[Pyogenic spondylitis after Corynebacterium striatum blood stream infection following allogeneic hematopoietic stem cell transplantation for malignant lymphoma].

Patient 1 was a 70-year-old woman with refractory diffuse large B-cell lymphoma who received allogeneic peripheral blood stem cell transplantation from an HLA-haploidentical related donor. Upper back pain appeared on day63, and Th8-Th9 pyogenic spondylitis was diagnosed based on magnetic resonance imaging (MRI). Blood culture on day14 identified Corynebacterium striatum as the causative bacteria of blood stream infection (BSI). The pyogenic spondylitis resolved after treatment with daptomycin for 2 months. Patient 2 was a 65-year-old man with relapsed angioimmunoblastic T-cell lymphoma who received bone marrow transplantation from an HLA-DR single-antigen-mismatched unrelated donor. Lower back pain appeared on day30, and L4-L5 pyogenic spondylitis was diagnosed based on MRI. Blood culture was negative. Daptomycin and clindamycin were selected for treatment based on the drug susceptibility of bacteria that had caused pre-engraftment BSI (Escherichia coli on day3 and Corynebacterium striatum on day9), and the pyogenic spondylitis resolved after 6 months of this treatment. Pyogenic spondylitis should be considered in the differential diagnosis of back pain accompanied by BSI before engraftment in allogeneic hematopoietic stem cell transplant recipients.

[Multiple myeloma with myelofibrosis at diagnosis and aggressive extramedullary relapse after autologous stem cell transplantation].

A 66-year-old man was diagnosed with symptomatic IgG-λ multiple myeloma based on the presence of anemia, thrombocytopenia, renal dysfunction, and a tumor on the right sixth rib. Bone marrow aspiration yielded a dry tap and biopsy revealed myelofibrosis grade 2. Partial response was achieved with Bd (bortezomib and dexamethasone) and VRd (bortezomib, lenalidomide, and dexamethasone). The patient received autologous stem cell transplantation, but the myeloma relapsed 3 months later, and liver tumors developed as well. DKd (daratumumab, carfilzomib, and dexamethasone) was administered, but the patient died due to disease progression. Autopsy revealed multiple extramedullary lesions in the liver, spleen, gallbladder, adrenal glands, kidneys, and multiple lymph nodes, as well as ascites.

[Plasmablastic lymphoma presenting with plasmacytosis and polyclonal hypergammopathy].

A 72-year-old woman presented with generalized lymphadenopathies and plasmacytosis accompanied by polyclonal hypergammopathy. 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) showed FDG accumulation in the systemic lymph nodes, spleen, and multiple bones. Human immunodeficiency virus antibody was negative. Lymph node histologic findings showed a monotonous population of plasma cells with a starry-sky appearance. The cells were positive for CD19, λ, and Epstein-Barr virus-encoded RNA, and negative for CD20 and CD56. The MIB-1 index was 80%. A diagnosis of plasmablastic lymphoma with plasmacytosis and polyclonal hypergammopathy was made, and complete metabolic response was achieved after six cycles of dose-adjusted-EPOCH therapy (etoposide, prednisolone, vincristine, cyclophosphamide, and doxorubicin).

Risk factors and outcome of Stenotrophomonas maltophilia infection after allogeneic hematopoietic stem cell transplantation: JSTCT, Transplant Complications Working Group.

Stenotrophomonas maltophilia (S. maltophilia) is an aerobic nonfermenting Gram-negative bacillus widely distributed in the environment that has inherent multidrug resistance to beta-lactam and carbapenem antibiotics. S. maltophilia infection (SMI) is known as an important fatal complication following allogeneic hematopoietic stem cell transplantation (HSCT), but its clinical characteristics have not been well clarified. A retrospective study to identify the incidence, risk factors, and outcomes of SMI after allogeneic HSCT was performed using the database of the Japanese nationwide registry, including 29,052 patients who received allogeneic HSCT in Japan between January 2007 and December 2016. A total of 665 patients developed SMI (sepsis/septic shock, 432; pneumonia, 171; other, 62). The cumulative incidence of SMI at 100 days after HSCT was 2.2%. Among risk factors identified for SMI (age ≥ 50 years, male, performance status 2-4, cord blood transplantation [CBT], myeloablative conditioning, Hematopoietic Cell Transplant-Comorbidity Index [HCT-CI] score 1-2, HCT-CI score ≥ 3, and active infectious disease at HSCT), CBT was the strongest risk factor (hazard ratio, 2.89; 95%CI, 1.94-4.32; p < 0.001). The survival rate at day 30 after SMI was 45.7%, and SMI before neutrophil engraftment was significantly associated with poor survival (survival rate 30 days after SMI, 40.1% and 53.8% in patients with SMI before and after engraftment, respectively; p = 0.002). SMI is rare after allogeneic HSCT, but its prognosis is extremely poor. CBT was a strong risk factor for SMI, and its development prior to neutrophil engraftment was associated with poor survival.

