Evaluation of Medication Adherence and Pharmacokinetics of Dasatinib for Earlier Molecular Response in Japanese Patients With Newly Diagnosed Chronic Myeloid Leukemia: A Pilot Study.

BACKGROUND: Tyrosine kinase inhibitors markedly improve the survival for patients with chronic myeloid leukemia (CML). However, a decrease in adherence leads to undesired therapeutic outcomes. In this study, the relationships among adherence, pharmacokinetics, response, and adverse effects for dasatinib treatment were prospectively investigated. METHODS: This study was a prospective cohort study of patients with newly diagnosed CML at 4 general hospitals and 1 university hospital. Patients started to receive dasatinib 100 mg once daily. A Medication Event Monitoring System was used to assess medication adherence and the medication possession ratio during the 12 months. Plasma concentrations of dasatinib were measured using liquid chromatograph-tandem mass spectrometry (LC-MS/MS), and therapy responses were assessed at 3, 6, and 12 months after treatment. RESULTS: Ten patients were included. An extremely high medication adherence for dasatinib was observed; the median medication possession ratio was 99.4%. All 9 CML patients with breakpoints in the major BCR-ABL achieved major molecular response (MMR; major BCR-ABL transcript level below 0.1% on the International Scale) within 12 months, and 5 achieved MMR within 6 months. The receiver operating characteristic curve analysis revealed that the cutoff value for the dasatinib area under the concentration-time curve was 336.1 ng × h/mL (accuracy 88.9%, sensitivity 80.0%, specificity 100%, and receiver operating characteristic curve-area under the concentration-time curve 0.800) for achieving MMR within 6 months. Two patients had interrupted dasatinib treatment because of pleural effusion and diarrhea with intestinal edema, respectively. These edematous adverse events developed after plasma dasatinib Cmin surpassed 3.0 ng/mL. CONCLUSIONS: A Medication Event Monitoring System was applied for the direct evaluation of oral dasatinib adherence for the first time, and the clinical effect of dasatinib was investigated under the strict monitoring of patient adherence. Although this study had a small sample size, the plasma concentration monitoring of dasatinib is considered to be useful to predict an earlier molecular response with fewer edematous adverse events.

[Drug-induced immune hemolytic anemia caused by cefmetazole].

A 56-year-old female who was diagnosed with acute calculous cholecystitis received intravenous administration of cefmetazole (CMZ) from the day of admission; she underwent laparoscopic cholecystectomy on the 13th hospital day. She was referred to our department because of hematuria that persisted for 3 days and progressive anemia on the day after the surgery. Laboratory data showed the following results: hemoglobin (Hb) level, 6.8 g/dl; reticulocyte count, 3.4%; serum lactate dehydrogenase, 1,505 IU/l; serum creatinine, 1.1 mg/dl; and undetectable haptoglobin. The direct globulin test showed that the patient was positive for IgG. Thus, drug-induced immune hemolytic anemia (DIIHA) was considered. All drugs, including CMZ, were immediately discontinued, and steroid was administered. The signs of hemolysis began to subside 3 days after the initiation of steroid therapy, and the administration of steroid was discontinued on the 5th day of the treatment. The patient's Hb level gradually increased, and the direct globulin test showed that the patient was negative for IgG on the 21st day from the onset of hematuria. Antibodies against CMZ-coated red blood cells were observed in the serum preserved at the onset of hemolysis. DIIHA is a rare but life-threatening disease. Immediate discontinuation of any suspected drugs and the initiation of steroid therapy as necessary are important in cases wherein DIIHA is suspected.

[Relapse in the nasal cavity of a patient with extranodal NK/T-cell lymphoma initially presenting as plantar subcutaneous tumor].

