Introduction
Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL) is a rare entity with distinct clinico-pathological features accounting for 5% of all Hodgkin lymphomas. Its optimal management is ...still debated, including the place of therapeutic abstention, and the role of rituximab. With the aim to report the management of the disease in a large series of patients (pts), we performed a retrospective study describing the characteristics of NLPHL at diagnosis, the therapeutic strategies, outcomes and the risk of late complications, including secondary malignancies.
Methods
We retrospectively analyzed adult pts with NLPHL treated in the Lymphoma Study Association (LYSA) centers between 1974 and 2012. Survival analysis were made according to the log-rank regression model. We also performed a competing risk analysis in order to better assess the risks of death, progression and secondary malignancies.
Results
314 pts, out of a total of 366 were retained for further analysis. Median age at diagnosis was 38 years. Most pts (82.5%) presented with localized, Ann Arbor stage I-II disease. Watchful waiting (WW) was the most frequent attitude at diagnosis, and concerned 114 pts (36%), mainly with localized disease (104 pts). 200 pts received a treatment, which comprised chemotherapy +/- rituximab for 68 pts (34% of pts with treatment), radiotherapy for 63 pts (31.5%), combined modality treatment (CMT, chemotherapy +/- rituximab followed by radiotherapy) for 40 pts (20%), and rituximab alone for 28 pts (14%). Among 155 pts with localized disease who received initial treatment, radiotherapy alone was delivered to 62 pts (42 with stage I, 20 with stage II disease), mainly on the cervical, supra-clavicular or axillar areas. The radiotherapy fields included the mediastinum in 7 localized pts treated by CMT. Among 55 pts with disseminated disease receiving initial treatment, chemotherapy +/- rituximab was administered to 32 pts. Most of them received anthracycline-based chemotherapy, and ABVD-derived chemotherapies were the preferred regimens with 19 pts; 8 pts received CHOP-like regimens.
With a median follow-up of 55.8 months, 112 pts relapsed or progressed. Among them, 37 pts (33%) received chemotherapy +/- rituximab, 27 pts (24%) radiotherapy alone, 19 pts (17%) rituximab alone, 7 pts (6%) CMT, and 2 pts rituximab + radiotherapy. WW concerned 19 pts (17%) at first relapse/progression.
The overall response rate (ORR) for the whole population was 83%, with 200 pts (79%) reaching CR or CRu, 3 months after diagnosis. The CR/CRu rate according to the different treatment modalities were 95% for radiotherapy alone, 89% for rituximab alone, 87% for chemotherapy +/- rituximab and 91% for CMT, respectively. In localized disease, 40 pts had persistent CR/CRu after radiotherapy alone. In disseminated disease, 45 pts who attained CR/CRu after chemotherapy +/- rituximab did not subsequently relapse.
The median PFS for the whole population was 112.1 months. There was no impact of Ann Arbor stage on PFS, but the attitude at diagnosis had a powerful impact. Compared to WW, the risk of progression was significantly reduced for pts treated by radiotherapy alone (Hazard ratio: 0.345 95% CI: 0.196; 0.610, p = 0.0002), chemotherapy +/- rituximab (HR: 0.476 0.266; 0.855, p = 0.0129), or CMT (HR: 0.292 0.148; 0.577, p = 0.0004), but not with rituximab alone. The risk reduction remained significant for pts who had complete surgical resection of the initial lesions and received any additional treatment vspts who were just watched after surgery (HR: 0.344 0.122; 0.974, p = 0.0444).
The estimated OS at 72 months is 96.9%. OS was not different according to the attitude at diagnosis, including WW. 10 pts died, 1 due to lymphoma progression, 5 of secondary malignancies and the remaining 4 of accident or unknown causes.
The competing risk analysis model confirmed that the risk of relapse/progression was significantly reduced with radiotherapy in stage I-II pts (HR : 0.474 0.277; 0.812), and with a treatment combining chemotherapy +/- rituximab +/- radiotherapy in the whole population (HR: 0.388 0.234; 0.643).
Conclusion
Our study supports the use of radiotherapy in localized disease, and of treatments combining chemotherapy +/- rituximab +/- radiotherapy, to improve disease control in adult patients with NLPHL.
No relevant conflicts of interest to declare.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Hodgkin lymphoma (HL) is a cancer that mostly affects young people, in which modern therapeutic strategies using chemotherapy and radiotherapy result in a cure rate exceeding 80%. Survivors are ...exposed to long-term consequences of treatments, such as secondary malignancies and cardiovascular diseases, whose mortality exceeds the one of the disease itself, with long-term follow-up. The current therapeutic strategy in HL, based on the assessment of initial risk factors, is the result of large clinical trials led by the main international cooperating groups. More recently, several groups have tried to develop treatment strategies adapted to the response to chemotherapy, evaluated by interim PET/CT scan. However to date, the combined treatment with chemotherapy followed by radiation therapy remains a standard in most of the above-diaphragmatic localized forms. Immune checkpoint inhibitors, and especially anti-PD1 antibodies, have shown dramatic results in some serious forms of relapsed or refractory HL, with limited toxicity, and may contribute in the future to reduce the toxicities of treatments.
