Pau Montesinos - Academia.edu (original) (raw)

Papers by Pau Montesinos

Cancer, 2015

Some copy number alterations (CNAs) have independent prognostic significance for adults with acut... more Some copy number alterations (CNAs) have independent prognostic significance for adults with acute lymphoblastic leukemia (ALL). This study analyzed via multiplex ligation-dependent probe amplification the frequency and prognostic impact of CNAs of 12 genetic regions in 142 adolescents and adults with de novo precursor B-cell ALL. The cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) deletion (59 of 142 or 42%) was the most frequent CNA, and it was followed by Ikaros family zinc finger 1 (IKZF1) losses (49 of 142 or 35%). IKZF1 deletions were more prevalent in Philadelphia chromosome (Ph)-positive ALL and were associated with advanced age and high white blood cell (WBC) counts. The multivariate analysis showed that advanced age and early B-cell factor 1 (EBF1) deletions were associated with chemotherapy resistance in both the whole series (hazard ratios, 0.949 and 0.135, respectively) and the Ph-negative subgroup (hazard ratios, 0.946 and 0.118, respectively). High WBC counts and focal IKZF1 deletions correlated with disease recurrence (hazard ratios, 1.005 and 1.869, respectively), whereas advanced age and CDKN2A/B losses influenced overall survival in both the whole series (hazard ratios, 1.038 and 2.545, respectively) and the Ph-negative subgroup (hazard ratios, 1.044 and 2.105, respectively). Deletions of EBF1, IKZF1, and CDKN2A/B have an independent adverse prognosis for adolescents and adults with B-precursor ALL, and this suggests that these CNAs should be included in the initial risk assessment of ALL. Cancer 2015. © 2015 American Cancer Society.

Biology of Blood and Marrow Transplantation, 2014

Total nucleated (TNCs) and CD34(+) cells are considered major determinants of outcome after umbil... more Total nucleated (TNCs) and CD34(+) cells are considered major determinants of outcome after umbilical cord blood (UCB) transplantation but the effect of other cell subtypes present in the graft is unknown. This single-center cohort study included patients with hematological malignancies who received UCB transplantation after a myeloablative conditioning regimen. UCB units were primarily selected according to cell content, both TNCs and CD34(+) cells, and also according to the degree of HLA matching. Counts of several cell subtypes of the infused UCB unit, together with HLA disparities and other patient- and transplantation-related characteristics, were analyzed by multivariable methodology for their association with myeloid and platelet engraftment, graft-versus-host disease, nonrelapse mortality (NRM), disease-free survival (DFS), and overall survival (OS). Two hundred patients (median age, 32 years) were included in the study. In multivariable analyses, a greater number of CD8(+) cells was significantly associated with better results for myeloid (P = .001) and platelet (P = .008) engraftment, NRM (P = .02), DFS (P = .007), and OS (P = .01). CD34(+) cell content was predictive of myeloid engraftment (P < .001). This study suggests that the outcome after UCB transplantation in adults with hematological malignancies could be better when UCB grafts had a greater CD8(+) cell content.

International Journal of Hematology, 2007

Infectious complications are a major cause of morbidity and mortality in patients who undergo aut... more Infectious complications are a major cause of morbidity and mortality in patients who undergo autologous stem cell transplantation (ASCT). We examined 476 patients with hematologic malignancies (401) or solid tumors (75) who underwent ASCT between February 1990 and May 2005. Anti-infectious prophylaxis consisted of different combinations of ciprofloxacin, cotrimoxazole, fluconazole, aerosolized amphotericin B, acyclovir, and intravenous immunoglobulins. Overall, 454 patients (95%) developed fever in the first 60 days after ASCT. In the majority of patients, initial antibiotic therapy consisted of broadspectrum β-lactamic with or without amikacin. A glycopeptide was administered as initial therapy in 86 cases. Overall, there were 132 (29%) clinically documented infections (37 pneumonias), 79 (17%) microbiologically documented infections (65 bacteremias), and 243 (54%) fevers of unknown origin. Coagulase-negative staphylococci (18, 25%) and E coli (18, 25%) were the organisms most frequently isolated. The pattern of infection did not change throughout the study except for a significantly higher incidence of bacteremia due to gram-positive bacteria in the first 5 years of the study. Infection-related mortality was 5% (21 cases), with pneumonia the most frequent cause of death. ASCT should be considered a low-risk procedure, although new therapeutic approaches for patients developing severe respiratory infections are still needed.

Haematologica, 2015

This phase Ib/II trial combined the pan-deacetylase inhibitor panobinostat with chemotherapy foll... more This phase Ib/II trial combined the pan-deacetylase inhibitor panobinostat with chemotherapy followed by panobinostat maintenance in elderly patients with newly diagnosed acute myeloid leukemia. Patients with prior history of myelodisplastic syndrome were excluded. Thirty-eight evaluable patients (median age, 71 years; range, 65-83) received an induction with idarubicin (8 mg/m2 iv days 1-3) plus cytarabine (100 mg/m2 iv days 1-7) plus panobinostat po at escalating doses (days 8, 10, 12, 15, 17 and 19), that could be repeated in non-responding patients. Patients achieving complete remission received a consolidation cycle with the same schema, followed by panobinostat maintenance (40 mg po 3 days/week) every other week until progression. Thirty-one patients were treated at the maximum tolerated dose of panobinostat in the combination (10 mg) with good tolerability. The complete remission rate was 64% with a time to relapse of 17.0 months (12.8-21.1). The median overall survival for the whole series was 17 months (5.5-28.4). Moreover, in 4 out of 5 patients with persistent minimal residual disease before maintenance, panobinostat monotherapy reduced its levels, with complete negativization in two of them. Maintenance phase was well tolerated being the most frequent adverse events thrombocytopenia (25% grades 3/4), and gastrointestinal toxicity, asthenia and anorexia mainly grades 1/2. Five patients required dose reduction during this phase, but only one discontinued due to toxicity. These results suggest that panobinostat is one of the first novel agents with activity in elderly acute myeloid leukemia patients, and warrants its investigation particularly in the context of maintenance therapy. The trial was registered in www.clinicaltrials.gov with number NCT00840346.

