Therapeutic Options in the Management of Acute Myelogenous Leukemia in
Adults
Ruben A. Saez, MD
Several advances in evaluation and treatment have improved
the prognosis of adults with acute myelogenous leukemia.
Background: The treatment of acute myelogenous leukemia has evolved in recent years
due to advances in supportive care, the identification of prognostic factors, and the
careful evaluation of chemotherapeutic modalities in randomized clinical trials.
Methods: The classification and prognostic features are reviewed, and the results
from clinical trials have been evaluated with an emphasis on randomized trials and on both
remission induction and postremission phases of management.
Results: The combination of an anthracycline and standard-dose Ara-C form the basis
of remission induction. High-dose Ara-C has greater toxicity. For postremission therapy,
high-dose Ara-C improves results in those with good risk features or normal cytogenetics.
Acute promyelocytic leukemia management includes all-trans-retinoic acid.
Conclusions: Once a patient relapses from a nontransplant approach, high-dose
therapy and allogeneic marrow transplantation are considered. Autologous stem cell
transplantation cures some patients who do not have a donor.
Introduction
Acute myelogenous leukemia (AML) is the most common subtype of acute leukemia in
adults, with a steep increase in incidence after the age of 50.1 As the
leukemic process replaces normal hematopoiesis, the clinical management revolves around
the manifestations of pancytopenia. Most patients present with fatigue or weakness and
evidence of capillary bleeding (petechiae). They rarely present with severe bleeding due
to disseminated intravascular coagulation (DIC) as it occurs in acute promyelocytic
leukemia (APL). Approximately one fourth of patients present with a severe infection such
as cellulitis, pneumonia, or septicemia.2
Bone marrow aspiration and biopsy with cytochemical stains, flow cytometry, and
cytogenetics are done not only to classify the disorder according to the
French-American-British (FAB) group, but also to define prognostic factors. The initial
therapy (induction phase) and subsequent therapy (postremission phase) will depend on
specific characteristics of the patients’ leukemia.
Classification and Prognosis
AML is classified according to the FAB convention into seven subtypes using morphology
and cytochemical stains.3 While some subtypes are associated with a typical
clinical scenario such as gum and skin infiltration (M5) and DIC (M3), defining a specific
subtype is not critical since the initial treatment is similar in all types (except in
APL). Certain FAB subtypes have poor-risk biologic features. Acute monoblastic leukemia
(M5) has a poor prognosis due to its association with hyperleucocytosis and abnormalities
of chromosome 11; these features are associated with high relapse rates.4
Similarly, minimally differentiated AML (M0) carries a poor prognosis.5 This
subset is associated with an early stem cell phenotype (CD34,TdT), coexistence of lymphoid
markers (80% for one marker, 48% for two markers), and cytogenetic abnormalities of
chromosomes 5, 7, or complex karyotypes. Acute erythroleukemia (M6) is difficult to
distinguish from the myelodysplastic syndromes and is characterized by abnormalities of
chromosome 5 and 7 in the same frequency as treatment-related AML (t-AML), with poor
response to therapy.6
Monoclonal antibodies are useful diagnostic tools in AML and are somewhat helpful as
prognostic factors.7,8 The findings of CD34, a marker associated with the
hematopoietic stem cell, and MDR1, a marker associated with the multidrug resistance
phenotype, confer a poor prognosis. In elderly patients (ie, those older than age 55) with
AML, the presence of MDR1 is associated with lower complete remission (CR) rates
independently of cytogenetics. Lymphoid markers occur commonly in AML and are usually
associated with common cytogenetic groups such as t(8,21), t(15,17), and inv(16).9,10
Except for the poor prognosis associated with CD7, lymphoid markers have no prognostic
significance.
Cytogenetic analysis in AML has become the most important tool for prognosis in newly
diagnosed patients.11,12 Abnormal karyotypes are found in 55% to 78% of adults,
of which half represent a single abnormality. While some abnormalities have a specific
association with an FAB subgroup, the opposite is not true. As shown in Table 1, these
cytogenetic abnormalities have prognostic significance and define the likelihood of
achieving CR and long-term survival based on standard chemotherapeutic approaches. As
occurred in childhood ALL, the prognostic implication of a particular abnormality will
also change as therapies improve. 
Additional chromosome abnormalities (secondary) are commonly present at diagnosis
and/or at relapse, but its prognostic significance is unknown.13 Some
abnormalities, such as deletion of a sex chromosome, have no prognostic significance,
while others [del 9q with t(8;21)] confer a worse prognosis. Chromosomal abnormalities
also provide pathogenetic information regarding the mechanisms of leukemogenesis in
addition to prognosis as shown in cases of secondary myelodysplasia (MDS) and AML.14,15
Deletions of 5/5q– and 7/7q– are seen as consequences of alkylator/radiation
exposure, while abnormalities of 11q23 are seen with drugs targeting topoisomerase II.
