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The use of tyrosine kinase inhibitors seems to restore the broadly compromised immune system described in chronic myeloid leukaemia (CML) patients at diagnosis leading to a re-activation of the effector-mediated immune surveillance. Here, we describe the expression dynamics of immune factors during the first year on imatinib therapy. Gene expression was evaluated in 132 peripheral blood samples from 79 CML patients, including 34 who were serially followed. An aliquot of the stored sample used to monitor BCR-ABL1 levels was retro-transcribed to cDNA and gene expression was quantified by real-time PCR. An elevated expression of ARG1 was observed at diagnosis, while TBET, CIITA, IL10 and TGFB1 were significantly decreased. Once on therapy, each gene displayed a particular behaviour. ARG1 normalized to control levels at 3 months only in optimal molecular responders and was identified as the major contributor to the difference among patients. TBET reached normal levels after 12 months in optimal responders and non-responders, regardless the Th1-response previously associated, and CIITA continued downregulated. IL10 and TGFB1 achieved normal levels early at 3 months in both groups, afterwards IL10 was sustained while TGFB1 was slightly increased after 1 year in responders. Our findings are in agreement with an immune re-activation after imatinib initiation; however, some immune mediators may require a longer exposition. The follow-up of novel and reliable biomarkers, such as ARG1, one of the principal mechanisms of myeloid-derived-suppressor cells to inhibit immune system, may be useful to deepen the characterization of early responder patients.

We aimed at analyzing the outcome of allogeneic stem cell transplant (ASCT) in adult patients with acute lymphoblastic leukemia (ALL), comparing Haploidentical (Haplo) with HLA-matched (sibling and unrelated) donors. Between 2008 and 2017, we collected data from 236 patients (median age 31 years; range 16–64; 90% HCT-CI 0–1) who underwent unmanipulated ASCT in first complete remission and subsequent remissions in 15 Argentinian centers. Donors were HLA-matched (n = 175; 74%) and Haplo (n = 61; 26%). Two-year overall survival (OS) was 55% (95% CI 47–63) for the HLA-matched group and 49% (95% CI 34–62) for the Haplo group (p = 0.351). For OS, crude HR, adjusted HR for covariates (HR 1.24; 95% CI 0.77–1.99; p = 0.363) and HR including a propensity score in the model (HR 1.22; 95% CI 0.71–2.08; p = 0.414) showed no impact of donor category on the OS. No difference was found in terms of nonrelapse mortality, relapse, leukemia-free survival, and grade 3–4 acute graft-versus-host disease (GVHD); 2-year incidence of chronic GVHD was higher in HLA-matched vs Haplo group (p = 0.028). Patients with ALL who underwent ASCT were young subjects with low HCT-CI. In this setting, a Haplo donor represents an alternative widely available in the absence of an HLA-matched donor. Relapse remains a challenge for all donor categories.

Introduction AML is a clonal disease that originates in myeloid progenitor cells, with a variable overall survival depending on cytogenetic and mutational anomalies. Objective To characterize the adult AML population in a public hospital in Buenos Aires province and their outcomes after induction chemotherapy treatment. Materials and Methods We performed a retrospective descriptive analysis of patients older than 16 years with a diagnosis of AML (non-promyelocytic) in the time period between January 2014 to June 2019. Forty-four patients were included, who received either chemotherapy with a 7+3 regimen (cytarabine + anthracicline), hypomethilating agents (decitabine or azacitidine), or supportive treatment. Results The total population consisted of 47 patients, 62% (n=29) men and 38% (18) female. The median age was 43 years (IQR 16–79). A cytogenetic study was performed in 43 patients, of which 38 had a correct number of metaphases. According to the ELN 2017 classification, of these 38 patients, 5 (13%) were favorable risk, 23 (60%) were intermediate risk, and 9 (24%) were adverse risk. All patients had a immunophenotyping study at diagnosis. AML subtype was “AML not otherwise specified” in 32 patients (68%). Mutational analysis (mainly FLT3 and NPM1 status) could only be performed in a routine fashion starting from January 2018. Of the 47 patients, 44 received an induction regimen of 7+3, 2 received hypomethilation agents, and 1 received support treatment only. The median overall survival was 10 months. Of the 44 patients treated with intensive chemotherapy, 31 (70%) achieved CR after one induction regimen, while 18 (40.9%) required a second induction regimen, and 4 (9.0%) were primarily refractory. Nine (20.45%) patients who received intensive induction chemotherapy died. The nine patients who died during induction treatment had a mean age of 47.67 years and a median age of 43. Their mean performance status score was 2.3. Their mean leukocyte count at diagnosis was 90151.11/mm3 with a median of 9000/mm3. Conclusions The outcomes in our population are similar to those reported in the international literature as the number of patients reaching CR status after induction treatment, with our mortality in this stage still being high.