[Successful alectinib monotherapy for residual disease after brentuximab vedotin combined chemotherapy in ALK-positive anaplastic large cell lymphoma].

A 28-year-old male patient presented with multiple lymphadenopathies and extranodal masses. He was diagnosed with stage IVB ALK-positive anaplastic large cell lymphoma after the right axillary lymph node biopsy. A partial metabolic response with fluorodeoxyglucose accumulation was observed in the residual disease of the upper left hilar lymph node after eight courses of brentuximab vedotin, cyclophosphamide, adriamycin, and prednisolone. We started alectinib at 600 mg daily, which achieved a complete metabolic response (CMR) after three months. The CMR was maintained and alectinib was continuously administered without adverse events at the last follow up. Alectinib showed high efficacy and tolerability, though the optimal period and long-term adverse effects of administration remain unclear. Therefore, further studies are necessary.

[Busulfan/thiotepa followed by autologous peripheral blood stem cell transplantation for refractory diffuse large B-cell lymphoma accompanied by hypopyon].

A 54-year-old male patient, who presented with multiple lymphadenopathies, bilateral leg edema, and oscheohydrocele, was diagnosed with diffuse large B-cell lymphoma (DLBCL) stage IVB. His lymphadenopathies disappeared after six courses of R-CHOP therapy, which consist of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone); however, right hypopyon and partly remaining testicular soft tissue masses with fluorodeoxyglucose accumulation were observed. Lymphoma cell infiltration was observed in the aqueous humor of the right anterior chamber and testis, which indicates DLBCL progression. Hypopyon disappeared after the first course of intrathecal chemotherapy combined with R-HDMA therapy, which consists of rituximab and high-dose methotrexate/cytarabine, but recurred in the third course. The patient then underwent busulfan and thiotepa (BuTT) therapy followed by autologous peripheral blood stem cell transplantation (auto-PBSCT) after four courses of R-HDMA therapy. Hypopyon promptly disappeared after BuTT therapy and no hypopyon recurrence was observed 9 months after auto-PBSCT. Therefore, BuTT therapy is effective for hypopyon associated with refractory DLBCL.

Toxoplasmosis after allogeneic hematopoietic stem cell transplantation: Impact of serostatus-based management.

Toxoplasmosis caused by Toxoplasma gondii (T. gondii) is a serious infectious complication after allogeneic hematopoietic stem cell transplantation (HSCT). The incidence of toxoplasmosis varies widely because of the variabilities of seroprevalence among patient populations. The incidence and the optimal management of toxoplasmosis after allogeneic HSCT in a patient population with a low seroprevalence have not been fully evaluated. We conducted a single-center retrospective study evaluating toxoplasmosis in Japanese patients who underwent allogeneic HSCT. Of the 728 evaluable patients, only 5 developed toxoplasmosis with a median onset of day 60 post-transplant (range, day 55-393). The cumulative incidence was 0.7% (95% CI: 0.3%-1.5%) at day 500 post-transplant. Four of the five patients succumbed due to toxoplasmosis. The more recently treated 220 patients (not the earlier 508 patients) were screened for the T. gondii serostatus, and prophylactic treatment with trimethoprim/sulfamethoxazole was applied. All five patients with toxoplasmosis were in the unscreened group, and there was no case of toxoplasmosis after the introduction of the screening and prophylactic treatment. Our results suggest that toxoplasmosis after allogeneic HST is rare but can develop as a life-threatening complication even in the populations with low seroprevalence, and that prophylactic treatment for seropositive patients could effectively prevent toxoplasmosis.

Association between Platelet-Associated Immunoglobulin G Levels and Response to Corticosteroid Therapy in Patients with Newly Diagnosed Immune Thrombocytopenia.

