Yutaka Tsukune

Activity and safety of combination chemotherapy with methotrexate, ifosfamide, l-asparaginase and dexamethasone (MILD) for refractory lymphoid malignancies: a pilot study

Optimal salvage chemotherapy has not been established for lymphoid malignancy, which is refractory to the conventional cyclophosphamide, doxorubicin, vincristine, and prednisone regimen. To explore an effective regimen, we conducted a phase I pilot study of combination chemotherapy with methotrexate, ifosfamide, l‐asparaginase and dexamethasone (MILD), which are unaffected by MDR1‐encoded P‐glycoprotein. A total of 18 patients with lethal lymphoid malignancy were enrolled over a 2‐yr period. The median age was 63 yr. Eleven patients had T/NK‐cell malignancies, six had B‐cell malignancies, and one was diagnosed with a blastic plasmacytoid dendritic cell neoplasm. Patients aged ≥60 and <60 yr were planned to receive a set of starting doses of methotrexate and ifosfamide, which should induce myelosuppression. Eleven patients completed two courses of MILD therapy. Treatment‐related death because of systemic mucormycosis was observed in one patient. Major treatment‐related adverse events were grade 3 or more hematologic toxicities, which included lymphopenia corresponding to dose‐limiting toxicity. The most common grade 3 non‐hematologic toxicity was febrile neutropenia. Of the 14 evaluated patients, three achieved a complete response, and four showed a partial response. The overall response rate was 57%. It was very interesting that all of seven responders had T/NK‐cell malignancies. MILD therapy was feasible and presented acceptable toxicity in patients with refractory or lethal lymphoid malignancies. The efficacy for T/NK‐cell malignancies should be further evaluated.

Thalidomide may induce interstitial pneumonia preferentially in Japanese patients

To the Editor: A 58-year-old Japanese man with multiple myeloma (immunoglobulin D-j) was admitted to our hospital due to general fatigue, renal dysfunction and an increased level of serum M-protein on June 2006. He had no history of drug allergy. The patient was treated with seven courses of VAD (vincristine, doxorubicin and dexamethasone) regimen following tandem autologous peripheral blood stem cell transplantation (auto-PBSCT). Before auto-PBSCT, the serum M-protein became undetectable and IgD level decreased to the normal range. After obtaining the informed consent of the patient and the approbation of the Institutional Review Board of our institute, we started daily 100 mg of thalidomide (Sauramide; Penn Pharmaceuticals, South Wales, UK) on March 2008 as a maintenance therapy (1, 2). On day 50 of thalidomide administration, night sweating began, and general fatigue and low-grade fever followed on day 80. Chest and abdominal X-rays showed no significant abnormalities at this point. Administration of levofloxacin and clarithromycin for 1 wk was ineffective. The symptoms gradually worsened and C-reactive protein (CRP) level elevated from 9.7 mg ⁄dL to 17.8 mg ⁄dL in a week. A computed tomography (CT) scan revealed diffuse, ground-glass opacities in both lungs on day 87 (Fig. 1A, B), although the patient showed no respiratory symptoms such as cough, sputum, and dyspnea. The pulse oximetry at room air was 97%, and blood gas analysis showed a slight decrease in bicarbonate which maybe due to slight hyperventilation (PO2 99.8 mmHg, PCO2 30.7 mmHg at room air). We suspected that thalidomide might cause the interstitial change of the lung. The agent was immediately discontinued. The persistent fever spontaneously improved in a few days, and the infiltrative shadow in the lungs improved in a week (Fig. 1C). The CRP level decreased to the normal range, and sweating and fatigue diminished. Because the patient’s condition improved rather rapidly, we failed to

Early CNS relapse in a good-risk primary mediastinal large B-cell lymphoma after combined chemo- and radio-therapy

