[Complete response with tirabrutinib for relapsed and refractory Bing-Neel syndrome].

A 62-year-old female patient was diagnosed with Waldenstrom's macroglobulinemia/lymphoplasmacytic lymphoma (WM/LPL) 8 years ago, which was resolved with rituximab (R) monotherapy. Five years ago, she experienced numbness of the lower limbs, followed by diminished lower limb muscle strength and hearing disturbance. PET-CT scans showed accumulations along the peripheral nerves of the upper and lower limbs together with clonal B lymphocytes in the cerebrospinal fluid, thus a diagnosis of relapse with Bing-Neel syndrome (BNS). After a temporal remission by high-dose cytarabine or bendamustine plus R regimens as salvage treatments, WM/LPL recurred for the third time accompanied by gait disturbances due to muscle weakness and urinary retention. Thus, tirabrultinib was started as a subsequent therapy, which significantly improved the neurological condition together with abnormal findings of magnetic resonance imaging or cerebrospinal fluids. This case is valuable since few relapsed BNS was reported in the literature with successful tirabrutinib treatment.

Clinical characteristics and risk factors associated with nosocomial COVID-19 infection in patients with hematological disorders in Japan.

Patients with cancer are considered at high risk of acquiring coronavirus disease (COVID-19). To identify patients who are likely to be diagnosed with severe COVID-19, we analyzed the risk factors for mortality in patients admitted to the hematology department at our institute. The mortality rate of all patients was as high as 62% (21 of the 34 patients), and most of these patients had malignant malignancies. Patients before an achievement of remission had a 10.8-fold higher risk of death than those in remission. The group receiving chemotherapy with steroids had a shorter survival time and had an 8.3-fold higher risk of death than that receiving chemotherapy without steroids. During the COVID-19 pandemic, it is necessary to carefully monitor or follow-up patients with active diseases and patients receiving steroid-containing chemotherapy.

[Successful steroid pulse therapy for COVID-19 associated respiratory failure initially mimicking bortezomib-induced lung injury].

From December 2019, a 71-year-old male underwent three cycles of a combination therapy of pomalidomide, bortezomib, and dexamethasone for relapsed multiple myeloma and a very good partial response was achieved. In March 2020, he developed a fever of 38.9°C and computed tomography revealed bilateral ground-glass opacities. Antibiotic therapy was ineffective. Bronchoscopy was performed and bortezomib-induced lung injury was initially suspected. Due to respiratory exacerbation, high-dose steroid therapy was administered, which resulted in a dramatic improvement of the patient's respiratory failure. Thereafter, reverse transcription polymerase chain reaction performed on a preserved bronchial lavage sample tested positive, and thus his diagnosis was corrected to COVID-19 pneumonia. It is difficult to discriminate COVID-19 pneumonia from drug-induced lung disease, as both disorders can present similar ground-glass opacities on computed tomography. Therefore, with this presented case, we summarize our experience with steroid therapy for COVID-19 associated respiratory distress at our institution.

Analysis of risk factors for lenalidomide-associated skin rash in patients with multiple myeloma.

The aim of the present study was to identify the risk factors for lenalidomide (Len)-associated skin rash. We retrospectively investigated the medical records of 144 multiple myeloma patients treated with Len-containing therapies. A total of 64 of 144 patients included in the study had skin rash (44.4%). 50 patients developed skin rash within 4 weeks of starting Len treatment. Further, in 29 patients, the skin rash appeared at an early stage (within 1 week) after treatment initiation. Univariate analysis revealed that the risk of skin rash significantly increased in patients with advanced age (p = 0.017), myeloma subtype (p = 0.014), no prior chemotherapy (p = 0.012), and Len dosage (p = 0.008). Multivariate logistic regression analysis demonstrated that advanced age (≥ 70 years), BJP-subtype of myeloma and no prior chemotherapy were significant risk factors for the skin rash associated with Len. Thus, patients with these risk factors should be carefully monitored for the appearance of skin rash during the treatment with Len.

