Pathophysiologic implications of elevated prevalence of hereditary alpha-tryptasemia in all mastocytosis subtypes.

BACKGROUND: Mastocytosis and monoclonal mast cell (MC) activation syndrome (MMAS) are heterogeneous conditions characterized by the accumulation of atypical MCs. Despite the recurrent involvement of KIT mutations, the pathophysiologic origin of mastocytosis and MMAS is unclear. Although hereditary α-tryptasemia (HαT, related to TPSAB1 gene duplication) is abnormally frequent in these diseases, it is not known whether the association is coincidental or causal. OBJECTIVE: We evaluated the prevalence of HαT in all mastocytosis subtypes and MMAS and assessed the pathophysiologic association with HαT. METHODS: Clinical data, laboratory data, KIT mutations, TPSAB1 duplication (assessed by droplet digital PCR), and HαT prevalence were retrospectively recorded for all patients with mastocytosis and MMAS registered in the French national referral center database and compared to a control cohort. To increase the power of our analysis for advanced systemic mastocytosis (advSM), we pooled our cohort with literature cases. RESULTS: We included 583 patients (27 with MMAS and 556 with mastocytosis). The prevalence of HαT in mastocytosis was 12.6%, significantly higher than in the general population (5.7%, P = .002) and lower than in MMAS (33.3%, P = .02). HαT+ patients were more likely to have anaphylactic reactions and less likely to have cutaneous lesions than HαT- patients (43.0% vs 24.4%, P = .006; 57.7% vs 75.6%, respectively, P = .006). In the pooled analysis, the prevalence of HαT was higher in advSM (11.5%) than in control cohorts (5.2%, P = .01). CONCLUSION: Here we confirm the increase incidence of anaphylaxis in HαT+ mastocytosis patients. The increased prevalence of HαT in all subtypes of systemic mastocytosis (including advSM) is suggestive of pathophysiologic involvement.

Characteristics and outcomes associated with CD2 and CD25 expression on bone marrow mast cells in patients with systemic mastocytosis.

Not available.

Histological characterization of liver involvement in systemic mastocytosis.

BACKGROUND AND AIMS: Systemic mastocytosis (SM) is characterized by the accumulation of atypical mast cells (MCs) in organs. Liver histology of SM has been marginally described and accurate histological classification is critical, given the consequences of aggressive SM diagnosis. We aimed to describe the histological features associated with liver SM using updated tools. METHODS: Using the database of the French Reference Centre for Mastocytosis, we retrospectively identified patients with a liver biopsy (LB) and a diagnosis of SM. All LB procedures were performed according to the local physician in charge and centrally reviewed by an expert pathologist. RESULTS: A total of 28 patients were included: 6 had indolent SM, 9 had aggressive SM, and 13 had SM with an associated hematologic neoplasm. Twenty-five (89%) patients presented hepatomegaly, and 19 (68%) had portal hypertension. The LB frequently showed slight sinusoid dilatation (82%). Fibrosis was observed in 3/6 indolent SM and in almost all advanced SM cases (21/22), but none of them showed cirrhosis. A high MC burden (>50 MCs/high-power field) was correlated with elevated blood alkaline phosphatase levels (p = .030). The presence of portal hypertension was associated with a higher mean fibrosis grade (1.6 vs. 0.8 in its absence; p = .026). In advanced SM, the presence of nodular regenerative hyperplasia (NRH) was associated with decreased overall survival (9.5 vs. 46.3 months, p = .002). CONCLUSIONS: MC infiltration induced polymorphic hepatic lesions and the degree of fibrosis is associated with portal hypertension. NRH identifies a poor prognosis subgroup of patients with advanced SM. Assessing liver histology can aid in SM prognostic evaluation.

Efficacy and safety of mammalian target of rapamycin inhibitors in systemic mastocytosis: A nationwide French pilot study.

