Ai Mihara

Myelitis associated with human herpes virus 6 (HHV-6) after allogeneic cord blood transplantation.

Human herpes virus 6 (HHV-6) has been recognized as 1 of the pathogens causing central nervous system diseases such as encephalitis after hematopoietic stem cell transplantation. We here report 2 patients who developed HHV-6-associated myelitis soon after allogeneic cord blood transplantation.

Pneumocystis jiroveci pneumonia detected by FDG-PET

Dear Editor, A 57-year-old woman suffered a relapse of follicular lymphoma and underwent high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation (auto-PBSCT). Six months after auto-PBSCT, she developed dyspnea on exertion. Her chest X-ray findings were normal (Fig. 1a). The laboratory data revealed increased serum levels of LDH (723 IU/l) and soluble interleukin-2 receptor (3,945 U/ml). A recurrence of follicular lymphoma was suspected, and a whole-body FDG-PET was performed. FDG-PET images showed patchy increased FDG uptake in both lungs (Fig. 1b). An elevated level of β-D glucan of 2,645 pg/ml and KL-6 of 814 U/ml suggested Pneumocystis jiroveci pneumonia (PCP). Computed tomography (CT) scanning revealed patchy interstitial infiltrates in both lungs (Fig. 1c). Bronchoscopy with transbronchial lung biopsies was performed. Bronchoscopy revealed normal airways, and the biopsies demonstrated nonspecific findings. Microscopy for Pneumocystis was negative but a PCR analysis of bronchoalveolar lavage fluid revealed the P. jiroveci DNA to be positive. She was therefore administered with sulfamethoxazole-trimethoprim (ST) and prednisolone and thereafter the symptoms clinically improved. FDG-PET images after ST treatment of PCP showed complete resolution of the abnormal uptake in both lungs (Fig. 1d). A gallium scan is known to demonstrate changes resulting from Pneumosystis pneumonia even before chest X-ray changes occur [1]. The use of FDG-PET imaging has been documented in human immunodeficiency virus disease [2–4] and in infectious diseases [5]. FDG-PET may therefore also play a role in the early diagnosis of P. jiroveci pneumonia in immunocompromised patients with hematological malignancies.

Cryotherapy for the prevention of high-dose melphalan-induced oral mucositis.

High-dose melphalan (X140mg/m) alone or in combination with other chemotherapeutic agents or total body irradiation has been frequently used as conditioning for autologous or allogeneic hematopoietic stem cell transplantation (HSCT). Severe mucositis, however, remains as one of the major complications of high-dose melphalan. We read with great interest the recent article by Lilleby et al., in which they reported the results of a prospective, randomized study of cryotherapy for the prevention of high-dose melphalan (200mg/m)-induced oral mucositits in patients undergoing autologous peripheral blood stem cell transplantation. They showed that oral cryotherapy contributes significantly to a decrease in the incidence and duration of grades 3–4 oral mucositis, as do the uses of narcotics and total parenteral nutrition. In their study, patients were instructed to continue cryotherapy for 7 h (30min before, 30min during and 6 h after the infusion of melphalan), but compliance with the cryotherapy was not universal owing to complaint(s) regarding the cold. In addition, the authors could not describe the exact mean or median duration of cryotherapy performed because of missing data. We have previously reported the efficacy of oral cryotherapy in the prevention of high-dose melphalan (140mg/m)-induced oral mucositis in patients undergoing allogeneic HSCT. In the present study, 18 patients underwent cryotherapy for 120min (15min before, 15min during and for 90min after the infusion of melphalan), and only two patients (11.1%) developed grades 2–3 oral mucositis. The incidence was significantly lower than that of historical group (85.7%; P1⁄4 0.001). This cryotherapy was well-tolerated, although 39% of the patients complained of coldness or chills. We have recently attempted to shorten the duration of cryotherapy to 60min (15min before, 15min during and for 30min after the infusion of melphalan), and have succeeded in reducing the unpleasant symptoms associated with cryotherapy without increasing the incidence and severity of oral mucositis. In our studies, the duration of cryotherapy was determined based on the pharmacokinetics of high-dose melphalan. A high dose of melphalan shows a biphasic plasma half-life (t1/2); a distribution phase t1/2, 6–16min and an elimination phase t1/2, 40–83min (Gouyete et al., 7 and an internal report of GlaxoSmithKein Inc.). We hypothesized that a higher concentration of melphalan in the distribution phase would play a more important role in causing oral mucositits, and therefore set a shorter duration of cryotherapy than that of Lilleby’s study. The results of our latest study confirm that cryotherapy during the distribution phase is as effective as cryotherapy of longer duration. Two previous studies demonstrating the efficacy of cryotherapy (during and 5 or 30min after melphalan infusion) for preventing melphalaninduced oral mucositits also reinforce our results. Because a variety of differences do exist between the report of Lilleby et al. and our two reports, including the dose of melphalan and stem cell sources, it is difficult to draw firm conclusions by simply comparing the results. Nevertheless, we think that the pharmacokinetics of highdose melphalan and the results of our studies strongly suggest that 6 h of oral cryotherapy after the infusion of melphalan for the prevention of oral mucositis seems excessive, and additional study should attempt to determine the optimal duration of cryotherapy.

