Real-world clinical characteristics of post-essential thrombocythemia and post-polycythemia vera myelofibrosis.

There are few prospective studies on patients with post-essential thrombocythemia myelofibrosis (PET-MF) and post-polycythemia vera myelofibrosis (PPV-MF). Therefore, we conducted a nationwide longitudinal prospective survey to clarify the clinical characteristics of these diseases. A total of 197 PET-MF and 117 PPV-MF patients diagnosed between 2012 and 2021 were analyzed. The median age at diagnosis was 70.0 years for both diseases. The time from diagnosis of ET or PV to that of MF was 9.6 and 10.4 years, respectively, with no significant difference. Patients with PPV-MF had higher hemoglobin levels and white blood cell counts than those with PET-MF, whereas those with PET-MF had higher platelet counts than those with PPV-MF. Although splenomegaly was more frequent in patients with PPV-MF at diagnosis, there was no difference in the frequency of constitutional symptoms. Ruxolitinib was the most common treatment administered to 74.6% and 83.8% of patients with PET-MF and PPV-MF, respectively. Patients with PET-MF and PPV-MF had similar prognoses, with 3-year overall survival (OS) of 0.742 in PET-MF and 0.768 in PPV-MF patients. In both diseases, leukemic transformation was the leading cause of death, followed by infection. The 3-year OS for patients with PET/PPV-MF and primary MF diagnosed during the same period was 0.754 and 0.626, respectively, with no significant difference. This survey provides real-world clinical features and prognostic data on secondary myelofibrosis in the ruxolitinib era.

[Successful pregnancy and delivery achieved with eculizumab administration initiated after a preceding missed abortion in a patient with paroxysmal nocturnal hemoglobinuria].

Pregnancy with paroxysmal nocturnal hemoglobinuria (PNH) poses a high risk of thrombosis, maternal death, miscarriage, and premature infants. Eculizumab lowers complications for pregnancy with PNH. A proposed protocol for the management of pregnancy in women with PNH by The National Research Group on Idiopathic Bone Marrow Failure Syndrome (the Japanese Guideline) recommends patients to start eculizumab at an early stage of pregnancy if they have not been treated with eculizumab or continue eculizumab during pregnancy. A 31-year-old female with PNH who was transfusion-independent but had occasional hemolysis was treated with eculizumab after a missed abortion and soon conceived. During pregnancy, the patient had neither hemolysis nor thrombosis and gave birth to a healthy child without using heparin. Heparin was initiated soon after delivery and continued for six weeks because of the known high postpartum risk of thrombosis. No postpartum complications were observed. PNH is a rare disease with fewer cases of pregnancy reported. Hence, it is essential to accumulate cases of PNH with pregnancy to establish the validity of the Japanese Guideline.

Indolent T-lymphoblastic proliferation concomitant with acinic cell carcinoma mimicking T-lymphoblastic lymphoma: case report and literature review.

AIMS: Indolent T-lymphoblastic proliferation (iT-LBP) is a non-clonal benign condition showing extrathymic proliferation of T-lymphoblasts positive for CD3, CD4, CD8, and TdT. Isolated iT-LBP has been observed, but the majority of iT-LBPs have been seen in conjunction with other disorders, including Castleman disease, hepatocellular carcinoma, follicular dendritic cell tumours, angioimmunoblastic T-cell lymphoma, myasthenia gravis, and acinic cell carcinoma (ACC). The clinical course of iT-LBP is indolent, and no therapy is usually required. A major concern is misdiagnosis as T-lymphoblastic lymphoma, and a correct diagnosis of iT-LBP often requires not only pathological analysis but also careful monitoring of the clinical course. The aim of this study was to broaden the knowledge of pathologists and physicians concerning this as yet not well-recognised entity. METHODS AND RESULTS: We report a case of iT-LBP concomitant with ACC, along with a literature review of all 14 cases of iT-LBP reported to date. CONCLUSIONS: iT-LBP should always be considered as a differential diagnosis of T-lymphoblastic lymphoma, as the two disorders show extremely similar traits.

[Transfusion independence achieved with pomalidomide therapy in a patient with primary myelofibrosis].

