Safety of nivolumab monotherapy in five cancer types: pooled analysis of post-marketing surveillance in Japan.

BACKGROUND: Nivolumab has been approved for treating ≥ 10 cancer types. However, there is limited information on the incidence of rare, but potentially serious, treatment-related adverse events (TRAEs), as well as notable TRAEs in patients with certain medical disorders or older patients in Japan. METHODS: We performed pooled analyses of data from published post-marketing surveillance in Japan of nivolumab monotherapy for patients with malignant melanoma, non-small cell lung cancer, renal cell carcinoma, head and neck cancer, and gastric cancer to determine the frequencies of 20 categories of TRAEs of special interest overall and in patient groups with higher perceived safety risks (history of autoimmune disease, interstitial lung disease, tuberculosis, or hepatitis B/C; patients vaccinated during nivolumab treatment; and older patients [≥ 75 years]). RESULTS: The overall population comprised 7421 patients treated with nivolumab. TRAEs were reported in 49.1% of patients, with grade ≥ 3 TRAEs in 16.7%. Endocrine disorders (14.4%), hepatobiliary disorders (10.9%), and interstitial lung disease (7.0%) were the three most common categories (any grade). The incidences of rare TRAEs with high risk of becoming serious, which occurred in < 1% of patients, were consistent with those in previous reports. The frequencies of TRAEs were not markedly increased in the specified patient groups relative to the overall population. CONCLUSION: To our knowledge, this is the largest study examining the safety of nivolumab-treated patients in real-world clinical practice including rare but potentially serious TRAEs. We found no new signals in the safety of nivolumab among the patient groups relative to the overall population, and no additional safety measures are required in these groups. Trial registration UMIN000048892 (overall analysis), JapicCTI-163272 (melanoma), Japic-163271 (non-small cell lung cancer), JapicCTI-184071 (head and neck cancer), JapicCTI-184070 (gastric cancer), and JapicCTI-184069 (renal cell cancer).

Real-world status of treatment for lymphoid neoplasms developed during the course of myeloproliferative neoplasms in Japan.

OBJECTIVES: Patients with myeloproliferative neoplasms (MPNs) are at higher risk of developing secondary malignancies. In this study, we focused on patients with MPNs that complicated lymphoid neoplasms. To analyze the real-world status of lymphoid neoplasm treatment in patients with pre-existing MPNs in Japan, we conducted a multicenter retrospective study. METHODS: Questionnaires were sent to collect the data on patients who were first diagnosed with either polycythemia vera, essential thrombocythemia or myelofibrosis and who later were complicated with lymphoid neoplasms defined as malignant lymphoma, multiple myeloma, or chronic lymphocytic leukemia/small cell lymphoma. RESULTS: Twenty-four patients with MPNs complicated by lymphoid neoplasms were enrolled (polycythemia vera, n = 8; essential thrombocythemia, n = 14; and primary myelofibrosis, n = 2). Among these, diffuse large B-cell lymphoma (DLBCL) was the most frequently observed (n = 13, 54.1%). Twelve (92.3%) of the patients with DLBCL received conventional chemotherapy. Among these 12 patients, regarding cytoreductive therapy for MPNs, 8 patients stopped treatment, one continued treatment, and two received a reduced dose. Consequently, most patients were able to receive conventional chemotherapy for DLBCL with a slightly higher dose of granulocyte colony-stimulating factor support than usual without worse outcomes. All 3 patients with multiple myeloma received a standard dose of chemotherapy. CONCLUSION: Our data indicate that if aggressive lymphoid neoplasms develop during the course of treatment in patients with MPNs, it is acceptable to prioritize chemotherapy for lymphoma.

Peripherally inserted central venous catheters decrease central line-associated bloodstream infections and change microbiological epidemiology in adult hematology unit: a propensity score-adjusted analysis.