CNS recurrence of non-Hodgkin lymphoma is fetal in most cases and tends to occur 5–12 months after the initial diagnosis [1]. Risk factors for CNS involvement include advanced stage, increased IPI, raised LDH, young age, [1 extranodal site, B symptoms, low albumin and retroperitoneal disease. A 19-year-old Japanese man presented to our hospital because of persistent cough on October 2007. A CT scan showed an anterior mediastinal tumor of 8 cm in diameter. LDH value and bone marrow examination were normal. After the total resection, the tumor was diagnosed as primary mediastinal large B-cell lymphoma (PMLBL). Involvement of right infraclavicular lymph nodes detected by Ga-SPECT and FDG-PET/CT determined the stage as IIA. One cycle of MACOP-B regime plus bi-weekly rituximab therapy started on November 2007. After confirming complete response (CR) by CT and Ga-SPECT, 30 Gy of involved field irradiation to the mediastinum and bilateral infraclavicular lymph nodes followed. On June 2008, 3 months after the chemoand radio-therapy, FDG-PET/CT revealed diminishment of abnormal accumulation. On July 2008, only 4 months after the completion of treatment, severe headache and nausea started. A cranial MRI scan showed an enhancing mass in the left frontal lobe with the right midline shift (Fig. 1). Although systemic evaluation revealed no recurrence in the other sites, brain biopsy confirmed infiltration of the lymphoma cells. Southern blot analysis of JH region of immunoglobulin heavy chain gene showed identical rearrangement bands in mediastinal tumor and CNS metastatic mass. The result confirmed that the CNS tumor is truly derived from primary mediastinal mass. The CNS lesion was resistant to two cycles of IVAM therapy containing high-dose methotrexate (MTX) and the following whole brain irradiation of 50 Gy. Then, after obtaining informed consent from the patient, we introduced via Ommaya reservoir three times of 10–25 mg of rituximab together with 3 ml of the autologous serum twice a week. The intracranial rituximab therapy failed to reduce the tumor size at least until day 15, when the patient’s condition rapidly deteriorated and subsequently he died of bacterial pneumonia. PMLBL is a relatively rare subtype of diffuse large B-cell lymphoma (DLBL) and usually occurs in young patients. MACOP-B regimen plus rituximab (R-MACOP-B) combined with local mediastinal radiation ([30 Gy) is recommended as a front-line therapy for the PMLBL patients [2]. This approach has demonstrated a stable progression-free survival in about 70% of the patients 2 years after the diagnosis. The presented patient was also treated with R-MACOP-B combined with involved field radiation and had no CNS risk factors except for young age, but he relapsed only 4 months after the completion of treatment. CNS relapse is reported in more than 10% of NHL arising from the testis, breast and paranasal sinuses, and CNS prophylaxis is recommended to these subtypes of DLBCL [3, 4]. Bishop et al. reported that CNS infiltration occurs in 4% of newly diagnosed PMLBL cases and in 11% of relapsed ones [5]. Although CNS recurrence has been reported in 2–10% of PMLBL patients [6–8], only one report has referred the CNS screening and prophylaxis in PMLBL [3]. Stefoni et al. reported a case of PMLBL M. Sasaki (&) K. Sugimoto A. Masuda Y. Tsukune Y. Yahata N. Komatsu Division of Hematology, Department of Internal Medicine, Juntendo University School of Medicine, 2-1-1 Hongo, Bunkyo-ku, Tokyo 113-8421, Japan e-mail: msasaki@juntendo.ac.jp

Clinical impact of serum soluble SLAMF7 in multiple myeloma

The signaling lymphocytic activation molecule family (SLAMF7; also known as CS1 or CD319) is highly expressed on plasma cells from multiple myeloma (MM) as well as natural killer (NK) cells and is a well-known therapeutic target of elotuzumab. The objective of this study was to evaluate the clinical significance of serum soluble SLAMF7 (sSLAMF7) levels in patients with MM (n=103) and furthermore the impact of sSLMF7 on the antitumor activity of anti-SLAMF7 antibody. Thirty-one percent of MM patients, but not patients with monoclonal gammopathy of undetermined significance and healthy controls, had detectable levels of serum sSLAMF7, which were significantly increased in advanced MM patients. Further, MM in sSLAMF7-postive patients exhibited aggressive clinical characteristics with shorter progression-free survival times in comparison with sSLAMF7-negative patients. In responders to MM therapy, the levels of sSLAMF7 were undetectable or decreased compared with those before treatment. In addition, the anti-SLAMF7 antibody-mediated antibody-dependent cellular cytotoxicity of NK cells against MM cell lines was inhibited by recombinant SLAMF7 protein. Thus, our findings suggest that high concentrations of sSLAMF7, which could transiently suppress the therapeutic effects of elotuzumab, may be a useful indicator of disease progression in MM patients.

Retrospective analysis of prognostic factors for Waldenstrӧm macroglobulinemia: a multicenter cooperative study in Japan.

Although population-based cancer registries have reported lower incidence of Waldenstrӧm macroglobulinemia (WM) in East Asia than in Western countries, previous retrospective analyses have found the clinical features of WM to be similar in these two populations. To clarify the characteristics of Japanese WM patients, we retrospectively analyzed clinical and laboratory characteristics, treatments, outcomes, and prognostic factors in 93 patients with WM. Based on the Second International Workshop on WM (IWWM-2) criteria, symptomatic WM was found in 73 (78.5%) and asymptomatic WM in 20 (21.5%) of cases examined. The median overall survival (OS) was similar to that in reports from Western countries. Patients receiving treatment regimens including rituximab exhibited significantly better survival than those not given rituximab. Although prognostic factors for WM in Western countries may not apply to Japanese patients, our finding that newly diagnosed WM patients with pleural effusion have a poorer prognosis suggests that this may be a novel predictor of adverse prognosis in symptomatic WM.

