Page 12 - 2020_07-Haematologica-web

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Editorials
mary and secondary iron overload disorders: preclinical models and
approaches. Hematol Oncol Clin North Am. 2014;28(2):387-401.
15. Preza GC, Ruchala P, Pinon R, et al. Minihepcidins are rationally designed small peptides that mimic hepcidin activity in mice and may be useful for the treatment of iron overload. J Clin Invest.
2011;121(12):4880-4888.
16. Ramos E, Ruchala P, Goodnough JB, et al. Minihepcidins prevent iron
overload in a hepcidin-deficient mouse model of severe hemochro-
matosis. Blood. 2012;120(18):3829-3836.
17. Casu C, Oikonomidou PR, Chen H, et al. Minihepcidin peptides as
disease modifiers in mice affected by beta-thalassemia and poly-
Hematology Am Soc Hematol Educ Program. 2019;2019(1):337-344. 21. Angelucci E. Hematopoietic stem cell transplantation in thalassemia.
Hematology Am Soc Hematol Educ Program. 2010;2010:456-462. 22. Thompson AA, Walters MC, Kwiatkowski J, et al. Gene therapy in patients with transfusion-dependent beta-thalassemia. N Engl J Med.
2018;378(16):1479-1493.
23. Galanello R, Origa R. Beta-thalassemia. Orphanet J Rare Dis.
2010;5:11.
24. Casu C, Nemeth E, Rivella S. Hepcidin agonists as therapeutic tools.
Blood. 2018;131(16):1790-1794.
25. Camaschella C, Nai A. Ineffective erythropoiesis and regulation of iron
status in iron loading anaemias. Br J Haematol. 2016;172(4):512-523. 26. Cappellini MD, Viprakasit V, Taher AT, et al. A phase 3 trial of lus- patercept in patients with transfusion-dependent beta-thalassemia.
N Engl J Med. 2020;382(13):1219-1231.
27. Busti F, Marchi G, Lira Zidanes A, Castagna A, Girelli D. Treatment
options for anemia in the elderly. Transfus Apher Sci. 2019;58(4):416-421.
cythemia vera. Blood. 2016;128(2):265-276.
18. Casu C, Chessa R, Liu A, et al. Minihepcidins improve ineffective
erythropoiesis and splenomegaly in a new mouse model of adult β-
thalassemia major. Haematologica. 2020;105(7):1835-1844.
19. Camaschella C. Treating iron overload. N Engl J Med. 2013;368(24):
2325-2327.
20. Coates TD. Iron overload in transfusion-dependent patients.
ABL-class fusion positive acute lymphoblastic leukemia: can targeting ABL cure ALL?
Thai Hoa Tran1 and Stephen P. Hunger2
1Division of Pediatric Hematology-Oncology, Charles-Bruneau Cancer Center, CHU Sainte-Justine, University of Montreal, Montreal, Quebec, Canada and 2Department of Pediatrics, The Center for Childhood Cancer Research, Children’s Hospital of Philadelphia, The Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
E-mail: STEPHEN HUNGER - hungers@email.chop.edu doi:10.3324/haematol.2020.252916
Five-year survival rates for pediatric acute lym- phoblastic leukemia (ALL), a malignancy that was
1
incurable in the 1950s, now exceed 90%. However,
15-20% of National Cancer Institute (NCI) high-risk (HR) B-lineage ALL (B-ALL) patients relapse, and post-relapse outcomes remain poor, particularly following early mar- row relapse [5-year overall survival (OS): 28%].2 Genomic advances have identified a novel B-ALL subtype charac- terized by a heterogeneous spectrum of kinase-activating alterations, producing a gene expression signature similar to that of Philadelphia chromosome-positive (Ph+) ALL, without the canonical BCR-ABL1 oncoprotein, referred to as BCR-ABL1-like ALL or Ph-like ALL, and now recog- nized as a provisional disease entity in the 2016 World Health Organization’s classification of acute leukemias.3,4 Ph-like ALL is associated with adverse clinical features and poor outcomes despite modern therapy.4-6 It occurs in approximately 15% of children with NCI HR B-ALL and over 25% of adults with B-ALL, and contributes dispro- portionately to relapses.4,6 Among Ph-like ALL patients, 10-14% of them harbor rearrangements of ABL-class genes (ABL1, ABL2, CSF1R, LYN, PDGFRA, PDGFRB) other than BCR-ABL1, collectively representing 2-3% of pediatric B-ALL cases.4-6 While there are anecdotal reports of the short-term efficacy of adding the ABL tyrosine kinase inhibitors (TKI) imatinib or dasatinib to chemotherapy,4,7,8 controlled data are lacking regarding the long-term efficacy of this approach. In this issue of Haematologica, Cario et al.9 provide important new infor- mation on treatment of children with ALL and ABL-class fusions.
They report 46 ABL-class fusion positive B-ALL patients (15 involving ABL1, 5 ABL2, 3 CSF1R, and 23
PDGFRB) who were originally enrolled on the AIEOP- BFM ALL 2000 and 2009 trials, and identified retrospec- tively. ABL-class fusion-positive cases had a substantially worse early treatment response than other patients, as reflected by prednisone-poor response (50% vs. 5.6%, P<0.0001) or minimal residual disease (MRD) ≥5x10-4 at end-induction (71.4% vs. 19.2%, P<0.0001) and end-pro- tocol Ib (51.2% vs. 5.1%, P<0.0001). Thirty-six of 46 patients (78.3%) were classified as HR (vs. 11.1% of ALL- BFM 2000 B-ALL patients overall), and more than half (25 of 46, 54.3%) underwent hematopoietic stem cell trans- plantation (HSCT) in first complete remission (CR1). For the cohort of 46 patients with ABL-class fusions, the 5- year event-free survival (EFS) and OS were 49.1±8.9% and 69.6±7.8%, respectively. The 5-year cumulative inci- dence of relapse (CIR) and treatment-related mortality (TRM) were 25.6±8.2% and 20.8±6.8%, respectively. Thirteen patients (13 of 46, 28.3%) received TKI in com- bination with chemotherapy post-induction; their out- comes were not significantly different from those in the no-TKI group (n=33) (5-year EFS 62.9% vs. 47.7%, P=0.98; 5-year OS 75.5% vs. 70.9%, P=0.64). In parallel, ABL-class patients treated with or without HSCT had similar outcomes (5-year EFS 47.9% vs. 55.0%, P=0.35; 5- year OS 66.7% vs. 84.0%, P=0.22). Notably, in the 33 patients treated without TKI, there was a trend towards lower CIR rate among patients who underwent HSCT (n=16) compared to those who did not (n=17) (13.2% vs. 43.8%, P=0.06). The TRM rate was, nevertheless, exceedingly high in the HSCT group (32.3% vs. 0.0%, P=0.034). Furthermore, the majority of events in the HSCT group were non-relapse events, while relapses pre- dominate in the no-HSCT group.
haematologica | 2020; 105(5)