Humoral and cellular responses after a third dose of SARS-CoV-2 BNT162b2 vaccine in patients with lymphoid malignancies.

Patients with hematological malignancies have impaired immune response after two doses of BNT162b2 (Pfizer/BioNTech) vaccine against SARS-CoV-2. Here, in this observational study (registration number HDH F20210324145532), we measure SARS-CoV-2 anti-Spike antibodies, neutralizing antibodies and T-cell responses after immune stimulation with a third dose (D3) of the same vaccine in patients with chronic lymphocytic leukemia (n = 13), B cell non-Hodgkin lymphoma (n = 14), and multiple myeloma (n = 16)). No unexpected novel side effects are reported. Among 25 patients with positive anti-S titers before D3, 23 (92%) patients increase their anti-S and neutralizing antibody titer after D3. All 18 (42%) initially seronegative patients remain negative. D3 increases the median IFN-γ secretion in the whole cohort and induces IFN-γ secretion in a fraction of seronegative patients. Our data thus support the use of a third vaccine dose amongst patients with lymphoid malignancies, even though some of them will still have vaccine failure.

The evolution of mature cystic teratomas of the ovary into squamous cell carcinoma: two case reports and review of the literature.

Mature Cystic Teratomas (MCT) of the ovary or Dermoid Cysts are common benign tumours found in 10-20% of women. However, 0.2-2% of those cysts underwent malignant transformation. Squamous Cell Carcinoma (SCC) is the most frequent histological type reported in the literature.As 2021, there are limited reports of malignant tumours arising from MCT with no guidelines related to the management of these atypical cases. Herein, we describe two cases of MCT that evolved into SCC with different stages and prognosis and we review the current literature to date highlighting the potential risk of malignant transformation of these considered benign cysts and the need for strong evidence protocols for staging and treatment of this atypical entity.IMPACT STATEMENTWhat is already known on this subject? Mature Cystic Teratomas are found in 10-20% of women. However, a malignant behavior is observed in 2% of cases.What do the results of this study add? Our paper will describe two cases of malignant transformation of dermoid cyst in an effort to highlight the possible malignant risk of this entity and the need for specific management guidelines.What are the implications of these findings for clinical practice and/or further research? The prognosis of this converted cyst is very poor. By elaborating a standard management protocol for this tumour and operating every large cyst (>10 cm) in postmenopausal women, we may prevent this event.

Third dose of anti-SARS-CoV-2 vaccine for patients with cancer: Should humoral responses be monitored? A position article.

Taking into account higher risk of severe coronavirus disease 2019 or death among patients with cancer, as well as impaired immunogenicity after anti-SARS-CoV-2 vaccines, in addition to waning immunity, booster dosing appears mandatory in this patient population. This review sought to provide reasonable evidence so as to assist oncologists in their daily practice, helping them decide when an anti-SARS-Cov2 antibody (Ab) dosage should be scheduled after a full two-dose vaccination and, if necessary, propose an early third dose (D3). Such D3 could apply to non-responder patients with anti-Spike (S) Abs titres <40 binding Ab unit (BAU)/mL. For lowresponder patients with anti-S Ab titres between 40 BAU/mL and 100/260 BAU/mL (suggested area of uncertainty), an early D3 may similarly be proposed. Nevertheless, this D3 could be administered in a less urgent manner, taking into account associated comorbidities and regional epidemic incidence rates. This latter strategy may comprise a monthly dosage of anti-S titres so as to better assess the kinetics of waning immunity. For responder patients with anti-S titres above 260 BAU/mL, we suggest to follow the recommendations outlined for the general population. Given this context, patients with anti-S titres above 1000 BAU/mL should be given the possibility to undergo anti-S titre control after three months, designed to assess rapid humoral waning immunity. We strongly recommend that patients with cancer be included into observational serological monitoring studies or clinical trials that are dedicated to severe immunocompromised patients without any humoral seroconversion after D3.

Current perspectives for SARS-CoV-2 vaccination efficacy improvement in patients with active treatment against cancer.

