Current treatment modalities in leukemia are limited by bone marrow (BM) toxicity, a common adverse effect of cytotoxic chemotherapy and transplant-related conditioning regimens, resulting in an increased risk of bleeding and infections. Strategies to protect the BM from cytotoxic injury could augment hematopoietic recovery and improve overall patient outcomes.
Hematopoietic recovery following cytotoxic therapies and irradiation is dependent on the maintenance of a rare population of hematopoietic stem cells (HSCs) - which have the ability to sustain long-term hematopoietic recovery.1,2 Following HSC transplant, there is evidence of decreased BM cellularity3 and diminished colony-forming capacity4-6 which could last up to approximately 5 years. Growing evidence attributes these functional defects to several intrinsic and extrinsic regulators which orchestrate radiation-induced senescent and pro-apoptotic programs, thereby dictating HSC fate.7,8 Several radioprotective agents have been identified,9 but very few mitigate radiation toxicity in the post-injury setting. Historically, mouse studies have informed post-irradiation strategies to promote HSC regeneration which are either cytokinebased, such as a combination of stem cell factor, FMS-like tyrosine kinase 3 ligand, megakaryocyte growth and development factor (MGDF) and Interleukin-3 (IL-3),10 single agent IL-33,11 or inhibitors targeting PTPσ12 - none of which have been confirmed in the clinical setting. Cognate receptors for sex hormones and luteinizing hormone (LH)-releasing hormone (LHRH) have been identified on HSC and implicated in their function.13-15 For example, LH can induce HSC expansion in vitro.13 Moreover, preclinical studies targeting the sex-steroid axis, have demonstrated enhanced hematopoietic stem cell function and immune recovery, following sex-steroid ablation16-18 and LHRH-antagonism.13
In this issue of Haematologica, Dalle and colleagues19 provide clinical evidence of BM recovery and long-term hematopoietic reconstitution following targeted therapy of the sex-steroid axis. They conducted a retrospective 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 longterm 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.
Figure 1.Schematic model of luteinizing hormone-releasing hormone antagonism mediated cytoprotection which promotes hematopoietic stem cell recovery following haematopoietic injury. Dalle et al.19 provide clinical evidence for bone marrow recovery and long-term hematopoietic reconstitution with luteinizing hormone-releasing hormone (LHRH) antagonism (leuprolide) in leukemia patients following chemotherapy. HSC: hematopoietic stem cell; HSPC: hematopoietic stem and progenitor cell; LHCGR: luteinizing hormone/ chor iogonadot ropin receptor; LH: luteinizing. hormone. Figure created with BioRender.com.
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 models. However, the study raises several unanswered questions. 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 diseases with BM involvement? Finally, from a mechanistic perspective, recent work demonstrating a role for estrogens 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 protect 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 leuprolide 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 hematological recovery in patients undergoing intensive chemotherapy and transplant conditioning regimens, by boosting post-injury long-term hematopoietic reconstitution; although follow-up clinical investigations are warranted 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 models to explore additional markers and molecular underpinnings which confer survival advantage in post-irradiated HSC and BM, as those discoveries will direct us to novel non-cellular approaches to promote hematopoietic recovery and serve as effective therapies against BM toxicity.