Bone Marrow Transplantation, 2014

EBV-associated post-transplant lymphoproliferative disease (PTLD) following Alemtuzumab-based all... more EBV-associated post-transplant lymphoproliferative disease (PTLD) following Alemtuzumab-based allo-SCT is a relatively uncommon and challenging clinical problem but has not received detailed study in a large cohort. Quantitative-PCR (qPCR) monitoring for EBV reactivation post allo-SCT is now commonplace but its diagnostic and predictive value remains unclear. Sixty-nine patients with PTLD following Alemtuzumab-based allo-SCT were studied. Marked clinicopathological heterogeneity was evident; lymphadenopathy was frequently absent, whereas advanced extranodal disease was common. The median viral load at clinical presentation was 49 300 copies/mL (50-65 200 000 copies/mL) and, notably, 23% and 45% of cases, respectively, had 10 000 and 40 000 copies/mL. The overall response rate to rituximab as first-line therapy was 70%. For rituximab failures, chemotherapy was ineffectual but DLIs were successful. A four-parameter prognostic index predicted response to therapy (OR 0.30 (0.12-0.74); P=0.009] and PTLD mortality (hazard ratio (HR) 1.81 (1.12-2.93) P=0.02) on multivariate analysis. This is the largest detailed series of EBV-associated PTLD after allo-SCT. At clinical presentation, EBV-qPCR values are frequently below customary thresholds for pre-emptive therapy, challenging current paradigms for monitoring and intervention. A four-point score identifies a proportion of patients at risk of rituximab-refractory disease for whom alternative therapy is needed.

The Pharmacogenomics Journal

The ABCB1 gene encodes for P-glycoprotein (P-gp), an efflux pump for a variety of xenobiotics. Th... more The ABCB1 gene encodes for P-glycoprotein (P-gp), an efflux pump for a variety of xenobiotics. The role of ABCB1 polymorphisms in acute myeloid leukemia (AML) outcomes of standard chemotherapy (cytarabine plus anthracyclines) remains controversial. A systematic search was made of studies evaluating the association between ABCB1 polymorphisms 1236C>T, 2677G>T/A and 3435C>T and effectiveness variables. We found seven cohort studies (1241 patients) showing a significantly higher overall survival (OS) among carriers of the variant allele of 1236C>T at year 4 (odds ratio (OR): 1.47, 95% confidence interval (CI): 1.07-2.01), 2677G>T/A at years 4-5 (OR: 1.37, 95% CI: 1.01-1.86) and 3435C>T at years 3 (OR: 1.41, 95% CI: 1.03-1.94) and 4-5 (OR: 1.42, 95% CI: 1.05-1.91). In the subgroup analysis according to ethnicity, Caucasians carrying variant allele showed consistent results in OS. ABCB1 influence upon complete remission could not be demonstrated. Future studies based on...

Biology of Blood and Marrow Transplantation, 2014

Graft failure is a severe treatment complication of unrelated donor umbilical cord blood transpla... more Graft failure is a severe treatment complication of unrelated donor umbilical cord blood transplantation (UCBT). Its incidence seems to be higher after UCBT than after transplantation with bone marrow or peripheral blood stem cells (PBSCs). The only curative option is to perform a second transplantation; however, both the ideal stem cell source and the conditioning regimen for this salvage transplantation remain unclear. We report a series of 11 patients who underwent haploidentical PBSC transplantation (PBSCT) as salvage therapy for graft failure after a previous UCBT. The reduced-intensity conditioning regimen consisted of fludarabine 150 mg/m(2) for 3 days and horse antithymocyte globulin 8 mg/kg for 4 days. Ex vivo CD34(+) positive selection was performed in all cases, and no post-transplantation graft-versus-host disease prophylaxis was used. Six of the 9 evaluable patients (67%) eventually engrafted, at a median time of 10 days. The cumulative incidence of engraftment at 28 days was 64% (95% confidence interval [CI], 35% to 92%). Two patients relapsed after PBSCT. The cumulative incidence of TRM was 55% at 2 years (95% CI, 25% to 84%), and the probability of overall survival at 2 years was 36%. Our findings suggest that haploidentical ex vivo T cell-depleted PBSCT is a feasible alternative for treating graft failure after UCBT.

Leukemia

In 2008, a European registry of relapsed acute promyelocytic leukemia (APL) was established by th... more In 2008, a European registry of relapsed acute promyelocytic leukemia (APL) was established by the European LeukemiaNet. Outcome data were available for 155 patients treated with arsenic trioxide (ATO) in first relapse. In hematological relapse (n=104), 91% of the patients entered complete hematological remission (CR), 7% had induction death and 2% resistance, 27% developed differentiation syndrome and 39% leukocytosis, whereas no death or side effects occurred in patients treated in molecular relapse (n=40). The rate of molecular (m)CR was 74% in hematological and 62% in molecular relapse (p=0.3). All patients with extramedullary relapse (n=11) entered clinical and mCR. After 3.2 years median follow-up, the three-year overall survival (OS) and cumulative incidence of second relapse were 68% and 41% in hematological relapse, 66% and 48% in molecular relapse and 90% and 11% in extramedullary relapse, respectively. After allogeneic or autologous transplantation in 2(nd) CR (n=93), the...

Biology of Blood and Marrow Transplantation, 2012

An abnormal increase of nonleukemic blastic-appearing lymphocytes in bone marrow (BM) specimens h... more An abnormal increase of nonleukemic blastic-appearing lymphocytes in bone marrow (BM) specimens has been reported after unrelated cord blood transplantation (UCBT). This study analyzed the incidence, chronology, biological features, and clinical significance of elevated numbers of these cells in a series of 165 consecutive adult patients demonstrating myeloid engraftment after myeloablative UCBT in a single institution. The patients' BM samples were routinely evaluated by cytomorphology at different time points after UCBT. When 55% of blastic-appearing cells were detected by cytomorphology in the BM, samples were also evaluated by multiparametric flow cytometry to characterize these cells. Systematic chimerism analyses of BM samples using PCR amplification of short tandem repeat markers were performed. Forty-three patients (cumulative incidence, 26.1%) demonstrated 55% of nonmalignant blastic-appearing cells in BM after a median of 101 days after UCBT (range, 28-377 days). All of these patients had full-donor chimerism and a clinical course without leukemic relapse. Multiparametric flow cytometry analyses performed in 36 of the 43 patients showed a polyclonal expansion of B lymphocytes with a broad spectrum of maturation stages. An increased number of nonmalignant blastic-appearing cells was significantly associated with a high number of lymphocytes infused at the time of UCBT and with low rates of acute and chronic extensive graft-versushost disease, suggesting a potential immunoregulatory role of these cells. The observation of $5% nonmalignant blastic-appearing cells in BM samples after myeloablative UCBT is frequent, and these should be distinguished from malignant blasts.

Annals of Hematology, 2015

Front-line treatment of acute promyelocytic leukaemia (APL) consists of all-trans retinoic acid (... more Front-line treatment of acute promyelocytic leukaemia (APL) consists of all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy. In this setting, a comparison of idarubicin and daunorubicin has never been carried out. Two similar clinical trials using ATRA and chemotherapy for newly diagnosed APL were compared using matched-pair analysis. One was conducted by the PETHEMA/HOVON group with idarubicin and the other by the International Consortium on APL (IC-APL) using daunorubicin. Three hundred and fifty patients from the PETHEMA/HOVON cohort were matched with 175 patients in the IC-APL cohort, adjusting for the significantly unbalanced presenting features of the two However, a higher toxic death rate during induction and consolidation therapy was observed in the IC-APL cohort. This trial was registered at www.clinicaltrials.gov as #NCT00408278 [ClinicalTrials.gov].

