Sevgi Kalayoglu Besisik

Single-agent lenalidomide in patients with mantle-cell lymphoma who relapsed or progressed after or were refractory to bortezomib: phase II MCL-001 (EMERGE) study.

PURPOSE Although dose-intensive strategies or high-dose therapy induction followed by autologous stem-cell transplantation have improved the outcome for patients with mantle-cell lymphoma (MCL), most eventually relapse and subsequently respond poorly to additional therapy. Bortezomib (in the United States) and temsirolimus (in Europe) are currently the only two treatments approved for relapsed disease. Lenalidomide is an immunomodulatory agent with proven tumoricidal and antiproliferative activity in MCL. The MCL-001 (EMERGE) trial is a global, multicenter phase II study examining the safety and efficacy of lenalidomide in patients who had relapsed or were refractory to bortezomib. PATIENTS AND METHODS Lenalidomide 25 mg orally was administered on days 1 through 21 every 28 days until disease progression or intolerance. Primary end points were overall response rate (ORR) and duration of response (DOR); secondary end points included complete response (CR) rate, progression-free survival (PFS), overall survival (OS), and safety. RESULTS In all, 134 patients were enrolled with a median age of 67 years and a median of four prior therapies (range, two to 10 prior therapies). The ORR was 28% (7.5% CR/CR unconfirmed) with rapid time to response (median, 2.2 months) and a median DOR of 16.6 months (95% CI, 7.7 to 26.7 months). Median PFS was 4.0 months (95% CI, 3.6 to 5.6 months), and median OS was 19.0 months (95% CI, 12.5 to 23.9 months). The most common grade 3 to 4 adverse events were neutropenia (43%), thrombocytopenia (28%), anemia (11%), pneumonia (8%), and fatigue (7%). CONCLUSION The MCL-001 study demonstrated durable efficacy of lenalidomide with a predictable safety profile in heavily pretreated patients with MCL who had all relapsed or progressed after or were refractory to bortezomib.

Acute renal failure due to leukaemic infiltration in chronic lymphocytic leukaemia: case report

A 73‐year‐old woman was presented with altered mental status and disorientation. She was diabetic and hypertensive, and she had experienced an ischemic cerebrovascular accident 3 years ago. Physical examination revealed the findings of chronic obstructive pulmonary disease, cor pulmonale and congestive heart failure. Hepatomegaly, splenomegaly and ascites were found and might be associated with postsinusoidal portal hypertension secondary to congestive heart failure. Laboratory tests showed uremia, lymphocytosis and thrombocytopenia. Neurologic findings were related with uremia and hypoxia. Multiple pathologic lymphadenopathies were seen in abdominal ultrasonography and thoracic computed tomography. Bone marrow histology indicated chronic lymphocytic leukaemia (CLL). The reason for acute renal failure was leukaemic infiltration of the kidneys due to CLL that was shown with renal biopsy. Blood urea nitrogen (BUN) and serum creatinine responded well to cyclophosphamide and methyl prednisolone treatment. In CLL, direct renal involvement is frequently seen in autopsy studies especially in advanced disease, however, renal failure due to leukaemic infiltration is extremely rare.

Longer-term follow-up and outcome by tumour cell proliferation rate (Ki-67) in patients with relapsed/refractory mantle cell lymphoma treated with lenalidomide on MCL-001(EMERGE) pivotal trial.

Patients with mantle cell lymphoma (MCL) generally respond to first‐line immunochemotherapy, but often show chemoresistance upon subsequent relapses, with poor outcome. Several studies of the immunomodulator, lenalidomide, have demonstrated its activity in MCL including the MCL‐001 study in relapsed/refractory patients who had failed defined prior therapies of anthracyclines or mitoxantrone, cyclophosphamide, rituximab and also bortezomib. We present here the long‐term efficacy follow‐up of the prospective phase II MCL‐001 study (N = 134), including new exploratory analyses with baseline Ki‐67 (MIB1), a biological marker of tumour proliferation. With longer follow‐up, lenalidomide showed a 28% overall response rate [ORR; 8% complete response (CR)/CR unconfirmed (CRu)]. Median duration of response (DOR), progression‐free survival and overall survival were 16·6, 4·0 and 20·9 months, respectively. Myelosuppression continued to be the most common grade 3/4 toxicity. Several studies of MCL patients treated with chemotherapy, rituximab and bortezomib have shown an inverse association between survival and Ki‐67. Ki‐67 data in 81/134 MCL‐001 patients showed similar ORRs in both low (<30% or <50%) versus high (≥30% or ≥50%) Ki‐67–expressing groups, yet lower Ki‐67 levels demonstrated superior CR/CRu, DOR and survival outcomes. Overall, lenalidomide showed durable efficacy with a consistent safety profile in heavily pretreated, relapsed/refractory MCL post‐bortezomib.

