Adult Acute Myeloid Leukemia

 

Treatment Option Overview
Untreated Adult Acute Myeloid Leukemia
Adult Acute Myeloid Leukemia In Remission
Recurrent Adult Acute Myeloid Leukemia

성인 급성골수성백혈병(AML) 치료법에 진전에 따라 실질적으로 완전관해율이 크게 향상되었다.  부분관해는 실질적인 생존율의 향상을 기대할 수 없기 때문에 완전관해에 도달하기 위해서는 보다 적극적인 치료방향을 설정해야 한다. 오늘 날 적절한 유도요법으로 서인형 AML은 약 60-70%의 완전관해를 기대할 수 있다. AML 15%에서 3년 이상의 생존을 기대할 수 있는데, 60세 이하에서는 65% 이상의 관해율과 함께 완전관해 도달한 환자의 25%에서는 3년 이상의 생존을 기대할 수 있다. 그리고 관해율은 나이에 역비례한다.

이러한 통계에 의하면 일단 관해에 도달하면 노령에서는 그 기간이 짧으며 사망률은 나이와 직접 관련이 있다. 다른 예후인자는 중추신경계의 백혈병 침윤, 진단시 전신성 감염증, 백혈구증가증, 치료유인성 AML, MDS 과거력 등이다. progenitor cell antigen CD34 과 P-glycoprotein (MDR1 gene product)을 가진 백혈병은 치료효과가 낮고, programmed cell death을 방해하는 bcl-2 oncoprotein을 나타내는 백혈병은 생존율이 상대적으로 떨어질 것으로 예상된다.

세포유전학적 분석소견으로 치료전 진단시 백혈병의 예후에 관한 정보를 얻을 수 있다. 염색체이상으로 t(8;21), inv(16), and t(15;17)은 양호한 예후를 의미하고, 정상 핵형은 중등도 예후군으로 분류한다. 또한 5번과 7번 염색체 장완의 부분 또는 완전 결실(monosomy), 3번 염색체의 전위형과 역위형, t(6;9), t(9;22), 11q23 등도 발견되는데 이들은 화학요법제에 대한 치료효과가 낮아 불량한 예후군으로 분류한다.

t(8;21)과 inv(16)에서 형성된 융합유전자는 역전사 중합효소연쇄반응법(reverse-transcriptase polymerase chain reaction, RT-PCR)으로 증명되는데 세포유전학적 핵형이 정상일 경우에도 나타날 수 있다. MLL gene (chromosome 11q23) 이상도RT-PCR을 이용하여 검출할 수 있는데 이 역시 정상 핵형에서도 발견된다.

AML 아형으로 급성골수아구성백혈병(acute myeloblastic leukemia, with or without maturation), 급성전골수구성백혈병(acute promyelocytic leukemia), 급성단구성백혈병(acute monocytic leukemia), 급성골수단구성백혈병(acute myelomonocytic leukemia), 적백혈병(erythroleukemia), 급성거핵아구성백혈병(acute megakaryoblastic leukemia) 등이 있다. 이들을 감별하는데 형태학적, 조직화학적, 면역학적, 그리고 세포유전학적 진단기준이 표준화 되어 있다. 각각의 진단기준은 그나름대로의 예후나 치료방향을 설정하는데 중요성을 가지고 실질적인 목적에도 활용되고 있다. 항백혈병 치료법은 모든 아형에서 비슷하다.

The large lysosomal granules seen in acute promyelocytic leukemia signal the high probability of severe hemorrhagic complications during early induction therapy. 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. 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. 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"). 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 appear to be comparable to those of allogeneic transplantation.

    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, 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. Results of allogeneic bone marrow transplantation have modestly improved since 1980, largely because of a reduction in transplant-related mortality; further follow-up of these and other studies is needed before firm recommendations can be made. It should be noted that transplant centers performing five or fewer transplants annually usually have poorer results than larger centers.

    Cytogenetic studies should be performed at the time of diagnosis. 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.

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

 

 

형태학적 분류 FAB 분류법

급성골수성백혈병(AML)은  FAB 진단기준에 따라 세포분화 정도와 성숙 정도로 구분한다. M1, M2, M3형 백혈병은 모두 과립구계 분화가 우세하지만 성숙 정도 및 성상은 서로 다르다. M4는 과립구와 단구계 분화, M5는 단구계 분화가 우세하고 M6은 적혈구계 분화가 우세하다. M7은 백혈병성 거핵구와 관련이 있다.

FAB-M1 : Myeloblastic leukemia without maturation

골수세포는 과립구로의 분화한다는 약간의 증거가 있는데, 아세포에서 myeloperoxidase 양성 세포가 3% 이상이고, 상당 수의 아세포는 아주르 호성 과립 또는 Auer 소체를 보인다. 백혈병세포는 성숙분화 과정중 아세포 단계에서 정지된 양상이어서 대부분의 세포는 실제 골수아세포(myeloblast)이다.