Similarly, t-AML with inv(16) or t(8;21) have similar prognosis as de novo AML with the
same karyotypes. Thus, when cytogenetic abnormalities and immunophenotyping are
considered, age, leucocyte count, and FAB subgroup have less prognostic significance in
the treatment of AML.
Induction Therapy
The goals of induction are to achieve a CR, to eradicate leukemic cells from the bone
marrow, and to normalize peripheral counts. Since almost all patients who do not receive
postremission therapy will relapse, persistent but undetected leukemic cells (subclinical
leukemia) remain. In large randomized trials, standard induction therapy -- seven days of
cytosine arabinoside (Ara-C) plus three days of an anthracycline (7+3) -- achieves CR in
52% to 72% of patients.16,17 Approximately half of the patients who do not
achieve CR fail because of resistant disease, and half die of toxicity (infection,
hemorrhage, multiorgan failure). Thus, attempts to improve the CR rate may increase the
toxic death rate. Attempts to improve on the 7+3 therapy by increasing the Ara-C dose from
100 to 200 mg/m2 or by adding 6-thioguanine have been unsuccessful. Similarly,
the addition of etoposide to the 7+3 regimen did not improve the CR rate or survival.
Regarding the choice of the anthracycline, randomized trials have demonstrated that
doxorubicin is more toxic (mucositis) than daunorubicin and that idarubicin is associated
with higher CR rates, remission duration, and survival.18 In vitro studies have
shown longer intracellular retention for idarubicin, which translates into more effective
growth inhibition of leukemic cells that display the MDR phenotype.19 The major
criticism of these studies is that the dose of daunorubicin in these randomized studies
(45 mg/m2) may not be the optimal dose (60 mg/m2). Nevertheless,
idarubicin is the anthracycline of choice for induction.
The most recent attempt to improve the CR rate uses high-dose Ara-C (HiDAC - 3 g/m2)
during induction. In vitro studies defined a steep dose response curve for cytarabine,
which was supported by clinical data from refractory AML.20 Two randomized
trials examined the role of HiDAC in induction for AML.21,22 The Australian
Leukemia Study Group21 randomized 301 patients to HiDAC (3 g/m2 x 8
doses) vs standard-dose Ara-C (100 mg/m2 x 7) in combination with daunorubicin
(50 mg/m2 x 3) plus etoposide (75 mg/m2 x 7). All patients received
two courses of standard-dose Ara-C x 5 plus daunorubicin x 2 plus etoposide x 5 as
consolidation. While the CR was similar (71% vs 74%), the remission duration was 45 months
in the HiDAC arm vs 12 months in the standard-dose arm (P=.0005) (Fig 1 -- Please
see hard copy of journal for Figure 1). No survival difference was seen between the two
arms. Mortality was higher during induction in the HiDAC arm (18%) vs the standard-dose
arm (11%, P=.09), and overall toxicity was higher. These results suggest that the
quality of remission was improved in the HiDAC arm. In the SWOG study,22
patients were randomized between HiDAC (2 g/m2 x 12) vs standard-dose Ara-C
(200 mg/m2 x 7) in combination with daunorubicin (45 mg/m2 x 3).
Patients in the HiDAC arm received one identical course for consolidation, while those in
the standard arm were randomized between two additional courses vs one course of HiDAC as
consolidation. HiDAC during induction did not improve the CR rate or the overall survival
but did improve relapse-free survival (33% vs 21%, P=.05). HiDAC was associated
with higher mortality and overall toxicity during induction. In addition, the use of one
cycle of HiDAC as consolidation was more toxic but no more effective than two cycles of
standard-dose Ara-C. Both of these studies show improved remission duration when HiDAC is
used during induction (but at a cost of increased toxicity) and no improvement in overall
survival. In a novel approach, a trial involving 94 patients added HiDAC (2 g/m2
x 6) to the 7+3 regimen, which achieved a high CR (89%) with 9% resistant disease and 2%
toxic deaths.23 These results have not yet been confirmed in a
multi-institutional setting.
A number of trials have evaluated the use of hematopoietic growth factors (GM-CSF,
G-CSF) as supportive care in the treatment of AML, while others have evaluated their use
to enhance chemosensitivity (priming).24 Most trials showed a reduction in the
duration of neutropenia with a variable effect in hospitalization and severe infections,
but no consistent improvement in CR, CR duration, or survival was seen. Similarly, there
was no evidence of decreased drug resistance when these agents were used as
chemosensitizers since they produced no effect on CR or survival. Their role in the
treatment of AML remains unclear.