A 36-year-old woman complained of a mass on the sole of her foot in February 200X. She was diagnosed with extranodal NK/T-cell lymphoma, nasal type (ENKL) by skin biopsy. Because the lesion was localized on the subcutaneous tissue of the sole, she was treated with RT/2/3DeVIC, resulting in a complete response (CR). In March of the following year, PET/CT showed significant uptake and mucosal thickening in the right nasal cavity, and a mucosal biopsy confirmed ENKL infiltration. Because the lesion was localized in the nasal cavity, she was re-treated with RT/2/3DeVIC, with a focus on local control, and she achieved a second CR. She subsequently received allogeneic hematopoietic stem cell transplantation in the hope of preventing systemic relapse. She has remained in CR for four years since the transplantation. Our case suggests that allogeneic hematopoietic stem cell transplantation to be a potentially promising approach to curative treatment for recurrent ENKL in younger patients. As nasal lesions may subsequently appear during the course of primary non-nasal ENKL, ongoing meticulous evaluation for nasal lesions is important.

[A patient with acute Philadelphia-chromosome-positive mixed phenotype leukemia developing ecthyma gangrenosum while undergoing combined imatinib mesylate chemotherapy].

A 67-year-old woman with acute Philadelphia-chromosome-positive mixed phenotype leukemia developed bilateral periorbital ecthyma gangrenousum (EG) subsequent to periorbital edema while undergoing combined imatinib mesylate (imatinib) chemotherapy. Although initial periorbital edema was considered an imatinib side effect, the lesion deteriorated rapidly with high fever in the neutropenic phase, and the woman died of septic shock. Cultures from blood and exudative fluid grew Pseudomonas aeruginosa, after which EG was diagnosed. EG is a well-recognized emergent cutaneous infection most commonly associated with Pseudomonas aeruginosa bactremia. Because some patients present with EG a few days prior to developing life-threatening septicemia, it is important that EG be diagnosed correctly. Imatinib side effects such as edema are usually tolerable, and imatinib is widely used to treat Philadelphia-chromosome-positive leukemia, particularly in those with acute lymphoblastic leukemia, and neutropenic patients undergoing imatinib therapy are expected to increase in number. Delay in initiating appropriate therapy is correlated with poor outcome, so drug side effects and EG must be carefully differentiated when skin edema with surrounding erythema is noted in neutropenic patients undergoing imatinib therapy.

Breakthrough disseminated zygomycosis induced massive gastrointestinal bleeding in a patient with acute myeloid leukemia receiving micafungin.

A 69-year-old man, who had been receiving prednisolone for 11 months for treatment of interstitial pneumonia, was diagnosed with acute myeloid leukemia. During induction therapy, he developed severe pneumonia. Although meropenem and micafungin were started, he died of circulatory failure owing to massive gastrointestinal bleeding. Autopsy specimens obtained from the stomach revealed fungal hyphae, which had invaded diffusely into submucosal vessels and caused the massive gastric bleeding. The same hyphae were also observed in both lungs. A diagnosis of disseminated zygomycosis was confirmed by its characteristic histopathological findings. Because zygomycetes are spontaneously resistant to the newer antifungal agents, such as voriconazole or micafungin, it seems likely that the prevalence of zygomycosis as a breakthrough infection may increase in the future. Zygomycosis is a rare, but life-threatening, deep fungal infection that appears in immunologically or metabolically compromised hosts. Its manifestations are clinically similar to those of invasive aspergillosis. In addition to the well-established epidemiology of zygomycosis, this case suggests the following new characteristics. (1) Although the gastrointestinal manifestation of zygomycosis is relatively rare, it is observed more frequently than invasive aspergillosis. (2) Gastrointestinal zygomycosis occasionally leads to the development of necrotic ulcers and may induce hemorrhagic shock.(3) We should be cautious of an occurrence of breakthrough zygomycosis when we use echinocandins for patients with known risk factors, especially steroid use and neutropenia. (4) For patients who are receiving broad-spectrum antibiotics and echinocandins, who are negative for culture studies and aspergillus antigen, and who present with unresolved fever, it is important to make a prompt clinical diagnosis of zygomycosis.

