Primary testicular diffuse large B-cell lymphoma (PTL) is characterized by high risk of contralateral testis and central nervous system (CNS) relapse. Chemoimmunotherapy with intrathecal (IT) CNS prophylaxis and contralateral testis irradiation eliminates contralateral recurrences and reduces CNS relapses. The IELSG30 phase 2 study investigated feasibility and activity of an intensified IT and IV CNS prophylaxis. Patients with stage I/II PTL who had not received treatment received 2 cycles of IV high-dose methotrexate (MTX) (1.5 g/m2) after 6 cycles of the R-CHOP regimen (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone, every 21 days). IT liposomal cytarabine was administered on day 0 of cycles 2 to 5 of 21-day R-CHOP regimen. Contralateral testis radiotherapy (25-30 Gy) was recommended. Fifty-four patients (median age: 66 years) with stage I (n = 32) or II (n = 22) disease were treated with R-CHOP, 53 received at least 3 doses of IT cytarabine, 48 received at least 1 dose of IV MTX, and 50 received prophylactic radiotherapy. No unexpected toxicity occurred. At a median follow-up of 6 years, there was no CNS relapse; 7 patients progressed, and 8 died, with 5-year progression-free and overall survival rates of 91% (95% confidence interval [CI], 79-96) and 92% (95% CI, 81-97), respectively. Extranodal recurrence was documented in 6 patients (in 2 without nodal involvement). In 4 cases, the relapse occurred >6 years after treatment. Causes of death were lymphoma (n = 4), second primary malignancy (n = 1), cerebral vasculopathy (n = 1), unknown (n = 2). Intensive prophylaxis was feasible and effective in preventing CNS relapses. Late relapses, mainly at extranodal sites, represented the most relevant pattern of failure. This trial was registered at www.clinicaltrials.gov as #NCT00945724.

