Luca Franceschini

Bortezomib-Melphalan-Prednisone-Thalidomide Followed by Maintenance With Bortezomib-Thalidomide Compared With Bortezomib-Melphalan-Prednisone for Initial Treatment of Multiple Myeloma: Updated Follow-Up and Improved Survival

PURPOSE Bortezomib-melphalan-prednisone (VMP) has improved overall survival in multiple myeloma. This randomized trial compared VMP plus thalidomide (VMPT) induction followed by bortezomib-thalidomide maintenance (VMPT-VT) with VMP in patients with newly diagnosed multiple myeloma. PATIENTS AND METHODS We randomly assigned 511 patients who were not eligible for transplantation to receive VMPT-VT (nine 5-week cycles of VMPT followed by 2 years of VT maintenance) or VMP (nine 5-week cycles without maintenance). RESULTS In the initial analysis with a median follow-up of 23 months, VMPT-VT improved complete response rate from 24% to 38% and 3-year progression-free-survival (PFS) from 41% to 56% compared with VMP. In this analysis, median follow-up was 54 months. The median PFS was significantly longer with VMPT-VT (35.3 months) than with VMP (24.8 months; hazard ratio [HR], 0.58; P < .001). The time to next therapy was 46.6 months in the VMPT-VT group and 27.8 months in the VMP group (HR, 0.52; P < .001). The 5-year overall survival (OS) was greater with VMPT-VT (61%) than with VMP (51%; HR, 0.70; P = .01). Survival from relapse was identical in both groups (HR, 0.92; P = .63). In the VMPT-VT group, the most frequent grade 3 to 4 adverse events included neutropenia (38%), thrombocytopenia (22%), peripheral neuropathy (11%), and cardiologic events (11%). All of these, except for thrombocytopenia, were significantly more frequent in the VMPT-VT patients. CONCLUSION Bortezomib and thalidomide significantly improved OS in multiple myeloma patients not eligible for transplantation.

Age and organ damage correlate with poor survival in myeloma patients: Meta-analysis of 1435 individual patient data from 4 randomized trials

Thalidomide and bortezomib are extensively used to treat elderly myeloma patients. In these patients, treatment-related side effects are frequent and full drug doses difficult to tolerate. We retrospectively analyzed data from 1435 elderly patients enrolled in 4 European phase III trials including thalidomide and/or bortezomib. After a median follow up of 33 months (95%CI: 10–56 months), 513 of 1435 patients (36%) died; median overall survival was 50 months (95%CI: 46–60 months). The risk of death was increased in patients aged 75 years or over (HR 1.44, 95%CI: 1.20–1.72; P<0.001), in patients with renal failure (HR 2.02, 95%CI: 1.51–2.70; P<0.001), in those who experienced grade 3–4 infections, cardiac or gastrointestinal adverse events during treatment (HR 2.53, 95%CI: 1.75–3.64; P<0.001) and in those who required drug discontinuation due to adverse events (HR 1.67, 95%CI; 1.12–2.51; P=0.01). This increased risk was restricted to the first six months after occurrence of adverse events or drug discontinuation and declined over time. More intensive approaches, such as the combination of bortezomib-thalidomide, negatively affected outcome. Bortezomib-based combinations may overcome the negative impact of renal failure. Age 75 years or over or renal failure at presentation, occurrence of infections, cardiac or gastrointestinal adverse events negatively affected survival. A detailed geriatric assessment, organ evaluation and less intense individualized approaches are suggested in elderly unfit subjects.

Prognostic Factors Associated With Progression of Smoldering Multiple Myeloma to Symptomatic Form

Smoldering multiple myeloma (SMM) presents a high risk of progression to symptomatic MM (sy‐MM). Herein, we analyzed some predictors of development of sy‐MM. In 144 patients with SMM, we also compared the risk of progression predicted by bone marrow plasma cell (BMPC) involvement on the bone marrow biopsy (BMB) versus bone marrow aspirates (BMA).

