Manuela Rizzo

Bortezomib-Melphalan-Prednisone-Thalidomide Followed by Maintenance With Bortezomib-Thalidomide Compared With Bortezomib-Melphalan-Prednisone for Initial Treatment of Multiple Myeloma: A Randomized Controlled Trial

PURPOSE The combination of bortezomib-melphalan-prednisone (VMP) is a new standard of care for newly diagnosed multiple myeloma. This phase III study examined the efficacy of the four-drug combination of bortezomib-melphalan-prednisone-thalidomide (VMPT) followed by maintenance with bortezomib-thalidomide (VMPT-VT) compared with VMP treatment alone in untreated multiple myeloma patients who are ineligible for autologous stem-cell transplantation. PATIENTS AND METHODS A total of 511 patients were randomly assigned to receive nine cycles of VMPT followed by continuous VT as maintenance, or nine cycles of VMP at the same doses with no additional therapy. The primary end point was progression-free survival. RESULTS The 3-year estimates of progression-free survival were 56% in patients receiving VMPT-VT and 41% in those receiving VMP (hazard ratio [HR], 0.67; 95% CI, 0.50 to 0.90; P = .008). At 3 years, the cumulative proportions of patients who did not go on to the next therapy were 72% with VMPT-VT and 60% with VMP (HR, 0.58; 95% CI, 0.50 to 0.90; P = .007). Complete response rates were 38% in the VMPT-VT group and 24% in the VMP group (P < .001). The 3-year overall survival was 89% with VMPT-VT and 87% with VMP (HR, 0.92; 95% CI, 0.53 to 1.60; P = .77). Grade 3 to 4 neutropenia (38% v 28%; P = .02), cardiologic events (10% v 5%; P = .04), and thromboembolic events (5% v 2%; P = .08) were more frequent among patients assigned to the VMPT-VT group than among those assigned to the VMP group; treatment-related deaths were 4% with VMPT-VT and 3% with VMP. CONCLUSION VMPT followed by VT as maintenance was superior to VMP alone in patients with multiple myeloma who are ineligible for autologous stem-cell transplantation.

Early Autologous Stem-Cell Transplantation Versus Conventional Chemotherapy as Front-Line Therapy in High-Risk, Aggressive Non-Hodgkin’s Lymphoma: An Italian Multicenter Randomized Trial

PURPOSE To evaluate the role of early intensification with high-dose therapy (HDT) and autologous stem-cell transplantation (ASCT) as front-line chemotherapy for patients with high-risk, histologically aggressive non-Hodgkins lymphoma (NHL). PATIENTS AND METHODS We planned a multicenter, randomized trial to compare a conventional chemotherapy regimen of methotrexate with leucovorin rescue, doxorubicin, cyclophosphamide, vincristine, prednisone, and bleomycin (MACOP-B; arm A) with an abbreviated regimen of MACOP-B (8 weeks) followed by HDT and ASCT (arm B) for intermediate-high-risk/high-risk patients (according to the age-adjusted International Prognostic Index). From September 1994 to April 1998, 150 patients with aggressive lymphoma were enrolled onto the trial. Seventy-five patients were randomly assigned to arm A and 75 patients were randomly assigned to arm B. In both arms, involved-field radiation therapy (36 Gy) was delivered to the site of bulky disease. RESULTS The rate of complete response was 68% in arm A and 76% in arm B (P = not significant [NS]). Three toxic deaths (4%) occurred in arm B and one (1%) occurred in arm A (P = NS). In arm B, 30 patients (40%) did not undergo HDT and ASCT. According to the intention-to-treat analysis at a median follow-up of 24 months, 5-year overall survival probability in arms A and B was 65% and 64% (P =.95), 5-year progression-free survival was 49% and 61% (P =.21), and 5-year relapse-free survival was 65% and 77% (P =.22), respectively. CONCLUSION Abbreviated chemotherapy followed by intensification with HDT-ASCT is not superior to conventional chemotherapy in patients with high-risk, aggressive NHL. Additional randomized trials will clarify whether HDT-ASCT as front-line therapy after a complete course of conventional chemotherapy improves survival in this group of patients.

Melphalan 200 mg/m 2 versus melphalan 100 mg/m 2 in newly diagnosed myeloma patients: a prospective, multicenter phase 3 study

High-dose (200 mg/m(2), MEL200) and intermediate-dose melphalan (100 mg/m(2), MEL100) showed significant activity in myeloma. In a phase 3 study, 298 patients were randomly assigned to receive 2 autologous transplantations after conditioning with MEL200 or MEL100. Ninety-six of 149 (64%) completed MEL200 and 103 of 149 (69%) MEL100. Best response to MEL200 was: complete remission 22 of 149 (15%); partial remission 95 of 149 (64%), for an overall response rate of 79%. Best response to MEL100 was: complete remission 12 of 149 (8%); partial remission 95 of 149 (64%), for an overall response rate of 72%. Overall survival did not differ (P = .13); median progression-free survival (31.4 vs 26.2 months, P = .01), median time to progression (34.4 vs 27.0 months, P = .014) were longer in the MEL200. Treatment-related mortality was 3.1% in the MEL200 and 2.9% in the MEL100 group. Severe neutropenia and infections were marginally superior, whereas severe thrombocytopenia, mucositis, gastrointestinal adverse events, and the overall occurrence of at least 1 nonhematologic grade 3 or 4 adverse event were significantly higher in the MEL200 cohort. We conclude that MEL200 leads to longer remission duration and should be considered the standard conditioning regimen for autologous transplantation. This study was registered at www.clinicaltrials.gov as #NCT00950768.