[Development of syndrome of inappropriate secretion of ADH and reversible posterior leukoencephalopathy during initial rituximab-CHOP therapy in a patient with diffuse large B-cell lymphoma].

A 61-year-old woman presented with a right mandibular tumor and was diagnosed with DLBCL clinical stage IIIA from the biopsy results of the tumor and CT examination. An initial rituximab was administrated a week after the first CHOP treatment. During the infusion of rituximab, she exhibited disorientation, seizure, and consciousness disturbance. Hyponatremia due to SIADH and hypertension were coincidentally observed. MRI revealed T2 and FLAIR hyperintense signals involving the bilateral occipital, parietal, frontal lobes and the cerebellum that were consistent with reversible posterior leukoencephalopathy syndrome (RPLS). Her consciousness level recovered in parallel with corrections in serum sodium levels and blood pressure. Although she presented with transient cortical blindness, all neurological abnormalities disappeared 40 hours after the occurrence of seizure. She received a further 7 cycles of CHOP followed by 7 cycles of rituximab treatment with no relapse of RPLS. After irradiation for a residual abdominal tumor, she has maintained complete remission for 2 years. Although RPLS is a rare complication of rituximab-CHOP chemotherapy, it should be considered in patients with DLBCL who present with acute neurological deterioration.

[A case of gastric stenosis due to primary gastric malignant lymphoma during administration of R-CHOP].

A 59-year-old man presented to his general practitioner(GP)complaining of gastric discomfort. Endoscopy revealed an irregular ulcerative region from the gastric lower body to the pylorus. The GP sent the patient to our hospital. With a diagnosis of diffuse large B-cell lymphoma(DLBCL)based on biopsy findings, the patient was treated with R-CHOP chemotherapy. After two courses of this regimen, the patient had vomiting on several occasions. A computed tomography(CT)examination and endoscopy showed that the tumor decreased, but a tight stenosis was located at the pylorus. Because he had trouble continuing chemotherapy, a gastrojejunal bypass operation was performed. The patient did not have vomiting and was able to take meals. After this chemotherapy, CT examination and biopsy findings confirmed that the DLBCL and lymph node metastases had disappeared. Gastrojejunal bypass is expected to be an effective method for treating gastric stenosis during the chemotherapy of DLBCL.

[Aggressive NK-cell leukemia with sustained relapse-free survival after allogeneic peripheral blood stem cell transplantation].

A 46-year-old Japanese man was admitted to our hospital because of prolonged fever. Laboratory examination demonstrated leukopenia, thrombocytopenia, marked liver dysfunction, and elevation of serum ferritin. A bone marrow examination showed several hemophagocytic macrophages, and a diagnosis of hemophagocytic syndrome was made. He was treated using HLH-94 protocol, and his clinical symptoms and laboratory data were rapidly improved. After 5 weeks, fever and liver dysfunction reappeared. A repeat bone marrow examination demonstrated that 28.4% of marrow nucleated cells were atypical lymphocytes, which were positive for CD2, CD7, CD16, CD56, and HLA-DR. Clonality of these proliferating NK cells was confirmed by an analysis of EB virus terminal repeat sequence and cytogenetic analysis, and final diagnosis of aggressive NK-cell leukemia was made. After induction chemotherapy consisting of dexamethasone, etoposide, ifosfamide, and L-asparaginase, the patient achieved partial remission. He received allogeneic peripheral blood stem cell transplantation from his one locus mismatched son, and is alive with no evidence of disease 20 months after transplantation.

[A patient with acute Philadelphia-chromosome-positive mixed phenotype leukemia developing ecthyma gangrenosum while undergoing combined imatinib mesylate chemotherapy].

