Factors Associated with Dose Modification of Lenalidomide Plus Dexamethasone Therapy in Multiple Myeloma.

Long-term combination treatment with lenalidomide and low-dose dexamethasone is important to achieve a curative effect in patients with multiple myeloma (MM). In this study, the plasma concentration of lenalidomide was measured at 3 h after oral administration, when the drug is in the elimination phase and can be easily measured in outpatients, to identify factors that may lead to the discontinuation of this combination therapy. Patients were assigned to continuation or discontinuation of therapy groups, and the baseline characteristics of patients, lenalidomide concentration, and concentration/dose (C/D) ratios reflecting oral clearance were compared between the two groups. The efficacy and severity of adverse events were also compared. The results showed that patients who discontinued or modified treatment had low plasma concentrations of lenalidomide and C/D ratios, indicating high oral clearance of lenalidomide. The estimated creatinine clearance rate was negatively correlated with the C/D ratio. The plasma concentrations of lenalidomide were independent from kidney function and differed significantly among patients. Taken together, the results indicate that low plasma concentrations of lenalidomide and low C/D ratios may lead to discontinuation of combination therapy in patients with MM. This suggests that early measurement of lenalidomide plasma continuation would help to prevent discontinuation of therapy or a delay in modifying the dose of lenalidomide.

A retrospective analysis of treatment outcomes in 45 patients with cardiac light-chain amyloidosis: a single-center experience in Japan.

The prognosis of cardiac light-chain (AL) amyloidosis is considered to be very poor. We studied the treatment efficacy and outcomes by retrospectively analyzing the clinical results of 45 patients with cardiac AL amyloidosis treated at our hospital between September 2008 and March 2016. The group of patients analyzed included 29 males and 16 females with a median age of 68 years. Their baseline median NT-proBNP, cTnT, and dFLC were 3167 pg/ml, 0.080 ng/ml, and 286.17 mg/l, respectively. Twenty-eight patients were in Cardiac Stage (CS) III and 17 patients were in Revised Prognostic Stage (RPS) IV. At the median follow-up of 10 months, the median overall survival (OS) was 16 months and 3-year OS was 35.9%. The patients in CS III showed significantly poorer survival rate than those in CS I or II (3-year OS: 12.2% vs. 65.8%, p = 0.0115) and the patients in RPS IV showed significantly poorer survival rate than those in RPS I, II, or III (3-year OS: 11.0% vs. 53.3%, p = 0.000914). Regardless of the therapeutic approaches, patients who achieved hematological CR or cardiac organ response demonstrated significantly improved prognosis. Therefore, achievement of hematological and organ responses is important in the treatment of cardiac AL amyloidosis.

[Spontaneous regression of primary gastric EBV-positive diffuse large B-cell lymphoma].

Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (DLBCL) in the elderly was revised from the category EBV-positive DLBCL not otherwise specified in WHO 2017. The prognosis of this lymphoma is very poor. We report a case of an 82-year-old woman diagnosed with gastric EBV-positive DLBCL (WHO 2008). Gastroduodenoscopy revealed multiple ulcers and fold thickening. She was followed-up without any treatment because of her old age. Repeat endoscopy one year and eight months later revealed a single ulcer with no lymphoma cells found in a biopsy specimen. Two years later, the lesion had spontaneously disappeared.

[Successful treatment of relapse/refractory multiple myeloma with carfilzomib, lenalidomide, and dexamethasone combination therapy following allogeneic bone marrow transplantation].

A 50-year-old male was diagnosed with multiple myeloma (MM) and treated by high-dose melphalan followed by autologous stem cell transplantation in April 2014. However, he relapsed and received non-myeloablative bone marrow transplantation from an unrelated HLA-matched donor (UR-BMT) in July 2016. After 100 days of UR-BMT, the disease remained stable disease and the patient was treated with carfilzomib, lenalidomide, and dexamethaonse (KRd) therapy. After 10 cycles of KRd, he obtained stringent complete response without exacerbation of graft-versus-host disease. We concluded that KRd after allogeneic stem cell transplantation is one of the useful treatment regimens for relapsed refractory MM.

[Latent essential thrombocythemia becoming perceptible after splenectomy].

