Page 14 - 2021_04-Haematologica-web

930
Editorials
study of premenopausal women with leukemia treated with intensive chemotherapy and investigated the impact of leuprolide (gonadotropin-releasing hormone analogue) on long-term hematopoietic reconstituting ability. Their findings established an association between leuprolide use in leukemic patients and sustained recovery in blood counts. Additionally, patients with acute myeloid leukemia treated with leuprolide showed higher long- term hemoglobin levels and fewer blood transfusions. Notably, leuprolide treatment had no impact on either overall or event free survival. Finally, multivariate analysis confirmed that leuprolide administration showed an independent association with long-term hematological recovery.
This retrospective clinical study seeks to build upon previous work showing that sex steroid ablation and abrogation of LH can have beneficial effects on hematopoietic reconstitution in preclinical mouse mod- els. However, the study raises several unanswered ques- tions. Firstly, what would be an ideal clinical window and dosage for leuprolide administration following chemotherapy and whether that impacts association with recovery? The preclinical studies with LHRH-antagonists were protective when administered within 24 hours after radiation.13 The current study was limited by sample size to determine statistical significance. Secondly, in relapse cases, where reinduction chemotherapy and irradiation is the standard of care, is additional leuprolide required to help boost hematological tolerance, thereby mitigating hematopoietic stress and temporary cytopenias? Thirdly, are the effects of leuprolide on hematopoietic recovery restricted to BM malignancies or could it be repurposed for treatment of other malignant and non-malignant dis- eases with BM involvement? Finally, from a mechanistic perspective, recent work demonstrating a role for estro- gens in regulating HSC proliferation and function14,15 begs the question: are these effects specific to LH or sex steroids? Considering the rationale for leuprolide to pro- tect against chemoradiation induced premature ovarian failure,20,21 preserved estrogen levels could explain the indirect beneficial effects of leuprolide on hematopoietic recovery. Hence, this warrants additional clinical studies accounting for ovarian failure, as that interpretation would restrict the potential utility of this therapy to a younger cohort. These findings also suggest a role of HSC extrinsic factors and raise the question whether leupro- lide has a similar cytoprotective effect on the BM microenvironment?
In conclusion, the work by Dalle et al.19 highlights a potential new therapeutic option for improving hemato- logical recovery in patients undergoing intensive chemotherapy and transplant conditioning regimens, by boosting post-injury long-term hematopoietic reconstitu- tion; although follow-up clinical investigations are war- ranted for the rational development of leuprolide as a stand-alone therapy, or in conjunction with other agents. This study also underscores the relevance of mouse mod- els to explore additional markers and molecular underpin- nings which confer survival advantage in post-irradiated HSC and BM, as those discoveries will direct us to novel non-cellular approaches to promote hematopoietic recov- ery and serve as effective therapies against BM toxicity.
Disclosures
MvdB has received research support and stock options from Seres; has received stock options from Notch Therapeutics; has received royalties from Wolters Kluwer; has consulted, received honorarium from or participated in advisory boards for Seres Therapeutics, Jazz Pharmaceuticals, Rheos, Therakos, WindMIL Therapeutics, Amgen, Merck & Co, Inc., Magenta Therapeutics, Frazier Healthcare Partners, Nektar Therapeutics, Notch Therapeutics, Forty Seven Inc., Priothera, Ceramedix, DKMS, Pharmacyclics (Spouse), Kite Pharmaceuticals (Spouse); has IP Licensing with Seres Therapeutics and Juno Therapeutics and holds a fiduciary role on the Foundation Board of DKMS (a nonprofit organization).
Contributions
HKE and MRMvdB have contributed equally.
References
1.Orkin SH, Zon LI. Hematopoiesis: an evolving paradigm for stem cell biology. Cell. 2008;132(4):631-644.
2. Bryder D, Rossi DJ, Weissman IL. Hematopoietic stem cells: the par- adigmatic tissue-specific stem cell. Am J Pathol. 2006;169(2):338-346. 3. Arnold R, Schmeiser T, Heit W, et al. Hemopoietic reconstitution after
bone marrow transplantation. Exp Hematol. 1986;14(4):271-277.
4. del Canizo C, Lopez N, Caballero D, et al. Haematopoietic damage persists 1 year after autologous peripheral blood stem cell transplan-
tation. Bone Marrow Transplant. 1999;23(9):901-905.
5. Domenech J, Linassier C, Gihana E, et al. Prolonged impairment of hematopoiesis after high-dose therapy followed by autologous bone
marrow transplantation. Blood. 1995;85(11):3320-3327.
6. Vellenga E, Sizoo W, Hagenbeek A, Lowenberg B. Different repopu- lation kinetics of erythroid (BFU-E), myeloid (CFU-GM) and T lym- phocyte (TL-CFU) progenitor cells after autologous and allogeneic
bone marrow transplantation. Br J Haematol. 1987;65(2):137-142.
7. Yukai Lu MH, Zihao Zhang, Yan Qi, Junping Wang. The regulation of hematopoietic stem cell fate in the context of radiation. Radiation
Medicine and Protection. 2020;1(1):31-34.
8. Shao L, Wang Y, Chang J, Luo Y, Meng A, Zhou D. Hematopoietic
stem cell senescence and cancer therapy-induced long-term bone
marrow injury. Transl Cancer Res. 2013;2(5):397-411.
9. Koukourakis MI. Radiation damage and radioprotectants: new con- cepts in the era of molecular medicine. Br J Radiol. 2012;85(1012):
313-330.
10. Drouet M, Mourcin F, Grenier N, et al. Single administration of stem
cell factor, FLT-3 ligand, megakaryocyte growth and development factor, and interleukin-3 in combination soon after irradiation pre- vents nonhuman primates from myelosuppression: long-term fol- low-up of hematopoiesis. Blood. 2004;103(3):878-885.
11. Huang P, Li X, Meng Y, et al. Interleukin-33 regulates hematopoietic stem cell regeneration after radiation injury. Stem Cell Res Ther. 2019;10(1):123.
12. Zhang Y, Roos M, Himburg H, et al. PTPsigma inhibitors promote hematopoietic stem cell regeneration. Nat Commun. 2019;10(1): 3667.
13. Velardi E, Tsai JJ, Radtke S, et al. Suppression of luteinizing hormone enhances HSC recovery after hematopoietic injury. Nat Med. 2018;24(2):239-246.
14.Mierzejewska K, Borkowska S, Suszynska E, et al. Hematopoietic stem/progenitor cells express several functional sex hormone recep- tors-novel evidence for a potential developmental link between hematopoiesis and primordial germ cells. Stem Cells Dev. 2015;24 (8):927-937.
15. Nakada D, Oguro H, Levi BP, et al. Oestrogen increases haematopoi- etic stem-cell self-renewal in females and during pregnancy. Nature. 2014;505(7484):555-558.
16. Khong DM, Dudakov JA, Hammett MV, et al. Enhanced hematopoi- etic stem cell function mediates immune regeneration following sex steroid blockade. Stem Cell Reports. 2015;4(3):445-458.
17.Dudakov JA, Goldberg GL, Reiseger JJ, Chidgey AP, Boyd RL. Withdrawal of sex steroids reverses age- and chemotherapy-related defects in bone marrow lymphopoiesis. J Immunol. 2009;182(10): 6247-6260.
18.Goldberg GL, Dudakov JA, Reiseger JJ, et al. Sex steroid ablation
haematologica | 2021; 106(4)