Postremission Therapy
Randomized studies have shown that chemotherapy, either as low-dose maintenance or as
repeat of the induction regimen, improves outcome in comparison to no further therapy.25,26
These studies defined two courses of consolidation as the standard postremission
treatment, with a cure rate of 20% to 25%. Nonrandomized studies using HiDAC as
consolidation suggested improved outcome when results were compared to historic controls.27
The Eastern Cooperative Oncology Group randomized patients in CR who were not candidates
for allogeneic bone marrow transplantation (allo-BMT) due to donor availability or age
(>40 years) to 24 months of maintenance with Ara-C plus 6-thioguanine vs one course of
HiDAC (3 g/m2 x 12) plus amsacrine (100 mg/m2 x 3).28 The
event-free survival (EFS) was better in the HiDAC arm (27% vs 16%, P=.068),
although the mortality rate was higher in the consolidation arm (21% vs 0%), particularly
in older patients. When a subgroup analysis was done in 104 patients younger than 41 years
of age, EFS and survival at four years were 42% and 42%, respectively, for allo-BMT, 30%
and 43% for HiDAC, and 14% and 19% for maintenance. The differences between allo-BMT and
maintenance were statistically significant, but those between allo-BMT and consolidation
were not. This trial suffered from small numbers and the fact that maintenance was not the
standard postremission therapy for AML. Nevertheless, it confirmed the previous single
institution experience of HiDAC as consolidation and challenged the role of allo-BMT as
the treatment of choice for AML in first complete remission (CR1).
The most important prospective study defining the role of HiDAC as consolidation was
conducted by the Cancer and Leukemia Group B (CALGB).29 A total of 596 patients
who achieved CR were randomized to four courses of three dosage levels of cytarabine as
postremission therapy: 100 mg/m2 x 5 doses, 400 mg/m2 x 5 doses, and
3 g/m2 x 6 doses. All patients subsequently received four monthly courses of
cytarabine (100 mg/m2 x 5) plus daunorubicin (45 mg/m2 x 1).
Disease-free survival differed by age (worse in those older than age 60) and by treatment
group; relative to the 100-mg group, the hazard ratio was 0.67 for the 3-g group and 0.75
for the 400-mg group. For patients age 60 years and younger, the probability of being
disease-free at four years was 24% in the 100-mg group, 29% in the 40-mg group, and 44% in
the 3-g group (P=0.002) (Fig 2 -- Please see hard copy of journal for Figure 2).
HiDAC was more toxic than the other arms in terms of hospitalization (71% of courses),
neurologic toxicity (12% serious events), and mortality in remission (5%). Patients who
were 60 years of age or younger were more likely to receive all four courses of HiDAC
(62%) than those older than age 60 (29%). An analysis of this trial by cytogenetic groups
showed HiDAC improved the outcome in the favorable and intermediate groups but not in the
unfavorable group.30 By multivariate analysis, leucocyte count, cytogenetic
group, Ara-C dosage, and induction cycles (in that order) predicted for overall outcome.
This study defined four cycles of HiDAC as the new postremission chemotherapy standard in
patients aged 60 years or younger, provided the cytogenetics are intermediate or
favorable.
Allogeneic Bone Marrow Transplantation
Allo-BMT is the most effective antileukemic treatment with cure rates of 50% to 60% in
CR1, 25% to 35% in second complete remission (CR2), and 10% to 15% in refractory disease
(Fig 3).31 The mechanisms of cure are twofold: the steep dose-response curve
that leukemic cells exhibit with radiation and chemotherapy (alkylating agents) and the
graft-vs-leukemia effect (GVL).32,33 The existence of a GVL effect is derived
from observations of decreased relapse rates in patients who develop graft-vs-host disease
(GVHD), increased relapse rates in patients who undergo T-cell depletion, and increased
relapse rates in syngeneic (identical twins) transplants. In addition, the administration
of donor leucocyte infusions achieves CR in one third of patients with relapsed AML after
allo-BMT.34
Allo-BMT is the only curative treatment for patients with AML who fail induction (15%
to 20%), and thus it is critical that patients and their families undergo HLA typing at
diagnosis in case they have resistant disease.35 Factors that predict relapse
after allo-BMT in CR1 include unfavorable cytogenetics and the intensity of GVHD
prophylaxis.36 In CR1, reasonable options are regimens based on busulfan and
total body irradiation.
