Bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukaemia: updated results of a randomized phase III trial.

The efficacy of bendamustine versus chlorambucil in a phase III trial of previously untreated patients with Binet stage B/C chronic lymphocytic leukaemia (CLL) was re-evaluated after a median observation time of 54 months in May 2010. Overall survival (OS) was analysed for the first time. At follow-up, investigator-assessed complete response (CR) rate (21·0% vs 10·8%), median progression-free survival (21·2 vs 8·8 months; P < 0·0001; hazard ratio 2·83) and time to next treatment (31·7 vs 10·1 months; P < 0·0001) were improved for bendamustine over chlorambucil. OS was not different between groups for all patients or those ≤65 years, >65 years, responders and non-responders. However, patients with objective response or a CR experienced a significantly longer OS than non-responders or those without a CR. Significantly more patients on chlorambucil progressed to second/further lines of treatment compared with those on bendamustine (78·3% vs 63·6%; P = 0·004). The benefits of bendamustine over chlorambucil were achieved without reducing quality of life. In conclusion, bendamustine is significantly more effective than chlorambucil in previously untreated CLL patients, with the achievement of a CR or objective response appearing to prolong OS. Bendamustine should be considered as a preferred first-line option over chlorambucil for CLL patients ineligible for fludarabine, cyclophosphamide and rituximab.

Thalidomide versus dexamethasone for the treatment of relapsed and/or refractory multiple myeloma: results from OPTIMUM, a randomized trial.

BACKGROUND: Thalidomide has potent antimyeloma activity, but no prospective, randomized controlled trial has evaluated thalidomide monotherapy in patients with relapsed/refractory multiple myeloma. DESIGN AND METHODS: We conducted an international, randomized, open-label, four-arm, phase III trial to compare three different doses of thalidomide (100, 200, or 400 mg/day) with standard dexamethasone in patients who had received one to three prior therapies. The primary end-point was time to progression. RESULTS: In the intent-to-treat population (N=499), the median time to progression was 6.1, 7.0, 7.6, and 9.1 months in patients treated with dexamethasone, and thalidomide 100, 200, and 400 mg/day, respectively; the difference between treatment groups was not statistically significant. In the per-protocol population (n=465), the median time to progression was 6.0, 7.0, 8.0, and 9.1 months, respectively. In patients who had received two or three prior therapies, thalidomide significantly prolonged the time to progression at all dose levels compared to the result achieved with dexamethasone. Response rates and median survival were similar in all treatment groups, but the median duration of response was significantly longer in all thalidomide groups than in the dexamethasone group. Adverse events reported in the thalidomide groups, such as fatigue, constipation and neuropathy, confirmed the known safety profile of thalidomide. CONCLUSIONS: Although thalidomide was not superior to dexamethasone in this randomized trial, thalidomide monotherapy may be considered an effective salvage therapy option for patients with relapsed/refractory multiple myeloma, particularly those with a good prognosis and those who have received two or three prior therapies. The recommended starting dose of thalidomide monotherapy is 400 mg/day, which can be rapidly reduced for patients who do not tolerate this treatment. ( CLINICAL TRIAL REGISTRATION NUMBER: NCT00452569).

High-dose imatinib induction followed by standard-dose maintenance in pre-treated chronic phase chronic myeloid leukemia patients--final analysis of a randomized, multicenter, phase III trial.

