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Acute Myelogenous Leukemia

Acute Myelogenous Leukemia

Introduction
Presentation
Diagnosis and Classification
Prognostic Factors
Treatment
References

Introduction

Acute myelogenous leukemia (AML) is a disorder marked by infiltration of the bone marrow by abnormal hematopoietic progenitors. These cells are unable to differentiate in a normal fashion into myeloid, erythroid, and/or megakaryocytic cell lines and, unlike normal progenitors, are capable of infiltrating vital organs. They also block the differentiation of the residual normal progenitors, resulting in thrombocytopenia, anemia, and/or granulocytopenia. Without treatment, a patient only rarely survives more than 6 to 12 months; death results from complications of marrow failure.

 

AML is a rare malignancy that affects approximately 4 persons per 100,000 in the United States and England annually [1,2]. Despite the continued development of new therapies and increased understanding of its biology, AML remains fatal in approximately 80% of treated patients. With the introduction of cytogenetic banding, better characterization of various subsets of AML is now possible, and higher cure rates can be observed in certain subsets [3-9]. The cure rate for AML can potentially increase if different cytogenetic subsets are targeted with specific therapies [6,7] and if detection of clinically relevant minimal residual disease becomes practical.

 

Presentation

Although AML occasionally is diagnosed on routine blood counts from asymptomatic patients, most patients are symptomatic at presentation. Commonly, the symptoms are those referable to various cytopenias or coagulopathies and consist mainly of weakness, bleeding, and infections. The infections most commonly seen are minor upper respiratory tract infections or vague flulike symptoms, although pneumonias occur in about 5% of cases. Bleeding is usually in the form of petechiae, which correlate with the degree of thrombocytopenia, or ecchymoses, which generally are caused by disseminated intravascular coagulation (DIC), commonly seen in patients with acute promyelocytic leukemia (APL) [10]. Rare symptoms include bone pain presumed to be secondary to marrow expansion, skin lesions secondary to leukemic infiltration (leukemia cutis), gum hypertrophy (especially common in the monocytic subtypes of AML), and abdominal pain caused by hepatosplenomegaly or adenopathy. Neurologic symptoms resulting from central nervous system (CNS) disease or leukostasis are also rare symptoms of AML.

 

Diagnosis and Classification

French-American-British Working Group

 

The diagnosis of AML is based on the revised criteria of the French-American-British (FAB) Working Group [11]. This classification relies entirely on morphologic features and cytochemical staining characteristics that can be seen by light microscopy. On rare occasions, electron microscopy and immunophenotyping are required to establish the diagnosis. The cytochemical stains used are myeloperoxidase (MPO), terminal deoxynucleotidyltransferase (TDT), nonspecific esterase (NSE), and Sudan black B (SBB). The diagnosis of AML is made when at least 30% of nucleated cells in the bone marrow or peripheral blood are blasts and when greater than or equal to 3% of these blasts are MPO positive by light microscopy, irrespective of the findings when other stains are used.

 

Instances of myeloid and lymphoid markers, found on the same or separate cells (lineage infidelity, biphenotypic leukemia), exist in a significant proportion of cases of AML, as we have defined the disease. Although they are not the focus of this chapter, such cases call attention to the arbitrary compartmentalization of acute leukemia as either AML or acute lymphocytic leukemia (ALL). Although SBB has been considered an alternative to MPO, due to the high rate of concordance when both stains are used, SBB should not be substituted, because 1.6% of ALL cases—MPO being negative by definition—are SBB positive. These cases would be misdiagnosed as AML [12]. It remains to be seen whether such cases would benefit more from ALL-type than AML-type therapy.

