Page 15 - 2020_02-Haematologica-web

Editorials
Hypo, Hyper, or Combo: new paradigm for treatment of acute myeloid leukemia in older people
Gunnar Juliusson,1 Martin Höglund2 and Sören Lehmann2,3
1Department of Hematology, Skåne University Hospital, Lund, and Department of Hematology, Stem Cell Center, Department of Laboratory Medicine, Lund University, Lund; 2Department of Medical Sciences, Uppsala University, Uppsala and 3Department of Medicine, Karolinska Institute, Stockholm, Sweden
E-mail: GUNNAR JULIUSSON - gunnar.juliusson@med.lu.se doi:10.3324/haematol.2019.238857
Acute myeloid leukemia (AML)1 is a serious disease. Using the combination of cytarabine and
2 daunorubicin developed during the 1970s, with
or without subsequent allogeneic stem cell transplanta- tion (alloSCT),3 we now cure more than half of all patients with de novo AML up to the age of 60 years.4 But the outcome of older patients, that constitute the vast majority, remains dismal. The median age of AML is over 70 years,5 and the 3-year overall survival (OS) of patients aged 70-84 years is still less than 20% with intensive chemotherapy, and much worse in AML arising after myelodysplastic syndrome (MDS) or myeloproliferative neoplasia (MPN),5-7 or with palliative treatment only.5 However, new treatment options are finally emerging.1
In this issue of Haematologica, Talati et al. present a large (n=980), retrospective, single-center study on AML patients aged 70 years and older diagnosed between 1995 and 2016.8 Intensive combination chemotherapy was given to 37%, hypomethylating agents (HMA) to 26%, and other low-intensity or palliative treatment to 37%. It is well established that specific AML therapy provides better outcome than palliation only.5,9 However, in this study, better survival rates were observed with HMA treatment than with intensive therapy (median 14.4 months vs. 10.8 months; P=0.004).
The currently approved HMA, 5-azacitidine (Aza) and decitabine (Dec, 5-aza-2'-deoxycytidine) are analogs of the natural pyrimidine cytidine. Dec incorporates into DNA while Aza mainly incorporates into RNA, and to a lesser extent into DNA (Figure 1). DNA incorporation causes hypomethylation by irreversible inhibition of DNA methyl transferases (DNMT) and upregulation of tumor suppressor genes, but it also leads to induction of DNA damage response.10 The cytotoxic effects are more evident at higher doses while hypomethylation seems to dominate at lower drug concentrations.11 Incorporation
into RNA leads to inhibition of transfer RNA methyla-
tion, ultimately resulting in impaired messenger RNA
10,12
transcription and protein synthesis. In addition, HMA
have been shown to affect the immune system in various ways, such as upregulation of tumor antigens and induc- tion of viral defense systems through upregulation of endogenous retroviruses.10,13 Intriguingly, it is still unclear what mechanisms are mostly responsible for the clinical effects of HMA in AML.
Aza and Dec were both synthesized in 1964, and bio- logical activity was shown in mice. Clinical trials started in the 1970s.14 Initially, the maximal tolerated doses of Dec (1.5-2.5 g/m2/course) were tested with clinical activ- ity but resulted in prolonged cytopenia.15 Subsequently de-escalated doses to the currently recommended 100- 150 mg/m2/course of Dec or 525 mg/m2/course of Aza became used for treatment of MDS, for which the US Food and Drug Administration (FDA) in 2004 approved Aza and in 2006 approved Dec. At the time of these stud- ies, the diagnosis entity MDS included patients with bone marrow blasts up to 30%. When MDS with 20- 30% blasts were later reclassified as AML,16 HMA was approved also for AML with low blast counts.17 Studies in AML with >30% blasts then started,18 leading to approval in 2015 of Aza for all patients with AML not eli- gible for intensive treatment.
The present study by Talati et al.8 confirms the activity of HMA in older patients and is the first to show improved survival with HMA in AML patients aged 70 years and older as compared to intensive treatment, in contrast to other studies19-22 (Table 1 and Figure 1). However, this discrepancy might be of limited impor- tance, for two reasons. Firstly, in clinical practice, we should try to find the optimal therapy for each individual patient, rather than 'one treatment fits all'. Secondly, rap- idly emerging therapeutic options may well replace
Table 1. Survival of older acute myeloid leukemia patients with hypomethylating or intensive treatment.
Talati 2019 8
Dombret 201518 Quintas-Cardama 201219 Pleyer 201720
Kantarjian 201227
Sw AML Reg 2012-2018
Study type
Single
RCT Single Registry RCT Registry
Age (years) Range Median
≥70 75 ≥65 71 ≥65 74 ≥65 77 ≥65 73 ≥70 75
Number Median OS (months) HMA Intensive HMA Intensive
231 305 14.4 10.8
43 44 13.3 12.2
1-year OS (%) HMA Intensive
55 43
56 51 31 34 51 NA 27 NA 36 46
557 114 6.5
193 NA 11.8
242 NA 7.7
276 532 8.5 11.1
6.7 NA NA
OS: overall survival; HMA: hypomethylating agents; NA: not assessed; Single: single-center study; RCT: multicenter randomized clinical study; Sw AML Reg: Swedish AML Registry, including patients diagnosed from 2012, with survival data updated in September 2019.
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