[Multiple myeloma with light chain deposition disease showing needle-like crystal inclusions in plasma cells and macrophages in multiple organs].

A 57-year-old Japanese man was referred to our hospital with the chief complaint of dizziness. Our investigations showed pancytopenia that necessitated bone marrow evaluation; this evaluation revealed plasma cell proliferation that was accompanied by numerous needle-shaped crystal inclusions. Clinical and laboratory examinations were used to establish a diagnosis of multiple myeloma (MM) accompanied by Fanconi syndrome. He was administered treatment with bortezomib, lenalidomide, or thalidomide; however, he died after experiencing upper abdominal pain of unknown etiology. Histopathological examination showed needle-like inclusions in the liver and kidney and macrophages in the bone marrow, suggesting light chain deposition disease (LCDD) that could contribute to multi-organ injury. We report the rare case of a patient with needle-shaped inclusions in MM that caused LCDD.

[Analysis of anti-SARS-CoV-2 IgG antibodies in hematologic patients with asymptomatic or mildly symptomatic COVID-19 infections].

At our institution, an outbreak of hospital-acquired coronavirus infection (COVID-19) occurred in the hematology department. We used immunochromatography to examine the anti-COVID-19 IgG antibody level in 10 COVID-19 positive patients who exhibited little or no symptoms. Six patients were negative for IgG antibody at an average of 26 days (range: 11-39 days) after the COVID-19 diagnosis. Among them, two had been negative on PCR twice and were discharged but subsequently became positive on PCR 2-4 weeks later and developed pneumonia. These patients were also positive for IgG antibody after the confirmed diagnosis based on PCR accompanied with the development of pneumonia. Our findings suggest an immune response delay to COVID-19 in immunocompromised patients, such as those with hematologic disorders. Thus, follow-up examinations with antibody testing are important in these patients.

[HHV-8-positive Castleman's disease with rapidly progressing multiorgan failure mimicking TAFRO syndrome].

A 60-year-old man was admitted to our hospital with multiple organ failure complicated by disseminated intravascular coagulation. He presented with thrombocytopenia, pleural effusion, ascites, high fever, and renal impairment, suggesting TAFRO syndrome. In addition to administering prednisolone, dialysis and mechanical ventilation were initiated for severe renal and respiratory insufficiencies, respectively. However, he died 5 days after admission. An autopsy was performed, resulting in the diagnosis of human herpesvirus (HHV)-8-positive plasma cell-type Castleman's disease. Furthermore, HHV-8 was detected in the vascular endothelium and lymph nodes on immunohistochemical study. His rapidly deteriorating clinical course with the lack of serum hypergammaglobulinemia is atypical for Castleman's disease. Therefore, HHV-8 may have incited the disorder's aggressive behavior, causing TAFRO syndrome.

[Retrospective analysis of nosocomial COVID-19: a comparison between patients with hematological disorders and other diseases].

Nosocomial coronavirus disease 2019 (COVID-19) had occurred at our hospital. We retrospectively analyzed the differences between patients with nosocomial COVID-19 and either hematological disease (n=40) or other diseases (n=57). The analysis was completed within 60 days for surviving patients. Among the patients with hematological disease and those with other diseases, there were 21 (52.5%) and 20 (35.1%) deaths, respectively. Although the patients with hematological disease received favipiravir more frequently than patients with other diseases (21 [52.5%] vs. 15 [35.3%], respectively; P<0.05), their median overall survival was poor (29 days; P=0.078). Furthermore, the median duration from oxygen therapy initiation to death or intubation was significantly shorter in the patients with hematological disease (5 days [range, 1-17 days] vs. 10 days [1-24 days], respectively; P<0.05). Furthermore, the patients with hematological disease and nosocomial COVID-19 exhibited more marked respiratory failure and poorer outcomes leading to death in a shorter time period than the patients with other diseases and nosocomial COVID-19.

[Pomalidomide/cyclophosphamide/dexamethasone combination therapy for relapsed/refractory multiple myeloma accompanied by extramedullary lesions].

