transplant ◽  
Relapse Rates

Background and Rationale: Relapse remains the leading cause of treatment failure for patients with high-risk acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) undergoing allogeneic blood or marrow transplantation (BMT). Although relapse rates vary based on patient population, age, and conditioning intensity, relapse is experienced in at least 30-50% after conventional BMT in high-risk AML/MDS. Initial safety and post-BMT relapse risk reduction results are reported by investigators at MD Anderson Cancer Center in a phase I study of ex vivo-expanded, donor-derived, haploidentical natural killer (NK)-cell infusion in conjunction with haploBMT. Of 13 patients with high-risk myeloid malignancies treated with NK cells, no infusion reactions or dose-limiting toxicities occurred and only 1 patient, treated at the lowest dose of 1×105 cells/kg, relapsed (Ciurea, Blood 2017). This experience supports investigation of CSTD002, a product derived from haploidentical donor NK cells and expanded ex vivo using plasma membrane (PM21) nanoparticles bearing membrane-bound IL-21 and 4-1BBL. This study represents a public-private partnership between the sponsor (Kiadis Pharma) and the Blood and Marrow Transplant Clinical Trials Network (BMT CTN), leveraging existing National Institutes of Health-supported clinical trials infrastructure to conduct a complex cellular immunotherapy trial. We used contemporary, unpublished data from the Center for International Blood and Marrow Transplant Research registry to determine baseline relapse rates that informed the statistical design. Doses of NK cells expanded by a novel method and exceeding those previously achieved in most published studies will be given in the peri-transplant period to test the hypothesis that haploidentical NK cells can mediate an effective anti-leukemia response. Trial Design and Methods: BMT CTN 1803 is a phase II, single-arm, open-label, multicenter trial designed to investigate the safety and efficacy of CSTD002 for the treatment of patients with high-risk AML or MDS undergoing haploBMT. An initial safety run-in phase will precede enrollment into the full study of approximately 60 patients. Major inclusion criteria of patients and donors are listed in the Table. Peripheral blood will be drawn from the donor to start the NK-cell expansion approximately 5 weeks before the planned haploBMT. Patients will receive intravenous (IV) melphalan 140 mg/m2 (100 mg/m2 for patients ≥60 years old) on Day -7; fludarabine 40 mg/m2 IV on Days -7, -6, -5, and -4; and 2 Gy of total body irradiation on Day -3. Donor bone marrow will be harvested and given on Day 0. Three doses of CSTD002 will be administered IV on Days -2, +7, and +28, relative to the haploBMT. The recommended dose of CSTD002 for administration will be formulated at 1×108 NK cells/kg of recipient body weight. Graft-versus-host disease (GVHD) prophylaxis is post-transplantation cyclophosphamide with tacrolimus and mycophenolate mofetil. The primary endpoint is cumulative incidence of relapse at 1 year post haploBMT in patients receiving at least 1 infusion of CSTD002. Secondary endpoints are safety and tolerability of CSTD002; overall survival; non-relapse mortality; relapse-free survival; GVHD-free survival; cumulative incidence of acute GVHD and chronic GVHD; hematologic recovery; donor-cell engraftment; primary and secondary graft failure; overall incidence of toxicity; and cumulative incidence of infections including cytomegalovirus re-activation and symptomatic BK virus hemorrhagic cystitis. Exploratory endpoints are systemic immunosuppression-free survival; immune reconstitution at Days 28, 100, and 365 post haploBMT; proportion of patients with detectable minimal residual disease at Days 28 and 100 post haploBMT; feasibility of administering the planned CSTD002 doses; and impact of NK-cell alloreactivity on relapse and survival. Disclosures Vasu: Boehringer Ingelheim: Other: Travel support; Seattle Genetics: Other: Clinical trial support. Bejanyan:Kiadis Pharma: Other: advisory board. Devine:Kiadis Pharma: Other: Protocol development (via institution); Magenta Therapeutics: Other: Travel support for advisory board; My employer (National Marrow Donor Program) has equity interest in Magenta; Bristol Myers: Other: Grant for monitoring support & travel support. Krakow:Bellicum Pharmaceuticals: Research Funding; Highpass Bio: Research Funding; Magnolia Innovations: Other: Personal fees. Logan:Eisai: Other: Personal fees; Astellas: Other: Grant; Kiadis (formerly Cytosen): Other: Grant; Novartis: Other: Personal fees; Kite: Other: Grant. Luznik:Merck: Research Funding, Speakers Bureau; Genentech: Research Funding; AbbVie: Consultancy; WindMiL Therapeutics: Patents & Royalties: Patent holder. Barrett:Kiadis Pharma (formerly Cytosen): Other: Personal fees; Biologics Consulting Company: Other: Personal fees. Shan:Kiadis Pharma (formerly Cytosen): Employment. Champlin:Actinium: Consultancy; Johnson and Johnson: Consultancy; Sanofi-Genzyme: Research Funding.

