Minimal Residual Disease

Hematologics pioneered the use of flow cytometry to detect residual disease in patients treated for acute leukemia. We prefer the term “Measurable Residual Disease” rather than “Minimal Residual Disease” as proposed by J.M. Goldman (1).

Using an approach of “Difference from Normal” the assays have been validated in blinded clinical studies in pediatric and adult patients for both acute lymphoblastic and acute myeloid leukemia treated conventionally or with bone marrow transplantation. In the current Children’s Oncology Group study of AML, detection of residual disease at the end of induction #1 by flow cytometry has replaced morphology in identifying response to therapy, defining high risk patients based on identification of low levels of aberrant myeloid progenitor cells.

The “Difference from Normal” technique can be used without a diagnostic phenotype (although a presentation fingerprint is vastly preferred) and can identify residual disease even if the phenotype changes, a common feature of AML. Cell sorting of the abnormal cell population followed by genetic or molecular tests confirm the presence of neoplastic cells.

Basic Studies of Hematopoiesis

  • Loken, MR, Terstappen LWMM, Civin CI, Fackler, MJ: Flow cytometric characterization of erythroid. lymphoid and monomyeloid lineages in normal human bone marrow. in Flow Cytometry in Hematology. Laerum OD, Bjerksnes R. eds. Academic Press, New York, pp 31-42, 1992
  • Loken MR, Wells DA: Normal antigen expression in hematopoiesis: Basis for interpreting leukemia phenotypes. In “Immunophenotyping”, Stewart C, Nicholson J. Eds. Wiley Liss, Inc. New York, 2000, pp133-160
  • Loken MR, Shah VO, Dattilio KA, Civin CI: Flow cytometric characterization of human bone marrow: I. Normal Erythroid Development. Blood. 69:255-263, 1987
  • Loken MR, Shah VO, Dattilio KL, Civin CI: Flow cytometric analysis of human bone marrow: II. Normal B Iymphoid development. Blood 70:1316, 1987
  • Terstappen LWMM, Johnsen S, Segers-Nolten I, Loken MR: Identification and characterization of plasma cells in normal human bone marrow by high resolution flow cytometry. Blood, 76:1739-1747, 1990
  • Terstappen LWMM, Safford M, Loken MR: Flow cytometric analysis of human bone marrow III. Neutrophil Maturation. Leukemia 4:657-663, 1990.
  • Terstappen LWMM, Hollander Z, Meiners H, Loken M: Quantitative comparison of myeloid antigens on five lineages of mature peripheral blood cells. J. Leuk. Biology 48:138-148 (1990).
  • Shah VO, Civin CI, Loken MR: Flow cytometric analysis of human bone marrow: IV. Differential quantitative expression of T200 common leukocyte antigen during normal hematopoiesis. J. Immunol 140:1861-1867, 1988
  • Terstappen LWMM, Konemann S, Safford M, Loken MR, Zurlutter K, Buchner Th, Hiddemann W, Wormann B: Flow cytometric characterization of Acute Myeloid Leukemia. Part I. Significance of light scattering properties. Leukemia, 5: 315-321, 1991.
  • Terstappen LWMM, Konemann S, Safford M, Loken MR, Zurlutter K, Buchner Th, Hiddemann W, Wormann B: Flow cytometric characterization of Acute Myeloid Leukemia. Part II. Phenotypic heterogeneity at diagnosis. Leukemia, 6: 70-80, 1991
  • Stelzer GT, Shults KE, Loken MR: CD45 gating for routine flow cytometric analysis of human bone marrow specimens Ann. NY. Acad. Sci. 677:265-280, 1993.

Monitoring Response to Therapy “Using Difference from Normal”

