Athanasios Anagnostopoulos

Osteonecrosis of the Jaw in Cancer After Treatment With Bisphosphonates: Incidence and Risk Factors

PURPOSE Osteonecrosis of the jaw (ONJ) has been associated recently with the use of pamidronate and zoledronic acid. We studied the incidence, characteristics, and risk factors for the development of ONJ among patients treated with bisphosphonates for bone metastases. PATIENTS AND METHODS ONJ was assessed prospectively since July 2003. The first bisphosphonate treatment among patients with ONJ was administered in 1997. Two hundred fifty-two patients who received bisphosphonates since January 1997 were included in this analysis. RESULTS Seventeen patients (6.7%) developed ONJ: 11 of 111 (9.9%) with multiple myeloma, two of 70 (2.9%) with breast cancer, three of 46 (6.5%) with prostate cancer, and one of 25 (4%) with other neoplasms (P = .289). The median number of treatment cycles and time of exposure to bisphosphonates were 35 infusions and 39.3 months for patients with ONJ compared with 15 infusions (P < .001) and 19 months (P = .001), respectively, for patients with no ONJ. The incidence of ONJ increased with time to exposure from 1.5% among patients treated for 4 to 12 months to 7.7% for treatment of 37 to 48 months. The cumulative hazard was significantly higher with zoledronic acid compared with pamidronate alone or pamidronate and zoledronic acid sequentially (P < .001). All but two patients with ONJ had a history of dental procedures within the last year or use of dentures. CONCLUSION The use of bisphosphonates seems to be associated with the development of ONJ. Length of exposure seems to be the most important risk factor for this complication. The type of bisphosphonate may play a role and previous dental procedures may be a precipitating factor.

Bortezomib reduces serum dickkopf-1 and receptor activator of nuclear factor-κB ligand concentrations and normalises indices of bone remodelling in patients with relapsed multiple myeloma

The effect of bortezomib on bone remodelling was evaluated in 34 relapsed myeloma patients. At baseline, patients had increased serum concentrations of dickkopf‐1 (DKK‐1), soluble receptor activator of nuclear factor‐κB ligand (sRANKL), sRANKL/osteoprotegerin ratio, C‐telopeptide of type‐I collagen (CTX) and tartrate‐resistant acid phosphatase isoform‐5b (TRACP‐5b); bone‐alkaline phosphatase and osteocalcin were reduced. Serum DKK‐1 correlated with CTX and severe bone disease. Bortezomib administration significantly reduced serum DKK‐1, sRANKL, CTX, and TRACP‐5b after four cycles, and dramatically increased bone‐alkaline phosphatase and osteocalcin, irrespective of treatment response. This is the first study showing that bortezomib reduces DKK‐1 and RANKL serum levels, leading to the normalisation of bone remodelling in relapsed myeloma.

Diagnosis and Management of Waldenstrom's Macroglobulinemia

PURPOSE To review the diagnostic criteria, prognostic factors, response criteria, and treatment options of patients with Waldenstroms macroglobulinemia (WM). METHODS A review of published reports was facilitated by the use of a MEDLINE computer search and by manual search of the Index Medicus. RESULTS WM should be regarded as a distinct clinicopathologic entity and confined to those patients with lymphoplasmacytoid lymphoma who have demonstrable serum immunoglobulin M monoclonal protein. Treatment decisions should rely on specific clinical and laboratory criteria. Initiation of therapy should not be based on serum monoclonal protein levels per se. The three main choices for systemic primary treatment of symptomatic patients with WM include alkylating agents (chlorambucil), nucleoside analogs (fludarabine and cladribine), and the monoclonal antibody rituximab. There are no data from prospective randomized studies to recommend the use of one first-line agent over another, although consideration of a patients candidacy for autologous stem-cell transplantation (ASCT) should be taken into account to avoid stem cell-damaging agents. There are preliminary data to suggest that combinations of nucleoside analogs and alkylating agents with or without rituximab may improve response rates at the expense of higher toxicity. CONCLUSION WM is a distinct low-grade lymphoproliferative disorder. When therapy is indicated, alkylating agents, nucleoside analogs, and rituximab are reasonable choices. Several factors, including the presence of cytopenias, need for rapid disease control, candidacy for ASCT, age, and comorbidities, should be taken into consideration when choosing the most appropriate primary treatment.

