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.

Presence and Onset of Chronic Kidney Disease as a Factor Involved in the Poor Prognosis of Patients with Essential Thrombocythemia.

Chronic kidney disease (CKD) is an important risk factor for cardiovascular disease, thrombosis, and all-cause death. However, few studies have examined the association between CKD and the prognosis of patients with essential thrombocythemia (ET). We collected ET patients who met the WHO classification 2017 and performed a retrospective clinical study to clarify the association between the presence and onset of CKD and prognosis. Of 73 patients who met the diagnostic criteria, 21 (28.8%) had CKD at the time of ET diagnosis. The age of patients with CKD was significantly higher, and a high proportion of these patients had the JAK2V617F gene mutation. The presence of CKD was a risk factor for the prognosis (hazard ratio (HR): 3.750, 95% confidence interval (CI): 1.196-11.760, P=0.023), and the survival curve was significantly poorer. Furthermore, we analyzed patients without CKD at the time of ET diagnosis using the onset of CKD as a time-dependent variable and identified the onset of CKD as a risk factor for the prognosis (HR: 9.155, 95% CI: 1.542-54.370, P=0.005). In patients with renal hypofunction at the time of ET diagnosis or those with a reduction in the kidney function during follow-up, strict renal function monitoring at regular intervals is necessary.

Clinical characteristics of Japanese patients with myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis.

Myelodysplastic/myeloproliferative neoplasm with ring sideroblasts and thrombocytosis (MDS/MPN-RS-T) is a rare disease, which presents with features of myelodysplastic syndromes with ring sideroblasts and essential thrombocythemia, as well as anemia and marked thrombocytosis. SF3B1 and JAK2 mutations are often found in patients, and are associated with their specific clinical features. This study was a retrospective analysis of 34 Japanese patients with MDS/MPN-RS-T. Median age at diagnosis was 77 (range, 51-88) years, and patients had anemia (median hemoglobin: 9.0 g/dL) and thrombocytosis (median platelet count: 642 × 109/L). Median overall survival was 70 (95% confidence interval: 68-not applicable) months during the median follow-up period of 26 (range: 0-91) months. A JAK2V617F mutation was detected in 46.2% (n = 12) of analyzed patients (n = 26), while an SF3B1 mutation was detected in 87.5% (n = 7) of analyzed patients (n = 8). Like those with myelodysplastic syndromes or myeloproliferative neoplasms, patients often received erythropoiesis-stimulating agents and aspirin to improve anemia and prevent thrombosis. This study, which was the largest to describe the real-world characteristics of Japanese patients with MDS/MPN-RS-T, showed that the patients had similar characteristics to those in western countries.

Catheter-related bloodstream infection associated with multiple insertions of the peripherally inserted central catheter in patients with hematological disorders.

Patients with hematological disorders are treated with multiple cycles of chemotherapy. As a result, they often require multiple insertions of the peripherally inserted central catheter (PICC) for prolonged periods of time. Although PICCs have been widely used worldwide in various patients, the safety and feasibility of the multiple insertions of the PICC in this population have not been fully verified. We performed a retrospective analysis to clarify the relationship between complications and multiple PICC insertions in patients with hematological disorders who were treated with either chemotherapy or immunotherapy. A total of 651 PICCs were inserted in 261 patients with a median age of 66 years. Acute myeloid leukemia (AML) and non-Hodgkin's lymphoma were the most common diseases in our patient cohort. The total catheter days (CDs) was 29,485 days, with a median catheter duration of 30 days. The rate of catheter-related bloodstream infection (CRBSI) in our patient cohort at high rate of re-insertion was 2.0/1000 CDs. Although multiple PICC insertions were not a risk factor of CRBSI, our findings suggest that a prolonged catheter dwell time may be associated with CRBSI. AML was an important risk factor of CRBSI. While the PICC dwell time depends on the treatment cycle, our findings indicate that it should be limited to approximately 30 days and catheters may be removed and re-inserted as needed.

Mucosa-associated lymphoid tissue lymphoma of the bladder: Case report.

We report the cases of patient with primary mucosa-associated lymphoid tissue (MALT) lymphoma of the bladder who successfully treated with local radiation therapy after transurethral resection of the bladder tumor. She maintains good activity of daily living without relapse. We recommend this strategy for localized MALT lymphoma of the bladder, because it provide better quality of life for elderly patients.

Marked Rebound of Platelet Count in the Early Postpartum Period in a Patient with Essential Thrombocythemia.

