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PURPOSE The PRIMA study (ClinicalTrials.gov identifier: NCT00140582 ) established that 2 years of rituximab maintenance after first-line immunochemotherapy significantly improved progression-free survival (PFS) in patients with follicular lymphoma compared with observation. Here, we report the final PFS and overall survival (OS) results from the PRIMA study after 9 years of follow-up and provide a final overview of safety. METHODS Patients (> 18 years of age) with previously untreated high–tumor-burden follicular lymphoma were nonrandomly assigned to receive one of three immunochemotherapy induction regimens. Responding patients were randomly assigned (stratified by induction regimen, response to induction treatment, treatment center, and geographic region) 1:1 to receive 2 years of rituximab maintenance (375 mg/m2, once every 8 weeks), starting 8 weeks after the last induction treatment, or observation (no additional treatment). All patients in the extended follow-up provided their written informed consent (data cutoff: December 31, 2016). RESULTS In total, 1,018 patients completed induction treatment and were randomly assigned to rituximab maintenance (n = 505) or observation (n = 513). Consent for the extended follow-up was provided by 607 patients (59.6%) of 1,018 (rituximab maintenance, n = 309; observation, n = 298). After data cutoff, median PFS was 10.5 years in the rituximab maintenance arm compared with 4.1 years in the observation arm (hazard ratio, 0.61; 95% CI, 0.52 to 0.73; P < .001). No OS difference was seen in patients randomly assigned to rituximab maintenance or observation (hazard ratio, 1.04; 95% CI, 0.77 to 1.40; P = .7948); 10-year OS estimates were approximately 80% in both study arms. No new safety signals were observed. CONCLUSION Rituximab maintenance after induction immunochemotherapy provides a significant long-term PFS, but not OS, benefit over observation.

The role of Ann Arbor staging in determining treatment intensity after achieving a negative positron emission tomography (PET) has not been established in classical Hodgkin lymphoma (cHL). Patients with stage I–IV cHL, received three cycles of ABVD (doxorubicin, bleomycin, vinblastine, dacarbazine) and an interim PET scan (PET3). PET3-negative patients received no further therapy. PET3-positive patients received three additional cycles of ABVD plus involved-field radiation therapy or salvage chemotherapy, if refractory to ABVD, and were re-evaluated by PET scan (PET6). Study endpoints were 3-year progression-free survival (PFS) and overall survival (OS) rates. Two hundred and thirty-nine patients with early-stage and 138 with advanced-stage were evaluable. Overall, 260 patients (70%) were PET3-negative and had higher 3-year PFS (90% vs. 65%; P < 0 0001) and OS (98% vs. 92%; P = 0 007) rates than PET3-positive patients. All PET3-negative patients, regardless of disease stage at diagnosis, achieved similarly good PFS (90–91%; P = 0 76) and OS (97–99%). The only independent prognostic factor for PFS was PET3-negativity (Hazard ratio 3 8; 95% confidence interval 2 4–6 3; P < 0 0001). This study suggests that cHL patients who achieve a negative PET3 following ABVD have an excellent outcome, regardless of stage at diagnosis. An appropriately powered, phase III trial will be necessary to confirm these findings. Fil: Pavlovsky, Astrid. Fundación Para Combatir la Leucemia; Argentina. Centro de Hematología Pavlovsky; Argentina Fil: Fernández, Isolda. Fundación Para Combatir la Leucemia; Argentina. Centro de Hematología Pavlovsky; Argentina Fil: Kurgansky, Nicolas. Doctus; Argentina Fil: Prates, Virginia. Hospital Italiano de La Plata; Argentina Fil: Zoppegno, Lucia. Hospital General San Martín; Argentina Fil: Negri, Pedro. Consejo Nacional de Investigaciones Científicas y Técnicas; Argentina. Instituto Privado de Hematología y Hemoterapia; Argentina Fil: Milone, Gustavo. Fundación Para Combatir la Leucemia; Argentina Fil: Cerutti, Ider. Idhea Clinica Hematologica Dr Cerutti Ider; Argentina Fil: Zabaljauregui, Soledad. Academia Nacional de Medicina de Buenos Aires; Argentina Fil: Mariano, Romina. Provincia de Entre Rios. Hospital San Martin; Argentina Fil: Grecco, Horacio F.. Sanatorio Dr. Julio Méndez; Argentina Fil: Basquiera, Ana Lisa. Hospital Privado Universitario de Cordoba.; Argentina Fil: Saba, Silvia. Hospital Rodolfo Rossi; Argentina Fil: Rudoy, Silvia. Clínica Modelo de Morón; Argentina Fil: Sackmann, Federico. Fundación Para Combatir la Leucemia; Argentina Fil: Castano, Vanesa. Idhea Clinica Hematologica Dr Cerutti Ider; Argentina Fil: Remaggi, Guillermina. Fundación Para Combatir la Leucemia; Argentina Fil: Cabrejo, María del Rosario. Sanatorio Dr. Julio Méndez; Argentina Fil: Roveri, Eriberto. Idhea Clinica Hematologica Dr Cerutti Ider; Argentina Fil: Casale, María Florencia. Instituto Privado de Hematología y Hemoterapia; Argentina. Hospital General Centeno; Argentina Fil: Cabane, Vanina. Clínica Dr. Roberto Raña; Argentina Fil: Taus, Rossana. Hospital Rodolfo Rossi; Argentina Fil: Venturini, Claudia. Instituto Privado de Hematología y Hemoterapia; Argentina Fil: Sakamoto, Francisco. Instituto Privado de Hematología y Hemoterapia; Argentina Fil: Varela, Ana I.. Sanatorio Las Lomas Sociedad Anonima.; Argentina Fil: Riddick, Maximiliano Luis. Consejo Nacional de Investigaciones Científicas y Técnicas. Centro Científico Tecnológico Conicet - La Plata; Argentina. Universidad Nacional de La Plata. Facultad de Ciencias Exactas. Departamento de Matemáticas; Argentina Fil: Pavlovsky, Santiago. Fundación Para Combatir la Leucemia; Argentina

Acute promyelocytic leukemia (APL) is a subtype of Acute Myeloid Leukemia (AML) in which a chromosomal translocation t (15; 17) (q22; q12) is generated by fusing produces a hybrid PML / RARα gene, generating an altered signal . The combination of transretinoic acid (ATRA) plus arsenic trioxide (ATO) has been shown to be superior to ATRA plus chemotherapy in the treatment of newly diagnosed standard risk patients with acute promyelocytic leukemia (APL) in several countries. The objective of the present study is to describe the frequency of remission in patients with acute promyelocytic leukemia who were administered as a first line Arsenic Trioxide (varitrinox) during the period from November 2017 to June 2020 in Colombian patients. Methods: Retrospective observational and descriptive study of 12 patients diagnosed with acute promyelocytic leukemia treated with ATO Arsenic trioxide (Varitrinox) as first line, the source of information was provided by the treating hematologists (medical records) by filling out the technical concept format. Active pharmacovigilance scientist in Colombia, this format keeps the identification information of the patient anonymized and the confidentiality of the data is guaranteed as well as compliance with the rules of good clinical practice. Results: Twelve patients with age range between 22 and 69 years with a median age of 34.0 were analyzed. It was found in the analysis that 100% had induction hematologic remission with a median of 45 days. 75% of patients received ATO + ATRA and were at low and intermediate risk, the remaining 25% received ATRA + ATO + Chemotherapy and were at high risk, and intermediate risk. 91.7% of molecular remission in consolidation was obtained and it was measured in cycle 3 by means of PCR (undetectable), 8.3% (n = 1) was positive 3% and is finishing consolidation. Regarding the most frequent adverse events, intravascular coagulation (n = 9), neutropenia (n = 6) and thrombocytopenia (n = 6) were observed. 75% of patients are disease-free, 16.7% are on maintenance (they received ATO + ATRA + Induction chemotherapy) and 8.3% are on consolidation. So far, none of the patients under study have died. Conclusions: Our results support the use of ATO (Varitrinox) in newly diagnosed APL patients (as first line), as a care strategy for low, intermediate and high risk patients. The role of ATRA-ATO is guaranteed in other studies where they manage patients of different risks. Key words: Arsenic trioxide, leukemia promyelocytic acute, leukemia myeloid acute, remission induction, tretinoin. Disclosures No relevant conflicts of interest to declare.

There are limited data on hematopoietic cell transplantation (HCT) in primary plasma cell leukemia (pPCL), an aggressive plasma cell disorder. We report outcomes of 147 patients with pPCL receiving autologous (n=97) or allogeneic (n=50) HCT within 18 months after diagnosis between 1995 and 2006. Median age was 56 years and 48 years for autologous HCT and allogeneic HCT, respectively. Progression-free survival (PFS) at 3 years was 34% (95% confidence interval (CI), 23-46%) in the autologous group and 20% (95% CI, 10-34%) in the allogeneic group. Cumulative incidence of relapse at 3 years was 61% (95% CI, 48-72%) in the autologous group and 38% (95% CI, 25-53%) in the allogeneic group. Overall survival (OS) at 3 years was 64% (95% CI, 52-75%) in the autologous group and 39% (95% CI, 26-54%) in the allogeneic group. Non-relapse mortality (NRM) at 3 years was 5% (95% CI, 1-11%) in the autologous group and 41% (95% CI, 28-56%) in the allogeneic group. The encouraging OS after autologous HCT, establishes the safety and feasibility of this consolidative treatment option after initial induction therapy for pPCL. Allogeneic HCT, although associated with a significantly lower relapse rate, carries a much higher risk of NRM and no OS benefit.

Optimal management of patients with relapsed/refractory chronic lymphocytic leukemia (CLL) has been the motive behind a large number of studies in recent years, and previous response, its duration, and development of clonal evolution appear to be the best indicators for the choice of a new regimen. Although alemtuzumab in relapsed/refractory CLL may be beneficial, the optimal dosage and risk of infection related to its use remain thus far deeply controversial issues. In this pilot phase II study we investigated the feasibility of, toxicity of, and response to alemtuzumab at a reduced dose (30 mg s.c. for 2 weeks and then once a week at extended intervals: every 2, 4, 6 weeks up to 1 year). The overall response rate was 95%, with 51% complete response. The complete response range was 55% in fludarabine-relapsed patients and 28% in patients with fludarabine-refractory disease, without significant difference between the two groups. The regimen was well tolerated with mild toxicity and few cytomegalovirus (CMV) infections. With a median follow-up of 27 months, the overall survival (46% at 3 years) appears to be similar to that with other regimens although with fewer adverse events. In conclusion, treatment with alemtuzumab at a reduced dose seems to be safe and increases the event-free survival of patients with relapsed/refractory CLL, compared with the standard dose. A randomized study comparing both regimens including a larger number of patients is warranted.

