Correspondence

Residual Disease in Chronic Myeloid Leukemia after Induction of Molecular Remission

N Engl J Med 2003; 349:1483-1484October 9, 2003

Article

To the Editor:

Reliable assessment of molecular remission after allografting for chronic myeloid leukemia requires assays capable of detecting one BCR-ABL–positive cell among 10⁵ to 10⁶ BCR-ABL–negative cells1 — a sensitivity achieved with nested reverse-transcriptase polymerase chain reaction (PCR) but not with real-time quantitative PCR.2 Molecular remission after allografting predicts a low risk of relapse.1 On the basis of negative results on quantitative PCR testing, molecular remission has also been reported in some patients treated with imatinib.3,4

The sensitivity of any PCR assay is ultimately limited by the number of cells analyzed. Only a fraction of the complementary DNA (cDNA) is routinely assayed, but the analysis of multiple cDNA aliquots in replicate reactions increases the sensitivity. With this approach, BCR-ABL transcripts become detectable in some healthy adults.5

We conducted a study in which 97 patients with chronic myeloid leukemia in the chronic phase who had been receiving imatinib for a median of 22 months (range, 0 to 38) were monitored with real-time quantitative PCR (sensitivity, 1:10⁴ to 1:10⁵) and in which negative samples were further tested by nested PCR (sensitivity, 1:10⁵ to 1:10⁶).1 Seventeen patients (all of whom were in complete cytogenetic remission) had at least one negative result on nested PCR (35 of 1051 samples [3.3 percent]). In 24 samples (from patients whose median time receiving imatinib was 19 months [range, 11 to 36]), cDNA was available for 10 replicate nested PCR reactions, each corresponding to more than 10⁶ white cells or bone marrow cells. Thirty-two samples from 23 patients in complete cytogenetic remission a median of 19 months (range, 5 to 130) after allografting and samples from 11 healthy persons were tested in an analogous fashion. Fourteen of the 24 samples from the patients receiving imatinib (58 percent) were positive in 1 to 10 (median, 3) of 10 replicate reactions, and 6 of the 32 samples obtained from patients who had undergone allografting (19 percent) were positive in 1 to 7 (median, 1) of 10 reactions (P=0.002 by chi-square analysis). A sample from 1 of the 11 healthy persons was positive in 3 of 10 replicate reactions, an incidence not different from that in the patients after allografting (P=0.45) (Table 1Table 1Results of Replicate Nested Reverse-Transcriptase PCR for BCR-ABL in Patients with Chronic Myeloid Leukemia Who Are Receiving Imatinib or Who Have Undergone Allografting and in Healthy Adults.).

Eight of the patients receiving imatinib (including five with newly diagnosed disease) had negative results on replicate tests. Of seven patients with follow-up data, two subsequently tested positive by single nested reverse-transcriptase PCR, and one had progression to cytogenetic relapse. Two tested positive in replicate assays. In two patients with newly diagnosed disease, test results have remained completely negative for 7 and 11 months, respectively.

Our findings suggest that most patients receiving imatinib harbor higher levels of residual disease than patients who have undergone allografting, even if they have negative test results on standard nested PCR. Only a few patients have equally profound remissions. Molecular remission after allografting is associated with a definite biologic end point: relapse-free survival. It currently is not known whether imatinib-induced negativity on PCR testing will be predictive of an equally low risk of relapse. Thus, the term “molecular remission” should be used cautiously in such patients.

Thoralf Lange, M.D.
Dietger W. Niederwieser, M.D.
University of Leipzig, 04103 Leipzig, Germany

Michael W.N. Deininger, M.D., Ph.D.
Oregon Health and Science University, Portland, OR 97239
deininge@ohsu.ed

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Citing Articles (6)

Citing Articles

1. 1

   T Lange, M Hubmann, R Burkhardt, G-N Franke, M Cross, M Scholz, S Leiblein, H K Al-Ali, J Edelmann, J Thiery, D Niederwieser. (2011) Monitoring of WT1 expression in PB and CD34+ donor chimerism of BM predicts early relapse in AML and MDS patients after hematopoietic cell transplantation with reduced-intensity conditioning. Leukemia 25:3, 498-505
   CrossRef

2. 2

   Michael W.N. Deininger. (2007) Optimizing therapy of chronic myeloid leukemia. Experimental Hematology 35:4, 144-154
   CrossRef

3. 3

   Ryuzo Ohno. (2006) Treatment of chronic myeloid leukemia with imatinib mesylate. International Journal of Clinical Oncology 11:3, 176-183
   CrossRef

4. 4

   Junia V Melo, Michael W.N Deininger. (2004) Biology of chronic myelogenous leukemia—signaling pathways of initiation and transformation. Hematology/Oncology Clinics of North America 18:3, 545-568
   CrossRef

5. 5

   Monique P Curran, Katherine F Croom, Karen L Goa. (2004) Spotlight on Imatinib Mesylate in Chronic Myeloid Leukemia1. BioDrugs 18:3, 207-210
   CrossRef

6. 6

   Monique P Curran, Katherine F Croom, Karen L Goa. (2003) Imatinib Mesylate. American Journal of Cancer 2:6, 439-454
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