Footnotes
Correspondence
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
- Orkin SH, Zon LI. Hematopoiesis: an evolving paradigm for stem cell biology. Cell. 2008; 132(4):631-644. https://doi.org/10.1016/j.cell.2008.01.025PubMedPubMed CentralGoogle Scholar
- Bryder D, Rossi DJ, Weissman IL. Hematopoietic stem cells: the paradigmatic tissue-specific stem cell. Am J Pathol. 2006; 169(2):338-346. https://doi.org/10.2353/ajpath.2006.060312PubMedPubMed CentralGoogle Scholar
- Arnold R, Schmeiser T, Heit W. Hemopoietic reconstitution after bone marrow transplantation. Exp Hematol. 1986; 14(4):271-277. Google Scholar
- del Canizo C, Lopez N, Caballero D. Haematopoietic damage persists 1 year after autologous peripheral blood stem cell transplantation. Bone Marrow Transplant. 1999; 23(9):901-905. https://doi.org/10.1038/sj.bmt.1701730PubMedGoogle Scholar
- Domenech J, Linassier C, Gihana E. Prolonged impairment of hematopoiesis after high-dose therapy followed by autologous bone marrow transplantation. Blood. 1995; 85(11):3320-3327. https://doi.org/10.1182/blood.V85.11.3320.bloodjournal85113320PubMedGoogle Scholar
- Vellenga E, Sizoo W, Hagenbeek A, Lowenberg B. Different repopulation kinetics of erythroid (BFU-E), myeloid (CFU-GM) and T lymphocyte (TL-CFU) progenitor cells after autologous and allogeneic bone marrow transplantation. Br J Haematol. 1987; 65(2):137-142. https://doi.org/10.1111/j.1365-2141.1987.tb02255.xPubMedGoogle Scholar
- 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. https://doi.org/10.1016/j.radmp.2020.01.002Google Scholar
- 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. Google Scholar
- Koukourakis MI. Radiation damage and radioprotectants: new concepts in the era of molecular medicine. Br J Radiol. 2012; 85:313-330. https://doi.org/10.1259/bjr/16386034PubMedPubMed CentralGoogle Scholar
- Drouet M, Mourcin F, Grenier N. Single administration of stem cell factor, FLT-3 ligand, megakaryocyte growth and development factor, and interleukin-3 in combination soon after irradiation prevents nonhuman primates from myelosuppression: long-term follow- up of hematopoiesis. Blood. 2004; 103(3):878-885. https://doi.org/10.1182/blood-2003-05-1400PubMedGoogle Scholar
- Huang P, Li X, Meng Y. Interleukin-33 regulates hematopoietic stem cell regeneration after radiation injury. Stem Cell Res Ther. 2019; 10(1):123. https://doi.org/10.1186/s13287-019-1221-1PubMedPubMed CentralGoogle Scholar
- Zhang Y, Roos M, Himburg H. PTPsigma inhibitors promote hematopoietic stem cell regeneration. Nat Commun. 2019; 10(1):3667. https://doi.org/10.1038/s41467-019-11490-5PubMedPubMed CentralGoogle Scholar
- Velardi E, Tsai JJ, Radtke S. Suppression of luteinizing hormone enhances HSC recovery after hematopoietic injury. Nat Med. 2018; 24(2):239-246. https://doi.org/10.1038/nm.4470PubMedPubMed CentralGoogle Scholar
- Mierzejewska K, Borkowska S, Suszynska E. Hematopoietic stem/progenitor cells express several functional sex hormone receptors- novel evidence for a potential developmental link between hematopoiesis and primordial germ cells. Stem Cells Dev. 2015; 24(8):927-937. https://doi.org/10.1089/scd.2014.0546PubMedPubMed CentralGoogle Scholar
- Nakada D, Oguro H, Levi BP. Oestrogen increases haematopoietic stem-cell self-renewal in females and during pregnancy. Nature. 2014; 505(7484):555-558. https://doi.org/10.1038/nature12932PubMedPubMed CentralGoogle Scholar
- Khong DM, Dudakov JA, Hammett MV. Enhanced hematopoietic stem cell function mediates immune regeneration following sex steroid blockade. Stem Cell Reports. 2015; 4(3):445-458. https://doi.org/10.1016/j.stemcr.2015.01.018PubMedPubMed CentralGoogle Scholar
- 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. https://doi.org/10.4049/jimmunol.0802446PubMedGoogle Scholar
- Goldberg GL, Dudakov JA, Reiseger JJ. Sex steroid ablation enhances immune reconstitution following cytotoxic antineoplastic therapy in young mice. J Immunol. 2010; 184(11):6014-6024. https://doi.org/10.4049/jimmunol.0802445PubMedGoogle Scholar
- Abou Dalle I, Paranal R, Zarka J. Impact of luteinizing hormone suppression on hematopoietic recovery after intensive chemotherapy in patients with leukemia. Haematologica. 2021; 106(4):1097-1105. Google Scholar
- Poorvu PD, Barton SE, Duncan CN. Use and effectiveness of gonadotropin-releasing hormone agonists for prophylactic menstrual suppression in postmenarchal women who undergo hematopoietic cell transplantation. J Pediatr Adolesc Gynecol. 2016; 29(3):265-268. https://doi.org/10.1016/j.jpag.2015.10.013PubMedGoogle Scholar
- Jadoul P, Kim SS, Committee IP. Fertility considerations in young women with hematological malignancies. J Assist Reprod Genet. 2012; 29(6):479-487. https://doi.org/10.1007/s10815-012-9792-0PubMedPubMed CentralGoogle Scholar
Data Supplements
Figures & Tables
Article Information
This work is licensed under a Creative Commons Attribution-NonCommercial 4.0 International License.