A 67-year-old woman with acute Philadelphia-chromosome-positive mixed phenotype leukemia developed bilateral periorbital ecthyma gangrenousum (EG) subsequent to periorbital edema while undergoing combined imatinib mesylate (imatinib) chemotherapy. Although initial periorbital edema was considered an imatinib side effect, the lesion deteriorated rapidly with high fever in the neutropenic phase, and the woman died of septic shock. Cultures from blood and exudative fluid grew Pseudomonas aeruginosa, after which EG was diagnosed. EG is a well-recognized emergent cutaneous infection most commonly associated with Pseudomonas aeruginosa bactremia. Because some patients present with EG a few days prior to developing life-threatening septicemia, it is important that EG be diagnosed correctly. Imatinib side effects such as edema are usually tolerable, and imatinib is widely used to treat Philadelphia-chromosome-positive leukemia, particularly in those with acute lymphoblastic leukemia, and neutropenic patients undergoing imatinib therapy are expected to increase in number. Delay in initiating appropriate therapy is correlated with poor outcome, so drug side effects and EG must be carefully differentiated when skin edema with surrounding erythema is noted in neutropenic patients undergoing imatinib therapy.

[Marked hyponatremia with consciousness disturbance probably caused by linezolid in a patient with acute myeloid leukemia].

We report the case of a 75-year-old man with acute myeloid leukemia who developed hyponatremia after linezolid administration. Because induction therapy did not achieve complete remission for this man, we initiated re-induction therapy with enocitabin and daunomycin. Seven days after chemotherapy, the patient experienced a catheter-related blood stream infection (CRBSI) due to methicilin resistant staphylococcus aureus (MRSA). When treatment with albekacin and fosfomycin was in effective, linezolid was administrated intravenously and he became afebrile. On day 8 after linezolid administration, however, he reported general fatigue and slight consciousness disturbance. His serum sodium concentration was 119 mEq/L and his urinary sodium excretion rose to 143 mEq/day, although intravenous sodium intake was 98 mEq/day. Because of the sufficiency of urine volume and weight loss, we surmise that inappropriate ADH secretion (SIADH) syndrome was unlikely. We diagnosed renal salt wasting syndrome (RSWS) based on calculation of the amount of sodium intake and the amount of sodium excreted from the kidneys. After linezolid was discontinued and aggressive treatment with sodium supplement begun, his consciousness cleared as his low serum sodium level rose. This is, to the best of our knowledge, the first case reported on the development of RSWS after linezolid treatment. Although the process remains unclear, our case suggests that linezolid may induce RSWS after intensive chemotherapy.

[Acute myeloid leukemia invasion of the central nervous system, detected only along the Virchow Robin space].

A 66year-old man with sustained fever was diagnosed as having acute myeloid leukemia with multilineage dysplasia. Induction therapy with etoposide and AraC was initiated, but was ineffective. Although fever had persisted for more than a few days, there was no evidence of any infection on radiological examination or culture studies. The patient was disorientated and demonstrated personality change. After a severe convulsive seizure, the patient died. Autopsy findings showed that the leukemic cells had permeated the Virchow Robin space, but without a mass lesion in the cerebral parenchyma. He was diagnosed as having had central nervous system leukemia (CNSL) that provoked sustained fever, consciousness disturbance and convulsive seizure. These findings suggested that the Virchow Robin space plays a particular role in the development of CNSL. Even with repeated cerebrospinal fluid examinations and radiological tests, we were unable to correctly diagnose CNSL before death, which may indicate the intractability of diagnosing CNSL spread along the Virchow Robin space. This case provides useful information about the pathophysiology and diagnosis of CNSL.

[Prolonged survival in a patient with human herpesvirus-8-negative primary effusion lymphoma after combination chemotherapy with rituximab].

