In blood cancers, remission is no longer a simple question of whether cancer is present or absent; it can exist at levels too small to see, but still biologically meaningful. Minimal Residual Disease (MRD) exposes microscopic levels of residual cancer cells after treatment, sometimes as few as one malignant cell among a million. This level of sensitivity provides clinicians with insights beyond imaging and routine blood tests, allowing much earlier assessment of relapse risk and treatment effectiveness.
Across leukemia, lymphoma, and myeloma, studies consistently show that achieving MRD-negative status is associated with a lower risk of relapse and longer overall survival. In some settings, MRD-negative patients demonstrate nearly double the long-term survival rates compared with those who remain MRD-positive[1].
In this article we explore how MRD is detected, how it guides treatment decisions across blood cancers, and why linking MRD detection to immune-based strategies may be critical to preventing relapse, particularly after stem cell transplantation, where relapse remains a devastating outcome.
MRD and how it’s Detected
MRD is measured using highly sensitive techniques capable of identifying microscopic numbers of cancer cells based on their proteins, genetic signatures, or circulating DNA fragments. These technologies include multiparameter flow cytometry, next-generation sequencing (NGS), PCR-based molecular assays, and liquid biopsy approaches, each with its distinct strengths depending on the disease context.
Flow cytometry (a laser-based analysis that examines individual cells from blood or bone marrow samples) is particularly effective in acute lymphoblastic leukemia (ALL), where surface antigen patterns are stable, well characterized, and reliably distinguish cancer cells from normal ones. NGS (a method for detecting specific DNA mutations in cancer cells) is particularly well-suited to acute myeloid leukemia (AML), allowing clinicians to track defined mutations such as FLT3-ITD or NPM1 over time. PCR-based testing (which amplifies microscopic amounts of disease-specific DNA so they can be measured) remains the backbone of chronic myeloid leukemia (CML) monitoring, because the disease is driven by a single, well-defined genetic abnormality; this allows clinicians to track changes in disease burden with extraordinary precision over time. Liquid biopsies (minimally invasive blood tests that detect tumor-derived DNA shed into the bloodstream) have emerged over the past decade as a powerful diagnostic approach across hematologic malignancies, offering a less invasive alternative to repeated bone marrow biopsies for longitudinal disease monitoring.
This degree of precision offers clinicians greater confidence in treatment decisions. MRD results can inform whether therapy should be intensified, maintained, modified, paused, or whether a patient should proceed to stem cell transplantation. Patients themselves often describe MRD results as more reassuring and meaningful than imaging, because MRD confirms remission at a molecular level, not just a visual one[1, 2].
MRD as a Treatment Compass
In ALL, MRD does more than predict outcomes: it actively directs therapy. This is because decades of clinical data have established that low levels of MRD are strongly predictive of relapse in ALL, making early intervention both necessary and clinically meaningful. Consistent with this strong prognostic value, the immunotherapy blinatumomab is approved for individuals with ALL who are in remission but remain MRD-positive, targeting residual disease before overt clinical relapse occurs. In clinical studies, blinatumomab has been shown to eliminate detectable MRD in approximately 78% of treated individuals and has been associated with significant improvements in relapse-free survival[1]. Despite these advances, however, relapse remains a significant challenge, particularly in settings of compromised immune function, and because eliminating detectable MRD does not necessarily address the underlying biology that drives disease recurrence.
AML illustrates a different, but equally important, application of MRD. Rather than directing a specific therapy, post-treatment MRD status plays a central role in risk stratification, helping determine whether stem cell transplantation (SCT) is warranted and how intensive conditioning should be. Persistent MRD after treatment signals a higher risk of relapse and may justify more aggressive transplant-based approaches, whereas MRD negativity can support less invasive strategies. Following SCT, continued MRD monitoring enables earlier detection of molecular relapse and creates opportunity for pre-emptive intervention[2]. However, even with MRD-guided risk stratification, relapse remains common in AML, reflecting the limitations of transplant-based strategies and the persistence of the disease beyond current detection thresholds.