Several randomized trials compared allo-BMT in those with HLA-matched sibling donors vs
chemotherapy. In these studies, the cure rate ranged from 40% to 64% with allo-BMT and
from 19% to 24% with chemotherapy. Since these trials were conducted before the use of
HiDAC as postremission therapy, their current relevance is uncertain. Advances in
prevention and treatment of GVHD have not translated into improved outcome due to
increased relapsed rates, and more intense preparatory regimens have resulted in increased
transplant-related mortality. Thus, the efficacy of allo-BMT in CR1 has not improved.
However, promising work is underway using targeted hematopoietic irradiation with 131I-anti-CD45
monoclonal antibody.37
Autologous Stem Cell Transplantation
Since only 25% to 30% of patients younger than age 56 are candidates for allo-BMT due
to the availability of an HLA-identical sibling donor, alternative stem cell sources are
needed. Autologous bone marrow or peripheral blood stem cells (auto-SCT) can rescue
patients from high-dose therapy. Since GVHD is avoided, this procedure can be offered to
older patients.
The efficacy with this procedure is related to the intensity of the preparatory regimen
since GVL is not present. A potential risk is tumor contamination of the graft, which
contributes to relapse and requires purging techniques. Several small studies have shown
disease-free survival of 25% (range = 14% to 52%) for auto-SCT in CR2.38
Differences in results relate to patient selection and the length of the first remission.
Results in CR1 show disease-free survival at four years to be 40% to 55% in nonrandomized
studies.39
The role of purging to improve the outcome of auto-SCT in AML is complex, and no
randomized study has been performed to provide conclusive data. Cells in the graft
contribute to relapse, as demonstrated by the elegant work of Brenner and colleagues40
using neomycin-resistant gene-marking studies. Several studies have used ex vivo
(4-hydroperoxycyclophosphamide [4-HC]/mafosfamide, monoclonal antibody) purging, while
others have used in vivo (HiDAC pre-stem cell collection) purging.41,42 These
studies suggest the potential benefit of purging is in patients transplanted early after
CR1 (three to six months), but there is no clear advantage for any particular strategy.
The effect of purging was evaluated in the Autologous Blood and Marrow Transplant Registry
of North America.43 In a paired analysis, the use of purging decreased late
relapses and overall treatment failure for patients in CR1 and CR2.
Overall Postremission Strategy for AML in CR1
The emergence of HiDAC as effective consolidation therapy and the success of auto-SCT
with low treatment mortality has challenged the traditional recommendation of allo-BMT in
CR1. Allo-BMT and auto-SCT have been compared in prospective fashion or through the
international and national registries.44,45 For patients in CR1 or CR2,
allo-BMT decreases relapse and improves leukemia-free survival at three years with respect
to auto-SCT. Zittoun et al46 recently reported
on a trial in which patients in CR1 following a course of standard consolidation were
either allocated to allo-BMT if they had a donor or randomized to auto-SCT or HiDAC (2 g/m2
x 8 doses) plus daunorubicin (45 mg/m2 x 3). The four-year disease-free
survival was highest in allo-BMT (55%), lower in auto-SCT (48%), and lowest in HiDAC
(30%). There were no differences in overall survival (allo-BMT was 59%, auto-SCT was 56%,
and HiDAC was 46%). It should be noted that HiDAC was 8 (2 g/m2) doses in this
study vs 24 (3 g/m2) doses given in the CALGB study.
If allo-BMT cures 25% to 35% in CR2 and HiDAC cures 44% in CR1, reserving allo-BMT for
relapse would achieve the same results as performing allo-BMT in CR1. Although this
strategy has not been tested, it implies that all patients who relapse can achieve a
second remission with salvage and can be candidates for allo-BMT, an unlikely scenario.
Gamberi et al47 analyzed the use of allo-BMT in 271 newly diagnosed patients
with AML. Only 113 were allo-BMT candidates because of age, and only 81 were typed. Of
those, 36 had an HLA-identical sibling but only 21 underwent an allo-BMT (8% of all newly
diagnosed patients, 19% of those who were candidates because of age criteria). Appelbaum
et al48 showed that patients transplanted in untreated first relapse did as
well as those transplanted in CR2. This study was small (62 patients) and nonrandomized,
and those in florid relapse (>30% marrow blasts) had a high relapse rate. Prospective
studies stratifying for the important prognostic factors (particularly cytogenetics) must
compare allo-BMT, auto-SCT, and HiDAC (CALGB dosing). In the meantime, individualized
treatment should be performed (Table 2). At this time, auto-SCT in CR1 should be performed
only as part of well-designed clinical trials.
