CLRA Reference Library:
"The Basics of Leukemias"
by George Marcoullis, MD, PhD Associate Professor of Medicine, New York Medical College
TYPES
OF LEUKEMIA:
Approximately
2.5 percent of all new cancers diagnosed every year in the USA are due to the
various forms of leukemias; roughly 10 new cases of leukemia are being diagnosed
annually per 100,000 Americans or 29,000 new cases in the entire population of
USA.
The
incidence of the various forms of leukemias varies by age. Sixty percent of
leukemias are due to acute forms of leukemias which signify rapidly progressing
diseases with a predominance of highly immature cell-forms or blasts as opposed
to chronic leukemias which denote slowly progressing diseases with greater cell
numbers and with more mature rather than immature cells present in the
peripheral blood.
Although
only about ten percent of all leukemias are diagnosed in children, leukemia
accounts for nearly thirty percent of all cancers in children; and of these
leukemias, seventy-five percent are acute lymphoblastic leukemias and twenty
percent are acute myelogenous leukemias. In general acute lymphoblastic leukemia
occurs predominantly in young children and older adults over the age of 65;
acute myelogenous leukemia occurs more uniformly in infants, adolescents and
older people but it is not usual in children of ages 2 to 10. Chronic leukemias
and especially chronic myelogenous leukemia account for the remaining five
percent of the leukemias of childhood; chronic lymphocytic leukemia rarely
occurs before the age of 40.
CAUSES
OF LEUKEMIA:
Leukemia
is not a genetic disease but certain individuals show a predisposition for its
development; in certain autosomal recessive disorders, like in Bloom's syndrome,
Fanconis anemia and ataxia telangiectasia which are characterized by Inherent
chromosome instability with an increased incidence of acute leukemia. There is a
twenty percent chance of a child developing acute leukemia if its identical twin
has developed acute leukemia before the age of 10 years. In disorders
characterized by congenital immuno-deficiency, such as Down's syndrome and
infantile x-Linked agammaglobulinemia there is an increased incidence of acute
leukemia as well. Leukemia is
generally not a transmissible disease but two rare forms of leukemia are
associated with human retroviruses: Adult T -cell leukemia appears to be related
to infection with the human T –cell lymphotropic virus type I (HTL V-1) which
is found in geographic clusters in Africa, the Caribbean basin, in Southwestern
Japan and also in the United States in chronically transfused patients and
intravenous drug users. Another human retrovirus, the HTL V-II has been found in
patients with a hairy cell leukemia-like syndrome; fortunately only 1% to 2% of
those infected with the HTLV-1 virus and after a latency period of 10-30 years
will develop acute leukemia in this setting.
Five
to 10 years after exposure, ionizing radiation increases the incidence of acute
myeloblastic and chronic myelogenous leukemia. Like in patients given radiation
therapy for ankylosing spondylitis and in survivors of the atomic bomb blasts in
Hiroshima and Nagasaki, Younger patients are more vulnerable than adults and the
incidence of leukemia increases with the intensity of radiation, that is the
leukemogenic effect increases with higher doses of radiation given over shol1er
periods of exposures.
Although
the incidence of chromosomal aberrations is higher in individuals residing in
areas of high natural background radiation (e.g. radon), the incidence of
leukemia does not seem to be consistently higher in this setting.
A
greatly publicized issue is the purported leukemogenic effect of extremely low
frequency electromagnetic fields such as emitted by high energy wires and step
down transformers; again there is no conclusive evidence in favor for this
association and if there is any leukemogenic effect at all its magnitude must be
of low statistical significance.
Benzene,
which makes up 1% of unleaded gasoline and is being used in industry as solvent
and in organic synthesis as well as benzene containing compounds such as
kerosene and carbon tetrachloride may cause bone marrow damage, aplastic anemia,
myelodysplasia and acute myelogenous leukemia. However, prolonged exposure and
high concentrations of these hazardous chemicals are required for the
leukemogenic effect to fully manifest itself.