Abstract Introduction : Cytogenetic abnormalities by fluorescence in situ hybridization (FISH) are clinically relevant prognostic factors in MM. Data in transplant ineligible patients treated with bortezomib or lenalidomide in first-line therapy for high-risk (HiR) patients is limited. Careful analysis of cytogenetic subgroups in trials comparing different treatments remains an important goal. This sub-analysis evaluates the impact of cytogenetics on outcomes in transplant-ineligible patients with newly diagnosed MM (NDMM) treated with bortezomib-based induction (BORT) or lenalidomide-based (LEN) treatment. Methods : In the GIMEMA-MM-03-05-trial, patients were randomized to bortezomib-melphalan-prednisone-thalidomide for 9 cycles followed by maintenance with bortezomib-thalidomide (VMPT-VT) vs VMP for 9 cycles, without maintenance. In the EMN01-trial, patients were randomized to melphalan-prednisone-lenalidomide (MPR) or cyclophosphamide-prednisone-lenalidomide (CPR) or lenalidomide plus low-dose dexamethasone (Rd) for 9 cycles, followed by maintenance with lenalidomide alone or plus prednisone continuously. Results of these studies have previously been reported (Palumbo A et al JCO 2010 and 2014; Magarotto V et al Blood 2016 127(9)). Cytogenetics were assessed using FISH. Patients were categorized into cytogenetic risk groups according to International Myeloma Working Group criteria. HiR cytogenetics included del(17p), t(4;14), and t(14;16); all other patients were categorized as standard risk (StR). Subgroup analyses were performed to determine the consistency of treatment effects of BOR vs LEN in the different subgroups using interaction terms between treatment and FISH, ISS, age, sex, Karnofsky PS and LDH. The different effect of BORT vs LEN in cytogenetic subgroups was confirmed by one sensitivity analysis where the follow-up of the BORT study was reduced to make the follow-up times similar; and by another sensitivity analysis with multiple imputation method for missing cytogenetic value. Results : 902 of 1165 patients from the intent-to-treat population had available cytogenetic profiles, with 243 (27%) patients in the HiR group and 659 (73%) in the StR group. In the BORT vs LEN groups, median age was 71 vs 73 years (p<0.001), ISS3 20% vs 27% (P=0.65), HiR patients were 29% vs 26%, StR patients were 71% vs 74% (p=0.32) and the median follow-up was 72.3 and 63.6 months, respectively. In the subgroup analysis, a significant difference was found in the cytogenetic subgroup with a superior advantage of BORT versus LEN in HiR group, whereas no significant difference was found between BORT and LEN in the other subgroups analyzed (ISS, age, sex, Karnofsky PS and LDH) (interaction-p=0.01) (Fig. 1 B). BORT treatment resulted in a reduced risk of death or progression compared with LEN in patients with HiR. In HiR patients, median PFS was 30.8 with BORT compared with 14.8 months with LEN (HR: 0.54; 95% CI: 0.41-0.72); in StR, median PFS was 29.1 with BORT compared with 22.1 months with LEN (HR: 0.87; 95%; CI: 0.72-1.05) (Fig. 1 A). Considering the standard of care VMP and Rd, in the HiR group (n=95) VMP resulted in a 48% reduced risk of death or progression compared with Rd (HR: 0.53; 95% CI: 0.34-0.83), whereas no significant difference in PFS was found in the StR group (n=273) (HR: 1.00; 95% CI: 0.75-1.33), interaction-p=0.02. BORT treatment resulted in a reduced risk of death in patients with HiR cytogenetics: median OS was 62.4 months with BORT compared with 43.2 months with LEN (HR: 0.68; 95% CI: 0.47-0.96); in StR, median OS was 78.1 months with BORT and was not reached with LEN (HR: 1.06; 95% CI: 0.82-1.36), interaction-p=0.04 (Fig. 1 A). In patients with del(17p) (n=131) median PFS was 18.0 vs 12.9 months for BORT vs LEN (HR: 0.71; 95% CI: 0.49-1.04), interaction-p=0.73. In patients with t(4;14) (n=118) median PFS was 31.5 vs 15.2 months for BORT vs LEN (HR: 0.41; 95% CI: 0.27-0.62) interaction-p=0.002. In patients with t(14;16) (n=31) median PFS was 36.2 vs 9.8 months for BORT vs LEN treated patients (HR: 0.34; 95% CI: 0.16-0.76), interaction-p=0.045. Conclusions : BORT treatment resulted in a PFS and OS benefit vs LEN in patients with HiR cytogenetics. Treatment with VMP led to a significant reduction of the risk of death or progression vs Rd in HiR patients. These results support VMP induction as a standard treatment option for patients with NDMM who are ineligible for transplant with HiR cytogenetics. Disclosures Larocca: Celgene: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Amgen: Honoraria. Offidani: celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees. Musto: Janssen: Honoraria; Celgene: Honoraria. Patriarca: MSD Italia: Honoraria; Janssen: Honoraria. Corradini: Gilead: Honoraria; Amgen: Honoraria; Janssen: Honoraria; Roche: Honoraria; Celgene: Honoraria; Sanofi: Honoraria; Takeda: Honoraria; Novartis: Honoraria. Bosi: Amgen: Honoraria; Celgene: Honoraria; Janssen: Honoraria; Takeda: Membership on an entity's Board of Directors or advisory committees. Petrucci: Celgene: Honoraria; Janssen: Honoraria; Bristol-Myers Squibb: Honoraria; Takeda: Honoraria; Amgen: Honoraria. Boccadoro: Bristol-Myers Squibb: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Novartis: Honoraria, Research Funding; Sanofi: Honoraria, Research Funding; Mundipharma: Research Funding; AbbVie: Honoraria.