A higher risk of death from coronavirus disease 19 has been shown for patients with solid cancers or haematological malignancies (HM). Thanks to the accelerated development of anti-SARS-SoV-2 vaccines in less than a year since the start of the global pandemic, patients with cancer were quickly prioritised in early 2021 for vaccination, however dependent on the very unequal availability at the global level. Impaired immunogenicity of SARS-CoV-2 mRNA vaccines in immunocompromised patients was rapidly reported as early as April 2021, although the vaccination fortunately appears to be generally effective without increasing the spacing. Worryingly, the humoral response of the SARS-CoV-2 vaccination is, however, considered insufficient in patients followed for HM, in particular when they are on anti-CD20 treatment. Thus, improving vaccination coverage by strengthening immune stimulation should be evaluated in patients under active treatment against cancer. Here, we discuss three different approaches: a third dose of early vaccine (repeated immune stimulation), heterologous prime-boost vaccination (multimodal immune stimulation) and a double-dose strategy (maximisation of immune response). Dedicated therapeutic trials, currently almost non-existent, seem rapidly necessary.

First-line therapy for chronic lymphocytic leukemia in patients older than 79 years is feasible and achieves good results: A FILO retrospective study.

The mean age at diagnosis of chronic lymphocytic leukemia (CLL) is 72 years, with 22.8% of patients being older than 80 years. However, the elderly are underrepresented in clinical studies of CLL. We performed a retrospective study of CLL patients aged 80 years or older at the initiation of first-line therapy in hospitals affiliated with the French intergroup on CLL (French Innovative Leukemia Organization) between 2003 and 2013. Here, we describe the clinical and biological characteristics, treatment, and outcomes for 201 patients. The median age of the cohort was 83.2 years (80-92 years). The median Cumulative Index Rating Scale comorbidity score was 5 and the median creatinine clearance was 48 mL/min (Cockcroft-Gault formula). At treatment initiation, Binet stage was A (26.4%), B (27.9%), or C (40.3%). Therapy consisted mainly of chlorambucil (65.7%), bendamustine (10.5%), and rituximab (44.3%) as follows: chlorambucil alone (45.3%) or immunochemotherapy (48.3%) with rituximab + chlorambucil (22.7%), rituximab + bendamustine (10.4%), or rituximab + cyclophosphamide + dexamethasone (5.5%). The overall response rate was 66.2% with 31.8% clinical complete remission. The median overall and progression-free survival from treatment initiation was 53.7 and 18.3 months, respectively. These results suggest that treatment is feasible in this age group, even with immunochemotherapy. Thus, prospective trials should target this population and oncogeriatric evaluation and new targeted therapies should be part of such future trials.

Management of central nervous system involvement in chronic lymphocytic leukaemia: a retrospective cohort of 30 patients.

Central nervous system involvement (CNSi) is a rare and poorly reported complication of chronic lymphocytic leukaemia (CLL). Establishing cause and effect between the CLL and the neurological symptoms remains challenging. We have analysed a retrospective cohort of 30 CLL patients with CNSi, documented by lymphocytic infiltration either by flow cytometry of the cerebrospinal fluid (CSF; n = 29) or CNS biopsy (n = 1). Neurological symptoms were heterogeneous. At the time of CNSi, less than half of the patients had a progressive CLL and 20 had never been treated for CLL. Initial treatment with fludarabine-based immuno-chemotherapy, with or without intra-CSF therapy, led to durable response in eight out of nine untreated patients. In contrast, 50% patients receiving various prior treatments needed additional therapy within a median of 4 months (1-16). Ibrutinib led to complete response in 4/4 heavily pre-treated patients. From CNSi, 5-year overall survival was 72% and 48% for treatment-naïve and previously treated patients respectively (P = 0·06); 5-year progression-free survival (PFS) was 43% and 0% (P = 0·125). 17p deletion was significantly associated with poor PFS (P = 0·006). CNSi may be the only sign of progression of CLL and should be considered an initiation criterion of systemic treatment. Prognosis seemed to be related to CLL characteristics rather than to CNSi itself.

Azacitidine-Induced Interstitial Pneumonitis.

Azacitidine is a demethylating and cytotoxic drug for the treatment of adult patients with (1) myelodysplastic syndromes, (2) chronic myelomonocytic leukemia, and (3) acute myeloid leukemia who are not eligible for induction treatment or hematopoietic stem cell transplantation. Widely described in the literature, the main adverse events are hematotoxicity, digestive toxicity, asthenia, cutaneous toxicity, and infections such as neutropenic sepsis and pneumonia. The pivotal phase III comparative and supporting studies did not point out interstitial pneumonitis as a significant adverse event. Rare clinical data from literature report interstitial lung disease secondary to azacitidine administration, which should therefore be considered as a serious potential adverse event. We, herein, report a case of an 86-year-old white woman with acute myeloid leukemia and azacitidine-induced interstitial pneumonitis.

