MRD in Ph+ ALL: How Do You Measure It and What Does It Mean?

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The outcomes of patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) have substantially improved over the past decade. This has been driven largely by the use of later-generation BCR-ABL1 tyrosine kinase inhibitors (TKIs) such as ponatinib (Iclusig; Takeda),¹ and more recently, the use of chemotherapy-free combination regimens with blinatumomab (Blincyto®; Amgen) plus a TKI.^2,3 These newer Ph+ ALL regimens are able to achieve rapid and deep reduction in disease burden, reflected by high rates of early measurable residual disease (MRD) negativity. Although it is well-established that MRD negativity plays an important prognostic role in Ph+ ALL, the optimal method to assess MRD in this disease and how to use this information therapeutically are still being established.

Methods to Assess MRD in Ph+ ALL

MRD is highly prognostic in ALL, as has been shown in dozens of studies and confirmed in a large meta-analysis.⁴ In B-cell ALL, blinatumomab achieves high rates of MRD negativity and is approved for the treatment of MRD-positive disease, highlighting the therapeutic importance of MRD in ALL.⁵ Common methods to assess MRD in ALL include multiparameter flow cytometry (usually reserved for Ph-negative ALL), polymerase chain reaction (PCR) for immunoglobulin (IG) or T-cell receptor (TR) gene rearrangements (used in some European countries but not in the US), PCR for BCR::ABL1 (for patients with Ph+ ALL), and next-generation sequencing (NGS) for IG/TR.⁶

Prognostic Importance of MRD in Ph+ ALL

Several studies have shown that achievement of a complete molecular response (CMR), ie, absence of detectable and/or quantifiable BCR::ABL1 transcripts by PCR, is associated with superior outcomes in Ph+ ALL. In one study of 85 patients with Ph+ ALL treated with hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) plus a TKI who did not undergo allogeneic stem cell transplantation (SCT) in first remission, patients who achieved a CMR by 3 months had a 4-year overall survival (OS) rate of 66% vs 36% for those with lesser responses (P=.0009).⁷ Importantly, achievement of CMR at 3 months was the only variable that was prognostic for OS on a multivariate analysis. In a subsequent analysis of 84 patients who achieved CMR at 3 months with frontline therapy, patients who received ponatinib had superior survival compared with those who received first- or second-generation TKIs (5-year OS 84% vs 60%-65%, respectively).⁸ This analysis suggests that not only is the depth of response important in Ph+ ALL but also the therapy used to achieve this response.

MRD Assessment in Ph+ ALL Can Inform Therapeutic Decision-Making

Although historically Ph+ ALL was considered a poor-risk subtype of leukemia that required intensive chemotherapy and allogeneic SCT for all eligible patients, relatively favorable outcomes can now be achieved in patients who do not undergo SCT in first remission, particularly when optimal frontline therapy is given using a potent TKI such as ponatinib. In a subgroup analysis of a study of hyper-CVAD plus ponatinib for patients with newly diagnosed Ph+ ALL, patients who achieved a CMR and did not undergo SCT in first remission had a 6-year OS rate of 87% in a landmark analysis.⁹ A recent retrospective, propensity score analysis of patients with Ph+ ALL who achieved CMR within 3 months showed that although allogeneic SCT was associated with a lower risk of relapse, this was counterbalanced by a higher risk of nonrelapse mortality; allogeneic SCT therefore did not have a significant impact on either relapse-free survival or OS.¹⁰ These studies highlight the emerging data suggesting that allogeneic SCT can be safely deferred for most patients with Ph+ ALL treated in the modern era.

Is PCR for BCR:: ABL1 the Optimal MRD Assay in Ph+ ALL?

Although PCR for BCR::ABL1 historically has been used to assess MRD in Ph+ ALL, PCR or NGS for IG/TR may be more sensitive and specific for MRD in this ALL subtype. Several studies have reported discordance between MRD assessed by PCR for BCR::ABL1 and by PCR or NGS for IG/TR, most commonly in the context of detectable BCR::ABL1 by PCR but MRD negativity by assays for IG/TR rearrangements.^11-14 This phenomenon has been described in both p190 and p210 BCR::ABL1 transcripts, although may be more common in those with p190 Ph+ ALL, thus distinguishing it from chronic myeloid leukemia (CML) in lymphoid blast phase. In one study, 23% of children with Ph+ ALL had detectable BCR::ABL1 by PCR but were MRD negative by PCR for IG/TR.¹² Cell sorting assays showed that in concordant cases (ie, patients who were MRD positive by both PCR assays), only the ALL blasts had detectable BCR::ABL1. However, in discordant cases, the BCR::ABL1 transcripts were detectable in the nonblast population, representing a CML-like biology distinct from both typical Ph+ ALL and CML in lymphoid blast phase. Although more data are needed, initial data suggest that the long-term survival of these 2 entities is similar.¹³

Next-Generation Sequencing-Based MRD in Ph+ ALL

More recently, NGS-based MRD for IG/TR has been increasingly used in clinical practice for prognostication in ALL. This MRD assay can achieve sensitivity of 1×10^–6 (1 to 2 logs deeper than standard flow cytometry or PCR assays) and can further risk stratify patients with ALL.^15-17 Most studies using this assay have been conducted in patients with Ph-negative ALL, where the NGS-based MRD assay has consistently outperformed conventional flow cytometry assays, though data in Ph+ ALL are relatively scant. In one retrospective analysis of patients with Ph+ ALL, MRD assessed by PCR for BCR::ABL1 and NGS for IG/TR were compared.¹⁴ Approximately one-third of patients had discordance between these 2 assays, and overall 15% to 30% of patients who achieved MRD negativity by the NGS MRD assay still had persistent low-level detectable BCR::ABL1 by PCR. Importantly, among those who were MRD negative by the NGS assay, PCR for BCR::ABL1 did not impact outcomes, and the 5-year OS for patients who were MRD positive by PCR but MRD negative by NGS was 94%. Thus, NGS-based MRD appears to identify patients with low-level detectable BCR::ABL1 who have a very low risk of relapse and who are unlikely to benefit from additional therapeutic interventions. Further studies are needed to validate these findings and to inform how to use both PCR for BCR::ABL1 and NGS for IG/TR in the treatment of patients with Ph+ ALL.

Unanswered Questions and Future Directions

Assessment of MRD is a fundamental component of ALL therapy, both informing prognosis and guiding therapeutic decision-making. With more potent TKI combinations, high rates of MRD negativity can be achieved in Ph+ ALL. These advances have transformed Ph+ ALL from one of the deadliest subtypes of ALL to one that can now be treated with chemotherapy-free regimens and without the need for allogeneic SCT for patients who rapidly achieve MRD negativity. Although significant progress has been made in the field of Ph+ ALL, several questions remain regarding how to use MRD information therapeutically in this disease. Early data suggest that NGS-based MRD for IG/TR may outperform conventional PCR for BCR::ABL1, but more studies are needed to confirm these findings. Furthermore, it remains uncertain whether patients with CML-like biology (ie, those who have detectable BCR::ABL1 by PCR despite achieving MRD negativity by other assays) have different outcomes than those with typical Ph+ ALL or whether they should be treated differently. For example, do these non-ALL clones harboring BCR::ABL1 have leukemogenic potential (and thus requiring indefinite TKI therapy)? Future studies are needed to address these important questions so that we can continue to optimize therapy and cure more patients with Ph+ ALL, while sparing patients the potential toxicity of both allogeneic SCT and long-term TKI therapy.

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