Latest treatment advances for acute myelogenous leukemia, The

latest treatment advances for acute myelogenous leukemia, The

Colvin, Gerald A

A cute leukemia is a stem cell disease that usually falls into two sub-types, myeloid or lymphoid. A total of 11,000 new cases of acute leukemia are diagnosed per year in the United States. Overall, acute leukemia is diagnosed in approximately 5 per 100,000 people each year. The incidence of acute myeloid leukemia (AML) is 3.6 per 100,000 people with the remainder having acute lymphoid leukemia (ALL).1 The median age of patients developing all is 4 years old, contrasted with 65 years for AML. The incidence of AML rises from 1.8 per 100,000 individuals below age 65 to 16.3 per 100,000 individuals at age 65 and over. This fact highlights the problem in treating patients with AML; most are too old for aggressive, potentially curative therapy such as a standard bone marrow transplant using a matched sibling or unrelated donor. Untreated, 95% of patients with acute leukemia will die within one year of diagnosis. Because the vast majority of acute leukemias are myeloid, we will focus on AML.

ACUTE MYELOID LEUKEMIA: CLASSIFICATION AND ETIOLOGY

New treatment strategies for AML have been, and continue to be, developed as a consequence of advances in the understanding of both cytogenetic and molecular pathogenesis. These new treatments have significantly improved the survival rate. Before 1970, the 5 year survival rate for AML was less than 15%; the current 5 year survival rate is about 40%. In older adults (>65 years of age), however, the 5 year survival rates are less than 10%.2

Eighty to 100% of newly diagnosed patients with AML have a chromosomal abnormality in myeloid cells.3 Most cases of AML are the result of genetic mutations that occur in hematopoietic progenitor cells and the majority of these mutations are acquired rather than inherited. The current French-American-British (FAB) classification of AML types M1 through M3 depends upon the varying degrees of granulocytic differentiation and maturation. Monocytic and granulocytic differentiation defects characterize AML-M4, whereas monocyte differentiation is the predominant feature of AML-M5. AML-M6 is characterized by erythroid morphology and AML-M7 by megakaryocytic features.

A recent retrospective analysis of nearly 2,000 patients has shown that the 5-year survival is directly related to the cytogenetic status of the hematopoietic cells at presentation.4 Patients with normal cytogenetics or with favorable cytogenetic abnormalities, such as t(8;21), t(15;17), and t(16;16), have better prognoses. Patients with deletions in the long arm of chromosome 7 and chromosome 5, deletions or inversions of chromosome 3, t(6;9), and the Philadelphia chromosome t(9;22), as well as abnormalities of chromosome 11q23, have relatively poor prognoses.5 Genetic deletions seem to be more characteristic of older AML patients, with 5q and 7q deletions found in approximately 17% of patients in this age group. In general, patients with AML whose cells have translocations seem to fare better than those whose cells have deletions. The poor prognosis associated with increased age may be related to the higher incidence of genetic deletions.

In AML, genes located at translocation breakpoints are typically responsible for cellular transcription and transduction of growth signals. Most translocations in de novo AML result in a fusion of the affected genes, with production of hybrid proteins. The (15; 17) translocation found in most promyelocytic leukemia (PML, M3) illustrates this mechanism where the promyelocytic leukemia (PML) gene on chromosome 15 is fused to the retinoic acid receptor (RAR) alpha gene on chromosome 17, leading to production of a nonfunctional RAR that does not respond to normal physiologic levels of circulating retinoic acid. Cell transcription and differentiation is thus arrested by the inability of the RAR to activate normal target genes. The PML gene seems to function as a histone deacetylator, which also serves to suppress gene transcription and cellular maturation. The administration of all-trans-retinoic acid (ATRA) allows the histone deacetylation complex to dissociate from the RAR-PML fusion protein, enabling the RAR to function appropriately, which, in turn, leads to cellular differentiation.

Another well-characterized gene rearrangement in AML involves the transcription factor complex core-binding factor (CBF). CBF is composed of an alpha subunit that directly contacts DNA and a CBF-beta subunit that facilitates binding of AML1 to DNA. Three genes (AML1, AML2, and AML3) encode the alpha subunit. It is thought that translocations involving the CBF result in the loss of normal CBF properties, converting CBF from transcriptional activator to inhibitor, thus leading to suppression of transcription of several target genes, including genes for interleukin-3 myeloperoxidase, granulocyte-macrophage colony-stimulating factor (GM-CSF), and the T-cell receptor beta.6

