Lara Pochintesta

MYD88 (L265P) mutation is an independent risk factor for progression in patients with IgM monoclonal gammopathy of undetermined significance

To the editor: MYD88 (L265P) is a recurrent somatic mutation in Waldenstrom macroglobulinemia (WM).[1][1][⇓][2][⇓][3]-[4][4] By means of allele-specific polymerase chain reaction (AS-PCR), the MYD88 mutation is detectable in almost all patients with WM and in roughly half the patients with IgM

Clues to pathogenesis of Waldenström macroglobulinemia and immunoglobulin M monoclonal gammopathy of undetermined significance provided by analysis of immunoglobulin heavy chain gene rearrangement and clustering of B-cell receptors

Abstract We characterized immunoglobulin heavy chain (IGH) gene rearrangements and searched for clusters of stereotyped B-cell receptors in 123 patients with Waldenström macroglobulinemia (WM; n = 59) or immunoglobulin M monoclonal gammopathy of undetermined significance (IgM-MGUS) (n = 64). A productive monoclonal IGHV-D-J rearrangement was obtained in 99/123 patients (80%). Immunoglobulin heavy chain variable (IGHV) genes were mutated in 94/99 patients (95%) with a median somatic hypermutation rate of 6.7% (2.1–14.5). Compared with the normal B-cell repertoire, patients with WM/IgM-MGUS showed an over-representation of the IGHV3 subgroup (83% vs. 55%, p < 0.0001) and an under-representation of IGHV1 (7% vs. 14%, p = 0.04) and IGHV4 (7% vs. 23%, p = 0.0001) subgroups. At the gene level, in WM/IgM-MGUS there was an over-representation of IGHV3-23 (24% vs. 12%, p = 0.0003), IGHV3-64 (3% vs. < 1%, p = 0.003), IGHV3-7 (12% vs. 4%, p = 0.0001) and IGHV3-74 (9% vs. 2%, p < 0.0001), while IGHV4-39 was never used (0 vs. 5%, p = 0.03). Intra-WM/IgM-MGUS search for HCDR3 similarity showed no association fulfilling criteria for stereotyped receptors. WM/IgM-MGUS sequences were unrelated to known chronic lymphocytic leukemia (CLL), splenic marginal zone lymphoma (SMZL) or mantle cell lymphoma (MCL) subsets. In conclusion, the IGHV gene usage in WM and IgM-MGUS is remarkably biased as compared to the normal B-cell repertoire. WM and IgM-MGUS-specific HCDR3 clusters do not occur with a frequency detectable with currently available databases, not supporting a B-cell receptor-driven pathogenesis in WM and IgM-MGUS.

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.

Monitoring for cytomegalovirus and Epstein-Barr virus infection in chronic lymphocytic leukemia patients receiving i.v. fludarabine-cyclophosphamide combination and alemtuzumab as consolidation therapy

The combination of fludarabine and cyclophosphamide (FC) has become the standard of care in chronic lymphocytic leukemia (CLL) patients. Due to the well-recognized F-related immunosuppression,[1][1] a higher risk of opportunistic infections could be expected by adding another immunosuppressive agent

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.

Good clinical activity and favorable toxicity profile of once weekly bortezomib, fotemustine, and dexamethasone (B-MuD) for the treatment of relapsed multiple myeloma.

Since multiple myeloma (MM) is still not‐curable, the management of relapse remains challenging. Given the known efficacy of alkylating agents in MM, we conducted a phase I/II study to test a new three drug combination in which Fotemustine (Muphoran), an alkylating agent of nitrosurea family, was added to bortezomib + dexamethasone backbone (B‐MuD) for the treatment of MM relapsed patients. Fotemustine was administered at two dose levels (80–100 mg/m2 i.v.) on day 1. The original 21‐day schedule was early amended for extra‐hematological toxicity and a 35‐day schedule was adopted (Bortezomib 1.3 mg/m2 i.v. on days 1, 8, 15, and 22, Dexamethasone 20 mg i.v. on days 1, 8, 15, and 22) for a total of six courses. Twenty‐four patients were enrolled. The maximum tolerated dose of Fotemustine was 100 mg/m2. The overall response rate was of 62% (CR 8%, VGPR 33%, and PR 21%). The median OS was 28.5 months, the median progression‐free survival (PFS) was 19.1 months. B‐MuD resulted effective in patients previous exposed to bortezomib without difference of response (P = 0.25) and PFS (P = 0.87) when compared to bortezomib‐naive patients. Thrombocytopenia was the most common AE overall. In conclusion, B‐MuD is an effective and well tolerated combination in relapsed MM patients even in advanced disease phase.

Panobinostat in combination with bortezomib and dexamethasone as induction therapy in patients with multiple myeloma, candidates for autologous transplant

1 Division of Hematology, Fondazione IRCCS Policlinico San Matteo, Pavia, Italy, 2 Department of Internal Medicine – Clinic of Hematology, Ospedale Valduce, Como, Italy, 3 Division of Hematology, Policlinico Ospedale Maggiore, Italy, 4 Department of Oncology-Hematology, Ospedale di Circolo, Busto Arsizio, Italy and 5 Division of Hematology, Fondazione IRCCS Istituto Nazionale Tumori, Milano, Italy

IGHV Unmutated Status Influences Outcome More Than IGHV1-69 Gene Usage Per Se in Patients With Chronic Lymphocytic Leukemia

In this study, IGHV1-69 gene usage was detected in 46 out of 379 cases (12%) of chronic lymphocytic leukemia (CLL). In comparison with patients using alternative immunoglobulin heavy-chain variable (IGHV) genes, patients with IgHV1-69 CLLs more often presented at advanced stage, lacked somatic hypermutation (unmutated cases, 87% vs. 35%; P = .00001), and expressed unfavorable biologic characteristics. In 12 patients (26%), common amino acid motifs within the heavy-chain third complementarity-determining region were identified, allowing assignment to previously reported stereotyped subsets. In our study, treatment-free survival of patients with unmutated IGVH1-69 did not differ significantly from that of patients expressing unmutated alternative IGHV genes. As such, IGHV1-69 gene usage per se did not seem to be predictive of progressive disease, progression being primarily related to the unmutated IGHV profile.

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