The association of lymphocyte phenotypes and outcomes after discontinuing eltrombopag in immune thrombocytopenia.

AIM: Eltrombopag is a highly effective treatment for immune thrombocytopenia (ITP). Cases of durable remission after the discontinuation of eltrombopag in adult ITP have recently been reported; however, the frequency and mechanisms responsible for this phenomenon remain unknown. In the present study, we examined the phenotypes of lymphocytes in ITP to clarify whether they predict outcomes after the discontinuation of eltrombopag. METHODS: We analysed 56 adult ITP patients treated with eltrombopag at our hospital between January 2008 and January 2020. Patients' characteristics at the initiation and discontinuation of eltrombopag, the prognostic significance of lymphocytes and other factors were evaluated. RESULTS: A total of 38 patients showed complete response (CR). Eltrombopag was discontinued in 28 of 38 patients who achieved CR. Among the 28 patients, 12 (42.8%) had an immediate relapse after discontinuing eltrombopag and 16 (57.2%) showed sustained response without additional ITP therapy, despite discontinuing eltrombopag, with a median follow-up of 42 months. No significant differences were observed in platelets, the median duration of eltrombopag, the absolute number of T, B and NK cells at the initiation of eltrombopag between patients who sustained response and those who relapsed after discontinuing eltrombopag. However, the number of B and NK cells at the discontinuation of eltrombopag was higher in patients who sustained response than in those who relapsed (P = .022 and P = .012 respectively). CONCLUSIONS: The present results indicate that the absolute number of B (≥0.20 × 109 /L) and NK (≥0.30 × 109 /L) cells at the discontinuation of eltrombopag contributes to the prediction of outcomes.

Effective upfront treatment with low-dose ibrutinib for a patient with B cell prolymphocytic leukemia.

B cell prolymphocytic leukemia (B-PLL) is a rare and aggressive disease that is associated with poor survival. Although initially asymptomatic patients do not require therapy, most patients will progress and inevitably require treatment. More than 50% of patients with B-PLL carry abnormalities in the TP53 tumor suppressor gene and/or complex karyotype and show resistance to conventional chemotherapy. The efficacy of ibrutinib, a B cell receptor inhibitor, for B-PLL with the TP53 abnormality as second-line therapy was recently demonstrated. We herein report that low-dose ibrutinib as upfront therapy induced a complete response in a B-PLL patient with the TP53 abnormality, whose condition has since remained stable with no recurrence for 12 months. Effective treatments for B-PLL are lacking and given its rarity, prospective comparative therapies are not yet available. This case suggests that upfront therapy with ibrutinib improves the outcome of B-PLL.

Successful treatment with brentuximab vedotin for relapsed and refractory adult T cell leukemia.

Although treatments for adult T-cell leukemia/lymphoma in the past two decades have advanced, the current standard treatment for aggressive adult T-cell leukemia/lymphoma, particularly in patients who are not eligible for stem cell transplantation, remains inadequate; therefore, treatments to prolong the duration of remission and provide relevant benefits in terms of survival and quality of life are needed. Adult T-cell leukemia/lymphoma tumor cells express CD30 in some cases and the increased expression of CD30 is considered to be one of the causes of constitutive NF-κB activation in adult T-cell leukemia/lymphoma cells. Brentuximab vedotin represents a major breakthrough in the treatment of CD30-positive lymphomas. Elderly patients treated with chemotherapy generally have higher rates of grade 3 or 4 adverse events; however a retrospective analysis demonstrated the safety and efficacy of brentuximab vedotin in adults ≥60 years with relapsed and refractory CD30-positive lymphomas. We herein report the clinical effects of brentuximab vedotin and the significance of CD30 expression in an elderly refractory/relapse adult T-cell leukemia/lymphoma patient. CD30 expression is associated with disease progression in adult T-cell leukemia/lymphoma patients and brentuximab vedotin may be a new and promising treatment option for these patients. Further investigations on the use of brentuximab vedotin for adult T-cell leukemia/lymphoma are needed.

Impact of the CD4:CD8 ratio in bone marrow on stem cell mobilization and engraftment in autologous stem cell transplant patients.

