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1. Clinical significance of chromatin-spliceosome acute myeloid leukemia: a report from the Northern Italy Leukemia Group (NILG) randomized trial 02/06

Author

Caprioli, C, Lussana, F, Salmoiraghi, S, Cavagna, R, Buklijas, K, Elidi, L, Zanghi', P, Michelato, A, Delaini, F, Oldani, E, Intermesoli, T, Grassi, A, Gianfaldoni, G, Mannelli, F, Ferrero, D, Audisio, E, Terruzzi, E, De Paoli, L, Cattaneo, C, Borlenghi, E, Cavattoni, I, Tajana, M, Scattolin, A, Mattei, D, Corradini, P, Campiotti, L, Ciceri, F, Bernardi, M, Todisco, E, Cortelezzi, A, Falini, B, Pavoni, C, Bassan, R, Spinelli, O, Rambaldi, A, Caprioli, Chiara, Lussana, Federico, Salmoiraghi, Silvia, Cavagna, Roberta, Buklijas, Ksenija, Elidi, Lara, Zanghi', Pamela, Michelato, Anna, Delaini, Federica, Oldani, Elena, Intermesoli, Tamara, Grassi, Anna, Gianfaldoni, Giacomo, Mannelli, Francesco, Ferrero, Dario, Audisio, Ernesta, Terruzzi, Elisabetta, De Paoli, Lorella, Cattaneo, Chiara, Borlenghi, Erika, Cavattoni, Irene, Tajana, Monica, Scattolin, Anna Maria, Mattei, Daniele, Corradini, Paolo, Campiotti, Leonardo, Ciceri, Fabio, Bernardi, Massimo, Todisco, Elisabetta, Cortelezzi, Agostino, Falini, Brunangelo, Pavoni, Chiara, Bassan, Renato, Spinelli, Orietta, Rambaldi, Alessandro, Caprioli, C, Lussana, F, Salmoiraghi, S, Cavagna, R, Buklijas, K, Elidi, L, Zanghi', P, Michelato, A, Delaini, F, Oldani, E, Intermesoli, T, Grassi, A, Gianfaldoni, G, Mannelli, F, Ferrero, D, Audisio, E, Terruzzi, E, De Paoli, L, Cattaneo, C, Borlenghi, E, Cavattoni, I, Tajana, M, Scattolin, A, Mattei, D, Corradini, P, Campiotti, L, Ciceri, F, Bernardi, M, Todisco, E, Cortelezzi, A, Falini, B, Pavoni, C, Bassan, R, Spinelli, O, Rambaldi, A, Caprioli, Chiara, Lussana, Federico, Salmoiraghi, Silvia, Cavagna, Roberta, Buklijas, Ksenija, Elidi, Lara, Zanghi', Pamela, Michelato, Anna, Delaini, Federica, Oldani, Elena, Intermesoli, Tamara, Grassi, Anna, Gianfaldoni, Giacomo, Mannelli, Francesco, Ferrero, Dario, Audisio, Ernesta, Terruzzi, Elisabetta, De Paoli, Lorella, Cattaneo, Chiara, Borlenghi, Erika, Cavattoni, Irene, Tajana, Monica, Scattolin, Anna Maria, Mattei, Daniele, Corradini, Paolo, Campiotti, Leonardo, Ciceri, Fabio, Bernardi, Massimo, Todisco, Elisabetta, Cortelezzi, Agostino, Falini, Brunangelo, Pavoni, Chiara, Bassan, Renato, Spinelli, Orietta, and Rambaldi, Alessandro