A 47-year-old male was admitted to our hospital because of left hypochondrium part pain and was diagnosed with splenomegaly with splenic infarctions in May 2016. His complete blood cell count was almost within normal limits, and a bone marrow biopsy revealed normal cellularity with no fibrosis. In addition, no abnormal uptake was noted on FDG PET/CT. In August 2016, he underwent splenectomy for splenomegaly. The histological examination revealed fibrotic stenosis of the blood vessels in the spleen. After splenectomy, his platelet count elevated and remained at >1,000×109/l 3 months later. Finally, he was diagnosed with latent essential thrombocythemia (ET) because the JAK2V617F mutation was positive. Accordingly, oral hydroxyurea was initiated. Thrombosis could be a complication in myeloproliferative neoplasms (MPN). In our case, ET was masked, perhaps, because of hypersplenism and splenomegaly because of splenic vein thrombosis. Hence, examination of the JAK2V617F mutation in patients with splanchnic vein thrombosis is recommended because of the possibility of latent MPN.

Immunosuppressive therapy with rabbit antithymocyte globulin therapy for acquired aplastic anemia: a multi-institutional retrospective study in Japanese adult patients.

We retrospectively analyzed efficacy and safety of therapy with rabbit antithymocyte globulin (rATG) in combination with cyclosporine A (CsA) in 30 Japanese adult patients with acquired aplastic anemia (AA) in the Kyoto Clinical Hematology Study Group. The median observation period was 31 months and the median age of the patients was 54 years. The objective response rates (ORRs) to rATG plus CsA increased over time until 18 months after the start of treatment; the rate of achievement of better than partial response at 18 months was 66.7%. The 2-year overall survival (OS) rate was 79% in all patients. In eight patients aged ≥ 75 years old, the ORR was 62.5% and the 2-year OS rate of 50% was not significantly inferior to that in patients aged ≤ 74 years old. The overall mortality rate was 16.7% in our cohort, while the mortality rate in patients aged ≥ 75 years old was 37.5%, which was higher than that in patients aged ≤ 74 years old (9.1%), although the difference was not statistically significant. Collectively, rATG combined with CsA is an effective and feasible treatment for AA, while patients should be appropriately selected.

[Agranulocytosis during therapy of chronic myeloid leukemia lymphoid blast crisis with dasatinib].

A 61-year-old female was diagnosed with a lymphoid crisis of chronic myeloid leukemia (CML) in February 201X and started chemotherapy combined with dasatinib (DAS). After 1 month of initiating second consolidation therapy, the neutrophils decreased to 1%, bone marrow examination revealed large granular lymphocytes (LGL) at 13%, and complete cytogenetic remission was attained (CCyR). Suspecting DAS-induced agranulocytosis, DAS was discontinued. After 2 weeks, LGL disappeared and neutrophils recovered. In this case, CCyR was attained for the first time when LGL increased. We considered that the expansion of LGL correlated with the clinical efficacy, and agranulocytosis was an off-target effect of DAS.

[Possible contribution of disseminated Mycobacterium shigaense infection to development of splenic marginal zone lymphoma].

A 73-year-old male who underwent splenectomy was diagnosed with splenic non-caseating granuloma in May 201X, and sarcoidosis was disregarded from the differential diagnosis. Owing to the persisting inflammation, the patient was carefully followed up with no treatment. Four months post splenectomy, the patient was hospitalized due to progressive dyspnea. Chest computed tomography revealed an encapsulated pleural effusion and lymphocytic infiltration in the left lower lung, with subclavian and mediastinal lymphadenopathy. Although the patient was treated with antibiotics, his condition showed no improvement; therefore, prednisolone 40 mg was administered, resulting in lung lesion improvement. A re-examination of the tissue obtained from the previously removed spleen revealed splenic marginal zone lymphoma (SMZL), a specific low-grade, small B-cell lymphoma. As a result, the patient was treated with rituximab combined with chemotherapy. During the fifth course of the chemotherapy, a subcutaneous abscess appeared in the cervical region, and Mycobacterium shigaense was isolated from the pus discharge, suggesting that the splenic granulomatous lesion formed due to M.shigaense, and dissemination of the Mycobacterium infection occurred following splenectomy and chemotherapy, when the patient was immunosuppressed. Overall, we consider that SMZL developed because of chronic inflammation resulting from a nontuberculous mycobacterial infection.

Pharmacokinetic Interaction Between Tacrolimus and Fentanyl in Patients Receiving Allogeneic Hematopoietic Stem Cell Transplantation.