Severe thrombocytopenia and alveolar hemorrhage represent two types of bleeding tendency during tirofiban treatment: case report and literature review

Tirofiban is a glycoprotein (GP) IIb/IIIa receptor antagonist used in the treatment of acute coronary syndrome (ACS). Thrombocytopenia is a well-known complication of GPIIb/IIIa inhibitors. Life-threatening complications such as alveolar and gastrointestinal system hemorrhages may occur in the course of thrombocytopenia. Platelet count should be monitored closely, including during the first few hours of the infusion. Adverse events may be prevented by prompt discontinuation of the therapy. Herein we present two cases of profound and sudden thrombocytopenia associated with tirofiban use in the treatment of ACS together with a review of the literature.

Folic Acid and vitamin B12 supplementation improves coronary flow reserve in elderly subjects with vitamin B12 deficiency.

BACKGROUND AND AIMS Major cardiovascular risk factors including hyperhomocysteinemia are frequently associated with decreased coronary flow reserve (CFR), an important physiological parameter of the coronary circulation. This study was designed to determine whether folate (5 mg) and vitamin B12 (500 μg) supplementation in elderly patients with vitamin B12 deficiency improved CFR, while reducing homocysteine levels. METHODS Forty-four patients aged >65 years showing serum vitamin B12 concentrations <180 mg/dL were randomized to take either oral folate (5 mg) plus vitamin B12 (500 μg) supplementation (n = 24) or placebo (n = 20) for 8 weeks. The study course consisted of two visits: visit 1 (pretreatment) included the baseline assessment of laboratory profile and CFR values with trans-thoracic Doppler echocardiography. Visit 2 was scheduled 8 weeks later to repeat CFR and laboratory tests after therapy. RESULTS In the treatment arm, oral supplementation with folate and vitamin B12 significantly improved total cholesterol, serum folate, serum vitamin B12, homocysteine, and insulin resistance. At 8 weeks, the treatment group had a significant increase from baseline in CFR values (baseline: 1.7 ± 0.2; postttreatment: 2.1 ± 0.2, p <0.001) that was not seen in the placebo group (baseline: 1.6 ± 0.2; posttreatment: 1.6 ± 0.2; P = ns). CONCLUSIONS In this study of elderly subjects with vitamin B12 deficiency, supplementation with folate and vitamin B12 was associated with a significant improvement in CFR values.

A068 Bone Marrow Renin-Angiotensin System in Multiple Myeloma

Background: High-dose therapy with melphalan and autoPBSCT induce remissions in multiple myeloma but are not able to cure this disease. Eventually, all patients relapse and require further treatment. One possibility suitable particularly for patients who had not been earlier treated with thalidomide is a combination of this drug with dexamethasone. Aims: To retrospectively assess the effectiveness of such treatment in a cohort of patients treated in a single center. The endpoints of the study were: response, EFS, OS and toxicity. Methods: Forty five multiple myeloma patients (23 female/22 male) with a median age of 54 years (range, 33-69 years) were included into the analysis between June 2005 and December 2007. Twenty seven patients were IgG, 10-IgA, 2-nonsecretory, 6-light chain. Clinical stage according ISS: 20 patients in stage 1, 9 in stage 2, 16 in stage 3. Patients have been initially treated with VAD protocol (vincristin/adriamycin/ dexamethasone) followed by cyclophosphamide mobilization and then by tandem high-dose melphalan with autoPBSCT. Relapsing patients were treated according to the following protocol: thalidomide 200 mg/day orally continuously until any sign of progressive disease or relapse, and dexamethasone 40 mg orally for 4 days every 3 weeks. Fifteen patients received enoxaparin and 30 patients acetylsalicylic acid prophylaxis. Response was evaluated using the International Myeloma Working Group Uniform Response Criteria. Moreover, overall survival (OS) and event-free survival (EFS) was assessed. Results: Altogether, 6 patients (13.3%) achieved complete response (CR), 7 patients (15.5%) very good partial response (VGPR), 18 patients (40%) partial response (PR), 11 patients (24.4%) stable disease (SD), and 3 patients (6.6%) progression disease (PD). The median time to response was 12 weeks (range, 12-28 weeks). Duration of treatment TD was 14.6 months (median; range, 3-48.6 months). The median EFS was 24 months (range, 14-41.3 months). The median OS has not been reached. The major adverse events of THALDEX were: peripheral neuropathy, 18 patients (40%); constipation, 12 patients (26.6%); somnolence, 5 patients (11.1%); deep-vein thrombosis, 1 patient (2.2%). Conclusion: THALDEX seem to be effective in multiple myeloma patients relapsing after high dose therapy and tandem PBSCT and well tolerated.