PET-negative pulmonary intravascular large B cell lymphoma diagnosed by a random transbronchial lung biopsy.

Dear Editor, An 84-year-old male consulted our hospital because of thrombocytopenia (platelets, 9.7×10/μl) and elevated serum lactate dehydrogenase (LDH, 641 IU/l) in October 2009. An infection, collagen disease, or malignant lymphoma was suspected, but microbiological examinations were negative, and the evaluation for autoimmune disease was unremarkable. Bone marrow aspiration and biopsy provided no evidence of a hematological malignancy. Neither a computed tomography scan nor chest Xrays detected any specific findings. The elevation of the soluble interleukin-2 receptor (2,238 U/ml) suggested the possibility of malignant lymphoma, but neither hepatosplenomegaly nor lymphadenopathy was found. Intravascular large B cell lymphoma (IVLBCL) was suspected, but a random skin biopsy showed no specific findings. In December 2009, he was admitted to our hospital because of progressive dyspnea and hypoxemia. His serum LDH was elevated at 1,120 IU/l. Arterial blood gasses revealed hypoxemia (53.3 mmHg) and hypocapnia (34.7 mmHg). The alveolo-arterial difference of oxygen partial pressure was markedly increased (53.1 mmHg). Chest perfusion scintigraphy was performed on suspicion of pulmonary artery thromboembolism, but no perfusion defect was found. A fluorodeoxyglucose positron emission tomography (FDG-PET) scan showed nonspecific findings except for mild FDG uptake (SUV max of 3.0) in the right hilar lymph node, but a fusion CT scan demonstrated no lymph node enlargement adjacent to this uptake (Fig. 1). Although there was no abnormal accumulation of FDG in bilateral lung fields, we strongly suspected pulmonary IVLBCL because of his clinical symptoms and the evidence of hypoxemia. A random transbronchial lung biopsy (TBLB) was performed, and the pathological analysis showed massive proliferation of large tumor cells in the lumina of the small vessels (Fig. 2a). The intravascular tumor cells were positive for CD20 (L26) (Fig. 2b) and CD79a, and they were negative for CD3. Based on these results, pulmonary IVLBCL was diagnosed. Combined chemotherapy consisting of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisolone (R-CHOP) was started immediately after the definitive diagnosis of IVLBCL. His clinical symptoms and laboratory findings were dramatically improved. He received a total of eight courses of RCHOP, and complete remission (CR) was achieved. He still remains in CR 15 months after treatment. IVLBCL is a rare lymphoma characterized by the presence of large tumor cells within the blood vessels [1]. It has been considered that IVLBCL is a highly malignant disease with a poor prognosis [2]. The disease T. Nakazato (*) :Y. Sanada :A. Mihara : C. Ito :Y. Aisa Department of Hematology, Yokohama Municipal Citizen’s Hospital, 56 Okazawa-cho, Hodogaya-ku, Yokohama 240-8555, Japan e-mail: n-tomo@eurus.dti.ne.jp

Total body irradiation and granulocyte colony-stimulating factor-combined high-dose cytarabine as a conditioning regimen in allogeneic hematopoietic stem cell transplantation for advanced myelodysplastic syndrome: a single-institute experience