Blood transfusion = Trasfusione del sangue, Jan 2, 2015

There are ABO antigens on the surface of platelets, but whether ABO compatible platelets are nece... more There are ABO antigens on the surface of platelets, but whether ABO compatible platelets are necessary for transfusions is a matter of ongoing debate. We retrospectively reviewed the ABO matching of platelet transfusions in a subset of patients undergoing autologous haematopoietic progenitor cell transplantation during a 14-year period. Our aim was to analyse the characteristics and outcomes of patients who received platelet transfusions that were or were not ABO identical. We analysed 529 consecutive patients with various haematological and non-haematological diseases who underwent 553 autologous progenitor stem cell transplants at the University Hospital la Fe between January 2000 and December 2013. We retrospectively analysed and compared transfusion and clinical outcomes of patients according to the ABO match of the platelet transfusions received. The period analysed was the time from transplantation until discharge. The patients received a total of 2,772 platelet concentrates, ...

Biology of Blood and Marrow Transplantation, 2009

There is no information on the efficacy and safety of anticytomegalovirus (CMV) prophylaxis with ... more There is no information on the efficacy and safety of anticytomegalovirus (CMV) prophylaxis with intravenous ganciclovir or oral valganciclovir after unrelated cord-blood transplantation (UCBT). This issue was addressed in 151 adults (117 CMV-seropositive) undergoing UCBT at a single institution. The first 38 CMV-seropositive recipients were assigned to receive prophylactic ganciclovir, and the next 79 were given valganciclovir after engraftment. The cumulative incidence (CI) of CMV infection and disease was similar in patients receiving valganciclovir or ganciclovir (59% versus 55%, P 5.59; and 9% versus 18%, P 5.33, respectively). The toxicity profile and CI of nonrelapse mortality (CMV) and infection-related mortality did not differ between drugs. Patients receiving valganciclovir required fewer visits to the day hospital (P 5.04). The CI of CMV infection and disease in 34 CMV-seronegative recipients was 12% and 6%, indicating that tight CMV monitoring is mandatory in this subset. The recipient's CMV serostatus, acute and extensive chronic graftversus-host disease (aGVHD, cGVHD) were the main risk factors for CMV infection, and aGVHD for CMV disease. This study suggests that prophylaxis with oral valganciclovir is as safe and effective as intravenous ganciclovir for preventing CMV infection and disease after UCBT, but valganciclovir reduces the use of hospital resources.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 20, 2014

Most patients with acute myeloid leukemia (AML) eventually experience relapse. Relapsed/refractor... more Most patients with acute myeloid leukemia (AML) eventually experience relapse. Relapsed/refractory AML has a dismal prognosis and currently available treatment options are generally ineffective. The objective of this large, international, randomized clinical trial was to investigate the efficacy of elacytarabine, a novel elaidic acid ester of cytarabine, versus the investigator's choice of one of seven commonly used AML salvage regimens, including high-dose cytarabine, multiagent chemotherapy, hypomethylating agents, hydroxyurea, and supportive care. A total of 381 patients with relapsed/refractory AML were treated in North America, Europe, and Australia. Investigators selected a control treatment for individual patients before random assignment. The primary end point was overall survival (OS). There were no significant differences in OS (3.5 v 3.3 months), response rate (23% v 21%), or relapse-free survival (5.1 v 3.7 months) between the elacytarabine and control arms, respecti...

Biology of Blood and Marrow Transplantation, 2005

Thirty-seven patients, median age 58 yrs (8 -69), with AML undergoing allogeneic stem cell transp... more Thirty-seven patients, median age 58 yrs (8 -69), with AML undergoing allogeneic stem cell transplantation (SCT) after reduced intensity conditioning (RIC) at three Swedish SCT centers were analyzed retrospectively. All except six patients received RIC due to high age or co-morbidity. Twenty-three patients were transplanted in first remission and 14 with more advanced disease. Donors were siblings (nϭ22) or matched unrelated donors (MUD, nϭ15). Conditioning was fludarabine ϩ busulfan Ϯ anti-thymocyte globulin (nϭ32), fludarabine ϩ treosulfan (nϭ3) or fludarabine ϩ 2 Gy total body irradiation (nϭ2). As stem cell source bone marrow was used in six patients and peripheral blood stem cells in 31. All patients engrafted. At a median follow-up of 15 months (3-63) acute graft-versus-host disease (GVHD) grade 0/I/II/III/IV developed in 22/7/5/0/1 recipients, respectively. Limited chronic GVHD was seen in five and extensive in seven patients among 33 patients at risk. Donor lymphocyte infusions were given to 16 patients due to mixed chimerism, minimal residual disease or relapse. In total 15 patients relapsed and 12 of them died. Only one patient died from a transplant related cause, acute GVHD. Kaplan-Meier probability for survival at 1 yr is 79% and for leukaemia-free survival (LFS) 68%. Among 23 patients, age 53 yrs (8 -69) transplanted in first remission with 16 sibling donors and seven MUD, eight relapsed (35%) and five of them died. There was no transplant-related mortality (TRM) among patients in first remission. Kaplan-Meier probability for survival and LFS at 1 yr is 86% and 72%, respectively for patients receiving transplantation in first remission. Reduced intensity conditioning with a fludarabine containing regimen and transplantation with a sibling or MUD gives a low TRM even in older patients with AML. Survival is encouraging but leukemia relapse remains a major problem. Randomized or controlled prospective trials comparing RIC with conventional conditioning for younger patients and trials comparing RIC to chemotherapy for elderly patients are urgently warranted.

Biology of Blood and Marrow Transplantation, 2015

The incidence, epidemiology, and risk factors of bloodstream infection (BSI) and their impact on ... more The incidence, epidemiology, and risk factors of bloodstream infection (BSI) and their impact on transplant outcomes after umbilical cord blood transplantation (UCBT) are not well defined. Between May 1997 and December 2012, 202 isolates in 189 episodes of BSI were registered in 134 of 241 patients who underwent single-unit myeloablative UCBT. Cumulative incidence (CI) of developing at least 1 episode of BSI was 21%, 29%, 34%, 42%, and 52% at days +7, +14, +30, +100, and +365, respectively. The median time of onset for the first BSI episode was day +10 (range, day -7 to +1217). Early BSI before day 7 was associated with increased nonrelapse mortality (relative risk [RR], 1.5; 95% confidence interval [CI], 1.1 to 2.3; P = .04), whereas BSI before day 14 was an independent adverse risk factor for neutrophil recovery (RR, .6; 95% CI, .5 to .9; P = .002). A higher CD8(+) cell dose of the graft was the only variable independently associated with reduced risk of BSI (RR, .1; 95% CI, .02 to .7; P = .02). The gram-negative rod (GNR) to gram-positive bacteria ratio was .9 before day +30 and 1.6 thereafter (P = .03). Escherichia coli (31%) and Pseudomonas sp. (28%) were the most frequently isolated among GNR. The overall crude mortality rate was 12% at day 7 and was higher for GNR (18%) compared with gram-positive bacteria (7%) (P = .03). These findings emphasize the importance of preventing bacterial infections during conditioning and the very early post-UCBT period.

