Minimal residual disease Mhawech-Fauceglia et al. [4] used a semiquanti-
tative method to evaluate MRD. Three separate 500- cell counts in three different fields were performed; the numbers of DBA.44-positive cells were counted and averaged. In a retrospective review of 17 of their patients treated with cladribine and followed for
a median of 55.4 months, patients with 1% MRD had no relapses, patients with 41% but 55%
MRD had 33% progression, and patients with 5% MRD had 75% progression. Immunohistochemical stains are a requisite in
evaluating remission status in bone marrow biopsy sections. Three to five percent bone marrow infiltration by HCL can easily be missed on hematoxylin and eosin (H&E) sections. CD20 and DBA.44 are sensitive but not specific markers for HCL. CD20 displays a granular membrane staining pattern while DBA.44 displays a granular cytoplas- mic staining pattern. The increasing use of ritux- imab in the treatment of HCL may decrease the usefulness of this marker in the detection of MRD. TRAP antibody is not as sensitive as CD20 and DBA.44 in detecting hairy cells; it displays a granular cytoplasmic pattern and is also positive in mast cells, osteoclasts, activated macrophages, and Gaucher cells. Cyclin D1 stains hairy cells in a dim nuclear pattern; it only stains a subset of hairy cells and is not as sensitive as CD20 or DBA.44. CD11c monoclonal antibody (moAb) 5D11 [5] detects a formalin-resistant epitope that is consis- tently expressed in HCL and rarely in B-chronic lymphocytic leukemia/small lymphocytic leukemia and mantle zone lymphoma. The intensity of staining is weaker in interstitial macrophages. The antibody is able to detect HCL to a level of 2%. Annexin A1 reliably distinguishes HCL from other B-cell lymphomas; however, it is strongly expressed in marrow myeloid cells, which limits its use in the detection of MRD. The combined positivity of DBA.44 and TRAP
has 97% specificity for HCL [6]. The use of CD20 and/or DBA.44 in combination with TRAP provides a sensitive and specific tool for evaluation of MRD. The addition of CD11c moAb 5D11 and/or cyclin D1 may further enhance specificity. Review of the Scripps experience [7] in 19 patients
with continuous and complete hematologic response after a median follow-up of 16 years following a single 7-day course of cladribine demonstrated that 9/19 (47%) patient samples had no evidence of residual disease, 7/19 (37%) had MRD, and 3/19 (16%) had morphologic evidence of relapse on H&E sections. These results indicate that prolonged hematologic responses can be maintained in patients withMRDand in patients whose residual disease can be detected on H&E sections.
63 The bonemarrow biopsy is one of many tools used
in establishing the remission status of a patient. Determination of remission status is based on an aggregate of findings that include spleen size, complete blood count, flow cytometry, and molecu- lar data, as well as the bone marrow H&E and immunohistochemical stains. The sensitivity of immunohistological stains in
detectingMRDinHCLhas not been well established; it is unclear whether 1% MRD can be reliably and reproducibly detected. In the era of immunohisto- chemistry, the prognostic relevance of CR based on H&E findings remains to be established. H&E quantitation of residual disease is a crude estimate of MRD. Larger studies correlating clinical outcome with percent hairy cells on biopsy are crucial in establishing the relevance ofCR andMRDdiagnostic criteria. Given the current published data, I would suggest classifying residual disease using a combination of immunohistochemical stains (CD20 and/or DBA.44 with TRAP or similar combinations) to detect residual disease. Cells having morphologic features of hairy cells and staining positively for CD20 or DBA.44 should be counted, performing three separate 500-cell counts in three different fields and averaging the results. Because of their sensitivity, I would suggest performing the 500-cell count using CD20 or DBA.44 once the presence of residual disease has been established using a combination of morphology and immunohistochemical stains.
. CR: absence of residual hairy cells by immuno- histochemistry;
. CR/MRD: presence of 1% residual hairy cells by immunohistochemistry;
. RD: presence of 41% residual hairy cells by immunohistochemistry.
The proposed definition of CR, CR/MRD, and RD is objective and reproducible; it will need to be validated by clinical outcome and antibody sensitivity studies.
Potential conflict of interest: A disclosure form provided by the author is available with the full text of this article at
www.informahealthcare.com/lal.
References
1. Kreitman RJ, Stetler-Stevenson M, Margulies I, et al. Phase II trial of recombinant immunotoxin RFB4(dsFV)-PE38 (BL22) in patients with hairy cell leukemia. J Clin Oncol 2009;27: 2983–2990.
2. Ravandi F, Jorgensen JL, O’Brien SM, et al. Eradication of minimal residual disease in hairy cell leukemia. Blood 2006; 107:4658–4662.
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