 

The FAB Working Group describes disease class M1 as acute myeloblastic leukemia without maturation. The blasts show a minimal tendency toward granulocytic maturation, with less than 10% of the marrow nucleated cells being progranulocytes or more mature granulocytes. In the M2 class, acute myeloblastic leukemia with maturation, maturation is more evident; the blasts show a lower nucleus-to-cytoplasm ratio, and more than 10% of the cells are progranulocytes or more mature granulocytes. M3, acute promyelocytic leukemia, occurs most commonly in its hypergranular form but also occurs in a variant or microgranular form [13,14]. Most cases have fewer than 30% blasts, but the number of progranulocytes is frequently greater than 75%. In M1, M2, and M3 classes, less than 20% of the cells are monocytic. Auer rods commonly are seen in M2 and especially M3, where they sometimes accumulate to form characteristic faggot cells. In M4 (acute myelomonocytic leukemia), M4Eo (M4 with abnormal eosinophils), and M5 (acute monoblastic leukemia), at least 20% of the bone marrow cells are monocytic; in M5, they are usually monoblasts. MPO can be negative in M5, but NSE is usually positive. In M6 (acute erythroleukemia), the MPO stain is negative, and cell-surface glycophorin A is positive [15]; at least 50% of the marrow cells are dysplastic erythroid cells, and at least 30% of nonerythroid cells are blasts. M7 is acute megakaryocytic leukemia. It is characterized by bone-marrow fibrosis, which makes aspiration difficult and impedes the diagnosis. It is the most common acute leukemia seen in patients with Down syndrome [16]. Because MPO also is negative in M7, the diagnosis should be based on the demonstration of platelet peroxidase by electron microscopy or glycoprotein IB or IIB/IIIA on the blast surface [17]. Rare cases wherein MPO, SBB, NSE, and TDT are negative but the cells express myeloid antigenic markers on the cell surface (CD13 or CD33) are classified as M0 [18]. The incidence of the different FAB Working Group subtypes is reported as M1, 18%; M2, 28%; M3, 8%; M4, 27%; M5, 10%; M6, 4%; and M7, 5% [19].

 

Cytogenetics

Although the FAB Working Group classification system has been widely adopted because it is easy to use, its prognostic value and hence clinical relevance are limited. More useful is the classification by leukemia cell karyotype [5,20]. In fact, the association of certain FAB Working Group subtypes with prognosis most likely results from their association with specific cytogenetic abnormalities: M3 with t(15;17) [21], M4Eo with inv(16) [22,23], M2 with t(8;21) [24], and M6 and M7 with complex karyotypes and frequent involvement of chromosomes 5 and/or 7 [25]. These observations, together with recent data showing that various cytogenetic subsets benefit from different therapies [6,7] and data demonstrating the direct relationship between cytogenetic abnormalities and leukemogenesis [26,27], make the cytogenetic classification of AML more clinically relevant than the FAB Working Group classification.

 

Of adults with AML, 60% to 90% were found to have cytogenetic abnormalities when tissue samples were studied with Giemsa or quinacrine banding [3,28]. This rate is dependent on factors such as the length of time in culture, banding techniques, and referral patterns of reporting centers [29]. High-resolution banding techniques suggest that almost all patients have cytogenetic abnormalities [4].

 

Abnormalities such as inv(16), t(8;21), and t(15;17) occur in 5% to 10% of patients. Such patients have the best prognosis when treated with conventional doses of cytarabine and anthracycline combinations (the “3+7” regimen refers to the number of days each drug is administered) [5,30]. These patients are younger than the average patient with AML and tend to have a lower incidence of antecedent hematologic disorders or prior exposure to cytotoxic therapy or radiation therapy. With the 3+7 regimen, complete remission (CR) rates are more than 90% for inv(16) and t(8;21) and nearly 70% for t(15;17). The 3-year disease-free survival rate is about 40% for all groups. Recent data have shown that the chimeric gene product resulting from the inversion in chromosome 16 is directly related to leukemogenesis [26].

