There are many therapies available for the management of low-grade lymphoma. With follicular lymphoma, for example, combination of chemotherapy and rituximab (immuno-chemotherapy) and consecutive ...maintenance therapy for 2 years is the current standard of care. To date, the most widely used regimen seems to be rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Substitution of liposomal doxorubicin in place of conventional doxorubicin may improve outcomes in this indication, although evidence for its use in low-grade lymphoma is not as relevant as in aggressive lymphoma. Bendamustine, in combination with rituximab, has shown very good efficacy and tolerability in several lymphoma types, particularly follicular lymphoma and other low-grade lymphomas. Other combinations, such as those including bortezomib and lenalidomide, are under investigation in low-grade lymphoma, and the duration of rituximab maintenance therapy following bendamustine-rituximab-containing induction is being researched by the German Study Group for Indolent Lymphoma (StiL).
Despite undergoing allogeneic hematopoietic stem cell transplantation (HCT), patients with acute myeloid leukemia (AML) with internal tandem duplication mutation in the
like tyrosine kinase 3 gene (
...ITD) have a poor prognosis, frequently relapse, and die as a result of AML. It is currently unknown whether a maintenance therapy using FLT3 inhibitors, such as the multitargeted tyrosine kinase inhibitor sorafenib, improves outcome after HCT.
In a randomized, placebo-controlled, double-blind phase II trial (SORMAIN; German Clinical Trials Register: DRKS00000591), 83 adult patients with
ITD-positive AML in complete hematologic remission after HCT were randomly assigned to receive for 24 months either the multitargeted and FLT3-kinase inhibitor sorafenib (n = 43) or placebo (n = 40 placebo). Relapse-free survival (RFS) was the primary endpoint of this trial. Relapse was defined as relapse or death, whatever occurred first.
With a median follow-up of 41.8 months, the hazard ratio (HR) for relapse or death in the sorafenib group versus placebo group was 0.39 (95% CI, 0.18 to 0.85; log-rank
= .013). The 24-month RFS probability was 53.3% (95% CI, 0.36 to 0.68) with placebo versus 85.0% (95% CI, 0.70 to 0.93) with sorafenib (HR, 0.256; 95% CI, 0.10 to 0.65; log-rank
= .002). Exploratory data show that patients with undetectable minimal residual disease (MRD) before HCT and those with detectable MRD after HCT derive the strongest benefit from sorafenib.
Sorafenib maintenance therapy reduces the risk of relapse and death after HCT for
ITD-positive AML.
Myelodysplastic syndromes (MDS) are hematopoietic disorders characterized by ineffective hematopoiesis and progression to acute leukemia. In patients ineligible for hematopoietic stem cell ...transplantation, azacitidine is the only treatment shown to prolong survival. However, with the availability of a growing compendium of cancer biomarkers and related drugs, analysis of relevant genetic alterations for individual MDS patients might become part of routine evaluation.
Therefore and in order to cover the entire bone marrow microenvironment involved in the pathogenesis of MDS, SNP array analysis and targeted next generation sequencing (tNGS) for the mostly therapy relevant 46 onco- and tumor-suppressor genes were performed on bone marrow biopsies from 29 MDS patients.
In addition to the detection of mutations known to be associated with MDS in NRAS, KRAS, MPL, NPM1, IDH1, PTPN11, APC and MET, single nucleotide variants so far unrelated to MDS in STK11 (n=1), KDR (n=3), ATM (n=1) and JAK3 (n=2) were identified. Moreover, a recurrent microdeletion was detected in Xq26.3 (n=2), causing loss of PHF6 expression, a potential tumor suppressor gene, and the miR-424, which is involved in the development of acute myeloid leukemia. Finally, combined genetic aberrations affecting the VEGF/VEGFR pathway were found in the majority of cases demonstrating the diversity of mutations affecting different nodes of a particular signaling network as an intrinsic feature in MDS patients.
We conclude that combined SNP array analyses and tNGS can identify established and novel therapy relevant genomic aberrations in MDS patients and track them in a clinical setting for individual therapy selection.
