Emanuela Anna Pesce

Long-Term Follow-Up Analysis of HD9601 Trial Comparing ABVD Versus Stanford V Versus MOPP/EBV/CAD in Patients With Newly Diagnosed Advanced-Stage Hodgkin's Lymphoma: A Study From the Intergruppo Italiano Linfomi

PURPOSE The Intergruppo Italiano Linfomi HD9601 trial compared doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) versus doxorubicin, vinblastine, mechloretamine, vincristine, bleomycin, etoposide, and prednisone (Stanford V [StV]) versus the combination of mechlorethamine, vincristine, procarbazine, prednisone (MOPP) with epidoxorubicin, bleomycin, vinblastine (EBV), lomustine, doxorubicin, and vindesine (CAD) (MOPP/EBV/CAD [MEC]) for the initial treatment of advanced-stage Hodgkins lymphoma to select which regimen would best support a reduced radiotherapy program (limited to two or fewer sites of either previous bulky or partially remitting disease). Superiority of ABVD and MEC to StV was demonstrated. We report analysis of long-term outcome and toxicity. PATIENTS AND METHODS Patients with stage IIB, III, or IV were randomly assigned among six cycles of ABVD, three cycles of StV, and six cycles of MEC; radiotherapy was administered in 76, 71, and 50 patients in the three arms, respectively. RESULTS Currently, the median follow-up is 86 months; in the prolonged observation period, eight additional failures, including two relapses, both in the StV arm, and six additional deaths in complete response were recorded. The 10-year overall survival rates were 87%, 80%, and 78% for ABVD, MEC, and StV, respectively (P = .4). The 10-year failure-free survival was 75%, 74%, and 49% in the ABVD, MEC, and StV arms, respectively (P < .001). The 10-year disease-free survival of patients treated or not with radiotherapy (RT) showed no difference for ABVD or MEC (85% v 80% and 93% v 68%), and a statistically significant difference for StV (76% v 33%; P = .004). No significant long-term toxicity was recorded. CONCLUSION The long-term analysis confirmed ABVD and MEC superiority to StV. The use of RT after StV was established as mandatory. ABVD is still to be considered as the standard treatment with a good balance between efficacy and toxicity.

Relevance of Stereotyped B-Cell Receptors in the Context of the Molecular, Cytogenetic and Clinical Features of Chronic Lymphocytic Leukemia

Highly homologous B-cell receptors, characterized by non-random combinations of immunoglobulin heavy-chain variable (IGHV) genes and heavy-chain complementarity determining region-3 (HCDR3), are expressed in a recurrent fraction of patients affected by chronic lymphocytic leukemia (CLL). We investigated the IGHV status of 1131 productive IG rearrangements from a panel of 1126 CLL patients from a multicenter Italian study group, and correlated the presence and class of HCDR3 stereotyped subsets with the major cytogenetic alterations evaluated by FISH, molecular prognostic factors, and the time to first treatment (TTFT) of patients with early stage disease (Binet A). Stereotyped HCDR3 sequences were found in 357 cases (31.7%), 231 of which (64.7%) were unmutated. In addition to the previously described subsets, 31 new putative stereotypes subsets were identified. Significant associations between different stereotyped HCDR3 sequences and molecular prognostic factors, such as CD38 and ZAP-70 expression, IGHV mutational status and genomic abnormalities were found. In particular, deletion of 17p13 was significantly represented in stereotype subset #1. Notably, subset #1 was significantly correlated with a substantially reduced TTFT compared to other CLL groups showing unmutated IGHV, ZAP-70 or CD38 positivity and unfavorable cytogenetic lesions including del(17)(p13). Moreover, subset #2 was strongly associated with deletion of 13q14, subsets #8 and #10 with trisomy 12, whereas subset #4 was characterized by the prevalent absence of the common cytogenetic abnormalities. Our data from a large and representative panel of CLL patients indicate that particular stereotyped HCDR3 sequences are associated with specific cytogenetic lesions and a distinct clinical outcome.

