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In the frontline high-dose phase 3 FIL-MCL0208 trial (NCT02354313), 8% of enrolled mantle cell lymphoma (MCL) patients could not be randomised to receive lenalidomide (LEN) maintenance vs observation after autologous stem cell transplantation (ASCT) due to inadequate hematological recovery and 52% of those who started LEN, needed a dose reduction due to toxicity. We therefore focused on the role played by CD34 + hematopoietic stem cells (PBSC) harvesting and reinfusion on toxicity and outcome. Overall, 90% (n = 245) of enrolled patients who underwent the first leukapheresis collected ≥ 4 × 106 PBSC/kg, 2.6% (n = 7) mobilized < 4 × 106 PBSC/kg and 7.7% (n = 21) failed the collection. Similar results were obtained for the planned second leukapheresis, with only one patient failing both attempts. Median count of reinfused PBSC was 5 × 106/kg and median time to recovery from neutropenia G4 was 10 days from ASCT. No impact of mobilizing subtype or number of reinfused PBSC on hematological recovery and LEN dose reduction was noted. At a median follow-up of 75 months from ASCT, PFS and OS of transplanted patients were 50% and 73%, respectively. A long lasting G4 neutropenia after ASCT (> 10 days) was associated with a worse outcome, both in terms of PFS and OS. In conclusion, although the harvesting procedures proved feasible for younger MCL patients, long-lasting cytopenia following ASCT remains a significant issue: this can hinder the administration of effective maintenance therapies, potentially increasing the relapse rate and negatively affecting survival outcomes. [ABSTRACT FROM AUTHOR]

Simple Summary: The prevalence of second neoplasms among patients with hairy cell leukemia (HCL) treated with cladribine is not negligible. Immunosuppression, high rate of cure, and aging may have a role in the pathogenesis of second cancers after HCL. We aimed to compare the risk of cancer between patients with HCL treated with cladribine and the general population. Concern has emerged about the prevalence of second cancers among patients with hairy cell leukemia (HCL) treated with purine analogs. We investigated 513 patients with HCL treated with cladribine over the last 30 years at 18 Italian centers and calculated their standardized incidence ratios (SIRs). We identified 24 patients with a second cancer diagnosed at a median time from treatment with cladribine of 59.9 months (range: 9.2–169.7 months). All patients with solid neoplasms presented with a limited-stage disease, except four cases of locally advanced cancer; multiple myeloma patients had a smoldering disease, while lymphoma patients had stage Ie and stage IV diseases. Response to therapy was complete in 19 cases; 1 patient is still receiving treatment for a relapsing bladder disease, while 2 patients progressed during treatment and died. These two patients died from unrelated causes: one from infection and one due to surgery complications. The median OS from HCL was 98.5 months (range: 38.4–409.2 months), while the median OS from second cancer was 27.6 months (range: 1–117.8 months). The SIR was 0.86 (95% CI: 0.54–1.30) for males and 1.13 (95% CI: 0.36–2.73) for females: no statistically significant differences were highlighted. We were not able to demonstrate an excess of second cancer or a significant association with the specific studied neoplasm. [ABSTRACT FROM AUTHOR]

Intraclonal diversification of immunoglobulin (Ig) variable (V) genes was evaluated in leukaemic cells from a B-cell chronic lymphocytic leukaemia (B-CLL) case over a 2-year period at four time points. Intraclonal heterogeneity was analysed by sequencing 305 molecular clones derived from polymerase chain reaction amplification of B-CLL cell IgV heavy (H) and light (C) chain gene rearrangements. Sequences were compared with evaluating intraclonal variation and the nature of somatic mutations. Although IgV intraclonal variation was detected at all time points, its level decreased with time and a parallel emergence of two more represented VHDJH clones was observed. They differed by nine nucleotide substitutions one of which only caused a conservative replacement aminoacid change. In addition, one VLJL rearrangement became more represented over time. Analyses of somatic mutations suggest antigen selection and impairment of negative selection of neoplastic cells. In addition, a genealogical tree representing a model of clonal evolution of the neoplastic cells was created. It is of note that, during the period of study, the patient showed clinical progression of disease. We conclude that antigen stimulation and somatic hypermutation may participate in disease progression through the selection and expansion of neoplastic subclone(s). [ABSTRACT FROM AUTHOR]