Abstract

Secondary acute myeloid leukemia (sAML) after myelodysplastic or myeloproliferative disorders is a high-risk category currently identified by clinical history or specific morphological and cytogenetic abnormalities. However, in the absence of these features, uncertainties remain to identify the secondary nature of some cases otherwise defined as de novo AML. To test whether a chromatin-spliceosome (CS) mutational signature might better inform the definition of the de novo AML group, we analyzed a prospective cohort of 413 newly diagnosed AML patients enrolled into a randomized clinical trial (NILG AML 02/06) and provided with accurate cytogenetic and molecular characterization. Among clinically defined de novo AML, 17.6% carried CS mutations (CS-AML) and showed clinical characteristics closer to sAML (older age, lower white blood cell counts and higher rate of multilineage dysplasia). Outcomes in this group were adverse, more similar to those of sAML as compared to de novo AML (overall survival, 30% in CS-AML and 17% in sAML vs 61% in de novo AML, P<0.0001; disease free survival, 26% in CS-AML and 22% in sAML vs 54% of de novo AML, P<0.001) and independently confirmed by multivariable analysis. Allogeneic transplant in first complete remission improved survival in both sAML and CS-AML patients. In conclusion, these findings highlight the clinical significance of identifying CS-AML for improved prognostic prediction and potential therapeutic implications. (NILG AML 02/06: ClinicalTrials.gov Identifier: NCT00495287).

Published
2021

2. GDNA qPCR is statistically more reliable than mRNA analysis in detecting leukemic cells to monitor CML

Author

Rainero, A, Angaroni, F, Conti, A, Pirrone, C, Micheloni, G, Tarara, L, Millefanti, G, Maserati, E, Valli, R, Spinelli, O, Buklijas, K, Michelato, A, Casalone, R, Barlassina, C, Barcella, M, Sirchia, S, Piscitelli, E, Caccia, M, Porta, G, Rainero A., Angaroni F., Conti A., Pirrone C., Micheloni G., Tarara L., Millefanti G., Maserati E., Valli R., Spinelli O., Buklijas K., Michelato A., Casalone R., Barlassina C., Barcella M., Sirchia S., Piscitelli E., Caccia M., Porta G., Rainero, A, Angaroni, F, Conti, A, Pirrone, C, Micheloni, G, Tarara, L, Millefanti, G, Maserati, E, Valli, R, Spinelli, O, Buklijas, K, Michelato, A, Casalone, R, Barlassina, C, Barcella, M, Sirchia, S, Piscitelli, E, Caccia, M, Porta, G, Rainero A., Angaroni F., Conti A., Pirrone C., Micheloni G., Tarara L., Millefanti G., Maserati E., Valli R., Spinelli O., Buklijas K., Michelato A., Casalone R., Barlassina C., Barcella M., Sirchia S., Piscitelli E., Caccia M., and Porta G.

Abstract

Chronic Myeloid Leukemia (CML) is a stem cell cancer that arises when t(9;22) translocation occurs in a hematopoietic stem cells. This event results in the expression of the BCR-ABL1 fusion gene, which codes for a constitutively active tyrosine kinase that is responsible for the transformation of a HSC into a CML stem cell, which then gives rise to a clonal myeloproliferative disease. The introduction of Tyrosine Kinase Inhibitors (TKIs) has revolutionized the management of the disease. However, these drugs do not seem to be able to eradicate the malignancy. Indeed, discontinuation trials (STIM; TWISER; DADI) for those patients who achieved a profound molecular response showed 50% relapsing within 12 months. We performed a comparative analysis on 15 CML patients and one B-ALL patient, between the standard quantitative reverse-transcriptase PCR (qRT-PCR) and our genomic DNA patient-specific quantitative PCR assay (gDNA qPCR). Here we demonstrate that gDNA qPCR is better than standard qRT-PCR in disease monitoring after an average follow-up period of 200 days. Specifically, we statistically demonstrated that DNA negativity is more reliable than RNA negativity in indicating when TKIs therapy can be safely stopped.