 

It is important to note that patients with inv(16) have a high likelihood of CNS relapse (about 35%) when treated with conventional-dose cytarabine-based regimens [23], but this complication is almost completely eradicated when high-dose cytarabine is used [6]. Patients with t(8;21) and inv(16) have a higher cure rate (more than 50%), when high-dose cytarabine is used [6,7]. The abnormality t(15;17) involves the promyelocytic leukemia (PML) transcription unit on chromosome 15 and the retinoic acid receptor-alpha (RARA) gene on chromosome 17, resulting in the chimeric gene product PML-RARA [30]. Patients with t(15;17) respond dramatically, at least initially, to all-trans-retinoic acid (ATRA) [31-35]. They commonly present with coagulopathy consistent with DIC or primary fibrinolysis [10], a complication that accounts for most of the deaths occurring during induction therapy, which is the only cause of failure to enter CR in patients with APL.

 

Trisomy of chromosome 8 or deletions or losses of chromosomes 5 or 7, alone or with additional abnormalities, are seen in approximately one third of patients. These patients are generally older and have a higher incidence of antecedent hematologic disorders and prior exposure to alkylating agents or radiation therapy [3,36,37]. They have the worst prognosis when treated with conventional-dose cytarabine and anthracycline combinations (40% to 50% CR rate; less than 5% 2-year continuous complete remission [CCR] rate).

 

Translocations of chromosome 11 at the q23 breakpoint, seen in 5% of patients, involve the mixed-lineage leukemia gene [38]. These abnormalities commonly are seen in patients previously treated with topoisomerase II-reactive drugs [39]. In adults, the leukemia tends to be monocytic (M4/M5), but, unlike childhood cases of AML [40], CNS disease and hepatosplenomegaly are not common features [41]. Adults with t(11q23) AML have a 60% CR rate and a 2-year CCR rate of less than 10%.

 

Nearly one third of patients have no cytogenetic abnormalities detected by Giemsa or quinacrine banding; these patients have an intermediate prognosis; 50% to 80% will achieve CR and 20% will remain in CR for more than 3 years when treated with the 3+7 regimen. It is unclear whether AML with a normal karyotype is a distinct entity or simply represents an abnormality missed by the techniques widely used. As techniques continue to improve, the decreasing incidence of AML with a normal karyotype tends to suggest that at least some of these cases represented undetected abnormalities.

When more than one cytogenetic abnormality is seen in the same patient, a hierarchic system that helps to assign such patients to various cytogenetic categories is generally used. This is especially important when treatment decisions are to be based on cytogenetics. Two systems are commonly used. The first system, devised by the Cancer and Leukemia Group B (CALGB), ranks abnormalities in the following order by decreasing priority: t(8;21), t(15;17), t(9;22), abnormal 16q22, abnormal 8q24, abnormal 11q23, 5q- or -5 and 7q- or -7, 5q-, -5, 7q-, -7, 6q-, +8, pseudodiploid, hyperdiploid, and hypodiploid [9]. The second system, suggested at the Sixth International Workshop on Chromosomes in Leukemia, follows a different order: abnormal 16, t(15;17), t(8;21), abnormal 5 and/or 7, abnormal 11q, pseudodiploid, hypodiploid, and hyperdiploid [8]. Given the limited information on the prognosis of patients with various combinations of abnormalities, both classifications are considered appropriate.

 

Finally, it should be noted that the different cytogenetic subsets themselves are prognostically heterogeneous. Although this heterogeneity may result, in part, from random variation, it is likely that other chararcteristics, some unknown and others described later in this chapter, influence prognosis within each cytogenetic subset.