Subcutaneous (SC) rituximab may be beneficial in terms of convenience and tolerability, with potentially fewer and less severe administration-related reactions (ARRs) compared to the intravenous (IV) form. This report presents the results of a phase IIIb study conducted in Italy. The study included adult patients with CD20+ DLBCL or FL having received at least one full dose of IV RTX 375 mg/m2 during induction or maintenance. Patients on induction received ≥4 cycles of RTX SC 1400 mg plus standard chemotherapy and FL patients on maintenance received ≥6 cycles of RTX SC. Overall, 159 patients (73 DLBCL, 86 FL) were enrolled: 103 (54 DLBCL, 49 FL) completed induction and 42 patients with FL completed 12 maintenance cycles. ARRs were reported in 10 patients (6.3%), 3 (4.2%) with DLBCL and 7 (8.1%) with FL, all of mild severity, and resolved without dose delay/discontinuation. Treatment-emergent adverse events (TEAEs) and serious adverse events occurred in 41 (25.9%) and 14 patients (8.9%), respectively. Two patients with DLBCL had fatal events: Klebsiella infection (related to rituximab) and septic shock (related to chemotherapy). Neutropenia (14 patients, 8.9%) was the most common treatment-related TEAE. Two patients with DLBCL (2.8%) and 6 with FL (7.0%) discontinued rituximab due to TEAEs. 65.2% and 69.7% of patients with DLBCL and 67.9% and 73.6% of patients with FL had complete response (CR) and CR unconfirmed, respectively. The median time to events (EFS, PFS, and OS) was not estimable due to the low rate of events. At a median follow-up of 29.5 and 47.8 months in patients with DLBCL and FL, respectively, EFS, PFS, and OS were 70.8%, 70.8%, and 80.6% in patients with DLBCL and 77.9%, 77.9%, and 95.3% in patients with FL, respectively. The switch from IV to SC rituximab in patients with DLBCL and FL was associated with low risk of ARRs and satisfactory response in both groups. This trial was registered with NCT01987505. [ABSTRACT FROM AUTHOR]

Summary: Treatment for follicular lymphoma (FL) in the elderly is not well standardized. A phase II, multicentre, single arm trial was conducted in this setting with a brief chemoimmunotherapy regimen. Treatment consisted in four monthly courses of rituximab, bendamustine and mitoxantrone (R‐BM) followed by 4 weekly rituximab as consolidation; rituximab maintenance was not applied because the drug was not licensed at the time of enrolment. The primary endpoint was the complete remission rate (CR). Seventy‐six treatment‐naive FL patients (aged 65–80 and a "FIT" score, according to the Comprehensive Geriatric Assessment) were enrolled. CR was documented in 59/76 patients (78%), partial remission in 12 (16%) and stable/progressive disease in five (6%) with an overall response rate in 71/76 (94%). Median follow‐up was 44 months with 3‐year progression‐free‐survival (PFS) and overall‐survival of 67% and 92% respectively. Nine deaths occurred, three of progressive disease. The regimen was well tolerated and the most frequent severe toxicity was neutropenia (18% of the cycles). Bcl‐2/IGH rearrangement was found in 40/75 (53%) of evaluated patients. R‐BM was highly effective in clearing polymerase chain reaction‐detectable disease: 29/31 (96%) evaluated patients converted to bcl‐2/IGH negativity at the end of treatment. A brief R‐BM regimen plus rituximab consolidation is effective and safe in "FIT" elderly, treatment‐naïve, FL patients, inducing high CR and molecular remission rates with prolonged PFS. [ABSTRACT FROM AUTHOR]

Summary: Mantle cell lymphoma is a rare and incurable lymphoproliferative disorder. In the MCL01 trial, patients were treated with the R‐HCVAD regimen [rituximab plus HyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone; R‐CVAD) alternating with high‐dose methotrexate and cytarabine (AM)] for four cycles followed by autologous stem cell transplantation (ASCT) for those who reached only a partial response. After a median follow‐up of 10·5 years, we reported 10‐year progression‐free and overall survival rates of 35% and 61% respectively, with a 10‐years cumulative incidence rate of second malignancies of 10·6%. Mature results of the MCL01 trial confirmed the efficacy of HyperCVAD‐AM as a frontline regimen for younger patients (≤65 years). [ABSTRACT FROM AUTHOR]

FDG-positron emission tomography (PET) performed early during therapy in advanced Hodgkin lymphoma patients has been confirmed as being important for progression-free survival. A group of patients with a negative interim-PET (i-PET) showed a positive end induction PET (e-PET). The aim of this study was to evaluate the clinical characteristics of patients with a positive e-PET as a secondary end point of the HD0801 study. A total of 519 patients with advanced-stage de novo Hodgkin lymphoma received initial treatment and underwent an i-PET. Patients with negative results continued the standard treatment. i-PET negative patients were then evaluated for response with an e-PET and those patients found to have a positive one were also then given a salvage therapy. Among 409 i-PET negative, 16 interrupted the therapy, 393 patients were evaluated with an e-PET, and 39 were positive. Sixteen out of 39 underwent a diagnostic biopsy and 15 were confirmed as HD. Seventeen out of 39 e-PET were reviewed according to the Deauville Score and, in sixteen, it was confirmed positive (10 DS 5, 6 DS 4). With the exception of high LDH value at diagnosis (p = 0.01; HR 95% CI 1.18-4.89), no clinical characteristics were significantly different in comparison with e-PET negative patients. Positive e-PET after a negative i-PET has a worse outcome when compared with i-PET positive patients salvaged with therapy intensification. It was not possible to identify clinical characteristics associated with a positive e-PET. [ABSTRACT FROM AUTHOR]

