Abstract Objectives This study assessed the prevalence and associated risk factors for valvular dysfunction (VD) observed in adult lymphoma survivors (LS) after autologous hematopoietic stem cell ...transplantation (auto-HCT), and to determine whether anthracycline-containing chemotherapy (ACCT) alone in these patients is associated with VD. Background The prevalence of and risk factors for VD in LS after auto-HCT is unknown. Anthracyclines may induce heart failure, but any association with VD is not well-defined. Methods This national cross-sectional study included all adult LS receiving auto-HCT from 1987 to 2008 in Norway. VD was defined by echocardiography as either more than mild regurgitation or any stenosis. Observations in LS were compared with a healthy age- and gender-matched (1:1) control group. Results In total, 274 LS (69% of all eligible) participated. Mean age was 56 ± 12 years, mean follow-up time after lymphoma diagnosis was 13 ± 6 years, and 62% of participants were males. Mean cumulative anthracycline dosage was 316 ± 111 mg/m2 , and 35% had received radiation therapy involving the heart (cardiac-RT). VD was observed in 22.3% of the LS. Severe VD was rare (n = 9; 3.3% of all LS) and mainly aortic stenosis (n = 7). We observed VD in 16.7% of LS treated with ACCT alone (n = 177), corresponding with a 3-fold increased VD risk (odds ratio: 2.9; 95% confidence interval: 1.5 to 5.8; p = 0.002) compared with controls. Furthermore, the presence of aortic valve degeneration was increased in the LS after ACCT alone compared with controls (13.0% vs. 2.9%; p < 0.001). Female sex, age >50 years at lymphoma diagnosis, ≥3 lines of chemotherapy before auto-HCT, and cardiac-RT >30 Gy were identified as independent risk factors for VD in the LS. Conclusions In LS, ACCT alone was significantly associated with VD and related to valvular degeneration. Overall, predominantly moderate VD was prevalent in LS, and longer observation time is needed to clarify the clinical significance of this finding.
Recently, Ennishi and colleagues 3 developed a double-hit gene-expression signature (DHITsig) that identifies most double-hit tumors defined by FISH in addition to high-risk tumors with a similar ...gene-expression profile. RNA was extracted from representative pre-treatment FFPE tissue and digital gene expression was performed, applying the DLBCL90 assay on the NanoString platform (NanoString Technologies, Seattle, WA). Abbreviations: COO, cell-of-origin; UNC, unclassified group; ABC, activated B-cell like subtype; IHC, immunohistochemistry; HGBL-DH/TH-BCL2, high-grade B-cell lymphoma with MYC and BCL2 rearrangements with or without a BCL6 rearrangement; HGBL-DH/TH-WHO, high-grade B-cell lymphoma with MYC and BCL2 and/or BCL6 rearrangements as defined by the WHO classification of 2016; MYC status, MYC rearrangement detected by FISH break-apart probes; BCL2 status, BCL2 rearrangement detected by FISH break-apart probes; BCL6 status, BCL6 rearrangement detected by FISH break-apart probes; DPE, double protein expression of MYC and BCL2 FISH results were available from 77 samples, and six (8%) were identified as HGBL-DH/TH-BCL2, all in the GCB subtype. Other reasons may be that the patients were relatively young (median age 55 years) and a selection bias for a more fit double-hit patient population than those presented in population-based cohorts.
Sexual function in male lymphoma survivors was examined and compared with that of age-matched controls.
This cross-sectional study included serum gonadal hormone levels (testosterone, sex ...hormone-binding globulin, luteinizing hormone LH, and follicle-stimulating hormone) and responses to questionnaires assessing sexual function (Brief Sexual Function Inventory BSFI), socioeconomic factors, quality of life, emotional distress, and fatigue. The lymphoma group included 246 men < or = 50 years old at diagnosis who were diagnosed from 1980 to 2002 and treated at the Norwegian Radium Hospital. For each lymphoma survivor, two age-matched controls (n = 492) were drawn from a normative sample with BSFI scores.
