New therapies in anti-MDA5 antibody-positive dermatomyositis.

PURPOSE OF REVIEW: This review focuses on treatments for anti-MDA5 antibody-positive dermatomyositis (MDA5-DM), which is a subgroup of dermatomyositis and characterized by frequent rapidly progressive interstitial lung disease and the high mortality rate. Despite conventional immunosuppressive therapies, there are still refractory cases. Newer treatment options are needed. RECENT FINDINGS: The triple combination therapy (high-dose glucocorticoids, calcineurin inhibitor, and intravenous cyclophosphamide) improved patient survival compared to high-dose glucocorticoids and step-wise addition of the immunosuppressants. The triple therapy now has been widely used, but there are still refractory cases. In addition to the conventional-type immunosuppressants, recently the efficacy of Janus kinase inhibitors, biologic agents such as rituximab, plasma exchange, and polymyxin B perfusion for refractory MDA5-DM patients have been reported. However, the majority of those reports regarding new treatments are limited to case series, retrospective studies, and small single-arm studies. Adding antifibrotic drugs to immunosuppressive therapies might have some ancillary benefits. SUMMARY: Several new therapies for MDA5-DM patients have emerged, although the optimal use of those therapies is still unknown. Further research and evidence accumulation will be needed. It is also noted that the intensive immunosuppressive therapies are associated with the higher infection risk.

Short-term and long-term outcomes of patients with anti-melanoma differentiation-associated gene 5 antibody-positive dermatomyositis.

OBJECTIVES: Anti-melanoma differentiation-associated gene 5 (MDA5) antibody-positive dermatomyositis (MDA5-DM) is a subtype of dermatomyositis characterized by frequent interstitial lung disease and reduced muscle involvement. This study aimed to determine the short-term and long-term outcomes of patients with MDA5-DM. METHODS: Information on baseline characteristics, treatments, and short-term and long-term outcomes of patients with MDA5-DM including survival, relapse, and the titer of anti-MDA5 antibody, was retrospectively collected. Descriptive statistics regarding clinical outcomes were calculated, and a comparison of clinical parameters between patients with and without relapse was performed. The short-term survival according to the use of Janus kinase inhibitors (JAKi) was also assessed. RESULTS: A total of 154 patients with MDA5-DM were included in the study. Forty patients (25.9%) died during the remission induction phase, with respiratory failure being the most common cause of mortality. Among the 114 patients who survived the remission induction phase, the 5-year cumulative survival and relapse-free survival rates were 96.8% and 77.4%, respectively, and 7.9% of patients achieved complete drug-free remission. Fifty-four patients achieved normalization of anti-MDA5 antibody titers and only two of them relapsed after normalization. In the severe patients, the 6-month survival rate became significantly higher after the emergence of the JAKi treatment compared with before its existence (p= 0.03). CONCLUSIONS: Although relapse often occurs, the long-term survival of MDA5-DM patients who survived the remission induction phase is generally favorable. The status of the anti-MDA5 antibody is associated with relapse. JAKi may improve the survival of refractory patients with severe MDA5-DM.

Allogeneic stem cell transplantation for children and adolescents/young adults with de novo blastic phase chronic myeloid leukemia in the tyrosine kinase inhibitor era.

The analysis of 165 children and adolescents/young adults with de novo blastic phase chronic myeloid leukemia showed disease status at hematopoietic stem cell transplantation was a strong prognostic factor and clearly separated the patient outcomes.

Pulmonary Actinomycosis and Mucormycosis Coinfection in a Patient With Philadelphia Chromosome-positive Acute Lymphoblastic Leukemia Undergoing Chemotherapy.

Mucormycosis is an opportunistic and progressive infection, while actinomycosis usually grows gradually and rarely develops in immunocompromised patients. Here we report a patient with Philadelphia chromosome-positive acute lymphoblastic leukemia who developed a pulmonary actinomycosis and mucormycosis coinfection. Once the diagnosis of actinomycosis was confirmed by bronchoscopy, lobectomy performed before stem cell transplantation revealed mucormycosis. The patient successfully underwent transplantation using a therapeutic antifungal agent for mucormycosis. When an immunocompromised patient develops an infection of unknown etiology, physicians should consider these pathogens as the possible cause. In addition, surgical intervention should be considered as an important treatment option.