T-Cell Lymphomas in South America and Europe

Peripheral T-cell lymphomas are a group of rare neoplasms originating from clonal proliferation of mature post-thymic lymphocytes with different entities having specific biological characteristics and clinical features. As natural killer cells are closely related to T-cells, natural killer-cell lymphomas are also part of the group. The current World Health Organization classification recognizes four categories of T/natural killer-cell lymphomas with respect to their presentation: disseminated (leukemic), nodal, extranodal and cutaneous. Geographic variations in the distribution of these diseases are well documented: nodal subtypes are more frequent in Europe and North America, while extranodal forms, including natural killer-cell lymphomas, occur almost exclusively in Asia and South America. On the whole, T-cell lymphomas are more common in Asia than in western countries, usually affect adults, with a higher tendency in men, and, excluding a few subtypes, usually have an aggressive course and poor prognosis. Apart from anaplastic lymphoma kinase-positive anaplastic large cell lymphoma, that have a good outcome, other nodal and extranodal forms have a 5-year overall survival of about 30%. According to the principal prognostic indexes, the majority of patients are allocated to the unfavorable subset. In the past, the rarity of these diseases prevented progress in the understanding of their biology and improvements in the efficaciousness of therapy. Recently, international projects devoted to these diseases created networks promoting investigations on T-cell lymphomas. These projects are the basis of forthcoming cooperative, large scale trials to detail biologic characteristics of each sub-entity and to possibly individuate targets for new therapies.

Chromosome 2p gain in monoclonal B-cell lymphocytosis and in early stage chronic lymphocytic leukemia.

Recent studies have described chromosome 2p gain as a recurrent lesion in chronic lymphocytic leukemia (CLL). We investigated the 2p gain and its relationship with common prognostic biomarkers in a prospective series of 69 clinical monoclonal B‐cell lymphocytosis (cMBL) and 218 early stage (Binet A) CLL patients. The 2p gain was detected by FISH in 17 patients (6%, 16 CLL, and 1 cMBL) and further characterized by single nucleotide polymorphism‐array. Overall, unfavorable cytogenetic deletions, i.e., del(11)(q23) and del(17)(p13) (P = 0.002), were significantly more frequent in 2p gain cases, as well as unmutated status of IGHV (P < 1 × 10−4) and CD38 (P < 1 × 10−4) and ZAP‐70 positive expression (P = 0.003). Furthermore, 2p gain patients had significantly higher utilization of stereotyped B‐cell receptors compared with 2p negative patients (P = 0.009), and the incidence of stereotyped subset #1 in 2p gain patients was significantly higher than that found in the remaining CLLs (P = 0.031). Transcriptional profiling analysis identified several genes significantly upregulated in 2p gain CLLs, most of which mapped to 2p. Among these, NCOA1 and ROCK2 are known for their involvement in tumor progression in several human cancers, whereas among those located in different chromosomes, CAV1 at 7q31.1 has been recently identified to play a critical role in CLL progression. Thus, 2p gain can be present since the early stages of the disease, particularly in those cases characterized by other poor prognosis markers. The finding of genes upregulated in the cells with 2p gain provides new insights to define the pathogenic role of this lesion. Am. J. Hematol. 2013.

Prospective validation of a risk score based on biological markers for predicting progression free survival in Binet stage A chronic lymphocytic leukemia patients: results of the multicenter O-CLL1-GISL study.

A risk score based on three biological features (CD38, ZAP‐70, and IGHV mutational status) was previously developed to predict progression‐free survival (PFS) in untreated Binet A CLL patients. Here we perform a score validation analysis in a prospective and independent cohort of patients. Biological markers (CD38, ZAP‐70, and IGHV mutational status) and gene expression profiles (GEP) of leukemic cells from CLL patients included in a prospective multicenter observational study (O‐CLL1‐GISL protocol, clinicaltrial.gov ID:NCT00917549) were used to assess the value and reproducibility of this score. To date, 468 Binet A patients were classified as low‐ (0 positive marker), intermediate‐ (1 positive marker), or high‐risk (2 or 3 positive markers) using the progression risk score. The 3‐year PFS probability was 91.7%, 82.9%, and 57.4% for low‐, intermediate‐, and high‐risk (P < 0.0001) cases, respectively. These values were similar to those found in the original cohort. At Cox multivariate analysis, Rai stage, absolute lymphocyte count, progression risk score, and β‐2 microglobulin maintained an independent prognostic impact on PFS. This score remained a predictor of progression when analysis was limited to 371 Rai 0 cases (P < 0.0001). Finally, the cells from the different CLL risk groups showed differences in their gene expression patterns. These results confirm the ability of this progression risk score to predict PFS among Binet A patients. The utility of the score was also extended by demonstrating that it retains prognostic value when applied exclusively to Rai 0 patients. Specific transcriptional patterns were significantly associated with risk groups. Am. J. Hematol. 89:743–750, 2014.

