Hepatitis C Virus (HCV) infection is associated with the B-cell non-Hodgkin lymphomas (NHL), preferentially marginal zone lymphomas (MZL) and diffuse large B-cell lymphomas (DLBCL). While chronic ...antigenic stimulation is a main determinant of lymphomagenesis in marginal zone lymphomas (MZL), a putative role of HCV infection of B-cells is supported by in vitro studies. We performed a pathological study within the "ANRS HC-13 LymphoC" observational study focusing on in situ expression of the oncogenic HCV non structural 3 (NS3) protein. Lympho-C study enrolled 116 HCV-positive patients with B-NHL of which 86 histological samples were collected for centralized review. Main histological subtypes were DLBCL (36%) and MZL (34%). Almost half of DLBCL (12/26) were transformed from underlying small B-cell lymphomas. NS3 immunostaining was found positive in 17 of 37 tested samples (46%). There was a striking association between NS3 detection and presence of high grade lymphoma features: 12 out of 14 DLBCL were NS3+ compared to only 4 out of 14 MZL (p = 0.006). Moreover, 2 among the 4 NS3+ MZL were enriched in large cells. Remarkably, this study supports a new mechanism of transformation with a direct oncogenic role of HCV proteins in the occurrence of high-grade B lymphomas.
The purpose of our study is to determine the outcome of patients with systemic non-Hodgkin lymphoma presenting with neurologic localization at diagnosis, as well as the impact of consolidation in ...terms of high-dose therapy followed by autologous stem cell transplantation. Newly diagnosed non-Hodgkin lymphoma patients with concomitant systemic and neurological involvement at diagnosis were included in this study. Sixty patients (37 males; 25 females) were included. Median age was 61 years (23-85 years). Histological subtype was mainly diffuse large B-cell lymphoma (n = 54; 90%). The International prognostic index was over 2 in 41 (72%) patients. Median number of extranodal sites was 2 (range: 1-5). Central nervous system involvement alone was documented in 48 patients. Paravertebral involvement with epidural mass and cord compression and positive cerebrospinal fluid were present in 7 patients. Five patients had both central nervous system and epidural involvement. First-line chemotherapy was mainly anthracycline-based (88%) plus high-dose methotrexate (74%) with or without cytarabine. Consolidation with high-dose therapy followed by autologous stem cell transplantation was performed in 19 patients. For the whole population, overall response rate after induction chemotherapy was 76%. Three-year progression-free survival and overall survival were 42 ± 7% and 44 ± 7%, respectively. For patients under 66 years of age, consolidation strategy using high-dose therapy followed by autologous stem cell transplantation positively impacted 3-year overall survival and progression free survival (P = 0.008) and (P = 0.003), respectively. In multivariate analysis, high-dose therapy had a positive impact on 3-year overall survival and progression-free survival for the whole population as well as for patients under 66 years old in CR after induction therapy (OS HR=0.22 (0.07-0.67) and progression-free survival HR = 0.17 (0.05-0.54)). In conclusion, non-Hodgkin lymphoma prognosis with concomitant systemic and neurological involvement at diagnosis is poor with a high risk of relapse when treated with conventional chemotherapies alone. This retrospective study supports the feasibility and the potential benefit of a consolidative strategy with high-dose therapy followed by autologous stem cell transplantation in this subset of patients. This strategy and the best intensive chemotherapy regimen remain to be validated in prospective trials.
The causal protein of amyloid light‐chain (AL) amyloidosis is a monoclonal immunoglobulin free light chain (mFLC), which must be quantified in the serum for patient diagnosis and monitoring. Several ...manufacturers commercialize immunoassays that quantify total kappa (κ) and lambda (λ) FLC, but results can differ greatly between these tests. Here, we compared a recently developed enzyme‐linked immunosorbent assay (ELISA) (Sebia) with N‐Latex immunonephelometry (Siemens) in 96 patients diagnosed with AL amyloidosis (histologically confirmed) and 48 non‐AL patients sent to our referral center for suspicion of cardiac amyloidosis. ELISA free‐light chain difference (dFLC) were lower than N‐Latex values, and agreement between methods was reduced in the case of involved λ FLC. Diagnosis sensitivity and specificity were >85% with both assays. A receiver operating characteristic analysis indicated that ELISA performances could be improved by using a higher value for the lower limit of the κ/λ ratio. We also assessed Freelite (The Binding Site) in a subgroup of these same AL patients, including 18 cases with normal κ/λ ratio by at least one assay. Only two patients had normal κ/λ ratio with all three assays. Overall, ELISA demonstrated slightly lower sensitivity than N‐Latex but may be an alternative to nephelometry/turbidimetry in certain difficult cases.