Essential thrombocythemia (ET) occurs predominantly in the elderly, but approximately 20% of patients are <40 years old. Unlike other myeloproliferative neoplasms, ET occurs more commonly in women. We encountered a 38-year-old women diagnosed with ET who exhibited elevated platelet count in early pregnancy. Her platelet count exceeded 1500 × 109/L by late pregnancy; interferon α was administered but failed to induce an adequate response. She underwent emergency cesarean delivery at 37 weeks of gestation. Although her platelet count was 1000 × 109/L immediately after delivery, it markedly increased to 3271 × 109/L approximately 2 weeks later. Cytoreductive therapy was resumed; the subsequent course was free from complications. Several review articles have indicated that because platelet counts of patients may again increase to the pregnancy level or rebound after delivery, cytoreductive therapy should be administered if necessary. However, there is insufficient information on when therapeutic interventions are necessary and how they should be performed. It remains unknown whether the platelet count will decrease after some time without treatment if it rebounds. We hope management guidelines will be established by collecting detailed data on the postpartum course as well as during pregnancy.

[Causes of catheter removal and complications depending on the insertion side of peripherally inserted central venous catheter in patients with hematologic disorders].

Central venous catheter (CVC) insertion is an essential medical procedure in patients with hematologic disorders. Recently, the use of peripherally inserted central venous catheters (PICCs) for CVC insertion has been increasing. However, the suitable arm for PICC insertion has not been fully discussed. This study retrospectively examined catheter-related complications on the insertion side of PICC in patients with hematologic disorders. Total 809 PICCs were inserted in 316 patients with hematologic disorders. The insertion side was the right upper arm for 515 PICCs and the left upper arm for 294 PICCs. In a direct comparison between the insertion side groups, there was no obvious difference in the basic demographic characteristics of the patients except the age at the time of insertion. Moreover, there was no significant difference in the reasons for PICC removal, and the incidence of catheter-related bloodstream infection was similar and low in both the study groups. During the selection of the insertion side for PICC, it may be possible to consider the side that seems more suitable for insertion by confirming the vessels in both upper arms with ultrasonography, and, if the conditions are equivalent, to consider the side where the patient wishes to insert the PICC.

Comparison of starting doses of anagrelide as a first-line therapy in patients with cytoreductive therapy-naïve essential thrombocythemia: difference between starting at 0.5 and 1.0 mg/day.

Anagrelide is widely used for cytoreductive therapy in patients with essential thrombocythemia who are at high risk for thrombosis. The recommended starting dose in the package insert of anagrelide varies by country. A high starting dose leads to an early onset of action, but causes a higher incidence of adverse events. This relationship indicates that both the onset of action and side effects of anagrelide are dose dependent. We retrospectively compared the efficacy and safety of anagrelide as a first-line drug between patients with essential thrombocythemia who started at 0.5 or 1.0 mg/day. Incidence of total adverse events and anagrelide-related palpitation, discontinuation rates, and the median daily dose of anagrelide were lower in the 0.5 mg/day group than in the 1.0 mg/day group; however, comparable platelet-lowering effects were achieved in both groups. These data suggest that a low starting dose of anagrelide followed by dose escalation may result in fewer adverse events and lower discontinuation rates, while providing desirable platelet-lowering effects. Initiating anagrelide at a lower dose may be a useful approach in actual clinical practice.

Successful Management of Primary Mediastinal Large B-cell Lymphoma during Pregnancy.

We experienced a pregnant woman with superior vena cava syndrome at 15 weeks of pregnancy who was diagnosed with primary mediastinal large B-cell lymphoma and given chemotherapy. In this case, the clinical courses of both the mother and infant were favorable without any serious complications because of close multidisciplinary cooperation. Based on a retrospective review of this case, the administration of CHOP-like regimens during the second and third trimesters appears relatively safe. Because pregnancy and continuation of pregnancy are rare in patients with hematopoietic malignancies, the accumulation of detailed information is important.

Efficacy and safety of anagrelide as a first-line drug in cytoreductive treatment-naïve essential thrombocythemia patients in a real-world setting.

OBJECTIVE: This study aimed to retrospectively assess the efficacy and safety of anagrelide in cytoreduction therapy-naïve essential thrombocythemia (ET) patients in a real-world setting. METHOD: Data from 53 ET patients who received anagrelide as a first-line therapy were reviewed for patient characteristics, antiplatelet status, cytoreduction status, therapeutic effects, adverse events, thrombohemorrhagic event development, progression to myelofibrosis or acute leukemia, and cause of death. RESULTS: The rate of achieving a platelet count of <600 × 109 /L during anagrelide monotherapy was 83.0%. Adverse events occurred in 32 of 53 patients, and tended to be slightly more severe in patients with cardiac failure; however, they were mostly tolerable. The therapeutic effect of anagrelide was consistent, regardless of genetic mutation profiles. The incidence of anemia as an adverse event was significantly higher in the CALR mutation-positive group. Favorable platelet counts were also achieved in patients for whom hydroxyurea was introduced as a replacement for anagrelide or in addition to anagrelide because of unresponsiveness or intolerance to treatment. CONCLUSION: In Japanese cytoreduction therapy-naïve ET patients, anagrelide administration as a first-line therapy demonstrated favorable effects in reducing platelet counts, and its safety profile that was generally consistent with those in previous reports.