Total body computed tomography scan in the initial work‐up of Binet stage A chronic lymphocytic leukemia patients: Results of the prospective, multicenter O‐CLL1‐GISL study

Total body computed tomography (TB‐CT) scan is not mandatory in the diagnostic/staging algorithm of chronic lymphocytic leukemia (CLL). The aim of this study was to determine the value and prognostic significance of TB‐CT scan in early stage CLL patients. Baseline TB‐CT scan was performed in 240 Binet stage A CLL patients (179 Rai low‐ and 61 Rai intermediate‐risk) included in a prospective multicenter observational study (clinicaltrial.gov ID:NCT00917549). The cohort included 69 clinical monoclonal B lymphocytosis (cMBLs). Patients were restaged considering only radiological data. Following TB‐CT scans, 20% of cases reclassified as radiologic Binet (r‐Binet) stage B. r‐Binet B patients showed a higher incidence of unfavorable cytogenetic abnormalities (P = 0.027), as well as a shorter PFS (P = 0.001). At multivariate analysis, r‐Binet stage [HR = 2.48; P = 0.004] and IGHV mutational status [HR = 3.01; P = 0.002] retained an independent predictive value for PFS. Among 179 Rai low‐risk cases, 100 were redefined as r‐Rai intermediate‐risk based upon TB‐CT scan data, showing a higher rate of cases with higher ZAP‐70 (P = 0.033) and CD38 expression (P = 0.029) and β2‐microglobulin levels (P < 0.0001), as well as a shorter PFS than those with r‐Rai low‐risk (P = 0.008). r‐Rai stage [HR = 2.78; P = 0.046] and IGHV mutational status [HR = 4.25; P = 0.009] retained a significant predictive value for PFS at multivariate analysis. Forty‐two percent of cMBL patients were reclassified as r‐small lymphocytic lymphomas (r‐SLLs) by TB‐CT scan. TB‐CT scan appears to provide relevant information in early stage CLL related to the potential and the timing of patients to progress towards the more advanced disease stages. Am. J. Hematol. 88:539–544, 2013.

Brentuximab vedotin followed by ABVD +/- radiotherapy in patients with previously untreated Hodgkin lymphoma: final results of a pilot phase II study.

The past few decades have seen major advances in understanding the pathobiology and clinical management of Hodgkin lymphoma (HL), making it one of the most successfully treated cancers worldwide.[1][1] At present, more than 90% of patients with early-stage, and up to 80% with advanced-stage disease

Is ZAP70 still a key prognostic factor in early stage chronic lymphocytic leukaemia? Results of the analysis from a prospective multicentre observational study

