Precision Oncology in Hematological Malignancies: Takeaways from the 2023 Precision Oncology Summit

i) Myeloid malignancies (with special focus on acute myeloid leukemia (AML))

Myeloid neoplasms encompass clonal disorders involving the myeloid compartment of the hematopoietic system, which includes red blood cells, platelets, and a range of white blood cells. The phenotype of myeloid disease is defined not only by the particular cell type that acquires the mutation but also by the biology of the mutation itself. The classification of these disorders is exhaustive, but for simple understanding, the four major categories include clonal hematopoiesis, myelodysplastic syndrome/neoplasm (MDS), myeloproliferative neoplasms (MPNs) and AML.^1,2 In 2013, The Cancer Genome Atlas (TCGA) Research Network published results of sequencing 200 AML cases to help define the mutation landscape of AML.³ The enhancement in our understanding of the biology of myeloid neoplasms has led to identification of multiple targets and development of therapies that have revolutionized the treatment.

In AML, FLT3 is mutated in about 20% of the cases making it one of the most commonly encountered mutations. Midostaurin was the first of the FDA approved FLT3 inhibitors based on the RATIFY trial that compared chemotherapy in combination with placebo or midostaurin in newly diagnosed FLT3-mutated AML patients aged less than 60 and fit for intensive chemotherapy. Overall survival was significantly longer in the midostaurin group than in the placebo group (HR, 0.78; p=0.009), as was event-free survival (EFS) (HR, 0.78; p=0.002). Although a higher proportion of patients underwent allogeneic stem cell transplant in the midostaurin group, the benefit of midostaurin was consistently seen in both the primary analysis as well as an analysis in which data for patients who underwent transplantation were censored.⁴ Midostaurin was followed by FDA approval for gilteritinib in 2018, for relapsed/refractory (R/R) AML. This was based on the ADMIRAL trial which compared gilteritinib versus salvage chemotherapy in FLT3 mutated R/R AML patients. The median OS in the gilteritinib group was significantly longer (9.3 months vs. 5.6 months; HR, 0.64; p<0.001). Adjusting for therapy duration, adverse events (AEs) of grade 3 or higher and serious AEs occurred less frequently in the gilteritinib.⁵ Most recently, in July 2023, FDA approved quizartinib with cytarabine and anthracycline induction and cytarabine consolidation, and as maintenance monotherapy following consolidation chemotherapy, for newly diagnosed FLT3-ITD AML based on QuANTUM-First trial. The median OS for the quizartinib arm was 31.9 months compared to 15.1 in the placebo arm (HR 0.78; p=0.0324). Notably, age was not used as a discriminator and about 40% of the patients were aged 60 or older unlike RATIFY trial.⁵ Quizartinib comes with a black box warning for increased incidence of prolonged QT as well as severe myelosuppression, and the requirement that providers complete a REMs training prior to being able to prescribe

The other successful molecular targets are the IDH1 and IDH2 mutations, present in around 30% of AML. Enasidenib is the first and only IDH2 inhibitor that has gained approval based on a single arm phase I/II study in R/R AML with IDH2 mutations. Median OS for all R/R AML patients was 9.3 months and 19.7 months patients who attained CR.⁶ Following enasidenib, ivosidenib received its initial approval for R/R AML in 2018, followed by approval in the front-line setting in patients at least 75 years old or who have comorbidities that preclude the use of intensive induction chemotherapy in 2019. Ivosidenib had a complete response plus complete response with partial hematologic recovery (CR+CRh) rate of 30% in R/R AML and 42% in the upfront setting.^7,8 In 2022, ivosidenib also received approval in combination with azacitidine for newly diagnosed IDH1 mutated AML in adults 75 years or older, or who have comorbidities that preclude use of intensive induction chemotherapy. Approval was based on the phase III AGILE trial which confirmed benefit in EFS, OS and CR rate.⁹ Finally, olutasidenib was approved in 2022 for R/R AML with IDH1 mutation based on a CR+CRh rate 35% in a single arm study.¹⁰ IDH inhibitors have the potential to cause differentiation syndrome which has to be monitored with caution.

