Bénédicte Deau

Classical Hodgkin’s lymphoma: the Lymphoma Study Association guidelines for relapsed and refractory adult patients eligible for transplant

The Hodgkin’s Lymphoma Committee of the Lymphoma Study Association (LYSA) gathered in 2012 to prepare guidelines on the management of transplant-eligible patients with relapsing or refractory Hodgkin’s lymphoma. The working group is made up of a multidisciplinary panel of experts with a significant background in Hodgkin’s lymphoma. Each member of the panel of experts provided an interpretation of the evidence and a systematic approach to obtain consensus was used. Grades of recommendation were not required since levels of evidence are mainly based on phase II trials or standard practice. Data arising from randomized trials are emphasized. The final version was endorsed by the scientific council of the LYSA. The expert panel recommends a risk-adapted strategy (conventional treatment, or single/double transplantation and/or radiotherapy) based on three risk factors at progression (primary refractory disease, remission duration < 1 year, stage III/IV), and an early evaluation of salvage chemosensitivity, including 18fluorodeoxy glucose-positron emission tomography interpreted according to the Deauville scoring system. Most relapsed or refractory Hodgkin’s lymphoma patients chemosensitive to salvage should receive high-dose therapy and autologous stem-cell transplantation as standard. Efforts should be made to increase the proportion of chemosensitive patients by alternating non-cross-resistant chemotherapy lines or exploring the role of novel drugs.

Sarcoidosis Occurring After Lymphoma: Report of 14 Patients and Review of the Literature

AbstractSarcoidosis is a granulomatous disease that most frequently affects the lungs with pulmonary infiltrates and/or bilateral hilar and mediastinal lymphadenopathy. An association of sarcoidosis and lymphoproliferative disease has previously been reported as the sarcoidosis-lymphoma syndrome. Although this syndrome is characterized by sarcoidosis preceding lymphoma, very few cases of sarcoidosis following lymphoma have been reported. We describe the clinical, biological, and radiological characteristics and outcome of 39 patients presenting with sarcoidosis following lymphoproliferative disease, including 14 previously unreported cases and 25 additional patients, after performing a literature review. Hodgkin lymphoma and non-Hodgkin lymphoma were equally represented. The median delay between lymphoma and sarcoidosis was 18 months. Only 16 patients (41%) required treatment. Sarcoidosis was of mild intensity or self-healing in most cases, and overall clinical response to sarcoidosis was excellent with complete clinical response in 91% of patients. Sarcoidosis was identified after a follow-up computerized tomography scan (CT-scan) or 18fluorodeoxyglucose-positron emission tomography/computerized tomography (18FDG-PET/CT) evaluation in 18/34 patients (53%). Sarcoidosis is therefore a differential diagnosis to consider when lymphoma relapse is suspected on a CT-scan or 18FDG-PET/CT, emphasizing the necessity to rely on histological confirmation of lymphoma relapse.

Sequential combination of gemcitabine, vinorelbine, pegylated liposomal doxorubicin and brentuximab as a bridge regimen to transplant in relapsed or refractory Hodgkin lymphoma

Among haematological malignancies, Hodgkin’s lymphoma (HL) remains a disease with a high cure rate and overall survival rate of >80% for patients under 60 years. Nevertheless, approximately 5–10% of HL patients are refractory to initial treatment and 10–30% relapse after achieving an initial

Peripheral blood 8 colour flow cytometry monitoring of hairy cell leukaemia allows detection of high-risk patients.