Clinical stages I and II Hodgkin's disease: a specifically tailored therapy according to prognostic factors.

1988 ◽  
Vol 6 (2) ◽  
pp. 239-252 ◽  
Author(s):  
P Carde ◽  
J M Burgers ◽  
M Henry-Amar ◽  
M Hayat ◽  
W Sizoo ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
Hodgkin's Disease ◽  
Hodgkin’S Disease ◽  
Clinical Stage ◽  
European Organization ◽  
Free Survival ◽  
Negative Laparotomy ◽  
Extended Field ◽  
The Difference ◽  
Better Than

The H5 program in clinical stage (CS) I to II supradiaphragmatic Hodgkin's disease (HD) was tailored to prognostic factors identified in former European Organization for the Research and Treatment of Cancer (EORTC) studies. Among the 494 adult patients included in the study, the 237 patients belonging to the favorable group (H5F) underwent a staging laparotomy (Sx) in order to select the patients who could be treated with limited radiotherapy (RT) only. Thus, 198 patients (84%) with negative laparotomy were treated with RT alone and randomized to either mantle irradiation (M) or extended field mantle plus para-aortic (M + PA) irradiation. Complete remission (CR) was achieved in 99% of the patients. There was no difference in the 6-year relapse-free survival (RFS) rate (74% and 72%, respectively) or survival rate (96% and 89%). Therefore, Sx helped to define those patients who could be treated with M alone in contrast to those who required more aggressive therapy. The 39 patients with positive laparotomy were treated as the unfavorable group (H5U) from onset and randomized to either total/subtotal nodal irradiation (TNI/STNI) or a sandwiched mechlorethamine, vincristine, procarbazine, and prednisone (MOPP) X 3, M irradiation, MOPP X 3 protocol (3M). Although the RFS rate was higher in the 3M arm (100% v 53%; P = .002), the 6-year survival was not significantly different between the two arms (overall, 92%). In the 257 patients with initial unfavorable disease, the Sx was avoided. They were randomized to either TNI/STNI or 3M. In complete responders (96%), the 6-year RFS was 91% in the 3M arm and 77% in the TNI/STNI arm (P = .02). The pattern of failure differed in the two arms: the inverted Y and spleen irradiation controlled occult infradiaphragmatic disease better than MOPP; conversely, less patients begun on MOPP recurred in the involved mantle areas. The difference in 6-year actuarial total survival (TS) (89% and 82%; P = .05 in favor of the 3M arm) was not retrieved after exclusion of the unrelated deaths from the analysis. The two arms produced similar TS in patients under 40 years of age. TNI retains interest, especially in young men wishing to preserve fertility. The overall result shows that when treatment is tailored to initial prognostic factors, excellent results can be obtained in all patient subgroups at minimal morbidity and toxic cost.

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.

The Clinical Usefulness of Novel Prognostic Factors in CLL: A Study of 477 Patients with Low-Risk (Non-11q, Non-17p) FISH and Known IGVH Mutation Status.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3079-3079 ◽  
Author(s):  
Constantine S. Tam ◽  
Michael J. Keating ◽  
Apostolia M. Tsimberidou ◽  
Susan O’Brien ◽  
Alessandra Tsimberidou ◽  
...  
Keyword(s):  
Prognostic Factors ◽  
High Risk ◽  
Hazard Ratio ◽  
Low Risk ◽  
P Value ◽  
Mutation Status ◽  
Trisomy 12 ◽  
The Impact ◽  
Standard Risk ◽  
Active Disease

