[Multiple myeloma with IgH::MYC and multiple extramedullary lesions].

A 41-year-old woman with right shoulder pain was found to have multiple tumors with osteolysis and M-proteinemia. Abnormal plasma cells (CD38+, CD138+, Igλ≫κ) were detected in 1.4% of bone marrow nucleated cells, and G-banding analysis revealed a 46,XX,t (8;14), (q24;q32) karyotype in 4 of 20 cells analyzed. A biopsy specimen from an extramedullary lesion had a packed proliferation of aberrant plasmacytoid cells with positive IgH::MYC fusion signals on fluorescence in situ hybridization. The patient was diagnosed with symptomatic multiple myeloma and treated with the BLd regimen, which significantly reduced M protein levels. Extramedullary lesions were initially reduced, but increased again after four cycles. The lesions disappeared with subsequent EPOCH chemotherapy and radiation, and complete remission was confirmed. The patient was then treated with high-dose chemotherapy with autologous peripheral blood stem cell transplantation. Complete remission was maintained for over one year with lenalidomide maintenance therapy. A solitary IgH::MYC chromosomal translocation is extremely rare in multiple myeloma and may be associated with high tumor proliferative capacity, multiple extramedullary lesions, and poor prognosis. Combined therapeutic modalities with novel and conventional chemotherapy and radiation might be a promising treatment strategy for patients with this type of multiple myeloma.

Severe Bone Marrow Aplasia Following Macrophage Activation Syndrome in Systemic Lupus Erythematosus.

Macrophage activation syndrome (MAS) is a potentially fatal complication of rheumatic diseases, characterized by activated macrophages with hemophagocytosis and multiple organ damage. We report a case of MAS associated with systemic lupus erythematosus that initially presented with severe liver dysfunction. Although it was improved with steroids and plasmapheresis, severe pancytopenia was subsequently experienced, and the bone marrow showed severe aplasia similar to aplastic anemia. Nevertheless, the administration of immunosuppressants resulted in the recovery of blood counts within two weeks. When severe MAS results in cytokine overproduction, bone marrow aplasia may occur, for which immunosuppressive therapy may be highly effective.

Umbilical Cord Blood Transplantation for Myelodysplastic Syndromes with Donor-Specific Anti-HLA Antibodies against HLA-DP.

The presence of donor-specific anti-human leukocyte antigen (HLA) antibodies (DSAs) against anti-HLA-A, -B, -C, and -DRB1 in HLA-mismatched hematopoietic stem cell transplantation (HSCT) is associated with graft failure. DSAs against HLA-A, -B, -C, and -DRB1 with a mean fluorescence intensity (MFI) of greater than > 1,000 was shown to increase the risk of graft failure in single-unit umbilical cord blood transplantation (UCBT). Nevertheless, the impact of DSAs against HLA-DP or -DQ on transplantation outcomes is not fully understood. In this report, we present a case of UCBT in a patient with myelodysplastic syndrome who was positive for DSAs against HLA-DP with MFI of 1,263 before UCBT but successfully achieved neutrophil engraftment. If HLA-DP or -DQ is mismatched in UCBT, evaluating DSAs against HLA-DP or -DQ is crucial to avoid graft failure. However, the criteria for DSAs against HLA-A, -B, -C, and -DRB1 may not be directly applicable to those against HLA-DP or -DQ.

Rapidly progressive glomerulonephritis in a patient with angioimmunoblastic T-cell lymphoma: a rare autopsy case showing IgA vasculitis and cylinder-like deposits.

Angioimmunoblastic T-cell lymphoma (AITL), a hematological malignancy, originates from follicular helper T cells. The primary site of AITL is the lymph nodes, but extranodal presentation is frequent in patients with advanced stages. Here, we report a rare case of a patient with AITL presenting with rapidly progressive glomerulonephritis (RPGN). The patient underwent computed tomography, which showed systemic lymph node swelling. RPGN was noted at the time of admission. Livedo was observed in the lower limbs with purpura on the foot. The patient was diagnosed with AITL based on lymph node biopsy. Skin biopsy revealed vasculitis with immunoglobulin A (IgA) deposits. Renal biopsy revealed endocapillary proliferative glomerulonephritis with massive subendothelial deposits and intraluminal thrombi. Immunofluorescence showed IgA, IgG, and complement component 3c-predominant granular staining pattern in the capillary and mesangial areas. Electron micrographs demonstrated dense cylindrical-like deposits in the subendothelial space. Chemotherapy drugs were administered, but the patient's respiratory distress increased until death. Upon autopsy, membranoproliferative glomerulonephritis and extensive necrotizing cellular crescent formation were observed in the glomeruli. Taken together, this case is a rare combination of AITL and RPGN showing both cylinder-like deposits suggestive of cryoglobulinemic glomerulonephritis (CN) and IgA vasculitis.