Primary effusion lymphoma (PEL) is a unique clinicopathological entity usually associated with human herpesvirus-8 (HHV-8) infection. It occurs almost exclusively in human immunodeficiency virus (HIV) -infected individuals. We presented a rare case of HIV-negative PEL in an elderly HHV-8-negative patient who developed cardiac tamponade due to pericardial effusion. The patient was treated with rituximab and cyclophosphamide, doxorubicin, vincristine and prednisolone (CHOP). This disease generally has a poor prognosis; however, this patient achieved complete remission and remains without signs of disease 30 months after the last treatment. Because most HIV-negative and HHV-8- negative PEL cases show pan-B-cell markers, there is considerable usage of rituximab, though its optimal usage for PEL is unclear. To the best of our knowledge, there have been five reported cases where rituximab treatment has been used against HIV-negative and HHV-8-negative PEL. The clinical courses of these cases were relatively good without specific adverse effects. HIV-negative and HHV-8-negative PEL appears to be a reasonably new clinicopathological entity. While further investigation will of course be needed, the use of rituximab is worth considering for treatment of such patients.

Selective blast cell reduction in elderly patients with acute myeloid leukemia secondary to myelodysplastic syndrome treated with methylprednisolone.

The management of elderly patients with acute myeloid leukemia (AML) and a poor performance status is challenging. An 89-year-old man with AML secondary to myelodysplastic syndrome (MDS) and a poor performance status (4) underwent treatment with methylprednisolone (mPSL) (125 mg/body), which resulted in a remarkable reduction of blast cells in the peripheral blood. Neutrophil counts were maintained or increased. Although the suppression was of short duration, mPSL was useful for disease control because it selectively reduced blast counts while maintaining the patient's performance status. In vivo and in vitro findings suggested that mPSL had direct inhibitory actions on the survival of blast cells. On the basis of this experience, we gave the same mPSL dose to other elderly patients with MDS/AML (n=5) or AML-M4 (n=1) who had a poor performance status (3 or higher) and appeared unable to tolerate standard cytotoxic chemotherapies. Selective and significant blast cell reduction was observed in 4 of the 5 patients with MDS/AML, whereas no effects were seen in the AML patient. Although our experience is limited, these findings may provide a clue to understanding the mechanisms regulating the survival of blast cells of MDS/AML and indicate that mPSL may provide a benefit to a subset of these patients.

[Multiple myeloma accompanying splenic amyloidosis and overwhelming pneumococcemia].

We present the case of an 84-year-old woman with multiple myeloma who developed overwhelming pneumococcemia. Significant pathologic findings of amyloidosis were confirmed in the spleen, adrenal glands, kidneys, liver and bone marrow on autopsy. In particular, the spleen was almost replaced by diffuse linear deposition of amyloid, and residual lymphoid tissue was scant. There is a well-established association between asplenia and a predisposition to fulmination, frequently with fatal bacterial infection. In this case, functional hyposplenism as a result of amyloid replacement of the spleen led to overwhelming pneumococcemia. Functional hyposplenism due to amyloidosis predisposes patients to septicemia. As bacterial infections are a common complication in patients with multiple myeloma, it is important to know whether they have accompanying splenic amyloidosis. If there are findings of hyposplenism, it may be necessary to establish strategies to prevent fatal infection. Thought needs to be given to providing detailed education, and prophylactic or stand-by antibiotics for such patients.

Diffuse Large B-cell Lymphoma during Corticosteroid Therapy for TAFRO Syndrome.

Thrombocytopenia, anasarca, myelofibrosis, renal dysfunction and organomegaly (TAFRO) syndrome is a variant of Castleman's disease recently identified in Japan. A 73-year-old man was diagnosed with TAFRO syndrome according to clinical findings, and his symptoms improved after corticosteroid therapy. Ten months later, lymphadenopathy worsened during tapering of corticosteroids. Histological findings of abdominal lymph nodes showed diffuse large B-cell lymphoma. After 6 cycles of R-CHOP therapy, he has remained in sustained complete remission. This is a rare case of the development of malignant lymphoma during the treatment of TAFRO syndrome, which suggests an association between diffuse large B-cell lymphoma and TAFRO syndrome.