ular menses. Among those who became pregnant, conception was spontaneous in 7, all of whom had regular menses. Nine pregnancies were achieved following gonadotrophin-induced ovulation, while intrauterine insemination was performed in 3 cases. Two patients developed gestational The life expectancy and quality of life of patients with thalassemia has significantly increased over the last few years due to an improvement in the management of a transfusional approach and iron chelation therapy. Despite these advances, hypogonadotropic hypogonadism is still a common problem [1] that has been associated with increased fetal and maternal complications during pregnancy [2] . As only a few studies have described the evolution of pregnancy in subjects with beta-thalassemia major when managed according to the most recent recommendations [3–5] , the present study investigated the methods of conception and the mode of delivery as well as the course and outcome of pregnancy in a cohort of 46 patients in North Sardinia during the period between 2001 and 2017. All patients provided informed consent and the study was approved by the local ethics committee. As shown in Figure 1 , 19 pregnancies occurred in 15 women with thalassemia major. The mean age at the time of the first pregnancy was 33 years (range 28–38). Of these, 4 were being treated with deferasirox, 6 with deferoxamine, 2 with deferiprone, and 3 with deferoxamine plus deferiprone. Chelation therapy was discontinued in all pregnancies. Three patients had primary amenorrhea, 1 had secondary amenorrhea, and 1 had oligomenorrhea, while 10 patients had basically regReceived: August 17, 2017 Accepted after revision: August 20, 2017 Published online: October 10, 2017

Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

In the GIMEMA LAL 0904 protocol, adult Philadelphia positive acute lymphoblastic leukemia patients were treated with chemotherapy for induction and consolidation, followed by maintenance with imatinib. The protocol was subsequently amended and imatinib was incorporated in the induction and post-remission phase together with chemotherapy. Due to the toxicity of this combined approach, the protocol was further amended to a sequential scheme based on imatinib plus steroids as induction, followed by consolidation with chemotherapy plus imatinib and, when applicable, by a hematopoietic stem cell transplant. Fifty-one patients (median age 45.9 years) were enrolled in the final sequential protocol. At the end of induction (day +50), 96% of evaluable patients (n=49) achieved a complete hematologic remission; after consolidation, all were in complete hematologic remission. No deaths in induction were recorded. Overall survival and disease-free survival at 60 months are 48.8% and 45.8%, respectively. At day +50 (end of imatinib induction), a more than 1.3 log-reduction of BCR-ABL1 levels was associated with a significantly longer disease-free survival (55.6%, 95%CI: 39.0–79.3 vs. 20%, 95%CI: 5.8–69.1; P=0.03), overall survival (59.1%, 95%CI: 42.3–82.6 vs. 20%, 95%CI: 5.8–69.1; P=0.02) and lower incidence of relapse (20.5%, 95%CI: 7.2–38.6 vs. 60.0%, 95%CI: 21.6–84.3; P=0.01). Mean BCR-ABL1 levels remained significantly higher in patients who subsequently relapsed. Finally, BCR-ABL1p190 patients showed a significantly faster molecular response than BCR-ABL1p210 patients (P=0.023). Though the study was not powered to evaluate the role of allogeneic stem cell transplant, allografting positively impacted on both overall and disease-free survival. In conclusion, a sequential approach with imatinib alone in induction, consolidated by chemotherapy plus imatinib followed by a stem cell transplant is a feasible, well-tolerated and effective strategy for adult Philadelphia positive acute lymphoblastic leukemia, leading to the best long-term survival rates so far reported. (clinicaltrials.gov identifier: 00458848).

Even though the pathogenesis of myelodysplastic syndromes (MDS) is dominated by specific molecular defects involving hematopoietic precursors, also immune mechanisms seem to play a fundamental functional role. In this review we will first describe the clinical and laboratory autoimmune manifestations often detectable in MDS patients. We will then focus on studies addressing the possible influence of different immune cell subpopulations on the disease onset and evolution. We will finally consider therapeutic approaches based on immunomodulation, ranging from immunosuppressants to vaccination and transplantation strategies.