Published
2018

3. High throughput molecular characterization of normal karyotype acute myeloid leukemia in the context of the prospective trial 02/06 of the northern italy leukemia group (NILG)

Author

Salmoiraghi, S, Cavagna, R, Zanghì, P, Pavoni, C, Michelato, A, Buklijas, K, Elidi, L, Intermesoli, T, Lussana, F, Oldani, E, Caprioli, C, Stefanoni, P, Gianfaldoni, G, Audisio, E, Terruzzi, E, De Paoli, L, Borlenghi, E, Cavattoni, I, Mattei, D, Scattolin, A, Tajana, M, Ciceri, F, Todisco, E, Campiotti, L, Corradini, P, Fracchiolla, N, Bassan, R, Rambaldi, A, Spinelli, O, Salmoiraghi, Silvia, Cavagna, Roberta, Zanghì, Pamela, Pavoni, Chiara, Michelato, Anna, Buklijas, Ksenija, Elidi, Lara, Intermesoli, Tamara, Lussana, Federico, Oldani, Elena, Caprioli, Chiara, Stefanoni, Paola, Gianfaldoni, Giacomo, Audisio, Ernesta, Terruzzi, Elisabetta, De Paoli, Lorella, Borlenghi, Erika, Cavattoni, Irene, Mattei, Daniele, Scattolin, Annamaria, Tajana, Monica, Ciceri, Fabio, Todisco, Elisabetta, Campiotti, Leonardo, Corradini, Paolo, Fracchiolla, Nicola, Bassan, Renato, Rambaldi, Alessandro, Spinelli, Orietta, Salmoiraghi, S, Cavagna, R, Zanghì, P, Pavoni, C, Michelato, A, Buklijas, K, Elidi, L, Intermesoli, T, Lussana, F, Oldani, E, Caprioli, C, Stefanoni, P, Gianfaldoni, G, Audisio, E, Terruzzi, E, De Paoli, L, Borlenghi, E, Cavattoni, I, Mattei, D, Scattolin, A, Tajana, M, Ciceri, F, Todisco, E, Campiotti, L, Corradini, P, Fracchiolla, N, Bassan, R, Rambaldi, A, Spinelli, O, Salmoiraghi, Silvia, Cavagna, Roberta, Zanghì, Pamela, Pavoni, Chiara, Michelato, Anna, Buklijas, Ksenija, Elidi, Lara, Intermesoli, Tamara, Lussana, Federico, Oldani, Elena, Caprioli, Chiara, Stefanoni, Paola, Gianfaldoni, Giacomo, Audisio, Ernesta, Terruzzi, Elisabetta, De Paoli, Lorella, Borlenghi, Erika, Cavattoni, Irene, Mattei, Daniele, Scattolin, Annamaria, Tajana, Monica, Ciceri, Fabio, Todisco, Elisabetta, Campiotti, Leonardo, Corradini, Paolo, Fracchiolla, Nicola, Bassan, Renato, Rambaldi, Alessandro, and Spinelli, Orietta

Abstract

By way of a Next-Generation Sequencing NGS high throughput approach, we defined the mutational profile in a cohort of 221 normal karyotype acute myeloid leukemia (NK-AML) enrolled into a prospective randomized clinical trial, designed to evaluate an intensified chemotherapy program for remission induction. NPM1, DNMT3A, and FLT3-ITD were the most frequently mutated genes while DNMT3A, FLT3, IDH1, PTPN11, and RAD21 mutations were more common in the NPM1 mutated patients (p < 0.05). IDH1 R132H mutation was strictly associated with NPM1 mutation and mutually exclusive with RUNX1 and ASXL1. In the whole cohort of NK-AML, no matter the induction chemotherapy used, by multivariate analysis, the achievement of complete remission was negatively affected by the SRSF2 mutation. Alterations of FLT3 (FLT3-ITD) and U2AF1 were associated with a worse overall and disease-free survival (p < 0.05). FLT3-ITD positive patients who proceeded to alloHSCT had a survival probability similar to FLT3-ITD negative patients and the transplant outcome was no different when comparing high and low-AR-FLT3-ITD subgroups in terms of both OS and DFS. In conclusion, a comprehensive molecular profile for NK-AML allows for the identification of genetic lesions associated to different clinical outcomes and the selection of the most appropriate and effective treatment strategies, including stem cell transplantation and targeted therapies.

