Gianmatteo Pica

A different schedule of zoledronic acid can reduce the risk of the osteonecrosis of the jaw in patients with multiple myeloma

Osteonecrosis of the jaw (ONJ) is a reported complication of bisphosphonate use. The incidence ranges between 6 and 13% and seems to be higher in people treated with zoledronic acid (ZA) than with pamidronate. We retrospectively evaluated the incidences of ONJ and skeletal-related events (SRE) in 106 patients with multiple myeloma divided in two groups according to the schedule of administration of bisphosphonates: 51 received monthly administrations until tolerated (group A, standard schedule), 55 were treated monthly during the first year and then every 3 months (group B, reduced schedule). The incidence of SRE was similar (15.1 per 100 person years in group A and 17.7 in group B). ONJ occurred in seven patients, six in group A and one in group B (P=0.049). The risk of ONJ was eight-fold lower with the reduced schedule than with the standard schedule. The only significant risk factor for ONJ was the type of bisphosphonate (P=0.006). The incidence of ONJ was significantly higher with ZA than with pamidronate + ZA (9.1 vs 1.6 per 100 person-years). No ONJ was observed in patients treated only with pamidronate. A reduced schedule of ZA may be safer than the standard schedule while maintaining anti-resorptive efficacy.

WT1 overexpression at diagnosis may predict favorable outcome in patients with de novo non-M3 acute myeloid leukemia

Abstract We reviewed the frequency and prognostic significance of FLT3 (fms-like tyrosine kinase receptor-3) and NPM (nucleophosmin) gene mutations and WT1 (Wilms’ tumor) and BAALC (brain and acute leukemia, cytoplasmic) gene expression in 100 consecutive patients with intermediate and poor cytogenetic risk de novo acute myeloid leukemia (AML) receiving conventional anthracycline–AraC based therapy. We observed a strict relationship between unfavorable karyotype and BAALC >1000 (p = 0.0001). Multivariate analysis of 81 patients with intermediate karyotype revealed that younger age (p = 0.00009), NPM gene mutation (p = 0.002), and WT1 >75th percentile (>2365) (p = 0.003) were independent, positive factors for complete remission (CR). WT1 expression above 2365 was correlated also to longer event-free survival (EFS) and overall survival (OS) in the same subset of patients (p = 0.003 and p = 0.02, respectively); the same finding occurred in younger patients with AML with intermediate karyotype (p = 0.008 and p = 0.01, respectively). In patients with intermediate karyotype, FLT3 internal tandem duplication (ITD) negatively affected EFS (EFS at 30 months: 30% vs. 6% in FLT3-ITD negative and FLT3 positive patients, respectively; p = 0.01) and OS (OS at 30 months: 38% vs. 20%, p = 0.03). The positive prognostic value of high WT1 expression does not have a clear explanation; it may be implicated either with WT1 anti-oncogenic function, or with the stimulating effect of WT1 oncogene on the leukemic cellular cycle, possibly associated with an enhanced response to chemotherapy.

Kinase domain mutations of BCR-ABL identified at diagnosis before imatinib-based therapy are associated with progression in patients with high Sokal risk chronic phase chronic myeloid leukemia

Acquired resistance to imatinib in the advanced phase of chronic myeloid leukemia (CML) has been associated with mutations in the kinase domain (KD) of BCR-ABL. On the contrary, the prognostic implication of KD mutations in early chronic phase (CP) patients at diagnosis before imatinib-based therapy has not yet been established. We have reviewed the status of mutations in 43 patients with early CP-CML on the samples collected at diagnosis. Mutations were identified by direct sequencing (DS) with BidDye Terminator v 1.1. cycle sequencing kit and analyzed with a 3130 ABI capillary electrophoresis system. Eight out 13 (61.5%) high Sokal risk patients showed the following mutations: Y253C, S265R, E255K, F359Y, N374S, E255V, E255V, E255V. Three patients progressed during imatinib and second-line inhibitors and died of blastic phase CML at 23, 33, and 69 months. Another patient with intermediate Sokal risk showed D363G mutation at diagnosis, progressed under imatinib, was allografted and he is now alive in major molecular remission (MMR). No low-risk patient carried KD mutation at diagnosis. In conclusion, KD mutations conferring high-level imatinib resistance are present in patients with de novo CML and in some of them lead to disease progression.

Changing pattern of presentation in monoclonal gammopathy of undetermined significance: a single-center experience with 1400 patients.

To assess whether the pattern of presentation and the outcome of monoclonal gammopathy of undetermined significance (MGUS) have changed over the last 3 decades, we evaluated 1400 patients, divided into 3 groups: group I (1975-1987), group II (1988-1997), and group III (1998-2007). We observed a significant increase in age (p = 0.001), IgM and biclonal MGUS (p = 0.003), hemoglobin (p < 0.0001), and albumin (p = 0.0001), and a significant reduction of monoclonal (M)-protein concentration (p < 0.0001), percentage of bone marrow plasma cells (p < 0.0001), and &bgr;2-microglobulin (p = 0.0001) over the 3 decades. The proportion of patients with M-protein <1.5 g/dL was significantly higher in group III (66%) than in group II (44%) and group I (26%) (p < 0.0001). By Kaplan-Meier analysis, group III had a significantly lower 5-year probability of transformation (5%) compared to group II (12%) and group I (22%) (p = 0.003). Patients with M-protein <1.5 g/dL had the same life expectancy as the general population (standardized mortality ratio 1.09; p = 0.41). In conclusion, we found that the pattern of presentation of MGUS has changed over time and now includes a higher proportion of patients with more favorable presenting features and probably a better outcome compared to patients presenting in the past. This changing scenario calls for revising the current concepts of the clinical significance of MGUS and the management of patients. Abbreviations: BMPC = bone marrow plasma cells, FLC = free light chains, M = monoclonal, MGUS = monoclonal gammopathy of undetermined significance, SMR = standardized mortality ratio.