BACKGROUND: Previous data suggest that the response of chronic myeloid leukemia cells to imatinib is dose-dependent. The potential benefit of initial dose intensification of imatinib in pre-treated patients with chronic phase chronic myeloid leukemia remains unknown. DESIGN AND METHODS: Two hundred and twenty-seven pre-treated patients with chronic myeloid leukemia in chronic phase were randomly assigned to continuous treatment with a standard dose of imatinib (400 mg/day; n=113) or to 6 months of high-dose induction with imatinib (800 mg/day) followed by a standard dose of imatinib as maintenance therapy (n=114). RESULTS: The rates of major and complete cytogenetic responses were significantly higher in the high-dose arm than in the standard-dose arm at both 3 and 6 months (major cytogenetic responses: 36.8% versus 21.2%, P=0.01 and 50.0% versus 34.5%, P=0.018; complete cytogenetic responses: 22.8% versus 6.2%, P<0.001 and 40.4% versus 16.8%, P<0.001) on the basis of an intention-to-treat analysis. At 12 months, the difference between treatment arms remained statistically significant for complete cytogenetic responses (40.4% versus 24.8%, P=0.012) but not for major cytogenetic responses (49.1% versus 44.2%, P=0.462). The rate of major molecular responses was also significantly better at 3 and 6 months in the high-dose arm (month 3: 14.9% versus 3.5%, P=0.003; month 6: 32.5% versus 8.8%, P<0.001). Overall and progression-free survival rates were comparable between arms, but event-free survival was significantly worse in the high-dose arm (P=0.014). CONCLUSIONS: Standard-dose imatinib remains the standard of care for pre-treated patients with chronic phase chronic myeloid leukemia (Clinicaltrials.gov identifier: NCT00327262).

High-dose imatinib improves cytogenetic and molecular remissions in patients with pretreated Philadelphia-positive, BCR-ABL-positive chronic phase chronic myeloid leukemia: first results from the randomized CELSG phase III CML 11 "ISTAHIT" study.

BACKGROUND: Imatinib 400 mg/day is the standard treatment for patients with chronic phase chronic myeloid leukemia. Recent reports suggested higher and more rapid cytogenetic and molecular responses with higher doses of imatinib. DESIGN AND METHODS: In this prospective international, multicenter phase III study, 227 patients with pre-treated Philadelphia chromosome-positive, BCR-ABL-positive chronic myeloid leukemia were randomized to a standard-dose imatinib arm (400 mg/day) or a high-dose imatinib arm (800 mg/day for 6 months followed by 400 mg/day as maintenance therapy). In this planned interim analysis hematologic, cytogenetic and molecular responses as well as toxicity were evaluated. RESULTS: Compared to the standard-dose, high-dose imatinib led to higher rates of major and complete cytogenetic responses at both 3 months (major: 21% versus 37%, P=0.01; complete: 6% versus 25%, P<0.001) and 6 months (major: 34% versus 54%, P=0.009; complete: 20% versus 44%, P<0.001). This was paralleled by a significantly higher major molecular response rate at 6 months in the high-dose imatinib arm (11.8% versus 30.4%; P=0.003). At 12 months, the rates of major cytogenetic response (the primary end-point) were comparable between the two arms (57% versus 59%). In contrast to non-hematologic toxicities, grade 3/4 hematologic toxicities were more common in the high-dose arm. Cumulative complete cytogenetic response rates were higher in patients without dose reduction in the high-dose arm (61%) than in the patients with no dose reduction in the standard-dose arm (36%) (P=0.014). CONCLUSIONS: This is the first randomized phase III trial in patients with pre-treated chronic phase chronic myeloid leukemia demonstrating improvements in major cytogenetic response, complete cytogenetic response and major molecular response rates with high-dose imatinib therapy (ClinicalTrials.gov Identifier: NCT00327262).

Reduction of Liver Iron Load in Adult Patients with ß-Thalassemia Major Treated with Modern Chelation Modalities.

