Targeting the Natural History of Clonal Hematopoiesis

STUDY TITLE: A Pilot Study of Enasidenib in People With Clonal Cytopenia of Undetermined Significance and Mutations in IDH2

CLINICALTRIALS.GOV IDENTIFIER: NCT05102370

PARTICIPATING CENTERS: Four centers across the U.S.

SPONSOR: Memorial Sloan Kettering Cancer Center

ACCRUAL GOAL: 15 patients

STUDY DESIGN: This small pilot study is open at several sites and designed to assess enasidenib in patients with clonal cytopenia of undetermined significance (CCUS) who have a mutation in IDH2. Eligible patients are 18 years or older and have unexplained cytopenia that persists for at least six months with a mutation in IDH2 at a variant allele frequency (VAF) >2%. Patients with a diagnosis of myelodysplastic syndrome (MDS) or another hematologic malignancy are excluded. The primary objective of the study is to assess the rate of hematologic improvement. Study participants will receive enasidenib 100 mg daily, which may be continued for up to 18 months or until confirmed progression to a myeloid malignancy.

STUDY TITLE: Ivosidenib for Patients With Clonal Cytopenia of Undetermined Significance and Mutations in IDH1

CLINICALTRIALS.GOV IDENTIFIER: NCT05030441

PARTICIPATING CENTERS: Three centers in the U.S., with a decentralized structure

SPONSOR: Washington University School of Medicine

ACCRUAL GOAL: 15 patients

STUDY DESIGN: The Preventing IDH Mutant Myeloid Neoplasm (PIMM) study is an open-label, decentralized pilot study of ivosidenib for adults with CCUS with a R132 IDH1 mutation. Eligible individuals must have unexplained cytopenia (defined as a hemoglobin level <10 g/dL, an absolute neutrophil count <1.8 × 10⁹/L, or a platelet count <100 × 10⁹/L), that persists for at least six months, in the presence of an IDH1 mutation. Patients with a myeloid malignancy are excluded. Participants will receive ivosidenib 500 mg daily for up to 18 months, unless there is progression to a myeloid malignancy. The primary outcome measure is the rate of hematologic improvement. Additional outcome measures include the change in mutant IDH1 VAF, rates of disease-free survival, and adverse events. Given the rareness of this patient population, this study is being conducted with a fully decentralized structure, meaning that all study interactions with participants may be performed remotely. Participants do not need to travel to the study site if they can be monitored locally.

RATIONALE: Somatic driver mutations associated with MDS and acute myeloid leukemia (AML) can also be found in the peripheral blood and bone marrow of healthy individuals without cancer. This phenomenon, known as clonal hematopoiesis, is strongly associated with aging. Clonal hematopoiesis is found in approximately 10% of individuals who are 70 to 79 years old and occurs at an even higher frequency in people who are 80 years or older.^1–3  Although clonal hematopoiesis is associated with an increased risk of myeloid malignancy, the chance that an individual with clonal hematopoiesis will develop AML or MDS is highly variable based on the specific mutations present and the presence of concomitant cytopenias.

The absence or presence of concomitant cytopenia (or cytopenias) distinguishes clonal hematopoiesis of indeterminate potential (CHIP) from CCUS.⁴  Overall, CHIP has a 0.5% to 1% risk of progression to myeloid malignancy per year, although this risk is higher for people with mutations such as SF3B1, SRSF2, U2AF1, and TP53.⁵  The risk of progression to myeloid malignancy is generally higher in CCUS than in CHIP.⁶  The Clonal Hematopoiesis Risk Score (CHRS) calculator incorporates multiple factors (including age, number of mutations, and the presence or absence of high-risk mutations and cytopenia) to help predict the risk that CHIP or CCUS will progress to a myeloid malignancy.⁷ 

Clonal hematopoiesis has also been associated with an increased risk of all-cause mortality and multiple issues including coronary artery disease, stroke, and chronic obstructive pulmonary disease (COPD).^8–10  However, there are currently no known effective preventive therapies for people with clonal hematopoiesis. The current standard of care for individuals who are known to have clonal hematopoiesis is active surveillance with complete blood count (CBC) monitoring. Several trials are now investigating interventions for clonal hematopoiesis. A randomized phase II trial (NCT05641831) called the IMPACT study is evaluating canakinumab for CCUS. Canakinumab is a monoclonal antibody targeting interleukin-1β that is currently approved for several autoimmune diseases.

Researchers have proposed that clonal hematopoiesis mutations increase inflammation; therefore, targeting inflammation with canakinumab may alter the natural history of clonal hematopoiesis.¹¹ 

In contrast to the canakinumab study, which is taking the approach of targeting inflammation, the two studies described above (NCT05102370 and NCT05030441) are evaluating targeted therapies, enasidenib and ivosidenib, in patients with CCUS with an IDH1 or IDH2 mutation. These mutations are relatively common in AML and are also found in MDS.¹²  IDH1 and IDH2 mutations lead to the production of an oncometabolite called 2-hydroxyglutarate (2-HG), which blocks cellular differentiation and drives the progression to leukemia.¹³  IDH1 and IDH2 mutations can also be found in CHIP and CCUS. Ivosidenib is an oral agent that specifically targets mutant IDH1 and is approved as a single agent for patients with relapsed or refractory (R/R) AML and R/R MDS and in combination with azacitidine for newly diagnosed patients with AML with an IDH1 mutation who are unfit for intensive induction chemotherapy. Similarly, enasidenib is an oral agent that targets mutant IDH2 and is approved for R/R AML with an IDH2 mutation. The trials for CCUS described here are the first studies to specifically evaluate mutation-selective therapies for clonal hematopoiesis. Although these are small pilot studies, information gathered from these trials may help inform future research of therapeutic interventions for clonal hematopoiesis.

COMMENT: Clonal hematopoiesis is increasingly being identified and is associated with an increased risk of progression to myeloid malignancy, as well as coronary artery disease, stroke, and COPD. However, the current standard of care for patients with CHIP and CCUS is CBC surveillance. The development of effective interventions for this patient population is critical, but the best strategy for developing them is currently unknown. Current approaches being studied include targeting inflammatory pathways and mutation-selective therapies. These pilot studies will help inform the design of future trials for people with clonal hematopoiesis. The decentralized ivosidenib study, which allows for remote subject participation, may also serve as a model for future clinical trials for rare diseases.