Intracoronary autologous bone marrow-derived mononuclear cell transplantation improves coronary collateral vessel formation and recruitment capacity in patients with ischemic cardiomyopathy: a combined hemodynamic and scintigraphic approach.

This study investigated the effects of intracoronary autologous bone marrow−derived mononuclear cell (BMC) transplantation on coronary microcirculation. Fifteen patients with ischemic cardiomyopathy were treated by intracoronary infusion of BMCs via the patent infarct-related artery. The thermodilution-derived coronary flow reserve, index of microvascular resistance, pressure-derived collateral flow index, and coronary wedge pressure were measured at baseline and at 6 months. Successive balloon inflations during BMC transplantation were performed to observe the recruitment in pressure-derived collateral flow index and coronary wedge pressure, and the percentage changes between baseline and 6 months were calculated. The mean (SD) coronary flow reserve increased from 1.3 (0.4) to 2.1 (0.5), and the mean (SD) index of microvascular resistance decreased from 44.9 (24.4) to 21.2 (14.1) (P = .001 for both). The mean (SD) improvement in pressure-derived collateral flow index (from 0.14 [0.05] to 0.22 [0.08]) was also statistically significant (P = .001). Similarly, the percentage improvements in pressure-derived collateral flow index and coronary wedge pressure were statistically significant (P = .01 for both). The percentage improvement in perfusion assessed by single-photon emission computed tomography strongly correlated with the percentage changes in pressure-derived collateral flow index (r = 0.88, P = .001) and coronary wedge pressure (r = 0.69, P = .01). These results demonstrate for the first time (to our knowledge) that intracoronary autologous BMC transplantation improves coronary collateral vessel formation and recruitment capacity in human subjects.

Technetium-99m 2-methoxy-isobutyl-isonitrile uptake scintigraphy in detection of the bone marrow infiltration in multiple myeloma: correlation with MRI and other prognostic factors.

Whole-body scintigraphy with Technetium-99m 2-methoxy-isobutyl-isonitrile (99mTc-MIBI) has been proposed as a useful method for demonstrating the areas of active bone marrow infiltration in multiple myeloma (MM). In this study, we compared the 99mTc-MIBI scan with magnetic resonance imaging (MRI), skeletal X-ray survey, and biochemical markers of disease activity in MM to determine its potential in predicting the extension of the disease. Twenty-four myeloma patients had undergone to the 99mTc-MIBI scan. Only two patients showed negative results in the 99mTc-MIBI scan; one had clinically active disease, and the other was on remission. MRI was performed to 18 clinically active patients, and 16 of them showed positive myelomatous bone marrow involvement. No significant difference was found between the 99mTc-MIBI scan and MRI in predicting the extension of bone marrow infiltration in MM (p = 0.11). 99mTc-MIBI scores were correlated with bone marrow neoplastic plasma cell ratio (p = 0.005), serum paraprotein level (p < 0.001), serum lactate dehydrogenase (p = 0.031), and beta-2 microglobulin (p = 0.045). The 99mTc-MIBI scan showed disease activity better than the skeletal X-ray survey (x2 = 5.299, p = 0.021). A significant decrease was found in posttreatment 99mTc-MIBI scores of the patients with positive overall response (p = 0.016). The 99mTc-MIBI scan is a noninvasive test that can show the extension of the disease in MM. It seems that the 99mTc-MIBI scan and MRI show extension and intensity of the myelomatous bone marrow infiltration equally well. The 99mTc-MIBI scan can be an alternative to MRI when it is not available or if there is any limitations for its usage.