Impact of melphalan dose during reduced-intensity conditioning on engraftment of cord blood transplantation for chronic Epstein-Barr virus-associated T or NK cell lymphoproliferative diseases.

The rejection rate in cord blood transplants for chronic Epstein-Bar virus-associated T or natural killer cell lymphoproliferative diseases using our standard reduced-intensity conditioning "LPAM140 regimen," which includes fludarabine, melphalan (LPAM), etoposide, and antithymocyte globulin, has been high. To ensure better engraftment, we increased the LPAM dose to 210 mg/m2 ("LPAM210 regimen"). Patient data (n = 22; LPAM140, n = 7; LPAM210, n = 15) were analyzed retrospectively. The engraftment rate after the LPAM210 regimen (100.0%) was significantly higher than that after the LPAM140 regimen (57.1%; P = .002). Fludarabine combined with melphalan (210 mg/m2 ) had a favorable impact on engraftment.

Intrathecal Infusion of Haploidentical Nondonor Lymphocytes for Central Nervous System Leukemic Relapse After Haploidentical Hematopoietic Stem Cell Transplantation.

Leukemic relapse in the central nervous system (CNS) after conventional treatment is associated with a poor prognosis. The effectiveness and safety of IV infusion of human leukocyte antigen (HLA)-mismatched lymphocytes for leukemia, and intrathecal (IT) infusion of HLA-mismatched lymphocytes for cerebrospinal fluid (CSF) dissemination of medulloblastoma have been reported. A 13-year-old girl (HLA-A31) was diagnosed as relapsing from Philadelphia chromosome-positive acute leukemia in the CNS after receiving chemotherapy, tyrosine kinase inhibitors, haploidentical hematopoietic stem cell transplantation (HSCT) from her father (HLA-A31), and craniospinal irradiation. We performed an IT infusion of haploidentical lymphocytes from her mother. Peripheral blood mononuclear cells obtained from her mother (HLA-A31) were administered by IT infusion weekly. Examination of CSF 1 week after first IT showed that lymphocyte counts had increased markedly and the breakpoint cluster region/abelson-bearing cells had disappeared. Furthermore, CD3 T cells in the CSF were negative for HLA-A31, and expressed high HLA-DR. These results indicate the infused non-HSCT-donor lymphocytes did not survive, and that the HSCT donor(father)-derived lymphocytes migrated to the CSF and were activated. The patient showed partial remission for 2 months following this therapy. Serious adverse reactions and graft versus host disease were not observed. To control leukemic CNS dissemination, haploidentical nondonor lymphocytes might contribute to a graft versus leukemia effect.

[Transurethral Injection Using Deflux for Vesicoureteral Reflux in Three Adult Women with Frequent Febrile Urinary Tract Infections].

We report three patients with frequent febrile urinary tract infections (fUTI) who underwent transurethral injection therapy with Deflux for vesicoureteral reflux (VUR). The first case was in a 52-yearold woman who was initially diagnosed with right grade II and left grade I VUR at 18 years of age. She frequently experienced fUTI due to VUR. The second case was in a 29-year-old woman. At age 23,she was diagnosed with right grade III VUR when she developed fUTI. After that,she repeatedly developed fUTI. The third case was in a 40-year-old woman who had frequently experienced fUTI since 25 years of age and had gradually become antibiotics-resistant. She was diagnosed with right grade III VUR when she was referred to our hospital. No visible reflux was confirmed by postoperative voiding cystourethrography after the patients underwent transurethral injection using Deflux. One patient developed fUTI once after surgery,but there were no perioperative complications and no recurrences. Transurethral injection using Deflux for VUR might therefore be safe and effective for treating VUR in adult female patients.

