Outcome of allogeneic haematopoietic cell transplantation in eosinophilic disorders: A retrospective study by the chronic malignancies working party of the EBMT (2022)

Hypereosinophilic syndrome (HES) and chronic eosinophilic leukaemia (CEL), not otherwise specified (NOS) are rare haematological disorders.1 Allogeneic haematopoietic cell transplantation (allo-HCT) has been reported in single case reports or small case series only for both refractory HES or CEL, NOS and outcomes remain ill-defined.1-3 HES normally demonstrates a male predominance, likely underrecognized, with a variable clinical course. Fulminant cases, however, are frequently associated with significant morbidity and indeed mortality. Even less common, CEL, NOS is an extremely rare myeloproliferative neoplasm (MPN), frequently demonstrating an aggressive clinical course with significant rates of acute transformation. We hereby report outcomes from a retrospective, European Group for Blood and Marrow Transplantation (EBMT)-registry-based study of 77 adult patients with a confirmed diagnosis of either HES or CEL, NOS who underwent allo-HCT, representing the largest cohort reported to date. Patient selection included patients undergoing first allo-HCT for either CEL or HES between 2000 and 2018, using either reduced intensity conditioning (RIC) or myeloablative conditioning (MAC) as defined by EBMT criteria.4 Patient, disease-, and transplant-related variables were expressed as median and interquartile range (IQR) for continuous variables and frequencies for categorical variables. Overall survival (OS) was calculated from the date of transplant until death of any cause or last follow-up and progression-free survival (PFS) was defined as the time from transplant to relapse or progressive disease or death, whichever came first. The Kaplan–Meier estimator and log-rank test were used to estimate OS and PFS. The crude cumulative incidence estimator and Grey's test were used to estimate non-relapse mortality (NRM) and relapse incidence (RI) within competing-risk settings, as well as acute graft versus host disease (aGVHD)/relapse or death before aGVHD and chronic graft versus host disease (cGVHD)/relapse or death before cGVHD. All estimates are reported with accompanying 95% confidence intervals (CIs) in parentheses. Statistical analyses were performed in R version 3.6.3 (R Foundation for Statistical Computing, Vienna, Austria. https://cran.r-project.org). A total of 77 patients, with a diagnosis of either HES (n = 47) or CEL, NOS (n = 30) were analysed, from 51 EBMT-registered transplant centres. Patient and transplant characteristics are detailed in Table 1. Median age of those with HES and CEL, NOS was 37.7 years [interquartile range (IQR), 30.1–44.0)] and 46.0 years (IQR,39.6–55.4), respectively. Patients were transplanted with a median time to allo-HCT of 15.1 months (IQR, 9.8–27.9) for CEL, NOS patients, and 22.2 months (IQR, 11.5–55.8; p = 0.01) for HES. Complete response at time of transplant was reported for five HES and eight CEL patients respectively (23% and 47% out of those with data on disease stage available) but disease status at the time of allo-HCT was missing for a considerable number (HES, n = 25; and CEL, n = 13). Regarding conditioning intensity, 52% of HES and 61% of CEL, NOS patients underwent MAC, respectively. The most frequent MAC regimen was busulphan and cyclophosphamide and for RIC, fludarabine and busulphan in both cohorts. T-cell depletion was employed in more than half of each disease cohort. Median follow-up (IQR) after transplantation was 102 months for HES (54–147) and 30 months (24–88) for CEL, NOS. Graft failure was reported in three patients (HES, n = 1; and CEL, NOS, n = 2). Outcomes after transplantation are detailed in Table 1. Median time to neutrophil engraftment was 18 (IQR 13–21) days in HES and 19 (14–23) days in CEL, NOS patients. Platelet engraftment (sustained platelet count >20 × 109/l) occurred at a median of 19 days (first quartile 14 days, third quartile not reached) in HES and 23 days (first quartile 18 days, third quartile not reached) in CEL, NOS. Acute GVHD grades II–IV incidence at 100 days after allo-HCT was 45% (30%–60%) in HES and 19% (4%–33%) in CEL, NOS (log-rank p = 0.03, Figure 1A). Chronic GVHD (limited/extensive) rates for HES and CEL, NOS at 12 months were 46% (95% CI 30–62%) and 39% (16–61%) respectively. NRM estimates at one and three years were 24% and 31% (HES) and 38% and 45% (CEL); log-rank p = 0.22 (Figure 1B). Main reported