Drug-based maintenance strategies post-allogeneic stem cell transplantation – are we there yet (and will we be)?

INTRODUCTION

Allogeneic stem cell transplantation (ASCT) is the mainstay of consolidation therapy for a variety of malignant hematologic diseases, including acute myeloid leukaemia (AML) myelodysplastic syndromes and acute lymphoblastic leukaemia (ALL). During the last decades, ASCT has become safer with the advent of reduced intensity conditioning regimens and improved supportive care. With decreasing transplant related mortality, relapse is the most common cause of treatment failure in AML after ASCT. About 20–30% relapses occur within in the first 1–2 years following ASCT and in relapsed AML the 1-year survival is less than 20% with limited treatment options.^1,2

We have seen promising developments with novel opportunities to manipulate the anti-leukaemic effect of the graft after transplant and ASCT is no longer seen as a static mode of treatment, but rather as part of the treatment continuum making therapy safer and reducing the risk of relapse. This can be done using the conditioning regimen, post-transplant immunosuppressive strategies and both drug-based and immunotherapeutic strategies in order to induce a direct anti-leukaemic effect through the elimination of any residual leukaemia as well as stimulate the graft-versus-leukaemia (GvL) effect without increasing the risk of GvHD.

DRUG-BASED MAINTENANCE - WHAT'S ON THE SHELF?

During the last years several drugs have become available, mainly in clinical trials for post-transplant maintenance aiming to reduce the risk of relapse after ASCT. The most widely studied class of drugs are the epigenetic modifying agents, such as azacytidine, decitabine and panobinostat. With the availability of novel targeted agents, such as FLT3-inhibitors, IDH-inhibitors, bcl2-inhibitors and menin-inhibitors, these have been incorporated into clinical trials (NCT04027309, NCT03839771, NCT04065399, NCT02400255).³ The FLT3-inhibitor sorafenib has been widely used^4,5 and results from novel agents in clinical trials are awaited.

The goal of post-transplant drug-based maintenance is to enhance the anti-leukaemic activity with the capability of eradicating emerging resistant clones, manipulate the kinetics of relapse and delay the requirement for DLI as well as augment the alloreactive effect with an acceptable safety profile, especially with regard to cytopenias, infections, GVHD, and NRM.

Targeting the epigenetic pathways – azacytidine, decitabine and panobinostat

Azacytidine has known anti-leukaemic activity in vitro and in vivo. Early pre-clinical animal models with azacytidine demonstrated both direct anti-leukaemic activity as well as activation of CD8+ tumour-specific T cells through upregulation of aberrant methylated leukemic antigens on leukemic cells and augments regulatory T cell activity potentially reducing the risk of GvHD in murine models.⁶

With the well-known and acceptable safety profile, azacytidine and decitabine are the most widely studied epigenetic modifying drugs post-allotransplant.⁷ The trials have often had limited numbers of patients, making the results difficult to interpret with confidence. Maintenance with oral azacitidine (Onureg) in the QUAZAR-AML-001 trial⁸ showed an improved overall survival and relapse-free survival after induction chemotherapy in older patients with AML in CR. This has prompted larger trials using oral azacytidine after ASCT for AML and MDS and the randomized placebo-controlled AMADEUS phase III trial (NCT04173533) is fully recruited and results will be expected soon.

Histone deacetylase inhibitors, such as panobinostat, have been shown to have both direct and immunomodulatory activity. Promising results were reported in the phase I/II PANOBEST trial in 42 patients with high-risk AML or MDS in CR after ASCT with 2-year overall survival (OS) and relapse-free survival are 81% and 75%, respectively. The cumulative incidence of relapse and non-relapse mortality across all dose levels was 20% and 5%.⁹ The confirmatory phase III ETAL-4/HOVON-145 trial (NCT04326764) was prematurely stopped.

Bcl2-inhibitors - venetoclax

Venetoclax has provided a novel backbone for the treatment of AML in a significant proportion of patients with promising CR rates and an excellent safety profile. Following this development, we are now seeing several studies investigating the safety and feasibility of venetoclax with or without the combination with hypomethylating agents after allotransplantation. The main side effect causing some concern in this setting is the marrow suppression with cytopenias complicating dosing.

A trial by Kent et al looking at Venetoclax post-transplant reported 6-month OS and progression-free survival (PFS) of 87% with Venetoclax 400 mg daily for 1 year. However, 11% of patients discontinued due to adverse effects or transplant complications and half required dose interruption and adjustments due to side effects including cytopenias and GI-related side effects.¹⁰ Wei and colleagues reported a 2-year OS of 85.2% and 2-year EFS of 84.7% with venetoclax 200 mg/day and low-dose decitabine in a phase II study in 20 patients.¹¹ The randomized phase 3 VIALE-T trial is currently recruiting (NCT04161885).

IDH inhibitors

The IDH1-inhibitor has received FDA approval in combination with azacytidine for patients >75 years old or unfit for intensive chemotherapy. Enasidenib is approved for IDH2-mutated relapsed or refractory AML. Both drugs have shown a favourable safety profile in relapsed AML and several post-transplant studies are ongoing (NCT03564821, NCT03515512, NCT03728335, NCT04522895).

