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Adult acute myeloid leukemia

Table of Contents

GENERAL INFORMATION
CELLULAR CLASSIFICATION
STAGE INFORMATION
Untreated
In remission
TREATMENT OPTION OVERVIEW
UNTREATED ADULT ACUTE MYELOID LEUKEMIA
ADULT ACUTE MYELOID LEUKEMIA IN REMISSION
RECURRENT ADULT ACUTE MYELOID LEUKEMIA

GENERAL INFORMATION

Advances in the treatment of adult acute myeloid leukemia (AML; also called acute nonlymphocytic leukemia or ANLL) have resulted in substantially improved complete remission rates.[1-5] Treatment should be sufficiently aggressive to achieve complete remission because partial remission offers no substantial survival benefit. Approximately 60% to 70% of adults with AML can be expected to attain complete remission status following appropriate induction therapy. More than 15% of adults with AML (about 25% of those who attain complete remission) can be expected to survive 3 or more years and may be cured. Remission rates in adult AML are inversely related to age, with an expected remission rate of greater than 65% for those younger than 60 years of age. Data suggest that once attained, duration of remission may be shorter in older patients. Increased morbidity and mortality during induction appear to be directly related to age. Other adverse prognostic factors include central nervous system involvement with leukemia, systemic infection at diagnosis, elevated white blood cell count (>100,000 per cubic millimeter), treatment- induced AML, and history of myelodysplastic syndrome. Leukemias that express the progenitor cell antigen CD34 and/or the P-glycoprotein (MDR1 gene product) have an inferior outcome.[6-8] Expression of the bcl-2 oncoprotein, which inhibits programmed cell death, has been shown to predict poor survival.[9] Cytogenetic analysis provides some of the strongest prognostic information available and is helpful in patients with newly diagnosed AML. Cytogenetic abnormalities which indicate a good prognosis include t(8;21), inv(16), and t(15;17). Normal cytogenetics portend average-risk AML. Patients with AML that is characterized by deletions of the long arms or monosomies of chromosomes 5 or 7; by translocations or inversions of chromosome 3, t(6;9), t(9;22); or by abnormalities of chromosome 11q23 have particularly poor prognoses with chemotherapy. The fusion genes formed in t(8;21) and inv(16) can be detected by reverse-transcriptase polymerase chain reaction (RT-PCR), which will indicate the presence of these genetic alterations in some patients with normal cytogenetics. Abnormalities of the MLL gene (chromosome 11q23) can also be detected using RT-PCR and may be detected in some cases of leukemia with normal cytogenetics. These molecular diagnostic techniques are not readily available.[1-4,10,11]

Subtypes of AML are acute myeloblastic leukemia (with or without maturation), acute promyelocytic leukemia, acute monocytic leukemia, acute myelomonocytic leukemia, erythroleukemia, and acute megakaryoblastic leukemia.[12] Morphologic, histochemical, immunologic, and cytogenetic criteria for these distinctions have been standardized.[13,14] Each criterion has subtle prognostic and treatment implications but, for practical purposes, antileukemic therapy is similar for all subtypes. The large lysosomal granules seen in acute promyelocytic leukemia signal the high probability of severe hemorrhagic complications during early induction therapy.[15,16] If the patient demonstrates evidence of disseminated intravascular coagulation, the early institution of low-dose heparin for anticoagulation is commonly used; however, there is some controversy on this point.[17] Aggressive transfusion support with fresh frozen plasma, cryoprecipitate, and platelets is often also necessary. Remission induction of acute promyelocytic leukemia with tretinoin (ATRA), alone or in combination with cytotoxic agents, is an area of clinical evaluation.[18,19] ATRA induction appears to normalize the coagulopathy more quickly than does conventional induction therapy, but it can be associated with the development of hyperleukocytosis and adult respiratory distress syndrome that is steroid-responsive (the so-called "retinoic acid syndrome").[20] Prophylactic heparin is not generally used in patients receiving ATRA induction. The optimal integration of ATRA into the treatment of M3 AML has not been defined (see the Untreated AML section of this summary).

Allogeneic bone marrow transplantation can be considered in patients younger than 60 years of age in first remission if a histocompatible sibling is available as a potential donor. Although data have shown that partially matched donors can also be used in some circumstances, the incidence of severe graft-versus-host disease, delayed engraftment, and graft rejection is significantly increased. Transfusion of blood products from potential donors should be avoided, and histocompatibility testing should be done at the earliest possible time. Although some data suggest that transplantation in patients during their first remission may improve long-term survival, these data need to be confirmed. In some studies, results from chemotherapy alone or high-dose chemotherapy with autologous bone marrow transplantation [21-31] appear to be comparable to those of allogeneic transplantation.[32,33]

As a generalization, most studies demonstrate that the rate of leukemic relapse is decreased following allogeneic bone marrow transplantation in first remission compared with chemotherapy alone. Because of the higher initial mortality with bone marrow transplantation caused by graft-versus-host disease and interstitial pneumonia, however, comparative analyses of the two approaches demonstrate similar overall survivals. An analysis of bone marrow transplant results has also suggested that the same factors that predict for shorter response durations with chemotherapy (i.e., high initial white blood cell count, monocytic morphology, and age) may also result in shorter remission duration following transplantation. Allogeneic bone marrow transplantation has yielded a high rate of complete response in patients for whom initial induction therapy failed,[34] and autologous bone marrow transplantation may produce long-term leukemia-free survival in approximately one third of patients in either first relapse or second complete remission.[35] Results of allogeneic bone marrow transplantation have modestly improved since 1980, largely because of a reduction in transplant-related mortality;[36] further follow-up of these and other studies is needed before firm recommendations can be made.[28,37] It should be noted that transplant centers performing five or fewer transplants annually usually have poorer results than larger centers.[38]

Cytogenetic studies should be performed at the time of diagnosis.[39] As noted above, there is increasing evidence of nonrandom chromosomal rearrangements in some of the subtypes in the French-American-British classification, which have important prognostic significance.[40]

The differentiation of AML from acute lymphocytic leukemia has important therapeutic implications. Histochemical stains, TdT determinations, and cell surface antigen determinations aid in discrimination.

References:

  1. Yates JW, Glidewell O, Wiernik P, et al.: Cytosine arabinoside with daunorubicin or Adriamycin for therapy of acute myelocytic leukemia: a CALGB study. Blood 60(2): 454-462, 1982.

  2. Champlin R, Gale RP: Acute myelogenous leukemia: recent advances in therapy. Blood 69(6): 1551-1562, 1987.

  3. Keating MJ, McCredie KB, Bodey GP, et al.: Improved prospects for long-term survival in adults with acute myelogenous leukemia. Journal of the American Medical Association 248(19): 2481-2486, 1982.

  4. Weinstein HJ, Mayer RJ, Rosenthal DS, et al.: Chemotherapy for acute myelogenous leukemia in children and adults: VAPA update. Blood 62(2): 315-319, 1983.

  5. Preisler HD, Anderson K, Rai K, et al.: The frequency of long-term remission in patients with acute myelogenous leukemia treated with conventional maintenance chemotherapy: a study of 760 patients with a minimal follow-up time of 6 years. British Journal of Haematology 71(2): 189-194, 1989.

  6. Myint H, Lucie NP: The prognostic significance of the CD34 antigen in acute myeloid leukaemia. Leukemia and Lymphoma 7(5-6): 425-429, 1992.

  7. Geller RB, Zahurak M, Hurwitz CA, et al.: Prognostic importance of immunophenotyping in adults with acute myelocytic leukaemia: the significance of the stem-cell glycoprotein CD34 (My10). British Journal of Haematology 76(3): 340-347, 1990.

  8. Campos L, Guyotat D, Archimbaud E, et al.: Clinical significance of multidrug resistance P-glycoprotein expression on acute nonlymphoblastic leukemia cells at diagnosis. Blood 79(2): 473-476, 1992.

  9. Campos L, Rouault JP, Sabido O, et al.: High expression of bcl-2 protein in acute myeloid leukemia cells is associated with poor response to chemotherapy. Blood 81(11): 3091-3096, 1993.

  10. Holmes R, Keating MJ, Cork A, et al.: A unique pattern of central nervous system leukemia in acute myelomonocytic leukemia associated with inv(16)(p13q22). Blood 65(5): 1071-1078, 1985.

  11. Dutcher JP, Schiffer CA, Wiernik PH: Hyperleukocytosis in adult acute nonlymphocytic leukemia: impact on remission rate and duration, and survival. Journal of Clinical Oncology 5(9): 1364-1372, 1987.

  12. Bennett JM, Catovsky D, Daniel MT, et al.: Proposals for the classification of acute leukemias. British Journal of Haematology 33(4): 451-458, 1976.