Abstract In order to develop integrated models utilizing commonly available prognostic factors, we studied the clinical signficance of IGVH mutation, CD38 and ZAP-70 in 477 CLL patients (pts) with low-risk (non-11q, non-17p) FISH findings. All pts were untreated at the time of FISH assessment, and were collected prospectively in the MD Anderson CLL database. Two hundred & fifteen pts (45%) had mono- (n=160) or bi-alleleic (n=55) deletion of 13q {DEL13Q}, 162 pts (34%) had a negative FISH panel {NEG}, and 100 pts (21%) had trisomy 12 as sole FISH abnormality (n=78) or in association with deletion 13q (n=22) {T12}. Compared to other FISH groups, DEL13Q pts had lower B2m (median 2.2 v 2.6mg/L, p=0.01) and were less likely to be IGVH unmutated (33% v 48%, p=0.001). In contrast, T12 pts were more likely to present with advanced stage disease (Rai≥2 36% v 23%, p=0.01), be CD38 positive (44% v 13%, p<0.001), and have karyotypic abnormalities (48% v 7%, p<0.001). One hundred and twenty-three pts had active disease requiring immediate therapy and 354 pts had stable disease, of whom 291 were evaluable for disease progression. At a median follow-up of 20 months, 73 pts had developed active disease with NCI-WG indication(s) for treatment. Actuarial 2 year time to treatment (TTT) was 26%, with no significant difference between 13q, NEG and T12 pts (p=0.27). TTT was associated with elevated B2m (≥1.5ULN), IGVH mutation status and ZAP-70 in DEL13Q and NEG pts, but not in T12 patients (Table). For DEL13Q/NEG pts, a simple model using IGVH mutation and B2m separated high risk pts (unmutated or high B2m, 2yr TTT 43%) from standard risk pts (mutated and low B2m, 2yr TTT 11%, p<0.0001). For T12 pts, a model based on CD38 positivity and karyotypic abnormalities separated high risk pts (2 factors, 2yr TTT 75%) from standard risk pts (0 or 1 factor, 2yr TTT 15%, p=0.008). These results show that the impact of prognostic factors on TTT is dependent on the underlying FISH karyotype, and underscores the need for future studies in CLL prognostic factors to take into account the complete risk profile of the pt. NEGATIVE FISH DELETION 13Q TRISOMY 12 p-value hazard ratio p-value hazard ratio p-value hazard ratio IGVH Mutation <0.001 8.0 0.003 2.9 0.97 0.98 B2m ≥1.5ULN <0.001 4.5 0.07 2.2 0.54 0.68 CD38 Positivity 0.05 2.5 0.05 2.4 0.06 7.4 Abn Cytogenetics <0.001 11.0 0.27 2.2 0.09 2.8 ZAP-70 0.02 2.9 0.007 3.1 0.70 1.3 Figure Figure Figure Figure

Complex Karyotypic Abnormalities Detected by Conventional Cytogenetic Analysis More Strongly Predict Survival Than FISH, ZAP70, or IgVH Mutation Status for Previously Treated Patients with CLL.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 2065-2065
Author(s):  
William G. Wierda ◽  
S. O’Brien ◽  
S. Faderl ◽  
A. Ferrajoli ◽  
G. Garcia-Manero ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Prognostic Factors ◽  
High Risk ◽  
Cytogenetic Analysis ◽  
Independent Predictor ◽  
Alkylating Agents ◽  
Mutation Status ◽  
Conventional Cytogenetic Analysis ◽  
Previously Treated Patients ◽  
Previously Treated

Abstract Recently, several novel prognostic factors have been identified; their significance has been demonstrated in selected patient (pt) populations and retrospective analyses. As a group, previously treated pts with CLL likely have their respective, relevant prognostic factors for clinical endpoints, which may be further impacted by treatment (Rx). We prospectively evaluated the significance of newer prognostic factors: FISH abnormalities (abn) (Vysis CLL panel), IgVH mutation status, ZAP70 expression (flow & immunohistochemistry), CD38 expression (≥30%); as well as traditional factors: conventional cytogenetic analysis perfomed on bone marrow metaphases, age, sex, # prior Rx, refractoriness to alkylating agents (ALK) or fludarabine (FLU), absolute lymphocyte count (ALC), HGB, PLT, β-2 microglobulin (B2M), ALB, LDH, creatinine, and Alk Phos as independent predictors for survival in previously treated pts. The group included 473 previously treated pts seen at M.D.Anderson (10/03–8/07), who were evaluated by bone marrow sampling with conventional and FISH cytogenetic analyses, and the new and traditional prognostic factors described above. The median (range) age was 63yrs(31–87) and # prior Rx was 2(1–13). Other characteristics were: 43% Rai high-risk; 35% FLU-refractory; and 39% ALK-refractory; 74% unmutated IgVH; 54% ZAP70+ (flow); 76% ZAP70+ (IHC); and 68% CD38+. FISH results were: 22% del 17p13, 21% del 11q22, 10% +12, and 48% del 13q14 or no abn by the hierarchical classification. Conventional cytogenetic analysis of bone marrow metaphases demonstrated 25% with a complex karyotypic abn (&gt;1 cell with &gt;1 chromosome abn), 58% diploid, 17% with single clonal abn (&gt;1 cell with 1 abn). Of the 100 pts with complex karyotypic abn, 50% had del 17p13, 28% del 11q22, 6% +12, 9% del 13q14, and 7% had no abn by FISH. Survival was measured from the time of prognostic factor characterization (FISH). The median follow-up time was 10mo(0–47). Univariate analyses identified the following significant (p≤.01) predictors for shorter survival: advanced age, # prior Rx, Rai high-risk, ALK- or FLU-refractory, FISH del 17p13; complex karyotypic abn (Figure 1), unmutated IgVH, high ALC, low HGB, low PLT, high B2M, low ALB, high LDH, and high Alk Phos. Multivariate analysis produced the following model with the following significant (p&lt;.05) independent predictors for survival: ALK- (HR 2.2) or FLU-refractory (1.9), complex karyotypic abn (HR 1.8), PLT (HR 0.99), and ALB (HR 0.35). We previously reported complex karyotypic abn as a significant independent predictor for shorter survival in previously treated patients receiving chemoimmunotherapy (JCO23:4070, 2005). These data indicate that for previously treated pts with CLL, a complex karyotypic abn detected by conventional cytogenetic analysis is a strong independent predictor for survival and appears superior to FISH, and other newer prognostic factors such as IgVH mutation status and ZAP70 expression. Figure Figure