The lymphoma survivors had a mean age at survey of 47.4 years, the mean duration of follow-up was 14.8 years, and 79% lived in committed relationships. All BSFI domain scores decreased significantly with age. Lymphoma survivors having low testosterone and/or elevated LH had lower BSFI scores than survivors with normal gonadal hormones. Multivariate analyses showed that increasing age, more emotional distress, poor physical health, and low testosterone and/or elevated LH were significantly associated with reduced sexual function within the lymphoma group. Lymphoma survivors had significantly lower BSFI domain scores than did controls on erection, ejaculation, and sexual satisfaction.
Lymphoma survivors had significantly poorer sexual function than normative controls. It is unclear whether the abnormal hormone levels directly cause the reduced sexual function within the lymphoma group or if a mediating factor is involved, such as aging, emotional distress, or perceived health status.
Multiparameter flow cytometry allows the detection of minor monoclonal B-cell populations. Using this technique combined with morphology, we were struck by the presence of minor populations of small ...monoclonal B cells in bone marrows of patients with diffuse large B-cell lymphoma in routine diagnostic samples and performed a systematic retrospective study.
Bone marrows of 165 patients with primary diffuse large B-cell lymphoma without histological evidence of concurrent non-Hodgkin's lymphoma were studied by routine microscopy of trephines and smears, immunohistochemistry and multiparameter flow cytometry.
Diffuse large B-cell lymphoma infiltration in marrows was documented in 11 of 165 patients. Morphological examination consistently revealed a higher tumor load than evidenced by flow cytometry. Of interest, only 3 of 119 patients with diffuse large B-cell lymphoma not otherwise specified, the largest subtype, showed marrow infiltration. By contrast, flow cytometry revealed a minor monoclonal B-cell population in 24 of 165 patients, none of whom showed diffuse large B-cell lymphoma infiltration by morphology. Of interest, morphological examination revealed the presence of small B cells in the marrows of those patients. Moreover, 11 of 39 (28.2%) of patients with diffuse large B-cell lymphoma not otherwise specified of ABC subtype and only 3 of 80 (3.7%) with the GCB subtype showed these monoclonal small B cells (P=0.0002). In addition 4 of 8 (50%), 4 of 15 (26.7%) and 2 of 3 (66.7%) patients with primary testicular, primary central nervous system and leg-type diffuse large B-cell lymphoma, respectively, showed monoclonal small B cells.
Bone marrow infiltration with diffuse large B-cell lymphoma in patients with diffuse large B-cell lymphoma not otherwise specified is rare at diagnosis. By contrast, a high number of diffuse large B-cell lymphoma not otherwise specified of the ABC subtype but not of GCB subtype is associated with monoclonal small B cells in the marrow. Whether these monoclonal small B cells are precursors of diffuse large B-cell lymphoma of the ABC type or arise in a common background that favors clonal B-cell expansion remains to be demonstrated.
Abstract ▪794▪This icon denotes a clinically relevant abstract
The optimal treatment schedule and best order of therapies are not well established for patients (pts) with indolent lymphoma. The aim ...of this trial was to evaluate the effect of adding interferon-alpha (IFN) to first-line rituximab (R) monotherapy, with extended dosing, in pts with CD20+indolent lymphoma and to define pts with no need of initial chemotherapy.
Pts with symptomatic, advanced indolent lymphoma (previously untreated or at first relapse after a short course of chlorambucil) were randomized to R (MabtheraR) 375 mg/m2 once-weekly for 4 consecutive weeks or R with 5 weeks IFN (Roferon-AR) as priming. Patients achieving either a complete response (CR), partial response (PR) or a minor response (MR) at evaluation 6 weeks after last R in this first cycle, were planned to receive a second cycle with four infusions of R alone or combined with IFN, according to the initial randomization. Primary endpoint was time to treatment failure (TTF), defined as the time period from randomization to one of the following events: progressive disease during treatment, death of any cause or initiation of new therapy.