The T-cell receptor (TCR) is the key player within the so called immunological synapse and the analysis of its repertoire offers a picture of both versatility and wideness of the whole immune T-cell compartment. Among the different approaches applied to its study the so-called spectratyping identifies the pattern of the third complementarity determining region (CDR3) length distribution in each one of the beta variable (TRBV) subfamilies encoded by the corresponding genes. This technique consists in a CDR3 fragment analysis through capillary electrophoresis, performed after cell separation, RNA extraction and reverse transcriptase PCR. This review will run through the most relevant studies which have tried to dissect the TCR repertoire usage in patients with different immune-mediated and infective diseases as well as solid or haematologic malignancies.

Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant disorder associated with a progression to multiple myeloma (MM). MM is a plasma cell malignancy with a chronic lymphoprol...

Fludarabine and Cytarabine Combination in the Induction of Adult Patients with Acute Myeloid Leukaemia Francesco Longu;Claudio Fozza;Laura Dessi;Maurizio Longinotti;Silvana Bonfigli;Maria Careddu;Lorenzo Coppola;Domenica Giannico;Rosa Nieddu;Luigi Podda;Simonetta Pardini;Fausto Dore;Simone Dore;Giovanni Sotgiu; Acta Haematologica

Because different findings suggest that an immune dysregulation plays a role in the pathogenesis of myelodysplastic syndrome (MDS), we analyzed a large cohort of patients from a homogeneous Sardinian population using ImmunoChip, a genotyping array exploring 147,954 single-nucleotide polymorphisms (SNPs) localized in genomic regions displaying some degree of association with immune-mediated diseases or pathways. The population studied included 133 cases and 3,894 controls, and a total of 153,978 autosomal markers and 971 non-autosomal markers were genotyped. After association analysis, only one variant passed the genome-wide significance threshold: rs71325459 (p = 1.16 × 10-12), which is situated on chromosome 20. The variant is in high linkage disequilibrium with rs35640778, an untested missense variant situated in the RTEL1 gene, an interesting candidate that encodes for an ATP-dependent DNA helicase implicated in telomere-length regulation, DNA repair, and maintenance of genomic stability. The second most associated signal is composed of five variants that fall slightly below the genome-wide significance threshold but point out another interesting gene candidate. These SNPs, with p values between 2.53 × 10-6 and 3.34 × 10-6, are situated in the methylene tetrahydrofolate reductase (MTHFR) gene. The most associated of these variants, rs1537514, presents an increased frequency of the derived C allele in cases, with 11.4% versus 4.4% in controls. MTHFR is the rate-limiting enzyme in the methyl cycle and genetic variations in this gene have been strongly associated with the risk of neoplastic diseases. The current understanding of the MDS biology, which is based on the hypothesis of the sequential development of multiple subclonal molecular lesions, fits very well with the demonstration of a possible role for RTEL1 and MTHFR gene polymorphisms, both of which are related to a variable risk of genomic instability.

Patients with myelodysplastic syndromes (MDS) and acute myeloid leukemia (AML) with multilineage dysplasia show several immunological abnormalities. In this clinical setting, by combining flow cytometry and CDR3 spectratyping we monitored the kinetic of the T-cell repertoire during Azacitidine treatment, in order to explore its potential ability to reverse the immune derangement typical of these disorders. We firstly demonstrated by flow cytometry an increase in both CD4+ and CD8+ T-cell frequencies after starting treatment. Moreover, when monitored by spectratyping our patients showed significant changes in their T-cell receptor (TCR) CDR3 profiles, which were much more evident in helper T-cells. In fact, the frequency of BV (beta variable) subfamilies showing a skewed CDR3 profile significantly decreased from baseline to the following evaluations in CD4+ T-cells (81% vs. 70%). This pattern was even more pronounced in patients responding to Azacitidine (90% vs. 61%). Our data show that the overall derangement of the T-cell repertoire detectable in patients with MDS and AML with multilineage dysplasia gradually improves during Azacitidine treatment. These findings therefore suggest that Azacitidine could be potentially able, not only to restore the hematopoietic function, but also to reverse the immune derangement typical of these hematologic disorders.

