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Las alteraciones citogenéticas (AC) constituyen uno de los factores pronósticos más importantes en los pacientes con mieloma múltiple (MM) permitiendo dividirlos en dos grupos de riesgo (estándar y alto) con diferente pronóstico y enfoque terapéutico. Actualmente las AC que tienen mayor relevancia para la estratificación de los pacientes con MM son: el índice de ploidía, los rearreglos del gen IGH, la inactivación del gen TP53 y las alteraciones del cromosoma 1 (deleción de 1p y/o ganancias de 1q). La técnica de elección para la detección de AC en el MM, tanto al momento del diagnóstico como en las evaluaciones posteriores, es la hibridación fluorescente in situ (FISH) realizada sobre una muestra con muy alta pureza de células plasmáticas (CP). La obtención de CP purificadas puede ser realizada por distintos métodos, de los cuales el que demostró mayor eficiencia es la citometría de flujo multiparamétrica (CFM) o cell sorting. El presente estudio muestra los resultados obtenidos al evaluar la presencia de AC en una cohorte de pacientes con MM de la vida real, comparando dos grupos: grupo S, en los que los estudios por FISH se realizaron sobre la población de células plasmáticas purificadas, y grupo NS en los que se realizaron sobre la muestra entera. Los resultados obtenidos son comparables a los publicados en otras series, y demuestran que la utilización del sorting previo a los estudios por FISH aumenta significativamente la sensibilidad de detección de AC en pacientes con MM, permitiendo una correcta estadificación y evaluación pronóstica, y optimizando las estrategias terapéuticas.

We compared the efficacy of lenalidomide-dexamethasone (Rd) based treatments for relapsed/refractory multiple myeloma patients (pts), in a real-world setting. In addition, we evaluated adverse even...

We compared the efficacy of lenalidomide-dexamethasone (Rd) based treatments for relapsed/refractory multiple myeloma patients (pts), in a real-world setting. In addition, we evaluated adverse events (AE), progression-free survival (PFS) and overall survival (OS).In our retrospective, multicentric study, 156 pts with RRMM were included. 74/156 pts (47%) were refractory to bortezomib (V) and 43/156 (27%) pts to lenalidomide (R), with 24/156 (15%) of pts double refractory. Eighty-six pts (55%) received Rd with carfilzomib (KRd), 30 pts (19%) bortezomib (VRd), 30 pts (19%) daratumumab (DRd), and 10 pts (6%) ixazomib (IRd).The overall response (ORR) (≥ partial response) for the entire cohort was 71%, with a very good partial response rate or better (≥VGPR) of 35%. We found no significant differences in CR or ≥VGRP rates between treatments (p:0.229). Regardless of the combination received, those patients who achieved CR had significantly improved PFS (p: 0.007). The most frequent cause of treatment discontinuation was disease progression in 55/156 pts (35%). 8 pts (5%) discontinued treatment due to treatment-related adverse events (AE).This is the first report of Rd combinations for the treatment of RRMM in Latin America. All combinations proved to be effective with an acceptable toxicity.

We retrospectively analyzed 570 adult patients who received allogeneic stem cell transplantation for malignant diseases. The outcomes were compared according to donor type. Most of the patients (60%) were transplanted for acute leukemia. Median follow-up was 1.6 years. Haploidentical allogeneic stem cell transplantation was more frequently performed for acute myeloid leukemia and in late stages than any other donor type. Non-relapse mortality at 100 days and one year for unrelated and haploidentical donors were similar, 19%-29% vs. 17%-28%, respectively. A significant better non-relapse mortality was observed for matched sibling donors (7%-15%; p0.001). Relapse rate was higher in haploidentical donors compared to matched sibling and unrelated donors (three year relapse rate 46%, 39%, 28%; respectively p0.001). Haploidentical donors resulted in lower three year progression-free survival and worse 3 year overall survival (32%; p0.001 and 42%; p0.001) compared with other donors (44% and 55% MSD, 40% and 42% UD, respectively). The incidence of grade II-IV acute graft-versus-host disease was higher in unrelated donors (51% unrelated, 35% haploidentical, 36% matched sibling; respectively; p = 0.001), with no difference in grades III-IV (p = 0.73) or in chronic graft-versus-host disease (p = 0.2) between groups. After multivariate analysis, haploidentical and unrelated donors remained negatively associated with non-relapse mortality (HR 1.95; 95% CI 1.10-3.20 and HR 2.70; 95% CI 1.63-4.46, respectively). Haploidentical donors were associated with a higher risk of relapse and worse overall survival. This analysis shows that haploidentical donors were associated with similar non-relpase mortality and higher relapse rates than unrelated donors. Better results in non-relapse mortality were observed for matched sibling donors.Se efectuó un análisis retrospectivo de 570 pacientes adultos que recibieron un trasplante alogénico de precursores hematopoyéticos, comparando los resultados según el tipo de donante. La mediana de seguimiento fue de 1.6 años. El 60% de la población se trasplantó por leucemias agudas. Los trasplantes haploidénticos se hicieron en su mayoría en leucemia mieloide aguda y en estadios tardíos en comparación a otros donantes. La mortalidad libre de enfermedad al día +100 y a 1 año fue similar para los donantes no emparentados y haploidénticos (19% y 29% vs. 17% y 28%, respectivamente). Se obtuvieron mejores resultados con donantes relacionados idénticos (7% y 15%; p0.001). La recaída fue mayor en los donantes haploidénticos (tres años 46% haploidénticos, 39% relacionados idénticos, 28% no emparentados; p0.003). El trasplante con donante haploidéntico presentó una menor supervivencia libre de progresión y menor supervivencia global a tres años (32%; p0.001 y 42%; p0.001). La incidencia de enfermedad injerto contra huésped aguda fue mayor en no emparentados (51%, 35% haploidénticos, 36% relacionados idénticos; p = 0.001), sin diferencias en grados III-IV (p = 0.73) o en EICH crónica (p = 0.2). Los trasplantes con donante haploidéntico y no emparentado mantuvieron su asociación negativa con mortalidad libre de enfermedad (HR 1.95; 95%IC 1.10-3.20 y HR 2.70; 95%IC 1.63-4.46), en análisis multivariado. El trasplante haploidéntico se asoció a mayor recaída y a menor supervivencia global. Esta experiencia mostró similar mortalidad libre de enfermedad entre trasplantes con donantes haploidénticos y no emparentados. Los trasplantes relacionados idénticos mostraron menores tasas de mortalidad libre de enfermedad.

Background: ALL in adults is considered a heterogeneous disease with poor prognosis. However, adolescents and young adults (AYA) display intermediate characteristics as compared with children. Risk groups and response predictors are essential to guide the treatment. Aims: The aim of this report was to evaluate the experience of Ph-negative ALL in AYA patients (pts) treated with the pediatric Argentine type-BFM protocol, assessing predictors of response in terms of overall survival (OS) and event-free survival (EFS). Methods: We performed a retrospective multicenter analysis of AYA pts diagnosed between 2013 to 2021, from 16 Argentine institutions who were treated following the pediatric Argentine type-BFM protocol. Response to prednisone (PR) at day(d) 8 ( Results: One hundred and seventy-three patients similarly distributed among private and public institutions were analyzed. The median (Md) age was 22 years (15-40) with a male predominance (66%). At diagnosis, 23% presented central nervous system (CNS) involvement, 79.5% B and 20.5% T immunophenotype, 29% CD20 positive, 16% adverse cytogenetic/molecular findings and 29% no data. Ph-like screening was not routinely performed assessed only in 13% revealing two CRLF2 and one PDGFRB rearrangements. Twenty-one (12%) of pts underwent allogeneic bone marrow transplantation (Allo-HSCT) at 1 st line, 20 with MRD negative and 1 MRD positive at the time of the procedure.Of 171 pts, 155 (91%) achieved MCR, 12 (7%) were refractory, 3 (2%) died prior/during induction and 1 (0.6%) patient dropped out of treatment; 144 (84%) achieved negative MRD, 22 (13%) positive MRD and 5 (3%) were not evaluated. The Md to reach CR and MRD (-) was 33d (IQR 31-42) and 35d (IQR 32-73), respectively. With a Md follow-up of 16 months (1-79), 52 pts (30%) relapsed and 68 pts (39%) died. Early deaths at 3 months occurred in 8 (5%) pts, 5 related to treatment and 3 to disease. The Md OS and EFS were 58 and 34 months, respectively. Prognostic predictors analyzed were sex, white blood counts (WBC) at diagnosis (limit of 30 x10 -9/L), age (limit of 30 years), CNS involvement, cytogenetic/molecular findings, PR at d8, MRD in bone marrow (BM) at d15, 33 and 78. In the univariate analysis, response at d8, MRD at d15, 33 and 78 were useful to predict both OS and EFS, adding age and WBC in terms of OS. Similar results were obtained when patients who underwent Allo-HSCT were censored at the time of the procedure. (Table). In the multivariate analysis, positive MRD at d33 and d78 (and WBC in OS) maintained their independent adverse prognostic impact in relation to OS and EFS. Allo-HSCT showed benefits in pts with MRD >0.1% at d33 and >0.01% at d78 in terms of OS (d33: NR vs. 11 m, p =0.048, HR 0.3, 95%CI [0.1-0.9]; d78: NR vs. 8 m, p =0.009, HR 0.4, 95%CI [0.2-0.8]) and EFS (d33: NR vs. 6 m, p =0.022, HR 0.2, 95%CI [0.1-0.8]; d78: NR vs. 5 m, p =0.003, 0.1 HR, 95%CI [0.02-0.5]). The adverse risk of positive MRD at day 33 and 78 in terms of OS and EFS was overcome when pts were transplanted. Summary/Conclusion: The results show that positive MRD at d33 and 78 independently impacted on OS and EFS in our series and that Allo-HSCT overcame their adverse risk. Our data confirms the relevance of using pediatric protocols in AYA. On the other hand, the importance of prognostic tools in order to improve the outcome of AYA patients, reinforcing their inclusion in current guidelines. Figure 1 Figure 1. Disclosures No relevant conflicts of interest to declare.

