Page 1429 - Williams Hematology ( PDFDrive )

1404 Part X: Malignant Myeloid Diseases Chapter 88: Acute Myelogenous Leukemia 1405

cells from AML, other than APL, have not found mutations of RAR- The immunomodulatory drug lenalidomide has also been exam-
α. Nevertheless, combinations of retinoids, growth factors, and che- ined in AML and has some activity in high doses in relapsed or refrac-
873
motherapeutic agents are being examined for therapeutic potential in tory AML. 907,908
874
AML. Leukemias with 11q, –5, and –7 chromosome abnormalities The IL-3 receptor α (CD123) is overexpressed in AML as compared
have high telomerase activity, which can be inhibited by maturation- with normal HSCs, so it has been proposed as a target for chimeric anti-
875
inducing agents. In one study, addition of ATRA to chemotherapy did gen receptors (CARS) as a bridge to allogeneic HSC transplantation. 909,910
not improve patient outcome but did result in a 25 percent increase in
876
apoptosis in AML marrow cells in vitro. ATRA has induced a com-
plete remission in a patient with acute myelomonocytic leukemia. 877,878 SPECIAL THERAPEUTIC CONSIDERATIONS
Arsenic trioxide induces apoptosis and cytotoxic effects in blasts from Acute Promyelocytic Leukemia
patients with AML other than APL, and it is not influenced by permea- General Consideration in Therapy Because of the early induction
bility glycoprotein (P-gp) expression. 879,880 mortality in APL, patients who are suspected based on morphology
and presence of coagulopathy should begin ATRA without waiting for
Antiangiogenesis Agents and Agents That Inhibit Microenvi- definitive FISH or molecular confirmation. There is now an International
ronmental Interactions Consortium on APL, the goal is to improve outcomes through educa-
Targeting the increased vascular density of marrow noted in AML tion and guidelines formulaton. While many trials with variations in
911
or cytokines secreted by marrow endothelium has been examined as the induction, consolidation, and maintenance phases are published,
881
880
means to inhibit AML cell growth. Amifostine, thalidomide, suni- the clinician is urged to consider clinical trials and to follow one proto-
tinib, and other agents that target VEGF and interleukin (IL)-8, as col plan through all the phases of therapy.
882
881
well as of the angiopoietin signaling pathway, are potential antiangio- Induction Treatment ATRA has become a standard component of
883
genic agents in the treatment of AML. Lenalidomide, which also has induction therapy for APL. Used alone, ATRA can induce a short-term
884
912
antiangiogenic properties, is used to treat deletion 5q– AML. Antago- remission in at least 80 percent of patients. However, ATRA should be
nists of the chemokine receptor CXCR4, which plays a role in retention combined with an anthracycline such as idarubicin or with arsenic tri-
of hematopoietic cells in marrow and of integrins or selectins, have been oxide during induction treatment for most benefit and to prevent drug
913
proposed as therapeutic agents to overcome stromal-mediated resis- resistance. Idarubicin by itself can induce remission in approximately
914
tance and to enhance chemotherapy-induced cell death. 885,886 75 percent of patients. A typical induction regimen for APL is ATRA
45 mg/m daily in divided doses with idarubicin at standard induction
2
Modulation of Drug Resistance doses (e.g., 12 mg/m on days 1 to 3). 915,916 Although cytarabine has been
2
887
Numerous mechanisms of drug resistance occur in AML, and several largely abandoned as part of induction, some studies show a high degree
917
attempts to overcome this resistance have been instituted, but none of of efficacy of high-dose cytarabine combined with ATRA. There is evi-
9
the agents used, such as cyclosporine or PSC-833, have had a significant dence that in patients who present with a white cell count of 10 × 10 /L
impact on AML outcomes to date. P-gp, MDR protein-1 (MRP-1), and or greater, the complete remission rate and overall survival may be supe-
breast cancer resistance protein (BCRP) expression all have been found rior when cytarabine is added to induction or consolidation regimens,
in AML. 888 especially if arsenic trioxide is not part of the induction regimen. 918,919
The addition of arsenic trioxide to ATRA and idarubicin in induction
Other Immunotherapy and Antisense DNA Approaches regimens results in approximately 95 percent complete remission rates.
Culture of AML blasts upregulates costimulatory molecules, and the This approach allows reduction in anthracycline usage and excellent
role of dendritic cells in antileukemia therapy is being examined. 889–891 overall survival (93 percent). In low- to intermediate-risk APL (WBC
920
Other approaches to generating autologous T-cell antileukemic activity <10 × 10 /L), the combination of ATRA and arsenic trioxide was found
9
include vaccination with AML-specific peptides, immunization with equal to, or possibly superior to, an ATRA plus chemotherapy regi-
AML blasts exhibiting dendritic cell phenotype and function, 892,893 and men. 921,922 Also, there was less hematologic toxicity and fewer infections
894
pulsing normal dendritic cells with AML-specific peptide sequences. with that combination of drugs. Older patients generally tolerate a com-
895
Natural killer cells may mediate antileukemia effects. Low doses bination of ATRA and an anthracycline. Combinations that include
923
of IL-2 have been used in the maintenance phase of AML, and some gemtuzumab ozogamicin are being examined for their effectiveness in
patients have remained on this regimen for 10 or more years without APL induction therapy, but this antibody is no longer marketed in the
significant side effects. However, low-dose IL-2 does not improve out- United States. The combination of ATRA and arsenic trioxide results
896
924
comes when used as maintenance treatment in older AML patients. in more rapid remissions and lower PML-RAR-α transcript levels than
897
925
The WT gene WT1 is expressed on AML blasts, and a WT1 vaccine either agent alone. Despite the high remission rates and frequency
may elicit cytotoxic T-cell responses against this protein. Peptides of long-term event-free survival achieved in this disease, controversies
898
derived from the mutated nucleophosmin I gene can elicit in vitro remain regarding therapy because of the 5 to 10 percent of patients who
129
926
CD4 and CD8 T-cell responses. Other proteins against which such die as a result of fatal intracranial hemorrhage. This relatively high
humoral responses have been elicited include minor HLA antigens and early death rate (17.3 percent) persisted despite use of ATRA in induc-
899
proteinase-3. Coinhibitory molecule signaling can hamper benefit tion therapy. Thus, there are several induction regimens that can be
927
of immune therapies, so efforts to modulate coinhibitory networks are chosen to treat APL based on WBC at diagnosis and, to a lesser extent,
underway in leukemias. Small interfering RNA (siRNA) targeting of patient age and ability to tolerate anthracyclines. For those with low-risk
900
transcription factors and GTI-2040, an antisense to ribonucleotide disease, a combination of ATRA plus arsenic trioxide, ATRA plus idaru-
901
reductase, have been used in AML therapy. In addition to CD33, bicin alone, or ATRA plus daunorubicin plus cytarabine can be used. In
902
CD45, CD66, and CD38 have been examined as targets for immuno- high-risk patients, ATRA plus daunorubicin and cytarabine, ATRA plus
therapy of AML. 903,904 Immunotoxin conjugates are being examined in idarubicin, or ATRA and arsenic trioxide with idarubicin (dose-adjusted
905
AML as well to increase potency of naked monoclonal antibodies. based on age) can be used. Table 88–8 lists APL induction regimens.
928
Alloreactive haploidentical KIR ligand-mismatched natural killer cells All-Trans Retinoic Acid: Dose and Mechanism of Action ATRA,
are also being examined in high-risk elderly AML cases. 906 an analogue of vitamin A, has been used to initiate the therapy of APL
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