 

Immunophenotyping

 

The use of highly specific monoclonal antibodies (MABs) to differentiation antigens has aided in defining lineage and diagnosing rare subtypes of acute leukemias. Groups of MABs that recognize the same antigens are designated cluster groups of differentiation (CD) [42]. CD positivity is defined arbitrarily as at least 20% of cells being reactive to the designated MAB. The myeloid-associated MABs are most valuable in cases of poorly differentiated AML, in which the diagnosis is unclear using standard morphologic and cytochemical analysis. The MABs against CD13, CD14, CD15, CD33, CD34, and human leukocyte antigen-DR (HLA-DR) are used most often to characterize AML. CD13, CD33, and HLA-DR are positive in most cases of AML except APL, where HLA-DR is almost always negative. This can aid in recognizing the microgranular variant of APL. The FAB Working Group classification incorporated immunophenotyping to aid in the diagnosis of FAB-M0 (negative cytochemical stains, myeloid markers positive) [18], M6 (glycophorin A antibody positive) [15], and M7 (platelet glycoproteins such as CD41, CD42, and CD61 positive) [25]. Despite considerable interest in and increasing recognition of acute leukemias expressing various combinations of markers, there is no consensus regarding the definition, terminology, diagnostic criteria, or biologic implications. This is partly because of the heterogeneity of cases, which can range from cases expressing one aberrant marker in otherwise typical ALL or AML to the more extreme cases of acute mixed-lineage leukemia.

 

Prognostic Factors

Prognostic factors in AML, as in all diseases with relatively low cure rates, change continuously, as do treatment strategies and understanding of the biology of the disease. Because several of the reported prognostic factors are interrelated, their independent importance is often unclear, and the same factors are often not similarly prognostic in different studies. This lack of reproducibility probably results from technical considerations (eg, failure to account for interactions in regression analyses) and from the differences in population seen in different centers, again suggesting the heterogeneity of the disease.

 

Prognostic factors in AML can be divided into factors associated with death during chemotherapy and factors associated with resistance to chemotherapy, manifested either by failure to enter CR despite surviving induction therapy or by a short CR duration. Patient characteristics predictive of early death include poor performance status, age older than 60 years, and abnormal organ function [43]. The factors often associated with resistance to chemotherapy include pretreatment karyotype, age, performance status, prior myelodysplastic syndrome, prior exposure to chemotherapy or radiation therapy for another malignancy, and an antecedent hematologic disorder, defined as an abnormality in blood counts for one or more months prior to the diagnosis of AML [5,43]. Perhaps the most important prognostic factor is the pretreatment karyotype, as detailed previously in the section on cytogenetic classification. Other factors such as white blood cell count, percent bone marrow blasts, various measures of organ function, Auer rods, immunophenotyping (eg, CD34, CD19 positivity), or multidrug resistance (MDR) expression have not been consistently found to be predictive of resistance to chemotherapy.

 

Treatment

Marked improvement in the outcome of patients with newly diagnosed AML has been seen in the past three decades. AML was an invariably fatal disease 30 years ago; now, 25% of patients might be cured with current therapies. Although this advance could be secondary to improvements in supportive care, blood-product availability, and better treatment of infections, it is more likely related to advances in chemotherapy and improved treatment strategies.

 

Therapy generally is divided into remission induction and postremission components. All studies so far have treated all patients with AML in the same way and generally have focused on finding the best induction regimen and the best approach for postremission therapy. Given the marked heterogeneity of patients with AML, future studies are more likely to focus on finding the best treatment for each cytogenetically defined patient subset.

 

Remission Induction

 

The most commonly employed chemotherapy regimen is a combination of cytarabine, at conventional doses of 100 to 200 mg/m²/d given intravenously (IV) by continuous infusion for 7 days, plus 3 days of an anthracycline, generally daunorubicin (Cerubidine), at 45 to 60 mg/m²/d IV bolus. This is called the 3+7 regimen, and it results in a CR rate of 65% to 70% [44-46].

 

In two randomized trials, inclusion of thioguanine in this regimen did not result in an improved CR rate [47,48]. The substitution of doxorubicin (Adriamycin, Rubex) for daunorubicin at equally myelotoxic doses resulted in a significantly greater appearance of necrotizing colitis in patients receiving doxorubicin, particularly in patients older than 60 years of age [44].