Published
2020

4. PROGNOSTIC VALUE OF CLONAL HEMATOPOIESIS-MUTATIONS DETECTED AT DIAGNOSIS IN ACUTE MYELOID LEUKEMIA PATIENTS WITH NORMAL KARYOTYPE

Author

Caprioli, C, Spinelli, O, Salmoiraghi, S, Intermesoli, T, Zanghi, P, Cavagna, R, Michelato, A, Buklijas, K, Elidi, L, Delaini, F, Oldani, E, Gianfaldoni, G, Bosi, A, Marmont, F, Audisio, E, Ferrero, D, Terruzzi, E, De Paoli, L, Rossi, G, Borlenghi, E, Cavattoni, I, Tajana, M, Scattolin, Am, Mattei, D, Corradini, P, Campiotti, L, Ciceri, F, Bernardi, M, Todisco, E, Cortelezzi, A, Cortelazzo, S, Falini, B, Pavoni, C, Bassan, R, Rambaldi, A, and Lussana, F

Published
2019

5. PF227 PROGNOSTIC VALUE OF CLONAL HEMATOPOIESIS-MUTATIONS DETECTED AT DIAGNOSIS IN ACUTE MYELOID LEUKEMIA PATIENTS WITH NORMAL KARYOTYPE

Author

Caprioli, C., primary, Spinelli, O., additional, Salmoiraghi, S., additional, Intermesoli, T., additional, Zanghì, P., additional, Cavagna, R., additional, Michelato, A., additional, Buklijas, K., additional, Elidi, L., additional, Delaini, F., additional, Oldani, E., additional, Gianfaldoni, G., additional, Bosi, A., additional, Marmont, F., additional, Audisio, E., additional, Ferrero, D., additional, Terruzzi, E., additional, De Paoli, L., additional, Rossi, G., additional, Borlenghi, E., additional, Cavattoni, I., additional, Tajana, M., additional, Scattolin, A.M., additional, Mattei, D., additional, Corradini, P., additional, Campiotti, L., additional, Ciceri, F., additional, Bernardi, M., additional, Todisco, E., additional, Cortelezzi, A., additional, Cortelazzo, S., additional, Falini, B., additional, Pavoni, C., additional, Bassan, R., additional, Rambaldi, A., additional, and Lussana, F., additional

Published
2019
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6. MOLECULAR PROLIFE BY NEXT GENERATION SEQUENCING OF ACUTE MYELOID LEUKEMIA WITH NORMAL KARYOTYPE: CLINICAL RESULTS FROM THE PROSPECTIVE TRIAL 02/06 OF THE NORTHERN ITALY LEUKEMIA GROUP (NILG)

Author

Spinelli, O, Salmoiraghi, S, Zanghi, P, Cavagna, R, Michelato, A, Buklijas, K, Zannino, L, Intermesoli, T, Lussana, F, Delaini, F, Oldani, E, Caprioli, C, Stefanoni, P, Gianfaldoni, G, Marmont, F, Ferrero, D, Terruzzi, E, De Paoli, L, Rossi, G, Borlenghi, E, Cavattoni, I, Tajana, M, Scattolin, Am, Mattei, D, Corradini, P, Campiotti, L, Ciceri, F, Bernardi, M, Todisco, E, Cortelezzi, A, Cortelazzo, S, Audisio, E, Bosi, A, Falini, B, Pavoni, C, Bassan, R, and Rambaldi, A

Published
2018

7. High Throughput Molecular Characterization of Normal Karyotype Acute Myeloid Leukemia in the Context of the Prospective Trial 02/06 of the Northern Italy Leukemia Group (NILG)

