Characteristics and Outcomes of Adult Patients with Malignancy-Associated Hemophagocytic Lymphohistiocytosis: A Single-Center, Prospective Analysis
Authors: Mohamed Shehab Fareed , Assi Rita , Ning Jing , Xiao Lianchun , Jabbour Elias J. , Pemmaraju Naveen , Kadia Tapan M. , Jain Nitin , DiNardo Courtney D. , Yilmaz Musa , Maiti Abhishek , Issa Ghayas C. , Short Nicholas J. , Bose Prithviraj , Masarova Lucia , Garcia-Manero Guillermo , Ravandi Farhad , Konopleva Marina , Kantarjian Hagop , Daver Naval 
Published: November 2021

Abstract

Background:
Hemophagocytic lymphohistiocytosis (HLH) is a life-threatening syndrome characterized by sustained immune overactivation and dysregulation. Malignancy-associated HLH (M-HLH) is associated with particularly dismal outcomes, likely perpetuated by inflammation from neoplastic cells, as well dysfunctional immune regulation secondary to the underlying malignancy and/or chemotherapy, infection, immunotherapies, or hematopoietic stem cell transplantation.
Methods: We retrospectively reviewed patients (pts) aged ≥ 18 years with an underlying hematological malignancy (HM) who fulfilled ≥5 HLH-2004 criteria at our institution between 2011 - 2020. High risk disease for the underlying HM was defined according to WHO Risk stratifications.
Results:
Forty-seven pts were diagnosed with M-HLH with a median age of 61 years (range, 19-81), 32 (68.1 %) were male, and most were Caucasian (87.3%). The underlying malignancy was myeloid in 70% and lymphoid in the rest. HLH was diagnosed during active malignancy in 33 (70%), malignancy in remission in four (8%), and during or after relapse in 10 (21%) pts. Table 1
The median (med) time from diagnosis of HM to HLH manifestations was 7.5 months (m) (range, 0 - 177). HLH preceded an overt diagnosis of HM in 4 cases (all 4 eventually diagnosed with AML and MDS). Forty pts (85%) had received prior treatment for their HM. Three pts were diagnosed with HLH 2.0m, 4.0m, and 7.5m following ASCT, while their HM was in remission. The median number of fulfilled HLH criteria in these 47 pts was 6 (range, 5-8): 33 (71%) pts met 5-6 variables and 14 (29%) met 7-8 criteria. At the time of HLH diagnosis, high-grade fever and splenomegaly were present in 44 (93%) and 27 (57%) pts, respectively. All pts had serum ferritin &gt;500 ng/mL at HLH diagnosis with a med of 56,707ng/mL (range, 3,059 - 47,1540); 30 (76.5%), 24 (51%), 14 (29%), and 9 (20%) patients had serum ferritin &gt;10,000 ng/mL, &gt;25,000 ng/mL, &gt;50,000 ng/mL, and &gt;100,000 ng/mL, respectively at diagnosis. Serum triglyceride (TG) level was 318 mg/dL (range, 8.6 - 971) and 64% of evaluable pts had elevated serum TG at diagnosis. Similarly, the plasma fibrinogen level at diagnosis was 241 mg/dL (range, 27 - 702). Of the 32-pts tested, the sIL2r level was 7010 U/mL (range, 749-127,000) and 72% had elevated sIL2r levels at diagnosis. NK function was decreased in 12 (66.6%) of 18 evaluated pts. Based on bone marrow, spleen, and/or liver assessments, hemophagocytosis was seen in 18 (43%) of pts. Table 2Mutation panels and were negative in (15 patients, 31.9%). The most common mutation identified was TP53 (7, 14.9%) patients.
We compared outcomes of pts who received etoposide and dexamethasone (DE) with those who received etoposide, dexamethasone, and tocilizumab (DET.) High-risk HM was observed in 13 of 17 pts treated with (DE) and in all 19-pts treated with (DET) (P=0.02). Of the 47 treated pts, seven (14.9%) had complete response, nine (19%) had PR and 31 (66%) did not respond. Eight of the 18 pts who received DE had either CR or PR, compared with five of 19 treated with DET (P=0.3133).