In MDS, luspatercept was approved in 2020 based on MEDALIST trial for the treatment of anemia failing an erythropoiesis stimulating agent (ESA) and requiring 2 or more red blood cell (RBC) units over 8 weeks in adult patients with very low- to intermediate-risk MDS with ring sideroblasts.¹¹ However, a recent development is its approval as first-Line treatment of anemia in adults with lower-risk MDS who may require transfusions based on the phase III COMMANDS trial.¹²

In the MPN space, there are new approvals opening up treatment options in addition to ruxolitinib. The first one is fedratinib which improved spleen volume reduction as well as systemic symptom burden in the JAKARTA and JAKARTA2 trial which studied this drug in the upfront and second line settings (after ruxolitinib), respectively. Fedratinib comes with an increased risk for Wernicke’s encephalopathy which has to be promptly recognized and treated with thiamine.^13,14 Momelotinib which was studied in MOMENTUM and SIMPLIFY1 trials has also been approved for intermediate- or high-risk MF.^15,16 Whereas, pacritinib is now a treatment option for MF patients with a platelet count under 50 × 10⁹/L.¹⁷

While there have been multiple advances in the field, there are multiple treatments on the horizon. In AML, therapies specifically tailored for TP53 mutated, NPM1 mutated or KMT2A rearranged AML are being studied. For MDS, IDH1/IDH2 and BCL2, and for MPNs, BET, LSDI and PI3K are potential targets.

ii) Acute Lymphocytic Leukemia (ALL)

The treatment paradigm of ALL has been evolving with the addition of highly effective targeted therapies (such as blinatumomab, inotuzumab ozogamicin and ponatinib) to frontline chemotherapy, development of chemotherapy free front-line regimens (BCR-ABL1 tyrosine kinase inhibitor (TKI)/blinatumomab, inotuzumab/blinatumomab), and introduction of CAR-T cell therapy. Some of the therapies in early development include Bcl-2, Bcl-XL, and Menin inhibitors.

In Philadelphia chromosome negative (Ph -) B-ALL, addition of rituximab to chemotherapy improved the EFS in adults aged 18 to 59. While there was no difference in the OS in the overall population, a post hoc sensitivity analysis with censoring of data at the time of transplantation for patients who received an allogeneic transplant during the first remission, showed an OS benefit.¹⁸ Blinatumomab (blina) is a promising bispecific T-cell engager (BiTE) incorporated in different ALL treatment regimens. SWOG 1318 was a phase II trial of blinatumomab followed by POMP maintenance in older patients (median age 75 years) with newly diagnosed Ph- B-ALL. 66% patients achieved CR, and the 3-year DFS and OS were 37% and 37%, respectively.¹⁹ Furthermore, ECOG-ACRIN E1910 phase III trial demonstrated that the addition of blina to consolidation chemotherapy resulted in a significantly better OS in pts with newly diagnosed B-ALL who were MRD negative after intensification chemotherapy.²⁰ Similarly, inotuzumab ozogamicin (InO) which is an antibody-drug conjugate directed against CD22, has shown activity in both R/R and newly diagnosed ALL in various studies. Notably, Alliance A041703 is a phase II trial employing a chemotherapy-free approach of induction with InO followed by consolidation with blina for older adults with newly diagnosed, Ph- B-ALL. This regimen showed an impressive cumulative CR rate of 85% and 97% through course IA/B/C and course II, and 1-year EFS and OS of 75% and 84%, respectively.²¹

In the pre-TKI era, long term survival was rare in Ph+ ALL. However, with the advent of TKIs (especially the second and third generation), outcomes have improved significantly and it is no longer a poor risk disease. Emergence of T315I mutation is the major route to TKI resistance, loss of response and relapse. Different clinical have shown that the T315I mutation was found in 70-75% of the patients at relapse.^22,23 This suggests that targeting T315I clones with ponatinib or blinatumomab may eliminate most relapses and eliminate the need for intensive approaches. Combinations of dasatinib or ponatinib with blinatumomab have shown excellent survival and disease-control outcomes in multiple studies ushering field into an era of chemotherapy free regimens for ALL.^24,25

iii) Multiple Myeloma (MM)

