Delayed Development of Hemolytic Anemia with Fragmented Red Blood Cells and Cardiac and Renal Impairments after High-Dose Chemotherapy and Autologous Hematopoietic Stem Cell Transplantation for Malignant Lymphoma.

Among 42 consecutive patients with malignant lymphoma who underwent high-dose chemotherapy (HDC) followed by autologous hematopoietic stem cell transplantation (AHSCT), 5 developed hemolytic anemia with fragmented red blood cells (HA-FrRBCs) on days 87-125 (median 107) of AHSCT. Nadir Hb levels ranged between 5.0 and 6.4 g/dL with 2.2-5.6% FrRBCs. All patients developed grade ≥3 hypoxia and heart failure, and 4 developed grade ≥3 hypertension. The ejection fraction of the left ventricle assessed by echocardiography was significantly reduced in 3 patients. Peak creatinine levels were >4 times above the baseline and estimated glomerular filtration rates were reduced to <30 mL/min/1.73 m2. One patient received plasma exchange, while the remaining 4 responded to treatment with diuretics and cardiovascular agents. Hematological parameters normalized within a median duration of 91 days after the development of HA-FrRBCs. Renal and cardiac functions gradually improved, even though renal function did not return to the baseline. HA-FrRBCs associated with cardiac and renal impairments may represent a thrombotic microangiopathy syndrome and are a delayed complication of HDC/AHSCT. The close monitoring of laboratory abnormalities and persistent treatment with cardiovascular agents and diuretics are the mainstay for the management of this condition.

Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia Is Separated into Two Subgroups Associated with Survival by BCR-ABL Fluorescence in situ Hybridization of Segmented Cell Nuclei: Report from a Single Institution.

Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) may include the lymphoid blast crisis of chronic myeloid leukemia (CML-BC). We applied fluorescence in situ hybridization (FISH) of the BCR-ABL fusion gene to peripheral blood and/or bone marrow smears to determine whether the fusion was restricted to mononuclear cell nuclei or if segmented cell nuclei representing mature neutrophils also carried the fusion (Seg-FISH). Among 20 patients with Ph+ ALL without a prior diagnosis of CML, 9 were Seg-FISH+ and 11 were Seg-FISH-. Seg-FISH+ cases were characterized by a higher rate of p210-type BCR-ABL transcripts, higher white cell and blast counts, and a higher rate of myeloid and T-lymphoid antigen expression than Seg-FISH- cases, in addition to 'major route' cytogenetic abnormalities associated with CML-BC. Eighteen patients were treated with tyrosine kinase inhibitors (TKIs) either alone or in combination with multiagent chemotherapy, and 7 underwent allogeneic hematopoietic stem cell transplantation. Progression-free and overall survivals were greater in the Seg-FISH+ group than in the Seg-FISH- group. These results suggest that the Seg-FISH+ group represents lymphoid CML-BC that occurs de novo, while the Seg-FISH- represents Ph+ ALL in the strict sense, and the two groups are associated with survival when treated with TKIs or TKI-combined therapy.

Outcomes of very elderly patients with aggressive B-cell non-Hodgkin lymphoma treated with reduced-dose chemotherapy.

BACKGROUND: Although the number of patients aged 80 years or older with aggressive B-cell non-Hodgkin lymphoma (B-NHL) has increased in the clinical setting, management has been challenging due to lower tolerability. The aim of the present study was to evaluate the efficacy and safety of reduced-dose chemotherapy for very elderly patients. METHODS: We retrospectively analyzed the clinical outcomes of patients aged ≥80 years old with diffuse large B-cell lymphoma (n = 58) or grade 3 follicular lymphoma (n = 3). RESULTS: Patient ages ranged from 80 to 93 years old, with a median of 83 years old. Twenty-four patients were treated with CHOP or THP-COP, the dosages of which were variably reduced, in combination with rituximab (R-vCHOP), while another 24 patients were treated with R-miniCHOP. Twelve R-vCHOP and 16 R-miniCHOP patients completed the chemotherapy cycles. The estimated 2-year progression-free and overall survival rates in the R-vCHOP and R-miniCHOP groups were 53 and 39 % (P = 0.92) and 53 and 48 % (P = 0.95), respectively. Performance status ≥2, lactate dehydrogenase level >normal, serum albumin ≤3.5 g/dL, C-reactive protein ≥2.0 mg/dL, age-adjusted International Prognostic Score 2/3, and withdrawal from the chemotherapy cycle were associated with poor survival. The frequency of chemotherapy-related hospitalization during the second or later cycles was significantly less in the R-miniCHOP group. CONCLUSIONS: The efficacies of R-vCHOP and R-miniCHOP were similar in patients aged ≥80 years old with aggressive B-NHL. The reduced frequency of hospitalization observed for R-miniCHOP treatment is beneficial for very elderly patients.

