High-dose chemotherapy supported by autologous stem cell transplantation (HDT/ASCT) has contributed to modify the natural history of follicular lymphoma (FL); however, an overall survival (OS) benefit has been demonstrated at relapse only after a rituximab-free chemotherapy regimen. A total of 655 patients with FL were reported to the Spanish GELTAMO (Grupo Espafiol de Linfomas y Trasplantes de Medula Osea) registry and underwent first ASCT between 1989 and 2007. A total of 203 patients underwent ASCT in first complete response (CR1), 174 in second complete response (CR2), 28 in third complete response (CR3), 140 in first partial response (PR1), 81 in subsequent PR, and 29 with resistant/refractory disease; 184 patients received rituximab before ASCT. With a median follow-up of 12 years from ASCT, median progression-free survival (PFS) and overall survival (OS) were 9.7 and 21.3 years, respectively. Actuarial 12-year PFS and OS were 63% (95% confidence interval [CI], 58%-68%) and 73% (95% CI, 68%-78%), respectively, for patients in CR (with a plateau in the curve beyond 15.9 years), 25% (95% CI, 19%-28%) and 49% (95% CI 42%-56%), respectively, for patients in PR, and 23% (95% CI, 8%-48%) and 28% (95% CI, 9%-45%), respectively, for patients with resistant/refractory disease <.001). In patients who received rituximab before ASCT, the estimated 9-year PFS and OS from ASCT were 59.5% (95% CI, 51%-67%) and 75% (95% CI, 68%-83%), respectively. Interestingly, for patients who underwent transplantation in CR >= 2 or PR >= 2 who had received rituximab before ASCT (n = 90), 9-year PFS and OS were 61% (95% CI, 51%-73%) and 75% (95% CI, 65%-80%), respectively, with no relapses occurring beyond 5.1 years after ASCT. The cumulative incidence of second malignancies in the global series was 6.7% at 5 years and 12.8% at 10 years. This analysis strongly suggests that ASCT is a potentially curative option for eligible patients with FL. In the setting of relapse, it is of especial interest in pretransplantation rituximab-sensitive patients with FL. (C) 2017 American Society for Blood and Marrow Transplantation.

The karyotype is an important predictor of outcome in acute lymphoblastic leukemia (ALL). Rearrangements of the 11q23 region involving the KMT2A gene confer an unfavorable prognosis. Forty-six adult ALL patients from the PETHEMA Group treated with risk-adapted protocols, with t(v;11q23) were selected for this study. Complete response (CR) was attained in 38 patients; 25 remained in CR after consolidation. Twelve (48%) received allogeneic hematopoietic stem cell transplantation (HSCT) and 13 delayed intensification and maintenance. The 5-year CR duration probability was 37% (95% CI, 19%-55%). A trend for a longer CR duration was observed in patients undergoing HSCT vs. those receiving chemotherapy. The 5-year overall survival (OS) probability was 20% (95% CI, 5%-35%). The OS was better, albeit not significant, in patients with a MRD level< 0.1% after induction (39% [95% CI, 14%-64%] vs. 13% [95% CI, 0%-36%]). Specific treatment approaches are required to improve the outcome of patients with KMT2A-rearrangements.

We designed a phase II clinical trial including Y-90 ibritumomab-tiuxetan as part of a reduced-intensity conditioning (RIC) allogeneic stem cell transplantation (AlloSCT) in high-risk non-Hodgkin lymphoma (Clinical Trials Identifier: NCT00644371). Eligible patients had high-risk relapsed refractory aggressive lymphoma. The conditioning regimen consisted of rituximab 250 mg (days-21 and -14), Y-90 ibritumomab IV (.4 m Ci/kg, day -14), fludarabine 30 mg/m(2) i.v. (days-3 and -2) plus melphalan 70 mg/m2 i.v. (days-3 and -2) or 1 dose of melphalan and thiotepa 5 mg/kg (day-8). Donors were related. Eighteen patients were evaluable. At the time of transplantation, responses were complete remission (CR) (n = 7, 39%), partial remission (n = 6, 33%) or refractory disease (n = 4, 28%). Y-90-ibritumomab infusions were well tolerated, with no adverse reactions. Nonrelapse mortality at 1 year was 28%. Median follow-up was 46 (range, 39 to 55) months. Estimated 1-year progression-free survival (PFS) was 50%, and 4-year overall survival (OS) and PFS were both 44.4%. CR at the moment of AlloSCT had significant impact on PFS (71% versus 27%, P =.046) and OS (71% versus 27%, P=.047). Our results show that Y-90-ibritumomab-tiuxetan as a component of RIC for AlloSCT is feasible in patients with high-risk B cell lymphoma. Development of phase III clinical trials is needed to clarify the contribution of radioimmunotherapy to RIC AlloSCT. (C) 2017 American Society for Blood and Marrow Transplantation.

