Clinical trial NCT01452646: Risk-adapted, MRD-directed Therapy for Young Adults With Newly Diagnosed Acute Myeloid Leukemia
Official title: Risk-adapted, MRD-directed Therapy for Young Adults With Newly Diagnosed Acute Myeloid Leukemia. GIMEMA Protocol AML1310. EudraCT Number 2010-023809-36
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Acute Myeloid Leukemia
Keywords: acute myeloid leukemia
risk-adapted therapy
MRD-directed therapy
young adults
Lead sponsor: Gruppo Italiano Malattie EMatologiche dell'Adulto
Sponsor class: OTHER
First posted: 2011-10-17
Enrollment: 515
Sex: ALL
Minimum age (years): 18
Maximum age (years): 60
Standard ages: ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Primary purpose: TREATMENT

Brief summary: The purpose of this study is to determine whether a risk-adapted, minimal-residual-disease directed therapy for young adults with newly diagnosed acute myeloid leukemia has positive results in terms of overall survival at 24 months.

Detailed description: The general objective of this study is that of setting up a multicentre, risk-adapted study that relies on pre-treatment cytogenetic/genetic features and post-consolidation assessment of Minimal Residual Disease (MRD) to establish the final risk assignment and treatment of younger (≤ 60 years) patients with Acute Myeloid Leukemia (AML). Aim of this clinical trial is to verify whether the delivery of a post remission therapy whose intensity is risk-driven will improve the outcome in terms of both increased anti-leukemic efficacy and reduced therapy-related toxicity.

All patients will receive induction and consolidation chemotherapy according to the Gruppo Italiano Malattie EMatologiche dell'Adulto (GIMEMA) LAM99P protocol. After the first consolidation, patients belonging to the low-risk category (core binding factor positive AML without c-Kit mutations, NPM1 positive FLT3 negative AML) will receive autologous stem cell transplantation, patients with high-risk features (adverse-risk karyotype, FLT3-ITD mutations), will be assigned to allogeneic stem cell transplantation. Patients with FLT3-TKD mutations or c-Kit mutated core binding factor positive AML and those belonging to the intermediate-risk karyotype category will be stratified according to MRD by flow cytometry and will receive risk-adapted treatment (autologous vs. allogeneic stem cell transplantation). All patients who meet the criteria for high-risk definition will be offered the allogeneic transplantation option regardless of the availability of a Human Leukocyte Antigen (HLA) identical sibling. In fact, for those lacking a HLA identical sibling all the other sources of hematopoietic stem cells (matched unrelated donor from international registry, unrelated cord blood, family haploidentical donor) will be considered. Autologous or allogeneic stem cell transplantation will be performed within 3 months from the end of consolidation therapy.

Eligibility criteria: Inclusion Criteria:

* Signed written informed consent according to ICH/EU/GCP and national/local laws
* Patients aged between 18 and 60 years
* Patients previously untreated for their AML by other chemotherapeutic agents (with the exception of no more than 7 days hydroxyurea (HU)), radiotherapy or more than 7 days corticosteroids
* Unequivocal diagnosis of untreated de novo AML according to WHO diagnostic criteria (at least 20% blasts in the bone marrow), with FAB classification other than M3 (acute promyelocytic leukemia), documented by bone marrow aspiration (or biopsy in case of dry tap) (not supervening after other myeloproliferative disease or myelodysplastic syndromes of more than 6 months duration)
* WHO performance status 0-3
* Adequate renal (serum creatinine \< 2 x the institutional Upper Limit of Normal (ULN)) and liver (total serum bilirubin \< 2 x ULN; serum ALT and AST ≤ 3 x ULN) function, unless considered due to organ leukemic involvement
* Left Ventricular Ejection Fraction (LVEF) \>50%, as determined by echocardiogram
* Absence of severe concomitant neurological or psychiatric diseases and congestive heart failure or active uncontrolled infection
* Absence of any psychological, familial, sociological and geographical condition potentially hampering compliance with the study protocol and the follow-up schedule.