Comparison between biosimilar filgrastim vs other granulocyte‐colony stimulating factor formulations (originator filgrastim, peg‐filgrastim and lenograstim) after autologous stem cell transplantation: a retrospective survey from the Rome Transplant Network

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Pre-treatment staging of multiple myeloma patients: comparison of whole-body diffusion weighted imaging with whole-body T1-weighted contrast-enhanced imaging.

Background Multiple myeloma (MM) is a hematologic malignancy characterized by the clonal proliferation of plasma cells. Accurate staging is of pivotal importance in the management of MM. Advanced imaging techniques, such as magnetic resonance imaging (MRI), are increasingly used for the initial diagnosis and staging of MM. Purpose To compare whole-body (WB) MR diffusion-weighted imaging with background body signal suppression (DWIBS) with (WB) MR fat-suppressed T1-weighted contrast-enhanced imaging (T1-CE) in the pre-treatment staging evaluation of multiple myeloma (MM) patients. Material and Methods Thirty-six patients with MM were included in the study. T1-CE and DWIBS were performed using a 3 T scanner. The Durie-Salmon plus staging system was used. Kappa statistics was used to assess agreement. Results For all MM stages good to very good agreement was found for both T1-CE and DWIBS. The unweighted kappa statistic indicated a moderate, good and very good agreement between T1-CE and DWIBS for stages I, II, and III, respectively. In particular, in 67% of patients the MM staging according to T1-CE was not different from DWIBS. In the remaining 33% of patients, the MM stage obtained with T1-CE was lower than that provided by DWIBS. Conclusion DWIBS and T1-CE were concordant in the majority of patients. In a minority of cases DWIBS evidenced areas of water restriction that did not correspond to contrast enhancement areas. Studies monitoring therapeutic response in relation to tumour burden and aggressiveness should be performed to assess the clinical relevance of DWIBS findings.

Cryotherapy reduces oral mucositis and febrile episodes in myeloma patients treated with high-dose melphalan and autologous stem cell transplant: a prospective, randomized study

Cryotherapy reduces oral mucositis and febrile episodes in myeloma patients treated with high-dose melphalan and autologous stem cell transplant: a prospective, randomized study

A case of oral mycosis fungoides successfully treated by combination of alemtuzumab and chemotherapy

Dear Editor, Mycosis fungoides (MF) represents the most common cutaneous T cell lymphoma [1]. Oral cavity involvement occurs in less than 1 % of MF patients [2] and is generally associated with a poor prognosis when treated with standard therapies (PUVA, etc.). Here, we report a 60-year-old man affected with MF that showed a mucosal involvement and that was successfully treated with systemic chemotherapy combined with alemtuzumab. In 2010, the patient referred the appearance of both an ulcerate tumor on his leg and a painless plaque on his upper left gingival buccal mucosa (Fig. 1) derived from an initial tender nodule appeared 2 years before. There was no palpable lymphadenopathy and no other cutaneous or extra-cutaneous involvement. A computed tomography scan (CT) showed an enlargement of both masseter muscle and parotid gland. The presence of a 1-cm submandibular lymph node was also found. In 2011, a needle biopsy of the oral lesion revealed fragments of muscle tissues with massive infiltration of atypical lymphocytes. A first diagnosis of peripheral T cell lymphoma unspecified was achieved. After a few months, a further biopsy better characterized the T cells phenotype which was: CD3++, CD2+, CD4+, CD8−, and CD7−, with a low proliferative fraction and the monoclonal expression of TCR (Figs. 1 and 2). The final diagnosis was MF. After an informed consent was obtained, the patient underwent six monthly cycles of CHOEP [3] . Chemotherapy was combined with alemtuzumab, 15 mg subcutaneously once a week on day +1,+8,+15, and +22. The treatment was well tolerated. One month after the end of therapy, the total-body positron emission (PET) CT showed absence of disease and the patient received photophoresis and interferon-alpha 18 MU/month, three doses per week for 6 months. After 6 months, the patients suffered a relapse and was again successfully treated with six cycles of chemotherapy, based on gemcitabine 1200 mg/mq on day +1 and day +8 [4] and alemtuzumab 15 mg on day 1. To date, the patient presents a skin stable disease and receives a regular maintenance treatment with photophoresis. During alemtuzumab treatment, we performed a preemptive therapy against CMV reactivation by weekly quantitative and qualitative PCR assay. No specific prophylaxis was performed, and there was no CMV reactivation. Prophylactic

Bowel ultrasonography as an aid for diagnosis of intestinal acute graft-versus-host-disease after allogeneic haematopoietic stem cell transplantation.