Systemic mastocytosis (SM) corresponds to a rare and heterogeneous spectrum of diseases characterized by the accumulation of atypical mast cells (MCs). Advanced mastocytosis (Adv-SM) is associated with poor survival; in contrast, patients with non-advanced SM (non-Adv-SM) usually have a normal life expectancy but may experience poor quality of life. Despite recent therapeutic progress including tyrosine kinase inhibitors, new treatment options are needed for refractory and/or intolerant patients with both severely symptomatic and Adv-SM. In vitro, the mTOR pathway is activated in MCs from patients bearing the KIT D816V mutation. Furthermore, rapamycin induces the apoptosis of KIT D816V MCs selectively. In this nationwide study, we report the outcomes of patients diagnosed with SM and treated with a mammalian target of rapamycin inhibitor (imTOR) within the French National Reference Center for mastocytosis (CEREMAST). All patients registered were relapsing, treatment-refractory, or ineligible for other cytoreductive therapy. Non-Adv-SM patients received imTOR as a monotherapy (rapamycin/everolimus), and Adv-SM patients received imTOR as a monotherapy or in combination with cytarabine. The objective response rate (ORR) in non-Adv-SM was 60% (partial response in 40% and major response in 20%), including reductions in skin involvement, mediator release symptoms, and serum tryptase. In the Adv-SM group, the ORR was 20% (including one major response and one partial response, both in patients with a KIT D816V mutation), which enabled a successful bridge to allogeneic stem cell transplantation in one patient. Our results suggest that imTOR treatment has potential benefits in patients with SM harboring a KIT D816V mutation.

Comparison of prognostic scores according to WHO classification in 170 patients with advanced mastocytosis and C-finding treated with midostaurin.

Advanced systemic mastocytosis (AdvSM) encompasses heterogeneous mastocytosis subtypes and is associated with poor outcomes. Although midostaurin was the first tyrosine kinase inhibitor to be approved for AdvSM patients, long-lasting responses are limited. The mutation-Adjusted Risk Score (MARS), the International Prognostic Scoring System for mastocytosis (IPSM) and the Global Prognostic Score for Systemic Mastocytosis (GPSM) have been established to characterize the outcomes of patients with overall AdvSM. However, given the outcome's dependency on the AdvSM subtype, prognostic characterization within each subtype is critical. We aimed to study the predictive ability using Harrell's concordance index of prognostic scores according to the AdvSM subtype. We conducted a nationwide retrospective study using the French mastocytosis reference center's registry and included all midostaurin-treated patients with C finding. Overall, 170 patients were identified: 46 aggressive SM (ASM), 11 mast cell leukemia (MCL), and 113 SM with associated hematological neoplasm (SM-AHN). All risk scores improved their discriminative value for overall survival (OS) when combined with the AdvSM subtype. The best predictive value was for adjusted MARS (C-index = 0.689), followed by GPSM (C-index = 0.677) and IPSM (C-index = 0.618). In a multivariable analysis, MARS stratification and the AdvSM subtype were both prognostic for OS. Accordingly, five subgroups of patients with AdvSM and a different median OS were identified: 9.9 months for MCL, 24 months for intermediate/high-risk SM-AHN, 33 months for intermediate/high-risk ASM, 58 months for low-risk SM-AHN and was not reached for low-risk ASM (p < 0.001). The AdvSM subtype and the MARS are the most predictive of OS and should prompt specific management.

Rehabilitation program combining physical exercise and heart rate variability biofeedback in hematologic patients: a feasibility study.