Ironically,
certain chemicals used successfully to treat cancer more notably the so called
alkylating agents, melphalan and nitrosureas appear to be associated with
leukemias which typically develop in a small proportion of patients 4 to 6 years
following exposure to chemotherapy, and these leukemias usually exhibit certain
chromosomal abnormalities of chromosomes 5 and 7 and sometimes of chromosome 8.
Another category of chemotherapeutic agents, epipodophylotoxins (etoposide,
tenisposide) has been found to increase the incidence of acute myelogenous
leukemia after a short latency period of 1 to 2 years. This leukemia was found
to be associated with abnormalities of the long arm of the chromosomes 11 and 21
(11 q23 and 21 q22). In some reports, Bimolane used in the treatment of
psoriasis, was also found to be associated with acute promyelocytic leukemia.
TREATMENT
OF ACUTE LEUKEMIAS; ACUTE MYELOGENOUS LEUKEMIA:
As
explained above 20% of the leukemias in children are due to acute myelogenous
leukemia. The conventional method of treatment of this disease is the
intravenous administration of 2 agents, that is cytosine arabinoside given at a
dose of 100-200
Mg/m2
daily for 7 days and
daunomycin 45 to 60 mgJm2
given intravenously per de for the first 3 days of chemotherapy. About
60% to 75% of the patients treated with this combination enter complete
remission (complete eradication of all identifiable malignant blasts from the
blood and the bone marrow of the patient). Idarubicin, a synthetic analogue of
daunomycin has been used instead of adriamycin at a dose of 12 mg/m2, per day
for 3 days along with the conventional cytosine arabinoside 7 day-course with a
complete response rate of 67% versus 58% with daunomycin. Another agent used in
the treatment of acute myelogenous leukemia is mitoxantrone given also at a dose
of 12 mg/m2 per day for 3 days and its combination with the standard 7
day-course of cytosine arabinoside is as effective as the daunomycin plus
ctyarabine combination, producing similar response rates.
The
majority of patients with AML treated with either of the induction regimen
described above will enter complete remission, but will invariably relapse
within a median duration of 4.1 months unless a form of post-remission
chemotherapy is followed.
These
post remission treatments comprise: consolidation chemotherapy, which refers to
therapy given shortly after induction in doses sufficient to cause severe
myelosuppression requiring hospitalization. Late intensification refers to
chemotherapy given at doses similar to those given for consolidation but given
after a delay of 6-12 months. Maintenance chemotherapy refers to post remission
chemotherapy given after prolonged periods of up to two years and at doses,
which usually do not require hospitalization.
A
form of post remission treatment is the use of 2 to 4 consolidation cycles
similar to the induction cycle which results in 1 year median disease-free
survival and 18 to 24 months overall survival. About 25% to 30% of these
complete responders are cured using this approach.
Patients
receiving 2 cycles of consolidation chemotherapy consisting of high dose
cytosine arabinosine of 2 gm/m2 every
12 hours for 6 days with standard daunomycin dosages appeared to do better than
those treated with the standard cytosine arabinoside doses. Similarly, 4 cycles
of cytosine arabinoside at 3.0 gm/m2 every 12 hours on days 1,3, and 5 resulted
in a superior outcome than with less intensive consolidation. However, these
high dose consolidation regimens are extremely toxic and only 50% of patients,
usually younger ones, become candidates for this form of consolidation
treatment.
In
addition to the post remission-consolidation treatments explained above, other
prospective randomized trials have shown that low dose maintenance chemotherapy given
as cytorabine and thioguanine alone or combined with vincristine and prednisone
prolongs remission duration and overall survival in adult AML.
Similarly
both prolonged disease-free survival and overall survival were shown to be
associated with patients treated in late intensification phase with a
combination of 6- mercaptopurine, metholtrexate, prednisone and vincristine
(POMP).
