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P. Merli et al.
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Figure 5. Immuno-characterization of the T lymphocytes present in bone marrow aspirates of patients who either did or did not experience graft failure (GF). (A) Flow cytometry analysis of CD4+ and CD8+ population in patients with GF and controls (CTRL). Distribution of naïve (CD45RA+/CCR7+), central memory (CD45RO+/CCR7+), effector memory (CD45RO+/CCR7–), effector terminal (CD45RA+/CCR7–), and NK-T (CD3+/CD56+) subsets in CD4+ (B) or CD8+ (C) T cells. Activation and exhaustion profile in both the CD4+ and CD8+ population by the analysis of CD95 (D), CD127 (E), and CD57 (F). (A, D, E, and F) Each patient or CTRL is repre- sented by a symbol and a horizontal line marks the median. (B and C) The average (+) and Median±Standard Deviation are shown. *P<0.05; **P<0.01; ***P<0.001; ****P<0.0001.
Emapalumab administration to patients after hematopoietic stem cell transplantation failure
Three patients with primary HLH who experienced GF together with disease reactivation after a first TCD HSCT from a PMFD were treated with emapalumab both before and after the second HSCT (details are reported in Online Supplementary Table S1). For all these patients, the use of the other parent as a donor was not possible because of non-eligibility due to viral hepatitis. The CU of ema- palumab was requested and obtained with the objective of controlling, without the use of myelosuppressive drugs other than those used in the conditioning regimen, HLH reactivation before and after a second HSCT. Emapalumab was administered at doses of 1-6 mg/kg every three days. Drug infusions were well tolerated and no significant safety event occurred. Two patients engraft- ed, while one rejected also the second HSCT without, however, experiencing a new HLH flare. This patient was successfully rescued with a third HSCT employing an unrelated cord blood (UCB) unit (notably, she received emapalumab until 3 days before UCB infusion). Remarkably, the two patients who engrafted upon treat- ment with emapalumab had very low levels of CXCL9 (i.e. below 102 pg/mL), indicating IFNγ neutralization, while this was not the case for the third patient at the time of the second transplant rejection. All these three patients are currently alive and disease-free, with a follow up of 24, 23 and 21 months, respectively.
Discussion
Diagnosis and treatment of GF in HSCT recipients remain challenging. Indeed, sign and symptoms (e.g. fever, increase in LDH or ferritin serum levels) associated with this transplant complication are non-specific; moreover, re-transplantation, although associated with relevant risk of tissue-toxicity and infections, represents the treatment of choice, since steroids and other immunosuppressive drugs are usually ineffective for rescuing these patients.2 In this study, we investigated humoral and cellular features of GF occurring after allogeneic HSCT in children, docu- menting a pivotal role played by IFNγ in the pathophysi- ology of this complication. Apart from the indirect evi- dence provided by the observation of very high rates of primary and secondary rejection after HLA-identical HSCT in patients with IFNγ-receptor 1 deficiency,21 cur- rently available clinical data about the role of IFNγ in GF in humans remain limited. Interestingly, we found that GF is characterized by the same clinical (including high-grade fever, hepato/splenomegaly, hemophagocytosis in BM)22,23 and laboratory (i.e. increased ferritin, IFNγ, CXCL9, CXCL10, sCD163 and sIL-2Rα levels)24-28 features found in patients with HLH, where a central role of IFNγ has been shown.29
Our data indicate that IFNγ levels, and even more CXCL9 levels measured in PB, can predict GF with high sensitivity and specificity already at day +3 after graft
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haematologica | 2019; 104(11)