Kappa light chain myeloma with initial cutaneous involvement

Dear Editor, Cutaneous involvement in multiple myeloma (MM) is rare and generally develops as a consequence of direct spread from an underlying osteolytic lesion or solitary plasmacytoma of the bone in the late stages of the disease [1]. We present a 45-year-old woman with weight loss, weakness, neck and shoulder pain and skin lesions. Her skin lesions were nontender, nonpruritic violaceous papules (up to 8 mm), had firm consistency and smooth surfaces, and located on her trunk and abdomen (Fig. 1a). Laboratory examination revealed increased erythrocyte sedimentation rate (90 mm/h), macrocytic anemia (hemoglobin 9.5 g/dl, mean corpuscular volume 102.7 fl), increased blood–urea–nitrogen (14.28 mmol/l), creatinine (256.36 μmol/l) and uric acid (487.7 μmol/l) levels with decreased gammaglobulin (5 g/l) level. Serum albumin was 36 g/l. Creatinine clearance and daily proteinuria were 0.517 ml/s and 13.5 g. Abdominal ultrasonography showed enlarged kidneys with increased renal parenchymal echogenicity. Skin biopsy revealed a dense perivascular and nodular neoplastic plasma cell infiltration, beginning at the papillary dermis and extending through the deep dermis-subcutaneous fat border (Fig. 1b). Nodular and interstitial neoplastic plasma cell infiltration (40%) with monotypic kappa light chain expression was seen in bone marrow biopsy (Fig. 1c). Beta-2-microglobulin was 18.97 mg/l. There were monoclonal kappa light chain bands on both serum (1940 mg/l) and urine (415 mg/l, 11%) immunoelectrophoreses. Serum immunoglobulin levels were IgA 720 mg/l, IgG 3,820 mg/l, IgM 420 mg/l, kappa 1,940 mg/l, and lambda 1,100 mg/l. MM with skin involvement was diagnosed. No lytic lesions were seen on skeletal x-rays. Chromosomal analysis revealed 46,XX. Renal biopsy showed cast nephropathy (Fig. 1d). After three consecutive VAD protocols (parenteral vincristine, adriamycine, and oral dexamethasone), skin lesions disappeared. However, control bone marrow biopsy revealed poor response. Thalidomide 400 mg/day and dexamethasone 40 mg/day were given, but stopped due to peripheric neuropathy. The treatment was changed to high-dose dexamethasone. Plasma cell leukemia developed 14 months after the first diagnosis, and she died with pneumonia and sepsis. Although generally occurs with direct extension from an underlying bone lesion of the disease, cutaneous lesions of MM can also be seen distinct from a bony focus, and even as the initial manifestation of the disease. They appear in the form of papules or cutaneous and subcutaneous nodules; those that can be measured are 1–5 cm in diameter, with firm consistency, smooth surface, and a red or violaceous color. Rarely larger lesions like plaques can be seen. They are generally localized to trunk and abdomen [1]. A review of the literature reveals that patients with MM and cutaneous plasmacytoma show IgG monoclonal immunoglobulin in 56%, IgA in 24%, free light chain in 12%, IgD in 4%, and IgM in 4% [2]. Recently, BayerGarner et al. [3] reviewed their MM patients with various skin lesions. They found skin lesions in 284 patients out of 2,357. Only 14 patients had the diagnosis of cutaneous plasmacytoma, 10 IgG-producing tumors (4 λ, 6 κ), 1 IgA κ, 1 IgM κ, 1 κ-light chain, and 1 nonsecretory after chemotherapy. Cutaneous plasmocytoma in Bence-Jones protein secreting MM is even rarer and generally occurs in the late stages of the disease [4]. Histopathologic examination of the cutaneous plasmacytomas in MM revealed two patterns: nodular or diffuse interstitial infiltration [2], which was B. Saka (*) . N. Erten . G. Oztürk . C. Yılmaz . S. K. Besisik Department of Internal Medicine, Istanbul Faculty of Medicine, Istanbul University, Millet Cad., 34270 Capa/Fatih/Istanbul, Turkey e-mail: sakab@medscape.com Tel.: +90-212-4142000 Fax: +90-212-5324208

Investigation of Gene Expressions of Myeloma Cells in the Bone Marrow of Multiple Myeloma Patients by Transcriptome Analysis

Background: Multiple myeloma is a plasma cell dyscrasia characterized by transformation of B cells into malignant cells. Although there are data regarding the molecular pathology of multiple myeloma, the molecular mechanisms of the disease have not been fully elucidated. Aims: To investigate the gene expression profiles in bone marrow myeloma cells via RNA-sequencing technology. Study Design: Cell study. Methods: Myeloma cells from four patients with untreated multiple myeloma and B cells from the bone marrow of four healthy donors were sorted using a FACSAria II flow cytometer. The patient pool of myeloma cells and the control pool of B cells were the two comparative groups. A transcriptome analysis was performed and the results were analyzed using bioinformatics tools. Results: In total, 18.806 transcripts (94.4%) were detected in the pooled multiple myeloma patient cells. A total of 992 regions were detected as new exon candidates or alternative splicing regions. In addition, 490 mutations (deletions or insertions), 1.397 single nucleotide variations, 415 fusion transcripts, 132 frameshift mutations, and 983 fusions, which were reported before in the National Center for Biotechnology Information, were detected with unknown functions in patients. A total of 35.268 transcripts were obtained (71%) (25.355 transcripts were defined previously) in the control pool. In this preliminary study, the first 50 genes were analyzed with the MSigDB, Enrichr, and Panther gene set enrichment analysis programs. The molecular functions, cellular components, pathways, and biological processes of the genes were obtained and statistical values were determined using bioinformatics tools and are presented as a supplemental file. Conclusion: EEF1G, ITM2C, FTL, CLPTM1L, and CYBA are identified as possible candidate genes associated with myelomagenesis.