Treatment of light chain (AL) amyloidosis with the combination of bortezomib and dexamethasone

Background and Objectives High-dose melphalan and autologous stem cell transplantation is currently the treatment of choice for selected patients with AL amyloidosis; however, new treatments are needed for patients who are ineligible for or relapse after this procedure. Bortezomib is a proteasome inhibitor with proven activity in multiple myeloma, and the addition of dexamethasone results in superior outcome. We evaluated the activity and feasibility of the combination of bortezomib and dexamethasone (BD) in patients with AL amyloidosis. Design and Methods Consecutive patients with histologically proven, symptomatic AL amyloidosis were treated with BD. Results Eighteen patients, including seven who had relapsed or progressed after previous therapies were treated with BD. Eleven (61%) patients had two or more organs involved; kidneys and heart were affected in 14 and 15 patients, respectively. The majority of patients had impaired performance status and high brain natriuretic peptide values; serum creatinine was elevated in six patients. Among evaluable patients, 94% had a hematologic response and 44% a hematologic complete response, including all five patients who had not responded to prior high dose dexamethasone-based treatment and one patient under dialysis. Five patients (28%) had a response in at least one affected organ. Hematologic responses were rapid (median 0.9 months) and median time to organ response was 4 months. Neurotoxicity, fatigue, peripheral edema, constipation and exacerbation of postural hypotension were manageable although necessitated dose adjustment or treatment discontinuation in 11 patients. Interpretation and Conclusions The combination of BD is feasible in patients with AL amyloidosis. Patients achieve a rapid hematologic response and toxicity can be managed with close follow-up and appropriate dose adjustment. This treatment may be a valid option for patients with severe heart or kidney impairment.

Serum concentrations of Dickkopf-1 protein are increased in patients with multiple myeloma and reduced after autologous stem cell transplantation.

Dickkopf‐1 (DKK‐1) protein, a soluble inhibitor of Wnt signalling, has been implicated in the pathogenesis of myeloma bone disease through the suppression of osteoblast differentiation. In this study, serum concentrations of DKK‐1 were measured in 50 myeloma patients (32 at diagnosis and 18 before and after autologous stem cell transplantation (ASCT), 18 patients with monoclonal gammopathy of undetermined significance (MGUS), and 22 healthy controls. Serum DKK‐1 levels were increased in MM at diagnosis compared with MGUS (mean ± SD: 67 ± 54 ng/mL vs. 38 ± 13 ng/mL; p = 0.006) and controls (31 ± 11 ng/mL; p = 0.02), while there was no difference between MGUS patients and controls. Although patients with stage 2 and 3 myeloma had higher DKK‐1 values than stage 1 patients (79 ± 63 vs. 40 ± 13; p = 0.005), no significant correlation between serum DKK‐1 and myeloma bone disease was observed. Myeloma patients before ASCT also had increased levels of DKK‐1 (63 ± 77 ng/mL; p = 0.03) compared with controls, supporting the notion that DKK‐1 may be responsible for the suppressed osteoblast activity even in patients with low tumor burden. After ASCT, there was a sustained decrease in DKK‐1 levels over time, while bone formation markers elevated, suggesting that the reduction of DKK‐1 levels after ASCT may correlate with the normalization of osteoblast function. These results could provide the basis for developing agents that block DKK‐1, thus restoring osteoblast function and counteracting the increased osteoclastogenesis observed in myeloma.

Role of receptor activator of nuclear factor-kappa B ligand (RANKL), osteoprotegerin and macrophage protein 1-alpha (MIP-1a) in monoclonal gammopathy of undetermined significance (MGUS)

The aim of this study was to evaluate the role of markers of bone remodelling, and osteoclast activation/function in patients with monoclonal gammopathy of undetermined significance (MGUS). We have measured serum levels of soluble RANKL (sRANKL), osteoprotegerin (OPG), macrophage inflammatory protein‐1alpha (MIP‐1α), markers of bone resorption [N‐telopeptide of collagen type‐I (NTX), and tartrate‐resistant acid phosphatase isoform‐5b (TRACP‐5b)] and bone formation [bone‐alkaline phosphatase (bALP)] in 40 MGUS patients. These parameters were compared with those of 42 newly diagnosed myeloma patients, and 45 healthy, gender‐ and age‐matched controls. MGUS patients had elevated levels of NTX, sRANKL, and sRANKL/OPG ratio compared with controls (P < 0·0001). Furthermore, TRACP‐5b, MIP‐1α and NTX were decreased in patients with MGUS compared with myeloma patients (P < 0·001), while OPG and bALP were increased (P < 0·001). Serum levels of MIP‐1α, as well as TRACP‐5b, and sRANKL/OPG ratio were reduced, while bALP was increased in MGUS patients, even when compared with myeloma patients who had stage I/II disease. These results demonstrate that increased osteoclastogenesis leading to increased bone resorption is present in MGUS but seems to be compensated for by normal bone formation, which is absent in MM. Furthermore MIP‐1α, bALP, and sRANKL/OPG may be useful tools for distinguishing between cases of MGUS and early myeloma.