causes of NRM by three years were GVHD (HES = 11% and CEL, NOS = 21%) and infectious complications (HES = 11% and CEL, NOS = 10%). The one- and three-year median OS estimates were 69% and 59% (HES), and 46% and 34% (CEL, NOS) respectively (p = 0.03; Figure 1C). Focussing on donor type, the three -year median OS estimates for HES were 75% (56%–94%) for matched sibling donors (MSD) and 48% (28%–68%) for unrelated donors (URD) respectively and for CEL, NOS, 65% (32%–97%) for MSD and 20% (1%–38%) for URD. Relapse-free survival (RFS) estimates at one and three years were 58% and 46% (HES) and 42% and 35% (CEL) respectively (p = 0.22; Figure 1D). Cumulative incidence of relapse is shown in Figure 1E. Analysis of conditioning intensity (RIC versus MAC) did not clearly define superiority of either approach with regard to either OS or relapse incidence. This study represents the largest cohort to date focussed on long-term outcomes of allo-HCT for both HES and CEL, NOS. As observed for HES, allo-HCT can offer durable disease-free survival (DFS) and OS, with more than 50% of reported patients alive at five years. Outcomes were significantly worse for CEL, NOS patients, with only approximately one third of patients alive at five years. Outcomes were better for those who had a MSD available compared to use of an URD. Transplant failure in both HES and CEL, NOS cohorts was predominantly accounted for by considerable rates of both NRM and relapse for this cohort. Clearly the decision of for whom and when to consider allo-HCT in both refractory, debilitating HES and CEL, NOS is difficult. Current British Committee for the Standards in Haematology guidelines on eosinophilic disorders suggest a potential role for allo-HCT in ‘cases with clonal eosinophilia with FGFR1 rearrangement, patients with CEL, NOS and those HES patients refractory to or intolerant of both conventional tyrosine kinase inhibitor (TKI) therapy and experimental medical therapy, where available, or who display progressive end-organ damage’.5 However, these guidelines were published in 2015 and certainly for HES there have been many advances in available therapeutic options, such as mepolizumab.1 Other potential investigational immunotherapeutic options include benralizumab and JAK inhibitors. How these agents will affect the transplant paradigm for HES remain unknown. CEL, NOS is characterized by an aggressive clinical course and short survival. Literature on the role of allo-SCT in CEL is lacking, reflecting the rarity of the disorder. Helbig et al. reported on 10 patients with CEL, NOS with a median age of 62 (23–73 years), frequently with an aggressive clinical course, five of whom developed acute transformation within two years from the time of diagnosis.6 Here, only one patient in the chronic phase successfully underwent allo-SCT. A more contemporary series from the Mayo clinic has recently been published.7 Of 1416 patients presenting with eosinophilia over an 11-year period, only 17 (1.2%) patients met strict criteria for CEL, NOS. Median OS was poor at 16 months. After a median follow-up of 13 months, nine patients had died, and three patients demonstrated transformation. Only one patient was reported to have undergone allo-HCT. Caveats with conclusions from our study are clearly those associated with the limitations of a retrospective, registry-based study of rare disease entities. The transplant decision and timing is likely based on physician and patient preference, patient-specific characteristics and donor availability. Moreover, conditioning regimens and T-cell depletion strategies were heterogeneous, and the reported cohort underwent allo-HCT over a long time period. Correct attribution of WHO diagnostic categories has changed over the period, also with the advent of wider availability of molecular analysis for eosinophilic disorders. Nonetheless, it should however be noted that allo-HCT can offer durable DFS and acceptable long-term survival rates in HES and may offer the only curative route in CEL. Contemporary practice needs to address considerable relapse and NRM rates and consider both pre-and post-transplant management strategies. Donal P. McLornan, Luuk Gras, Ivonne Martin, Tiarlan Sirait, Juan Carlos Hernández-Boluda, Tomasz Czerew and Ibrahim Yakoub-Agha were involved in study design, analysis and drafting the paper. All other co-authors contributed data to the study, critically revised the paper and approved the submitted and final version. The authors have no competing interests.