|
Adult Acute Leukemia: Anything New Out There?
Introduction
The ECCO 11 Conference in Lisbon, Portugal, on October 21-25, 2001, was a bit disappointing from the perspective of papers regarding hematologic malignancy. While several interesting studies were presented and will be discussed below, many of the accepted posters were simply not there, and even 2 of the 8 oral presentations[1,2] were not given, as the speakers were absent. Nonetheless, some interesting new data were available for those who braved the weather and political turmoil to attend.
Acute Myeloblastic Leukemia (AML)
Over the past decade, aside from gemtuzumab ozogamicin for the treatment of elderly patients with relapsed or refractory AML, new therapies for adults with AML have simply not become available. Now, interesting results have been presented by Fiedler and colleagues,[3] who studied SU5416, a small molecule that is a potent and selective inhibitor of phosphorylation of the vascular endothelial growth factor receptors 1 and 2 (VEGF-R1 and VEGF-R2); and of c-kit, the receptor for stem cell factor (SCF).
SCF, secreted by AML blasts or by activated endothelial cells, promotes growth of AML cells. VEGF is secreted by the AML blasts in approximately 70% of patients, while VEGF-R1 and VEGF-R2 are expressed on the blasts of about 20% to 50% of AML patients. VEGF/VEGF-R signaling prevents apoptosis of AML blasts in vitro, and also induces proliferation of endothelial cells (neoangiogenesis), with production of various cytokines, such as SCF, granulocyte colony-stimulating factor, granulocyte-macrophage colony-stimulating factor, and others, which induce proliferation of AML blasts. The blockade of either SCF or VEGF/VEGF-R signaling might thus serve as a potential target for therapeutic intervention.
With this in mind, SU5416 was administered intravenously over 1 hour, at a dose of 145 mg/m2, twice weekly, for 4 weeks to a group of 43 patients with primary refractory or relapsed AML. The median age of the patients was 65 years (range, 27-79). Six of these patients had prior myelodysplastic syndrome, and 18 had unfavorable karyotypes.
All patients had either primary refractory AML, or had relapsed after receiving at least 2 prior regimens of chemotherapy, with the exception of a subset of 11 elderly patients who had been deemed medically unfit for receipt of such chemotherapy. All types of AML were represented, with the exception of FAB-M3 (acute promyelocytic leukemia [APL]) which was excluded.
A total of 21 patients were evaluable at the time of this study. Seven partial remissions (33.3%), lasting from 1 to 5 months, were achieved, while an additional patient had a "morphologic response" (disappearance of blasts from the peripheral blood, and < 5% blasts from marrow without normalization of peripheral counts), lasting 2 months.
Three potentially serious adverse events were encountered, including acute hepatic failure with death in 1 patient, grade 4 pancreatitis in 1, and grade 3 polyneuropathy in 1. A statistically significant relationship was found between response and expression of VEGF by the AML blasts, although no such relationship was evident in terms of c-kit expression. While very preliminary, this study does demonstrate the biologic activity of VEGF/VEGF-R blockade in the management of patients with AML. Further work is clearly indicated.
Acute Promyelocytic Leukemia (APL)
APL (FAB-M3) was among the first diseases to prove the clinical utility and importance of pathogenesis-based therapy.[4] The classic chromosomal abnormality in this disease is t (15;17), leading to the molecular expression of PML/retinoic acid receptor-alpha (RARa) on the leukemic cells, and expression at the protein level of an abnormal RAR-a on these blasts.[4,5] This chromosomal abnormality is seen in no other human malignancy, and serves to define both the pathogenesis and potential therapy of APL.
Use of all-trans-retinoic acid (ATRA) allows entry of retinoic acid into these abnormal blasts without the need for the normal receptor, with resultant full differentiation and apoptosis of the leukemic cells.[4-6] Approximately 80% of APL patients may be cured with a combination of ATRA and chemotherapy.[7]
In a very interesting set of studies performed by Dan Douer and colleagues,[8] from the University of Southern California, the prevalence of APL among Latino/Hispanic patients in Los Angeles was shown to be statistically increased, when compared with the prevalence of the disease among other racial/ethnic groups.
These studies led to several additional questions. First, who, exactly, were these "Latino" patients? Did they represent individuals of European descent, or of Indian descent ("mestizo") from Central or South America? Second, was the increased prevalence of APL in Latinos due to environmental or hereditary factors?
