Prognostic significance of minimal residual disease in high risk B-ALL: a report from Children’s Oncology Group study AALL0232

Abstract

• MRD measured by flow cytometry is prognostic in childhood B-ALL even with more effective high-dose methotrexate therapy.• Intensive therapy in MRDpositive patients altered the timing of relapse but did not overcome the poor prognostic significance of MRD.Minimal residual disease (MRD) is highly prognostic in pediatric B-precursor acute lymphoblastic leukemia (B-ALL). In Children's Oncology Group high-risk B-ALL study AALL0232, we investigated MRD in subjects randomized in a 2 3 2 factorial design to receive either highdose methotrexate (HD-MTX) or Capizzi methotrexate (C-MTX) during interim maintenance (IM) or prednisone or dexamethasone during induction. Subjects with end-induction MRD ‡0.1% or those with morphologic slow early response were nonrandomly assigned to receive a second IM and delayed intensification phase. MRD was measured by 6-color flow cytometry in 1 of 2 reference labs, with excellent agreement between the two. Subjects with end-induction MRD <0.01% had a 5-year event-free survival (EFS) of 87% 6 1% vs 74% 6 4% for those with MRD 0.01% to 0.1%; increasing MRD amounts was associated with progressively worse outcome. Subjects converting from MRD positive to negative by end consolidation had a relatively favorable 79% 6 5% 5-year disease-free survival vs 39% 6 7% for those with MRD ‡0.01%. Although HD-MTX was superior to C-MTX, MRD retained prognostic significance in both groups (86% 6 2% vs 58% 6 4% for MRD-negative vs positive C-MTX subjects; 88% 6 2% vs 68% 6 4% for HD-MTX subjects). Intensified therapy given to subjects with MRD >0.1% did not improve either 5-year EFS or overall survival (OS). However, these subjects showed an early relapse rate similar to that seen in MRD-negative ones, with EFS/OS curves for patients with 0.1% to 1% MRD crossing those with 0.01% to 0.1% MRD at 3 and 4 years, thus suggesting that the intensified therapy altered the disease course of MRD-positive subjects. Additional interventions targeted at the MRD-positive group may further improve outcome. This trial was registered at www.clinicaltrials.gov as #NCT00075725. (Blood. 2015;126(8):964-971) IntroductionMinimal residual disease (MRD) is highly predictive of relapse in children, adolescents, and young adults treated for acute lymphoblastic leukemia (ALL). [1][2][3][4][5][6] MRD is typically measured either by assessment of clone-specific markers of immunoglobulin and/or T-cell receptor gene rearrangements using polymerase chain reaction (PCR) or by flow cytometry, taking advantage of the fact that leukemic cells have phenotypes that allow them to be distinguished from normal cells. The Children's Oncology Group (COG) has been assessing MRD by flow cytometry at the end of 4 weeks of induction therapy in subjects with newly diagnosed ALL since 1999, and has previously demonstrated that this is the most powerful predictor of outcome in children, adolescents, and young adults with B-precursor ALL (B-ALL). Because MRD is known to be such a strong prognostic factor, most studies of childhood ALL use this to deter...

Refining risk classification in childhood B acute lymphoblastic leukemia: results of DFCI ALL Consortium Protocol 05-001

“…High levels of minimal residual disease (MRD) at the end of 4 weeks of multiagent induction chemotherapy are associated with an increased risk of subsequent relapse in children with B-ALL. [5][6][7] On Dana-Farber Cancer Institute (DFCI) protocol 05-001, we incorporated end-induction MRD response into risk stratification for patients with Philadelphia chromosome (Ph)-negative (P 2 ) B-ALL, and piloted an intensified regimen for patients with very high risk (VHR) features, defined as high end-induction MRD and/or adverse cytogenetics (KMT2A rearrangements or hypodiploidy). In addition, we assessed the prognostic impact of IKZF1 gene deletion, an abnormality that has been identified in ;15% of Ph 2 childhood B-ALL patients, and is associated with an inferior outcome.…”

Minimal residual disease–guided therapy in childhood acute lymphoblastic leukemia

“…Pediatric oncologists treating children and adolescents with ALL have pioneered the use of MRD to monitor response to treatment, and all major pediatric oncology centers and cooperative groups worldwide now systematically use MRD levels to guide treatment decisions (Table 1). [8][9][10][11][12][13][14][15][16][17][18][19][20] Because precise measurements of MRD have important prognostic and therapeutic implications, it is essential to understand their clinical significance in the context of presenting clinical and biologic features, treatment regimen, and time interval at which MRD is measured.…”

Multimodality Technologies in the Assessment of Hematolymphoid Neoplasms

“…With the development of numerous commercially available antibod-ies, fluorochromes, multilaser flow cytometers, and sophisticated analytic software, it has now become a widely used diagnostic tool in the phenotypic analysis of hematolymphoid neoplasms. [24][25][26][27][28] Flow cytometry has several important strengths over paraffin immunohistochemistry. Major strengths include the ability to analyze the expression of multiple antigens as well as the physical properties (eg, size and cytoplasmic complexity) of individual cells, and to identify normal and abnormal cell populations present in the same specimen simultaneously.…”

“…The potential for flow cytometry to detect minute cell populations has also been used to monitor for minimal residual disease, providing one of the most important predictive markers for early disease relapse and poor treatment outcome in AML, B-ALL, and plasma cell myeloma. 28 The ability of flow cytometry to determine the expression of surface antigens with high accuracy and specificity has facilitated the development of targeted therapy with monoclonal antibodies and chimeric antigen receptor T cells. Examples include rituximab in CD20 þ B-cell lymphomas, the anti-CD33 antibody-drug conjugate gemtuzumab ozogamicin, and the anti-CD123 antibody CSL362 in refractory AMLs; the anti-CD38 antibody daratumumab in plasma cell myeloma; and CD19-chimeric antigen receptor T cells in B-ALLs.…”