Acute myeloid leukemia medical therapy
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- Editor-In-Chief: C. Michael Gibson, M.S., M.D. [1]; Associate Editor(s)-in-Chief: Raviteja Guddeti, M.B.B.S. [2]
Overview
The mainstay therapy from acute myeloid leukemia is chemotherapy and usually includes a combination of daunorubicin, cytarabine and etoposide or mitoxantrone and anabolic steroids. Supportive care includes intravenous nutricion, antimycrobial therapy, and replacement of blood products.
Medical Therapy
Chemotherapy
Treatment of acute myeloid leukemia consists primarily of chemotherapy, and is divided into two phases: induction and postremission (or consolidation) therapy. The goal of induction therapy is to achieve a complete remission by reducing the amount of leukemic cells to an undetectable level; the goal of consolidation therapy is to eliminate any residual undetectable disease and achieve a cure.
In addition, specific treatment plans may be used, depending on the type of leukemia that has been diagnosed. Whatever the plan, it is important for the patient to understand the treatment that is being given and the decision-making process behind the choice.
Acute Myelogenous Leukemia
It is most common for adults; more men than women are affected. Many different chemotherapeutic plans are available for the treatment of acute myeloid leukemia. Overall, the strategy is to control bone marrow and systemic (whole-body) disease while offering specific treatment for the central nervous system (CNS), if involved. In general, most oncologists rely on combinations of drugs for the initial, induction phase of chemotherapy. Such combination chemotherapy usually offers the benefits of early remission (lessening of the disease) and a lower risk of disease resistance. Consolidation or "maintenance" treatments may be given to prevent disease recurrence once remission has been achieved. Consolidation treatment often entails a repetition of induction chemotherapy or the intensification chemotherapy with added drugs. By contrast, maintenance treatment involves drug doses that are lower than those administered during the induction phase.
Initial treatment of Acute myeloid leukemia
Initial treatment of acute myeloid leukemia usually begins with induction chemotherapy using a combination of drugs such as daunorubicin (DNR), cytarabine (ara-C), idarubicin, thioguanine, etoposide, or mitoxantrone and anabolic steroids.
Follow-up treatment
Follow-up therapy for such patients may involve:
- Supportive care, such as intravenous nutrition and treatment with oral antibiotics (e.g., ofloxacin, rifampin), especially in patients who have prolonged granulocytopenia; that is too few mature granulocytes (neutrophils), the bacteria-destroying white blood cells that contain small particles, or granules (< 100 granulocytes per cubic millimeter for 2 weeks)
- Injection with colony-stimulating factors such as granulocyte colony-stimulating factor (G-CSF), which may help to shorten the period of granulocytopenia that results from induction therapy
- Transfusions with red blood cells and platelets
Patients with newly diagnosed disease also may be considered for stem cell transplantation (SCT), either from the bone marrow or other sources. Allogeneic bone marrow transplant (alloBMT) is reserved primarily for patients under 55 years of age who have a compatible family donor. Approximately half of newly diagnosed acute myeloid leukemia patients are in this age group, with 75% achieving a complete remission (CR) after induction and consolidation therapy. Allogeneic bone marrow transplant is available for about 15% of all patients with acute myeloid leukemia. Unfortunately, it is estimated that only 7% of all acute myeloid leukemia patients will be cured using this procedure.
People who receive stem cell transplantation (SCT, alloBMT) require protective isolation in the hospital, including filtered air, sterile food, and sterilization of the microorganisms in the gut, until their total white blood cell (WBC) count is above 500.
Treatment of central nervous system leukemia, if present, may involve injection of chemotherapeutic drugs (e.g., cytarabine or ara-C, methotrexate) into the areas around the brain and spinal cord.