Background: Angioimmunoblastic T-cell lymphoma (AITL) is a rare and unique subtype of peripheral T-cell lymphoma (PTCL) with distinct clinicopathologic features. Clinical presentation is varied with an aggressive course and dismal outcomes. Curative treatment modalities in AITLs are still an unmet need. Aims: In this study, we aimed to advance our understanding of clinical characteristics, prognostic factors, treatment strategies in patients with AITL in the international prospective T-Cell Project (TCP). Patients and methods: We did a sub-analysis of 282 patients with AITL out of 1,553 cases enrolled between 2006 and 2018 in the TCP, a global prospective registry of patients with PTCL involving 74 institutions in 13 countries in Europe, North/South America, and Asia. Eligible patients were >18 years old with baseline clinical data necessary for disease staging, treatment type, and follow-up for at least 5 years. The primary and secondary endpoints were 5-year OS and PFS. Additionally, we analyzed prognostic factors and POD24. The TCP is registered on ClinicalTrials.gov , NCT01142674 . Results: The median age at diagnosis was 64 years (range 22–88) and 63% of patients were >60 years old. The advanced stage had 90% of patients and 60% were males. According to the IPI, PIT, and PIAI, the majority of cases were in the high-risk groups. Anthracyclinecontaining chemotherapy was received by 81% of patients, and 27 (12.5%) underwent HDT/ASCT as consolidation. Five-year OS and PFS were 44% and 32%, respectively. CR was achieved in 106 patients. ASCT was associated with superior OS (89% vs 52%, p = 0.05) and PFS (79% vs 31, p = 0.02). In multivariate analysis, older age (p=0.003), ECOG PS >2 (p=0.0001), CRP>ULN (p=0.003) and Beta2 microglobulin >ULN (p=0.002) showed an independent prognostic value on PFS. Finally, POD24 was a powerful predictor of outcome: the 5-year PFS for patients with or without POD24 was 2% and 48%, respectively (p=0.0001). Conclusions: Our data confirmed the poor outcome of AITL, mostly in patients exhibiting POD24, and the promising efficacy of ASCT in CR1. Moreover, the collected data gave a better understanding of the need for more effective therapies and the importance to continue prospective studies in a real-world population.

Dasatinib was approved at 100 mg once daily for imatinib-resistant or -intolerant patients with chronic myeloid leukemia (CML) in chronic phase, based on results of the phase 3 CA180-034 (NCT00123474) study. Here we present the final 7-year analysis of this pivotal study, the longest follow-up to date of any second-generation BCR-ABL1 tyrosine kinase inhibitor (TKI). Patients (n = 670) with imatinib-resistant or -intolerant CML in chronic phase received dasatinib. Nineteen percent of patients continued on study treatment, with a greater proportion in the 100 mg once daily arm remaining on therapy. Seven-year rates for major molecular response (MMR), progression-free survival (PFS), and overall survival (OS) were similar across doses; MMR, PFS, and OS results were 46, 42, and 65% at 100 mg once daily, respectively. Improved PFS and OS rates were reported in patients who achieved BCR-ABL1 ≤10% at 3 and 6 months. No new safety signals were identified. The incidence of drug-related pleural effusion was 28% at 100 mg once daily and 35% at the other three dose groups. Incidence of drug-related pulmonary hypertension and pulmonary arterial hypertension remained low (≤3% across all doses). Arterial ischemic events occurred in ≤4% of patients across all doses. These data support the long-term efficacy and well-established safety profile of dasatinib for patients with imatinib-resistant or -intolerant CML in chronic phase. Am. J. Hematol. 91:869-874, 2016. © 2016 Wiley Periodicals, Inc.

Dasatinib is a highly potent BCR-ABL inhibitor with established efficacy and safety in imatinib-resistant/-intolerant patients with chronic myeloid leukemia (CML). In the phase 3 DASISION trial, patients with newly diagnosed chronic-phase (CP) CML were randomized to receive dasatinib 100 mg (n = 259) or imatinib 400 mg (n = 260) once daily. Primary data showed superior efficacy for dasatinib compared with imatinib after 12 months, including significantly higher rates of complete cytogenetic response (CCyR), confirmed CCyR (primary end point), and major molecular response (MMR). Here, 24-month data are presented. Cumulative response rates by 24 months in dasatinib and imatinib arms were: CCyR in 86% versus 82%, MMR in 64% versus 46%, and BCR-ABL reduction to ≤ 0.0032% (4.5-log reduction) in 17% versus 8%. Transformation to accelerated-/ blast-phase CML on study occurred in 2.3% with dasatinib versus 5.0% with imatinib. BCR-ABL mutations, assessed after discontinuation, were detected in 10 patients in each arm. In safety analyses, fluid retention, superficial edema, myalgia, vomiting, and rash were less frequent with dasatinib compared with imatinib, whereas pleural effusion and grade 3/4 thrombocytopenia were more frequent with dasatinib. Overall, dasatinib continues to show faster and deeper responses compared with imatinib, supporting first-line use of dasatinib in patients with newly diagnosed CML-CP. This study was registered at ClinicalTrials.gov: NCT00481247.

In imatinib-treated patients with chronic myeloid leukemia (CML), BCR-ABL mutations are the most common mechanism of resistance. Here we report the first multicenter Argentinean study investigating mutations in those patients with CML who fail or lose response to imatinib, with or without previous interferon treatment. Point mutations were detected in 36 of 154 patients by direct sequencing. In our series, the single most common mutations were G250E, E255K/V, and M351T. The presence of mutations correlated significantly with accelerated phase, lack of molecular response, and lower cytogenetic and hematological responses. While overall survival did not differ between patients with or without mutations, the probability of progression was higher in patients with mutations. Cases with non-P-loop mutations showed a significantly better overall survival from diagnosis. Multivariate analysis showed that the most significant variables related to the development of mutations were accelerated phase, duration of imatinib treatment, and time delay to starting imatinib. Our results demonstrated that mutation frequency increased with the progression of disease, and suggest that imatinib treatment should be started early.

The presence of the Philadelphia chromosome is a poor prognosis factor in acute lymphoblastic leukemia (ALL), in both children and adults. Using molecular techniques of the gen bcr/abl, it is possible to detect the abnormality, in up to the 40% of adult patients. The unsatisfactory results with conventional chemotherapy schemes have determined the intensification of the treatments and the consideration of allogenic bone marrow transplants as the best therapeutic instance. The development of tyrosine kinase inhibitors have become a therapeutic improvement in the treatment of Philadelphia chromosome-positive ALL, being combined with chemotherapy schemes, only in a selected group of patients, even in therapeutic programs that include transplant.

Allogeneic hematopoietic stem cell transplantation (AHSCT) is a curative approach for patients with myelodysplastic syndrome (MDS).In this multicenter retrospective study, we analyzed the outcome of adult patients with MDS who underwent AHSCT in Argentina and evaluated the prognostic factors associated with progression-free survival (PFS), overall survival (OS), cumulative incidence (CI) of relapse, and non-relapse mortality (NRM).We analyzed data from 87 adults (median age: 43 years, range 18-66) who underwent SCT after myeloablative (n = 60) or non-myeloablative conditioning (n = 27), and from related (n = 62) or unrelated (n = 25) donors. For all patients, unadjusted 4-year PFS and OS were 37% and 38%, respectively; no significant differences were found between recipients of related or unrelated donors. One-year CI of relapse and NRM were 21% and 20%, respectively. In the multivariate analysis, intermediate disease risk index (DRI) and acute graft versus host disease AGVHD of all grades (I-IV) were independent variables associated with better PFS and lower relapse CI; only intermediate DRI was associated with better OS.AHSCT is a feasible procedure in Argentina, with more than 30% of the patients achieving long-term survival. Recipients with unrelated donors had at least similar outcome than those with related donors. DRI may be useful to identify patients at higher risk of relapse after transplantation.

As a group of more than 100 experts in chronic myeloid leukemia (CML), we draw attention to the high prices of cancer drugs, with the particular focus on the prices of approved tyrosine kinase inhibitors for the treatment of CML. This editorial addresses the multiple factors involved in cancer drug pricing and their impact on individual patients and health care policies, and argues for the need to (1) lower the prices of cancer drugs to allow more patients to afford them and (2) maintain sound long-term health care policies.