OBJECTIVE: Platelet-associated immunoglobulin G (PA-IgG) refers to IgG attached to the surface of platelets, while the immature platelet fraction (IPF) reflects the state of platelet production in bone marrow. Since PA-IgG and IPF are increased in patients with immune thrombocytopenia (ITP), reflecting amounts of platelet antibodies and compensatory platelet production, respectively, we hypothesized that these laboratory findings may provide useful markers for predicting treatment response in patients with ITP. We therefore retrospectively investigated associations between levels of these markers at diagnosis and response to first-line therapy in patients with ITP. METHODS: Forty-three patients diagnosed with ITP at Oita Kouseiren Tsurumi Hospital between May 2010 and November 2018 were included. Patients were divided into 2 groups based on response to corticosteroid as first-line therapy. Laboratory findings were compared between responders and nonresponders. RESULTS: Median PA-IgG was 285 ng/107 cells (range, 45.5-18,200 ng/107 cells), and median IPF was 15.5% (range, 5.4-62.1%). Median levels were higher than the respective upper limits of normal range (PA-IgG, 0-46 ng/107 cells; IPF, 1.1-9.5%). First-line therapy was performed using standard-dose prednisolone (0.5-1.0 mg/kg/day) in 32 patients and high-dose dexamethasone (40 mg/day, 4 days) or methylprednisolone (125-1,000 mg/day, 3-4 days) in 11 patients. Twenty-four patients (55.8%) responded to first-line therapy. In univariate analysis, type of corticosteroid (p = 0.17) tended to differ between groups but did not differ significantly, and no difference in IPF level was apparent between responders (15.35%; range, 5.4-41.5%) and nonresponders (16.7%; range, 6.3-62.1%; p = 0.15). PA-IgG was significantly higher among nonresponders (430 ng/107 cells; range, 101-18,200 ng/107 cells) than among responders (254.5 ng/107 cells; range, 45.5-470 ng/107 cells; p = 0.004). Multivariate analysis revealed PA-IgG was independently associated with response to first-line therapy (odds ratio, 1.000; 95% confidence interval, 1.000-1.010; p = 0.029). CONCLUSION: Our data suggested that PA-IgG at diagnosis could offer a useful predictor of response to first-line corticosteroid therapy for ITP.

[Intravenous immunoglobulin in combination with ibrutinib for the treatment of IgM-type M protein associated peripheral neuropathy complicated with chronic lymphocytic leukemia].

We report the case of a 79-year-old man with chronic lymphocytic leukemia (CLL) with IgM-kappa type monoclonal gammopathy according to immunophenotypes and a negative result for MYD88 L265P mutation of leukemic cells. Abnormal lymphocytes and IgM increased under observation, and he experienced paresthesia. The diagnosis of IgM-type M protein associated peripheral neuropathy was confirmed by nerve conduction test, and negativity of myelin-associated glycoprotein and glycolipid antibodies. He was placed on intravenous immunoglobulin (IVIg) in combination with ibrutinib. His symptoms dramatically subsided and did not recur. Treatment with IVIg and ibrutinib may be useful for the rare complication of peripheral neuropathy with CLL.

[Successful treatment of HHV8-negative effusion-based lymphoma with drainage of pleural effusion].

Two cases of human herpesvirus 8 (HHV8)-negative effusion-based lymphoma (EBL) involving unilateral pleural effusion that regressed only after drainage are reported. Cases 1 and 2 were 91- and 81-year-old men with right and left pleural effusion, respectively. No chemotherapy was administered to either patient because of their advanced age and the presence of cardiac comorbidities. They completely recovered after effusion drainage alone without relapse till the last observation. Thus, this study suggests that some patients with HHV8-negative EBL can be safely managed with effusion drainage alone.

[Carfilzomib-induced renal impairment with albuminuria in a patient with relapsed/refractory multiple myeloma].

A 70-year-old woman was diagnosed with multiple myeloma in 2014. She achieved complete remission (CR) after bortezomib, cyclophosphamide, dexamethasone (VCD) therapy and lenalidomide, dexamethasone (Rd) therapy; however, she relapsed in 2017. Although she achieved second CR by carfilzomib, dexamethasone (Kd) therapy, serum creatinine levels increased with urinary protein after 17 courses of Kd therapy. Urinary protein test revealed albuminuria, whereas M-protein was undetectable. Carfilzomib-induced renal impairment was suspected due to absence of other causes, such as progression of myeloma or autoimmune disease. On discontinuation of Kd therapy, urinary protein decreased rapidly with improvement of serum creatinine levels within a month. Carfilzomib-induced nephrotoxicity is a rare but important adverse event.

[Concurrent subcutaneous panniculitis-like T-cell lymphoma and myelodysplastic syndrome with fibrosis].

