Clinical significance of high-dose chemotherapy with autologous stem cell transplantation in the era of novel agents in patients older than 65 years with multiple myeloma.

High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) is the standard treatment for symptomatic multiple myeloma (MM) in patients under 65 years of age. However, the performing of ASCT in older patients > 65 years without comorbidities or complications is controversial. Introduction of novel drugs, such as daratumumab, has improved the long-term survival of patients with MM who are ineligible for ASCT. This retrospective study aimed to evaluate the clinical significance of ASCT in older patients, even in the era of novel drugs. A total of 55 patients aged 65-74 years (15 ASCT recipients and 40 ASCT-ineligible patients) newly diagnosed with MM between March 2013 and October 2021 at our institution were analyzed in this study. There were no significant differences in the 3-year overall survival (84.6% vs. 90.6%, p = 0.72) and progression-free survival (PFS) (61.2% vs. 75.1%, p = 0.40) between ASCT recipients and ASCT-ineligible patients. There was also no significant difference in complete response (CR) with minimal residual disease (MRD)-negative rate between the two groups (27% vs. 33%, p = 1.0). Multivariate analysis showed that CR was an independent predictor of PFS (hazard ratio [HR], 0.26; 95% confidence interval, 0.08-0.76; p = 0.01). In this retrospective study, despite patients who were determined to be intolerant to ASCT, the non-ASCT group was non-inferior to the ASCT group in PFS and overall response rate. The results of this study confirm that the significance of ASCT is diminishing in patients 65 years of age and older because newer agents can achieve good responses without ASCT.

[Plasmablastic myeloma initially presented with ascites].

This paper reports a case of a 56-year-old male with IgG lambda plasmablastic myeloma exhibiting multiple chromosomal abnormalities. The patient initially presented with plasmablastic ascites and underwent early auto stem cell transplantation and achieved minimal residual disease-negative status but relapsed after 1.5 months and became refractory to novel drugs, such as proteasome inhibitor and daratumuab. Performing differential diagnosis of plasmablastic myeloma with extramedullary masses or fluid retention observed at the initial presentation in comparison to plasmablastic lymphoma and pleural effusion lymphoma is difficult, and patients often have a poor prognosis even with novel drugs. Hence, finding a treatment strategy for such patients is difficult. Thus, further novel drugs are expected to emerge in the future.

[Prognostic factors in light-chain cardiac amyloidosis: a retrospective analysis].

Among cases of amyloid light-chain (AL) amyloidosis, cardiac amyloidosis is particularly known to be associated with a poor prognosis. However, a few established prognostic indicators exist that consider other organ involvements and a patient's general condition. Between 2012 and 2019, we retrospectively reviewed 27 patients, who were diagnosed with AL amyloidosis at our hospital. The 3-year overall survival rate of patients with cardiac involvement was 20% (95% confidence interval [CI], 0.035-0.461) and that of patients without cardiac involvement was 85.7% (95%CI, 0.334-0.979) (p=0.021). Poor prognostic factors of AL amyloidosis included left ventricular ejection fraction <60%, hemoglobin < 10 g/dl, NT pro-BNP>1,800 pg/ml, BNP>400 pg/ml, difference free light chains>180 mg/l, New York Heart Association classification ≥3, Mayo stage IV disease, and cardiac amyloidosis. A study on four patients who died within 6 months of diagnosis revealed that all the patients had cardiac amyloidosis and Mayo stage IV disease, and they all did not receive sufficient chemotherapy. Although the number of treatment options for AL amyloidosis is expected to increase in the future, patients with poor prognostic factors have a poor prognosis and careful treatment decisions, including palliative care, are required.

Intravascular large B-cell lymphoma involving large blood vessels, three autopsy cases.