  • Wells DA, Sale GE, Shulman HE, Myerson D, Bryant E, Gooley T, Loken MR: Multidimensional flow cytometry of marrow can differentiate leukemic lymphoblasts from normal lymphoblasts and myeloblasts following chemotherapy and/or bone marrow transplant. Am. J. Clin. Path. 110:84-94 (1998).
  • Foster, JH, Hawkins, DR, Loken MR, Wells, DW, Thomson B. Minimal residual disease detected prior to hematopoietics cell transplant. Pediatric Blood Cancer DOI 10.102/pbc.23079
  • Shulman HM, Wells DA, Gooley T, Myerson D, Bryant E, Loken, MR: Biologic significance of rare peripheral blasts after hematopoietic cell transplant is predicted by multidimensional flow cytometry. Am. J. Clin. Path. 112:513-523, 1999
  • CL Reading, EH Estey, YO Huh, DF Claxton, G Sanchez, LW Terstappen, MC O’Brien, S Baron and AB Deisseroth Expression of unusual immunophenotype combinations in acute myelogenous leukemia Blood 1993 81:3083-3090;
  • Sievers, EL, Lang BJ, Buckley JD, Smith FO, Wells DA, Daigneault-Creech CA, Shults KE, Bernstein ID, Loken, MR: Prediction of relapse of pediatric acute myeloid leukemia by use of multidimensional flow cytometry. J. Nat. Can. Inst. 88:1483-1488, 1996.
  • Eric L. Sievers, Beverly J. Lange, Todd A. Alonzo, Robert B. Gerbing, Irwin D. Bernstein, Franklin O. Smith, Robert J. Arceci, William G. Woods, and Michael R. Loken Immunophenotypic evidence of leukemia after induction therapy predicts relapse: results from a prospective Children’s Cancer Group study of 252 patients with acute myeloid leukemia Blood 101: 3398-3406 2003
  • Larson RA, Sievers EL, Stadtmauer EA, Lowenberg B, Estey EH, Dombret H, Theobald M, Voliotis D, Bennett JM, Richie M, Leopold LH, Berger MS, Sherman ML, Loken MR, van Dongen JJ, Bernstein ID, Appelbaum FR. Final report of the efficacy and safety of gemtuzumab ozogamicin (Mylotarg) in patients with CD33-positive acute myeloid leukemia in first recurrence. Cancer 104:1442-52 (2005).
  • Walter, RB, Gooley, TG, van der Velden, VHJ, Loken, MR, van Dongen, JJM, Flowers, DA, Bernstein, ID, Appelbaum, FR CD33 expression and P-glycoprotein–mediated drug efflux inversely correlate and predict clinical outcome in patients with acute myeloid leukemia treated with gemtuzumab ozogamicin monotherapy Blood, 109:4168-4179 (2007).
  • Jessica A. Pollard, Todd A. Alonzo, Michael Loken, Robert B. Gerbing, Phoenix A. Ho, Irwin D. Bernstein, Susana C. Raimondi, Betsy Hirsch, Janet Franklin, Roland B. Walter, Alan Gamis, Soheil Meshinchi: Correlation of CD33 Expression Level with Disease Characteristics and Response to Gemtuzumab Ozogamicin Containing Chemotherapy in Childhood AML. Blood. 2012 Apr 19;119(16):3705-11. Epub 2012 Feb 29.
  • Loken MR, Alonzo TA, Pardo L, Gerbing RB, Raimondi SC, Hirsch BA, Ho PA, Franklin J, Cooper TM, Gamis AS, Meshinshi S. Residual disease detected by multidimensional flow cytometry signifies high relapse risk in patients with de novo acute myeloid leukemia: a report
  • Chu, S. C., Wang, T. F., Su, Y. C., Kao, R. H., Wu, Y. F., Li, D. K., … & Loken, M. R. (2014). Prognostic significance of flow cytometric residual disease, dysregulated neutrophils/monocytes, and hematogones in adult acute myeloid leukemia in first remission. International journal of hematology, 99(3), 296-304.
  • Horan, J. Meshinchi, S., Loken, M. R., Alonzo, T. A., Aplenc, R., Davies, S. M., Gerbing, R. B., & Gamis, A. S. (2013). Impact of Residual Disease On Survival In Pediatric Patients Receiving Allogeneic Hematopoietic Cell Transplantation For Acute Myeloid Leukemia In First Complete Remission. Blood, 122(21), 65-65. (abstract)
  • Loken, M. R. (2013). Residual disease in AML, a target that can move in more than one direction. Cytometry Part B: Clinical Cytometry.
  • Bradfield SM, Radish JP, Loken MR. Graft-versus-leukemia effect in acute lymphoblastic leukemia: the importance of tumor burden and early detection. Leukemia. 2004 Jun;18(6):1156-8.
  • Meshinchi S, Thomson, B, Finn LS, Leisenring W, Green C, Radish JP, Loken M, Hawkins D. J Comparison of multidimensional flow cytometry with standard morphology for evaluation of early marrow response in pediatric acute lymphoblastic leukemia. Pediatr Hematol Oncol. 2001 Dec;23(9):585-90.

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