Background Acute promyelocytic leukemia is a subtype of acute myeloid leukemia characterized by the t(15;17). The incidence and prognostic significance of additional chromosomal abnormalities in acute promyelocytic leukemia is still a controversial matter. Design and Methods Based on cytogenetic data available for 495 patients with acute promyelocytic leukemia enrolled in two consecutive PETHEMA trials (LPA96 and LPA99), we analyzed the incidence, characteristics, and outcome of patients with acute promyelocytic leukemia with and without additional chromosomal abnormalities who had been treated with all-trans retinoic acid plus anthracycline monochemotherapy for induction and consolidation. Results Additional chromosomal abnormalities were observed in 140 patients (28%). Trisomy 8 was the most frequent abnormality (36%), followed by abn(7q) (5%). Patients with additional chromosomal abnormalities more frequently had coagulopathy (P=0.03), lower platelet counts (P=0.02), and higher relapse-risk scores (P=0.02) than their counterparts without additional abnormalities. No significant association with FLT3/ITD or other clinicopathological characteristics was demonstrated. Patients with and without additional chromosomal abnormalities had similar complete remission rates (90% and 91%, respectively). Univariate analysis showed that additional chromosomal abnormalities were associated with a lower relapse-free survival in the LPA99 trial (P=0.04), but not in the LPA96 trial. However, neither additional chromosomal abnormalities overall nor any specific abnormality was identified as an independent risk factor for relapse in multivariate analysis. Conclusions The lack of independent prognostic value of additional chromosomal abnormalities in acute promyelocytic leukemia does not support the use of alternative therapeutic strategies when such abnormalities are found.

Purpose We analyzed the incidence, risk factors, and outcome of therapy-related myeloid neoplasms (t-MNs) in patients with acute promyelocytic leukemia (APL) in first complete remission (CR). Patients and Methods From 1996 to 2008, 1,025 patients with APL were enrolled onto three sequential trials (LPA96, LPA99, and LPA2005) of the Programa Español para el Tratamiento de Enfermedades Hematológicas and received induction and consolidation therapy with all-trans-retinoic acid (ATRA) and anthracycline-based chemotherapy. Results Seventeen of 918 patients who achieved CR developed t-MN (10 with < 20% and seven with ≥ 20% of bone marrow blasts) after a median of 43 months from CR. Partial and complete deletions of chromosomes 5 and 7 (nine patients) and 11q23 rearrangements (three patients) were the most common cytogenetic abnormalities. Overall, the 6-year cumulative incidence of t-MN was 2.2%, whereas in low-, intermediate-, and high-risk patients, the 6-year incidence was 5.2%, 2.1%, and 0%, respectively. Multivariate analysis identified age more than 35 years and lower relapse risk score as independent prognostic factors for t-MN. The median overall survival time after t-MN was 10 months. Conclusion t-MN is a relatively infrequent, long-term, and severe complication after first-line treatment for APL with ATRA and anthracycline-based regimens. Therapeutic strategies to reduce the incidence of t-MN are warranted.

Differentiation syndrome (DS) can be a life-threatening complication in patients with acute promyelocytic leukemia (APL) undergoing induction therapy with all-trans retinoic acid ( ATRA). Detailed knowledge about DS has remained limited. We present an analysis of the incidence, characteristics, prognostic factors, and outcome of 739 APL patients treated with ATRA plus idarubicin in 2 consecutive trials (Programa Espanol de Tratamientos en Hematologa [PETHEMA] LPA96 and LPA99). Overall, 183 patients (24.8%) experienced DS, 93 with a severe form (12.6%) and 90 with a moderate form (12.2%). Severe but not moderate DS was associated with an increase in mortality. A bimodal incidence of DS was observed, with peaks occurring in the first and third weeks after the start of ATRA therapy. A multivariate analysis indicated that a WBC count greater than 5 x 10(9)/L and an abnormal serum creatinine level correlated with an increased risk of developing severe DS. Patients receiving systematic prednisone prophylaxis (LPA99 trial) in contrast to those receiving selective prophylaxis with dexamethasone (LPA96 trial) had a lower incidence of severe DS. Patients developing severe DS showed a reduced 7-year relapse-free survival in the LPA96 trial (60% vs 85%, P = .003), but this difference was not apparent in the LPA99 trial (86% vs 88%). (Blood. 2009; 113: 775-783)

A previous report of the Programa de Estudio y Tratamiento de las Hemopatías Malignas (PETHEMA) Group showed that a risk-adapted strategy combining all-trans retinoic acid (ATRA) and anthracycline monochemotherapy for induction and consolidation in newly diagnosed acute promyelocytic leukemia results in an improved outcome. Here we analyze treatment outcome of an enlarged series of patients who have been followed up for a median of 65 months. From November 1999 through July 2005 (LPA99 trial), 560 patients received induction therapy with ATRA plus idarubicin. Patients achieving complete remission received 3 courses of consolidation followed by maintenance with ATRA and low-dose chemotherapy. The 5-year cumulative incidence of relapse and disease-free survival were 11% and 84%, respectively. These results compare favorably with those obtained in the previous LPA96 study (P = .019 and P = .04, respectively). This updated analysis confirms the high antileukemic efficacy, low toxicity, and high degree of compliance of a risk-adapted strategy combining ATRA and anthracycline monochemotherapy for consolidation therapy.

Nonsecretory myeloma (NSM) accounts for

Relapse is the overwhelming cause of treatment failure after autologous transplantation for multiple myeloma (MM). For patients with a syngeneic donor, twin transplants provide a healthy graft that is free of myeloma. The relative impact of the graft on posttransplant relapse can be estimated by comparing risk of relapse after hematopoietic cell transplantation from genetically identical twins versus autotransplants because confounding differences in minor or major histocompatibility antigens are absent in the syngeneic transplant setting. Outcomes of 43 subjects who received twin transplants for MM were compared to 170 matched autotransplant recipients reported to the Center for International Blood and Marrow Transplant Research (CIBMTR). Multivariate analysis was performed by fitting a Cox model stratified on matched pairs. The matched transplant patients studied were similar with respect to subject-, disease-, and transplant-related characteristics. Cumulative incidence of relapse/progression was significantly lower, and progression-free survival (PFS) was significantly higher following twin transplants. In multivariate analysis, the probability of relapse/progression was lower in twins (relative risk [RR] = 0.49, 95% confidence interval [CI] 0.28-0.86, P = .011). Twin transplants have a significantly lower relapse risk than autotransplants in MM, suggesting that graft composition may impact outcomes following high-dose chemotherapy.

An understanding of the prognostic factors associated with the various forms of induction mortality in patients with acute promyelocytic leukemia (APL) has remained remarkably limited. This study reports the incidence, time of occurrence, and prognostic factors of the major categories of induction failure in a series of 732 patients of all ages (range, 2-83 years) with newly diagnosed APL who received all-trans retinoic acid (ATRA) plus idarubicin as induction therapy in 2 consecutive studies of the Programa de Estudio y Tratamiento de las Hemopatias Malignas (PETHEMA) Group. Complete remission was attained in 666 patients (91%). All the 66 induction failures were due to induction death. Hemorrhage was the most common cause of induction death (5%), followed by infection (2.3%) and differentiation syndrome (1.4%). Multivariate analysis identified specific and distinct pretreatment characteristics to correlate with an increased risk of death caused by hemorrhage (abnormal creatinine level, increased peripheral blast counts, and presence of coagulopathy), infection (age >60 years, male sex, and fever at presentation), and differentiation syndrome (Eastern Cooperative Oncology Group [ECOG] score >1 and low albumin levels), respectively. These data furnish clinically relevant information that might be useful for designing more appropriately risk-adapted treatment protocols aimed at reducing the considerable problem of induction mortality in APL.

We studied the clinical impact of CD38 expression in 226 chronic lymphocytic leukemia patients (CLL) at disease presentation and during follow up to determine its prognostic significance, progression free survival (PFS) and overall survival (OS), and to verify whether this parameter changed over time. Various patients' characteristics were studied including gender, Rai and Binet stages, immunoglobulin light chain expression, lymphocyte doubling time and CD38 expression. After a median follow up of 53 months (range 6-282), 62% CD38 positive(+) patients required therapy. PFS and OS at 84 months were significantly lower for CD38(+) patients: 20 and 71% respectively, compared to CD38 negative(-): 70 and 96%. At multivariate analysis CD38(+) showed to be the best factor for predicting progression: HR 3.3, 95%CI 2.10-5.14, p = 0.000. Its expression did not change in 98% re-evaluated patients. We confirm that CD38(+) is a stable parameter for the identification of CLL patients with a more aggressive disease course.

For adults with high-risk or recurrent acute lymphoblastic leukemia (ALL) who lack a suitable sibling donor, the decision between autologous (Auto) and unrelated donor (URD) hematopoietic stem cell transplantation (HSCT) is difficult due to variable risks of relapse and treatment-related mortality (TRM). We analyzed data from two transplant registries to determine outcomes between Auto and URD HSCT for 260 adult ALL patients in first (CR1) or second (CR2) complete remission. All patients received a myeloablative conditioning regimen. The median follow-up was 77 (range 12-170) months. TRM at 1 year post-transplant was significantly higher with URD HSCT; however, there were minimal differences in TRM according to disease status. Relapse was higher with Auto HSCT and was increased in patients transplanted in CR2. Five year leukemia-free (37% vs. 39%) and overall (38% vs. 39%) survival rates were similar for Auto HSCT vs. URD HSCT in CR1. There were trends favoring URD HSCT in CR2. The long follow-up in this analysis demonstrated that either Auto or URD HSCT can result in long-term leukemia free and overall survival for adult ALL patients. The optimal time (CR1 vs. CR2) and technique to perform HSCT remains an important clinical question for adult ALL patients.

The role of autologous stem cell transplantation (AuSCT) in older multiple myeloma patients is unclear. Using data from the Autologous Blood and Marrow Transplant Registry, we compared the outcome of 110 patients/=the age of 60 (median 63; range 60-73) years, undergoing AuSCT with that of 382 patients60 (median 52; range 30-59) years. The two groups were similar except that older patients had a higher beta(2)-microglobulin level at diagnosis (P=0.016) and fewer had lytic lesions (P=0.007). Day 100 mortality was 6% (95% confidence interval 4-9) and 1-year treatment-related mortality (TRM) was 9% (6-13) in patients60 years, compared with 5% (2-10) and 8% (4-14), respectively, in patients/=60 years. The relapse rate, progression-free survival (PFS) and overall survival (OS) in the two groups were also similar. Multivariate analysis of all patients identified only an interval from diagnosis to AuSCT12 months and the use of two prior chemotherapy regimens within 6 months of AuSCT as adverse prognostic factors. Our results indicate that AuSCT can be safely performed in selected older patients: the best results were observed in patients undergoing AuSCT relatively early in their disease course.

All- trans -retinoic acid (ATRA) increases the efficacy of chemotherapy when used for induction and maintenance treatment of acute promyelocytic leukemia (APL), but its role in consolidation is unknown. Since November 1996, 426 patients with newly diagnosed APL have received induction therapy with ATRA and idarubicin. Before November 1999 (LPA96 study), consolidation therapy consisted of 3 courses of anthracycline monochemotherapy. After November 1999 (LPA99 study), patients with intermediate and high risks of relapse received consolidation therapy with ATRA and increased doses of anthracyclines. Of the 384 patients who achieved complete remission (90%), 382 proceeded to consolidation therapy. Seven patients died in remission (1.8%). The 3-year cumulative incidence of relapse for patients in the LPA96 and LPA99 studies was 17.2% and 7.5%, respectively ( P = .008). Patients treated with ATRA in consolidation therapy showed an overall reduction in the relapse rate from 20.1% to 8.7% ( P = .004). In intermediate-risk patients the rate decreased from 14.0% to 2.5% ( P = .006). This improved antileukemic efficacy also translated into significantly better disease-free and overall survival. A risk-adapted strategy combining anthracycline monochemotherapy and ATRA for induction and consolidation therapy of newly diagnosed APL results in improved antileukemic efficacy and a high degree of compliance.

