Varient CML

BCR-ABL Positive
• Chronic myelogenous leukemia (CML) is a
multipotential hematopoietic stem cell
disease characterized by
• anemia,
• extreme blood granulocytosis and
granulocytic immaturity, basophilia,
• often thrombocytosis,
• and splenomegaly
 Variant Ph chromosome
• Variant Ph chromosome translocations occur in
approximately 5-10 percent of subjects with CML and
involve complex rearrangements (three chromosomes), and
every chromosome except the Y chromosome can be
involved. In almost all the cases with variant Ph
chromosome, the BCR-ABL rearrangement can be
detected by molecular methods or by fluorescence in situ
hybridization (FISH).
• Simple variant:
– 22q−, is present, but the gross exchange of chromosomal material
involves a chromosome other than 9
• Complex variant
– involves exchange of material among chromosomes 9 and 22 and a
third or more chromosomes
• Complex translocations involving chromosome 3 have been
notable.
• In rare cases, a reciprocal translocation with a chromosome
other than 9 to chromosome 22 is larger than usual, and the
post-translocation shortening of the long arms of 22 is not
apparent. This circumstance has been referred to as a
masked Ph chromosome or masked translocation because
the 22q− is not evident by microscopic examination,
although t(9;22) may occur as judged by banding techniques
or molecular probes.

• Approximately 10 percent of patients have a deletion of the

derivative 9 chromosome adjacent to the chromosome
breakpoint. Although this deletion is thought to be an
important factor in resistance to drug effects with IFN
therapy, it does not appear to be significant with the use of
imatinib.
 BCR-ABL1–POSITIVE
THROMBOCYTHEMIA
• This may precede the overt signs of CML or its accelerated phase
– Thrombocythemia with the Ph chromosome and BCR-ABL1
rearrangement
– Thrombocythemia without a Ph chromosome but with the BCR-ABL1
rearrangement

• It mimics classic essential thrombocythemia initially:

– marked platelet elevation,
– extreme megakaryocytic hyperplasia,
– normal or mildly elevated white cell count,
– no or very slight myeloid immaturity in the blood,
– and minimal anemia.
• Minor bleeding, such as epistaxis, erythromelalgia, or signs of
thrombosis, such as cerebral or limb ischemia, are occasionally
present.
• In some cases, the absolute basophil count is mildly elevated.
 NEUTROPHILIC CHRONIC
MYELOGENOUS LEUKEMIA
• A rare variant of BCR-ABL1–positive leukemia
• Elevated white cell count is composed principally of
• Mature neutrophils
• The white cell count is lower (on average: 30 to 50 ˟109/L) at the time of
diagnosis than is the case with classic CML (median:100 to 150 ˟109/L).
• Usually do not have basophilia,
• Notable myeloid immaturity in the blood,
• Prominent splenomegaly, or
• Low leukocyte alkaline phosphatase scores.
• The cells of these patients have the Ph chromosome but have an
unusual BCR-ABL1 fusion gene (230 kDa).
• This variant usually has an indolent course, which may be the result
of very low levels of mRNA for p230 and the undetectable or barely
detectable p230 protein in cells.
 MINOR-BCR BREAKPOINT–
POSITIVE CHRONIC
MYELOGENOUS LEUKEMIA
• A small portion of patients with BCR-ABL1–positive CML
have the breakpoint on the BCR gene in the first intron
(m-bcr), resulting in a 190-kDa fusion protein instead of
the classic 210-kDa protein observed in most patients
with CML
– monocytes are more prominent,
– the white cell count is lower on average,
– and basophilia and splenomegaly are less prominent than in
disease with classic BCR breakpoint (M-bcr).

• The few reported cases had a short interval before either

myeloid or lymphoid blast transformation developed
 Undetected BCR–ABL1 fusion
gene Neutrophilia
• Occasionally patients present with leucocytosis
with a prominent neutrophilia, when Philadelphia
chromosome and the BCR–ABL1 fusion gene
are both undetected;
– after exclusion of cryptic variant t(9;22) and atypical
BCR–ABL1 transcripts,
• a diagnosis of either
– atypical chronic myeloid leukaemia (aCML) or
– chronic neutrophilic leukaemia (CNL)
 Atypical CML
• Myeloproliferative and myelodysplastic disorders.
• Patients usually present with leucocytosis, mainly
caused by increased number of neutrophils and their
precursors.
• Maturation is dysplastic, and in contrast to CML and
chronic myelomonocytic leukaemia (CMML), basophilia,
monocytosis and eosinophilia are rare.
• Patients with aCML fare poorly and often die from
marrow failure
• or transformation to AML.
 CNL
• Like CML and aCML, CNL is characterized by
leucocytosis with a predominant neutrophilia.
However, unlike aCML, neutrophil morphology is
normal in CNL. Neutrophil precursors such as
metamyelocytes, myelocytes and promyelocytes
are <10% of circulating cells in CNL, which
differentiates this disease from CML.
• The course of CNL is variable, though
neutrophilia is usually progressive, accompanied
by cytopenia of other lineages resulting in
marrow failure, or transformation to AML.
Juvenile CML
• Rare.
• Affecting children <12 year-old.
• C/F – anaemia, or lymphadenopathy with
hepatosplenomegaly, skin rashes.
• Lab findings – leucocytosis with variable
numbers of blast in the peripheral blood.
• Marrow is hypercellular but lacks chromosomal
abnormalities.
• Responds poorly to standard cytotoxic drugs.