Purpose We compared the efficacy of ofatumumab (O) versus rituximab (R) in combination with cisplatin, cytarabine, and dexamethasone (DHAP) salvage treatment, followed by autologous stem-cell ...transplantation (ASCT) in patients with relapsed or refractory diffuse large B-cell lymphoma (DLBCL). Patients and Methods Patients with CD20
DLBCL age ≥ 18 years who had experienced their first relapse or who were refractory to first-line R-CHOP (cyclophosphamide, doxorubicin, vincristine, prednisone)-like treatment were randomly assigned between three cycles of R-DHAP or O-DHAP. Either O 1,000 mg or R 375 mg/m
was administered for a total of four infusions (days 1 and 8 of cycle 1; day 1 of cycles 2 and 3 of DHAP). Patients who experienced a response after two cycles of treatment received the third cycle, followed by high-dose therapy and ASCT. Primary end point was progression-free survival (PFS), with failure to achieve a response after cycle 2 included as an event. Results Between March 2010 and December 2013, 447 patients were randomly assigned. Median age was 57 years (range, 18 to 83 years); 17% were age ≥ 65 years; 63% had stage III and IV disease; 71% did not achieve complete response (CR) or experience response for < 1 year on first-line R-CHOP. Response rate for O-DHAP was 38% (CR, 15%) versus 42% (CR, 22%) for R-DHAP. ASCT on protocol was completed by 74 patients (33%) in the O arm and 83 patients (37%) in the R arm. PFS, event-free survival, and overall survival were not significantly different between O-DHAP versus R-DHAP: PFS at 2 years was 24% versus 26% (hazard ratio HR, 1.12; 95% CI, 0.89 to 1.42; P = .33); event-free survival at 2 years was 16% versus 18% (HR, 1.10; P = .35); and overall survival at 2 years was 41% versus 38% (HR, 0.90; P = .38). Positron emission tomography negativity before ASCT was highly predictive for superior outcome. Conclusion No difference in efficacy was found between O-DHAP and R-DHAP as salvage treatment of relapsed or refractory DLBCL.
The Danish National Lymphoma Register (LYFO) prospectively includes information on all lymphoma patients newly diagnosed at hematology departments in Denmark. The validity of the clinical information ...in the LYFO has never been systematically assessed.
To test the coverage and data quality of the LYFO.
The coverage was tested by merging data of the LYFO with the Danish Cancer Register and the Danish National Patient Register, respectively. The validity of the LYFO was assessed by crosschecking with information from medical records in subgroups of patients. A random sample of 3% (N = 364) was made from all patients in the LYFO. In addition, four subtypes of lymphomas were validated: CNS lymphomas, diffuse large B-cell lymphomas, peripheral T-cell lymphomas, and Hodgkin lymphomas. A total of 1,706 patients from the period 2000-2012 were included. The positive predictive values (PPVs) and completeness of selected variables were calculated for each subgroup and for the entire cohort of patients.
The comparison of data from the LYFO with the Danish Cancer Register and the Danish National Patient Register revealed a high coverage. In addition, the data quality was good with high PPVs (87% to 100%), and high completeness (92% to 100%).
The LYFO is a unique, nationwide clinical database characterized by high validity, good coverage and prospective data entry. It represents a valuable resource for future lymphoma research.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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Introduction: Diffuse large B-cell lymphoma (DLBCL) is the largest subgroup of malignant lymphoma. Today more than 80% of the patients will achieve partial or complete remission. However more than ...20 % will either relapse or present with refractory disease. The standard approach for patients without major comorbidity is salvage treatment followed by high dose therapy with autologous stem cell transplant (HDT). This potentially curative treatment is toxic with many side effects and procedure related mortality, and therefore identification of patients eligible for HDT is a difficult challenge.
Objectives: Patients with relapse of de novo DLBCL and transformed indolent lymphoma (TIL) were included. The aim was to identify clinical prognostic markers that can identify patients who will not benefit from HDT.