The (8;21) translocation, seen in approximately 46% of AML-M2 patients, results in the production of a fusion protein known as ETO/AML, of which the ETO portion from chromosome 8 is involved in histone deacetylation.7 This, in turn, serves to block activation of AML1 gene expression, resulting in lack of IL-3 and GMCSF receptor activation and loss of cellular differentiation/maturation. Inv(16), found in AML-M4 with eosinophilia, is associated with fusion of CBFb to the smooth muscle myosin heavy chain (MYH11) gene. This CBFb-MYH11 chimeric protein directly represses AML1-mediated transcriptional activity by forming inactive complexes in the cellular cytoplasm.8

Chemotherapy-related AML, especially following use of topoisomerase II inhibitors, seems to involve translocations at locus 11q23 (the MLL gene). A site within the MLL breakpoint cluster region has been identified as being prone to double-stranded DNA breaks as a result of exposure to topoisomerase II inhibition.9,10 To date, at least 38 different translocations have been identified that involve the MLL gene, but the mechanisms of action have yet to be worked out.

TRADITIONAL CHEMOTHERAPY FOR NEWLY DIAGNOSED ACUTE MYELOID LEUKEMIA

The treatment of AML has involved the administration of intensive combination chemotherapy with an anthracycline (i.e., daunorubicin (Dnr)) and cytarabine arabinoside (Ara-C). Treatment hasn’t changed since the late 1960s. Dnr and Ara-C have produced long-term survival in about 15% of those patients achieving complete remission.11

In general, treatment for AML consists of an induction phase (e.g., Dnr and Ara-C) followed by a post-remission consolidation phase. The necessity for consolidation treatment was demonstrated in a randomized study in which patients who were treated with induction therapy alone experienced a higher rate of relapse following a shorter period of remission.12 Subsequent clinical investigation demonstrated that consolidation is essential, whether treatment is given immediately following remission or delayed for several months.13

A retrospective review of patients treated with induction Dnr and Ara-C in 5 clinical trials conducted between 1976 and 1994 showed a complete remission rate of 62%, but 76% of these patients relapsed or died.14 Overall survival at 5 years was 15%, ranging between 9% and 33% for patients less than 55 years old, and between 6% and 15% for patients 55 years old and older. Both disease-free and overall survival was better in younger patients, when more intensive post-remission treatments were employed.

NEWER INDUCTION CHEMOTHERAPY APPROACHES IN AML

Histone acetylation plays a significant role in cellular transcription and leukemogenesis. Histone acetylation allows for greater exposure of DNA to transcription factors by enabling DNA/histone contacts to loosen or relax, thus promoting gene expression and cellular differentiation. Conversely, histone deacetylation is expected to inhibit gene expression and arrest cellular differentiation. The fusion genes PML-RAR and AML-1/ETO have already been described as promoting histone deacetylation. Thus, histone acetylation promoters and histone deacetylation (HDAC) inhibitors are logical agents for clinical study in AML. Several HDAC inhibitors are currently under clinical investigation. These include depsipeptide, sodium butyrate, and retinoic acid. Phase 1 trials showed minimal histone deacetylation activity in vitro with the use of maximally tolerated doses of sodium phenylbutyrate, precluding further single-agent studies. In one effort to overcome this obstacle, retinoic acid and sodium phenylbutyrate were combined. As a result, significant cellular differentiation was achieved, prompting further clinical investigation.15

Angiogenesis seems to play a role in leukemogenesis. Overexpression of fibroblast growth factor and vascular endothelial growth factor has been demonstrated in lymphoid and myeloid leukemia, respectively.16,17 There are a number of potential targets for angiogenic inhibition, including suppression of angiogenic factor release, binding of the free circulating factor, receptor blockade, or direct interference with endothelial cell function. Clinical trials with thalidomide and the tyrosine kinase inhibitors, SU5416 and SU6668, are in progress.

Using the success of ATRA as a base, investigators have looked at other retinoid compounds for use in leukemia. Fenretinide (N-[4-hydroxyphenyl]retinamide), first developed as a chemopreventive agent,18 was shown to induce apoptosis in malignant cells whether or not these cells possessed an RAR.19 Phase 1 testing demonstrated acceptable toxicity, with cases of reversible night blindness being reported.20

Protein kinase C (PKC) activation has been linked with the development of nucleoside analogue resistance. Bryostatin, a PKC inhibitor, has been studied in a number of solid and hematologic malignancies and because of low single agent activity, is currently being testing in combination with cytarabine, fludarabine, and 2-chlorodeoxyadenosine, as well as in combination with ATRA. UCN-01 (7-hydroxystaurosporine), a selective, but nonspecific, kinase inhibitor with good activity against PKC, has been shown to reverse cytarabine resistance in leukemic cell lines.21 Moreover, both bryostatin and UCN-01 have been shown to promote apoptosis via phosphorylation of Bcl-2. Other strategies for overcoming drug resistance are being tested, including reversal of the multi-drug resistance protein gene with quinine and cyclosporine.