Overall survival (OS) is the gold-standard end point for studies evaluating autologous stem cell transplantation (ASCT) in follicular lymphoma (FL), but assessment may be elusive due to the lengthy disease course. We analyzed the validity of two earlier end points, proposed in the setting of first-line chemo-/immunotherapy, as surrogates for OSprogression-free survival (PFS) status at 24months (PFS24) and complete response at 30months (CR30) post-ASCT. We also have investigated the clinical features of patients with early progression after ASCT. Data were available for 626 chemosensitive FL patients who received ASCT between 1989 and 2007. Median follow-up was 12.2years from ASCT. In the PFS24 analysis, 153 (24%) patients progressed within 24months and 447 were alive and progression-free at 24months post-ASCT (26 who died without disease progressions within 24months were excluded). Early progression was associated with shorter OS (hazard ratio [HR], 6.8; P=0.00001). In the subgroup of patients who received an ASCT in the setting or relapse after being exposed to rituximab, the HR was 11.3 (95% CI, 3.9-30.2; P<0.00001). In the CR30 analysis, 183 of 596 (31%) response-evaluable patients progressed/died with 30months post-ASCT. The absence of CR30 was associated with shorter OS (HR, 7.8; P<0.00001), including in patients with prior rituximab (HR, 8.2). PFS24 and CR30 post-ASCT are associated with poor outcomes and should be primary end points. Further research is needed to identify this population to be offered alternative treatments.

Romiplostim, a thrombopoietin-receptor agonist (TPO-ra), is a highly effective option in primary immune thrombocytopenia (ITP), with 80-90% of patients achieving platelet responses after few weeks of treatment. The evidence showing remissions, that is, sustained platelet counts after romiplostim discontinuation, in patients with ITP refractory to immunosuppressive therapy is steadily increasing. However, there is a lack of guidelines or recommendations addressing how and when to taper romiplostim in clinical practice in patients maintaining elevated and stable platelet counts. Furthermore, given the high heterogeneity of ITP patients, no associated predictive factors have been currently identified. Here, we present 4 representative clinical cases of the daily clinical practice in Spain comprising newly diagnosed, persistent, and both splenectomized and nonsplenectomized chronic ITP patients treated with romiplostim, achieving and maintaining clinical remission (platelet count >= 50 x 10(9)/L for 24 consecutive weeks in the absence of any treatment for ITP) after treatment tapering and discontinuation, without observed safety concerns. Prospective studies identifying clinical and biological predictive factors of sustained response are warranted.

BACKGROUNDOlder adults with relapsed/refractory B-precursor acute lymphoblastic leukemia (r/r ALL) are reported to have a poor prognosis and few therapeutic options. In the current study, the authors evaluated treatment with single-agent blinatumomab in adults aged 65 years with r/r ALL. METHODSA total of 261 adults with r/r ALL who were examined across two phase 2 studies received blinatumomab in cycles of 4-week continuous infusion and 2-week treatment-free intervals. The primary endpoint in each study was complete remission (CR) or CR with partial hematologic recovery (CRh) during the first 2 cycles. Data were pooled and analyzed according to patient age at screening (aged 65 years vs aged <65 years). RESULTSOf 36 older adults, 56% (95% confidence interval [95% CI], 38%-72%) achieved CR/CRh during the first 2 cycles compared with 46% (225 patients) (95% CI, 40%-53%) of younger adults. Complete minimal residual disease responses were 60% in older and 70% in younger responders. Three older responders (15%) and 61 younger responders (59%) proceeded to allogeneic hematopoietic stem cell transplantation. Kaplan-Meier curves overlapped for relapse-free and overall survival for both age groups. Older adults were found to have a similar incidence of grade 3 adverse events (AEs) as younger adults (86% vs 80%) but more grade 3 neurologic events (28% vs 13%). Cytokine release syndrome occurred in 7 older (19%) (1 case of grade 3) and 23 younger (10%) (4 cases of grade 3) adults. There were no treatment-related fatal AEs reported. CONCLUSIONSOlder adults with r/r ALL who were treated with single-agent blinatumomab were found to have similar hematologic response rates and incidence of grade 3 AEs compared with younger adults but had more neurologic events, which were reversible and primarily resolved with treatment interruption. Cancer 2016;122:2178-85. (c) 2016 American Cancer Society. Older adults with relapsed/refractory B-precursor acute lymphoblastic leukemia typically have a worse prognosis and fewer therapy options compared with younger patients. In this analysis of pooled data from two phase 2 studies of single-agent blinatumomab therapy in patients with this disease, older (aged 65 years) and younger (aged <65 years) adults had similar treatment outcomes.