In the last years much progress has been made in understanding the biology of acute lymphoblastic leukemia which is now recognized as an expanding group of heterogene‐ ous entities. Recognition of distinct gene expression patterns may identify patient sub‐ group with unique response to therapy and prognosis. Accurate definition of prognostic subgroups based on cytogenetic molecular marker has allowed institution of risk orient‐ ed therapies. [2] The Philadelphia (Ph1+) chromosome was first described in 1960 in a patient with chronic myeloid leukemia (CML). This is the product of the fusion of chromosomes 9 and 22, t (9;22), which results in a BCR-ABL hybrid gene. [2]

Ph+ ALL represents approximately about 25 to 40% of adults patients with ALL. In children, Ph+ ALL is much less common. Different breakpoint in the bcr gene, major and minor, produce fusion genes resulting in either a 210 or a 190 KDa protein respectively. It appears that major breakpoint fusion (p210) originates in hematopoietic stem cells whereas minor breakpoint fusion (p190) has a B cell progenitor origin, suggesting that p190 ALL and p210 Ph+ ALL may be distinct biological and clinical entities. [1] BMT is the first option for consolidation the complete remission in this patients. The proportion of patients able to undergo BMT in CR1 (Complete Remission) has increased with imatinib-based induc‐ tion and early post-remission therapy, and there is currently no evidence that imatinib has an adverse effect on transplant-related morbidity or mortality (TMR). In addition, donor availability has benefitted from results showing equivalence of sibling and matched unrelated donors in terms of remission duration, non-relapse mortality and overall survival (OS).[1, 2] Several studies have shown improved post-transplant outcome of patients previously receiving imatinib-based treatment when compared with historic control groups, which have been dealt with in the previous chapter. As a consequence, most ALL study groups currently consider imatinib-based treatment, followed by matched related or unrelated allogeneic SCT (allo-SCT) in CR1, to be the gold standard of first-line therapy for Ph+ ALL. [3], Imatinib-based treatment not followed by SCT has been suggested to achieve OS and Disease Free Survival (DFS) similar to that obtained after SCT in one study, [4] and the results of MDACC study showed only a trend towards better OS in transplant‐ ed patients. [5] It still needs to be determined whether therapy based on second genera‐ tion TKI may be equivalent or superior to BMT in a subset of patients, particularly those at high risk of TRM

Monitoring minimal residual disease (MRD) by real-time quantitative polymerase chain reaction (RT-PCR) in chronic myeloid leukemia (CML) patients is mandatory in the era of tyrosine kinase inhibitors. Achieving a major molecular response (MMR) at 12 and 18 months predicts a better progression and event-free survival.The objective of this prospective, multicentric study was to evaluate MRD by standardized RT-PCR in 178 patients with chronic-phase CML who were treated with imatinib at different institutions in Argentina and Uruguay and to determine if achievement of a stable MMR (BCR-ABL transcript levels0.1%) identifies a low-risk cytogenetic relapse group. The median age of the patients was 50 years, and 55% of them had received imatinib as first-line therapy. BCR-ABL transcript levels were measured after achievement of complete cytogenetic remission (CCyR) and at 6-month intervals.MMR was detected in 44% patients at the start of the study. This value increased to 79% at month 36 of evaluation. Complete molecular response (CMR) also increased from 24% to 52% of patients. Not achieving a stable MMR determined a higher risk of cytogenetic relapse (9% of MMR patients not achieving an MMR vs. 1% of patients who achieved MMR). Patients with sustained MMR had a significantly better cytogenetic relapse-free survival at 48 months (97% vs. 87%; P = .008) but showed no differences in overall survival. Patients who did not remain in CCyR changed treatment.A stable MMR is a strong predictor for a durable CCyR. Standardized molecular monitoring could replace cytogenetic analysis once CCyR is obtained. These results emphasize the validity and feasibility of molecular monitoring in all standardized medical centers of the world.

Purpose Dasatinib is a BCR-ABL inhibitor, 325-fold more potent than imatinib against unmutated BCR-ABL in vitro. Phase II studies have demonstrated efficacy and safety with dasatinib 70 mg twice daily in chronic-phase (CP) chronic myelogenous leukemia (CML) after imatinib treatment failure. In phase I, responses occurred with once-daily administration despite only intermittent BCR-ABL inhibition. Once-daily treatment resulted in less toxicity, suggesting that toxicity results from continuous inhibition of unintended targets. Here, a dose- and schedule-optimization study is reported. Patients and Methods In this open-label phase III trial, 670 patients with imatinib-resistant or -intolerant CP-CML were randomly assigned 1:1:1:1 between four dasatinib treatment groups: 100 mg once daily, 50 mg twice daily, 140 mg once daily, or 70 mg twice daily. Results With minimum follow-up of 6 months (median treatment duration, 8 months; range, < 1 to 15 months), marked and comparable hematologic (complete, 86% to 92%) and cytogenetic (major, 54% to 59%; complete, 41% to 45%) response rates were observed across the four groups. Time to and duration of cytogenetic response were similar, as was progression-free survival (8% to 11% of patients experienced disease progression or died). Compared with the approved 70-mg twice-daily regimen, dasatinib 100 mg once daily resulted in significantly lower rates of pleural effusion (all grades, 7% v 16%; P = .024) and grade 3 to 4 thrombocytopenia (22% v 37%; P = .004), and fewer patients required dose interruption (51% v 68%), reduction (30% v 55%), or discontinuation (16% v 23%). Conclusion Dasatinib 100 mg once daily retains the efficacy of 70 mg twice daily with less toxicity. Intermittent target inhibition with tyrosine kinase inhibitors may preserve efficacy and reduce adverse events.

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

Background: Dasatinib is a potent BCR-ABL tyrosine kinase inhibitor (TKI) currently approved at 100 mg once daily (QD) as a first-line therapy in CML-CP pts and a second-line therapy in pts with CML resistant/intolerant to prior therapy. CA180-034 (NCT00123474), a prospective, randomized phase 3 study, was designed to compare the dose and schedule of dasatinib therapy for the optimal benefit/risk ratio among pts with imatinib-resistant or -intolerant CML-CP. Results from this study have previously demonstrated significant efficacy of dasatinib in this pt population. Here, we report the final 7-yr analysis of efficacy and safety outcomes of CA180-034, which represents the longest follow-up of any second-generation BCR-ABL TKI to date. Methods: The CA180-034 2 X 2 factorial study design has previously been described (Shah 2010, J Clin Oncol). Pts (n=670) were randomized to dasatinib: 100 mg QD (n=167), 50 mg twice daily (BID; n=168), 140 mg QD (n=167), or 70 mg BID (n=168). To manage inadequate response or adverse events (AEs), dose escalation (up to a total daily dose [TDD] of 180 mg) and dose interruption or reduction (down to a TDD of 20 mg) were allowed. After 2 yrs, the protocol was amended to allow switching to a QD regimen with the same TDD after at least one dose reduction for recurrent anemia, thrombocytopenia, neutropenia, pleural effusion, or any other fluid retention during study progress or at the investigator’s discretion (Shah 2014, Blood). Results: Approximately 55% (50 mg BID) and 51% (70 mg BID) of pts treated after the protocol amendment switched to QD dosing by the last recorded dose. The overall median duration of therapy was longer for the 100 mg QD group (37.4 months [mos]) compared with the 50 mg BID, 140 mg QD, and 70 mg BID groups (28.1 mos, 26.6 mos, and 28.9 mos, respectively).At 7 yrs of follow-up, progression-free survival (PFS) andoverall survival (OS) rates were similar for all doses, as were the proportions of pts with a best on-study molecular response of MMR (Table 1). In an exploratory landmark analysis, pts in the 100 mg QD arm with BCR-ABL ≤10% (on the International Scale) at 3 mos had improved PFS and OS rates at 7 yrs relative to pts with BCR-ABL>10% (Table 2). BCR-ABL mutations were assessed in pts prior to the start of dasatinib (baseline), at the time of disease progression, or at end of treatment. Three mutations persisted or developed in pts who discontinued dasatinib due to loss of response on 100 mg QD: V299L (n=3), T315I (n=6), and F317L (n=7). For 100 mg QD, most nonhematologic and hematologic AEs (all grades) typically first occurred within the first 24 mos of treatment. Rates of nonhematologic AEs (all grades) over 7 yrs for 100 mg QD compared with other treatment arms included fluid retention (51% vs 54%), diarrhea (42% vs 47%), nausea/vomiting (27% vs 43%), myalgias/arthralgias (38% vs 33%), fatigue (37% vs 34%), and rash (33% vs 36%). Within yr 7 of the study, new cases of pleural effusion occurred in 5% (2/42) of pts at risk treated with dasatinib 100 mg QD compared with 8% (7/88) in other treatment arms. Severe (grade 3–4) AEs (any relationship) occurred less frequently in the 100 mg QD group (98/165, 59%) relative to other treatment arms (341/497, 69%). Three pts died due to study drug toxicity (1 due to sepsis; 1 due to pulmonary edema, congestive heart failure, neck pain, and pleural effusion; 1 due to necrosis of the colon). Conclusions: Long-term follow-up of dasatinib continues to demonstrate durable efficacy and benefit for pts with CML-CP following imatinib therapy, particularly if achieving BCR-ABL ≤10% at 3 mos. Dasatinib is well-tolerated amongst pts, with most AEs occurring early on during the course of treatment; however, pleural effusion did occur through 7 yrs of treatment. No new safety signals were detected. Table 1 Efficacy results Patients 100 mg QD (n=167) 50 mg BID (n=168) 140 mg QD (n=167) 70 mg BID (n=168) MMR in assessed treated patients, n (%) 73 (46) 70 (44) 68 (44) 69 (46) PFS at 7 yrs, % (95% CI) 42 (33–51) 44 (35–53) 38 (30–47) 44 (35–52) OS at 7 yrs, % (95% CI) 65 (56–72) 70 (62–77) 73 (65–80) 68 (60–75) Table 2 Landmark analysis: Efficacy rates at 7 yrs Patients 100 mg QD (n=165) BCR-ABL ≤ 10% at 3 mos BCR-ABL > 10% at 3 mos PFS, % (95% CI) 56 (43–67) 21 (10–34) OS, % (95% CI) 72 (60–81) 56 (42–68) Transformation-free,a% (95% CI) 93 (84–97) 88 (67–96) a Limited to events during the study therapy as reason for progression not collected in follow-up. Disclosures Shah: ARIAD: Research Funding; Bristol-Myers Squibb: Research Funding. Rousselot:Bristol-Myers Squibb: Consultancy, Research Funding. Schiffer:Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Ariad: Research Funding; Teva: Membership on an entity's Board of Directors or advisory committees; Pfizer: DSMB Other. Rea:Bristol-Myers Squibb: Honoraria; Pfizer: Honoraria; Novartis: Honoraria; Ariad: Honoraria. Cortes:Ariad: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Consultancy, Research Funding. Milone:Roche: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squibb: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Mohamed:BMS: Employment. Healey:Bristol-Myers Squibb: Employment. Kantarjian:ARIAD: Research Funding; Pfizer: Research Funding; Amgen: Research Funding. Hochhaus:Bristol-Myers Squibb: Research Funding; Novartis: Research Funding; Pfizer: Research Funding; Ariad: Research Funding; MSD: Research Funding. Saglio:BMS: Consultancy, Fees for occasional speeches Other; Novartis: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; Pfizer: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other; ARIAD: Consultancy, Fees for occasional speeches, Fees for occasional speeches Other.

