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.

Association of CD8 + T cells expressing nivolumab-free PD-1 with clinical status in a patient with relapsed refractory classical Hodgkin lymphoma.

A 37-year-old man with refractory classical Hodgkin lymphoma (cHL) underwent PD-1 blockade therapy with nivolumab, which resulted in a partial response. However, treatment was discontinued due to immune-related adverse events (irAEs), including myasthenia gravis and myositis. Retreatment with nivolumab resulted in a complete metabolic response and hepatic irAE. Subsequently, nivolumab was administered at extended dosing intervals. Intermittent infusion of ten doses of nivolumab for a total dose of 2400 mg/body helped control the relapsed/refractory cHL over three years. During nivolumab treatment, disease progression and emergence of irAEs were associated with the proportion of CD8 + T cells expressing nivolumab-free PD-1 relative to the total number of CD8 + T cells. The findings in this nivolumab-sensitive patient highlight the clinical utility of monitoring immune cells expressing nivolumab-free PD-1 in patients with cHL who have been treated with nivolumab and have experienced irAEs.

Dimethyl Fumarate Suppresses the Proliferation of HTLV-1-infected T Cells by Inhibiting CBM Complex-triggered NF-B Signaling.

BACKGROUND/AIM: Adult T-cell leukemia (ATL) is a peripheral T-lymphocytic malignancy influenced by human T-cell leukemia virus type 1 (HTLV-1) infection. Aggressive ATL has a poor prognosis, therefore newer agents are desperately needed. We revealed that dimethyl fumarate (DMF) causes ATL cell death via inhibition of nuclear factor-kappa B (NF-B) and signal transducer and activator of transcription 3 signaling. Here, we evaluated the specific mechanism of DMF effects on NF-B signaling in MT-2 HTLV-1-infected T-cells. MATERIALS AND METHODS: We examined the effects of DMF on the caspase recruitment domain family member 11 (CARD11)-BCL10 immune signaling adaptor (BCL10)-mucosa-associated lymphoid tissue lymphoma translocation protein 1 (MALT1) (CBM) complex and upstream signaling molecules which are critical for NF-B signaling in MT-2 cells by immunoblotting. We also explored its effects on cell-cycle distribution. Furthermore, we assessed whether the BCL2 apoptosis regulator (BCL2)/BCL2-like 1 (BCL-xL) inhibitor navitoclax promoted the inhibitory effect of DMF on cell proliferation and apoptosis-associated proteins by trypan blue exclusion test and immunoblotting, respectively. RESULTS: DMF inhibited constitutive phosphorylation of CARD11 followed by suppression of inhibitory-B kinase α/ß phosphorylation at serine in a dose-dependent fashion in MT-2 cells. Furthermore, DMF inhibited MALT1 and BCL10 expression in the same fashion. However, DMF did not prevent the phosphorylation of protein kinase C-ß, an upstream signaling molecule of CARD11. Cell-cycle analysis highlighted that DMF treatment at 75 µM resulted in the accumulation of cells at the sub-G1 and G2/M phases. Navitoclax modestly promoted DMF-induced suppression of MT-2 cells via inhibition of cellular inhibitor of apoptosis protein-2 expression and c-JUN N-terminal kinase phosphorylation. CONCLUSION: The suppression of MT-2 cell proliferation by DMF makes its further evaluation as an innovative agent for therapy of ATL worthwhile.

Dimethyl Fumarate Induces Apoptosis via Inhibiting NF-κB and STAT3 Signaling in Adult T-cell Leukemia/Lymphoma Cells.

BACKGROUND/AIM: Adult T-cell leukemia (ATL) is a peripheral T lymphocytic malignancy caused by human T-cell leukemia virus type 1 (HTLV-1) infection. Despite treatment that includes novel agents that have been developed, most of ATL patients relapse and acquire multidrug resistance. As a result, the creation of newer agents is critical. Dimethyl fumarate (DMF) has several effects in cancer cells, including cell signaling, proliferation and cell death. However, its antitumor effects on ATL cells remain unknown. In this study, we looked at DMF's antitumor effects on ATL cells. MATERIALS AND METHODS: We examined the effects of DMF on proliferation and apoptosis using the trypan blue exclusion assay and annexin V/propidium iodide staining in HTLV-1-infected and transformed T-cell lines, MT-1 and MT-2 cells. We also evaluated the effects of DMF on the nuclear factor-kappa B (NF-κB) and signal transducers and activators of transcription 3 (STAT3) signaling pathways and anti-apoptotic proteins by immunoblotting. RESULTS: DMF inhibited proliferation and induced apoptosis in MT-1 and MT-2 cells by activating poly ADP-ribose polymerase (PARP). Furthermore, DMF inhibited the constitutive activation of both canonical and non-canonical NF-κB pathways in MT-2 cells and the non-canonical NF-κB pathway in MT-1 cells. DMF also inhibited the constitutive tyrosine phosphorylation of STAT3 and the expression of anti-apoptotic proteins, c-IAP2 and survivin in both cells. CONCLUSION: These results indicate that DMF inhibits proliferation and induces apoptosis in HTLV-1-infected and transformed T-cells by suppressing NF-κB and STAT3 signaling pathways. DMF should be investigated further as a novel agent for ATL.