Follicular lymphoma (FL) is a disease of paradoxes-incurable but with a long natural history. We hypothesized that a combination of lymphokine-activated killer (LAK) cells and monoclonal antibodies might provide a robust synergistic treatment and tested this hypothesis in a phase II clinical trial (NCT01329354). In this trial, in addition to R-CHOP, we alternated the administration of only rituximab with rituximab and autologous LAK cells that were expanded ex vivo. Our objective was to determine the in vitro capability of LAK cells generated from FL patients to produce cytotoxicity against tumor cell lines and to determine rituximab- and obinutuzumab-induced cytotoxicity via antibody-dependent cellular cytotoxicity (ADCC) activity. We analyzed the LAK cell-induced cytotoxicity and rituximab (R)- and obinutuzumab (GA101)-induced ADCC activity. We show that LAK cells generated from FL patients induce cytotoxicity against tumor cell lines. R and GA101 enhance cytolysis through ADCC activity of LAK cells. Impaired LAK cell cytotoxicity and ADCC activity were detected in 50 % of patients. Percentage of NK cells in LAK infusions were correlated with the R- and GA101-induced ADCC. Our results indicate that the combination of R or GA101 and LAK cells should be an option as frontline maintenance therapy in patients with FL.

Background/Aims: Rituximab-cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) every 14 days seems to achieve better outcomes than R-CHOP every 21 days in diffuse large B-cell lymphoma (DLBCL) patients. Currently, the standard regimen is R-CHOP every 21 days. Methods: This is a phase II clinical trial of treatment with 6 cycles of R-CHOP-14 with pegfilgrastim support in 2 populations of previously untreated DLBCL patients aged >= 65 years (n = 73) or <65 years (n = 51) with low-risk International Prognostic Index scores (0-2). Results: With a median follow-up of 63.7 months, the 5-year event-free survival rate was 53.8% in patients aged >= 65 years and 71.0% in patients aged <65 years. The 5-year overall survival rate was 71.4 and 89.8%, respectively. The complete remission rate was 69.9% for older and 80.4% for younger patients. The median relative dose intensity of cytotoxic drugs was 143.2% in the elderly and 149.1% in the young patients. Febrile neutropenia was the most common grade 3-4 adverse event, being higher in elderly patients (21.3 vs. 9.3%). Eight deaths (7 in elderly patients) were considered treatment related. Conclusion: In conclusion, the R-CHOP-14 regimen is feasible and very active, though it is more toxic in elderly patients mainly due to an increased incidence of infections. New strategies, such as new monoclonal antibodies or new targeted therapies, are needed to improve the outcomes of DLBCL patients. (C) 2016 S. Karger AG, Basel

Bendamustine is an increasingly used hybrid alkylating agent that is active in lymphoid neoplasias via a novel mechanism of action. There are some pending questions about its use in clinical practice because of its developmental features. A consensus panel of several leading Spanish hematologists with broad experience in the clinical use of bendamustine has established recommendations for the management and treatment of hematological patients with bendamustine based on available clinical data and theexperience of the participants. These recommendations address the dose and treatment regimen fordifferent clinical indications, the management of toxicity, and support therapy. This article contains the conclusions of this consensus panel, which are intended to serve as guidelines for the use of bendamustine.

Diffuse large B cell lymphoma (DLBCL) is a heterogeneous group of aggressive lymphomas that can be classified into three molecular subtypes by gene expression profiling (GEP): GCB, ABC and unclassified. Immunohistochemistry-based cell of origin (COO) classification, as a surrogate for GEP, using three available immunohistochemical algorithms was evaluated in TMA-arranged tissue samples from 297 patients with de novo DLBCL treated by chemoimmunotherapy (R-CHOP and R-CHOP-like regimens). Additionally, the prognostic impacts of MYC, BCL2, IRF4 and BCL6 abnormalities detected by FISH, the relationship between the immunohistochemical COO classification and the immunohistochemical expression of MYC, BCL2 and pSTAT3 proteins and clinical data were evaluated. In our series, non-GCB DLBCL patients had significantly worse progression-free survival (PFS) and overall survival (OS), as calculated using the Choi, Visco-Young and Hans algorithms, indicating that any of these algorithms would be appropriate for identifying patients who require alternative therapies to R-CHOP. Whilst MYC abnormalities had no impact on clinical outcome in the non-GCB subtype, those patients with isolated MYC rearrangements and a GCB-DLBCL phenotype had worse PFS and therefore might benefit from novel treatment approaches.