This phase-II study assessed activity and toxicity of substituting conventional doxorubicin with nonpegylated liposomal doxorubicin in the conventional ABVD regimen for the treatment of elderly or cardiopathic patients with HL. Stage I–IIA and IIB–IV patients were treated with three courses of MBVD plus radiotherapy, or six courses of MBVD, respectively, plus radiotherapy limited to bulky or residual disease areas. The primary endpoints were CR rate and the rate of cardiac events. Forty-seven patients were enrolled. Median age was 75 years, 13 had stage I–II disease. Overall, CR was achieved by 36 patients (77%, 95% CI: 62–88), 100% and 68% in stage I–II and III–IV, respectively. With a median follow-up of 40 months (IQR: 36–45). Three-year overall survival (OS) and progression-free survival (PFS) were 70% and 43%, respectively. Cardiac events grades 3–5 were reported in two patients. In conclusion, MBVD's activity and safety profile was comparable to historical ABVD data. [ABSTRACT FROM AUTHOR]

Summary: Splenectomy in addition to immunotherapy with rituximab can provide quick and sometimes durable disease control in patients with splenic marginal zone lymphoma (SMZL). However, systemic chemotherapy is ultimately required in many cases. The BRISMA (Bendamustine‐rituximab as first‐line treatment of splenic marginal zone lymphoma)/IELSG (International Extranodal Lymphoma Study Group)36 trial is an open‐label, single arm phase II study designed by the IELSG in cooperation with the Fondazione Italiana Linfomi and the lymphoma Study Association according to Simon's two‐stage method. The primary endpoint was complete response rate. Fifty‐six patients with SMZL diagnosis confirmed on central revision were treated with bendamustine (90 mg/m2 days 1, 2) and rituximab (375 mg/m2 day 1) every 28 days for six cycles (B‐R). The overall response and CR rates were 91% and 73%, respectively. Duration of response, progression‐free survival and overall survival at 3 years were 93% (95% confidence interval [CI] 81–98), 90% (95% CI 77–96) and 96% (95% CI 84–98), respectively. Toxicity was mostly haematological. Neutropenia grade ≥3 was recorded in 43% of patients; infections and febrile neutropenia in 5·4% and 3·6%. Overall, 14 patients (25%) experienced serious adverse events. Five patients (9%) went off‐study because of toxicity and one patient died from infection. In conclusion, B‐R resulted in a very effective first‐line regimen for SMZL. Based on the results achieved in the BRISMA trial, B‐R should be considered when a chemotherapy combination with rituximab is deemed necessary for symptomatic SMZL patients. [ABSTRACT FROM AUTHOR]

Background: The prognosis of young patients with diffuse large B-cell lymphoma at high risk (age-adjusted International Prognostic Index [aa-IPI] score 2 or 3) treated with R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone) is poor. The aim of this study was to investigate the possible benefit of intensification with high-dose chemotherapy and autologous stem-cell transplantation as part of first-line treatment in these patients.Methods: We did a multicentre, open-label, randomised, controlled, phase 3 trial with a 2 × 2 factorial design to compare, at two different R-CHOP dose levels, a full course of rituximab-dose-dense chemotherapy (no transplantation group) versus an abbreviated course of rituximab-dose-dense chemotherapy followed by consolidation with R-MAD (rituximab plus high-dose cytarabine plus mitoxantrone plus dexamethasone) and high-dose BEAM chemotherapy (carmustine, etoposide, cytarabine, and melphalan) plus autologous stem-cell transplantation (transplantation group) in young patients (18-65 years) with untreated high-risk diffuse large B-cell lymphoma (aa-IPI score 2-3). At enrolment, patients were stratified according to aa-IPI score and randomly assigned (1:1:1:1) to receive R-CHOP (intravenous rituximab 375 mg/m2, cyclophosphamide 750 mg/m2, doxorubicin 50 mg/m2, and vincristine 1·4 mg/m2 on day 1, plus oral prednisone 100 mg on days 1-5) delivered in a 14-day cycle (R-CHOP-14) for eight cycles; high-dose R-CHOP-14 (R-MegaCHOP-14; R-CHOP-14 except for cyclophosphamide 1200 mg/m2 and doxorubicin 70 mg/m2) for six cycles; R-CHOP-14 for four cycles followed by R-MAD (intravenous rituximab 375 mg/m2 on day 1 or 4 plus intravenous cytarabine 2000 mg/m2 and dexamethasone 4 mg/m2 every 12 h on days 1-3 plus intravenous mitoxantrone 8 mg/m2 on days 1-3) plus BEAM (intravenous carmustine 300 mg/m2 on day -7, intravenous cytarabine 200 mg/m2 twice a day on days -6 to -3, intravenous etoposide 100 mg/m2 twice a day on days -6 to -3, plus intravenous melphalan 140 mg/m2 on day -2) and autologous stem-cell transplantation (day 0); or R-MegaCHOP-14 for four cycles followed by R-MAD plus BEAM and autologous stem-cell transplantation. The primary endpoint was failure-free survival at 2 years in the intention-to-treat population. This study is registered with EudraCT (2005-002181-14; 2007-000275-42) and with ClinicalTrials.gov, number NCT00499018.Findings: Between Jan 10, 2006, and Sept 8, 2010, 399 patients were randomly assigned to receive transplantation (n=199) or no transplantation (n=200); 203 patients were assigned to receive R-CHOP-14 and 196 were assigned to receive R-MegaCHOP-14. With a median follow-up of 72 months (IQR 57-88), 2-year failure-free survival was 71% (95% CI 64-77) in the transplantation group versus 62% (95% CI 55-68) in the no transplantation group (hazard ratio [HR] 0·65 [95% CI 0·47-0·91]; stratified log-rank test p=0·012). No difference in 5-year overall survival was observed between these groups (78% [95% CI 71-83] versus 77% [71-83]; HR 0·98 [0·65-1·48]; stratified log-rank test p=0·91). Grade 3 or worse haematological adverse events were reported in 183 (92%) of 199 patients in the transplantation group versus 135 (68%) of 200 patients in the no transplantation group. Grade 3 or worse non-haematological adverse events were reported in 90 (45%) versus 31 (16%); the most common grade 3 or worse non-haematological adverse event was gastrointestinal (49 [25%] vs 19 [10%]). Treatment-related deaths occurred in 13 (3%) patients; eight in the transplantation group and five in the no transplantation group.Interpretation: Abbreviated rituximab-dose-dense chemotherapy plus R-MAD plus BEAM and autologous stem-cell transplantation reduced the risk of treatment failure compared with full course rituximab-dose-dense chemotherapy in young patients with diffuse large B-cell lymphoma at high risk. However, these results might not be clinically meaningful, since this improvement did not reflect an improvement in overall survival. These results do not support further consideration of the use of intensification of R-CHOP as an upfront strategy in patients with diffuse large B-cell lymphoma with poor prognosis.Funding: Fondazione Italiana Linfomi. [ABSTRACT FROM AUTHOR]