PURPOSE: Hematologic patients have a poorer health-related quality of life due to the disease and its treatments. Non-pharmacological interventions represent an opportunity in tertiary cancer prevention to manage persistent symptoms and support patients in their return to active daily living. This interventional study aimed to evaluate the feasibility of a program combining physical exercise (PE) and heart rate variability biofeedback (HRVB) in hematologic patients. METHOD: Hematologic patients in remission within 6 months participated in a 12-week rehabilitation program including 24 supervised sessions of PE associated with 10 supervised sessions of HRVB and daily home-based practice of paced breathing. We assessed patient adherence, fatigue, physical function, and heart rate variability. RESULTS: Twenty patients were included, 17 completed the protocol and 3 dropped out due to disease progression or time constraints; no adverse events or incidents were reported. Participation rates were 85% for PE and 98% for HRVB-supervised sessions. Significant improvements of physical capacity (6-min walk test, p < 0.001; 50-foot walk test, p < 0.001), muscle strength (grip force test, p < 0.01), and flexibility (toe-touch test, p < 0.001; back scratch test, p < 0.05) were measured. Coherence ratio (p < 0.001) and low-frequency spectral density of HRV signal (p < 0.003) increased significantly, suggesting improved autonomic function. Fatigue, static balance, and other time and frequency indicators of HRV were not improved (all p > 0.05). CONCLUSION: A rehabilitation program combining PE and HRVB is feasible in hematologic patients and effective on physical function. Further research with a larger sample size is needed to investigate effectiveness on patients' autonomic functions and their impacts on symptomatology.

Blood transfusion in hematologic intensive care unit.

BACKGROUND: There is increasing evidence that excessive blood transfusion may be associated with impaired survival or cardiovascular events. One way to reduce the number of red blood cells (RBCs) is to transfuse 1 unit (1RBC) instead of 2 units of RBCs (2RBC). STUDY DESIGN AND METHODS: Patients requiring blood transfusions in hematologic intensive care unit were included in a prospective study using a single RBC unit per transfusion and were compared with an historical cohort who received 2 RBC units per transfusion. RESULTS: A total of 1323 units were transfused to 126 patients between 2013 and 2014. The 186 patients in the comparative cohort received a total of 1824 RBC units in a 2-RBC-unit policy between 2010 and 2012. The mean number of units was 7.35 (SD, 5.9 units; 95% confidence interval [CI], 6.5-8.2 units) in the 1RBC group and 8.14 units (SD, 6.2 units; 95% CI, 7.3-8.9 units) in the 2RBC group. The absolute mean difference was -0.79 (95% CI, -1.98 to 0.40; p = 0.09). In the 1RBC allogeneic hematopoietic stem cell transplantation (allo-HSCT) subgroup, a significant reduction in the number of RBC units transfused was observed in comparison with the historical 2RBC allo-HSCT group (5 units vs. 7.7 units; p = 0.01). No anemia-related side effects were reported. Overall survival did not differ between the two groups. CONCLUSION: The 1RBC transfusion policy made is feasible in patients with transient hematologic toxicity after chemotherapy. The number of units transfused between the two groups was not different. However, in the allo-HSCT group, the use of a single RBC unit reduced significantly RBC consumption. A randomized trial comparing the two strategies is planned with a medicoeconomic evaluation.

Mantle cell lymphoma epidemiology: a population-based study in France.

Only limited population-based data are available on mantle cell lymphoma (MCL), a relatively rare and aggressive mature B cell non-Hodgkin lymphoma (NHL) entity. We conducted an epidemiological study based on the three French registries devoted to haematological malignancies over the period 2002-2006. Main clinical features and management characteristics were collected. Incidence and survival rates were estimated, and independent prognostic factors were analysed. MCL was diagnosed in 135 patients between 2002 and 2006. Seventy-four percent of patients were men. Age-standardised incidence rate of MCL (per 100,000) was 1.1 in men and 0.26 in women. Median age at diagnosis was 72 years (range 30-92). Advanced-stage (III or IV) disease was diagnosed in 81.5 % of patients, and 55 % of them were identified as high risk according to MCL International Prognostic Index (MIPI). Median net survival time was 41 months (95 % confidence interval (CI), 38-62). Main independent prognostic factors were age at diagnosis, performance status and use of rituximab in first-line treatment. Median overall survival was 36 months (95 % CI, 27-40) for high MIPI and 60 months (95 % CI, 35-74) for low/intermediate MIPI patients (p = 0.02). This study confirms that MCL remains an aggressive NHL with a median overall survival less than 4 years and demonstrates that the use of rituximab has modified overall survival duration.

[Secondary cancers following allogeneic hematopoietic stem cell transplantation: Guidelines from the Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC)]. / Cancers secondaires après allogreffe de cellules souches hématopoïétiques : recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC).

