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TRANSFORM-1 initial results: navitoclax + ruxolitinib in patients with previously untreated MF
Myelofibrosis (MF), a chronic myeloproliferative neoplasm, disrupts the bone marrow microenvironment and causes bone marrow fibrosis, which is associated with anemia and progressive splenomegaly.1 Patients with MF commonly exhibit genetic abnormalities that contribute to the upregulation of the JAK/STAT pathway, resulting in an increased drive for cell proliferation and differentiation.2 Inhibition of this pathway with JAK inhibitors such as ruxolitinib has successfully reduced splenomegaly and improved symptoms of MF in previous clinical trials (COMFORT-1/2; NCT00952289; NCT00934544), establishing ruxolitinib monotherapy as the current standard of care (SoC) for patients with MF.
ASH 2023 saw the presentation of initial findings from the ongoing Phase III TRANSFORM-1 trial (NCT04472598) by Naveen Pemmaraju, MD, The University of Texas MD Anderson Cancer Center, Houston, TX. This trial evaluates the efficacy and safety of the combination of navitoclax plus ruxolitinib (NAV + RUX) compared with placebo plus ruxolitinib (PBO + RUX) in previously untreated MF.
The primary endpoint of the trial was met, with 63.2% of patients in the NAV + RUX arm achieving a spleen volume reduction of ≥35% at week 24 (SVR35W24), compared to 31.5% in the PBO + RUX arm (p<0.0001).
Serious adverse events (AEs) were experienced by 26% of patients in the NAV + RUX arm compared to 32% in the PBO + RUX arm, including anemia and thrombocytopenia, but these were managed with dose modification of NAV. This trial establishes NAV + RUX combination therapy as an effective treatment option for splenomegaly in MF, with durable responses and manageable safety concerns. Additional long-term analysis of data is ongoing.3
FLAIR: MRD-directed duration of treatment with ibrutinib plus venetoclax is superior to FCR in previously untreated CLL
Synergistic blockade of BTK and BCL2 signaling with the chemotherapy-free combination of ibrutinib plus venetoclax has shown to improve the outcomes of patients with chronic lymphocytic leukemia (CLL) and gained approval following the Phase III GLOW trial (NCT03462719). However, the optimal treatment duration remains undefined; mathematical disease modelling favors personalizing treatment duration depending on individual patient sensitivity.
Peter Hillmen, MB ChB, PhD, University of Leeds, Leeds, UK, reported findings from the multi-center UK-based Phase III FLAIR trial (ISRCTN01844152), comparing ibrutinib plus venetoclax (I+V) to fludarabine, cyclophosphamide and rituximab (FCR) in previously untreated CLL.
The study hypothesized that personalizing treatment duration using measurable residual disease (MRD) response will optimize patient outcomes. In this trial, 523 patients were randomized to FCR (n=263) and I+V (n=260) across 96 UK centers. The results revealed the superior safety and efficacy of I+V versus FCR, with hazard ratios for progression-free survival (PFS) and overall survival (OS) of 0.13 and 0.31 respectively. Patients in the I+V arm demonstrated higher rates of MRD negativity in both bone marrow (BM) and peripheral blood (PB), with respective odds ratios of 2.03 (BM) and 3.91 (PB). Using MRD rates to direct the duration of I+V treatment maximized outcomes, with a PFS of 97.2% after three years. This trial provides evidence for using I+V with MRD-guided duration as a new standard for CLL treatment.4
Optimizing outcomes for patients with DLBCL in complete remission: CAR-T therapy versus autoSCT
Both autologous stem cell transplantation (autoSCT) and CAR-T therapy have demonstrated efficacy in relapsed diffuse large B-cell lymphoma (DLBCL), allowing patients to maintain a state of complete remission (CR). At ASH 2023, Mazyar Shadman, MD, Fred Hutchinson Cancer Research Center, Seattle, WA, discussed a comparative analysis of PFS and OS outcomes for patients with DLBCL treated with CAR-T therapy versus autoSCT.
Patient data was obtained from the Center for International Blood & Marrow Research (CIBMTR) registry, including patients aged 18-75 with DLBCL or primary mediastinal lymphoma who received autoSCT between 2015 and 2021 or CAR-T therapy between 2018 and 2021 while in a CR. The analysis revealed a lower rate of two-year PFS in patients treated with CAR-T versus autoSCT (47.8% versus 66.2%) and a lower two-year OS (65.6% versus 78.9%).