Production of insulin antibody associated with relapsed hodgkin's lymphoma.

A 72-year-old man with type 2 diabetes mellitus with good glucose control for 20 years and maintained on oral hypoglycaemic agents was diagnosed with Hodgkin's Lymphoma (HL) and started on insulin glargine for glycaemic control. Despite increased doses of insulin, his blood glucose levels went up dramatically. The anti-insulin antibody test proved to be positive, and Scatchard plot analysis showed 2 binding sites with relatively low-affinity constants: K 1 = 0.0032, K 2 = 0.0002 (108/M); and high binding capacities: R 1 = 98.4, R 2 = 372 (10-8 M), which were compatible with the features of antibody of insulin autoimmune syndrome (IAS). However, hypoglycaemia was not noted throughout the course of treatment. Since the insulin binding ratio of the antibody decreased from 87.3% to 62% after the termination of insulin treatment, it was suggested that the antibody reacted mainly to exogenously injected insulin. Switching insulin preparations or introducing insulin secretagogues did not improve elevated blood glucose levels. The initiation of brentuximab vedotin (BV), a therapeutic agent for relapsed HL, resulted in a remarkable improvement in glycaemic control despite the absence of insulin therapy and partial remission of HL. This case suggested that HL triggered anti-insulin antibody production, which resulted in poor glycaemic control, and that BV could be a new treatment option for autoimmune diseases associated with HL. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-021-00550-1.

Burkitt leukemia with precursor B-cell features that developed after ruxolitinib treatment in a patient with hydroxyurea-refractory JAK2V617F-myeloproliferative neoplasm.

A 62-year-old woman, who had a 16-year history of JAK2V617F-mutated myeloproliferative neoplasm (MPN), developed Burkitt leukemia (BL) 16 months after treatment with ruxolitinib to control hydroxyurea-refractory conditions. BL cells were CD10+, CD19+, CD20-, CD34-, cytoplasmic CD79a+, and TdT+, and lacked surface immunoglobulins but expressed the cytoplasmic µ heavy chain. In the bone marrow, nuclear MYC+ BL cells displaced the MPN tissues. t(8;14)(q24;q32) occurred at a CG dinucleotide within MYC exon 1 and at the IGHJ3 segment, and an N-like segment was inserted at the junction. The V-D-J sequence of the non-translocated IGH allele had the unmutated configuration. DNA from peripheral blood at a time of the course of MPN exhibited homozygous JAK2V617F mutation, while that at BL development included both JAK2V617F and wild-type DNAs. Although the association between JAK1/2 inhibitor therapy for MPN and secondary development of aggressive B-cell neoplasm remains controversial, this report suggests that, in selected patients, close monitoring of clonal B-cells in the BM is required before and during treatment with JAK1/2 inhibitors.

Resolution of bone, cutaneous, and muscular involvement after haploidentical hematopoietic stem cell transplantation followed by post-transplant cyclophosphamide in adult T-cell leukemia/lymphoma.

Haploidentical hematopoietic stem cell transplantation followed by post-transplant cyclophosphamide provides a well-tolerated and potentially curable treatment for chemorefractory acute-type adult T-cell leukemia/lymphoma.

Combination of multicolor flow cytometry for circulating lymphoma cells and tests for the RHOAG17V and IDH2R172 hot-spot mutations in plasma cell-free DNA as liquid biopsy for the diagnosis of angioimmunoblastic T-cell lymphoma.

We applied two-step multicolor flow cytometry (FCM) for circulating lymphoma cells in the blood of 20 patients with angioimmunoblastic T-cell lymphoma (AITL) and confirmed neoplastic T-cells in all. Eleven exhibited dim expression of CD3 and 7 lost its expression. The proportion of CD10+ lymphoma cells ranged widely from 0 to 100%, with a median of 15.7%. Ten patients demonstrated expansion of a single T-cell receptor ß-chain repertoire. Lymphoma cells comprised 0.01 to 18.22% (median, 0.26%) of white cells and the absolute numbers ranged from 0.5 to 1491.6 cells (median, 29.3 cells) per microliter of blood. We next found that 14 (70%) and 3 (15%) patients carried RHOAG17V and IDH2R172 mutations, respectively, in cell-free DNA (cfDNA) in the plasma. The combination of multicolor FCM of the blood, and tests for RHOAG17V and IDH2R172 hot-spot mutations in plasma cfDNA provides a blood-based 'liquid biopsy' for the diagnosis of AITL.

A unique subtype of diffuse large B-cell lymphoma primarily involving the bone marrow, spleen, and liver, defined by fluorodeoxyglucose-positron emission tomography combined with computed tomography.