We aimed to evaluate the revised International Prognostic Index (R-IPI) to predict the outcome of relapsed/refractory diffuse large B-cell lymphoma patients and try to establish the relationship between biological parameters and outcome. Neither R-IPI at diagnosis or relapse nor the immunohistochemical parameters evaluated identified, risk groups with different overall response rates. Only absolute lymphocyte count identified patients who were less likely to achieve an overall response. This highlights the significance of host immunity in determining clinical outcomes in non-Hodgkin lymphoma. Introduction: Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous entity, showing a highly variable outcome. In patients with DLBCL relapsed/refractory to first-line treatment with rituximab the usefulness of the revised International Prognostic Index (R-IPI) as a prognostic tool remains unexplored. Some biological parameters (B-cell lymphoma 6 [Bcl-6], Bcl-2, p53, and multiple nnyeloma 1 [MUM1]) and blood populations (lymphocyte and monocyte counts) have been described as International Prognostic Index-independent prognostic factors. The objective was to evaluate the R-IPI to predict the outcome of DLBCL patients at the time of relapse after a front-line treatment with chemotherapy and rituximab and to establish in this population the relationship between biological parameters and outcome. Patients and Methods: We included patients with refractory/relapsed DLBCL after first-line treatment with rituximab-containing regimens; patients must have already finished a rescue treatment also including rituximab. Immunohistochemical assessment of Bcl-2, Bcl-6, p53, and MUM1 expression were undertaken in available biopsies. R-IPI factors were identified from the clinical data at diagnosis and at relapse. Response was assessed using National I Cancer Institute-sponsored Working Group guidelines. Results: R-IPI prognosis at relapse was not significantly associated with overall response rate (ORR) after Rituximab-chemotherapy rescue therapy. None of the immunohistochemical parameters analyzed correlated with rescue therapy results. In contrast, patients with absolute lymphocyte count (ALC) >= 1 x 10(9)/L at relapse were more likely to respond than patients with ALC < 1 x 10(9)/L (P = .05). Conclusion: The R-IPI score calculated at relapse could not predict the ORR to second-line treatment. Lymphopenia is a simple and useful predictor for outcome in relapsed/refractory DLBCL and the only prognostic factor that in our hands could predict the overall response to a second-line treatment with rituximab and chemotherapy. (C) 2015 Elsevier Inc. All rights reserved.

We conducted a multicentre, phase II study of interim positron emission tomography (PET) as a guide to risk-adapted therapy in high-risk patients with newly diagnosed diffuse large B-cell lymphoma (DLBCL). Patients achieving negative fluorodeoxyglucose (FDG)-PET after three courses of R-MegaCHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone) received three additional courses, whereas PET-positive patients received two courses of R-IFE (rituximab, ifosfamide, etoposide) followed by BEAM (BCNU, etoposide, cytarabine, melphalan) and autologous stem-cell transplantation. The primary endpoint was progression-free survival (PFS). 71 patients (median age 55years, range 25-69) were enrolled. With a median follow-up of 428months (range 72-584), the estimated 4-year PFS and overall survival (OS) were 67% and 78%, respectively, for the global series. Patients in complete remission after interim PET (N=36) had significantly better 3-year PFS than those with partial response (N=30) [81% vs. 57%, Hazard ratio (HR)=26, 95% confidence interval (CI)=102-665] but not a statistically significant longer OS. A retrospective PET central review was done for 51 patients. According to semiquantitative analysis, 3-year PFS (81% vs. 33%; HR=69, 95% CI=235-206) and OS (95% vs. 33%, HR=194, 95% CI=389-970) were significantly better for negative than for positive interim PET patients. Early PET assessment is valuable for risk stratification in DLBCL; for this purpose semiquantitative evaluation is a better predictor than visual criteria.

Lymphoma patients with persistent disease undergoing autologous transplantation have a very poor prognosis in the rituximab era. The addition of radioimmunotherapy to the conditioning regimen may improve the outcome for these patients. In a prospective, phase 2 study, we evaluated the safety and efficacy of the addition of Y-90-ibritumomab tiuxetan to the conditioning chemotherapy in patients with refractory diffuse large B-cell lymphoma. Thirty patients with induction failure (primary refractory; n=18) or refractory to salvage immunochemotherapy at relapse (n=12) were included in the study. The median age of the patients was 53 years (range, 25-67). All patients were given Y-90-ibritumomab tiuxetan at a fixed dose of 0.4 mCi/kg (maximum dose 32 mCi) 14 days prior to the preparative chemotherapy regimen. Histological examination showed that 22 patients had de novo diffuse large B-cell lymphoma and eight had transformed diffuse large B-cell lymphoma. All patients had persistent disease at the time of transplantation, with 25 patients considered to be chemorefractory. The median time to neutrophil recovery (>500 white blood cells/mu L) was 11 days (range, 9-21), while the median time to platelet recovery (>20,000 platelets/mu L) was 13 days (range, 11-35). The overall response rate at day +100 was 70% (95% CI, 53.6-86.4) with 60% (95% CI, 42.5-77.5) of patients obtaining a complete response. After a median follow-up of 31 months for alive patients (range, 16-54), the estimated 3-year overall and progression-free survival rates are 63% (95% CI, 48-82) and 61% (95% CI, 45-80), respectively. We conclude that autologous transplantation with conditioning including Y-90-ibritumomab tiuxetan is safe and results in a very high response rate with promising survival in this group of patients with refractory diffuse large B-cell lymphoma with a very poor prognosis.