OBJECTIVE Aim of our prospective study was to investigate accuracy of bowel ultrasonography in detecting gastrointestinal acute graft versus host disease (GVHD), when using clinical assessment as gold standard. In a subgroup of patients, bowel ultrasonography was compared with colonoscopy and histology in diagnosing of gastrointestinal acute GVHD. METHODS Fifty-two patients underwent allogeneic hematopoietic stem cell transplantation and developed gastrointestinal symptoms. RESULTS Clinical assessment lead to a diagnosis of gastrointestinal acute GVHD in 17/52 patients, no gastrointestinal acute GVHD was detected in 20/52 patients, while 15 patients were not able to complete the study. Bowel ultrasonography detected either bowel wall thickness of the ileum and the colon or dilation in 16/17 patients and showed 94% sensitivity (95% CI 0.69-0.99), 95% specificity (95% CI 0.73-0.99), and 94.5% accuracy. Colonoscopy was performed in 13/52 patients, showing gastrointestinal acute GVHD in 11/13. In these 11 patients, histology confirmed the diagnosis of gastrointestinal acute GVHD, and bowel ultrasonography detected findings compatible with gastrointestinal acute GVHD in all 11 patients, and was negative in the 2 patients with no gastrointestinal acute GVHD. CONCLUSION Bowel ultrasonography can be considered a valuable tool to add to clinical assessment for patients with suspected gastrointestinal acute GVHD for addressing a prompt and appropriate treatment.

Minimal tumour burden in haematological diseases: a step forward with quantitative assessment of Bence‐Jones in nephelometry?

