Nora Viniou

Treatment of Waldenström’s Macroglobulinemia With Rituximab

PURPOSE Waldenströms macroglobulinemia (WM) is a low-grade lymphoplasmacytic lymphoma in which CD20 is usually expressed on tumor cells. There is evidence that patients with WM may benefit from treatment with the anti-CD20 monoclonal antibody rituximab. We performed a prospective phase II study to clearly define the activity of rituximab in patients with this disease. PATIENTS AND METHODS Twenty-seven patients with WM were treated with rituximab 375 mg/m(2) intravenously (IV) for 4 weeks. Three months after completion of rituximab, patients without evidence of progressive disease received repeat 4-week courses of this agent. All patients were symptomatic, their median age was 72 years, and 15 patients were previously untreated. RESULTS Twelve patients (44%; 95% confidence interval, 25.5% to 64.7%) achieved a partial response after treatment with rituximab. Median time to response was 3.3 months (range, 2.2 to 7.1 months). Responses occurred in six (40%) of 15 previously untreated patients and in six (50%) of 12 pretreated patients. Patients with a serum immunoglobulin M less than 40 g/L had a significantly higher response rate. The median time to progression for all patients was 16 months, and with a median follow-up of 15.7 months, nine of 12 responding patients remain free of progression. Treatment with rituximab was well tolerated, with approximately one fourth of patients experiencing some mild form of infusion-related toxicity, usually fever and chills. CONCLUSION Our prospective data indicate that rituximab is well tolerated and active in patients with WM. Previously untreated and pretreated patients seem to benefit equally. Repeat 4-week courses of rituximab may prolong the duration of response of the disease, but this observation requires confirmation in prospective, randomized trials. Furthermore, studies that will combine rituximab with chemotherapy may be relevant.

Treatment of Waldenstrom's macroglobulinemia with thalidomide

PURPOSE We performed a prospective phase II study to assess the activity of thalidomide in patients with Waldenstroms macroglobulinemia (WM). PATIENTS AND METHODS Twenty patients with WM were treated with thalidomide at a starting dose of 200 mg daily with dose escalation in 200-mg increments every 14 days as tolerated to a maximum of 600 mg. All patients were symptomatic, their median age was 74 years, and 10 patients were previously untreated. RESULTS On an intent-to-treat basis, five (25%) of 20 patients achieved a partial response after treatment. Responses occurred in three of 10 previously untreated and in two of 10 pretreated patients. None of the patients treated during refractory relapse or with disease duration exceeding 2 years responded to thalidomide. Time to response was short, ranging between 0.8 months to 2.8 months. Adverse effects were common but reversible and consisted primarily of constipation, somnolence, fatigue, and mood changes. The daily dose of thalidomide was escalated to 600 mg in only five patients (25%), and in seven patients (35%), this agent was discontinued within 2 months because of intolerance. CONCLUSION Our data indicate that thalidomide has activity in WM but only low doses were tolerated in this elderly patient population. Confirmatory studies as well as studies that will combine thalidomide with chemotherapy or with rituximab may be relevant.

Tartrate-resistant acid phosphatase isoform 5b: a novel serum marker for monitoring bone disease in multiple myeloma.

Tartrate‐resistant acid phosphatase isoform‐5b (TRACP‐5b), a new marker reflecting osteoclast activity, and osteoprotegerin (OPG) were measured in 121 patients with multiple myeloma (MM) at diagnosis, and in 63 of them during pamidronate administration, to define their correlation with the extent of bone disease and disease activity in MM. Radiographic evaluation of the skeleton, measurement of other markers of bone remodelling, including N‐terminal cross‐linking telopeptide of type‐I collagen (NTX), bone alkaline phosphatase and osteocalcin and of markers of disease activity (beta2‐microglobulin, paraprotein, interleukin‐6 (IL‐6), were also performed. Levels of TRACP‐5b were increased (p < .0001), while OPG was decreased in MM patients compared to controls (p < .01). TRACP‐5b levels were associated with the radiographically assessed severity of bone disease (p < .0001) as well as with levels of NTX, IL‐6 and beta2‐microglobulin (p < .001, for each biochemical parameter, respectively). The combination of pamidronate with VAD‐chemotherapy produced a reduction in TRACP‐5b, NTX, IL‐6, paraprotein and beta2‐microglobulin levels from the 2nd month of treatment, with no effect on bone formation and OPG. A strong correlation was observed between changes in TRACP‐5b and changes in NTX, IL‐6 and beta2‐microglobulin, while TRACP‐5b predicted the disease progression in 5 patients. These findings suggest that TRACP‐5b is increased in MM, reflects the extent of myeloma bone disease and may have a predictive value. TRACP‐5b has also proved to be very useful for monitoring antimyeloma treatment, which had no effect on OPG levels.