  13. Second MIC Cooperative Study Group: Morphologic, immunologic and cytogenetic (MIC) working classification of the acute myeloid leukaemias. British Journal of Haematology 68(4): 487-494, 1988.

  14. Cheson BD, Cassileth PA, Head DR, et al.: Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia. Journal of Clinical Oncology 8(5): 813-819, 1990.

  15. Sanz MA, Jarque I, Martin G, et al.: Acute promyelocytic leukemia: therapy results and prognostic factors. Cancer 61(1): 7-13, 1988.

  16. Kantarjian HM, Keating MJ, Walters RS, et al.: Acute promyelocytic leukemia: M.D. Anderson Hospital experience. American Journal of Medicine 80(5): 789-797, 1986.

  17. Goldberg MA, Ginsburg D, Mayer RJ, et al.: Is heparin administration necessary during induction chemotherapy for patients with acute promyelocytic leukemia. Blood 69(1): 187-191, 1987.

  18. Warrell RP, Frankel SR, Miller WH, et al.: Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans-retinoic acid). New England Journal of Medicine 324(20): 1385-1393, 1991.

  19. Frankel SR, Eardley A, Heller G, et al.: All-trans retinoic acid for acute promyelocytic leukemia: results of the New York study. Annals of Internal Medicine 120(4): 278-286, 1994.

  20. Frankel SR, Eardley A, Lauwers G, et al.: The "retinoic acid syndrome" in acute promyelocytic leukemia. Annals of Internal Medicine 117(4): 292-296, 1992.

  21. Tallman MS, Kopecky KJ, Amos D, et al.: Analysis of prognostic factors for the outcome of marrow transplantation or further chemotherapy for patients with acute nonlymphocytic leukemia in first remission. Journal of Clinical Oncology 7(3): 326-337, 1989.

  22. Appelbaum FR, Fisher LD, Thomas ED: Chemotherapy vs marrow transplantation for adults with acute nonlymphocytic leukemia: a five-year follow-up. Blood 72(1): 179-184, 1988.

  23. Geller RB, Saral R, Piantadosi S, et al.: Allogeneic bone marrow transplantation after high-dose busulfan and cyclophosphamide in patients with acute nonlymphocytic leukemia. Blood 73(8): 2209-2218, 1989.

  24. Clift RA, Buckner CD, Thomas ED, et al.: The treatment of acute non-lymphoblastic leukemia by allogeneic marrow transplantation. Bone Marrow Transplantation 2(3): 243-258, 1987.

  25. Cassileth PA, Andersen J, Lazarus HM, et al.: Autologous bone marrow transplant in acute myeloid leukemia in first remission. Journal of Clinical Oncology 11(2): 314-319, 1993.

  26. Beatty PG, Clift RA, Mickelson EM, et al.: Marrow transplantation from related donors other than HLA-identical siblings. New England Journal of Medicine 313(13): 765-771, 1985.

  27. Rees JKH, Swirsky D, Gray RG, et al.: Principal results of the Medical Research Council's 8th acute myeloid leukaemia trial. Lancet 2(8518): 1236-1241, 1986.

  28. Dutcher JP, Wiernik PH, Markus S, et al.: Intensive maintenance therapy improves survival in adult acute nonlymphocytic leukemia: an eight-year follow-up. Leukemia 2(7): 413-419, 1988.

  29. International Bone Marrow Transplant Registry: Transplant or chemotherapy in acute myelogenous leukaemia. Lancet 1(8647): 1119-1122, 1989.

  30. McMillan AK, Goldstone AH, Linch DC, et al.: High-dose chemotherapy and autologous bone marrow transplantation in acute myeloid leukemia. Blood 76(3): 480-488, 1990.

  31. Champlin R, Gajewski J, Nimer S, et al.: Postremission chemotherapy for adults with acute myelogenous leukemia: improved survival with high-dose cytarabine and daunorubicin consolidation treatment. Journal of Clinical Oncology 8(7): 1199-1206, 1990.

  32. Cassileth PA, Lynch E, Hines JD, et al.: Varying intensity of postremission therapy in acute myeloid leukemia. Blood 79(8): 1924-1930, 1992.

  33. Biggs JC, Horowitz MM, Gale RP, et al.: Bone marrow transplants may cure patients with acute leukemia never achieving remission with chemotherapy. Blood 80(4): 1090-1093, 1992.

  34. Petersen FB, Lynch MH, Clift RA, et al.: Autologous marrow transplantation for patients with acute myeloid leukemia in untreated first relapse or in second complete remission. Journal of Clinical Oncology 11(7): 1353-1360, 1993.

  35. Bortin MM, Horowitz MM, Gale RP, et al.: Changing trends in allogeneic bone marrow transplantation for leukemia in the 1980s. Journal of the American Medical Association 268(5): 607-612, 1992.

  36. McGlave PB, Haake RJ, Bostrom BC, et al.: Allogeneic bone marrow transplantation for acute nonlymphocytic leukemia in first remission. Blood 72(5): 1512-1517, 1988.

  37. Horowitz MM, Przepiorka D, Champlin RE, et al.: Should HLA-identical sibling bone marrow transplants for leukemia be restricted to large centers? Blood 79(10): 2771-2774, 1992.

  38. Larson RA, Le Beau MM, Vardiman JW, et al.: The predictive value of initial cytogenetic studies in 148 adults with acute nonlymphocytic leukemia: a 12-year study (1970-1982). Cancer Genetics and Cytogenetics 10(3): 219-236, 1983.

  39. Keating MJ, Smith TL, Kantarjian H, et al.: Cytogenetic pattern in acute myelogenous leukemia: a major reproducible determinant of outcome. Leukemia 2(7): 403-412, 1988.

  40. Bloomfield CD, de la Chapelle A: Chromosome abnormalities in acute nonlymphocytic leukemia: clinical and biologic significance. Seminars in Oncology 14(4): 372-383, 1987.

CELLULAR CLASSIFICATION

Acute myeloid leukemia (AML) is classified morphologically according to the French-American-British criteria by the degree of differentiation along different cell lines and the extent of cell maturation.[1-3]

M1, M2, and M3 leukemia show predominantly granulocytic differentiation and differ from one another in the extent and nature of granulocytic maturation; M4 shows both granulocytic and monocytic differentiation; M5 shows predominantly monocytic differentiation; and M6 shows predominantly erythroblastic differentiation. M7 is associated with leukemic megakaryocytes.

Myeloblastic leukemia without maturation (M1)

The cells in the bone marrow show some evidence of granulocytic
differentiation, with 3% or more of the blasts myeloperoxidase positive or
with a varying proportion of blasts containing at least a few azurophilic
granules, Auer rods, or both. Further maturation is not seen.

Myeloblastic leukemia with maturation (M2)
M2 can be distinguished from M1 by the presence of maturation at or beyond
the promyelocyte stage. The leukemic cells are often nucleated and have
varying amounts of cytoplasm, usually with many azurophilic granules; cells
containing Auer rods, almost always single, are common. In M2 (in contrast
to M1), myelocytes, metamyelocytes, and mature granulocytes may be found in
varying proportions. A specific chromosomal translocation (8;21) is
frequently associated with this morphology.

Promyelocytic leukemia (M3)
Characteristics of this disorder:
a. The great majority of cells are abnormal promyelocytes, with a characteristic pattern of heavy granulation.

b. The nucleus varies greatly in size and shape and is often reniform or bilobed.

Disseminated intravascular coagulation (DIC) and t(15;17) are almost
invariably associated with M3 histology.

M3 variant (M3V)
A minority of patients with acute promyelocytic leukemia have multiple
granules detectable only by electron microscopy. Disseminated intravascular
coagulation and t(15;17) are also found in such patients.[4]

Myelomonocytic leukemia (M4)
Both granulocytic and monocytic differentiation are present in varying
proportions in the bone marrow and peripheral blood. M4 resembles M2 in all
respects except that the proportion of promonocytes and monocytes exceeds
20% of the nucleated cells in the bone marrow, the peripheral blood, or the
blood. However, promonocytes and promyelocytes may not always be readily
distinguishable in Romanowsky-stained preparations unless the cytochemical
reactions specific for monocytes are carried out.

M4E
A variant of M4 AML has a variable (usually <10%) number of morphologically
abnormal eosinophils present in the bone marrow.[5,6]

Of note is that most such cases are associated with abnormalities of
chromosome 16 and may be associated with an improved overall prognosis and
an increased propensity for central nervous system involvement.