BACKGROUND Tacrolimus and fentanyl are well-known cytochrome P450 (CYP) 3A4 substrates with a narrow therapeutic range. However, the pharmacokinetic interaction between tacrolimus and fentanyl is unclear. The aim of this study was to determine whether drug interaction exists between tacrolimus and fentanyl. MATERIAL AND METHODS A retrospective study was performed in 6 patients who had received allogeneic hematopoietic stem cell transplantation between April 2010 and March 2015. The patients received continuous intravenous infusion of fentanyl with concomitant use of tacrolimus, and the blood concentrations of tacrolimus were evaluated using fluorescence polarization immunoassay. RESULTS The clearance (CL) of tacrolimus decreased significantly from 1.28 to 0.68 mL/min/kg with concomitant use of fentanyl. The CL changed with time and dose of fentanyl administration. In addition, the CL of tacrolimus was reverted by stopping fentanyl infusion. Horn's drug interaction probability scale indicated a probable category or possible category, suggesting a drug interaction between tacrolimus and fentanyl. No patient showed a difference in hepatic or renal function before and after fentanyl administration. No additional administration of other CYP3A4 inhibitors was observed, suggesting that the drug interaction was mediated by CYP3A4. CONCLUSIONS The influence of fentanyl on the pharmacokinetics of tacrolimus was demonstrated to be of clinical importance. It is proposed that the dose of tacrolimus be reduced by 40% when used in combination with fentanyl.

Combination of lenalidomide and low-dose dexamethasone therapy promotes the anticoagulant activity of warfarin in patients with immunoglobulin light-chain amyloidosis.

The present study aimed to evaluate the drug interactions between warfarin and combination chemotherapy with lenalidomide and low-dose dexamethasone in immunoglobulin light-chain (AL) amyloidosis patients with unstable international normalized ratios (INR). The changes to INR values over time in 3 AL amyloidosis patients treated with warfarin and a combination of lenalidomide and low-dose dexamethasone between March 2011 and February 2015 were analyzed retrospectively. The mean INR value was 1.52 prior to the combination chemotherapy, and the value increased 1.7-fold during treatment. The median time to reach maximum values was 17 days. Horn's drug Interaction Probability Scale indicated a possible interaction between lenalidomide and warfarin. These patients exhibited no marked alterations in hepatic function or serum albumin concentrations prior to and following combination chemotherapy and no additional administration of CYP2C9 inhibitors or vitamin K supplements was conducted. In addition, no patient experienced chemotherapy-induced nausea or appetite loss. These findings suggest that the total clearance or protein binding of warfarin remained unchanged. Therefore, the combination of warfarin and lenalidomide may cause a pharmacodynamic interaction, more likely by inhibiting the production of interleukin-6. In conclusion, clinically important interactions between warfarin and lenalidomide and low-dose dexamethasone therapy were observed in AL amyloidosis patients, where INR values signi ficantly increased. Therefore, close and regular monitoring of patients during the course of treatment is important, and the dose of warfarin should be reduced if required.

CEA-producing multiple myeloma with meningeal invasion during relapse.

Here we describe the case of a 62-year-old woman diagnosed with multiple myeloma (IgA-κ type) who had a high serum CEA level of 27.7 ng/ml. Upper and lower gastrointestinal endoscopy and PET/CT scan showed no abnormality. After two courses of VAD therapy, the serum CEA level decreased to 5.7 ng/ml, with a decrease in the IgA level, suggesting the diagnosis of CEA-producing myeloma. After 4 years and 1 month, she had a relapse with an increase in the LDH level and myeloma cells in the blood, followed by cognitive loss and convulsion. She died 1 month after the onset of neurological symptoms. Several myeloma cells were detected in the cerebral spinal fluid, which suggested the diagnosis of myelomatous meningitis. Myelomatous meningitis is a rare disease and accounts for 1% of all myelomas. This is the fourth reported case of CEA-producing myeloma.

Renal artery stenosis following nilotinib administration in a patient with chronic myelogenous leukemia.

