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the CAPTURE study mitigates the introduction of this new technology in clinical practice. Well designed clinical trials obtain their credibility from the definition of a priori hypotheses that helps researchers to avoid drawing wrong conclusions, and negative results are as useful as positive results in guiding medical treatments.
However, even when the primary outcome of a clinical trial fails, new research opportunities open up.8 Hopefully, a careful analysis of the CAPTURE data will lead to future research in the field. Additional laboratory studies are probably required to i) gain further insight into the damage that UV-C irradiation causes to platelets apart from pathogen inactivation and to ii) develop strategies to improve the quality of Theraflex treated products.
Concerns regarding the possible transfusion transmis- sion of SARS-CoV-2 at the beginning of the ongoing pan- demic have revamped the interest in approaches capable of protecting the blood supply from known and newly emerging threats.9 As Brixen and colleagues remind us, safe and effective pathogen reduction methods are still an unmet need.
Disclosures
DP sits on advisory boards, has received travel or research grants, as well as speaking and teaching fees from Macopharma,
Ortho Clinical Diagnostics, Grifols, Terumo, Immucor, Diamed, Diatech Pharmacogenetics.
References
1. Heddle NM, Cardoso M, van der Meer PF. Revisiting study design and methodology for pathogen reduced platelet transfusions: a round table discussion. Transfusion. 2020;60(7):1604-1611.
2. Rebulla P, Garban F, van der Meer PF, Heddle NM, McCullough J. A crosswalk tabular review on methods and outcomes from random- ized clinical trials using pathogen reduced platelets. Transfusion. 2020;60(6):1267-1277.
3. Rebulla P. The long and winding road to pathogen reduction of platelets, red blood cells and whole blood. Br J Haematol. 2019;186(5):655-667.
4. Estcourt LJ, Malouf R, Hopewell S, et al. Pathogen-reduced platelets for the prevention of bleeding. Cochrane Database Syst Rev. 2017;7(7):CD009072.
5. Brixner V, Bug G, Pohler P, et al. Efficacy of UVC-treated, pathogen- reduced platelets versus untreated platelets: a randomized controlled non-inferiority trial. Haematologica. 2021;106(4):1086-1096.
6. Rebulla P, Vaglio S, Beccaria F, et al. Clinical effectiveness of platelets in additive solution treated with two commercial pathogen-reduc- tion technologies. Transfusion. 2017;57(5):1171-1183.
7. Mauri L, D'Agostino RB Sr. Challenges in the design and interpreta- tion of noninferiority trials. N Engl J Med. 2017;377(14):1357-1367.
8.Pocock SJ, Stone GW. The primary outcome fails - what next? N Engl J Med. 2016;375(9):861-870.
9. Stanworth SJ, New HV, Apelseth TO, et al. Effects of the COVID-19 pandemic on supply and use of blood for transfusion. Lancet Haematol. 2020;7(10):e756-e764.
Editorials
Understanding how retinoic acid derivatives induce differentiation in non-M3 acute myelogeneous leukemia
Martin Carroll
Division of Hematology and Oncology, University of Pennsylvania, Philadelphia, PA, USA E-mail: MARTIN CARROLL - carroll2@pennmedicine.upenn.edu
doi:10.3324/haematol.2020.275412
Over 30 years ago, Huang and colleagues published the startling result that all trans-retinoic acid (ATRA) could induce clinical remissions without myelosuppression in patients with acute promyelocytic leukemia (APML).1 Analysis in this report and subsequent analysis demonstrated that responses are due to induced differentiation of the leukemic clone and not the induc- tion of cell death in the malignant cells. This work intro- duced the concept of differentiation therapy to the world of leukemia therapeutics. Other recently developed ther- apeutics for acute myeloid leukemia (AML) including FLT3 and IDH inhibitors in some patients with the target- ed mutations are now known to induce differentiation.2,3 However, there remain two outstanding questions in this field that stem from those original remarkable observa- tions. First, what is the role of retinoic acid or its deriva- tives in controlling normal myeloid maturation? Second, how can this information be used to develop retinoic acid based therapeutics for non-M3 AML? di Martino and col- leagues provide exciting new insights into these ques- tions in this issue of Haematologica.4
To understand the complexity of these questions, it is valuable to first briefly introduce how retinoids and their derivatives function. Conceptually, retinoic acid (RA)
functions through one of the retinoic acid receptors (RAR) which are members of the nuclear hormone receptor family. To simplify, binding of RA to the RAR induces binding to DNA. Commonly, this binding leads to recruit- ment of factors that promote gene transcription (such as histone acetyl transferases) and displacement of inhibitors of transcription such as nuclear receptor core- pressor (NCOR1). There are many levels of complexity in these gene regulatory events.5 Importantly, there are actu- ally three isoforms of RAR. RAR can function as homod- imers, heterodimers with themselves or heterodimers with other members of the nuclear hormone receptor superfamily including retinoic X receptors (RXR), Vitamin D receptors (VDR) and peroxisome proliferator activated receptor (PPAR). Thus, there are many combinatorial pos- sibilities for gene targets and multiple levels of redundan- cy that have made defining the specific role of the nuclear hormone receptor superfamily in myeloid maturation and leukemia therapy challenging.
To address these questions, Di Martino and colleagues first use a murine model of AML induced using the KMT2A fusion protein, KMT2A-AF9. The leukemic cells were transduced with reporter constructs that are quite specific for activation by isoforms of RAR or RXR, trans-
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