Although intravascular large B-cell lymphoma (IVLBCL) is an extranodal lymphoma characterized by the selective growth of lymphoma cells within the lumina of small vessels, we here report three autopsy cases of IVLBCL characterized by the proliferation within large blood vessels. These three cases were diagnosed as IVLBCL of the bone marrow or skin biopsy. Two cases died suddenly before treatment, whereas the other died during treatment. Autopsies showed a large embolus of dense lymphoma cells extending from the truncus pulmonalis to the pulmonary arteries in Case 1, emboli of lymphoma cells in the aorta and carotis in Case 2, and a mass of lymphoma cells blocking the lumen of the aortic arch in Case 3. This is the first report of IVLBCL involving large blood vessels, and it is essential to note that this type of IVLBCL might cause sudden death because of tumor emboli within large blood vessels.

[Successful lung transplantation after long-term ventilator and extracorporeal membrane oxygenation support in a patient with severe bronchiolitis obliterans following allogeneic bone marrow transplantation].

A 29-year-old man was diagnosed with acute myeloid leukemia at 20 years of age; he achieved a second complete remission at 22 years of age after an allogeneic unrelated bone marrow transplantation. After 14 months, he developed bronchiolitis obliterans (BO) due to chronic graft-versus-host disease. Home ventilator management was continuously performed for 3 years, but the patient required extracorporeal membrane oxygenation (ECMO) after progression to type 2 respiratory failure. A matched brain-dead lung donor was found after 5 months of intensive care management on ECMO, and bilateral lung transplantation was successfully performed. BO is a progressive refractory respiratory disease with poor prognosis. Careful management of infection, monitoring organ function, and lung transplantation at the appropriate time of initiation of mechanical ventilation or ECMO may save a patient's life. However, it is crucial to collaborate with higher education institutions or medical professionals in other departments.

Intravascular lymphoma forming massive aortic tumors complicated with sarcoidosis and focal segmental glomerulosclerosis: a case report and literature review.

BACKGROUND: Intravascular large B-cell lymphoma (IVLBCL) is a rare subtype of extranodal diffuse large B-cell lymphoma characterized by proliferation of B cells within small vessels. Herein, we report a case of a 77-year-old man who presented with IVLBCL and massive tumor formation on the aortic wall who was previously diagnosed with sarcoidosis and focal segmental glomerulosclerosis (FSGS). To our knowledge, this is the first reported case of an IVLBCL with aortic tumor formation. CASE PRESENTATION: A 77-year-old ambulatory man with sarcoidosis and FSGS had neurological symptoms for nine months. The patient presented to the emergency department with sudden left leg pain, and was diagnosed with acute femoral artery occlusion. Emergency thrombectomy was performed subsequently. Pathological evaluation of the thrombi revealed that its surface was filled with large atypical B cells. Bone marrow biopsy showed infiltration of large atypical B cells within the small vessels. IVLBCL was suspected and further examination was planned, but the patient died due to sudden respiratory and cardiac arrest on hospital day twelve. Autopsy revealed intravascular tumors adherent to the aortic arch, left ventricle, and the abdominal aorta. All enlarged lymph nodes and the ventricular septum of the heart showed hyalinized lesions with granular formation consistent with sarcoidosis. The patient was diagnosed with IVLBCL with aortic tumor formation complicated with sarcoidosis and FSGS. CONCLUSIONS: IVLBCL may present with tumor formation on the aortic wall. Although the cause of its affinity to the aortic wall is yet unknown, autopsy findings imply that arteriosclerosis may have contributed to the tumor formation. The literature suggests that T-cell abnormalities could possibly be the common etiology of intravascular lymphoma, sarcoidosis, and FSGS.

[Young adult myelodysplastic syndrome with central nervous system involvement diagnosed following cerebral embolism].

While acute myeloid leukemia (AML) could cause an invasion of the central nervous system (CNS), the invasion of the CNS in myelodysplastic syndrome (MDS) is rare. Here, we report a case of juvenile MDS with cerebral infarction concerning the invasion of the CNS by leukemia cells. A 25-year-old male was admitted to our institution because of difficulty in extending the left arm. Magnetic resonance imaging revealed acute-stage cerebral infarction in the right parietal lobe and a diffuse edematous lesion in the surrounding site. In addition, leukemia cells were detected in the spinal fluid. Based on the bone marrow examination finding, he was diagnosed with MDS with excess blast 1. However, no clear disseminated intravascular coagulation and thrombotic diathesis were found in the blood test. If cerebral artery thrombosis occurs in MDS, the invasion of the CNS should be considered as a complication.