Although purine analogues have significantly improved the outcome of hairy cell leukaemia (HCL) patients, 30–40% relapse, illustrating the need for minimal residual disease (MRD) markers that can aid personalized therapeutic management. Diagnostic samples from 34 HCL patients were used to design an 8‐colour flow cytometry (8‐FC) tube for blood MRD (B/RD) analysis (188 samples) which was compared to quantitative IGH polymerase chain reaction (Q‐PCR) on 83 samples and to qualitative consensus IGH PCR clonality analysis on 165 samples. Despite heterogeneous HCL phenotypes at diagnosis, discrimination from normal B lymphocytes was possible in all cases using a single 8‐FC tube, with a robust sensitivity of detection of 10−4, comparable to Q‐PCR at this level, but preferable in terms of informativeness, simplicity and cost. B/RD assessment of 15 patients achieving haematological complete remission after purine analogues was predictive of a clinically significant relapse risk: with a median follow‐up of 95 months; only one of the nine patients with reproducible 8‐FC B/RD levels below 10−4 (B/RDneg) relapsed, compared to 5/6 in the B/RDpos group (P = 0·003). These data demonstrate the clinical interest of a robust 8‐FC HCL B/RD strategy that could become a surrogate biomarker for therapeutic stratification and new drug assessment, which should be evaluated prospectively.

Human Herpesvirus-6 cytopathic inclusions: an exceptional and recognizable finding on skin biopsy during HHV6 reactivation after autologous stem-cell transplantation.

Skin rash are common in immunocompromised patients, particularly after bone marrow transplantation. Human herpes virus 6 (HHV6) reactivation is often suspected, but its clinical presentation and the routine laboratory tests may be unspecific, thus leading to late diagnosis. In this case, we report specific intralymphocytic cytopathic inclusions on skin biopsy as a sign of systemic HHV6 reactivation. A 56-year-old patient presented progressive erythroderma and fever occurring after autologous hematopoietic stem-cell transplantation for mantle cell lymphoma. The skin biopsy showed a perivascular infiltrate of medium-to-large lymphocytes with irregular nuclei containing a large central basophilic inclusion surrounded by a clear halo. High levels of HHV-6 genomic in skin biopsy confirm HHV-6-induced cytopathic effect. The clinical course improved with intravenous foscavir. The specific histopathological findings encountered in this case are exceptional but recognizable, and along with HHV-6 DNA detection allow a prompt recognition of HHV6 skin rash.

Acute monocytic leukemia with coexpression of minor BCR–ABL1 and PICALM–MLLT10 fusion genes along with overexpression of HOXA9

The t(9;22)(q34;q11) translocation occurs in chronic myeloid leukemia (CML) and adult B‐cell acute lymphoblastic leukemia (ALL), leading to fusion of BCR to ABL1 and constitutive activation of ABL1 tyrosine kinase activity. The main BCR–ABL1 breakpoints result in P190 BCR–ABL1 or P210 BCR–ABL1 fusion proteins. The latter is found in almost all cases of CML and in one third of the cases of t(9;22)‐positive adult B‐ALL. P190 BCR–ABL1 is found in the remaining two thirds of t(9;22)‐positive adult B‐ALL cases but only exceptionally in CML. We describe here the first case of t(9;22)(q34;q11) associated with t(10;11)(p13;q14) in acute monocytic leukemia. The recurrent t(10;11)(p13;q14) translocation, usually found in acute myeloid leukemia (AML) and T‐ALL, merges PICALM to MLLT10. RT‐PCR enabled identification of PICALM–MLLT10 and BCR–ABL1 e1–a2 fusion transcripts; in the context of chronic and acute myeloid leukemia, the latter usually has a monocytic presentation. We also identified overexpression of HOXA9, a gene essential to myeloid differentiation that is expressed in PICALM–MLLT10 and MLL‐rearranged acute leukemias. This case fits with and extends a recently proposed multistage AML model in which constitutive activation of tyrosine kinases by mutations (BCR–ABL1) are associated with deregulation of transcription factors central to myeloid differentiation (HOXA9 secondary to PICALM–MLLT10).

Hemophagocytic Lymphohistiocytosis Due to Acute Myeloid LeukemiaRelapse: A Very Unusual Association

Hemophagocytic lymphohistiocytosis (HLH) diagnosed in the course of acute myeloid leukemia (AML) is generally triggered by treatment-induced infections. AML-induced HLH is a very rare situation for which no diagnostic or therapeutic guidelines are available. We report the occurrence of HLH in an AML5 post-transplant relapse. In our case, the absence of detectable pathogen and the parallel evolution between HLH and leukemia burden suggested a direct link between AML and HLH. We suggest that the diagnostic of AML-related HLH should be promptly considered in front of unexplained fever, cytopenia, liver dysfunction or neurological symptoms as therapeutic intervention is urgent in this life-threatening situation.