BACKGROUND: Management of beta-thalassemia major (TM) requires life-long hemotransfusions leading to iron overload. Iron elimination is enhanced by the use of modern chelators. AIM: To assess the effect of modern chelation therapy by dynamics of serum ferritin concentration and liver MRI T2*. PATIENTS AND METHODS: Forty-six patients with TM (male to female ratio =1:1, mean age 33.2±10.9 years) were prospectively studied between 2011 and 2014. Twenty-one patients (45.7%) were treated with deferasirox, 17 (37%) - with deferiprone, and 8 (17.3%) - with deferiprone in combination with deferoxamine. Ferritin was measured by ELISA. MRI T2* was assessed by Siemens Magnetom Avanto 1.5T. The patients were allocated into 3 groups based on their initial ferritin level and liver MRI T2*. Statistical analysis was performed using SPSS v. 18 for Windows. Data were analysed by descriptive analysis, analysis of variance and correlative analysis, means were compared using t-test and one-way ANOVA. RESULTS: In 2011, 9 (19.5%) patients had normal liver MRI T2*; in 2014 they were 17 (37%). The patients with mild grade liver siderosis were 12 (26%) in 2011, and in 2014 they were 14 (30.4%). In 2011, the patients with moderate liver siderosis were 14 (30.4%), and in 2014 - 12 (26.0%). Eleven patients (23.9%) had severe liver siderosis in 2011 and only two patients (4.0%) were diagnosed with the condition in 2014. CONCLUSION: A reduction of iron overload was found in all studied groups. This positive effect is attributed to the use of modern chelators and the ease of access to accurate monitoring.

Poems syndrome--a rare variant of plasma cell dyscrasia. Case report and review of literature.

POEMS syndrome (polyneuropathy, organomegaly, M-protein, and skin changes) is a rare plasma cell disease with small tumour mass and multisystem involvement. Since 2003 POEMS syndrome has been a nosological entity with approved diagnostic criteria, though its etiology and pathogenesis are still not clear. Males are more often affected, with peak incidence in the 5th and 6th decades. The major diagnostic problems are difficult detection of plasma cell infiltration in the osteosclerotic lesions and M-gradient most often low concentration IgA (lamda). We present a case of POEMS syndrome in a 47-year-old male patient who initially presented with edema of the lower limbs, moderate lymphadenopathy, hepatosplenomegaly, histological findings of Castleman disease with marked sinusoidal angioproliferation in the lymph nodes and multiple osteosclerotic lesions. Pleural effusion, ascitis, renal failure, progressive lower limbs polyneuropathy with invalidisation of the patient developed later. The attempts to detect lymphoproliferative process by myelogram, trephine biopsy, histological examination of lymph node and the spleen were ineffective and deceptively non-informative, neither did immunoelectrophoresis reveal M-grade. Diagnosis was made after bone biopsy of the largest osteosclerotic lesion and immunofixation (monoclonal IgA, lamda in the serum). The patient underwent treatment with alkylating agents and corticosteroids, radiation of the predominant osteosclerotic lesions and therapy with radioactive strontium. The general condition improved, lymphadenomegaly, skin lesions, pleural effusion and ascitis regressed and renal function was restored. There was a minor improvement of the neurological symptoms. Autollogous stem-cell transplantation is also recommended in literature for patients with generalized bone lesions or progressive and disease-resistant therapy.

Osteonecrosis of the jaw in patients on bisphosphonate treatment. review of literature with contribution of a case of multiple myeloma.

In recent years, the incidence of osteonecrosis of the jaw (ONJ) as an unknown complication in patients receiving bisphosphonates (BP) has been on the increase. According to literature data it is in the range of 0.83% to 11.9%. ONJ has been mostly reported in patients with malignancies--mainly in multiple myeloma (MM) patients, followed by patients with bone metastases from breast and prostatic cancer. The view that is supported by a growing body of researchers in the discussion on the etiopathogenetic relationship between ONJ and BPs is that ONJ seems to be a class-specific side effect rather than a result of the use of a specific drug. The major risk factor for development of ONJ is not the BP type, but the time of their administration and accumulation in the bone structures. More than 70% of the ONJ patients report preceding dental problems. The immunosuppressive effects of chemo- and radiotherapy, the impaired bone remodeling resulting from corticoid therapy, the antiangiogenetic properties of thalidomide slow down the reparative processes in the oral cavity and appear as a predisposing factor for the development of ONJ. Possibilities for successful treatment are limited; conservative approaches and least surgery, if larger areas are involved, are recommended. Dental prophylaxis is of particular importance. We present a 66-year-old man with multiple myeloma, IgG, BJ(k), II A KC (after Durie and Salmon staging system). ONJ was diagnosed one year after the disease onset, during which the patient received chemotherapy and was administered concurrently 14 cycles of BPs (pamidronate/zolendronate). The diagnosis was based on clinical, radiologic and histological evidence. Surgical removal of the necrotic sequesters and antibiotic treatment produced a clinical improvement. This rare, refractory complication requires the joint efforts of hematologists, oncologists, and maxillofacial surgeons to diagnose, manage prophylactically and treat.