Primary myelofibrosis (PMF) is commonly associated with anemia. IMiD® immunomodulatory drugs including thalidomide and lenalidomide have been shown to be effective in improving anemia associated with PMF. However, because of adverse events, their use has been restricted. Herein we report the case of a 67-year-old male patient with transfusion-dependent PMF treated with the immunomodulatory drug pomalidomide in a clinical trial. Significant improvements in anemia and thrombocytopenia were observed with pomalidomide, and the patient recovered from transfusion dependence for 8 months. Although phase 3 trial failed to show the superiority of pomalidomide over placebo, pomalidomide may have some benefit in selected patients with transfusion-dependent PMF.

Clinical benefits of bortezomib-containing regimens for newly diagnosed AL amyloidosis with severe cardiac impairment.

Cardiac amyloid light-chain amyloidosis (AL amyloidosis) is a rare disease with a very poor prognosis, associated with plasma cell dyscrasias such as monoclonal gammopathy of undetermined significance and multiple myeloma. Though bortezomib-containing regimens have achieved high hematologic response rates, there are still few reports describing the outcomes of Japanese patients. Six patients with severe cardiac AL amyloidosis were treated with bortezomib-containing regimens. Involved free light chain (iFLC) decreased immediately in most of these cases. However, the condition of heart failure and N-terminal pro-B-type natriuretic peptide (NT-proBNP) worsened in the early phase of this treatment and then improved several months later. At 29 months, the median duration of follow-up (2-47months), all patients remain alive except one who died of sudden cardiac arrest. Bortezomib-containing regimens are considered to be among the effective treatments for severe cardiac AL amyloidosis.

[Successful management of orthopedic operations requiring general anesthesia in a PNH patient after introduction of eculizumab].

Paroxysmal nocturnal hemoglobinuria (PNH) is a rare clonal hematopoietic stem cell disorder that presents with hemolytic anemia, thrombosis, and bone marrow failure. Stressors such as infection and pregnancy have been known to exacerbate hemolysis in PNH patients. Surgery can also trigger prominent complement activation and is an important risk factor for hemolysis. Furthermore, the postoperative thrombosis risk is high. Eculizumab, which is a humanized monoclonal antibody against C5, suppresses hemolysis and prevents thrombosis, and thus improves quality of life for PNH patients. However, few reports have focused on eculizumab-treated PNH patients undergoing surgery. We report a 79-year-old PNH patient receiving eculizumab treatment who underwent three consecutive orthopedic surgeries requiring general anesthesia. Perioperative management was carried out routinely, as in non-PNH patients, and no postoperative complications developed. Surgery was formerly considered to be a high risk event for PNH patients, but this case raises the possibility that even elderly PNH patients may undergo surgery safely when maintained on eculizumab treatment.

[Fulminant hepatitis possibly caused by L-asparaginase during induction chemotherapy in a patient with acute lymphoblastic leukemia].

We report a 44-year-old man with acute lymphoblastic leukemia (ALL) presenting with fever and lymphadenopathy. Induction chemotherapy was initialed according to the JALSG ALL202 protocol, and L-asparaginase (L-asp) was given on days 20, 22, and 24 of therapy. Abrupt elevations of liver transaminase and bilirubin levels were observed on day 26. On day 30, coagulopathy and hepatic encephalopathy appeared. He was diagnosed with fulminant hepatitis and plasma exchange was performed, but he died on day 32, possibly due to L-asp-induced hepatitis. The common side effects of L-asp are hypersensitivity, ammonemia, coagulopathy, pancreatitis, convulsions, anaphylaxis, hepatotoxicity, and thrombosis. Although rare, reports of deaths due to hepatic failure during treatment with L-asp exist. L-asp is currently used for treatment of a wide range of hematological malignancies such as ALL and NK/T-cell lymphoma. A retrospective analysis of patients treated with L-asp should be carried out to elucidate the incidence and risk factors of liver dysfunction and fulminant hepatitis during L-asp treatment.

Vitamin B6 Deficiency Anemia Attributed to Levodopa/Carbidopa Intestinal Gel Therapy for Parkinson's Disease: A Diagnostic Pitfall for Myelodysplastic Syndrome with Ring Sideroblasts.