Here we describe two Caucasian brothers who developed adult T-cell leukemia/lymphoma (ATLL), within a short period of time. These two patients have never left Argentina. Their parents are dead and according to the family history it is possible that the mother may have been affected by spastic paraparesis. The daughters reported that their mother had suffered from increasing difficulty in walking for many years which finally made it impossible for to her walk. There are no other data to support the presumptive diagnosis. One of the patients presented with acute disease while the other had a lymphoma type disorder. Both were positive for HTLV 1. The first patient died with disease progression ten months after diagnosis and the second is in partial remission 13 months after diagnosis. Immunophenotyping showed CD4+, CD5+, CD3+, CD2+, CD8 (-). Two asymptomatic brothers with positive HTLV 1 serology were detected. This is the first family case that has been reported in Argentina.

Materials and Methods We retrospectively reviewed 137 medical records of patients older than 50 years receiving an allogeneic hematopoietic stem cell transplant (HSCT) in 9 centers from Argentina. We evaluated the following characteristics: sex, age, diagnosis, stage, comorbidities (according to the HCT-CI score), type of donor, histocompatibility, source, conditioning and immunosupression. We analyzed the incidence and severity of acute Graft-vs-Host disease (aGVHD) with Chi Square, Overall Survival (OS) and Disease Free Survival (DFS) with Kaplan Meier and Relapse, Non Relapse Mortality y chronic GVHD (cGVHD) with CI. For multivariate analysis (MA) we included variables that in univariate had a p Results Patients characteristics are listed in table 1. Between January 1997 and July 2013, 137 transplants were performed in adults older than 50 years, with a median follow up 1.3 years. Acute GVHD incidence was 41% (19% were grade II and 7.3% III-IV). The only variable associated with aGVH clinically significant (G II-IV) was AML that was protective (14% vs 35%, p Conclusion HSCT is a valid therapeutic option for older patients. In this retrospective analysis of patients older than 50 years, we found that the main risk factors that impact in transplant outcome are patients comorbidities and not age, whereas transplant related toxicities increase with the number of comorbidities and therefore decrease OS and DFS. Beyond the fact that certain disease experienced more aGHVD (AML) or cGVHD and higher NRL (MPN) the other factor significantly related in transplant outcome was the use of tacrolimus vs CSA. Disclosures: No relevant conflicts of interest to declare.

Abstract 2031 Background: The role of High-Dose Therapy (HDT) and Autologous Stem Cell Transplantation (ASCT) as salvage therapy in relapsed Follicular Lymphoma (FL) has been questioned since the introduction of Rituximab in the treatment of FL. Our objectives were to evaluate the long-term event-free survival (EFS) and overall survival (OS) rates of patients with relapsed or refractory FL who received HDT and ASCT as salvage therapy. Our secondary objective was to compare EFS of patients who received ASCT before and after 2002 (the year Rituximab become fully available for use in our country). Patients and Methods: We conducted a retrospective analysis of 123 consecutive patients with relapsed or refractory FL who had received HDT and ASCT as salvage therapy in five Argentinean transplant centers from 1992 to 2012. Results: One hundred twenty tree patients (median age: 48 years, range: 23–72) were transplanted, 71 (58%) male, 37/106 (35%) had FL Grade 1, 47/106 (44%) FL Grade 2 and 22/106 (21%) FL Grade 3; 75/102 (73%) of patients have a stage III-IV disease at the moment of diagnosis and 27/102 (26%) have a disease stage I-II. Before transplantation 78/121 (64%) patients were in Complete Response (CR), 42/121 (35%) were in Partial Response (PR) and one patient had a Progressive Disease. Fifty four patients (44%) were transplanted before 2002 (before Rituximab era in our country). The conditioning regimens used were CBV 94 (76%), BEAM/BEAC 27 (22%), others regimens two patients; only one patient received TBI containing conditioning regimen and was excluded for conditioning regimen PFS curve calculation. The median time from FL diagnosis to ASCT was 29 (range 1–300) months. The transplant related mortality (until day 90 after ASCT) was 5%. With a median follow-up of 52 (range 0–247)months, the median EFS was reached at 44 months and a plateau on the EFS curve was evident starting at 6 years after ASCT. The 10 years-projected EFS was 36% (Figure 1). The median OS was not reached during follow-up. Median EFS for patients who were transplanted before 2002 (before Rituximab era) and for those who were transplanted after 2002 was 41 months and 47 months respectively [HR 1.01; IC (0.61–1.65); p=0.97]. EFS rates difference was not statically significant between patients who previously transplantation have achieved a CR or a PR, median EFS 47 and 68 months respectively [HR 0,94; IC (0,56–1,58); p= 0,82]. There was no difference in EFS rates between patients who received CBV as conditioning regimen and patients who received BEAM/BEAC, median EFS 57.6 months and 16.3 months respectively [HR 0.67; IC (0,34–1.35); p=0.2]. The median EFS rate for patients with FL Grade 1, FL Grade 2 and FL grade 3 were 58, 44 and 16 months respectively, P for trend = 0.78. Seven cases (5,7%) of secondary malignancies were detected, six cases (6/94; 6,4%) in patients who received CBV as conditioning regimen (urotelial carcinoma, pancreas carcinoma, lynfoprolipherative disorders, non-melanoma skin malignancies and prostate carcinoma) and one case (1/27; 3,7%) in patients who received BEAM (urotelial carcinoma), p=0,85; there were no reports of secondary myelodysplastic syndromes/acute myeloid leukemia. Conclusion: In this study, 50% of the patients analyzed were free from progression after 44 months of ASCT and approximately a 30% of patients achieve long term remission. According to this, patients with relapsed or refractory FL can achieve long-term EFS with HDT followed by ASCT. Disclosures: No relevant conflicts of interest to declare.

Abstract 4582 Introduction: Introduction of imatinib mesylate has changed the approach towards bone marrow transplantation in Chronic Myeloid Leukemia (CML). Historically considered as a curative therapeutic option, with a probability of disease free survival ranging from 40 to 60%. Its indicated use has been restricted to patients with treatment failure to prior tyrosin-kinase inhibitors or blast crisis. Objective: To assess the outcome of patients with CML who undergo BMT Materials and methods: 66 patients who underwent allogeneic BMT between the years 1994 and 2011 in two health care facilities were analyzed. 63 (93%) were performed between 1994 and 2005. At the time of transplantation, patient status was: 56 patients in 1st Chronic Phase and 10 in advanced phases. Fourteen patients received Unrelated Donor BMT and 37 had Related Donor BMT. Transplant risk was assessed, based on the European Bone Marrow Transplantation (EBMT) score (sc). The conditioning regimens which were used included: for patients in chronic phase, cyclophosphamide (Cy) and busulfan (Bu) and for patients in accelerated phase etoposide (VP 16) was added to the previous regimen, and for unrelated donors BuCy + ATG or alentuzumab was used. Prophylaxis for Graft vs Host Disease (GVHD) was performed with a two-drug regimen (cyclosporine, methotrexate), with or without methylprednisone. Result: 66 patients were recorded (28 female/38 male), with a mean age of 35 years at the time of transplantation (range 8–55). The source of Stem Cell was bone marrow in 60 patients and peripheral blood in 6 patients. 43% of patients developed GVHD: (29 patients) according to clinical criteria established by the European Cooperative Group. Overall Survival (OS) was 50% with a mean follow-up of 48 months. Analyzed according to the EBMT risk score, OS was 64% in the 0–2 score group and 31% in patients with a 3–5 score. Procedure-related mortality was 16%, and the most frequent causes included: hepatic veno-occlusive disease, infections, GVHD, and graft failure. Conclusions: BMT in patients with CML has been substantially reduced since the introduction of tyrosin-kinase inhibitors. In our experience, this shows its healing potential with an extended follow-up and a prolonged survival. Disclosures: No relevant conflicts of interest to declare.

