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MRD in ALL
The Importance of MRD Testing in Acute Lymphoblastic Leukemia

Released: July 27, 2018

Expiration: July 26, 2019

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MRD is a Prognostic Indicator in ALL at CR
Acute lymphoblastic leukemia (ALL) can have a high remission rate of ~90% in adult patients.  However, the long-term outcome is less encouraging, with an overall long-term survival of 40-50%, showing that approximately 50% of patients relapse over time. Several studies have shown the persistence of minimal residual disease, or measurable residual disease (MRD) as it is now called, in patients with ALL in CR. These patients have a high risk of relapse and a poor outcome.  Clinicians used to assess MRD at different time points and adjust the treatment accordingly, which is a model of therapy for pediatric ALL. Today, in adult ALL, assessing for MRD at CR at the end of treatment is becoming a standard of care.

In a meta-analysis by Berry and colleagues in 2017, more than 11,000 pediatric and adult patients with ALL were assessed for MRD.  The meta-analysis showed that patients with persistent MRD had a poor outcome, regardless of testing method.  These patients had a median survival rate of approximately 1 year, compared to 3, 4, or 5 years for patients who are MRD-negative. The meta-analysis has established that the presence of MRD is indicative of disease refractiveness and therefore, poor outcome.

How to Measure MRD
We measure minimal disease by different methods. European clinicians primarily use PCR, reviewing immunoglobulin rearrangement for B-cell and T-cell receptors. It’s a laborious task, but it’s quite sensitive(10-4–10-5). In the US, we assess for MRD by 6- or 8-color flow cytometry, examining the phenotype and cluster differentiation markers on the cells. The sensitivity is 10-3–10-4.  Now, clinicians are also using next-generation sequencing (NGS), where every cell has what you call a barcode targeting the immunoglobulin chain rearrangement in B-cells. This provides greater sensitivity in detecting MRD (10-6) than flow cytometry or PCR, allowing us to better identify good responders from patients who are not responding as well.

Outcomes in Patients with ALL
As an example, let us consider a patient with persistent residual disease in ALL. What is the outcome? As I mentioned, on average, these patients survive one year or less. Recently, the only treatment option for these patients was to consider bone marrow transplantation (HSCT). This can improve the outcome compared to standard chemotherapy but not to the level of patients who are MRD-negative. For example, there was a study by PETHEMA in Spain where they first performed bone marrow transplantation on patients who have persistent measurable disease. Those who achieved MRD negativity received standard chemotherapy. The results showed that the outcomes with HSCT are not as good as for patients who have MRD negativity, which tells us that MRD stands as one of the most important factors predicting the long-term outcome of patients with ALL. Currently, there are two elements that are crucial for gauging the long-term outcome in patients with ALL. First, the disease biology at baseline (eg, certain gene deletions and abnormalities), and second, the persistence of measurable disease.

What’s Changing?
There was a small study by Topp and colleagues which treated patients with MRD-positive ALL with blinatumomab and showed that 80% of these patients converted to MRD negativity followed by HSCT. There were some outliers in the study who did not undergo HSCT and still had a good outcome. In the phase 2 BLAST trial by Gökbuget and colleagues, 116 patients in first year of CR or beyond who were MRD positive (defined by PCR at 10-3–10-4) were given blinatumomab therapy of one cycle (4 wks on, 2 wks off blinatumomab 15 μg/m2/day IV). Patients who achieved MRD negativity underwent HSCT or received subsequent therapy of up to 4 cycles of blinatumomab. The rate of conversion to MRD negativity (defined by PCR at 10-4) was 78%.  Median survival for patients who responded was 38.9 months compared with 12.5 months for non-responders. The researchers also did propensity score matching of blinatumomab versus HSCT and showed that the blinatumomab arm suggested better outcomes. Based on these data, the FDA granted an approval for blinatumomab for patients with MRD-positive ALL.

Topp and colleagues presented long-term follow-up data at ASCO 2018 on blinatumomab followed by transplantation in responding patients with relapsed/refractory or MRD-positive ALL. The MRD-positive group had superior outcomes, including median OS of 37 months (vs 20 months in relapsed/refractory patients), with even better outcomes for patients who are younger than 35 years of age and/or who responded after Cycle 1 (median OS not reached).

The Future of Detecting and Treating Patients with MRD
The question now is: Do we continue to perform HSCT moving forward? With the data currently available, the answer is unclear. Studies are needed to address the question of whether HSCT is needed for patients who receive blinatumomab and become MRD negative. As to the best tool to assess MRD and at what time point the testing should be done, we need more sensitive techniques, but I suspect that NGS will become the standard of care.  We must rely on MRD and the baseline disease biology to predict outcomes in our patients. The FDA is accepting MRD as an endpoint for studies in leukemias. Testing for MRD, having effective treatments available, and going beyond the traditional factors of white cell count and patient age are all critical to improving outcomes for our patients.

Key Take Home Points
I have 3 key take-home messages for MRD in ALL: first, it is essential to assess for MRD in our patients.  Second, patients with MRD positivity have refractory disease, even though the timepoint is debatable. These patients should not undergo HSCT in this setting.  Finally, if MRD positivity is identified at CR or at least at 3 months, patients should receive blinatumomab, which is the only effective treatment available for these patients, followed by HSCT.

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In your clinical practice, do you routinely test for MRD in patients in CR?
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