Page 4 - Illustrated Pathology of the Bone Marrow

Disease-specific changes after therapy 127
that cell maturation is occurring and to confirm loss of the
characteristic t(15;17) of this disease.
Chronic myelogenous leukemia
Busulfan, hydroxyurea, and α-interferon therapies have
been commonly used to treat chronic myelogenous
leukemia (CML), with some variation in the degree of
bone marrow response. Some patients achieve clinical fea-
tures of remission, with improvement of peripheral blood
counts (Facchetti et al., 1997; Thiele et al., 2000). With
busulfan, the bone marrow usually remains hypercellu-
lar with an elevated myeloid-to-erythroid ratio. Megakary-
ocytes tend to be increased with therapy, and this increase
is associated with an increase in marrow fibrosis. With
hydroxyurea, the marrow cellularity decreases somewhat,
but usually remains above normal with only a moderate
correction in the myeloid-to-erythroid ratio. The number
of megakaryocytes and degree of marrow fibrosis, how-
ever, tend to decrease with hydroxyurea. With α-interferon,
complete normalization of peripheral blood counts may
occur. The bone marrow remains slightly hypercellular in
most patients, but approximately one-quarter of patients
will develop normal bone marrow features on α-interferon
(Facchetti et al., 1997). The number of marrow megakary-
ocytes remains elevated, with associated fibrosis, and bone
marrow macrophages are also reportedly increased in these
marrows. Despite the improvement in marrow cellularity,
most patients continue to show cytogenetic evidence of
clonal marrow disease.
Bone marrow transplantation is a standard treatment
for CML in some centers (Snyder & McGlave, 1990).
After transplantation, the marrow undergoes the expected
changes of aplasia followed by regeneration. A majority of
CML patients treated with transplantation are cured and
will show normocellular or hypocellular marrows with-
out specific abnormalities. Relapse specimens of patients
treated with transplantation show changes similar to de
novo disease, with granulocytic hyperplasia, basophilia,
and hypercellularity, and are usually not diagnostic
dilemmas.
Currently, many patients with all phases of CML are
treated with imatinib mesylate, a tyrosine kinase inhibitor
(Gleevec: Novartis, Hanover, NJ), that directly blocks the
effects of the BCR/ABL fusion of t(9;22) (Kantarjian et al.,
2002). It results in a clinical, morphologic, and at least par-
tial cytogenetic remission in many patients, with reduc-
tion in marrow cellularity, normalization of the myeloid-
to-erythroid ratio, and normalization of megakaryocyte
number and morphology (Braziel et al., 2002; Hasserjian
et al., 2002). The peripheral blood is the first to respond
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Figure 14.5. Post-imatinib therapy for chronic myelogenous
leukemia. Note the decreased, normal-appearing cellularity.
However, there are still residual stigmata of CML seen, including
(inset) atypical, dwarf megakaryocytes.
to imatinib mesylate therapy, with a return to normal of
the white blood cell count, decrease in basophils, and nor-
malization of the platelet count, with normal-appearing
platelets occurring after about two months of therapy. The
hemoglobin level tends to decrease slightly during therapy.
A subset of patients may develop neutropenia or throm-
bocytopenia while receiving the drug. The bone marrow
hypercellularity gradually decreases and by 8–11 months
the marrow is normocellular or hypocellular, with a normal
or decreased myeloid-to-erythroid ratio in most patients.
Bone marrow blast cells and megakaryocytes decrease,
the number of hypolobated megakaryocytes decrease, and
megakaryocyte clustering becomes less common as the
marrow cellularity decreases (Fig. 14.5). This therapy has
also been reported to gradually eliminate the marrow
fibrosis that is prominent is some cases of CML (Beham-
Schmid et al., 2002; Braziel et al., 2002; Hasserjian et al.,
2002). Patients with accelerated or blast phases of CML
show similar changes, with rapid decreases in peripheral
blood and bone marrow blast cell counts (Hasserjian et al.,
2002).
Because most therapies for CML result in near-normal
cellularity and myeloid-to-erythroid ratios, it is often diffi-
cult to determine by morphologic features alone whether
the disease is still present in the marrow. The most common
clues to residual disease are hypercellularity, the presence
of clusters of atypical megakaryocytes, and in some cases
the continued presence of clusters of Gaucher-like histio-
cytes. Despite these clues, cytogenetic or molecular genetic
studies for t(9;22) are needed to definitely determine the
presence of continued involvement of disease.