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.

Management of Adult Chronic Immune Thrombocytopenia in Japan: Patient and Hematologist Perspectives from a Multi-center Cross-sectional Questionnaire Survey.

Objective The objective of this study was to explore the perspective of hematologists and their patients regarding the management of adult chronic immune thrombocytopenia (ITP). Methods This was a multi-center, questionnaire-based, cross-sectional study conducted between 2012 and 2013 throughout Japan. Patients Hematologists, members of the Japanese Society of Hematology in 171 institutions, and their patients were invited to participate in this study. The hematologists were mainly asked about their treatment strategies, while patients were asked about their opinion of the applied treatments, treatment effect, impact on their quality of life (QOL), and treatment satisfaction. Results Questionnaires from 204 hematologists and 213 patients were collected. One hundred sixty hematologists (78.4%) started treatment based on the patients platelet count. Corticosteroids were considered to be the most effective treatment (44.1%). Forty-six percent of hematologists responded that treatment would be started after the platelet count fell below 20×10(9)/L with bleeding symptoms, compared to 62.9% for patients with no bleeding symptoms. A platelet count of 50×10(9)/L or lower was acceptable for 94.0% of hematologists and 66.8% of patients. Fatigue was most frequently experienced by patients (44.6%). Patients also experienced psychological symptoms (feeling of anxiety or depressive mood: 29.1%, labyrinthitis: 23.5%). While 70.6% of hematologists assumed that the patient QOL was impaired to a moderate to substantial degree, the QOL was impaired in 34.3% of patients. Conclusion A substantial gap which exists between hematologists and their patients highlights a need for better understanding of potential conflicts for establishing effective strategies for ITP management.

Clinical and microbiological effects of biapenem in febrile neutropenic patients with hematologic malignancies

Dear Sir, Several therapeutic guidelines for febrile neutropenia (FN) recommend carbapenem usage as a first choice in high-risk febrile patients [1 3]. Although the therapeutic effect of carbapenems has been shown promising, inappropriate use may increase the risk of emergence of carbapenem-resistant species including metallo-b-lactamase (MBL)-producing strains [4]. Biapenem (BIPM) is a new parenteral carbapenem antibiotic with broad spectrum of antibacterial activity [5]. We conducted a pilot study to evaluate the clinical and microbiological effects of BIPM in high-risk FN patients with hematologic malignancies under a strict administration schedule. The high-risk group was defined as patients with severe neutropenia (a neutrophil count ofB1000/ml with a predicted decrease toB500/ml) prolonged over 7 d. Between August 2006 and July 2007, 47 patients met this criterion after chemotherapy and developed FN. Among them, 13 patients received BIPM administration. Venous blood of all patients was collected and tested for culture and other laboratory examinations. Surveillance culture from throat and stool was performed on both d 1 (or 3) and d 8 in the 13 patients after obtaining informed consent. Prophylactic levofroxacin (LVFX) or ciprofloxacin (CPFX) had been administered to the patients before starting BIPM therapy. They received 300 mg of BIPM every 6 h by drip-infusion for at least 72 h (total 12 doses). Continuation of BIPM monotherapy was decided after clinical and laboratory evaluation. Responders were defined as acquired defervescence and improvement in C-reactive protein values within 3 d. Among them, 4 patients were diagnosed to have documented infection, i.e. 3 bacteremia (2 Psuedomonas aeruginosa and 1 Neisseria sicca) and 1 pneumonia (not specified). Although both P. aeruginosa isolates were susceptible to LVFX and CPFX, the N. sicca strain was resistant to them. Clinical effect was observed in 8 patients (61.5%) including 2 bacteremia cases, and 5 patients received additional treatment with other antibiotics and antifungal drugs. The 8 responders received BIPM for up to 18 d (median, 9 d). After administration of BIPM, none of 13 patients developed BIPM associated adverse reaction. Although this study was not designed as a randomized control trial, the clinical effect of BIPM was similar to that observed in the defined neutropenic patients treated with meropenem during the same period (7 of 11 patients, 63.6%). BIPM showed favorable clinical effect without any adverse events even after pretreatment with LVFX or CPFX. Surveillance culture detected several bacterial species (Table I). Some BIPM-resistant enterococci had already been detected in stool specimens at the beginning of the BIPM therapy. Moreover,