Monocytic leukemia (M5)
Two subtypes occur:
a. Poorly differentiated (monoblastic) is characterized by large blasts with delicate lacy chromatin, and one--occasionally up to three--large prominent vesicular nucleoli. The cytoplasm is basophilic and voluminous and often shows one or more pseudopods. A low percentage of promonocytes may be present.

b. Differentiated is characterized by monoblasts, promonocytes, and monocytes; but the proportion of monocytes in the peripheral blood is higher than in the bone marrow, in which the predominant cell is the promonocyte. This cell is similar to the monoblast but has a large nucleus with a cerebriform appearance; nucleoli may be present, but the cytoplasm is less basophilic, has a grayish ground-glass appearance, and often has fine azurophilic granules scattered throughout. Extramedullary tissue infiltrations, particularly of the skin and gingiva, are most common in patients with this morphologic subtype.

Erythroleukemia (M6)
The erythropoietic component usually exceeds 50% of all the nucleated cells
in the bone marrow. The erythroblasts show, in varying degree, bizarre
morphological features -- especially multiple lobation of the nucleus with
variation in size of the lobes, multiple nuclei, presence of one or more
nuclear fragments, giant forms, and megaloblastic features. The
granulopoietic cells show an increased proportion of myeloblasts and
promyelocytes, and Auer rods may be seen. The percentage of myeloblasts and
promyelocytes accompanying these dyserythropoietic changes is variable, but
when it is less than 30% of all the nucleated cells, an alternative
diagnosis such as myelodysplastic syndrome should be considered.

Megakaryoblastic leukemia (M7)
The blasts can either resemble immature megakaryocytes or be quite
undifferentiated in morphology and resemble lymphoblasts. By definition,
the blasts stain negative for myeloperoxidase. The diagnosis can be
confirmed by the ultrastructural demonstration of platelet peroxidase or the
use of antibodies directed against platelet antigens.[7] M7 leukemia is
often accompanied by intense marrow fibrosis.

AML with minimal differentiation (M0)
Cases of AML are categorized as M0 if they lack definite myeloid
differentiation by conventional morphologic or cytochemical analysis.
Myeloid differentiation must be demonstrated by immunophenotyping, with
reactivity to at least one lineage-specific myeloid antigen, such as CD13 or
CD33, or by ultrastructural evidence of peroxidase-positive granules. M7
leukemia should be excluded by negative studies for platelet glycoproteins
(e.g., CD41 or CD62) and/or platelet-specific peroxidase (by electron
microscopy). Several small series have suggested a low rate of remission
attainment and short remission duration for cases of M0.[8-10]

Isolated granulocytic sarcoma (chloroma)
Rarely, patients present with isolated tumors of myeloblasts. These tumors
require histochemical or immunohistochemical stains to identify their
myeloid etiology. Granulocytic sarcomas may present viscerally, in soft
tissue or skin, head or neck, bone, or the central nervous system. In a
review of the world's literature on granulocytic sarcoma, 66% of 90 patients
developed AML at a median of 9 months. Newly diagnosed patients with
granulocytic sarcoma are usually treated with aggressive chemotherapy as if
they have AML; cures are not attained with surgery or radiation therapy.[11]
The presence of granulocytic sarcoma in patients with the otherwise good-risk
t(8;21) AML may be associated with a lower complete remission rate and
decreased remission duration.[12]

References:

  1. Bennett JM, Catovsky D, Daniel MT, et al.: Proposals for the classification of acute leukemias. British Journal of Haematology 33(4): 451-458, 1976.

  2. Bennett JM, Catovsky D, Daniel MT, et al.: Proposed revised criteria for the classification of acute myeloid leukemia: a report of the French-American-British Cooperative Group. Annals of Internal Medicine 103(4): 620-625, 1985.

  3. Cheson BD, Cassileth PA, Head DR, et al.: Report of the National Cancer Institute-sponsored workshop on definitions of diagnosis and response in acute myeloid leukemia. Journal of Clinical Oncology 8(5): 813-819, 1990.

  4. Golomb HM, Rowley JD, Vardiman JW, et al.: "Microgranular" acute promyelocytic leukemia: a distinct clinical, ultrastructural, and cytogenetic entity. Blood 55(2): 253-259, 1980.

  5. Holmes R, Keating MJ, Cork A, et al.: A unique pattern of central nervous system leukemia in acute myelomonocytic leukemia associated with inv(16)(p13q22). Blood 65(5): 1071-1078, 1985.

  6. Larson RA, Williams SF, Le Beau MM, et al.: Acute myelomonocytic leukemia with abnormal eosinophils and inv(16) or t(16:16) has a favorable prognosis. Blood 68(6): 1242-1249, 1986.

  7. Bennett JM, Catovsky D, Daniel MT, et al.: Criteria for the diagnosis of acute leukemia of megakaryocyte lineage (M7): a report of the French-American-British Cooperative Group. Annals of Internal Medicine 103(3): 460-462, 1985.

  8. Lee EJ, Pollak A, Leavitt RD, et al.: Minimally differentiated acute nonlymphocytic leukemia: a distinct entity. Blood 70(5): 1400-1406, 1987.

  9. Yokose N, Ogata K, Ito T, et al.: Chemotherapy for minimally differentiated acute myeloid leukemia (AML-M0): a report on five cases and review of the literature. Annals of Hematology 66(2): 67-70, 1993.

  10. Stasi R, Del Poeta G, Venditti A, et al.: Analysis of treatment failure in patients with minimally differentiated acute myeloid leukemia (AML-M0). Blood 83(6): 1619-1625, 1994.

  11. Imrie KR, Kovacs MJ, Selby D, et al.: Isolated chloroma: the effect of early antileukemic therapy. Annals of Internal Medicine 123(5): 351-353, 1995.

  12. Byrd JC, Weiss RB, Arthur DC, et al.: Extramedullary leukemia adversely affects hematologic complete remission rate and overall survival in patients with t(8;21)(q22;q22): results from Cancer and Leukemia Group B 8461. Journal of Clinical Oncology 15(2): 466-475, 1997.

STAGE INFORMATION

There is no clear-cut staging system for this disease.

Untreated

Untreated adult acute myeloid leukemia (AML) is defined as newly diagnosed leukemia with no prior treatment. The patient exhibits the following features: abnormal bone marrow with more than 30% blasts and signs and symptoms of the disease, usually accompanied by an abnormal white blood cell count and differential, hematocrit/hemoglobin, and platelet count.

In remission

Adult AML in remission is defined as a normal peripheral blood cell count and normocellular marrow with less than 5% blasts in the marrow, and no signs or symptoms of the disease. In addition, there are no signs or symptoms of central nervous system leukemia or other extramedullary infiltration.

TREATMENT OPTION OVERVIEW

Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. Refer to the PDQ levels of evidence summary for more information.

Successful treatment of acute myeloid leukemia (AML) requires the control of bone marrow and systemic disease and specific treatment of central nervous system (CNS) disease, if present. The cornerstone of this strategy includes systemically administered combination chemotherapy. Because only 5% of patients with AML develop CNS disease, prophylactic treatment is not indicated.[1-3]

Treatment is divided into two phases: induction (to attain remission) and postremission (to maintain remission). Maintenance therapy for AML was previously administered for several years but is not included in most current treatment clinical trials in the United States (see the adult AML in remission section of this summary). Other studies have used more intensive "consolidation" therapy administered for a shorter duration of time after which treatment is discontinued.[4] Consolidation therapy appears to be effective when given either immediately after remission is achieved [4] or when delayed for 9 months.[3]

Since myelosuppression is an anticipated consequence of both the leukemia and its treatment with chemotherapy, patients must be closely monitored during therapy. Facilities must be available for hematologic support with multiple blood fractions including platelet transfusions, as well as for the treatment of related infectious complications.[5] Randomized trials have shown similar outcomes for patients who received prophylactic platelet transfusions at a level of 10,000 per cubic millimeter rather than 20,000 per cubic millimeter.[6] The incidence of platelet alloimmunization was similar among groups randomly assigned to receive pooled platelet concentrates from random donors; filtered, pooled platelet concentrates from random donors; ultraviolet B-irradiated, pooled platelet concentrates from random donors; or filtered platelets obtained by apheresis from single random donors.[7] Colony- stimulating factors, e.g., granulocyte colony-stimulating factor (G-CSF) and granulocyte-macrophage colony-stimulating factor (GM-CSF), have been studied in an effort to shorten the period of granulocytopenia associated with leukemia treatment.[8] If used, these agents are administered after completion of induction therapy. GM-CSF was shown to improve survival in one randomized trial of AML in patients 55 to 70 years of age (median survival was 10.6 months versus 4.8 months). In this trial, patients were randomized to receive GM-CSF or placebo following demonstration of leukemic clearance of the bone marrow.[9] However, GM-CSF did not show benefit in a separate similar randomized trial in patients aged 60 and older.[10] In the latter study, clearance of the marrow was not required before initiating cytokine therapy. In a randomized trial of G-CSF given following induction therapy to patients over age 65, complete response was higher in patients who received G-CSF, due to a decreased incidence of primary leukemic resistance. Growth factor administration did not impact on mortality or on survival.[11]

The administration of GM-CSF or other myeloid growth factors before and during induction therapy, to augment the effects of cytotoxic therapy through the recruitment of leukemic blasts into cell cycle (growth factor priming), has been an area of active clinical research. Evidence from randomized studies of GM-CSF priming have come to opposite conclusions. A randomized study of GM-CSF priming during conventional induction and consolidation therapy showed no difference in outcomes between patients who received GM-CSF and those who did not receive growth factor priming.[12,13][Level of evidence: 1iiA] In contrast, a similar randomized placebo-controlled study of GM-CSF priming in patients with AML 55 to 75 years of age showed improved disease-free survival in the group receiving GM-CSF (median disease-free survival for patients who achieved complete remission was 23 months versus 11 months; 2-year disease-free survival was 48% versus 21%), with a trend towards improvement in overall survival (2-year survival was 39% versus 27%, p=0.082) for patients 55 to 64 years of age.[14][Level of evidence: 1iiDi]

The designations in PDQ that treatments are "standard" or "under clinical evaluation" are not to be used as a basis for reimbursement determinations.