Peripherally inserted central venous catheters (PICCs) have a potential advantage in preventing central line-associated bloodstream infection (CLABSI) compared with the centrally inserted ones (CICCs). However, due to a limited number of studies with insufficient statistical evaluation, the superiority of PICCs is difficult to be generalized in adult hematology unit. We conducted a single-center retrospective study and compared the risk of CLABSI between 472 CICCs and 557 PICCs inserted in adult patients with hematological disorders through conventional multivariate models and a propensity score-adjusted analysis. The overall CLABSI incidence in CICCs and PICCs was 5.11 and 3.29 per 1000 catheter days (P = 0.024). The multivariate Cox regression analysis (hazard ratio [HR]: 0.48; 95% confidence interval [CI]: 0.31-0.75; P = 0.001) and Fine-Gray subdistribution analysis (HR: 0.59; 95% CI: 0.37-0.93; P = 0.023) demonstrated that PICC was independently associated with a reduced risk of CLABSI. Moreover, the stabilized inverse probability of treatment weighting analysis, which further reduced the selection bias between CICCs and PICCs, showed that PICCs significantly prevented CLABSI (HR: 0.58; 95% CI: 0.35-0.94; P = 0.029). Microbiologically, PICCs showed a significant decrease in gram-positive cocci (P = 0.001) and an increase in gram-positive bacilli (P = 0.002) because of a remarkable reduction in Staphylococci and increase in Corynebacterium species responsible for CLABSI. Our study confirmed that PICC was a superior alternative to CICC in preventing CLABSI in the adult hematology unit, while it posed a microbiological shift in local epidemiology.

Real-world safety and effectiveness of nivolumab for advanced renal cell carcinoma in Japan: a post-marketing surveillance.

BACKGROUND: This all-case post-marketing surveillance (PMS) evaluated the real-world safety and effectiveness of nivolumab monotherapy in Japanese patients with un-resectable or metastatic renal cell carcinoma (RCC). METHODS: This multicenter, open-label, non-interventional, observational PMS study (registered from August 2016 to January 2017) was conducted in patients who were newly initiated on nivolumab monotherapy. Assessments included treatment-related adverse events (TRAEs) of special interest, patient characteristics affecting safety, and effectiveness over 12 months. RESULTS: Overall, 580 patients were enrolled; 555 and 554 patients comprised the safety and effectiveness analysis sets, respectively. The median (range) age of the population was 66 (14-90) years. Nivolumab was initiated as 1st-, 2nd-, and ≥ 3rd-line treatment in 0.2%, 42.0%, and 57.8% of patients, respectively. TRAEs were reported in 275 (49.5%) patients. The most common TRAEs of special interest included thyroid dysfunction (9.5%), hepatic dysfunction (8.6%), and interstitial lung disease (6.7%). The incidence of TRAEs was significantly higher in elderly patients (≥ 65 vs < 65 years; ≥ 75 vs < 75 years); patients with lower C-reactive protein levels (< 5 vs ≥ 5 mg/dL); and patients with vs without a past medical history, including hepatic, thyroid, and autoimmune diseases. The 6- and 12-month survival rates were 71.8% and 57.9%, respectively. CONCLUSION: The safety profile of nivolumab monotherapy in Japanese patients with advanced RCC was similar to that in the phase 3 CheckMate 025 trial. No new safety signals were observed in this study.

Validation of an online application to identify potential immune-related adverse events associated with immune checkpoint inhibitors based on the patient's symptoms.

