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I. Abou Dalle et al.
of origin.32 Use of leuprolide was found to enhance T-cell recovery following allogeneic bone marrow transplanta- tion in a mouse model through enhanced thymic reconsti- tution.33 Velardi and colleagues demonstrated that LH blockade protects HSC from the damaging effects of chemotherapy or radiation in mice. LHRH antagonism led to quiescence in early hematopoietic progenitors. The HSC pool was maintained by preventing early progenitors from entering the cell cycle thus protecting them from chemotherapy or radiation damage.9 This mechanism is very similar to the fertility preserving effect of leuprolide.34 LHRH blockade in preclinical models halted recruitment of primordial quiescent follicles after treatment with chemotherapy thereby preserving the functional potential of the ovary. This has been validated in clinical studies and is now one of the strategies to preserve fertility in women receiving chemotherapy.35,36 It is plausible that this observed protective effect on HSC seen with leuprolide is mediated through a downstream effect on estrogen or other sex hormones.7,37 In a mouse model, estrogen increased hematopoietic stem-cell self-renewal in females and during pregnancy.37 However, levels of these hor- mones were not assessed in patients included in our analy- sis.
We report the first clinical evidence indicating a correla- tion between use of leuprolide and improved transfusion requirements in addition to improved long-term blood count recovery in women with acute leukemia receiving intensive chemotherapy. We observed an improvement in neutrophil, lymphocyte and platelet counts mostly when the corresponding lineage was not affected by leukemia. Some of the improvement in transfusion requirements could be related to a decrease in uterine bleeding through the hormonal suppression induced by LH blockade. However, we were unable to accurately quantify bleeding episodes from corresponding medical records. We also could not determine whether patients prone to bleeding preferentially received leuprolide which could affect the interpretation of ours results, however we tried to correct for selection bias through propensity score matching and the multivariate analysis. We found in our analysis that patients who received leuprolide and a FLT3 inhibitor added to their induction chemotherapy had a reduced platelet count recovery. Given that the FLT3 receptor is expressed by immature hematopoietic cells, and is restricted in normal bone marrow to early progenitors, tar- geting FLT3 could affect normal hematopoiesis leading to thrombocytopenia and delayed count recovery after chemotherapy.38 Thrombocytopenia is reported in 12- 46% of patients receiving sorafenib, the FLT3 inhibitor most commonly used in this cohort. Sorafenib is a multi- kinase inhibitor that could affect numerous other path- ways important for normal hematopoiesis and platelet generation from long-term HSC, therefore explaining this observation.39 There was no effect of LH blockade on rates of leukemia relapse or death in both AML and ALL cohorts, indicating that the theoretical risk of leuprolide
protecting leukemia stem cells potentially expressing the LH receptor was not clinically meaningful in our study. Prospective studies are needed in order to confirm our findings and evaluate the effect of LH blockade on safety and count recovery following intensive chemotherapy in all hematologic malignancies. There are several ongoing clinical trials evaluating the effect of leuprolide on immune function following bone marrow transplantation (clinicaltrials gov. Identifier: 00275262, 01746849 and 01338987).
Repurposing old approved drugs in the field of cancer is gaining more importance given the high global burden of cancer and its substantial costs.40 LH antagonism, which allows for a reversible ablation of this hormonal axis, has a strong safety profile in other cancers such as breast and prostate cancer. Our findings potentially add another indi- cation for use of leuprolide in women receiving high doses of chemotherapy by (i) minimizing uterine bleeding, (ii) decreasing the risk of ovarian failure and preserving fertil- ity and (iii) protecting HSC from damage and improving long-term count recovery. Another hypothesis worth test- ing is whether LH blockade would reduce expansion of clonal hematopoiesis of indeterminate potential (CHIP) cells following chemotherapy or radiation, thus reducing the risk of therapy-related myeloid malignancies (assum- ing CHIP clones express the LHCGR).41
In summary, use of leuprolide in patients with newly diagnosed acute leukemia receiving intensive chemother- apy was associated with decreased transfusion require- ments and improved long-term blood count recovery. Further studies are needed to validate these findings.
Disclosures
NJS received research funding from Takeda Oncology, consul- tancy fees from AstraZeneca, Takeda Oncology and Amgen. JEC received research funding from Ambit BioSciences, ARIAD, Arog, Astellas Pharma, AstraZeneca, Bristol-Myers Squibb, Celator, Celgene, Novartis, Pfizer, Sanofi, Sun Pharma, Teva; consultant fees from Ambit BioSciences, ARIAD, Astellas Pharma, BiolineRx, Bristol-Myers Squibb, Novartis; Pfizer. EJJ received research funding and consultancy fees from Takeda, BMS, Adaptive, Amgen, AbbVie, Pfizer and Cyclacel LTD. GCI received research funding from Celgene, Syndax and Novartis and served on an advisory board for Novartis.
Contributions
IA wrote the manuscript; IA, RMP, JZ, SP, KS, NJS, MO, JEC, EJJ contributed to data collection and analysis; WL and JN analyzed the data and performed the statistical analysis; GCI designed the study, supervised the analysis and wrote the manu- script.
Funding
The study was supported by Leukemia Texas (PI – Issa GC), the National Cancer Institute K12 Paul Calabresi Clinical Scholarship Award (NIH/NCI K12 CA088084 to Issa GC) and the Cancer Center Support Grant (NCI Grant P30 CA016672).
References
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4.Kantarjian H, O'Brien S, Cortes J, et al. Results of intensive chemotherapy in 998 patients age 65 years or older with acute
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