Patients with acute myeloid leukemia (AML) and a FLT3 internal tandem duplication (ITD) have poor outcomes to current treatment. A phase 2 hypothesis-generating trial was conducted to determine ...whether the addition of the multitargeted kinase inhibitor midostaurin to intensive chemotherapy followed by allogeneic hematopoietic cell transplantation (alloHCT) and single-agent maintenance therapy of 12 months is feasible and favorably influences event-free survival (EFS) compared with historical controls. Patients 18 to 70 years of age with newly diagnosed AML and centrally confirmed FLT3-ITD were eligible: 284 patients were treated, including 198 younger (18-60 years) and 86 older (61-70 years) patients. Complete remission (CR) rate, including CR with incomplete hematological recovery (CRi) after induction therapy, was 76.4% (younger, 75.8%; older, 77.9%). The majority of patients in CR/CRi proceeded to alloHCT (72.4%). Maintenance therapy was started in 97 patients (34%): 75 after alloHCT and 22 after consolidation with high-dose cytarabine (HiDAC). Median time receiving maintenance therapy was 9 months after alloHCT and 10.5 months after HiDAC; premature termination was mainly a result of nonrelapse causes (gastrointestinal toxicity and infections). EFS and overall survival at 2 years were 39% (95% confidence interval CI, 33%-47%) and 34% (95% CI, 24%-47%) and 53% (95% CI, 46%-61%) and 46% (95% CI, 35%-59%) in younger and older patients, respectively. EFS was evaluated in comparison with 415 historical controls treated within 5 prospective trials. Propensity score-weighted analysis revealed a significant improvement of EFS by midostaurin (hazard ratio HR, 0.58; 95% CI, 0.48-0.70; P < .001) overall and in older patients (HR, 0.42; 95% CI, 0.29-0.61). The study was registered at www.clinicaltrials.gov as #NCT01477606.
•Midostaurin plus intensive chemotherapy can be safely administered in older FLT3-ITD-positive patients with AML.•Compared with historical controls, midostaurin significantly improved event-free survival in older and younger FLT3-ITD positive patients with AML.
Summary
Objectives
Invasive fungal infections caused by Lomentospora prolificans are associated with very high mortality rates and can be challenging to treat given pan‐drug resistance to available ...antifungal agents. The objective of this study was to describe the clinical presentation and outcomes in a cohort of patients with invasive L prolificans infections.
Methods
We performed a retrospective review of medical records of patients with invasive L prolificans infection in the FungiScope® registry of rare invasive fungal infections. Patients diagnosed between 01 January 2008 and 09 September 2019 were included in for analysis.
Results
The analysis included 41 patients with invasive L prolificans infection from eight different countries. Haematological/oncological malignancies were the most frequent underlying disease (66%), disseminated infection was frequent (61%), and the lung was the most commonly involved organ (44%). Most infections (59%) were breakthrough infections. Progression/deterioration/treatment failure was observed in 23/40 (58%) of patients receiving antifungal therapy. In total, 21/41 (51%) patients, and 77% of patients with underlying haematological/oncological malignancy, had a fatal outcome attributed to invasive fungal infection. Combination antifungal therapy was frequent (24/40) and associated with improved survival. In particular, treatment regimens including terbinafine were significantly associated with higher treatment success at final assessment (P = .012), with a positive trend observed for treatment regimens that included voriconazole (P = .054).
Conclusions
Lomentospora prolificans infections were associated with mortality rates of 77% and above in patients with underlying haematological/oncological malignancies and those with disseminated infections. While combination therapy is the preferred option for now, the hope lies with novel antifungals currently under development.
There are many therapies available for the management of low-grade lymphoma. With follicular lymphoma, for example, combination of chemotherapy and rituximab (immuno-chemotherapy) and consecutive ...maintenance therapy for 2 years is the current standard of care. To date, the most widely used regimen seems to be rituximab combined with cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP). Substitution of liposomal doxorubicin in place of conventional doxorubicin may improve outcomes in this indication, although evidence for its use in low-grade lymphoma is not as relevant as in aggressive lymphoma. Bendamustine, in combination with rituximab, has shown very good efficacy and tolerability in several lymphoma types, particularly follicular lymphoma and other low-grade lymphomas. Other combinations, such as those including bortezomib and lenalidomide, are under investigation in low-grade lymphoma, and the duration of rituximab maintenance therapy following bendamustine-rituximab-containing induction is being researched by the German Study Group for Indolent Lymphoma (StiL).
Background:
The StiL NHL1-2003 trial demonstrated that Bendamustine-Rituximab (B-R) is a highly effective treatment for patients with WM achieving a median PFS of 69.5 months. Rituximab (R) ...maintenance is part of a standard treatment for follicular lymphoma. In WM, however, the role of R maintenance is unclear. In this study we compared the effect of 2 years R maintenance vs. observation after first-line treatment with B-R in patients with previously untreated WM.