Obinutuzumab is the second next-generation monoclonal anti-CD20 antibody (after ofatumumab) to enter clinical practice in chronic lymphocytic leukemia. Its superiority in association with ...chlorambucil as compared with chlorambucil alone has led to its approval as a first-line treatment for chronic lymphocytic leukemia, for patients who are not candidates for a more intensive treatment.
We have reported previously that after 1-year follow up, gonadotropin-releasing hormone agonist (GnRHa) did not prevent chemotherapy-induced premature ovarian failure (POF) in patients with lymphoma, ...but may provide protection of the ovarian reserve. Here, we report the final analysis of the cohort after 5 years of follow up.
A total of 129 patients with lymphoma were randomly assigned to receive either triptorelin plus norethisterone (GnRHa group) or norethisterone alone (control group) during chemotherapy. Ovarian function and fertility were reported after 2, 3, 4, and 5 to 7 years of follow up. The primary end point was POF, defined as at least one follicle-stimulating hormone value of > 40 IU/L after 2 years of follow up.
Sixty-seven patients 26.21 ± 0.64 years of age had available data after a median follow-up time of 5.33 years in the GnRHa group and 5.58 years in the control group (P = .452). Multivariate logistic regression analysis showed a significantly increased risk of POF in patients according to age (P = .047), the conditioning regimen for hematopoietic stem cell transplant (P = .002), and the cumulative dose of cyclophosphamide > 5 g/m(2) (P = .019), but not to the coadministration of GnRHa during chemotherapy (odds ratio, 0.702; P = .651). The ovarian reserve, evaluated using anti-Müllerian hormone and follicle-stimulating hormone levels, was similar in both groups. Fifty-three percent and 43% achieved pregnancy in the GnRHa and control groups, respectively (P = .467).
To the best of our knowledge, this is the first long-term analysis confirming that GnRHa is not efficient in preventing chemotherapy-induced POF in young patients with lymphoma and did not influence future pregnancy rate. These results reopen the debate about the drug's benefit in that it should not be recommended as standard for fertility preservation in patients with lymphoma.
Increased-dose bleomycin, etoposide, doxorubicin, cyclophosphamide, vincristine, procarbazine, and prednisone (BEACOPPescalated) improves progression-free survival in patients with advanced Hodgkin ...lymphoma compared with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD), but is associated with increased risks of haematological toxicity, secondary myelodysplasia or leukaemia, and infertility. We investigated whether PET monitoring during treatment could allow dose de-escalation by switching regimen (BEACOPPescalated to ABVD) in early responders without loss of disease control compared with standard treatment without PET monitoring.
AHL2011 is a randomised, non-inferiority, phase 3 study done in 90 centres across Belgium and France. Eligible patients were aged 16–60 years and had newly diagnosed Hodgkin lymphoma, excluding nodular lymphocyte predominant subtype, an Eastern Cooperative Oncology Group performance status score less than 3, a life expectancy of at least 3 months, an Ann Arbor disease stage III, IV, or IIB with mediastinum-to-thorax ratio of 0·33 or greater than or extranodal localisation, and had received no previous treatment for Hodgkin lymphoma. Randomisation was unmasked and done centrally by the permuted block method. Patients were randomly assigned to standard treatment (BEACOPPescalated given every 21 days for six cycles) or PET-driven treatment. All patients received two cycles of upfront BEACOPPescalated, after which PET assessment was done (PET2). In the standard treatment group, PET2 patients completed two additional cycles of BEACOPPescalated induction therapy irrespective of PET2 findings. In the PET-driven treatment group, patients with positive PET2 scans received the further two cycles of BEACOPPescalated and those with a negative PET2 scan switched to two cycles of ABVD for the remaining induction therapy. In both treatment groups, PET at the end of induction therapy was used to decide whether to continue with consolidation therapy in those with negative scans or start salvage therapy in patients with positive scans (either two cycles of ABVD in PET2-negative patients in the PET-driven arm or two cycles of BEACOPPescalated). BEACOPPescalated consisted of bleomycin 10 mg/m2 and vincristine 1·4 mg/m2 intravenously on day 8, etoposide 200 mg/m2 intravenously on days 1–3, doxorubicin 35 mg/m2 and cyclophosphamide 1250 mg/m2 intravenously on day 1, 100 mg/m2 oral procarbazine on days 1–7, and 40 mg/m2 oral prednisone on days 1–14. ABVD was given every 28 days (doxorubicin 25 mg/m2, bleomycin 10 mg/m2, vinblastine 6 mg/m2, and dacarbazine 375 mg/m2 intravenously on days 1 and 15). The primary endpoint was investigator-assessed progression-free survival. Non-inferiority analyses were done by intention to treat and per protocol. The study had a non-inferiority margin of 10%, to show non-inferiority of PET-guided treatment versus standard care with 80% power and an alpha of 2·5% (one-sided). This study is registered with ClinicalTrials.gov, number NCT01358747.