The Outcome in AML Is Predicted by Cytogenetics, NPM1/FLT3 Mutation, Age and Sex, but Not by Treatment Variables.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 593-593 ◽  
Author(s):  
Thomas Buchner ◽  
Wolfgang E. Berdel ◽  
Utz O. Krug ◽  
Torsten Haferlach ◽  
Claudia Haferlach ◽  
...  
Keyword(s):  
Predictive Factor ◽  
De Novo ◽  
Normal Karyotype ◽  
Prognostic Impact ◽  
Mutation Status ◽  
Younger Patients ◽  
Female Sex ◽  
Flt3 Mutation ◽  
Mutation Age ◽  
Age And Sex

Abstract In order to test current risk factors in a prospective multicenter setting we evaluated the AMLCG 99 trial. Patients were randomly assigned to induction by TAD-HAM (HAM with araC 3 for age <60y and 1 for age ≥60y g/m2 × 6), or HAM-HAM, and also to TAD consolidation and maintenance or (age <60y) myeloablative chemotherapy and autologous SCT. Patients with histocompatible family donors preferentially underwent allogeneic SCT. Since any randomization was done up-front, informations from completely unselected patients were available. 2547 patients of 16–85 (median 61) y entered the trial. 1858 pts had de-novo and 689 pts secondary AML. The CR rate was 61%, 54% in older (60) and 69% in younger patients. The overall survival (OS) at 4 years was 27%, 15% in older and 41% in younger patients. The relapse risk (RR) was 65%, 80% in older and 50% in younger patients and the relapse-free survival (RFS) was 30%, 14% and 44%, respectively. In the entire patients complete outcome (CR, OS, RR, RFS) was predicted by favorable and unfavorable karyotype. Among patients with any abnormal karyotype complete outcome was predicted by unfavorable karyotype in the older and favorable karyotype in the younger age group. In both age groups with normal karyotype outcome for the complete parameters was predicted by the NPM1+/FLT3- ITD- mutation status. As a new finding in patients of <60 years with normal karyotype female sex turned out being an independent predictive factor for longer OS (HR 1.45;95%CI 1.04–2.03), longer RFS (HR1.64;95%CI 1.10–2.44), and lower RR (HR 0.59;95%CI 0.38–0.92). Female sex was the only predictive factor besides the NPM1/FLT3 mutation status in this group. The OS at 4 years in patients of <60y with normal karyotype is 52% in women and 40% in men (log-rank P=0.047), the RR is 37% and 52% (P=0.016), and the RFS is 55% in women and 42% in men (P=0.025). Furthermore, the favorable NPM1+/FLT3- mutation status was more frequent in women than in men (35% vs 26%; P=0.0075). Remarkably, the NPM1+/FLT3- mutation status was equally predictive in patients of ≥60y as in those of <60y with HR for OS of 2.51 (95% CI 1.75–3.61) and 3.27 (95%CI 2.11–5.05) and HR for RR of 0.33 (95% C 0.21–0.51) and 0.29 (95%CI 0.17–0.49). The difference in the OS at 4 years between patients with NPM1+/FLT3- mutation and those with other NPM1/FLT3 combinations was 42% vs 18% (P=<0.001) in the older, and 69% vs 34% (P<0.001) in the younger patients. The related differences in RR were 58% vs 84% (P<0.001) in the older, and 22% vs 59% (P<0.001) in the younger patients. Among the NPM1/FLT3 mutations the favorable +/− constellation accounted for 27% of older, and 35% of younger patients (P=0.0197). Besides karyotypes and mutations, also age, de-novo AML, blast clearance, LDH and WBC partly predicted outcomes. In contrast no prognostic impact was found by multi-and univariate analyses of treatment alternatives. Conclusion: As from a large multicenter prospective trial the outcome in AML is mainly determined by cytogenetics, NPM1/FLT3 mutation, age and sex, but not by the assigned treatment variables.

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 ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 226-226 ◽  
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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