Feasibility of Cancer Immunotherapy with WT1 Peptide Vaccination for Solid and Hematological Malignancies in Children.

BACKGROUND: Advances in cancer immunotherapy in the pediatric field are needed in order to improve the prognosis of children with malignancies. We conducted a prospective phase I/II study of WT1 peptide vaccination for children with relapsed or refractory malignancies. METHODS: The main eligibility criteria were affected tissues or leukemic cells expressing the WT1 gene, and patients (and donors for allogeneic hematopoietic stem cell transplantation) having HLA-A*24:02. Vaccination using the WT1 peptide (CYTWNQMNL), which was modified for higher affinity to this HLA-type molecule with the adjuvant Montanide ISA51, was performed weekly 12 times. RESULTS: Twenty-six patients were enrolled and 13 (50.0%) completed the vaccination 12 times. Evidence for the induction of WT1-specific cytotoxic T-lymphocyte (CTL) responses without severe systemic side effects was obtained. Two out of 12 patients with bulky disease exhibited a transient clinical effect (one mixed response and one stable disease), three out of six patients with minimal residual disease achieved transient molecular remission, and five out of eight patients without a detectable level of the molecular marker, but with a high risk of relapse, had the best outcome of long-term continuous complete remission. CONCLUSIONS: WT1 vaccination is a safe immunotherapy and induced WT1-specific CTL responses in children; however, as a single agent, vaccination only provided patients in remission, but with a high risk of relapse, with "long-term benefits" in the context of its use for relapse prevention. WT1 peptide-based treatments in combination with other modalities, such as anti-tumor drugs or immunomodulating agents, need to be planned.

The Suppressive Effect of Quercetin on Toll-Like Receptor 7-Mediated Activation in Alveolar Macrophages.

Respiratory viral infections that cause chronic airway and lung disease can result in the activation of the innate immune response. Alveolar macrophages (AMs), one of the first lines of defense in the lung, are abundantly located in alveoli and the respiratory tract. Flavonoids found in fruits and vegetables exhibit cytoprotective effects on various cell types. In this study, we investigated the effect of quercetin on activation of AMs that had been exposed to imiquimod, a ligand of Toll-like receptor (TLR) 7. In both a mouse AM cell line (AMJ2-C11 cells) and mouse bronchoalveolar fluid cells, we demonstrated that quercetin attenuated TLR7-induced the expression of TNF-α and IL-6. In AMJ2-C11 cells, quercetin also attenuated the TLR7-induced CD40 expression; attenuated the translocation of p65; induced translocation of Nrf2 from cytosol to nucleus; and induced heme oxygenase (HO)-1 expression. Notably, tin protoporphyrin IX (SnPP), an inhibitor of HO-1, also attenuated TLR7-induced transcription of the TNF-α and IL-6 genes, suggesting that the effect of quercetin is mediated by HO-1. These results suggest that dietary supplementation with quercetin may have efficacy in the treatment of respiratory viral infection.

Umbilical cord blood as an alternative source of reduced-intensity hematopoietic stem cell transplantation for chronic Epstein-Barr virus-associated T or natural killer cell lymphoproliferative diseases.

Chronic Epstein-Barr virus-associated T/natural killer cell lymphoproliferative diseases represented by chronic active Epstein-Barr virus infection are lethal but are curable with several courses of chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT). Recently, we reported that reduced-intensity conditioning (RIC) provided better outcomes than myeloablative conditioning because RIC was less toxic. However, it was unclear whether cord blood transplantation (CBT) works in the context of RIC. We retrospectively analyzed 17 patients who underwent RIC followed by bone marrow transplantation (RIC-BMT) and 15 patients who underwent RIC followed by CBT (RIC-CBT). The representative regimen was fludarabine and melphalan based. The overall survival rates with RIC-BMT and RIC-CBT were 92.9% ± 6.9% and 93.3% ± 6.4%, respectively (P = .87). One patient died of lung graft-versus-host disease after RIC-BMT, and 1 patient died of multiple viral infections after RIC-CBT. Although cytotoxic chemotherapy was also immunosuppressive and might contribute to better donor cell engraftment after RIC-HSCT, the rate of engraftment failure after RIC-CBT was still higher than that after RIC-BMT (not significant); however, patients who had experienced graft failure were successfully rescued with a second HSCT. Unrelated cord blood can be an alternative source for RIC-HSCT if a patient has no family donor.