The results of intensive immunochemotherapy were analyzed in human immunodeficiency virus (HIV)-related Burkitt lymphoma/leukemia (BLL) in two cohorts (Spain and Germany). Alternating cycles of chemotherapy were administered, with dose reductions for patients over 55 years. Eighty percent of patients achieved remission, 11% died during induction, 9% failed and 7% died in remission. Four-year overall survival (OS) and progression-free survival (PFS) probabilities were 72% (95% confidence interval [CI]: 62-82%) and 71% (95% CI: 61-81%). CD4 T-cell count < 200/mu L and bone marrow involvement were associated with poor OS (hazard ratio [HR] 3.2 [1.2-8.3] and HR 2.7 [1.1-6.6]) and PFS (HR 3.5 [1.3-9.1] and HR 2.4 [1-5.7]), bone marrow involvement with poor disease-free survival (DFS) (HR 14.4 [1.7-119.7] and Eastern Cooperative Oncology Group (ECOG) score > 2 (odds ratio [OR] 11.9 [1.4-99.9]) with induction death. In HIV-related BLL, intensive immunochemotherapy was feasible and effective, but toxic. Prognostic factors were performance status, CD4 T-cell count and bone marrow involvement.

Background No standard first-line systemic treatment for mucosa-associated lymphoid tissue (MALT) lymphoma is available. In a phase 2 study we aimed to assess the safety and activity of a response-adapted combination of bendamustine plus rituximab as upfront treatment for this type of lymphoma. Methods In a multicentre, single-arm, non-randomised, phase 2 trial, we enrolled patients with MALT lymphoma at any site and stage and treated them with bendamustine (90 mg/m(2) on days 1 and 2) plus rituximab (375 mg/m(2) on day 1), every 4 weeks. Inclusion criteria were measurable or evaluable disease, age 18-85 years, and unequivocal active lymphoma; we also enrolled patients with MALT lymphoma arising in the stomach after failure of Helicobacter pylori eradication and primary cutaneous cases after failure of local therapies. Exclusion criteria included evidence of histological transformation, CNS involvement, and active hepatitis B or C virus or HIV infection. After three cycles, patients achieving complete response received one additional cycle (total four cycles) and those achieving partial response received three additional cycles (total six cycles). The primary endpoint was 2-year event-free survival. Analysis was by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01015248. Findings 60 patients from 19 centres in Spain were enrolled between May 27, 2009, and May 23, 2011, and received treatment; 57 patients were evaluable for the primary endpoint. Only 14 (25%) patients needed more than four cycles of treatment. After a median follow-up of 43 months (IQR 37-51), median event-free survival was not reached. Event-free survival at 2 years was 93% (95% CI 84-97) and at 4 years was 88% (95% CI 74-95). The most frequently observed grade 3-4 adverse events were haematological: lymphopenia in 20 (33%) patients, neutropenia in 12 (20%) patients, and leucopenia in three (5%) patients. Grade 3-4 febrile neutropenia or infections were reported in three (5%) and four (7%) patients, respectively. Interpretation This response-adapted schedule of bendamustine plus rituximab appears to be an active and well tolerated first-line treatment for patients with MALT lymphoma.

BACKGROUNDThe karyotype is a predictor of outcomes in adults with acute lymphoblastic leukemia (ALL). The unfavorable prognostic significance of complex karyotype (CK) has been reported, whereas the prognostic relevance of monosomal karyotype (MK) has not been consistently evaluated. We aimed to assess the prognostic value of CK and MK in adults with ALL treated with risk-adapted protocols of the Spanish PETHEMA Group. METHODSThe karyotypes of 881 adult ALL patients treated according to the protocols of the PETHEMA Group between 1993 and 2012 were centrally reviewed. CK and MK were assessed according to Moorman's criteria, and Breem's criteria, respectively. Specific analyses according to the risk groups and to the presence of t(9:22) were performed. RESULTSOf 364 evaluable patients 33 (9.2%) had CK, and 68 of 535 evaluable patients (12.8%) had MK. Complete remission rate, remission duration, and overall survival were not significantly different according to the presence of CK or MK in the whole series, according to the B or T lineage, in the high-risk group, or in patients with t(9;22), regardless of imatinib treatment, and in patients who received chemotherapy alone or chemotherapy followed by stem cell transplantation CONCLUSIONSOur study shows that CK and MK were not associated with a worse prognosis in adult patients with ALL treated with risk-adapted or subtype-oriented protocols. In patients with Ph+ ALL, MK did not have an impact on prognosis irrespective of imatinib treatment. Cancer.(c) 0000 American Cancer SocietyCancer 2014;120:3958-3964. (c) 2014 American Cancer Society. After reviewing the karyotypes of 881 adult ALL patients treated according to the protocols of the PETHEMA Group between 1993 and 2012, the complex karyotype and the monosomal karyotype did not confer worse prognosis.