POST-REMISSION CHEMOTHERAPY STRATEGIES

The extraordinarily high relapse rate suggests that most patients have residual disease after the completion of induction chemotherapy. Treatment options include consolidation therapy with high dose Ara-C based chemotherapy regimens, high-dose chemo(radio)therapy followed by autologous blood or marrow stem cell support, or highdose myeloablative therapy followed by allogeneic blood or marrow transplantation (alloBMT). Although the use of protracted “maintenance” therapy following induction and consolidation does not appear, in general, beneficial, some data suggest that maintenance therapy seems to confer disease-free and overall survival advantages, particularly in APL and in older adults with AML.

Most nontransplant consolidation chemotherapy regimens incorporate high dose Ara-C (HiDAc). The mortality rate of giving these treatments is around 10% to 20% per treatment and overall disease-free survival rates ranges from 20% to 50% in several published studies.22-25 Subset analysis indicates that HiDAc was beneficial for patients

TREATING AML IN OLDER ADULTS

Most patients fall into the unfavorable prognostic risk group since the median age at presentation for AML is 65 years. Older adults also tend to have other co-morbid conditions that make treatment even more difficult. Clearance of cytotoxic drugs may also be impacted by impaired hepatic or renal function. Additional data have disclosed that multi-drug resistance gene overexpression is found in more than 70% of de novo AML patients over the age of 55 years and is highly predictive for failure to achieve complete remission.27 Also, there is a greater incidence of AML arising from prior myelodysplasia, which, in turn, is accompanied by less favorable cytogenetic anomalies. All of these factors contribute to the poor prognosis for AML in older adults.

A large, retrospective review that examined long-term survival among 2882 patients with newly diagnosed AML, treated with various protocols between 1973 and 1996, included 944 patients over the age of 55 years.14 An update of the long term follow-up data showed that, compared with an overall median survival of 11 months, the median survival in older patients was only 6 months, with a 5-year survival rate of 7.6% (compared with 15% for the entire patient cohort). Another report from a large multicenter randomized trial showed a 9-month median survival and a 5-year survival rate of 8% in patients older than 60 years.28 A third study reported a 5-year survival rate of less than 5% in patients aged over 60 years.29 In older adults high dose consolidation with Ara-C with or without mitoxantrone has not been found to confer any survival benefit.30 Finally, older patients do not benefit by delaying treatment until clinical deterioration occurs.”

Monoclonal antibody (MAb) use, although a novel way to treat AML, has a low response rate, has an impressive amount of toxicity and is not curative. Gemtuzumab ozogamicin for example is known for causing liver dysfunction (~20% grade 3-4). Gemtuzumab is composed of an anti-CD33 IgG4 antibody, bound to calicheamicin, an anti-tumor antibiotic toxin that generates doublestranded DNA breaks, resulting in cellular death. Some of other agents include unconjugated anti-CD52, alemtuzumab. Gemtuzumab has been approved by the FDA for relapsed/refractory CD33-positive AML in patients aged 60 years or older who are not considered candidates for other types of cytotoxic chemotherapy.32

POST-REMISSION BLOOD OR MARROW TRANSPLANTATION

An alloBMT from a human leukocyte antigen (HLA) matched sibling can cure 50% to 60% of recipients, even more so than a syngeneic (identical twin) BMT, with less than a 20% risk of relapse following transplantation after first complete remission.33-35 However, the benefits of this treatment are mollified by upfront mortality due to organ damage, immunosuppression increasing susceptibility to opportunistic infections, acute and chronic graft-vs-host disease (GVHD), hepatic veno-occlusive, interstitial pneumonias, and graft failure. GVHD is responsible for the general restriction of alloBMT to patients younger than 55 years, but GVHD is also responsible for the reduced relapse rate as compared to syngeneic BMT by the graft-vs-leukemia (GVL) effect.