Serum levels of OPG, RANKL and RANKL/OPG ratio in newly-diagnosed patients with multiple myeloma. Clinical correlations.

Serum levels of OPG and RANKL and their clinical correlations were analyzed in 66 newly-diagnosed patients with multiple myeloma (MM). RANKL and RANKL /OPG ratio were significantly increased in advanced clinical stages and high grade myeloma bone disease (MBD), while OPG showed a tendency to decrease. Renal failure modified the expression of OPG. RANKL and RANKL/OPG ratios are informative markers for myeloma tumor burden and MBD.

Multiple Myeloma with Advanced Bone Disease and Low Tumor Burden - Different Clinical Presentation but Similar Outcome after Bortezomib-Based Therapy and Radiotherapy.

There is a small but well recognized group of patients with multiple myeloma (MM), characterized by multiple bone lesions and low tumor burden, the so-called macrofocal form of MM (MF-MM). The aim of the study was to analyze the incidence, clinical manifestation, therapeutic outcome and prognosis of patients with MF-MM treated with bortezomib-based therapy and radiotherapy, in comparison to classic MM. There were 148 MM patients treated with bortezomibbased regimens, with 15 (10.1%) of them meeting the criteria for MF-MM. Comparative analysis involved disease- and therapy-related variables and markers of bone metabolism in MF-MM and classic MM groups. Event-free survival (EFS) and median survival (MS) were analyzed. Patients in MF-MM and classic MM groups had similar mean age and sex distribution. Patients with MF-MM had advanced myeloma bone disease (MBD), significantly lower clonal plasma cell infiltration in bone marrow, and lower paraprotein level. These patients were predominantly in an early International Staging System stage, showed non-secretory and light-chain variants, and significant association with extramedullary plasmacytomas. EFS was 20 months in MF-MM group versus 13 months in classic MM group (nonsignificant difference). MS was 42 months in both MF-MM and classic MM groups. MF-MM presents with imbalance of the minimal tumor burden and massive bone involvement. Along with advanced skeletal manifestations, these patients showed features of preserved bone marrow and no end-organ damages. Following bortezomib-based therapy and radiotherapy, the EFS and MS did not differ between MF-MM and classic MM groups.

Bone lesions in multiple myeloma--the OPG/RANK-ligand system.

Multiple myeloma has recently been found to induce considerable imbalance in the newly identified system of osteoprotegerin (OPG), receptor activator of nuclear factor KB ligand (RANKL) and RANK. The binding of RANKL to RANK on the surface of osteoclastic precursors in the presence of m-CSF activates the signalling pathways for differentiation and proliferation of an osteoclastic line. OPG is a decoy circulating receptor for RANKL which blocks its binding to RANK. There are at least three mechanisms by which myeloma cells affects the OPG/ RANKL/RANK system: 1: The adhesion between the myeloma / stromal cells and the osteoblastic precursors stimulates the system by increasing the production of RANKL. 2: Some myeloma lines produce independently membrane-bound or free RANKL. 3: The normal and mutated plasma cells bind, degrade and block the OPG production from the stromal cells. The OPG/RANKL/RANK system is the latest therapeutic target in the treatment of myeloma bone disease. The first results from the application of a synthetic analogue of OPG, as well as of RANKL antagonists or RANK inhibitors show decrease of the number of osteoclasts, osteolytic lesions and M-gradient.

Treatment with fluorated quinolones of febrile neutropenia in patients with hematologic malignancies.