Induction
As of 2006, all FAB subtypes except M3 are usually given induction chemotherapy with cytarabine (ara-C) and an anthracycline (such as daunorubicin or idarubicin).[1] Other alternatives, including high-dose ara-C alone, may also be used.[2][3] Because of the toxic effects of therapy, including myelosuppression and an increased risk of infection, induction chemotherapy may not offered to the very elderly. Induction chemotherapy usually requires a hospitalization of about 1 month to receive the chemotherapy and recover from its side effects.
Induction chemotherapy is known as "7 and 3" because the cytarabine is given as a continuous IV infusion for seven consecutive days, while the anthracycline is given for three consecutive days as an IV push. Up to 70% of patients will achieve a remission with this protocol.[4]
The M3 subtype of acute myeloid leukemia, also known as acute promyelocytic leukemia, is almost universally treated with the drug ATRA (all-trans-retinoic acid) in addition to induction chemotherapy.[5][6][7] Care must be taken to prevent disseminated intravascular coagulation (DIC), complicating the treatment of APL when the promyelocytes release the contents of their granules into the peripheral circulation. APL is eminently curable with well-documented treatment protocols.
The goal of the induction phase is to reach a complete remission. Complete remission does not mean that the disease has been cured; rather, it signifies that no disease can be detected with available diagnostic methods (i.e., <5% leukemic cells remain in the bone marrow).[1] Complete remission is obtained in about 50%–75% of newly diagnosed adults, although this may vary based on the prognostic factors described above.[8]
The durability of remission depends on the prognostic features of the original leukemia. In general, all remissions will fail without consolidation (post-remission) chemotherapy, and consolidation has become an important component of treatment.[9]
Consolidation
Even after complete remission is achieved, leukemic cells likely remain in numbers too small to be detected with current diagnostic techniques. If no further postremission or consolidation therapy is given, almost all patients will eventually relapse.[10] Therefore, more therapy is necessary to eliminate non-detectable disease and prevent relapse — that is, to achieve a cure.
The specific type of postremission therapy is individualized based on a patient's prognostic factors (see above) and general health. For good-prognosis leukemias (i.e. inv(16), t(8;21), and t(15;17)), patients will typically undergo an additional 3–5 courses of intensive chemotherapy, known as consolidation chemotherapy.[11][12] For patients at high risk of relapse (e.g. those with high-risk cytogenetics, underlying MDS, or therapy-related acute myeloid leukemia), allogeneic stem cell transplantation is usually recommended if the patient is able to tolerate a transplant and has a suitable donor. The best postremission therapy for intermediate-risk acute myeloid leukemia (normal cytogenetics or cytogenetic changes not falling into good-risk or high-risk groups) is less clear and depends on the specific situation, including the age and overall health of the patient, the patient's personal values, and whether a suitable stem cell donor is available.[12]
If, however, the acute myeloid leukemia patient has resistant disease (about 15%) or relapses (about 70%), second remissions sometimes are achieved by treating them with:
- Conventional induction chemotherapy
- High-dose ara-C (HDAC), with/without other drugs
- Etoposide or other single chemotherapeutic agents
Elderly acute myeloid leukemia patients have special treatment concerns. They may be less able to tolerate the septicemia (blood poisoning) associated with granulocytopenia, and they often have higher rates of myelodysplastic syndromes. Individuals who are over age 75 or who have significant medical conditions can be treated effectively with low-dose ara-C. High-dose post-induction chemotherapy is unlikely to be tolerated by elderly patients.
Until recently, the treatment plans and responses of children with acute myeloid leukemia did not differ much from those of adults. Yet new, more intensive induction and consolidation treatments have resulted in higher remission rates and prolonged survivals. Many induction trials have produced good results using combinations of cytarabine (ara-C) plus an anthracycline (e.g., daunorubicin, doxorubicin). In children under 3 years of age, the anthracycline used for induction should be chosen with care, since doxorubicin produces more toxicity and related deaths than daunorubicin.
Consolidation therapy is complex, but it should include at least two courses of high-dose ara-C (HDAC). Children who have hyperleukocytosis (too many white blood cells), especially monocytic M5 leukemia, have a poor prognosis.