BACKGROUND: Immune checkpoint inhibitors (ICIs) are increasingly being used to treat malignancies. Some patients experience immune-related adverse events (irAEs), which may affect any organ/tissue. IrAEs are occasionally fatal and usually have nonspecific symptoms. We developed a three-step application (https://irae-search.com/) to provide healthcare professionals with information on the diagnosis, treatment options, and published reports for 38 categories of irAEs encountered in clinical practice. METHODS: IrAEs reported in ≥5 cases were identified from articles published between October 2018 and August 2020 by searching Japanese (SELIMIC, JAPIC-Q Service, and JMED Plus) and international (MEDLINE, EMBASE, Derwent Drug File) databases. The cases' symptoms were entered into the application to identify irAEs, which were verified using the reported diagnosis, to evaluate the application's sensitivity and specificity. RESULTS: Overall, 1209 cases (1067 reports) were analyzed. The three most common categories of irAEs were pituitary or adrenal disorders (14% of cases), skin disorders (13%), and diabetes mellitus (10%). The top three primary diseases were lung cancer (364 cases), melanoma (286 cases), and renal cell carcinoma (218 cases). The average sensitivity was 90.8% (range 44.4%-100.0%) initially, and improved to 94.8% (range 83.3%-100.0%) after incorporating the symptoms reported in published cases into the application's logic for two irAE categories. The average specificity was 79.3% (range 59.1% [thyroid disorders]-98.2% [arthritis]). CONCLUSION: irAE Search is an easy-to-use application designed to help healthcare professionals identify potential irAEs in ICI-treated patients in a timely manner to facilitate prompt management/treatment. The application showed high sensitivity and moderate-to-high specificity for detecting irAEs.

Selective targeting of multiple myeloma cells with a monoclonal antibody recognizing the ubiquitous protein CD98 heavy chain.

Cancer-specific cell surface antigens are ideal therapeutic targets for monoclonal antibody (mAb)-based therapy. Here, we report that multiple myeloma (MM), an incurable hematological malignancy, can be specifically targeted by an mAb that recognizes a ubiquitously present protein, CD98 heavy chain (hc) (also known as SLC3A2). We screened more than 10,000 mAb clones raised against MM cells and identified R8H283, an mAb that bound MM cells but not normal hematopoietic or nonhematopoietic cells. R8H283 specifically recognized CD98hc. R8H283 did not react with monomers of CD98hc; instead, it bound CD98hc in heterodimers with a CD98 light chain (CD98lc), a complex that functions as an amino acid transporter. CD98 heterodimers were abundant on MM cells and took up amino acids for constitutive production of immunoglobulin. Although CD98 heterodimers were also present on normal leukocytes, R8H283 did not react with them. The glycoforms of CD98hc present on normal leukocytes were distinct from those present on MM cells, which may explain the lack of R8H283 reactivity to normal leukocytes. R8H283 exerted anti-MM effects without damaging normal hematopoietic cells. These findings suggested that R8H283 is a candidate for mAb-based therapies for MM. In addition, our findings showed that a cancer-specific conformational epitope in a ubiquitous protein, which cannot be identified by transcriptome or proteome analyses, can be found by extensive screening of primary human tumor samples.

Clinicopathological analysis of diffuse large B-cell lymphoma lacking surface immunoglobulin light chain restriction on flow cytometry.

Although diffuse large B-cell lymphoma (DLBCL) occasionally lacks surface immunoglobulin light chain restriction (iLCR) on flow cytometry (FCM), little evidence is available for iLCR-negative DLBCL. We retrospectively compared clinicopathological features of iLCR-positive and iLCR-negative DLBCL diagnosed at our institute between April 2007 and March 2018. iLCR-positive was defined as a κ/λ ratio less than 0.5 or greater than 3 in the gated population on dual-color FCM, and iLCR-negative as other values. Of 81 DLBCL cases with available immunophenotyping by FCM, 63 iLCR-positive DLBCL (78%) and 18 iLCR-negative DLBCL (22%) cases were identified. Survival outcomes of patients with iLCR-negative DLBCL were comparable with those of patients with iLCR-positive DLBCL. Pathological analysis revealed no significant difference except for the lower expression of BCL6 in iLCR-negative DLBCL (12.5% vs 65.5%, p < 0.001), although there was a slightly higher frequency of necrosis (47.1% vs 20.7%, p = 0.058) and lower expression of CD10 (11.8% vs 35.0%, p = 0.078) in iLCR-negative DLBCL than in iLCR-positive DLBCL. The underlying mechanism remains unclear; however, low expression of germinal center markers and tumor necrosis may be associated with the loss of iLCR in DLBCL.

