Minimal residual disease–guided therapy in childhood acute lymphoblastic leukemia

Abstract

A 3-year-old boy presented with a leukocyte count of 5.9 3 10 9 /L and was found to have near-haploid B-lineage acute lymphoblastic leukemia (ALL) with a 27, X, 1Y, 113, 118, 121 karyotype. He was enrolled in the St. Jude Children's Research Hospital Total Therapy XV study. After 19 days of remission induction therapy with 1 high dose of methotrexate, 14 days of prednisone, 2 doses of vincristine and daunorubicin, and 6 doses of Escherichia coli-derived asparaginase, flow cytometry examination of his bone marrow revealed the presence of minimal residual disease (MRD) amounting to 3 leukemic cells per 10 000 mononucleated cells (0.03%). Upon completion of the remaining remission induction therapy consisting of 1 dose of cyclophosphamide, 14 days of mercaptopurine, and 8 onceper-day doses of cytarabine, he attained a morphologic remission on day 46, with undetectable (,0.01%) MRD by flow cytometry and polymerase chain reaction. Because of the near-haploid ALL karyotype and negative day 46 MRD, he was assigned to receive intensive chemotherapy for 3 years. MRD remained undetectable throughout treatment. He has remained in continuous complete remission for 11.6 years. Case 2A 9-year-old boy presented with a 3-month history of progressive pallor and upper respiratory tract infection. He had no hepatosplenomegaly or mediastinal mass. An abnormal blood count with hemoglobin 3.4 g/dL, leukocytes 4.2 3 10 9 /L with 15% neutrophils, 52% lymphocytes, 33% blasts, and platelets 123 3 10 9 /L prompted a bone marrow examination which disclosed 96% replacement with leukemic lymphoblasts. By flow cytometry, the blasts expressed CD45, surface CD3, CD2, CD7, T-cell receptor g/d, CD11b, and CD13, with a subset of cells positive for CD56, a cell profile indicative of T-cell ALL. He was enrolled on the Total Therapy XV study and began remission induction therapy with high-dose methotrexate followed by prednisone once per day, vincristine once per week, daunorubicin once per week, and E coli-derived asparaginase 3 times per week. On day19 of treatment, 62.9% of bone marrow mononucleated cells were leukemic lymphoblasts by flow cytometry (31% of all cells were blasts by morphology). Three additional doses of asparaginase were given, and the remaining remission induction therapy consisted of cyclophosphamide, mercaptopurine, and cytarabine. On day 46, he attained morphologic remission (with 3% lymphoblasts), but MRD by flow cytometry was 5.82%. After consolidation treatment with 4 courses of high-dose methotrexate plus mercaptopurine as well as 1 course of re-intensification therapy with dexamethasone, etoposide, high-dose cytarabine, and asparaginase, MRD decreased to 0.18%. He attained MRD-negative status (,0.01%) after a second course of re-intensification treatment and subsequently underwent a matched-related allogeneic hematopoietic stem cell transplantation. He has remained in continuous complete remission for 11.9 years.

Flow-cytometric vs. -morphologic assessment of remission in childhood acute lymphoblastic leukemia: a report from the Children’s Oncology Group (COG)

“…26–28 While our analysis demonstrates that morphologic and flow cytometric assessment of remission was concordant in the vast majority of cases, the use of an MRD-based definition of remission is further supported by several findings of this analysis. First, we found that clinical characteristics associated with morphologic induction failure (older age, higher WBC at presentation, unfavorable cytogenetics, ETP phenotype in T-ALL) 20 are also associated with MRD-defined induction failure in patients with M1 marrows.…”

A QA Program for MRD Testing Demonstrates That Systematic Education Can Reduce Discordance Among Experienced Interpreters

“…The presence of MRD after induction therapy as detected by flow cytometry (FCM) is an important prognostic factor in several hematological malignancies including multiple myeloma, chronic lymphocytic leukemia, acute myeloid and acute lymphoblastic leukemia (ALL) (1)(2)(3)(4)(5)(6)(7)(8)(9). Most clinical trials in North America have used either one or small numbers of specialized reference laboratories to conduct these studies (2,(10)(11)(12)(13)(14)(15)(16). However, as the clinical need for these measures has become more important for the routine management of patients with these diseases, there is a recognized need to ensure that all laboratories involved in testing of these patients can reproducibly detect small populations of leukemic cells.…”

Blockade of CD7 expression in T cells for effective chimeric antigen receptor targeting of T-cell malignancies

“…[19][20][21] Intensive chemotherapy and/or allogeneic hematopoietic stem cell transplant often do not prevent treatment-refractory relapse; for these patients, and those with other high-risk features, such as adult age, there is a dearth of treatment options. 19,[22][23][24][25] A major obstacle to the development of effective CAR T cells for T-cell malignancies is that the surface marker profile of malignant T cells (which generally lack CD19 or CD22 expression) largely overlaps that of activated T lymphocytes. 19,26 CARs directed against such targets are likely to lead to the self-elimination of the CAR T cells.…”