However
in both, the low dose maintenance trial and in the high dose late
intensification trial, patients entered on those trials were treated with only
moderate-dose consolidation chemotherapy which maybe taken to indicate that the
benefits observed were due to inferior responses associated with the patients in
the arm that had received moderate dose induction treatments.
ACUTE
LYMPHOBLASTIC
LEUKEMIA:
Children
with ALL attain complete response and disease-free survival at rates of 90% and
60% to 70%1 respectively. The corresponding figures in adults are 70% and 25°/D
to 35%, respectively.
Combinations
of an anthracycline prednisone, vincristine and L-asparaginase are standard
ingredients in the treatment of ALL with the optional addition of
cycylophosphamide and cytarabine with response rates ranging from 65% to 85%.
Like in AML, the use of high dose cytosine arabinoside alone or in combination
with an anthracycline yield a complete remission of 70%, which is not superior
to that attained with the conventional combination.
Patients
with adult ALL attaining completed remission will invariably relapse unless post
remission chemotherapy with CNS prophylaxis is provided. Unlike AML, 35% of
patients with ALL in remission without post remission CNS treatment will relapse
in CNS. Only 10% of the ALL patients in remission and CNS prophylaxis will
develop CNS relapse.
Intense
consolidation is warranted in ALL and it comprises combinations of cytosine
arabinoside, cyclophosphamide and an anthracycline. Also maintenance treatment
may be important in ALL but the form, duration and intensity have not been
worked out completely as yet. However, with the post remission regimens
explained above 30% to 35% of ALL patients in CR will remain disease-free for
longer than 5 years and can tie considered as cured.
TROPICAL
RAIN FOREST PLANTS:
A
parenthesis will be made at this point with regard to vincristine which is a
common agent used in the treatment of ALL. Vincristine as explained above is an
essential ingredient in the combination used to treat acute leukemias and more
notably the ALL. Both vincristine and vinblastine are alkaloids found in the
Madagascar periwinkle, Caharanthus roseus (formerly classified as Vinca rosea,
which led to these compounds becoming called vinca alkaloids). These compounds
and their semi synthetic derivatives vindesine and vinorelbine, all work by
inhibiting mitosis (cell division) in metaphase. These compounds bind to tubulin
thus preventing the cell from making spindles it needs to be able to move its
chromosome around as it divides. These alkaloids also seem to interfere with the
cells ability to synthesize DNA and RNA.
In
the treatment of acute leukemia, vincristine is being administered intravenously
in a dose of 1.4 mg/m2 once weekly for a variable number of doses. Its serum
half-life is 65 hours and neurotoxicity is the dose-limiting factor (it may
cause damage to the peripheral nervous system). Vincristine and its derivations
are fatal if administered any other way and can cause tissue irritation and
necrosis if they leak out of the vein.
Although
the plant Rosy Periwinkle is unlikely to be useful against leukemia, it was a
healer's claim that the plant was effective against diabetes that led scientists
to investigate it. The active chemicals extracted from the leaves of the plant,
called vinca alkaloids, were discovered when scientists were screening some 400
medicinal plants seeking chemicals active against the P-38 mouse leukemia cell
line.
As
explained above vincristine combined with other chemicals especially with an
anthracycline, prednisone, L-asparaginase with or without cyclophosphamide and
cytorabine can lead to up to 90% complete response rates in ALL in children and
up to 65% to 85% in adults.
HEMATOPOIETIC
STEM CELL TRANSPLANTATION; ACUTE MYELOGENOUS LEUKEMIA:
The
median disease-free survival and overall survival in adult patients with AML
treated with high dose cytarabine as consolidation are 1 year and 18 to 24
months, respectively and approximately only 25 to 30% of those patients
achieving complete remission with this approach are eventually cured.
For
these reasons high dose chemotherapy with or without radiation followed by stem
cell transplantation has become increasingly used as consolidation treatment in
AML.
Transplantation
using stem cells from HLA-identical siblings is a form of allogeneic bone marrow
transplantation and patients who receive this form of consolidation while in CR
show a disease-free survival at 5 years of 45% to 55%.