Exclusion Criteria:

* Patients aged less than 18 or more than 60 years
* Patients already treated for their AML by other chemotherapeutic agents (with the exception of no more than 7 days HU), radiotherapy or more than 7 days corticosteroids
* Acute promyelocytic leukaemia
* Blast crisis of chronic myeloid leukaemia
* AML supervening after other myeloproliferative disease
* AML supervening after antecedent myelodysplastic syndromes of more than 6 months duration
* Other progressive malignant diseases. However, secondary AML following previously cured malignancies may be included as well as secondary AML following previous exposure to alkylating agents or radiation for other reason
* Inadequate renal or liver function (metabolic abnormalities \> 3 times the normal upper limit)
* Severe heart failure requiring diuretics
* Ejection fraction \< 50%
* Uncontrolled infections
* WHO performance status = 4
* Severe concomitant neurological or psychiatric diseases
* Patients who are pregnant or adults of reproductive potential not employing an effective method of birth control. Women of childbearing potential must have a negative serum pregnancy test within 48 hrs prior to administration of chemotherapy. Post-menopausal women must be amenorrhoeic for at least 12 months to be considered of non-childbearing potential. Male and female patients must agree to employ an effective barrier method of birth control throughout the study and for up to 3 months following discontinuation of study drug.

Primary outcomes:
measure: Treatment strategy in terms of Overall Survival (OS) at 24 months.
timeFrame: 24 months from study entry.
Secondary outcomes:
measure: Estimation of Disease Free Survival (DFS) from Complete Response (CR) evaluation.
timeFrame: At 24 months from study entry
measure: Estimation of Event Free Survival (EFS) from study entry.
timeFrame: at 24 months from study entry
measure: Rate of patients in CR after induction therapy
timeFrame: At 31 days from study entry if pts are in CR or at 69 days from study entry if pts are in PR after 1 induction cycle
measure: Toxicity according to Common Toxicity Criteria for Adverse Events (CTCAE) version 4.0
timeFrame: From study entry to study completion (6 months therapy + 18 months follow-up)
measure: Estimation of OS, EFS, DFS and Cumulative Incidence of Relapse (CIR) according to risk groups (Low, Intermediate, High)
timeFrame: At 24 months from study entry
measure: Estimation of OS, EFS, DFS and CIR according to the Minimal Residual Disease (MRD) level at each evaluation step
timeFrame: At 24 months from study entry
measure: Rate of CR patients and estimation OS, EFS, DFS and CIR according to baseline characteristics such as age, performance status, white blood cell (WBC), morphology, cytogenetic and molecular features.
timeFrame: At 24 months from study entry
measure: Quality of Life evaluation
timeFrame: Before treatment starts, after induction, at one year after baseline evaluation.
Other outcomes:
Locations:
city: Tricase
country: Italy
facility: U.O. di Ematologia - Azienda Ospedaliera - Pia Fondazione di Culto e di Religione Card. G.Panico
state: (le)
city: Roma
country: Italy
facility: Complesso Ospedaliero S. Giovanni Addolorata
state: (rm)
city: Rome
country: Italy
facility: Policlinico di Tor Vergata
state: (rm)
city: Alessandria
country: Italy
facility: S.O.C. di Ematologia - Azienda Ospedaliera - SS. Antonio e Biagio e Cesare Arrigo
city: Ancona
country: Italy