We evaluated transplant-related mortality (TRM), leukaemia relapse, leukaemia-free survival (LFS) and overall survival (OS) in patients receiving busulphan and cyclophosphamide (BuCy) or cyclophosphamide and total body irradiation (CyTBI) prior to allogeneic bone marrow transplantation (BMT) for acute myelogenous leukaemia (AML) in first remission. Outcomes of 381 human leucocyte antigen (HLA)-matched sibling transplants using BuCy were compared with 200 transplants using CyTBI performed between 1988 and 1996. The incidence of hepatic veno-occlusive disease was higher with BuCy (13%) than with CyTBI (6%) (P = 0.009). Risks of acute and chronic GVHD were similar. In multivariate analysis, relapse risk was higher in the BuCy group [relative risk (RR) = 1.72; 95% confidence interval (CI), 1.05-2.81; P = 0.031]. Eleven of 373 evaluable patients in the BuCy group had a central nervous system relapse in contrast to none of 194 evaluable patients in the CyTBI group (P = 0.016). There were no differences in TRM, LFS and OS. CyTBI conditioning may lower relapse risk but produces comparable TRM, LFS and OS to BuCy for HLA-matched sibling transplantation in first remission AML.

HSV can cause oral lesions that exacerbate chemotherapy-related mucositis. Intravenous acyclovir is effective in preventing HSV reactivations, but expensive. Valacyclovir has good bioavailability and has not been studied for prophylaxis of HSV among PCT patients. We compared the efficacy and costs of valacyclovir in preventing HSV reactivation among HSV seropositive autologous progenitor cell transplantation (APCT) patients with historical controls in whom intravenous acyclovir or no HSV prophylaxis were used. Valacyclovir group: From October 1997 to April 1999 108 adult patients received valacyclovir 500 mg twice daily from day −3 of APCT until neutropenia recovery or day +30. Valacyclovir was switched to intravenous acyclovir in cases of oral intolerance (17 patients) or suspected HSV reactivation (five patients). Intravenous acyclovir group: From January 1996 to October 1997 43 patients received 5 mg/kg twice-daily intravenous acyclovir from day −3 until recovery from neutropenia. No prophylaxis group: 38 patients from January 1996 to October 1997 did not receive HSV prophylaxis. HSV reactivations were seen in 2.7%, 2% and 45% of patients in the valacyclovir, intravenous acyclovir, and no prophylaxis groups, respectively. Valacyclovir was well tolerated and was the least expensive strategy. Oral valacyclovir was as effective as intravenous acyclovir for the prophylaxis of HSV reactivation in APCT patients. Bone Marrow Transplantation (2002) 29, 263–267. doi:10.1038/sj.bmt.1703354

The aim of this study was to increase disease-free survival (DFS) in AML in CR1 using a high-dose cytarabine consolidation plus G-CSF as in vivo purging and mobilization of CD34+ cells before ablative therapy and peripheral blood autograft.Fifty-six consecutive AML patients (pts) (including 11 children15 years), with a median age of 32 years, were analyzed. After achievement of CR with cytarabine-mitoxantrone (7 + 3) in adults and a BFM-like protocol in children, pts were intensified with cytarabine 2 g/m2 x six doses plus mitoxantrone for adults, or, 3 g/m2 x six doses plus etoposide for children, followed by G-CSF 5 micrograms/kg SC daily. The ablative regimens used were busulfan and cyclophosphamide (Bu/Cy) in standard-risk pts plus etoposide (2400 mg/m2) for high-risk pts.For the 54 pts who underwent autologous transplant, the median time to reach1.0 x 10(9)/l neutrophils was 13 days (8-48), and to reach platelets25 x 10(9)/l 32 days (8-364), and the median numbers of red blood cell and platelet units transfused were 3 and 5, respectively. Six pts had treatment-related deaths (11%). The disease-free survival and overall survival at 30 months (mos) for the 56 eligible pts were 61% and 62%, respectively. Only two relapses were observed after 21 mos, while there were 12 relapses within 12 mos.The above treatment results in a similar DFS rate as does rescue with bone marrow cells, with faster neutrophil and platelet recovery.

Allogeneic hematopoietic cell transplantation in multiple myeloma is limited by prior reports of high treatment-related mortality. We analyzed outcomes after allogeneic hematopoietic cell transplantation for multiple myeloma in 1207 recipients in 3 cohorts based on the year of transplantation: 1989-1994 (n = 343), 1995-2000 (n = 376), and 2001-2005 (n = 488). The most recent cohort was significantly older (53% > 50 years) and had more recipients after prior autotransplantation. Use of unrelated donors, reduced-intensity conditioning and the blood cell grafts increased over time. Rates of acute graft-versus-host (GVHD) were similar, but chronic GVHD rates were highest in the most recent cohort. Overall survival (OS) at 1-year increased over time, reflecting a decrease in treatment-related mortality, but 5-year relapse rates increased from 39% (95% confidence interval [CI], 33%-44%) in 1989-1994 to 58% (95% CI, 51%-64%; P < .001) in the 2001-2005 cohort. Projected 5-year progression-free survival and OS are 14% (95% CI, 9%-20%) and 29% (95% CI, 23%-35%), respectively, in the latest cohort. Increasing age, longer interval from diagnosis to transplantation, and unrelated donor grafts adversely affected OS in multivariate analysis. Survival at 5 years for subjects with none, 1, 2, or 3 of these risk factors were 41% (range, 36%-47%), 32% (range, 27%-37%), 25% (range, 19%-31%), and 3% (range, 0%-11%), respectively (P < .0001).

Background To establish stringent complete remission (SCR) in patients with multiple myeloma (MM), it is currently recommended to obtain a normal serum free light chains (sFLC) ratio. The appearance of serum oligoclonal bands (OB) after autologous stem cell transplantation (ASCT) is considered a favorable prognostic factor. The objective of this study was to examine sFLC for assessing SCR in patients with MM, and ASCT with OB. We also examined how capillary electrophoresis (CE) compares with agarose gel electrophoresis (Aga) in identifying oligoclonal bands. Methods Out of 238 patients studied in our institution between April 1992 and December 2008 a serum protein electrophoresis (SPE) was performed by means of CE and sFLC determination on 37 patients with MM in complete remission (CR), ASCT and OB presence were assigned by conventional Aga electrophoresis and IF. Results Statistically significant differences (SSD) were found when comparing CE vs. Aga, regarding BO visualization in SPE, favoring the latter. In connection with sFLC, the group of patients with an abnormal ratio presented elevated values in the γ-globulin zone of the SPE, whereas the group of patients with a normal ratio of sFLC presented with normal values resulting in SSD between the groups. Conclusions It is essential to perform immunofixation to certify the presence of OB, especially if CE is used as it is difficult to distinguish them using this method. A normal sFLC was observed in most of the patients with OB and normal values of the SPE γ-globulin zone. The above-mentioned information might demonstrate a limitation of sFLC test in SCR evaluation for patients with MM, ASCT and CR if OB has been detected.

BACKGROUND: Patients with follicular lymphoma can have long survival times, but disease progression typically occurs 3-5 years after initial treatment. We assessed the potential benefit of 2 years of rituximab maintenance after first-line treatment in patients with follicular lymphoma receiving a rituximab plus chemotherapy regimen. METHODS: The randomised, open-label PRIMA study was undertaken in 223 centres in 25 countries. 1217 patients with previously untreated follicular lymphoma needing systemic therapy received one of three non-randomised immunochemotherapy induction regimens used in routine practice. 1019 patients achieving a complete or partial response were then randomly assigned to receive 2 years of rituximab maintenance therapy (375 mg/m(2) every 8 weeks) or observation. Treatment was assigned equally by centralised block randomisation, stratified by induction regimen, response, region, and centre. Neither the participants nor those giving the interventions, assessing outcomes, and analysing data were masked to group assignments. The primary endpoint was progression-free survival (PFS). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00140582. FINDINGS: 505 patients were assigned to rituximab maintenance and 513 to observation (one patient died during randomisation). With a median follow-up of 36 months (IQR 30-42), PFS was 74·9% (95% CI 70·9-78·9) in the rituximab maintenance group (130 patients progressed) and 57·6% (53·2-62·0) in the observation group (218 progressed; hazard ratio [HR] 0·55, 95% CI 0·44-0·68, p

Few studies have examined the outcome of large numbers of patients with the microgranular variant (M3V) of acute promyelocytic leukemia (APL) in the all-trans retinoic acid era. Here, the outcome of 155 patients treated with all-trans retinoic acid–based therapy on 3 clinical trials, North American Intergroup protocol I0129 and Programa para el Estudio de la Terapéutica en Hemopatía Maligna protocols LPA96 and LPA99, are reported. The complete remission rate for all 155 patients was 82%, compared with 89% for 748 patients with classical M3 disease. The incidence of the APL differentiation syndrome was 26%, compared with 25% for classical M3 patients, and the early death rate was 13.6% compared with 8.4% for patients with classical M3 morphology. With a median follow-up time among survivors of 7.6 years (range 3.6-14.5), the 5-year overall survival, disease-free survival, and cumulative incidence of relapse for patients with M3V were 70%, 73%, and 24%, respectively. With a median follow-up time among survivors of 7.6 years (range 0.6-14.3), the 5-year overall survival, disease-free survival, and cumulative incidence of relapse among patients with classical M3 morphology were 80% (P = .006 compared with M3V), 81% (P = .07), and 15% (P = .005), respectively. When outcomes were adjusted for the white blood cell count or the relapse risk score, none of these outcomes were significantly different between patients with M3V and classical M3 APL.

The expression of CD56 antigen in acute promyelocytic leukemia (APL) blasts has been associated with short remission duration and extramedullary relapse. We investigated the clinical significance of CD56 expression in a large series of patients with APL treated with all-trans retinoic acid and anthracycline-based regimens. Between 1996 and 2009, 651 APL patients with available data on CD56 expression were included in 3 subsequent trials (PETHEMA LPA96 and LPA99 and PETHEMA/HOVON LPA2005). Seventy-two patients (11%) were CD56+ (expression of CD56 in ≥ 20% leukemic promyelocytes). CD56+ APL was significantly associated with high white blood cell counts; low albumin levels; BCR3 isoform; and the coexpression of CD2, CD34, CD7, HLA-DR, CD15, and CD117 antigens. For CD56+ APL, the 5-year relapse rate was 22%, compared with a 10% relapse rate for CD56− APL (P = .006). In the multivariate analysis, CD56 expression retained the statistical significance together with the relapse-risk score. CD56+ APL also showed a greater risk of extramedullary relapse (P < .001). In summary, CD56 expression is associated with the coexpression of immaturity-associated and T-cell antigens and is an independent adverse prognostic factor for relapse in patients with APL treated with all-trans-retinoic acid plus idarubicin–derived regimens. This marker may be considered for implementing risk-adapted therapeutic strategies in APL. The LPA2005 trial is registered at http://www.clinicaltrials.gov as NCT00408278.

