Lecture 9 in hematology by Dr.Alaa Fadhil Alwan
CHRONIC LEUKEMIAS
1.CHRONIC LYMPHOCYTIC LEUKEMIA(CLL)
CLL is typically a leukemia of elderly people and accounts for about 20% of all NHLs. CLL
has a clear male predominance and characterized by the monoclonal accumulation of small,
mature-appearing lymphoid cells. The typical CLL belongs to the entity of peripheral B-cell
neoplasms, whereas about 5% of all CLLs have a T-cell phenotype. With a sensitive
cytogenetic analysis, most cases of CLL have chromosome aberrations. Frequent markers are
trisomy 12, aberrations of chromosome 13q, usually predict clinical unresponsiveness.
Another important risk factor is Expression of ZAP-70, as well as unmutated status of the
immunoglobulin heavy chain genes confers a poorer prognosis.
Clinical Features
Most patients present with enlarged lymph nodes. In early stages, the patients are
asymptomatic and have a leukocytosis as the only sign of disease. In later stages, anemia,
splenomegaly, and hepatomegaly develop. Some patients also have bruising due to
thrombocytopenia, and frequent infections due to neutropenia and hypogammaglobulinemia.
Classification
Rai classification Binet classification
Stage 0 Lymphocytosis 5000–15000/L Stage A 0, 1, or 2 lymphatic areas enlarged
Stage I Lymphocytosis + Lymphadenopathy Stage B 3, 4, or 5 areas enlarged
Hb >10 g/dL, Platelets > 100000/L
Stage II As 0 + hepato- and/or splenomegaly
Stage III As 0 + anemia (Hb <11 g/dL) Stage C Any lymphatic involvement
Stage IV As 0 + thrombocytopenia Hb <10, and/or platelets <100,000
(platelets <100000/L) .
Laboratory Features
CBP show leucocytosis with mainly lymphocytosis which may be as low as 5000 or higher
than 200,000/L. In advanced stages, anemia and/or thrombocytopenia are present. Bone
marrow aspiration shows infiltration of the bone marrow with CLL cells (at least 25% of the
aspirate, but in many cases as high as 90%). Bone marrow biopsy shows a nodular, diffuse, or
mixed infiltration. The bone marrow trephine biopsy may not be necessary in all cases of
CLL, as a nodular infiltration has been not confirmed as independent prognostic factor.in
advanced, cases, the serum immunoglobulins are decreased (hypogammaglobulinemia).
About 5% of patients terminally transform into an aggressive NHL (Richter syndrome).
Prognosis
The prognosis of B-CLL depends on clinical and molecular laboratory features. In early
stages, the survival is more than 12 yr (Binet A). In contrast, in advanced stages (Binet C, Rai
IV) the median survival is less than 2 yr.
Treatment
The conventional treatment of CLL aims at the palliation of symptoms, not at a cure. In the
early stages (Rai 0–II or Binet A or B) the disease may be stable for several years; therefore,
no treatment is indicated. If the disease progresses rapidly, if B-symptoms develop, or if the
disease leads to complications such as frequent infections or an autoimmune hemolytic
anemia, treatment with alkylating agents or fludarabine is indicated in later stages.
Supportive therapy plays a major role in the management of patients with CLL. Infections
need prompt treatment. Patients with hypogammaglobulinemia and frequent infections may
benefit from prophylactic antibiotics or the administration of polyvalent immunoglobulins in
case of life-threatening infections.
SINGLE-AGENT CHEMOTHERAPY:1.Chlorambucil 2. fludarabine .
COMBINED CHEMOTHERAPY:fludarabine and cyclophosphamide (FC) is the best
choice. Others e.g COP (cyclophosphamide, Oncovin,and prednisone), CHOP.
2.CHRONIC MYELOGENOUS LEUKEMIA
CML occurs predominantly in adults with a median age of approx 50 yr. It has an incidence
of 1–2 per 100,000. CML is a clonal stem cell disorder with a classic cytogenetic
abnormality, the Philadelphia chromosome (Ph1), which results from a reciprocal
translocation between chromosomes 9 and 22 . At the molecular level, this translocation fuses
the BCR gene to the ABL gene on chromosome 9, resulting in a chimeric gene BCR-ABL
protein. This BCR-ABL species is typically found in Ph1-positive acute lymphoblastic
leukemia. Approximately 90% of patients with CML are found to have the Philadelphia
chromosome by routine cytogenetics
Clinical Manifestations
There is usually an insidious onset of symptoms and the diagnosis may be made after a
routine blood test for unrelated reasons. Symptoms may relate to the hypermetabolic state
associated with a large tumor burden, such as fevers and night sweats. Splenomegaly may
cause a feeling of upper abdominal fullness or early satiety. Marked hyperleukocytosis (white
blood cell [WBC] >100,000/L) can cause neurological symptoms (such as decreased
alertness, confusion, or seizures), visual changes, or, in rare cases, painful erection (priapism).
On physical examination, splenomegaly is common, and the spleen may be massively
enlarged. Less commonly, hepatomegaly.
Laboratory Abnormalities
In patients with chronic phase CML, the WBC count is invariably increased and may be
higher than 200,000/L. The platelet count is frequently increased; thrombocytopenia suggests
accelerated or blast phase CML. The hemoglobin concentration is usually normal. The
peripheral blood smear is consistent with the diagnosis of CML when the differential includes
the spectrum of myeloid cells including metamyelocytes, myelocytes, promyelocytes, and
occasional blasts. In the bone marrow, the cellularity is typically 90–100% and it
demonstrates marked myeloid hyperplasia with a myeloid:erythroid ratio of 20:1 or higher.
The number of blast cells in the bone marrow may be increased, but is below 15%. The
leukocyte alkaline phosphatase (LAP) test result is characteristically low in CML, in contrast
to leukemoid reactions, for which there is an elevated LAP score. As a consequence of the
increased cell turnover, the lactate dehydrogenase (LDH) and uric acid are often increased.
Accelerated phase
Blasts 10–19% in the peripheral blood and/or bone marrow
Basophils ≥20% in the peripheral blood
Persistent thrombocytopenia
Increasing spleen size and white blood cell count despite therapy
Cytogenetic evidence of clonal evolution
Blast phase
Blasts ≥20%
Extramedullary blast proliferation
Large aggregates or clusters of blasts in the bone marrow
2.4. Treatment
There are two prinicpal therapeutic options available: medical therapy with imatinib and
allogeneic stem cell transplantation (SCT). Imatinib mesylate is the first “targeted therapy”
for leukemia. imatinib 400 mg/d was remarkably effective in this patient population that
otherwise had a poor prognosis. Normalization of the peripheral blood counts (complete
hematological response) was observed in 95% of patients. Most pt achieve a complete
hematological and cytogenetic and molecular response.
Other treatment options interferon alfa, Hydroxyurea.
Pt with blast phase treated as acute leukemia .