A 63-year-old male was diagnosed as having chronic phase CML in 2001. He obtained a major molecular response with imatinib (IM). In 2012, amulodipin was started for hypertension. In January 2013, IM was switched to nilotinib (NIL) in a clinical trial, and in February 2015, NIL was discontinued because MR4.5 had been maintained for two years. One month later, he was admitted to our hospital because of headache and high blood pressure (194/108 mmHg). His urine test showed protein 3+ and occult blood 2+. His eGFR rapidly deteriorated from 45.6 to 28.5 after admission. MR angiography showed left renal artery stenosis. He thus underwent angioplasty of the left renal artery with a stent implantation. His renal function subsequently improved. Cardiovascular events such as PAOD (peripheral artery occlusive disease) during NIL treatment were recently reported. However, to date, only four cases including our present patient with renal artery stenosis associated with NIL have been reported. These observations suggest assessment of risk factors for cardiovascular events at the start of NIL and careful monitoring to be important during tyrosine kinase inhibitor treatment of CML patients.

[REACTIVATION OF TUBERCULOSIS PRESENTING WITH EMPYEMA DUE TO ANTICANCER CHEMOTHERAPY FOR DIFFUSE LARGE B CELL LYMPHOMA].

A 79-year-old man with a history of tuberculosis was found to have chronic empyema in the right lung and was diagnosed with malignant diffuse large-cell lymphoma (Ann Arbor stage IIE). After completion of one course of rituximab plus cyclophosphamide, pirarubicin, vincristine, and prednisolone (R-CHOP) chemotherapy, the patient developed lung abscess and sepsis caused by Streptococcus intermedius. This condition was treated with antimicrobial agents, and chemotherapy was resumed. After the second course, the chemotherapy regimen was continued without prednisolone, and after administration of the third course, a chest wall mass was found in the right lung. An acid-fast bacillus smear test of the abscess aspirate was positive, and Mycobacterium tuberculosis was detected in a polymerase chain reaction assay, leading to a diagnosis of perithoracic tuberculosis. Chemotherapy for the lymphoma was discontinued, and treatment with four oral antitubercular agents was started. This treatment led to remission of perithoracic tuberculosis. In Japan, tuberculous scar and chronic empyema are relatively common findings, and relapse of tuberculosis should always be considered for patients with these findings during chemotherapy and immunosuppressive therapy.

[Transition to aggressive phase in a multiple myeloma patient with IgH/CCND1 translocation and diffuse osteosclerotic lesions].

CASE: A 71-year-old woman had been diagnosed as having osteosclerotic myeloma (BJP-λ type) three years prior to the current presentation, based on tumor biopsy from the forehead showing plasmacytoma with systemic osteosclerotic lesions. At 71 years of age, she underwent transverse colectomy for a tumor in the hepatic flexure of the large intestine, and it was diagnosed as IgH/CCND-1-positive plasmacytoma of the large intestine. Although serum vascular endothelial cell growth factor (VEGF) was not elevated, the plasmacytoma was largely positive for VEGF staining. She subsequently experienced transformation to aggressive myeloma over a short period of time. Osteosclerotic myeloma is a rare disease that accounts for less than 3% of all myelomas, and requires differentiation from POEMS syndrome. In this case, peripheral nerve symptoms, which are necessary for the diagnosis of POEMS syndrome, were not confirmed. Thus, this case was diagnosed as having osteosclerotic myeloma. By contrast, abnormal IgH/CCND-1 is confirmed in 15% of patients with myeloma, and 25% of those with POEMS syndrome. While it is unclear whether this genetic abnormality is involved in the development of an osteosclerotic lesion, it is expected that data from patients with osteosclerotic myeloma and POEMS syndrome will be accumulated in the future, allowing clarification of the relationship between the genetic abnormality and osteosclerosis.

The interaction between oral melphalan and gastric antisecretory drugs: Impact on clinical efficacy and toxicity.

The aim of the present study was to clarify whether gastric antisecretory drugs affect the clinical efficacy and toxicity of orally administered melphalan in patients with multiple myeloma. A total of 10 patients receiving bortezomib plus oral melphalan and prednisolone (VMP) therapy between December 2011 and November 2014 were analyzed retrospectively. The patients were divided into a control group (seven patients) and a concomitant group (three patients, who were also administered with gastric antisecretory drugs). The gastric antisecretory drugs included rabeprazole sodium (two patients) and famotidine (one patient). No significant differences between the groups were observed in either the characteristics of the patients or the VMP regimen. The levels of monoclonal protein (M protein) in the control group tended to decrease (with a VMP cycle-dependency), although they were primarily stable in the concomitant group. During the second and third VMP cycles, the levels of M protein were markedly lower in the control group compared with the concomitant group. All the patients in the control group achieved a partial response, whereas those in the concomitant group exhibited stable disease. Hematological toxicity levels were revealed to be comparable between the two groups, whereas gastrointestinal toxicity was more prevalent in the control group. In conclusion, the results of the present study suggested that the clinical efficacy of melphalan may be reduced by the co-administration of gastric antisecretory drugs. This interaction may result in decreased toxicity and clinical efficacy of melphalan.