[Unidentified Inflammatory Disease Induced by Azacitidine Therapy for Myelodysplastic Syndrome].

We report a 73-year-old woman with myelodysplastic syndromes (MDS) of the refractory anemia with excess of blasts-1 subtype, which was diagnosed in April 2014 on the basis of cytopenia for two cell types. After completing 3cycles of azacitidine (AZA) therapy, the patient was admitted to our hospital based on an initial presentation of high fever. During hospitalization, the high fever and increasing inflammatory reaction persisted. We reevaluated the effect of MDS in this patient and concluded that the AZA administration was successful and the MDS was extremely stable. On medical examination and inspection, the patient had an unidentified inflammatory disease. First, we treated her with high-dose steroid pulse therapy. However, the effect of the treatment was transient. Furthermore, the effects of cyclosporin A and oral steroid therapy were poor; therefore, we initiated tocilizumab administration. Nevertheless, she died of multiorgan failure. An increasing serum IL- 6 level induced by the AZA therapy was later confirmed. Recent studies have reported the immunomodulatory effects stimulated by AZA therapy in MDS. This case is a valuable reminder that an unidentified inflammatory disease can be induced in the course of AZA therapy for MDS.

WT1-guided pre-emptive therapy after allogeneic hematopoietic stem cell transplantation in patients with acute myeloid leukemia.

Measurable residual disease (MRD)-guided pre-emptive therapies are now widely used to prevent post-transplant hematological relapse in patients with acute myeloid leukemia (AML). This single-center retrospective study aimed to clarify the significance of pre-emptive treatment based on Wilms' tumor gene-1 mRNA (WT1) monitoring for MRD in patients with AML who underwent allogeneic hematopoietic stem cell transplantation (allo-HSCT). Patients with AML who received chemotherapy for hematological relapse or WT1 increase after allo-HSCT were eligible for inclusion. From January 2017 to June 2022, 30 patients with a median age of 57 (16-70) years were included and stratified into two groups: 10 with WT1 increase and 20 with hematological relapse. The median times from HCT to WT1 increase or hematological relapse were 309 days (range: 48-985) or 242 days (range: 67-1116), respectively. Less intensive chemotherapy using azacitidine or cytarabine was selected for all patients with WT1 increase and 12 (60%) with hematological relapse. The 1-year overall survival and event-free survival rates for WT1 increase and hematological relapse were 70% vs. 44% (P = 0.024) and 70% vs. 29% (P = 0.029), respectively. These real-world data suggest that WT1-guided pre-emptive therapy may be superior to therapy after hematological relapse in patients with AML who have undergone allo-HSCT.

Pretransplantation Inflammatory and Nutritional Status in Elderly Allogeneic Hematopoietic Stem Cell Transplantation: Prognostic Value of C-Reactive Protein-to-Albumin Ratio.