Purpose Minimal residual disease (MRD) is an important prognostic factor in adults with acute lymphoblastic leukemia (ALL) and may be used for treatment decisions. The Programa Espanol de Tratamientos en Hematologia (PETHEMA) ALL-AR-03 trial (Treatment of High Risk Adult Acute Lymphoblastic Leukemia [LAL-AR/2003]) assigned adolescent and adult patients (age 15 to 60 years) with high-risk ALL (HR-ALL) without the Philadelphia (Ph) chromosome to chemotherapy or to allogeneic hematopoietic stem-cell transplantation (allo-HSCT) according to early cytologic response (day 14) and flow-MRD level after consolidation. Patients and Methods Patients with good early cytologic response (< 10% blasts in bone marrow at day 14 of induction) and a flow-MRD level less than 5 x 10(-4) at the end of consolidation were assigned to delayed consolidation and maintenance therapy, and allo-HSCT was scheduled in patients with poor early cytologic response or flow-MRD level >= 5 x 10(-4). Results Complete remission was attained in 282 (87%) of 326 patients, and 179 (76%) of 236 patients who completed early consolidation were assigned by intention-to treat to receive allo-HSCT (71) or chemotherapy (108). Five-year disease-free survival (DFS) and overall survival (OS) probabilities were 37% and 35% for the whole series, 32% and 37% for patients assigned to allo-HSCT, and 55% and 59% for those assigned to chemotherapy. Multivariable analysis showed poor MRD clearance (>= 1 x 10(-3) after induction and >= 5 x 10(-4) after early consolidation) as the only prognostic factor for DFS and OS. Conclusion Prognosis for Ph-negative HR-ALL in adolescents and adults with good early response to induction and low flow-MRD levels after consolidation is quite favorable when allo-HSCT is avoided. In this study, the pattern of MRD clearance was the only prognostic factor for DFS and OS. (C) 2014 by American Society of Clinical Oncology

BACKGROUND: The use of rituximab together with intensive chemotherapy in Burkitt's lymphoma or leukemia (BL) has been scarcely explored. This study prospectively evaluated and compared the outcome and toxicity of human immunodeficiency virus (HIV)-positive and HIV-negative patients with BL who were treated in an intensive immunochemotherapy-based and age-adapted trial. METHODS: A total of 118 adult patients (80 HIV-negative and 38 HIV-positive) aged 15 to 83 years were treated with 4 (nonbulky stages I-II) or 6 (stages II bulky, III-IV) cycles of intensive chemotherapy combined with rituximab. Reduction in chemotherapy doses and modification of the cycle schedules was performed in patients older than 55 years. RESULTS: The clinical characteristics of HIV-positive patients were comparable with those who were HIV-negative. Complete remission rates were 82% and 87%, respectively, and 9 patients died in induction, 9 died in remission, and 7 relapsed. After a median follow-up of 2.5 years, nonsignificant differences were observed in the 4-year disease-free survival and overall survival (OS) probabilities (77% and 63% for HIV-positive and 80% and 78% for HIV-negative patients, respectively). Young HIV-infected patients presented higher incidences of grade 3 or 4 mucositis and severe infectious episodes. Poor general status and bone marrow involvement, but not advanced age, were associated with a shorter OS, allowing the definition of 3 prognostic groups, with the OS ranging from 50% to 92%. CONCLUSIONS: Age-adapted intensive immunochemotherapy is highly effective in both HIV-negative and HIV-positive patients, with a higher toxicity in the latter group. Poor general status and bone marrow involvement had a negative impact on survival. Cancer 2013; 119: 1660-8. (C) 2013 American Cancer Society.

The prognosis for fit patients with mantle cell lymphoma has improved with intensive strategies. Currently, the role of maintenance/consolidation approaches is being tested as relapses continue to appear. In this trial we evaluated the feasibility, safety and efficacy of rituximab-hyperCVAD alternating with rituximab-methotrexatecytarabine followed by consolidation with Y-90-ibritumomab tiuxetan. Patients received six cycles followed by a single dose of Y-90-ibritumomab tiuxetan. Thirty patients were enrolled; their median age was 59 years. Twenty-four patients finished the induction treatment, 23 achieved complete remission (77%, 95% confidence interval 6093) and one patient had progressive disease (3%). Eighteen patients (60%), all in complete remission, received consolidation therapy. In the intent-to-treat population, failure-free, progression-free and overall survival rates at 4 years were 40% (95% confidence interval 20.4-59.6), 52% (95% confidence interval 32.4-71.6) and 81% (95% confidence interval 67.28-94.72), respectively. For patients who received consolidation, failure-free and overall survival rates were 55% (95% confidence interval 31.48-78.52) and 87% (95% confidence interval 70-100), respectively. Hematologic toxicity was significant during induction and responsible for one death (3.3%). After consolidation, grade 3-4 neutropenia and thrombocytopenia were observed in 72% and 83% of patients, with a median duration of 5 and 12 weeks, respectively. Six (20%) patients died, three due to secondary malignancies (myelodysplastic syndrome and bladder and rectum carcinomas). In conclusion, in our experience, rituximab-hyperCVAD alternated with rituximab-methotrexate-cytarabine and followed by consolidation with Y-90-ibritumomab tiuxetan was efficacious although less feasible than expected. The unacceptable toxicity observed, especially secondary malignancies, advise against the use of this strategy. Trial registration: clinical.gov identifier: NCT2005-004400-37

