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To report the activity of venetoclax in patients with relapsed mantle cell lymphoma (MCL), we identified 81 patients treated with venetoclax monotherapy (n=50, 62%) or in combination with a BTK inhibitor (n=16, 20%), an anti-CD20 monoclonal antibody (n=11, 14%), or others at 12 US academic medical centers. Patients had high-risk disease features including Ki67 >30% (61%), blastoid/pleomorphic histology (29%), complex karyotype (34%), and TP53 alterations (49%), and received a median of 3 prior treatments including BTK inhibitors in 91%. Venetoclax alone or in combination resulted in an overall response rate (ORR) of 40% and median progression-free (PFS) and overall survival (OS) of 3.7 and 12.5 months, respectively. The receipt of ≤ 3 prior treatments was associated with higher odds of response to venetoclax in a univariable analysis. In a multivariable analysis, having a high-risk MIPI score prior to venetoclax and disease relapse or progression within 24 months of diagnosis were associated with inferior OS whereas the use of venetoclax in combination was associated with superior OS. Although most patients (61%) had low risk for tumor lysis syndrome (TLS), 12.3% of patients developed TLS despite the implementation of several mitigation strategies. In conclusion, venetoclax resulted in good ORR but short PFS in high-risk patients with MCL and may have a better role in earlier lines of treatment and/or in combination with other active agents. TLS remains an important risk in patients with MCL who initiate treatment with venetoclax.

Secondary hemophagocytic lymphohistiocytosis (HLH) is an acquired syndrome of immune dysregulation.1-3 Depending on the severity of manifestations, therapy ranges from observation alone to combinations of corticosteroids, etoposide, and/or cyclosporine, based on treatment data in familial HLH.4,5 Notably, there is a paucity of data on salvage therapies.6-8 Key inflammatory cytokines that propagate HLH bind to receptors that signal via the JAKs, which phosphorylate the STAT transcription factors.9,10 The JAK/STAT cascade promotes expression of genes that further expand the hyperinflammatory state. Das et al11 developed a murine model of secondary HLH in which repeated cytosine guanine dinucleotide DNA injection into wild-type B6 mice triggered the innate immune response via Toll-like receptor 9. Subsequent inhibition of JAK1/2 via ruxolitinib led to resolution of splenomegaly and cytopenias, reduction of inflammatory cytokines, and attenuation of pathologic T-cell expansion. Maschalidi et al12 observed such findings in perforin knockout mice. Using these same models, Albeituni et al13 showed the superiority of ruxolitinib over interferon-γ inhibition (the target of emapalumab-lzsg), providing broader immune normalization and improving symptoms and survival. Here we describe 2 consecutive cases in which ruxolitinib was used as salvage therapy for refractory secondary HLH. Ruxolitinib resulted in rapid and complete resolution of clinical manifestations, obviating the need for further intensive chemotherapy or allogeneic stem cell transplantation.