Impact of previous anthracycline therapy in patients with acute myeloid leukemia receiving venetoclax.

Venetoclax (VEN) combination regimens are now recognized as effective against acute myeloid leukemia (AML). However, the prognosis of patients who do not attain a composite complete response (cCR) is extremely poor, and clinical determinants of response remain unknown. Medical records of 57 patients with AML treated with VEN combination regimens from April 2021 to March 2022 at six institutions were retrospectively analyzed. The primary endpoint was cCR, complete remission, or complete remission with incomplete hematologic recovery after one cycle of VEN combination regimen. Five patients had previously relapsed after allogeneic hematopoietic stem cell transplantation (allo-SCT). The treatment regimen was azacitidine-VEN in 48 patients (84%) and low-dose cytarabine-VEN in 9 patients (16%). Thirty patients (53%) achieved cCR after one cycle of a VEN regimen. In univariate analysis, the number of prior chemotherapy regimens, post-allo-SCT relapse, and cytogenetic risk category were associated with a decreased likelihood of achieving cCR. In multivariate analysis, second-line chemotherapy remained a significant predictor of response. Patients who received anthracycline immediately before the VEN regimen had a higher cCR rate than patients who did not receive anthracycline. In this study, prior chemotherapy/allo-SCT and cytogenetic risk were associated with VEN treatment outcomes.

Transformed Mycosis Fungoides with a Cytotoxic T-Cell Phenotype.

Mycosis fungoides (MF) is a cutaneous T-cell lymphoma and occasionally undergo large cell transformation (transformed MF, TMF), resulting in a poorer clinical outcome. We describe a case of TMF with an immunophenotypic shift. MF showed the CD4 + CD8- T-cell phenotype, while TMF exhibited the CD4-CD8 + T-cell phenotype. Moreover, TMF expressed cytotoxic markers of TIA1 and Granzyme B. A PCR analysis of T-cell receptor genes revealed peak sizes that were the same in both biopsies, indicating that these two lymphomas were derived from the same clone.

Clonally Related Plasmablastic Lymphoma Simultaneously Occurring with Diffuse Large B-Cell Lymphoma.

Plasmablastic lymphoma (PBL) is a rare aggressive lymphoma. Although it was first described in HIV- (human immunodeficiency virus-) infected patients, PBL has been diagnosed in patients with other immunodeficiencies as well as in immunocompetent patients. PBL immunohistochemically expresses plasmacytic markers and lacks pan B-cell markers. The cells of origin of PBL are considered to be plasmablasts. MYC gene rearrangement and MYC overexpression are frequently found in PBL, but the pathogenesis of PBL is yet to be elucidated. Here, we report a case of composite lymphoma of PBL and diffuse large B-cell lymphoma (DLBCL); that is, PBL in the urinary bladder and DLBCL in the nasal cavity occurred simultaneously. We extracted DNA from the two lymphomas for polymerase chain reaction and sequenced the amplified immunoglobulin heavy variable genes and the complementarity-determining region- (CDR-) 3. The sequence of the CDR3 region of both tumors matched. MYC rearrangement was found in the bladder tumor but not in the nasal tumor. The patient was treated with R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone), and durable remission had been obtained. The results of the DNA analysis indicated that both PBL and DLBCL emerged from common postgerminal B cells. This case may help to elucidate the pathogenesis of PBL.

The Inhibitor of Apoptosis Protein Livin Confers Resistance to Fas-Mediated Immune Cytotoxicity in Refractory Lymphoma.