 

 

  FAB-M1

 

 


FAB-M2 : Myeloblastic leukemia with maturation

M2는 전골수구 단계 이후의 세포들이 나타나므로 인해 M1과 구별된다. 백혈병세포는 핵인을 보이고, 세포질 양은 다양하나 azure 과립이 풍부하며 auer 소체도 흔하게 발견된다. M1과 달리 골수구, 후골수구, 성숙형의 과립구가 많이 나타나고, 염색체검사에서는 특이한 염색체 전위형 (8;21)가 발견된다.

아래 사진은 t(8;21)(q22;q22) 염색체 이상을 가진 FAB-M2의 골수상이다. FAB 분류(1976)에서는, 아구는 아즈르 과립을 포함하지 않는 I형 아세포(typeⅠblast)와 소수의 과립을 가지는 II형 아세포(typeⅡblast)로 구별한다. 명료한 핵인, 미세한 핵크로마틴 등은 아구의 공통된 특징이다. TypeⅡ blast는 미세한 아즈르 과립을 몇 개 정도 가지지만, 그 과립의 사이즈와 수에 대해서 명확한 규정은 없다. 그것이 세포 분류의 혼란을 일으키는 원인의 하나이지만, 미세한 아즈르 과립을 계산하는 일은 없다.

M2의 30∼40%에서 t(8,21) 즉 8번 염색체와 21번 염색체의 상호전좌가 발견되며, 예후인자로서 중요하다. 또한 t(8,21) 염색체 이상을 가지는 경우 특징 있는 세포형태를 나타내어 그 염색체 이상 유무를 어느 정도 예측 할 수 있다고 한다.

  FAB-M2 with t(8;21)(q22;q22)

 


FAB-M3 : Promyelocytic leukemia (M3)

형태학적 특징으로 대부분의 세포는 heavy granulation을  특징적 소견을 보이는 비정상 전골수구이다. 또한 세포핵은 크기와 모양을 달리하면서 흔히 신장 모양 또는 이엽성(bilobed)이다. 미만성혈관내응고증(disseminated intravascular coagulation, DIC),  t(15;17), FAB-M3 세포형태는 서로간에 깊은 관련성을 가진다.

전형적인 FAB-M3에서는 백혈병세포의 세포질에서는 다수의 Auer 소체가 모여 집합체(faggots)로 나타난다. FAB-M3는 급성골수성백혈병 중에서 특이한 변형으로서 인정되고 있는데 그 이유는 DIC가 자주 병발해 강한 출혈 경향을 보이고, ATRA (All-trans retinoic acid)에 의한 분화유도요법으로 높은 관해율을 얻을 수 있는 점이다.

        M3V :    M3 variant (변이형)

급성전골수구성 백혈병(APL: acute promyelocytic leukemia)의 소수 환자에서는 전자현미경을 통해서만 다발성과립을 확인할 수 있고, DIC와 염색체검사에서 t(15;17)도 발견된다. 아래 사진의 증례에서는 말발굽(horse shoe) 혹은 신장 모양(kidney-shaped)으로 AML-M3에 특징적인 형태를 두고는 있지만, 아즈르 과립은 지극히 미세하다. 그러나 peroxidase 염색에는 강양성, esterase 염색에서는 음성 결과를 확인할 수 있다. t(15,17) 염색체 이상도 발견되어 ATRA에 의한 분화유도요법이 유효하다.

말초혈액 표본에서 위와 같은 증례에 만났을 때 항상 M3의 가능성을 염두에 두고 출혈 경향의 유무, 혈소판수, 응고섬용계 검사 등으로 DIC 소견을 신중하게 확인해서 즉시 담당의사에게 보고한다.

 

 

 

 

  FAB-M3 (APL)

 

  FAB-M3V :  M3 variant

 FAB-M3V :  M3 variant

 


Myelomonocytic leukemia (M4)

과립구와 단구계 분화가 골수와 말초혈액에서 동시에 나타난다. AML-M4는 여러 측면에서 M2와 매우 유사하지만 골수와 말초혈액에서 전단구(promonocytes)와 단구(monocytes)가 유핵세포중 20% 이상을 차지한다. 그러나 이들 단구계 세포가 단구에 특이한 세포화학 염색을 시행하지 않는다면 단순히  Romanowsky-염색 슬라이드만으로 구별하기가 어려울 수도 있다.

M4E  : AML-M4 변이형으로 비정상 호산구가 보통 10% 이내로 골수에 출현하는 질환이다. 대부분 16번 염색체 이상[inv(16)(p13q22)]이 발견되고, 치료효과 측면에서는 양호한 예후군에 포함되지만 중추신경계 백혈병이 병발하는 경우가 많다.

     

    Mixed populations of myeloblasts (smaller, eccentric nuclei) and monoblasts (larger, abundant cytoplasm). Inset: dual esterase shows chloroacetate esterase positive granules (blue) and alpha-napthyl butyrate esterase positive monocytes (green/brown).

 

 

  

  Bone marrow smear, May-Giemsa stain, x1000

 Bone marrow smear, May-Giemsa stain, x1000

 

 

  Bone marrow smear, Peroxidase stain, x1000

 

Bone marrow smear, alpha-naphthyl butyrate esterase and chloroacetate esterase stains, x1000

 

 

 

Bone marrow smear, alpha-naphthyl butyrate esterase and chloroacetate esterase stains, x1000

Bone marrow smear, May-Giemsa stain, x1000

 


Monocytic leukemia (M5)

  • 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.
  • Differentiated (monocytic) 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.
 

