Dr Luger Shares Refined Prognosis and Detection Methods of MRD in ALL

Selina Luger, MD, FRCPC, Professor of Medicine, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania, presented updates of measurable residual disease (MRD) in acute lymphoblastic leukemia (ALL) as a viable assessment indicator of disease outcomes during the virtual Great Debates & Updates in Hematologic Malignancies.

Dr Luger clarified that MRD was once referred to as minimal residual disease, as there is no morphologic evidence of disease. However, there must be a present measurable disease during testing with different modalities and various sensitivities. 

Nonquantifiable and non-detectable MRD in ALL are situated below 0.0001% and substantially lower at 0.0000001%, respectively.

“We know that MRD in ALL is an important prognostic indicator of outcome that was shown in pediatrics for many years, but we now know this to be true in adults as well. It can be used to define the intensity of post-remission treatment. It can be combined with genotypic and immunophenotypic data to refine prognosis. And it can be useful for evaluation of novel targeted therapies,” Dr Luger said.

In prognosis, survival is decreased in patients with MRD. A metanalyses in pediatric and adult patients with ALL demonstrates that those who are negative for MRD have a significantly improved survival rate in comparison to those with any detectable evidence of MRD, regardless of methodology, the period at which it is observed, or subgroup testing. 

Dr Luger shared results of the Intergroup C10403 Pediatric Inspired Trial in Adolescent and Young Adults, where investigators evaluated MRD as a prognostic indicator to learn that young patients who were MRD positive had an event-free survival (EFS) rate of 35% versus substantially increased outcomes in those who were MRD negative with an EFS rate of 80%.

Outcomes in MRD as favorable versus unfavorable in AYA and adults have been evaluated in a multitude of trials in both Europe and the United States within the past decade. 

“When looking at the different responses in those who are MRD undetectable versus detectable, we can see that in the GRAAL trial, 5-year relapse was 23-30% vs 60%, in the GMALL trial overall survival was 83% vs 68%, and so forth. Every trial shows a benefit in those who are MRD negative or undetectable versus those with detectable MRD,” Dr. Luger continued.

Dr Luger presented an additional metanalyses to observe MRD relapse and complete remission (CR) rates and showed that those who are MRD positive have a significantly higher relapse rate and CR duration than those who are MRD negative. 

Survival by MRD can be looked at during various times, specifically at day 14 of induction, she said. According to a trial led by Dr Josep Maria Ribera and published in Blood Advances in 2021, patients with lower MRD levels or who are negative have an overall improved survival. Patients with MRD levels <0.01% after 2 weeks, at the end of induction, and at the end of early consolidation have outstanding outcomes.

When making treatment decisions based on MRD, Dr Luger advised that stem cell transplant (SCT) in first remission is beneficial for poor MRD responders, as supported by data from the GRAAL trial.

For those with high-risk, Ph-negative ALL, findings from Dr Ribera further explain that patients who were allocated to hematopoietic stem cell transplantation (HSCT) based on their high-risk and MRD status would receive lower MRD statuses with time and induction cycles.

Clinical data demonstrates that MRD status prior to transplant was high for 74% of patients at day 14, and 23% had a higher level versus 64% who expressed a low level at day 35. Just 2% had a high MRD status by the end of the trial. 
Regardless of whether patients had a high MRD level or transplant, their relapse and survival rates were similar.

As for MRD and novel therapies, Dr Luger shared results from the BLAST trial, which was a phase 2, open-label, single-arm study of adults with ALL that remained MRD positive after treatment with standard chemotherapy. Eligible patients had to be in hematologic CR but with MRD (>10-3) despite a minimum of 3 blocks of intensive chemotherapy.

The primary end point of the trial was complete MRD response status after 1 cycle. The study enrolled 116 patients with a median age of 45. They received up to 4 cycles of blinatumomab, cIV infusion, and MRD assessment with eligibility to receive HSCT after at least 1 treatment cycle. The outcome was 2-year efficacy with a 5-year survival follow up. 