Purpose: To assess the predictive value of 18F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) for disease recurrence after immunochemotherapy (R-CHT) and mediastinal irradiation (RT), using the recently published criteria of the Lugano classification to predict outcomes for patients with primary mediastinal large B-cell lymphoma.Methods and Materials: Among 125 patients prospectively enrolled in the IELSG-26 study, 88 were eligible for central review of PET/CT scans after completion of RT. Responses were evaluated using the 5-point Deauville scale at the end of induction R-CHT and after consolidation RT. According to the Lugano classification, a complete metabolic response (CMR) was defined by a Deauville score (DS) ≤3.Results: The CMR (DS1, -2, or -3) rate increased from 74% (65 patients) after R-CHT to 89% (78 patients) after consolidation RT. Among the 10 patients (11%) with persistently positive scans, the residual uptake after RT was slightly higher than the liver uptake in 6 patients (DS4; 7%) and markedly higher in 4 patients (DS5; 4%): these patients had a significantly poorer 5-year progression-free survival and overall survival. At a median follow-up of 60 months (range, 35-107 months), no patients with a CMR after RT have relapsed. Among the 10 patients who did not reach a CMR, 3 of the 4 patients (positive predictive value, 75%) with DS5 after RT had subsequent disease progression (within the RT volume in all cases) and died. All patients with DS4 had good outcomes without recurrence.Conclusions: All the patients obtaining a CMR defined as DS ≤3 remained progression-free at 5 years, confirming the excellent negative predictive value of the Lugano classification criteria in primary mediastinal large B-cell lymphoma patients. The few patients with DS4 also had an excellent outcome, suggesting that they do not necessarily require additional therapy, because the residual 18F-fluorodeoxyglucose uptake may not reflect persistent lymphoma. [ABSTRACT FROM AUTHOR]

Single-agent bortezomib (B) has shown activity in heavily pretreated patients with relapsed/refractory indolent lymphoma. On the basis of these findings, we performed a phase II study of B combined with rituximab (R) in patients with relapsed follicular lymphoma (FL). Forty-five patients with fairly good prognostic profiles were enrolled from 2007 to 2011 and received a total of 6 cycles of the B+R combination. The endpoints were the overall response rate (ORR), progression-free survival (PFS), duration of remission (DoR), overall survival (OS), and toxicity evaluation. When considering all the enrolled patients the ORR was 64%. At 5 years, the estimated PFS, DoR, and OS were 34, 49, and 70%, respectively. After excluding the 7 R-naïve patients, the ORR was 58%, with a PFS of 19 months. The most common grade >2 toxicities were thrombocytopenia (18%), peripheral neuropathy (13%), and neutropenia (2%). Our study shows the feasibility, long-term efficacy, and excellent tolerability of the B+R combination. We are aware that our study has specific limitations, such as the small sample size consisting of patients with a relatively good prognostic profile. However, because FL patients will be treated with subsequent chemotherapy regimens, a well-tolerated and effective chemotherapy-free therapy could be considered an additional tool for long-term disease control. [ABSTRACT FROM AUTHOR]