Bone marrow (BM) damage after previous chemotherapy, such as that involving alkylating agents, and radiation therapy alone cannot explain poor hematopoietic progenitor cell mobilization. We examined the T lymphocytes of BM in 67 autologous peripheral blood stem cell transplant (auto-PBSCT) patients with non-Hodgkin lymphoma (NHL) or multiple myeloma (MM) to establish whether the cellular phenotype predicts mobilization and engraftment between January 2000 and January 2020 at the Japanese Red Cross Society Wakayama Medical Center. The total number of mobilized CD34+ cells was <2 × 106 /kg in 30 patients (group A) and ≥2 × 106 /kg in 37 (group B). The median absolute number of CD3+CD4+ cells was lower in group A than in group B (P = .013), and the median absolute number of CD3+CD8+ cells was higher in group A than in group B (P = .016). A low CD4:CD8 ratio was observed in all patients in group A, whereas all patients in group B showed a normal CD4:CD8 ratio (P < .001). A strong correlation was found between the CD4:CD8 ratio and median total CD34+ cells yield (r = .723, P < .001). The present results showed that a lower CD4:CD8 ratio correlated with later neutrophil and platelet engraftment (r = .662, P = .007 and r = .571, P = .008, respectively). The present results indicate that the CD4:CD8 ratio in BM contributes to the prediction of mobilization and engraftment in auto-PBSCT patients.

Clinical effects of CD45 on the prognosis of extramedullary myeloma relapse.

WHAT IS KNOWN AND OBJECTIVES: The incidence of extramedullary relapse (EMR) arising during the clinical course of multiple myeloma (MM) has increased in recent years. Therefore, we herein investigated the effects of immunophenotyping on the prognosis of MM patients with EMR. METHODS: We conducted a retrospective review on data collected from MM patients with EMR between January 2007 and December 2018 at the Japanese Red Cross Society Wakayama Medical Center. Patient characteristics at the diagnosis of EMR, the prognostic significance of immunophenotyping and other factors were evaluated. RESULTS AND DISCUSSION: Extramedullary relapse was detected in 55 of 231 patients (23.8%). At the diagnosis of EMR, CD45, the leucocyte common antigen, was detected in 54.5% of cases. CD45 negativity in bone marrow correlated with thrombocytopenia and higher serum LDH levels. Moreover, high-risk cytogenetics was more frequently observed in CD45- than in CD45+ patients. A univariate analysis showed that overall survival (OS) was significantly shorter in CD45- than in CD45+ patients. Thrombocytopenia, higher serum LDH levels and high-risk cytogenesis were also associated with shorter OS. A multivariate analysis confirmed that CD45 negativity, higher serum LDH levels and high-risk cytogenesis were independent adverse prognostic factors for OS. A Kaplan-Meier analysis revealed the potential of CD45- as a prognostic factor in patients with EMR and that it correlated with shorter survival. WHAT IS NEW AND CONCLUSION: The present results showed that the expression of CD45 in the neoplastic plasma cells of MM patients with EMR was associated with patient prognosis independent of other prognostic factors. The establishment of a treatment strategy for EMR patients with CD45- MM cells is needed to improve poor outcomes.

Successful treatment with pomalidomide and intrathecal injections for central nervous system plasmacytoma in a patient under haemodialysis.

WHAT IS KNOWN AND OBJECTIVES: The involvement of the central nervous system (CNS) in multiple myeloma (MM) is uncommon and has an extremely poor prognosis, and optimal treatment strategies for the CNS MM patients have not yet been established. CASE SUMMARY: A 71-year-old MM patient with severe renal impairment exhibited extramedullary relapse in the CNS and progression while being treated with lenalidomide and dexamethasone. However, she achieved very good partial remission after a treatment with pomalidomide, cyclophosphamide and dexamethasone (PCD) in combination with intrathecal chemotherapy. WHAT IS NEW AND CONCLUSION: This is the first case report to describe MM with CNS involvement in a patient who had responded to PCD under haemodialysis. The combined intrathecal administration of cytotoxic agents and PCD may prolong survival and is tolerated well by patients with severe renal impairment.

Autoimmune Cytopenias Occurring after Treatment with Chemoimmunotherapy for Non-Hodgkin Lymphomas.

Autoimmune diseases, including autoimmune hemolytic anemia and immune thrombocytopenic purpura, have been described in patients with non-Hodgkin lymphoma (NHL) after immunochemotherapy. However, the underlying pathogenesis remains unclear. We examined NHL patients with autoimmune cytopenia and all patients were treated with rituximab-containing therapy. The present results showed reversed imbalances in helper/suppressor T-cell populations, and an immune system imbalance may have contributed to immunological abnormalities. Although the relationship between imbalances in helper/suppressor T-cell populations and the development of auto-antibody production after chemotherapies currently remains unclear, the immunosuppressive effects of immunochemotherapy may be a contributing factor. The long-term monitoring of T-cell populations after immunochemotherapies is important.

Successful retreatment with lenalidomide for relapsed and refractory multiple myeloma previously treated with bortezomib, lenalidomide and pomalidomide.