6535 Background: BOS is an orally active, dual Src/Abl tyrosine kinase inhibitor (TKI). Methods: This open-label, phase 1/2 trial evaluated safety and efficacy of BOS as 3rd-line therapy in patient...

Abstract 4850 Background The Secondary Myelodysplastic Syndrome (sMDS) represents a severe complication in the treatment of cancer. They are associated to the use of alkylating agents, radiation and immunosuppressive therapy. Their prognosis is unfavorable. Conventional chemotherapy is mainly palliative whereas allogenic bone marrow transplantation allows the cure of a small percentage of cases. Aims: To characterize and to describe the clinical presentation, therapeutic conduct and evolution in sMDS. This results where compared with those of primary MDS (pMDS) in patients enrolled into the observational study of Sociedad Argentina de Hematología from January 2007 to June 2009 Methods There were analyzed 253 patients with diagnosis of MDS. sMDS correspond to 12.2 % (31/253)of the total, mean age 71 years old (r 23-84), relation M: F of 1:2.8 (being 1:2.2 in pMDS). Previous pathologies were: solid tumors in 17 patients (54%); 6 prostate Ca, 5 breast Ca, 4 GI Ca, 1 thyroid Ca, 1 bladder Ca, 1 pharynx Ca. Hematology malignancies were found in 7 patients: 2 Non Hodgkin Lymphoma, 2 Hodgkin Lymphoma, 1 Myeloma Multiple, 1 Chronic Myelomonocyticleukemia, 1p aplastic anemia. Six patients (23%) received immunosuppressive treatment for kidney transplantation, Wegener disease and glomerulonephritis. 85% of the patients received previous chemotherapy and/or radiotherapy. Result: There were analyzed 217 karyotypes (85.7%), 25 in the sMDS group and 189 in the pMDS, abnormal karyotypes in 14/25 (56%) vs 55/189 (29%) (p=0.006), complex karyotypes (unfavorable): 6/25 (24%) vs 8/189 (7%) (P=0.002). Twenty eight patients requiered treatment 28/31 (90.3%) vs 167/222 (75.2%) (p=0.09), transfusional therapy 23/31 (77.55%) vs 93/222 (42%) (p=0.001). Hypomethylating agents were used in 22,5% in sMDS vs 21,1% in pMDS and Erythropoyetin in 45,2% vs 48,6%. With a median follow up of 136 days (r:4-650), 8/31 progressed to AML (25.8%) vs 28/222 (13%) (p=0.005). Fourteen patients (45%) were death vs 47/222 (20.6%) (p=0.005); 17/31 (54.8%) of patients were alive in the sMDS group and 153/189 (80%) in the pSMD group (p= 0.005). Summary and Conclusions sMDS constituted 12.2% of the total of MDS that were reported. This entity has in our experience presence of unfavorable karyotype in more than the 50% of the cases, greater transfusion request, greater evolution to acute myeloid leukemia with high mortality and greater mortality than pMDS. This results confirm the bad prognosis of sMDS. Disclosures No relevant conflicts of interest to declare.

7007 Background: The recommended dosing regimen of dasatinib for CML-CP is now 100 mg once daily (QD) (previously 70 mg twice daily [BID]), based upon a phase III dose-optimization study (CA180–034) that enrolled patients (pts) with CML-CP with resistance, intolerance, or suboptimal response to imatinib. While therapeutic milestones have been established for pts with CML-CP treated with imatinib, they have not been well established for pts treated with second-line TKIs. Methods: Pts were randomized using a 2 × 2 factorial design to one of four treatment arms: 100 mg QD (n = 167), 70 mg BID (n = 168), 140 mg QD (n = 167), or 50 mg BID (n = 168). Details of study design and endpoints have been described previously. Results: After a minimum of 24 months of follow-up, the 24-month PFS rate with 100 mg QD was 80% (vs. 75%-76% in other arms) and the overall survival rate was 91% (vs. 88%-94%). In all arms, high response rates were achieved in pts with or without a baseline BCR-ABL mutation. Dasatinib 100 mg QD was well tolerated and rates of key side effects showed only a minimal increment from 12 to 24 months. Among the four treatment arms, significant differences were observed in rates of drug-related pleural effusion (all grades: p = 0.049) and cytopenia (p = 0.003 for grade 3/4 thrombocytopenia), with lowest rates observed for 100 mg QD. Dasatinib 100 mg QD treatment resulted in the lowest rates of treatment interruption, reduction, and discontinuation. In addition to providing 36-month follow-up, the likelihood of achieving long-term endpoints based on cytogenetic status at 6, 12, and/or 18 months will be presented. Conclusions: Dasatinib 100 mg once daily remains the optimal dosing schedule for pts with CML-CP. The landmark analyses to be presented should provide useful information to clinicians treating imatinib-resistant, -suboptimally responding, or -intolerant CML-CP pts with dasatinib 100 mg once daily based on cytogenetic response at key intervals. [Table: see text]

Dasatinib (SPRYCEL®) is an effective BCR-ABL inhibitor and is 325-fold more potent than imatinib in vitro against unmutated BCR-ABL. CA180-034 is a randomized, phase III, open-label study in patients with CML-CP (N=670) who have resistance, suboptimal response, or intolerance to prior imatinib 400–800 mg/d. Patients were randomized using a 2×2 factorial design to one of four treatment arms: 100 mg once daily (QD), 70 mg twice daily (BID), 140 mg QD, or 50 mg BID. Time to and duration of response, progressionfree survival (PFS), and overall survival (OS) were estimated using Kaplan-Meier analysis. Earlier reports demonstrated that dasatinib 100 mg QD (the currently approved dose in CML-CP) maintains efficacy while significantly minimizing adverse events (AEs). This finding was supported by pharmacokinetic analyses, which have demonstrated a correlation between low dasatinib steady-state trough plasma concentration (achieved with 100 mg QD dosing) and less frequent key toxicities and fewer dose interruptions. With a minimum of 2 years of follow-up in all patients, dasatinib 100 mg QD treatment resulted in a MCyR rate of 63% and a CCyR rate of 50%, and rates were similar in the other 3 arms (MCyR: 61%–63%; CCyR 50%–54%) (Table). Rates were similar when 14 patients with Ph-negative BCR-ABL-positive disease were excluded. Among responding patients in the 100 mg QD arm, median time to MCyR was 12.4 weeks and to CCyR was 13.0 weeks, and after 24 months, 87% of patients had maintained their MCyR and 89% had maintained their CCyR, with similar results in other arms. The 24-month PFS rate with 100 mg QD was 80% (vs 75%–76% in other arms) and OS rate was 91% (vs 88%–94%). In all arms, high response rates were achieved in patients with or without a baseline BCR-ABL mutation (CCyR rates for 100 mg QD: 40% vs 54%, respectively). Dasatinib was well tolerated and the incidence of treatment-related AEs after a minimum of 2 years of follow-up was similar to rates after a minimum of 1 year. In the 100 mg QD arm, overall 2-year rates (vs 1 year) were 2% (vs 2%) for grade 3 pleural effusion (grade 4: 0%), 23% (vs 22%) for grade 3/4 thrombocytopenia, and 35% (vs 34%) for grade 3/4 neutropenia. Among the 4 treatment arms, significant differences were observed in the overall incidences of drug-related pleural effusions (all grades: p=0.049) and cytopenias (p=0.003 for grade 3/4 thrombocytopenia), with lowest rates observed for 100 mg QD. After a minimum of 2 years of 100 mg QD treatment, 12% of patients discontinued therapy following drug toxicity (vs 6% after 1 year), compared with 2-year rates of 16%–21% in other arms. Overall, 2-year data from CA180-034 extend previous findings and demonstrate that dasatinib dose optimization at 100 mg QD is associated with minimal incidence of key grade 3/4 toxicities in Year 2, and maintains long-term efficacy, in patients with CML-CP following resistance, suboptimal response, or intolerance to prior imatinib. Response duration and PFS with dasatinib 100 mg QD are similar to other dose schedules. Table 100 mg QD 70 mg BID 140 mg QD 50 mg BID All randomized patients n=167 n=168 n=167 n=168 CHR (%) 92 88 87 92 MCyR (%) 63 61 63 61 Median time to MCyR (wks) 12.4 12.3 12.3 12.3 MCyR maintained at 24 mos (%) 87 88 68 88 CCyR (%) 50 54 50 50 Median time to CCyR (wks) 13.0 12.9 13.8 12.9 CCyR maintained at 24 mos (%) 89 85 78 93 24-month PFS (%) 80 76 75 76 24-month OS (%) 91 88 94 90 Excluding Ph(−) BCR-ABL(+) n=164 n=163 n=163 n=166 MCyR (%) 63 61 63 61 CCyR (%) 49 53 50 50 All treated patients n=165 n=167 n=163 n=167 Pleural effusion (drug-related), grade 3/4 (%) 2 5 5 4 Neutropenia, grade 3/4 (%) 35 45 44 47 Thrombocytopenia, grade 3/4 (%) 23 38 41 36 Dose interruption (%) 62 77 79 72 Dose reduction (%) 39 62 62 46