Author

Renato Bassan, Chiara Pavoni, Pamela Zanghì, Elisabetta Todisco, Nicola Stefano Fracchiolla, Anna Michelato, Leonardo Campiotti, Federico Lussana, Roberta Cavagna, Annamaria Scattolin, Giacomo Gianfaldoni, Chiara Caprioli, Erika Borlenghi, Fabio Ciceri, Ernesta Audisio, Alessandro Rambaldi, Lorella De Paoli, Tamara Intermesoli, Elisabetta Terruzzi, Orietta Spinelli, Ksenija Buklijas, Lara Elidi, Silvia Salmoiraghi, Paola Stefanoni, Paolo Corradini, Daniele Mattei, Irene Cavattoni, Monica Tajana, Elena Oldani, Salmoiraghi, S, Cavagna, R, Zanghì, P, Pavoni, C, Michelato, A, Buklijas, K, Elidi, L, Intermesoli, T, Lussana, F, Oldani, E, Caprioli, C, Stefanoni, P, Gianfaldoni, G, Audisio, E, Terruzzi, E, De Paoli, L, Borlenghi, E, Cavattoni, I, Mattei, D, Scattolin, A, Tajana, M, Ciceri, F, Todisco, E, Campiotti, L, Corradini, P, Fracchiolla, N, Bassan, R, Rambaldi, A, Spinelli, O, Salmoiraghi, S., Cavagna, R., Zanghi, P., Pavoni, C., Michelato, A., Buklijas, K., Elidi, L., Intermesoli, T., Lussana, F., Oldani, E., Caprioli, C., Stefanoni, P., Gianfaldoni, G., Audisio, E., Terruzzi, E., Paoli, L. D., Borlenghi, E., Cavattoni, I., Mattei, D., Scattolin, A., Tajana, M., Ciceri, F., Todisco, E., Campiotti, L., Corradini, P., Fracchiolla, N., Bassan, R., Rambaldi, A., and Spinelli, O.

Subjects
Oncology, Acute Myeloid Leukemia, Cancer Research, medicine.medical_specialty, NPM1, Context (language use), Gene mutation, Molecular marker, lcsh:RC254-282, Article, 03 medical and health sciences, 0302 clinical medicine, Internal medicine, hemic and lymphatic diseases, Medicine, Prospective cohort study, molecular marker, business.industry, Induction chemotherapy, medicine.disease, lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens, Transplantation, Leukemia, 030220 oncology & carcinogenesis, NGS, embryonic structures, business, 030215 immunology, Cohort study
Abstract

By way of a Next-Generation Sequencing NGS high throughput approach, we defined the mutational profile in a cohort of 221 normal karyotype acute myeloid leukemia (NK-AML) enrolled into a prospective randomized clinical trial, designed to evaluate an intensified chemotherapy program for remission induction. NPM1, DNMT3A, and FLT3-ITD were the most frequently mutated genes while DNMT3A, FLT3, IDH1, PTPN11, and RAD21 mutations were more common in the NPM1 mutated patients (p &lt, 0.05). IDH1 R132H mutation was strictly associated with NPM1 mutation and mutually exclusive with RUNX1 and ASXL1. In the whole cohort of NK-AML, no matter the induction chemotherapy used, by multivariate analysis, the achievement of complete remission was negatively affected by the SRSF2 mutation. Alterations of FLT3 (FLT3-ITD) and U2AF1 were associated with a worse overall and disease-free survival (p &lt, 0.05). FLT3-ITD positive patients who proceeded to alloHSCT had a survival probability similar to FLT3-ITD negative patients and the transplant outcome was no different when comparing high and low-AR-FLT3-ITD subgroups in terms of both OS and DFS. In conclusion, a comprehensive molecular profile for NK-AML allows for the identification of genetic lesions associated to different clinical outcomes and the selection of the most appropriate and effective treatment strategies, including stem cell transplantation and targeted therapies.

Published
2020

8. Clinical significance of chromatin-spliceosome acute myeloid leukemia: a report from the Northern Italy Leukemia Group (NILG) randomized trial 02/06