Thirty-eight of the 47 pts have died. With a median follow-up of 8.8m (95% CI, 4.43 - NR), the estimated med OS was 0.95m (95% CI, 0.59-3.25) with a 1-year survival probability of 16.6% (95% CI, 7.91%-34.6%. Patients with lymphoid malignancies had improved OS (95%CI, 0.1865-0.9092, P=0.027,) Fig 1. Pts with CR/PR response had improved OS compared with non-responders (95% CI, 0.1377-0.6664) P=0.03). Pts with ferritin &lt;50,000 had better OS than those with higher ferritin (95% 1.0245-4,004, P=_0.04_) and IL_10 was associated with a higher risk of death (HR=1.0008, p=0.0443).
The OS was higher in patients treated with DE compared with DET, (95%CI,1.1407-5.3375, P=0.02) Fig 2. DET group had higher proportion of high-risk disease, admitted more to the ICU, more use of pressor and increase in length of stay. Table 3
Conclusion
M-HLH remains a highly fatal disease with a 1-year survival &lt;20% despite therapy. In our report, etoposide-based therapies with or without malignancy-directed therapy induced a response in only about 35% of pts and achieving a response improved survival. The OS was improved in patients treated with (DE), with lymphoid malignancies and those with ferritin level less than 50,000 (P=0.04). The implementation of adult specific HLH programs and multidisciplinary collaboration are required to foster directed clinical guidelines and improve outcomes.
Figure 1 Figure 1.

Disclosures
Jabbour: Amgen, AbbVie, Spectrum, BMS, Takeda, Pfizer, Adaptive, Genentech: Research Funding. Pemmaraju: Sager Strong Foundation: Other; ASH Communications Committee: Membership on an entity's Board of Directors or advisory committees; Plexxicon: Other, Research Funding; Incyte: Consultancy; HemOnc Times/Oncology Times: Membership on an entity's Board of Directors or advisory committees; ASCO Leukemia Advisory Panel: Membership on an entity's Board of Directors or advisory committees; Springer Science + Business Media: Other; Samus: Other, Research Funding; Affymetrix: Consultancy, Research Funding; MustangBio: Consultancy, Other; Dan's House of Hope: Membership on an entity's Board of Directors or advisory committees; Daiichi Sankyo, Inc.: Other, Research Funding; Novartis Pharmaceuticals: Consultancy, Other: Research Support, Research Funding; Protagonist Therapeutics, Inc.: Consultancy; Roche Diagnostics: Consultancy; Clearview Healthcare Partners: Consultancy; Cellectis S.A. ADR: Other, Research Funding; LFB Biotechnologies: Consultancy; Abbvie Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; Aptitude Health: Consultancy; Celgene Corporation: Consultancy; DAVA Oncology: Consultancy; Stemline Therapeutics, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other, Research Funding; CareDx, Inc.: Consultancy; Blueprint Medicines: Consultancy; Bristol-Myers Squibb Co.: Consultancy; ImmunoGen, Inc: Consultancy; Pacylex Pharmaceuticals: Consultancy. Kadia: Cure: Speakers Bureau; AstraZeneca: Other; Genentech: Consultancy, Other: Grant/research support; Sanofi-Aventis: Consultancy; Ascentage: Other; Genfleet: Other; Dalichi Sankyo: Consultancy; Liberum: Consultancy; Jazz: Consultancy; BMS: Other: Grant/research support; Amgen: Other: Grant/research support; Aglos: Consultancy; AbbVie: Consultancy, Other: Grant/research support; Pfizer: Consultancy, Other; Novartis: Consultancy; Pulmotech: Other; Cellonkos: Other; Astellas: Other. Jain: Fate Therapeutics: Research Funding; Genentech: Honoraria, Research Funding; Adaptive Biotechnologies: Honoraria, Research Funding; Aprea Therapeutics: Research Funding; Beigene: Honoraria; Bristol Myers Squibb: Honoraria, Research Funding; Servier: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding; ADC Therapeutics: Honoraria, Research Funding; Incyte: Research Funding; Cellectis: Honoraria, Research Funding; TG Therapeutics: Honoraria; Precision Biosciences: Honoraria, Research Funding; Pfizer: Research Funding; Janssen: Honoraria; AbbVie: Honoraria, Research Funding; Pharmacyclics: Research Funding. DiNardo: Takeda: Honoraria; Agios/Servier: Consultancy, Honoraria, Research Funding; Novartis: Honoraria; Notable Labs: Current holder of stock options in a privately-held company, Membership on an entity's Board of Directors or advisory committees; AbbVie: Consultancy, Research Funding; GlaxoSmithKline: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Honoraria, Research Funding; ImmuneOnc: Honoraria, Research Funding; Forma: Honoraria, Research Funding; Foghorn: Honoraria, Research Funding; Celgene, a Bristol Myers Squibb company: Honoraria, Research Funding. Yilmaz: Daiichi-Sankyo: Research Funding; Pfizer: Research Funding. Issa: Kura Oncology: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Syndax Pharmaceuticals: Research Funding. Short: Novartis: Honoraria; NGMBio: Consultancy; Jazz Pharmaceuticals: Consultancy; AstraZeneca: Consultancy; Astellas: Research Funding; Takeda Oncology: Consultancy, Research Funding; Amgen: Consultancy, Honoraria. Bose: BMS: Honoraria, Research Funding; Pfizer: Research Funding; Astellas: Research Funding; Novartis: Honoraria; Constellation Pharmaceuticals: Research Funding; Kartos Therapeutics: Honoraria, Research Funding; Celgene Corporation: Honoraria, Research Funding; Promedior: Research Funding; Sierra Oncology: Honoraria; NS Pharma: Research Funding; CTI BioPharma: Honoraria, Research Funding; Blueprint Medicines: Honoraria, Research Funding; Incyte Corporation: Honoraria, Research Funding. Ravandi: Astex: Honoraria, Research Funding; Agios: Honoraria, Research Funding; AstraZeneca: Honoraria; AbbVie: Honoraria, Research Funding; Novartis: Honoraria; Taiho: Honoraria, Research Funding; Jazz: Honoraria, Research Funding; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Xencor: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Prelude: Research Funding; Syros Pharmaceuticals: Consultancy, Honoraria, Research Funding; Bristol Myers Squibb: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Konopleva: Rafael Pharmaceuticals: Other: grant support, Research Funding; Stemline Therapeutics: Research Funding; KisoJi: Research Funding; Ascentage: Other: grant support, Research Funding; Ablynx: Other: grant support, Research Funding; Cellectis: Other: grant support; AstraZeneca: Other: grant support, Research Funding; Novartis: Other: research funding pending, Patents & Royalties: intellectual property rights; Reata Pharmaceuticals: Current holder of stock options in a privately-held company, Patents & Royalties: intellectual property rights; Eli Lilly: Patents & Royalties: intellectual property rights, Research Funding; Agios: Other: grant support, Research Funding; AbbVie: Consultancy, Honoraria, Other: Grant Support, Research Funding; Sanofi: Other: grant support, Research Funding; Forty Seven: Other: grant support, Research Funding; Calithera: Other: grant support, Research Funding; Genentech: Consultancy, Honoraria, Other: grant support, Research Funding; F. Hoffmann-La Roche: Consultancy, Honoraria, Other: grant support. Kantarjian: Astellas Health: Honoraria; Aptitude Health: Honoraria; Ascentage: Research Funding; AbbVie: Honoraria, Research Funding; Immunogen: Research Funding; NOVA Research: Honoraria; Ipsen Pharmaceuticals: Honoraria; BMS: Research Funding; Jazz: Research Funding; Astra Zeneca: Honoraria; Amgen: Honoraria, Research Funding; Daiichi-Sankyo: Research Funding; KAHR Medical Ltd: Honoraria; Novartis: Honoraria, Research Funding; Pfizer: Honoraria, Research Funding; Precision Biosciences: Honoraria; Taiho Pharmaceutical Canada: Honoraria. Daver: Novimmune: Research Funding; Trovagene: Consultancy, Research Funding; Hanmi: Research Funding; Sevier: Consultancy, Research Funding; Daiichi Sankyo: Consultancy, Research Funding; FATE Therapeutics: Research Funding; Amgen: Consultancy, Research Funding; Glycomimetics: Research Funding; Novartis: Consultancy; Trillium: Consultancy, Research Funding; Abbvie: Consultancy, Research Funding; ImmunoGen: Consultancy, Research Funding; Gilead Sciences, Inc.: Consultancy, Research Funding; Astellas: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Genentech: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Jazz Pharmaceuticals: Consultancy, Other: Data Monitoring Committee member; Dava Oncology (Arog): Consultancy; Celgene: Consultancy; Syndax: Consultancy; Shattuck Labs: Consultancy; Agios: Consultancy; Kite Pharmaceuticals: Consultancy; SOBI: Consultancy; STAR Therapeutics: Consultancy; Karyopharm: Research Funding; Newave: Research Funding.