Assessment of fatty acid metabolism in taxan-induced myocardial damage with iodine-123 BMIPP SPECT: comparative study with myocardial perfusion, left ventricular function, and histopathological findings.

UNLABELLED: We investigated myocardial fatty acid metabolism in taxan-induced myocardial damage in patients with advanced lung cancer. PATIENTS AND METHODS: Twenty-five patients with non-small-cell lung cancer were treated with taxan combined with carboplatin intravenously for three cycles. Myocardial SPECT imaging using 99mTc-methoxyisobutyl isonitrile (MIBI) and 123I-15-(p-iodophenyl)-3-(R,S)-methylpentadecanoic acid (BMIPP) was performed successively before and after chemotherapy. Regional uptake scores of BMIPP and MIBI were visually assessed and total uptake scores and the number of abnormal segments were calculated. Left ventricular ejection fraction (LVEF) was obtained by first-pass radionuclide angiocardiography using MIBI. Postmortem pathological examination was performed in 5 patients. RESULTS: Total BMIPP uptake scores after chemotherapy were significantly lower than those before chemotherapy (23.4 +/- 3.4 vs. 26.6 +/- 0.8; p < 0.001). Mean LVEF showed a significant decrease after chemotherapy. Of the 25 patients, 4 exhibited a decrease in LVEF of more than 10%, 1 had a decrease in LVEF to below 50%, and 1 developed congestive heart failure. These 6 patients had significant decreases in total BMIPP uptake scores and increases in the number of abnormal segments as compared with the other 19 patients. Histopathological examination of myocardial tissue showed interstitial edema and disarrayed myocardial cells. CONCLUSION: Taxan impairs myocardial fatty acid metabolism. 123I-BMIPP myocardial SPECT is useful for evaluating the cardiotoxicity induced by taxan.

A potential activity of valproic acid in the stimulation of interleukin-3-mediated megakaryopoiesis and erythropoiesis.

OBJECTIVE: Although the anticancer activities of histone deacetylase (HDAC) inhibitors have been studied, a role for HDAC in normal hematopoiesis has not been clearly defined. Previous studies have shown that the potent HDAC inhibitor FK228 stimulates interleukin (IL)-3-mediated erythropoiesis. Here, we examined whether the widely used valproic acid (VPA) affects megakaryopoiesis as well as erythropoiesis. MATERIALS AND METHODS: CD34(+) cells were incubated in serum-free or serum-containing cultures with cytokines, with or without VPA. RESULTS: In the serum-free cultures containing IL-3+stem cell factor (SCF), VPA significantly increased generation of CD61(+)GPA(-) megakaryocytic and a CD61(+)GPA(+) mixture of megakaryocytic and erythroid precursors from CD34(+) hematopoietic precursors at a pharmacological concentration (100 microg/mL). The increase in generation of megakaryocytic and erythroid precursors by VPA was confirmed by replating cultured cells with thrombopoietin+SCF and erythropoietin+SCF, respectively. VPA was as potent as FK228. In cultures with granulocyte-macrophage colony-stimulating factor+SCF, where CD61(-)GPA(+) erythroid precursors were mostly developed, VPA mainly enhanced the generation of CD61(-)GPA(+) erythroid precursors. In serum-containing cultures, only low numbers of CD61(+) or GPA(+) cells were developed with IL-3+SCF. Nevertheless, a substantial number of these cells were generated with VPA. Furthermore, these stimulating effects of VPA were observed by incubating CD34(+) cells from patients with myelodysplastic syndrome. Quantitative reverse transcription polymerase chain reaction showed that VPA enhanced GATA-2, but not GATA-1, messenger RNA expression with IL-3+SCF. CONCLUSIONS: These results indicate a novel role for VPA in enhancing the potential of IL-3 to stimulate megakaryopoiesis as well as erythropoiesis and suggest a new therapeutic approach of epigenetic therapy for hematological disease.