Successful re-treatment of a relapsed V600E mutated HCL patient with low-dose vemurafenib.

Hairy cell leukemia (HCL) is a chronic B-cell lymphoproliferative disorder that accounts for 2% of all leukemia. Recent identification of the recurrent V600E BRAF mutation in a majority of HCL patients has led some teams to evaluate the clinical potential of vemurafenib, a BRAF V600 specific inhibitor in a limited number of refractory HCL patients. Recently, we published the case of an HCL patient successfully treated with a low dose of vemurafenib. Eight months after the ending of treatment this patient relapsed. We present here the successful retreatment of this patient with a second line of vemurafenib. Our data suggest for the first time that vemurafenib at the dose of 240 mg once a day could be sufficient to maintain a complete hematological remission after an initial induction treatment with low-dose vemurafenib (2 × 240 mg) daily without inducing major toxicity.

High-dose chemotherapy with carmustine, etoposide, cytarabine and melphalan followed by autologous stem cell transplant is an effective treatment for elderly patients with poor-prognosis lymphoma.

Autologous stem cell transplant (ASCT) after high-dose chemotherapy (HDT) increases overall survival when used in relapsed non-Hodgkin lymphoma (NHL) in patients under 65 years old. Limited experience is available for older patients. We present a retrospective analysis of 73 consecutive patients aged over 65 years treated for aggressive or relapsed lymphoma by HDT with carmustine, etoposide, cytarabine and melphalan (BEAM) at full dosage followed by ASCT. Patient data were obtained from medical charts from two institutions. Median age was 67 years (65-74). Significant comorbidities were present in 24.7% of patients. The median number of days for grade 4 neutropenia was 9 (5-18). The early treatment-related mortality rate (<100 days) was 2.7%. The estimated 2-year progression-free survival and overall survival rates were 67.2% and 78.5%, respectively. In conclusion, the full-dose HDT-ASCT regimen is feasible, safe and efficient in selected patients over 65 years old.

Are nilotinib-associated vascular adverse events an under-estimated problem?

Vascular adverse events have been reported with nilotinib, a tyrosine kinase inhibitor prescribed for chronic myeloid leukaemia. However, few data specify their incidence, or whether they occur in predisposed patients. Hence, we prospectively studied 30 consecutive patients to assess the frequency of such adverse reactions and determine whether the patients presenting with these adverse events bear predisposing factors. From 3 to 73 months after nilotinib initiation, 10 of the 30 patients experienced vascular events. Three patients of these 10 were devoid of any patent cardiovascular risk factor, except for age. This study points out an occurrence more frequent than expected of vascular adverse events associated with nilotinib (> 30% vs. < 1% in summary of product characteristics), and particularly of vascular events of late onset in patients with no pre-existing risk factors.

Recommendations of the SFH (French Society of Haematology) for the diagnosis, treatment and follow-up of hairy cell leukaemia.

Hairy cell leukaemia (HCL) is a rare haematological malignancy, with approximately 175 new incident cases in France. Diagnosis is based on a careful examination of the blood smear and immunophenotyping of the tumour cells, with a panel of four markers being used specifically to screen for hairy cells (CD11c, CD25, CD103 and CD123). In 2011, the V600E mutation of the BRAF gene in exon 15 was identified in HCL; being present in HCL, it is absent in the variant form of HCL (HCL-v) and in splenic red pulp lymphoma (SRPL), two entities related to HCL. The management of patients with HCL has changed in recent years. A poorer response to purine nucleoside analogues (PNAs) is observed in patients with more marked leukocytosis, bulky splenomegaly, an unmutated immunoglobulin variable heavy chain (IgVH) gene profile, use of VH4-34 or with TP53 mutations. We present the recommendations of a group of 11 experts belonging to a number of French hospitals. This group met in November 2013 to examine the criteria for managing patients with HCL. The ideas and proposals of the group are based on a critical analysis of the recommendations already published in the literature and on an analysis of the practices of clinical haematology departments with experience in managing these patients. The first-line treatment uses purine analogues: cladribine or pentostatin. The role of BRAF inhibitors, whether or not combined with MEK inhibitors, is discussed. The panel of French experts proposed recommendations to manage patients with HCL, which can be used in a daily practice.