Patients similarly transplanted but while they were in second remission
or in untreated first relapse both do less well with a disease-free survival at
5 years down to 25% while those transplanted in resistant relapse do the poorest
with a disease free-survival at 5 years of only 10%.
In
spite the above superior survival rates in AML patients, most comparative
studies still show no significant survival differences between any kind of stem
cell transplant approaches and high dose consolidation with cytarabine.
Treatment failures due to recurrence are significant at 25% for transplantations
performed in first remission, 40% for transplantations performed in second
remission and over 50% for transplantations performed in refractory relapses.
Other significant causes of treatment failure and death are interstitial
pneumonia, graft versus host disease (GVHD), infections and veno-occlusive
disease of the liver with the following respective mortality rates of 10%, 5% to
10%, 5% to 10%, and 5%, respectively.
Patients
with an identical sibling who have resistant AML should be offered allogeneic
stem cell transplantation since only this form of treatment is associated with a
10 to 15%, long-term disease-free survival.
Many
authorities in the treatment of AML have difficulty in choosing between further
conventional chemotherapy or allogeneic transplantation for patients achieving
first remission: one school of thought advocates the strategy of transplantation
in first remission which is associated with reported cure rates of 40% to 64%.
Others advocate the strategy of combination of initial chemotherapy, with a 25%
to 30% cure rate, followed by transplantation as salvage chemotherapy in the
relapsing patients. In this setting an additional 25% cure rate can be achieved
for the remaining 70% to 75% of the initial patients who are thus transplanted
in relapse. Thus, the combined cumulative cure rates for all patients cured
either by induction chemotherapy alone or by the subsequent salvage
transplantation in the relapsing patients can be estimated to be as high as 44%
to 48%. In this approach the 25% to 30% of the patients who are cured by the
initial induction and consolidation chemotherapy are therefore spared the toxic
and other devastating sequalae of allogeneic stem cell transplantation.
AML
patients with favorable prognostic factors and in particular those with the t
(8:21) and t (15:17) translocations and the inv (16) are more likely to be
associated with higher rates of prolonged disease-free survival and cure. These
patients may be offered a conventional induction/consolidation approach
initially and high dose chemotherapy with stem cell transplantation at relapse
only. Many patients have no HLA identical siblings or other suitable donors and
autologous bone or stem cell transplantation is now a commonly used approach for
patients in second remission where long-term disease-free survival rates of 30%
to 35% have been reported. Although most investigators accept the premise that
autologous transplantation is more likely to lead to cure, no prospective study
has definitely shown an advantage of autologous transplantation in second
remission over continued chemotherapy.
Recent
randomized studies showed that autologous transplantation in first remission is
associated with a superior leukemia-free survival rate than that seen with
conventional consolidation ranging from 40% to 55% disease-free survival at 3
years.
STEM
CELL TRANSPLANTATION IN ACUTE LYMPHOBLASTIC LEUKEMIA
More
than in AML patients, 10% to 20% of patients with resistant ALL transplanted
with HLA-identical stem cells can achieve long-term disease-free survival;
similarly transplanted patients in second remission enjoy 35% disease-free
survival at 5 years.
Children
who have had a prolonged, more than 18 months, first remission can be cured if
transplanted in second remission; although this pediatric age group could still
be cured with conventional salvage chemotherapy alone thus arguing against stem
cell transplantation in children in second remission. The probability for cure
using conventional chemotherapy in adult ALL patients is significantly inferior
and most investigators advocate the use of stem cell transplant in this setting.
Superior 35% to 65% long-term disease-free survival can be achieved in ALL adult
patients transplanted in first remission; the International Bone Marrow
Transplantation Registry has reported a 50% disease-free survival at 4 years
following transplantation in first remission with an actuarial relapse rate of
25%. Again, patient selection possibly has contributed to the improved survival
rates quoted above, and the value of transplantation in this setting is
considered unsettled.