 

  FAB-M6 (erythroleukemia)

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. 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.

 

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. 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.

 

Treatment Option Overview

Note: 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 summary on Levels of Evidence 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.

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. Consolidation therapy appears to be effective when given either immediately after remission is achieved or when delayed for 9 months.

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. 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. 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. 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. However, GM-CSF did not show benefit in a separate similar randomized trial in patients aged 60 and older. 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.

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.[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.[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.

 

 

Untreated Adult Acute Myeloid Leukemia

Note: 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 summary on Levels of Evidence 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. Idarubicin appeared to be more effective than daunorubicin, although the doses of idarubicin and daunorubicin may not have been equivalent. No significant difference between daunorubicin and mitoxantrone has been reported.

The role of high-dose cytarabine in induction therapy is controversial. Two randomized studies have suggested that dose intensification of cytarabine during induction therapy improved disease-free survival, although the portion of patients achieving successful remission induction was comparable to conventionally dosed cytarabine.[Level of evidence: 1iiDi];[Level of evidence: 1iiDi] However, two additional randomized trials showed no improvement in survival or disease-free survival when high-dose cytarabine was included in remission induction clinical trials. Post-hoc analyses of both of these latter trials suggested potential benefit for the intensified therapy in subsets of patients at high risk for treatment failure.

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.[Level of evidence: 3iiiDi]

Supportive care during remission induction treatment should routinely include red blood cell and platelet transfusions when appropriate. Empiric broad spectrum antimicrobial therapy is an absolute necessity for febrile patients who are profoundly neutropenic. 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. 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. Prophylactic oral antibiotics may be appropriate in patients with expected prolonged, profound granulocytopenia (<100 per cubic millimeter for 2 weeks). 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. 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 (all-transretinoic acid (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). 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. 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. A randomized study has shown that the relapse rate was reduced in patients treated with concomitant ATRA and chemotherapy compared to ATRA induction followed by chemotherapy given in remission (relative risk of relapse at 2 years, 0.41, P=.04). [Level of evidence: 1iiDi] This trial also showed a disease-free survival benefit to maintenance therapy, which consisted of either 6-mercaptopurine plus methotrexate (relative risk of relapse, 0.41), intermittent ATRA (relative risk of relapse, 0.62), or a combination of all three drugs. The use of 6-mercaptopurine and methotrexate also produced an improvement in overall survival (relative risk of relapse, 0.36, P=.0057). Two concurrent clinical trials separately conducted in Italy and Spain included ATRA plus anthracycline induction followed by 3 cycles of consolidation and maintenance therapy. The 2 treatment protocols differed only in the addition of non-anthracycline drugs during consolidation cycles in the Italian study; doses of anthracyclines were identical between the 2 trials. Essentially identical relapse-free survival suggests that the non-anthracycline drugs (cytarabine, etoposide, and 6-thioguanine) may not contribute significantly to the outcome of patients with acute promyelocytic leukemia induced with ATRA plus anthracycline.

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. 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. Although most patients currently receive ATRA in their induction therapy, for patients who do not, careful management of coagulopathy is required. Coagulopathy is occasionally a problem in patients undergoing induction with ATRA plus 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.

Treatment options for remission induction therapy:

 

One of the following equivalent combination chemotherapy regimens:
dose-intensive cytarabine-based induction therapy.
cytarabine + daunorubicin.
cytarabine + idarubicin.
cytarabine + daunorubicin + thioguanine.
mitoxantrone + etoposide.

 

Treatment of central nervous system leukemia, if present:

intrathecal cytarabine or methotrexate.

 

Clinical trials.

 


Adult Acute Myeloid Leukemia in Remision

Note: 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 summary on Levels of Evidence for more information.)

Although individual patients have been reported to have long disease-free survival or cure with a single cycle of chemotherapy, 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. 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%. 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. 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. The duration of consolidation therapy has ranged from one cycle to four or more cycles. 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 and/or pulmonary toxic effects 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%. 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%. Retrospective analysis of data from the International Bone Marrow Transplant Registry suggests that consolidation chemotherapy does not lead to an improvement in disease-free or overall survival for patients in first remission undergoing allogeneic bone marrow transplant from an HLA-identical sibling.[Level of evidence: 3iiiA]

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. 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) or mafosphamide , or monoclonal antibodies, such as anti-CD33. 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.[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. 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. 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. 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%.[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.[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. 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. 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.

 

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.

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. A study with mitoxantrone and cytarabine was successful in 50% to 60% of patients who experienced relapse after initially obtaining a complete remission. Other studies using idarubicin and cytarabine or high-dose etoposide and cyclophosphamide reported similar results.

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. 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. 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%. Therefore, some investigators advocate allogeneic bone marrow transplantation in early first relapse to avoid the toxic effect of re-induction chemotherapy. Allogeneic bone marrow transplantation can salvage some patients whose disease fails to go into remission with intensive chemotherapy. 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.

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

  


This page was last modified on 12-Jan-2001