Extracorporeal Membrane Oxygenation with rituximab-combined chemotherapy in AIDS-associated primary cardiac lymphoma: A case report.

Although effective combination of antiretroviral medications is being developed, the incidence of non-Hodgkin lymphoma (NHL) with human immunodeficiency/acquired immunodeficiency syndrome (HIV/AIDS) still remains significantly higher than that in individuals without infection. Primary cardiac lymphoma (PCL) is an NHL that involves the heart and/or the pericardium. PCL is very rare and often causes serious complications, which can be a diagnostic challenge. To our knowledge, no study has reported the measurement of rituximab concentration under venoarterial extracorporeal membrane oxygenation (VA-ECMO). Herein, we report the case of a 54-year-old male patient with AIDS-associated primary cardiac NHL who developed right ventricular outflow tract obstruction. The patient experienced fatigue and dyspnea on exertion. Contrast-enhanced computed tomography showed a bulky tumor mass in his right atrium and ventricle, and an echocardiogram revealed severe hypokinesis of his heart and poor cardiac output. A biopsy was performed, and immunohistochemistry revealed diffuse large B-cell lymphoma. Therefore, he was treated with rituximab-combined chemotherapy under VA-ECMO. Blood levels of rituximab were measured during chemotherapy with VA-ECMO. Thereafter, he was temporarily discharged from the hospital. This clinical case suggests that VA-ECMO and rituximab-combined chemotherapy are useful in rescuing patients with severe cardiopulmonary failure due to AIDS-associated PCL.

Importance of diagnosis-to-treatment interval in newly diagnosed patients with diffuse large B-cell lymphoma.

Treatment of patients with malignancy sometimes be delayed due to various reasons. Several studies revealed that an influence of diagnosis-to-treatment interval (DTI) on outcomes differs depending on the type of malignancy. In this study, we evaluated the influence of DTI on clinical outcomes in newly diagnosed patients with diffuse large B-cell lymphoma (DLBCL). A total of 199 patients were identified with a median DTI of 22 days. At 2 years, patients with short DTI (0-22 days) showed significantly poorer OS (62.7% vs 86.4%) and PFS (55.1% vs 75.9%) compared to those with long DTI (over 22 days). Although short DTI was strongly correlated with several known adverse factors, it remained to be an independent prognostic factor by multivariate analysis. In conclusion, our study confirmed the importance of DTI in patients with DLBCL. Researchers should consider DTI as one of the important prognostic factors and plan clinical trials to be able to enroll patients with aggressive disease requiring urgent treatment.

Donor stem cell-derived paroxysmal nocturnal hemoglobinuria after umbilical cord blood transplantation.

Donor cell-derived hematological disorder (DCHD) is a rare complication of allogeneic hematopoietic stem cell transplantation (HSCT). The number of reports of DCHD has been increasing in the last decade, which likely reflects the growing number of HSCTs and the improved ability to identify the donor cell origin. Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired hematological disorder arising in the context of clonal expansion of hematopoietic stem cells harboring a somatic mutation in phosphatidylinositol glycan anchor biosynthesis, class A. We report here a patient with adult T-cell leukemia/lymphoma, who developed PNH 7 years after umbilical cord blood transplantation. The patient has maintained complete remission with full-donor chimerism after HSCT. Thus, PNH was derived from stem cells of donor origin. The immature immune environment in the recipient after cord blood transplantation might have contributed to the rapid clonal expansion for neonatal stem cells in cord blood to develop typical symptomatic PNH in a short period. To the best of our knowledge, this is the first report in the literature of a case of PNH that developed in donor stem cells after HSCT.

Diagnosis of a difficult to differentiate case of early-onset hyperviscosity syndrome caused by IgM type multiple myeloma: a case report.

