Background and Aims

Cytotoxic-T-lymphocyte-antigen-4 (CTLA-4) insufficiency, caused by heterozygous germline mutations in CTLA4, presents as a complex immune dysregulation syndrome. An increased risk of malignancies in CTLA-4-insufficient patients has been reported in a cohort of the 184 CTLA4 mutation carriers.

Methods

We collected and evaluated clinical information of a worldwide cohort of 203 CTLA4 mutation carriers, which included 144 affected mutation carriers and 59 unaffected mutation carriers. When patients were diagnosed with a malignancy, a malignancy-specific questionnaire was obtained.

Results

We documented 20 malignancies. The incidence of malignancy was 14% in affected CTLA4 mutation carriers. The average age of diagnosis of malignancy was 39 years. The ratio of male to female was eleven to nine. There were eleven hematopoietic malignancies including six Hodgkin lymphomas, four diffuse large B cell lymphomas, one Burkitt lymphoma, one multiple myeloma, and nine solid tumors including five gastric adenocarcinomas, two breast cancers, one squamous cell carcinoma, and one metastatic melanoma. Seven lymphomas and two gastric cancers were EBV-associated. Nine patients, five of which had EBV-associated malignancies, had received immunosuppressive medications when diagnosed with the malignancy. Chemotherapy, surgery, radiotherapy, and hematopoietic stem cell transplantation were undertaken; however, seven patients, five of which had lymphomas, one gastric cancer, and one metastatic melanoma, died.

Conclusions

Half of the malignancies in patients with CTLA-4 insufficiency were lymphomas and EBV-associated. The monitoring of lymphoproliferation and EBV viral load should be carefully performed, especially for affected mutation carriers under immunosuppressive therapy.

Background and Aims

Idiopathic-CD4-lymphopenia (ICL, CD4-T-cells<300μL without known cause), is a heterogenous clinical syndrome characterized by an increased risk of opportunistic infections. We hypothesized that ICL would also be associated with an increased risk of malignancies.

Methods

The prevalence of solid-organ-cancers and lymphoproliferative-disorders was evaluated in the NIH-ICL-cohort and compared with age-adjusted-rates from the Surveillance-Epidemiology-and-End-Results-database (SEER). T- and NK-cells immunophenotyping was performed in healthy-subjects (HC), ICL-patients with (ICL-CA) or without (ICL-nCA) malignancies.

Results

30 solid-organ-cancers and 3 lymphoproliferative-disorders were identified in 22 of the 90 ICL patients (24%): 6 ICL-CA had synchronous/metachronous malignancies. Squamous-cell carcinomas [SCC-skin, -anogenital, -head/neck] were the most common malignancies (n=14) in addition to other non-melanoma-skin-cancers (NMSC) [basal-cell-carcinoma (n=8), verrucous-carcinoma (n=3) and Kaposi`s sarcoma]. Papillary-thyroid-cancer, breast-lobular-adenocarcinoma, soft-tissue-sarcoma and thymoma were other solid-organ cancers identified. ICL had higher prevalence of malignancies (even excluding NMSC not recorded in SEER) compared to the general population (14.4% vs 3.6%, p<0.001). ICL-CA had higher prevalence of HPV-related-diseases (59 vs 26%, p<0.05), but not of other opportunistic infections compared to ICL-nCA (45% vs 44%). Although age (45 vs 44 years) and follow-up (5 years) were similar, the CD4- and CD8-T-cells were lower in ICL-CA compared to ICL-nCA (39 vs 104cells/μL; 63 vs 169cells/μL respectively, p<0.01). ICL-CA had a lower proportion of effector-memory-CD4-T-cells expressing the skin-homing receptor CLA but not the gut-homing receptor CCR9, compared to ICL-nCA. ICL-CA had also a lower proportion of CLA+CD56dim-NK-cells compared to HC.

Conclusions

The increased prevalence of malignancies and HPV-related-diseases in ICL is associated with lower numbers and altered trafficking of CD4- and CD8-T-cells.

Background and Aims

Germline gain-of-function STAT3 mutations are identified in early-onset multiorgan autoimmune diseases. Somatic STAT3 mutations are associated with 40% of adult T-cell large granular lymphocytic (LGL) leukemia. The two phenotypes are thought to be distinct.

Methods

We describe a child with Evans syndrome who developed in the young adult age a T-cell LGL leukemia.

Results

The patient was born from non-consanguineous healthy parents. From the age of 2, he suffered of pyogenic infections, autoimmune neutropenia, unexplained splenomegaly and hypergammaglobulinemia. At the age of 9, he presented tri-lineage autoimmunity.

At the pediatric age, whole exome sequencing identified a de novo activating p.Y640F STAT3 mutation in blood but not in fibroblasts. He had recurrent mouth ulcers, persistent splenomegaly and severe neutropenia. He received immunoglobulins or steroid pulses and preventive sequential G-CSF. Repeated blood and marrow smears showed no leukemia.

At the age of 21, splenomegaly and neutropenia worsened and a clonal proliferation of large granular lymphocytes CD3+ CD5+ CD7+ CD8+ TiA1+, granzyme B+ perforine+ CD57+ was identified on blood smears, marrow aspirate and biopsy. Ruxolitinib was initiated: 3 months later, the spleen regressed, neutrophil count improved and G-CSF was stopped.