Treatment of Relapsed/Refractory AML
Options are limited if a patient does not achieve an initial CR after two induction
attempts and a compatible sibling (HLA-identical or 5/6 family donor) is not available.
HiDAC-based chemotherapy, etoposide/ mitoxantrone +/– Ara-C, and fludarabine-based
chemotherapy have been explored in this setting with CR rates of 30% to 50% and remission
duration of three to four months.49,50 As these patients exhibit the MDR
phenotype, the use of cyclosporine or quinine in addition to standard induction regimens
has been explored in an attempt to reverse drug resistance, with promising results in
phase I/II studies.51
Another option is to explore investigational chemotherapy regimens in well-designed
NCI-sponsored trials. An approach for younger patients is to undergo allo-BMT using an
alternative donor (3-4/6 family donor or unrelated donor). An analysis of 2,055
transplants reported to the International Bone Marrow Transplant Registry showed that the
use of alternative donors increased the treatment-related mortality when compared to the
use of sibling-matched transplants, thus resulting in inferior leukemia-free survival.52
These differences were less prominent with advanced leukemias due to the decreased relapse
associated with increased GVHD. Alternative donor transplants would be a reasonable option
for induction failures, CR1 with poor cytogenetics, CR2, and refractory disease.
The outcome of patients who relapse from CR1 depends on the remission duration. Only
20% of patients whose first remission lasts more than two years will be alive at five
years when treated by chemotherapy, in contrast to no survivors when initial remission is
shorter. Allo-BMT from a compatible family donor offers the best chance of cure for these
patients. For those without a donor, allo-BMT using an alternative donor or auto-SCT are
viable options. The former is associated with a high treatment-related mortality and the
latter with high relapse rates. If the patient is young and has a good match, alternative
donor transplant is the better option, while an older patient with a good-risk leukemia
(normal cytogenetics and long remission) would benefit from an auto-SCT. While patients in
early relapse might be transplanted without reinduction, most patients will require
chemotherapy. The choice of salvage will be dictated by patient- and disease-specific
characteristics, but since the CR rate will be lower than at initial diagnosis, an
intensive regimen such as the ones used for induction failures is usually recommended. If
an auto-SCT is planned (with or without purging) and the marrow has not been collected
previously, a cycle of consolidation is given prior to stem cell collection. This same
scenario would apply to the unrelated donor setting due to the time it takes to find a
donor and perform the transplant.
Patients whose AML is secondary to previous therapy or to MDS have a poor prognosis due
to a low CR rate and short remission duration with few, if any, cures.53 Most
patients have detectable clonal abnormalities and usually involve chromosomes 5 and/or 7.
Since the CR rate is 35% to 40%, an issue is whether these patients should undergo
allo-BMT without prior induction. The tempo of the disease, availability of a donor, and
socioeconomic factors will affect this decision. Anderson et al54 reported data
on 46 patients with secondary AML who underwent allo-BMT without induction. The five-year
disease-free survival was 24%, the relapse rate was 31%, and the nonrelapse mortality rate
was 44%. Factors associated with improved outcome included younger age, shorter time from
diagnosis to BMT (less nonrelapse mortality), and lower peripheral blast count (lower
relapse rate). A nonrandomized comparison with patients with t-AML who underwent induction
showed similar overall outcome. Thus, transplantation as soon as this complication is
diagnosed, hopefully in the MDS phase, will offer the best chance of cure. Perhaps
induction should be reserved for those with high tumor burden, since the relapse rate is
more than 50%, and for those who require an unrelated donor search.
Treatment of Acute Promyelocytic Leukemia
Acute promyelocytic leukemia (APL) comprises 10% of AML in adults. APL clinically
presents with a bleeding diathesis that is often exacerbated by chemotherapy with an early
mortality of 10% to 20%. The mechanisms of bleeding are multiple and include DIC,
fibrinolysis, and thrombocytopenia.55,56 APL is characterized by the t(15;17),
which fuses the promyelocytic leukemia (PML) gene on chromosome 15 to the retinoic acid
receptor alpha gene on chromosome 17 (PML/RAR proportional), which leads to
leukemogenesis. All-trans-retinoic acid (ATRA) mediates granulocytic differentiation
leading to CR in the majority of patients with resolution of the bleeding diathesis.57,58
The treatment with ATRA has two drawbacks: (1) patients relapse unless cytotoxic
chemotherapy is given after achievement of CR, and (2) the retinoic acid syndrome can
result, which can be fatal. A French trial by Fenaux et al59 studied 26
patients treated with ATRA followed by chemotherapy (daunorubicin plus Ara-C x 4 courses),
and 25 (96%) achieved CR. The EFS was 77% at 18 months. A randomized study comparing ATRA
plus chemotherapy vs chemotherapy alone was terminated early because the EFS at 12 months
favored the ATRA arm (79% vs 50%).60 A similar trial was done in the United
States by the intergroup mechanism.61 Surprisingly, the induction deaths were
similar in both groups since the bleeding deaths in the chemotherapy arm were balanced by
deaths secondary to the retinoic acid syndrome in the ATRA arm. The 12-month disease-free
survival was 57% in the chemotherapy arm vs 92% in the ATRA arm (P=.0001).
