Haploidentical α/β T-cell and B-cell depleted stem cell transplantation in severe mevalonate kinase deficiency

Abstract

Objective Mevalonic aciduria represents the most severe form of mevalonate kinase deficiency (MKD). Patients with mevalonic aciduria have an incomplete response even to high doses of anti-cytokine drugs such as anakinra or canakinumab and stem cell transplantation (SCT) represents a possible therapy for this severe disease. Methods We report the first two children affected by severe MKD who received haploidentical α/β T-cell and B-cell depleted SCT. Both patients received a treosulfan-based conditioning regimen and one received a second haploidentical-SCT for secondary rejection of the first. Results Both patients obtained a stable full donor engraftment with a complete regression of clinical and biochemical inflammatory signs, without acute organ toxicity or acute and chronic GvHD. In both, the urinary excretion of mevalonic acid remained high post-transplant in the absence of any inflammatory signs. Conclusion Haploidentical α/β T-cell and B-cell depleted SCT represents a potential curative strategy in patients affected by MKD. The persistence of urinary excretion of mevalonic acid after SCT, probably related to the ubiquitous expression of MVK enzyme, suggests that these patients should be carefully monitored after SCT to exclude MKD clinical recurrence. Prophylaxis with anakinra in the acute phase after transplant could represent a safe and effective approach. Further biological studies are required to clarify the pathophysiology of inflammatory attacks in MKD in order to better define the therapeutic role of SCT.

Increased core body temperature exacerbates defective protein prenylation in mouse avatars of mevalonate kinase deficiency

“…Furthermore, plasma MA levels remained high in Mvk VI/Δ91 animals even after replacement with wildtype bone marrow. This is entirely consistent with reports that severe MKD patients that underwent successful haematopoietic stem cell transplantation (HSCT) maintained persistently elevated levels of urinary MA despite alleviation of fever and inflammatory symptoms (Faraci et al, 2021; Neven et al, 2007). Hence, urinary and/or plasma MA levels are not appropriate indicators of the success of HSCT therapy in MKD patients, reinforcing the need for careful monitoring of disease recurrence (Faraci et al, 2021).…”

“…Furthermore, statin therapy (which blocks MA synthesis) is considered not to be generally beneficial in the treatment of MKD (Lachmann, 2017), did not reduce the severity, frequency or occurrence of flares despite lowering MA urinary levels (Simon et al, 2004a), and even caused severe clinical crisis in two mevalonic aciduria patients (Hoffmann et al, 1993). Finally, MA levels remained persistently elevated in several MKD patients after HSCT despite the alleviation of fever and inflammatory symptoms (Faraci et al, 2021;Neven et al, 2007). Together, these observations strongly suggest that elevated MA is not the main underlying cause of inflammation in MKD although MA (or its derivative mevalonolactone) perhaps contributes to the neurological features of mevalonic aciduria (Cecatto et al, 2017).…”

“…We show here that mice bearing combinations of hypomorphic and amorphic mutations in Mvk recapitulate the characteristic biochemical features of HIDS, the milder form of MKD. Like humans heterozygous for pathogenic MVK variants, who have reduced MK activity (Faraci et al, 2021; Houten et al, 1999; Neven et al, 2007) but lack any detectable defect in protein prenylation (Munoz et al, 2017; Munoz et al, 2019), heterozygous Mvk mutant mice showed normal prenylation of small GTPases despite a 25-50% decrease in MK activity. Homozygous Mvk VI/VI mice, harbouring the most frequent, hypomorphic HIDS missense mutation p.V377I (Boursier et al, 2021; Govindaraj et al, 2020; Houten et al, 2000; Ter Haar et al, 2016), had a mild prenylation phenotype that closely resembled the defect in PBMCs from a HIDS patient of the same genotype ( MVK V377I/V377I ) (Munoz et al, 2017; Munoz et al, 2019).…”

Compromised Protein Prenylation as Pathogenic Mechanism in Mevalonate Kinase Deficiency

“…Recently, two MA patients were described who received an a/b T-cell and B-cell depleted stem cell transplantation that led to remission of inflammation in both patients. However, urinary mevalonic acid levels remained increased, probably due to MK deficiency still being present in other tissues (109).…”

Vasculitis in a patient with mevalonate kinase deficiency (MKD): a case report

“…The use of either anakinra or canakinumab have been found to be efficacious in controlling and preventing flares in most patients with MKD [14,15] such as for the patient described herein. However, in some cases the disease may not be well controlled and for these patients haematopoetic stem cell transplantation may be a therapeutic option [16,17]. An earlier diagnosis of MKD could have been considered prior to us seeing this patient given the medical history of early onset recurrent fevers associated with maculopapular rashes and some gastrointestinal symptoms, all features of MKD [7,18].…”