In this study, we retrospectively evaluated the efficacy and safety of total body irradiation (TBI) and granulocyte colony-stimulating factor (G-CSF)-combined high-dose cytarabine as a conditioning regimen for allogeneic hematopoietic stem cell transplantation (HSCT) in patients with advanced myelodysplastic syndrome (MDS). We evaluated 22 patients with advanced MDS, including refractory anemia with excess blasts (RAEB; n=10), RAEB in transformation (n=2), acute myelogenous leukemia transformed from MDS (n=6) and chronic myelomonocytic leukemia (n=4). The conditioning regimen consisted of 12 Gy of TBI and high-dose cytarabine (3 g/m2) every 12 h for 4 days, and the cytarabine was combined with continuous administration of G-CSF. The stem cell sources were bone marrow or peripheral blood stem cells from human leukocyte antigen (HLA)-identical siblings (n=12) and bone marrow from HLA serologically matched unrelated donors (n=10). Three patients experienced disease relapse, two of whom died of disease progression. Of 22 patients, 16 are currently alive and disease-free. The 5-year estimated overall survival, disease-free survival, relapse and non-relapse mortality rates are 76.7, 72.2, 16.6 and 14.1%, respectively. These results suggest that G-CSF-combined high-dose cytarabine could be a promising component of the conditioning regimen of allogeneic HSCT for advanced MDS, providing a low incidence of both relapse and treatment-related mortality.

Immune-mediated motor polyneuropathy after hematopoietic stem cell transplantation.

The peripheral neuropathies that develop after hematopoietic stem cell transplantation (HSCT) are very heterogeneous.1 Immune-mediated motor polyneuropathies including Guillain–Barre syndrome (GBS) and chronic inflammatory demyelinating polyneuropathy (CIDP) are rare but serious complications of HSCT, because they are characterized by potentially life-threatening motor deficits.1 Although both GBS and CIDP share many features, including flaccid paralysis, elevated CSF protein levels and electromyographic findings, they are considered separate clinical entities.2 Clinically, CIDP is distinguished from GBS by its course, which consists of a gradual progression over more than 2 months.2 Since the relevant literature has been almost exclusively limited to case reports, the clinical characteristics of GBS and CIDP after HSCT have yet to be elucidated.

Lenalidomide is active for extramedullary disease in refractory multiple myeloma

Dear Editor, An 87-year-old male was diagnosed with multiple myeloma (IgG lambda, Durie and Salmon stage 3A, ISS stage 2) in January 2007. He received eight courses of chemotherapy with melphalan and prednisolone (MP) and thus maintained a partial remission. Because he became refractory to MP, he was then treated with 15 courses of high-dose dexamethasone from December 2007 to September 2010 and had another partial remission. However, he showed a progressive rise in IgG with a drop in hemoglobin. A laboratory evaluation revealed a serum IgG level of 5,364 mg/dl and hemoglobin of 7.6 g/dl, while the IgA and IgM levels were low. He was treated with one course of vincristine/ cyclophosphamide/doxorubicin/prednisolone, but there was no response. A CT scan revealed extramedullary plasmacytomas in the right chest wall and paravertebral space (Fig. 1). These abnormalities were not seen on CT scans performed 2 months before that presentation. Combination treatment with lenalidomide (10 mg orally, everyday continuously) and dexamethasone (20 mg/day, 4 days) was started. However, after 10 days, it was necessary to discontinue lenalidomide treatment because of febrile neutropenia and bacterial pneumonia. Despite the short duration of the administration of lenalidomide, a dramatic clinical improvement was achieved within 2 weeks. There was a significant reduction in the size of the palpable chest wall plasmacytoma, and his serum IgG level also decreased from 5,364 to 2,455 mg/dl. Repeat CT scans showed a marked reduction in the size of the extramedullary plasmacytomas in the right chest wall and paravertebral space (Fig. 2). Unfortunately, it was not possible to restart lenalidomide treatment because of his advanced age and poor performance status. Although he has not received any further treatment for his myeloma, the patient was still alive without any evidence of disease progression at the 6-month follow-up examination. Extramedullary (EM) disease of multiple myeloma may be present either at diagnosis or may occur during the course of the disease. Few studies have so far systematically evaluated the incidence of EM disease in patients with multiple myeloma. A longitudinal study of EM disease in 1,003 consecutive myeloma patients showed a rising incidence of EM in the last few decades from 4% in the period from 1971 to 1993 to 12% between 2000 and 2007 [1]. This trend has been attributed to more sensitive imaging techniques and prolonged patient survival. The presence of EM disease at any time during the course of the disease was associated with a significantly shorter overall