In multiple myeloma, MRD assessment is beginning to change long-term treatment strategies, with MRD negativity opening up the possibility of treatment de-escalation in selected settings. Several trials showing prolonged remission even when the therapy is reduced or paused[1]. By contrast, chronic lymphocytic leukemia (CLL) illustrates the limits of MRD as a universal marker: some therapies improve survival without achieving MRD negativity, underscoring that while MRD is a powerful tool, it must be interpreted in the context of disease biology and the treatment mechanism rather than applied uniformly across all blood cancers[1].
Why MRD Matters More in Blood Cancers
Blood cancers are unique because the malignant cells originate from the immune system itself. This creates a distinct biological challenge: immune cells must recognize and eliminate a mutated version of themselves. Many hematologic malignancies exploit immune checkpoints to survive, suppressing T-cell activity through inhibitory receptors such as PD-1 and Tim-3. In AML, exhausted T cells are particularly enriched in the bone marrow, where their function is further dampened by a local microenvironment that limits nutrient availability, increases inhibitory signaling, and favors leukemia survival over immune activation[3].
The tumor microenvironment (referring, in blood cancers, to the bone marrow and surrounding cellular niches) adds another layer of protection. For instance, in multiple myeloma, cancer-associated fibroblasts form a physical and biochemical barrier around malignant cells, releasing factors that impair immune function, including the activity of CAR-T cells (T cells collected from the patient and genetically engineered in the lab to target cancer cells). These mechanisms help explain why relapse can occur, even in patients who initially respond well to treatment[4].
Stem Cell Transplantation and the Power of Donor Immunity
SCT adds a critical immune dimension to MRD-guided cancer care. Beyond the initial reduction of cancer cell burden through chemotherapy or conditioning regimens, allogeneic SCT introduces donor immune cells capable of recognizing and eliminating residual malignant cells through a process known as graft-versus-leukemia (GvL) effect, the most effective path to long-term remission. MRD monitoring is central in this context, enabling detection of residual or re-emerging disease at the molecular level, often well before clinical relapse becomes apparent, and creating a window for proactive intervention.
Donor lymphocyte infusion (DLI) exemplifies MRD-guided immune modulation. In chronic myeloid leukemia (CML), DLI has successfully restored remission and MRD negativity following post-transplant relapse by reactivating donor immune responses. Similar strategies are being explored across other hematologic malignancies, although their effectiveness varies depending on disease biology and immune context.
At the same time, significant effort is focused on preserving the beneficial GvL effect while minimizing graft-versus host disease (GvHD), a complication in which donor immune cells attack the recipient’s own tissues. Approaches under investigation include regulatory T-cell (Treg) infusion, targeted modulation of immune signaling pathways, and refinement of conditioning regimens. In each case, MRD serves as a critical tool to guide timing, intensity, and patient selection for these interventions[5, 6].
The Challenge of Post-Transplant Relapse
Despite these advances in transplantation and MRD-guided monitoring, relapse after SCT remains one of the most difficult challenges in blood cancer care. Outcomes following post-transplant relapse of hematological malignancies are often dismal, and therapeutic options are limited.
This reflects the complex biology of relapse in the post-transplant setting. Residual malignant cells may persist below detection thresholds, evade immune surveillance, or exploit immunosuppressive microenvironments. At the same time, donor immune function can be compromised by exhaustion, prior therapies, or ongoing immunosuppression. Together, these factors limit the durability of existing strategies and underscore the need for approaches that go beyond chemotherapy and conventional targeted inhibitors.
LEUMUNA: Connecting MRD Detection to Immune Activation
LEUMUNA™ (ulodesine hemiglutarate, LR 09) is an oral metabolic immune checkpoint modulator in development by Helix BioPharma for patients who relapse with acute leukemia after allogeneic SCT. By inhibiting purine nucleoside phosphorylase (PNP), an enzyme responsible for the breakdown of guanosine (a naturally occurring building block of RNA), LEUMUNA increases the availability of guanosine within the immune environment and functionally enhances signaling through Toll-like receptor 7 (TLR7), an innate immune sensor that initiates inflammatory signaling and helps mobilize donor immune cells against residual leukemia. This activation promotes cytokine production and triggers a GvL response in the post-transplant setting.