Methods:
Patients needed to have advanced stage of disease with indication for treatment (e.g. B-symptoms, anemia, hyperviscosity syndrome, etc.). Primary endpoint was progression free survival (PFS). Secondary endpoints included response rates, overall survival (OS), and toxicity. All patients were treated with up to 6 cycles of B-R plus 2 additional R cycles. Only patients responding to B-R were randomized to either R maintenance (q 2 months for 2 years) or observation.
Results:
Of 293 registered patients, 5 were excluded due to lack of data and other reasons. Median time of follow-up was 70.2 months at the time of this analysis (July 2019). 257 of 288 patients with a median age of 67 years were evaluable for response evaluation. The median baseline value of IgM was 31.3 g/l, and of Hb 10.1 g/dl. Median PFS for all patients (intention to treat) was 78.0 months. The median OS was not yet reached, with an estimated 5-year-survival of 78%. A total of 38 secondary malignancies were recorded, with 1 AML during observation and 1 MDS in R maintenance. 235 patients (91.4%) responded to B-R induction, with the majority of patients (231, 89.9%) achieving a partial remission. Of 218 randomized patients, 109 (50%) were randomized to R maintenance and 109 (50%) to observation. Median age of randomized patients was 67 years, patient characteristics were comparable for both groups. The 2-year R maintenance provided a better disease control with a median PFS of 101 months in the R maintenance group compared to the median PFS of 83 months in the observation group, however, this difference was not statistically significant with a hazard ratio of 0.80 (95% CI 0.51 - 1.25, p = 0.32). The median PFS of the group of all patients receiving treatment with B-R induction only was 65.3 months and is consistent with the results of the previous StiL NHL1-2003 trial (69.5 months). This group of 179 patients includes both non-randomized patients (B-R non-responder, not randomized for any reason) and patients randomized to observation. There was no difference in OS with the median not yet reached for both R maintenance and observation.
Conclusions: We confirmed that induction with B-R is a highly effective treatment for WM. After a median observation time of 5.9 years the results could not demonstrate an improvement in PFS or OS after a 2-year R-maintenance when compared with observation after B-R induction in patients with WM.
Rummel:Sandoz: Honoraria; Janssen: Honoraria; Celgene: Honoraria; Roche Pharma AG: Honoraria, Research Funding. Hensel:Roche: Honoraria, Other: travel expenses. Buske:Hexal: Honoraria, Speakers Bureau; Roche: Honoraria, Research Funding, Speakers Bureau; Bayer: Research Funding; Janssen: Honoraria, Research Funding, Speakers Bureau; Pfizer: Honoraria; Celltrion: Honoraria, Speakers Bureau; Amgen: Research Funding. Schmidt:Janssen-Cilag: 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; Abbvie: Honoraria, Membership on an entity's Board of Directors or advisory committees; Incyte: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Hexal: Honoraria, Membership on an entity's Board of Directors or advisory committees; Biotest: Honoraria, Membership on an entity's Board of Directors or advisory committees; Bristol-Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees; Daiichi-Sankyo: Honoraria, Membership on an entity's Board of Directors or advisory committees. Willenbacher:IQVIA: Membership on an entity's Board of Directors or advisory committees; oncotyrol: Employment, Research Funding; European Commission: Research Funding; Gilead Science: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Sandoz: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: 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; Celgene: Consultancy, Honoraria, 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; Bristol-Myers Squibb: 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; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Consultancy, Membership on an entity's Board of Directors or advisory committees; Abbvie: Consultancy, Honoraria; Sanofi: Membership on an entity's Board of Directors or advisory committees; Fujimoto: Consultancy, Honoraria; Myelom- und Lymphomselbsthilfe Österreich: Consultancy, Honoraria. Dürig:Celgene: Consultancy, Other: Travel or accommodations, Speakers Bureau; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel support. Barth:Takeda: Honoraria; Lilly Pharma: Honoraria; Roche: Honoraria; Medac: Honoraria; Hexal: Honoraria. Hinke:Roche: Honoraria. Greil:Genentech: Honoraria, Research Funding; Eisai: Honoraria; Celgene: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Honoraria; Amgen: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Ratiopharm: Research Funding; Boehringer Ingelheim: Honoraria; AstraZeneca: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Novartis: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; MSD: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Gilead: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Pfizer: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Mundipharma: Honoraria, Research Funding; Merck: Consultancy, Honoraria, Research Funding; Sandoz: Honoraria; Roche: Consultancy, Honoraria, Other: Travel/accomodation expenses, Research Funding; Sanofi Aventis: Honoraria; GSK: Research Funding; Daiichi Sankyo: Consultancy, Honoraria.
