Systemic peripheral T-cell lymphomas (PTCLs) respond poorly to conventional therapy. To evaluate the efficacy of a dose-dense approach consolidated by up-front high-dose chemotherapy (HDT) and ...autologous stem-cell transplantation (ASCT) in PTCL, the Nordic Lymphoma Group (NLG) conducted a large prospective phase II study in untreated systemic PTCL. This is the final report, with a 5-year median follow-up, of the NLG-T-01 study.
Treatment-naive patients with PTCL age 18 to 67 years (median, 57 years) were included. Anaplastic lymphoma kinase (ALK) -positive anaplastic large-cell lymphoma (ALCL) was excluded. An induction regimen of six cycles of biweekly CHOEP (cyclophosphamide, doxorubicin, vincristine, etoposide, and prednisone) was administered (in patients age > 60 years, etoposide was omitted). If in complete or partial remission, patients proceeded to consolidation with HDT/ASCT.
Of 166 enrolled patients, 160 had histopathologically confirmed PTCL. The majority presented with advanced-stage disease, B symptoms, and elevated serum lactate dehydrogenase. A total of 115 underwent HDT/ASCT, with 90 in complete remission at 3 months post-transplantation. Early failures occurred in 26%. Treatment-related mortality was 4%. At 60.5 months of median follow-up, 83 patients were alive. Consolidated 5-year overall and progression-free survival (PFS) were 51% (95% CI, 43% to 59%) and 44% (95% CI, 36% to 52%), respectively. Best results were obtained in ALK-negative ALCL.
Dose-dense induction followed by HDT/ASCT was well tolerated and led to long-term PFS in 44% of treatment-naive patients with PTCL. This represents an encouraging outcome, particularly considering the high median age and adverse risk profile of the study population. Therefore, dose-dense induction and HDT/ASCT are a rational up-front strategy in transplantation-eligible patients with PTCL.
Elderly Hodgkin lymphoma (HL) patients are poorly characterized and under-represented in studies. In this national population- based study, we investigated cause-specific survival using ...competing-risk analysis in elderly HL patients compared to the normal population. Patients ≥60 years of age diagnosed between 2000-2015 were identified by the Cancer Registry of Norway, and records were reviewed in detail and compared to data from the Norwegian Cause of Death Registry for patients and cancer-free controls. Of 492 patients, 81 (17%) were ineligible for treatment directed specifically towards HL, mostly because of an underlying other lymphoma entity, whereas 74 (15%) and 337 (69%) were treated with palliative or curative intent, respectively. Median overall survival in patients ineligible for assessment of HL-directed therapies was 0.5 years (95% Confidence Interval CI: 0.4-0.6), and for palliatively and curatively treated patients 0.8 (0.4-1.2) and 9.1 (7.5-10.7) years, respectively. After correction of discrepancies in registry data, with 359 deaths, 108 (30%) died of HL, the most common cause of death. In curatively treated patients, treatment-related mortality was 6.5% and the risk difference of dying from HL compared to controls was 28% (95% CI: 23-33%) after ten years. These numbers indicate disease control in a majority of elderly patients eligible for curative treatment, compared to risk differences for death from HL of 59% (48-71%) and 42% (31-53%) after ten years in the palliative and ineligible groups, respectively. There was an increased risk of dying from hematologic malignancies other than HL in all groups, but not from other competing causes of death, showing no excess mortality from long-term treatment complications.
The Nordic Lymphoma Group has conducted a phase ll trial in newly diagnosed primary central nervous system lymphoma patients applying an age-adjusted multi-agent immunochemotherapy regimen, which in ...elderly patients included temozolomide maintenance treatment. Patients aged 18-75 years were eligible. Thirty-nine patients aged 18-65 years and 27 patients aged 66-75 years were enrolled. The median age of the two age groups was 55 and 70 years, respectively. The overall response rate was 73.8% for the entire cohort: 69.9% in the younger and 80.8% in the elderly subgroup. With a median follow up of 22 months, the 2-year overall survival probability was 60.7% in patients aged 65 years or under and 55.6% in patients aged over 65 years (P=0.40). The estimated progression-free survival at two years was 33.1% (95%CI: 19.1%-47.9%) in patients aged under 65 years and 44.4% (95%CI: 25.6%-61.8%) in the elderly subgroup (P=0.74). Median duration of response was ten months in the younger subgroup, and not reached in the elderly patient subgroup (P=0.33). Four patients aged 64-75 years (6%) died from treatment-related complications. Survival in the two age groups was similar despite a de-escalation of induction treatment in patients aged over 65 years. Duration of response in elderly patients receiving maintenance temozolomide was longer than in the younger age subgroup. While toxicity during induction is still of concern, especially in the elderly patients, we conclude from these data that de-escalation of induction therapy in elderly primary central nervous system lymphoma patients followed by maintenance treatment seems to be a promising treatment strategy. (clinicaltrials.gov identifier:01458730).