 

The use of idarubicin (Idamycin), 12 to 13 mg/m²/d for 3 days, instead of daunorubicin, 45 to 50 mg/m²/d for 3 days, in combination with conventional-dose cytarabine resulted in higher CR rates in three randomized trials [49-51]. In addition, two of these trials reported that significantly fewer patients required two courses before entering CR in the idarubicin arm [49,50]. It is unclear whether idarubicin and daunorubicin were used at equally myelotoxic doses, because one of the trials reported a significantly longer duration of myelosuppression with idarubicin [50]. Although most investigators agree that idarubicin is potentially superior to daunorubicin, some believe that more experience is needed before substitution of this more costly anthracycline for daunorubicin becomes routine.

 

The addition of etoposide (VePesid), 75 mg/m²/d for 7 days, to the 3+7 regimen (“7+3+7”) in a randomized trial by the Australian Leukemia Study Group (ALSG) resulted in a similar CR rate. Patients who received 7+3+7 instead of 3+7 had a higher frequency of stomatitis [52]. However, this study suggested that the remission duration of patients receiving 7+3+7 was longer. Longer follow-up is needed to evaluate the role of etoposide in AML therapy, especially because more recent data from the ALSG suggest inferior results with 7+3+7 in a subsequent cohort of patients [53].

 

Because cytarabine seems to be a cornerstone in AML therapy, higher doses of cytarabine (HDAC) given in various schedules have been studied intensively. Its role in induction has been examined in two large, randomized trials by the ALSG and the Southwest Oncology Group (SWOG) [54,55]. In both trials, no benefit of the HDAC regimen over the 3+7 regimen was observed. However, a follow-up report from the ALSG in which all patients were given the same postremission therapy indicated that the remission duration and the projected percentage of patients disease free at 5 years were significantly better in the HDAC arm [53]. Therefore, dismissal of HDAC from induction therapy seems premature at this time. Representative studies used in remission induction are summarized in Table 1.

Table 1. Representative Randomized Trials Addressing the Question of
“The Best Induction Regimen” in AML
Source Regimen N CR rate Comments
Omura et al [47]
1982
“3+7” vs
DAT
39652%
50%
Thioguanine adds no benefit to “3+7.”
Preisler et al [48]
1987
“3+7” vs
DAT
42753%
57%
Thioguanine adds no benefit to “3+7.”
Yates et al [44]
1982
“3 doxo+7”
“3 doxo+7”
44060%
48%
Daunorubicin is superior to doxorubicin.
More enterocolitis with doxorubicin.
Berman et al [49]
1991
“3 ida+7”
“3 dauno+7”
12080%
58%
 
Wiernik et al [50]
1992
“3 ida+7”
“3 dauno+7”
20870%
59%
Idarubicin is a superior anthracycline.
Less patients required two courses to achieve CR with idarubicin in 2 studies [49,50].
Vogler et al [51]
1992
“3 ida+7”
“3 dauno+7”
21871%
58%
Duration of myelosuppression is longer with idarubicin.
Bishop et al [52]
1991
“7VP+3+7”
“3+7”
26459%
56%
Etoposide does not improve CR rate, but increases CR duration. It results in more stomatitis. It does not enhance survival.
Bishop et al [53]
1994
HDAC+“3+7VP”
“7VP+3+7”
30171%
74%
HDAC is not better for induction.
CR duration longer with HDAC.
Weick et al [55]
1992
HDAC+3 dauno

“3+7”
63954% (< 50 y)
45% (> 50 y)
59% (< 50 y)
54% (> 50 y)
HDAC worse in patients 50 to 64 years of age.
“3+7” = daunorubicin 45–50 mg/m²/d days 1–3 IV bolus + cytarabine 100 [33–35,40] or 200 [38,41] mg/m²/d CI days 1–7
DAT = “3+7” + thioguanine 100 mg/m² orally twice daily for 5–7 days
dauno = daunorubicin
doxo = doxorubicin 30 mg/m²/d days 1–3 IV bolus
HDAC = 2 g/m² every 12 hours × 8 doses, [39] or 2 g/m² every 12 hours × 12 doses [41]
ida = idarubicin 12 [14,16] or 13 [15] mg/m²/d days 1–3 IV bolus
N = total number of patients evaluable in both arms
VP = etoposide 75 mg/m²/d days 1–7.