References:

  1. Scheinberg DA, Maslak P, Weiss M: Acute leukemias. In: DeVita VT Jr, Hellman S, Rosenberg SA, eds.: Cancer: Principles and Practice of Oncology. Philadelphia, Pa: Lippincott-Raven Publishers, 5th ed., 1997, pp 2293-2321.

  2. Wiernik PH: Diagnosis and treatment of acute nonlymphocytic leukemia. In: Wiernik PH, Canellos GP, Dutcher JP, et al., Eds.: Neoplastic Diseases of the Blood. New York: Churchill Livingstone, 3rd ed., 1996, pp 283-302.

  3. Morrison FS, Kopecky KJ, Head DR, et al.: Late intensification with POMP chemotherapy prolongs survival in acute myelogenous leukemia - results of a Southwest Oncology Group Study of Rubidazone versus Adriamycin for remission induction, prophylactic intrathecal therapy, late intensification, and levamisole maintenance. Leukemia 6(7): 708-714, 1992.

  4. Cassileth PA, Lynch E, Hines JD, et al.: Varying intensity of postremission therapy in acute myeloid leukemia. Blood 79(8): 1924-1930, 1992.

  5. Supportive Care. In: Wiernik PH, Canellos GP, Dutcher JP, et al., Eds.: Neoplastic Diseases of the Blood. New York: Churchill Livingstone, 3rd ed., 1996, pp 779-967.

  6. Rebulla P, Finazzi G, Marangoni F, et al.: The threshold for prophylactic platelet transfusions in adults with acute myeloid leukemia. New England Journal of Medicine 337(26): 1870-1875, 1997.

  7. The Trial to Reduce Alloimmunization to Platelets Study Group: Leukocyte reduction and ultraviolet B irradiation of platelets to prevent alloimmunization and refractoriness to platelet transfusions. New England Journal of Medicine 337(26): 1861-1869, 1997.

  8. Geller RB: Use of cytokines in the treatment of acute myelocytic leukemia: a critical review. Journal of Clinical Oncology 14(4): 1371-1382, 1996.

  9. Rowe JM, Andersen JW, Mazza JJ, et al.: A randomized placebo-controlled phase III study of granulocyte-macrophage colony-stimulating factor in adult patients (>55 to 70 years of age) with acute myelogenous leukemia: a study of the Eastern Cooperative Oncology Group (E1490). Blood 86(2): 457-462, 1995.

  10. Stone RM, Berg DT, George SL, et al.: Granulocyte-macrophage colony-stimulating factor after initial chemotherapy for elderly patients with primary acute myelogenous leukemia. New England Journal of Medicine 332(25): 1671-1677, 1995.

  11. Dombret H, Chastang C, Fenaux P, et al.: A controlled study of recombinant human granulocyte colony-stimulating factor in elderly patients after treatment for acute myelogenous leukemia. New England Journal of Medicine 332(25): 1678-1683, 1995.

  12. Buchner T, Hiddemann W, Wormann B, et al.: GM-CSF multiple course priming and long-term administration in newly diagnosed AML: hematologic and therapeutic effects. Blood 84(10, Suppl 1): A-95, 27a, 1994.

  13. Lowenberg B, Boogaerts MA, Daenen SM, et al.: Value of different modalities of granulocyte-macrophage colony-stimulating factor applied during or after induction therapy of acute myeloid leukemia. Journal of Clinical Oncology 15(12): 3496-3506, 1997.

  14. Witz F, Sadoun A, et al. for the Groupe Ouest Est Leucemies Aigues Myeloblastiques (GOELAM): A placebo-controlled study of recombinant human granulocyte-macrophage colony-stimulating factor administered during and after induction treatment for de novo acute myelogenous leukemia in elderly patients. Blood 91(8): 2722-2730, 1998.

UNTREATED ADULT ACUTE MYELOID LEUKEMIA

Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. Refer to the PDQ levels of evidence summary for more information.

The two-drug regimen of daunorubicin given in conjunction with cytarabine will result in a complete response rate of approximately 65%. Some physicians opt to add a third drug, thioguanine, to this regimen, although there is little evidence that this three-drug regimen is better therapy. However one study has suggested that the addition of etoposide during induction therapy may improve response duration.[1] Clinical trials are testing the addition of other drugs (for example, amsacrine, mitoxantrone, or higher doses of cytarabine). Idarubicin, a new anthracycline, and mitoxantrone have been compared with daunorubicin in randomized trials in newly diagnosed patients. Idarubicin appeared to be as effective or more effective than daunorubicin, although the doses of idarubicin and daunorubicin may not have been equivalent.[2-5] No significant difference between daunorubicin and mitoxantrone has been reported.[6]

Two randomized studies suggest that the dose intensity of cytarabine administered during induction may have a significant impact on disease-free survival. In an Australian study, patients were randomized to receive high- dose bolus cytarabine in combination with daunorubicin and etoposide or a conventional dose of continuous-infusion cytarabine in combination with the same drugs. Both groups received identical conventional cytarabine-based consolidation chemotherapy. While the complete response rate was identical, disease-free survival was superior in the group induced with high-dose cytarabine.[7] A Children's Cancer Group study randomized pediatric patients receiving two courses of cytarabine-based induction therapy to receive the second course of cytarabine either following hematopoietic recovery, as in conventional "7 plus 3" chemotherapy, or in a planned timed sequence beginning on day 10 of therapy, during aplasia. This timed sequence was based on similarly timed chemotherapy developed in adults with AML.[8] As in the Australian study, both arms had identical remission rates. Patients who received the timed sequential chemotherapy had superior disease-free survival regardless of the postremission therapy administered: consolidation chemotherapy or allogeneic or autologous bone marrow transplantation.[9,10] In contrast to earlier studies, a definitive phase III trial did not show a survival advantage to cytarabine dose intensity during induction therapy.[11][Level of evidence: 1iiDi]

AML arising from myelodysplasia or secondary to previous cytotoxic chemotherapy has a lower rate of remission than de novo AML. A retrospective analysis of patients undergoing allogeneic bone marrow transplantation in this setting showed that the long-term survival for such patients was identical regardless of whether or not patients had received remission induction therapy (disease- free survival was approximately 20%). These data suggest that patients with these subsets of leukemia may be treated primarily with allogeneic bone marrow transplant if their overall performance status is adequate, potentially sparing patients the added toxic effect of induction chemotherapy.[12][Level of evidence: 3iiiDi]

Supportive care during remission induction treatment should routinely include red blood cell and platelet transfusions when appropriate.[13,14] Empiric broad spectrum antimicrobial therapy is an absolute necessity for febrile patients who are profoundly neutropenic.[15,16] Careful instruction in personal hygiene, dental care, and recognition of early signs of infection are appropriate in all patients. Elaborate isolation facilities (including filtered air, sterile food, and gut flora sterilization) are not routinely indicated but may benefit transplant patients.[17,18] Rapid marrow ablation with consequent earlier marrow regeneration decreases morbidity and mortality. White blood cell transfusions can be beneficial in selected patients with aplastic marrow and serious infections that do not respond to antibiotics.[19] Prophylactic oral antibiotics may be appropriate in patients with expected prolonged, profound granulocytopenia (<100 per cubic millimeter for 2 weeks).[20] Norfloxacin and ciprofloxacin have both been shown to decrease the incidence of gram-negative infection and time to first fever in randomized trials. The combination of ofloxacin and rifampin has proven superior to norfloxacin in decreasing the incidence of documented granulocytopenic infection.[21-23] Serial surveillance cultures may be helpful in such patients to detect the presence or acquisition of resistant organisms.