A 66-year-old male presented with fever and erythema at our hospital, and leukoerythroblastosis, anemia, thrombocytopenia, and multiple low-density lesions in the moderately enlarged spleen were detected. Skin tissue revealed CD8+ T cells with the expression of cytotoxic molecule markers involving fat lobules, and subcutaneous panniculitis T-cell lymphoma (SPTCL) was diagnosed. The bone marrow displayed no infiltration of lymphoid tumor cells, but hyperplasia of granulocytes and megakaryocytes with grade 2 stromal fibrosis. In addition, the bone marrow exhibited diffuse 18F-fluorodeoxyglucose (FDG) accumulation on FDG positron-emission tomography/computed tomography (FDG-PET/CT). Although chemotherapy improved SPTCL, the patient died from leukocytosis with leukoerythroblastosis. We obtained negative results for the JAK2 V617F mutation, and CD34+ cells were elevated in the bone marrow compared with the levels at initial examination. The final diagnosis was concurrent myelodysplastic syndrome (MDS) with fibrosis and SPTCL. This report highlights that it is essential to consider MDS or other myeloproliferative neoplasms (MPN) as possible complications when malignant lymphoma complicates myelofibrosis in the absence of bone marrow infiltration of lymphoma cells. Perhaps, the assessment of clonal markers of MPN and FDG accumulation patterns in the bone marrow by FDG-PET/CT could enable differentiation.

[Ibrutinib therapy for a blastoid variant mantle cell lymphoma patient with early extranodal relapse after autologous stem cell transplantation].

A 65-year-old man with multiple lymphadenopathy presented to our hospital and was diagnosed with StageIVA blastoid-variant mantle cell lymphoma (MCL), with a Ki-67 index of 93%. Partial response was achieved after four courses of CHASER (cyclophosphamide, cytarabine, dexamethasone, etoposide, and rituximab) chemotherapy, and complete response was achieved after autologous stem cell transplantation (ASCT). Six months after ASCT, the MCL relapsed with occurrence of tumors one on the left upper arm and one in the cerebrum, which were proved to be resistant to the conventional chemotherapy and progressed rapidly. These tumors disappeared with scarring following the local irradiation (45 Gy). However, the unirradiated regions became enlarged. The bulky abdominal lesion was treated with local irradiation (41 Gy) combined with 560 mg of ibrutinib but still resulted in progressive disease 1 month after initiating the ibrutinib treatment. Finally, the patient died 5 months post-relapse. The prognosis of patients with blastoid-variant MCL with high Ki-67 index is extremely poor. Furthermore, the risk of central nervous system (CNS) involvement is very high. Therefore, ibrutinib maintenance therapy post ASCT might be a treatment option to prevent CNS involvement. Further efforts might be needed to improve the outcomes of blastoid-variant MCL with a high Ki-67 index.

[Successful treatment of myelodysplastic syndrome-associated autoinflammatory lymphedema with azacytidine].

An 84-year-old woman presented pancytopenia. She was diagnosed with myelodysplastic syndromes (MDS) with excess blasts-1, however, she declined treatment with azacitidine (AZA). Ten months later, bilaterally symmetrical, non-pitting edema appeared on the lower legs. A skin biopsy of the lower leg revealed lymphedema. The appearance and location of the lymphedema suggested an immunologic etiology; however, tests for autoimmune diseases yielded negative results. Therefore, a relationship between MDS and lymphedema was, therefore, speculated. Consequently, treatment with AZA was started, which led to marked improvement in both the lymphedema and pancytopenia. Based on the skin tissue pathology and the improvement in MDS after treatment with AZA, MDS-related autoinflammatory lymphedema was diagnosed.

[Successful diagnosis of lymphoplasmacytic lymphoma with IgG paraprotein using MYD88 L265P mutation analysis].

A 76-year-old woman presented to our hospital with leukocytosis and abnormal lymphocytes. M protein of the immunoglobulin G (IgG) type was detected using immunoelectrophoresis. A bone marrow biopsy revealed infiltration of small mature lymphocytes, lymphoplasmacytoid cells with Dutcher bodies, grape cells, and Russell bodies. The MYD88 L265P mutation was detected in the abnormal peripheral lymphocytes, and a diagnosis of lymphoplasmacytoid lymphoma was established. MYD88 L265P mutation analysis is useful for making a diagnosis of non-IgM lymphoplasmacytoid lymphoma because it enables the differentiation from other low-grade B-cell malignancies.

Development of acquired hemophilia A during treatment of multiple myeloma with lenalidomide.