From May 19, 2011, to April 29, 2014, 823 patients were enrolled—413 in the standard care group and 410 in the PET-driven group. 346 (84%) of 410 patients in the PET-driven treatment group were assigned to receive ABVD and 51 (12%) to continue receiving BEACOPPescalated after PET2. With a median follow-up of 50·4 months (IQR 42·9–59·3), 5-year progression-free survival by intention to treat was 86·2%, 95% CI 81·6–89·8 in the standard treatment group versus 85·7%, 81·4–89·1 in the PET-driven treatment group (hazard ratio HR 1·084, 95% CI 0·737–1·596; p=0·65) and per protocol the values were 86·7%, 95% CI 81·9–90·3 and 85·4%, 80·7–89·0, respectively (HR 1·144, 0·758–1·726; p=0·74). The most common grade 3–4 adverse events were leucopenia (381 92% in the standard treatment group and 387 95% in the PET-driven treatment group), neutropenia (359 87% and 366 90%), anaemia (286 69% vs 114 28%), thrombocytopenia (271 66% and 163 40%), febrile neutropenia (145 35% and 93 23%), infections (88 22% and 47 11%), and gastrointestinal disorders (49 11% and 48 11%). Serious adverse events related to treatment were reported in 192 (47%) patients in the standard treatment group and 114 (28%) in the PET-driven treatment group, including infections (84 20% of 412 vs 50 12% of 407) and febrile neutropenia (21 5% vs 23 6%). Six (1%) patients in the standard care group died from treatment-related causes (two from septic shock, two from pneumopathy, one from heart failure, and one from acute myeloblastic leukaemia), as did two (<1%) in the PET-driven treatment group (one from septic shock and one from acute myeloblastic leukaemia).
PET after two cycles of induction BEACOPPescalated chemotherapy safely guided treatment in patients with advanced Hodgkin lymphoma and allowed the use of ABVD in early responders without impairing disease control and reduced toxicities. PET staging allowed accurate monitoring of treatment in this trial and could be considered as a strategy for the routine management of patients with advanced Hodgkin lymphoma.
Programme Hospitalier de Recherche Clinique.
To study the outcome of histologic transformation (HT) in a large prospective cohort of patients with follicular lymphoma (FL) who previously responded to immunochemotherapy.
After a median 6-year ...follow-up of 1,018 randomly assigned patients from the PRIMA trial, disease progression was observed in 463 patients, 194 of whom had histologic documentation.
Forty patients had histology consistent with HT, and 154 had untransformed FL (median time to recurrence, 9.6 v 22.8 months, respectively; P = .018). Thirty-seven percent of biopsies performed during the first year of follow-up showed HT corresponding to 58% of all HTs. Altered performance status, anemia, high lactate dehydrogenase level, "B" symptoms, histologic grade 3a, and high Follicular Lymphoma International Prognostic Index scores at diagnosis were identified as HT risk factors. Response (complete v partial) to immunochemotherapy or rituximab maintenance had no impact on the risk of HT. After salvage treatment, patients with HT had less frequent complete response (50.3% v 67.4%; P = .03) and more disease progression (28.2% v 9.6%; P < .001) than patients without HT. Estimated overall survival for the patients with HT was poorer (median, 3.8 v 6.4 years; hazard ratio, 3.9; 95% CI, 2.2 to 6.9). Autologous stem cell transplantation improved the outcomes of patients with HT (median overall survival, not reached v 1.7 years) but not of patients with persistent FL histology.
HT in patients with FL who previously responded to immunochemotherapy is an early event associated with a poor outcome that may deserve intensive salvage with autologous stem cell transplantation. These data emphasize the necessity for biopsy at the first recurrence of FL.
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