Publications by authors named "Anna Maria Testi"

64 Publications

Myeloid Sarcoma: Diagnostic and Treatment Tools from a Monocentric Retrospective Experience.

Acta Haematol 2021 Jul 20:1-5. Epub 2021 Jul 20.

Hematology, Department of Translational and Precision Medicine, "Sapienza" University, Rome, Italy.

Myeloid sarcoma (MS) is a very rare disease in both adults and children. Prognosis is poor in adults; in the pediatric age, the prognostic impact of extramedullary disease is controversial. Systemic therapy represents the mainstay of treatment even in isolated MS, but a comparison between different induction regimens is very limited in the literature. To date, it is still not clear if induction treatment should differ from that of other acute myeloid leukemias and stem cell transplant is considered for consolidation in both leukemic patients and in those with isolated disease. Our study describes a retrospective series of 13 cases of MS (adults and children), diagnosed and treated at our institute over 18 years. We report the results of immunophenotypic, cytogenetic and molecular studies, therapeutic approaches, and outcome, in order to establish the best strategy for patients' workup.
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http://dx.doi.org/10.1159/000517389DOI Listing
July 2021

Mutational profile of ZBTB16-RARA-positive acute myeloid leukemia.

Cancer Med 2021 Jun 27;10(12):3839-3847. Epub 2021 May 27.

Department of Biomedicine and Prevention, University Tor Vergata Rome, Rome, Italy.

Background: The ZBTB16-RARA fusion gene, resulting from the reciprocal translocation between ZBTB16 on chromosome 11 and RARA genes on chromosome 17 [t(11;17)(q23;q21)], is rarely observed in acute myeloid leukemia (AML), and accounts for about 1% of retinoic acid receptor-α (RARA) rearrangements. AML with this rare translocation shows unusual bone marrow (BM) morphology, with intermediate aspects between acute promyelocytic leukemia (APL) and AML with maturation. Patients may have a high incidence of disseminated intravascular coagulation at diagnosis, are poorly responsive to all-trans retinoic acid (ATRA) and arsenic tryoxyde, and are reported to have an overall poor prognosis.

Aims: The mutational profile of ZBTB16-RARA rearranged AML has not been described so far.

Materials And Methods: We performed targeted next-generation sequencing of 24 myeloid genes in BM diagnostic samples from seven ZBTB16-RARA+AML, 103 non-RARA rearranged AML, and 46 APL. The seven ZBTB16-RARA-positive patients were then screened for additional mutations using whole exome sequencing (n = 3) or an extended cancer panel including 409 genes (n = 4).

Results: ZBTB16-RARA+AML showed an intermediate number of mutations per patient and involvement of different genes, as compared to APL and other AMLs. In particular, we found a high incidence of ARID1A mutations in ZBTB16-RARA+AML (five of seven cases, 71%). Mutations in ARID2 and SMARCA4, other tumor suppressor genes also belonging to SWI/SNF chromatin remodeling complexes, were also identified in one case (14%).

Discussion And Conclusion: Our data suggest the association of mutations of the ARID1A gene and of the other members of the SWI/SNF chromatin remodeling complexes with ZBTB16-RARA+AMLs, where they may support the peculiar disease phenotype.
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http://dx.doi.org/10.1002/cam4.3904DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8209618PMC
June 2021

Can patients with epilepsy become bone marrow donors? A case report of allogeneic hematopoietic stem transplantation from child with seizures.

Seizure 2021 Jul 7;89:48-50. Epub 2021 May 7.

Department of Translational and Precision Medicine, Division of Hematology, Sapienza University of Rome, Italy.

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http://dx.doi.org/10.1016/j.seizure.2021.05.002DOI Listing
July 2021

Autoimmune Hemolitic Anemia in a Boy With Inactive Ulcerative Colitis.

Inflamm Bowel Dis 2021 Apr;27(5):e63-e64

Hematology, Department of Translational and Precision Medicine, Sapienza University, Rome, Italy.

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http://dx.doi.org/10.1093/ibd/izaa363DOI Listing
April 2021

Adolescent and young adult acute lymphoblastic leukemia. Final results of the phase II pediatric-like GIMEMA LAL-1308 trial.

Am J Hematol 2021 03 29;96(3):292-301. Epub 2020 Dec 29.

Hematology, Department of Translational and Precision Medicine, Sapienza University, Rome, Italy.

Adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) represent a unique patient population with specific characteristics and needs. Growing evidences suggest that pediatric-inspired approaches improve the outcome in AYA. These results prompted the design of a pediatric AIEOP-BFM ALL 2000-based regimen - the GIMEMA LAL-1308 protocol - for newly diagnosed AYA (range 18-35 years) with Philadelphia negative (Ph-) ALL. The protocol included minimal residual disease (MRD) analysis at two different time-points (TP), that is, at the end of induction IA and consolidation IB, and a modulation in post-consolidation intensity according to MRD. Seventy-six patients were eligible between September 2010 and October 2014. The regimen was well tolerated, with 2.7% induction deaths and no deaths in the post-consolidation phase. The complete response (CR) rate was 92%; the 48-month overall survival (OS) and disease-free survival (DFS) were 60.3% and 60.4%. Both OS and DFS were significantly better in T-ALL than B-ALL. A molecular MRD <10 at TP1 was associated with a significantly better OS and DFS (77% vs 39% and 71.9% vs 34.4%, respectively);similar results were documented at TP2 (OS and DFS 74.5% vs 30.6% and 71.5% vs 25.7%, respectively). The LAL-1308 results were compared to those from similar historic AYA populations undergoing the two previous GIMEMA LAL-2000 and LAL-0904 protocols. Both OS and DFS improved significantly compared to the two previous protocols. These results indicate that this pediatric-inspired and MRD-oriented protocol is feasible and effective for Ph- AYA ALL patients, and underline the prognostic value of MRD determinations at specific TPs.
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http://dx.doi.org/10.1002/ajh.26066DOI Listing
March 2021

Apparent recessive inheritance of sideroblastic anemia type 2 due to uniparental isodisomy at the SLC25A38 locus.

Haematologica 2020 12 1;105(12):2883-2886. Epub 2020 Dec 1.

Dip. di Medicina Molecolare e Biotecnologie Mediche, Universita degli Studi di Napoli Federico II, Napoli, Italy; CEINGE Biotecnologie Avanzate.

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http://dx.doi.org/10.3324/haematol.2020.258533DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC7716369PMC
December 2020

Polyostotic Fibrous Dysplasia Mimicking Bone Involvement in Hodgkin Lymphoma: A Pediatric Case and Literature Review.

Acta Haematol 2021 24;144(2):212-217. Epub 2020 Jul 24.

Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy,

Bone involvement in Hodgkin lymphoma (HL) is rare. The differential diagnosis between HL bone localization and other malignant or benign skeletal diseases is challenging. We report the case of a girl affected by classic HL, initially staged IVA because of supradiaphragmatic lymph nodes and skeletal involvement. After 6 ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) cycles, positron emission tomography (PET) showed a complete metabolic response of the nodal localizations and a persistent, high metabolic activity of bone lesions. Salvage treatment followed by autologous stem cell transplant was carried out. After the transplant, the bone lesions maintained a high metabolic activity at PET. A targeted bone biopsy led to the diagnosis of a fibrous dysplasia excluding the presence of HL. To our knowledge, the concomitant presence of HL and fibrous dysplasia has not been previously reported. An in-depth evaluation of disease response to frontline treatment with a biopsy of the PET-hypercaptant bone lesions could have avoided overtreatment in this patient.
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http://dx.doi.org/10.1159/000508261DOI Listing
April 2021

A review of current induction strategies and emerging prognostic factors in the management of children and adolescents with acute lymphoblastic leukemia.

Expert Rev Hematol 2020 07 1;13(7):755-769. Epub 2020 Jun 1.

Hematology, Department of Translational and Precision Medicine, 'Sapienza" University of Rome , Rome, Italy.

Introduction: Acute lymphoblastic leukemia is the most frequent hematologic malignancy in children. Almost 95% of children potentially achieve a complete remission after the induction treatment, but over the last years, new insights in the genomic disease profile and in minimal residual disease detection techniques have led to an improvement in the prognostic stratification, identifying selected patients' subgroups with peculiar therapeutic needs.

Areas Covered: According to a comprehensive search of peer-review literature performed in Pubmed, in this review we summarize the recent evidences on the induction treatment strategies comprised in the children acute lymphoblastic leukemia scenario, focusing on the role of key drugs such as corticosteroids and asparaginase and discussing the crucial significance of the genomic characterization at baseline which may drive the proper induction treatment choice.