There are no clear criteria for selecting elderly patients with hematologic malignancies eligible for allogeneic hematopoietic stem cell transplantation (HSCT). This study aimed to evaluate inflammatory and nutritional status biomarkers as prognostic indicators of allogeneic HSCT in elderly patients. We compared the prognostic effects of 4 representative pretransplantation biomarkers: C-reactive protein-to-albumin ratio (CAR), Glasgow Prognostic Score (GPS), prognostic nutritional index (PNI), and albumin-to-globulin ratio (AGR). A total of 143 patients age ≥60 years who underwent their first allogeneic HSCT for a hematologic malignancy were enrolled between 2010 and 2020 in our single-center cohort. The median patient age was 65 years (range, 60 to 72 years). Pretransplantation high CAR, high GPS, and low PNI scores were associated with poor overall survival (OS), but the AGR was not associated with OS. Among the 4 biomarkers, CAR stratified OS most significantly (P < .001). Multivariate analyses identified only high CAR as an independent prognostic factor associated with OS (hazard ratio [HR], 1.98; P = .031) and showed that a Hematopoietic Cell Transplantation-Specific Comorbidity Index (HCT-CI) score ≥3 also was associated with OS (HR, 2.04; P = .012). High CAR was correlated with poor performance status, male sex, and high Disease Risk Index, but not with high HCT-CI score. When the patients were stratified into 3 groups according to a composite risk assessment using CAR and HCT-CI, the 3-year OS decreased significantly with increasing scores (82.8%, 50.3%, and 27.0%, respectively; P < .0001). In conclusion, CAR is the most useful prognostic indicator among the inflammatory and nutritional status biomarkers for allogeneic HSCT in elderly patients. Inflammatory and nutritional status in the elderly may be important prognostic factors for allogeneic HSCT independent of HCT-CI score.

Bridging to transplant and post-transplant maintenance therapy with FLT3 inhibitors in patients with relapsed or refractory FLT3 mutated acute myeloid leukemia.

OBJECTIVES AND METHODS: This single-center retrospective study was performed to evaluate the safety and efficacy of FMS-like tyrosine kinase 3 (FLT3) inhibitors before and after allogeneic hematopoietic cell transplantation (HCT) in relapsed/refractory patients with FLT3-mutation positive acute myeloid leukemia (AML). RESULTS: Ten patients who met the eligibility criteria were included. Eight of them achieved hematological remission at HCT, within a median span of 79 days (range: 43-197). In post-HCT, patients started maintenance therapy (MT; median time-to-start 79 days, range: 43-197), and the median duration of MT was 390 days (range: 67-815). Grade 3 hematological adverse events (AEs) were found in two patients, and non-hematological AEs were found in five patients. Nine patients underwent either dose reduction, discontinuation of therapy, or a switch to another FLT3 inhibitor due to AEs. Disease relapse occurred in one patient during MT. At the time of the last follow-up, seven patients are alive and disease-free, while three have died due to infection or transplant complications. CONCLUSION: In relapsed/refractory FLT3 mutation-positive AML, the use of FLT3 inhibitors can lead to high response rates and provide a safe bridge from HCT to MT. If sufficient attention is paid to safety, this therapy is expected to prevent disease relapse even with reduced dosages.

Case Report: A Case of Myeloproliferative Neoplasm Complicated by Alopecia Areata.

Myeloproliferative neoplasms (MPNs) are caused by genetic abnormalities in the stem cells and manifest with various systemic symptoms. Here, we describe a case of MPN complicated by alopecia areata. A 51-year-old woman visited our hematology department for further evaluation of a slight platelet elevation. Her recent medical history included 3 years of concurrent severe alopecia, mild fatigue, and hot flashes but no fever and weight loss. Physical examination revealed unilateral hair loss on the entire body but no hepatosplenomegaly. Laboratory analysis revealed a normal hemoglobin level, normal white blood cell count, and platelet count of 377,000/µL. Genetic testing confirmed the presence of the JAK2 V617F mutation. Bone marrow examination revealed no morphologic dysplasia in any stem cell lineage and no fibrotic change. Skin biopsy revealed lymphocyte infiltration around the hair follicles. We diagnosed MPN, unclassifiable, which was believed to be the cause of alopecia. About 6 months after treatment with ruxolitinib began, the patient's hair growth dramatically improved. The differential diagnosis of MPNs should include hematological diseases when affected patients have alopecia areata.

Successful treatment of invasive tracheobronchial pulmonary aspergillosis with venovenous extracorporeal membrane oxygenation and combined systemic, intratracheal instillation of liposomal amphotericin B: a case report.