Based on clinical data from the BLAST study presented by Nicola Gökbuget, MD, after 1 cycle of treatment, 78% of patients became MRD negative. After cycle 2, 80% were MRD negative. This response was seen regardless of the type of patient that went into transplant. 

“More recently, there’s been interest in combining chemotherapy and immunotherapy and seeing whether or not early use of drugs that are known to decrease MRD will improve outcomes. Clinical trials seek to answer if an addition of immune targeted agents eradicate MRD and improve EFS and OS,” Dr Luger continued.

Trials, such as ECOG 1910, investigated standard ALL therapy and treated patients who were MRD negative and gave them blinatumomab in addition to consolidation therapy after cycle 3. 

The most recent and ongoing study, the phase III Alliance Trial, evaluates post-induction status and randomizes patients with or without inotuzumab to observe MRD eradication and improvements in outcome, which leads to C10403 consolidation and maintenance. 

Dr Luger said that the most recent Ph-positive ALL ongoing study in the United States Intergroup is piloted and open with patients randomized to either TKI and steroids plus blinatumomab or TKI and steroids plus chemotherapy. Based on MRD statuses after 2 cycles, patients will either continue therapy or be crossed over to an alternate maintenance therapy.

“There are multiple MRD testing techniques that can be used. In the US, we typically use flow cytometry (FC) with a sensitivity range of 10-4 to 10-5, its reproducibility varies amongst labs, it is widely available, and requires a first pull bone marrow sample,” Dr Luger said.

Other ALL MRD testing methods include polymerase chain reaction (PCR) using allele-specific oligonucleotides in ASO-PCR with a sensitivity range of 10-5 to 10-6. This testing method has high reproducibility; however, it is not widely available in the US and can potentially be done on blood MRD tests. Next generation sequencing shows potential with sensitivity at 10-6, high reproducibility, commercial availability, and can be performed on blood.

There are 2 methods of observing MRD in Ph-positive ALL, whether MRD in CML measured routinely by Major-BCR/ABL1 transcript quantification or MRD in ALL observing lymphoblasts that are measured by DNA based Ig/TCR rearrangements.

Dr Luger provided a correlative assessment of BCR ABL and Ig TCR MRD that showed 18% of patient samples will remain BCR ABL positive even when their results of PCR are negative. This means that not all BCR ABL positive ALL are the same.

In terms of which type of MRD should be used for ALL treatment stratification, Dr Luger highlighted four viable options. In BCR-ABLnegc/pre-B-ALL, FC or PCR have been used, both are useful for chemotherapy, however FC may be incompatible with immunotherapy when observing targeted agents as flow markers. 

In T-cell acute ALL, FC is less sensitive than PCR, but PCR is not always applicable and both methods are needed for complete coverage. For KMT2A-rearranged B-cell precursor (BCP) ALL, FC characterizes target antigen expression, but KMT2A-RQ-PCR is more sensitive. With BCR-ABLpos ALL, the BCR-ABL can be analyzed, but if it is positive in the setting of B-cell directed therapy, additional PCR or FC is recommended.

“In the cumulative incidence of relapse according to 4-gene signature and MRD, those who have both positive +gen/+MRD have a higher rate of relapse in comparison to patients with both -gen/-MRD,” Dr Luger continued.
Further, in pediatric ALL, relapse was correlated with MRD kinetics at the speed at which the patient decreases their MRD status influences the likelihood of relapse. 

“MRD is an important prognostic indicator in ALL. MRD technique and timing lead to different outcomes and interpretations. A very early assessment at day 15 will show in almost all samples as positive using conventional MRD methods. Later MRD assessment requires robustness, specificity, and speed,” Dr Luger said.

Dr Luger concluded that blinatumomab is the first drug approved for eradication of MRD in ALL and durable molecular remissions can be achieved with and perhaps without transplant. 

Immune targeting to eradicate MRD is now a focus of frontline combination trails in ALL, she said. 

New MRD detection methods, such as next generation high throughput sequencing, will increase sensitivity. Essentially, combining molecular and genetic features further refines prognostic ability and provides interesting insights into disease kinetics, Dr Luger concluded.—Alexa Stoia