Minimal Residual Disease in Adult ALL

As part of a multidisciplinary team education project on acute lymphocytic leukemia (ALL), ACCC recently released an environmental scan that provides an overview of the current landscape for ALL diagnosis and treatment, along with potential opportunities to improve care for this patient population. In this second post in a three-part series, guest blogger Michael J. Borowitz, MD, PhD, provides an update on the role of minimal residual disease (MRD) in caring for adult patients with ALL (also known as acute lymphoblastic leukemia).

Minimal residual disease (MRD) refers to the presence of leukemic cells below the threshold of detection conventional morphologic methods allow. It has been known for at least three decades that patients with MRD following therapy for acute lymphoblastic leukemia (ALL) are at greater risk for relapse than those patients for whom the disease clears more rapidly.  Because of the prevalence in ALL in childhood, and because there have been large scale clinical trials of ALL both in the U.S. and internationally, it quickly became established that MRD was the most important prognostic factor to predict relapse; assessing MRD is now generally considered standard of care in childhood ALL and is used to assign patients to the most appropriate risk groups for therapy.

Although MRD is also prognostic in adult ALL, fewer studies have been done, and there is less consensus about its importance when compared to pediatric ALL.  A recent survey looked at the rate of MRD testing among oncologists treating adult patients with ALL compared to that of oncologists treating pediatric patients with ALL. While pediatric oncologists surveyed reported 93% of patients received MRD testing, oncologists who treated adults with ALL reported testing 73% of patients. Moreover, in community settings only 67% of adult patients received MRD testing.¹  The survey also revealed that in pediatric patients assessment of MRD was more consistently measured at specific timepoints and was used to inform therapy, while for the adult patient population there was less consensus about the best time to measure MRD and on what actions to take.

Several prospective studies, mostly coming out of Europe, have not only shown the prognostic importance of MRD in adult ALL, but also have incorporated results from these measurements to assign patients to therapy.² Because of the high frequency of Philadelphia chromosome positive (Ph+) ALL in adults, and because of the unique responsiveness of Ph+ ALL to tyrosine kinase inhibitor therapy, Ph+ and Ph- ALL are managed differently. In Ph+ ALL, MRD monitoring is much more consistently a part of standard of care, no doubt because of the long-term practice of monitoring MRD in chronic myeloid leukemia (CML), which shares the same distinctive cytogenetic abnormality.

Because of the poor outcome in patients with MRD, many studies have used MRD positivity as a criterion to take patients to allogeneic hematopoietic stem cell transplantation (HSCT). Conversely, because of the toxicity of allogeneic HSCT, patients with “good risk” clinical characteristics who remain MRD negative are often continued on conventional chemotherapy (or in the case of Ph+ ALL, on tyrosine kinase inhibitor therapy).  MRD measurement to determine transplant is becoming increasingly popular with the advent of so-called “pediatric-type” chemotherapy regimens used in treatment of younger adult patients up to about age 39.  Patients who become MRD negative with these regimens have particularly good outcomes and so potentially more patients can be spared transplant. However as patients get older, these therapies become more toxic and are rarely used; because conventional therapies are not as effective, MRD negativity is less common and isn’t typically used to help guide transplant decisions.  

Recently, however, the availability of immunologic therapies, most notably the bispecific T-cell-engaging anti-CD19 antibody blinatumomab, has led to a growth in the use of MRD measurement for treatment decisions in ALL.  Compared to HSCT, this therapy is relatively less toxic, and both relapsed/refractory patients and those who are MRD-positive can achieve MRD-negativity with this immunotherapy. Many trials now in progress incorporate routine measurements of MRD and use testing results to assign patients to treatment with blinatumomab. Recent National Comprehensive Cancer Center (NCCN) guidelines for ALL state that MRD data can be used to select therapies including blinatumomab for adults of different ages, and separately for patients with Ph+ and Ph- ALL.³

However, still missing from these guidelines and from any broad consensus are clear recommendations on:

• when during treatment MRD should be measured,
• the level of MRD that should be used to define intervention, and
• the optimal method for measuring MRD.
  

While these issues are specified in many clinical trials, extrapolating this information to patients treated off-trial is not always easy.  Broadly speaking, however, it is becoming increasingly clear that after the intensive early phases of chemotherapy, patients who remain MRD positive at a level of at least 1/10000 cells by any method of measurement should be managed differently from those who are MRD negative.  In addition, although consensus criteria for so-called “MRD relapse” are not yet defined, patients who become MRD positive after having been in remission also fare poorly and might benefit from intervention.

References

1. Kim C, Delaney K, McNamara M, Romanov V. Cross-sectional physician survey on the use of minimal residual disease testing in the management of pediatric and adult patients with acute lymphoblastic leukemia. Hematol. 2019;(24)1:70-78.

    

2. Bassan R, Intermesoli T, Scattolin A, et al. Minimal residual disease assessment and risk-based therapy in acute lymphoblastic leukemia. Clin Lymphoma Myeloma Leuk. 2017;17:S1,S2-9.

    

3. National Comprehensive Cancer Network. NCCN guideline with evidence blocks. Acute Lymphoblastic Leukemia. Last accessed January 2019.