Vitamin B6 (VB6) is essential to heme synthesis, and its deficiency can lead to anemia. VB6 deficiency anemia is typically microcytic, hypochromic, and sideroblastic. VB6 deficiency is a well-recognized complication of levodopa/carbidopa therapy, as metabolism of levodopa to dopamine is VB6-dependent, and carbidopa irreversibly forms bonds and deactivates VB6. We herein report a 75-year-old man with advanced Parkinson's disease who developed severe VB6 deficiency anemia due to levodopa/carbidopa intestinal gel therapy. His anemia was promptly resolved with simple oral supplementation of pyridoxal phosphate hydrate. VB6 deficiency anemia can mimic myelodysplastic syndrome and thus is an important differential diagnosis for patients administered levodopa/carbidopa.

Abnormal Exacerbation of Moderately Differentiated Gastric Adenocarcinoma in a Patient with TAFRO Syndrome: An Impaired Tumor Immunity?

TAFRO syndrome is a relatively new disease entity first reported in 2010. We report a case of TAFRO syndrome accommodated by abnormal exacerbation of moderately differentiated gastric adenocarcinoma. The pathophysiology of TAFRO syndrome is largely unknown, but because the disease often responds to immunosuppressive therapy and also because T follicular helper (Tfh) cells are reported to be drastically decreased in TAFRO syndrome, involvement of a dysregulated immune system can be speculated. Growing evidence points toward a pivotal role of Tfh cells in tumor immunity through supporting ectopic lymphoid structures, which are recruitment sites for cells directly engaging in antitumor activity such as CD8+ T cells, NK cells, and macrophages. In fact, Tfh cells are reported to positively correlate with longer survival in human colorectal and breast cancer. Combined with our observations of hyperprogressive gastric cancer in the presented patient, an impaired tumor immunity is strongly indicated in TAFRO syndrome.

Hodgkin Lymphoma on Hemodialysis Successfully Treated with Extended Courses of Brentuximab Vedotin.

Chemotherapy for hemodialysis (HD) patients is a challenging situation because HD patients are generally frail, and the pharmacokinetics and pharmacodynamics of most chemotherapeutics in HD patients are unknown. We report a classical Hodgkin lymphoma (cHL) patient successfully treated with 34 courses of brentuximab vedotin (BV) monotherapy, of which 30 courses were carried out during HD. Although grade 2 peripheral sensory neuropathy and one occasion of febrile neutropenia were observed, treatment was well-tolerated overall and effective. This is the first report of successful BV administration in a cHL patient on HD, and also the first to report efficacy and safety of extended courses of BV in an HD patient. Treatment options for cHL in the HD patient are limited, and extended courses of BV monotherapy may be an optimal treatment approach for some patients.

Interferon therapy for pregnant patients with essential thrombocythemia in Japan.

Essential thrombocythemia (ET) mainly affects the elderly, but can also develop in women of childbearing age. The risk of miscarriage and other complications during pregnancy in ET patients are reported to be higher than that compared to the general population. Therefore, management of pregnancy in ET patients requires special considerations. Several groups recommend interferon (IFN) therapy for ET patients with high-risk pregnancies, but currently no guidelines are available in Japan. We report the outcomes of nine ET patients with ten consecutive high-risk pregnancies. All patients were successfully managed with IFN-α during their pregnancies. All patients also received aspirin and switched to unfractionated heparin around 36 weeks of gestation. As for the seven pregnancies in which IFN-α was started after detection of pregnancy, median platelet counts decreased from 910 to 573 × 109/L after 2 months of IFN-α therapy, and median platelet counts at the time of delivery for all ten pregnancies was 361 × 109/L. All patients gave birth to healthy children. IFN-α was well tolerated, safe, and effective as a cytoreductive therapy for all patients. Although evidence is limited and the use of IFN is not approved in Japan, we suggest considering IFN therapy for high-risk ET pregnancies.

Splenic Marginal Zone Lymphoma with Prominent Myelofibrosis Mimicking Triple-Negative Primary Myelofibrosis.

Myelofibrosis (MF) can occur due to a wide variety of causes including malignant lymphoma. We report a case of splenic marginal zone lymphoma complicated by MF mimicking primary myelofibrosis (PMF). The JAK2, CALR and MPL mutations are detected in more than 90% of PMF cases, and when detected, the diagnosis of PMF is usually straight forward. Mutational analysis should be done in all cases of MF, and in triple-negative cases, an exhaustive investigation of other causes of MF should be carried out before a diagnosis of triple-negative PMF is rendered.