Expert Opinion: Current induction strategies already produce durable remissions in a significant proportion of standard-risk children with acute lymphoblastic leukemia. A broader knowledge of the biologic features related to acute lymphoblastic leukemia subtypes with worse prognosis, and an optimization of targeted drugs now available, might lead to the achievement of long-term molecular remissions in this setting.
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http://dx.doi.org/10.1080/17474086.2020.1770591DOI Listing
July 2020

Outcome of adolescent patients with acute lymphoblastic leukaemia aged 10-14 years as compared with those aged 15-17 years: Long-term results of 1094 patients of the AIEOP-BFM ALL 2000 study.

Eur J Cancer 2019 11 17;122:61-71. Epub 2019 Oct 17.

Department of Pediatrics, Christian-Albrechts-University Kiel and University Medical Center Schleswig-Holstein, Kiel, Germany.

Background: Adolescents (aged 10-17 years) with acute lymphoblastic leukaemia (ALL) have unfavourable disease features and an inferior outcome when compared with younger children, but it is still unclear if differences in disease biology and prognosis exist between adolescents older or younger than 15 years.

Methods: We retrospectively analysed outcomes of 1094 adolescents with ALL, aged 10-17 years, treated within the AIEOP-BFM ALL 2000 trial, overall and by the age groups 10-14 and 15-17 years.

Findings: Compared with younger children (aged 1-9 years, n = 3647), adolescents had a statistically inferior 5-year event-free survival (EFS) [74.6% (1.3) vs. 84.4% (0.6)] and overall survival (OS) [83.4% (1.1) vs. 92.7% (0.4); p < 0.001]. Clinical and biological disease characteristics did not differ between the two subgroups of adolescents, including minimal residual disease (MRD) results during initial therapy, except for ETV6-RUNX1 frequency and gender. With a median follow-up of 8.8 years, the 5-year EFS and OS were 76.2% (1.5) and 84.9% (1.3), respectively, for those aged 10-14 years and 70.0% (2.8) and 78.8% (2.5) for those aged 15-17 years (p = 0.06; 0.05). There was no significant difference in the cumulative incidence of relapses [17.8% (1.4) and 18.3% (2.4); p = 0.98], while the incidence of treatment-related deaths as a first event was 2.6% (0.6) versus 7.4% (1.6) (p < 0.001) with, in particular, a higher incidence in the high-risk arm.

Interpretation: Further prospective studies and biological investigations are required to define optimal treatment for adolescents, in particular for those aged 15-17 years. Newer agents (immunotherapy, targeted therapy) in early treatment phases of patients at higher risk of treatment failure could replace most toxic treatment elements, with the aim of reducing both toxicity and the risk of relapses.
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http://dx.doi.org/10.1016/j.ejca.2019.09.004DOI Listing
November 2019

Atypical Chronic Myeloid Leukemia in a Patient with Aplastic Anemia.

Acta Haematol 2019 21;142(3):185-186. Epub 2019 May 21.

Hematology, Department of Translational and Precision Medicine, Sapienza University of Rome, Rome, Italy.

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http://dx.doi.org/10.1159/000497137DOI Listing
February 2020

Long-term results with the adapted LMB 96 protocol in children with B-cell non Hodgkin lymphoma treated in Iraq: comparison in two subsequent cohorts of patients.

Leuk Lymphoma 2019 05;60(5):1224-1233

b College of Medicine-Iraq, Department of Pediatrics , Children's Welfare Teaching Hospital-Baghdad , Baghdad , Iraq.

Since 2000, an adapted LMB 96 protocol was implemented at the Children-Welfare-Teaching-Hospital in Baghdad for the treatment of childhood B-cell non-Hodgkin lymphoma. The first experience (2000-2005) demonstrated efficacy and feasibility of this protocol in Iraq. In 2006, further adjustments were made in an attempt to reduce therapy-related toxicities. The outcome of the second cohort of 190 children (2006-2010) and the comparison with the previous study are hereby reported. Out of the 180 treated patients, 120 achieved a complete response; during treatment 51 died and 9 abandoned. The 60-month overall survival (OS) and event-free survival (EFS) were 64.7 and 56.3%, respectively. No differences were observed in the 24-month OS and EFS between the 2000-2005 and 2006-2010 cohorts (66.3% vs. 65.1%; p = .89 and 53.3% vs. 57.3%; p = .28, respectively). Therapeutic group-B in the second cohort showed better outcome, although not significant, compared to the first one (EFS 62.9% vs. 53.8%; p = .088). Therapy-related mortality remained high.
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http://dx.doi.org/10.1080/10428194.2018.1519810DOI Listing
May 2019

Risk-adapted treatment of acute promyelocytic leukemia: results from the International Consortium for Childhood APL.