Validation of previous prognostic models for thrombosis and exploration of modified models in patients with essential thrombocythemia.

OBJECTIVE: We examined the prognostic factors to validate previous prognostic models for survival and thrombosis with large-scale data on Japanese patients with essential thrombocythemia (ET). METHOD: We conducted a study in 352 patients with ET to validate previous prognostic models and search for new prognostic factors. RESULTS: The International Prognostic Score for essential thrombocythemia (IPSET), the conventional risk classification and the International Prognostic Score for thrombosis in essential thrombocythemia (IPSET-T) were confirmed to be reproducible in Japanese patients. However, no significant difference was observed between the low-risk and intermediate-risk categories according to the revised IPSET-T, which does not allow direct comparison of the four risk groups. We reevaluated the risk using a modified revised IPSET-T, which was derived from the revised IPSET-T by scoring the factors as follows: one point for age > 60 years, two points for past history of thrombosis, two points for JAK2 gene mutation-positive; total points of 0 = very low risk, 1 =  low risk, 2 =  intermediate risk, 3 and above = high risk, with significantly different thrombosis-free survival. CONCLUSION: The modified revised IPSET-T has been useful for 4-group stratification to predict a population that requires therapeutic intervention, irrespective of the treatment regimens.

The Relationship between Multiple Myeloma with Renal Failure and Metastatic Calcification.

While cases of multiple myeloma (MM) with metastatic calcification have been reported, the mechanisms for this calcification have yet to be explained. We observed a case of MM in a patient with end-stage renal failure who developed vascular and pulmonary calcification. A 51-year-old male was diagnosed with Bence-Jones type MM and required maintenance hemodialysis. He was treated with bortezomib-dexamethasone, vincristine-doxorubicin-dexamethasone, the M2 protocol, and lenalidomide-dexamethasone (Rd) therapy. During the sixth cycle of Rd therapy, he complained of pain in both lower legs. Well-demarcated ulcers with severe pain had developed on the right lower leg, both exterior thighs, and penis. We found that the patient's serum intact parathyroid hormone level was elevated, while it had previously been permissively controlled. Computed tomography scan showed widespread centrilobular opacities of the bilateral lungs and high-density lesions along small blood vessels in the trunk and all four extremities. Histological calcifications were identified in small blood vessels and the alveolar walls. The risk of metastatic calcification in MM appears to be associated with renal failure, but not with MM itself.

Cutaneous Mycobacterium chelonae infection following autologous peripheral blood stem cell transplantation for POEMS syndrome.

Although hematopoietic stem cell transplantation (HSCT) may increase the curability of refractory hematologic diseases, it requires complication management due to a long-term immunocompromised state. We experienced a case who received an autologous peripheral blood stem cell transplantation (Auto-PBSCT) for POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, and skin changes) and developed cutaneous Mycobacterium chelonae infection. It is clear that attention needs to be paid to prevent bacterial, fungal and viral infection after HSCT. It is also important to keep in mind that tuberculous and nontuberculous mycobacteria (NTM), in rare cases, lead to lethal complications.

[Essential thrombocythemia complicated by intracranial thrombohemorrhagic events].

Although the life expectancy if patients with essential thrombocythemia (ET) is considered to be almost similar to that of the general population, advanced age, leukocytosis, and a previous history of thrombosis are poor prognostic factors, and it is important to prevent thrombohemorrhagic events, leukemic transformation, and secondary malignancies. We report an 85-year-old ET patient with a history of asymptomatic lacunar infarction, who developed symptomatic cerebral infarction and even chronic subdural hematoma. It is necessary to follow patients who have asymptomatic cerebral infarction or chronic ischemic change and to examine the necessity of brain imaging and treatment intervention at the time of diagnosis.

Acute undifferentiated leukemia (stem cell acute leukemia) showing differentiation to Langerhans cell-like cells in lymph nodes.

A 75-year-old woman was referred to our hospital with suspected leukemia. Complete blood count demonstrated WBC 3,810/µl with 26% blasts, Hb of 11.7 g/dl and Plt of 18.0×104/µl. Bone marrow aspiration revealed blasts (86.3%) with expressions of CD34, CD7, TdT, CD33, and CD117. MPO was negative. Chromosomal analysis of the bone marrow showed isolated trisomy 10 in all leukemic cells (20/20). Swelling of superficial lymph nodes was also observed. Cervical lymph node biopsy revealed leukemic blasts which had the same phenotype as those in the bone marrow except that proliferation of Langerhans cell-like cells (LCs) was observed in the paracortex. LCs had pale cytoplasm and grooved nuclei, and were positive for both CD1a and S100 protein. Trisomy 10 was detected in both the leukemic blasts and the LCs by fluorescence in situ hybridization. This rare case strongly suggests leukemic cells to differentiate into LCs.