Survival rates for elderly Hodgkin Lymphoma ( HL) have not improved substantially in recent years, mainly because of a lack of prospective randomized studies, due to difficulties in enrolling patients. Between 2002 and 2006, 54 untreated HL patients, aged between 65 and 80 years and considered 'non-frail' according to a comprehensive geriatric evaluation, were enrolled into a phase III randomized trial to compare a reduced-intensity regimen (vinblastine, cyclophosphamide, procarbazine, prednisone, etoposide, mitoxantrone, bleomycin; VEPEMB) with standard ABVD (adriamycin, bleomycin, vinblastine, dacarbazine). Primary endpoint was progression-free survival ( PFS). Seventeen patients were in early stage (I- IIA), while 37 were advanced stage. Median age was 72 years and median follow-up was 76 months. Five-year PFS rates were 48% vs. 70% [adjusted Hazard ratio ( HR) = 2·19, 95% confidence interval ( CI) = 0·94-5·10, P = 0·068] and 5-year overall survival ( OS) rates were 63% vs. 77% (adjusted HR = 1·67, 95% CI = 0·69-4·03, P = 0·254) for VEPEMB compared to ABVD. Overall treatment-related mortality was 4%. World Health Organization grade 4 cardiac and lung toxicity occurred in four patients treated with ABVD versus no cases in the VEPEMB arm. Standard ABVD regimen resulted in better PFS and OS than the VEPEMB, although the differences were not statistically significant. The low toxicity of both treatments was probably attributable to stringent selection of patients based on a Comprehensive Geriatric Assessment that excluded frail patients. [ABSTRACT FROM AUTHOR]

Background: Lenalidomide, an immunomodulatory drug with antineoplastic and antiproliferative effects, showed activity in many single-group studies in relapsed or refractory mantle cell lymphoma. The aim of this randomised study was to examine the efficacy and safety of lenalidomide versus best investigator's choice of single-agent therapy in relapsed or refractory mantle cell lymphoma.Methods: The MCL-002 (SPRINT) study was a randomised, phase 2 study of patients with mantle cell lymphoma aged 18 years or older at 67 clinics and academic centres in 12 countries who relapsed one to three times, had Eastern Cooperative Oncology Group performance status of 0-2, at least one measurable lesion to be eligible, and who were ineligible for intensive chemotherpy or stem-cell transplantation. Using a centralised interactive voice response system, we randomly assigned (2:1) patients in a permuted block size of six to receive lenalidomide (25 mg orally on days 1-21 every 28 days) until progressive disease or intolerability, or single-agent investigator's choice of either rituximab, gemcitabine, fludarabine, chlorambucil, or cytarabine. Randomisation was stratified by time from diagnosis, time from last anti-lymphoma therapy, and previous stem-cell transplantation. Individual treatment assignment between lenalidomide and investigator's choice was open label, but investigators had to register their choice of comparator drug before randomly assigning a patient. Patients who progressed on investigator's choice could cross over to lenalidomide treatment. We present the prespecified primary analysis results in the intention-to-treat population for the primary endpoint of progression-free survival, defined as the time from randomisation to progressive disease or death, whichever occurred first. Patient enrolment is complete, although treatment and collection of additional time-to-event data are ongoing. This study is registered with ClinicalTrials.gov, number NCT00875667.Findings: Between April 30, 2009, and March 7, 2013, we enrolled 254 patients in the intention-to-treat population (170 [67%] were randomly assigned to receive lenalidomide, 84 [33%] to receive investigator's choice monotherapy). Patients had a median age of 68·5 years and received a median of two previous regimens. With a median follow-up of 15·9 months (IQR 7·6-31·7), lenalidomide significantly improved progression-free survival compared with investigator's choice (median 8·7 months [95% CI 5·5-12·1] vs 5·2 months [95% CI 3·7-6·9]) with a hazard ratio of 0·61 (95% CI 0·44-0·84; p=0·004). In the 167 patients in the lenalidomide group and 83 patients in the investigator's choice group who received at least one dose of treatment the most common grade 3-4 adverse events included neutropenia (73 [44%] of 167 vs 28 [34%] of 83) without increased risk of infection, thrombocytopenia (30 [18%] vs 23 [28%]), leucopenia (13 [8%] vs nine [11%]), and anaemia (14 [8%] vs six [7%]).Interpretation: Patients with relapsed or refractory mantle cell lymphoma ineligible for intensive chemotherapy or stem-cell transplantation have longer progression-free survival, with a manageable safety profile when treated with lenalidomide compared with monotherapy investigator's choice options.Funding: Celgene Corporation. [ABSTRACT FROM AUTHOR]