Biology of Blood and Marrow Transplantation, 2010

Clinical studies focused on outcomes of umbilical cord blood transplantation (UCBT) for patients ... more Clinical studies focused on outcomes of umbilical cord blood transplantation (UCBT) for patients with chronic myelogenous leukemia (CML) in need of allogeneic stem cell transplantation and lacking an HLA-matched adult donor are limited. We analyzed the outcome of 26 adults with CML receiving single-unit UCBT from unrelated donors after myeloablative conditioning at a single institution. Conditioning regimens were based on combinations of thiotepa, busulfan, cyclophospamide or fludarabine, and antithymocyte globulin. At the time of transplantation, 7 patients (27%) were in first chronic phase (CP), 11 (42%) were in second CP, 2 (8%) were in accelerated phase (AP), and 6 (23%) were in blast crisis (BC). The cumulative incidence (CI) of myeloid engraftment was 88% at a median time of 22 days and was significantly better for patients receiving higher doses of CD34(+) cells. The CI of acute graft-versus-host disease (GVHD) grade II-IV was 61%, that of acute GVHD grade III-IV was 39%, and that of chronic extensive GVHD was 60%. Treatment-related mortality (TRM) was 41% for patients undergoing UCBT while in first or second CP and 100% for patients in AP or BC (P < .01). After a median follow-up of 8 years, none of the patients relapsed, giving an overall disease-free survival (DFS) at 8 years of 41%. The DFS for patients undergoing UCBT while in any CP was 59%. These results demonstrate that UCBT from unrelated donors can be a curative treatment for a substantial number of patients with CML. Advances in supportive care and better selection of cord blood units and patients are needed to improve TRM.

Cancer, 2014

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

Biology of Blood and Marrow Transplantation, 2010

Clinical studies focused on disease-specific outcomes of cord blood transplant (CBT) from unrelat... more Clinical studies focused on disease-specific outcomes of cord blood transplant (CBT) from unrelated donors are limited. We analyzed the outcome and prognostic factors of 49 adults with high-risk acute myelogenous leukemia (AML) receiving single-unit CBT from unrelated donors after myeloablative (MA) conditioning at a single institution. Conditioning regimens were based on the combination of thiotepa, busulfan (Bu), cyclophospamide (Cy), or fludarabine (Flu), and antithymocyte globulin (ATG). Cumulative incidence of myeloid and platelet engraftment was 96% and 73% at a median time of 20 and 62 days, respectively. Engraftment was significantly faster for patients receiving higher doses of CD34 1 cells. Confidence Interval of graft-versushost disease (GVHD), acute GVHD (aGVHD) grade II-IV, III-IV, and extensive chronic GVHD (cGVHD) were 26%, 15%, and 30%, respectively. Leukemia-free survival (LFS), nonrelapse mortality (NRM), and relapse at 2 years were 42%, 39%, and 19%, respectively. Low number of total nucleated cells (TNC) had a negative impact on NRM and LFS. Patients transplanted in first complete remission (CR1) receiving TNC above 2 Â 10 7 /kg had a 4-year LFS of 75%. These results show that CBT from unrelated donors is a curative treatment for a substantial number of patients with high-risk AML, particularly if transplant is performed with highly cellular units in patients in first CR.

The Journal of Molecular Diagnostics, 2012

Recently, many novel molecular abnormalities were found to be distinctly associated with acute my... more Recently, many novel molecular abnormalities were found to be distinctly associated with acute myeloid leukemia (AML). However, their clinical relevance and prognostic implications are not well established. We developed a new combination of high-resolution melting assays on a LightCycler 480 and direct sequencing to detect somatic mutations of ASXL1 (exon 12), IDH1 (exon 4), IDH2 (exon 4), and c-CBL (exons 8 and 9) genes to know their incidence and prognostic effect in a cohort of 175 patients with de novo AML: 16 patients (9%) carried ASXL1 mutations, 16 patients had IDH variations (3% with IDH1(R132) and 6% with IDH2(R140)), and none had c-CBL mutations. Patients with ASXL1 mutations did not harbor IDH1, [corrected] or CEBPA mutations, and a combination of ASXL1 and IDH2 mutations was found only in one patient. In addition, we did not find IDH1 and FLT3 or CEBPA mutations concurrently or IDH2 with CEBPA. IDH1 and IDH2 mutations were mutually exclusive. Alternatively, NPM1 mutations were concurrently found with ASXL1, IDH1, or IDH2 with a variable incidence. Mutations were not significantly correlated with any of the clinical and biological features studied. High-resolution melting is a reliable, rapid, and efficient screening technique for mutation detection in AML. The incidence for the studied genes was in the range of those previously reported. We were unable to find an effect on the outcome.

Acta Haematologica, 2013

The clinical heterogeneity of patients with acute myeloid leukemia (AML) or myelodysplastic syndr... more The clinical heterogeneity of patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) with trisomy 8 as the sole abnormality may result from cytogenetically undetectable genetic changes. The purpose of this study was to identify hidden genomic aberrations not detected by metaphase cytogenetics (MC) using high-resolution single nucleotide polymorphism array (SNP-A)-based karyotyping in AML/MDS patients with a sole trisomy 8. The study group included 8 patients (3 AML and 5 MDS) and array-based karyotyping was done using whole-genome SNP-A (SNP 6.0 and SNP 2.7M). By SNP-A, additional genomic aberrations not detected by MC were identified in 2 patients: 1 AML patient exhibited a copy-neutral loss of heterozygosity (CN-LOH) of 3q21.1-q29 and 11q13.1-q25 and the other patient with MDS (refractory cytopenia with unilineage dysplasia) had CN-LOH of 2p25.3-p15. In particular, the latter patient progressed to AML 18 months after the diagnosis. In 3 patients, aberrations in addition to trisomy 8 were not identified by SNP-A. In the remaining 3 patients, SNP-A could not detect trisomy 8, while trisomy 8 was found in 25-67% of metaphase cells by MC. This study suggests that additional genomic aberrations may in fact be present even in cases of trisomy 8 as sole abnormality by MC, and SNP-A could be a useful karyotyping tool to identify hidden aberrations such as CN-LOH.