facility: Azienda Ospedaliera - Nuovo Ospedale "Torrette"
city: Avellino
country: Italy
facility: Az. Ospedaliera S. G. Moscati
city: Bari
country: Italy
facility: Unità Operativa Ematologia 1 - Università degli Studi di Bari
city: Barletta
country: Italy
facility: UOC Ematologia Ospedale " Monsignor Raffaele Dimiccoli"
city: Bologna
country: Italy
facility: Ist.Ematologia e Oncologia Medica L.e A. Seragnoli
city: Brindisi
country: Italy
facility: Divisione di Ematologia Ospedale A. Perrino
city: Cagliari
country: Italy
facility: Servizio di Ematologia - CTMO - ASL 8 P.O. Binaghi
city: Caserta
country: Italy
facility: Unità Operativa Complessa di Onco-Ematologia - A.O. S.Anna e S.Sebastiano
city: Catania
country: Italy
facility: Università di Catania - Cattedra di Ematologia - Ospedale "Ferrarotto"
city: Catanzaro
country: Italy
facility: Azienda Ospedaliera Pugliese Ciaccio
city: Civitanova
country: Italy
facility: Marche U.O. di Medicina Interna - ASUR Marche 8 - Ospedale Civile
city: Cona
country: Italy
facility: Azienda Ospedaliero Universitaria Arcispedale Sant'Anna Dipartimento di Scienze Mediche Sezione di Ematologia e Fisiopatologia dell'Emostasi
city: Cremona
country: Italy
facility: Sezione di Ematologia C.T.M.O. Istituti Ospitalieri
city: Ferrara
country: Italy
facility: Sez.Ematologia e Dip. scienze Biomediche Arcispedale S. Anna
city: Foggia
country: Italy
facility: Struttura Complessa di Ematologia Ospedali Riuniti Foggia - Azienda Ospedaliero-Universitaria
city: Genova
country: Italy
facility: Clinica Ematologica - Università degli Studi
city: Latina
country: Italy
facility: Divisione di Ematologia Ospedale "Santa Maria Goretti"
city: Lecce
country: Italy
facility: ASL Le/1 P.O. Vito Fazzi - U.O. di Ematol
city: Meldola
country: Italy
facility: Istituto Scientifico Romagnoli per lo Studio e la Cura dei Tumori- IRST
city: Messina
country: Italy
facility: Azienda Ospedaliera Universitaria - Policlinico G. Martino Dipartimento di Medicina Interna - U.O. Messina
city: Messina
country: Italy
facility: Divisione di Ematologia - Azienda Ospedaliera Ospedali Riuniti "Papardo Piemonte"
city: Milano
country: Italy
facility: Ospedale Niguarda " Ca Granda"
city: Milano
country: Italy
facility: UO Centro Trapianti di Midollo - IRCCS Ospedale Maggiore Policlinico
city: Modena
country: Italy
facility: Centro Oncologico Modenese - Dipartimento di Oncoematologia
city: Napoli
country: Italy
facility: Azienda Ospedaliera Universitaria - Università degli Studi di Napoli "Federico II" - Facoltà di Medicina e Chirurgia
city: Nocera Inferiore
country: Italy
facility: Pr. Alfonso Maria D'Arco
city: Novara
country: Italy
facility: S.C.D.U. Ematologia - DIMECS e Dipartimento Oncologico - Università del Piemonte Orientale Amedeo Avogadro
city: Orbassano
country: Italy
facility: Ospedale S. Luigi Gonzaga
city: Padova
country: Italy
facility: Università degli Studi di Padova - Ematologia ed Immunologia Clinica
city: Palermo
country: Italy
facility: Ospedale Riuniti "Villa-Sofia-Cervello"
city: Palermo
country: Italy
facility: Divisione di Ematologia con trapianto di midollo - A.U. Policlinico "Paolo Giaccone"
city: Parma
country: Italy
facility: Cattedra di Ematologia CTMO Università degli Studi di Parma
city: Perugia
country: Italy
facility: Sezione di Ematologia ed Immunologia Clinica - Ospedale S.Maria della MIsericordia
city: Pesaro
country: Italy
facility: Div. di Ematologia di Muraglia - CTMO Ospedale San Salvatore
city: Pescara
country: Italy
facility: Azienda ASL di Pescara