We retrospectively evaluated the efficacy of pomalidomide/cyclophosphamide/dexamethasone (PCd) treatment in seven patients with extramedullary disease (EMD). Three of the seven patients achieved VGPR (very good partial response) with PCd therapy. We handled a patient complicated with secondary plasma cell leukemia, which was completely cured with PCd regimen and succeeded to autologous stem cell transplantation. In addition, there were no severe infections during the treatment period. This is the first report demonstrating the efficiency and tolerability of PCd treatment for EMD.

Nilotinib treatment induced large granular lymphocyte expansion and maintenance of longitudinal remission in a Philadelphia chromosome-positive acute lymphoblastic leukemia.

It is well known that the second-generation tyrosine kinase inhibitor dasatinib evokes an immunological reaction as an off-target effect and induces large granular lymphocytes (LGLs) expansion in 30% of patients. However, LGLs expansion in nilotinib-treated patients is rare. We report the case of a 65-year-old patient with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) who showed LGLs expansion during nilotinib treatment. The patient achieved complete remission (CR) after multi-agent chemotherapy combined with dasatinib treatment. However, ALL relapsed in the central nervous system and bone marrow when treatment was interrupted due to interstitial pneumonia. Nilotinib treatment was subsequently started and the patient achieved second CR. Marked peripheral blood lymphocytosis emerged after the start of nilotinib treatment. CD8 + CD57 + cytotoxic T cells were predominantly expanded and showed strong cytocidal activity against K562 Ph-positive leukemia cells. These results suggest that similar to dasatinib, nilotinib can induce LGLs expansion, possibly contributing to long-term remission in patients with Ph-ALL.

[Impact of time to hematological response on survival in patients treated with azacytidine: a single-center retrospective study].

We analyzed 95 cases of MDS (n=78), CMML (n=8) and AML (n=9) with blast counts of <30%, treated by AZA since March 2011, for a possible association of hematological improvement (HI) and overall survival duration (OS). We defined four categories as follows: stable disease (SD): no exacerbation of disease even if HI was not achieved after nine cycles of AZA treatment; early and late response (ER, LR): achievement of HI within and beyond three cycles, respectively; and drop out (DO): termination of treatment within nine cycles due to disease progression or complication without obtaining HI. OS was significantly longer in the LR than in the ER. The OS of ER was significantly shorter than that of the SD group. Patients in ER group who relapsed had significantly shorter survival than those who were able to maintain HI. Additionally, 3 out of 11 SD cases achieved HI after 10 cycles. We conclude that AZA should be continued until disease progression besides an achievement of HI.

[Cauda equina syndrome as the first presentation of intravascular large B-cell lymphoma: a lung biopsy case].

A 65-year-old male was admitted for bladder and rectal dysfunction with lower-limb sensory disturbance. Although no abnormalities were detected on magnetic resonance imaging of the brain and spinal cord, an elevation in the serum anti-cytomegalovirus (CMV) -IgM level and pneumonia suggest viral meningomyelitis. However, steroid pulse and anti-CMV treatments did not resolve the patients' symptoms. Lung and skin biopsies revealed an invasion of atypical lymphoid cells into small vessels, consistent with intravascular large B-cell lymphoma (IVLBCL). Chemotherapy comprising R-CHOP and intrathecal administration of methotrexate resolved neurological complications quickly, and the patient remains in complete remission after 2 years. Notably, IVLBCL with cauda equina syndrome is highly rare.

[Successful management of drug-induced skin rash in a relapsed multiple myeloma patient with pomalidomide desensitization].

A 71-year-old man diagnosed with IgG-κ type multiple myeloma 11 years ago was treated with low doses of pomalidomide (POM, 1 mg/daily) and dexamethasone (20 mg/week) as the third-line of salvage regimen. The treatment was terminated 4 days later owing to the appearance of a severe skin rash, which had also occurred after previous treatment with lenalidomide. After 2 months, POM was readministered via an outpatient desensitization protocol under prednisolone administration. During five cycles of POM-treatment, no severe skin rash appeared, and partial remission was obtained even though the final POM dose was as low as 1 mg/day.