Similarly, the use of ATRA during maintenance decreased relapses (16% vs 43%).
The retinoic acid syndrome is manifested by fever, dyspnea, diffuse pulmonary
infiltrates, weight gain, edema, and episodic hypotension. It occurs two to 21 days after
initiation of ATRA and is associated with renal and hepatic dysfunction often in the
setting of a rising leucocyte count (not always).62 Its pathophysiology is
related to the expression of cellular adhesion molecules and the release of growth factors
and cytokines by leukemic cells upon stimulation by ATRA. Two treatment approaches with
good success include the use of chemotherapy once the leucocyte count begins to rise
(European), and use of high-dose corticosteroids at the earliest clinical suspicion
(MASK).
As most patients are cured with ATRA plus chemotherapy, the use of bone marrow
transplant is reserved for relapses. The use of RT-PCR will allow detection of minimal
disease and help in deciding when to perform the transplant.
References
1. Ries LA, Miller BA, Hankey BF, et al, eds. SEER Cancer Statistics Review,
1973-1991: Tables and Graphs. Bethesda, Md: National Cancer Institute, NIH Publ No
94-2789; 1994.
2. Ho WG, Winston DJ. Infection and transfusion therapy in acute leukaemia. Clin
Haematol. 1986;15:873-904.
3. Bennett JM, Catovsky D, Daniel MT, et al. Proposed revised criteria for the
classification of acute myelogenous leukemia: a report of the French-American British
Cooperative Group. Ann Intern Med. 1985;103:620-625.
4. Janvier M, Tobelem G, Daniel MT, et al. Acute monoblastic leukemia: clinical,
biological data and survival in 45 cases. Scand J Haematol. 1984;32:385-390.
5. Venditti A, Del Poeta G, Buccisano F, et al. Minimally differentiated acute myeloid
leukemia (AML-M0): comparison of 25 cases with other French-American-British subtypes. Blood.
1997;89:621-629.
6. Olopade OI, Thangavelu M, Larson RA, et al. Clinical, morphologic, and cytogenetic
characteristics of 26 patients with acute erythroblastic leukemia. Blood.
1992;80:2873-2882.
7. Wang JC, Beauregard P, Soamboonsrup P, et al. Monoclonal antibodies in the
management of acute leukemia. Am J Hematol. 1995;50:188-199.
8. Leith CP, Kopecky KJ, Godwin J, et al. Acute myeloid leukemia in the elderly:
assessment of multidrug resistance (MDR1) and cytogenetics distinguishes biologic
subgroups with remarkably distinct responses to standard chemotherapy: a Southwest
Oncology Group Study. Blood. 1997;89:3323-3329.
9. Ball ED, Davis RB, Griffin JD, et al. Prognostic value of lymphocyte surface markers
in acute myeloid leukemia. Blood. 1991;77:2242-2250.
10. Reading CL, Estey EH, Huh YO, et al. Expression of unusual immunophenotype
combinations in acute myelogenous leukemia. Blood. 1993;81:3083-3090.
11. Schiffer CA, Lee EJ, Tomiyasu T, et al. Prognostic impact of cytogenetic
abnormalities in patients with de novo acute nonlymphocytic leukemia. Blood.
1989;73:263-270.
12. Mrozek K, Heinonen K, de la Chapelle A, et al. Clinical significance of
cytogenetics in acute myeloid leukemia. Semin Oncol. 1997;24:17-31.
13. Schoch C, Haase D, Haferlach T, et al. Secondary chromosome aberrations in acute
myeloid leukemia with t(8;21)(q22;q22), inv(16)(p13q22) or t(15;17)(q22;q21). Blood.
1995;86(suppl 1):43a. Abstract.
14. Pedersen-Bjergaard J, Pedersen M, Roulston D, et al. Different genetic pathways in
leukemogenesis for patients presenting with therapy-related myelodysplasia and
therapy-related acute myeloid leukemia. Blood. 1995;86:3542-3552.
15. Quesnel B, Kantarjian H, Bjergaard JP, et al. Therapy-related acute myeloid
leukemia with t(8;21), inv(16), and t(8;16): a report on 25 cases and review of the
literature. J Clin Oncol. 1993;11:2370-2379.