Feasibility of HLA-haploidentical hematopoietic stem cell transplantation with post-transplantation cyclophosphamide for advanced pediatric malignancies.

BACKGROUND: Patients with advanced malignancies in non-complete remission (CR) have a dismal prognosis after HLA-matched hematopoietic stem cell transplantation (HSCT). T-cell-replete HLA-haploidentical HSCT has remarkable anti-leukemia/tumor effects on these patients, but also a high risk of severe/extensive graft-versus-host disease (GHVD). Post-transplantation cyclophosphamide (PTCY) is regarded as a GVHD-specific immunosuppressant in adults, but its feasibility is unknown in children. METHODS: We performed a prospective feasibility study of PTCY at 50 mg/kg on day 3 for children with advanced leukemias or malignant solid tumors: refractory to chemotherapy or relapsed after conventional allogeneic HSCT. Conditioning consisted of fludarabine (180 mg/m2) and melphalan (140-210 mg/m2). RESULTS: Long-term engraftments were achieved in 11 patients (73.3%) after bone marrow transplantation (BMT, n = 13) or peripheral blood (PB) stem cell transplantation (n = 2). The incidence of severe acute GHVD was 25.0% and that of extensive chronic GVHD 0.0% after evaluable BMT. CR was achieved in 6/15 and partial response in 4/15 as the best response. Finally, 11/15 experienced disease progression/relapse, 2/15 suffered treatment-related mortality without evidence of disease, and 2/15 are alive in continuous CR. CONCLUSIONS: PTCY is feasible in children; however, for a better outcome in such patients with advanced malignancies, some modifications are anticipated.

Roxadustat-Induced Central Hypothyroidism in Renal Anemia Patients: Insights From Antineutrophil Cytoplasmic Antibody-Related Vasculitis Cases.

The introduction of hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors in Japan in 2019 for treating renal anemia in hemodialysis patients has resulted in an adverse event: central hypothyroidism. Although this adverse event was not widely recognized by the public, it was first documented in Japan in 2021. Despite limited case reports on roxadustat, an oral HIF-PH inhibitor that induces central hypothyroidism, this condition typically improves rapidly upon discontinuation of the drug. In this report, we present rare cases of roxadustat-induced central hypothyroidism in two patients: a woman in her 80s and a man in his 60s, neither of whom had prior thyroid disease. Both patients developed central hypothyroidism shortly after starting roxadustat treatment for renal anemia associated with antineutrophil cytoplasmic antibody-related vasculitis. Notably, neither patient had pituitary tumors or other pituitary hormone disorders. Thyroid function improved with levothyroxine treatment, even when oral roxadustat was continued. Roxadustat may induce central hypothyroidism, highlighting the importance of regularly measuring and evaluating thyroid function when administering this drug to monitor possible changes in thyroid hormone levels.

Feasibility of reduced-intensity allogeneic stem cell transplantation with imatinib in children with philadelphia chromosome-positive acute lymphoblastic leukemia.

Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph + ALL) in children is one of the highest-risk ALL groups. Improved outcome in combination with imatinib has been reported. However, intensive chemotherapy or myeloablative conditioning followed by hematopoietic stem cell transplantation (HSCT) can be associated with significant adverse late effects. We report a case series of five children with Ph + ALL underwent reduced-intensity allogeneic HSCT (RIST) after induction and consolidation in chemotherapy combined with imatinib. Four of the five patients remain first complete remission for a median of 3.1 years after RIST. These results are preliminary, but suggest the feasibility and effectiveness of RIST with imatinib.

