MRD Status an Important Prognostic Factor in Pediatric B-Lymphoblastic Leukemia, Study Says

Minimal residual disease (MRD), a measure of how many cancer cells remain in a patient during or following chemotherapy or stem cell transplant, is a potent indicator of whether or not a patient is likely to relapse.

Using a group of 362 out of 437 (75 were lost to death or follow-up) pediatric patients (aged 1-17 years; median age, 6 years) who were treated for B-lymphoblastic leukemia (B-ALL) at Indus Hospital in Pakistan, a group of researchers investigated the associations between MRD status and certain prognostic risk factors after both induction and consolidation. These risk factors covered National Cancer Institute classification, central nervous system (CNS) status, and cytogenetic abnormalities (BCR-ABL1, MLL rearrangement, TEL-AML (ETV6-RUNX1) as detected by fluorescence in situ hybridization (FISH).¹ Their study appeared in a recent issue of Pakistan Journal of Medical Sciences.

MRD is measured 2 ways:

1. Flow cytometry evaluates cell characteristics, usually in bone marrow and the peripheral blood.²
2. Polymerase chain reaction reproduces DNA segments specifically to amplify genetic material for analysis.³

For this study, the authors used flow cytometry because it “has comparatively faster turnaround time, [and is] cost effective and less labor intensive.” So, 35 days after induction, flow cytometry was used to determine MRD status. Consolidation testing at day 52 was only performed if the initial MRD status was positive.

Post induction, 229 (63.3%) patients were MRD negative,⁴ meaning there were no detectable cancer cells in their blood, and 133 (36.7%) were MRD positive. Of the MRD-negative group, 50% (115) were considered “standard-risk” per NCI criteria (age: <10 years; total leukocyte count [TLC], <50,000) and 50%, “high-risk” (age, >10 years; TLC, >50,000). In the MRD-positive group, these numbers came in at 41% (54) and 59% (79), respectively. The CNS results were not statistically significant (P = .807).¹

Post consolidation, 44% (49/111) with residual disease once against tested positive for MRD. however, no significant differences were seen in regard to gender, TLC, and prophase response (P = .05). In children older than 10 years, there were more instances of MRD positivity compared with MRD negativity (39% vs 18%; P = .013). The NCI standard- and high-risk groups, too, had high rates of MRD positivity (45% and 55%, respectively; P = .002).¹

Cytogenetic testing via FISH revealed there was a greater association between MRD negativity and cytogenetic abnormality following induction. For example¹:

1. 63% (169) of patients who were MRD negative had BCR-ABL-negative disease versus 37% (101) of patients who were MRD positive.
2. 58% (115) had TEL-AML-negative disease versus 42% (85), respectively.
3. 64% (172) had MLL-negative disease versus 36% (98)

There were no significant associations between cytogenetic abnormality and MRD status post consolidation.

CNS involvement was “associated with adverse prognostic features.” Still, there was no significant difference in MRD status after induction. The authors posit this is because “CNS disease does not indicate a less chemo-sensitive leukemia.” Post consolidation, however, the difference was significant (P <.05).

So, what was their conclusion? “Studies of MRD considerably enhance the precision of risk assessment, a task of paramount importance in the treatment of childhood ALL,” they wrote.

Still, they recommend further research, using a larger sample size, into how patients respond to chemotherapy agents, because their study had a higher-than normal MRD-positivity group.

References

1. Meraj F, Jabbar N, Nadeem K, Taimoor M, Mansoor N. Minimal residual disease in childhood B lymphoblastic leukemia and its correlation with other risk factors. Pak J Med Sci. 2020;36(1):S20-S26. doi: 10.12669/pjms.36.ICON-Suppl.1721. http://www.pjms.org.pk/index.php/pjms/article/view/1721/348

2. Flow cytometry. ScienceDirect website. sciencedirect.com/topics/neuroscience/flow-cytometry. Accessed January 22, 2020.

3. Polymerase chain reaction (PCR) fact sheet. National Human Genome Research Institute website. genome.gov/about-genomics/fact-sheets/Polymerase-Chain-Reaction-Fact-Sheet. Updated June 16, 2015. Accessed January 22, 2020.

4. Minimal residual disease. Leukemia & Lymphoma Society website. lls.org/sites/default/files/National/USA/Pdf/Publications/FS35_MRD_Final_2019.pdf. Accessed January 22, 2020.