Diffuse large B-cell lymphoma (DLBCL) is an aggressive disease influenced by genetic and environmental factors. The role of the HLA system in tumor antigen presentation could be involved in susceptibility and disease control. We analyzed the phenotypic frequencies of HLA-A, HLA-B, HLA-C, HLA-DRB1, and HLA-DQB1 in 250 DLBCLs, comparing them with 1940 healthy individuals. We also evaluated the influence of HLA polymorphisms on survival in those patients treated with curative intention using cyclophosphamide, doxorubicin, vincristine, and prednisolone (CHOP)-like regimen without (n = 64, 26%) or with (n = 153, 61%) rituximab. DLBCL patients have a higher phenotypic frequency of HLA-DRB1*01 (29% vs 19.5%, P=.0008, Pc=.0104) and a lower frequency of HLA-C*03 (6.4% vs 17.9%, P < .0005, Pc = .007) compared with healthy individuals. Irrespective of the age-adjusted International Prognostic Index, those patients receiving a CHOP-like plus rituximab regimen and carrying the HLA-B44 supertype had worse 5-year progression-free (54% vs 71%, P=.019) and 5-year overall (71% vs 92%, P=.001) survival compared with patients without this supertype. Our data suggest that some HLA polymorphisms influence the development and outcome of DLBCL, allowing the identification of an extremely good-risk prognostic subgroup. However, these results are preliminary and need to be validated in order to exclude a possible population effect.

Bendamustine is a alkylating agent with a purine-like benzamidazole ring currently approved in Europe for indolent non-Hodgkin lymphoma (NHL), chronic lymphocytic leukemia (CLL) and multiple myeloma. Our aim was to analyze retrospectively the efficacy and toxicity of bendamustine in NHL and CLL in Spain in the bendamustine Compassionate Use Program. Patients with relapsed/refractory NHL or CLL were eligible. Any regimen containing bendamustine was eligible. 109 patients were included from 22 institutions. Forty-nine patients had indolent NHL, 18 aggressive NHL and 42 CLL, being 44 patients (40%) refractory to previous treatment. 63% of patients had adverse events grade 3-4, mainly hematological. Overall response rate (ORR) was 66%, complete responses 30%. ORR observed in refractory patients was 45%. The median progression-free survival (PFS) was 13 months. Outcome was influenced by histology, number of previous treatments, resistance to previous chemotherapy and type of response achieved with bendamustine. Alone or in combination, bendamustine shows a meaningful clinical antitumor activity in patients with relapsed or refractory NHL or CLL, with an acceptable toxicity profile.

For establishing the true effect of different response categories in patients with multiple myeloma (MM) treated with autologous stem cell transplantation, we evaluated, after a median follow-up of 153 months, 344 patients with MM who received a transplant between 1989 and 1998. Overall survival (OS) at 12 years was 35% in complete response (CR) patients, 22% in near complete response (nCR), 16% in very good partial response (VGPR), and 16% in partial response (PR) groups. Significant differences in OS and progression-free survival were found between CR and nCR groups (P = .01 and P = .002, respectively), between CR and VGPR groups (P = .0001 and P = .003), or between CR and PR groups (P = .003 and P = < 10(-5)); no differences were observed between the nCR and VGPR groups (P = .2 and P = .9) or between these groups and the PR group (P = .1 and P = .8). A landmark study found a plateau phase in OS after 11 years; 35% patients in the CR group and 11% in the nCR+VGPR+PR group are alive at 17 years; 2 cases had relapsed in the nCR+VGPR+PR group. In conclusion, MM achieving CR after autologous stem cell transplantation is a central prognostic factor. The relapse rate is low in patients with > 11 years of follow-up, possibly signifying a cure for patients in CR.