[Relapsed acute myeloid leukemia concomitant with TET2-mutated peripheral T-cell lymphoma, not otherwise specified].

A 70-year-old female was initially diagnosed with acute myeloid leukemia (AML) and achieved complete remission by conventional chemotherapy. She presented with leukocytosis and pleural effusion six years later, and was diagnosed with myelodysplastic/myeloproliferative neoplasms (MDS/MPN) by bone marrow (BM) analysis. Pyrexia and lymphadenopathy developed one year later, and lymph node biopsy confirmed peripheral T-cell lymphoma, not otherwise specified (PTCL-NOS). Chemotherapy achieved a partial remission. Fifty-two days after her last chemotherapy treatment, increased blasts in the peripheral blood along with marked lymphadenopathy were observed, which were considered to be indicative of the simultaneous development of AML and lymphoma. TET2 mutations were confirmed in BM and lymph node samples. Development of AML and PTCL-NOS might be due to clonal hematopoiesis associated with aging and chemotherapy.

Hypercalcemia and osteolytic bone lesions as the major symptoms in a chronic lymphocytic leukemia/small lymphocytic lymphoma patient: a rare case.

We report a 40-year-old woman who presented with multiple osteolytic bone lesions and hypercalcemia, which are rarely caused by chronic lymphocytic leukemia/small lymphocytic lymphoma (CLL/SLL). Although receiving intensive chemotherapy and allogeneic transplantation, the patient had a poor outcome with an overall survival of 2 years. To our knowledge, this presentation is extremely rare for B-chronic lymphocytic leukemia, and new treatment strategies may be needed for long-term control of the disease.

[FGFR1-mutated B-cell acute lymphoblastic leukemia transforming to myelodysplastic / myeloproliferative neoplasm and acute myeloid leukemia].

A 77-year-old male with hyperleukocytosis and thrombocytopenia was diagnosed with Philadelphia chromosome (Ph) -negative B-cell acute lymphoblastic leukemia (ALL) ; he was treated with induction chemotherapy. Despite an initial complete remission, hyperleukocytosis was returned 18 months later. A bone marrow smear revealed a substantial increase in the number of myeloid cells with each stage of differentiation, which was markedly different from the initial presentation, resulting in the diagnosis of Ph-negative myelodysplastic syndrome/myeloproliferative neoplasm (MDS/MPN). After a month, an autopsy revealed that the disease had progressed to acute myelogenous leukemia (AML). Since the first diagnosis, a chromosomal translocation, t (8;13) (p12;q12), was identified; this was subsequently confirmed by fluorescence in situ hybridization (FISH) analysis to comprise a genomic rearrangement of the fibroblast growth factor receptor 1 (FGFR1) gene. Collectively, this is a rare case of a myeloid/lymphoid neoplasm with an FGFR1 genomic rearrangement that initially presented as B-cell ALL, before developing into MDS/MPN and finally into AML. In the literature, although a transformation of MPN into ALL is often reported, the transformation of B-cell ALL into MPN is an infrequent event.

Methotrexate-associated Intravascular Large B-cell Lymphoma in a Patient with Rheumatoid Arthritis: A Very Rare Case.

We herein report a rare case of methotrexate (MTX)-associated intravascular large B-cell lymphoma (IVLBCL) in a man with rheumatoid arthritis. Two episodes of a fever of unknown origin accompanied by elevated levels of serum lactate dehydrogenase and the soluble interleukin-2 receptor occurred within a year, so the patient was suspected of having an MTX-associated lymphoproliferative disorder. His clinical symptoms resolved after the cessation of MTX. However, after treatment with iguratimod, another disease-modified anti-rheumatic drug, markedly similar symptoms recurred, and random skin biopsies resulted in a diagnosis of IVLBCL. The patient received a rituximab-containing chemotherapy and achieved complete remission.