Hyperviscosity syndrome (HVS) can cause multiple organ damage if not treated immediately. IgM multiple myeloma (IgM MM) is a very rare form of myeloma with clinical features such as elevated serum IgM, and anemia, that resemble Waldenström macroglobulinemia (WM). Distinguishing between these two diseases is important, but can be a challenging problem. It is well known that MyD88 mutations and t(11;14) translocations are useful for differential diagnosis. We diagnosed HVS in a 29-year-old male with IgM MM. He was treated with triplet therapy, autologous hematopoietic stem cell transplantation, and carfilzomib consolidation therapy. His clinical course was monitored by serum IgM levels, and bone marrow myeloma cell counts by multiparameter flow cytometry analysis. After this series of treatments, his HSV disappeared and he reached stringent complete response. In cases of early onset of HVS, IgM MM should be considered in addition to WM.

Human herpesvirus 8-positive multicentric Castleman disease with germinotropic plasmablastic aggregates: Overlapping spectrum of human herpesvirus 8-associated lymphoproliferative disorder.

The diagnosis of human herpesvirus 8 (HHV8)-associated lymphoproliferative disorder (LPD) is challenging because of the rarity and extended spectrum of each entity. A 43-year-old, human immunodeficiency virus seropositive, Japanese man was referred to our department because of persistent fever, generalized lymphadenopathy, jaundice and anasarca. Biopsy of a left axially lymph node demonstrated relatively preserved nodal structure with multicentric Castleman disease (MCD) features. In the germinal center, there were aggregates of HHV8-infected plasmablasts that were diffusely positive for CD38, MUM1/IRF4, LCA, IgM and λ; partially positive for CD30, c-MYC, p53; and negative for CD138, CD20, PAX-5, κ, CD2, CD3 and CD5. A small number of Epstein-Barr virus encoded small RNA (EBER)-positive large cells infiltrated in the outer part of the germinal center and the mantle layer, but the cells copositive for EBER and HHV8 were not evident. We diagnosed the patient as HHV8-positive MCD with germinotropic plasmablastic aggregates, which demonstrated intermediate pathologic features between HHV8-positive MCD and germinotropic lymphoproliferative disorder. The pathogenesis of each HHV8-associated LPD differs in cellular origin, host immune status, cytoplasmic immunoglobulin expression, clonality pattern and EBV infection; however, these factors sometimes overlap and induce extended clinical and pathologic presentations.

Hodgkin-like adult T-cell leukemia/lymphoma that developed during the follow-up of HTLV-1 associated myelopathy/tropical spastic paraparesis.

Hodgkin-like adult T-cell leukemia/lymphoma (ATLL) is a rare variant of ATLL, which represents the early neoplastic phase of ATLL that follows an indolent clinical course compared with typical ATLL. Human T-lymphotropic virus type 1 (HTLV-1)-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is a neurological disorder characterized by the paralysis of lower limbs and urinary disturbance. Although these diseases are caused by HTLV-1 infection, there are no reports describing the coexistence of Hodgkin-like ATLL and HAM/TSP. Here, we report the first case of Hodgkin-like ATLL complicated by HAM/TSP. The patient was a 56-year-old man with right inguinal lymphadenopathy who had been using the neurology outpatient service for 13 years after being diagnosed with HAM/TSP. He was unable to receive intensive chemotherapy or allogeneic stem cell transplantation due to a poor performance status, but his condition was stable for approximately two years.

[Human herpes virus 8-negative primary effusion lymphoma-like lymphoma recurring as a tumor adjacent to the left atrium].