Cancer, 2015

Some copy number alterations (CNAs) have independent prognostic significance for adults with acut... more Some copy number alterations (CNAs) have independent prognostic significance for adults with acute lymphoblastic leukemia (ALL). This study analyzed via multiplex ligation-dependent probe amplification the frequency and prognostic impact of CNAs of 12 genetic regions in 142 adolescents and adults with de novo precursor B-cell ALL. The cyclin-dependent kinase inhibitor 2A/B (CDKN2A/B) deletion (59 of 142 or 42%) was the most frequent CNA, and it was followed by Ikaros family zinc finger 1 (IKZF1) losses (49 of 142 or 35%). IKZF1 deletions were more prevalent in Philadelphia chromosome (Ph)-positive ALL and were associated with advanced age and high white blood cell (WBC) counts. The multivariate analysis showed that advanced age and early B-cell factor 1 (EBF1) deletions were associated with chemotherapy resistance in both the whole series (hazard ratios, 0.949 and 0.135, respectively) and the Ph-negative subgroup (hazard ratios, 0.946 and 0.118, respectively). High WBC counts and focal IKZF1 deletions correlated with disease recurrence (hazard ratios, 1.005 and 1.869, respectively), whereas advanced age and CDKN2A/B losses influenced overall survival in both the whole series (hazard ratios, 1.038 and 2.545, respectively) and the Ph-negative subgroup (hazard ratios, 1.044 and 2.105, respectively). Deletions of EBF1, IKZF1, and CDKN2A/B have an independent adverse prognosis for adolescents and adults with B-precursor ALL, and this suggests that these CNAs should be included in the initial risk assessment of ALL. Cancer 2015. © 2015 American Cancer Society.

Biology of Blood and Marrow Transplantation, 2014

Total nucleated (TNCs) and CD34(+) cells are considered major determinants of outcome after umbil... more Total nucleated (TNCs) and CD34(+) cells are considered major determinants of outcome after umbilical cord blood (UCB) transplantation but the effect of other cell subtypes present in the graft is unknown. This single-center cohort study included patients with hematological malignancies who received UCB transplantation after a myeloablative conditioning regimen. UCB units were primarily selected according to cell content, both TNCs and CD34(+) cells, and also according to the degree of HLA matching. Counts of several cell subtypes of the infused UCB unit, together with HLA disparities and other patient- and transplantation-related characteristics, were analyzed by multivariable methodology for their association with myeloid and platelet engraftment, graft-versus-host disease, nonrelapse mortality (NRM), disease-free survival (DFS), and overall survival (OS). Two hundred patients (median age, 32 years) were included in the study. In multivariable analyses, a greater number of CD8(+) cells was significantly associated with better results for myeloid (P = .001) and platelet (P = .008) engraftment, NRM (P = .02), DFS (P = .007), and OS (P = .01). CD34(+) cell content was predictive of myeloid engraftment (P < .001). This study suggests that the outcome after UCB transplantation in adults with hematological malignancies could be better when UCB grafts had a greater CD8(+) cell content.

International Journal of Hematology, 2007

Infectious complications are a major cause of morbidity and mortality in patients who undergo aut... more Infectious complications are a major cause of morbidity and mortality in patients who undergo autologous stem cell transplantation (ASCT). We examined 476 patients with hematologic malignancies (401) or solid tumors (75) who underwent ASCT between February 1990 and May 2005. Anti-infectious prophylaxis consisted of different combinations of ciprofloxacin, cotrimoxazole, fluconazole, aerosolized amphotericin B, acyclovir, and intravenous immunoglobulins. Overall, 454 patients (95%) developed fever in the first 60 days after ASCT. In the majority of patients, initial antibiotic therapy consisted of broadspectrum β-lactamic with or without amikacin. A glycopeptide was administered as initial therapy in 86 cases. Overall, there were 132 (29%) clinically documented infections (37 pneumonias), 79 (17%) microbiologically documented infections (65 bacteremias), and 243 (54%) fevers of unknown origin. Coagulase-negative staphylococci (18, 25%) and E coli (18, 25%) were the organisms most frequently isolated. The pattern of infection did not change throughout the study except for a significantly higher incidence of bacteremia due to gram-positive bacteria in the first 5 years of the study. Infection-related mortality was 5% (21 cases), with pneumonia the most frequent cause of death. ASCT should be considered a low-risk procedure, although new therapeutic approaches for patients developing severe respiratory infections are still needed.

Haematologica, 2015

This phase Ib/II trial combined the pan-deacetylase inhibitor panobinostat with chemotherapy foll... more This phase Ib/II trial combined the pan-deacetylase inhibitor panobinostat with chemotherapy followed by panobinostat maintenance in elderly patients with newly diagnosed acute myeloid leukemia. Patients with prior history of myelodisplastic syndrome were excluded. Thirty-eight evaluable patients (median age, 71 years; range, 65-83) received an induction with idarubicin (8 mg/m2 iv days 1-3) plus cytarabine (100 mg/m2 iv days 1-7) plus panobinostat po at escalating doses (days 8, 10, 12, 15, 17 and 19), that could be repeated in non-responding patients. Patients achieving complete remission received a consolidation cycle with the same schema, followed by panobinostat maintenance (40 mg po 3 days/week) every other week until progression. Thirty-one patients were treated at the maximum tolerated dose of panobinostat in the combination (10 mg) with good tolerability. The complete remission rate was 64% with a time to relapse of 17.0 months (12.8-21.1). The median overall survival for the whole series was 17 months (5.5-28.4). Moreover, in 4 out of 5 patients with persistent minimal residual disease before maintenance, panobinostat monotherapy reduced its levels, with complete negativization in two of them. Maintenance phase was well tolerated being the most frequent adverse events thrombocytopenia (25% grades 3/4), and gastrointestinal toxicity, asthenia and anorexia mainly grades 1/2. Five patients required dose reduction during this phase, but only one discontinued due to toxicity. These results suggest that panobinostat is one of the first novel agents with activity in elderly acute myeloid leukemia patients, and warrants its investigation particularly in the context of maintenance therapy. The trial was registered in www.clinicaltrials.gov with number NCT00840346.