Death receptor Fas-mediated apoptosis not only eliminates nonspecific and autoreactive B cells but also plays a major role in antitumor immunity. However, the possible mechanisms underlying impairment of Fas-mediated induction of apoptosis during lymphomagenesis remain unknown. In this study, we employed our developed syngeneic lymphoma model to demonstrate that downregulation of Fas is required for both lymphoma development and lymphoma cell survival to evade immune cytotoxicity. CD40 signal activation significantly restored Fas expression and thereby induced apoptosis after Fas ligand treatment in both mouse and human lymphoma cells. Nevertheless, certain human lymphoma cell lines were found to be resistant to Fas-mediated apoptosis, with Livin (melanoma inhibitor of apoptosis protein; ML-IAP) identified as a driver of such resistance. High expression of Livin and low expression of Fas were associated with poor prognosis in patients with aggressive non-Hodgkin's lymphoma. Livin expression was tightly driven by bromodomain and extraterminal (BET) proteins BRD4 and BRD2, suggesting that Livin expression is epigenetically regulated in refractory lymphoma cells to protect them from Fas-mediated apoptosis. Accordingly, the combination of CD40-mediated Fas restoration with targeting of the BET proteins-Livin axis may serve as a promising immunotherapeutic strategy for refractory B-cell lymphoma. SIGNIFICANCE: These findings yield insights into identifying risk factors in refractory lymphoma and provide a promising therapy for tumors resistant to Fas-mediated antitumor immunity. GRAPHICAL ABSTRACT: http://cancerres.aacrjournals.org/content/canres/80/20/4439/F1.large.jpg.

Sinusitis caused by Exserohilum rostratum after cord blood transplantation for myelodysplastic syndrome: A case report and literature review.

Invasive fungal disease is a serious infectious complication of allogeneic hematopoietic stem cell transplantation (HSCT). Exserohilum rostratum is a species causing phaeohyphomycosis, which rarely causes invasive disease in humans. We treated a case of sinusitis caused by E. rostratum after cord blood transplantation (CBT). A 60-year-old man with myelodysplastic syndrome, who had a medical history of an operation to correct deviation of the nasal septum, developed sinusitis caused by E. rostratum under prolonged profound neutropenia after a second CBT because of the graft rejection of the first transplantation. Liposomal amphotericin B improved the sinusitis. A literature review revealed nine reported cases of sinusitis caused by E. rostratum, including our case. Although five cases had severe neutropenia at onset (HSCT recipients, n = 2; aplastic anemia, n = 3), the remaining four had no preexisting immunosuppressive conditions. However, three of the four patients had preexisting nasal diseases with or without a history of surgery, as in our case. Excluding our case, the outcome was fatal in five neutropenic patients, whereas the four patients without neutropenia recovered. Although sinusitis caused by E. rostratum is rare, E. rostratum should be recognized as a possible pathogen causing sinusitis in highly immunosuppressed patients such as HSCT recipients. Preexisting nasal disease and/or nasal surgery could be risks for this infection.

FZR1 loss increases sensitivity to DNA damage and consequently promotes murine and human B-cell acute leukemia.

FZR1 (fizzy-related protein homolog; also known as CDH1 [cell division cycle 20 related 1]) functions in the cell cycle as a specific activator of anaphase-promoting complex or cyclosome ubiquitin ligase, regulating late mitosis, G1 phase, and activation of the G2-M checkpoint. FZR1 has been implicated as both a tumor suppressor and oncoprotein, and its precise contribution to carcinogenesis remains unclear. Here, we examined the role of FZR1 in tumorigenesis and cancer therapy by analyzing tumor models and patient specimens. In an Fzr1 gene-trap mouse model of B-cell acute lymphoblastic leukemia (B-ALL), mice with Fzr1-deficient B-ALL survived longer than those with Fzr1-intact disease, and sensitivity of Fzr1-deficient B-ALL cells to DNA damage appeared increased. Consistently, conditional knockdown of FZR1 sensitized human B-ALL cell lines to DNA damage-induced cell death. Moreover, multivariate analyses of reverse-phase protein array of B-ALL specimens from newly diagnosed B-ALL patients determined that a low FZR1 protein expression level was an independent predictor of a longer remission duration. The clinical benefit of a low FZR1 expression level at diagnosis was no longer apparent in patients with relapsed B-ALL. Consistent with this result, secondary and tertiary mouse recipients of Fzr1-deficient B-ALL cells developed more progressive and radiation-resistant disease than those receiving Fzr1-intact B-ALL cells, indicating that prolonged inactivation of Fzr1 promotes the development of resistant clones. Our results suggest that reduction of FZR1 increases therapeutic sensitivity of B-ALL and that transient rather than tonic inhibition of FZR1 may be a therapeutic strategy.

IgG4-related Disease with Bone Marrow Involvement.