WHAT IS KNOWN AND OBJECTIVES: Optimal strategies for treating patients with very advanced relapsed and refractory multiple myeloma (RRMM) have not been clarified. CASE SUMMARY: A 80-year-old patient with RRMM experienced extramedullary relapse following treatment with bortezomib, lenalidomide and pomalidomide. However, he achieved very good partial remission after retreatment with lenalidomide. WHAT IS NEW AND CONCLUSION: This report illustrates that patients with very advanced RRMM can still respond to prior therapy even after being exposed and refractory to several agents. Considering the depth or duration of response to prior treatment, "retreatment" may improve the outcome of frail RRMM.

[Successful Treatment with Pomalidomide, Bortezomib, and Dexamethasone in a Patient with Frail Refractory and Relapsed Multiple Myeloma with Extramedullary Disease].

An 85-year-old female was diagnosed with multiple myeloma(MM)(IgG-l)with t(4 ;14)(p16;q32)in 200X. She received bortezomib with dexamethasone(Vd)therapy and lenalidomide with dexamethasone(Ld)therapy, and she subsequently maintained a very good partial response(VGPR). On day 731, she experienced relapse and was treated with 2 courses of elotuzumab with Ld therapy. However, on day 794, she experienced relapse with plasmacytoma, and was treated with 2 courses of pomalidomide and low-dose dexamethasone(Pd), 2 courses of cyclophosphamide with Pd(PCd), and bortezomib with Pd(PVd)therapies. After 3 courses of PVd therapy, she achieved PR. She has continued to receive 11 courses of PVd therapy and has not suffered any adverse events(BGrade 3). These findings suggest that PVd therapy is a relatively safe and highly efficacious treatment for frail patients with relapsed and refractory MM who have previously received both lenalidomide and bortezomib. Further studies are needed to establish treatment efficacy and safety in frail patients with relapsed and refractory MM with extramedullary disease.

Successful management of venous thromboembolism with apixaban in a multiple myeloma patient on lenalidomide therapy.

A 69-year-old man was diagnosed with multiple myeloma (IgG-κ) in January 2012. He received autologous hematopoietic stem cell transplantation in August 2012 and subsequently maintained a stringent complete remission. In March 2016, he relapsed and was treated with lenalidomide and low-dose dexamethasone (Ld). On day22, he developed an asymptomatic venous thromboembolism (VTE) despite receiving prophylactic aspirin treatment. Thus, heparin and warfarin were administered. However, his prothrombin time-international normalized ratio did not remain within the target range of 2-3. Therefore, 10 mg/day of apixaban, a factor Xa inhibitor, was administered. The apixaban treatment resulted in favorable and effective control of the patient's VTE on day33. He has continued to receive Ld treatment and has suffered no further VTE or bleeding. Further large studies are needed to assess the efficacy and safety of factor Xa inhibitors for the treatment of MM-associated VTE.

Chronic GVHD complicated with polymyositis and cardiomyopathy after myeloablative hematopoietic stem cell transplantation.

A 50-year-old woman presented with leukocytosis, anemia, and thrombocytopenia in June 2013. She was diagnosed with de novo acute myeloid leukemia with the t(16;21)(q24;q22) translocation. She received an allogeneic hematopoietic stem cell transplant from an HLA-DRB1 locus-mismatched unrelated donor in June 2014. The myeloablative preparative regimen consisted of cyclophosphamide at 60 mg/kg for 2 days and total body irradiation at 12 Gy. On Day 55, she was treated with prednisolone at 20 mg/day for acute GVHD (Grade III; Skin Stage 2, Gut Stage 2, Liver Stage 0) and gradually improved. She had fever, myalgia in the upper limbs, and asymptomatic sinus tachycardia on Day 145. Laboratory tests showed elevated CK, CKMB, aldolase, and troponin I. Electromyographic examination revealed myopathic abnormalities compatible with the diagnosis of myositis. Electrocardiography showed tachycardia and anteroseptal ST elevation, and echocardiography showed hypokinesia of the left interventricular septal wall without evidence of infection or leukemia relapse. She was immediately treated with 40 mg/day prednisolone after the diagnosis of polymyositis and cardiomyopathy, associated with chronic GVHD. The polymyositis and cardiomyopathy improved promptly after the administration of prednisolone and the patient remains in remission with a current maintenance program of prednisolone at 5 mg/day.

Development of donor cell leukemia mimicking hematogones after unrelated cord blood transplantation for relapsed acute lymphoblastic leukemia.

A 26-year-old woman, who developed ALL when she was eighteen years old, achieved remission after chemotherapy. Her ALL relapsed when she was twenty-two years old. After re-induction therapy, she underwent cord blood transplantation. Her bone marrow examination on the 42nd day revealed a lymphoblast count of 16%. She was observed without any therapy, but her bone marrow blast count continued to be around 6% for three years without any symptoms. The bone marrow blast fraction originated from the cord blood. Surface marker analysis of the blast fraction initially revealed a pattern of hematogones that was CD10 and CD19 positive, but then showed a myeloblast pattern that was CD13 and CD33 positive. AML developed as donor cell leukemia. When blasts appear in the early phase after transplantation and persist, an observation period is necessary with molecular chimerism, morphology, and surface marker analysis of the blast fraction to consider relapse, hematogones, or donor cell leukemia.