Effect of pamidronate administration on markers of bone turnover and disease activity in multiple myeloma.

Abstract: Aim: Bisphosphonates are potent inhibitors of osteoclastic activity and are used in the treatment of multiple myeloma (MM) in combination with chemotherapy. The effect of pamidronate on markers of bone resorption [cross‐linked N‐telopeptides of type I collagen (NTx)], markers of bone formation [serum alkaline phosphatase (BAP) and osteocalcin (OSC)], interleukin‐6 (IL‐6), β2‐microglobulin, CRP, paraprotein and disease‐related pain and skeletal events has been evaluated in 62 newly diagnosed patients with MM. Patients and methods: The patients were randomly assigned to two groups: the first included 32 patients under chemotherapy and pamidronate (group I) and the second 30 patients on chemotherapy only (group II). Pamidronate was administered at a monthly dose of 90 mg iv, and the above parameters were evaluated at the beginning of this study and after 1, 3, 6, 9, 12 and 14 months of treatment. Results: The addition of pamidronate to chemotherapy resulted in a significant reduction of NTx, IL‐6 and paraprotein from the 3rd month and of β2‐microglobulin, CRP and pain from the 6th month of treatment. No changes of NTx, IL‐6, β2‐microglobulin, CRP or skeletal events were observed in patients of group II, while paraprotein was significantly reduced after 6 months of treatment. The differences in NTx, IL‐6, paraprotein and β2‐microglobulin were statistically significant between the two groups. Multivariate analysis revealed a significant correlation between changes of NTx, changes of IL‐6 in both groups and reduction of pain and paraprotein in group I. Conclusions: These results suggest that pamidronate may have a synergistic action with chemotherapy in decreasing osteoclastic activity, in reducing markers of myeloma activity and myeloma related pain and in improving the quality of life in patients with MM.

Significance of macrophage inflammatory protein-1 alpha (MIP-1α) in multiple myeloma

Macrophage inflammatory protein-1 alpha (MIP-1α) is a member of the CC chemokine family and is primarily associated with cell adhesion and migration. It is produced by myeloma (MM) cells and directly stimulates osteoclast formation and differentiation in a dose dependent way. MIP-1α protein levels were elevated in the bone marrow plasma of MM patients and correlated with disease stage and activity. MIP-1α was also elevated in the serum of myeloma patients with severe bone disease and correlated positively with bone resorption markers providing evidence for a causal role of MIP-1α in the development of lytic bone lesions in MM. MIP-1α has also been found to stimulate proliferation, migration and survival of plasma cells. Mice, which were inoculated with myeloma cells and treated with a monoclonal rat anti-mouse MIP-1α antibody, showed a reduction of both paraprotein and lytic lesions. In addition, MIP-1α enhanced adhesive interactions between myeloma and marrow stromal cells, increasing the expression of RANKL and IL-6, which further increased bone destruction and tumor burden. Myeloma patients with high MIP-1α serum levels have poor prognosis. The positive correlation between MIP-1α and β2-microglobulin that has been observed in MM patients at diagnosis further supports the notion that MIP-1α is not only a chemokine with osteoclast activity function but is also implicated in myeloma growth and survival. Therefore, MIP-1α pathway may serve as a target for the development of novel anti-myeloma therapies.