Introduction. The prognosis of patients with follicular lymphoma (FL) has improved during recent years following the introduction of immuno-chemotherapy and Rituximab maintenance. Nevertheless, some ...patients still relapse early and have a poor prognosis. Several prognostic scoring systems have been developed using clinical, laboratory as well as molecular data, while the early identification of high-risk patients remains a challenge. In this context, the relevance of circulating bcl2/IgH levels for patient stratification is not clear. We could show that high circulating bcl2/IgH levels in the peripheral blood (PB) before therapy were an independent adverse prognostic factor for progression free survival (PFS) in patients receiving R-CHOP or Bendamustine-Rituximab (B-R) in the NHL1 study of the German StiL group (Zohren et al, Blood 2015).
Methods. Using a sensitive quantitative PCR method as previously described (Zohren et al, Blood 2015), a total of 2,491 circulating bcl-2/IgH level analyses were performed on PB samples before (n=415) and after (n=305) 6 cycles first-line immuno-chemotherapy and during follow-up (n=1,771). Results of these molecular studies were correlated with clinical outcome. We first present a 10-year update of the 107 bcl2/IgHpositive patients from the StiL-NHL1-trial. Secondly, we report the results from the StiL-NHL7-trial including bcl2/IgH analyses of 308 bcl2/IgHpositive patients who received B-R and Rituximab maintenance.
Results. With a median follow-up of 10 years in the 107 bcl2/IgHpositive patients from the StiL-NHL1-trial, high PB bcl-2/IgH levels (bcl-2/IgH to reference gene (tPA) ratio >1) before treatment as compared to low (ratio <1) levels remained a major independent prognostic factor for PFS (median 22 vs 71 months, HR 2.27, 95% CI 1.37-3.75; p=0.001). We also confirm that patients who were still bcl-2/IgHpositive after six cycles of immuno-chemotherapy had significantly inferior PFS (13 vs 79 months, Hazard Ratio (HR) 2.97, 95% CI 1.53-5.78; p=0.001) and overall survival (OS, 128 months vs not reached , HR 3.90, 95% CI 1.39-11.00; p=0.010).
In contrast, among the 308 bcl-2/IgHpositive patients of the StiL-NHL7-trial, who all received B-R and Rituximab maintenance, PB bcl-2/IgH levels (ratio >1 vs <1) before therapy were no longer prognostic for PFS (99 months vs not reached, HR 1.06, 95% CI 0.66 - 1.69; p=0.814) or OS. On the other hand, being bcl-2/IgHpositive after 6x B-R remained a poor prognostic factor for PFS (43 months vs not reached, HR 2.44, 95% CI 1.18-5.04; p=0.016 ) and OS (72 months vs not reached, HR 4.03, 95% CI 1.82-8.96; p=0.001) despite Rituximab maintenance.
When comparing StiL-NHL1 and StiL-NHL7 patients with respect to bcl-2/IgH levels and the effect of Rituximab maintenance, we found that Rituximab maintenance led to a significantly better PFS. In patients with low (ratio <1) bcl-2/IgH levels before therapy the hazard ratio of 1.7 was modest (71 months vs not reached, HR 1.70, 95% CI 1.16-2.50; p=0.006) in comparison to 3.46 as observed in patients with high (ratio >1) bcl-2/IgH levels (22 vs 99 months, HR 3.46, 95% CI 1.93-6.20; p<0.000). These findings suggest that patients with high bcl-2/IgH levels before therapy have a greater benefit from Rituximab maintenance therapy. There was no difference with regard to OS between StiL-NHL1 and StiL-NHL7 patients who were still bcl-2/IgHpositive after 6 cycles of immuno-chemotherapy implying that these patients may not benefit from Rituximab maintenance.
Conclusion. High circulating bcl-2/IgH levels in the PB before first line therapy identify a subgroup of patients with advanced FL who have significantly shorter PFS after standard immuno-chemotherapy. These patients greatly benefit from the addition of Rituximab maintenance, because pre-treatment bcl-2/IgH levels lose their predictive value with Rituximab maintenance therapy. On the other hand, patients who remain bcl-2/IgHpositive after standard immuno-chemotherapy have short PFS and OS despite treatment with Rituximab maintenance and therefore are candidates for experimental treatment approaches.