Conclusions

The mutation identified in this patient with early-onset Evans syndrome belongs to the hotspots associated with LGL leukemia. G-CSF use should be limited in this context. The JAK-STAT3 pathway is involved in various germline or somatic diseases. New avenues on pathophysiology, natural history and targeted therapies are opened. Those rare patients require specific care by specialized teams wit a special attention for the transition period.

Background and Aims

NBS is a DNA repair disorder with immunodeficiency and high predisposition to malignancies.

Methods

From 2012 to 2019 22 NBS patients received HSCT in our center (MSD –5, MUD –17), 12 of them had malignancies before transplantation: 4 –ALL, 7 –non-Hodgkin B-cell lymphomas, 2 –T-cell lymphoma. All were in complete remission at the time of HSCT. Conditioning regimen (CR) consisted of busulfan (4 mg/kg) or treosulfan (30 mg/m²) with fludarabine (150 mg/m2), cyclophosphamide (40 mg/m2), r-ATG (5 mg/kg) and rituximab (100 mg/m2).

Results

The median follow-up time after HSCT was 2.38 years (0,73–5,54). All patients had primary engraftment. Four of 22 patients had neoplasms after HSCT, all patients received low dose busulfan-based CR. Two patients died, 1 of T-cell lymphoma relapse on d+41. One patient rejected graft 11 months after HSCT and died 6 months later from newly developed high-grade T-cell lymphoma. Two patients developed PTLD. In one, PTLD was limited to peripheral lymph nodes at 6 months after HSCT. He received rituximab 375 mg/m²/week №4 with complete response. Second had small lung focus of EBV-associated lymphomatoid granulomatosis before HSCT, but the radiologic enlargement of this mass was detected at d+41. Lesion biopsy showed CD30+ B-cell PTLD, patient received brentuximab vedotin (1,2 mg/m² every 3 wks №6) accompanied by CD45RA+ depleted donor lymphocyte infusions, which resulted in PTLD resolution.

Conclusions

HSCT is a potential option to reduce the risk of lymphoid malignancies development and relapses in NBS patients, but longer follow-up and bigger cohort of patients are needed to evaluate HSCT efficacy.

Background and Aims

Merkel cell carcinoma (MCC) is a rare, aggressive skin cancer. MCC risk is elevated in older patients (mean age 70s) and those with secondary immunodeficiency, including HIV, Chronic Lymphoblastic leukemia (CLL), and solid organ transplants. Diagnosis of MCC before age 40 is vanishingly rare. We describe two patients with MCC presenting at young age who were diagnosed with MAGT1 deficiency, a rare immunodeficiency associated with T cell lymphopenia, chronic EBV viremia, and lymphoma susceptibility.

Methods

Clinical course, laboratory tests and imaging were reviewed.

Results

Patient 1 presented at 14 years with metastatic MCC, which was successfully treated with chemotherapy, radiation therapy and an autologous stem cell transplant. His history included recurrent ear and lung infections, zoster, and splenomegaly. He had CD4 lymphopenia, B cell lymphocytosis, and post- chemotherapy had hypogammaglobulinemia requiring immune globulin replacement therapy. Ten years later he reports good health without recurrence of the MCC. Whole Exome sequencing (WES) analysis detected a hemizygous MAGT1 c.486+1G>T splice site mutation . Patient 2 presented at 22 years of age with Stage III MCC treated with surgical resection and radiation therapy. His history included recurrent ear and lung infections, prolonged Coxsackie and influenza infections, extensive molluscum, chronic EBV viremia, chronic elevated liver enzymes and mucocutaneous candidiasis. CD4 lymphopenia and B cell lymphocytosis were present with preserved IgG and specific antibodies. WES analysis showed a hemizygous c.991C>T (p.Arg331Ter) pathogenic variant in MAGT1.

Conclusions

MAGT1 deficiency is associated with young-onset MCC, expanding the malignancy association beyond lymphomas. MCC has been reported in GATA2 deficiency, also characterized by viral susceptibility and malignancy.

Background and Aims

Malignancies are known manifestation of primary immunodeficiencies, with highest rate being in the DNA-repair disorders (DNA-RD). There is no universal opinion on tumor treatment regiments in DNA-RDT, treatment protocols vary between centers.

Methods

We analyzed DNA-RD patients (42 with Nijmegen breakage syndrome (NBS), 33 with ataxia-telangiectasia (AT) treated in our Center in 2014-2019.

Results

Malignancies were diagnosed in 26 NBS (62%) and in 11 AT (33%) patients (table). 4 NBS and 1 AT patient developed second tumors. Majority of NBS patients received chemotherapy without dose reduction, and no major toxicity or complications. 15 NBS patients underwent hematopoietic stem cell transplantation (HSCT), 12 are alive. All AT patients received reduced doses of chemotherapy due to toxicity and infectious complication, 8 are currently alive.

Conclusions

In our experience, malignancies in DNA-RD group require variable therapeutic approach: while reduced chemotherapy doses are needed for AT, patients with NBS benefit from full dose chemotherapy protocols with supportive IVIG treatment in all cases, followed by HSCT.