UNLABELLED: The use of fluoroquinolones in the treatment of cytotoxic therapy-induced febrile neutropenia is controversial. AIM: The aim of the study was to compare the therapeutic effect of fluoroquinolones with that of standard antibiotic regimens in patients with hematologic malignacies and febrile neutropenia following antineoplastic chemotherapy. PATIENTS AND METHODS: This is a prospective randomized study including 129 patients with 141 neutropenic episodes divided into two groups. Fluoroquinolones are used in the trial group and broad-spectrum beta-lactam antibiotics in the control group. The data are analyzed using alternative analysis, non-parametrical chi-square test and Student-Fisher t-test. RESULTS: The febrile neutropenic episodes were classified as fever of unknown origin (50.4%) and documented infection (49.6%). In the category "fever of unknown origin" no statistically significant difference was found in the clinical effect, patient survival, general and infectious lethality between the trial and control group. In the category "documented infection" the trial group showed significantly lower therapeutic effect and lower infection-free survival of the patients. The clinical effect and infection-free survival after treatment with fluoroquinolones were significantly lower in the category "documented infection" than in the category "fever of unknown origin". CONCLUSION: Fluoroquinolones can be alternative drugs to the standard antibiotic regimens in the treatment of febrile neutropenia in cases of fever of unknown origin. Fluoroquinolone monotherapy is not recommended in cases of febrile neutropenia with documented infection.

A case of encephalomyelopolyneuropathy in vitamin B12 deficiency.

UNLABELLED: A case of a 44-years-old patient with unusual clinical presentation of encephalomyelopolyneuropathy in vitamin B12 deficiency is presented. The disease manifested itself with gastrointestinal bleeding, which necessitated emergency hospitalisation in surgical clinic. Clinical examinations revealed atrophic gastritis, pernicious anemia, neurological and mental complications. The diagnosis was made according to the following criteria: physical examination--smooth tongue, atrophic gastritis, mild hepatosplenomegaly; laboratory findings--pernicious anemia, low vitamin B12 serum levels; neurological examination--syndrome of combined damage of the posterior and lateral columns of the spinal cord; magnetic resonance imaging--typical hyperintense areas on T2-weighted images in the posterior columns in the cervical regions of the spinal cord; transcranial magnetic stimulation--prolonged central motor conduction time of the motor evoked potentials bilaterally; psychological examination--cognitive decline. After treatment with vitamin B12 an improvement of the hematological findings, neurological deficit and cognitive impairments was found. CONCLUSION: Neurological complications could be an early manifestation of vitamin B12 deficiency. In diagnostic aspect similar complaints require examination of the serum levels of vitamin B12. The delay in diagnosis and inadequate therapy bear the risk of incomplete recovery of the neurological deficit. The current problem of "cognitive decline" necessitates routine examination of the serum levels of vitamin Bl2 in all patients with initial cognitive impairments and their prompt and approapriate treatment.

Bisphosphonate-associated osteonecrosis of the jaws -- report of three cases in Bulgaria and review of the literature.

A severe complication of the administration of bisphosphonate-containing medications is known as bisphosphonate-associated osteonecrosis of the jaws (BONJ). A case series of three patients affected by BONJ is presented. These patients currently represent the only described cases of BONJ in Bulgaria. Exposed necrotic bone of the mandible was observed in two patients and the maxilla was affected in the third case. Two of the patients had been treated with zoledronate for metastatic prostate cancer and one patient for metastatic endometrioid cancer. All three patients underwent surgical treatment. One of the patients received conservative surgical debridement, i.e. removal of necrotic bone only, and primary wound closure. Conservative surgical debridement and application of local medications without wound closure were used in the other two patients. All three patients received systemic antibiotic treatment. No evidence of disease progression was observed during the follow-up period of 3 to 12 months. The surgical approach utilized in the present study is discussed in the light of the etiopathogenesis, prevention and treatment of BONJ.

Phase III randomized study of bendamustine compared with chlorambucil in previously untreated patients with chronic lymphocytic leukemia.

PURPOSE: This randomized, open-label, parallel-group, multicenter study was designed to compare the efficacy and safety of bendamustine and chlorambucil in previously untreated patients with advanced (Binet stage B or C) chronic lymphocytic leukemia (CLL). PATIENTS AND METHODS: Patients (