Relapsed acute myeloid leukemia
Despite aggressive therapy, however, only 20%–30% of patients enjoy long-term disease-free survival. For patients with relapsed acute myeloid leukemia, the only proven potentially curative therapy is a stem cell transplant, if one has not already been performed.[13][14][15] In 2000, Mylotarg (gemtuzumab ozogamicin) was approved in the United States for patients aged more than 60 years with relapsed acute myeloid leukemia who are not candidates for high-dose chemotherapy.[16]
Patients with relapsed acute myeloid leukemia who are not candidates for stem cell transplantion, or who have relapsed after a stem cell transplant, should be strongly considered for enrollment in a clinical trial, as conventional treatment options are limited. Agents under investigation include cytotoxic drugs such as clofarabine as well as targeted therapies such as farnesyl transferase inhibitors, decitabine, and inhibitors of MDR1 (multidrug-resistance protein). Since treatment options for relapsed acute myeloid leukemia are so limited, another option which may be offered is palliative care.
For relapsed acute promyelocytic leukemia (APL), arsenic trioxide has been tested in trials and approved by the Food and Drug Administration. Like ATRA, arsenic trioxide does not work with other subtypes of acute myeloid leukemia.[17]
Novel FDA-Approved Agents
In general, these recent FDA approvals largely stem from the identification and characterization of unique molecular subtypes.
- Midostaurin:
- Mechanism of action: Midostaurin is a multikinase inhibitor that inhibits FLT3 receptor signaling and cell proliferation. Importantly it also inhibits KIT, VEGFR2, and PDGFRa/b.
- Clinical trial data: In the midostaurin trial, about 700 patients were randomized to either standard chemotherapy plus midostaurin, or standard chemotherapy plus placebo. Patients were stratified based on FLT3 status (FLT3 tyrosine kinase domain mutation, FLT3 internal tandem duplication, or FLT3 wild-type). Patients with fLt3 internal tandem duplication were subdivided into high allelic ratio or low alleic ratio for the FLT3 aberration). Patients also received midostaurin maintanence if they were in remission after consolidation. The primary endpoint was overall survival. Midostaurin was shown to improve overall survival.
- FDA approval: It is FDA approved for newly diagnosed AML with a FLT3 mutation, at a dose of 50mg PO twice daily on days 8-21, as well as with consolidation HIDAC.
Supportive Therapy
Replacement of Blood Products
Indications for blood products replacement include:
- Hemoglobin concentration is lower than 7-8 g/d or higher if the patient has cardiovascular and pulmonary co-morbidities - packed red blood cells are given.
- Platelet count is lower than 10,000-20,000/µL - platelets are transfused
- In patients with gastrointestinal or pulmonary bleeding transfusions are done to maintain a platelet count of more than 50,000/µL.
- Patients with CNS hemorrhage should have transfusions to maintain a count of more than 100,000/µL.
- Prolonged prothrombin time - fresh frozen plasma
- Low fibrinogen levels - cryoprecipitate.
Antibiotics
Antibiotics with broad spectrum coverage (e.g third generation cephalosporin with or without vancomycin) should be given to all febrile patients.
Dietary Measures
- Neutropenic diet - no fresh fruits, no fresh vegetables
- All foods should be cooked well including meat.
Drugs Approved for acute lymphoblastic leukemia
The following pharmaclogic agents have been aproved for the treatment of acute myeloid leukemia:
- Arsenic Trioxide
- Daunorubicin Hydrochloride
- Cyclophosphamide
- Cytarabine
- Doxorubicin Hydrochloride
- Idarubicin Hydrochloride
- Mitoxantrone Hydrochloride
- Arsenic Trioxide
- Vincristine Sulfate
Drug Combinations Used in acute myeloid leukemia
Chemotherapy is often given as a combination of drugs called ADE
- Drugs in the ADE combination:
- A= Cytarabine (Ara-C)
- D= Daunorubicin Hydrochloride
- E= Etoposide
Pregnancy
Acute leukemias normally require prompt, aggressive treatment, despite significant risks of pregnancy loss and birth defects, especially if chemotherapy is given during the developmentally sensitive first trimester. How it is handled depends primarily on the type of leukemia.[18]
References
- ↑ 1.0 1.1 Abeloff, Martin et al. (2004), pp. 2835–39.
