Alessandra Pompa

Monoclonal gammopathy of undetermined significance: a new proposal of workup

Diagnostic criteria for monoclonal gammopathy of undetermined significance (MGUS) require quantification of bone marrow plasma cells (BMPCs) and skeletal survey to discriminate between MGUS and multiple myeloma (MM). By contrast, recent published guidelines suggest that these procedures could be avoided in the presence of serum monoclonal spike (M‐spike) of small amount (≤1.5 g/dL). Aim of this study is to better quantify the risk of missing a diagnosis of MM, not performing bone marrow aspirate and skeletal survey in patients with M‐spike ≤ 1.5 g/dL asymptomatic for bone pain.

Correlation between burden of 17P13.1 alteration and rapid escape to plasma cell leukaemia in multiple myeloma

Brodsky, R.A., Chen, A.R., Dorr, D., Fuchs, E.J., Huff, C.A., Luznik, L., Smith, B.D., Matsui, W.H., Goodman, S.N., Ambinder, R.F. & Jones, R.J. (2010) High-dose cyclophosphamide for severe aplastic anemia: long-term follow-up. Blood, 115, 2136–2141. Di Bona, E., Rodeghiero, F., Bruno, B., Gabbas, A., Foa, P., Locasciulli, A., Rosanelli, C., Camba, L., Saracco, P., Lippi, A., Lori, A.P., Porta, F., De Rossi, G., Comotti, B., Lacopino, P., Dufour, C. & Bacigalupo, A. (1999) Rabbit antithymocyte globulin (r-ATG) plus cyclosporine and granulocyte colony stimulating factor is an effective treatment for aplastic anaemia patients unresponsive to a first course of intensive immunosuppressive therapy. British Journal of Haematology, 107, 330–334. Kosaka, Y., Yagasaki, H., Sano, K., Kobayashi, R., Ayukawa, H., Kaneko, T., Yabe, H., Tsuchida, M., Mugishima, H., Ohara, A., Morimoto, A., Otsuka, Y., Ohga, S., Bessho, F., Nakahata, T., Tsukimoto, I. & Kojima, S. (2008) Prospective multicenter trial comparing repeated immunosuppressive therapy with stem-cell transplantation from an alternative donor as second-line treatment for children with severe and very severe aplastic anemia. Blood, 111, 1054–1059. Li, X., Shi, J., Ge, M., Shao, Y., Huang, J., Huang, Z., Zhang, J., Nie, N. & Zheng, Y. (2013) Outcomes of optimized over standard protocol of rabbit antithymocyte globulin for severe aplastic anemia: a single-center experience. PLoS One, 8, e56648. Olnes, M.J., Scheinberg, P., Calvo, K.R., Desmond, R., Tang, Y., Dumitriu, B., Parikh, A.R., Soto, S., Biancotto, A., Feng, X., Lozier, J., Wu, C.O., Young, N.S. & Dunbar, C.E. (2012) Eltrombopag and improved hematopoiesis in refractory aplastic anemia. New England Journal of Medicine, 367, 11–19. Passweg, J.R. & Tichelli, A. (2009) Immunosuppressive treatment for aplastic anemia: are we hitting the ceiling? Haematologica, 94, 310–312. Scheinberg, P., Nunez, O. & Young, N.S. (2006) Retreatment with rabbit anti-thymocyte globulin and cyclosporin for patients with relapsed or refractory severe aplastic anaemia. British Journal of Haematology, 133, 622–627. Stevenson, H.C., Green, I., Hamilton, J.M., Calabro, B.A. & Parkinson, D.R. (1991) Levamisole: known effects on the immune system, clinical results, and future applications to the treatment of cancer. Journal of Clinical Oncology, 9, 2052–2066. Tichelli, A., Passweg, J., Nissen, C., Bargetzi, M., Hoffmann, T., Wodnar-Filipowicz, A., Signer, E., Speck, B. & Gratwohl, A. (1998) Repeated treatment with horse antilymphocyte globulin for severe aplastic anaemia. British Journal of Haematology, 100, 393–400. Young, N.S., Calado, R.T. & Scheinberg, P. (2006) Current concepts in the pathophysiology and treatment of aplastic anemia. Blood, 108, 2509– 2519.