BACKGROUND: Invasive pulmonary Aspergillus and invasive bronchial aspergillosis is a life-threatening opportunistic fungal infection that predominantly affects immunocompromised hosts. A case series and review found that the mortality rate of invasive bronchial aspergillosis is high, at about 40%, and 23.7% of invasive bronchial aspergillosis patients require mechanical ventilator management. There are few reports of life-saving cases with venovenous extracorporeal membrane oxygenation as rescue therapy in invasive pulmonary Aspergillus and invasive bronchial aspergillosis. Here, we report a case of invasive bronchial aspergillosis and invasive pulmonary Aspergillus that was successfully treated with venovenous extracorporeal membrane oxygenation, and combined systemic and intratracheal instillation of liposomal amphotericin B. CASE PRESENTATION: We present the case of a 61-year-old Japanese man with invasive tracheobronchial-pulmonary aspergillosis while receiving chemotherapy for malignant lymphoma. Bronchoscopy revealed trachea covered with pseudomembranous necrotizing tissue, the culture revealed Aspergillus fumigatus, and the histological findings of pseudomembranous revealed fungal hyphae. The patient required venovenous extracorporeal membrane oxygenation because of respiratory failure for atelectasis and obstructive pneumoniae. While continuing systemic administration of liposomal amphotericin B, intratracheal instillation liposomal amphotericin B was performed by bronchoscopy three times a week. Although the respiratory conditions improved and the patient was discontinued on venovenous extracorporeal membrane oxygenation, he ultimately died of recurrence of malignant lymphoma. CONCLUSION: Intratracheal instillation of liposomal amphotericin B is safe, and liposomal amphotericin B instillation allowed a targeted high local drug concentration, which led to improvement in the invasive bronchial aspergillosis. In addition, since the patient was supported with venovenous extracorporeal membrane oxygenation, we were able to perform safe bronchoscopic debridement of airway lesions and intratracheal instillation of liposomal amphotericin B.

Cardiac arrest following cardiac tamponade caused by mycosis fungoides malignant pericarditis.

Mycosis fungoides is a low-grade lymphoma, but on reaching the tumor stage, it can cause cardiac tamponade owing to epicardial infiltration. Myocardial infiltration, even in the absence of abnormal imaging findings, requires attention because it can lead to arrhythmia and cardiac arrest.

Clinical and prognostic significance of t(4;14) translocation in multiple myeloma in the era of novel agents.

Translocation t(4;14) is an independent prognostic factor for adverse outcome in multiple myeloma (MM). However, reports concerning the therapeutic effects of novel drugs on t(4;14) MM are few. We retrospectively investigated the clinical and prognostic significance of symptomatic MM cases with t(4;14) treated with novel therapies. Ninety-three patients (IgG, 56; IgA, 23; BjP, 14) newly diagnosed with MM were included (median age, 71 years; median observation period, 27.8 months). t(4;14) MM was diagnosed in 17 (IgG, 7; IgA, 9; BjP, 1) patients (18%). An association between t(4;14) and the IgA isotype was confirmed (p = 0.02). Overall survival (OS) at 3 years was lower in the t(4;14) patients than without t(4;14) group (81.2% vs 66.7%, p = 0.04). Multivariate analysis showed that t(4;14) was an independent predictor of OS (hazard ratio [HR], 7.58; 95.0% confidence interval [CI], 1.43-39.9; p = 0.0017). The ORR after autologous blood stem cell transplantation (ASCT) did not differ with or without t(4;14); progression-free survival tended to be prolonged in the group without t(4;14) (p = 0.088). Thus, even in the era of novel drugs, t(4;14) MM still has a poor prognosis, and triplet consolidation therapy should be continued.

Anaplastic lymphoma kinase-positive anaplastic large cell lymphoma presenting as diffuse pulmonary infiltrates.

Anaplastic large cell lymphoma has a characteristic sinusoidal growth pattern that presents as pulmonary lymphangitic involvement causing respiratory distress. Recognition and prompt treatment of this entity can result in dramatic response to therapy.

Retrospective Study of Acute Kidney Injury Incidence in Patients with Newly Diagnosed Acute Promyelocytic Leukemia.