Translocation t(4;11)(q21;p15) is a rare recurrent change associated to T-cell acute leukemia. In most cases, this alteration appears as the only abnormality or as part of a simple karyotype. In this report, we present the first case of T acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) with the unbalanced translocation der(11)t(4;11)(q21;p15) as part of a very complex karyotype with multiple chromosome abnormalities, most of them not previously described in the literature. FISH (fluorescence in situ hybridization) and spectral karyotype (HiSKY) analysis confirmed the presence of complex alterations. The patient, a 16-year-old male, showed poor response to treatment and short survival (11 months). A detailed review of previously reported cases with t(4;11)(q21;p15) is also provided. The description of this type of alterations may contribute to the identification of new molecular mechanism associated to neoplastic development. Fil: Colli, Sandra. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina Fil: Furforo, Lilian. Dirección Nacional de Instituto de Investigación. Administración Nacional de Laboratorios e Institutos de Salud "Dr. Carlos G. Malbrán". Centro Nacional de Genética Médica; Argentina Fil: Rojo Pisarello, Eduardo. Hospital de Alta Complejidad “Presidente Juan Domingo Perón"; Argentina Fil: Maidana, Marcela. Hospital de Alta Complejidad “Presidente Juan Domingo Perón"; Argentina Fil: Martín, Carlos. Consultorio de Hematopatología; Argentina Fil: Bordone, Javier. Hospital de Alta Complejidad “Presidente Juan Domingo Perón"; Argentina Fil: Slavutsky, Irma Rosa. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; Argentina

Summary Objective To evaluate in a multivariate analysis the prognostic factors associated with hematopoietic recovery and the supportive care requirements after autotransplant of progenitor cells (PC) from various sources: bone marrow (BMPC), BMPC & peripheral blood (PBPC), and PBPC alone. Patients and methods A total of 570 patients with hematological malignancies and solid tumors underwent high-dose therapy followed by autotransplant. PBPC were obtained after mobilization with chemotherapy and/or cytokines. One-hundred five patients received BMPC, 217 received BMPC & PBPC and 248 PBPC alone; all of the patients received G-CSF or GM-CSF after infusion. Results In a multivariate analysis the recovery of neutrophils was adversely associated with low numbers of nucleated cells infused (P < 0.13), bone marrow progenitor cell source, and diagnosis of multiple myeloma and acute leukemia (P < 0.001). The factors that adversely affected platelet recovery were low number of nucleated cells and diagnosis of multiple myeloma and acute leukemia (P < 0.001). Conclusion We conclude that BMPC adversely affect neutrophil recovery while low numbers of nucleated cells and diagnosis of multiple myeloma and acute leukemia adversely affect both neutrophil and platelet recovery.

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

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.

A 44-year-old male with Ph + chronic myeloid leukaemia (CML) underwent histoidentical allogeneic bone marrow transplantation 18 months after initial diagnosis. He received pretransplant conditioning with busulphan and cyclophosphamide (Bucy). GVHD prophylaxis consisted of methotrexate, cyclosporine (CsA) and methyl-prednisolone. On day +50, he developed a microangiopathic haemolytic anaemia with indirect bilirubinaemia, 10% fragmented red cells (FC) and an elevated LDH (1213 U/l: normal range 100-185 U/l). Clinical symptoms consisted of edema and hypertension. The patient was not febrile and had no neurological changes. A clinical diagnosis of severe (grade 4) multifactorial (acute GVHD, CMV infection and cyclosporine) BMT-TM was made. He responded following 19 plasma exchanges with replacement with fresh frozen plasma.

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.

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

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

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.

Response to single-agent thalidomide and eligibility to undergo autotransplant for patients with multiple myeloma refractory to VAD