Quincke's edema and hypersensitivity pneumonitis induced by lenalidomide for multiple myeloma.

A 64-year-old man with recurrent multiple myeloma (BJP-κ type) was treated with 15 mg of lenalidomide (LEN) and dexamethasone. He developed Quincke's edema on his eyelid on day 4. Since the edema improved after withdrawal of LEN, the drug was subsequently re-administered at a decreased dose. However, the edema developed again on day 4. After withdrawal of LEN, the drug was administered again with gradually dose escalation, while confirming the absence of eyelid edema. Although edema did not develop, eosinophils and basophils were increased, and the CRP level was elevated. During the third course of LEN administration, his chest CT showed bilateral ground-glass opacity, and LEN-induced hypersensitivity pneumonitis was diagnosed. The pneumonitis resolved after LEN withdrawal and prednisolone administration. These observations suggested that Quincke's edema, eosinophilia and basophilia, CRP elevation, and hypersensitivity pneumonitis might occur due to the immunological effects of LEN, which is classified as an immunomodulatory drug.

The longitudinal analysis of large granular lymphocytosis in patients with Philadelphia chromosome-positive leukemia treated with dasatinib.

Dasatinib, a 2nd-generation tyrosine kinase inhibitor (TKI), can specifically induce large granular lymphocytes (LGL) in some patients with Philadelphia chromosome (Ph)-positive leukemia. To investigate the properties of the induced LGLs, we performed prospective and longitudinal analyses. From Feb 2011 to Jan 2013, a total of 17 patients with Ph-positive leukemia who were previously untreated or refractory to imatinib were enrolled. T cell receptor (TCR)-γ/δ gene rearrangements and phenotypic profiles of lymphocytes were examined before and during administration of dasatinib. LGL lymphocytosis was observed in half of the dasatinib-treated cases (LGL+ group), showing a relation to increased achievement of complete cytogenetic response within 6 months. The phenotypes of the increased lymphocytes were revealed to be mostly natural killer cells. In the LGL+ group, clonal TCR-γ gene rearrangements were frequently detected at diagnosis (six of nine cases) and persisted during therapy, compared with only two of eight in the LGL- group. The proportion of regulatory T cells to CD4+ T cells at diagnosis was lower in the LGL+ compared with the LGL- group (median 4.2 vs. 6.6 %), and this disparity was sustained throughout the therapeutic period. These results demonstrate that immunological condition at diagnosis may affect LGL lymphocytosis in some dasatinib-treated patients.

[Successful treatment with pseudo-autologous blood stem cell transplantation for an adolescent-onset multiple myeloma who relapsed after allogenic bone marrow transplantation].

A 14-year-old male with multiple myeloma (IgG-λ, ISS stage 3) received myeloablative matched unrelated bone marrow transplantation, and achieved a complete response. At 16 months after the transplantation, he relapsed. The relapse was resistant to bortezomib and thalidomide. Peripheral blood showed mixed chimerism with 10% recipient cells. Peripheral blood stem cells (PBSC) were collected and pseudo-autologous PBSC transplantation (PASCT) was performed following high-dose melphalan without graft-versus-host disease prophylaxis. Hematopoietic recovery was prompt and a partial response was obtained without graft-versus-host disease exacerbation. We have presented a rare case of adolescent-onset multiple myeloma, obtaining a transient response with PASCT following post-allogeneic transplant relapse.

[Light chain escape followed by leukemic transformation in a patient with IgD myeloma].

A 63-year-old male with multiple myeloma (IgD-λ) received autologous peripheral blood stem cell transplantation (PBSCT) after induction of VAD in March 2008, and obtained a very good partial response. However, he required BOR/DEX and a second PBSCT for relapse, and in August 2012, treatment with LEN/DEX was started. After 4 cycles of LEN/DEX, IgD decreased but FLC-λ increased paradoxically, indicating a clonal change. In January 2013, an LCD regimen was started and after 4 cycles, IgD showed normalization, but his condition worsened as FLC-λ increased. This case showed a fulminant clinical course with light chain escape in this era of treating multiple myeloma with novel agents.