Page 16 - 2019_08-Haematologica-web

1508
Editorials
10. Pollyea DA, Pratz KW, Jonas BA, et al. Venetoclax in Combination with Hypomethylating Agents Induces Rapid, Deep, and Durable Responses in Patients with AML Ineligible for Intensive Therapy. Blood. 2018;132(Suppl 1):285-285.
11. DiNardo CD, Pratz KW, Letai A, et al. Safety and preliminary effica- cy of venetoclax with decitabine or azacitidine in elderly patients with previously untreated acute myeloid leukaemia: a non-ran- domised, open-label, phase 1b study. Lancet Oncol. 2018;19(2):216- 228.
12. Kubasch AS, Wehner R, Bazzurri S, et al. Clinical, molecular, and immunological responses to pembrolizumab treatment of synchro- nous melanoma and acute myeloid leukemia. Blood Adv. 2018;2(11):1187-1190.
13. Daver N, Garcia-Manero G, Basu S, et al. Efficacy, Safety, and Biomarkers of Response to Azacitidine and Nivolumab in Relapsed/Refractory Acute Myeloid Leukemia: A Nonrandomized, Open-Label, Phase II Study. Cancer Discov. 2019;9(3):370-383.
14. Nand S, Othus M, Godwin JE, et al. A phase 2 trial of azacitidine and gemtuzumab ozogamicin therapy in older patients with acute myeloid leukemia. Blood, 2013;122(20):3432-3439.
15. Daver N, Kantarjian H, Ravandi F, et al. A phase II study of decitabine and gemtuzumab ozogamicin in newly diagnosed and
relapsed acute myeloid leukemia and high-risk myelodysplastic syn-
drome. Leukemia. 2016;30(2):268-273.
16. Garcia-Manero G, Fenaux P, Al-Kali A, et al; ONTIME study investi-
gators. Rigosertib ver- sus best supportive care for patients with high- risk myelodysplastic syndromes after failure of hypomethylat- ing drugs (ONTIME): a rando- mised, controlled, phase 3 trial. Lancet Oncol. 2016;17(4):496-508.
17. Navada SC, Garcia-Manero G, Atallah EL, et al. Phase 2 Expansion Study of Oral Rigosertib Combined with Azacitidine (AZA) in Patients (Pts) with Higher-Risk (HR) Myelodysplastic Syndromes (MDS): Efficacy and Safety Results in HMA Treatment Naïve & Relapsed (Rel)/Refractory (Ref) Patients. Blood. 2018;132(Suppl 1):230.
18. Medyouf H. The microenvironment in human myeloid malignan- cies: emerging concepts and therapeutic implications. Blood. 2017;129(12): 1617-1626.
19. Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017;130(6):722-731.
20. Cortes J, Perl AE, Döhner H, et al. Quizartinib, an FLT3 inhibitor, as monotherapy in patients with relapsed or refractory acute myeloid leukaemia: an open-label, multicentre, single-arm, phase 2 trial. Lancet Oncol. 2018;19(7):889-903.
Discontinuation of tyrosine kinase inhibitors in patients with chronic myelogeneous leukemia – You can do this at home if you read the instructions
Charles A. Schiffer
Joseph Dresner Chair for Hematologic Malignancies, Departments of Oncology and Medicine, Wayne State University School of Medicine, Karmanos Cancer Institute, Detroit, MI, USA
E-mail: CHARLES A. SCHIFFER - Schiffer@karmanos.org doi:10.3324/haematol.2019.222216
The exciting story of the clinical use of imatinib mesylate for the treatment of leukemias driven by the bcr/abl mutation began in the late 1990s and dramatic effectiveness was immediately apparent in all stages of the diseases. Although there was concern that these benefits might not persist, we now know, after almost twenty years of follow up, that a high proportion of chronic phase patients attain deep molecular responses and enjoy an overall survival comparable to that of age- matched controls.1 It was originally expected that life- long treatment would be needed, but in recent years, tri- als from around the world have shown that tyrosine kinase inhibitors (TKI) can be successfully discontinued in some patients who have achieved sustained deep molecular responses.2,3
These were conducted as part of clinical trials at CML research institutions by experienced CML clinicians. In this issue of the Journal, Italian clinicians from a wide range of institutions of the Gruppo Italiano Malattie Ematologiche dell'Adulto (GIMEMA) describe a large group of chronic phase patients who had therapy discon- tinued, many presumably as a consequence of patients’ requests to doctors, who were now comfortable with the accumulated results.4 With a median follow up of 34 months, 60% of patients remained in what has been termed “treatment-free remission” (TFR),5 a result consis- tent with or perhaps slightly superior to those from earli- er trials. As in other trials, the relapse rate was somewhat lower in patients with longer exposures to TKI and all
patients who had molecular relapse were successfully retreated with either their original TKI or were switched to another TKI if their motivation for discontinuation was toxicity; these retreated patients usually achieved the level of their original response.
Most CML patients in the US (and to some extent else- where) are not followed in specialty hematology centers. This means that the next question in the TKI saga is whether discontinuation can be managed safely by non- specialist oncologists. The process is not very difficult to understand and there are few risks if patients are selected and followed appropriately. The criteria for study entry and monitoring differed somewhat amongst the pub- lished trials, but a consensus approximation would include:
- TKI treatment for a minimum of three years;
- continuous deep molecular response [minimum MR4 (BCR-ABL1 ≤0.01% using the International Scale, IS)] on multiple testing for at least two years. Some studies required reduction to < MR4.5, although outcomes seem comparable (including the results from this GIMEMA experience) using either molecular cutoff;
- use of a quantitative polymerase chain reaction (qPCR) test sensitive to a level of at least MR4.5 in a lab- oratory with a rapid turn-around time;
- monitoring of peripheral blood transcripts every 4-6 weeks for 6-8 months, then bimonthly for approximately one year followed by every three months thereafter for a minimal follow up of three years;
haematologica | 2019; 104(8)