The International Extranodal Lymphoma Study Group (IELSG) 26 study was designed to evaluate the role of 18F-fluorodeoxyglucose (18FDG) positron emission tomography/ computed tomography (PET/CT) in the management of primary mediastinal (thymic) large B-cell lymphoma (PMBCL). We examined the prognostic impact of functional PET parameters at diagnosis. Metabolic activity defined by the maximum standardized uptake value (SUVmax), metabolic tumor volume (MTV), and total lesion glycolysis (TLG) was measured on baseline 18FDG PET/CT following a standard protocol in a prospectively enrolled cohort of 103 PMBCL patients. All received combination chemoimmunotherapy with doxorubicin- and rituximab-based regimens; 93 had consolidation radiotherapy. Cutoff values were determined using the receiver-operating characteristic curve. At a median follow-up of 36 months, progression-free survival (PFS) and overall survival (OS) were 87% and 94%, respectively. In univariate analysis, elevated MTV and TLG were significantly associated with worse PFS and OS. Only TLG retained statistical significance for both OS (P= .001) and PFS (P<.001) in multivariate analysis. At 5 years, OS was 100% for patients with low TLG vs 80% for those with high TLG (P = .0001), whereas PFS was 99% vs 64%, respectively (P< .0001). TLG on baseline PET appeared to be a powerful predictor of PMBCL outcomes and warrants further validation as a biomarker. [ABSTRACT FROM AUTHOR]

The management of patients with Hodgkin lymphoma ( HL) recurring after stem cell transplantation ( SCT) and multiply relapsed disease remains challenging. We report on 41 such patients who received bendamustine hydrochloride, a bifunctional mechlorethamine derivative mechanistically unrelated to traditional alkylators, after a median of four prior chemotherapy lines, including SCT in 85% of cases. Bendamustine was given at doses of 90-120 mg/m2 every 21 or 28 d. At first assessment (2-4 cycles), the overall response rate ( ORR) was 78% with 12 (29%) complete ( CR) and 20 (49%) partial responses ( PR). Upon treatment prolongation to 6-8 courses, 40% of PRs progressed, yielding a final ORR of 58% with 31% of CRs. Eight patients (two CRs, six PRs) were subsequently allotransplanted. Median progression-free and overall survival exceeded 11 and 21 months respectively; complete responders displayed a median disease-free survival above 9 months with a relapse rate of only 30%. Outcomes were independent of disease chemosensitivity, previous transplant and bendamustine dose-intensity. No life-threatening or unexpected adverse events occurred. Within the limits of a retrospective analysis and schedule heterogeneity, these results appear very encouraging and prompt prospective trials to confirm bendamustine as a valuable option in the palliative setting and in cytoreductive strategies before allotransplantation. [ABSTRACT FROM AUTHOR]

BACKGROUND: Indolent nonfollicular non-Hodgkin B-cell lymphomas (INFLs) are clonal mature B-cell proliferations for which treatment has not been defined to date. METHODS: In this phase 2 study of patients with advanced INFL, the authors evaluated the efficacy and safety of first-line rituximab, fludarabine, and cyclophosphamide (FCR) as induction immunochemotherapy (rituximab 375 mg/m2 intravenously on day 1 of each cycle and on days 1 and 14 of cycles 4 and 5; fludarabine 25 mg/m2 intravenously on days 2-4, cyclophosphamide 250 mg/m2 intravenously on Days 2-4) every 28 days for 6 cycles followed by a maintenance phase with 4 infusions of rituximab (375 mg/m2 intravenously on day 1) every 2 months for responders. RESULTS: Forty-seven patients were enrolled. Among 46 evaluable patients (28 men; median age, 59 years), 19 were diagnosed with lymphoplasmacytic lymphoma, 21 were diagnosed with small lymphocytic lymphoma, and 6 were diagnosed with nodal marginal zone lymphoma. The overall response rate after maintenance was 89.1% with a 67.4% complete remission (CR) rate (CR/unconfirmed CR) and a 21.7% partial response rate. After a median follow-up of 40.9 months, the failure-free survival and progression-free survival rates both were 90.1%, and the overall survival rate was 97.4%. The main toxicity was hematologic, and related grade 3 and 4 neutropenia was observed in 55.3% of patients. CONCLUSIONS: FCR induction therapy followed by a short maintenance phase is a highly effective regimen with acceptable toxicity. Cancer 2012. © 2011 American Cancer Society. [ABSTRACT FROM AUTHOR]

Summary This study investigated the clinical activity and toxicity of R-HCVAD-AM [rituximab plus HyperCVAD (R-HCVAD) alternating with high-dose cytarabine and methotrexate (AM)] in patients with newly diagnosed Mantle Cell Lymphoma (MCL). Patients aged ≤70 years with confirmed MCL received four alternating cycles each of R-HCVAD and AM. Patients who obtained a partial response proceeded to autologous stem cell transplant. Sixty-three patients were enrolled and 60 were fully eligible. Median age was 57 years (22-66); 60%, 33% and 7% were classified at low (L)-, intermediate (I)- or high (H)-risk, respectively, according to the MCL International Prognostic Index (MIPI). Only 22 patients (37%) completed the four cycles and three patients died during therapy. Overall response and complete response rates were 83% and 72% respectively. After a median follow-up of 46 months (range 1-72) the estimated 5-year overall survival (OS) and progression-free survival rates were 73% [95% confidence interval (CI) 59-83%], and 61% (95%CI 45-73%) respectively. MIPI maintained the prognostic value with an estimated 5-year OS of 89%, 80% and 24% for L, I, and H groups respectively ( P < 0·001). This multicentre study confirms that R-HCVAD-AM is an active regimen for the initial treatment of patients with MCL, but is associated with significant toxicity. [ABSTRACT FROM AUTHOR]