Fetal hemoglobin inducers are a promising therapeutic strategy for patients with beta thalassemia major and other hemoglobinopathies. Hydroxyurea and histone deacetylase inhibitors improve the α/β chain imbalance typical of these diseases 1. Immunomodulator compounds such as pomalidomide and lenalidomide slow erythroid maturation, increase the proliferation of immature erythroid cells, and modulate hemoglobin transcription, thus resulting in a strong induction of fetal Hb 2. Use of thalidomide in patients with transfusion dependent thalassemia (TDT) is anecdotal 3, 4, but no data are available for patients with non-transfusion dependent thalassemia (NTDT). We report here two cases in which thalidomide was used as erythroid stimulating agent for NTDT. Case 1: A 48-year-old woman had been diagnosed with NTDT at the age of 6 years. Direct sequencing revealed: (a) an heterozygous state for the β039 and β06 mutations, with a ATG–>ACG heterozygous point mutation involving the initiation codon of the α2 gene; (b) a homozygous state for the polymorphism Gγ-158 C–>T, which is associated with an increase in fetal hemoglobin synthesis 5; (c) absence of the known single point mutations in the gamma-globin promoter, associated with hereditary persistence of fetal haemoglobin (HPFH). Splenectomy was performed in 2002 at the age of 32. In May 2012 at the age of 42 years she required chronic transfusion treatment and received 2 packed red blood cell (PRBC) units roughly every 2 weeks until December 2012, when severe post-transfusional alloimmune hemolytic anaemia ensued (Figure 1). She was firstly treated with high dose steroids plus azatioprine 100 mg and then since November 2013 with rituximab 375 mg/m2 up to eight cycles. This approach was unsuccessful with Hb levels fluctuating between 6 and 8 g/dL. In April 2014, while her Hb was 7.35 g/dL (HbF 96%) on azatioprine 50 mg daily and her indirect Coombs test was still positive with an anti-Jkb titer of 1:8, she was started on thalidomide 50 mg/100 mg on alternate days. Quite strikingly her Hb level rose up to 9.99 g/dL within the first month and then to 10.7 g/dL in the second one, notwithstanding a dose reduction for thalidomide to 50 mg daily. After 4 months of treatment and a further dose reduction to 50 mg every other day, thalidomide was stopped with a Hb of 10 g/dL. Within one month Hb dropped to 8.75 g/dL but, after restarting thalidomide at a dose of 50 mg 5 days a week, a further response was achieved within one month. Ten months after starting thalidomide the patient is still responding with Hb above 10 g/dL. Case 2: A patient with homozygosity for the β039 mutation, and for α-thalassemia, received her first transfusion at the age of 13 years and was splenectomized at the age of 28 years. At the age of 48 she developed a recurrent post-transfusional alloimmune hemolytic anaemia. In February 2011, at age 56, with an overall transfusional burden of 10 PRBC units she presented with a Hb of 2.6 g/dL (HbF 98%). All the hemolytic indexes as well as both direct and indirect Coombs test were highly positive (anti -IgG, C3b, C3d). After an unsuccessful first line treatment with high doses steroid, she was started on thalidomide 50 mg/100 mg on alternate days together with mycophenolate mofetil 500 mg/day and high dose poly-specific IV Ig (5 cycles with 20 g for 5 days up to day +115 of thalidomide therapy). With this treatment her Hb level rose to 3.3 g/dL within the first month and to 6.5 g/dL in the second one. Mycophenolate mofetil was tapered and stopped at day +105 and she maintained a stable Hb level of 8–9 g/dL thereafter. The thalidomide dose was slowly tapered to the current one of 50 mg every other day. After 4 years of continuous treatment with thalidomide her Hb remains above 8 g/dL (HbF = 98%), with no detectable thalidomide-related side effects These two cases highlight a possible beneficial role of thalidomide in NTDT: since baseline Hb in these two patient was almost completely represented by HbF, it is not possible to determine the role of Hb F induction vs. immunomodulatory effects. The failure of various immunomodulatory approaches suggests a prominent role for the former mechanism. Epigenetic mechanisms have been hypothesized to promote a sustained fetal hemoglobin production even in thalassemic patients not engrafting after bone marrow transplantation 6. Such epigenetic modifications, which have been advocated to explain the efficacy of thalidomide as a HbF inducer at least in vitro 7, would deserve to be specifically explored in thalassemic patients. Hemoglobin values (black line) from the time the patient became transfusion dependent and during rituximab and thalidomide therapy. CF wrote the paper; SP, DBG, CT, AAD, PS, EA and FD were involved in the patient management, provided fundamental intellectual feed-back and reviewed the manuscript. Claudio Fozza,1* Simonetta Pardini,1 Domenica Barbara Giannico,1 Clara Targhetta,2 Anna Angela Di Tucci,2 Paolo Dessalvi,2 Emanuele Angelucci,2 and Fausto Dore1 1Dipartimento Di Scienze Biomediche, Università Di Sassari, 07100 Sassari, Italy; 2UO Ematologia E Centro Trapianti Ospedale Oncologico Di Riferimento Regionale "Armando Businco, Cagliari, Italy