Long Term Evaluation of the Impact of Autologous Peripheral Blood Stem Cell Transplantation in Multiple Myeloma: A Cost-Effectiveness Analysis

Background High-dose therapy with autologous peripheral stem cell transplantation represents today the standard approach for younger multiple myeloma patients. This study aimed to evaluate the long term economic impact of autologous transplantation with respect to conventional therapy. Methods We retrospectively reviewed the charts of multiple myeloma patients diagnosed at our department between 1986 and 2003 and treated according to the therapy considered standard at the time of diagnosis. Analysis of costs was done by assessing resource utilization and direct costs were measured and monetized before proceeding with the analysis, based on public health service tariffs. Results Group A including 78 patients treated with Melphalan and Prednisone was compared with Group B including 74 patients who received an autologous transplant. The median overall survival was 3.2 and 5.4 years respectively (p = 0.0002). Mean cost per patient was significantly higher in group B with respect to group A (102373€ vs 23825€; p<0.001). The final quality-adjusted-life-year gain in group B patients as compared to group A was 1.73 QALY, with an incremental cost-effectiveness ratio of 45460€. With a threshold of 75000€ per QALY gained, the cost effectiveness acceptability curve indicated that the probability that autologous transplantation in multiple myeloma is a cost-effective intervention is 90%. Conclusions The cost of autologous transplantation remains high. The calculated incremental cost-effectiveness ratio, however, given the significant prolongation of overall survival obtained with autologous transplantation, is within an acceptable threshold. Notwithstanding, its high cost should be taken into account when considering the whole cost of multiple myeloma.

Serum C terminal telopeptide maintains its correlation with bone disease in patients with myeloma even under treatment with bisphosphonates

Osteolytic disease is a major complication of multiple myeloma (MM) that may lead to devastating skeletal-related events (SREs) such as pathological fractures, vertebral collapse and spinal cord compression. Conventional radiography, although it has limitations (limited sensitivity and specifi city), remains the gold standard for the evaluation of bone disease in patients with MM [1]. Computed tomography (CT), magnetic resonance imaging (MRI) and nuclear medicine imaging are all used in the attempt to increase the possibility of early detection and to better defi ne the extent of bone disease in MM. Nevertheless, these technologies cannot be used routinely because they are expensive and time-consuming; hence they are generally adopted in selected patients. A recent guideline recommends that in monitoring patients with MM after initial staging, radiography, CT or MRI should be performed only when clinically indicated. With this strategy, however, new osteolytic lesions can occur before symptoms become evident and, consequently, can expose patients to the risk of a major skeletal event. Biochemical markers of bone turnover may represent an interesting alternative to monitor bone disease in patients with myeloma. One of the most promising bone markers is the carboxy terminal telopeptide (CTX) of collagen type 1, which refl ects the resorptive osteoclastic activity. Several studies have demonstrated its correlation with the presence of osteolytic lesions, and in some other studies its prognostic role has been also shown. Some studies, however, have underlined how bisphosphonates, by inhibiting osteoclastic activity and consequently decreasing CTX levels, can lessen the importance of this bone marker in monitoring bone disease once treatment with bisphosphonates is undertaken [2 – 6]. Th e aim of this retrospective study was to determine the eff ectiveness of the CTX test in predicting the development of bone disease in patients with MM during bisphosphonate therapy. A cohort of 84 patients out of 838 diagnosed with multiple myeloma and followed at our division between August

Global methylation patterns in primary plasma cell leukemia

Primary plasma cell leukemia (pPCL) is a rare and very aggressive variant of multiple myeloma (MM). Specific clinical, biological and molecular patterns distinguish pPCL from MM. Here, we performed a genome-wide methylation analysis by high-density array in 14 newly diagnosed pPCL patients along with 60 MMs, and 5 patients affected by monoclonal gammopathy of uncertain significance (MGUS). Our analysis revealed a global hypomethylation profile associated with pPCL. Additionally, differential methylation patterns were found related to distinct chromosomal aberrations and DIS3 mutations, affecting genes with roles in bone metabolism, cell migration, transcription regulation or DNA damage response. When compared with MM patients, pPCL showed a distinct methylation profile mostly characterized by hypomethylated probes specific for genes involved in several processes like cell adhesion and migration. Furthermore, decreasing methylation levels were evidenced for genes significantly modulated in the progressive phases of plasma cell dyscrasias, from MGUS to MM and pPCL. Overall, our data provide new insights into the molecular characterization of pPCL, thus being potentially useful in the prognostic stratification or identification of novel molecular targets.