Background: Over the last 20 years, high dose therapy followed by hemopoietic stem cell transplantation has been employed in patients with multiple myeloma (MM). During 16 years of follow-up, the degree of tumor response and survival in 238 patients with autologous stem cell transplantation (ASCT) and changes in the serum protein electrophoretic pattern were analyzed. Methods: Agarose gel electrophoresis with densitometric analysis and immunofixation were performed to evaluate serum monoclonal protein. IgM, IgA, IgG and β2-microglobulin (β2M) were quantitated. Urine protein electrophoresis with IF was performed on cellulose acetate gel using colloidal silver staining without concentrating. Results: After 34 months of follow-up (range 1–160 months), eight patients (3.4%) showed a distinct monoclonal protein band that was different from their original isotype switch. This was observed to be a transient phenomenon (22.2 months). Thirty-seven patients (15.5%) developed oligoclonal bands (OB) between the first and the twentieth month after ASCT (mean 4.4 months), which persisted for 7.9 months (1–36 months). The mean overall survival time was statistically different (p Conclusions: The occurrence of OB could be a potential favorable prognostic marker after transplantation due to the prolonged survival observed. Close follow-up of anomalous protein bands, either in serum or urine, is essential due to the additional difficulty in interpretation when the therapeutic response and evolution are evaluated. Clin Chem Lab Med 2010;48:727–31.

The International staging system (ISS) for multiple myeloma (MM) is a validated alternative to the Durie Salmon staging system (DSS) for predicting survival at diagnosis. We compared these staging systems for predicting outcomes after upfront autologous stem cell transplantation by analyzing the outcomes of 729 patients between 1995 and 2002. With a median follow-up of 56 months the univariate probabilities (95% CI) of non-relapse mortality (NRM), relapse, progression free (PFS) and overall survival (OS) at 5 years were 7%, 68%, 25% and 52%, respectively. The median overall survival for stages I, II, III by DSS and ISS were 82, 68, 50 and 64, 68, 45 months, respectively. The concordance between the two staging systems was only 36%. Staging systems were formally compared using Cox models fit with DSS and ISS stages. Relative risks of PFS and OS were significantly different for stages I vs. II and II vs. III for DSS but only for stages II vs. III for ISS. Although both systems were predictive of PFS and OS; the DSS was superior in formal statistical comparison using Brier Score. However, neither system was strongly predictive of outcomes indicating the need for newer schemes incorporating other prognostic markers.

Philadelphia (Ph) chromosome in acute lymphoblastic leukemia (ALL) is found nearly in 20-30% adults and 5% children. Ph chromosome results from the reciprocal translocation t(9;22)(q34;q11) joining the tyrosine kinase c-ABL1 proto-oncogene on chromosome 9 to BCR gene on chromosome 22. The majority of Ph breakpoint in ALL occurs in the minor breakpoint cluster region at first intron of the BCR gene, and results in the fusion of BCR exon 1 to ABL1 exon 2 (e1a2) generating the oncoprotein p190BCR-ABL1. Ph+ ALL patients present an aggressive disease with a poor prognosis. Current treatment includes potent chemotherapy and tyrosine kinase inhibitors, such as imatinib. The aim of this study was to quantify BCR-ABL1 transcripts in ALL Ph+ patients at different stages of treatment in order to evaluate the kinetics of the tumor clone in response to treatment. We reported a preliminary analysis of the clinical trial GATLA LLA-Ph+2011 (Grupo Argentino de Tratamiento de la Leucemia Aguda LLA-Ph+) that includes patients from 1 to 21 years old newly diagnosed Ph+ ALL. Written informed consent was obtained from all subjects. Diagnosis of Ph+ALL was confirmed by the presence of Ph chromosome and/or positive molecular analysis for detection of BCR-ABL1 fusion transcripts. All patients received induction treatment consisting of vincristine, daunorubicin, prednisolone, asparaginase, and metrotexate. Imatinib was administered 300 mg/m2/day from day 15 of induction until the initiation of conditioning for alloHSCT or to the end of maintenance therapy. The clinical protocol consist in an induction IA (33 days) and IB (28 days), consolidation RA1, RA2 and RA3, re-induction (Protocol II A and B, 36 days each) and maintenance to complete 2 years of treatment. Eligible patients are transplanted after the third block. Minimal residual disease (MRD) monitoring was performed by one-step quantitative RT-PCR assays in bone marrow and/or peripheral blood, using RotorGene® Qiagen; at the end of induction AI, previous RA1, RA2, RA3 and protocol II Fase IIA, IIB and during maintenance or post-alloHSCT. BCR-ABL1 quantification was expressed relative to the amount of ABL1 mRNA. We studied a control group of pediatrics positive P190 isoform bone marrow samples at diagnosis in order to establish our basal reference to estimate the logarithmic reduction of BCR-ABL1 transcripts for our cohort. The obtained mean value of BCR-ABL1(e1a2)/ABL1 in the control group was 55.5% (range 29% - 92%). The molecular response was defined as optimal (OMR, OMR-undetectable) if the BCR-ABL1/ABL1 ratio was lower than 0.055%. A total of 25 subjects (male: female = 16: 9) were enrolled into the study from November 2011 to July 2014. The median age was 7 (range 2 - 19) years old. Type of BCR breakpoint was minor (e1a2) in 96% of patients, and only one present a rearrangement corresponding to major BCR (b3a2). During the follow up (median: 15 months), five patients (20%) died: 3 by sepsis, 1 by post alloHCT complications, and 1 due to disease progression. Two patients had to rotate to dasatinib because of disease relapse: one in central nervous system and the other post alloHCT. Our preliminary results showed that the overall survival was 79%±10% and the survival free of event (death, molecular and disease relapse) was 67%±10% at 12 months. We serially measured BCR-ABL1 at different trial stage (AI, RA1, RA2, RA3, Protocol II) and OMR was 13.3%, 41.2%, 33.3%, 45.5% and 76.9%, respectively. Among 17 evaluable patients on maintenance and post alloHCT, 88% (15/17) obtained OMR values, and among them, 87% (13/15) presented OMR-undetectable values. We evaluated the kinetics of the tumor clone under treatment regarding prognostic factors. Patients older than 10 years showed a higher rate of OMR at RA1 (83% vs 27%, p=0.05). However, all evaluated younger patients reached an OMR at protocol II stage (100% vs 33%, p=0.045), showing a sustained and deeper molecular response. Other evaluated parameters did not show a relationship with OMR at different stages. Our preliminary data showed that BCR-ABL1 quantification may be a good marker to evaluate response to treatment in Ph+ positive ALL patients. BCR–ABL1 transcripts dropped to undetectable levels in 76% (13/17) of evaluable cases at the later stage of treatment. Also, 77% of patients achieved an OMR at Protocol II not only might provide a better chance for receiving alloHSCT but also might contribute to durable remissions. Disclosures No relevant conflicts of interest to declare.

Bone marrow transplantation (BMT) can cure myelodysplastic syndrome (MDS), although transplantation carries significant risks of morbidity and mortality. Because the optimal timing of HLA-matched BMT for MDS is unknown, we constructed a Markov model to examine 3 transplantation strategies for newly diagnosed MDS: transplantation at diagnosis, transplantation at leukemic progression, and transplantation at an interval from diagnosis but prior to leukemic progression. Analyses using individual patient risk-assessment data from transplantation and nontransplantation registries were performed for all 4 International Prognostic Scoring System (IPSS) risk groups with adjustments for quality of life (QoL). For low and intermediate-1 IPSS groups, delayed transplantation maximized overall survival. Transplantation prior to leukemic transformation was associated with a greater number of life years than transplantation at the time of leukemic progression. In a cohort of patients under the age of 40 years, an even more marked survival advantage for delayed transplantation was noted. For intermediate-2 and high IPSS groups, transplantation at diagnosis maximized overall survival. No changes in the optimal transplantation strategies were noted when QoL adjustments were incorporated. For low- and intermediate-1-risk MDS, delayed BMT is associated with maximal life expectancy, whereas immediate transplantation for intermediate-2- and high-risk disease is associated with maximal life expectancy.

BACKGROUND The objective of this analysis was to evaluate the role of autologous stem cell transplantation (ASCT) in prolonging disease free survival (DFS) and overall survival (OS) in patients with chronic myeloid leukemia (CML) who received autografts of Philadelphia chromosome (Ph) positive or Ph negative cell harvests. METHODS Over a 4-year period (1994–1999), 53 patients who underwent ASCT for CML were reported to the Argentine Group of Bone Marrow Transplantation (GATMO) Registry. RESULTS Ph negative cell products were harvested in only 18 patients (34%). Comparison of disease status at the time of autograft, duration of neutropenia, thrombocytopenia, days of antibiotics, and transfusional requirements of red blood cells and platelets did not reveal statistical significant differences between the Ph positive group and the Ph negative group. Only days of hospitalization were increased significantly in patients who received Ph positive autografts. Although DFS at 36 months was significantly longer after infusion of Ph negative cell products (54% vs. 14%; P ≤ 0.005), OS differences between the Ph negative group and the Ph positive group (68% vs. 53%; P ≤ 0.134) were not significant. CONCLUSIONS ASCT with Ph negative cell harvests after myeloablative chemotherapy resulted in prolonged periods of hematologic and cytogenetic remission or stable disease after cytogenetic/molecular recurrence in some patients with CML. A superior DFS was observed without any benefit observed for OS. Cancer 2002;95:2339–45. © 2002 American Cancer Society. DOI 10.1002/cncr.10931

The aim of this registry-based retrospective study was to analyze the outcome of second alloSCT (alloSCT2) performed in patients with malignant lymphoma who had relapsed after a first alloSCT (alloSCT1).Another purpose was to identify prognostic factors which might influence outcome after alloSCT2. Primary endpoint was disease-free survival (DFS) measured from alloSCT2; secondary endpoints were overall survival (OS), non-relapse mortality (NRM), and incidence of relapse (REL). Eligible were patients >=18 years who were registered within the EBMT and had received an alloSCT2 for relapse of lymphoma between 2000-2011 with a minimum interval of 3 months between alloSCT1 and alloSCT2. Centers with eligible patients were contacted to provide additional treatment and follow-up information. Statistical analysis was descriptive and employed log rank comparisons for univariate assessment of the impact of baseline characteristics on survival endpoints. Results 229 patients were identified who fulfilled the inclusion criteria. Additional information upon center request was provided for 84 them, resulting in exclusion of 19 patients who had been re-grafted for reasons other than relapse. The final study sample of 65 patients had a median age of 39 (18-67) years, a median interval from diagnosis to alloSCT1 of 21 (4-107) months, and a median interval from alloSCT1 to alloSCT2 of 18 (3-169) months. Diagnosis was Hodgkin's lymphoma (HL) in 29%, diffuse large B cell lymphoma (DLCL) in 14%, T cell lymphoma (TCL) in 12%, lymphoblastic lymphoma in 12%, follicular lymphoma (FL) in 11%, mantle cell lymphoma (MCL) in 11%, and other lymphoma in 11% of the patients. Remission status at alloSCT2 was CR/PR in 28% and more advanced in 72%. The same donor was used in 55% of the second allotransplants, whereas an alternative donor was used in 45%. Conditioning was myeloablative in 32% and less intensive in 68% of the alloSCT2 procedures. With a median observation time after alloSCT2 of 73 (13-73) months, DFS, OS, REL, and NRM were 26%, 37%, 55%, and 19% at 2 years; and 19%, 27%, 61%, and 19% at 5 years after alloSCT2. 45 patients died (26 from relapse and 19 from other reasons, mainly multi organ failure due to GVHD, infectious complications or toxicity). 15% of the patients suffered from grade 3/4 acute GVHD. The cumulative incidence of chronic GVHD was 34% at 2 years. Whilst DFS and OS were adversely affected by non-remission at alloSCT2 (p=0.017 and p=0.004) and interval between alloSCT1 and alloSCT2 Conclusions Although disease recurrence remains a problem, second allogeneic transplantation is a reasonable option in patients with lymphoma relapse after a first allogeneic transplantation, resulting in long-term remission in a substantial proportion of patients – in particular if the interval between alloSCT1 and alloSCT2 is 12 months or longer. Disclosures: No relevant conflicts of interest to declare.