Special consideration must be given to induction therapy for acute promyelocytic leukemia (PML). It is now well-recognized that oral administration of tretinoin (ATRA; 45 milligrams per square meter per day) can induce remission in 70% to 90% of patients with M3 AML (ATRA is not effective in patients with AML that resembles M3 morphologically but does not demonstrate the t(15;17) or typical PML-RAR-alpha gene rearrangement).[24-30] ATRA induces terminal differentiation of the leukemic cells, followed by restoration of non- clonal hematopoiesis. Administration of ATRA leads to rapid resolution of coagulopathy in the majority of patients, and heparin administration is not required in patients receiving ATRA. However, randomized trials have not shown a reduction in morbidity and mortality during ATRA induction when compared with chemotherapy. Administration of ATRA can lead to hyperleukocytosis, as well as a syndrome of respiratory distress now known as the "retinoic acid syndrome." Prompt recognition of the syndrome and aggressive administration of steroids can prevent severe respiratory distress.[31] The optimal management of ATRA- induced hyperleukocytosis has not been established; neither has the optimal post-remission management of patients who receive ATRA induction. However, two large cooperative group trials have demonstrated a statistically significant relapse-free and overall survival advantage to patients with M3 AML who receive ATRA at some point during their antileukemic management.[32,33] Presence of the unique fusion transcript PML-RAR-alpha (measured in bone marrow by polymerase chain reaction) in patients who achieve complete remission may indicate those who are likely to relapse early.[34] In addition, a retrospective review of randomized trials from the Southwest Oncology Group has suggested that the dose-intensity of daunorubicin administered in induction and consolidation chemotherapy may significantly impact on remission rate, disease- free survival, and overall survival in patients with M3 AML.[35] Patients undergoing induction therapy for M3 AML which does not include ATRA need careful management of the coagulopathy which is often severe and usually increases during cytotoxic chemotherapy. This coagulopathy can lead to catastrophic intracranial bleeding, but can be well-controlled with low-dose heparin infusion, or with aggressive replacement of platelets and clotting factors.[36]

Treatment options for remission induction therapy:

One of the following equivalent combination chemotherapy regimens:
dose-intensive cytarabine-based induction therapy.[7,8]
cytarabine + daunorubicin.[37,38]
cytarabine + idarubicin.[2-5]
cytarabine + daunorubicin + thioguanine.[39]
mitoxantrone + etoposide.[40]

Treatment of central nervous system leukemia, if present:
intrathecal cytarabine or methotrexate.

Clinical trials.

References:

  1. Bishop JF, Lowenthal RM, Joshua D, et al.: Etoposide in acute nonlymphocytic leukemia. Blood 75(1): 27-32, 1990.

  2. Wiernik PH, Banks PL, Case DC, et al.: Cytarabine plus idarubicin or daunorubicin as induction and consolidation therapy for previously untreated adult patients with acute myeloid leukemia. Blood 79(2): 313-319, 1992.

  3. Vogler WR, Velez-Garcia E, Weiner RS, et al.: A phase III trial comparing idarubicin and daunorubicin in combination with cytarabine in acute myelogenous leukemia: a Southeastern Cancer Study Group. Journal of Clinical Oncology 10(7): 1103-1111, 1992.

  4. Berman E, Heller G, Santorsa J, et al.: Results of a randomized trial comparing idarubicin and cytosine arabinoside with daunorubicin and cytosine arabinoside in adult patients with newly diagnosed acute myelogenous leukemia. Blood 77(8): 1666-1674, 1991.

  5. Mandelli F, Petti MC, Ardia A, et al.: A randomised clinical trial comparing idarubicin and cytarabine to daunorubicin and cytarabine in the treatment of acute non-lymphoid leukaemia. European Journal of Cancer 27(6): 750-755, 1991.

  6. Arlin Z, Case DC, Moore J, et al.: Randomized multicenter trial of cytosine arabinoside with mitoxantrone or daunorubicin in previously untreated adult patients with acute nonlymphocytic leukemia (ANLL): Lederle Cooperative Group. Leukemia 4(3): 177-183: 1990.

  7. Bishop JF, Matthews JP, Young GA, et al.: A randomized study of high-dose cytarabine in induction in acute myeloid leukemia. Blood 87(5): 1710-1717, 1996.

  8. Geller RB, Burke PJ, Karp JE, et al.: A two-step timed sequential treatment for acute myelocytic leukemia. Blood 74(5): 1499-1506, 1989.

  9. Woods WG, Kobrinsky N, Buckley JD, et al.: Timed-sequential induction therapy improves postremission outcome in acute myeloid leukemia: a report from the Children's Cancer Group. Blood 87(12): 4979-4989, 1996.

  10. Woods WG, Neudorf S, Gold S, et al.: Aggressive post-remission (REM) chemotherapy is better than autologous bone marrow transplantation (BMT) and allogeneic BMT is superior to both in children with acute myeloid leukemia (AML). Proceedings of the American Society of Clinical Oncology 15: A-1091, 368, 1996.

  11. 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 88(8): 2841-2851, 1996.

  12. Anderson JE, Gooley TA, Schoch G, et al.: Stem cell transplantation for secondary acute myeloid leukemia: evaluation of transplantation as initial therapy or following induction chemotherapy. Blood 89(7): 2578-2585, 1997.

  13. Slichter, SJ: Controversies in platelet transfusion therapy. Annual Review of Medicine 31: 509-540, 1980.

  14. Murphy MF, Metcalfe P, Thomas H, et al.: Use of leucocyte-poor blood components and HLA-matched-platelet donors to prevent HLA alloimmunization. British Journal of Haematology 62(3): 529-534, 1986.

  15. Hughes WT, Armstrong D, Bodey GP, et al.: Guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever. Journal of Infectious Diseases 161(3): 381-396, 1990.

  16. Rubin M, Hathorn JW, Pizzo PA: Controversies in the management of febrile neutropenic cancer patients. Cancer Investigation 6(2): 167-184, 1988.

  17. Armstrong, D: Protected environments are discomforting and expensive and do not offer meaningful protection. American Journal of Medicine 76: 685-689, 1984.

  18. Sherertz RJ, Belani A, Kramer BS, et al.: Impact of air filtration on nosocomial Aspergillus infections: unique risk of bone marrow transplant recipients. American Journal of Medicine 83(4): 709-718, 1987.

  19. Schiffer CA: Granulocyte transfusions: an overlooked therapeutic modality. Transfusion Medicine Reviews 4(1): 2-7, 1990.

  20. Wade JC, Schimpff SC, Hargadon MT, et al.: A comparison of trimethoprim-sulfamethoxazole plus nystatin with gentamicin plus nystatin in the prevention of infections in acute leukemia. New England Journal of Medicine 304(18): 1057-1062, 1981.

  21. Karp JE, Merz WG, Hendricksen C, et al.: Oral norfloxacin for prevention of gram-negative bacterial infections in patients with acute leukemia and granulocytopenia. Annals of Internal Medicine 106(1): 1-7, 1987.

  22. Gruppo Italiano Malattie Ematologiche Maligne dell' Adulto (GIMEMA): Prevention of bacterial infection in neutropenic patients with hematologic malignancies: a randomized, multicenter trial comparing norfloxacin with ciprofloxacin. Annals of Internal Medicine 115(1): 7-12, 1991.

  23. Bow EJ, Mandell LA, Louie TJ, et al.: Quinolone-based antibacterial chemoprophylaxis in neutropenic patients: effect of augmented gram-positive activity on infectious morbidity. Annals of Internal Medicine 125(3): 183-190, 1996.

  24. Huang M, Ye Y, Chen S, et al.: Use of all-trans retinoic acid in the treatment of acute promyelocytic leukemia. Blood 72(2): 567-572, 1988.

  25. Castaigne S, Chomienne C, Daniel MT, et al.: All-trans retinoic acid as a differentiation therapy for acute promyelocytic leukemia. I. clinical results. Blood 76(9): 1704-1709, 1990.

  26. Warrell RP, Frankel SR, Miller WH, et al.: Differentiation therapy of acute promyelocytic leukemia with tretinoin (all-trans-retinoic acid). New England Journal of Medicine 324(20): 1385-1393, 1991.

  27. Chen Z, Xue Y, Zhang R, et al.: A clinical and experimental study on all-trans retinoic acid-treated acute promyelocytic leukemia patients. Blood 78(6): 1413-1419, 1991.

  28. Muindi J, Frankel SR, Miller WH, et al.: Continuous treatment with all-trans retinoic acid causes a progressive reduction in plasma drug concentrations: implications for relapse and retinoid "resistance" in patients with acute promyelocytic leukemia. Blood 79(2): 299-303, 1992.