Kobbe:Amgen: Honoraria, Research Funding; Roche: Honoraria, Research Funding; Celgene: Honoraria, Other: Travel Support, Research Funding. Zohren:Pfizer Inc.: Employment. Buske:Roche: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Bayer: Research Funding. Germing:Celgene: Honoraria, Research Funding; Janssen: Honoraria; Novartis: Honoraria, Research Funding. Greil:Sandoz: Honoraria, Research Funding; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; MSD: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Abbvie: Consultancy, Membership on an entity's Board of Directors or advisory committees; Merck: Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Astra Zeneca: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Research Funding; Janssen: Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Schroeder:Celgene: Consultancy, Honoraria, Research Funding. Rummel:Gilead: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria; Astellas: Honoraria; Eisai: Honoraria; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Symbio: Honoraria; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees.
▪
Introduction: Factor XIII (FXIII) is a coagulation factor, playing an important role in the coagulation process by keeping the hemostatic clot and allowing tissue repair. The incidence of FXIII ...deficiency in acute leukemia is not well characterized. FXIII deficiency is known to have a high bleeding risk and cannot be detected by lab evaluation of aPTT and/or INR levels. In combination with thrombocytopenia in patients (pts) presenting with acute leukemia, FXIII deficiency increases bleeding risk (for example in invasive procedures or for intracranial hemorrhage). In 2013 a study was conducted in 9 pediatric pts (6 acute leukemias, 1 burkitt, and 2 solid tumors) in whom FXIII deficiency was found. These pts had bleeding complications that were resolved by FXIII concentrate substitution (Wiegering. V. et al. Haematologica, June, 10, 2013).Patients affected from AML and ALL could easily be screened at diagnosis regarding FXIII level. In the setting of newly diagnosed acute leukemia pts in whom thrombocytopenia is frequently occurring, a preemptive substitution of FXIII could be considered in order to reduce the risk of bleeding complications.
Methods: In this retrospective analysis (Jan. 2009 to June 2014) we identified a total of 103 ptspresentingwithnewly diagnosed acute leukemia in whom we assessed FXIII level. In 95 pts FXIII level was available at initial diagnosis of acute leukemia and during treatment. Substitution of FXIII concentrate have been used in case of factor’s deficiency below 70% (normal range 70%-130%).
Results: Patients presented withAML (64 primary AML and 20 secondary AML), or ALL (10), or 1 AUL. Median age was 67 years (range: 25-95). Thirty-four pts (35.8%) were younger than 60 years, 61 pts (64.2 %) were older than 60 years.
FXIII deficiency was found in 35/95 pts (36.8%) with a median level of 49% (range: 21%-68%). Of those 35 pts with FXIII deficiency 33 had AML (1 AML M0, 9 AML M1, 2 AML M1/2, 5 AML M2, 6 AML M4, 5 AML M5). All pts (5/95) with AML M3 showed a deficiency with a median level of 28%. A level below 70% could be found in 7 out of 13 FLT3-ITD positive pts (53.8%) and in 7 out of 24 NPM1 positive pts (29.2 %). Median FXIII level was 34% for FLT3-ITD positive pts, respectively 30% for NPM1. FXIII substitution in deficient pts was well tolerated and effective. No patient showed intracranial hemorrhage. In addition, invasive procedures like bone marrow biopsy and central line insertion were possible without clinically relevant bleeding complications. In responding pts achieving remission following chemotherapy, a trend towards higher concentration of factor XIII during treatment was observed.
Conclusions: Patients affected by AML or ALL are presenting usually with thrombocytopenia and have a high bleeding risk. In case of FXIII deficiency, risk of bleeding is increased potentially leading to a higher leukemia-related morbidity and mortality. Detection of FXIII deficiency is an established method and routinely available. Substitution of FXIII decreases the risk of bleeding and can reduce leukemia associated morbidity and mortality. In our study FXIII deficiency occurred in more than a third of our pts, including all AML M3 patients. We found a trend for more FXIII deficiency in FLT3-ITD high risk group patients. We suggest screening at diagnosis and during treatment of all acute leukemia pts and FXIII substitution in case of deficiency. To evaluate further the role of FXIII assessment and substitution in case of FXIII deficiency in acute leukemia, a prospective trial should be considered.
No relevant conflicts of interest to declare.