A 61-year-old Japanese woman with anemia, submandibular gland swelling, and enlarged lymph nodes was diagnosed with IgG4-related disease (IgG4-RD) by lymph node biopsy. Bone marrow involvement of IgG4-RD was detected by 18F-fluorodeoxyglucose positron emission tomography/computed tomography (FDG-PET/CT) and immunohistochemically proven by bone marrow biopsy in this patient. Anemia progressed gradually, and prednisolone treatment was initiated. Anemia and submandibular gland swelling improved soon after prednisolone treatment was initiated. We report a rare case of IgG4-RD involving the bone marrow. FDG-PET/CT and bone marrow biopsy were useful for diagnosis in this case.

Itraconazole may increase the risk of early-onset bortezomib-induced peripheral neuropathy.

Bortezomib (BOR) is an effective drug for the treatment of multiple myeloma and BOR-induced peripheral neuropathy (BIPN) is a major adverse event. BIPN tends to occur after two or three cycles of treatment (late-onset BIPN), but may occur during the first treatment cycle (early-onset BIPN). BIPN severity was retrospectively assessed and graded in 48 patients with relapsed or refractory multiple myeloma treated with BOR for the first time between June 2007 and February 2011 at Keio University Hospital. PN grade 2 or higher occurring within the first cycle of BOR was defined as early-onset severe BIPN. Early-onset severe BIPN occurred in 13 patients. Concomitant use of itraconazole [ITCZ: odds ratio (OR) 29.14 (3.02-281.56), p = 0.004] and a proton pump inhibitor [OR 9.00 (1.05-77.1), p = 0.04] were identified by univariate analysis, as risk factors for developing early-onset severe BIPN. Based on multivariate analysis, concomitant use of ITCZ was the only significant risk factor for developing early-onset severe BIPN [OR 19.00 (1.89-190.96), p = 0.01]. Concomitant use of ITCZ with BOR significantly increased the incidence of early-onset severe BIPN in our study population, suggesting that administration of ITCZ in patients receiving BOR should be avoided.

[Early onset of paralytic ileus caused by simultaneous administration of bortezomib and azole antifungals in multiple myeloma patients].

We herein report two patients (70- and 45-year-old men) with refractory multiple myeloma who developed paralytic ileus shortly after starting bortezomib therapy. Bortezomib (1.3 mg/m(2)) was given on days 1, 4, 8, and 11 with daily oral solution itraconazole or voriconazole. Twelve and 15 days after beginning the therapy, each patient developed paralytic ileus. Interestingly, no other signs of peripheral neuropathy such as fingertip numbness were observed at the onset of ileus. Sporadic cases of paralytic ileus after bortezomib therapy have been reported, most of which developed ileus after several courses of bortezomib therapy. Our cases developed paralytic ileus shortly after initiating bortezomib, strongly suggesting that autonomic neuropathy due to bortezomib was induced by the concomitant use of itraconazole or voriconazole.

[Fatal disseminated toxoplasmosis after unrelated bone marrow transplantation for myelodysplastic syndrome].

A 44-year-old man with myelodysplastic syndrome (RAEB-2) underwent allogeneic bone marrow transplantation from an unrelated donor after being conditioned with myeloablative regimen. Tacrolimus and short-term methotrexate were given for prophylaxis against graft-versus-host disease (GVHD). Engraftment was achieved on Day 17. He developed Grade II acute GVHD involving the skin and gastrointestinal tract and methylprednisolone (2 mg/kg) was initiated. On Day 60, he developed fever and liver dysfunction followed by diffuse interstitial infiltration of the lungs. Respiratory and cardiac failure rapidly progressed and the patient died on Day 66 despite treatment with antimicrobial agents and intravenous immunoglobulin. Autopsy findings revealed disseminated toxoplasmosis involving the lungs, heart, liver, gastrointestinal tract, and kidneys. Toxoplasmosis after allogeneic hematopoietic stem cell transplantation (HSCT) generally manifests as encephalopathy or brain abscess; however, disseminated disease has been sporadically reported. It should be recognized as a possible cause of rapidly progressing interstitial pneumonitis and cardiac dysfunction after allogeneic HSCT.