Primary effusion lymphoma (PEL) is a rare type of non-Hodgkin lymphoma, usually presenting as serous effusions without detectable tumor masses, and it is universally associated with the human herpesvirus 8 (HHV8). In contrast, cases of HHV8-negative effusion lymphoma have been reported and termed as HHV8-negative PEL-like lymphoma. Here, we have reported a rare case of HHV8-negative PEL-like lymphoma that developed in the left atrium tumor 4 years after the pericardial drainage. A 74-year-old female was admitted due to cardiac tamponade caused by massive pericardial effusion. Pericardial drainage was performed, and cytopathologic examination of the fluid revealed atypical lymphoid cells consistent with an effusion lymphoma of B-cell lineage. The pericardial effusion was completely drained, and complete remission was achieved. After 4 years of the drainage, she developed syncope caused by arrhythmia. A computed tomography scan revealed a large tumor in the left atrium and multiple swollen mediastinal lymph nodes. Biopsy of one of the lymph nodes was performed, and its histology was consistent with diffuse large B-cell lymphoma. She was treated with chemotherapy, including rituximab, and complete remission was achieved again. Thus, our experience suggests that careful follow-up may be required in patients with HHV8-negative PEL-like lymphoma after complete remission has been achieved by the drainage.

[Durable remission of Langerhans cell sarcoma attained by autologous hematopoietic stem cell transplantation following surgical resection].

Langerhans cell sarcoma (LCS) is a rare neoplastic proliferation of Langerhans cells with a poor prognosis. Owing to its rarity, standard treatment for LCS has not been established to date. Here, we report a case of LCS occurring in multiple lymph nodes in the right cervix in which remission is maintained by autologous hematopoietic stem cell transplantation (auto-HSCT) after surgical resection. A 58-year-old male presented with enlarged right submandibular lymph nodes. Positron-emission tomography/computed tomography (PET/CT) revealed multiple lymphadenopathies in his right cervix. We performed a lymph node biopsy, and he was diagnosed with LCS. We selected the CHOP regimen as the first-line chemotherapy; however, rapid disease progression was observed soon after the first cycle of the therapy. The neck dissection was performed on day 16 of the CHOP therapy. As the residual tumor was suspected, we started the second-line chemotherapy with a combination of etoposide, cisplatin, ifosfamide, and gemcitabine; complete remission was confirmed by PET/CT. Subsequently, the patient was administered high-dose chemotherapy with auto-HSCT. After 2 years of auto-HSCT, complete remission has been maintained. Although there is no report of auto-HSCT for LCS, it could be an effective therapeutic tool for the disease.

Feasibility of the imatinib stop study in the Japanese clinical setting: delightedly overcome CML expert stop TKI trial (DOMEST Trial).

BACKGROUND: Treatment-free remission (TFR), the ability to maintain a molecular response (MR), occurs in approximately 50% of patients with chronic myelogenous leukemia (CML) treated with tyrosine kinase inhibitors (TKIs). METHODS: A multicenter phase 2 trial (Delightedly Overcome CML Expert Stop TKI Trial: DOMEST Trial) was conducted to test the safety and efficacy of discontinuing imatinib. Patients with CML with a sustained MR of 4.0 or MR4.0-equivalent for at least 2 years and confirmed MR4.0 at the beginning of the study were enrolled. In the TFR phase, the international scale (IS) was regularly monitored by IS-PCR testing. Molecular recurrence was defined as the loss of MR4.0. Recurrent patients were immediately treated with dasatinib or other TKIs including imatinib. RESULTS: Of 110 enrolled patients, 99 were evaluable. The median time from diagnosis to discontinuation of imatinib was 103 months, and the median duration of imatinib therapy was 100 months. Molecular recurrence-free survival rates were 69.6%, 68.6% and 64.3% at 6, 12, and 24 months, respectively. After discontinuation of imatinib therapy, 26 patients showed molecular recurrence, and 25 re-achieved deep MR after dasatinib treatment. Molecular response MR4.0 was achieved in 23 patients within 6 months and 25 patients within 12 months. Multivariate analysis revealed that a longer time from diagnosis to discontinuation of imatinib therapy (p = 0.0002) and long duration of imatinib therapy (p = 0.0029) predicted a favorable prognosis. CONCLUSIONS: This DOMEST Trial showed the feasibility of TKI discontinuation in a Japanese clinical setting.