Analysis of secondary outcomes revealed higher rates of relapse after two years in patients treated with CAR-T therapy (48% versus 27.8%) and no difference in two-year treatment-related mortality (TRM). Specifically focusing on patients with early (12 months) treatment failure, CAR-T therapy was associated with a higher two-year relapse rate and inferior two-year PFS. This real-world analysis supports the use of autoSCT over CAR-T therapy to maintain CR in patients with relapsed DLBCL.5
MRD and FLT3 mutations can predict outcomes of alloSCT in NPM1-mutated AML: an analysis from AML17 and AML19
Abnormalities in the NPM1 gene are common in adult acute myeloid leukemia (AML), contributing to clonal hematopoiesis.6 This can be treated in the first complete remission (CR1) with allogeneic stem cell transplantation (alloSCT), but not all patients are responsive. MRD status and internal tandem duplication (ITD) abnormalities in the FLT3 gene can determine which patients will benefit the most from alloSCT.
Jad Othman, MBBS, King’s College and Guy’s & St Thomas’ NHS Foundation Trust, London, UK, presented an analysis of findings from the UK-based AML17 (ISRCTN55675535) and AML19 (ISRCTN78449203) studies, comparing the outcomes of alloSCT in CR1 for patients with NPM1-mutated AML according to FLT3-ITD and molecular MRD status. 737 patients with NPM1-mutated AML were included in this analysis, and both studies found poor outcomes for patients who were MRD positive, with a three-year OS of 25% in AML17 and 51% in AML19.
Across both trials, there was a significant survival benefit for MRD positive patients treated with alloSCT in CR1 versus those who were not: three-year OS of 61% versus 24%. This was also seen in MRD positive patients who had FLT3-ITD mutations: the three-year OS in those who received alloSCT versus those who did not was 45% versus 18%, respectively.
There was no evidence for a survival benefit of alloSCT in patients who were MRD negative, regardless of FLT3-ITD mutational status.
These findings support the use of molecular MRD status to influence decisions on which patients with NPM1-mutated AML should receive alloSCT in CR1. Patients who are MRD negative are at a low risk of relapse and will likely not benefit from alloSCT, whereas those who are MRD positive are more likely to benefit.7
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References
- Gangat N, Tefferi A. Myelofibrosis biology and contemporary management. British Journal of Haematology. 2020 Mar; 191: 152-170.
- Ross DM, Babon JJ, Tvorogov D, et al. Persistence of myelofibrosis treated with ruxolitinib: biology and clinical implications. Haematologica. 2021 May; 106(5):1244-1253.
- Pemmaraju N, Mead AJ, Somervaille TCP, et al. Transform-1: A Randomized, Double-Blind, Placebo-Controlled, Multicenter, International Phase 3 Study of Navitoclax in Combination with Ruxolitinib Versus Ruxolitinib Plus Placebo in Patients with Untreated Myelofibrosis. Blood. 2023 Nov; 142 (Supplement 1): 620.
- Hillmen P, Cairns DA, Bloor AJC, et al. Ibrutinib Plus Venetoclax with MRD-Directed Duration of Treatment Is Superior to FCR and Is a New Standard of Care for Previously Untreated CLL: Report of the Phase III UK NCRI FLAIR Study. Blood. 2023 Nov; 142 (Supplement 1): 631.
- Shadman M, Wooahn K, Kaur M, et al. Autologous Transplant (auto-HCT) Is Associated with Improved Clinical Outcomes Compared to CAR-T Therapy in Patients (pts) with Large B-Cell Lymphoma (LBCL) Achieving a Complete Remission. Blood. 2023 Nov; 142 (Supplement 1): 781.
- Hindley A, Catherwood MA, McMullin MF, et al. Significance of NPM1 Gene Mutations in AML. International Journal of Molecular Sciences. 2021 Sep; 22(18):10040.
- Othman J, Potter N, Ivey A, et al. The Benefit of Allogeneic Transplant in 1 st Complete Remission in NPM1 Mutated AML with or without FLT3 ITD Is Restricted to Those Testing MRD Positive after Induction – an Analysis of the UK NCRI AML17 and AML19 Studies. Blood. 2023 Nov; 142 (Supplement 1): 425.
Edited by Thomas Southgate & Anya Dragojlovic Kerkache