Methods: From the national lymphoma registry patients with relapse of B-cell lymphoma in Denmark in the period 2000-2012, who underwent HDT, were extracted. Medical records were reviewed for clinical, pathological, and treatment information, and outcome. Patients were followed until death or emigration or until February 1, 2015. The Kaplan-Meier method was used to estimate overall survival (OS) and progression free survival (PFS). Cox regression models were used to assess prognostic factors.
Results: A total of 370 patients were included, 174 with de novo DLBCL, and 196 with TIL, 143 of the 196 had histologically confirmed transformation. Median age was 58 (22-73), and 59% of the patients were male.
With a median follow-up of 82 months from HDT, the 5-year OS was 52% and the 5-year PFS was 44% (median PFS 3.2 years). For the DLBCL patients the 5-year OS was 43% and the 5-year PFS was 38%. For TIL patients the OS was 62% and the PFS 49% (figure 1).
During the first 100 days, 29 patients (8%) were admitted to the intensive care unit (14 DLBCL), and only four of these patients were alive at six months. The non-relapse mortality (NRM) at day 100 was 6 % for both groups, after five years 25% for DLBCL and 15% for TIL.
No significant difference in 5-year PFS was seen between sexes or age, but patients younger than 58 had better 5-year OS compared to patients aged 58 or above (p=0.047).
There was no difference in relapse treatment (DHAP vs ICE). Smoking (ever vs. never) caused a significantly worse OS (p=0.034). All IPI-factors, except Ann Arbor stage, was of prognostic importance (PFS). Primary refractory disease was of poor prognostic importance (p=0.001), and in patients, for whom the time from last salvage treatment to reinfusion of stem cells was more than 2 months, had a worse outcome (p=0.006). Patients, with less than 20 days of hospital admission in the period from the date of relapse to start of HDT, had a significantly higher survival (OS and PFS) (p>0.001).
In a multivariate analysis (PFS), LDH above upper normal reference, HR 1.4 (95% CI: 1.0;2.1), involvement of more than one extranodal site, HR 1.6 (1.1;2.3) primary refractory disease, HR 1.6 (1.1;2.3) and more than two earlier relapses, HR 1.9 (1.1;3.5) were all factors associated with adverse outcome.
For OS, the multivariate analysis showed, that patients with TIL had a better outcome, HR 0.7 (0.5;0.9), compared to DLBCL. Age above 58, HR 1.5 (1.1;2.1), involvement of more than one extranodal site, HR 1.9 (1.4;2.8), and primary refractory disease, HR 1.6 (1.1;2.3) were factors associated with adverse outcome.
Discussion:
In this population based study we find a 5-year OS of 52% after HDT and a 5-year PFS of 44%. Patients with TIL have a significantly higher 5-year PS (49%) than patients with de novo DLBCL (38%) whereas NRM is identical for the two groups at day 100 (6%). However, NRM increases subsequently more for DLBCL than for TIL over time to 25% and 15 % respectively after five years. Furthermore we show that hospitalization days less than 20 and postponement of stem cell infusion beyond 2 month after harvest may be useful parameters that can identify patients that have better or worse outcome after HDT.
This nationwide study cohort with the long follow-up period is applicable to a general population of patients, and this may explain the somewhat lower outcome compared to other published HDT cohorts.
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Brown:Bayer: Consultancy; Roche: Consultancy, Speakers Bureau.