Background: R-maintenance for 2 years is part of a standard treatment approach for previously untreated follicular lymphoma. In this study we compared the efficacy and safety of 4 versus 2 years of ...R-maintenance following first-line treatment with B-R.
Methods: Patients included in the study were required to have stage II (bulky disease >7 cm), III, or IV disease. Patients were treated with up to 6 cycles of B-R plus 2 additional cycles of Rituximab. All responding patients received 2 years R-maintenance (375 mg/m2 every 2 months). Patients who tolerated treatment for the entire 2 years and who were still in remission hereafter were subsequently randomized to 2 more years of R-maintenance or observation. The primary endpoint was progression-free survival (PFS). Secondary endpoints included response rates, overall survival (OS), and toxicity.
Results: A total of 612 patients with follicular lymphoma were enrolled in the study. Of enrolled patients, 555 were evaluable for response and 497 (90%) responded to B-R induction, with 181 patients (33%) achieving a complete remission. A total of 261 patients discontinued treatment during induction or the first 2 years of R-maintenance. The most frequent reasons for discontinuation included progression in 85 of 261 pts (33%), patient's or doctor's choice in 55 pts (21%), toxicity or infections in 29 pts (11%), Rituximab intolerance in 14 pts (5%), or death in 11 pts (4%) with a median age of 70 years and 5 pts who died from infections. Of 351 patients randomized to 2-years or 4-years of R-maintenance, 350 were evaluable (n = 172 and n = 178, respectively). The median age was 60 years and patient characteristics were comparable between groups. The median observation time was 36 months following randomization. Median PFS and OS have not yet been reached in either arm. PFS appears superior with 4 years versus 2 years of R-maintenance with a hazard ratio (HR) of 0.63 (95% CI 0.36-1.11; fig. 1). There was no difference in OS between groups. One patient died from a progressive multifocal leukoencephalopathy (PML, randomized to 4 years of Rituximab). A historical comparison for PFS between responding patients given 2 years of R-maintenance in this MAINTAIN trial and subjects from the former StiL NHL1 study (B-R versus CHOP-R) who received B-R only appears to favor R-maintenance with a HR of 0.78 (95% CI 0.54-1.04). Data analysis is ongoing and updated results will be presented at the ASH meeting.
Conclusions: Results at the time of this analysis appear to favor 4-years over 2-years of R-maintenance and 2-years over observation compared to a historical control. Further analysis including the updated dataset will be presented at the ASH meeting and should provide more definitive evidence regarding the benefit of prolonged R-maintenance.
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Rummel:Roche: Honoraria, Other: PrefMab is sponsored by F. Hoffmann-La Roche Ltd. Third-party Medical Writing assistance, under the direction of Mathias Rummel, was provided by Lynda McEvoy of Gardiner-Caldwell Communications, and was funded by F. Hoffmann-La Roche Ltd, Research Funding. Buske:Hexal: Honoraria; Celltrion, Inc.: Consultancy, Honoraria; Pfizer: Honoraria; Gilead: Honoraria; Janssen: Honoraria, Research Funding; Roche: Honoraria, Research Funding. Balser:Sanofi-Aventis: Other: Travel support; IOMEDICO: Other: Travel support. Behringer:Roche: Consultancy, Honoraria; BMS: Consultancy, Honoraria. Dürig:Lead Discovery Center: Research Funding. Maschmeyer:Gilead: Honoraria; Pfizer: Honoraria, Travel support; Merck-Serono: Honoraria; Celgene: Honoraria; Bristol-Meyers Squibb: Honoraria; Basilea: Honoraria; Janssen-Cilag: Honoraria; Astellas: Honoraria; AstraZeneca: Honoraria; Boehringer-Ingelheim: Honoraria; Amgen: Honoraria; Bristol-Meyers Squibb: Other: Travel support. Schliesser:Bayer: Equity Ownership; Roche: Equity Ownership. Burchardt:Celgene: Honoraria; Roche: Honoraria; CSL: Honoraria; Medac: Honoraria. Barth:Celegene: Honoraria; CSL: Honoraria, Other: Travel support; BMS: Honoraria; Hexal: Honoraria; Johnson & Johnson: Honoraria; Medac: Honoraria; Mundipharma: Honoraria; Novartis: Honoraria; Roche: Honoraria; Takeda: Honoraria; Gilead: Other: Travel support; Amgen: Other: Travel support. Greil:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: travel support, Research Funding; Novartis, Celgene: Research Funding; Takeda: Honoraria, Research Funding; BMS, Amgen: Honoraria.
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