In total, 313 patients were randomized. The median age was 59 years, 51% were females, 90% Ann Arbor stage III or IV and 31% showed elevated LDH. The clinical characteristics were well-balanced between the treatment groups. Pathology review showed 127 follicular lymphoma (FL) grade I, 110 grade II and 9 grade IIIA. In total, 4 pts in each arm did not fulfill inclusion criteria: 5 DLBCL/ transformed, 2 MCL and one Hodgkin. Most patients were previously untreated, but 10 pts in the R group and 13 with R+IFN had had a previous response to chlorambucil and 18 and 9 had had local radiotherapy. respectively. After cycle 1, response rates among all 313 randomized pts were 8.6 % CR/CRu, 47.9 % PR, 22.4 % MR and 16.9 % of pts were considered resistant (SD/PD). In total 244 pts were qualified for cycle 2. Overall response rates after cycle 2 were 82% and 74%, in the R+IFN- and the R-group, respectively (n.s), but the CR/CRu rates were higher with the combination (41% vs 22.4%, p< 0.01). Also pts with FLIPI 3–5 (45% of all pts) showed a deeper response with R+IFN (CR/Cru 38.0% compared to 23.1%). More patients in the combination arm improved their responses from PR/MR in cycle 1, to CR after cycle 2. In the intention–to treat (ITT) population (n=313), median time to TTF was 21 and 28 months in the R and R+IFN group, respectively. Most events consisted of initiation of new therapy including chlorambucil, COP or CHOP, but in 7 patients in the R group, relapse treatment was single R (in one case with the addition of IFN) and in the R+IFN group 10 pts had R (3 with IFN). Two pts in the R-group and 12 pts in the R+IFN group had late relapses treated with local irradiation. After a median follow-up time of 60.7 months, for surviving pts, 35 % of the ITT patients were still event-free with 90% survivors, but with no difference between the treatment groups. Patients with FL grade II and IIIA showed a longer TTF than pts with grade I (p=0,05).
This randomized phase III trial demonstrates that extended rituximab therapy is safe and effective as first-line therapy in patients with symptomatic low-grade B-cell lymphoma, with improved responses and a delayed time to early failure if combined with IFN. The long term FU suggests that more than 1/3 of this patient population does not need initial chemotherapy, but predictive markers for response to R and new biological combinations are needed.
Kimby:Roche: Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Gilead: Membership on an entity's Board of Directors or advisory committees.
In the primary analysis of the pivotal JULIET trial of tisagenlecleucel, an autologous anti-CD19 chimeric antigen receptor (CAR) T-cell therapy, the best overall response rate was 52% and the ...complete response rate was 40% in 93 evaluable adult patients with relapsed or refractory aggressive B-cell lymphomas. We aimed to do a long-term follow-up analysis of the clinical outcomes and correlative analyses of activity and safety in the full adult cohort.
In this multicentre, open-label, single-arm, phase 2 trial (JULIET) done at 27 treatment sites in ten countries (Australia, Austria, Canada, France, Germany, Italy, Japan, the Netherlands, Norway, and the USA), adult patients (≥18 years) with histologically confirmed relapsed or refractory large B-cell lymphomas who were ineligible for, did not consent to, or had disease progression after autologous haematopoietic stem-cell transplantation, with an Eastern Cooperative Oncology Group performance status of 0–1 at screening, were enrolled. Patients received a single intravenous infusion of tisagenlecleucel (target dose 5 × 108 viable transduced CAR T cells). The primary endpoint was overall response rate (ie, the proportion of patients with a best overall disease response of a complete response or partial response using the Lugano classification, as assessed by an independent review committee) at any time post-infusion and was analysed in all patients who received tisagenlecleucel (the full analysis set). Safety was analysed in all patients who received tisagenlecleucel. JULIET is registered with ClinialTrials.gov, NCT02445248, and is ongoing.
Between July 29, 2015, and Nov 2, 2017, 167 patients were enrolled. As of Feb 20, 2020, 115 patients had received tisagenlecleucel infusion and were included in the full analysis set. At a median follow-up of 40·3 months (IQR 37·8–43·8), the overall response rate was 53·0% (95% CI 43·5–62·4; 61 of 115 patients), with 45 (39%) patients having a complete response as their best overall response. The most common grade 3–4 adverse events were anaemia (45 39%), decreased neutrophil count (39 34%), decreased white blood cell count (37 32%), decreased platelet count (32 28%), cytokine release syndrome (26 23%), neutropenia (23 20%), febrile neutropenia (19 17%), hypophosphataemia (15 13%), and thrombocytopenia (14 12%). The most common treatment-related serious adverse events were cytokine release syndrome (31 27%), febrile neutropenia (seven 6%), pyrexia (six 5%), pancytopenia (three 3%), and pneumonia (three 3%). No treatment-related deaths were reported.