Bone Marrow Transplantation, 2014

EBV-associated post-transplant lymphoproliferative disease (PTLD) following Alemtuzumab-based all... more EBV-associated post-transplant lymphoproliferative disease (PTLD) following Alemtuzumab-based allo-SCT is a relatively uncommon and challenging clinical problem but has not received detailed study in a large cohort. Quantitative-PCR (qPCR) monitoring for EBV reactivation post allo-SCT is now commonplace but its diagnostic and predictive value remains unclear. Sixty-nine patients with PTLD following Alemtuzumab-based allo-SCT were studied. Marked clinicopathological heterogeneity was evident; lymphadenopathy was frequently absent, whereas advanced extranodal disease was common. The median viral load at clinical presentation was 49 300 copies/mL (50-65 200 000 copies/mL) and, notably, 23% and 45% of cases, respectively, had 10 000 and 40 000 copies/mL. The overall response rate to rituximab as first-line therapy was 70%. For rituximab failures, chemotherapy was ineffectual but DLIs were successful. A four-parameter prognostic index predicted response to therapy (OR 0.30 (0.12-0.74); P=0.009] and PTLD mortality (hazard ratio (HR) 1.81 (1.12-2.93) P=0.02) on multivariate analysis. This is the largest detailed series of EBV-associated PTLD after allo-SCT. At clinical presentation, EBV-qPCR values are frequently below customary thresholds for pre-emptive therapy, challenging current paradigms for monitoring and intervention. A four-point score identifies a proportion of patients at risk of rituximab-refractory disease for whom alternative therapy is needed.

The Pharmacogenomics Journal

The ABCB1 gene encodes for P-glycoprotein (P-gp), an efflux pump for a variety of xenobiotics. Th... more The ABCB1 gene encodes for P-glycoprotein (P-gp), an efflux pump for a variety of xenobiotics. The role of ABCB1 polymorphisms in acute myeloid leukemia (AML) outcomes of standard chemotherapy (cytarabine plus anthracyclines) remains controversial. A systematic search was made of studies evaluating the association between ABCB1 polymorphisms 1236C>T, 2677G>T/A and 3435C>T and effectiveness variables. We found seven cohort studies (1241 patients) showing a significantly higher overall survival (OS) among carriers of the variant allele of 1236C>T at year 4 (odds ratio (OR): 1.47, 95% confidence interval (CI): 1.07-2.01), 2677G>T/A at years 4-5 (OR: 1.37, 95% CI: 1.01-1.86) and 3435C>T at years 3 (OR: 1.41, 95% CI: 1.03-1.94) and 4-5 (OR: 1.42, 95% CI: 1.05-1.91). In the subgroup analysis according to ethnicity, Caucasians carrying variant allele showed consistent results in OS. ABCB1 influence upon complete remission could not be demonstrated. Future studies based on...

Biology of Blood and Marrow Transplantation, 2014

Graft failure is a severe treatment complication of unrelated donor umbilical cord blood transpla... more Graft failure is a severe treatment complication of unrelated donor umbilical cord blood transplantation (UCBT). Its incidence seems to be higher after UCBT than after transplantation with bone marrow or peripheral blood stem cells (PBSCs). The only curative option is to perform a second transplantation; however, both the ideal stem cell source and the conditioning regimen for this salvage transplantation remain unclear. We report a series of 11 patients who underwent haploidentical PBSC transplantation (PBSCT) as salvage therapy for graft failure after a previous UCBT. The reduced-intensity conditioning regimen consisted of fludarabine 150 mg/m(2) for 3 days and horse antithymocyte globulin 8 mg/kg for 4 days. Ex vivo CD34(+) positive selection was performed in all cases, and no post-transplantation graft-versus-host disease prophylaxis was used. Six of the 9 evaluable patients (67%) eventually engrafted, at a median time of 10 days. The cumulative incidence of engraftment at 28 days was 64% (95% confidence interval [CI], 35% to 92%). Two patients relapsed after PBSCT. The cumulative incidence of TRM was 55% at 2 years (95% CI, 25% to 84%), and the probability of overall survival at 2 years was 36%. Our findings suggest that haploidentical ex vivo T cell-depleted PBSCT is a feasible alternative for treating graft failure after UCBT.

Leukemia

In 2008, a European registry of relapsed acute promyelocytic leukemia (APL) was established by th... more In 2008, a European registry of relapsed acute promyelocytic leukemia (APL) was established by the European LeukemiaNet. Outcome data were available for 155 patients treated with arsenic trioxide (ATO) in first relapse. In hematological relapse (n=104), 91% of the patients entered complete hematological remission (CR), 7% had induction death and 2% resistance, 27% developed differentiation syndrome and 39% leukocytosis, whereas no death or side effects occurred in patients treated in molecular relapse (n=40). The rate of molecular (m)CR was 74% in hematological and 62% in molecular relapse (p=0.3). All patients with extramedullary relapse (n=11) entered clinical and mCR. After 3.2 years median follow-up, the three-year overall survival (OS) and cumulative incidence of second relapse were 68% and 41% in hematological relapse, 66% and 48% in molecular relapse and 90% and 11% in extramedullary relapse, respectively. After allogeneic or autologous transplantation in 2(nd) CR (n=93), the...

Biology of Blood and Marrow Transplantation, 2012

An abnormal increase of nonleukemic blastic-appearing lymphocytes in bone marrow (BM) specimens h... more An abnormal increase of nonleukemic blastic-appearing lymphocytes in bone marrow (BM) specimens has been reported after unrelated cord blood transplantation (UCBT). This study analyzed the incidence, chronology, biological features, and clinical significance of elevated numbers of these cells in a series of 165 consecutive adult patients demonstrating myeloid engraftment after myeloablative UCBT in a single institution. The patients' BM samples were routinely evaluated by cytomorphology at different time points after UCBT. When 55% of blastic-appearing cells were detected by cytomorphology in the BM, samples were also evaluated by multiparametric flow cytometry to characterize these cells. Systematic chimerism analyses of BM samples using PCR amplification of short tandem repeat markers were performed. Forty-three patients (cumulative incidence, 26.1%) demonstrated 55% of nonmalignant blastic-appearing cells in BM after a median of 101 days after UCBT (range, 28-377 days). All of these patients had full-donor chimerism and a clinical course without leukemic relapse. Multiparametric flow cytometry analyses performed in 36 of the 43 patients showed a polyclonal expansion of B lymphocytes with a broad spectrum of maturation stages. An increased number of nonmalignant blastic-appearing cells was significantly associated with a high number of lymphocytes infused at the time of UCBT and with low rates of acute and chronic extensive graft-versushost disease, suggesting a potential immunoregulatory role of these cells. The observation of $5% nonmalignant blastic-appearing cells in BM samples after myeloablative UCBT is frequent, and these should be distinguished from malignant blasts.

Annals of Hematology, 2015

Front-line treatment of acute promyelocytic leukaemia (APL) consists of all-trans retinoic acid (... more Front-line treatment of acute promyelocytic leukaemia (APL) consists of all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy. In this setting, a comparison of idarubicin and daunorubicin has never been carried out. Two similar clinical trials using ATRA and chemotherapy for newly diagnosed APL were compared using matched-pair analysis. One was conducted by the PETHEMA/HOVON group with idarubicin and the other by the International Consortium on APL (IC-APL) using daunorubicin. Three hundred and fifty patients from the PETHEMA/HOVON cohort were matched with 175 patients in the IC-APL cohort, adjusting for the significantly unbalanced presenting features of the two However, a higher toxic death rate during induction and consolidation therapy was observed in the IC-APL cohort. This trial was registered at www.clinicaltrials.gov as #NCT00408278 [ClinicalTrials.gov].

