Akihito Yonezawa

Disseminated Mycobacterium abscessus Complex Infection Manifesting as Multiple Areas of Lymphadenitis and Skin Abscess in the Preclinical Stage of Acute Lymphocytic Leukemia.

A 37-year-old woman was admitted to a hospital due to a prolonged fever and a rash on her legs. She had systemic lymphadenitis and a skin abscess on her left leg. Pathological findings of a left leg skin biopsy revealed abscess formation with granulomatous dermatitis, Mycobacterium abscessus complex was cultured from the resected left supraclavicular lymph node, and disseminated M. abscessus complex infection was diagnosed. She was treated with combination treatment with antimicrobials and percutaneous drainage, and her clinical findings improved. Four months later, she developed acute lymphocytic leukemia. Leukemia is a risk factor for disseminated M. abscessus complex infection, even before developing leukemia.

Pharmacokinetics of nilotinib in imatinib-resistant/intolerant chronic myeloid leukemia patients on hemodialysis for chronic renal failure†

To the editor: Nilotinib is a second-generation tyrosine kinase inhibitor used to treat patients with imatinib-resistant/intolerant chronic myeloid leukemia (CML). The safety and efficacy of nilotinib are well established [1]; however, very little data is available for patients with end-stage renal disease. Here, we report successful treatment of three CML patients on maintenance hemodialysis (HD) for chronic renal failure (CRF). To evaluate the pharmacokinetics of nilotinib in patients on HD, plasma nilotinib levels were determined by high-performance liquid chromatography [2]. Patient 1: In 2008, a 46-year-old woman on maintenance HD for polycystic kidney disease was diagnosed as Philadelphia-positive CML chronic-phase and initially administrated imatinib 300-mg QD. Although plasma imatinib levels reached 1,400 ng/ml and no ABL point mutations were detected, a major molecular response (MMR) was not achieved after 2 years of imatinib treatment. She was therefore switched to nilotinib 200 mg BID. The only adverse event was grade-2 muscle pain, and a MMR was achieved 6 months after switching to nilotinib. Patient 2: In 2007, a 61-year-old man on HD for CRF was diagnosed with CML chronic-phase and was started on imatinib 200-mg QD. A complete cytogenetic response was achieved in 12 months, but he was forced to stop imatinib after developing interstitial pneumonia and gastric bleeding. He was then switched to nilotinib 200-mg BID. One month later, the nilotinib treatment had to be interrupted due to QT interval prolongation, and reduction of the dose to 200-mg QD was necessary to resolve this adverse event. Nonetheless, a MMR was achieved 8 months after switching to nilotinib. Patient 3: In 2010, a 78-year-old woman on HD for diabetic nephropathy was diagnosed with CML chronic-phase and started on imatinib 400-mg QD. After 3 months, the imatinib was discontinued due to nausea and vomiting that persisted even though she received adequate supportive care. She was then switched to nilotinib 200-mg BID. The nilotinib also caused nausea initially, but it gradually disappeared, enabling the patient to continue taking the drug without a dose reduction. A MMR was achieved 3 months after switching to nilotinib. Pharmacokinetics of Nilotinib: There were no significant differences between the plasma nilotinib concentrations before and after HD in the three patients described above (P 5 1.0000, Wilcoxon signed-rank test, Table 1). This suggests that nilotinib in plasma is not cleared by HD, nor are the pharmacokinetics of nilotinib influenced by HD. Moreover, the dose-adjusted AUCs for nilotinib in patients on HD are similar to those previously observed in a Japanese Phase I/II study [3]. Our results indicate that the pharmacokinetics of nilotinib likely do not change in patients on HD for end-stage renal disease. Thus, although we reduced the dosage of nilotinib to prevent unexpected adverse events in one of these three patients, our findings indicate that, as with imatinib [4,5], the standard dose of nilotinib can be safely administered to patients on HD with renal failure at any stage.

急性骨髄性白血病に対する化学療法中に合併した Stenotrophomonas maltophilia 肺炎による致死性肺出血

A 63-year-old man had been treated with intensive chemotherapy for acute myeloid leukemia. On the 49th hospital day, he had febrile neutropenia after the second course of induction chemotherapy. On the 53 rd hospital day, he presented with hemoptysis and developed acute respiratory failure requiring ventilator support within several hours. On the 54th hospital day, the patient died with hemorrhagic respiratory infection. Stenotrophomonas maltophilia was detected in bacterial cultures of his blood, bronchoalveolar lavage, and sputum. To our knowledge, nine cases of fatal hemorrhagic pneumonia caused by S. maltophilia have been reported in the literature. All the patients had hematological neoplasms and were severely neutropenic after one or two intensive chemotherapy regimens. They died shortly (within 3 days) after the onset of the hemorrhagic pneumonia. Management of the infection caused by S. maltophilia is hampered by high-level intrinsic resistance to multiple antibiotics and the increasing occurrence of acquired resistance to co-trimoxazole and fluoroquinolones. It would be important to keep in mind that hemorrhagic respiratory infection caused by S. maltophilia may lead to a fulminant and lethal course in severely neutropenic patients with hematological neoplasms and to recognize which antibiotic agents are more sensitive to S. maltophilia in each institution.