Postremission Therapy

 

Evidence that postremission therapy in AML is needed comes from two randomized trials in which patients entering CR were assigned to either observation alone or low-dose cytarabine plus thioguanine [56,57]. Despite the modest doses of active drugs used and the short duration of therapy, prolonged remission duration in the treatment arm was observed in both trials.

The debate over what represents the best approach for postremission therapy continues. Strategies include maintenance therapy using doses lower than those used during induction, consolidation by repeating the induction regimen, intensification with a dose-intensified schedule of the drugs used during induction, or ablative therapy with allogeneic or autologous bone marrow transplantation (BMT).

 

Even more controversial is the necessary duration of therapy. There has been no demonstrated advantage to continuing postremission therapy for more than one year compared with shorter lengths of time [48,58]. Most investigators administer two to four courses of chemotherapy in CR. Representative studies addressing the best postremission therapies are presented in Table 2.

 

Table 2. Representative Randomized Trials Addressing the Question
of “The Best Postremission Therapy”
SourceInduction therapyCR
rate
Postremission therapyNumber in CRMedian CR duration (months)Number of patients remaining in CRComments
Cassileth et al [56] 1988DAT64%Cytarabine, thioguanine
vs no treatment
518.0

4.0
22% at 1 yr

< 5%
Some maintenance is better than none
Embury et al [57] 1977DAT?Cytarabine, thioguanine  
vs no treatment
2610.3
 6.7
30% at 1 yr
0
 
Preisler et al [48] 1987“3+7”, DAT, or “3+10”56%DATOP for 8 mo vs
DATOP for 3 6 mo
1519.9

16.3
39% at 2 yr

39% at 2 yr
8 mo maintenance is equivalent to 36 mo
Cassileth et al [59] 1984DAT65%DAT × 2 + maintenance for 24 mo vs no DAT +
same maintenance
2839.2 vs


7.8
28% at 2 yr


14% at 2 yr
Consolidation
improves DFS
Mayer et al [45] 1994“3+7”64%Cytarabine 100 mg/m²/d d1–5 CI in intensification

Cytarabine 400 mg/m²/d







HDAC 3 g/m² every 12 hours every other day × 6 doses
596 24% at 4 yr




29%








44%
HDAC improves DFS


Effect varied by days 1–5 CI karyotype {inv (16) and t(8;21) benefit more from HDAC

Benefit was limited to patients < age 60
Cassileth et al [60] 1992DAT Cytarabine, thioguanine × 24 mo

HDAC 3 g/m² every 12 hours every other day × 12 doses
143 15% at 2 yr



28%
HDAC consolidation is superior

AMSA adds toxicity (12% toxic deaths in patients < age 60)
AMSA = m-amsacrine
CI = continuous infusion
DAT = “3+7” + thioguanine 100 mg/m² orally twice daily for 5–7 days
DATOP = daunorubicin, cytarabine, thioguanine, vincristine, prednisone
DFS = disease-free survival, HDAC = 2 g/m² every 12 hours × 8 doses,[39] or 2 g/m² every 12 hours × 12 doses[41]
“3+7” = daunorubicin 45–50 mg/m²/d days 1–3 IV bolus + cytarabine 100 [33–35,40] or 200 [38,41] mg/m²/d CI days 1–7

Consolidation and Intensification

 

In a randomized trial by the Eastern Cooperative Oncology Group (ECOG), 283 patients entered CR after receiving cytarabine/daunorubicin/thioguanine (DAT). They then received either two courses of DAT as consolidation followed by 24 months of maintenance or the same maintenance regimen alone. This trial showed that the CR duration was significantly longer in the consolidation arm [59]. These results, with the CALGB observation of similar disease-free survival in patients receiving 8 vs 36 months of maintenance as the only postremission therapy [48], suggest that the use of higher doses for shorter periods postremission is superior to lengthy maintenance.