Lenalidomide Is Effective for the Treatment of Bortezomib-Resistant Extramedullary Disease in Patients With Multiple Myeloma: Report of 2 Cases

Introduction Extramedullary (EM) disease of multiple myeloma (MM) may occur either at diagnosis or during the course of the disease. The presence of EM disease at any time in the course of disease is associated with significantly shorter overall survival and progression-free survival. There are few studies focusing on the treatment of patients with MM and EM disease. Bortezomib has been reported to be the preferred choice of treatment for MM with EM disease. Lenalidomide is a more potent immunomodulatory drug (IMiD) that has made significant impact in the management of patients with relapsed/refractory MM. However there is little information regarding the effect of lenalidomide on EM disease in patients with MM. Here we report 2 cases of MM with bortezomib-resistant EM disease that were successfully treated with lenalidomide and dexamethasone.

Sustained complete remission in an elderly patient with a blastic plasmacytoid dendritic cell neoplasm following autologous peripheral blood stem cell transplantation

Dear Editor, A 67-year-old male presented with a solitary 3-cm skin lesion on his left shoulder. The lesion comprised dark-red maculopapules without itching and pain (Fig. 1a). The patient was in a good general condition with no weight loss or systemic disorders. A skin biopsy showed diffuse dermal infiltrates composed of monomorphic medium-sized blasts with irregular nuclei and finely dispersed chromatin. The flow cytometric analysis showed that the tumor cells were positive for CD4 and CD56, and negative for CD19, CD20, CD34, CD117, cCD3, NKp46, and myeloperoxidase (MPO). Immunohistological staining showed that the tumor cells were positive for CD4 and CD56 and were also positive for CD123 (Fig. 1b). Based on these results, a diagnosis of blastic plasmacytoid dendritic cell neoplasm (BPDCN) was made. The skin lesions increased in size and then subsequently spread over the whole body. A complete blood count showed a white blood cell count of 10,800/μl with 28 % blastoid cells. The patient’s serum lactate dehydrogenase level was significantly elevated at 4930 IU/L. A bone marrow smear showed 87.5 % similar medium-sized blastoid cells (Fig. 1c). The cytochemical stainings showed that these blastoid cells were negative for MPO and for both specific and nonspecific esterases. A flow cytometric analysis of the bone marrow blastoid cells showed that they were identical to those of the skin, thus suggesting a similar clonal origin. The patient was treated with three cycles of CHOP. The skin lesions resolved, and the peripheral blasts disappeared promptly. As reported previously in BPDCN patients, while the response to initial chemotherapy usually results in CR, relapses occur rapidly. For this reason, we subsequently performed peripheral blood stem cell collection after one course of ESHAP therapy. He then received high-dose chemotherapy (MCE regimen; CY 60 mg/kg on days 7 and 6, VP16 500 mg/m on days 6 to 4, and MCNU 250 mg/m on days 3 and 2) and auto-PBSCT during the first remission. The patient has sustained a CR for 40 months after auto-PBSCT without any complications, and his general condition is good. BPDCN is a rare aggressive neoplasm that has been recognized as an independent entity in the WHO 2008 classification [1]. BPDCN is highly refractory to conventional chemotherapy, and it has a dismal overall prognosis. Although many of the patients initially respond to chemotherapy, most relapse within a year [2]. The median overall survival is only 13 months, and the Y. Sanada : T. Nakazato (*) :A. Mihara :C. Ito :Y. Aisa Department of Hematology, Yokohama Municipal Citizen’s Hospital, 56 Okazawacho, Hodogaya-ku, Yokohama 240-8555, Japan e-mail: n-tomo@eurus.dti.ne.jp

Acute renal failure caused by intravenous acyclovir for disseminated varicella zoster virus infection

Acyclovir is often used for herpes simplex virus and varicella zoster virus (VZV) infection. Although acyclovir is generally well tolerated, the drug at a high dose (greater than 1500 mg/m2/d) has ...