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> The Basics of Leukemias

Overview of Acute and Chronic Leukemias and Related Disorder
An Introduction to New Technology in the Treatment of Leukemia and Lymphoma
New Directions in Chemotherapy of Acute Myeloid Leukemia in Adults

 

by George Marcoullis, MD, PhD
Associate Professor of Medicine, New York Medical College

 
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.

Transplantation with autologous stem cells in patients with ALL in second remission is associated with a long-term disease-free survival of 20% to 30%; autologous transplantation of patients in first remission results in 36% disease-free survival rate with no obvious advantage over conventional chemotherapy.

 
 

 

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