Page 1050 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 59 Clinical Manifestations and Treatment of Acute Myeloid Leukemia 933

Acute myeloid leukemia

Yes • ATRA plus arsenic trioxide( anthracycline)
APL
• ATRA plus anthracycline
No
Yes • High-dose cytarabine
CBF AML
-FLAG anthracycline or gemtuzumab
• Age No Age
• Performance status 60 yrs
• Comorbidities Other AML • Cytarabine/anthracycline-based
• Karyotype
• Genotype Age 60 yrs
• Low-dose cytarabine
• Hypomethylating agents
• Cytarabine/anthracycline-based
• Clinical study
Fig. 59.14 GENERAL APPROACH TO ACUTE MYELOID LEUKEMIA THERAPY. AML, Acute
myeloid leukemia; APL, acute promyelocytic leukemia; ATRA, all-trans retinoic acid; CBF, core binding factor;
FLAG, fludarabine, cytarabine (ara-C), and granulocyte colony-stimulating factor.

outcome by early intervention, and (3) support in decision to inten- measures including transfusion services and symptom control have
sify postremission therapy (transplant) or not. Efficacy of preemptive played an important part in improving the outcome of patients with
therapy based on MRD has been established for APL but data in AML over the last decade.
support for other subtypes of AML are still accumulating. The general approach to AML therapy is summarized in Fig.
MRD can be detected by reverse-transcriptase polymerase chain 59.14. Besides AML subtype (APL, CBF leukemias, other) attention
reaction (RT-PCR) or multiparameter flow cytometry (MPFC). Both needs to be paid to age and a more global assessment of fitness
assays have comparable sensitivity. RT-PCR requires a suitable (performance status, comorbidities, geriatric assessment scores).
molecular target such as fusion transcripts (e.g., PML-RARA, Treatment of patients “unfit” for standard intensive induction therapy
RUNX1-RUNX1T1, CBFB-MYH11, DEK-CAN) or overexpressed (often equaled to patients older than 60 to 65 years) is frequently
(WT1) or mutated genes, and thus applies to a more limited number approached differently from that of younger patients, and hence this
of patients than MPFC. MPFC is based on the identification of a chapter addresses therapy separately for each age group. It should be
leukemia-associated immunophenotype, which can be detected in the understood, though, that age alone is increasingly considered inad-
majority of patients with AML in various ways: a) “different-from equate to assess a patient’s fitness status.
normal” antigen expression in leukemic blasts; b) detection of Treatment of AML consists of induction and postremission
lineage-foreign markers; c) asynchronous expression of markers; d) therapy. The goal of induction is to produce a CR and that of pos-
altered density of surface antigens; e) detection of surrogate marker tremission therapy to maintain it by eliminating residual disease. CR
profiles (associated with cytogenetic–molecular markers); f) detection is defined as achievement after chemotherapy of less than 5% marrow
8
of leukemia stem cells. Commonly, a level of 0.1% has been deter- blasts, a neutrophil count of greater than 1000/µL, a platelet count
mined to distinguish patients with MRD from those without. This of greater than 100,000/µL, independence of red blood cell transfu-
level is a log higher than what defines the threshold for MRD in ALL sions, and resolution of all signs and symptoms referable to AML.
(<0.01%). MRD levels following induction or early in consolidation CR defines a landmark point in time because patients who achieve
have been associated with relapse and survival in all age groups CR on any given day after beginning therapy have longer survival
regardless of cytogenetic and mutational status. Even though MRD subsequent to that day than patients who are resistant to therapy on
levels tend to be higher in patients with unfavorable pretreatment the day in question. Lesser response criteria (CR without platelet
characteristics, the prognostic impact of MRD extends to all risk recovery, CR with incomplete blood recovery including neutropenia,
groups and has shown to improve standard risk classification inde- partial remission, morphologic leukemia-free state) may serve as
pendently of cytogenetic–molecular markers. Evaluation of MRD has useful end points in the context of investigational studies (phase I,
led to renewed interest in strategies for its elimination. Besides II, or III), but they do not carry the same significance for survival as
intensification of therapy by means of hematopoietic stem cell does CR. Postremission therapy consists of repeated cycles of chemo-
transplantation (HSCT) as a response to persistence of MRD, other therapy or HSCT in its various forms (autologous, allogeneic, hap-
approaches have been or are being pursued: maintenance therapy loidentical, cord blood, reduced intensity). The role of HSCT for
(interleukin-2 [IL-2] based), cellular therapy (dendritic cell vaccina- AML therapy will be the topic of a separate chapter of this book. The
tion, T-cell manipulations), monoclonal antibodies (e.g., anti- debate as to which patients should receive chemotherapy consolida-
CD123), epigenetic priming, or maintenance. tion versus HSCT is most divisive for patients with intermediate-risk
disease. In this population, characterization of the genotype has
become helpful in guiding that decision.
THERAPY: FRONTLINE Leukemia has been at the forefront of the development of “tar-
geted” therapy, mostly small-molecule drugs directed against defined
AML therapy is one of the most challenging of oncologic interven- intracellular proteins (e.g., kinases). Given the increasing number of
tions. Treatment often needs to be fast, physicians need to deal with genetic abnormalities and the identification of diverse intracellular
a multitude of complications (disease or treatment related), and from pathways of blast cells, the specter of “personalized therapy” looms
the start a patient’s condition can deteriorate rapidly. Given its high in AML therapy. Yet, despite intense research activity, to date
complexity, treatment of patients with AML requires a multidisci- no “targeted” drug has been approved for any type of AML (excep-
plinary effort including oncologists, pharmacists, a well-educated and tions: gemtuzumab ozogamicin [GO], an anti-CD33 monoclonal
committed nursing staff, and various consulting services (e.g., infec- antibody–calicheamicin conjugate with activity in some subtypes of
tious disease, pulmonology, nephrology, cardiology). Supportive care AML was approved in 2000, but then withdrawn in the United States