[Establishment of "Anaphylaxis Scoring Aichi (ASCA)," a new symptom scoring system to be used in an oral food challenge (OFC)].

BACKGROUND: An original symptom score sheet named "Anaphylaxis Scoring Aichi (ASCA)" was created to quantitatively determine the severity of allergic symptoms provoked in an oral food challenge. METHODS: ASCA lists and sorts subjective and objective symptoms into five organs (respiratory, skin-mucosal, gastrointestinal, psycho-neurological and cardiovascular). The organ scores were given (0 to 60 points) in accordance with the severity of each symptom. The total score was defined as the sum of the highest 5 organ scores (maximum 240 points) observed throughout the course of an OFC. This study evaluated the ASCA score in 253 cases of a positive food challenge (age 1-16 years, mean 5.3±3.2 years) conducted from April to August 2011 in our institute. The results were compared to the modified anaphylaxis grading presented in the Japanese Pediatric Guideline for Oral Food Challenge Test in Food Allergy 2009. At the same time, we evaluated the indications of symptomatic treatment using ASCA score. RESULTS: The total score closely correlated with the anaphylaxis grading, but there was a wide range of overlap between grade 2 and grade 3. All cases with a total score≥60 points were equivalent to grade 4 or 5, and that were consisted of three or more organ symptoms. These severe cases contained respiratory or skin/mucosal symptoms, and despite the early induction of initial therapy, the symptoms became worse. CONCLUSION: ASCA is therefore considered to be a useful tool for use in an oral food challenge test.

Fulminant myocarditis with adult-onset Still's disease: case-based review.

Myocarditis has been reported as a life-threatening complication of adult-onset Still's disease (AOSD), but fulminant myocarditis with AOSD is very rare. We hereby report a case of a 43-year-old female with fulminant myocarditis with AOSD. She had a refractory AOSD and cardiogenic shock with markedly elevated ferritin level up to 67,370 ng/mL. She was successfully treated with canakinumab and mechanical circulatory support (MCS) such as venoarterial extracorporeal membrane oxygenation and Impella CP. We also reviewed the previous cases of fulminant myocarditis with AOSD published from 1976 to December 2022, and only 8 cases of fulminant myocarditis with AOSD have been reported. The characteristics of these cases showed that the average age at presentation was 37.6 years (range 24-47 years). The time to myocarditis from the onset of AOSD ranged from 2 weeks to 2 years; however, most cases developed myocarditis within 1 year. Initial presenting symptoms included fever, dyspnea, chest pain, myalgia, rash, and sore throat. The median peak ferritin was 13,000 ng/mL. Left ventricular ejection fractions were not greater than 35%. Our case was the first reported case successfully treated with canakinumab and MCS. This review suggests that myocarditis may be an early phase of the complication in patients with AOSD, and the severity of AOSD may correlate with the severity of myocarditis. Canakinumab for AOSD and MCS for fulminant myocarditis may be one of the choices for overcoming the comorbidities.

Severe persistent bone marrow failure following therapy with 2-chlorodeoxyadenosine for relapsing juvenile xanthogranuloma of the brain.

2-Chlorodeoxyadenosine (2-CdA) has been successfully used in children to treat refractory Langerhans cell histiocytosis and juvenile xanthogranuloma (JXG) as salvage therapy. Although 2-CdA is generally well-tolerated, with temporary myelosuppression as the primary dose-limiting toxicity, prolonged myelosuppressive, and immunosuppressive effects have been reported. We describe an adolescent patient with refractory multiple central nervous system JXG, with the lesion size markedly reduced after treatment with 2-CdA. However, severe transfusion-dependent bone marrow failure developed after five courses of 2-CdA. He underwent successful bone marrow transplantation from his HLA compatible sister with reduced intensity conditioning.

Radiation-sparing reduced-intensity unrelated umbilical cord blood transplantation for rare hematological disorders in children.