PURPOSE: Acute promyelocytic leukemia (APL) constitutes 5-10% of all cases of newly diagnosed acute myeloid leukemia. However, data on the epidemiology and risk factors for acute kidney injury (AKI) in patients with newly diagnosed APL are lacking. This study determined the incidence rate of AKI during induction chemotherapy for patients with newly diagnosed APL and the risk factors for AKI. PATIENTS AND METHODS: We conducted a retrospective observational study of patients with newly diagnosed APL in the Shonan Kamakura General Hospital between April 2004 and April 2020. Data of 27 patients with newly diagnosed APL were analyzed. The patients were classified as no AKI and AKI stages 1, 2 or 3. RESULTS: The incidence rate of AKI during induction chemotherapy was 40% (11/27). Among patients who developed AKI, four patients experienced AKI stage 3, and two patients required renal replacement therapy. No significant differences were found in the white blood cell count and baseline renal function between the groups; however, D-dimer and C-reactive protein levels upon admission were significantly higher in patients with AKI than in patients without AKI. Among patients who developed AKI, in hospital mortality at 90 days was 36% (4/11), which was significantly higher than among patients without AKI (p = 0.02). Patients who developed AKI were administered vancomycin more frequently, while almost all blood culture results were negative. CONCLUSION: Incidence of AKI development in patients with newly diagnosed APL during induction chemotherapy was approximately 40%. Moreover, patients who developed AKI tended to be administered vancomycin more frequently. Unnecessary use of vancomycin should be avoided in patients with newly diagnosed APL, and using alternative non-nephrotoxic drugs should be considered for patients at risk of AKI.

Disseminated Cryptococcosis in a Patient with Multiple Myeloma Treated with Daratumumab, Lenalidomide, and Dexamethasone.

We report a case of disseminated cryptococcosis in a patient with multiple myeloma (MM) during treatment with daratumumab, lenalidomide, and dexamethasone (DRd). A 62-year-old woman, who was diagnosed with IgGλ type MM, was treated with three cycles of bortezomib and dexamethasone and subsequently treated with three cycles of DRd before admission. She reached a stringent complete response and presented with lethargy and seizure. Laboratory findings revealed severe CD4 lymphopenia, and Cryptococcus neoformans was detected in her cerebrospinal fluid and blood culture. The risk of developing an opportunistic infection should be considered in patients treated with daratumumab.

JAK2 V617F-positive essential thrombocythemia with subsequent development of immune thrombocytopenia: A case report.

RATIONALE: Although essential thrombocythemia (ET) and immune thrombocytopenia (ITP) have different etiologies, 3 previous reports have described ET development in ITP patients, all of whom were positive for the JAK2 V617F mutation. Here, we report the first published case of ITP following ET in the absence of other platelet disorders. PATIENT CONCERNS: A 70-year-old woman with a five-year history of ET with JAK2 V617F mutation treated with hydroxycarbamide for five months presented with petechiae on her limbs. DIAGNOSIS: Her platelet count was 3 × 10/L, with the immature platelet fraction being 29%. White blood cell count and hemoglobin level were normal. Bone marrow examination showed increased number of megakaryocytes, but no morphologic dysplasia in any lineage. G-band analysis revealed no abnormalities. Platelet transfusion and cessation of hydroxycarbamide did not affect the platelet count. Thrombocytopenia was unlikely to have been induced by drugs, heparin, systemic lupus erythematosus, or human immunodeficiency virus. Hence, a diagnosis of ITP was made. INTERVENTIONS: The patient received oral prednisolone combined with intravenous immunoglobulin. OUTCOMES: Her platelet count rose to 310 × 10/L and remained stable, while her steroid dose was reduced. Further blood tests revealed the presence of antibodies against Helicobacter pylori, and appropriate treatment was administered. Resumption of hydroxycarbamide did not induce thrombocytopenia. LESSONS: Although ET and ITP have different etiologies, chronic inflammation and immune deregulation underlie both and may play an important role in the progression from one to the other. Further research is warranted to understand the relationship between ET and ITP.