Serum and urine free light chains (FLCs) monoclonal immunoglobulin (k and k) are important markers in the diagnosis and monitoring of B cell proliferative disorders, such as Multiple Myeloma (MM), Monoclonal Gammopathy (MG), Monoclonal Gammopathy of Undetermined Significance (MGUS), Amyloidosis (AL) and related disorders (Bird et al, 2009; Kyle et al, 2010). MM is a progressive neoplastic disease characterized by bone marrow plasmacytosis (plasma cell tumour) and overproduction of an intact monoclonal immunoglobulin (IgG, IgA, IgM, IgD or IgE) and/or Bence Jones protein. The presence of one of the three following criteria allows the diagnosis of myeloma in affected patients: layers or clusters of plasma cells in the bone, osteolytic lesions (without the presence of metastatic cancer or granulomatous disease) or Bence Jones proteinuria (Durie et al, 2006). Determination of the Bence Jones protein (BJP) is essential when clinical suspicion of MG persists and serum tests are negative; moreover it is useful to establish a diagnosis of MG (Bird et al, 2009; Dimopoulos et al, 2011) and to monitor response to therapy in MM. It has been suggested that the FLCs assay can replace the traditional 24-h urine protein electrophoresis and immunofixation as part of a diagnostic screen (International Myeloma Working Group 2003; Eslick & Talaulikar, 2013). The excess production of FLCs (over 10–30 g/day) by a neoplastic clone of plasma cells saturates their absorption in the proximal renal tubules, causing damage and proteinuria, with large amounts of FLCs detectable in the urine. Urine FLCs (BJP) analysis can probably still be useful for initiating therapy and to highlight minimal tumour burden in patients with MM (Eslick & Talaulikar, 2013; Paiva et al, 2015a) and related disorders. There is growing interest in Minimal Residual Disease (MRD) monitoring, which can be used as a prognostic factor and to predict patients’ outcomes in MM (Paiva et al, 2015b). Guidelines recommend that immunofixation (IFE) of urine should be used to detect BJP (Durie et al, 2006; Bird et al, 2009). Currently, BJP quantification must be carried out on spot urine sample by densitometry of the corresponding immunoelectrophoretic band. This method is complicated by the different affinity for used dyes, the coincidental migration of other proteins and is operator dependent; therefore, quantitative analysis could be performed by nephelometric/turbidimetric assay. Although IFE is the ‘gold standard’ for the determination of BJP, a new nephelometric method, based on monoclonal antibodies, has been developed (Pretorius et al, 2012). The monoclonal antibodies provide a more accurate measurement reducing a possible overestimation when polyclonal antibodies are used. The aim of the present study was to compare the performance of nephelometric assay to IFE agarose gel in urine samples and to assess the correlation between the results of these two tests and the clinical diagnosis (negative or positive for B cell proliferative disorders). Serum and urine samples were collected from 378 patients (186 female and 192 male; one sample for each patient: no follow-up sample needed for this type of analysis) who presented to “Tor Vergata University Hospital”. Patients were evaluated with serum electrophoresis (SPE), urine immunofixation (IFE) and nephelometric assays for urine FLCs and additional routine analyses. Exclusion criteria were history and/or signs of chronic disease as primary renal failure or patients undergoing dialysis. FLCs measurement was performed using the N Latex FLC kit based on a mixture of monoclonal antibodies for use on the BN ProSpec System analyser (Siemens GmbH, Marburg, Germany) (Pretorius et al, 2012). BJP was determined by immunofixation on a semi-automated agarose electrophoresis system (Hydragel 4 BJ and Hydrasys; Sebia, Florence, Italy). The gels were evaluated for the presence of FLCs by three independent operators and reported as positive or negative. The evaluation was performed without knowledge of the outcome from the nephelometric assays. Data obtained show a significant correlation between nephelometric and IFE assays (Spearman correlation r = 0 82, P < 0 001). We analysed the Receiver-Operator Characteristic (ROC) curves for kappa and lambda nephelometric FLCs assay with respect to diagnosis (Fig 1A and B). The areas under ROC curves were 1 for both kappa and lambda BJP. We found 99% and 100% sensitivity and 100% and 99% specificity, for kappa and lambda FLCs, respectively, and the optimal cutoff for kappa FLCs was 0 25 mg/l and 0 11 g/l for lambda FLCs. We made a new correlation of the nephelometric data with respect to diagnosis that was re-assessed and shown to be more significant (r = 0 98, P < 0 001; Spearman correlacorrespondence

Impact of IFN lambda 3/4 single nucleotide polymorphisms on the cytomegalovirus reactivation in autologous stem cell transplant patients

Cytomegalovirus (CMV) infection represents one of the main cause mortality after Stem Cell Transplantation. Recently, a protective effect of the T allele of rs12979860 IL28B Single Nucleotide Polymorphisms (SNPs) against CMV infection in the allogenic stem cell transplantation was suggested. We investigate whether the rs12979860 IL28B SNP and the relative rs368234815 (IFNλ4) genotype may affect the incidence of active CMV infection in Autologous stem cell transplantation (Auto-SCT) setting. The study included 99 patients who underwent to Auto-SCT. IL28 and IFNΔ4 SNPs were correlated with CMV reactivation along with other clinical and treatment parameters. CMV reactivation by CMV DNAemia was evaluated once a week until day 100 from Auto-SCT. CMV reactivation was documented in 50% (TT-ΔG/ΔG), 35% (CC-TT/TT) and 29.2% (CT-TT/ΔG) of the patients respectively. No differences in CMV copies number were recorded at reactivation between different IL28/IFNλ4 genotypes. The analysis of patients older than 60 years showed a significantly higher incidence of active CMV infection in the TT-ΔG/ΔG (83%) population with respect to CC-TT/TT (21%) and CT-TT/ΔG (40%) patients. Our data suggest a negative role of TT-ΔG/ΔG genotype in the CMV reactivation in Auto-SCT. The exposure to rituximab and the pre-infusion presence of anti CMV IgG also significantly influenced CMV reactivation.