  29. Licht JD, Chomienne C, Goy A, et al.: Clinical and molecular characterization of a rare syndrome of acute promyelocytic leukemia associated with translocation (11;17). Blood 85(4): 1083-1094, 1995.

  30. Gallagher RE, Li YP, Rao S, et al.: Characterization of acute promyelocytic leukemia cases with PML-RARalpha break/fusion sites in PML exon 6: identification of a subgroup with decreased in vitro responsiveness to all-trans retinoic acid. Blood 86(4): 1540-1547, 1995.

  31. Frankel SR, Eardley A, Lauwers G, et al.: The "retinoic acid syndrome" in acute promyelocytic leukemia. Annals of Internal Medicine 117(4): 292-296, 1992.

  32. Fenaux P, Le Deley MC, Castaigne S, et al.: Effect of all transretinoic acid in newly diagnosed acute promyelocytic leukemia: results of a multicenter randomized trial. Blood 82(11): 3241-3249, 1993.

  33. Tallman MS, Andersen J, Schiffer CA, et al.: Phase III randomized study of all-trans retinoic acid (ATRA) vs daunorubicin (D) and cytosine arabinoside (A) as induction therapy and ATRA vs observation as maintenance therapy for patients with previously untreated acute promyelocytic leukemia (APL). Blood 86(Suppl 1): A-488, 125a, 1995.

  34. Lo Coco F, Diverio D, Pandolfi PP, et al.: Molecular evaluation of residual disease as a predictor of relapse in acute promyelocytic leukaemia. Lancet 340(8833): 1437-1438, 1992.

  35. Head D, Kopecky KJ, Weick J, et al.: Effect of aggressive daunomycin therapy on survival in acute promyelocytic leukemia. Blood 86(5): 1717-1728, 1995.

  36. Stone RM, Mayer RJ: The unique aspects of acute promyelocytic leukemia. Journal of Clinical Oncology 8(11): 1913-1921, 1990.

  37. Yates JW, Glidewell O, Wiernik P, et al.: Cytosine arabinoside with daunorubicin or Adriamycin for therapy of acute myelocytic leukemia: a CALGB study. Blood 60(2): 454-462, 1982.

  38. Dillman RO, Davis RB, Green MR, et al.: A comparative study of two different doses of cytarabine for acute myeloid leukemia: a phase III trial of Cancer and Leukemia Group B. Blood 78(10): 2520-2526, 1991.

  39. Gale RP, Foon KA, Cline MJ, et al.: Intensive chemotherapy for acute myelogenous leukemia. Annals of Internal Medicine 94(6): 753-757, 1981.

  40. Bow EJ, Sutherland JA, Kilpatrick MG, et al.: Therapy of untreated acute myeloid leukemia in the elderly: remission-induction using a non-cytarabine-containing regimen of mitoxantrone plus etoposide. Journal of Clinical Oncology 14(4): 1345-1352, 1996.

ADULT ACUTE MYELOID LEUKEMIA IN REMISSION

Some citations in the text of this section are followed by a level of evidence. The PDQ editorial boards use a formal ranking system to help the reader judge the strength of evidence linked to the reported results of a therapeutic strategy. Refer to the PDQ levels of evidence summary for more information.

Although individual patients have been reported to have long disease-free survival or cure with a single cycle of chemotherapy,[1] postremission therapy is always indicated in therapy that is planned with curative intent. In a small randomized study conducted by the Eastern Cooperative Oncology Group, all patients who did not receive postremission therapy experienced a relapse after a short median complete remission duration.[2] Current approaches to postremission therapy include short-term, relatively intensive chemotherapy with cytarabine-based regimens similar to "standard" induction clinical trials (consolidation chemotherapy), consolidation chemotherapy with more dose- intensive cytarabine-based treatment, high-dose chemotherapy or chemoradiotherapy with autologous bone marrow rescue, and high-dose marrow- ablative therapy with allogeneic bone marrow rescue. While older studies have included longer-term therapy at lower doses ("maintenance"), there is no convincing evidence in AML that maintenance therapy provides prolonged disease- free survival beyond shorter-term, more dose-intensive approaches, and few current treatment clinical trials include maintenance therapy.

Nontransplant consolidation therapy using cytarabine-containing regimens has treatment-related death rates that are usually less than 10% to 20% and have yielded reported disease-free survival rates from 20% to 50%.[3-6] A large randomized trial that compared three different cytarabine-containing consolidation regimens showed a clear benefit in survival to patients younger than 60 years of age who received high-dose cytarabine.[3] In contrast to these results for consolidation therapy with cytarabine, a definitive phase III trial did not show a survival advantage to cytarabine dose intensity during induction therapy.[7] The duration of consolidation therapy has ranged from one cycle [4,6] to four or more cycles.[3,5] The optimal doses, schedules, and duration of consolidation chemotherapy have not been determined. Therefore, to address these issues, patients with AML should be included in clinical trials at institutions that treat large numbers of such patients.

Dose-intensive cytarabine-based chemotherapy can be complicated by severe neurologic [8] and/or pulmonary toxic effects [9] and should be administered by physicians experienced in these regimens at centers that are equipped to deal with potential complications. In a retrospective analysis of 256 patients who received high dose bolus cytarabine at a single institution, the most powerful predictor of cytarabine neurotoxicity was renal insufficiency. The incidence of neurotoxicity was significantly greater in patients treated with twice daily doses of 3 grams per square meter per dose when compared with 2 grams per square meter per dose.

Allogeneic bone marrow transplantation results in the lowest incidence of leukemic relapse, even when compared with bone marrow transplantation from an identical twin (syngeneic bone marrow transplantation). This has led to the concept of an immunologic graft-versus-leukemia effect, similar to (and related to) graft-versus-host disease. The improvement in freedom from relapse using allogeneic bone marrow transplantation as the primary postremission therapy is offset, at least in part, by the increased morbidity and mortality caused by graft-versus-host disease, veno-occlusive disease of the liver, and interstitial pneumonitis. Disease-free survival rates using allogeneic transplantation in first complete remission have ranged from 45% to 60%.[10-12] The use of allogeneic bone marrow transplantation as primary postremission therapy is limited by the need for a human leukocyte antigen (HLA)-matched sibling donor and the increased mortality from allogeneic bone marrow transplantation of patients who are older than 50 years of age. The mortality from allogeneic bone marrow transplantation that uses an HLA-matched sibling donor ranges from 20% to 40%, depending on the series. The use of matched, unrelated donors for allogeneic bone marrow transplantation is being evaluated at many centers but has a very substantial rate of treatment-related mortality, with disease-free survival rates less than 35%.[13]

Autologous bone marrow transplantation yielded disease-free survival rates between 35% and 50% in patients with AML in first remission. Autologous bone marrow transplantation has also cured a lesser proportion of patients in second remission.[14-20] Treatment-related mortality rates of patients who have had autologous peripheral blood or marrow transplantation range from 10% to 20%. Ongoing controversies include the optimum timing of autologous stem cell transplantation, whether it should be preceded by consolidation chemotherapy, and the role of ex vivo treatment of the graft with chemotherapy, such as 4-hydroperoxycyclophosphamide (4-HC) [18] or mafosphamide [19], or monoclonal antibodies, such as anti-CD33.[20] Purged marrows have demonstrated delayed hematopoietic recovery; however, most studies that use unpurged marrow grafts have included several cycles of consolidation chemotherapy and may have included patients who were already cured of their leukemia. In a prospective trial of patients with AML in first remission, City of Hope investigators treated patients with one course of high-dose cytarabine consolidation, followed by unpurged autologous bone marrow transplantation following preparative therapy of total body irradiation, etoposide, and cyclophosphamide. In an intent-to-treat analysis, actuarial disease-free survival was approximately 50%, which is comparable to other reports of high-dose consolidation therapy or purged autologous transplantation.[21][Level of evidence: 3iiDi] A randomized trial by the Eastern Cooperative Oncology Group comparing autologous bone marrow transplantation using 4-HC-purged bone marrow with high-dose cytarabine consolidation therapy has been completed. Results are not yet available. Another area of active clinical research is modulation of the immune system following autologous bone marrow transplantation using cytokines or cyclosporine in an attempt to induce a graft-versus-leukemia-like effect. A randomized trial has compared the use of autologous bone marrow transplantation in first complete remission to consolidation chemotherapy, with the latter group eligible for autologous bone marrow transplantation in second complete remission. The two arms of the study had equivalent survival.[22] Two randomized trials in pediatric AML have shown no advantage of autologous transplantation following busulfan/cyclophosphamide preparative therapy and 4HC-purged graft when compared to consolidation chemotherapy including high- dose cytarabine.[23,24] An additional randomized trial of autologous bone marrow transplantation versus intensive consolidation chemotherapy in adult AML, using unpurged bone marrow, also showed no advantage to receiving autologous bone marrow transplantation in first remission.[25] It is possible that certain subsets of AML may specifically benefit from autologous bone marrow transplantation in first remission. In a retrospective analysis of 999 patients with de novo AML treated with allogeneic or autologous bone marrow transplantation in first remission in whom cytogenetic analysis at diagnosis was available, patients with poor-risk cytogenetics (abnormalities of chromosomes 5, 7, 11q, or hypodiploidy) had less favorable outcomes following allogeneic bone marrow transplantation than patients with normal karyotypes or other cytogenetic abnormalities. Leukemia-free survival for the patients in the poor-risk groups was approximately 20%.[26][Level of evidence: 3iiiDi] While secondary myelodysplastic syndromes have been reported following autologous bone marrow transplantation, the development of new clonal cytogenetic abnormalities following autologous bone marrow transplantation does not necessarily portend the development of secondary myelodysplastic syndromes or AML.[27][Level of evidence: 3iiiD] Whenever possible, patients should be entered on clinical trials of post-remission management.