Author

Anna Michelato, Fabio Ciceri, Dario Ferrero, Lorella De Paoli, Renato Bassan, Chiara Caprioli, Paolo Corradini, Silvia Salmoiraghi, Brunangelo Falini, Chiara Cattaneo, Giacomo Gianfaldoni, Agostino Cortelezzi, Federica Delaini, Alessandro Rambaldi, Francesco Mannelli, Leonardo Campiotti, Anna Maria Scattolin, Pamela Zanghì, Erika Borlenghi, Federico Lussana, Massimo Bernardi, Ksenija Buklijas, Daniele Mattei, Elena Oldani, Monica Tajana, Tamara Intermesoli, Roberta Cavagna, Anna De Grassi, Irene Cavattoni, Ernesta Audisio, Elisabetta Terruzzi, Orietta Spinelli, Lara Elidi, Elisabetta Todisco, Chiara Pavoni, Caprioli, C, Lussana, F, Salmoiraghi, S, Cavagna, R, Buklijas, K, Elidi, L, Zanghi', P, Michelato, A, Delaini, F, Oldani, E, Intermesoli, T, Grassi, A, Gianfaldoni, G, Mannelli, F, Ferrero, D, Audisio, E, Terruzzi, E, De Paoli, L, Cattaneo, C, Borlenghi, E, Cavattoni, I, Tajana, M, Scattolin, A, Mattei, D, Corradini, P, Campiotti, L, Ciceri, F, Bernardi, M, Todisco, E, Cortelezzi, A, Falini, B, Pavoni, C, Bassan, R, Spinelli, O, Rambaldi, A, Caprioli, Chiara, Lussana, Federico, Salmoiraghi, Silvia, Cavagna, Roberta, Buklijas, Ksenija, Elidi, Lara, Zanghi', Pamela, Michelato, Anna, Delaini, Federica, Oldani, Elena, Intermesoli, Tamara, Grassi, Anna, Gianfaldoni, Giacomo, Mannelli, Francesco, Ferrero, Dario, Audisio, Ernesta, Terruzzi, Elisabetta, De Paoli, Lorella, Cattaneo, Chiara, Borlenghi, Erika, Cavattoni, Irene, Tajana, Monica, Scattolin, Anna Maria, Mattei, Daniele, Corradini, Paolo, Campiotti, Leonardo, Ciceri, Fabio, Bernardi, Massimo, Todisco, Elisabetta, Cortelezzi, Agostino, Falini, Brunangelo, Pavoni, Chiara, Bassan, Renato, Spinelli, Orietta, and Rambaldi, Alessandro

Subjects
Acute Myeloid Leukemia, Oncology, medicine.medical_specialty, Myeloid, Cytogenetics and Molecular Genetics, Myelodysplastic Syndromes, Article, law.invention, Cytogenetics and Molecular Genetic, 03 medical and health sciences, 0302 clinical medicine, Randomized controlled trial, law, hemic and lymphatic diseases, Internal medicine, medicine, Humans, Secondary Acute Myeloid Leukemia, Clinical significance, Prospective Studies, Prospective cohort study, neoplasms, Aged, Myeloproliferative Disorders, business.industry, Myelodysplastic syndromes, Myeloid leukemia, Hematology, Prognosis, medicine.disease, Chromatin, Leukemia, Myeloid, Acute, Leukemia, medicine.anatomical_structure, Spliceosomes, business, 030215 immunology
Abstract

Secondary acute myeloid leukemia (sAML) after myelodysplastic or myeloproliferative disorders is a high-risk category currently identified by clinical history or specific morphological and cytogenetic abnormalities. However, in the absence of these features, uncertainties remain to identify the secondary nature of some cases otherwise defined as de novo AML. To test whether a chromatin-spliceosome (CS) mutational signature might better inform the definition of the de novo AML group, we analyzed a prospective cohort of 413 newly diagnosed AML patients enrolled into a randomized clinical trial (NILG AML 02/06) and provided with accurate cytogenetic and molecular characterization. Among clinically defined de novo AML, 17.6% carried CS mutations (CS-AML) and showed clinical characteristics closer to sAML (older age, lower white blood cell counts and higher rate of multilineage dysplasia). Outcomes in this group were adverse, more similar to those of sAML as compared to de novo AML (overall survival, 30% in CS-AML and 17% in sAML vs 61% in de novo AML, P

Published
2020
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9. gDNA qPCR is statistically more reliable than mRNA analysis in detecting leukemic cells to monitor CML