- ↑ Weick JK, Kopecky KJ, Appelbaum FR, et al: A randomized investigation of high-dose versus standard-dose cytosine arabinoside with daunorubicin in patients with previously untreated acute myeloid leukemia: A Southwest Oncology Group Study. Blood 1996;88:2841–2851. PMID 8874180
- ↑ Bishop JF, Matthews JP, Young GA, et al: A randomized study of high-dose cytarabine in induction in acute myeloid leukemia. Blood 1996;87:1710–1717. PMID 8634416
- ↑ Bishop J (1997). "The treatment of adult acute myeloid leukemia". Semin Oncol. 24 (1): 57–69. PMID 9045305.
- ↑ Huang ME, Ye YC, Chen SR, et al: Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 1988;72:567–572. PMID 3165295
- ↑ Tallman MS, Anderson JW, Schiffer CA, et al: All-trans-retinoic acid in acute promyelocytic leukemia. N Engl J Med 1997;337:1021–1028. PMID 9321529
- ↑ Fenaux P, Chastang C, Chevret S, et al: A randomized comparison of all transretinoic acid (ATRA) followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed acute promyelocytic leukemia. The European APL Group. Blood 1999;94:1192–1200. PMID 10438706
- ↑ Estey E (2002). "Treatment of acute myelogenous leukemia". Oncology (Williston Park). 16 (3): 343–52, 355–6, discussion 357, 362, 365–6. PMID 15046392.
- ↑ Cassileth P, Harrington D, Hines J, Oken M, Mazza J, McGlave P, Bennett J, O'Connell M (1988). "Maintenance chemotherapy prolongs remission duration in adult acute nonlymphocytic leukemia". J Clin Oncol. 6 (4): 583–7. PMID 3282032.
- ↑ Cassileth PA, Hines JD, Oken MM, et al: Maintenance chemotherapy prolongs remission duration in adult acute nonlymphocytic leukemia. J Clin Oncol 1988;6(4):583–587. PMID 3282032
- ↑ Mayer RJ, Davis RB, Schiffer CA, et al: Intensive post-remission chemotherapy in adults with acute myeloid leukemia. N Engl J Med 1994;331:896–903. PMID 8078551
- ↑ 12.0 12.1 O'Donnell MR, Appelbaum FR, Baer MR, et al: NCCN practice guidelines for acute myelogenous leukemia. Oncology NCCN Proc 2000;14:53–61. PMID 11195419
- ↑ Abeloff, Martin et al. (2004), pp. 2840–41.
- ↑ Appelbaum FR: Who should be transplanted for AML? editorial. Leukemia 2001;15:680–682. PMID 11368380
- ↑ Appelbaum FR: Hematopoietic cell transplantation beyond first remission keynote Address. Leukemia 2002;16:157–159. PMID 11840278
- ↑ Sievers EL, Larson RA, Stadmauer EA, et al: Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse. J Clin Oncol 2001;19:3244–3254. PMID 11432892
- ↑ Soignet SL, Frankel SR, Douer D, et al: United States multicenter study of arsenic trioxide in relapsed acute promyelocytic leukemia. J Clin Oncol 2001;19:3852–3860. PMID 11559723
- ↑ Shapira T, Pereg D, Lishner M (September 2008). "How I treat acute and chronic leukemia in pregnancy". Blood Rev. 22 (5): 247–59. doi:10.1016/j.blre.2008.03.006. PMID 18472198.