We describe a 67-year-old female demonstrating symptomatic multiple myeloma (MM) with anemia and bone lesions initially diagnosed in 2009. Although a partial response was achieved after bortezomib and dexamethasone treatment, MM recurred in 2012. Therefore, treatment with lenalidomide, cyclophosphamide, and dexamethasone was commenced. Coagulation tests conducted prior to the chemotherapy were normal. Lenalidomide was discontinued after 10 days due to exacerbation of renal dysfunction. Simultaneously, activated partial thromboplastin time (APTT) was prolonged to 89.5 seconds. The mixing test showed an inhibitor pattern, with factor VIII at 2% and factor VIII inhibitor at 4.85 BU/ml. A diagnosis of acquired hemophilia A was made, and treatment with prednisolone was started, after which APTT improved to 36.4 seconds and factor VIII inhibitor decreased to 1.09 BU/ml. The factor VIII inhibitor level again increased concomitantly with restarting lenalidomide, which was, therefore, discontinued, while immunosuppressive therapy was administered with the addition of cyclophosphamide. Factor VIII inhibitor gradually disappeared from the patient's blood over the next four months. To the best of our knowledge, this is the first description of lenalidomide as a possible cause of acquired hemophilia A. Our experience indicates that we need to pay attention to acquired hemophilia A after initiating lenalidomide therapy in patients with hematologic malignancies.

[Hypofibrinogenemia associated with steroid therapy for the patients who developed GVHD after allogeneic stem cell transplantation].

Hypofibrinogenemia (plasma fibrinogen level <150 mg/dl) is occasionally observed after allogeneic hematopoietic stem cell transplantation, and its etiology is often difficult to determine. We herein report that steroids administered for the treatment of graft-versus-host disease (GVHD) are associated with the development of hypofibrinogenemia. We retrospectively analyzed the plasma fibrinogen (Fg) levels in 15 consecutive patients who had been administered 1 mg/kg/day (1 mg/kg group) or 2 mg/kg/day (2 mg/kg group) methylprednisolone for the treatment of Grade II to IV acute GVHD. Hypofibrinogenemia had developed in 8 of the 15 patients (53%) by day 50 after the start of steroid treatment, and was observed in 2 of 6 patients in the 1 mg/kg group and 6 of 9 in the 2 mg/kg group. A significant decrease in the Fg level was observed in the 2 mg/kg group (the median value before starting steroid treatment and that on the 20th day after starting steroid treatment were 506 mg/dl and 180 mg/dl, respectively, P=0.0013). Other possible causes of hypofibrinogenemia, including liver dysfunction or disseminated intravascular coagulation, were confirmed in only 3 patients during the observation period. In conclusion, hypofibrinogenemia commonly occurs in patients treated with steroids, especially those administered 2 mg/kg/day methylprednisolone for the treatment of GVHD.

[Successful treatment with high-dose methotrexate/cytarabine regimen in a patient in SMILE regimen-resistant extranodal natural killer/T-cell lymphoma].

A 28-year-old man complained of pain in the oral mucosa and pharynx in March 2011, and then developed fever and generalized swelling of the cheek. In March 2012, a gum biopsy led to a diagnosis of extranodal natural killer/T-cell lymphoma (ENKL). (18)F-FDG-PET revealed significant uptake in the mouth, tonsils, jawbone, shoulder blade, humerus, ilium, femur, and spleen. After two courses of the SMILE (dexamethasone, methotrexate (MTX), ifosfamide, L-asparaginase, etoposide) regimen, the response was stable disease. However, a high-dose MTX/cytarabine (MA) regimen was effective. After three courses of the MA regimen, a partial response was achieved. Then, allogeneic bone marrow transplantation from an unrelated donor was performed. At 10 months after transplantation, there was no sign of recurrence. Although the optimal treatment for ENKL refractory to the SMILE regimen has yet to be established, our case suggests the MA regimen to be a potentially effective treatment option.

Evaluation of safety and efficacy of transjugular liver biopsy in allogeneic hematopoietic stem cell transplant recipients.

We retrospectively evaluated the safety and utility of transjugular liver biopsy (TJLB) in allogeneic hematopoietic stem cell transplant (HSCT) recipients. Ten patients underwent HSCT between 1991 and 2013. Eight patients with thrombocytopenia received platelet transfusions before and/or during TJLB. No complications associated with TJLB were observed. Samples adequate for a pathological diagnosis were obtained in 9 of the 10 patients, and the diagnoses made by TJLB were graft-versus-host-disease in eight patients and non-specific hepatitis in one. These results suggest that TJLB is a safe and effective procedure for the evaluation of liver injury in HSCT recipients.