Because bone marrow transplantation can cure about 30% of patients who experience relapse following chemotherapy, some investigators suggested that allogeneic bone marrow transplantation can be reserved for early first relapse or second complete remission without compromising the number of patients who are ultimately cured.[28] However, clinical and cytogenetic information can define certain subsets of patients with predictable better or worse prognoses using consolidation chemotherapy. Good-risk factors include t(8;21), inv(16) associated with M4 AML with eosinophilia, and t(15;17) associated with M3 AML. Poor-risk factors include deletion of 5q and 7q, trisomy 8, t(6;9), t(9;22), and a history of myelodysplasia or antecedent hematologic disorder. Patients in the good-risk group have a reasonable chance of cure with intensive consolidation, and it may be reasonable to defer transplantation in that group until early first relapse. The poor-risk group is unlikely to be cured with consolidation chemotherapy, and allogeneic bone marrow transplantation in first complete remission is a reasonable option for patients with an HLA-identical sibling donor. The efficacy of autologous stem cell transplantation in the poor-risk group has not been reported to date but is the subject of active clinical trials. Patients with normal cytogenetics are in an intermediate-risk group, and postremission management should be individualized or, ideally, managed according to a clinical trial.

The rapid engraftment kinetics of peripheral blood progenitor cells demonstrated in trials of high-dose therapy for epithelial neoplasms has led to interest in the alternative use of autologous and allogeneic peripheral blood progenitor cells as rescue for myeloablative therapy for the treatment of AML. One pilot trial of the use of autologous transplantation with unpurged peripheral blood progenitor cells in first remission had a 3-year disease-free survival of 35%; detailed prognostic factors for these patients were not provided.[29] This result appears inferior to the best results of chemotherapy or autologous bone marrow transplantation and suggests that the use of peripheral blood progenitor cells be limited to clinical trials. Similarly, peripheral blood allogeneic stem cell transplantation is under evaluation. There is some evidence that this modality may carry a high risk of chronic graft-versus-host disease, and thus should also be restricted to clinical trials.[30]

References:

  1. Vaughn WP, Karp JE, Burke PJ: Long chemotherapy-free remissions after single-cycle timed-sequential chemotherapy for acute myelocytic leukemia. Cancer 45(5): 859-865, 1980.

  2. Cassileth PA, Harrington DP, Hines JD, et al.: Maintenance chemotherapy prolongs remission duration in adult acute nonlymphocytic leukemia. Journal of Clinical Oncology 6(4): 583-587, 1988.

  3. Mayer RJ, Davis RB, Schiffer CA, et al.: Intensive postremission chemotherapy in adults with acute myeloid leukemia. New England Journal of Medicine 331(14): 896-903, 1994.

  4. Champlin R, Gajewski J, Nimer S, et al.: Postremission chemotherapy for adults with acute myelogenous leukemia: improved survival with high-dose cytarabine and daunorubicin consolidation treatment. Journal of Clinical Oncology 8(7): 1199-1206, 1990.

  5. Rohatiner AZ, Gregory WM, Bassan R, et al.: Short-term therapy for acute myelogenous leukemia. Journal of Clinical Oncology 6(2): 218-226, 1988.

  6. Geller RB, Burke PJ, Karp JE, et al.: A two-step timed sequential treatment for acute myelocytic leukemia. Blood 74(5): 1499-1506, 1989.

  7. 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 88(8): 2841-2851, 1996.

  8. Baker WJ, Royer GL, Weiss RB: Cytarabine and neurologic toxicity. Journal of Clinical Oncology 9(4): 679-693, 1991.

  9. Haupt HM, Hutchins GM, Moore GW: ARA-C lung: noncardiogenic pulmonary edema complicating cytosine arabinoside therapy of leukemia. American Journal of Medicine 70(2): 256-261, 1981.

  10. Clift RA, Buckner CD, Thomas ED, et al.: The treatment of acute non-lymphoblastic leukemia by allogeneic marrow transplantation. Bone Marrow Transplantation 2(3): 243-258, 1987.

  11. Reiffers J, Gaspard MH, Maraninchi D, et al.: Comparison of allogeneic or autologous bone marrow transplantation and chemotherapy in patients with acute myeloid leukaemia in first remission: a prospective controlled trial. British Journal of Haematology 72(1): 57-63, 1989.

  12. Bostrom B, Brunning RD, McGlave P, et al.: Bone marrow transplantation for acute nonlymphocytic leukemia in first remission: analysis of prognostic factors. Blood 65(5): 1191-1196, 1985.

  13. Busca A, Anasetti C, Anderson G, et al.: Unrelated donor or autologous marrow transplantation for treatment of acute leukemia. Blood 83(10): 3077-3084, 1994.

  14. Chao NJ, Stein AS, Long GD, et al.: Busulfan/etoposide - initial experience with a new preparatory regimen for autologous bone marrow transplantation in patients with acute nonlymphoblastic leukemia. Blood 81(2): 319-323, 1993.

  15. Linker CA, Ries CA, Damon LE, et al.: Autologous bone marrow transplantation for acute myeloid leukemia using busulfan plus etoposide as a preparative regimen. Blood 81(2): 311-318, 1993.

  16. Sanz MA, de la Rubia J, Sanz GF, et al.: Busulfan plus cyclophosphamide followed by autologous blood stem-cell transplantation for patients with acute myeloblastic leukemia in first complete remission: a report from a single institution. Journal of Clinical Oncology 11(9): 1661-1667, 1993.

  17. Cassileth PA, Andersen J, Lazarus HM, et al.: Autologous bone marrow transplant in acute myeloid leukemia in first remission. Journal of Clinical Oncology 11(2): 314-319, 1993.

  18. Jones RJ, Santos GW: Autologous bone marrow transplantation with 4-hydroperoxycyclophosphamide purging. In: Gale RP, Ed.: Acute Myelogenous Leukemia: Progress and Controversies. Wiley-Liss, 1990, pp 411-419.

  19. Gorin NC, Aegerter P, Auvert B, et al.: Autologous bone marrow transplantation for acute myelocytic leukemia in first remission: a European survey of the role of marrow purging. Blood 75(8): 1606-1614, 1990.

  20. Robertson MJ, Soiffer RJ, Freedman AS, et al.: Human bone marrow depleted of CD33-positive cells mediates delayed but durable reconstitution of hematopoiesis: clinical trial of MY9 monoclonal antibody-purged autografts for the treatment of acute myeloid leukemia. Blood 79(9): 2229-2236, 1992.

  21. Stein AS, O'Donnell MR, Chai A, et al.: In vivo purging with high-dose cytarabine followed by high-dose chemoradiotherapy and reinfusion of unpurged bone marrow for adult acute myelogenous leukemia in first complete remission. Journal of Clinical Oncology 14(8): 2206-2216, 1996.

  22. Zittoun RA, Mandelli F, Willemze R, et al.: Autologous or allogeneic bone marrow transplantation compared with intensive chemotherapy in acute myelogenous leukemia. New England Journal of Medicine 332(4): 217-223, 1995.

  23. Ravindranath Y, Yeager AM, Chang MN, et al.: Autologous bone marrow transplantation versus intensive consolidation chemotherapy for acute myeloid leukemia in childhood. New England Journal of Medicine 334(22): 1428-1434, 1996.

  24. Woods WG, Neudorf S, Gold S, et al.: Aggressive post-remission (REM) chemotherapy is better than autologous bone marrow transplantation (BMT) and allogeneic BMT is superior to both in children with acute myeloid leukemia (AML). Proceedings of the American Society of Clinical Oncology 15: A-1091, 368, 1996.