BackgroundStyrene is an important industrial chemical used in the manufacture of numerous plastic products. The general population is exposed to low levels of styrene while workers in the reinforced ...plastics industry encounter much higher exposure levels. Increased occurrence of cancer of the lymphohaematopoietic system has been suggested among exposed workers and styrene is classified as possibly carcinogenic to humans.MethodsWe followed a cohort of 77,292 workers of 456 small and medium-sized Danish reinforced plastics companies 1968-2011 for incident cases of lymphohaematopoietic malignancies. Detailed quantitative exposure assessment was based on job task survey data and information on occupation, product, process, year of employment, gender, and 3630 styrene measurements in the study companies since the 1960s. In internal analyses we estimated rate ratios (RR) adjusted for age, gender, and calendar year in discrete time hazard models.ResultsWe observed a total of 762 cases of lymphohaematological malignancies. The RR of acute myeloid leukaemia (AML) (p-value 0.02) and Hodgkin lymphoma (p-value 0.01) increased with cumulated styrene exposure during the initial 10 years after first exposure. An almost 10-fold increased RR of AML was seen in the highest exposure tertile (RR = 9.53, 95% confidence interval = 1.09 to 83.6). A similar pattern was seen for diffuse large B-cell lymphomas 10 or more years since first exposure (p-value 0.04).ConclusionStyrene exposure may exert short and long term carcinogenic effects on haematopoietic cells translating into certain myeloid and lymphoid neoplasms. These findings may have implications for the classification of styrene as a human carcinogen.
Introduction:Diffuse large B-cell lymphoma (DLBCL) is the largest subgroup of malignant lymphoma. Prognosis has increased after introduction of rituximab, and today more than 80% of the patients will ...achieve partial or complete remission after standard immunochemotherapy. However, approximately 30% will either present with refractory disease or develop relapse. The standard approach for younger patients with relapsed disease and without major comorbidity is salvage treatment followed by high dose therapy with autologous stem cell transplant (ASCT). This potentially curative treatment is toxic with many side effects, and social outcomes for patients need to be investigated.
Objectives:Patients with relapse of de novo DLBCL and transformed indolent lymphoma (TIL) were included. The aim was to describe social outcome after ASCT in form of return to work (RTW).
Methods: Patients with B-cell lymphoma in the period 2000-2012, who received ASCT as relapse treatment, were extracted from the Danish National Lymphoma Registry. Medical records were reviewed for clinical, pathological, and treatment information. Individual information on socioeconomic factors and social outcomes were achieved by cross-reference to national administrative registries. Patients were included in RTW analyses, if they received public welfare benefits in at least four weeks including the week of stem cell reinfusion. RTW was defined as four consecutive weeks without receiving welfare benefits; retirement, disability pension and death was regarded as competing events. Patients were followed until RTW, emigration, permanent withdrawal from the labour market, death, or December 31, 2015, whichever came first.
Results: A total of 369 patients were identified. At the time of ASCT, 164 (44%) patients received public welfare benefits in form of either sick leave or unemployment benefits. Furthermore, 61 (17%) received disability pension or similar, 102 (28%) received old age pension, and 41(11%) patients did not receive any welfare benefits.
The 164 patients receiving sick leave or unemployment benefits were included in the analysis. Median age was 54 years (25-65), 16 patients were above the age of 60, and 104 were male (64%). A total of 54 patients had primary refractory disease; median time to relapse was 1.7 years. Both diagnoses were equally represented with 78 (48%) patients with TIL, IPI score at relapse was available for 118 patients, 22 % had a score of high-intermediate or high. Furthermore, socioeconomic factors at time of relapse showed, that 36 (22%) patients had only basic (mandatory) education, 39 (24%) patients lived alone and 60 (37%) patients had a low disposable income, corresponding to the 1st or 2nd quintile of the Danish population with the same gender and in the same age-group. Most of the patients, n=118 (72%), did not have comorbidities, but 46 patients had one or more at time of relapse. (Table 1)
Median time to return to work was 420 days, ranging from 13 to 909 days. One year after year after ASCT, 57 (35%) patients had returned to work, 15 (10%) received disability pension, and 7 (4%) received old age pension. A total of 48 (29%) were still on sick leave, and 37 (23%) had died. (Figure 1)
Conclusion: In this nationwide population based study we found that after one year only 35% of the patients had returned to work, 14% had been retired and 23% had died. This emphasizes that this patient group is at risk of impaired social status. There is an unmet need of focused social rehabilitation.
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No relevant conflicts of interest to declare.