Autologous blood and marrow transplantation (autoBMT), first performed in 1977,36 also allows for the administration of dose-intensive chemotherapy, but, unlike alloBMT, does not help survival with the GVL effect. One reason may be that autoBMT may be associated with reinfusion of leukemic cells. Beginning in 1985, peripheral blood hematopoietic progenitor cells (PBSC) were successfully harvested, cryopreserved and later reinfused. PBSC may have a lower tumor burden than marrow.37-39 The role of graft purging (depletion)of tumor cells has not yet been proven to have any benefit except in small, single institution studies.40 Both PBSCT and autoBMT produce disease-free survival rates ranging between 35% and 50% in AML patients after first remission. Treatment-related mortality ranges from 10% to 20%.

Comparison of purged or unpurged autoBMT versus high dose consolidation in patients achieving a first complete remission has yielded equivalent results. In addition, alloBMT and autoBMT after first remission produced equivalent survival. Comparable survival was achieved in the high dose chemotherapy arm when relapsed patients subsequently underwent autoBMT as salvage treatment.41-45

RELAPSED AND REFRACTORY AML: NEXT STEPS

For the majority of AML patients treated with chemotherapy alone, disease recurrence remains the major obstacle to overcome. The most important factor is duration of first remission.45 Patients whose remission has lasted for 2 years or more before recurrence will achieve a second remission in 50% to 60% of cases, even when the same initial treatment regimen is repeated. When the first remission lasted 12-14 months a 40% chance is found. In patients whose remissions lasted less than 1 year or who failed to achieve a first remission (primary refractory disease), only 10% to 20% ever attained complete remission. Long term survival at 3 years in the longer duration remission group is approximately 20% to 25%, while the shorter duration remission groups have no appreciable survival.47 Therefore, treatment decisions must be based, in large part, upon an individuals potential for obtaining and maintaining a second remission. Those patients who are at greater risk for failure should not be offered standard therapies as a matter of course.

Ideally, patients with short duration first remissions, barring other complicating factors, should be considered as candidates for alloBMT and autoBMT, which can achieve approximately 30% long-term survival rates.48,49 Survival is similar whether or not chemotherapy precedes transplantation for either type of transplant.50,51

If younger than 55 years with primary refractory disease, alloBMT is superior to autoBMT.52,53 Transplant registry data show a leukemia-free survival advantage of 41% for alloBMT vs 17% for autoBMT for patients younger than 30 years old with at least 1 year or more of initial complete remission.54 If older than 30 years with less than 1 year of initial complete remission, either transplant modality had a higher 3-year leukemia-free survival compared with chemotherapy (18% vs 7%, respectively).55

An investigational new approach is to maximize the GVL effect and to minimize the toxicity to the vital organs from high dose chemotherapy. A single institution study open at Roger Williams Medical Center has already shown exciting results and may hold the key for universal treatment of relapsed or poor-prognosis AML patients of any age.56 While only 35% of patients otherwise eligible for allogeneic, nonmyeloablative, blood or marrow transplantation have an HLA-identical sibling donor, nearly 100% of patients have HLA-haploidentical related donors. Relapsed or refractory patients receive very low dose whole body radiation (10OcGy) as conditioning for the graft and then receive a PBSCT containing a precise number of CD3+ cells (T cells). Three of 4 evaluable patients with AML achieved a complete response and one patient who is not yet fully evaluable has achieved a partial response. Of interest, all responses occurred outside of detectable chimerism at 2 weeks after PBSCT (transplanted cells were not detectable). This is an outpatient treatment protocol with well defined toxicities (mainly transient pancytopenia) well tolerated by elderly and infirm patients. This is the first report of successful HLA-haploidentical cellular immunotherapy achieving a complete response for patients with end-stage, refractory hematologic malignancies. Further refinement using interactions between killer immunoglobulin-like receptors (KIR) and HLA class I ligands may even enhance success of this treatment.57

SUMMARY

The research into pathogenesis and mechanisms behind AML is advancing rapidly, but in general, translation into global application for the majority of patients is wanting. As more becomes known about the cytogenetic and molecular characteristics of leukemia cells and the pathways of leukemogenesis are further elucidated, it is hoped that future therapies will be directed more specifically toward the least toxic method to eradicate clonal malignant cells. HLA-haploidentical and alloBMT using KIR mismatch may dramatically improve survival for many more patients.

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Gerald A. Calvin, DO, and Gerald J. Elfenbein, MD

Gerald A. Calvin, DO, is Assistant Professor of Medicine, Boston University School of Medicine.

CORRESPONDENCE:

Gerald A. Colvin, DO

Adele R. Decof Cancer Center

Roger Williams Medical Center

825 Chalkstone Avenue

Providence, RI 02908

Phone: (401)456 5316

Fax: (401) 456-5759

e-mail: gcolvin@rwmc.org

Copyright Rhode Island Medical Society Aug 2003

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