Interim 2-[18F]Fluoro-2-deoxy-D-glucose Positron Emission Tomography performed after two chemotherapy cycles (PET-2) is the most reliable predictor of treatment outcome in ABVD-treated Hodgkin Lymphoma (HL) patients. We retrospectively analysed the treatment outcome of a therapeutic strategy based on PET-2 results: positive patients switched to BEACOPP, while negative patients continued with ABVD. Between January 2006 and December 2007, 219 newly diagnosed HL patients admitted to nine centres were enrolled; 54 patients, unfit to receive this treatment were excluded from the analysis. PET-2 scans were reviewed by a central panel of nuclear medicine experts, according to the Deauville score (). After a median follow up of 34 months (12-52) the 2-year failure free survival (FFS) and overall survival for the entire cohort of 165 patients were 88% and 98%; the FFS was 65% for PET-2 positive and 92% for PET-2 negative patients. For 154 patients in which treatment was correctly given according to PET-2 review, the 2-year FFS was 91%: 62% for PET-2 positive and 95% for PET-2 negative patients. Conclusions: this strategy, with BEACOPP intensification only in PET-2 positive patients, showed better results than ABVD-treated historic controls, sparing BEACOPP toxicity to the majority of patients (Clinical Trials.gov Identifier NCT00877747). [ABSTRACT FROM AUTHOR]

Indolent non-follicular non-Hodgkin lymphomas (INFL) are a heterogenous subset whose treatment has been poorly investigated. In this context we have evaluated the efficacy and safety of combined fludarabine and cyclophosphamide (FC) upfront therapy. Sixty-three patients with advanced INFL were enrolled in the study. Therapy consisted in FC combination (25 and 250 mg/m, i.v., respectively, for three consecutive days) every 28 days for six courses. After histological review, 61 patients (36 men, median age 64 years, range 40-70 years) were evaluated (22 small lymphocytic, 11 lymphoplasmacytic, 25 marginal zone and 3 CD5-negative non-Hodgkin lymphomas not otherwise specified). Further two patients were excluded for lack of essential data; six patients were withdrawn before the third cycle because of WHO grade III and IV toxicity. At the final evaluation, the overall response rate was 83% with 40.7% of complete remission. Intention-to-treat analysis showed that at the median follow-up of 36 months, overall survival, progression-free survival and failure-free survival were respectively 78%, 60% and 46%; remission duration among the 49 patients achieving complete remission/partial remission at the end of treatment was 65% (44-78) without significant differences between the main histotypes. The most frequent grade III and IV toxic events were haematological (neutropaenia 34%, anaemia 18% and thrombocytopaenia 11%) and infectious (10%). FC is effective for advanced untreated INFL. Early deaths and haematological toxicity suggest careful patient selection and monitoring. [ABSTRACT FROM AUTHOR]

The article discusses a study which examined the effect of adding high-dose cytarabine to methotrexate in patients with newly diagnosed primary central nervous system (CNS) lymphoma. The open, randomized phase two trial was conducted in 24 centers in six countries, and involved 79 patients ages 18 to 75 yeas with non-Hodgkin lymphoma exclusively localized into the CNS, cranial nerves or eyes. The patients were randomly assigned by computer to receive four courses of either methotrexate on day one, or methotrexate on day one combined with cytarabine twice a day on days two to three. Main variable measured was complete remission rate following chemotherapy. Interpretation of the research findings indicate the efficacy of the drug.

The article discusses the survival rate of the patients with folicular lymphoma under new treatment options. It says that patients were treated with bleomycin, epidoxorubicin, cyclophosphamide, vincristine, and prednisone (BACOP) plus fludarabine, mitoxantrone, and dexamethasone (FND). Under the treatment, the complete remission rate for BACOP/FND was 62% ad its failure-free survival (FFS) and overall survival (OS) rates were 53% and 77% respectively.