Blood 2018 07 22;132(4):405-412. Epub 2018 May 22.

Pediatric Oncology, VU University Medical Center, Amsterdam, The Netherlands.

Pediatric acute promyelocytic leukemia (APL) can be cured with all- retinoic acid (ATRA) and anthracycline. However, most published trials have employed high cumulative doses of anthracyclines. Here, we report the outcome of newly diagnosed APL patients enrolled in the International Consortium for Childhood APL (ICC-APL-01) trial, which reduced anthracycline exposure but extended that of ATRA. The study recruited 258 children/adolescents with molecularly/cytogenetically proven APL. Patients were stratified into standard-risk (SR) and high-risk (HR) groups according to baseline white blood cell counts (<10 × 10/L or ≥10 × 10/L); both groups received identical induction treatment with ATRA and 3 doses of idarubicin. Two or 3 blocks of consolidation therapy were administered to SR and HR patients, respectively, while maintenance therapy with low-dose chemotherapy and ATRA cycles was given to all patients for 2 years. The cumulative dose of daunorubicin equivalent anthracyclines in SR and HR patients was lower than that of previous studies (355 mg/m and 405 mg/m, respectively). Hematologic remission was obtained in 97% of patients; 8 children died of intracranial hemorrhage in the first 2 weeks following diagnosis. Five-year overall and event-free survival for the whole cohort were 94.6% and 79.9%, respectively; they were 98.4% and 89.4% in SR patients and 84.3% and 74.2% in HR patients ( = .002 and = .043, respectively). These data demonstrate that extended use of ATRA coupled to a risk-adapted consolidation can achieve high cure rates in childhood APL and limit anthracycline exposure. The trial was registered at www.clinicaltrials.gov as EudractCT 2008-002311-40.
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http://dx.doi.org/10.1182/blood-2018-03-836528DOI Listing
July 2018

Reduced-Intensity Delayed Intensification in Standard-Risk Pediatric Acute Lymphoblastic Leukemia Defined by Undetectable Minimal Residual Disease: Results of an International Randomized Trial (AIEOP-BFM ALL 2000).

J Clin Oncol 2018 01 17;36(3):244-253. Epub 2017 Nov 17.

Martin Schrappe, Kirsten Bleckmann, Anja Möricke, and Gunnar Cario, University Hospital Schleswig-Holstein, Campus Kiel, Kiel; Martin Zimmermann and Gudrun Göhring, Hannover Medical School, Hannover; Claus R. Bartram, Institute of Human Genetics, Ruprecht-Karls University, Heidelberg; Charlotte Niemeyer, University of Freiburg, Freiburg; Rita Beier, University Hospital, Essen; Wolf-Dieter Ludwig, HELIOS Medical Center Berlin-Buch, Berlin; Paul-Gerhardt Schlegel, University of Würzburg, Würzburg, Germany; Andrea Biondi, Carmelo Rizzari, Maria Grazia Valsecchi, and Valentino Conter, University of Milano-Bicocca; Andrea Biondi, Carmelo Rizzari, and Valentino Conter, Ospedale San Gerardo, Monza; Franco Locatelli, University of Pavia and Istituto di Ricovero e Cura a Carattere Scientifico Ospedale Pediatrico Bambino Gesù; Anna Maria Testi, University La Sapienza, Rome; Elena Barisone, Regina Margherita Children's Hospital, Turin; Ottavio Ziino, Azienda di Rilievo Nazionale ad Alta Specializzazione Ospedali Civico Di Cristina, Palermo; Rosanna Parasole, Santobono-Pausilipon Children's Hospital; Fiorina Casale, University of Naples, Naples; Giuseppe Basso, University of Padova, Padova, Italy; Andishe Attarbaschi, Georg Mann, and Renate Panzer-Grümayer, St Anna Children's Hospital and Medical University of Vienna, Vienna, Austria; and Felix Niggli and Beat Schäfer, University Hospital Zürich, Zürich, Switzerland.