  25. Harousseau JL, Cahn JY, Pignon B, et al.: Autologous bone marrow transplantation (ABMT) versus intensive consolidation chemotherapy (ICC) as post remission therapy in adult acute myeloblastic leukemia (AML): final analysis of the GOELAM randomized study. Proceedings of the American Society of Clinical Oncology 15: A-1051, 358, 1996.

  26. Ferrant A, Labopin M, et al., on behalf of the Acute Leukemia Working Party of the European Group for Blood and Marrow Transplantation (EBMT): Karyotype in acute myeloblastic leukemia: prognostic significance for bone marrow transplantation in first remission: a European Group for Blood and Marrow Transplantation study. Blood 90(8): 2931-2938, 1997.

  27. Imrie KR, Dube I, Prince HM, et al.: New clonal karyotypic abnormalities acquired following autologous bone marrow transplantation for acute myeloid leukemia do not appear to confer an adverse prognosis. Bone Marrow Transplantation 21(4): 395-399, 1998.

  28. Schiller GJ, Nimer SD, Territo MC, et al.: Bone marrow transplantation versus high-dose cytarabine-based consolidation chemotherapy for acute myelogenous leukemia in first remission. Journal of Clinical Oncology 10(1): 41-46, 1992.

  29. Sanz MA, de la Rubia J, Sanz GF, et al.: Busulfan plus cyclophosphamide followed by autologous blood stem-cell transplantation for patients with acute myeloblastic leukemia in first complete remission: a report from a single institution. Journal of Clinical Oncology 11(9): 1661-1667, 1993.

  30. Bishop MR, Tarantolo S, Pavletic S, et al.: Low incidence of early death and early relapse following allogeneic blood stem cell transplantation. Proceedings of the American Society of Clinical Oncology 15: A-6, 85, 1996.

RECURRENT ADULT ACUTE MYELOID LEUKEMIA

Treatments with new agents under clinical evaluation are particularly appropriate in patients with recurrent acute myeloid leukemia (AML) and should be considered when possible.[1]

There are a number of newer agents with activity in recurrent AML, including amsacrine, mitoxantrone, diaziquone, high-dose cytarabine, homoharringtonine, idarubicin, and etoposide; some of these agents are being tested in combination regimens.[2-8] A study with mitoxantrone and cytarabine was successful in 50% to 60% of patients who experienced relapse after initially obtaining a complete remission.[9] Other studies using idarubicin and cytarabine or high-dose etoposide and cyclophosphamide reported similar results.[8,10-12]

A subset of relapsed patients treated aggressively may have extended disease- free survival; however, cures in patients following a relapse are thought to be more commonly achieved using bone marrow transplantation.[12] A retrospective study from the International Bone Marrow Transplant Registry compared adults younger than 50 years of age with AML in second complete remission who received HLA-matched sibling transplantation versus a variety of consolidation approaches.[13] The chemotherapy approaches were heterogeneous; some patients received no consolidation therapy. The transplantation regimens were similarly diverse. Leukemia-free survival appeared to be superior for patients receiving bone marrow transplants for two groups: patients older than 30 years of age whose first remission was less than one year; and patients younger than 30 years of age whose first remission was longer than one year.

Allogeneic bone marrow transplantation in early first relapse or in second complete remission provides a disease-free survival rate of approximately 30%.[14] Therefore, some investigators advocate allogeneic bone marrow transplantation in early first relapse to avoid the toxic effect of re-induction chemotherapy.[14-16] Allogeneic bone marrow transplantation can salvage some patients whose disease fails to go into remission with intensive chemotherapy.[12] Autologous bone marrow transplantation is a reasonable option for patients in second complete remission, offering a disease-free survival that may be comparable to autografting in first complete remission.[17-19]

Studies exploring the utility of autologous bone marrow transplantation in early first relapse are in progress.[20] Low-dose palliative radiation therapy may be considered in patients with symptomatic recurrence either within or outside the central nervous system.[21]

References:

  1. Estey E, Plunkett W, Gandhi V, et al.: Fludarabine and arabinosylcytosine therapy of refractory and relapsed acute myelogenous leukemia. Leukemia and Lymphoma 9(4/5): 343-350, 1993.

  2. Legha SS, Keating MJ, McCredie KB, et al.: Evaluation of AMSA in previously treated patients with acute leukemia: results of therapy in 109 adults. Blood 60(2): 484-490, 1982.

  3. Estey EH, Keating MJ, Smith TL, et al.: Prediction of complete remission in patients with refractory acute leukemia treated with AMSA. Journal of Clinical Oncology 2(2): 102-106, 1984.

  4. Warrell RP, Coonley CJ, Gee TS: Homoharringtonine: an effective new drug for remission induction in refractory nonlymphoblastic leukemia. Journal of Clinical Oncology 3(5): 617-621, 1985.

  5. Herzig RH, Wolff SN, Lazarus HM, et al.: High-dose cytosine arabinoside therapy for refractory leukemia. Blood 62(2): 361-369, 1983.

  6. Hines JD, Oken MM, Mazza JJ, et al.: High-dose cytosine arabinoside and M-AMSA is effective therapy in relapsed acute nonlymphocytic leukemia. Journal of Clinical Oncology 2(6): 545-549, 1984.

  7. Hiddemann W, Kreutzmann H, Straif K, et al.: High-dose cytosine arabinoside and mitoxantrone: a highly effective regimen in refractory acute myeloid leukemia. Blood 69(3): 744-749, 1987.

  8. Brown RA, Herzig RH, Wolff SN, et al.: High-dose etoposide and cyclophosphamide without bone marrow transplantation for resistant hematologic malignancy. Blood 76(3): 473-479, 1990.

  9. Paciucci PA, Dutcher JP, Cuttner J, et al.: Mitoxantrone and Ara-C in previously treated patients with acute myelogenous leukemia. Leukemia 1(7): 565-567, 1987.

  10. Lambertenghi-Deliliers G, Maiolo AT, Annaloro C, et al.: Idarubicin in sequential combination with cytosine arabinoside in the treatment of relapsed and refractory patients with acute non-lymphoblastic leukemia. European Journal of Cancer and Clinical Oncology 23(7): 1041-1045, 1987.

  11. Harousseau JL, Reiffers J, Hurteloup P, et al.: Treatment of relapsed acute myeloid leukemia with idarubicin and intermediate-dose cytarabine. Journal of Clinical Oncology 7(1): 45-49, 1989.

  12. Forman SJ, Schmidt GM, Nademanee AP, et al.: Allogeneic bone marrow transplantation as therapy for primary induction failure for patients with acute leukemia. Journal of Clinical Oncology 9(9): 1570-1574, 1991.

  13. Gale RP, Horowitz MM, Rees JK, et al.: Chemotherapy versus transplants for acute myelogenous leukemia in second remission. Leukemia 10(1): 13-19, 1996.

  14. Clift RA, Buckner CD, Thomas ED, et al.: The treatment of acute non-lymphoblastic leukemia by allogeneic marrow transplantation. Bone Marrow Transplantation 2(3): 243-258, 1987.

  15. Clift RA, Buckner CD, Appelbaum FR, et al.: Allogeneic marrow transplantation during untreated first relapse of acute myeloid leukemia. Journal of Clinical Oncology 10(11): 1723-1729, 1992.

  16. Brown RA, Wolff SN, Fay JW, et al.: High-dose etoposide, cyclophosphamide, and total body irradiation with allogeneic bone marrow transplantation for patients with acute myeloid leukemia in untreated first relapse: a study by the North American Marrow Transplant Group. Blood 85(5): 1391-1395, 1995.

  17. Meloni G, De Fabritiis P, Petti MC, et al.: BAVC regimen and autologous bone marrow transplantation in patients with acute myelogenous leukemia in second remission. Blood 75(12): 2282-2285, 1990.

  18. Chopra R, Goldstone AH, McMillan AK, et al.: Successful treatment of acute myeloid leukemia beyond first remission with autologous bone marrow transplantation using busulfan/cyclophosphamide and unpurged marrow: The British Autograft Group experience. Journal of Clinical Oncology 9(10): 1840-1847, 1991.

  19. Gorin NC, Labopin M, Meloni G, et al.: Autologous bone marrow transplantation for acute myeloblastic leukemia in Europe: further evidence of the role of marrow purging by mafosfamide. Leukemia 5(10): 896-904, 1991.

  20. Petersen FB, Lynch MH, Clift RA, et al.: Autologous marrow transplantation for patients with acute myeloid leukemia in untreated first relapse or in second complete remission. Journal of Clinical Oncology 11(7): 1353-1360, 1993.

  21. Gray JR, Wallner KE: Reversal of cranial nerve dysfunction with radiation therapy in adults with lymphoma and leukemia. International Journal of Radiation Oncology, Biology, Physics 19(2): 439-444, 1990.

Date Last Modified: 07/1999


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