Author

Andrea Conti, Anna Michelato, Cristina Barlassina, Giovanni Micheloni, Alessia Rainero, Giorgia Millefanti, Matteo Barcella, Francesca D'Avila, Eleonora Piscitelli, Ksenija Buklijas, Silvia M. Sirchia, Cristina Pirrone, Orietta Spinelli, Emanuela Maserati, Fabrizio Angaroni, R. Casalone, Giovanni Porta, Lucia Tararà, Massimo Caccia, Roberto Valli, Rainero, A, Angaroni, F, Conti, A, Pirrone, C, Micheloni, G, Tarara, L, Millefanti, G, Maserati, E, Valli, R, Spinelli, O, Buklijas, K, Michelato, A, Casalone, R, Barlassina, C, Barcella, M, Sirchia, S, Piscitelli, E, Caccia, M, and Porta, G

Subjects
Male, 0301 basic medicine, Cancer Research, Immunology, Fusion Proteins, bcr-abl, Leukemia, Myelogenous, Chronic,Treatment Outcome, Real-Time Polymerase Chain Reaction, Article, Follow-Up Studie, Fusion gene, Young Adult, 03 medical and health sciences, Cellular and Molecular Neuroscience, 0302 clinical medicine, Cancer stem cell, Leukemia, Myelogenous, Chronic, BCR-ABL Positive, Precursor B-Cell Lymphoblastic Leukemia-Lymphoma, hemic and lymphatic diseases, Humans, Medicine, RNA, Messenger, lcsh:QH573-671, Protein Kinase Inhibitors, Aged, Cell Biology, Reverse Transcriptase Polymerase Chain Reaction, business.industry, lcsh:Cytology, Reproducibility of Results, Myeloid leukemia, DNA, Middle Aged, Protein-Tyrosine Kinases, medicine.disease, genomic DNA, Leukemia, Haematopoiesis, Treatment Outcome, 030104 developmental biology, Real-time polymerase chain reaction, 030220 oncology & carcinogenesis, Imatinib Mesylate, Neoplastic Stem Cells, Cancer research, Female, Stem cell, business, Follow-Up Studies
Abstract

Chronic Myeloid Leukemia (CML) is a stem cell cancer that arises when t(9;22) translocation occurs in a hematopoietic stem cells. This event results in the expression of the BCR-ABL1 fusion gene, which codes for a constitutively active tyrosine kinase that is responsible for the transformation of a HSC into a CML stem cell, which then gives rise to a clonal myeloproliferative disease. The introduction of Tyrosine Kinase Inhibitors (TKIs) has revolutionized the management of the disease. However, these drugs do not seem to be able to eradicate the malignancy. Indeed, discontinuation trials (STIM; TWISER; DADI) for those patients who achieved a profound molecular response showed 50% relapsing within 12 months. We performed a comparative analysis on 15 CML patients and one B-ALL patient, between the standard quantitative reverse-transcriptase PCR (qRT–PCR) and our genomic DNA patient-specific quantitative PCR assay (gDNA qPCR). Here we demonstrate that gDNA qPCR is better than standard qRT–PCR in disease monitoring after an average follow-up period of 200 days. Specifically, we statistically demonstrated that DNA negativity is more reliable than RNA negativity in indicating when TKIs therapy can be safely stopped.

Published
2018
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10. Sequential allogeneic transplantation and ruxolitinib maintenance for a synchronous PCM1-JAK2 positive myeloid sarcoma and acute B-lymphoblastic leukemia.

Author

Rizzuto G, Leoncin M, Imbergamo S, Taurino D, Mico MC, Tosi M, Michelato A, Buklijas K, Spinelli O, Lussana F, Lessi F, Pizzi M, Bonaldi L, Binotto G, Rambaldi A, and Gurrieri C

Abstract

The translocation t(8;9)(p22;p24) results in the production of a chimeric PCM1 - JAK2 fusion protein leading to the constitutive activation of the Janus Kinase 2 that renders this disease potentially sensitive to ruxolitinib. Here, we report an interesting case of PCM1 - JAK2  myeloproliferative neoplasm evolving in myeloid sarcoma and B precursor ALL., Competing Interests: The authors declare no conflicts of interest., (© 2022 The Authors. Clinical Case Reports published by John Wiley & Sons Ltd.)