Pamidronate is superior to ibandronate in decreasing bone resorption, interleukin‐6 and β2‐microglobulin in multiple myeloma

Abstract: Objectives: Bisphosphonates have been found to reduce skeletal events in patients with multiple myeloma (MM). This is the first randomised trial to compare the efficacy of pamidronate and ibandronate, a third‐generation aminobisphosphonate, in bone turnover and disease activity in MM patients. Methods: Patients with MM, stage II or III, were randomly assigned to receive either pamidronate 90 mg (group I: 23 patients) or ibandronate 4 mg (group II: 21 patients) as a monthly intravenous infusion in addition to conventional chemotherapy. Skeletal events, such as pathologic fractures, hypercalcaemia, and bone radiotherapy were analysed. Bone resorption markers [N‐terminal cross‐linking telopeptide of type‐I collagen (NTX) and tartrate‐resistant acid phosphatase type 5b (TRACP‐5b)], bone formation markers (bone alkaline phosphatase and osteocalcin), markers of disease activity (paraprotein, CRP, β2‐microglobulin), and interleukin‐6 (IL‐6) were also studied. Results: In both groups, the combination of chemotherapy with either pamidronate or ibandronate produced a reduction in bone resorption and tumour burden as measured by NTX, IL‐6, paraprotein, CRP, and β2‐microglobulin from the second month of treatment, having no effect on bone formation. TRACP‐5b also had a significant reduction in the pamidronate group from the second month of treatment and in the ibandronate group from the sixth month. However, there was a greater reduction of NTX, IL‐6, and β2‐microglobulin in group I than in group II, starting at the second month of treatment (P = 0.002, 0.001, and 0.004, respectively) and of TRACP‐5b, starting at the fourth month (P = 0.014), that being continued throughout the 10‐month follow‐up of this study. There was no difference in skeletal events during this period. A significant correlation was observed between changes of NTX and changes of TRACP‐5b, IL‐6, and β2‐microglobulin from the second month for patients of both groups. Conclusions: These results suggest that a monthly dose of 90 mg of pamidronate is more effective than 4 mg of ibandronate in reducing osteoclast activity, bone resorption, IL‐6, and possibly tumour burden in MM. TRACP‐5b has also proved to be a useful new marker for monitoring bisphosphonates treatment in MM.

Recurrent ETNK1 mutations in atypical chronic myeloid leukemia

Despite the recent identification of recurrent SETBP1 mutations in atypical chronic myeloid leukemia (aCML), a complete description of the somatic lesions responsible for the onset of this disorder is still lacking. To find additional somatic abnormalities in aCML, we performed whole-exome sequencing on 15 aCML cases. In 2 cases (13.3%), we identified somatic missense mutations in the ETNK1 gene. Targeted resequencing on 515 hematological clonal disorders revealed the presence of ETNK1 variants in 6 (8.8%) of 68 aCML and 2 (2.6%) of 77 chronic myelomonocytic leukemia samples. These mutations clustered in a small region of the kinase domain, encoding for H243Y and N244S (1/8 H243Y; 7/8 N244S). They were all heterozygous and present in the dominant clone. The intracellular phosphoethanolamine/phosphocholine ratio was, on average, 5.2-fold lower in ETNK1-mutated samples (P < .05). Similar results were obtained using myeloid TF1 cells transduced with ETNK1 wild type, ETNK1-N244S, and ETNK1-H243Y, where the intracellular phosphoethanolamine/phosphocholine ratio was significantly lower in ETNK1-N244S (0.76 ± 0.07) and ETNK1-H243Y (0.37 ± 0.02) than in ETNK1-WT (1.37 ± 0.32; P = .01 and P = .0008, respectively), suggesting that ETNK1 mutations may inhibit the catalytic activity of the enzyme. In summary, our study shows for the first time the evidence of recurrent somatic ETNK1 mutations in the context of myeloproliferative/myelodysplastic disorders.