The Francophone Society of Bone Marrow Transplantation and Cellular Therapy (SFGM-TC) held the 13th edition of the Clinical Practices Harmonization Workshops. Our workgroup reviewed the current data on the incidence, screening methods and international guidelines for the prevention of secondary solid cancers following allogeneic hematopoietic stem cell transplantation. The purpose of this workshop was to provide recommendations for the screening and prevention of secondary malignancies to Francophone transplantation centers.

One Haemolytic Anaemia May Hide Another: Paroxysmal Nocturnal Haemoglobinuria Masquerading As Plasmodium Falciparum Infection.

Background: Paroxysmal nocturnal haemoglobinuria (PNH) is a rare, genetic and acquired haematologic disease that causes complement-mediated intravascular haemolytic anaemia, thrombosis and bone marrow failure. Case description: A 27-year-old migrant patient attended the emergency department in a context of fever and chills over the previous few days as well as chronic fatigue, dyspnoea and chest pain. His medical history included chronic anaemia and erectile dysfunction. Initial biology showed a haemoglobin of 6.3 g/dl, platelets of 25,000/µl, total leucocytes of 3,500/µl with 1,500 neutrophils. B12 vitamin, folic acid, ferritin and thyroid stimulating hormone were normal. Lactate dehydrogenase levels were high and haptoglobin was non-measurable. C-reactive protein was 46.1 mg/l. A thick blood smear revealed Plasmodium falciparum infection with 0.1% parasitaemia. The patient was treated with an oral combination of artemether and lumefantrine. Three weeks later, the patient consulted the infectious disease department given the lack of clinical improvement. The cytopenias worsened, and lactate dehydrogenase (LDH) and reticulocytes increased. Tests for schistocytes, a thick blood smear for malaria and a direct Coombs test were negative; a myelogram was reassuring. An abdominal, pelvic and thoracic CT scan showed a mild hepatomegaly with no focal lesion and no splenomegaly or adenomegaly. A 12-colour flow cytometry unveiled a PNH clone on 90.9545% of neutrophils and 80.7371% of monocytes. Discussion: PNH patients can be vulnerable to parasites infection (such as P. falciparum) as it may trigger breakthrough haemolysis through uncontrolled resurgence of activity of the complement system. In our patient, P. falciparum infection was a confounding factor, as it commonly causes haemolytic anaemia and thrombocytopenia, and patients living in malaria-endemic regions can carry low parasitaemia while being slightly symptomatic or asymptomatic. LEARNING POINTS: Plasmodium falciparum infection can cause breakthrough haemolysis in patients with paroxysmal nocturnal haemoglobinuria.Low P. falciparum parasitemia in patients living in malaria-endemic regions is not always significant as these patients often carry acquired immunity.Patients from malaria-endemic regions presenting with severe sickness and low P. falciparum parasitemia must be assessed for other diseases, as it cannot explain heavy illness.Patients presenting with haemolytic anaemia, no schistocytes, a negative direct Coombs test and other unexplained cytopenia such as thrombocytopenia/neutropenia and other unexplained clinical manifestations such as dyspnoea, chest pain or erectile dysfunction should be assessed for paroxysmal nocturnal haemoglobinuria.

[A rare case of non-secretory multiple myeloma]. / Un cas rare de myélome multiple non-sécrétant.

An 88-year-old man is sent to hospital because of a rapid worthening of his general state. A myelogram is obtained following the discovery of hypercalcemia associated with a diminished glomerular filtration rate and the discovery of osteolytic lesions, showing a massive proliferation of plasma cells. The lack of plasma and urine detection of both monoclonal antibodies and immunoglobulin light chains, as well as an immature plasma cell phenotype, suggest the diagnosis of non-secretory multiple myeloma. This article aims to describe the atypical clinical presentation of a rare case of multiple myeloma.

Effective Anti-SARS-CoV-2 Immune Response in Patients With Clonal Mast Cell Disorders.