Abbonizio, F., Giampaolo, A., Arcieri, R. & Hassan, H.J. & the Associazione Italiana Centri Emofilia (AICE). (2011) Registro Nazionale delle Coagulopatie Congenite. Rapporto 2011. Rapporti ISTISAN 12/55. http://www.iss.it/binary/ publ/cont/12_55_web.pdf Binny, C., McIntosh, J., Della Peruta, M., Kymalainen, H., Tuddenham, E.G., Buckley, S.M., Waddington, S.N., McVey, J.H., Spence, Y., Morton, C.L., Trasher, A.J., Gray, J.T., Castellino, F.J., Tarantal, A.F., Davidoff, A.M. & Nathwani, A.C. (2012) AAV-mediated gene transfer in the perinatal period results in expression of FVII at levels that protect against fatal spontaneous hemorrhage. Blood, 119, 957–966. Borhany, M., Pahore, Z., UI Qadr, Z., Rehan, M., Khan, A., Ansari, S., Farzana, T., Nadeem, M., Raza, S.A. & Shamsi, T. (2010) Bleeding disorders in the tribe: result of consanguineous in breeding. Orphanet Journal of Rare Diseases, 5, 23. Di Minno, M.N., Dolce, A. & Mariani, G. (2013) Bleeding symptoms at disease presentation and prediction of ensuing bleeding in inherited FVII deficiency. Thrombosis and Haemostasis, 109, 1051–1059. Farah, R.A., Hamod, D., Melick, N., Giansily-Blaizot, M. & Sallah, S. (2007) Successful prophylaxis against intracranial hemorrhage using weekly administration of activated recombinant factor VII in a newborn with severe factor VII deficiency. Journal of Thrombosis and Haemostasis, 5, 433–434. Giansily-Blaizot, M., Aguilar-Martinez, P., BironAndreani, C., Jeanjean, P., Igual, H. & Schved, J.F. (2001) Study Group of Factor Seven Deficiency. Analysis of the genotypes and phenotypes of 37 unrelated patients with inherited factor VII deficiency. European Journal of Human Genetics, 9, 105–112. Jouannic, J.M., Tachdjian, G., Costa, J.M. & B enifla, J.L. (2008) Coelomic fluid analysis: the absolute necessity to prove its fetal origin. Reproductive Biomedicine Online, 16, 148–151. Mariani, G., Herrmann, F.H., Dolce, A., Batorova, A., Etro, D., Peyvandi Wulff, F.K., Schved, J.F., Auerswald, G., Ingerslev, J., Bernardi, F. & International Factor VII Deficiency Study Group. (2005) International Factor VII Deficiency Study Group. Clinical phenotypes and factor VII genotype in congenital factor VII deficiency. Thrombosis and Haemostasis, 93, 481–487. Morfini, M., Batorova, A., Mariani, G., Auerswald, G., Bernardi, F., Di Minno, G., Dolce, A., Fede, C., Giansily-Blaizot, M., Ingerslev, J., Martinowitz, U., Napolitano, M., Pinotti, M. & Schved, J. (2014) for the International FVII (IF7) and the Seven Treatment Evaluation Registry (STER) Study Groups. Pharmacokinetic properties of recombinant FVIIa in inherited FVII deficiency account for a large volume of distribution at steady state and a prolonged pharmacodynamics effect. Thrombosis and Haemostasis, 112, 424– 425. Napolitano, M., Giansily-Blaizot, M., Dolce, A., Schvend, J.F., Auerswald, G., Ingerslev, J., Bjerre, J., Altisent, C., Charoenkwan, P., Michaels, L., Chuansumrit, A., Di Minno, G., Caliskan, U. & Mariani, G. (2013) Prophylaxis in congenital factor VII deficiency: indications, efficacy and safety. Results from the Seven Treatment Evaluation Registry (STER). Hematologica, 98, 538– 544.

T-Cell Project: an international, longitudinal, observational study of patients with aggressive peripheral T-cell lymphoma

Peripheral T-cell lymphomas (PTCLs) comprise a heterogeneous group of neoplasms that are derived from post-thymic lymphoid cells at different stages of differentiation and with different morphological patterns, phenotypes, and clinical presentations. PTCLs are highly diverse, reflecting the diverse cells from which they can originate and are currently sub-classified using World Health Organization (WHO) 2008 criteria. Peripheral T-Cell Lymphomas account for 5%-10% of all lymphoproliferative disorders in the Western hemisphere, with an overall incidence of 0.5-2 per 100,000 individuals per year, and have a striking epidemiological distribution, with higher incidence in Asia. The clinical features of PTCL are extremely heterogeneous. PTCLs express even more clinical diversity than B-cell non-Hodgkins lymphomas, and there is a close, though not absolute, relationship between some unusual clinical features and certain histological subtypes.

Nonpegylated liposomal doxorubicin combination regimen in patients with diffuse large B‐cell lymphoma and cardiac comorbidity. Results of the HEART01 phase II trial conducted by the Fondazione Italiana Linfomi

The purpose of this phase 2, multicenter study was to determine the activity and safety of nonpegylated liposomal doxorubicin as part of “R‐COMP” combination in patients with diffuse large B‐cell lymphoma and coexisting cardiac disorders. The study was conducted using a Bayesian continuing assessment method using complete remission rate and rate of cardiac events as study endpoints. Between November 2009 and October 2011, 50 evaluable patients were enrolled (median age, 76 years). Median baseline left ventricular ejection fraction (LVEF) was 60%. Ischemic cardiopathy was the most frequent preexisting cardiac disorder (35%), followed by atrial fibrillation (15%), left ventricular hypertrophy (13%), and baseline LVEF <50% (12%). Based on the intent to treat analysis, overall response rate was 72%, including 28 patients in complete remission (complete remission rate, 56%), and 8 in partial remission (16%). At the end of treatment, grades 3 to 4 cardiac events were observed in 6 patients. No significant modifications from baseline values of LVEF were observed during treatment and follow‐up. Nonpegylated liposomal doxorubicin instead of doxorubicin in the R‐CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) regimen is a feasible option for patients with diffuse large B‐cell lymphoma presenting with concomitant cardiac disorders.