We describe 10 cases of diffuse large B-cell lymphoma (DLBCL) confined to the bone marrow (BM), spleen, and liver, as evidenced by the uniformly increased uptake of fluorodeoxyglucose (FDG) on positron emission tomography combined with computed tomography (PET/CT). Ages ranged from 56 to 87. All, but one patient presented with 'B' symptoms, a poor performance status, and hepatosplenomegaly. All patients showed cytopenia and elevated lactate dehydrogenase levels and were classified into the high-risk category of the International Prognostic Index scoring. BM infiltration was diffuse, interstitial/intrasinusoidal, or mixed, and all showed the nongerminal center B immunophenotype. Five patients had a rearrangement involving 3q27/BCL6, while six had increased copies of MYC, BCL2, or BCL6. All patients were initially treated with rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone, leading to complete responses in six out of eight evaluable patients. We propose BM, spleen, and liver-type DLBCL, which is defined by the findings of FDG-PET/CT.

B-cell prolymphocytic leukemia carrying t(8;14)(q24;q32), associated with both autoimmune hemolytic anemia and pure red cell aplasia.

An 80-year-old man was referred to our department because of lymphocytosis. His white cell count was 17.1 × 10(3)/µL, with 64% prolymphocytes. He did not exhibit splenomegaly or lymphadenopathy. Prolymphocytes were CD5(+), CD10(-), CD19(+), CD20(+), CD21(+weak), CD22(+), CD23(-), and HLA-DR(+), and expressed µÎ´/λ cell-surface immunoglobulins. G-banding and fluorescence in situ hybridization using c-MYC and immunoglobulin heavy-chain (IgH) gene probe revealed that leukemia cells carried the t(8;14)(q24;q32)/c-MYC-IgH fusion gene, and breakage and reunion occurred within the non-coding region of c-MYC exon 1 as well as the α switch region of IgH. Nine months after the initial presentation, the patient's hemoglobin level fell to 5.7 g/dL. Coombs' test was positive and marked hypoplasia of erythroid precursors was detected in his bone marrow. The patient was treated with prednisolone followed by 4 weekly doses of rituximab, which led to resolution of the anemia and complete response of the underlying leukemia. The role of t(8;14)(q24;q32)/c-MYC-IgH in the pathogenesis of B-cell prolymphocytic leukemia (B-PLL) may not be identical to that in aggressive lymphoid neoplasms, and, in the present case, autoantibodies targeting both mature red cells and erythroid precursors may have been concurrently produced in the setting of B-PLL.

Outbreak of pandemic 2009 influenza A/H1N1 infection in the hematology ward: fatal clinical outcome of hematopoietic stem cell transplant recipients and emergence of the H275Y neuraminidase mutation.

We report an outbreak of pandemic 2009 influenza A/H1N1 virus (2009 H1N1) infection that occurred in the hematology ward of our institution during the 2010-2011 influenza season. A total of seven hospitalized patients with hematologic tumors, including five recipients of hematopoietic stem cell transplantation (HSCT), successively developed rapid influenza detection test (RIDT)-positive influenza A; four patients had laboratory-confirmed 2009 H1N1 infection. Three HSCT recipients required mechanical ventilation support and two were admitted to the intensive care unit; they died of progressive respiratory failure despite receiving available anti-viral drugs. We implemented outbreak-control measures including transferal of RIDT-positive patients to a single-patient room and chemoprophylaxis with oseltamivir. We note that the H275Y neuraminidase mutation was detected in respiratory specimens from three patients, who were administered therapeutic or prophylactic dosages of oseltamivir. The present report demonstrates that the nosocomial 2009 H1N1 outbreak in the hematology ward led to fatal clinical outcomes and the emergence of a resistant virus at a markedly high rate.

Short- and long-term effects of rituximab for the treatment of thrombotic thrombocytopenic purpura: four case reports.

We report four cases of thrombotic thrombocytopenic purpura (TTP) successfully treated with rituximab in combination with plasma exchange and other immunosuppressive agents. All four cases fulfilled the diagnostic criteria of TTP with severe deficiencies in ADAMTS13 activity and a detectable anti-ADAMTS13 inhibitor. Four weekly doses of 375 mg/m(2) rituximab were initiated on day 3-29 of presentation as a salvage treatment for relapsing/refractory disease in three patients and as a first-line treatment in one. Resolution of clinical symptoms and hematological abnormalities occurred as early as the second dose and, after the completion of treatment, all four patients achieved complete response (CR). They are currently free from relapse and the duration of CR has been 13-72 months. During the treatment course, the level of ADAMTS13 activity and the titer of the inhibitor correlated well with resolution or exacerbation of the disease. This report suggests that rituximab exhibits short- and long-term favorable effects for the treatment of TTP and that a severe ADAMTS13 deficiency and ADAMTS13 inhibitor positivity may support early administration of rituximab in both acute/refractory and relapsing cases.