Antifungal treatment in the hematological patient has reached a high complexity with the advent of new antifungals and diagnostic tests, which have resulted in different therapeutic strategies. The use of the most appropriate treatment in each case is essential in infections with such a high mortality. The availability of recommendations as those here reported based on the best evidence and developed by a large panel of 48 specialists aimed to answer when is indicated to treat and which agents should be used, considering different aspects of the patient (risk of fungal infection, clinical manifestations, galactomanann test, chest CT scan and previous prophylaxis) may help clinicians to improve the results.

Diffuse large B-cell lymphoma (DLBCL) prognostication requires additional biologic markers. miRNAs may constitute markers for cancer diagnosis, outcome, or therapy response. In the present study, we analyzed the miRNA expression profile in a retrospective multicenter series of 258 DLBCL patients uniformly treated with chemoimmunotherapy. Findings were correlated with overall survival (OS) and progression-free survival (PFS). miRNA and gene-expression profiles were studied using microarrays in an initial set of 36 cases. A selection of miRNAs associated with either DLBCL molecular subtypes (GCB/ABC) or clinical outcome were studied by multiplex RT-PCR in a test group of 240 cases with available formalin-fixed, paraffin-embedded (FFPE) diagnostic samples. The samples were divided into a training set (123 patients) and used to derive miRNA-based and combined (with IPI score) Cox regression models in an independent validation series (117 patients). Our model based on miRNA expression predicts OS and PFS and improves upon the predictions based on clinical variables. Combined models with IPI score identified a high-risk group of patients with a 2-year OS and a PFS probability of < 50%. In summary, a precise miRNA signature is associated with poor clinical outcome in chemoimmunotherapy-treated DLBCL patients. This information improves upon IPI-based predictions and identifies a subgroup of candidate patients for alternative therapeutic regimens.

Background: The aim of this study was to compare the long-term safety and efficacy of oral busulfan 12 mg/kg plus melphalan 140 mg/m(2) and melphalan 200 mg/m(2) as conditioning regimens for autologous stem cell transplantation in newly diagnosed patients with multiple myeloma in the GEM2000 study. Design and methods: The first 225 patients received oral busulfan 12 mg/kg plus melphalan 140 mg/m(2); because of a high frequency of veno-occlusive disease, the protocol was amended and a further 542 patients received melphalan 200 mg/m(2). Results: Engraftment and hospitalization times were similar in both groups. Oral busulfan 12 mg/kg plus melphalan 140 mg/m(2) resulted in higher transplant-related mortality (8.4% versus 3.5%; P=0.002) due to the increased frequency of veno-occlusive disease in this group. Response rates were similar in both arms. With respective median follow-ups of 72 and 47 months, the median progression-free survival was significantly longer with busulfan plus melphalan (41 versus 31 months; P=0.009), although survival was similar to that in the melphalan 200 mg/m(2) group. However, access to novel agents as salvage therapy after relapse/progression was significantly lower for patients receiving busulfan plus melphalan (43%) than for those receiving melphalan 200 mg/m(2) (58%; P=0.01). Conclusions: Conditioning with oral busulfan 12 mg/kg plus melphalan 140 mg/m(2) was associated with longer progression-free survival but equivalent survival to that achieved with melphalan 200 mg/m(2) but this should be counterbalanced against the higher frequency of veno-occlusive disease-related deaths. This latter fact together with the limited access to novel salvage therapies in patients conditioned with oral busulfan 12 mg/kg plus melphalan 140 mg/m(2) may explain the absence of a survival difference. Oral busulfan was used in the present study; use of the intravenous formulation may reduce toxicity and result in greater efficacy, and warrants further investigation in myeloma patients. (Clinicaltrials.gov identifier: NCT00560053).

Background About one half of adults with acute lymphoblastic leukemia are not cured of the disease and ultimately die. The objective of this study was to explore the factors influencing the outcome of adult patients with relapsed acute lymphoblastic leukemia. Design and Methods We analyzed the characteristics, the outcome and the prognostic factors for survival after first relapse in a series of 263 adult patients with acute lymphoblastic leukemia (excluding those with mature B-cell acute lymphoblastic leukemia) prospectively enrolled in four consecutive risk-adapted PETHEMA trials. Results The median overall survival after relapse was 4.5 months (95% CI, 4-5 months) with a 5-year overall survival of 10% (95% CI, 8%-12%); 45% of patients receiving intensive second-line treatment achieved a second complete remission and 22% (95% CI, 14%-30%) of them remained disease free at 5 years. Factors predicting a good outcome after rescue therapy were age less than 30 years (2-year overall survival of 21% versus 10% for those over 30 years old; P<0.022) and a first remission lasting more than 2 years (2-year overall survival of 36% versus 17% among those with a shorter first remission; P<0.001). Patients under 30 years old whose first complete remission lasted longer than 2 years had a 5-year overall survival of 38% (95% CI, 23%-53%) and a 5-year disease-free survival of 53% (95% CI, 34%-72%). Conclusions The prognosis of adult patients with acute lymphoblastic leukemia who relapse ...