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Blood, Vol. 92 No. 10 (November 15), 1998:
pp. 3582-3590
Kinetics of the Graft-Versus-Leukemia Response After Donor Leukocyte
Infusions for Relapsed Chronic Myeloid Leukemia After Allogeneic
Bone Marrow Transplantation
Herrad Baurmann,
Stefan Nagel,
Thomas Binder,
Andreas Neubauer,
Wolfgang Siegert, and
Dieter Huhn
From the Abteilung für Innere Medizin mit Schwerpunkt
Hämatologie/Onkologie, Virchow Klinikum der Humboldt
Universität zu Berlin, Berlin, Germany.
Little is known about the mechanisms and the kinetics of the
so-called graft-versus-leukemia (GVL) response induced by donor lymphocyte infusions (DLI) in patients with leukemic relapse after allogeneic bone marrow transplantation (BMT). We sought to elucidate this problem by sequentially studying three patients with relapsed chronic myeloid leukemia after sex-mismatched BMT from time before donor leukocyte infusion until achievement of complete molecular remission. Lineage-specific chimerism was assessed longitudinally by a
combined fluorescent immunophenotyping and sex chromosome-specific in
situ hybridization approach. Results were related to quantitative detection of bcr-abl transcripts by competitive differential reverse transcriptase-polymerase chain reaction (RT-PCR),
qualitative bcr-abl RT-PCR, and multiplex PCR-based DNA donor/recipient
chimerism. All patients had predominant donor lymphopoiesis at the time
of DLI, suggesting a state of tolerance to recipient leukemic
and/or normal cells. In contrast, granulopoiesis and
erythropoiesis were mainly recipient derived in both patients with
hematologic relapse and partly recipient derived in the patient with
molecular relapse. Eighty percent, 90%, and 8% of CD34+
cells, respectively, were found to be of recipient origin at relapse,
and few donor stem cells predicted for cytopenia post-DLI. Responses
were seen after a time lag of 5 to 13 weeks after DLI and resulted in
reversal to full donor chimerism within a critical switch period of 4 to 5 weeks. A sudden decrease in recipient cells was paralleled by a
sharp decrease in bcr-abl transcript numbers detectable several weeks
before achievement of molecular remission and onset of clinical
graft-versus-host disease (GVHD). This response pattern was confirmed
by retrospective RT-PCR analysis in an additional five patients.
Prospective monitoring of stem cell chimerism and response may enable
us to individually tailor adoptive immunotherapy in the future.
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