Fathi et al reported results from a phase I trial of ivosidenib maintenance following ASCT for IDH1-mutated AML. Treatment was initiated between days 30 and 90 and given for up to 12 28-day cycles at a recommended phase 2 dose of 500 mg daily in 16 patients. The 2-year cumulative incidences of relapse and NRM were 19% and 0%, respectively. The 2-year PFS was 81%, and the 2-year OS was 88%, showing safety and tolerability as well as promising PFS and OS in this setting.¹²

Fathi et al also reported results with the IDH2-inhibitor enasidenib post-transplant for 19 patients with IDH2 mutated myeloid malignancies. Two-year PFS and OS were 69% (95% CI: 39-86%) and 74% (95% CI, 44-90%), respectively.¹³

FLT3 inhibitors

FLT3 mutations (FLT3-ITD and FLT3-TKD) are among the most common genetic molecular abnormalities in patients with AML, resulting in uncontrolled proliferation of leukemic blasts.^14,15 There is increasing evidence that measurable residual disease (MRD) predicts an increased risk of relapse after allogeneic stem cell transplantation¹⁶ and there is great interest in approaches to eradicate residual disease post-transplantation with drugs to enhance the GvL effect or with tyrosine kinase inhibitors targeting the FLT3 mutation.

The SORMAIN trial with post-transplant sorafenib maintenance was pivotal in showing a reduced risk of relapse. In this trial, 83 patients were randomized to sorafenib or placebo starting 60 to 100 days post-transplant for 24 months duration or until disease progression or intolerability. The 2-year RFS of 85 % vs 53,3% in the sorafenib and placebo groups, respectively. There was a higher rate of acute and chronic GVHD in the sorafenib group (76.8%) versus the control group (59.8%).⁴ More recent data seem to reproduce these findings in an open-label, randomized phase III trial.⁵ This trial administered sorafenib for a shorter duration than recommended by current consensus guidelines and included exclusively patients aged 18–60 years and myeloablative conditioning regimens.

Midostaurin is approved for first-line treatment of FLT3+ AML and maintenance after chemotherapy. The AML-SG 16–10 and Radius trials looked at the impact of midostaurin as maintenance therapy post-transplant. The RADIUS trial showed that midostaurin could be safely added to standard-of-care after ASCT and improved RFS at 18 months after ASCT. The trial was not powered to detect treatment difference, but showed a trend toward benefit with midostaurin.¹⁷ In the AML-SG 16–10 trial, midostaurin was given during induction chemotherapy and as a 1-year maintenance. Results were compared with a historical cohort of 415 patients treated on 5 prior AMLSG trials and with patients treated on the placebo arm of the Cancer and Leukemia Group B (CALGB) 10603/RATIFY trial. In comparison with historical controls, the addition of midostaurin to intensive therapy led to a significant improvement in outcomes in younger and older patients with AML and FLT3-ITD.¹⁸

Gilteritinib is a novel FLT3-inhibitor and has been approved for the treatment of relapsed and refractory FLT3+ AML. Ongoing trials include maintenance post-induction (NCT04027309). The MORPHO trial studied gilteritinib as post-transplant maintenance for FLT3-ITD.³ Although the trial did not achieve its primary study endpoint of relapse-free survival at the primary analysis, the data prospectively demonstrated a correlation between MRD and survival in post-HCT therapy in FLT3-ITD AML, thus providing important data for the rationale of MRD-guided therapy for these patients. In MRD+ patients pre- or post-transplant 43 out of 91 patients relapsed in the placebo group versus 26 out of 89 patients in the gilteritinib group.

Menin-inhibitors

One of the currently most promising classes of drugs are the menin-inhibitors. These drugs stop the genes affected by altered KMT2A or NPM1 from being expressed and have significant anti-leukaemic activity in these subgroups of AML.¹⁹ In the AUGMENT-101 trial for R/R AML with KMT2A rearrangement, 9 patients resumed revumenib. CRc was maintained in 6 of 9 patients on maintenance. One patient with reported MRD after HSCT converted to MRD-negative status following initiation of revumenib maintenance therapy. Long-term responses, including conversion to MRD-negative status, were seen in heavily pre-treated patients with AML with a safety profile consistent with that previously reported for the AUGMENT-101 study.²⁰

CONCLUSION

There is increasing evidence that transplant outcomes may be improved with the use of post-transplant interventions, including drugs with anti-leukaemic activity or with the ability to enhance the GvL effect. The choice of treatment must be tailored to each patient's disease and transplant characteristics, including the risk of toxicity of drug-drug interactions, active GvHD and/or active infections. Some high-risk mutations with a historically poor prognosis, like FLT3-ITD, have targeted therapy options that may prove valuable in reducing the risk of relapse. This may be true also for KMT2A- and MLL-mutated AML with novel menin-inhibitor.

It seems important to start early, enabling the eradication of remaining leukaemic cells and/or accelerating GVL reconstitution. The duration of maintenance is yet to be determined and the question of monotherapy vs combination therapy is also not clear. Also, the financial burden of adding high-cost treatment after ASCT can be an issue. Patients need to be enrolled in clinical trials whenever possible.

CONFLICT OF INTEREST

Consulting for Arog Pharmaceuticals

FUNDING

None

ACKNOWLEDGEMENTS

None

REFERENCES

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Posted on 1 May 202425 June 2024