Background: 90Y-ibritumomab tiuxetan (Zevamab®; ZEV; Bayer-Schering Pharma- Argentina) has been approved for the treatment of relapsed, refractory and transformed (high grade) follicular lymphomas. Methods: Between Sep. 2005 and Feb. 2008, 45 patients (pts) [22 F & 23 M; median age 62 yrs (45–83)] with refractory/relapsed lymphoma were enrolled. Diagnoses: 37 follicular lymphoma (FL), 5 were mantle cell lymphoma (ML) and 3 transformed lymphoma (TL); 18 pts had bulky disease, 8 had bone marrow involvement and 21 had stage III–IV disease. Median time from diagnosis was 5 yrs (0.5– 29). Twenty two pts had received 1–2 previous treatments, and 23 pts had received 3–5 previous treatments including 5 pts with autologous bone marrow transplantation. All had previously received anti-CD20 monoclonal antibody therapy. Six pts received previous radiotherapy. ZEV was administered at 0.3 or 0.4 mCi, based on initial platelet count. Seven days before, and the same day of the ZEV administration, pts received standard rituximab 250 mg/m2. In 3 pt, ZEV was part of the conditioning regimen of autologous bone marrow transplantation. Results: Forty pts were evaluable for response: 34 (86%) pts responded – 19 CR (48%), 15 PR (38%). Overall survival and PFS for the entire group at 18 months was 63% and 37% respectively, with a median follow-up of 12 months (1–29 months). Of the 45 patients, 5 pts (11%) had died before third month and response was not assessed, 6 pts (13%) did not respond, 3 (7%) died with response from other causes, 14 pts (31%) responded and subsequently relapsed. Finally 17 pts (38%) continue to be in response, 9 (20%) lasting more than twelve months (long lasting responders). Slight differences in duration of response and survival were observed between FL vs ML and TL favouring FL (RR 2.047). Forty six per cent of pts required filgrastim for neutropenia, 24% required platelet transfusions, 22% had neutropenia plus fever and were admitted for complicated pancytopenia, and 20% required red blood cells transfusion. Two patient died 30 & 40 days after treatment with hypoplastic bone marrow complicated with sepsis in the post autologous bone marrow transplantation period. Four pts with previous bone marrow transplantation required filgrastim, transfusions and 2/3 had febrile neutropenia. Conclusion: Our experience with ZEV in relapsed and refractory FL shows 48 % CR. Even heavily treated pts that had previous bone marrow transplantation were able to receive ZEV, although they required extra support. Our experience supports the use of ZEV in relapsed and refractory lymphomas even after autologous bone marrow transplantation.

The radionucleid conjugate with monoclonal antibodies (antiCD20/90Y-ibritumomab tiuxetan) have been approved for the treatment of relapsed, refractory and transformed (high grade) follicular lymphomas. Between September 2005 and August 2007, 41 patients with refractory/relapsed lymphoma were enrolled. Median age was 62 yrs old (45–83). Twenty were women and 21 were men. Thirty three were follicular and 5 were mantle cell lymphoma and 3 transformed lymphoma. Eighteen patients had bulky disease, 8 had bone marrow involvement and 21 had stage III-IV disease. Median time from diagnosis was 5 years (0.5–29). Twenty one had received 1–2 previous treatments, and 20 pts had received 3–5 previous treatments including 5 pts with autologous bone marrow transplantation. All had previously received anti-CD20 monoclonal antibody therapy. Six pts received previous radiotherapy. 90Y-Ibritumomab (Zevamab™ Bayer-Schering Argentina) was administered at 0.3 or 0.4 mCi, based on initial platelet count. Seven days before, and on the same day of the immunoconjugate administration, pts received rituximab 250 mg/m2. Thirty eight were evaluable for response. Thirty four (89%) pts responded: 20 CR (53%) and 14 PR (36%). With a median follow-up of 10 months, 60% of pts were expected to continue in CR at 18 months. Overall survival at the same period for the entire group was 89%. Nineteen pts (46%) required filgrastim administration for neutropenia, Ten pts (24%) required platelet transfusions, 10 pts had neutropenia plus fever and they had to be admitted for complicated pancytopenia, 8 pts required red blood cells transfusion. Two patient died 30 and 40 days after treatment with hypoplastic bone marrow complicated with septicemia and in the post autologous bone marrow transplantation period, respectively. Four pts with previous bone marrow transplantation, required filgrastim, transfusions and 2/3 had febrile neutropenia. Our experience with 90Y-ibritumomab in relapsed and refractory folicullar lymphoma shows 53% CR. Even heavily treated pts, that had previous bone marrow transplantation were able to receive the radioimmunoconjugate, although they required extra support. Our experience favours the use of 90Y-Ibritumomab tiuxetan in relapsed and refractory lymphomas even if they had received previous autologous bone marrow transplantation.

It has been proved that Rituximab is a useful drug for the treatment of patients with lymphoma. Being a humanized antibody, it presents high specificity. Rituximab is a well tolerated medicine, although a slow infusion rate given in many hours is recommended to avoid reactions derived from the liberation of cytokines. As a consequence, patients need admissions for a treatment that can take hours. The recent demostration of its usefulness in the maintenance of the response of patients with follicular lymphomas has concluded in the revision of hospitalization time, proposing a faster infusion. We are presenting our experience with RIR, on a group of patients with lymphoproliferative diseases. We used RIR with the aim to observe the toxicity and to reduce the time of hospitalization in patients with lymphoma. We evaluated the adverse events and tested the feasibility of a 90 minutes infusion schedule for rituximab (20% of the dose administered in the first 30 minutes, remaining administered over 60 minutes). Premedication included oral paracetamol and intravenous hidrocortisone and diphenhydramine. Sixty seven RIR were used to treated 31 patients (27 non-Hodgkin Lymphoma and 4 Chronic Lymphocitic Leukemia). All of them had previously received one or more rituximab conventional infusion without grade 3 or 4 toxicity. Twenty nine patients received also CHOP or CHOP-like chemotherapy and the other two Rituximab alone as maintenance therapy. Overall RIR was well tolerated. There were 5 adverse events. Four patients developed grade one adverse events: one patient had an hypotension episode, one presented chest pain and the other two had abdominal pain. Only one patient developed a grade 3 adverse event (abdominal pain) and withdrew the RIR schedule. We conclude that rapid infusion rituximab is safe and well tolerated. The adoption of this schedule in clinical practice reduces in many hours the time of hospitalization for patients with lymphoma and may be a cost-effective strategy.

7004 Background: Previous data with dasatinib (SPRYCEL®), a short-acting oral multitargeted kinase inhibitor of BCR-ABL and SRC family kinases, have shown the safety and efficacy of the 70 mg BID dose in CP-CML patients. Surprisingly, phase-I data (NEJM 2006;354:2531) demonstrated complete hematologic (CHR) and major cytogenetic responses (MCyR) among CP-CML patients at total daily doses (TDD) of 100 mg and 140 mg in both the BID and QD schedule, despite the achievement of only transient inhibition of BCR-ABL by dasatinib when administered once daily. Methods: Patients with CP-CML resistant or intolerant to imatinib were randomized to one of 4 dasatinib arms: 1) 100 mg QD; 2) 50 mg BID; 3) 140 mg QD; 4) 70 mg BID. In this randomized, prospective, open-label trial, the primary objective compared the CyR rate among the BID and QD arms. Secondary objectives included comparison of the CyR rate between TTDs of 100 and 140 mg and the safety among the 4 arms. Results: 662 patients were randomized from July 2005 to March 2006 and received treatment. Response rates, with a median duration of treatment of 8 months, are shown below. Duration of CyR and progression-free survival were similar across all 4 arms. There was significantly less grade (Gr) 3–4 neutropenia (P=0.035), thrombocytopenia (P=0.001), anemia (P=0.032), and pleural effusions (P=0.028) in the 100-mg QD arm compared to the other 3 arms combined. No differences were seen across the 4 arms in the rates of other adverse events. There were fewer interruptions and reductions and the least number of patients discontinuing treatment for drug-related toxicity in the 100-mg QD arm. Conclusions: Dasatinib 100 mg QD offers the most favorable benefit-risk ratio in CP-CML. This trial provides the first evidence that intermittent kinase inhibition can achieve deep clinical remissions and is associated with an improved safety profile. One-year follow-up on all subjects, molecular response rates, and BCR-ABL mutation data will be presented. [Table: see text] [Table: see text]