Purpose Delayed intensification (DI) is an integral part of treatment of childhood acute lymphoblastic leukemia (ALL), but it is associated with relevant toxicity. Therefore, standard-risk patients of trial AIEOP-BFM ALL 2000 (Combination Chemotherapy Based on Risk of Relapse in Treating Young Patients With ALL) were investigated with the specific aim to reduce treatment intensity. Patients and Methods Between July 2000 and July 2006, 1,164 patients (1 to 17 years of age) with standard-risk ALL (defined as the absence of high-risk cytogenetics and undetectable minimal residual disease on days 33 and 78) were randomly assigned to either experimental reduced-intensity DI (protocol III; P-III) or standard DI (protocol II; P-II). Cumulative drug doses of P-III were reduced by 30% for dexamethasone and 50% for vincristine, doxorubicin, and cyclophosphamide, which shortened the treatment duration from 49 to 29 days. The study aimed at noninferiority of reduced-intensity P-III; analyses were performed according to treatment given. Results For P-III and P-II, respectively, the 8-year rate of disease-free survival (± SE) was 89.2 ± 1.3% and 92.3 ± 1.2% ( P = .04); cumulative incidence of relapse, 8.7 ± 1.2% and 6.4 ± 1.1% ( P = .09); and overall survival, 96.1 ± 0.8% and 98.0 ± 0.6% ( P = .06). Patients with ETV6-RUNX1-positive ALL and patients 1 to 6 years of age performed equally well in both arms. The incidence of death during remission was comparable, which indicates equivalent toxicity. The 8-year cumulative incidence rate of secondary malignancies was 1.3 ± 0.5% and 0.6 ± 0.4% for P-III and P-II, respectively ( P = .37). Conclusion Although the criteria used for the standard-risk definition in this trial identified patients with exceptionally good prognosis, reduction of chemotherapy was not successful mainly because of an increased rate of relapse. The data suggest that treatment reduction is feasible in specific subgroups, which underlines the biologic heterogeneity of this cohort selected according to treatment response.
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http://dx.doi.org/10.1200/JCO.2017.74.4946DOI Listing
January 2018

Predictors of thrombohemorrhagic early death in children and adolescents with t(15;17)-positive acute promyelocytic leukemia treated with ATRA and chemotherapy.

Ann Hematol 2017 Sep 8;96(9):1449-1456. Epub 2017 Jun 8.

Department of Hematology, Hospital Universitari i Politecnic La Fe, Department of Medicine, University of Valencia, Valencia, Spain.

Clinical trials on childhood acute promyelocytic leukemia (APL) report early death (ED) rates of 3-8%, but predictors of thrombohemorrhagic (TH)-ED are not well understood. In a retrospective study, we aimed to determine the incidence and predictors of TH-ED in childhood APL. Data were analyzed from children and adolescents with t(15;17)-positive APL (n = 683) who started treatment with all-trans retinoic acid (ATRA) and chemotherapy in different international studies. Demographic data; initial white blood cell (WBC), peripheral blood (PB) blast, and platelet counts; hemoglobin value; coagulation parameters; morphologic variant (M3 or M3v); and induction details were analyzed. Early death was defined as death occurring within 30 days of presentation. The incidence of ED was 4.7% (32 of 683 patients). Predictors of TH-ED were identified by univariable and multivariable Cox proportional hazard regression analyses (n = 25). In univariable analysis, high WBC (>10 × 10/L) (P < 0.001) and high PB blast (>30 × 10/L) (P < 0.001), M3v (P < 0.01), and black ethnicity (P < 0.001) were independent predictors of TH-ED. In multivariable analysis, high WBC count (P < 0.01) and obesity (i.e., body mass index ≥95th percentile for age) (P = 0.03) were predictors of TH-ED. Initial high WBC counts and obesity are likely predictors of TH-ED in childhood APL. The efficacy of novel drugs for APL-associated coagulopathy or of frontline arsenic trioxide and ATRA combination regimens in reducing ED rates in childhood APL remains to be established.
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http://dx.doi.org/10.1007/s00277-017-3042-6DOI Listing
September 2017

Clinical significance of recurrent copy number aberrations in B-lineage acute lymphoblastic leukaemia without recurrent fusion genes across age cohorts.

Br J Haematol 2017 08 25;178(4):583-587. Epub 2017 Apr 25.