Reduced sexual function may have negative implications on health related quality of life among lymphoma survivors. A national cross-sectional study among long-term lymphoma survivors after high-dose ...therapy with autologous stem-cell transplantation auto-SCT treated during 1987-2008 was conducted in 2012-2014. The current study explored sexual functioning among these survivors. Sixty-six percent (n = 159) of eligible men with complete questionnaire data were included, median age was 55 years. The Brief Sexual Function Inventory (BSFI) was used to assess sexual function and sexual satisfaction, compared with age-matched controls. In addition, sexual problems were defined based on predetermined cutoff values for BSFI domain scores. Sexual drive and erections firm enough to have sexual intercourse were reported to be present only a few days or less last month among 30% and 41% of survivors, respectively. Sexual satisfaction was reported by 39% of survivors. The survivors had significantly lower scores on all BSFI domains and an increased risk of problems with sexual drive and erection compared with controls. In multivariable models, cardiovascular disease was significantly associated with worse erectile function, while age > 55 years, chronic fatigue, and physical inactivity were significantly associated with lower sexual functioning overall. Chronic fatigue and anxiety were related to lower sexual satisfaction.
Purpose The aim of this prospective study was to investigate the prognostic value of metabolic tumor volume (MTV) and apparent diffusion coefficient (ADC) from baseline FDG PET/MRI compared to ...established clinical risk factors in terms of progression free survival (PFS) at 2 years in a cohort of diffuse large B-cell Lymphoma (DLBCL) and high-grade-B-cell lymphoma (HGBCL). Methods Thirty-three patients and their baseline PET/MRI examinations were included. Images were read by two pairs of nuclear medicine physicians and radiologists for defining lymphoma lesions. MTV was computed on PET, and up to six lymphoma target lesions with restricted diffusion was defined for each PET/MRI examination. Minimum ADC (ADC.sub.min) and the corresponding mean ADC (ADC.sub.mean) from the target lesion with the lowest ADC.sub.min were included in the analyses. For the combined PET/MRI parameters, the ratio between MTV and the target lesion with the lowest ADC.sub.min (MTV/ADC.sub.min) and the corresponding ADC.sub.mean (MTV/ADC.sub.mean) was calculated for each patient. Clinical, histological, and PET/MRI parameters were compared between the treatment failure and treatment response group, while survival analyses for each variable was performed by using univariate Cox regression. In case of significant variables in the Cox regression analyses, Kaplan-Meier survival analyses with log-rank test was used to study the effect of the variables on PFS. Results ECOC PS scale greater than or equal to2 (p = 0.05) and ADC.sub.mean (p = 0.05) were significantly different between the treatment failure group (n = 6) and those with treatment response (n = 27). Survival analyses showed that ADC.sub.mean was associated with PFS (p = 0.02, HR 2.3 for 1 SD increase), while combining MTV and ADC did not predict outcome. In addition, ECOG PS greater than or equal to2 (p = 0.01, HR 13.3) and histology of HGBCL (p = 0.02 HR 7.6) was significantly associated with PFS. Conclusions ADC.sub.mean derived from baseline MRI could be a prognostic imaging biomarker for DLBCL and HGBCL. Baseline staging with PET/MRI could therefore give supplementary prognostic information compared to today's standard PET/CT. Keywords: PET/MRI, Lymphoma, Metabolic tumor volume, Apparent diffusion coefficient
Lymphoma survivors after high-dose therapy with autologous stem-cell transplant (HDT-ASCT) are at risk of several late effects, which might impair their health-related quality of life (HRQoL). We ...assessed the total late effect burden in this population, and how it affects HRQoL. All lymphoma survivors treated with HDT-ASCT as adults in Norway between 1987 and 2008 were identified, and 271 (68%) attended both a comprehensive clinical assessment and completed a questionnaire. Severity of 45 conditions in 12 organ-system categories were graded as mild, moderate, severe or life-threatening, according to a modified version of CTCAEv4.03. At a median of 8 years after HDT-ASCT, 98% of survivors had at least one moderate or more severe late effect and 56% had severe or life-threatening late effects. Fourteen percent had low, 39% medium and 47% high late effect burden, defined as having moderate or more severe late effects in 0-1, 2-3 and >3 organsystems, respectively. Female sex, increasing age, B-symptoms at diagnosis and >1 treatment line prior to HDT-ASCT were independently associated with having high late effect burden. The survivors had significantly poorer physical and mental HRQoL assessed by the Short Form-36 compared to age- and sex-matched controls. The prevalence of poor physical and mental HRQoL increased with higher late effect burden (both P<0.001), and the low burden group had better physical HRQoL than controls (P<0.001). In conclusion, lymphoma survivors after HDT-ASCT have impaired HRQoL, seemingly driven by a high late effect burden. This highlights the importance of prevention, regular assessments for early detection and treatment of late effects and modifiable risk factors.