Autologous stem cell transplantation (ASCT) is the standard treatment for patients with relapsed diffuse large B-cell lymphoma (DLBCL) or transformed indolent lymphoma (TIL). The treatment is mainly ...considered for younger patients still available for the work market. In this study, social outcomes after ASCT in terms of return to work (RTW) are described.
Information from national administrative registers was combined with clinical information on patients, who received ASCT for relapse of DLBCL or TIL between 2000 and 2012. A total of 164 patients were followed until RTW, disability or old-age pension, death, or December 31, 2015, whichever came first. A total of 205 patients were followed with disability pension as the event of interest. Cox models were used to determine cause-specific hazards.
During follow-up, 82 (50%) patients returned to work. The rate of returning to work in the first year following ASCT was decreased for patients being on sick leave at the time of relapse (hazard ratio HR 0.3 0.2;0.5) and increased for patients aged ≥55 years (HR 1.9 1.1;3.3). In all, 56 (27%) patients were granted disability pension. Being on sick leave at the time of relapse was positively associated with receiving a disability pension in the first 2 years after ASCT (HR 3.7 1.8;7.7).
Patients on sick leave at the time of relapse have a poorer prognosis regarding RTW and have a higher rate of disability pension. Furthermore, patients >55 are more likely to RTW compared to younger patients. These results indicate an unmet need for focused social rehabilitation.
Background: Aggressive non-Hodgkin lymphoma (aNHL) relapsing after high-dose therapy or, in not transplant-eligible patients, after 1st-line chemotherapy represents an unmet clinical need. Therefore, ...we aimed at evaluating a salvage combination regimen based on pixantrone, an aza-anthracenadione recently approved in Europe for patients with multiply relapsed aNHL. Etoposide and bendamustine were chosen as companion compounds due to available feasibility data in combination with anthracenadions, and a well-documented efficacy in salvage regimens for relapsed aNHL. Rituximab was added, if the relapse tumor biopsy was CD20+.
Aim: The aim of the present analysis was to summarize the preliminary clinical experience with the PREBEN/PEBEN regimen gathered, on a compassionate need basis, at different European sites and representing the platform for a currently ongoing Nordic phase 1/2 trial in relapsed aNHL.
Methods: The adopted schedule consisted of pixantrone 50 mg/m2 i.v. day 1+8, etoposide 100 mg i.v. day 1, bendamustine 90 mg i.v. day 1 with or without the addition of rituximab 375 mg/m2 i.v. day 1 (PREBEN/PEBEN). If feasible, each cycle was given at 3-weekly intervals for a maximum of 6 cycles. All patients were assessed for chemosensitivity with PET/CT, already after cycle 1 or 2. G-CSF support was applied and administered according to local practice.
Results: A total of 30 heavily pre-treated patients (19 males and 11 females, age range 49-81 yrs; mean N of previous regimens: 3, range 1-7) with aNHL were treated according to the PREBEN/PEBEN schedule. Seventeen had diffuse large B-cell (DLBCL), six transformed indolent (tIND), and seven peripheral T-cell lymphoma (PTCL). All patients had intermediate or high risk IPI prior to start of salvage therapy. Eight patients (27%) had a complete metabolic response (CMR) and seven (23%) a partial one (PMR), resulting in an overall response rate (ORR) of 50%. Among the histological subtypes, the patients with DLBCL, PTCL and tIND had an ORR of 53% (CMR 35%), 57% (CMR 14%), and 33% (CMR in one out of two responders), respectively. Most responses were achieved early (prior to course nr. 4). Response durations ranged between 2 and 23+ months. Among the 17 patients with DLBCL, nine were frail, non transplant-eligible with relapsed disease, six had primary refractory lymphoma progressing through anthracycline-containing 1st line and platinum-containing salvage therapies, and two had relapses occurring after a post-transplant remission period. While most of the relapsed patients with DLBCL responded , i.e. seven (five CMR and two PMR) of the nine (78%) frail relapsed patients and one of the two (50%) patients with post-transplant relapses, only one out six (17%) primary refractory patients exhibited some chemosensitivity. Interestingly, four out of seven PTCL patients achieved a PMR or CMR allowing them to undergo non-myeloablative allogeneic transplant with subsequent sustained response durations. The treatment schedule was feasible and most patients received it on an out-patient basis. The most common grade 3-4 toxicity was of hematological type (mainly neutropenia and thrombocytopenia), occurring in 52% of the patients. Grade 3-4 infections were observed at a frequency of 21%. No septic deaths were recorded. A previously anthracycline exposed, heavily pre-treated 60-year old female PTCL patient developed symptomatic congestive heart failure effectively reversed by angiotensin converting enzyme inhibitors with normalization of the myocardial ejection fraction. One previously ibritumomab tiuxetan exposed, heavily pretreated patient with tIND developed acute myeloid leukemia with therapy-related cytogenetic features.