Successful treatment of systemic AL amyloidosis with autologous hematopoietic stem cell transplantation combined with cell-free and concentrated ascites reinfusion therapy.

Key Clinical Message: AL patients develop the unique toxicities of fluid retention and non-cardiogenic pulmonary edema during the course of stem cell mobilization. We propose mobilization with CART as effective and safe treatment for AL patients with refractory anasarca. Abstract: We describe a 63-year-old male with systemic immunoglobulin light chain (AL) amyloidosis with cardiac, renal, and liver involvement. After four courses of CyBorD, mobilization with G-CSF at 10 µg/kg was initiated and CART was simultaneously performed for fluid retention. No adverse events were observed during collection or reinfusion. Anasarca gradually disappeared and he underwent autologous hematopoietic stem cell transplantation. The complete remission of AL amyloidosis has been maintained, and the condition of the patient has remained stable for 7 years. We propose mobilization with CART as an effective and safe treatment option for AL patients with refractory anasarca.

Antimicrobial Effects of Lactoferrin against Helicobacter pylori Infection.

Helicobacter (H.) pylori is the primary causative agent of various gastroduodenal diseases. H. pylori is an adapted microorganism that has evolved to survive in the acidic conditions of the human stomach, possessing a natural strategy for colonizing harsh environments. Despite the implementation of various eradication regimens worldwide, the eradication rate of H. pylori has decreased to less than 80% in recent years due to the emergence of antibiotic-resistant strains. This has posed a significant challenge in treating H. pylori infection, as antibiotic resistance and side effects have become increasingly problematic. Lactoferrin, a member of the transferrin family, is an iron-binding protein with antioxidant, antibacterial, antiviral, and anti-inflammatory properties that promote human health. The concentrations of lactoferrin in the gastric juice and mucosa significantly increase during H. pylori infection and are strongly correlated with the severity of gastric mucosal inflammation. Numerous researchers have studied the antimicrobial properties of lactoferrin both in vitro and in vivo. In addition, recent studies have investigated the addition of oral lactoferrin supplementation to H. pylori eradication therapy, even though monotherapy with lactoferrin does not eradicate the microorganism. In this article, we reviewed the survival strategy of H. pylori to evade the antimicrobial activity of human lactoferrin and explore the potential of lactoferrin in H. pylori eradication therapy.

Elevated plasma and bile levels of corisin, a microbiota-derived proapoptotic peptide, in patients with severe acute cholangitis.

BACKGROUND: Acute cholangitis is a severe, life-threatening infection of the biliary system that requires early diagnosis and treatment. The Tokyo Guidelines recommend a combination of clinical, laboratory, and imaging findings for diagnosis and severity assessment, but there are still challenges in identifying severe cases that need immediate intervention. The microbiota and its derived products have been implicated in the pathogenesis of acute cholangitis. Corisin is a microbiome-derived peptide that induces cell apoptosis, acute tissue injury, and inflammation. This study aimed to evaluate the potential of plasma and bile corisin as a biomarker of acute cholangitis. METHODS: Forty patients with acute cholangitis associated with choledocholithiasis or malignant disease were enrolled. Nine patients without acute cholangitis were used as controls. Corisin was measured by enzyme immunoassays in plasma and bile samples. Patients were classified into severe and non-severe groups. The associations of plasma and bile corisin with the clinical grade of acute cholangitis and other parameters were analyzed by univariate and multivariate regression analysis. RESULTS: Plasma and bile corisin levels were significantly higher in patients with acute cholangitis than in controls. Patients with severe acute cholangitis had significantly higher plasma and bile corisin levels than those with non-severe form of the disease. Bile corisin level was significantly correlated with markers of inflammation, coagulation, fibrinolysis, and renal function. Univariate analysis revealed a significant association of bile corisin but a weak association of plasma corisin with the clinical grade of acute cholangitis. In contrast, multivariate analysis showed a significant relationship between plasma corisin level and the disease clinical grade. The receiver operating characteristic curve analysis showed low sensitivity but high specificity for plasma and bile corisin to detect the severity of acute cholangitis. The plasma and bile corisin sensitivity was increased when serum C-reactive protein level was included in the receiver operating characteristic curve analysis. CONCLUSIONS: Overall, these findings suggest that plasma and bile corisin levels may be useful biomarkers for diagnosing and monitoring acute cholangitis and that corisin may play a role in the pathophysiology of the disease by modulating inflammatory, coagulation and renal pathways.