Blood transfusion = Trasfusione del sangue, Jan 2, 2015

There are ABO antigens on the surface of platelets, but whether ABO compatible platelets are nece... more There are ABO antigens on the surface of platelets, but whether ABO compatible platelets are necessary for transfusions is a matter of ongoing debate. We retrospectively reviewed the ABO matching of platelet transfusions in a subset of patients undergoing autologous haematopoietic progenitor cell transplantation during a 14-year period. Our aim was to analyse the characteristics and outcomes of patients who received platelet transfusions that were or were not ABO identical. We analysed 529 consecutive patients with various haematological and non-haematological diseases who underwent 553 autologous progenitor stem cell transplants at the University Hospital la Fe between January 2000 and December 2013. We retrospectively analysed and compared transfusion and clinical outcomes of patients according to the ABO match of the platelet transfusions received. The period analysed was the time from transplantation until discharge. The patients received a total of 2,772 platelet concentrates, ...

Biology of Blood and Marrow Transplantation, 2009

There is no information on the efficacy and safety of anticytomegalovirus (CMV) prophylaxis with ... more There is no information on the efficacy and safety of anticytomegalovirus (CMV) prophylaxis with intravenous ganciclovir or oral valganciclovir after unrelated cord-blood transplantation (UCBT). This issue was addressed in 151 adults (117 CMV-seropositive) undergoing UCBT at a single institution. The first 38 CMV-seropositive recipients were assigned to receive prophylactic ganciclovir, and the next 79 were given valganciclovir after engraftment. The cumulative incidence (CI) of CMV infection and disease was similar in patients receiving valganciclovir or ganciclovir (59% versus 55%, P 5.59; and 9% versus 18%, P 5.33, respectively). The toxicity profile and CI of nonrelapse mortality (CMV) and infection-related mortality did not differ between drugs. Patients receiving valganciclovir required fewer visits to the day hospital (P 5.04). The CI of CMV infection and disease in 34 CMV-seronegative recipients was 12% and 6%, indicating that tight CMV monitoring is mandatory in this subset. The recipient's CMV serostatus, acute and extensive chronic graftversus-host disease (aGVHD, cGVHD) were the main risk factors for CMV infection, and aGVHD for CMV disease. This study suggests that prophylaxis with oral valganciclovir is as safe and effective as intravenous ganciclovir for preventing CMV infection and disease after UCBT, but valganciclovir reduces the use of hospital resources.

Journal of clinical oncology : official journal of the American Society of Clinical Oncology, Jan 20, 2014

Most patients with acute myeloid leukemia (AML) eventually experience relapse. Relapsed/refractor... more Most patients with acute myeloid leukemia (AML) eventually experience relapse. Relapsed/refractory AML has a dismal prognosis and currently available treatment options are generally ineffective. The objective of this large, international, randomized clinical trial was to investigate the efficacy of elacytarabine, a novel elaidic acid ester of cytarabine, versus the investigator's choice of one of seven commonly used AML salvage regimens, including high-dose cytarabine, multiagent chemotherapy, hypomethylating agents, hydroxyurea, and supportive care. A total of 381 patients with relapsed/refractory AML were treated in North America, Europe, and Australia. Investigators selected a control treatment for individual patients before random assignment. The primary end point was overall survival (OS). There were no significant differences in OS (3.5 v 3.3 months), response rate (23% v 21%), or relapse-free survival (5.1 v 3.7 months) between the elacytarabine and control arms, respecti...

Biology of Blood and Marrow Transplantation, 2005

Thirty-seven patients, median age 58 yrs (8 -69), with AML undergoing allogeneic stem cell transp... more Thirty-seven patients, median age 58 yrs (8 -69), with AML undergoing allogeneic stem cell transplantation (SCT) after reduced intensity conditioning (RIC) at three Swedish SCT centers were analyzed retrospectively. All except six patients received RIC due to high age or co-morbidity. Twenty-three patients were transplanted in first remission and 14 with more advanced disease. Donors were siblings (nϭ22) or matched unrelated donors (MUD, nϭ15). Conditioning was fludarabine ϩ busulfan Ϯ anti-thymocyte globulin (nϭ32), fludarabine ϩ treosulfan (nϭ3) or fludarabine ϩ 2 Gy total body irradiation (nϭ2). As stem cell source bone marrow was used in six patients and peripheral blood stem cells in 31. All patients engrafted. At a median follow-up of 15 months (3-63) acute graft-versus-host disease (GVHD) grade 0/I/II/III/IV developed in 22/7/5/0/1 recipients, respectively. Limited chronic GVHD was seen in five and extensive in seven patients among 33 patients at risk. Donor lymphocyte infusions were given to 16 patients due to mixed chimerism, minimal residual disease or relapse. In total 15 patients relapsed and 12 of them died. Only one patient died from a transplant related cause, acute GVHD. Kaplan-Meier probability for survival at 1 yr is 79% and for leukaemia-free survival (LFS) 68%. Among 23 patients, age 53 yrs (8 -69) transplanted in first remission with 16 sibling donors and seven MUD, eight relapsed (35%) and five of them died. There was no transplant-related mortality (TRM) among patients in first remission. Kaplan-Meier probability for survival and LFS at 1 yr is 86% and 72%, respectively for patients receiving transplantation in first remission. Reduced intensity conditioning with a fludarabine containing regimen and transplantation with a sibling or MUD gives a low TRM even in older patients with AML. Survival is encouraging but leukemia relapse remains a major problem. Randomized or controlled prospective trials comparing RIC with conventional conditioning for younger patients and trials comparing RIC to chemotherapy for elderly patients are urgently warranted.

Biology of Blood and Marrow Transplantation, 2015

The incidence, epidemiology, and risk factors of bloodstream infection (BSI) and their impact on ... more The incidence, epidemiology, and risk factors of bloodstream infection (BSI) and their impact on transplant outcomes after umbilical cord blood transplantation (UCBT) are not well defined. Between May 1997 and December 2012, 202 isolates in 189 episodes of BSI were registered in 134 of 241 patients who underwent single-unit myeloablative UCBT. Cumulative incidence (CI) of developing at least 1 episode of BSI was 21%, 29%, 34%, 42%, and 52% at days +7, +14, +30, +100, and +365, respectively. The median time of onset for the first BSI episode was day +10 (range, day -7 to +1217). Early BSI before day 7 was associated with increased nonrelapse mortality (relative risk [RR], 1.5; 95% confidence interval [CI], 1.1 to 2.3; P = .04), whereas BSI before day 14 was an independent adverse risk factor for neutrophil recovery (RR, .6; 95% CI, .5 to .9; P = .002). A higher CD8(+) cell dose of the graft was the only variable independently associated with reduced risk of BSI (RR, .1; 95% CI, .02 to .7; P = .02). The gram-negative rod (GNR) to gram-positive bacteria ratio was .9 before day +30 and 1.6 thereafter (P = .03). Escherichia coli (31%) and Pseudomonas sp. (28%) were the most frequently isolated among GNR. The overall crude mortality rate was 12% at day 7 and was higher for GNR (18%) compared with gram-positive bacteria (7%) (P = .03). These findings emphasize the importance of preventing bacterial infections during conditioning and the very early post-UCBT period.