[Immune-mediated neuropathy with anti-ganglioside antibodies in diffuse large B-cell lymphoma].

A 70-year-old man having a mass lesion on his right lower abdomen for 2 months was admitted to our hospital for diagnosis. Upon admission, the patient experienced bilateral upper and lower limb weakness, which aggravated. He underwent nerve conduction study and was diagnosed with axonal neuropathy. Diagnosis of diffuse large B-cell lymphoma (DLBCL) was accomplished via biopsy of the mass lesion, with positive laboratory tests for anti-ganglioside antibodies. Based on these results, immune-mediated DLBCL-induced polyneuropathy was suspected, and chemotherapy (R-CHOP) was immediately started. Limb weakness improved and completely resolved. After six courses of R-CHOP, no evidence of DLBCL was observed on PET/CT (i.e., complete metabolic remission). The patient lived without DLBCL relapse or neurological symptoms after remission. Only few reports regarding immune-mediated polyneuropathy induced by malignant lymphoma are available in the literature, which, together with this case, suggest that prompt control of malignant lymphoma is crucial for favorable prognosis of neuropathy.

Successful Cord Blood Transplantation for Myeloid/Natural Killer Precursor Acute Leukemia: A Case Report and Literature Review.

A 21-year-old man was diagnosed with myeloid/natural killer precursor leukemia (MNKPL) with bone marrow infiltration of blasts of cyCD3+, CD7+, CD33+, CD34dim, CD56+/-, HLA-DR+, cyMPO+, and TdT- immunophenotypes. Although hyper-CVAD therapy was unsuccessful, induction treatment with idarubicin and cytarabine resulted in complete remission (CR). The patient subsequently underwent cord blood transplantation with a myeloablative conditioning regimen, which resulted in durable CR and complete donor chimerism. He had been in good health without relapse for over nine months since transplantation. Timely allogeneic hematopoietic stem cell transplantation using an available donor source may be a promising treatment strategy for MNKPL.

Real-world retrospective analysis of immune checkpoint inhibitor therapy for relapsed or refractory Hodgkin's lymphoma.

Immune checkpoint inhibitors (ICI) are promising therapeutic agents for relapsed or refractory classical Hodgkin's lymphoma (RRcHL). This retrospective study evaluated patients with RRcHL registered in the clinical research program Tohoku-Hematology-Forum-26, between 2016 and 2020, and treated with ICI in 14 centers in Northeast Japan. We analyzed the usage, efficacy, and safety of ICI therapy (ICIT). Among a total of 27 patients with RRcHL, 21 and nine were treated with nivolumab and/or pembrolizumab, respectively. The best response was complete response (CR), partial response (PR), stable disease (SD), and progressive disease in 11 (40.8%), seven (25.9%), eight (29.6%), and one (3.7%) patient, respectively. In all patients undergoing ICIT, the 2-year progression-free survival and 2-year overall survival (OS) were 48.6% and 87.4%, respectively. The 2-year OS for patients with CR, PR, and SD were 100%, 68.6%, and 87.5%, respectively. A total of 36 events of immune-related adverse events (irAEs) or immune-related like adverse events (irlAEs) were observed in 19 of the 27 patients (70.4%). Two thirds of these irAEs or irlAEs were grade 1-2 and controllable. During the observation period, ICIT was discontinued in 22 of 27 (81.4%) patients due to CR, inadequate response, irAE and patient circumstances in five (22.7%), seven (31.8%), eight (36.4%) and two patients (9.1%), respectively. Therapy-related mortality-associated irAE were observed in only one patient during ICIT. These results suggest that ICIT for RRcHL is effective and safe in real-world settings. The optimal timing of induction and duration of ICIT remains to be established.

Favorable outcome of unrelated cord blood transplantation for Philadelphia chromosome-positive acute lymphoblastic leukemia.

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph(+)ALL) is one of the highest-risk ALL groups. Whenever possible, patients with Ph(+)ALL should undergo allogeneic hematopoietic stem cell transplantation (HSCT) after induction of remission. Although unrelated cord blood transplantation (CBT) has become a common treatment in adult patients who lack a sibling donor, data on the efficacy of CBT for Ph(+)ALL are limited. We analyzed the clinical outcomes of 20 Ph(+)ALL patients who underwent CBT (n = 8) or unrelated bone marrow transplantation (BMT) (n = 12). The median age was 41 years (range, 17-55 years). All but one of the patients were treated with an imatinib-based regimen before HSCT, and 19 patients were in first complete remission (CR) and 1 patient was in second CR at the time of HSCT. Seventeen patients received a myeloablative conditioning regimen containing 12 Gy of total-body irradiation, and 3 received a reduced-intensity conditioning regimen. After a median of 26 months of follow-up, estimated 3-year overall and leukemia-free survival rates were 100% and 85%, respectively, after CBT, and 49% and 38%, respectively, after unrelated BMT. The CBT group had significantly better overall survival than the BMT group (P = .02). Although BCR-ABL transcript was detected in 4 of 8 CBT patients at transplantation, 7 patients remained in molecular CR. Our findings suggest that CBT may be a viable option as postinduction therapy for Ph(+)ALL in patients lacking a sibling donor.