Tisagenlecleucel shows durable activity and manageable safety profiles in adult patients with relapsed or refractory aggressive B-cell lymphomas. For patients with large B-cell lymphomas that are refractory to chemoimmunotherapy or relapsing after second-line therapies, tisagenlecleucel compares favourably with respect to risk–benefit relative to conventional therapeutic approaches (eg, salvage chemotherapy).
Novartis Pharmaceuticals.
To determine whether a combination of high-dose therapy and autologous stem-cell transplantation (ASCT) is superior to conventional-dose consolidation and maintenance chemotherapy as postremission ...therapy in adults with lymphoblastic lymphoma.
One hundred nineteen patients were entered onto this prospective randomized trial from 37 centers. Patients received standard remission induction therapy, and responding patients were randomized either to continue with a conventional consolidation/maintenance protocol (CC) or to receive high-dose therapy and ASCT. In some centers, patients with HLA-identical sibling donors were registered on the trial but proceeded to allogeneic bone marrow transplantation (BMT) without randomization.
Of the 119 patients entered, 111 were assessable for response to induction therapy. The overall response rate was 82% (56% complete response, 26% partial response). Of the 98 patients eligible for randomization, 65 were randomized, 31 to ASCT and 34 to CC. Reasons for failure to randomize included patient refusal (12 patients), early progression or death on induction therapy (eight patients), excessive toxicity of induction regimen (six patients), and elective allogeneic BMT (12 patients). With a median follow-up of 37 months, the actuarial 3-year relapse-free survival rate is 24% for the CC arm and 55% for the ASCT arm (hazards ratio = 0.55 in favor of the ASCT arm; 95% confidence interval CI, 0.29 to 1.04; P =.065). The corresponding figures for overall survival are 45% and 56%, respectively (hazards ratio = 0.87 in favor of the ASCT arm; 95% CI, 0.42 to 1.81; P =.71).
The use of ASCT in adults with lymphoblastic lymphoma in first remission produced a trend for improved relapse-free survival but did not improve overall survival compared with conventional-dose therapy in this small randomized trial.
Six cycles of R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) are the standard treatment for aggressive B-cell non-Hodgkin lymphoma. In the FLYER trial, we assessed ...whether four cycles of CHOP plus six applications of rituximab are non-inferior to six cycles of R-CHOP in a population of patients with B-cell non-Hodgkin lymphoma with favourable prognosis.
This two-arm, open-label, international, multicentre, prospective, randomised phase 3 non-inferiority trial was done at 138 clinical sites in Denmark, Israel, Italy, Norway, and Germany. We enrolled patients aged 18–60 years, with stage I–II disease, normal serum lactate dehydrogenase concentration, ECOG performance status 0–1, and without bulky disease (maximal tumour diameter <7·5 cm). Randomisation was computer-based and done centrally in a 1:1 ratio using the Pocock minimisation algorithm after stratification for centres, stage (I vs II), and extralymphatic sites (no vs yes). Patients were assigned to receive either six cycles of R-CHOP or four cycles of R-CHOP plus two doses of rituximab. CHOP comprised cyclophosphamide (750 mg/m2), doxorubicin (50 mg/m2), and vincristine (1·4 mg/m2, with a maximum total dose of 2 mg), all administered intravenously on day 1, plus oral prednisone or prednisolone at the discretion of the investigator (100 mg) administered on days 1–5. Rituximab was given at a dose of 375 mg/m2 of body surface area. Cycles were repeated every 21 days. No radiotherapy was planned except for testicular lymphoma treatment. The primary endpoint was progression-free survival after 3 years. The primary analysis was done in the intention-to-treat population. Safety was assessed in all patients who received at least one dose of assigned treatment. A non-inferiority margin of −5·5% was chosen. The trial, which is completed, was prospectively registered at ClinicalTrials.gov, NCT00278421.