Importantly, this mechanism is designed to address relapse, not simply minimal residual disease. Rather than acting through direct cytotoxicity or by targeting a specific leukemia antigen or mutation, LEUMUNA leverages innate immune sensing to engage donor-derived immune responses in settings where immune surveillance has failed and relapse has occurred. The mechanism builds on clinical experience with earlier PNP inhibitors like forodesine, which produced complete remissions in some post-transplant relapsed T-ALL patients[7]. In mouse models of B-cell ALL relapse conducted at the Fred Hutchinson Cancer Center, LEUMUNA has been shown to significantly reduce the risk of leukemia-related death by enhancing GvL activity, with no statistically significant increase in GvHD-associated death.
Looking Forward
MRD is redefining how remission is measured, how relapse risk is understood, and how therapy is timed across blood cancers. When combined with advances in immunology and transplantation science, MRD is helping shift care away from one-size-fits-all approaches toward treatment strategies that are increasingly informed by disease biology, immune context, and risk dynamics. The future of blood cancer care will integrate MRD testing, targeted therapies, immunotherapy, transplantation, and metabolic modulation into more coherent treatment pathways guided by disease biology and immune dynamics.
At Helix, our mission is to help accelerate this evolution. By advancing such as LEUMUNA and contributing to the scientific understanding of MRD-guided immune activation, we aim to expand options for patients facing post-transplant relapse, a setting where unmet need remains profound. Through continued research, collaboration, and engagement with the scientific community, we remain committed to supporting longer survival, deeper disease control, and more durable immune recovery.
References:
1. Chandhok NS, Sekeres MA. Measurable residual disease in hematologic malignancies: a biomarker in search of a standard. EClinicalMedicine. 2025 Jul 10;86:103348. doi: 10.1016/j.eclinm.2025.103348. PMID: 40666170; PMCID: PMC12257026.
2. Ngai LL, Kelder A, Janssen JJWM, Ossenkoppele GJ, Cloos J. MRD Tailored Therapy in AML: What We Have Learned So Far. Front Oncol. 2021;10:603636. Published 2021 Jan 15. doi:10.3389/fonc.2020.603636
3. Tan J, Yu Z, Huang J, Chen Y, Huang S, Yao D, Xu L, Lu Y, Chen S, Li Y. Increased PD-1+Tim-3+ exhausted T cells in bone marrow may influence the clinical outcome of patients with AML. Biomark Res. 2020 Feb 13;8:6. doi: 10.1186/s40364-020-0185-8. PMID: 32082573; PMCID: PMC7020501.
4. Duan J, Wang Y, Jiao S. Checkpoint blockade-based immunotherapy in the context of tumor microenvironment: Opportunities and challenges. Cancer Med. 2018 Sep;7(9):4517-4529. doi: 10.1002/cam4.1722. Epub 2018 Aug 7. PMID: 30088347; PMCID: PMC6144152.
5. Biernacki MA, Sheth VS, Bleakley M. T cell optimization for graft-versus-leukemia responses. JCI Insight. 2020 May 7;5(9):e134939. doi: 10.1172/jci.insight.134939. PMID: 32376800; PMCID: PMC7253012.
6. Pacini CP, Soares MVD, Lacerda JF. The impact of regulatory T cells on the graft-versus-leukemia effect. Front Immunol. 2024;15:1339318. Published 2024 Apr 22. doi:10.3389/fimmu.2024.1339318
7. Balakrishnan K, Verma D, O’Brien S, Kilpatrick JM, Chen Y, Tyler BF, Bickel S, Bantia S, Keating MJ, Kantarjian H, Gandhi V, Ravandi F. Phase 2 and pharmacodynamic study of oral forodesine in patients with advanced, fludarabine-treated chronic lymphocytic leukemia. Blood. 2010 Aug 12;116(6):886-92. doi: 10.1182/blood-2010-02-272039. Epub 2010 Apr 28. PMID: 20427701; PMCID: PMC2924226.