Waldenstrom Macroglobulinemia (WM) is a rare and indolent lymphoma of B-cell origin characterized by elevated monoclonal IgM, with MYD88L265P mutation and CXCR4 mutation as common molecular alterations. B-cell Acute Lymphoblastic Leukemia (B-ALL) is clinically heterogeneous, characterized by abnormal proliferation and aggregation of immature lymphocytes in the bone marrow and lymphoid tissue. WM and ALL are hematologic malignancies of B-cell origin with completely different clinical manifestations and biological features. KMT2D and MECOM mutations are very rare in ALL and usually indicate poor disease prognosis. The coexistence of WM and ALL with KMT2D and MECOM mutations have not been reported.
A 74-year-old female patient was diagnosed with WM in July 2018 and received four cycles of chemotherapy of bortezomib and dexamethasone. In November 2018, she received immunomodulator thalidomide as maintenance therapy. In November 2020, Bruton\'s Tyrosine Kinase inhibitors (BTKi) has been introduced into the Chinese market and she took zanubrutinib orally at a dose of 80 mg per day. The disease remained in remission. In December 2021, she presented with multiple enlarged lymph nodes throughout the body. Bone marrow and next-generation sequencing (NGS) suggested the coexistence of WM and B-ALL with KMT2D and MECOM mutations. The patient was treated with zanubrutinib in combination with vincristine and dexamethasone, after which she developed severe myelosuppression and septicemia. The patient finally got remission. Due to the patient\'s age and poor status, she refused intravenous chemotherapy and is currently treated with zanubrutinib.
The coexistence of WM and B-ALL is very rare and has not been reported. The presence of both KMT2D and MECOM mutations predicts a poor prognosis and the possibility of insensitivity to conventional treatment options. BTKi achieves its anti-tumor effects by inhibiting BTK activation and blocking a series of malignant transformations in B-cell tumors. In addition, it also acts on T-cell immunity and tumor microenvironment. Combination therapy based on BTKi may improve the prognosis of this patient.

Lymphoplasmacytic lymphoma (LPL) is a rare subtype of B cell-derived non-Hodgkin lymphoma characterized by the abnormal growth of transformed clonal lymphoplasmacytes and plasma cells. This tumor almost always displays the capability of secreting large amounts of monoclonal immunoglobulins (Ig) of the M class (Waldenström Macroglobulinemia, WM). The clinical manifestations of WM/LPL may range from an asymptomatic condition to a lymphoma-type disease or may be dominated by IgM paraprotein-related symptoms. Despite the substantial progresses achieved over the last years in the therapy of LPL/WM, this lymphoma is still almost invariably incurable and exhibits a propensity towards development of refractoriness to therapy. Patients who have progressive disease are often of difficult clinical management and novel effective treatments are eagerly awaited. In this review, we will describe the essential clinical and pathobiological features of LPL/WM. We will also analyze some key aspects about the current knowledge on the mechanisms of drug resistance in this disease, by concisely focusing on conventional drugs, monoclonal antibodies and novel agents, chiefly Bruton\'s Tyrosine Kinase (BTK) inhibitors. The implications of molecular lesions as predictors of response or as a warning for the development of therapy resistance will be highlighted.

Methotrexate (MTX) is an immunosuppressor that is widely used to treat autoimmune diseases, including rheumatoid arthritis (RA). However, it can have serious adverse effects including a lymphoma: MTX-associated lymphoproliferative disorder (MTX-LPD). Extranodal lesions are common in MTX-LPD patients. However, MTX-LPD in the central nervous system (CNS) is extremely rare with few reported cases. Here, we describe a case of primary CNS MTX-LPD in a patient with RA, with a review of the literature. A 68-year-old woman who had received MTX for her RA for more than 10 years was referred to our hospital. Head magnetic resonance imaging (MRI) showed multiple lesions with heterogeneous contrast enhancement scattered throughout both hemispheres. As immunosuppression caused by MTX was suspected, MTX was discontinued, based on a working diagnosis of MTX-LPD. We performed an open biopsy of her right temporal lesion. Histopathologic examination showed atypical CD20+ lymphoid cells, leading to a definitive diagnosis of diffuse large B-cell lymphoma (DLBCL). In situ hybridization of an Epstein-Barr virus-encoded small RNA (EBER) was positive. Sanger sequencing confirmed that both MYD88 L265 and CD79B Y196 mutations were absent. The LPD regressed after stopping MTX. Follow-up head MRI at 8 months after surgery showed no evidence of recurrence. Although primary CNS MTX-LPD is extremely rare, it should be included in the differential diagnosis when a patient receiving MTX develops CNS lesions. Diagnosis by biopsy and MTX discontinuation are required as soon as possible.

Primary cutaneous diffuse large B-cell lymphoma, leg type, is an exceedingly rare and aggressive variant of primary cutaneous lymphoma. An 84-year-old male presented to an oncologist for new skin lesions on his abdomen and right thigh. Excisional biopsy followed by histopathology and immunohistochemistry confirmed the diagnosis of primary cutaneous diffuse large B-cell lymphoma, leg type. His clinical course was complicated by multiple relapses and refractory disease. Ultimately, he achieved complete response with fourth-line ibrutinib therapy. Due to the contentious nature of this disease, poor prognosis, and higher rates of recurrence, prompt identification and aggressive treatment are recommended. Given the different cellular pathways and genomic alterations identified in its carcinogenesis, various chemotherapy regimens and targeted immunotherapies have emerged as potential therapeutic options to halt disease progression and prevent future relapses.

We described for the first time a female patient with the simultaneous presence of two homozygous mutations in MYD88 and CARD9 genes presenting with pyogenic bacterial infections, elevated IgE, and persistent EBV viremia. In addition to defective TLR/IL1R-signaling, we described novel functional alterations into the myeloid compartment. In particular, we demonstrated a defective production of reactive oxygen species exclusively in monocytes upon E. coli stimulation, the inability of immature mono-derived DCs (iDCs) to differentiate into mature DCs (mDCs) and the incapacity of mono-derived macrophages (MDMs) to resolve BCG infection in vitro. Our data do not provide any evidence for digenic inheritance in our patient, but rather for the association of two monogenic disorders. This case illustrates the importance of using next generation sequencing (NGS) to determine the most accurate and early diagnosis in atypical clinical and immunological phenotypes, and with particular concern in consanguineous families. Indeed, besides the increased susceptibility to recurrent invasive pyogenic bacterial infections due to MYD88 deficiency, the identification of CARD9 mutations underline the risk of developing invasive fungal infections emphasizing the careful monitoring for the occurrence of fungal infection and the opportunity of long-term antifungal prophylaxis.