16. Yates J, Glidewell O, Wiernik P, et al. Cytosine arabinoside with daunorubicin or
Adriamycin for therapy of acute myelocytic leukemia: a CALGB study. Blood.
1982;60:454-462.
17. Preisler H, Davis RB, Kirshner J, et al. Comparison of three remission induction
regimens and two postinduction strategies for the treatment of acute non-lymphocytic
leukemia: a Cancer and Leukemia Group B study. Blood. 1987;69:1441-1449.
18. 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. 1991;77:1666-1674.
19. Berman E, McBride M. Comparative cellular pharmacology of daunorubicin and
idarubicin in human multidrug-resistant leukemia cells. Blood. 1992;79:3267-3273.
20. Rustum YM, Preisler HD. Correlation between leukemic cell retention of
1-beta-D-arabinofuranosylcytosine 5’-triphosphate and response to therapy. Cancer
Res. 1979;39:42-49.
21. Bishop JF, Matthews JP, Young GA, et al. A randomized study of high-dose cytarabine
in induction in acute myeloid leukemia. Blood. 1996;87:1710-1717.
22. Weick JK, Kopecky KJ, Appelbaum FR, et al. A randomized investigation of high-dose
versus standard-dose cytosine arabinoside with daunorubicin in patients with previously
untreated acute myeloid leukemia: a Southwest Oncology Group study. Blood.
1996;88:2841-2851.
23. Mitus AJ, Miller KB, Schenkein DP, et al. Improved survival for patients with acute
myelogenous leukemia. J Clin Oncol. 1995;13:560-569.
24. Schiffer CA. Hematopoietic growth factors as adjuncts to the treatment of acute
myeloid leukemia. Blood. 1996;88:3675-3685.
25. Cassileth PA, Harrington DP, Hines JD, et al. Maintenance chemotherapy prolongs
remission duration in adult acute nonlymphocytic leukemia. J Clin Oncol.
1988;6:583-587.
26. Cassileth PA, Begg CB, Bennett JM, et al.4 A randomized study of the efficacy of
consolidation therapy in adult acute nonlymphocytic leukemia. Blood.
1984;63:843-847.
27. Wolff SN, Herzig RH, Phillips GL, et al. High-dose cytosine arabinoside and
daunorubicin as consolidation therapy for acute nonlymphocytic leukemia in first
remission: an update. Semin Oncol. 1987;14(2 suppl 1):12-17.
28. Cassileth PA, Lynch E, Hines JD, et al. Varying intensity of postremission therapy
in acute myeloid leukemia. Blood. 1992;79:1924-1930.
29. Mayer RJ, Davis RB, Schiffer CA, et al. Intensive postremission chemotherapy in
adults with acute myeloid leukemia: Cancer and Leukemia Group B. N Engl J Med.
1994;331:896-903.
30. Bloomfield CD, Lawrence D, Arthur DC, et al. Curative impact of intensification
with high-dose cytarabine (HiDAC) in acute myeloid leukemia (AML) varies by cytogenetic
group, Blood. 1994:84(suppl 1):111a.
31. Clift RA, Buckner CD, Thomas ED, et al. The treatment of acute non-lymphoblastic
leukemia by allogeneic marrow transplantation. Bone Marrow Transplant.
1987;2:243-258.
32. Clift RA, Buckner CD, Appelbaum FR, et al. Allogeneic marrow transplantation in
patients with acute myeloid leukemia in first remission: a randomized trial of two
irradiation regimens. Blood. 1990;76:1867-1871.
33. Weiden PL, Flournoy N, Thomas ED, et al. Antileukemic effect of graft-versus-host
disease in human recipients of allogeneic-marrow grafts. N Engl J Med.
1979;300:1068-1073.
34. Kolb HJ, Schattenberg A, Goldman JM, et al. Graft-versus-leukemia effect of donor
lymphocyte transfusions in marrow grafted patients: European Group for Blood and Marrow
Transplantation working Party Chronic Leukemia. Blood. 1995;86:2041-2050.
35. Biggs JC, Horowitz MM, Gale RP, et al. Bone marrow transplants may cure patients
with acute leukemia never achieving remission with chemotherapy. Blood.
1992;80:1090-1093.
36. Fagioli F, Bacigalupo A, Frassoni F, et al. Allogeneic bone marrow transplantation
for acute myeloid leukemia in first complete remission: the effect of FAB classification
and GVHD prophylaxis. Bone Marrow Transplant. 1994;13:247-252.