Abstract 1619 Background: Positron emission tomography using 18F-fluoro-2-deoxy-d-glucose (FDG-PET-CT) is an important tool for treatment response assessment in Hodgkin Lymphoma (HL) treated with ABVD. It can predict response and overall outcome. The negative predictive value for PET-CT in patients (pts.) with HL is 90–94%. New recommendations define complete remission (CR) for HL as the lack of signs and symptoms of lymphoma with a negative PET-CT. OBJECTIVES: Reduce therapy in pts. who achieve early CR with negative PET-CT. Intensify treatment, only in pts. with positive PET-CT after 3 cycles of ABVD. Achieve CR, event free survival (EFS) and overall survival (OS), as good as in our historical control, when we used 3 or 6 cycles of ABVD plus involved field radio therapy (IFRT) in all pts.(LH-96) PATIENTS AND METHOD: Since October 2005, 200 newly diagnosed pts. with HL have been included in a prospective multicenter clinical trial (LH-05) All pts. received 3 cycles of ABVD and were then evaluated with a PET-CT (PET-CT +3) Pts. with a negative PET-CT+3 and absence of other signs or symptoms of lymphoma were considered in CR and received no further therapy. Pts with more than 50% of anatomic reduction of initial masses but persistent hyper metabolic lesions were considered in partial response (PR) and completed 6 cycles of ABVD and IFRT on PET-CT positive areas. Pts with less than PR received high doses of chemotherapy and an autologous stem cell transplant (ASCT). All pts were re-evaluated at the end of treatment with a new PET CT. One hundred and ninety three pts. have been evaluated. The median age at diagnosis was 29 years. One hundred and twenty five (65%) had localized stage (I-II) non bulky and 68 (35%) presented with advanced stage (III-IV), or bulky disease, 33 (17%) had bulky disease. RESULTS: One hundred and forty-eight (77%) achieved CR with negative PET-CT + 3. Forty-five (21%) were PET-CT+3 positive, 5 showed progressive disease. The other 40 pts. were in PR and completed a total of 6 ABVD + IFRT in PET-CT positive areas. Twenty eight achieved CR and 12 persisted with hypermetabolic lesions. Three died of progressive disease. After finishing planned treatment 178 pts. (92%) were in CR. With a median follow up of 39 months the EFS and OS at 36 months is 80% and 97% respectively. Patients with negative PET-CT +3 have an EFS of 86% compared to 61% for pts. with positive PET-CT+3 (P=0,001). We perform a multivariate analysis for EFS which included age, stage, IPS, bulky disease, extranodal areas and the result of the PET –CT+ 3. This last parameter together with age were the only ones with statistical significance (p=0.001 and 0.046 respectively). When comparing the results LH-05 with LH-96 there is no difference in EFS and OS at 36 months (83% vs. 85% and 97 vs. 96%) but in LH-05 only 23% received 6 cycles of ABVD and IFRT compared to 61% and 100% in LH-96. This reduces the exposure to chemo and radiotherapy. CONCLUSION: With PET-CT adapted therapy after 3 cycles of ABVD, 148 pts.(77%) received only 3 cycles of ABVD as initial therapy with an EFS and OS of 80% and 97% at 36 months. In the Cox regression model, PET-CT at completion of treatment was the most significant factor associated to EFS. In this interim analysis of PET-CT adapted therapy to all stages of HL, treatment with 3 cycles of ABVD can be adequate for pts. with negative PET-CT+3. Continuing with ABVD after a positive PET-CT +3 can be considered insufficient. A longer follow-up and a larger number of pts. are necessary to confirm these results. Disclosures: No relevant conflicts of interest to declare.

Abstract 1788 The GELA-sponsored intergroup PRIMA Phase III study was designed to investigate the potential benefit of 2-years of rituximab maintenance in high tumour burden follicular lymphoma patients responding to one of three non-randomised first line immunochemotherapy treatments. The results of the pre-planned interim analysis with 24 months median follow-up were positive and demonstrated a significant reduction in the risk of progression for patients randomized to rituximab maintenance (Salles et al., ASCO 2010). We present here the updated efficacy and safety results after an additional year of follow-up, when all randomized patients had completed the observation/maintenance period. From December 2004 until April 2007, 1217 patients were enrolled from 223 centres. Complete data are available for 1193 patients who had the following pre-induction treatment characteristics: median age 56 years [range 22–87]; 52% male; 90% Ann Arbor stage III-IV; 33% B symptoms; 55% bone marrow involvement; 4% ECOG performance status >1; 34% elevated LDH; 32% β2-microglobulin≥3mg/L; FLIPI score 0–1 (21%), FLIPI 2 (36%), FLIPI 3–5 (43%). Most patients (74%) received R-CHOP induction (22% R-CVP, 4% R-FCM). Patients responding to induction therapy were stratified based on their immunochemotherapy regimen and response [CR/CRu versus PR], and randomized to observation or rituximab maintenance, 1 infusion (375 mg/m2) every 8 weeks for 2 years. A total of 1018 randomised patients were analyzed according to the ITT principle (513 observation/505 rituximab maintenance). All initial pre-treatment characteristics were well balanced between arms and the response status at time of randomization was CR=39%; CRu=31% and PR=29% (others 1%). After a median follow-up of 36 months, 3-year progression free survival was 60.3% (95% confidence interval [CI] 55.8 – 64.5%) in the observation arm and 78.6% (95% CI 74.7 – 82%) in the rituximab maintenance arm, respectively (stratified Log-Rank, P The most common adverse events reported were infections, which occurred in 24% and 39% of the patients in the observation and rituximab maintenance arms respectively. Grade 3–4 adverse events were reported in 17% of patients in the observation arm and 24% in the rituximab maintenance arm (neutropenia 1% vs 4%; infections 1% vs 4%, respectively) but these lead to treatment discontinuation in only 8 and 19 patients, respectively. In conclusion, after an additional year of follow-up, these data demonstrate a sustained benefit of 2 years of rituximab maintenance therapy after immunochemotherapy, resulting in improved progression free survival and complete response rates. No additional or unexpected toxicities were observed. All randomized patients have an excellent survival to date and longer follow-up will explore factors affecting overall survival in these patients. The PRIMA results indicate that rituximab maintenance should be considered in all follicular lymphoma patients who have responded to first line immunochemotherapy. Disclosures: Salles: Roche: Consultancy, Honoraria. Off Label Use: The use of rituximab maintenance in follicular lymphoma patients. Catalano:Celgene: Research Funding; Roche: Honoraria, Research Funding, Travel Grants. Feugier:roche: Consultancy, Honoraria. Belada:Roche: Consultancy, Honoraria. Tilly:Amgen: Honoraria. Leppa:Roche: Honoraria. Soubeyran:Roche: Honoraria, Research Funding. Hagenbeek:roche: Consultancy. Lister:Allos: Consultancy; Bioconnections: Consultancy; Astra Zeneca: Consultancy; Tenet: Consultancy; GSK: Chairman of Safety Monitoring Committee. Lopez-Guillermo:Roche: Consultancy, Honoraria. Seymour:Roche: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau, Travel support; Bayer-Schering: Honoraria, Travel Support.

Abstract 1772 Background: Hodgkin Lymphoma (HL) is the most curable type of Lymphoma with an overall survival at 5 years of 80%. ABVD can be considered as gold standard for first line treatment for all stages of HL. Dividing patients (pts.) in different prognostic groups has aimed to reduce chemo and radio toxicity in those patients with good prognosis. A negative PET-CT, either early during treatment of ABVD or after completion of it, has shown to be a powerful prognostic tool (Hutchings: Blood 2006; Gallamini: Haematologica 2006). Our cooperative group has an experience with 584 patients with HL in early or advanced stage treated with 3 or 6 cycles of ABVD plus involved field radiotherapy with a complete remission (CR) of 91% and an event free survival (EFS) and overall survival (OS) at 60 months of 79% and 95%.(S Pavlovsky, Clin Lymp My & Leuk, 2010). Aims: Test the efficacy of treatment to all stages of HL adjusted to PET-CT results after 3 cycles of ABVD. Evaluate the outcome of pts. who have a negative PET-CT after 3 cycles of ABVD and receive no further treatment. Intensify therapy only in pts. who have persistent hyper metabolic lesions in PET-CT after 3 cycles of ABVD. Method: Since October 2005, 198 newly diagnosed pts. with HL have been included in a prospective multicenter trial. Initially all patients received 3 cycles of ABVD. After the third cycle, pts. were evaluated with a PET-CT. Those pts. who achieved CR with a negative PET-CT, received no further treatment. Those with more than 50% of anatomic reduction of initial masses but persistent hyper metabolic lesions by PET-TC after 3 ABVD were considered in partial remission (PR) and completed 6 cycles of ABVD and radiotherapy (RT) on PET-CT positive areas. Those patients with less than PR after 3 cycles of ABVD received ESHAP and if CR, high doses of chemotherapy and an autologous stem cell transplant (ASCT). All patients were re-evaluated at the end of treatment. The median follow up is of 30 months (3-62). Results: One hundred and seventy three patients completed three cycles of ABVD followed by a PET-CT. The median age at diagnosis was 29 years. One hundred and thirty-six (79%) had localized stage (I-II) at diagnosis and 37 (21%) presented with advanced stage (III-IV). Of 155 pts. 77 (50%) pts had IPS 0–1, 66 (43%) had IPS 2–3 and 12 (8%) had IPS 4–5. Twenty six (17%) pts. had bulky disease at diagnosis. One hundred and thirty-seven (79%) pts. achieved CR with negative PET-CT after 3 cycles of ABVD. Thirty-six (21%) were PET-CT positive, of them 32 pts achieved PR and completed a total of 6 cycles of ABVD plus RT in hyper metabolic lesions. Twenty five achieved CR (72%), 5 persisted with PR and 2 died of progressive disease. Four pts showed progressive disease (PD) after 3 ABVD and received ESHAP and ASCT, 2 achieved and remained in CR, 1 is in PR and 1 died of progressive disease. Of 173 pts who completed treatment with ABVD × 3 cycles, ABVD × 6 cycles plus RT on PET-TC positive areas or ESHAP plus ASCT, 164 pts (95%) achieved CR. Of these 164 pts., 14 pts (8%) relapsed. The EFS and OS at 36 months is 83% and 97% respectively. Patients with early negative PET-TC have an event-free survival of 87% compared to 62% (P=0,001) for pts with early positive PET CT. The OS at 36 months was 100% versus 86% respectively ( Conclusion: Treating patients with ABVD, evaluating response after 3 cycles with PET-CT, and adapting further therapy, leads to a high rate of CR avoiding more aggressive chemotherapy and radiotherapy. Three courses of ABVD without RT are adequate in patients with early CR defined by negative PET-CT. In early positive PET-CT it is possible to intensify therapy improving the otherwise bad prognosis; more aggressive treatment might also be suitable. These results need to be confirmed by a larger group of patients and a longer follow-up. Disclosures: No relevant conflicts of interest to declare.