Haematology, Department of Cellular Biotechnologies and Haematology, Policlinico Umberto 1, Sapienza University, Rome, Italy.

Copy number aberrations (CNAs) represent cooperating events in B-lineage acute lymphoblastic leukaemia (B-ALL); however, their clinical relevance across different age cohorts is unclear. We analysed the recurrent CNAs in 157 age-stratified B-ALL negative cases for recurrent rearrangements (B-NEG ALL), and their association with patients' clinico-biological features. We found that: (i) CDKN2A/RB1-deleted and EBF1-deleted adults had a shorter disease-free survival than those with wild-type, (ii) among the unfavourable markers, CDKN2A/RB1 deletions and K/NRAS mutations retained their impact in multivariate analysis, encouraging the evaluation of CDKN2A/RB1 deletions and RAS mutations in the diagnostic/prognostic workflow to refine ALL risk assessment.
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http://dx.doi.org/10.1111/bjh.14721DOI Listing
August 2017

Very late relapse in a patient with acute promyelocytic leukemia (APL) rescued with a chemotherapy-free protocol.

Leuk Lymphoma 2017 04 23;58(4):999-1001. Epub 2016 Sep 23.

a Department of Cellular Biotechnologies and Hematology , 'Sapienza', University , Rome , Italy.

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http://dx.doi.org/10.1080/10428194.2016.1222377DOI Listing
April 2017

Independent prognostic impact of CD15 on complete remission achievement in patients with acute myeloid leukemia.

Hematol Oncol 2017 Dec 12;35(4):804-809. Epub 2016 Jul 12.

Department of Cellular Biotechnologies and Hematology, Sapienza University of Rome, Rome, Italy.

The prognostic role of CD15 in acute myeloid leukemia (AML) has been tested in different studies with conflicting results. To address this issue, we retrospectively evaluated a cohort of 460 AML patients of all ages with the exclusion of acute promyelocytic leukemia (M/F 243/217, median age 50.6 years [range 0.9-81.2]) intensively treated at our institute between January 1999 and December 2010. CD15 positivity was found in 171 of 406 evaluable patients (42.1%). Complete remission (CR) was achieved by 334 patients (72.6%), while 82 (17.8%) were resistant and 44 (9.6%) died during induction: the median CR duration was 15.5 months (range 0.6-176.0), with 2-year disease-free survival rate of 45.1% (95% confidence interval 39.6-50.6). The median overall survival was 14.4 months (range 0.3-177.0), with 2-year overall survival rate of 42.2% (95% confidence interval 37.5-46.9). At univariate analysis for CR achievement, age < 60 years (P < .001), World Health Organization classification (P = .045), low-risk karyotype (P < .001), no high-risk karyotype (P = .006), positivity for AML-ETO (P = .004)/CBFβ-MYH11 (P = .003)/CD15 (P = .006)/CD11b (P = .013), negativity for FLT3-ITD (P = .001), Hb > 8 g/dL (P = .020), and white blood cell < 50 × 10 /L (P = .034) had a favorable impact. At a multivariate logistic regression model, CD15 positivity (P = .002), age < 60 years (P = .008), white blood cell < 50 × 10 /L (P = .017), and low-risk/no high-risk karyotype (P = .026/P = .025) retained an independent prognostic role on CR achievement. The baseline assessment of CD15 positivity appears to have a role in the risk evaluation for CR achievement in AML patients undergoing intensive chemotherapy and should be assessed in prospective studies together with other clinical and biologic features already reported.
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http://dx.doi.org/10.1002/hon.2331DOI Listing
December 2017

Comparative analysis between RQ-PCR and digital-droplet-PCR of immunoglobulin/T-cell receptor gene rearrangements to monitor minimal residual disease in acute lymphoblastic leukaemia.

Br J Haematol 2016 Aug 12;174(4):541-9. Epub 2016 May 12.

Department of Cellular Biotechnologies and Haematology, "Sapienza" University of Rome, Rome, Italy.