Treatment of patients with metastatic urothelial carcinoma and impaired renal function with single-agent docetaxel

OBJECTIVES To evaluate the efficacy and toxicity of single-agent docetaxel in patients with metastatic urothelial carcinoma and impaired renal function. METHODS Eleven consecutive patients previously untreated for metastatic disease with renal impairment (median serum creatinine level of 2.6 mg/dL) were treated with intravenous docetaxel 100 mg/m2 for 1 hour every 21 days. Granulocyte colony-stimulating factor was administered at a dose of 5 microg/kg/day subcutaneously from days 5 to 14. RESULTS Five of 11 patients achieved a partial response, with time to progression of responding patients ranging from 5 to 22 months or more. The median overall survival rate was 11 months. Renal function improved in 5 of 8 patients with tumor-related renal impairment. Toxicity was primarily hematologic, with 5 patients developing grade 3 or 4 neutropenia; nonhematologic toxicities were manageable. CONCLUSIONS Our preliminary data indicate that single-agent docetaxel therapy may represent an effective therapeutic alternative for patients with advanced urothelial carcinoma and renal insufficiency precluding cisplatin-based combination chemotherapy.

Multiple myeloma in elderly patients: prognostic factors and outcome

Abstract:  Objectives: Purpose of this study was to compare prognostic factors and outcome of patients with multiple myeloma (MM) aged >70 yr at diagnosis with those of younger patients. We also applied the recently proposed International Staging System (ISS) for MM in these patients. Patients and methods: Among 1,162 newly diagnosed, symptomatic MM patients included in our database, 357 (31%) were >70 yr of age. Clinical and laboratory variables were evaluated in patients >70 yr and in younger patients and were assessed for possible correlation with survival in patients >70 yr of age. Results: Most clinical and laboratory features were similar in the two groups of patients but older patients presented more frequently with advanced ISS (P = 0.02). Despite similar response rates to primary treatment, younger patients survived longer than patients >70 yr of age (40 vs. 28 months, P = 0.001). There was a longer survival of younger patients than that of older patients diagnosed with ISS stage 1 (median 71 vs. 54 months, P = 0.007) and ISS stage‐2 patients (median: 38 vs. 26 months, P = 0.0008) but for patients with ISS stage 3 median survival was similarly poor in the younger and older age group (21 and 20 months, P = 0.283). Other variables associated with impaired prognosis were severe anemia, extensive bone marrow plasmacytosis and elevated serum LDH. Conclusions: Older patients with MM present more often with advanced ISS and have significantly shorter survival than younger patients. The ISS retained its prognostic significance within the group of elderly patients.

Treatment of Waldenstrom's macroglobulinemia with rituximab: prognostic factors for response and progression.

Recent data have suggested that rituximab is an active agent for the treatment of Waldenstroms macroglobulinemia (WM). However, the patients that are more likely to benefit have not been clearly defined. In order to address this question we evaluated 52 patients who were treated with single-agent rituximab in the context of prospective studies. Several clinical and laboratory variables were assessed for their correlation with response and time to progression. Twenty-three (44%) patients achieved a partial response after treatment with rituximab. Previously untreated and pretreated patients had the same probability for response. Higher response rates were noted in patients with serum monoclonal protein < 40 g/l, with serum albumin > or = 35 g/l and with kappa light chain. The median time to progression for all patients was 13.8 months. A multivariate analysis indicated that elevated serum monoclonal protein levels and low serum albumin were the dominant variables associated with shorter progression. Presence of two, one or none of these adverse prognostic factors was associated with time to progression of 3.6 months, 11 months and more than 40 months, respectively. We conclude that rituximab is an effective treatment modality for patients with WM. Patients with both low levels of monoclonal protein and normal albumin are the best candidates for treatment with standard dose rituximab.

Serum concentrations of angiogenic cytokines in Waldenstrom macroglobulinaemia: the ratio of angiopoietin-1 to angiopoietin-2 and angiogenin correlate with disease severity

Angiogenesis represents an essential step of disease progression in several haematological malignancies. Microvessel density is increased in 30% of patients with Waldenstrom macroglobulinaemia (WM), but there is very limited information regarding the role of angiogenic cytokines in this disease. Serum levels of vascular endothelial growth factor (VEGF), VEGF‐A, angiogenin, angiopoietin (Ang)‐1 and ‐2, and basic fibroblast growth factor (bFGF) were evaluated in 56 WM patients at different disease phases (24 untreated, 20 relapsed/refractory and 12 patients at remission) and 11 patients with immunoglobulin M type monoclonal gammopathy of undetermined significance (IgM‐MGUS). All patients had increased levels of angiogenin, VEGF, VEGF‐A, and bFGF compared with controls. The Ang‐1/Ang‐2 ratio was reduced in WM but not in IgM‐MGUS patients. Angiogenin levels correlated with disease status: when compared with healthy subjects, patients with IgM‐MGUS and untreated WM patients had increased angiogenin serum levels, which were higher in untreated WM patients than in MGUS. WM patients at remission had lower angiogenin serum levels compared with untreated patients, but these levels were increased again in active disease post‐therapy. Angiogenin also correlated with albumin levels, while VEGF‐A correlated with β2‐microglobulin (β2M). Ang‐1/Ang‐2 ratio showed a strong, negative correlation with β2M, and positive correlation with albumin, haemoglobin and lymphadenopathy. Our results indicate a potential use of angiogenin levels for follow‐up in WM and angiogenic molecules as targets for the development of novel anti‐WM agents.