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LH suppression and hematopoietic recovery
Figure 4. Overall survival in acute myeloid leukemia and acute lymphoblastic leukemia patients with and without leuprolide before and after propensity score matching. AML: acute myeloid leukemia; ALL: acute lymphoblastic leukemia.
in the leuprolide groups compared to the control groups prior to propensity score matching (Figure 4A-B). However, after propensity score matching there was no association between leuprolide administration and sur- vival outcomes. The 5-year OS for patients with AML who had received leuprolide was 60% (95% CI: 47-76) compared to 57% (95% CI: 48-67) in the matched control cohort (P=0.96) (Figure 4C). The 5-year OS for patients with ALL who had received leuprolide was 65% (95% CI: 52-81) compared to 58% (95% CI: 49-70) in the matched control cohort (P=0.47) (Figure 4D). Similarly, there was no difference in EFS comparing patients with AML with leuprolide and the matched control group (P=0.29) (Online Supplementary Figure S3) and no difference in ALL patients with leuprolide and their matched control group (P=0.85) (Online Supplementary Figure S3).
Discussion
In this study, we show that use of leuprolide in pre- menopausal women with acute leukemia receiving chemotherapy was associated with less transfusions and better long-term count recovery. Bone marrow suppression caused by cytotoxic chemotherapy is a common dose lim- iting adverse event in cancer treatment, especially in hema-
tologic malignancies. It leads to increased morbidity and mortality because of the higher risk of infection and bleed- ing. Myelosuppression is caused by apoptosis of highly proliferative multipotent and hematopoietic progeni- tors.22,23 Moreover, use of cytotoxic chemotherapy can lead to long-term bone marrow damage by various mecha- nisms including induction of apoptosis, senescence of HSC, or damage to bone marrow stromal cells.6,24 After chemotherapy insult, dormant HSC transiently proliferate to replenish blood cells and sustain hematopoietic home- ostasis.25 An unbalanced HSC proliferation and exit from dormancy could lead to long-term bone marrow suppres- sion, and an increased risk of DNA damage.26,27 Therefore, there is a critical need to limit the damaging effects of cyto- toxic chemotherapy on HSC and preserve the HSC pool.
There is growing evidence that several pituitary hor- mone receptors including LH, follicle-stimulating hor- mone, prolactin, and growth hormone receptors, are expressed by human HSC and are directly implicated in HSC self-renewal, proliferation and differentiation.7,8,28 Notably, patients with history of germ cell tumors have an increased risk of developing myeloid neoplasms.29-31 While this had been attributed in some cases to therapy-related leukemogenesis, recent genomic analysis demonstrated that these neoplasms could be clonally related, thus indi- cating shared ancestry between the corresponding tissues
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