The aim of the current study was to investigate the diagnostic performance of FDG PET/MR compared to PET/CT in a patient cohort including Hodgkins lymphoma, diffuse large B-cell lymphoma, and ...high-grade B-cell lymphoma at baseline and response assessment. Sixty-one patients were examined with FDG PET/CT directly followed by PET/MR. Images were read by two pairs of nuclear medicine physicians and radiologists. Concordance for lymphoma involvement between PET/MR and the reference standard PET/CT was assessed at baseline and response assessment. Correlation of prognostic biomarkers Deauville score, criteria of response, SUVmax, SUVpeak, and MTV was performed between PET/MR and PET/CT. Baseline FDG PET/MR showed a sensitivity of 92.5% and a specificity 97.9% compared to the reference standard PET/CT (
κ
0.91) for nodal sites. For extranodal sites, a sensitivity of 80.4% and a specificity of 99.5% were found (
κ
0.84). Concordance in Ann Arbor was found in 57 of 61 patients (
κ
0.92). Discrepancies were due to misclassification of region and not lesion detection. In response assessment, a sensitivity of 100% and a specificity 99.9% for all sites combined were found (
κ
0.92). There was a perfect agreement on Deauville scores 4 and 5 and criteria of response between the two modalities. Intraclass correlation coefficient (ICC) for SUVmax, SUVpeak, and MTV values showed excellent reliability (ICC > 0.9). FDG PET/MR is a reliable alternative to PET/CT in this patient population, both in terms of lesion detection at baseline staging and response assessment, and for quantitative prognostic imaging biomarkers.
Sexual function in female lymphoma survivors after high-dose therapy with autologous stem-cell transplantation (auto-SCT) is largely unstudied. Female lymphoma survivors treated with auto-SCT in ...Norway 1987-2008 were eligible participants (n = 157). A multi-item questionnaire including a complete Sexual Activity Questionnaire was returned by 70% (n = 110) of the women. A comparison to age-matched normative controls was performed. Sexual inactivity was equal among survivors and controls. The survivors reported personal issues more frequent as reason for inactivity compared with controls (44% vs. 28%, p = 0.04). The sexually active survivors reported more sexual discomfort, greater reduction in frequency of sexual activity, and more sex-related tiredness compared with controls (p value and effect size 95% confidence interval; p ≤ 0.001, 0.70 0.44, 0.97, p = 0.03, -0.29 -0.55, -0.03 and p ≤ 0.001, 0.64 0.37, 0.90, respectively). Sexual activity was related to older age (odds ratio (OR) 0.58 0.43, 0.82 per 10 years), being in a relationship (OR 28.6 6.9, 118.9) and hormonal replacement therapy (OR 6.0 1.49, 24.2). Tiredness in relation to sexual activity was associated with younger age, chronic fatigue and mental distress. Sexual inactivity due to personal issues was more frequent and among those sexually active, a higher rate of sexual dysfunction exists among auto-SCT survivors compared with controls. Hence, sexual function should be addressed at regular timepoints during the cancer trajectory.
Chemotherapy-induced peripheral neuropathy (CIPN) is a dose-limiting side effect of Hodgkin's lymphoma (HL) treatment. We aimed to describe the prevalence of CIPN associated symptoms in long-term HL ...survivors compared to controls, and determine associated factors, including impact on health-related quality of life (HRQoL).
A questionnaire, including EORTC QLQ-CIPN-20 for CIPN related symptoms and SF-36 for HRQoL, was completed by 303 HL survivors at a median of 16 years after diagnosis. CIPN results were compared to a normative population (n = 606). CIPN associated factors were identified by linear regression analysis.
Total CIPN score and subscores were significantly higher in HL survivors compared to controls. In multivariate analysis of HL survivors, a number of comorbidities (p < 0.001) and female gender (p = 0.05) were significantly associated with more CIPN. No association with disease or treatment factors was found. In a multivariate analysis including survivors and controls, the number of comorbidities (p < 0.001) and caseness (p < 0.001) were significantly associated with more CIPN. In HL survivors higher CIPN score was associated with reduced HRQoL (p < 0.001).
HL survivors more than a decade after treatment report higher neuropathy-related symptom burden than controls, with a negative impact on HRQoL. Symptoms may be related to factors other than neurotoxic chemotherapy.
The bone disease in multiple myeloma is caused by an uncoupling of bone formation from bone resorption. A key difference between patients with and patients without osteolytic lesion is that the ...latter have fewer and less active osteoblasts. Hepatocyte growth factor (HGF) is often produced by myeloma cells and is found at high concentrations in the bone marrow of patients with multiple myeloma. Here we show that HGF inhibited bone morphogenetic protein (BMP)–induced in vitro osteoblastogenesis. Thus, HGF inhibited BMP-induced expression of alkaline phosphatase in human mesenchymal stem cells (hMSCs) and the murine myoid cell line C2C12, as well as mineralization by hMSCs. Furthermore, the expression of the osteoblast-specific transcription factors Runx2 and Osterix was reduced by HGF treatment. HGF promoted proliferation of hMSCs, and the BMP-induced halt in proliferation was overridden by HGF, keeping the cells in a proliferative, undifferentiating state. BMP-induced nuclear translocation of receptor-activated Smads was inhibited by HGF, providing a possible explanation of how HGF inhibits BMP signaling. The in vitro data were supported by the observation of a negative correlation between HGF and a marker of osteoblast activity, bone-specific alkaline phosphatase (rho = −0.45, P = .008), in sera from 34 patients with myeloma. These observations suggest that HGF inhibits bone formation in multiple myeloma.
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