37. Matthews DC, Appelbaum FR, Eary JF, et al. 131I-anti-CD45 antibody plus
busulfan/cyclophosphamide in matched related transplants for AML in first remission. Blood.
1996;88:142a.
38. 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. J
Clin Oncol. 1991;9:1840-1847.
39. McMillan AK, Goldstone AH, Linch DC, et al. High-dose chemotherapy and autologous
bone marrow transplantation in acute myeloid leukemia. Blood. 1990;76:480-488.
40. Brenner MK, Rill DR, Moen RC, et al. Gene-marking to trace origin of relapse after
autologous bone marrow transplantation. Lancet. 1993;341:85-86.
41. 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. 1990;75:1606-1614.
42. 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. J Clin Oncol.
1996;14:2206-2216.
43. Miller CB, Rowlings PA, Jones RJ, et al. Autotransplants for acute myelogenous
leukemia (AML): effect of purging with 4-hydroperoxycyclophosphamide (4HC). Blood.
1995;86:100a.
44. Ferrant A, Doyen C, Delannoy A, et al. Allogeneic or autologous bone marrow
transplantation for acute non-lymphocytic leukemia in first remission. Bone Marrow
Transplant. 1991;7:303-309.
45. Keating A, Rowlings PA, Horowitz MM, et al. Comparison of HLA-identical sibling and
autologous bone marrow transplants for acute myelogenous leukemia (AML). Blood.
1994;84:201a.
46. Zittoun RA, Mandelli F, Willemze R, et al. Autologous or allogeneic bone marrow
transplantation compared with intensive chemotherapy in acute myelogenous leukemia:
European Organization for Research and Treatment of Cancer (EORTC) and the Gruppo Italiano
Malattie Ematologiche Maligne dell’Adulto (GIMEMA) Leukemia Cooperative Groups. N
Engl J Med. 1995;332:217-223.
47. Gamberi B, Bandini G, Visani G, et al. Acute myeloid leukemia from diagnosis to
bone marrow transplantation: experience from a single centre. Bone Marrow Transplant.
1994;14:69-72.
48. Appelbaum FR, Clift RA, Buckner CD, et al. Allogeneic marrow transplantation for
acute nonlymphoblastic leukemia after first relapse. Blood. 1993;61:949-953.
49. Amadori S, Arcese W, Isacchi G, et al. Mitoxantrone, etoposide, and
intermediate-dose cytarabine: an effective and tolerable regimen for the treatment of
refractory acute myeloid leukemia. J Clin Oncol. 1991;9:1210-1214.
50. Estey E. Treatment of refractory AML. Leukemia. 1996,10:932-936.
51. List AF. Role of multidrug resistance and its pharmacological modulation in acute
myeloid leukemia. Leukemia. 1996;10:937-942.
52. Szydlo R, Goldman JM, Klein JP, et al. Results of allogeneic bone marrow
transplants for leukemia using donors other than HLA-identical siblings. J Clin Oncol.
1997;15:1767-1777.
53. Smith MA, McCaffrey RP, Karp JE. The secondary leukemias: challenges and research
directions. J Natl Cancer Inst. 1996;88:407-418.
54. 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. 1997;89:2578-2585.
55. Warrell R Jr, de The H, Wang ZY, et al. Acute promyelocytic leukemia. N Engl J
Med. 1993;329:177-189.
56. Tallman MS, Kwaan HC. Reassessing the hemostatic disorder associated with acute
promyelocytic leukemia. Blood. 1992;79:543-553.
57. Chen ZX, Xue YQ, Zhang R, et al. A clinical and experimental study on all-trans
retinoic acid-treated acute promyelocytic leukemia patients. Blood.
1991;78:1413-1419.
58. Tallman MS. Differentiating therapy with all-trans retinoic acid in acute myeloid
leukemia. Leukemia. 1996;10(suppl 1):12-15.
59. Fenaux P, Castaigne S, Dombret H, et al. All-trans-retinoic acid followed by
intensive chemotherapy gives a high complete remission rate and may prolong remissions in
newly diagnosed acute promyelocytic leukemia: a pilot study on 26 cases. Blood.
1992;80:2176-2181.
60. Fenaux P, Le Deley MC, Castaigne S, et al. Effect of all-trans-retinoic acid in
newly diagnosed promyelocytic leukemia: results of a multicenter randomized trial. Blood.
1993;82:3241-3249.
61. 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
promyelocytic leukemia (APL). Blood. 1995;86:488a.
62. Frankel SR, Eardley A, Lauwers G, et al. The "retinoic acid syndrome" in
acute promyelocytic leukemia. Ann Intern Med. 1992;117:292-296.
Back to Cancer Control Journal Volume 4 Number 5