 

With this as a background, intensification was tested mostly with higher doses of cytarabine, the key drug in AML therapy. In a CALGB trial, 596 patients in CR were randomized to receive four courses of cytarabine at 100 mg/m²/d for 5 days by continuous infusion, 400 mg/m²/d for 5 days by continuous infusion, or 3 g/m² every 12 hours twice daily every other day for six doses. After a median follow-up of 52 months, the 4-year CCR rate was significantly higher in the HDAC arm only in patients younger than 60 years of age [45].

Similarly, in an ECOG trial, patients in CR were randomized to receive either HDAC plus amsacrine or conventional doses of cytarabine plus thioguanine [60]. The 2-year CCR rate was significantly higher in the HDAC arm. However, the death rate caused by the toxic effects of HDAC plus amsacrine intensification was very high (12% in patients younger than 60 years), suggesting that the addition of amsacrine to HDAC during intensification confers more harm than benefit.

 

Bone Marrow Transplantation

 

High-dose ablative chemotherapy with BMT support can be considered another form of postremission intensification. In addition to its ability to eliminate residual leukemic cells through its dose-intensified schedule, this schedule offers the presumed immune-mediated antileukemic effect whereby donor lymphoid cells recognize and eradicate leukemic cells (the graft-vs-leukemia effect). Its usefulness in AML therapy, however, has been hampered by the multiple prerequisites needed for patients to be eligible. They include younger age, good performance status, normal organ function, absence of other comorbid conditions, and availability of HLA-matched siblings for allogeneic BMT. Most studies also require patients to be in the first CR after induction chemotherapy. These criteria, when applied to all patients with AML seen at two large centers, were met in only 6.2% to 8.6% of patients [61,62].

This extreme preselection for BMT results in a group of patients who represent the best responders to standard chemotherapy and, thus, makes comparison between BMT and standard chemotherapy for patients in first CR very difficult. Moreover, event-free survival time in most BMT reports typically is calculated from the time the preparative regimen is started rather than from the time of CR. Therefore, patients who relapse very early, who, by definition, have more resistant disease or patients who die or have infectious complications while being screened for BMT, are not included in the transplantation registries.

 

Allowing for these considerations, several prospective trials were undertaken to attempt to compare allogeneic BMT with postremission chemotherapy in patients in first CR [60,63-70]. Although all trials reported a greatly diminished likelihood of relapse in the transplant cohort, most studies [60,63-67] indicate that the increased treatment-related mortality rate in patients who underwent BMT results in similar or statistically insignificant differences in event-free and overall survival rates in the two groups.

The role of autologous BMT in first CR has been explored primarily by European centers. Advantages of this modality over allogeneic BMT include its applicability to older patients and use of unmatched donors. Disadvantages include the lack of the presumed benefit from the graft-vs-leukemia effect and the possible contamination of the harvested marrow with residual leukemic cells. The latter problem has been dealt with by treating the stored marrow with chemotherapeutic agents or antileukemic monoclonal antibodies (ie, purging) [71-74]. Trials directly comparing autologous with allogeneic BMT found either a lower relapse rate and a longer disease-free survival rate with allogeneic BMT when purging was not used [69,75,76] or a similar disease-free survival rate and relapse rate when purging was used [77]. Comparisons between autologous BMT and intensive chemotherapy, in two small studies, revealed similar disease-free survival and relapse rates [69,75].

 

A recent report compared patients assigned to undergo allogeneic BMT (160 patients) with patients randomized to receive either unpurged autologous BMT or intensive chemotherapy (254 patients) in first CR [70]. In an intention-to-treat analysis, relapse rates with allogeneic BMT, autologous BMT, and chemotherapy were 57%, 41%, and 24%, respectively. Disease-free survival rates in the two transplant arms were similar and were longer than those seen with chemotherapy. The overall survival rate, however, was similar in all three groups, because relapses after chemotherapy were salvaged with transplantation.