Vitamin B6 deficiency is prevalent in primary and secondary myelofibrosis patients.

Vitamin B6 (VB6) deficiency contributes to oncogenesis and tumor progression in certain cancers, and is prevalent in cancer patients in general. VB6 is also an essential element of heme synthesis, and deficiency can lead to anemia. Primary myelofibrosis (PMF) and secondary myelofibrosis (sMF) are myeloproliferative neoplasms often presenting with anemia along with other cytopenias. We performed a prospective study to determine whether PMF and sMF patients suffer from VB6 deficiency, and whether VB6-deficient patients show improvement of anemias with VB6 supplementation. Twelve PMF patients and 11 sMF patients were analyzed. A total of 16 of 23 patients (69.6%) were found to have VB6 deficiency, but VB6 supplementation with pyridoxal phosphate hydrate did not elevate hemoglobin levels in deficient patients. None of the patients presented with vitamin B12, iron, or copper deficiencies. Four patients showed serum folate levels below the lower limit of normal and eight patients showed serum zinc levels below the lower limit of normal; however, these deficiencies were marginal and unlikely to contribute to anemia. Compared to VB6-sufficient patients, VB6-deficient patients showed significantly lower serum folate levels and higher serum copper levels. Studies elucidating the relationship of VB6 deficiency and etiology of PMF/sMF are warranted.

Iron overload patients with unknown etiology from national survey in Japan.

Transfusion is believed to be the main cause of iron overload in Japan. A nationwide survey on post-transfusional iron overload subsequently led to the establishment of guidelines for iron chelation therapy in this country. To date, however, detailed clinical information on the entire iron overload population in Japan has not been fully investigated. In the present study, we obtained and studied detailed clinical information on the iron overload patient population in Japan. Of 1109 iron overload cases, 93.1% were considered to have occurred post-transfusion. There were, however, 76 cases of iron overload of unknown origin, which suggest that many clinicians in Japan may encounter some difficulty in correctly diagnosing and treating iron overload. Further clinical data were obtained for 32 cases of iron overload of unknown origin; median of serum ferritin was 1860.5 ng/mL. As occurs in post-transfusional iron overload, liver dysfunction was found to be as high as 95.7% when serum ferritin levels exceeded 1000 ng/mL in these patients. Gene mutation analysis of the iron metabolism-related genes in 27 cases of iron overload with unknown etiology revealed mutations in the gene coding hemojuvelin, transferrin receptor 2, and ferroportin; this indicates that although rare, hereditary hemochromatosis does occur in Japan.

Accurate flow cytometric gating of the large lymphocyte region is a powerful screening method for detecting hairy cell leukemia presenting with a low tumor burden.

Hairy cell leukemia typically presents with pancytopenia and often mimics aplastic anemia. Making an accurate diagnosis is crucial, as treatment with the purine analogues cladribine and pentostatin brings about durable complete remission in the majority of patients. Surface kappa and lambda flow cytometric analyses of peripheral blood or bone marrow are a powerful screening tool, although routine gating of the entire lymphocyte region may fail to show light chain restriction due to a low tumor burden. We herein demonstrate that accurate subgating of the large lymphocyte region is essential and recommend the application of this method in all cases of pancytopenia of unknown etiology.

Ischemic Cardiomyopathy with a Rapid Progression from Thrombotic Thrombocytopenic Purpura.

An 83-year-old woman who complained of dizziness and nausea visited our hospital. An electrocardiogram showed ST-segment elevation in multiple leads and an echocardiogram showed severe hypokinesis of the anteroseptal wall of the left ventricle. However, emergency coronary angiography showed no stenotic lesions in any coronary arteries. A laboratory examination showed thrombocytopenia, renal dysfunction, and hemolysis. We therefore diagnosed the patient with thrombotic thrombocytopenic purpura (TTP). While we were preparing to initiate plasma exchange therapy, she suddenly developed cardiopulmonary arrest. A postmortem examination revealed microthrombi in the small vessels of the myocardium. We herein report a case of ischemic cardiomyopathy with a rapid progression from TTP.