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Editorials
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the characteristics of the patient population should be taken into account. For instance, in Ph-negative ALL, achievement of identical laboratory major molecular response levels following treatment with intensive chemotherapy and tyrosine kinase inhibitors, was shown to predict considerably different relapse-free survival rates for newly diagnosed versus relapsed patients (26.1 vs. 12 months, respectively).5,6 Notably, progression-free sur- vival for relapsing patients who achieved MRD negativity with inotuzumab ozogamicin treatment was as short as 8.6 months.7 Thus, in different clinical settings, identical laboratory results may be associated with completely dif- ferent predicted outcomes.
The LAL1509 trial, while demonstrating feasibility of a chemotherapy-free regimen for some patients, has also highlighted that biological differences within the Ph+ALL patient population go far beyond the presence or absence of BCR/ABL mutations such as T315I. In this trial, patients presenting with genetic aberrations in IKZF1 plus CDKN2A/B and/or PAX5 (IKZF1+) demonstrated a relapse-free survival rate of 0%. This combination of genetic abnormalities is known to portend poor prognosis even in patients undergoing allo-SCT. Yet, the relapse- free survival rates reported in previous studies using intensive induction regimens have been better.8 Moreover, the GIMEMA group has lately reported results of using a still more attractive combination of steroids, dasatinib and blinatumomab,9 that has led to considerable improvement in the survival of all patients, including those presenting with IKZF1+ aberrations.
What have we learned from the current trial? First, induction death in Ph+ALL is preventable and for some patients even non-intensive induction should be consid- ered. Second, the way MRD negativity is achieved influ- ences its clinical implications. Third, routine screening for IKZF1+abnormalities is advised and may be considered when the intensity of an induction regimen is selected. And last but definitely not least, a combination of steroids, tyrosine kinase inhibitors and blinatumomab, given as first-line therapy, is an attractive option for
Ph+ALL patients and is currently being studied as part of a large intergroup prospective phase III trial, led by ECOG-ACRIN, EA9181 (clinicaltrials gov. Identifier: NCT04530565).10
Disclosures
No conflicts of interest to disclose.
References
1. Vignetti M, Fazi P, Cimino G, et al. Imatinib plus steroids induces complete remissions and prolonged survival in elderly Philadelphia chromosome-positive patients with acute lymphoblastic leukemia without additional chemotherapy: results of the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) LAL0201-B protocol. Blood. 2007;109(9):3676-3678.
2. Foa R, Vitale A, Vignetti M, et al. Dasatinib as first-line treatment for adult patients with Philadelphia chromosome-positive acute lym- phoblastic leukemia. Blood. 2011;118(25):6521-6528.
3. Chiaretti S, Ansuinelli M, Vitale A, et al. A multicenter total therapy strategy for de novo adult Philadelphia chromosome positive acute lymphoblastic leukemia patients. Final results of the GIMEMA LAL 1509 protocol. Haematologica. 2021;106(7):1828-1838.
4.FDA Guidance Document: Hematologic Malignancies: Regulatory Considerations for use of minimal residual disease in development of drug and biological products for treatment. Available at https://www.fda.gov/media/134605/download. Accessed in December, 2020.
5. Short NJ, Jabbour E, Sasaki K, et al. Impact of complete molecular response on survival in patients with Philadelphia chromosome-pos- itive acute lymphoblastic leukemia. Blood. 2016;128(4):504-507.
6. Abou Dalle I, Kantarjian HM, Short NJ, et al. Philadelphia chromo- some-positive acute lymphoblastic leukemia at first relapse in the era of tyrosine kinase inhibitors. Am J Hematol. 2019;94(12):1388- 1395.
7. Jabbour E, Gokbuget N, Advani A, et al. Impact of minimal residual disease status in patients with relapsed/refractory acute lymphoblas- tic leukemia treated with inotuzumab ozogamicin in the phase III INO-VATE trial. Leuk Res. 2020;88:106283.
8. Pfeifer H, Raum K, Markovic S, et al. Genomic CDKN2A/2B dele- tions in adult Ph(+) ALL are adverse despite allogeneic stem cell transplantation. Blood. 2018;131(13):1464-1475.
9. Foa R, Bassan R, Vitale A, et al. Dasatinib-Blinatumomab for Ph-pos- itive acute lymphoblastic leukemia in adults. N Engl J Med. 2020; 383(17):1613-1623.
10. Testing the use of steroids and tyrosine kinase inhibitors with blina- tumomab or chemotherapy for newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia in adults. Available at https://clinical- trials.gov/ct2/show/NCT04530565. Accessed in December, 2020.
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