Hodgkin's Lymphoma in Older Patients: an Orphan Disease?

Hodgkin Lymphoma HL can be cured in the large majority of younger patients, but prognosis for older patients, especially those with advanced-stage disease, has not improved substantially. The percentage of HL patients aged over 60 ranges between 15% and 35%. A minority of them is enrolled into clinical trials. HL in the elderly have some specificities: more frequent male sex, B-symptoms, advanced stage, sub diaphragmatic presentation, higher percentage of mixed cellularity, up to 50% of advanced cases associated to EBV. Very old age (>70) and comorbidities are factor of further worsening prognosis. Like in younger patients, ABVD is the most used protocol, but treatment outcome remains much inferior with more frequent, severe and sometimes specific toxicities. Few prospective studies with specific protocols are available. The main data have been published by the Italian Lymphoma Group with the VEPEMB schedule and the German Hodgkin Study Group with the PVAG regimen. Recently, the Scotland and Newcastle Lymphoma Study Group published the SHIELD program associating a prospective phase 2 trial with VEPEMB and a prospective registration of others patients. Patients over 60y with early-stage disease received three cycles plus radiotherapy and had 81% of 3-year overall survival (OS). Those with advanced-stage disease received six cycles, with 3-year OS of 66%. The role of geriatric and comorbidity assessment in the treatment's choice for HL in the elderly is a major challenge. The combination of loss of activities of daily living combined with the age stratification more or less 70y has been shown as a simple and effective survival model. Hopes come from promising new agents like brentuximab-vedotin (BV) a novel antibody-drug conjugate. The use of TEP to adapt the combination of chemotherapy and radiotherapy according to the metabolic response could also be way for prospective studies.

Monosomal karyotype improves IPSS-R stratification in MDS and AML patients treated with Azacitidine.

IPSS-R classifies cytogenetic abnormalities into five prognostic groups for survival. Monosomal karyotype (MK) is not a subgroup of IPSS-R. Additional prognostic information from MK in poor and very poor karyotype has been recently shown. The aim of our study was to determine the prognostic value of IPSS-R and MK for response and survival in AZA-treated high-risk MDS and AML with 20-30% of blasts patients. The study population included 154 patients who were classified according to IPSS-R. IPSS-R was not predictive of response (intermediate, 64%; poor, 44%; very poor, 56%; P = 0.28) or survival (intermediate, 25 months; poor, 12 months; very poor, 11 months; P = 0.14). Twenty-one patients (15%) presented with MK and had a median OS of 9 months. Patients with a very high IPSS-R score without MK had a median OS of 15 months, while patients with a high IPSS-R score without MK had a median OS of 13 months (P = 0.18). We reclassified patients into the following three groups to include MK status: very high (MK only; OS median: 9 months), high (very high IPSS-R without MK and high IPSS-R without MK; OS median: 14 months) and intermediate (OS median: 25 months). As in recent publication including MK prognostic, we confirmed that this classification was predictive for survival in AZA treated patients (P = 0.008). IPSS-R failed to discriminate between the prognostic subgroups. Stratification with MK has value in the prognosis of our cohort of AZA-treated patients.

Interleukin-10 gene polymorphisms are associated with freedom from treatment failure for patients with Hodgkin lymphoma.