Salvage Cord Blood Transplantation for Sustained Remission of Acute Megakaryoblastic Leukemia That Relapsed Early after Myeloablative Transplantation.

Acute megakaryoblastic leukemia (AMKL) is a rare subtype of acute myeloid leukemia accompanied by an aggressive clinical course and dismal prognosis. We herein report a case of AMKL preceded by mediastinal germ cell tumor that relapsed early after allogeneic hematopoietic stem cell transplantation with myeloablative conditioning but was successfully treated using salvage cord blood transplantation (CBT) with reduced-intensity conditioning. Although several serious complications developed, sustained remission with a favorable general condition was ultimately achieved. Although an optimal therapeutic strategy remains to be established, the graft-versus-leukemia effect of CBT may be promising, even for the treatment of refractory AMKL.

Successful Cord Blood Stem Cell Transplantation for Primary Cutaneous CD8-positive Aggressive Epidermotropic Cytotoxic T-cell Lymphoma Complicated with Cerebral Infiltration.

A 16-year-old boy, who had been initially examined for bilateral blepharedema and slight eruption, presented with rapidly deteriorating symptoms in associating with headache and consciousness disturbance. He was diagnosed to have primary cutaneous CD8-positive aggressive epidermotropic cytotoxic T-cell lymphoma (PCAE-CTL) by a biopsy of the skin and brain. After whole-brain radiation and some courses of chemotherapy, cord blood transplantation was performed with myeloablative conditioning. After transplantation, the cerebral dysfunction gradually improved. Disease remission was confirmed by the disappearance of any abnormal findings on electroencephalogram and magnetic resonance imaging. PCAE-CTL is reported to be an extremely aggressive disease with a poor prognosis, but the timely performance of cord blood transplantation is considered to be a promising treatment strategy.

Detection of Minimal Bone Marrow involvement of Blastic Plasmacytoid Dendritic Cell Neoplastic Cells - CD303 immunostaining as a diagnostic tool.

Blastic plasmacytoid dendritic cell (pDC) neoplasm (BPDCN) is a relatively rare hematological malignancy with significantly complex clinicopathological features that are still unclear. This study aimed to analyze the clinicopathological data of BPDCN and evaluate immunohistochemical detection of minimal bone marrow (BM) involvement. In this study, we examined skin and BM lesions from 6 patients with BPDCN. Neoplastic cells tested positive for CD303 (polyclonal, 100%; monoclonal, 40%) in the skin lesions and for CD303 (polyclonal, 100%; monoclonal, 67%) in the BM clots. Although immunostaining of CD4, CD56, CD123, CD303, and TCLl detected minimal BM involvement in 3 patients, morphological identification was challenging in the BM clots stained with hematoxylin-eosin. In conclusion, our results demonstrate the significance of observing BM smears to detect neoplastic cells and that immunohistochemical examination, including CD303 antibodies, is useful to detect minimal BM involvement. This study is the first to report the expression of thymic stromal lymphopoietin (TSLP) and its receptor in BPDCN cells. Therefore, the TSLP/TSLP receptor axis may be associated with the proliferation of BPDCN, and consequently, the survival of patients.

Impact of TET2 deficiency on iron metabolism in erythroblasts.

Sideroblastic anemia is characterized by the presence of ring sideroblasts (RSs), which are caused by iron accumulation in the mitochondria of erythroblasts and are present in both the acquired and congenital forms of the disease. However, the mechanism leading to RS formation remains elusive. Acquired sideroblastic anemia is usually observed in myelodysplastic syndrome (MDS). Because a subset of MDS harbors a somatic mutation of TET2, it may be involved in iron metabolism and/or heme biosynthesis in erythroblasts. Tet2 knockdown (Tet2trap) induced exhibited mild normocytic anemia and elevated serum ferritin levels in 4-month-old mice. Although typical RSs were not observed, increased mitochondrial ferritin (FTMT) amounts were observed in the erythroblasts of Tet2-knockdown mice. Quantitative real-time polymerase chain reaction demonstrated significant dysregulation of genes involved in iron and heme metabolism, including Hmox1, Fech, Abcb7, and Sf3b1 downregulation. After the identification of a cytosine-guanine island in the promoters of Fech, Abcb7, and Sf3b1, we evaluated DNA methylation status and found significantly higher methylation levels at the CpG sites in the erythroblasts of Tet2-knockdown mice. Furthermore, Tet2 knockdown in erythroblasts resulted in decreased heme concentration and accumulation of FTMT. Therefore, TET2 plays a role in the iron and heme metabolism in erythroblasts.