Prognostic value of early 18F-FDG PET scanning evaluation in immunocompetent primary CNS lymphoma patients

Primary central nervous system lymphoma (PCNSL) is a rare topographic variant of diffuse large B-cell lymphoma (DLBCL). While prognostic scales are useful in clinical trials, no dynamic prognostic marker is available in this disease. We report here the prognostic value of early metabolic response by 18F-FDG PET scanner (PET) in 25 newly diagnosed immunocompetent PCNSL patients. Induction treatment consisted of four cycles of Rituximab, Methotrexate and Temozolamide (RMT). Based on patients general condition, consolidation by high-dose Etoposide and Aracytine was given to responding patients. Brain MRI and PET were performed at diagnosis, after two and four cycles of RMT, and after treatment completion. Two-year progression-free (PFS) and overall survival (OS) were 62% and 74%, respectively for the whole cohort. Best responses after RMT induction were 18 (72%) complete response (CR)/CR undetermined (CRu), 4 (16%) partial response, 1 (4%) progressive disease and 2 (8%) stable disease. Response evaluation was concordant between MRI and PET at the end of induction therapy. Nineteen patients (76%) had a negative PET2. Predictive positive and negative values of PET2 on end-of-treatment (ETR) CR were 66.67% and 94.74%, respectively. We observed a significant association between PET2 negativity and ETR (p = 0.001) and longer PFS (p = 0.02), while having no impact on OS (p = 0.32). Two years PFS was 72% and 33% for PET2– and PET2+ patients, respectively (p < 0.02). PET2 evaluation may help to early define a subgroup of CR PCNSL patients with a favorable outcome.

Efficacy of chemotherapy or chemo-anti-PD-1 combination after failed anti-PD-1 therapy for relapsed and refractory hodgkin lymphoma: A series from lysa centers

Anti‐PD‐1 therapy provides high response rates in Hodgkin lymphoma (HL) patients who have relapsed or are refractory (R/R) to autologous stem cell transplantation (ASCT) and brentuximab vedotin (BV), but median progression free survival (PFS) is only one year. The efficacy of treatment following anti‐PD‐1 is not well known. We retrospectively investigated the efficacy of salvage therapies for unsatisfactory response to anti‐PD‐1 therapy, assessed by PET‐CT according to the Lugano criteria, in 30 R/R HL patients. Patients were highly pretreated before anti‐PD‐1 (70% received ASCT and 93% BV). Unsatisfactory responses to anti‐PD1 therapy were progressive disease (PD) (n = 24) and partial response (PR) (n = 6). For the 24 PD patients, median anti‐PD‐1 related PFS was 7.5 months (95%CI, 5.7‐11.6); 17 received subsequent CT alone (Group 1) and 7 received CT in addition to anti‐PD‐1 (Group 2). 16/24 patients (67%) obtained an objective response. In the 15 patients treated with the same CT, twelve obtained PR or complete response (CR). In Group 1, there were 7 CR (41%), 3 PR (18%), and 7 PD (41%). In Group 2, there were 4 CR (57%), 2 PR (29%), and 1 SD (14%). No unexpected toxicity was observed. Six patients who achieved response proceeded to allogeneic SCT. With a median follow‐up of 12.1 months (7‐14.7), the median PFS following the initiation of CT was 11 months (95% CI 6.3‐not reached) and the median of overall survival was not reached. These observations in highly pretreated HL patients suggest that anti‐PD‐1 therapy might re‐sensitize tumor cells to CT.

The role of radiotherapy as salvage and/or consolidation treatment in relapsed/refractory and high-risk diffuse large B-cell lymphoma

Many salvage therapies have been proposed for relapsed/refractory (R/R) diffuse large B‐cell lymphomas or for consolidation in the case of suboptimal response. Radiotherapy (RT) is one modality of salvage therapy, but its place is currently not well defined.