 

Therapy for Relapsed or Refractory AML

 

Most patients with newly diagnosed AML who achieve a complete remission later experience a relapse of the disease and die. Approximately 5% of all patients who are in first relapse or who were refractory to initial induction therapy and 15% of such patients who achieve a second CR are expected to be alive at 5 years [78]. The likelihood of achieving a second CR is heavily dependent on the duration of the first CR [78-80]. The CR rate in patients refractory to initial therapy or with a first CR shorter than 6 to 12 months is approximately 20%, compared with a CR rate of 60% in patients with a longer first CR.

The treatment of choice for patients with relapsed AML who are younger than 50 years of age is allogeneic BMT [78]. Patients who are not eligible for allogeneic BMT should receive investigational therapy if their first CR is shorter than one year or an induction regimen similar to that used initially if their first CR is longer than one year. Relapses after allogeneic BMT in first or second CR can be treated with a second allogeneic BMT [81] or an infusion of donor buffy coat or granulocyte-colony stimulating factor, which presumably stimulates the graft-vs-leukemia effect [82].

 

Therapy for APL

 

The distinguishing features of APL (FAB Working Group M3) are as follows: younger median age of patients at presentation [83], frequent presentation with leukopenia or pancytopenia [84], life-threatening bleeding diathesis seen at presentation or relapse attributed to DIC or primary fibrinolysis [10], an almost invariable association with t(15;17) detected either by banded cytogenetics or polymerase chain reaction [21,85], achievement of CR without the obligatory chemotherapy-induced marrow aplasia [86,87], increased sensitivity to anthracycline antibiotics [88-92], and response to the differentiation agent ATRA in its oral [31-35] or liposomally encapsculated [93] form.

 

Complete response rates of 68% to 80% and, in one study [92], a CR duration of 24 months were observed in patients with APL treated with single-agent daunorubicin [89,92] or idarubicin [88,91]. Regimens including cytarabine in addition to anthracyclines did not result in higher CR rates or longer CR duration [90,94-96]. With chemotherapy, high promyelocyte or blast counts may persist in the marrow on day 21. However, further improvement to complete remission can be expected [86,87] unless DIC persists or recurs. With the use of ATRA, CR rates over 90% in otherwise untreated patients were observed [35]. In addition, coagulopathy appears to resolve more rapidly with ATRA than with chemotherapy [31-34]. ATRA generally is given at 45 mg/m²/d until CR is achieved (average, 40 days). Despite the high CR rates achieved with ATRA, remissions maintained with ATRA alone have been brief [35], and the administration of anthracycline-based chemotherapy is necessary. In a randomized trial in France, ATRA and chemotherapy (daunorubicin plus cytarabine), added either in CR or when leukocytosis developed during induction, resulted in lower relapse and longer disease-free survival rates than those seen when chemotherapy alone was used for induction and maintenance [97,98].

 

Induction therapy with ATRA can be complicated by two potentially life-threatening side effects: hyperleukocytosis and retinoic acid syndrome. Hyperleukocytosis, initially reported by the French group [99], can lead to pulmonary and CNS toxicity. This can be controlled effectively by the early initiation of chemotherapy [97,98]. The second life-threatening side effect, retinoic acid syndrome, is seen in up to 25% of patients [100]. This is a constellation of findings that develop between days 2 and 28 of treatment. The syndrome is characterized by fever, respiratory distress, pulmonary infiltrates, pleuropericardial effusion, edema, and hypotension. Concomitant leukocytosis is common but not uniformly seen. The discontinuation of ATRA and treatment with high-dose steroids are necessary when severe symptoms are seen [100], whereas low-dose steroid treatment (dexamethasone, 10 mg twice daily for 3 days) without discontinuation of ATRA is usually adequate if started at the earliest indication [30] of such side effects.

References

References

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