In an attempt to answer these questions, Douer and colleagues studied the break-points on the PML gene of the 15;17 translocation in a group of Latino APL patients from Los Angeles, and found an overrepresentation of the "long" or Bcr 1 isoform of the PML/RAR-a break point when compared with previous studies in other population groups.[9] This work suggested a possible hereditary or genetic predisposition for the disease.
Santillana and colleagues,[10] from Peru, have now studied the same question in a group of 22 APL patients from Peru, all of whom had molecular evidence of PML/RAR rearrangements, characteristic of the disease. Similar to the data on Latino patients from Los Angeles, the most common break-point isoform seen in the PML gene was long or Bcr 1, occurring in 73% of the patients. These individuals were all of mestizo or Indian descent from Peru, indicating that the predilection for APL among Latinos may indeed represent a genetic predisposition, perhaps restricted to Latinos of Indian or South American descent. Additional collaborative work is expected to further clarify this interesting aspect of the pathogenesis of APL.
Blast Crisis of Chronic Myelogenous Leukemia (CML)
Until very recently, there have been exceedingly few treatment options for patients with myeloid blast crisis of CML, and median survival has been in the range of only 2-3 months in patients treated with various chemotherapeutic regimens.[11]
The recent licensure of STI571, a specific, targeted tyrosine kinase inhibitor, represented the first potentially efficacious therapy ever developed for this disease.[12] Nonetheless, while complete remissions have been documented in approximately 11% of patients and the overall response rate is approximately 55% in STI571-treated patients with myeloid blast crisis of CML, remissions may be of short duration.[12]
In an oral presentation at ECCO 11, Jolivet and colleagues discussed their results with troxacitabine, a deoxycytidine nucleoside analogue, chemically related to cytosine arabinoside, and to the antiretroviral agent lamivudine.[13] Troxacitabine is a substrate for deocytidine kinase, and is a DNA chain terminator, resistant to deamination.
In a phase 1 study in patients with relapsed/refractory AML, the appropriate dose for phase 2 studies was found to be 8 mg/m2, given daily over 30 minutes, for 5 consecutive days.[14] With a prolonged half-life, the major toxicities of the drug included hand/foot syndrome, mucositis, and skin rash.
The current phase 2 study was performed in 17 patients with nonlymphoid blast crisis of CML. Troxacitabine was administered at a dose of 8 mg/m2 daily x 5, repeated every 7 weeks. Four patients had no prior therapy for blast crisis CML, while 13 had failed prior therapy, including STI571. Of great interest, 6/17 (35%) attained a second chronic-phase CML after troxacitabine treatment, lasting from 3 up to 18 months. Three of these patients had received no prior therapy for blast crisis, 1 had failed STI571 as sole prior therapy, and 2 had failed prior chemotherapy alone.
Similar to the phase 1 studies, toxicity included skin rash in 8 patients (grade 2 in 7, grade 3 in 1); hand/foot syndrome in 11 (grade 2 in 6, grade 3 in 5); and mucositis in 3 (grade 4 in 2). These data indicate the potential for a second regimen, in addition to STI571, effective in patients with myeloid blast crisis of CML. Further work is awaited with great interest.
Acute Lymphoblastic Leukemia (ALL)
While ALL is curable in approximately 70% to 80% of affected children, adults with the disease fare quite poorly, with only a minority achieving long-term, disease-free survival. In an oral session, Troncy and colleagues presented their data on 378 consecutive adult patients with ALL, over a 21-year period, all managed and diagnosed at the Hôpital Edouard Herriot in Lyon, France.[15]
After conventional chemotherapy, complete remission was attained in 79% of patients, indicating that the problem in adult ALL is not necessarily attainment of an initial complete remission status, but rather maintenance of leukemia-free survival. The results are summarized in the Table.
End Point
3-Year
5-Year
8-Year
Leukemia-free survival
30%
26%
24%
Overall survival
32%
24%
22%
ALL, acute lymphoblastic leukemia
Median leukemia-free survival was 14 months and median overall survival was 18 months.
Factors associated with statistically prolonged leukemia-free survival included: T-lineage ALL and younger age. Factors associated with statistically prolonged overall survival included: younger age, T-lineage ALL, standard risk features in non-T cases. Long-term survival was defined as those patients who were alive, without evidence of leukemia, at 3 or more years from diagnosis, and included only 23% of all evaluable patients.