Biology of Blood and Marrow Transplantation, 2010

Clinical studies focused on outcomes of umbilical cord blood transplantation (UCBT) for patients ... more Clinical studies focused on outcomes of umbilical cord blood transplantation (UCBT) for patients with chronic myelogenous leukemia (CML) in need of allogeneic stem cell transplantation and lacking an HLA-matched adult donor are limited. We analyzed the outcome of 26 adults with CML receiving single-unit UCBT from unrelated donors after myeloablative conditioning at a single institution. Conditioning regimens were based on combinations of thiotepa, busulfan, cyclophospamide or fludarabine, and antithymocyte globulin. At the time of transplantation, 7 patients (27%) were in first chronic phase (CP), 11 (42%) were in second CP, 2 (8%) were in accelerated phase (AP), and 6 (23%) were in blast crisis (BC). The cumulative incidence (CI) of myeloid engraftment was 88% at a median time of 22 days and was significantly better for patients receiving higher doses of CD34(+) cells. The CI of acute graft-versus-host disease (GVHD) grade II-IV was 61%, that of acute GVHD grade III-IV was 39%, and that of chronic extensive GVHD was 60%. Treatment-related mortality (TRM) was 41% for patients undergoing UCBT while in first or second CP and 100% for patients in AP or BC (P < .01). After a median follow-up of 8 years, none of the patients relapsed, giving an overall disease-free survival (DFS) at 8 years of 41%. The DFS for patients undergoing UCBT while in any CP was 59%. These results demonstrate that UCBT from unrelated donors can be a curative treatment for a substantial number of patients with CML. Advances in supportive care and better selection of cord blood units and patients are needed to improve TRM.

Cancer, 2014

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

Biology of Blood and Marrow Transplantation, 2010

Clinical studies focused on disease-specific outcomes of cord blood transplant (CBT) from unrelat... more Clinical studies focused on disease-specific outcomes of cord blood transplant (CBT) from unrelated donors are limited. We analyzed the outcome and prognostic factors of 49 adults with high-risk acute myelogenous leukemia (AML) receiving single-unit CBT from unrelated donors after myeloablative (MA) conditioning at a single institution. Conditioning regimens were based on the combination of thiotepa, busulfan (Bu), cyclophospamide (Cy), or fludarabine (Flu), and antithymocyte globulin (ATG). Cumulative incidence of myeloid and platelet engraftment was 96% and 73% at a median time of 20 and 62 days, respectively. Engraftment was significantly faster for patients receiving higher doses of CD34 1 cells. Confidence Interval of graft-versushost disease (GVHD), acute GVHD (aGVHD) grade II-IV, III-IV, and extensive chronic GVHD (cGVHD) were 26%, 15%, and 30%, respectively. Leukemia-free survival (LFS), nonrelapse mortality (NRM), and relapse at 2 years were 42%, 39%, and 19%, respectively. Low number of total nucleated cells (TNC) had a negative impact on NRM and LFS. Patients transplanted in first complete remission (CR1) receiving TNC above 2 Â 10 7 /kg had a 4-year LFS of 75%. These results show that CBT from unrelated donors is a curative treatment for a substantial number of patients with high-risk AML, particularly if transplant is performed with highly cellular units in patients in first CR.

The Journal of Molecular Diagnostics, 2012

Recently, many novel molecular abnormalities were found to be distinctly associated with acute my... more Recently, many novel molecular abnormalities were found to be distinctly associated with acute myeloid leukemia (AML). However, their clinical relevance and prognostic implications are not well established. We developed a new combination of high-resolution melting assays on a LightCycler 480 and direct sequencing to detect somatic mutations of ASXL1 (exon 12), IDH1 (exon 4), IDH2 (exon 4), and c-CBL (exons 8 and 9) genes to know their incidence and prognostic effect in a cohort of 175 patients with de novo AML: 16 patients (9%) carried ASXL1 mutations, 16 patients had IDH variations (3% with IDH1(R132) and 6% with IDH2(R140)), and none had c-CBL mutations. Patients with ASXL1 mutations did not harbor IDH1, [corrected] or CEBPA mutations, and a combination of ASXL1 and IDH2 mutations was found only in one patient. In addition, we did not find IDH1 and FLT3 or CEBPA mutations concurrently or IDH2 with CEBPA. IDH1 and IDH2 mutations were mutually exclusive. Alternatively, NPM1 mutations were concurrently found with ASXL1, IDH1, or IDH2 with a variable incidence. Mutations were not significantly correlated with any of the clinical and biological features studied. High-resolution melting is a reliable, rapid, and efficient screening technique for mutation detection in AML. The incidence for the studied genes was in the range of those previously reported. We were unable to find an effect on the outcome.

Acta Haematologica, 2013

The clinical heterogeneity of patients with acute myeloid leukemia (AML) or myelodysplastic syndr... more The clinical heterogeneity of patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS) with trisomy 8 as the sole abnormality may result from cytogenetically undetectable genetic changes. The purpose of this study was to identify hidden genomic aberrations not detected by metaphase cytogenetics (MC) using high-resolution single nucleotide polymorphism array (SNP-A)-based karyotyping in AML/MDS patients with a sole trisomy 8. The study group included 8 patients (3 AML and 5 MDS) and array-based karyotyping was done using whole-genome SNP-A (SNP 6.0 and SNP 2.7M). By SNP-A, additional genomic aberrations not detected by MC were identified in 2 patients: 1 AML patient exhibited a copy-neutral loss of heterozygosity (CN-LOH) of 3q21.1-q29 and 11q13.1-q25 and the other patient with MDS (refractory cytopenia with unilineage dysplasia) had CN-LOH of 2p25.3-p15. In particular, the latter patient progressed to AML 18 months after the diagnosis. In 3 patients, aberrations in addition to trisomy 8 were not identified by SNP-A. In the remaining 3 patients, SNP-A could not detect trisomy 8, while trisomy 8 was found in 25-67% of metaphase cells by MC. This study suggests that additional genomic aberrations may in fact be present even in cases of trisomy 8 as sole abnormality by MC, and SNP-A could be a useful karyotyping tool to identify hidden aberrations such as CN-LOH.