Between Dec 2, 2005, and Oct 7, 2016, 592 patients were enrolled, of whom 295 patients were randomly assigned to receive six cycles of R-CHOP and 297 were assigned to receive four cycles of R-CHOP plus two doses of rituximab. Four patients in the four-cycles group withdrew informed consent before the start of treatment, so 588 patients were included in the intention-to-treat analysis. After a median follow-up of 66 months (IQR 42–100), 3-year progression-free survival of patients who had four cycles of R-CHOP plus two doses of rituximab was 96% (95% CI 94–99), which was 3% better (lower limit of the one-sided 95% CI for the difference was 0%) than six cycles of R-CHOP, demonstrating the non-inferiority of the four-cycles regimen. 294 haematological and 1036 non-haematological adverse events were documented in the four-cycles group compared with 426 haematological and 1280 non-haematological adverse events in the six-cycles group. Two patients, both in the six-cycles group, died during study therapy.
In young patients with aggressive B-cell non-Hodgkin lymphoma and favourable prognosis, four cycles of R-CHOP is non-inferior to six cycles of R-CHOP, with relevant reduction of toxic effects. Thus, chemotherapy can be reduced without compromising outcomes in this population.
Deutsche Krebshilfe.
Hodgkin's lymphoma survivors (HLSs) commonly report chronic fatigue, defined as high levels of fatigue for 6 months or more. Underlying mechanisms are poorly understood. Based upon knowledge from ...other populations, lifestyle parameters may be related to this increased and persistent fatigue. The primary objective of the present study was to assess self-reported levels of physical activity, smoking habits and sleep patterns in HLSs with and without chronic fatigue. The secondary objective was to compare these results with data from age and gender adjusted data from the general population (Gen-Pop).
The Fatigue Questionnaire (FQ) and questions about daily smoking, sleep patterns and level of physical activity were completed by 476 HLSs treated at Rikshospitalet-Radiumhospitalet Trust (RR). The Gen-Pop data was derived from 56.999 inhabitants in a Norwegian county responding to a mail survey. Fischer's exact test, chi square test and t-tests were used to compare groups. P-values < .05 were considered statistically significant. A logistic regression analysis was performed in comparing the Gen-Pop with the HLSs.
Level of physical activity, smoking habits and sleep patterns did not differ significantly between HLSs with and without chronic fatigue. The multivariate logistic regression analysis adjusting for different covariates, showed significantly more physically active men among HLSs compared with the Gen-Pop (OR = 1.50, CI 1.04 - 2.17), p = .031. No significant difference was found among females (OR = 1.20, CI = 0.83 - 1.74), p = .33.
Lifestyle parameters did not seem to be related to increased and persistent fatigue among HLSs. The results may indicate that the experience of Hodgkin's lymphoma increases the level of physical activity among male HLSs.
The pattern and frequency of secondary chromosome abnormalities in t(14;18)-carrying non-Hodgkin lymphomas (NHL) were evaluated for differences in relation to histologic NHL subtype and patients' ...outcome.
One hundred and forty-nine NHL patients with t(14;18) and complete cytogenetic, morphologic, and clinical information were selected.
One hundred and twelve cases were follicular lymphoma (FL) and 37 were diffuse large B-cell lymphoma (DLBCL). One hundred and forty cases showed secondary aberrations (94%, median = 6.0). The most frequent were losses from chromosome arms 1p and 6q and +7 (26%). Loss from 1q, +7, and +12 were more frequent in DLBCL than in FL. Loss from 1p, Xp, and -16 were more frequent in FL grade 3 than in FL grades 1 and 2. Patients with <6.0 secondary cytogenetic aberrations had better prognosis than did those with a higher number of aberrations. Trisomy 21 was associated with shorter patient survival. FLIPI score, the number of secondary chromosomal aberrations, and +21 were all of independent prognostic value in Cox multivariate analysis. FL grade 1-3a patients that had received chemotherapy, showed a higher frequency of i(6p) and loss from 6q.
Secondary chromosomal aberrations showed some correlation with the morphologic subgroups of t(14;18)-NHL. Trisomy 21 and the presence of >6.0 secondary cytogenetic aberrations both correlated with shorter overall survival.
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