Monday, May 29, 2023
| Characteristic | HM (n = 113) | HM-HLH (n = 112) | P | |
|---|---|---|---|---|
| Age at diagnosis, median (25%, 75%), y | 66 (60, 75.5) | 62 (53, 69) | .0002 | |
| Female/male, N (%) | 47 (42)/66 (58) | 48 (43)/64 (57) | .89 | |
| T/NK-cell lymphoma, N (%) | 32 (28) | 26 (23) | .45 | |
| PTCL | 11 (10) | 8 (7) | ||
| Anaplastic large cell lymphoma | 4 (4) | 4 (4) | ||
| CTCL | 3 (3) | 2 (2) | ||
| AITL | 5 (4) | 2 (2) | ||
| GDHSTCL | 2 (2) | 1 (1) | ||
| Nasal/other NK/T-cell lymphoma | 7 (6) | 9 (8) | ||
| B-cell lymphoma, N (%) | 47 (42) | 44 (39) | .89 | |
| DLBCL | 26 (23) | 24 (21) | ||
| IVLBCL | 5 (4) | 7 (6) | ||
| Follicular lymphoma | 6 (5) | 3 (3) | ||
| T-cell/histiocyte-rich large B-cell lymphoma | 1 (1) | 3 (3) | ||
| Other types of B-cell lymphoma | 9 (8) | 7 (6) | ||
| Hodgkin lymphoma, N (%) | 9 (8) | 9 (8) | ||
| AML, N (%) | 7 (6) | 11 (10) | .34 | |
| MDS, N (%) | 8 (7) | 10 (9) | .64 | |
| MPN, N (%) | 6 (5) | 6 (5) | 1 | |
| CLL, N (%) | 4 (3) | 6 (5) | .54 | |
| Eastern | Japan | 62 (55) | 19 (17) | |
| Western | Israel | 23 (20) | 45 (40) | |
| United States | 28 (25) | 48 (43) | ||
Table 1. General characteristics of the entire study cohort
P values were calculated with Fisher's exact test.
AITL, angioimmunoblastic T-cell lymphoma; AML, acute myeloid leukemia; CLL, chronic lymphocytic leukemia; CTCL, cutaneous T-cell lymphoma; DLBCL, diffuse large B-cell lymphoma; GDHSTCL, gamma delta hepatosplenic T-cell lymphoma; IVLBCL, intravascular large B-cell lymphoma; MDS, myelodysplastic syndrome; MPN, myeloproliferative neoplasms; PTCL, peripheral T-cell lymphoma.
This activity is intended for hematologists, oncologists, internists, geneticists, and other clinicians caring for patients with hemophagocytic lymphohistiocytosis (HLH), a life-threatening inflammatory syndrome that may complicate hematologic malignancies (HMs).
The goal of this activity is to describe the most useful diagnostic and prognostic parameters and optimized laboratory cutoff values, alone and combined in the ‘optimized HLH inflammatory’ (OHI) index, and diagnostic performance of the OHI index, according to an international cohort of 225 adult patients with various HMs both with and without HLH and for whom HLH-2004 criteria were available.
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Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening inflammatory syndrome that may complicate hematologic malignancies (HMs). The appropriateness of current criteria for diagnosing HLH in the context of HMs is unknown because they were developed for children with familial HLH (HLH-2004) or derived from adult patient cohorts in which HMs were underrepresented (HScore). Moreover, many features of these criteria may directly reflect the underlying HM rather than an abnormal inflammatory state. To improve and potentially simplify HLH diagnosis in patients with HMs, we studied an international cohort of 225 adult patients with various HMs both with and without HLH and for whom HLH-2004 criteria were available. Classification and regression tree and receiver-operating curve analyses were used to identify the most useful diagnostic and prognostic parameters and to optimize laboratory cutoff values. Combined elevation of soluble CD25 (>3900 U/mL) and ferritin (>1000 ng/mL) best identified HLH-2004–defining features (sensitivity, 84%; specificity, 81%). Moreover, this combination, which we term the optimized HLH inflammatory (OHI) index, was highly predictive of mortality (hazard ratio, 4.3; 95% confidence interval, 3.0–6.2) across diverse HMs. Furthermore, the OHI index identified a large group of patients with high mortality risk who were not defined as having HLH according to HLH-2004/HScore. Finally, the OHI index shows diagnostic and prognostic value when used for routine surveillance of patients with newly diagnosed HMs as well as those with clinically suspected HLH. Thus, we conclude that the OHI index identifies patients with HM and an inflammatory state associated with a high mortality risk and warrants further prospective validation.
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening hyperinflammatory syndrome with genetic and acquired etiologies. Familial HLH (FHL) is a genetic disorder caused by granule-mediated lymphocyte cytotoxic function defects occurring mainly in young children.[1] By contrast, most adults with HLH lack FHL genetic variants[2] and ~50% have an underlying cancer, of which hematologic malignancies (HMs) are the most common.[3,4] The diagnosis and treatment of HLH occurring in the context of HMs (HM-HLH) are largely based on extrapolations from clinical experience with FHL, along with expert opinion.[3,5–8]
Overall, HLH affects ~1% of adults with an HM,[9] although the incidence may reach 2.8% in cases with B-cell and T-cell lymphomas.[10] T-cell lymphomas are more commonly associated with the development of HLH (35% of HM-HLH cases) than B-cell lymphoma (32% of HM-HLH cases),[4,5] and myeloid malignancies may also be complicated by HM-HLH.[11–14] HM-HLH has the worst prognosis of all HLH subgroups, with 5-year overall survival ranging from 10% to 30%.[15,16]
HLH is commonly defined by using the enrollment criteria from the HLH-2004 study, which were developed to diagnose pediatric FHL. HLH is diagnosed when a causative genetic mutation is identified or suspected based on family history or when a patient fulfills ≥5 of the HLH-2004 diagnostic criteria.[17] The appropriateness of these criteria for the diagnosis of HM-HLH has not been determined. Furthermore, diagnostic cutoff levels for laboratory markers of HLH have not been optimized or validated in HM-HLH.[18] In addition, although a number of these features are driven by inappropriate immune activation in FHL,[19] their presence in HM may represent nonimmunologic effects of the malignant clone itself, such as infiltration of the marrow or spleen or soluble CD25 (sCD25) production by neoplastic cells. This has led to the suggestion that the syndrome of HM-HLH may be a "mimic" of the syndrome seen in patients with FHL and that patients may not benefit or may even be harmed by the use of HLH-directed therapy.[20] As a result, there is no consensus regarding whether patients fulfilling HLH-2004 diagnostic criteria should be treated with tumordirected therapy, HLH-directed therapy, or both.[7]
Another scoring system, the HScore, was developed to determine the diagnosis of HLH in adults.[21] Although valuable in some contexts, the HScore is imperfect as it was derived from a cohort of patients who were retrospectively defined as having HLH and because sCD25 results were not included in the score due to a lack of data. Moreover, HMs were significantly under-represented in the non-HLH group, limiting the use of the HScore in diagnosing HM-HLH.[21] Tamamyan et al[18] proposed a tool with extended diagnostic criteria for malignancy-associated HLH, adding selected variables to the HLH-2004 that were described in association with adult HLH. This tool was intended to supplement the HLH-2004 criteria to facilitate diagnosis of the syndrome in its early phase and thus reduce early mortality.
We conducted the current study to optimize and simplify HM-HLH diagnosis based on HLH-2004–defining features and used disease outcomes as an external validation measure.