Patient: Male, 64 Final Diagnosis: Acute myeloid leukemia (AML) Symptoms: — Medication: — Clinical Procedure: — Specialty: — Objective: Unusual clinical course Background: Central nervous system (CNS) involvement is a sporadic presenting finding in patients with acute myeloid leukemia (AML) both at diagnosis and at relapse. Moreover patients with CNS localization are often asymptomatic, while sometimes show meningeal signs and symptoms or, extremely rarely, signs of cranial nerve impairment. Case Report: Here we report on a patient with refractory AML who suddenly developed strabismus and diplopia. Both neurological and ophtalmologic examinations were suggestive of a bilateral VI cranial nerve palsy. Noteworthy, both a cranial CT and MRI were substantially normal, while a rachicentesis was performed and cerebrospinal fluid examination was clearly suggestive of a meningeal involvement by AML. Conclusions: This is to our knowledge the first reported case in which the clinical picture of meningeal localization in an AML patient was dominated by an isolated abducens cranial nerve impairment. Moreover it highlights as unexplained strabismus and diplopia can be considered as a potential sign of CNS involvement, even if conventional imaging is negative.

Although a number of studies suggest that different immune pathways may play a role in the pathogenesis of non‐Hodgkin's lymphomas (NHL), the shape of the T‐cell compartment has been only superficially explored in these patients. In our study, we analyzed the peripheral T‐cell receptor (TCR) repertoire and the distribution of different T‐cell subsets – including regulatory T cells (Treg) – in 30 patients with NHL, by combining flow cytometry and spectratyping. We first demonstrated by flow cytometry an increased frequency of expanded T‐cell subpopulations expressing the same TCR beta variable (BV) subfamilies in CD8+ cells from NHL patients when compared with healthy controls, beside a higher frequency of Treg. Moreover, NHL patients were characterized by a higher percentage of BVs showing a skewed CDR3 profile both in CD4+ and CD8+ cells when analyzed by spectratyping. Our data suggest that the T‐cell branch of the immune system of patients with B‐cell NHL is deeply deranged, as witnessed by the increased degree of activation and skewing of their TCR repertoire along with the higher frequency of Treg.

The initial analysis of the oral combination melphalan, prednisone, and thalidomide (MPT) in newly diagnosed patients with myeloma showed significantly higher response rate and longer progression-free survival (PFS) than did the standard melphalan and prednisone (MP) combination and suggested a survival advantage. In this updated analysis, efficacy and safety end points were updated. Patients were randomly assigned to receive oral MPT or MP alone. Updated analysis was by intention to treat and included PFS, overall survival (OS), and survival after progression. After a median follow-up of 38.1 months, the median PFS was 21.8 months for MPT and 14.5 months for MP (P = .004). The median OS was 45.0 months for MPT and 47.6 months for MP (P = .79). In different patient subgroups, MPT improved PFS irrespective of age, serum concentrations of beta(2)-microglobulin, or high International Staging System. Thalidomide or bortezomib administration as salvage regimens significantly improved survival after progression in the MP group (P = .002) but not in the MPT group (P = .34). These data confirm activity of MPT for PFS but failed to show any survival advantage. New agents in the management of relapsed disease could explain this finding. The study is registered at www.clinicaltrials.gov as #NCT00232934.