Bleomycin is a cytotoxic antibiotic and a component of chemotherapy regimens of germ cell tumors and lymphoma. Bleomycin lung injuries occur in 10% of patients, and lead to severe interstitial ...pneumonia in 3% of patients. Pulmonary toxicity is related to endothelial cells injury induce by free radicals and inflammatory cytokines. Diagnosis of bleomycin-induced lung toxicity is based on the combination of clinical and radiological features, and requires to rule out differential diagnoses including pneumocystis. "Bleomycin-induced pneumonitis" is the most frequent pattern; eosinophilic pneumonitis and organizing pneumonia are rarer. Occurrence of bleomycin lung toxicity requires an immediate and often permanent discontinuation. Treatment is based on steroid. Regular clinical and pulmonary function tests monitoring are mandatory for early detection of bleomycin-induced lung toxicity.
CNS relapse is reported in 2–5% of diffuse large B‐cell lymphoma (DLBCL) patients, dramatically decreasing overall survival (OS). Very few studies address incidence and risk factors of CNS relapse in ...very elderly patients, a challenging population to treat given their commonly associated comorbidities. A retrospective analysis was performed of 270 DLBCL patients >80 years treated between 2004 and 2013 in two multicentre phase II LYSA trials (LNH03‐7B, LNH09‐7B) evaluating the addition of rituximab or ofatumumab to mini‐CHOP as front‐line therapy. No patients received CNS prophylaxis. CNS relapse was evaluated according to cumulative incidence, patient characteristics, risk factors, and survival. Median age was 83 years (range: 79–95). After a median follow‐up of 28.7 months, eight patients had CNS relapse (3.0%). Median time between inclusion and CNS relapse was 19.2 months (range: 3.2–32.6). Patients survived a median of 1.5 months after CNS relapse (range: 0.4–4.1). Median OS from relapse was significantly lower in CNS relapse patients (1.5 months, 95% CI: 0.4–3.5) compared to patients with non‐CNS relapse (6.6 months; 95% CI: 4.6–11.9). No baseline characteristics were associated with CNS relapse. The proportion of patients with CNS disease did not differ significantly between patients with low‐intermediate risk according to CNS‐IPI and patients with high risk (3% vs. 2.8%, P = 1.00). CNS relapse cumulative incidence in very elderly treatment‐naive patients is 1.8% at 2 years and is associated with poor survival. This population had a long median time to CNS relapse. Absence of prophylaxis did not strongly impact CNS relapse incidence.
Cumulative incidence of CNS relapse at 2 years in patients with diffuse large B‐cell lymphoma aged over than 80 is 1.8% and is associated with a very poor survival. The absence of prophylaxis did not appear to have a strong impact on CNS relapse incidence. Consequently CNS prophylaxis can be avoided in this population given the potential for a negative impact of the associated toxicities.
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FZAB, GIS, IJS, KILJ, NLZOH, NUK, OILJ, SAZU, SBCE, SBMB, UL, UM, UPUK
The response evaluation criteria in patients with Hodgkin lymphoma (HL) were designed for the assessment of chemotherapy and targeted molecular agents. We investigated the accuracy of 3-mo 18F-FDG ...PET/CT for the identification of HL patients responding to immune-checkpoint blockade by anti-programmed death 1 antibodies (anti-PD1). We also reported the frequency of new immune patterns of response and progression. Methods: Retrospectively, we recruited consecutive HL patients treated by anti-PD1 (pembrolizumab or nivolumab) at Gustave Roussy from 2013 to 2015. 18F-FDG PET/CT and contrast-enhanced CT scans were acquired every 3 mo. We recorded the best overall response according to the International Harmonization Project Cheson 2014 criteria and LYmphoma Response to Immunomodulatory therapy Criteria (LYRIC) (2016 revised criteria). Patients achieving an objective response at any time during the anti-PD1 treatment were classified as responders. Results: Sixteen relapsed or refractory classic HL patients were included. The median age was 39 y (age range, 19-69 y). The median previous lines of therapy was 6 (range, 3-13). The mean follow-up was 22.6 mo. Nine of 16 patients (56%) achieved an objective response. Two deaths occurred due to progressive disease at 7 mo. 18F-FDG PET/CT detected all responders at 3 mo and reclassified best overall response in 5 patients compared with CT alone. A decrease in tumor metabolism and volume (SUVmean, metabolic tumor volume) and increase in healthy splenic metabolism at 3 mo were observed in responders (area under the curve > 0.85, P < 0.04). Five of 16 patients (31%) displayed new imaging patterns related to anti-PD1; we observed 2 transient progressions consistent with indeterminate response according to the LYRIC (2016) (IR2b at 14 mo and IR3 at 18 mo) and 3 patients with new lesions associated with immune-related adverse events. Conclusion: Three-month 18F-FDG PET/CT scans detected HL patients responding to anti-PD1. New patterns were encountered in 31% of patients, emphasizing the need for further evaluation in larger series and close collaboration between imaging and oncology specialists on a per-patient basis.
