Targeting therapeutic vulnerabilities in T-PLL

In this issue of Blood, von Jan and colleagues present results from an ex vivo drug screen for T-cell prolymphocytic leukemia (T-PLL), demonstrating selective sensitivity of T-PLL cells to idasanutlin and romidepsin, with subsequent validation of these agents in combination with cladribine in syngeneic and patient-derived xenograft mouse models of T-PLL.¹ 

Over the past 2 decades, advances in our understanding of the molecular pathogenesis and tumor-specific dependencies of hematologic neoplasms have ushered in an era of rational targeted therapy. Notable successes include tyrosine kinase inhibitors for chronic myeloid leukemia and Philadelphia chromosome-positive acute lymphoblastic leukemia, JAK/STAT pathway inhibitors for myeloid malignancies, as well as B-cell receptor signaling inhibitors and BCL2 inhibitors for chronic lymphocytic leukemia that have transformed therapeutic paradigms. Nevertheless, despite unprecedented technical advances afforded by next-generation sequencing and functional genomics, the development of novel therapeutics for rare tumor types is lagging, hampered by a paucity of patient biospecimens and animal models for preclinical research. Such is the case with T-PLL, where the management of transplant-ineligible patients who inevitably relapse following frontline alemtuzumab clearly represents an unmet clinical need.² The collaborative effort by the authors to investigate targeted therapy for T-PLL based on actionable tumor-specific vulnerabilities is therefore important and timely.

Early insights into the genetic basis of T-PLL stem from the observation that T-PLL frequently develops in patients with ataxia telangiectasia, an inherited syndrome characterized by inactivating germ line mutations of ATM that functions as a master regulator of cellular response to DNA double-strand breaks. This implicates DNA damage response defect as an important component underlying T-PLL pathogenesis. The latter is substantiated by the genomic landscape of sporadic T-PLL, characterized by predominantly clonal ATM somatic mutations or deletions observed in >80% of patients that give rise to monoallelic or biallelic ATM loss. Beyond ATM alterations, the vast majority of T-PLLs harbor concurrent TCL1 gene alterations that promote prosurvival signaling.³ Previous work by the authors demonstrated cooperativity between ATM and TCL1 gene alterations, wherein defective ATM fails to ameliorate DNA double-stranded breaks or induce p53-dependent apoptosis in response to cellular oxidative stress and telomere shortening potentiated by TCL1 dysregulation, with detrimental consequence for genome stability.⁴ ATM and TCL1 aberrations may thus represent synergistic initiating events in T-PLL leukemogenesis, facilitating the subsequent acquisition of additional, predominantly subclonal genomic alterations involving MYC, epigenetic modifiers (eg, EZH2), microRNA processing (eg, AGO2) and JAK/STAT signaling during the course of tumor progression.⁵ 

Building on this work, the authors postulated that pathogenic mechanisms arising from these genetic defects constitute tumor-specific vulnerabilities in T-PLL that could be therapeutically targeted. Specifically, given that apoptotic resistance in T-PLL emerges predominantly from a failure of p53 induction secondary to ATM dysfunction rather than inactivating TP53 mutations (a rarer event seen in <5%-15% of T-PLLs), the investigators proposed p53 reactivation as a rational strategy to therapeutically target T-PLL. This could be achieved through inhibition of MDM2 that targets p53 for proteasomal degradation or histone deacetylases (HDAC) that epigenetically repress p53 activity. Additional complementary strategies to promote p53-dependent apoptosis include the induction of DNA damage, inhibition of the antiapoptotic protein BCL2, or suppression of the JAK/STAT pathway as well as cyclin-dependent kinases that promote tumor survival and proliferation. These strategies were tested across a panel of primary T-PLL tumor samples and healthy peripheral blood mononuclear cells, in which MDM2 inhibition with idasanutlin emerged as the most potent and specific treatment against T-PLL cells, followed by HDAC inhibition with romidepsin. Although other strategies were effective in some or most T-PLL tested, their activity was less selective, highlighting functional defects of the ATM-Chk2-p53 axis as an important T-PLL-specific dependency (see figure).

These results corroborated earlier data from a screen of 301 compounds showing that p53 activators were among the most pharmacologically active agents against T-PLL cells and from CRISPR/Cas9 screens on TP53 wild-type T-cell leukemia/lymphoma lines that identified MDM2 as a cellular vulnerability.^6,7 On the contrary, the more heterogenous response to BCL2 and JAK1/2 inhibitors could be attributed partly to variability in BCL2 dependence, which the authors demonstrated, and to the subclonal nature of activating JAK/STAT mutations in T-PLL. The investigators further showed that cladribine, although being among the most potent DNA damaging agents against T-PLL cells, was insufficient to fully liberate p53 from its inactive MDM2-bound state. The latter was achieved through cotreatment with idasanutlin, underpinning the synergism between cladribine and idasanutlin, which was confirmed in syngeneic and patient-derived xenograft mouse models of T-PLL, alongside cladribine and idasanutlin combinations with romidepsin. Cotreatment with cladribine and idasanutlin also augmented promoter accessibility of p53 targets, providing a tantalizing window into the epigenetic regulation of genome stability in T-PLL that could yield additional therapeutic targets and thus warrants further investigation.

Collectively, the data presented by von Jan and colleagues provide a strong foundation for the clinical study of idasanutlin and romidepsin combinations with cladribine in T-PLL. In this regard, several potential caveats should be considered. First, although no major hematologic toxicity was reported in mice treated with idasanutlin in the current study, spontaneous p53 activity can occur in healthy cells in the absence of MDM2 activity,⁸ with myelosuppression and infections being frequent adverse events in clinical trials of MDM2 inhibitors.⁹ This justifies caution in the assessment and monitoring of treatment-related toxicities, particularly in view of the elderly T-PLL patient demographics. Second, given that intact p53 function is a prerequisite for therapeutic response to MDM2 inhibitor, assessment of baseline TP53 status is of critical importance to ensure that patients with TP53 mutations receive alternative treatments. Moreover, the acquisition of inactivating TP53 mutations during treatment should be anticipated as a potential mechanism of therapeutic resistance.¹⁰ Looking into the future, studies to better understand longitudinal clonal dynamics and tumor-immune microenvironmental interactions in T-PLL may open up additional possibilities for the treatment of this devastating disease.

Conflict-of-interest disclosure: The authors declare no competing financial interests.