Real-time quantitative polymerase chain reaction (RQ-PCR) is a standardized tool for minimal residual disease (MRD) monitoring in acute lymphoblastic leukaemia (ALL). The applicability of this technology is limited by the need of a standard curve based on diagnostic DNA. The digital droplet PCR (ddPCR) technology has been recently applied to various medical fields, but its use in MRD monitoring is under investigation. In this study, we analysed 50 ALL cases by both methods in two phases: in the first, we established analytical parameters to investigate the applicability of this new technique; in the second, we analysed MRD levels in 141 follow-up (FU) samples to investigate the possible use of ddPCR for MRD monitoring in ALL patients. We documented that ddPCR has sensitivity and accuracy at least comparable to those of RQ-PCR. Overall, the two methods gave concordant results in 124 of the 141 analysed MRD samples (88%, P = 0·94). Discordant results were found in 12% borderline cases. The results obtained prove that ddPCR is a reliable method for MRD monitoring in ALL, with the advantage of quantifying without the need of the calibration curves. Its application in a cohort of patients with a longer FU will conclusively define its clinical predictive value.
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http://dx.doi.org/10.1111/bjh.14082DOI Listing
August 2016

RNA sequencing unravels the genetics of refractory/relapsed T-cell acute lymphoblastic leukemia. Prognostic and therapeutic implications.

Haematologica 2016 08 5;101(8):941-50. Epub 2016 May 5.

Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy

Despite therapeutic improvements, a sizable number of patients with T-cell acute lymphoblastic leukemia still have a poor outcome. To unravel the genomic background associated with refractoriness, we evaluated the transcriptome of 19 cases of refractory/early relapsed T-cell acute lymphoblastic leukemia (discovery cohort) by performing RNA-sequencing on diagnostic material. The incidence and prognostic impact of the most frequently mutated pathways were validated by Sanger sequencing on genomic DNA from diagnostic samples of an independent cohort of 49 cases (validation cohort), including refractory, relapsed and responsive cases. Combined gene expression and fusion transcript analyses in the discovery cohort revealed the presence of known oncogenes and identified novel rearrangements inducing overexpression, as well as inactivation of tumor suppressor genes. Mutation analysis identified JAK/STAT and RAS/PTEN as the most commonly disrupted pathways in patients with chemorefractory disease or early relapse, frequently in association with NOTCH1/FBXW7 mutations. The analysis on the validation cohort documented a significantly higher risk of relapse, inferior overall survival, disease-free survival and event-free survival in patients with JAK/STAT or RAS/PTEN alterations. Conversely, a significantly better survival was observed in patients harboring only NOTCH1/FBXW7 mutations: this favorable prognostic effect was abrogated by the presence of concomitant mutations. Preliminary in vitro assays on primary cells demonstrated sensitivity to specific inhibitors. These data document the negative prognostic impact of JAK/STAT and RAS/PTEN mutations in T-cell acute lymphoblastic leukemia and suggest the potential clinical application of JAK and PI3K/mTOR inhibitors in patients harboring mutations in these pathways.
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http://dx.doi.org/10.3324/haematol.2015.139410DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4967573PMC
August 2016

Prognostic and therapeutic role of targetable lesions in B-lineage acute lymphoblastic leukemia without recurrent fusion genes.

Oncotarget 2016 Mar;7(12):13886-901

Hematology, Department of Cellular Biotechnologies and Hematology, Sapienza University, Rome, Italy.

To shed light into the molecular bases of B-lineage acute lymphoblastic leukemia lacking known fusion transcripts, i.e. BCR-ABL1, ETV6-RUNX1, E2A-PBX1, and MLL rearrangements (B-NEG ALL) and the differences between children, adolescents/young adults (AYA) and adults, we analyzed 168 B-NEG ALLs by genome-wide technologies. This approach showed that B-NEG cases carry 10.5 mutations and 9.1 copy-number aberrations/sample. The most frequently mutated druggable pathways were those pertaining to RAS/RTK (26.8%) and JAK/STAT (12.5%) signaling. In particular, FLT3 and JAK/STAT mutations were detected mainly in AYA and adults, while KRAS and NRAS mutations were more frequent in children. RAS/RTK mutations negatively affected the outcome of AYA and adults, but not that of children. Furthermore, adult B-NEG ALL carrying JAK/STAT mutations had a shorter survival. In vitro experiments showed that FLT3 inhibitors reduced significantly the proliferation of FLT3-mutated primary B-NEG ALL cells. Likewise, PI3K/mTOR inhibitors reduced the proliferation of primary cells harboring RAS and IL7R mutations. These results refine the genetic landscape of B-NEG ALL and suggest that the different distribution of lesions and their prognostic impact might sustain the diverse outcome between children, adults and partly AYA - whose genomic scenario is similar to adults - and open the way to targeted therapeutic strategies.
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http://dx.doi.org/10.18632/oncotarget.7356DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4924686PMC
March 2016

Early T-cell precursor acute lymphoblastic leukaemia in children treated in AIEOP centres with AIEOP-BFM protocols: a retrospective analysis.