Abstract 3541
Poster Board III-478
Quantitative analysis of chimerism after allogeneic hematopoïetic stem cell transplantation (allo-HSCT) for acute leukemia is routinely used to monitor the kinetic ...of engrafment. Usually, chimerism is assessed by variable number tandem repeat (VNTR) or short tandem repeat (STR) amplification by polymerase chain reaction (PCR), which have a sensitivity of 1 to 5 %. Many studies have shown that these methods were not sensitive enough to predict relapse. Insertion/Deletion (InDel) polymorphism analysis by real-time quantitative PCR (InDel-QPCR) is a more sensitive method and thus it should be able to predict relapse earlier.
We conducted a retrospective unicentric study including all consecutive patients transplanted for acute leukemia from May 2004 to January 2009 in the Pitié Salpétrière Hospital (Paris France). Seventy four patients (53 acute myeloblastic leukemia and 21 acute lymphoblastic leukemia) were included. Median age was 41 years (18-67). Conditionning regimen was myeloablative in 51 patients (69%). The donor was a HLA-identical sibling for 31 patients. The source of stem cell was bone marrow in 35 patients (47%), peripheral blood in 35 (47%) and umbilical cord blood in 4 (6%). Sixty four patients (86%) were in complete remission (CR) at the time of transplantation. InDel-QPCR was performed every month in peripheral blood samples with a reproducible sensitivity of 0.1% at least. An increasing mixed chimerism was defined as a one log increase between two successive chimerism assays when recipient rate was inferior to 0.1% and as any increase beyond this limit (0.1%).
In this 74 patients population, overall survival was 65% at one year, with a median follow up of the survivors of 651days (129-1809). Thirty six patients developed an acute GVHD (2-4) and 21 a chronic GVHD. Eighteen patients (24%) presented a cytological relapse, at a median time of 203 days (63-1001) after transplant. In two patients, the quantification of recipient DNA rate was constantly superior to 1% at each time point post transplant and these patients presented an early relapse (at 3 and 4 months after transplant). In the 72 remaining patients, DNA rate was inferior to 1%: in 63 patients inferior to 0.1% and in 41 patients inferior to 0.01%. Among the 62 patients who presented an increasing mixed chimerism (IMC) at one point, 18 relapsed. Among the 24 patients who presented an IMC at two successive points, 16 relapsed. In univariate analysis, factors associated with higher risk of relapse were the status of disease at transplant (refractory disease+CR2 versus CR1, p=0.002, hazard ratio=9.54) and 2 successive IMC (p=0.0001, hazard ratio=8.74 (CI: 3.33-22.9). In multivariate analysis both factors remained significantly correlated with the incidence of relapse (status of disease p=0.003, hazard ratio=4.24(CI: 1.6-11.2) and two IMC p<0.0001, hazard ratio=9.20(CI: 3.44-24.57)).
The median interval between the first IMC and the diagnosis of relapse was 45 days (7-154). At the time of the first IMC, the peripheral blood cell count was normal in all except one patient who had persistent post-transplant thrombocytopenia.
Analysis of chimerism by using In/Del polymorphism is a sensitive technique with a reproducible detection threshold inferior to 0.1%. The detection of two successive IMC is highly predictable of relapse in patients transplanted for acute leukemia. Therefore, the detection of an increasing chimerism should incite to perform a rapid control, in order to make a precocious diagnosis of relapse and to provide an early therapeutic intervention. This analysis could help to monitor minimal residual disease in post transplant patients without a more specific molecular marker of malignancy.
No relevant conflicts of interest to declare.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The SARS-CoV-2 pandemic still represents a threat for immunosuppressed and hematological malignancy (HM) bearing patients, causing increased morbidity and mortality. Given the low anti-SARSCoV-2 IgG ...titers post-vaccination, the COVID-19 threat prompted the prophylactic use of engineered anti-SARS-CoV-2 monoclonal antibodies. In addition, potential clinical significance of T cell responses has been overlooked during the first waves of the pandemic, calling for additional in-depth studies. We reported that the polarity and the repertoire of T cell immune responses govern the susceptibility to SARS-CoV-2 infection in health care workers and solid cancer patients. Here, we longitudinally analyzed humoral and cellular immune responses at each BNT162b2 mRNA vaccine injection in 47 HM patients under therapy. Only one-third of HM, mostly multiple myeloma (MM) bearing patients, could mount S1-RBD-specific IgG responses following BNT162b2 mRNA vaccines. This vaccine elicited a S1-RBD-specific Th1 immune response in about 20% patients, mostly in MM and Hodgkin lymphoma, while exacerbating Th2 responses in the 10% cases that presented this recognition pattern at baseline (mostly rituximab-treated patients). Performing a third booster barely improved the percentage of patients developing an S1-RBD-specific Th1 immunity and failed to seroconvert additional HM patients. Finally, 16 patients were infected with SARS-CoV-2, of whom 6 developed a severe infection. Only S1-RBD-specific Th1 responses were associated with protection against SARS-CoV2 infection, while Th2 responses or anti-S1-RBD IgG titers failed to correlate with protection. These findings herald the paramount relevance of vaccine-induced Th1 immune responses in hematological malignancies.
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