PBSC mobilization in lymphoma patients: analysis of risk factors for collection failure and development of a predictive score based on the kinetics of circulating CD34+ cells and WBC after chemotherapy and G-CSF mobilization

Autologous stem cell transplantation (ASCT) is a potentially curative treatment of lymphoma, but peripheral blood stem cell (PBSC) mobilization fails in some patients. PBSC mobilizing agents have recently been proved to improve the PBSC yield after a prior mobilization failure. Predictive parameters of mobilization failure allowing for a preemptive, more cost‐effective use of such agents during the first mobilization attempt are still poorly defined, particularly during mobilization with chemotherapy + granulocyte colony‐stimulating factor (G‐CSF). We performed a retrospective analysis of a series of lymphoma patients who were candidates for ASCT, to identify factors influencing PBSC mobilization outcome. Premobilization parameters—age, histology, disease status, mobilizing protocol, and previous treatments—as well as white blood cell (WBC) and PBSC kinetics, markers potentially able to predict failure during the ongoing mobilization attempt, were analyzed in 415 consecutive mobilization procedures in 388 patients. We used chemotherapy + G‐CSF in 411 (99%) of mobilization attempts and PBSC collection failed (<2 × 106 CD34+ PBSC/kg) in 13%. Multivariable analysis showed that only a low CD34+ PBSC count and CD34+ PBSC/WBC ratio, together with the use of nonplatinum‐containing chemotherapy, independently predicted mobilization failure. Using these three parameters, we established a scoring system to predict risk of failure during mobilization ranging from 2 to 90%, thus allowing a selective use of a preemptive mobilization policy. Copyright

Efficacy and safety of fotemustine for the treatment of relapsed and refractory multiple myeloma patients

To the editor: Multiple Myeloma (MM) is highly sensitive to alkylating agent, particularly to melphalan. Despite the emerging role of new biological agents (thalidomide, lenalidomide, bortezomib), melphalan still remains a milestone in the treatment of MM (1). It is effective in conjunction with autologous stem cells support (2), as well as conventional dose therapy with prednisone with or without new drugs [melphalan, prednisone, revlimid (MPR), melphalan, prednisone, thalidomide (MPT), velcade, melphalan, prednisone (VMP)] (3). Although the outcome has significantly improved in the last decade MM remains incurable. Thus it is important to identify new compounds active against the plasmacell clone. Fotemustine (Muphoran , Servier; Thissen Laboratoires, Braine L’alleud, Belgium) (4), a cytotoxic alkylating agent belonging to the nitrosoureas family, has been successfully used as single agent or in combination for the treatment of neoplasm such as metastatic melanoma and brain tumours. Only one phase II study has been reported in relapsed or refractory MM (5). Here we report our experience with single agent fotemustine used on a compassionate basis in five heavily pre-treated MM patients (two males, three females, and age range 41–64). All patients had a poor performance status and compromised haematological conditions. Two patients had chronic renal failure. All patients had received at least five prior lines of therapy, including thalidomide and bortezomib. We adopted the schedule reported by Dumonet et al. that consists of an induction with two doses of fotemustine 100 mg ⁄m delivered intravenously 1 wk apart. This was followed by a dose of fotemustine 100 mg ⁄m every 3 wks until progression or unacceptable toxicity, to a maximum of 16 administrations. No hospitalisation was required for treatment administration. Table 1 reports the most relevant clinical data and the therapeutic history of each patient. Table 2 summarised haematological characteristics, the type and the incidence of adverse events, and the outcome of treatment according to European group for blood and bone marrow transplant (EMBT) uniform response criteria (6). Two of five patients completed the 16 scheduled doses achieving a partial response (PR). One is in partial remission and the other in progression after 17 and 18 months, respectively, from starting fotemustine. Three patients did not complete the programme: two patients died of progressive disease after 9 months and 4 months of therapy, one patient died of encephalitis while in partial remission after 12 months of therapy. No dose reduction was needed, even in the two patients with renal impairment. Most common grade 4 National cancer institute (NCI) haematological toxicity was thrombocytopenia (20 episodes), followed by neutropenia (six episodes) and anaemia (three episodes). Infection was the most common extraematological toxicity: three episodes of NCI grade 3 infection without neutropenia, one grade 4 febrile neutropenia, one herpes zoster reactivation, a fatal encephalitis. In particular, regarding the adverse event encephalitis, no infectious agent could be identified despite cerebrospinal co-cultures both for bacterial and mycotic agents and polymerase chain reaction for brain tropic viruses were made; no abnormalities were detected in peripheral blood lymphocytes count. In conclusion, fotemustine as a single agent appears manageable and safe for the treatment of heavily pretreated relapsed or refractory MM patients. PR was the best response

A striking response to bortezomib in a patient with pleural localization of multiple myeloma.

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