BACKGROUND: Mast cells are key players in innate immunity and the TH2 adaptive immune response. The latter counterbalances the TH1 response, which is critical for antiviral immunity. Clonal mast cell activation disorders (cMCADs, such as mastocytosis and clonal mast cell activation syndrome) are characterized by abnormal mast cell accumulation and/or activation. No data on the antiviral immune response in patients with MCADs have been published. OBJECTIVE: To study a comprehensive range of outcomes in patients with cMCAD with PCR- or serologically confirmed coronavirus disease 2019 and to characterize the specific anti-severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) immune response in this setting. METHODS: Clinical follow-up and outcome data were collected prospectively over a 12-month period by members of the French Centre de Référence des Mastocytoses rare disease network. Anti-SARS-CoV-2-specific T-cell activity was measured with an ELISA, and humoral responses were evaluated by assaying circulating levels of specific IgG, IgA, and neutralizing antibodies. RESULTS: Overall, 32 patients with cMCAD were evaluated. None required noninvasive or mechanical ventilation. Two patients were admitted to hospital for oxygen and steroid therapy. The SARS-CoV-2-specific immune response was characterized in 21 of the 32 patients. Most had high counts of circulating SARS-CoV-2-specific, IFN-γ-producing T cells and high titers of neutralizing antispike IgGs. The patients frequently showed spontaneous T-cell IFN-γ production in the absence of stimulation; this production was correlated with basal circulating tryptase levels (a marker of the mast cell burden). CONCLUSIONS: Patients with cMCADs might not be at risk of severe coronavirus disease 2019, perhaps due to their spontaneous production of IFN-γ.

Heart rate variability biofeedback in chronic disease management: A systematic review.

BACKGROUND: Heart rate variability biofeedback (HRVB) is a non-pharmacological intervention used in the management of chronic diseases. METHOD: A systematic search was performed according to eligibility criteria including adult chronic patients, HRVB as main treatment with or without control conditions, and psychophysiological outcomes as dependent variables. RESULTS: In total, 29 articles were included. Reported results showed the feasibility of HRVB in chronic patients without adverse effects. Significant positive effects were found in various patient profiles on hypertension and cardiovascular prognosis, inflammatory state, asthma disorders, depression and anxiety, sleep disturbances, cognitive performance and pain, which could be associated with improved quality of life. Improvements in clinical outcomes co-occurred with improvements in heart rate variability, suggesting possible regulatory effect of HRVB on autonomic function. CONCLUSIONS: HRVB could be effective in managing patients with chronic diseases. Further investigations are required to confirm these results and recommend the most effective method.

[Establishment of Hematopoietic cell transplantation program in developing countries : Guidelines from the francophone Society of bone marrow transplantation and cellular therapy (SFGM-TC)]. / Mise en place d'un programme de greffe de cellules souches hématopoïétiques dans les pays en voie de développement. Recommandations de la Société francophone de greffe de moelle et de thérapie cellulaire (SFGM-TC).

Hematopoietic cell transplantation (HCT) is the curative treatment for many malignant and non-malignant blood disorders and some solid cancers. However, transplant procedures are considered tertiary level care requiring a high degree of technicality and expertise and generating very high costs for hospital structures in developing countries as well as for patients without health insurance. During the 11th annual harmonization workshops of the francophone Society of bone marrow transplantation and cellular therapy (SFGM-TC), a designated working group reviewed the literature in order to elaborate unified guidelines, for developing the transplant activity in emerging countries. Access to infrastructure must comply with international standards and therefore requires a hospital system already in place, capable of accommodating and supporting the HCT activity. In addition, the commitment of the state and the establishment for the financing of the project seems essential.

Adapted physical activity and cardiac coherence in hematologic patients (APACCHE): study protocol for a randomized controlled trial.