Published
2022
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11. High Throughput Molecular Characterization of Normal Karyotype Acute Myeloid Leukemia in the Context of the Prospective Trial 02/06 of the Northern Italy Leukemia Group (NILG).

Author

Salmoiraghi S, Cavagna R, Zanghì P, Pavoni C, Michelato A, Buklijas K, Elidi L, Intermesoli T, Lussana F, Oldani E, Caprioli C, Stefanoni P, Gianfaldoni G, Audisio E, Terruzzi E, De Paoli L, Borlenghi E, Cavattoni I, Mattei D, Scattolin A, Tajana M, Ciceri F, Todisco E, Campiotti L, Corradini P, Fracchiolla N, Bassan R, Rambaldi A, and Spinelli O

Abstract

By way of a Next-Generation Sequencing NGS high throughput approach, we defined the mutational profile in a cohort of 221 normal karyotype acute myeloid leukemia (NK-AML) enrolled into a prospective randomized clinical trial, designed to evaluate an intensified chemotherapy program for remission induction. NPM1 , DNMT3A, and FLT3 -ITD were the most frequently mutated genes while DNMT3A , FLT3 , IDH1 , PTPN11 , and RAD21 mutations were more common in the NPM1 mutated patients ( p < 0.05). IDH1 R132H mutation was strictly associated with NPM1 mutation and mutually exclusive with RUNX1 and ASXL1 . In the whole cohort of NK-AML, no matter the induction chemotherapy used, by multivariate analysis, the achievement of complete remission was negatively affected by the SRSF2 mutation. Alterations of FLT3 ( FLT3- ITD) and U2AF1 were associated with a worse overall and disease-free survival ( p < 0.05). FLT3- ITD positive patients who proceeded to alloHSCT had a survival probability similar to FLT3- ITD negative patients and the transplant outcome was no different when comparing high and low-AR- FLT3 -ITD subgroups in terms of both OS and DFS. In conclusion, a comprehensive molecular profile for NK-AML allows for the identification of genetic lesions associated to different clinical outcomes and the selection of the most appropriate and effective treatment strategies, including stem cell transplantation and targeted therapies.

Published
2020
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12. Molecular Detection of Minimal Residual Disease before Allogeneic Stem Cell Transplantation Predicts a High Incidence of Early Relapse in Adult Patients with NPM1 Positive Acute Myeloid Leukemia.

Author

Lussana F, Caprioli C, Stefanoni P, Pavoni C, Spinelli O, Buklijas K, Michelato A, Borleri G, Algarotti A, Micò C, Grassi A, Intermesoli T, and Rambaldi A

Abstract

We analyzed the impact of alloHSCT in a single center cohort of 89 newly diagnosed NPM1 mut AML patients, consecutively treated according to the Northern Italy Leukemia Group protocol 02/06 [NCT00495287]. After two consolidation cycles, the detection of measurable residual disease (MRD) by RQ-PCR was strongly associated with an inferior three-year overall survival (OS, 45% versus 84%, p = 0.001) and disease-free survival (DFS, 44% versus 76%, p = 0.006). In MRD-negative patients, post-remissional consolidation with alloHSCT did not provide a significant additional benefit over a conventional chemotherapy in terms of overall survival [OS, 89% (95% CI 71-100%) versus 81% (95% CI 64-100%), p = 0.59] and disease-free survival [DFS, 80% (95% CI 59-100%) versus 75% (95% CI 56-99%), p = 0.87]. On the contrary, in patients with persistent MRD positivity, the three-year OS and DFS were improved in patients receiving an alloHSCT compared to those allocated to conventional chemotherapy (OS, 52% versus 31%, p = 0.45 and DFS, 50% versus 17%, p = 0.31, respectively). However, in this group of patients, the benefit of alloHSCT was still hampered by a high incidence of leukemia relapse during the first year after transplantation (43%, 95% CI 25-60%). Consolidative alloHSCT improves outcomes compared to standard chemotherapy in patients with persistent NPM1 mut MRD positivity, but in these high-risk patients, the significant incidence of leukemia relapse must be tackled by post-transplant preemptive treatments.

Published
2019
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