Abstract 53 Prior studies have demonstrated a graft-versus-malignancy effect following allogeneic HSCT that is variably linked to acute or chronic GVHD. Although a graft vs. Myeloma (MM) effect has been shown after myeloablative allogeneic HSCT, a higher treatment related mortality (TRM) risk leads to inferior survival compared with autologous HSCT. Non-myeloablative (NMA) and reduced intensity conditioning (RIC) approaches are used to reduce the risk of TRM while preserving the graft vs. MM effect. The clinical benefit of lower intensity conditioning regimens is thus especially dependent on the impact of acute or chronic GVHD on graft vs. MM effect and TRM. We analyzed the outcomes of 177 matched sibling allogeneic HSCT recipients reported to the CIBMTR between 1997 and 2005 following NMA (n=120) or RIC (n=57) performed within 18 months of diagnosis. Median age was 50 (range 24-69) years and 62% were Durie-Salmon Stage III. Tandem autologous followed by allogeneic HSCT (autologous+ allogeneic) recipients (n=105) were more likely to receive NMA conditioning vs. recipients of an upfront allogeneic HSCT (n=72). Majority (98%) received peripheral blood stem cell grafts. Outcomes at a median follow-up of 36 (3 - 98) months are summarized in table 1. In order to assess the impact of GVHD on outcomes, Cox proportional hazards regression models were built with GVHD as the main effect treating it as a time dependent covariate (Table 2). Other covariates in the multivariate models included age, sex, performance status, IgG vs. non IgG myeloma, disease status and chemosensitivity, prior lines of chemotherapy, donor-recipient sex match, NMA vs. RIC and year of transplant. AGVHD was associated with an increased risk of TRM. Tandem autologous + allogeneic HSCT was associated with reduced relapse risk (RR= 0.49, p=0.008). AGVHD had no impact on relapse/progression of MM while cGVHD was associated with a reduced risk of relapse (Figure. 1). The protective effect of cGVHD on relapse was significant in the non IgG MM subgroup. AGVHD had no impact on PFS whereas cGVHD was associated with superior PFS and lower risk of treatment failure. Later year of HSCT was also associated with superior PFS. Overall survival was not affected by cGVHD while recipients of tandem autologous + allogeneic HSCT had a higher mortality in the presence of aGVHD (RR=3.60, p= 0.01). After matched sibling allogeneic HSCT for MM, aGVHD is associated with a higher risk of TRM whereas cGVHD decreases the risk of relapse and improves PFS. The effect of cGVHD may vary with the type of MM with greater impact in non IgG MM. Further study to identify subtypes of MM susceptible to an immune mediated graft vs. MM effect is suggested. Disclosures: Lonial: Celgene: Consultancy; Millennium: Consultancy, Research Funding; BMS: Consultancy; Novartis: Consultancy; Gloucester: Research Funding.

54 Despite its curative potential, the role of allogeneic stem cell transplant (allo-SCT) in MM has been limited by high treatment related mortality (TRM). Autologous stem cell transplant (auto-SCT) thus remains the standard of care for eligible patients (pts) with MM. Recently interest in allo-SCT has been increasing due to the incurable nature of MM, better risk stratification models, improved supportive care and finally the increasing experience with less toxic reduced intensity conditioning. We analyzed the trends in practice of allo-SCT for MM over the past two decades. A total of 1211 pts undergoing allo-SCT for MM between 1989 and 2005, reported to the CIBMTR were analyzed in three cohorts based on year of allo-SCT: 1989–1994 (n=346), 1995–2000 (n=285), and 2001–2005 (n=580). Probabilities of progression-free survival (PFS) and overall survival (OS) and cumulative incidence estimates of TRM and relapse were calculated. Patient characteristics are summarized in [table 1][1]. Patients transplanted in the later cohort (2001–2005) were of higher age with 53% above age 50 years (vs. 12% in 1989–1994). There was decreasing use of myeloablative regimens and bone marrow grafts over time (82% vs. 62% vs. 9% for myeloablative regimens and 99%, 62% and 13% for marrow grafts respectively). Increasing number of pts in the later cohort received an auto-SCT prior to allo-SCT ([Table 1][1]). The proportion of unrelated allo-SCTs increased over time (5% vs. 21% vs. 33%). Graft versus host (GVH) prophylaxis changed over time with increasing use of cyclosporine with agents other than methotrexate and increasing use of ATG in the recent years. Median survival increased over the three time periods from 1989 – 2005: 11.1 months (mos.) vs. 12.2 mos vs. 20.3 mos. The 100 day mortality decreased steadily over successive time periods; 35% (95% CI; 29–31), 29% (24–35) and 19% (16–23) respectively. Similarly, the TRM at 5 years remained steady between the first two periods, but decreased in the last period (40 & 48% vs. 29%). The incidence of chronic GVHD increased in the later cohort but the incidence of acute GVHD was similar over the years. While PFS was the lowest for the most recent group (15% at 5 years), the overall survival at 5 years was similar among the groups (30, 32, and 29 mos). Long term PFS at 10 years was 18% in the 1989–1994 cohort and 17% in 1995–2000. Long term OS at 10 years was 23% in 1989 – 1994 and 1995–2000 cohorts. Results are summarized in [table 1][1]. A clear trend towards reduced intensity conditioning, unrelated donor SCT, use of PBSC grafts and selection of older patients was noted. There was increasing use of tandem auto-allo SCT with an increasing proportion of patients with a prior auto-SCT. While the TRM has decreased significantly in the last cohort, this did not translate into an improvement in survival primarily because of increased risk of relapse in the latter cohort. Long term (>10yr) progression free survival which may approach a cure has remained unchanged over the past two decades at

532 Primary Plasma cell leukemia (PCL) is a rare plasma cell disorder characterized by an aggressive clinical course. The efficacy of autologous and allogeneic HCT in PCL is uncertain due to the small number of patients that have been reported in the literature. To determine the potential for long-term disease control using HCT in PCL, we performed a retrospective review of 160 patients with primary PCL who received autologous (n=107), allogeneic (n=52) or syngeneic (n=1) HCT and were reported to the CIBMTR between 1995 and 2006. Kaplan–Meier analysis was used for overall survival (OS) and progression free survival (PFS). Cumulative incidence estimates of non-relapse mortality (NRM), relapse, acute and chronic GVHD were calculated. Median age at the time of autologous HCT was 57 years (range, 32-74 years) and allogeneic HCT was 48 years (range, 24-62 years). Median time from initial treatment to autologous HCT was 7 months and allogeneic HCT was 6 months. At the time of transplant, in the autologous HCT group, 19% patients were in complete remission, 56% in partial remission and 1% had relapsed/progressive disease; in the allogeneic HCT group, 17% were in complete remission, 46% in partial remission and 10% had relapsed/progressive disease. In the allogeneic HCT group, 83% of the patients received myeloablative conditioning regimens and 17% received nonmyeloablative/reduced-intensity conditioning. The rate of acute GVHD was 35% (95% confidence interval [CI], 22%-49%) and the rate of chronic GVHD at 3 years was 27% (95% CI, 13%-40%). After a median follow-up of 38 months, 20 of the 52 patients (38%) are alive in the allogeneic HCT group and 68 of the 107 pts (64%) are alive in the autologous HCT group ([Figure 1][1]). Progressive disease accounted for 38% of the deaths in the allogeneic HCT group and 86% of the deaths in the autologous HCT group. The outcomes are summarized in [table 1][2]. The remarkable overall survival of patients after autologous HCT in this analysis is noteworthy and indicates that autologous HCT is a safe and acceptable treatment option for patients with primary PCL. Although relapse rates are lower, allogeneic HCT carries a much higher risk of NRM and should be considered primarily in the context of a clinical trial. | Outcomes | Allogeneic Probability (95% CI) | Autologous Probability (95% CI) | |:-----------------:| ------------------------------- | ------------------------------- | | TRM @ 1 year | 26 (15 - 39) | 2 (0 - 5) | | TRM @ 3 years | 40 (27 - 55) | 5 (1 - 10) | | Relapse @ 3 years | 40 (26 - 54) | 61 (49 - 72) | | PFS @ 3 years | 20 (10 - 33) | 34 (24 - 46) | | OS @ 3 years | 39 (25 - 53) | 62 (51 - 73) | Table 1. ![Figure 1:][3] Figure 1: Disclosures: Lonial: Celgene: Consultancy; Millennium: Consultancy, Research Funding; BMS: Consultancy; Novartis: Consultancy; Gloucester: Research Funding. [1]: #F1 [2]: #T1 [3]: pending:yes