Global subendocardial late gadolinium enhancement on cardiac magnetic resonance imaging in severe cardiac AL amyloidosis

A 55-year-old male presented with a 6-month history of progressive dyspnea on exertion. He was admitted to our hospital with a diagnosis of congestive heart failure. Physical examination showed macroglossia, scleral icterus, and coarse crackles in the bilateral lower lung fields. Hematological tests revealed a white blood cell count of 7.60 9 10/l, hemoglobin concentration of 15.0 g/dl, and a platelet count of 128 9 10/l. Serum biochemistry showed alkaline phosphatase (ALP) 313 IU/l, total bilirubin (T-Bil) 2.4 mg/dl, blood urea nitrogen (BUN) 17.3 mg/dl, creatinine (Cr) 0.80 mg/dl, and lactate dehydrogenase (LDH) 211 U/l. Chest X-P showed cardiomegaly and bilateral pleural effusion, electrocardiogram showed remarkable low voltage in all limb leads, and echocardiography revealed severe diastolic dysfunction and moderate systolic dysfunction with thickening of both ventricles. On cardiovascular magnetic resonance (CMR), global biventricular subendocardial late gadolinium enhancement (LGE) was observed (Fig. 1). Right ventricular endomyocardial biopsy confirmed the diagnosis of cardiac amyloid lightchain (AL) amyloidosis (Fig. 2). Lambda-type Bence Jones protein was identified by both serum and urinary immunoelectrophoresis. A bone marrow aspirate detected 18 % plasma cells, which were immunophenotypically positive for CD38, CD138, and cytoplasmic lambda. The patient did not exhibit myeloma-related organ impairment, such as lytic bone lesions or hypercalcemia. Finally, he was diagnosed as AL amyloidosis. Serum NT-pro BNP and troponin T were elevated to 5500 pg/ml and 0.094 ng/ml, respectively, indicative of very severe cardiac amyloidosis. Cardiovascular magnetic resonance imaging has recently emerged as a valuable non-invasive tool for the diagnosis of cardiac amyloidosis [1]. Late gadolinium enhancement represents interstitial expansion from amyloid deposition. Global subendocardial LGE, as observed in this case, is typical in cardiac amyloidosis and can be used to distinguish amyloidosis from other types of cardiomyopathies. Abnormal LGE precedes echocardiographic left ventricular thickness, and some patients with less advanced cardiac amyloidosis show patchy focal LGE. Thus, LGE-CMR may enable early detection of cardiac amyloidosis. Cardiovascular magnetic resonance imaging is useful for prognostic evaluation of cardiac amyloidosis as well. It has been reported that abnormal findings on CMR, including LGE patterns, biventricular hypertrophy, pericardial effusion, and hypointense myocardial signal on T2-weighted images, are associated with poor prognosis [2, 3]. It is also known that serum NT-pro BNP is a very sensitive marker of heart toxicity caused by AL amyloidosis [4]. In addition, it has been shown that NT-pro BNP levels in cardiac amyloidosis are closely related to cardiac mass and the extent of LGE [5]. Accordingly, LGE-CMR may enable the prompt detection of amyloid cardiomyopathy in patients with monoclonal gammopathy, particularly when serum NT-pro BNP is elevated.

Improvement of cutaneous anaplastic large cell lymphoma by brentuximab vedotin monotherapy

©Copyright 2018 by Turkish Society of Hematology Turkish Journal of Hematology, Published by Galenos Publishing House Brentuximab vedotin (BV) is an antibody-drug conjugate composed of a CD30-directed monoclonal antibody and monomethyl auristatin E [1]. BV monotherapy showed good response rates for cases of refractory and relapsed anaplastic large cell lymphoma (ALCL), but only a few case reportsare available for cutaneous localized ALCL (cALCL). We herein report the treatment with BV of relapsed cALCL with an excellent response. An 82-year-old female with relapsed cALCL had generalized erythema accompanied by desquamation and could not extend her fingers enough (Figure 1), with no lymph node lesions. Due to the previous treatment with radiation, steroid ointment, and systemic chemotherapy, we chose BV monotherapy for her, dosing at 1.8 mg/kg every 21 days. After the third infusion, her generalized erythemaand her finger movement were improved (Figure 2). She did not have any severe adverse effects or infusion reaction except for hematologic toxicity (leukocytopenia). She has finished 6 courses of BV infusion and maintained remission of skin lesions. There are several reports that showed the effectiveness of BV treatment for cALCL [2,3], but the optimal treatment interval and cycles, and the necessity of maintenance therapy by using BV, are unclear. Further studies are needed to evaluate BV treatment in cases of cALCL.

Drug interaction between tacrolimus and nilotinib in a patient with chronic myeloid leukemia after renal transplant

Nilotinib, a BCR‐ABL tyrosine kinase inhibitor, is a known inhibitor of CYP3A4 and could increase the concentration of drugs metabolized by CYP3A4. An immunosuppressive drug for nilotinib‐treated patients following transplant should be administered with careful pharmacokinetic monitoring because of its interaction with nilotinib.

Direct hemoperfusion using polymyxin-B immobilized fiber for severe septic patients with hematological disorders: A single-center analysis

The benefit of endotoxin absorption therapy (direct hemoperfusion with polymyxin B-immobilized fiber: PMX-DHP) for severe septic patients is still controversial. There are limited data on the clinical experience and efficacy of PMX-DHP for septic patients with hematological disorders. At our institution, 16 patients with hematological diseases underwent PMX-DHP therapy for gram-negative septic shock from February 2006 to March 2012. Most of the patients had severe neutropenia (median neutrophil counts: 7/μL) due to intensive chemotherapy for their hematological diseases. After the PMX-DHP therapy, six patients recovered from the shock status (favorable group) and ten died of the sepsis (unfavorable group). We analyzed the differences between the two groups based on clinical characteristics just before PMX-DHP therapy. Regarding sequential organ failure assessment (SOFA) score, which is a scoring system to determine the degree of organ dysfunction, all patients in the favorable group scored less than 11. The sensitivity and specificity of SOFA score less than 11 for the therapeutic efficacy were 100% and 80%, respectively. Our results suggest that septic patients with hematological diseases may not be a candidate for PMX-DHP therapy when they have already developed serious organ dysfunction.