Of interest, a difference between T-cell and non-T-cell lineage ALL was evident in terms of the results of stem cell transplantation. Thus, a total of 74% of patients with T-ALL attained long-term disease-free survival after allogeneic transplantation performed in first complete remission, while less than 50% of patients with B-ALL attained long-term leukemia-free survival after this procedure.
The results of this large study are consistent with other reports, suggesting that T-ALL has a superior prognosis in adults with ALL, when compared with B-lineage disease. Nonetheless, a great deal more work will be required in order to advance our ability to effect long-term, disease-free survival in adult patients with ALL.
References
Saleh M, White CA, Witzig TE, et al. Zevalin radioimmunotherapy offers safe and effective therapy for relapsed or refractory B cell non-Hodgkin's lymphoma. Eur J Cancer. 2001;37(suppl 6):32. Abstract 119.
Bertoni F, Conconi A, Capella C, et al. Gastric MALT lymphomas prospective LY 03 randomised cooperative trial. Preliminary results of the molecular follow up. Eur J Cancer. 2001;37(suppl 6):32. Abstract 121.
Fiedler W, Staib P, Kuse R, et al. Treatment of patients with refractory, C-KIT positive, acute myeloid leukemia with SU 5416, a novel receptor tyrosine kinase inhibitor. Eur J Cancer. 2001;37(suppl 6):32. Abstract 117.
Grignani F, Fagioli M, Alcalay M, et al. Acute promyelocytic leukemia: from genetics to treatment. (Review). Blood. 1994;83:10-25.
Gallagher RE, Willman CL, Slack JL, et al. Association of PML-RARa fusion mRNA type with pretreatment hematologic characteristics but not treatment outcome in acute promyelocytic leukemia: an Intergroup molecular study. Blood. 1997;90:1656-1663.
Slack JL, Rusiniak ME. Current issues in the management of APL (review). Ann Hematol. 2000;79:227-238.
Fernaux P, Chastang C, Chevret S, et al. A randomized comparison of ATRA followed by chemotherapy and ATRA plus chemotherapy and the role of maintenance therapy in newly diagnosed APL. Blood. 1999;94:1192-1200.
Douer D, Preston-Martin S, Nichols PW, et al. High frequency of acute promyelocytic leukemia among Latinos with acute myeloid leukemia. Blood. 1996;87:308-313.
Chang E, Levine AM, Slovak M, Forman S, Douer D. Acute promyelocytic leukemia in Latino patients is associated with a high frequency of the Bcr 1 breakpoint site in the rearranged PML gene. Blood. 1996;88:665a.
Santillana S, Leon J, Samanez C, et al. Molecular biology of acute promyelocytic leukemia (APL) in Peruvian patients: PML/RAR alfa isoforms distribution in Latino patients. Eur J Cancer. 2001;37(suppl 6):32. Abstract 324.
Faderl S, Talpaz M, Estrov Z, Kantarjian HM. Chronic myelogenous leukemia: biology and therapy. Ann Intern Med. 1999;131:207-219.
Druker BJ, Sawyers CL, Kantargian H, et al. Activity of a specific inhibitor of the bcr-abl tyrosine kinase in the blast crisis of chronic myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia chromosome. N Engl J Med. 2001;344:1038-1042.
Giles F, Talpaz M, Bgivins C, Jolivet J, Kantarjian H. Troxatyl is effective in non-lymphoid blastic phase chronic myeloid leukemia. Eur J Cancer. 2001;37(suppl 6):32. Abstract 118.
Giles FJ, Cortes JE, Baker SD, et al. Troxacitabine, a novel dioxolane nucleoside analog, has activity in patients with advanced leukemia. J Clin Oncol. 2001;19:762-771.
Thomas X, Danaila C, Le QH, et al. Long term follow up of patients with newly diagnosed adult acute lymphoblastic leukemia (ALL): a single institution experience of 378 consecutive patients over a 21 year period. Eur J Cancer. 2001;37(suppl 6):32. Abstract 116
Source: Medscape
CMLSupport Home Page This site was last updated on Nov. 17, 2001 Copyright © 2000-2001 CMLSupport.com. All rights reserved. The fine print: These contents may not be reproduced in whole or in part without the express written permission of the author. Or she will beat you up and stuff. This site is best viewed with Internet Explorer, but we won't stop you from using another Web browser. Congratulations if you've read all of this! (But we're sorry to say, the person before you got our last cash prize!) |