Epigenetic therapy with a hypomethylating agent is becoming the standard of care in some intermediate and high-risk myelodysplastic syndromes (MDS). The DNA-targeted hypomethylating agent, decitabine (DACOGEN, Janssen Cilag Farmaceutica S.A. and Eisai Inc.), has been approved for patients (pts) with intermediate-1 (INT-1), intermediate-2 (INT-2), and high-risk MDS in Argentina. An alternative regimen with decitabine 20 mg/m2 IV over 1 hour once daily for 5 consecutive days repeating every 4 weeks, permits its use in the outpatient clinic. Clinical and hematological response and safety were analyzed retrospectively for pts with all FAB subtypes of MDS who had received this dosing regimen at 17 centers in our country between July 2007 and June 2008. Inclusion criteria were: ≥18 years of age; de novo or secondary MDS; and International Prognosis Scoring System (IPSS) score ≥0.5. Exclusion criteria were: diagnosis of acute myeloid leukemia (AML) or other progressive malignant disease. Patients with prior therapy were not excluded. The primary endpoint was overall response, assessed by IWG 2006 criteria. Thirty-eight pts were enrolled: median age 67 years; 71% male and 29% female. The diagnosis was de novo MDS in 34 pts (89%) and secondary MDS in 4 (11%). The median time from diagnosis to first dose of decitabine was 7 months. Eastern Cooperative Oncology Group performance status scores were 0 (21%), 1 (47%), 2 (26%) and 3 (5%). IPSS scores were INT-1 (50%), INT-2 (8%), and high-risk (42%). Cytogenetic abnormalities were found in 37% of pts. FAB classification was: RA (21%), RARS (8%), RAEB (18%), RAEB-T (24%) and CMML (29%). A median of 3.5 cycles (range, 1–8) were given. Dosage had to be reduced in 7 pts (18%) due to comorbidity and cytopenias. Overall improvement rate in the intent-to-treat population was 45% (Table), including: 9% complete response (CR), 5% marrow complete response (mCR), 5% partial response (PR) and 26% hematological improvement (HI). Two pts (5%) had stable disease. Four pts (11%) were non-evaluable for response. Most pts had their first hematological response by cycle 2 and their best response by cycle 4. The mean ± SD time to best response was 2.7±3 months. No differences in clinical and hematological response were observed between pts with INT-2/High compared to INT-1 (8/19 and 9/19, respectively); red cell and platelet transfusion requirements resolved during the first 2 cycles in 13/16 and 7/8 pts, respectively. Overall improvement rates were similar in pts with more and less than 1 year since MDS diagnosis (9/18 and 8/20, respectively). Overall survival was 71% during the observational period (up to 11 months). The most frequent adverse events were neutropenia without fever (47%) and with fever (21%), especially during cycle 2, and thrombocytopenia (23%). This study showed prompt clinical activity for an alternative 5-day dosing schedule of decitabine in the outpatient setting and an overall improvement rate of 45%, with an initial response by cycle 2, the best response by cycle 4, and acceptable tolerability. <>Table. Response to 5-Day Decitabine Dosing Schedule IWG 2006 Criteria ITT (N=38) Overall Improvement Rate (CR+mCR+PR+HI) 17 (45%) CR (Complete Response) 3 (9%) mCR (Marrow Complete Response) 2 (5%) PR (Partial Response) 2 (5%) HI (Hematological Improvement) 10 (26%) SD (Stable Disease) 2 (5%) Failure (Progressive Disease or Death) 15 (39%) Non-Evaluable 4 (11%)

Background: Obesity is increasing in prevalence worldwide and has potential implications on chemotherapy dosing and selection of patients for therapy. Auto HCT improves outcomes for patients with MM, but optimal chemotherapy dosing for obese patients is poorly defined. Methods: We identified 1087 patients reported to the CIBMTR between 1995 and 2003 who underwent auto HCT for MM as part of initial therapy, defined as within 18 months of diagnosis, and received high-dose melphalan conditioning, with or without total body irradiation (TBI). We categorized patients by body mass index (BMI) as normal (18.5– 24.9), overweight (25–29.9), obese (30–34.9), or severely obese (≥35). Underweight patients (BMI

The new international (ISS) staging system is easier to compute and a better predictor of survival after diagnosis (dx) of MM than the Durie Salmon staging system (DSS). It is not known if either system predicts treatment failure following upfront AuHCT. We compared the ISS vs DSS at dx for predicting progression free survival (PFS) after AuHCT. The outcomes of 729 recipients of AuHCT done ≤12 months of dx reported to the CIBMTR between 1995–2002 were analyzed. Treatment failure (progression or death) after AuHCT was modeled using Cox proportional hazards regression. Risk factors considered were age, gender, Karnofsky score, immunochemical subtype, number of lines of chemotherapy, chemotherapy sensitivity, disease status pre transplant, serum creatinine, time from dx to transplant and year of transplant. Cox models were then fit with DSS and ISS stages in addition to covariates identified as significant. The percentage of explained variability (R2) was calculated using Brier scores. The Brier score estimates the predictive performance of prognostic schemes for survival data. A smaller Brier score and a larger R2 indicate better predictive performance. 61% of patients were male; 62% had performance scores ≥90 and 82% had chemosensitive disease. Single (91%) or tandem (9%) AuHCT was performed at a median of seven mo after dx; 73% used melphalan-based regimens. With a median follow up of 56 mo after AuHCT, univariate probabilities of treatment related mortality (TRM), relapse, PFS and overall survival at 5 years were 7 (95% confidence interval [CI], 5–9)%, 68 (64–72)%, 25 (21–29)% and 52 (47–56)%, respectively. In multivariate analysis, significant risk factors for treatment failure were resistance to chemotherapy pre transplant, no remission pre transplant and longer delay from dx to transplant. Most patients were in DSS stage III (62%). Patients were more evenly distributed across the 3 ISS stages; only 36% were concordant between systems (Table 1). Cohen’s kappa (a measure of agreement between scores) indicated little concordance between DSS and ISS (K=0.09 [95% CI: 0.04–0.13]). Both systems suggested patients well for PFS and OS. Median PFS times for stages I, II and III by DSS and ISS systems were 58, 31, 24 mo and 33, 27 and 23 mo, respectively. Corresponding median survival times for stages I, II, III by DSS and ISS were 82, 68, 50 and 64, 68, 45 mo, respectively. Compared to the ISS, DSS demonstrated a lower BS and higher R2 (Table 2) consistent with a marginally superior predictive ability for 1, 3 and 5 year PFS (Figure). However, neither system is strongly predictive of outcome after AuHCT since the R2 (measure of explained variability) is low ( Table 1 ISS, N(%) DS, N(%) I II III I 26 (4) 20 (3) 4 (1) II 92 (13) 104 (14) 34 (5) III 134 (18) 183 (25) 132 (18) Table 2 BS R2,% Time DSS ISS DSS ISS 1 year 0.1855 0.1860 4.1 3.9 3 years 0.2323 0.2343 4.2 3.4 5 years 0.1818 0.1846 2.7 1.2 Figure Figure

BACKGROUND: Non-secretory myeloma (NSM), where immunofixation fails to detect a monoclonal protein in serum and/or urine, accounts for METHODS: We compared the probabilities of treatment-related mortality (TRM), disease progression, progression-free survival (PFS) and overall survival (OS) after AuHCT for patients with NSM versus SM transplant between 1989 and 2003, reported to the CIBMTR. Immunofixation reports were reviewed to confirm the diagnosis of NSM. 110 patients with NSM were matched to 438 patients with SM using a propensity score (PS) approach. PS were calculated using age at transplant, Durie-Salmon stage at diagnosis, sensitivity to pretransplant therapy, time from diagnosis to transplant and year of transplant. A logistic regression model was fit and a numerical score derived for each case (NSM recipients). Controls (SM) were matched in random order to cases with similar PS. Multivariate Cox proportional hazards regression models were stratified on matched pairs. Recipients who had a planned second transplant (whether they received their 2nd transplant or not) were excluded. RESULTS: The two groups were similar with respect to disease characteristics at diagnosis (bone marrow plasmacytosis, ISS, renal function) and at transplant (performance status,β2-microglobulin, prior therapy and presence of bone disease). Patients with SM were more anemic and had lower serum albumin levels at diagnosis, while those with NSM were more likely to have preceding plasmacytoma and radiation therapy, presumably to the plasmacytoma. 5-year outcomes, with a median follow-up of 66 months (range, 1 – 177) were as follows: Outcome, Probability (95% CI) NSM SM P-value TRM, % 8 (3 – 14) 7 (5 – 10) 0.86 Disease progression, % 65 (55 – 75) 72 (67 – 76) 0.21 PFS, % 27 (18 – 37) 20 (16 – 25) 0.20 OS, % 51 (40 – 67) 43 (38 – 48) 0.22 In multivariate analysis, based on a Cox model stratified on matched pairs and adjusted for covariates not considered in the propensity score, we found no difference in outcome between the NSM and SM groups. The causes of death were similar between the two groups with disease progression accounting for 75% of deaths. CONCLUSION: In this large cohort of patients undergoing AuHCT, we found no difference in the outcome of patients with NSM compared to those with SM. With increasing use of the free light chain assay, the majority of patients with NSM are expected to have detectable light chain abnormalities thus making them oligosecretory rather than truly non-secretory. This group of patients is generally underrepresented in prospective clinical trials of MM. This study establishes that the post transplant outcomes of this subset of patients are not different and suggests that they should not be excluded from clinical trials.

Background: Central nervous system (CNS) relapse can complicate the course of patients with acute promyelocytic leukemia (APL) treated with all-trans retinoic acid (ATRA) and chemotherapy, especially of those with high WBC at diagnosis (≥10 × 109/L). While ATRA and anthracyclines do not crosses the cerebrospinal fluid barrier, some trials for APL includes the use of intratechal prophylaxis or high-dose cytarabine, at least in high-risk patients, to avoid the CNS relapses. However, the convenience of CNS prophylaxis in APL patients is a matter of controversy. Objectives: Analyze the incidence and characteristics of CNS involvement at first relapse, in patients with newly diagnosed APL treated with ATRA and reinforced anthracycline monochemotherapy, without CNS prophylaxis. Methods: From 1999 to 2005, 564 patients (median age 40 years, range 2-83) were included in the PETHEMA LPA99 trial. Induction therapy consisted of ATRA and idarubicin. Patients in CR received 3 monthly courses of risk-adapted consolidation therapy as follows: “low-risk” patients (WBC 40×109/l), idarubicin 5 mg/m2/d × 4 (course #1), mitoxantrone 10 mg/m2/d × 5 (course #2), and idarubicin 12 mg/m2/d × 1 (course #3); “intermediate-risk “ (WBC 10×109/l) patients received ATRA (45 mg/m2/d × 15) in combination with reinforced chemotherapy (Idarubicin 7 mg/m2/d in the course #1 and two days instead of one in the course #3). Maintenance therapy consisted of low-dose oral chemotherapy (mercaptopurine and methotrexate with ATRA). We measured the cumulative incidence (CI) of CNS involvement at first relapse during the course of APL patients who achieved the CR. Results: CR was achieved in 511 patients (91%). The median follow-up of the cohort was 57 months (range 20–94 months). Overall, 52 patients relapsed, of whom 5 presented a first relapse in CNS. In all cases, CNS relapses occurred without bone marrow or other extramedullary involvement. CNS relapses occurred after a median of 14 months (range 10–41 months) from the achievement of CR. At the initial diagnosis, APL were classified, according to the Sanz score, as low-, intermediate- and high-risk, in 0, 2, and 3 patients, respectively. The median WBC at diagnosis was 34.5 × 109/L (range 1.9–68.8 × 109/L), and 4 patients showed a Bcr3 PML-RARalpha isoform. Using a competitive-risk method, the overall 5 year CI of CNS relapse was 1.03%. The 5 year CI of CNS relapse in low-, intermediate- and high-risk patients was 0%, 0.77% and 2.71%, respectively (low- vs high-risk and intermediate vs high-risk; p=0.12 and p=0.11, respectively). The 5 year CI of CNS relapse in patients with Bcr3 and Bcr1 PML-RARalpha isoform was 0.45% and 2.44%, respectively (p=0.12). Conclusion: Despite the lack of intratechal prophylaxis or high-dose cytarabine in the therapeutic schedule of the LPA99 trial, the overall 5 year CI of CNS relapse was very low (1%). Our results does not hold up the systematic use of CNS prophylaxis in APL patients treated with ATRA and reinforced anthracycline monochemotherapy.