Conclusions: The PREBEN/PEBEN salvage regimen was feasible in a heavily pre-treated cohort of elderly patients with high-risk aNHL. In individual patients it elicited substantial and durable responses early in the course of therapy. In some younger patients, it proved useful as bridging strategy to a non-myeloablative allogeneic transplant. A phase 1/2 study in relapsed (non-refractory) aNHL was launched in June 2016 (ClinicalTrial.gov identifier: NCT02678299; EudraCT number: 2015-000758-39) and is currently accruing (N=5 pr. Aug 1st, 2016).
Clausen:Takeda: Research Funding; Novartis: Other: Travel expences; Abbvie: Other: Travel expences. Leppa:Mundipharma: Research Funding; Roche: Honoraria, Other: Travel expenses, Research Funding; Bayer: Research Funding; Janssen: Research Funding; Takeda: Honoraria, Other: Travel expenses; CTI Life Sciences: Honoraria; Amgen: Research Funding; Merck: Other: Travel expenses. Willenbacher:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; European Commision: Research Funding. d'Amore:Servier: Honoraria, Other: Advisory Boards; CTI LIfe Sciences: Honoraria, Other: Advisory Boards.
Background: Salvage chemoimmunotherapy, followed by high-dose therapy and autologous stem cell transplantation (ASCT) for responding patients, is standard treatment for fit patients with diffuse ...large B-cell lymphoma (DLBCL) failing first line rituximab-CHOP treatment. Response to salvage treatment is critical for a durable progression free survival (PFS) following ASCT. The 3-year event free survival (EFS) for patients treated with rituximab (R) in first-line regimens who received salvage chemotherapy in combination with R was only 21% (ref-1). The anti-CD20 monoclonal antibody ofatumumab (O) has shown efficacy in R resistant lymphoma cell lines and in patients with relapsed or refractory intermediate grade lymphoma when combined with chemotherapy (ref-2). In this randomised phase III study we compared the efficacy of O versus R in combination with DHAP (cisplatin, cytarabine, dexamethasone), aiming to improve PFS following salvage treatment and ASCT (NCT01014208).
Methods: CD20+ DLBCL patients, aged ≥18y, in first relapse or not responding (<CR) to first-line R-CHOP-like treatment, with FDG-PET positive measurable disease, were randomised 1:1 between 3 cycles of R-DHAP or O-DHAP. Randomisation was stratified for risk factors: relapse >1y vs ≤1y (including PR, SD or PD) and secondary age adjusted IPI (sAAIPI) 0-1 vs 2-3. Either O 1000 mg or R 375 mg/m2was administered for a total of 4 infusions on days 1 and 8 of cycle 1, and day 1 of cycles 2 and 3 of DHAP. DHAP was dosed as published (ref 1). Peripheral blood stem cells (PBSC) were harvested during cycle 2 or 3. Responding patients (PR+CR) after 2 cycles received the third cycle followed by high-dose therapy and ASCT. Response after 2 cycles was determined by CT scans, and response after 3 cycles and 3 months after ASCT was determined by combined CT+FDG-PET scans according to RRCML criteria by an independent review. Patients with SD after cycle 2 or progressive disease did not proceed to ASCT. The primary endpoint was PFS, defined as time from randomisation to SD after cycle 2, PD or death, whichever came first. EFS included new therapy as an event in addition to the definitions for PFS.