BACKGROUND: Hematologic malignancies and their treatments are recognized for their significant long-term adverse effects on health-related quality of life. As a part of cancer treatment, physical exercise is known to improve physical functioning, but there are still questions regarding its impact on psychological and emotional functioning. Nonetheless, heart rate variability biofeedback (HRVB) is recognized for its positive effects on autonomic nervous system balance and emotional self-regulation. The Adapted Physical Activity and Cardiac Coherence in Hematologic Patients (APACCHE) protocol is a randomized, controlled superiority trial designed to evaluate the effects of HRBV training combined with an adaptive physical activity (APA) program compared to APA alone on the post-treatment quality of life of adult hematologic patients. METHODS: Seventy patients aged 18-70 years, with various forms of hematological malignancies, in post-treatment remission within six months prior to beginning the study and who have been prescribed APA by a hematologist, will be randomly allocated in a 1:1 ratio to two 12-week treatment groups: HRVB + APA versus APA alone. APA sessions will consist of aerobic and resistance training for 1-h twice weekly. The HRVB training will consist of controlled breathing exercises with biofeedback of heart rate variability for 10 sessions and will include a daily home-based practice. The primary outcome will be to evaluate health-related quality of life (QLQ-C30, SF-36). The secondary outcomes will be to evaluate fatigue (MFI-20); anxiety and depression (HADS); clinical status with blood pressure, progression-free survival, overall survival, and body mass index; heart rate variability level and cardiac coherence score. All of these assessments will be evaluated initially (T1), 6 weeks after (T2), at the end of the 12 weeks (T3), and then at a 12-week post-intervention follow-up (T4). DISCUSSION: To our knowledge, this is the first protocol to investigate the additional value of HRVB on physical exercise. In addition, there has been no study previously published about HRVB in hematologic patients. We hypothesize that overall quality of life and psychological and physical functioning will be improved, potentially offering a better understanding of supportive cancer care in hematology and inferring new perspectives in psychophysiological research in cancer. TRIAL REGISTRATION: Current randomized controlled trial was registered 29 November 2017 on Clinical Trials.gov (NCT number: NCT03356171).

Increased frequencies of circulating and tumor-resident Vδ1+ T cells in patients with diffuse large B-cell lymphoma.

Gamma-delta (γδ) T cells contribute to the innate immune response against cancer. In samples of 20 patients upon DLBCL diagnosis, we found that Vδ1+ T cells were the major γδ T cell subset in tumors and PBMCs of patients, while Vδ2 T cells were preponderant in PBMCs of healthy subjects. Interestingly, the germinal center (GC) subtype was associated with an increase in Vδ1+ T cells in tumors, whereas the non-GC subtype was associated with a lower frequency of γδ T cells. While circulating Vδ1+ T cells of patients or HSs mostly exhibited a naïve phenotype, the majority of tumor Vδ1+ T cells showed a central memory phenotype. Resident or circulating γδ T cells from patients were not functionally impaired since they produced high levels of IFN-γ. Collectively, our findings are in favor of γδ T cell activation in tumors and open new perspectives for their modulation in DLBCL immunotherapy.

Epidemiology of Monoclonal Gammopathy of Undetermined Significance (MGUS): The experience from the specialized registry of hematologic malignancies of Basse-Normandie (France).

Multiple myeloma (MM) is the third most common haematologic malignancy in European countries, and is usually preceded by Monoclonal Gammopathy of Undetermined Significance (MGUS). Therefore epidemiologic studies of MGUS are very limited in a population-based status. Here we report all new cases of MGUS exhaustively recorded by the Basse-Normandie Regional Registry for Hematologic Malignancies (a French region registry) between January 1997 and December 2005, and analyze outcome of patients until 2009 in term of evolution in MM or death. All cases were analyzed by an expert file review, and MGUS diagnosis was retained for: evidence of a monoclonal component <30 g/l and no CRAB criteria (hyperCalcemia, renal insufficiency, anemia, bone lesions). We showed that the world standardized incidence rate (WSR) for MGUS was 3.76 ± 0.26 per 100,000 inhabitants, increasing regularly with age, and that the median overall survival (OS) was 115.9 months (CI 95%: 10.5-130.2 months) with 78.3% patients alive at 5 years (CI 95%: 74.1-81.9%). We also observed a rate of progression to multiple myeloma of 1.41% per year, concordant with previous reports in a reallife exhaustive registry.