Background. In our experience, in Argentina, the use of rituximab + chemotherapy in relapsed/refractory CD20+ follicular (FL) non-Hodgkin’s lymphoma results in Methods. Between September 2005 and November 2005, we recruited 10 patients (pts; 6 male/4 female; median age = 56 yr [range: 45–71 yr]) with platelets >100,000/mm3 and bone marrow involvement 5 cm). Three pts were Ann Arbor stage I or II and 7 pts were stage IV. Three pts had received 1–2 cycles of rituximab + chemotherapy and 7 pts had received 3–5 previous cycles. Three pts had undergone autologous transplant. Pts received rituximab 250 mg/m2 IV on days 0 and 7. After the second dose of rituximab, pts received 11 MBq (0.3 mCi) 90Y-Zevalin per kg or 15 MBq (0.4 mCi) 90Y-Zevalin per kg based on platelet counts, with a maximum dose of 32 mCi. Blood counts were monitored weekly until week 10 post-treatment and monthly thereafter. Patient tumor response was reevaluated 3 and 6 months after treatment according to standard criteria. Results. Five pts received a complete dose of 0.4 mCi 90Y-Zevalin per kg and 5 received a reduced dose of 0.3 mCi 90Y-Zevalin per kg. The overall response rate was 60% (CR = 5, PR = 1). Table 1 summarizes the responses. The 5 pts with a CR remained disease-free 8 months later. The pt with a PR progressed with adenopathies and visceromegaly 7 months after treatment. Seven of 10 pts experienced hematologic toxicity: 5 of these 7 pts required G-CSF because of grade 3/4 neutropenia and 3 of these pts developed neutropenic fever. Four of the 7 pts required platelet transfusions and 2 of them required red blood cell transfusions. All 3 pts with previous autologous transplant were in the group with hematologic toxicity. All of these pts required G-CSF and transfusion support, and 2 of these 3 pts were admitted to the clinic for this treatment; hematologic recovery occurred by week 9 post-treatment. Conclusion. The use of 90Y-Zevalin in the relapsed/refractory NHL setting resulted in better response rates and longer disease-free survival than with standard chemoimmunotherapy. Our finding with 50% CR in a heavily pretreated cohort, including 42.8% CR in stage IV pts and 33% CR after autologous transplantation, is encouraging. We are continuing to follow these patients. Table CR PR NR/PD Previous transplant (n=3) 1 1 1 Mantle cell (n=1) 0 0 1 Follicular (n=9) 5 1 3 Tumor volume > 5cm (n=4) 1 0 3 Tumor volume

Background: fludarabine (F) is licensed for the management of indolent non-Hodgkin lymphoma in countries such as Canada and Switzerland. Clinical evidence suggests that fludarabine monotherapy is as least as effective, than conventional therapies such as cyclophosphamide, vincristine, prednisone (CVP) for the first and second line treatment of B-cell low grade NHL achieving objective response rates. Better response rates can be achieved combining F with Mitoxantrone (N) and Dexamethasone (D) in indolent NHL patients (pts). The GATLA (Grupo Argentino de Tratamiento de la Leucemia Aguda) started a prospective multicenter national study to evaluate the use FND as a first line treatment for low grade NHL. Aims: to assess the response rate, safety, disease free survival (DFS) and overall survival (OS) of FND as first line treatment for indolent NHL during (2002–2006). Methods: Ninety-six patients in the period of January 2002 to April 2006 were recruited. Sixty-nine patients were valuable at the time of analysis. Median age 54 years old (range: 21–79). Gender: male 51% and female 49%. Inclusion criteria for low grade NHL-LG was: non-previous, age > 18 years old with symptomatic disease, ECOG performance status 0–2 and written informed consent. Ann Arbor staging: 5,8%, 14,5%, 24,6% and 55%. FND treatment consisted of F 25 mg/m2 i.v. (days 1–3), N 10 mg/m m2 i.v. (day 1) and D 20 mg (days 1–5) each 28 days for 6 cycles. All patients received oral antibiotics for intestinal decontamination, antifungal prophylaxis and Trimethoprim-Sulfamethoxazole as P. carinii prophylaxis for one year. Results: on this low grade NHL cohort the overall response rate (ORR) was 93% (ORR) with 70% (48 pts) with complete response (CR) and 23% (16 pts) with partial response; progressive disease and non-response 7% (5 pts). The probability of event free survival (EFS) and overall survival (OS) at 24 months was 60% and 90% respectively. Two patients developed secondary malignancies after treatment and one died. Only one patient died in CR. Conclusions: in this population FND treatment demonstrate a high CR rate with low toxicity and high probability of EFS and OS as previous experience published in the literature.

Introduction: The prognostic significance of the expression pattern of certain cell surface markers in APL is controversial. Objectives: Analyse the impact of the expression of certain cell surface markers on complete remission rate (CR), overall survival (OS) and relapse free survival (RFS) in patients with APL included in multicenter trials PETHEMA LPA96 y LPA99. Material and methods: Between 1996 and 2005, 734 patients were included in these 2 consecutive trials. Induction therapy consisted of ATRA and idarubicin, followed by three consolidation courses of anthracycline monochemotherapy with or without ATRA and followed by maintenance. Bone marrow immunophenotype analysis was performed at local or reference laboratories. Positivity was defined as more than 20% blasts expressing a specific antigen for the following antigens: CD34 (527 patients), CD33 (521), CD15 (520), CD13 (513), HLA-DR (495), CD2 (443), CD19 (433), CD7 (403), CD117 (395), CD56 (392), y CD11b (335). We performed univariate analysis to establish the impact of antigen positivity on CR rate, OS and RFS. Significant values were included in the multivariate analysis. Results: A total of 664 patients (90%) achieved CR. The following variables were associated with decreased CR rate: WBC > 10x109/L, serum level creatinine > 1.4 mg/dl, age > 60 years, ECOG > 1, M3v and male gender. None of the cell surface antigens were significantly associated with CR rate. WBC, creatinine, age and gender were found to be independent prognostic factors for CR. Median follow up was 55 months. OS at 8 years was inferior in those patients with WBC > 10x109/L (67% vs 85%, p < 0.01), M3v (70% vs 83%, p < 0.01), age > 60 (56% vs 86%, p < 0.01), male gender (78% vs 83%, p=0.03), LPA96 trial (74% vs 84%, p=0.01) and CD2+ (76% vs 84%, p=0.04). Age, WBC and gender were independent factors for OS. RFS was inferior in those patients with WBC > 10x109/L (69% vs 93%, p < 0.01), high vs intermediate vs low risk (69% vs 91% vs 95%, p < 0.01), M3v (76% vs 88%, p < 0.01), BCR2 vs BCR3 vs BCR1 transcript (71% vs 81% vs 89%, p < 0.01), male gender (83% vs 90%, p=0.03), LPA96 trial (82% vs 87%, p=0.02) and CD2+ (75% vs 91%, p < 0.01). The risk of relapse category was the only independent factor for RFS. CD2+ APL (115/443 patients) was significantly associated with WBC > 10x109/L, M3v, BCR3, CD34+, CD56+, CD7+, and HLA-DR negative. Conclusion: Of all the cell surface antigens analysed, only expression of CD2 was associated with an lower OS and RFS, due to its association with WBC > 10x109/L. In patients taking part in PETHEMA trials, immunophenotype analysis at presentation does not give additional prognostic impact from the previously established risk factors.

6600 Background: Alemtuzumab is the only immunotherapy that is effective as a single agent in patients with B-CLL who are refractory to, or who have relapsed after, fludarabine therapy. The optimized schedule for alemtuzumab that achieves maximal efficacy with manageable toxicity is still being explored. We report the first interim analysis of a new, less intensive schedule of alemtuzumab SC to patients with refractory/relapsed B-CLL. Methods: Alemtuzumab was dose escalated from 10 to 20 mg during the first week, 30 mg bid during the second and third weeks, and 30 mg once weekly during weeks 4, 6, 8, 10, 12, 16, 20, 24, 28, 34, and 40. Antiviral prophylaxis included TMP/SMX bid 3 times a week and acyclovir 200 mg tid. Results: Patients (N = 36) with refractory (19%) or relapsed (81%) B-CLL had a median age of 67 years (range, 43–86 years), 28 were male, 61%/39% had Binet stage B/C disease, and 2 had B-cell prolymphocytic transformation. The median number of prior therapies was 1 (range, 1–4). The median duration of treatment was 7 weeks (range, 2–24 weeks), with a median cumulative alemtuzumab dose of 412 mg (range, 150–1,080 mg). Thirty-two patients were evaluable for response. The overall response rate of 93%: complete response (CR), 34%; unconfirmed CR, 6%; partial response (PR), 53%. Two patients (7%) did not respond to therapy. Of the 7 refractory patients, 5 had a PR, 1 did not respond, and 1 was not yet evaluable. Median overall survival was 10 months, which correlated with response and pretreatment status. Minimal residual disease (MRD) was measured by flow cytometry in 5 patients who achieved a CR: 3 patients had No significant financial relationships to disclose.

PURPOSE: Preparative regimens involving total-body irradiation (TBI) produce significant late toxicities in some children who receive bone marrow transplants, including impaired growth and intellectual development. Busulfan is often used as an alternative to TBI, but there are few data regarding its relative efficacy. PATIENTS AND METHODS: We compared outcomes of HLA-identical sibling transplants for acute lymphoblastic leukemia (ALL) in children (< 20 years of age) who received cyclophosphamide plus TBI (CY/TBI) (n = 451) versus those who received busulfan plus cyclophosphamide (Bu/CY) (n = 176) for pretransplant conditioning. Patients received transplants between 1988 and 1995 and their results were reported to the International Bone Marrow Transplant Registry by 144 participating institutions. The CY/TBI and Bu/CY groups did not differ in gender, immune phenotype, leukocyte count at the time of diagnosis, chromosome abnormalities, remission status, or length of initial remission. T-cell depletion was used more frequently in the CY/TBI group; the Bu/CY group included a higher proportion of children who were less than 5 years of age. The median follow-up period was 37 months. RESULTS: The 3-year probabilities of survival were 55% (95% confidence interval [CI], 50% to 60%) with TBI/CY and 40% (95% CI, 32% to 48%) with Bu/CY (univariate P = .003). The 3-year probabilities of leukemia-free survival were 50% (95% CI, 45% to 55%) and 35% (95% CI, 28% to 43%), respectively (univariate P = .005). In a multivariate analysis, the risks of relapse were similar in the two groups (relative risk [RR], 1.30 for Bu/CY v CY/TBI; P = .1). Treatment-related mortality was higher in the Bu/CY group (RR, 1.68; P = .012). Death and treatment failure (relapse or death, inverse of leukemia-free survival) were more frequent in the Bu/CY group (RR, 1.39; P = .017 for death; RR, 1.42; P = .006 for treatment failure). CONCLUSION: These data indicate superior survival with CY/TBI conditioning, compared with Bu/CY conditioning, for HLA-identical sibling bone marrow transplants in children with ALL.