Treatment Protocol for Newky Diagnosed Adult Ph Positive ALL

The goal of this prospective, multicenter, open observational study is to assess the efficacy and safety of the treatment for acute lymphoblastic leukemia Ph' positive adult patients with approved combinations of chemotherapy and tyrosine kinase inhibitor (TKI). Efficay refers to the rate of Complete Molecular Response (BCR::ABL1/ABL1 ratio 0.01%) in eah treatment arm. Safety refers to measurement of i) Adverse events (AEs) and serious adverse events (SAEs) according to standard clinical and laboratory tests (hematology and chemistry, physical examination, vital sign measurements, and diagnostic tests), ii) incidence and degree of cytopenias and iii) incidence and degree of infections. Low-dose chemotherapy will be given together with the TKI imatinib to patients of all ages as induction to remission phase. Consolidation treatment will continue with low-dose chemotherapy with imatinib if the patient fullfills both criteria: to show a measurable residual disease (MRD) value lower than 0,01% at 3 month of therapy, and not showing IKZF1plus genetics Those patients have any of these 2 conditions will be considered high-risk patients and will recieve consolidation treatment intensification with low-dose chemotherapy plus ponatinib as TKI and allogeneic stem cell transplantation (allo SCT). The remaining patients (standard-risk) will receive maintenance chemotherapy together with imatinib or ponatinib and will not be submitted to alloSCT.

Sex

All

Minimum age

18 Years

Inclusion Criteria:

1. Patients with de novo avute lymphoblastic leukeima (ALL) Philadelphia chromosome-positive (BCR::ABL1) aged ≥18 years.
2. CML blast crisis will be included. These patients will always receive transplantation, regardless of the molecular response or the genetic risk, following the recommendations of the SEHH CML group (Chronic Myleoid Leukemia Group from the Spanish Society of Hematology).
3. Performance status 0-2; patients with performance status\>2 attributable to ALL can be included.
4. Patients without functional alteration of organs; liver function: total bilirubin, GOT, GPT, GGT and alkaline phosphatase less than 3 times the upper limit of the normal range of the laboratory; renal function: serum creatinine \<2 mg/dl or creatinine clearance \> 30 ml/min (except altered renal function attributable to ALL); normal heart function: EF ventricular \> 50%; absence of severe chronic respiratory disease. In case that the alterations are secondary to the disease, it is at the discretion of the physician to determine if the patient can be included in the study.

Exclusion Criteria:

1. Any other subtype of ALL.
2. Patients with chronic liver disease.
3. Patients with chronic respiratory failure.
4. Renal failure not due to ALL.
5. Lipase and amylase\>1.5× ULN.
6. Patients with positive HIV serology.
7. Serious neurological alterations not due to ALL.
8. Serious general condition condition (grades 3 or 4 on the WHO scale) not attributable to ALL.
9. Pregnant or breastfeeding women.
10. Impaired cardiac function (defined by an ejection fraction less than 50%), any clinically significant active or uncontrolled cardiovascular condition, uncontrolled hypertension, arrhythmias, ischemic cardiovascular or neurological events, deep vein thrombosis, pulmonary thromboembolism, history of acute pancreatitis in the year before diagnosis of ALL or history of chronic pancreatitis and triglycerides \>450 mg/dL.

• BACKGROUNDChiaretti S, Vitale A, Cazzaniga G, Orlando SM, Silvestri D, Fazi P, Valsecchi MG, Elia L, Testi AM, Mancini F, Conter V, te Kronnie G, Ferrara F, Di Raimondo F, Tedeschi A, Fioritoni G, Fabbiano F, Meloni G, Specchia G, Pizzolo G, Mandelli F, Guarini A, Basso G, Biondi A, Foa R. Clinico-biological features of 5202 patients with acute lymphoblastic leukemia enrolled in the Italian AIEOP and GIMEMA protocols and stratified in age cohorts. Haematologica. 2013 Nov;98(11):1702-10. doi: 10.3324/haematol.2012.080432. Epub 2013 May 28. PMID 23716539
• BACKGROUNDFielding AK, Rowe JM, Buck G, Foroni L, Gerrard G, Litzow MR, Lazarus H, Luger SM, Marks DI, McMillan AK, Moorman AV, Patel B, Paietta E, Tallman MS, Goldstone AH. UKALLXII/ECOG2993: addition of imatinib to a standard treatment regimen enhances long-term outcomes in Philadelphia positive acute lymphoblastic leukemia. Blood. 2014 Feb 6;123(6):843-50. doi: 10.1182/blood-2013-09-529008. Epub 2013 Nov 25. PMID 24277073
• BACKGROUNDRibera JM, Oriol A, Gonzalez M, Vidriales B, Brunet S, Esteve J, Del Potro E, Rivas C, Moreno MJ, Tormo M, Martin-Reina V, Sarra J, Parody R, de Oteyza JP, Bureo E, Bernal MT; Programa Espanol de Tratamiento en Hematologia; Grupo Espanol de Trasplante Hemopoyetico Groups. Concurrent intensive chemotherapy and imatinib before and after stem cell transplantation in newly diagnosed Philadelphia chromosome-positive acute lymphoblastic leukemia. Final results of the CSTIBES02 trial. Haematologica. 2010 Jan;95(1):87-95. doi: 10.3324/haematol.2009.011221. Epub 2009 Oct 1. PMID 19797728
• BACKGROUNDDaver N, Thomas D, Ravandi F, Cortes J, Garris R, Jabbour E, Garcia-Manero G, Borthakur G, Kadia T, Rytting M, Konopleva M, Kantarjian H, O'Brien S. Final report of a phase II study of imatinib mesylate with hyper-CVAD for the front-line treatment of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Haematologica. 2015 May;100(5):653-61. doi: 10.3324/haematol.2014.118588. Epub 2015 Feb 14. PMID 25682595
• BACKGROUNDChiaretti S, Vitale A, Vignetti M, Piciocchi A, Fazi P, Elia L, Falini B, Ronco F, Ferrara F, De Fabritiis P, Luppi M, La Nasa G, Tedeschi A, Califano C, Fanin R, Dore F, Mandelli F, Meloni G, Foa R. A sequential approach with imatinib, chemotherapy and transplant for adult Ph+ acute lymphoblastic leukemia: final results of the GIMEMA LAL 0904 study. Haematologica. 2016 Dec;101(12):1544-1552. doi: 10.3324/haematol.2016.144535. Epub 2016 Aug 11.