Lancet Haematol 2016 Feb 26;3(2):e80-6. Epub 2016 Jan 26.

Department of Woman and Child Health, Hemato-Oncology Division, University of Padova, Azienda Ospedale Padova, Padova, Italy.

Background: Early T-cell precursor acute lymphoblastic leukaemia was recently recognised as a distinct leukaemia and reported as associated with poor outcomes. We aimed to assess the outcome of early T-cell precursor acute lymphoblastic leukaemia in patients from the Italian Association of Pediatric Hematology Oncology (AIEOP) centres treated with AIEOP-Berlin-Frankfurt-Münster (AIEOP-BFM) protocols.

Methods: In this retrospective analysis, we included all children aged from 1 to less than 18 years with early T-cell precursor acute lymphoblastic leukaemia immunophenotype diagnosed between Jan 1, 2008, and Oct 31, 2014, from AIEOP centres. Early T-cell precursors were defined as being CD1a and CD8 negative, CD5 weak positive or negative, and positive for at least one of the following antigens: CD34, CD117, HLADR, CD13, CD33, CD11b, or CD65. Treatment was based on AIEOP-BFM acute lymphoblastic leukaemia 2000 (NCT00613457) or AIEOP-BFM acute lymphoblastic leukaemia 2009 protocols (European Clinical Trials Database 2007-004270-43). The main differences in treatment and stratification of T-cell acute lymphoblastic leukaemia between the two protocols were that in the 2009 protocol only, pegylated L-asparaginase was substituted for Escherichia coli L-asparaginase, patients with prednisone poor response received an additional dose of cyclophosphamide at day 10 of phase IA, and high minimal residual disease at day 15 assessed by flow cytometry was used as a high-risk criterion. Outcomes were assessed in terms of event-free survival, disease-free survival, and overall survival.

Findings: Early T-cell precursor acute lymphoblastic leukaemia was diagnosed in 49 patients. Compared with overall T-cell acute lymphoblastic leukaemia, it was associated with absence of molecular markers for PCR detection of minimal residual disease in 25 (56%) of 45 patients; prednisone poor response in 27 (55%) of 49 patients; high minimal residual disease at day 15 after starting therapy in 25 (64%) of 39 patients (bone marrow blasts ≥ 10%, by flow cytometry); no complete remission after phase IA in 7 (15%) of 46 patients (bone marrow blasts ≥ 5%, morphologically); and high PCR minimal residual disease (≥ 5 × 10(-4)) at day 33 after starting therapy in 17 (85%) of 20 patients with markers available. Overall, 38 (78%) of 49 patients are in continuous complete remission, including 13 of 18 after haemopoietic stem cell transplantation, with three deaths in induction, five deaths after haemopoietic stem cell transplantation, and three relapses. Severe adverse events in the 2009 study were reported in 10 (30%) of 33 patients with early T-cell precursor acute lymphoblastic leukaemia versus 24 (15%) of 164 patients without early T-cell precursor acute lymphoblastic leukaemia and life-threatening events in induction phase IA occurred in 4 (12%) of 33 patients with early T-cell precursor acute lymphoblastic leukaemia versus 7 (4%) of 164 patients without early T-cell precursor acute lymphoblastic leukaemia. No difference was seen in the subsequent consolidation phase IB of protocol I.

Interpretation: Early T-cell precursor acute lymphoblastic leukaemia is characterised by poor early response to conventional induction treatment. Consolidation phase IB, based on cyclophosphamide, 6-mercaptopurine, and ara-C at conventional (non-high) doses is effective in reducing minimal residual disease. Although the number of patients and observational time are limited, patients with early T-cell precursor acute lymphoblastic leukaemia treated with current BFM stratification and treatment strategy have a favourable outcome compared with earlier reports. The role of innovative therapies and haemopoietic stem cell therapy in early T-cell precursor acute lymphoblastic leukaemia needs to be assessed.

Funding: None.
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http://dx.doi.org/10.1016/S2352-3026(15)00254-9DOI Listing
February 2016