Key Points: The oral PI3K-δ,γ inhibitor duvelisib demonstrated clinical activity and a favorable safety profile in patients with CTCL and PTCL. Duvelisib induced cell-autonomous killing of TCL lines and reprogrammed PTCL-associated macrophages in vivo.

T- and NK-cell lymphomas (TCL) are a heterogenous group of lymphoid malignancies with poor prognosis. In contrast to B-cell and myeloid malignancies, there are few preclinical models of TCLs, which has hampered the development of effective therapeutics. Here we establish and characterize preclinical models of TCL. We identify multiple vulnerabilities that are targetable with currently available agents (e.g., inhibitors of JAK2 or IKZF1) and demonstrate proof-of-principle for biomarker-driven therapies using patient-derived xenografts (PDXs). We show that MDM2 and MDMX are targetable vulnerabilities within TP53-wild-type TCLs. ALRN-6924, a stapled peptide that blocks interactions between p53 and both MDM2 and MDMX has potent in vitro activity and superior in vivo activity across 8 different PDX models compared to the standard-of-care agent romidepsin. ALRN-6924 induced a complete remission in a patient with TP53-wild-type angioimmunoblastic T-cell lymphoma, demonstrating the potential for rapid translation of discoveries from subtype-specific preclinical models.

There is a pressing need for more effective therapies to treat patients with T-cell lymphomas (TCLs), including first-line approaches that increase the response rate to cyclophosphamide, adriamycin, vincristine, and prednisone (CHOP) chemotherapy. We characterized the mitochondrial apoptosis pathway in cell lines and patient-derived xenograft (PDX) models of TCL and assessed the in vitro efficacy of BH3 mimetics, including the BCL2 inhibitor venetoclax, the BCL2/BCL-xL inhibitor navitoclax, and the novel MCL1 inhibitor AZD5991. The abundance of antiapoptotic BCL2 family members based on immunoblotting or RNA transcript levels correlated poorly with the activity of BH3 mimetics. In contrast, the functional approach BH3 profiling reliably predicted sensitivity to BH3 mimetics in vitro and in vivo. We used BH3 profiling to select TCL PDX that were dependent on MCL1. Mice xenografted with these PDX and treated with AZD5991 had markedly improved survival. The combination of AZD5991 and CHOP achieved synergy based on survival improvement beyond a mathematical “sum of benefits” model. Thus, MCL1 inhibition is a promising strategy as both a single agent and in combination with chemotherapy for patients with TCL and functional dependence on MCL1.

Anaplastic lymphoma kinase (ALK) tyrosine kinase inhibitors (TKIs) show potent efficacy in several ALK-driven tumors, but the development of resistance limits their long-term clinical impact. Although resistance mechanisms have been studied extensively in ALK-driven non–small cell lung cancer, they are poorly understood in ALK-driven anaplastic large cell lymphoma (ALCL). Here, we identify a survival pathway supported by the tumor microenvironment that activates phosphatidylinositol 3-kinase γ (PI3K-γ) signaling through the C-C motif chemokine receptor 7 (CCR7). We found increased PI3K signaling in patients and ALCL cell lines resistant to ALK TKIs. PI3Kγ expression was predictive of a lack of response to ALK TKI in patients with ALCL. Expression of CCR7, PI3Kγ, and PI3Kδ were up-regulated during ALK or STAT3 inhibition or degradation and a constitutively active PI3Kγ isoform cooperated with oncogenic ALK to accelerate lymphomagenesis in mice. In a three-dimensional microfluidic chip, endothelial cells that produce the CCR7 ligands CCL19/CCL21 protected ALCL cells from apoptosis induced by crizotinib. The PI3Kγ/δ inhibitor duvelisib potentiated crizotinib activity against ALCL lines and patient-derived xenografts. Furthermore, genetic deletion of CCR7 blocked the central nervous system dissemination and perivascular growth of ALCL in mice treated with crizotinib. Thus, blockade of PI3Kγ or CCR7 signaling together with ALK TKI treatment reduces primary resistance and the survival of persister lymphoma cells in ALCL.

Initial treatment with the monoclonal anti-CD52 antibody alemtuzumab induces responses in the majority of patients with T-cell prolymphocytic leukemia (T-PLL). In eligible patients, allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an option to consolidate hematological remissions. Here, we report our experience with 10 patients who received allo-HSCT against T-PLL. Notably, 3 patients with complete remission at transplantation and durable full-donor chimerism relapsed at months 12, 59, and 84 after transplantation, respectively. This relapse was associated with rapid progressive leukemia in 1 patient and extralymphatic lymphoma growth in the other 2. Despite CD52 positivity at relapse, alemtuzumab retreatment, donor lymphocyte infusions, and/or chemotherapy including salvage therapy, allo-HSCT yielded a transient partial response, only. Alemtuzumab induction and consolidative allo-HSCT enabled prolonged disease-free survival in these patients but failed to procure cure.