The current standard of care in MM largely employs a one-size-fits-all approach where multiagent induction therapy is followed by either autologous stem cell transplant (ASCT) and maintenance in transplant-eligible or continuous therapy in transplant-ineligible patients. Although the survival in MM continues to improve, outcomes are different between the patients. With our improved understanding of disease biology and behavior, MM should be considered a group of disorders with a common morphology yet with distinct genetic subgroups. This may enable personalization of therapy by using multidrug combinations or specific class of drugs, varying the duration of therapy, or targeting a particular level of response.

Historically, tandem ASCT had a place in high-risk MM, but that approach has become less utilized with the availability of better therapies. Studies have also been done to justify using two drugs for maintenance in high-risk MM.²⁶ Additionally, continuous therapy has significantly improved PFS1, PFS2, and OS compared with fixed duration.²⁷ The depth of response also has prognostic value, with minimal residual disease-negative status associated with long-term survival.²⁸

Venetoclax in t(11;14) MM serves as a prototypical example of precision medicine in MM with an ORR of around 40%.²⁹ However, personalization of therapy for MM is fraught with difficulties, and newer strategies such as basket, umbrella, or platform trial designs may pave the way for bringing more drugs from bench to bedside. The Myeloma-Developing Regimens Using Genomics (MyDRUG) (NCT02884102) trial is one such example that aims at treating patients with drugs targeted to affect specific mutated genes.³⁰ Novel therapeutic strategies such as dendritic cell-based vaccines are also under study in early phase trials in MM.³¹

Iv) Diffuse Large B-cell Lymphoma (DLBCL)

While our knowledge of DLBCL biology has increased over time, it has been a challenge to translate this clinically. R-CHOP has remained the standard of care in the treatment of diffuse large B-cell lymphoma (DLBCL) and many strategies attempted to improve upon R-CHOP have failed. Recently, a double-blind, placebo-controlled, phase 3 trial (POLARIX) compared polatuzumab-vedotin with R-CHP with R-CHOP, in patients with newly diagnosed, intermediate- or high-risk DLBCL. After a median follow-up of 28.2 months, the PFS was significantly higher in the pola-R-CHP group than in the R-CHOP group (76.7% vs. 70.2% at 2 years; HR, 0.73; P=0.02). Overall survival at 2 years did not differ significantly between the groups (88.7% versus 88.6%; HR, 0.94; p=0.75). The safety profile was similar in the two groups. The subgroup analysis showed that patients with activated B-cell subtype and higher IPI scores (3-5) seemed to derive more benefit from pola-R-CHP.³² However, given the lack of OS benefit, pola-R-CHP should be considered an additional option rather than a clear winner over R-CHOP. It should also be emphasized that despite these two regimens, nearly 40% of the patients will still relapse highlighting the unmet need of better therapies.

There has been interest in employing BTK inhibitors in the front line treatment of DLBCL. In the phase III (PHOENIX) trial, addition of ibrutinib to R-CHOP did not meet its primary end point (EFS) therefore it has not made it to the standard of care. Although, a pre-planned analysis showed improved EFS, PFS, and OS with manageable safety in patients younger than 60.³³ Trials are underway studying acalabrutinib, zanubrutinib and orelabrutinib in combination with R-CHOP.

CAR-T cell therapy (axicabtagene ciloleucel) as monotherapy, and BiTEs (epcoritamab, glofitamab) in combination with chemotherapy are also being studied in the first line setting and their utility remains to be established.

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Author Contributions

I. conception and design: Abdul Moiz Khan
II. data collection and assembly: Abdul Moiz Khan
III. data analysis, manuscript writing: Abdul Moiz Khan
IV. Other – Review: Shaji Kumar, Inas Abu Ali, Hannah Abrams, and Ivy Riano

All authors have approved this manuscript.