Measurement of coagulation factor antibody levels is useful for diagnosis and determining therapeutic efficacy in hemorrhagic patients with autoantibodies to coagulation factor VIII and factor V: results from a single center in Japan.

Coagulation factor inhibitors (CFIs) sometimes cause fatal bleeding conditions. Determination of an inhibitor titer (INH-titer) using the Bethesda method is essential for diagnosing diseases associated with CFIs and examining the effects of immunosuppressive therapy. We reviewed 17 cases with CFIs (acquired hemophilia A, n = 11; FV inhibitor, n = 6) to examine the usefulness of determining quantities of an autoantibody to a coagulation factor (CF-IgG) by ELISA for diagnosis and therapeutic efficacy, as compared with INH-titer. One patient with an INH-titer and no evidence of CF-IgG was lupus anticoagulant (LA)-positive, and thus the positive INH-titer may have been a false positive caused by LA. Although INH-titer alone was insufficient to correctly identify patients with CFI, determination of CF-IgG appeared to be useful. In addition, even after INH-titer disappearance, hemorrhagic conditions recurred when CF-IgG was detected. These findings suggest that the presence of a clearance antibody against the coagulation factor might reduce the activity of that coagulation factor even after disappearance of the corresponding neutralizing antibody. Although the diagnosis and therapeutic efficacy can also be determined by INH-titer disappearance and improvement of corresponding coagulation factor activity, determination of CF-IgG by ELISA can improve the accuracy of these assessments.

[Treatment of secondary engraftment failure with granulocyte colony-stimulating factor and eltrombopag after allogeneic peripheral blood stem cell transplantation in adult T-cell leukemia/lymphoma].

A 67-year-old woman diagnosed with adult T-cell leukemia/lymphoma received an induction chemotherapy and showed a partial response. She then underwent allogeneic peripheral blood stem cell transplantation from an HLA-identical sibling donor. Although cyclosporine (CS) was stopped at 120 days after transplantation, chronic graft-versus-host disease (cGVHD) of the skin developed. She was treated with a topical steroid, without exacerbation of the GVHD. She was admitted to our hospital due to the sudden development of pancytopenia at 212 days after the transplantation. She had an EB virus-associated post-transplant lymphoproliferative disorder (PTLD) in the hilum of the lung. The cGVHD of the skin resolved after the administration of prednisolone and CS. However, pancytopenia and PTLD persisted. Treatment with four cycles of rituximab (4×375 mg/m2/week) led to the complete resolution of PTLD, but transfusion-dependent cytopenia did not improve. Secondary engraftment failure was diagnosed, and granulocyte colony-stimulating factor (G-CSF) and eltrombopag (100 mg/day) were administered, leading to gradual improvement of pancytopenia. It was observed that persistent pancytopenia was caused by secondary engraftment failure due to cGVHD in this case. This case suggested that the treatment with G-CSF and eltrombopag is effective for cGVHD-associated secondary engraftment failure.

Role and Therapeutic Targeting of SDF-1α/CXCR4 Axis in Multiple Myeloma.

The C-X-C chemokine receptor type 4 (CXCR4) is a pleiotropic chemokine receptor that is expressed in not only normal hematopoietic cells but also multiple myeloma cells. Its ligand, stromal cell-derived factor 1α (SDF-1α) is produced in the bone marrow microenvironment. The SDF-1α/CXCR4 axis plays a pivotal role in the major physiological processes associated with tumor proliferation, survival, invasion, dissemination, and drug resistance in myeloma cells. This review summarizes the pleiotropic role of the SDF-1α/CXCR4 axis in multiple myeloma and discusses the future perspective in the SDF-1α/CXCR4 axis-targeted therapies in multiple myeloma.

Successful Treatment with Nivolumab in a Patient with Metastatic Salivary Duct Carcinoma.

Salivary duct carcinoma (SDC) is a rare and highly aggressive malignancy. A 58-year-old man presented with a right-sided submandibular mass and metastatic lesions in the right supraclavicular and inferior internal jugular nodes. He underwent right submandibulectomy and right neck dissection followed by adjuvant chemoradiotherapy. However, relapse occurred in the hilar lymph node and lumbar spine. Although radiotherapy was performed, a second relapse appeared in the hilar lymph nodes and sacral bone. Immunohistochemical analysis revealed negativity for programmed death ligand-1 (PD-L1) in the primary tumor specimen. The patient then received the anti-programmed death-1 (PD-1) antibody nivolumab. His metastatic lesions were completely eliminated after 48 weeks of therapy. This case reveals that anti-PD-1 antibodies are effective even against PD-L1-negative SDC.