Leukemogenic risk of hydroxyurea therapy as a single agent in polycythemia vera and essential thrombocythemia: N- and K-ras mutations and microsatellite instability in chromosomes 5 and 7 in 69 patients.

Polycythemia vera (PV) and essential thrombocythemia (ET) are chronic myeloproliferative diseases that carry intrinsically the potential for leukemic transformation. The aims of this study were (1) to detect involvement of N-and K-ras mutations in codons 12 and 13 in the pathogenesis of the chronic and blastic phases of PV and ET, (2) to study the occurrence of microsatellite instability (MSI) in chromosomes 5 and 7 during the chronic phase and blastic transformation of the disease, and (3) to examine the incidence of leukemia in patients treated with hydroxyurea (HU). Samples of PV and ET patients were analyzed with a polymerase chain reaction. No N-or K-ras mutations were detected. A positive score for MSI in chromosome 7 was found in 1 patient with PV during leukemic transformation. Three of 69 patients developed acute myelogenous leukemia, 2 with PV and 1 with ET. As of this report, the overall incidence of leukemic transformation is 5.7% (2/35 patients) in PV and 3.3% (1/30 patients) in ET patients treated with HU. These results indicate that (1) MSI is a genetic marker that can be detected, even in a small group of patients, at the blastic phase of the disease and (2) no increased leukemogenicity was noted in this group of patients treated with HU.

Detection of CD55- and/or CD59-Deficient Red Cell Populations in Patients With Plasma Cell Dyscrasias

Paroxysmal nocturnal hemoglobinuria (PNH) is an acquired clonal disorder characterized by a decrease or absence of gly-cosylphosphatidylinositol (GPI)-anchored molecules such as CD55 and CD59 from the surface of affected cells, resulting in intravascular hemolysis, cytopenia, and venous thrombosis. A PNH-like phenotype has been detected in various hematologi-cal disorders, mainly in aplastic anemia and myelodysplastic syndromes, but also in lymphoproliferative syndromes (LPSs).To the best of our knowledge, CD55- or CD59-deficient red cells have not been detected in plasma cell dyscrasias (PCDs). The aim of this study was the detection of CD55- and/or CD59-deficient red cell populations in patients with PCD. Seventy-seven patients were evaluated; 62 with multiple myeloma (MM), 7 with Waldenström macroglobulinemia (WM), 6 with monoclonal gammopathy of undetermined significance (MGUS), and 2 with heavy chain disease (HCD). The sephacryl gel microtyping system was applied; Ham and sucrose lysis tests were also performed on all samples with CD55- or CD59-negative populations. Red cells deficient in both molecules were detected in 10 (12.9%) of 77 patients with PCD: 2 (28.6%) of 7 with WM, 1 (16.6%) of 6 with MGUS, 6 (9.6%) of 62 with MM, and 1 of 2 patients with HCD. Isolated CD55 deficiency was found in 28.5% of all PCD patients, whereas isolated CD59 deficiency was not observed in any patients.These findings illustrate the existence of the PNH phenotype in the red cells of patients with PCD; further investigation is needed into the mechanisms and significance of this phenotype.

Behcet's Disease in a Patient With Chronic Myelogenous Leukemia Under Hydroxyurea Treatment: A Case Report and Review of the Literature

Behcets disease (BD) is a chronic, relapsing vasculitis of unknown etiology. Its association with chronic myelogenous leukemia (CML) is extremely rare, and typical manifestations of BD were observed in a very few patients with CML, mainly under interferon‐alpha (IFN‐α) treatment. Skin pathergy test, being positive in about 50% of patients with BD, is also positive in some IFN‐α‐treated patients with CML without any evidence of BD symptoms. We describe a 62‐year‐old woman with CML who developed characteristic features of BD, including a positive skin hyperactivity test, during treatment with hydroxyurea. Hydroxyurea has been implicated in the appearance of skin vasculitic ulceration, but this is the first case, according to our knowledge, where the development of BD was observed during hydroxyurea maintenance in the chronic phase of CML. Am. J. Hematol. 66:57–58, 2001.