Although a double autologous peripheral blood stem cell transplant (APBSCT) is an effective therapy for patients (pts) with multiple myeloma and extends progression-free survival and overall survival, pts show a continued pattern of recurrent disease. The feasibility and tolerability of thalidomide (Thal) administered in the post-transplantation period as maintenance therapy was tested in 17 pts at a dose of 100 mg/d starting between 3 and 5 months after the second transplantation and continuing either until toxicity precluded further therapy or until pts had disease progression. After a median administration of 13 months (range: 3–26), 76.5% (13 pts) failed to tolerate Thal because of: transiet ischemic attack (three pts), severe fatigue (two), neutropenia (one), piastrinopenia (one), severe opportunistic infectious (two), erectile impotence (one), gastointestinal toxicity (anorexia with weight loss one), peripheral neuropathy (two). After a median follow-up of 36 months (range: 10–59) from the second transplant, 13 patients attained a CR + near CR (with a conversion rate from 47.1% to 76.5%). In conclusion, Thal as maintenance therapy after double ASCT is associated with low feasibility and high toxicity and could prevent a lengthy use of this antineoplastic agent. [ABSTRACT FROM AUTHOR]

Objectives: To compare two different schedules of two different anthracycline-containing regimens, where length of treatment is modulated according to the international prognostic index (IPI) in patients with aggressive non-Hodgkin's Lymphoma (NHL). Methods: In 1993 the Gruppo Italiano per lo Studio dei Linfomi (GISL) started a randomized 2 × 2 factorial phase III clinical trial for patients with newly diagnosed aggressive NHL comparing ProME(Epidoxorubicin)CE-CytaBOM (PE-C) to ProMI(Idarubicin)CE-CytaBOM (PI-C) and a fixed to a flexible treatment schedule where anthracycline dose was to be modulated according to observed hematological toxicity. Patients with low or low-intermediate IPI (IPI 0-2) and those with intermediate-high or high IPI (IPI 3-5) should receive six or eight courses, respectively. Involved-field radiotherapy was allowed for patients with initial bulky disease or with residual masses. Results: Three hundred and fifty-six patients were registered into the study and randomized. Patients were well balanced among the four study arms in terms of clinical characteristics and prognostic factors. Three hundred and forty-five patients were available for evaluation of study endpoints. At the end of induction therapy complete remission rate was 61%, 5-year failure-free survival (FFS) rate was 40% and 5-year overall survival (OS) rate was 59%; no differences were observed according to treatment arms. Patients in the flexible arm received higher dose intensity of anthracycline ( P < 0.001) with no apparent increase in toxicity. However, the flexible schedule was not superior to the fixed one. Patients with IPI 3–5 showed lower response rates (45% vs. 67%: P < 0.0001) and lower 5-year FFS (29% vs. 45%: P < 0.0001) compared to those with IPI 0–2. Conclusions: six courses of fixed or flexible PE-C or PI-C can determine a promising success rate in patients with advanced aggressive NHL with IPI 0–2, whereas the same regimens are less effective in patients with IPI 3–5, even if two additional courses are delivered. For the latter group of patients innovative approaches are warranted. [ABSTRACT FROM AUTHOR]

Objectives: Solid second primary cancers (SPC) have become an issue of extensive research. The purpose of the present study was to estimate the standardised incidence ratio (SIR) and the absolute excess risk (AER) of SPC in patients with splenic marginal zone lymphoma (SMZL). Methods: We investigated the incidence of additional cancers in 129 patients consecutively diagnosed with SMZL in three Italian haematological centres, asking the cooperating doctors for additional information on initial and subsequent therapies and on the onset and type of second cancers. Results: Twelve SPC were recorded (9.3%); the 3- and 5-yr cumulative incidence rates were 5.5% and 18.3% respectively, with an SIR of 2.03 [95% confidence interval (CI): 1.05–3.56; P < 0.05; AER = 145.81]. Of 12 SPC observed, four were urinary tract neoplasms (SIR, 3.70; 95% CI: 1.01–9.48; P < 0.05; AER = 70.06), four were lung cancers (SIR, 9.16; 95% CI: 1.41–13.25; P < 0.05; AER = 85.50) and the other four were hepatic carcinoma, endometrial cancer, breast cancer and colorectal cancer. Conclusions: Our findings evidence a high frequency of additional cancers in patients with SMZL and suggest that the incidence rate of SPC is significantly different from that expected in the general population. The frequency of cases with urinary tract and lung malignancies in our series is higher than expected. Although confirmatory data are needed, it is our opinion that SMZL patients are at risk of second cancer and should be carefully investigated on diagnosis and monitored during the follow-up. [ABSTRACT FROM AUTHOR]

Abstract: This study evaluates the prognostic value of molecular monitoring of minimal residual disease (MRD) in 20 patients with multiple myeloma (MM) following autologous (peripheral blood stem cell transplantation, PBSCT) and non-myeloablative allogeneic (NMT) transplant. All patients completed their program, with a treatment-related mortality (TRM) of 20% and a 2-year progression-free survival (PFS) of 51%. After PBSCT, only 3 patients (15%) achieved PCR-negativity, versus 12 (60%) after NMT. The eradication of MRD had a favorable impact on 2-year OS. In fact, 76% of patients with no detectable MRD was still alive versus 34% of persistently IgH-positive cases (p =0.03). PCR status did not correlate with chimerism percentage: Seventy-five percent of patients achieved full donor chimerism, which was more frequently observed in cases presenting cGHVD (p =0.01). These data sustain the relevant role of molecular monitoring in MM patients undergoing NMT. MRD monitoring would assist physicians in making additional therapeutic decisions to better control this hematological malignancy. [Copyright &y& Elsevier]