Frontline Dasatinib Treatment in a “Real-Life” Cohort of Patients Older than 65 Years with Chronic Myeloid Leukemia

Dasatinib (DAS) has been licensed for the frontline treatment in chronic myeloid leukemia (CML). However, very few data are available regarding its efficacy and toxicity in elderly patients with CML outside clinical trials. To address this issue, we set out a “real-life” cohort of 65 chronic phase CML patients older than 65 years (median age 75.1 years) treated frontline with DAS in 26 Italian centers from June 2012 to June 2015, focusing our attention on toxicity and efficacy data. One third of patients (20/65: 30.7%) had 3 or more comorbidities and required concomitant therapies; according to Sokal classification, 3 patients (4.6%) were low risk, 39 (60.0%) intermediate risk, and 20 (30.8%) high risk, whereas 3 (4.6%) were not classifiable. DAS starting dose was 100 mg once a day in 54 patients (83.0%), whereas 11 patients (17.0%) received less than 100 mg/day. Grade 3/4 hematologic and extrahematologic toxicities were reported in 8 (12.3%) and 12 (18.5%) patients, respectively. Overall, 10 patients (15.4%) permanently discontinued DAS because of toxicities. Pleural effusions (all WHO grades) occurred in 12 patients (18.5%) and in 5 of them occurred during the first 3 months. DAS treatment induced in 60/65 patients (92.3%) a complete cytogenetic response and in 50/65 (76.9%) also a major molecular response. These findings show that DAS might play an important role in the frontline treatment of CML patients >65 years old, proving efficacy and having a favorable safety profile also in elderly subjects with comorbidities.

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

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

Recurrent Sweet's syndrome in a patient with multiple myeloma

We report on a case of Sweets syndrome associated with multiple myeloma, as harbinger for disease relapse.

Identification of i(X)(p10) as the sole molecular abnormality in atypical chronic myeloid leukemia evolved into acute myeloid leukemia

The World Health Organization classifies atypical chronic myeloid leukemia (aCML) as a myeloproliferative/myelodisplastic hematological disorder. The primary manifestations are leukocytosis with disgranulopoiesis, absence of basophilia and/or monocytosis, splenomegaly and absence of Philadelphia chromosome or BCR/ABL fusion. Overall 50-65% of patients demonstrate karyotypic abnormalities, although no specific cytogenetic alterations have been associated with this disease. X chromosome alterations have been rarely reported in myeloid malignancies. Although Isodicentric X, idic(X)(q13) is well known in females with myelodysplastic syndromes (MDS), little data are available on X isochromosome and its pathogenetic potential in these disorders. i(X)(p10) is observed in a variety of hematologic malignancies, both myeloid and lymphoid, as a unique abnormality, as well as part of a more complex karyotype, in females and less frequently in male patients. The present report describes the first patient with aCML, with documented isolated i(X)(p10), who developed a secondary acute myeloid leukemia (sAML).

A105 A Phase III Study of MEL200 Versus MEL100 in Newly Diagnosed Myeloma Young Patients

Introduction and Aims: New agents have been introduced as induction prior to autologous stem cell transplantation (ASCT) and as consolidation/maintenance thereafter to improve complete response (CR) rates. We evaluate bortezomib plus pegylatedlyposomal-doxorubicin and dexamethasone (PAD) as induction prior to reduced intensity ASCT, followed by consolidation with lenalidomide and prednisone (LP) and maintenance with lenalidomide alone (L). Materials and Methods: Newly diagnosed multiple myeloma patients aged 65-75 years were eligible. Induction consisted of four 21-day PAD cycles (bortezomib 1.3 mg/m2 days 1, 4, 8, 11; pegylated-lyposomal-doxorubicin 30 mg/m2 day 4; dexamethasone 40 mg days 1-4, 8-11, and 15-18). Patients were conditioned with tandem melphalan 100 mg/m2 (MEL100) followed by stem cell support. After ASCT patients received consolidation with four 28-day LP cycles (lenalidomide 25 mg days 1-21, prednisone 50 mg every other day) followed by lenalidomide maintenance (10 mg days 1-21). Primary objectives were safety (grade 3 nonhematologic toxicity 35%). Results: One-hundred and two patients entered the study. After PAD, 94% of patients achieved at least partial response (PR) and 59% at least very good partial response (VGPR) including 13% CR. After tandem MEL100, 88% of patients obtained at least VGPR and 41% CR. After LP all patients achieved PR, 88% at least VGPR including 53% CR. After a median follow-up of 14 months, 1-year progression-free survival (PFS) was 92%, and 1-year overall survival was 92%. PFS was not significantly affected by b2-microglobulin levels (P = .10), presence of chromosome 13 deletion (P = .5) or t(4;14)(P = .61). During PAD, grade 3/4 adverse events included thrombocytopenia (13%), neutropenia (11%), infections (18%), gastrointestinal toxicities (12%), peripheral neuropathy (11%) and deep vein thrombosis (DVT) (6%). During LP, grade 3/4 toxicities included neutropenia (18%), thrombocytopenia (6%), infections (6%) and DVT (6%). The other grade 3/4 toxicities occurred in less than 5% of patients. Conclusion: Bortezomib as induction, followed by lenalidomide as consolidation/maintenance is a highly effective regimen in elderly patients. Updated results will be presented at the meeting.