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 evaluation of response to imatinib in CML patients (pts) as guide to clinical management is undergoing substantial changes of criteria. The degree of reduction of total leukemia cell mass by imatinib as measured by FISH and RQ-PCR studies, correlates with progression-free survival. Therapeutic decisions, as dose scalation, is mandatory in pts with rising level of bcr/abl transcripts. Purpose: To determine the potential of RQ-PCR to predict the duration of response in pts in complete cytogenetic remission (CCyR). Patients and Methods: A total of 160 CML pts in first chronic phase, in CCyR treated with imatinib 400mg daily were studied prospectively since November 2005 (147 pts from 30 hematology centers in Argentina and 13 pts from 2 centers in Uruguay). According to previous treatment they were divided in two groups: 83 pts (51%) received as first line treatment IFN/Cytarabine and 77 pts (49%) received imatinib as first line. According to Sokal Index, 72% were low risk, 19% intermediate risk and 9% high risk. At baseline all pts were first evaluated by FISH and RQ-PCR under EAC program protocol and recommendations of T.P. Hughes, et al (Blood 108:28–37, 2006). Only RQ-PCR is being performed at 6 and 18 months from the beginning of the study. The median duration since beginning with imatinib treatment was 28 months (range 6–58). Results: At the time of first RQ-PCR evaluation, 93% had undetectable bcr/abl fusion gene by FISH and 7% had low level FISH positivity ( 0,1 – 5%). The distribution of the type of molecular responses (MR) in the 160 pts was: Complete (CMR)≥4 log red, U/2 log red, 1–0,1 % bcr-abl/c-abl : 34%; MiMR < 2log red, 10–1% bcr-abl/c-abl : 15%; Nule (NuMR) 10%bcr-abl/c-abl : 11%. Pts with Fish (+) showed association with MiMR. Thirty eight percent of pts with a follow-up between 6–24 months since the beginning of imatinib treatment achieved MaMR and CMR, similar rate as the observed in the group with > 24 months on imatinib (42%). Up to July 2006, 53 pts underwent a 2nd RQ-PCR evaluation at 6 months: 15% of pts improved molecular response, 68% maintained it while 17% showed worse response. The 87.5% of pts with decreasing bcr-abl transcripts level at 2nd evaluation corresponded to imatinib treatment as first line. The 78% of pts with rising levels at 2nd evaluation showed MiMR at beginning of this study. Up to now, no pts showed hematological relapse. Conclusion: This is an on-going study in CML pts in CCyR, where 93% showed a negative FISH study, and 7% had low FISH positivity. By RQ-PCR, 40% of pts presented CMR or MaMR (≥3 log red). In 2nd RQ-PCR evaluation, 83% of pts improved or maintained the molecular response. Up to now all pts remain in hematological remission.

Phase II studies of dasatinib (SPRYCEL®, formerly BMS-354825), an oral multi-targeted kinase inhibitor of BCR-ABL and SRC kinases, have demonstrated the efficacy and safety of a 70mg twice daily (BID) dose in CML-CP patients (pts) with resistance or intolerance to imatinib (im). A phase I trial of dasatinib (N Engl J Med 2006;354:2531–41) had shown complete hematologic responses (CHR) and major cytogenetic responses (MCyR) at total daily doses of 100mg and 140mg daily in both BID and once daily (QD) schedule in CML-CP pts. The primary objective of the present study was to compare 6 month (mo) cytogenetic response (CyR) rates among the BID and QD regimens of dasatinib. Secondary objectives included estimating differences in CyR rates between the total daily doses of 100 and 140mg, and safety across the arms to optimize the dose and schedule of the drug. Dasatinib was administered according to one of 4 arms: 50mg BID, 70mg BID, 100mg QD or 140mg QD. Dose escalation to 90mg BID or 180mg QD and reduction to 40mg BID or 80mg QD were allowed for inadequate response or adverse events (AEs), respectively. Evaluation included complete blood counts every 2 weeks x 6 then every 3 mo; bone marrow cytogenetics at mo 3, 6 and then every 6 mo; and qPCR monthly x 3 then every 3 mo. A total of 670 pts were randomized and 663 treated in 139 worldwide sites from July 2005 to March 2006. Median age was 55 years and 47% were male. The median time from CML diagnosis to randomization was 54 mo. All pts received prior im: 600mg/d. The best previous response to im was CHR in 83% and MCyR in 42%. Prior treatment for CML included interferon alpha in 52%, chemotherapy in 27% and stem cell transplantation in 5% of cases. With a median follow-up of 3 mo, the overall CHR rate for the entire population is 80% and MCyR rate is 37% as of August 2006. 44% of pts required a dose interruption; 25% were due to hematologic toxicity and 14% due to non-hematologic toxicity; 28% required a dose reduction of which 13% were due to hematologic toxicity and 6% due to non-hematologic toxicity; the remainder of dose interruptions and reductions were due to other (including dosing error) or unknown reasons. 3% of pts had a dose escalation typically due to lack of CHR after 3 mo or no decrease in WBC after 1 mo. 601 (90%) pts remain on the trial with the majority of discontinuations for disease progression or study drug toxicity. Grade 3–4 neutropenia and thrombocytopenia occurred in 35% and 30% of pts, respectively. AEs considered drug related by the investigators included headache 24%, diarrhea 20%, nausea 16%, fatigue 12%, rash 11%, edema 10%, dyspnea 7%, pleural effusion 7%, myalgia 7%, arthralgia 5%, anorexia 4%, pneumonia 1%, and gastrointestinal hemorrhage 1%. Rare AEs that were considered drug-related by the investigators included congestive heart failure in 4 pts, and cardiac dysfunction, pulmonary hypertension, pulmonary edema and pericardial effusion in 3 pts each. Other AEs regardless of relationship to study drug included grade 3–4 creatinine elevation in 4%, grade 3–4 transaminase elevation in

Imatinib induces complete cytogenetic response (CCyR) in 82% of patients with CML in chronic phase. There is a subset of patients who either failed to achieve or lose hematological/CCyR. Kinase domain mutations have emerged as a potential cause for treatment failure. Aims: In the current study we have investigated ABL kinase domain mutations, amplifications and quantification of BCR-ABL transcripts by Q-PCR in Imatinib resistant patients. Patients and Methods: A total of 84 patients (pts) with CML treated with Imatinib were studied and 82 were evaluable. Sixty-one (74%) were in chronic phase (CP), eleven (14%) were in accelerated phase (AP), and ten (12%) were in blast crisis (BC).We analyzed the DNA from blood samples. Mutations were screened by conformation sensitive gel electrophoresis (CSGE). The amplification products displaying an abnormal pattern were sequenced using automatic system. The amplification of BCR-ABL rearrangement was studied in interphase nuclei using Vysis extra-signaling probe. Real time quantitative PCR (RQ-PCR) of BCR-ABL transcripts was performed in a subset of 44 patients to assess molecular response, using Light Cycler (Roche®), Syber Green Method. Results: Eleven mutations from 82 evaluable patients were detected (13%). Seven were in p- loop: M244R (1), L247A (1), G250E (2), Q252H (1), E255K (2), and four in the Imatinib binding: T315I (3), H318L (1). Two patients had BCR-ABL amplifications with 4–6 signals in interphase nucleous and one of them showed extramedullary involvement in skin nodules. Five patients had clonal evolution with double Ph chromosome. Most of mutations were found in patients in late chronic phase (6/11: 54%). The detection occurred at a median of 49 months (range 12–154) after diagnosis. Eighty four percent of cases studied with RQ-PCR, had null molecular response ( Conclusion: This is the first multicentric study in spanish-speaking South America. T315I was the most frequent mutation detected in our study and was associated with poor outcome. We found 13% of resistant cases with point mutations, all of them located in the p-loop or imatinib binding.This is an ongoing study and further recruitment is needed to confirm these findings. Early detection of mutations can have prognostic implication and allow therapeutic intervention such as dose escalation, combination therapy or second generation tyrosine kinase inhibitors.

Background: Patients with Refractory/Relapsed (R/R) acute leukemia (AL) have a poor prognosis. Objective: We aimed to evaluate the chemotherapy regimen fludarabine, cytarabine, granulocyte colony-stimulating factor, and idarubicin (FLAG-IDA) in patients with R/R AL. Patients: We studied 16 patients with R/R AL (five female; eleven male). Distribution of the AL subtype was: lymphoblastic n=5 (31%), myeloblastic n=10 (62%) and bifenotipic n=1 (7%). The median of time from diagnosis to the beginning of FLAG-IDA was 320 days. Indication of FLAG-IDA was as follows: relapsed (n=12), refractory (n=2) and consolidation after relapsed (n=1) or refractory (n=1). Before administering FLAG-IDA, six patients were in their first relapse after conventional chemotherapy and six patients had received at least two different chemotherapy protocols (anti-CD33 monoclonal antibody was combined with chemotherapy in 3 of these patients). Two patients were in relapse after autologous peripheral stem cell transplantation and two after related allogeneic bone marrow transplantation. Results: At the beginning of FLAG-IDA, the median age was 29.6 years old (range 11–56) and 5 out of 16 patients (31.2%) had a performance status of ≥2. All patients had at least one episode of febrile neutropenia in a median of 8.5 days (range 3–17) with positive blood cultures in 50% of the events. Grade 5 toxicity occurred in 4 patients resulting in a mortality of 25%. All of the deaths were due to sepsis. In patients with hematological recovery the median time to neutrophils recovery (> 0.5 × 109/l) was 26.5 days (range 17–38); platelet levels of more than 20 × 109/l and 50 × 109/l were reached in a median time of 28 (range 23–44) and 31 days (range 25–51), respectively. Complete remission (CR) was achieved in 7 cases (43%). In the univariate analysis factors significantly associated with CR were the level of hemoglobin in day 0 (CR 10.2 g/dl versus non-CR 7.7 g/dl; p=0.03) and a desfavorable prognostic karyotype at the diagnosis of AL (CR 1/6 versus 5/5 non-CR; p=0.013). After CR, five patients underwent allogeneic transplantation and two patients received a second course of FLAG-IDA. Six out of seven patients (85.7%) who achieved CR with FLAG-IDA relapsed at a median of 248 days (95% CI 22.17 to 473.82 days). Overall survival after FLAG-IDA in the surviving cohort had a median of 131 days (95% CI 121 a 565 days) and one year-survival was 35.71%. We found a significantly better overall survival in patients who received allogeneic transplantation post-FLAG-IDA than those who did not (median 694 vs. 121 days; HR 0.24; 95% CI 0.06 to 0.98; p=0.0157). Conclusions: In our series, FLAG-IDA demonstrated to be an effective salvage chemotherapy regimen but with a high rate of treatment-related deaths probably related to bad performance status. We found that the benefit in survival of this rescue treatment was restrained to patients who underwent allogeneic transplantation.