city: Piacenza
country: Italy
facility: Unità Operativa Ematologia e Centro Trapianti - Dipartimento di Oncologia ed Ematologia - AUSL Ospedale di Piacenza
city: Pisa
country: Italy
facility: Università di Pisa - Azienda Ospedaliera Pisana - Dipartimento di Oncologia, dei Trapianti e delle nuove Tecnologie in Medicina - Divisione di Ematologia
city: Potenza
country: Italy
facility: Ematologia - Ospedale San Carlo
city: Ravenna
country: Italy
facility: Ospedale S.Maria delle Croci
city: Reggio Calabria
country: Italy
facility: Dipartimento Emato-Oncologia A.O."Bianchi-Melacrino-Morelli"
city: Reggio Emilia
country: Italy
facility: Unità Operativa Complessa di Ematologia - Arcispedale S. Maria Nuova
city: Rimini
country: Italy
facility: Ospedale "Infermi"
city: Roma
country: Italy
facility: Divisione Ematologia - Università Campus Bio-Medico
city: Roma
country: Italy
facility: Università Cattolica del Sacro Cuore - Policlinico A. Gemelli
city: Roma
country: Italy
facility: Az. Ospedaliera "Sant' Andrea"-Università la Sapienza Seconda Facoltà di Medicina e Chirurgia
city: Roma
country: Italy
facility: S.C. di Ematologia e Trapianti - I.F.O. Istituto Nazionale Tumori Regina Elena
city: Roma
country: Italy
facility: Università degli Studi "Sapienza" - Dip Biotecnologie Cellulari ed Ematologia - Divisione di Ematologia
city: Rome
country: Italy
facility: Ospedale S. Camillo
city: Rome
country: Italy
facility: U.O.C. Ematologia - Ospedale S.Eugenio
city: Rozzano
country: Italy
facility: Sezione di Ematologia Cancer Center Humanitas
city: San Giovanni Rotondo
country: Italy
facility: Istituto di Ematologia - IRCCS Ospedale Casa Sollievo della Sofferenza
city: Sassari
country: Italy
facility: Serv. di Ematologia Ist. di Ematologia ed Endocrinologia
city: Siena
country: Italy
facility: U.O.C. Ematologia e Trapianti - A.O. Senese - Policlinico " Le Scotte"
city: Taormina
country: Italy
facility: UOC di Ematologia Generale P.O. S.Vincenzo
city: Taranto
country: Italy
facility: U.O.C. di Ematolgia - A.O. " SS Annunziata" - P.O. S.G. Moscati
city: Treviso
country: Italy
facility: Azienda U.L.S.S.9 - U.O. di Ematologia
city: Udine
country: Italy
facility: Policlinico Universitario - Clinica Ematologia
Study officials:
affiliation: Policlinico Tor Vergata di Roma
name: Adriano VENDITTI, Pr.
role: PRINCIPAL_INVESTIGATOR
References:
citation: Buccisano F, Palmieri R, Piciocchi A, Arena V, Candoni A, Melillo L, Calafiore V, Cairoli R, de Fabritiis P, Storti G, Salutari P, Lanza F, Martinelli G, Luppi M, Capria S, Maurillo L, Del Principe MI, Paterno G, Irno Consalvo MA, Ottone T, Lavorgna S, Voso MT, Fazi P, Vignetti M, Arcese W, Venditti A. ELN2017 risk stratification improves outcome prediction when applied to the prospective GIMEMA AML1310 protocol. Blood Adv. 2022 Apr 26;6(8):2510-2516. doi: 10.1182/bloodadvances.2021005717.
citation: Venditti A, Piciocchi A, Candoni A, Melillo L, Calafiore V, Cairoli R, de Fabritiis P, Storti G, Salutari P, Lanza F, Martinelli G, Luppi M, Mazza P, Martelli MP, Cuneo A, Albano F, Fabbiano F, Tafuri A, Chierichini A, Tieghi A, Fracchiolla NS, Capelli D, Foa R, Alati C, La Sala E, Fazi P, Vignetti M, Maurillo L, Buccisano F, Del Principe MI, Irno-Consalvo M, Ottone T, Lavorgna S, Voso MT, Lo-Coco F, Arcese W, Amadori S. GIMEMA AML1310 trial of risk-adapted, MRD-directed therapy for young adults with newly diagnosed acute myeloid leukemia. Blood. 2019 Sep 19;134(12):935-945. doi: 10.1182/blood.2018886960. Epub 2019 Aug 8.