Lamivudine prophylaxis prevents hepatitis B virus reactivation in anti-HBc positive patients under rituximab for non-Hodgkin lymphoma

BACKGOUND A significant proportion of hepatitis B surface antigen (HBsAg) negative/anti-hepatitis B core antigen (anti-HBc) positive patients with non-Hodgkin lymphoma (NHL) undergoing rituximab-based chemotherapy (R-CT) may suffer hepatitis B virus (HBV) reactivation. AIMS We wanted to assess efficacy and safety of lamivudine (LMV) prophylaxis to prevent this complication. METHODS Eighty-five consecutive HBsAg negative/anti-HBc positive NHL patients (71 years, 100% serum HBV DNA undetectable, 74% anti-HBs positive) received LMV coadministered with R-CT and for 18 months after the end of R-CT. Serum ALT, HBsAg, anti-HBs and HBV DNA were assessed every 4 months during and after end of LMV. RESULTS During 39 (2-108) months of study period, including 21 months of LMV and 27 additional months after LMV discontinuation, one patient (2%) had HBV reactivation, 31 months after stopping LMV and during administration of new immunosuppressive regimens, without LMV prophylaxis, owing to incomplete oncological response. A 50% decline of anti-HBs titers occurred in 22/63 (35%) patients, including 12 who became anti-HBs seronegative. Five (6%) patients had ALT increase during R-CT but none required R-CT discontinuation. Seventeen (20%) patients died, all for tumour progression. CONCLUSION LMV prophylaxis is safe and effective in preventing HBV reactivation in HBsAg negative/anti-HBc positive NHL patients receiving R-CT.

Corneal sub-basal neural damage pattern in multiple myeloma patients treated with bortezomib: an in vivo confocal study

Painful sensory peripheral neuropathy represents the main Bortezomib dose-limiting toxicity. Although the once-weekly schedule and the sub-cutaneous administration have significantly improved Bortezomib safety profile, peripheral neuropathy (Bor-PN) still remains relatively frequent [1,2]. In addition, at present, there are no tools for its early identification. The main symptoms of Bor-PN are paresthesias, burning dysesthesias, numbness and, in severe cases, neuropathic pain, which is responsible for treatment discontinuation [3–6]. As far as pathogenesis is concerned, Bor-PN especially affects small un-myelinated fibers (C fibers), causing a neural damage pattern similar to that detected in diabetic peripheral neuropathy [7,8]. The cornea is the most innervated tissue in the human body, especially by small sensitive fibers, is a known site of diabetic neural damage and likely could represent a possible target of Bor-PN. Corneal confocal microscopy (CCM) is a novel rapid, diagnostic technique that allows in vivo detailed visualization of all corneal layers. The noninvasive nature of this technique makes tolerable reiterative examinations on the same patients across time, providing information on the evolving pattern of neural damage. At present, CCM is used for early identification and follow-up of diabetic PN [9–11]. Given the similar pathogenesis of Bortezomib and diabetic neuropathy and the known sensitivity and specificity of CCM for identification of diabetic neural damage, we supposed that CCM could be likely used for early identification of Bortezomib-related PN in Multiple Myeloma (MM) patients. In order to test this hypothesis we designed a pilot study on 26 MM patients treated with Bortezomib compared with 20 healthy controls. The study was approved by our local ethic committee; all patients signed informed consent before confocal microscopy evaluation. Control group morphometric findings were similar to data on a healthy population reported by the literature. PN was evaluated by clinical assessment and graded according to NCI-CTCAE toxicity scale. Among MM patients included in the study, Figure 1. Corneal nerve examination with in vivo confocal microscopy. Example of reduction in length and number and increase of tortuosity of corneal sub-basal nerve plexus pattern in one myeloma patients exposed to bortezomib (right image) compared with one healthy control (left image).