Introduction: the second neoplasm, are pathologies described during the post transplant evolution, often associated to immunosuppression. The post transplant lymphoproliferative syndromes, habitually associated to viruses are the most frequent. The BMT is a procedure clearly different from the rest of the transplants, and this difference would also be observed on the incidence and type of tumor in its evolution. The incidence of second malignancies after BMT is low, and is related to the use of chemotherapy, particulary alkylating. agents radiotheraphy and immunosuppression. Objective: To analyze the incidence and characteristics of second neoplasm of the patients undergoing BMT in our Institute. Results: Between 06/93 and 04/05 over a total of 416 transplants, 132 Allogenic and 284 Autologous, 6 cases of second tumor in variable intervals post procedure were stated. Table 1. The data reflects an incidence of second neoplasias of 1,4% (6/416). None of then received radiotherapy in conditioning. No lymphoproliferative syndrome was observed; 2 cases of acute leukemias; being the rest solid tumors with expected evolutions for each pathology. Table 1 Case Disease Conditioning BMT 2nd Tumor Time betwen BMT-Tumor Evolution 1 MM L-PAM AUTO Lung Cancer 120 months Dead 2 CML BuCy ALLO Colon Cancer 72 months Dead 3 MDS BuCy ALLO Merckel cells tumor 60 months Dead 4 NHL CBV AUTO AML 65 months Dead 5 NHL CBV AUTO Bladder Cancer 58 months Alive 26 months 6 NHL CBV AUTO AML 4 months Dead

Several studies (GELA 98.5, MInT) have demonstrated the benefit of combination rituximab (R) with chemotherapy to improve event free and overall survival in patients with DLBCL. We analyzed retrospectively the safety of combination R-CHOP for 6 cycles (rituximab 375 mg/m2 day 1; cyclophosphamide 750 mg/m2 day 1; doxorrubicin 50 mg./m2 day 1; vincristine 1.4 mg/m2 day 1 and prednisone 100 mg/m2 day 1 to 5) the tolerance and adverse effects. We evaluated the response (R), event free survival (EFS) and the overall survival (OS). Between March to December 2004, 28 patients with DLBCL were evaluated, 17 men and 11 women, with a median age 57 years old (range 28 – 84). They were IPI low 21,4 %, low - intermediate 25%, high - intermediate 35,7 % and high risk 17,9 %. Elevated LDH was present en 14 patients, bulky disease > 7 cm in 50% of cases. During the treatment they presented hematologic toxicity grade III 21,4 % and grade IV 25% of cases; 1 patient had anaphilactic reaction; 2 patients pneumonia; 1 patient sepsis; 4 patients neutropenia and fever; and gastric bleeding 1 patient. Response was achieve in 71,4 %: complete response (CR) in 57,1%, parcial (PR) in 14.3 %, and there was no response in 8 patients (28.6%). With follow up of 10 months (range 2 to 18.5) 15 patients were in CR 53,6%, 8 patients died, 7 of then primary no responders. Analyzed by IPI, 60% of CR in intermediate high and high was obtained. The R-CHOP combination is a feasible and safe treatment in our hospitals, and 71,4 % of response was obtained in all patients and 60% of CR in high risk group.

The relapse post ABMT is a terminal stage complication in HD. The allogenic transplant contributes to a different therapeutic approach through the immune anti tumor effect of the Graft versus Host Disease (GVHD) The NST variant of the procedure diminishes the risks of transplant related mortality (TRM) and is associated with induction of mixed hematopoietic chimerism when either HLA-identical sibling or unrelated donor are used, and that powerful GVT effects can be achieved against advanced chemotherapy/resistant hematology disease. The feasibility, risk and effectiveness of the NST, is analyzed in 13 patients with relapsed HD after ABMT. Seven women and six men with a median age of 26 years old. They had received ≥ of 3 therapeutic lines that included the high doses and the ABMT. The period betwen the diagnosis to NST, had a median time of 36 months. The patients were conditioned with Fludarabine based schemes plus: Melphalan 8, Cyclofosfamide 3, TBI 1, Busulfan 1. The sources of stem cells were, with a HLA-identical sibiling donors in 12 patients, and in 1 with non related donor. 4 patients died due to complications associated with the BMT (TRM 28 %): shock 2, sepsis 1, thrombotic microangiophaty 1. Half of the patients developed some form of GVHD, or it was induced by donor lymphocytes infusion. With an average follow up of 15 months (range: 1–56), 7 patients are alive, 5 of them developed GVHD and are in CR, the other 2 have a short follow up (28 and 75 days). Of 4 patients who progressed only 1 present GVHD. The NST is a feasible procedure in HD relapsed post ABMT. The TRM is 28 %. In this group there is a clear relationship between the control of HD and the appearance of GVHD.

The galectins are a family of carbohydrate-binding proteins that are distributed widely in vertebrate organisms. Each galectin exhibits a specific pattern of expression in various cells and tissues. Although these proteins are found mainly in the cytoplasm, some of them are secreted from cells and interact with other glycosylated molecules at the cell surface or with the extracellular matrix. There is no information about the interaction of Gal-1 and hematopoietic progenitor cells (HPC). We studied the effect of rat recombinant galectin-1 (rGal-1) on the clonogenic capability and the morphologic differentiation of the human umbilical cord blood HPC in methylcellulose cultures. The quantification of total anti-Gal-1 binding capability (total receptors) was also determined by flow citometry. First, the cells of 10 human cord blood units were collected and CD34+ selected using an indirect immunomagnetic method (MidiMACS, Miltenyi, Biotec). Ten thousand events were acquired in a flow cytometer (FACScan, Becton Dickinson), employing 105 CD34+ cells, rabbit anti Gal-1 antiserum and anti-rabbit IgG FITC antibody. Finally the CD34+ cells were cultured in a semisolid methylcellulose medium (Methocult GF+ H4435, StemCell) by triplicate at 37°C, 5% CO2 and 100% humidity during 14 days, employing 24 wells culture plates (Nunc) in presence or not of different concentrations of rGal-1 (2, 4, 6 and 20 μg/ml). We analyzed the number of GEMM-CFU (mix colonies), GM-CFU (granulocyte- macrophage colonies), BFU-E (erythroid colonies) and the presence of signals of abnormal morphologic differentiation. Control of inhibition with thiodigalactoside (TDG) and lactose (Lac) 100 mM was done in every case to determine the assay specificity. Histograms show a total receptor mean expression (mean+/−SEM) in CD34+ cells of 18.2+/−2.44% which was significantly inhibited (p

Immune cytopenias (IC) frequently require prolongued administration of immunosupressors, especially when associated with lymphoproliferative disorders (LPD). Rituximab causes in vivo selective destruction of B lymphocytes and supresses the production of antibodies. Three mechanisms are involved; complement dependent cytotoxicity, antibody dependent cellular citotoxicity and the induction of apoptosis. We present 10 patients with IC: 8 autoimmune hemolytic anemia (AIHA), and 2 AIHA plus immune thombocytopenia (Evans’ syndrome). Seven patients had IC associated with LPD, and 3 were idiopathic. LPD were: 3 follicular lymphoma (1 Grade 1, 1 Grade 2, 1 Grade 3), 1 small lymphocytic lymphoma, 3 chronic lymphocytic leukemia. Three patients with idiopathic cytopenias had a long history of recurrent AIHA (2) and Evans’ syndrome (1). Ages ranged between 43 and 81 (median 63 yrs); 6 were female gender and 4 male. All AIHA cases, except 1 pts with cryogrobulins, presented with warm IgG antibodies. Previous evolution included splenectomy in 2 pts and all pts received multiple courses of immunosupression with steroids and others, like azathioprine and cyclophosphamide. All patients with LPD received one or more chemotherapeutic regimens with alkylating agents, fludarabine or CHOP combination. Median time to IC in 7 pts with LPD was 75 months (2–228). Idiopathic cases had 12, 132 and 204 months of previous evolution. Rituximab was administered at 375 mg/m2 every 1 to 3 weeks for 3 to 8 doses (median 4). Six pts received rituximab as monotherapy and 4 pts in combination with chemotherapy. Toxicity was mainly related to the first cycle of rituximab and consisted in chills and fever grade I-II in three pts. Clinical resolution of cytopenia occured in 9/10 pts (90%). 4 of them (44%) resolved with negative direct antiglobuline test. Median time to response was 4 weeks (2–8). One AHIA died with hemolysis progression, six months after rituximab, and 1 pts with AHIA and follicular lymphoma died 8 months after rituximab treatment with progression of LPD without evidence of hemolysis. The rest of the patients remained without IC for 2–42 months (median 18). Rituximab, originally designed to treat B-cell neoplasms, is an active immunosupressive agent in either lymphoproliferative associated or idiopathic autoimmune cytopenias even in non splectomized pts. Its use may avoid the secondary effects of long term administration of steroids, alkylating agents or transfusions.

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