We performed a prospective, randomized study of single (arm A) versus double (arm B) autologous stem-cell (SC) transplantation (ASCT) for younger patients with newly diagnosed multiple myeloma. A total of 321 patients were enrolled in the study and were randomly assigned to receive either a single course of SC-supported melphalan, 200 mg/m2 (MEL-200) (n=163 patients) or MEL-200 followed, 3 to 6 months apart, by melphalan, 120 mg/m2, and busulfan, 12 mg/kg (n=158 patients). As compared with arm A, randomization to receive double ASCT significantly increased the probability to attain at least a near (n) complete response (CR) (33% vs 47%, respectively; P=0.008). Patients who responded to induction therapy had a CR or nCR rate following either single or double ASCT of 73% and 52%, respectively (P=0.010). Both these values were much higher than those observed among patients who failed to respond to induction therapy, whose posttransplantation ≥ nCR rate was 11% in arm A and 12% in arm B (P=0.20). On multivariate analysis, randomization to double ASCT (P<0.001) and partial response to induction therapy (P<0.001) were independent significant predictors of posttransplantation attainment of CR or nCR. In comparison with a single autotransplantation, double ASCT resulted in a significant prolongation of both relapse-free survival (RFS) (median: 42 vs 23 months, respectively; P<0.001) and event-free survival (EFS) (median: 35 vs 23 months, respectively; P=0.001). The most important and independent variable favorably influencing RFS and EFS in a multivariate model was ≥nCR (P<0.001 for both RFS and EFS). Additional prognostic factors for extended EFS included baseline platelet count greater than 150.000/μL (P=0.004), randomization to double ASCT (P=0.005), hemoglobin level greater than 10 g/dL at diagnosis (P=0.01) and less than 55 years of age (P=0.04). Administration of a second transplantation and of novel agents, including thalidomide or bortezomib, for the treatment of sequential relapses in up to 50% of patients who were randomized to single transplantation likely contributed to prolong the survival duration of the whole group, whose 7-year rate (46%) was similar to that of the double-transplant group (43%) (P=0.9). Prolonged OS was significantly related to baseline hemoglobin concentration greater than 10 g/dL (P<0.001), serum creatinine level less than 177 μmol/L at diagnosis (P=0.001) and ≥ nCR (P=0.001). Benefits offered by double ASCT in terms of extended RFS and EFS were particularly evident among patients who failed at least nCR after the first autologous transplantation (P<0.001 for both RFS and EFS). At the opposite, among patients achieving CR or nCR following one transplantation, final outcomes of ASCT(s) were not significantly influenced by study randomization. Because of its potential of inducing long-term EFS and OS in the 30% to 50% range, double ASCT still remains the standard of care for younger patients with newly diagnosed MM. Attainment of CR is a surrogate marker of extended RFS, EFS and OS, and represents an important objective of novel treatment strategies combining high-dose chemotherapy with agents targeting the bone marrow microenvironment.

In this hospital-based, multicenter case-control study we investigated the prevalence of hepatitis B virus (HBV)-related markers and HBV/hepatitis C virus (HCV) co-infection among B-cell non-Hodgkin's lymphoma (B-NHL) cases and controls. Four hundred newly diagnosed B-NHL cases and 392 controls from other departments of the same hospitals were studied. The prevalence of positivity for hepatitis B surface antigen (HBsAg) was 8.5% among B-NHL cases and 2.8% among controls (adjusted odds ratio, 3.67; 95% confidence interval, 1.75-7.66). HBV/HCV co-infection was found in four cases, but in no controls. The finding of a positive association between HBV infection and B-NHL raises the possibility that HBV may play an etiologic role in the induction of B-NHL.