Results: Between March 2010 and December 2013, 447 patients were randomised: 222 O-DHAP, 225 R-DHAP. Two patients in the R-DHAP arm were excluded from the ITT-population in accordance with the protocol because they did not receive any study treatment. The database cut-off date was Feb 28, 2014. Patient characteristics were evenly distributed between study arms: median age 57y (range, 18-83); 39% ≥60y; male 61%; Caucasian 72%; LDH >ULN 49%; ECOG PS >1 8%; stage III/IV 63%; sAAIPI 2-3 40%; and response to first line therapy: CR >1y 29%, CR ≤1y 11%, PR 36%, SD 8%, PD 16%. PFS, EFS and OS were not significantly different in the O-arm vs R-arm: PFS-2y 21% vs 26% (HR 1.14, 95% CI 0.90-1.45, p=0.27); EFS-2y 14% vs 17% (HR 1.12, p=0.27); OS-2y 41% vs 36% (HR 0.86, p=0.25). sAAIPI and response duration after first-line treatment were risk factors significantly associated with PFS and OS. In all, 102 (46%) patients in the O-arm and 113 (51%) in the R-arm died, 79% due to disease progression. Response to salvage was not significantly different between the study arms; ORR: O-arm 38% (CR 15%) vs R-arm 42% (CR 22%). ASCT on protocol was completed by 74 (33%) patients in the O-arm and 81 (36%) in the R-arm. Off protocol SCT was completed by 37 (17%) patients in the O-arm and 26 (12%) in the R-arm. No major differences in clinically relevant toxicity were observed between the arms. Rash (22% vs 9%) and raised serum creatinine (24% vs 16%) were increased in the O-arm. Time to neutrophil (ANC >0.5x109/L and increasing) and platelet (PLT >10x109/L and increasing) recovery after each cycle of DHAP therapy, and PBSC harvest, did not differ between the arms. Time to engraftment (PLT ≥20x109/L and 3 consecutive days of ANC ≥0.5x109/L, prior to day 42) after ASCT was shorter in the R-arm vs the O-arm (HR 0.62, p=0.05).
Conclusion: In this large international study no difference in efficacy was found between ofatumumab and rituximab in combination with DHAP as salvage treatment for refractory or relapsed DLBCL. Improved treatment for patients failing first line R-CHOP treatment is urgently needed.
Ref 1: Gisselbrecht, J Clin Oncol; 2010:28:4184
Ref 2: Matasar, Blood; 2013 122: 499
Off Label Use: Ofatumumab is an anti-CD20 monoclonal antibody. Ofatumumab is not indicated in DLBCL. Matasar:Genentech, Merck: Membership on an entity’s Board of Directors or advisory committees. Radford:Millennium, Seattle Genetics, Cell Medica: Consultancy, Equity Ownership, Honoraria, Research Funding, Speakers Bureau, Wife is a GSK/AZ Share Holder Other. Ardeshna:Roche, Gilead, Millenium: Consultancy, Honoraria, Speakers Bureau. Kim:Novartis, Takeda, Celgene: Research Funding. Hong:Fudan University Shanghai Cancer Center: Employment. Davies:Hoffman LaRoche, GSK: Honoraria, Membership on an entity’s Board of Directors or advisory committees, Research Funding. Ogura:GlaxoSmithKline Jansen Pharma Takeda, Eisai, Symbio, Zenyakuu, Pfizer, Chugai, Celgene, Astra Zeneca, Mundi, Sorasia, GSK, Takeda: Honoraria, Research Funding. Fennessy:GlaxoSmithKline: Employment, Equity Ownership. Liao:GlaxoSmithKline: Employment, Equity Ownership. Lisby:Genmab: Employment. Lin:GlaxoSmithKline: Employment, Equity Ownership. Hagenbeek:Milennium, Genmab: Membership on an entity’s Board of Directors or advisory committees.
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