Primary hemophagocytic lymphohistiocytosis (HLH), including familial HLH and some inherited immune deficiency syndromes, is a rare, life-threating disease. It is caused by mutations of several genes that impair lymphocytes’ cytotoxic machinery. The mutations mostly generate defects in perforin- and granzyme-dependent pathway, resulting in the inability of NK cells and cytotoxic T lymphocytes to down-regulate the immune response. It is characterized by dysregulated hyperinflammatory response that results in hypercytokinemia. Hematopoietic stem cell transplantation (HSCT) is the only curative option for patients with primary HLH. After the HLH 94-2004 studies conducted by the Histiocyte Society, the 5 year survival rate is improved by HSCT from about 50% to 66%.¹ HSCT is associated with high incidence of complications, such as infections, sinusoidal obstructive syndrome (SOS), respiratory complications and high transplant related mortality (TRM).

In spite of international collaboration, survival after HSCT has not changed significantly in the last two decades in primary HLH. Unavailability of matched donors, susceptibility to conditioning-related toxicities, and high frequency of mixed chimerism remain challenge for this hyperinflammatory immune-regulatory disorder. Debates about best preparative regimens are ongoing without resolution. Recently, the use of reduced-intensity conditioning (RIC) regimens has shown favorable outcomes and lower rate of acute complications when compared to conventional HSCT.² Prospective RIC national HCT trial for HLH/primary immunodeficiency resulted in low early mortality and 1-year overall survival (OS) of 80% (HLH only disease 82%), but 66.7% 18-month OS (HLH only disease 68%).¹ HLH disease can recur when donor chimerism declines to less than approximately 20%. RIC regimens need to be optimized to decrease the mixed chimerism. It is very interesting that there are two articles publishing in this issue to address this question in different angle.

In the article by Wustrau et al³, a retrospective multicenter study in Germany and Austria describes 60 patients with primary HLH who received transplants between 2009-16. A multivariate logistic regression model was applied to analyze the five potential risk factors for substantial mixed chimerism including donor type, graft source, conditioning alkylating agent, condition serotherapy and remission status before conditioning. They found that the donor matching status, whether 10/10 or not, is the only factor with significant impact on the prevalence of substantial mixed chimerism (defined as while blood donor Chimerism equal or less than 25% and / or secondary cell therapy such as donor lymphocyte infusion (DLI), stem cell boost, or secondary HSCT). The article by Ali et al⁴ in this issue describes different preparative regimen associated with mixed chimerism. Ali’s group studied 36 HLH patients from single institution with 9 patients received reduced-toxicity regimen (RTC) conditioning with the combination of treosulfan, cyclophosphamide, fludarabine and thymoglobulin for allogeneic HSCT between 2015-19. They found that RTC cohort had the best compound event-free survival (EFS) (lack of relapse, graft failure, second transplant or additional donor cell infusions, or death) of 89% comparing 73% in conventional myeloablative (Conv MA) regimen and 42% in RIC regimen while kept similar 2-year OS of 89% comparing with 73% in Conv MA regimen and 83% with RIC regimen.⁴ According to these two groups’ results, 10/10 matching with RTC regimen can result in better outcome for HSCT in primary HLH.

Optimization of preparative regimen for HLH transplant is the key to get better donor chimerism and avoid secondary intervention (See summary in table). Serotherapy is a crucial factor for patient’s survival and the development of mixed chimerism. Serotherapy is definitely needed for transplant in this hyperinflammatory disease as shown in Slatter’s study (50% early mortality).⁵ Willemsen et al⁶ have shown that alemtuzumab was more likely to result in long-term mixed chimerism than ATG. Interestingly, in multivariate analysis serotherapy agent was not associated with mixed chimerism in Wustrau et al’s article in this issue³. The timing and dosing of alemtuzumab greatly affect HLH patients after HSCT whether they develop mixed chimerism or GVHD. Both proximal administration and distal schedule with alemtuzumab more than 2mg/kg have been shown with increased mixed chimerism with 53% patients needing more secondary stem cell intervention in Marsh et al’s study.⁷ Intermediate alemtuzumab schedule with 1mg/kg divided by 5 days started on day -14 combined with fludarabine and melphalan generated better results with less mixed chimerism.⁷ Ali’s article concluded that ATG, combined with treosulfan and second alkylator cyclophosphamide in their RTC cohort, had the best result with 2-year OS and EFS of 89%.⁴ In both articles in this issue, treosulfan combined with other alkylator cyclophosphamide/thiotepa yielded the best result with least mixed chimerism. Treosulfan is currently available in Europe – Asia but not in US. Wustrau et al noted that treosulfan versus melphalan did not change the incidence of mixed chimerism but adding thiotepa decreased that incidence from 50% to 25%. Similar observation was made in recently published article by Naik et al.⁸How active disease status affects patients survival is not widely studied. As the new IFN-γ targeting therapy-Emapalumab is approved for primary HLH treatment, it is encouraging that more patients will proceed to HSCT in remission. Vallurupalli and colleague’s study showed that 65% of the relapsed /refractory HLH patients had overall remission and proceeded to HSCT with 90.9% post-HSCT survival.⁹ The recent phase 2-3 study confirmed that 65% of total of 26 primary HLH patients had response in 8-week treatment period of Emapalumab and 70% were able to proceed to transplant with 89.5% estimated 12 months’ survival.¹⁰

It is suggested that in primary immunodeficiency disorders, peripheral blood stem cell transplant (PBSCT) can ensure sustained high-level donor chimerism in more than 90% patients.¹¹ It is reasonable to think about PBSCT as a better stem cell source. These two articles in current issue provide food for thought to conduct prospective multicenter trial including melphalan/treosulfan with cyclophosphamide/thiotepa with ATG as serotherapy may be with PBSCT as stem cell source.

Table. Summary of different conditions and their outcomes in the transplant of HLH ^a.