Graft failure is a major pitfall of unrelated umbilical cord blood transplantation (CBT) in children with rare hematological disorders other than acute leukemia, such as acquired and inherited bone marrow failure, myelodysplastic syndrome, juvenile myelomonocytic leukemia, and chronic myeloid leukemia. We developed a less-toxic conditioning regimen for CBT that achieves a higher rate of complete donor chimerism, and retrospectively compared it against two other conditioning regimens for CBT performed at our single institution. The engraftment rate with complete donor chimerism was 100% and 5-year event-free survival (5y-EFS) was 90.9% in patients using our latest regimen (n = 11) of reduced-intensity conditioning (RIC) containing fludarabine (Flu) 180 mg/m2, melphalan (MEL) 210 mg/m2, and low-dose rabbit anti-thymocyte globulin (LD-rATG) 2.5 mg/kg without irradiation (regimen C). Outcomes were better than in patients (n = 10) treated with previous regimens involving irradiation (5y-EFS 30.0%, p = 0.004): regimen A, consisting of myeloablative conditioning containing cyclophosphamide (CY) and total body irradiation (TBI) with 8-12 Gy, or regimen B, consisting of RIC with Flu, CY, horse ATG, and thoracoabdominal irradiation (TAI) with 6 Gy. In conclusion, Flu/MEL/LD-rATG (regimen C) without TBI/TAI may be preferable as RIC for unrelated CBT in children with rare hematological disorders.

A retrospective analysis of azacitidine treatment for juvenile myelomonocytic leukemia.

Juvenile myelomonocytic leukemia (JMML) is a pediatric hematological malignancy with a poor prognosis. Although several case series have been published describing hematological and molecular responses to azacitidine (AZA) treatment in patients with JMML, the efficacy and safety profile of AZA is not well investigated, especially in Asian children and children undergoing hematopoietic stem cell transplantation (HSCT). We retrospectively analyzed 5 patients who received a total of 12 cycles (median 2 cycles) of AZA treatment in Japan. All five patients were boys and their ages at the time of treatment were 21, 23, 24, 26, and 46 months, respectively. All five patients tolerated AZA treatment, including four patients who received AZA after HSCT. Therapeutic toxicity with AZA was mostly limited to hematological toxicity. The only serious non-hematological adverse event was hyperbilirubinemia (grades III-IV) observed in a patient who received AZA after a second HSCT. Two out of five patients treated with AZA achieved a partial response (PR), while three patients treated for post-transplant relapse did not have an objective response. Future prospective studies should be conducted to develop combination therapies with AZA and other molecular targeted drugs for high-risk patients.

HLA-haploidentical peripheral blood stem cell transplantation following reduced-intensity conditioning with very low-dose antithymocyte globulin for relapsed/refractory acute leukemia in pediatric patients: a single-institution retrospective analysis.

The prognosis of relapsed/refractory (R/R) pediatric acute leukemia is extremely poor. We retrospectively reviewed 20 consecutive pediatric patients with R/R acute leukemia who underwent a first HLA-haploidentical peripheral blood stem cell transplantation following reduced-intensity conditioning (haplo-RIC-PBSCT) with very low-dose antithymocyte globulin (ATG) between 2012 and 2019. Of these 20 patients, 7 patients had acute lymphoblastic leukemia, and 13 had acute myeloid leukemia. At the time of haplo-RIC-PBSCT, 15 patients had active disease. The median follow-up duration for survivors was 56 months (range 22-108 months). Graft-versus-host disease (GVHD) prophylaxis consisted of tacrolimus, short-term methotrexate, methylprednisolone, and ATG 1.25 mg/kg on day-2. The 2-year cumulative incidence of transplant-related mortality and relapse were 5.0% [95% confidence interval (CI) 0.7-30.5%)] and 57.8% (95% CI 37.4-79.6%), respectively. Among the 20 patients, 16 (80.0%) developed grade III-IV acute GVHD, and 2 developed severe chronic GVHD. The 2-year event-free survival and overall survival rates were 40.0% (95% CI 19.3-60.0%) and 50.0% (95% CI 27.1-69.2%), respectively. Although the sample size is small, the survival outcomes of the present study are encouraging.