BACKGROUND: Hodgkin lymphoma (HL) is a lymphoid malignancy characterized by the production of various cytokines possibly involved in immune deregulation. Interleukin-10 (IL-10) serum levels have been associated with clinical outcome in patients with HL. Because host genetic variations are known to alter the expression and function of cytokines and their receptors, we investigated whether genetic variations influence clinical outcome of patients with HL. METHODS: A total of 301 patients with HL who were treated within randomized trials by the German Hodgkin Study Group were included in this exploratory retrospective study. Gene variations of IL-10 (IL-10(-597AC), rs1800872; IL-10(-824CT), rs1800871; IL-10(-1087AG), rs1800896; IL-10(-3538AT), rs1800890; IL-10(-6208CG), rs10494879; IL-10(-6752AT), rs6676671; IL-10(-7400InDel)), IL-13 (IL-13(-1069CT), rs1800925; IL-13(Q144R), rs20541), and IL-4R (IL-4R(I75V), rs1805010; IL-4R(Q576R), rs1801275) were genotyped. RESULTS: Inferior freedom from treatment failure (FFTF) was found in patients harboring the IL-10(-597AA), IL-10(-824TT), or the IL-10(-1087AA) genotype. In contrast, the IL-10(-1087G-824C-597C) haplotype present in about 48% of analyzed HL patients is nominally significant for a better FFTF in a Cox-Regression model accounting for stage and treatment. No associations were observed between the other IL-10 gene variations, IL-13(-1069CT), IL-13(Q144R), IL-4R(I75V), IL-4R(Q576R) and the clinical outcome of patients with HL. CONCLUSIONS: Our study provides further evidence that proximal IL-10 promoter gene variations are associated with clinical course of patients with HL. However, treatment success and survival rates are already at a very high rate, supporting the need to design studies focusing on identification of predictors to reduce the side effects of therapy.

Treatment decisions for elderly patients with haematological malignancies: a dilemma.

Over the past decade, haematological malignant diseases have been diagnosed with increasing frequency in patients older than 65 years. The management of these diseases is particularly difficult in elderly patients, as non-tumour-related life expectancy is highly variable and the benefit-to-risk ratio for oncological treatments depends on comorbidities and pharmacological factors. Very few data are available in very old or frail patients, and management decisions are usually based on data obtained in younger patients. Patients might, therefore, be overtreated or undertreated without clear clinical or biological justification. In this Review we discuss the management of haematological malignant diseases in the elderly, with respect to biology or pharmacokinetic and pharmacodynamic features. We focus on acute myeloid leukaemia and aggressive lymphoma. Additionally, we discuss how the implementation of geriatric tools, such as comprehensive geriatric assessment scores, in the clinical management of elderly patients might help to adapt treatment to meet individual patients' needs.

Depsipeptide induces cell death in Hodgkin lymphoma-derived cell lines.

A variety of genetic and epigenetic abnormalities were characterized over the last years in Hodgkin and Reed-Sternberg (H-RS) cells of classic Hodgkin Lymphoma (cHL). It was speculated that simultaneous inhibition of multiple signalling pathways might be a promising strategy to target this tumor entity. In the present study we tested the effect of histone deacetylase (HDAC) inhibition using depsipeptide (also known as romidepsin, FK228, FR901228 or NSC-630176) in cHL cell lines in vitro. Molecular mechanisms of toxicity were analyzed using RNA expression analysis and functional assays. It is shown that depsipeptide is effective at submicromolar concentrations and acts mainly by apoptosis induction, upregulation of p21 and cell cycle inhibition in G2/M. Of special note, HDAC mediated toxicity in H-RS cells does not require RelA/p65 downregulation, which was previously shown to drive the malignant phenotype of H-RS cells. In summary, depsipeptide induced protein acetylation results in transcriptional changes of a large number of pathogenetically relevant genes and increased RelA/p65 binding activity in cHL cell lines. Our preclinical data suggest that HDAC inhibition using depsipeptide might be a promising approach for the treatment of cHL patients.

Elevated pretreatment interleukin-10 serum level is an International Prognostic Score (IPS)-independent risk factor for early treatment failure in advanced stage Hodgkin lymphoma.

Early treatment failure is still a clinical challenge despite high cure rates in Hodgkin lymphoma (HL) patients. To identify the biological risk factors predicting early treatment failure, we performed a retrospective case-control study. Forty-seven pretherapeutic serum samples were available from 47 advanced stage HL patients with early treatment failure and from 47 matched controls in complete remission. All patients were treated within German Hodgkin Study Group phase 3 trials. Matching was done according to treatment, stage, age, gender, International Prognostic Score (IPS) and histological subtype. Pretreatment serum levels of 30 cytokines, chemokines and soluble receptors were determined using immunoassays and flow cytometer based cytometric bead arrays. Only interleukin-10 serum levels were significantly associated with early treatment failure after statistical correction for multitesting (paired-sign test, p = 0.0008). In summary, pretherapeutic interleukin-10 levels are associated with early treatment failure within 12 months after the end of treatment in advanced stage HL independently from known clinical factors such as age or IPS.