Experience of Peripherally Inserted Central Venous Catheter in Patients with Hematologic Diseases.

Objective Although use of the peripherally inserted central venous catheter (PICC) has become increasingly common, there are few reports of PICCs used for patients with hematologic diseases. In this study, we analyzed the safety of PICC placement in patients with hematologic diseases where PICCs had been placed to perform blood collection, blood transfusion, drug administration, and hematopoietic stem cell transplantation. Methods This study included 142 PICCs placed in 95 patients managed at our department from November 2013 to December 2015. The PICCs used were the Groshong® Catheter (NXT single-lumen; BARD Inc.). Results A total of 95 patients underwent the placement of 142 PICCs. The mean patient age was 65.5 years. The total duration of catheterization was 8,089 days, with a mean duration of 57.0 days. Chemotherapy was administered through 107 catheters. Stem cells were injected through 12 catheters. Although a fever was observed in association with 103 catheters, it was generally controlled by antimicrobial therapy. There were 18 catheter-related bloodstream infection (CRBSI) cases, an incidence equivalent to 2.1 cases per 1,000 catheter-days. Conclusion The present study demonstrated a low CRBSI incidence rate and found no evidence of serious complications with PICC placement. PICCs can be used for blood collection, blood transfusion, drug administration, and hematopoietic stem cell transplantation without problems. Thus, PICC placement appears to be a safe procedure for patients with hematologic diseases. Safe catheters are therefore urgently needed for these patients. We expect that PICCs will be widely adopted in Japan in the near future.

CD5-negative mantle cell lymphoma resembling extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue : a case report.

A 71-year-old male underwent an upper gastrointestinal endoscopy ; as a result of a biopsy, extranodal marginal zone lymphoma of mucosa-associated lymphoid tissue (MALT lymphoma) was suspected. Abdominal computed tomography scan disclosed an approximately 4-cm-large mass in the ileocecal region. After ileocecal resection, the patient was diagnosed with MALT lymphoma (CD79a(+), CD20(+), CD3(-), CD5(-), CD10(-), and cyclin D1(-)). He achieved complete remission after receiving chemotherapy. However, four years after the primary onset, he was diagnosed with recurrence. Although he achieved remission again by salvage therapy, six years after the primary onset, he was referred to our hospital with second recurrence. Colonoscopy revealed the appearance of multiple lymphomatous polyposis and biopsy specimens showed monotonous proliferation of centrocyte-like cells (CD79a(+), CD20(+), CD3(-), CD5(-), CD10(-), and cyclin D1(+)), which were consistent with mantle cell lymphoma (MCL) except for CD5. The result of reactivity to cyclin D1 was different from that at initial diagnosis, so we reexamined the initial surgical specimens, the histological and histochemical features of which were proven to be the same as those of colonic biopsy specimens. Finally, the patient was diagnosed with CD5-negative MCL (marginal zone-like variant). As MALT lymphoma and MCL sometimes show similar histological features, they are difficult to distinguish from each other. It is necessary to take the possibility of this rare phenotype of MCL into consideration and to reexamine the initial diagnosis, especially if the clinical course is unusual for MALT lymphoma. This case is very interesting in view of its indolent clinical feature and phenotype.

Heparin-induced thrombocytopenia in essential thrombocytosis.

We report a 67-year-old woman with essential thrombocytosis who developed cerebral infarction and heparin-induced thrombocytopenia during treatment for the cerebral infarction. She developed additional cerebral infarcts, acute femoral artery occlusion, and thrombophlebitis of her lower extremities. She was successfully treated with argatroban. This is the first report of a patient with essential thrombocytosis who developed heparin-induced thrombocytopenia and serious conditions, which included multiple thromboembolisms and coagulation disorders mimicking disseminated intravascular coagulation.

Primary effusion lymphoma of the left scrotum.

A 51-year-old man without human immunodeficiency virus, hepatitis B virus or hepatitis C virus was admitted with left scrotum swelling and hydrocele. The cytological finding of fluid in the left scrotum revealed malignant lymphoma, and the immunophenotypic analysis and monoclonal rearrangement of immunoglobulin heavy chain demonstrated B-cell lymphoma. However, no solid tumor of lymphoma was identified in the specimen following a left orchiectomy, or in any other body site and genomic human herpes virus-8 and Epstein-Barr virus were not detected in the lymphoma cells. So we interpreted this as a primary effusion lymphoma without any ethological viral infection. Subsequently, he underwent chemo-radiation therapy and has remained in remission.