Therapy of acute myelogenous leukemia

Over the past 10 years, there have been substantial advances in the treatment of AML. Intensive induction chemotherapy using 7-day courses of cytarabine and daunorubicin or amsacrine produce remission in 60% to 85% of patients. Median remission duration is 9 to 16 months. In some series, 20% to 40% of patients are in continuous remission for 2 years or more; many of these patients remain in remission for 5 years or longer and some may be cured. Bone marrow transplantation has evolved as a useful therapeutic modality capable of achieving long-term survival in some circumstances in which chemotherapy is relatively ineffective. Its precise role in the initial therapy of AML remains to be defined, but it is likely to be beneficial in selected patients. These data indicate substantial recent progress in the treatment of this disease, which was almost uniformly fatal 30 years ago. The fact that most patients relapse within 1 to 2 years reflects a lack of progress in developing effective postremission therapy. Maintenance chemotherapy, immunotherapy, and CNS prophylaxis have little role in AML. It is unclear whether consolidation or intensification extend remissions or increase the proportion of long-term survivors; controlled randomized trials should answer this question within the next few years. Future progress in the treatment of AML awaits the development of more sensitive methods for detecting residual leukemia, more effective use of current therapeutic modalities and the introduction of new effective drugs. Most data suggest that early intensive treatment is of key importance for achieving cures. However, we cannot presently distinguish between patients cured by initial treatment and those who required further chemotherapy.     

Treatment of refractory undifferentiated acute myelogenous leukemia with all-trans-retinoic acid

A patient is described with undifferentiated acute myeloblastic leukemia refractory to two courses of daunorubicin and cytosine arabinoside. Because some the myeloblasts developed morphologic features of promyelocytes, the patient was treated with all-trans-retinoic acid (ATRA) in an attempt to promote maturation. Cytogenetic studies and sensitive molecular analysis did not reveal any abnormality classically associated with acute promyelocytic leukemia. Serial bone marrow biopsies demonstrated myeloid maturation, and the patient uneventfully went into a sustained complete remission. A review of the literature confirms this to be an apparently hitherto undescribed response to ATRA that may have therapeutic implications in similar patients. © 1994 Wiley-Liss, Inc.     

Hypocholesterolemia in acute myelogenous leukemia

Plasma-cholesterol concentrations were determined in 85 acute myelogenous leukemia patients. Measurements were repeated in 28 cases during remission. Mean plasma-cholesterol concentration (+/- SD) at diagnosis was 3.95 mmol/l (+/- 1.29). 47 patients (55.3%) had hypocholesterolemia (less than 3.87 mmol/l). Among the main clinical, hematologic and biochemical parameters, only high leukocyte counts were correlated with hypocholesterolemia. As far the FAB subtypes are concerned, the lowest cholesterol levels were observed in leukemias with monocytic component. However, although the same FAB subtypes showed significantly higher leucocytes counts than the other subtypes, both parameters were independently related to low cholesterol levels. Remission was associated with a significant increase in cholesterol levels in those patients with low cholesterol concentrations or high leukocyte counts at diagnosis. These results support the idea that initial hypocholesterolemia in acute myelogenous leukemia is related to the tumoral mass present at diagnosis.     

Treatment of 61 patients with acute myelogenous leukemia at first relapse

Treatment results in the 61 adult patients with AML in first relapse were analyzed to establish a better strategy for this group of patients. These patients received reinduction chemotherapy during 1979-1988. Complete remission (CR) was obtained in 57.4% of the cases, and the probability of survival and remaining in CR at five years was 11.9% and 17.9%, respectively. The longer duration of initial remission was favorable factor for achieving second CR. Type of reinduction regimens which were different from those used in the initial induction phase did not influence the second CR rate. The use of different consolidation regimen appeared to favorably affect the survival and probability of remaining in CR.     

Therapy of acute myelogenous leukemia.

Treatment of acute myelogenous leukemia (AML) is divided into remission induction and post-remission therapy. Remission induction is usually with cytarabine and an anthracycline. Daunorubicin is commonly used but recent data suggest idarubicin or mitoxantrone are equally effective, possibly better. High-dose cytarabine has also been used for remission induction but is not proven superior. Post-remission treatment is typically with two or more courses of drugs similar to those used for remission induction. Other studies use non-cross resistant drugs and/or high-dose cytarabine. Although some data favor use of high-dose cytarabine, no approach is clearly superior. There is considerable controversy whether persons in first remission and with an HLA-identical sibling should receive a bone marrow transplant immediately or after relapse. Although transplant results appear superior, especially in persons less than 20 years of age, the most effective strategy may be reserving transplants for persons failing chemotherapy. This strategy also applies to persons receiving autologous transplants or transplants from alternative donors, like HLA-matched related or unrelated persons.     

Molecular targets in acute myelogenous leukemia

Acute myeloid leukemia (AML) remains the most common form of leukemia and the most common cause of leukemia death. Although conventional chemotherapy can cure between 25 and 45% of AML patients, most patients will either die of relapse or die from the complications associated with treatment. Thus, more specific and less toxic treatments for AML patients are needed. Recently, a small molecular inhibitor (STI571 or Gleevec) that targets the BCR-ABL gene was found to have a dramatic clinical effect in patients with chronic myelogenous leukemia (CML). These results have encouraged investigators to search for additional small molecular inhibitors and other targeted therapies that may be applicable to other forms of leukemia. In this review, we examine some of the signaling pathways that are aberrantly regulated in AML, focusing on the tyrosine kinase/RAS/MAP kinase and JAK/STAT pathways. After reviewing these two pathways, we explore some of the targeted therapies directed at these pathways that are under development for AML, many of which are already in clinical trials.     

Leukemic hypopyon in acute myelogenous leukemia

We encountered a patient with acute myelogenous leukemia (AML) who developed leukemic hypopyon. Leukemia initially spread into the pharynx, gingiva, lymphnode, and bone marrow. He achieved complete remission after chemotherapy but developed blurred vision and hypopyon. Anterior chamber paracentesis disclosed leukemic infiltration of the anterior chamber. Infiltration of the central nervous system also occurred. He received systemic chemotherapy, intrathecal chemotherapy, and local chemotherapy. However, he did not achieve prolonged remission. These findings suggest that these chemotherapy treatments have an inadequate effect for AML with anterior chamber infiltration. This rare complication is associated with extramedullary infiltration of leukemia. Received: 13 September 1999 / Accepted: 23 December 1999     

Farnesyltransferase inhibitor therapy in acute myelogenous leukemia

Acute myelogenous leukemia (AML) remains a clinical challenge with poor long-term survival. Low remission rates and high treatment-related mortality persist as major obstacles, particularly in older patients. The design of novel agents based on the identification of genetic lesions and aberrant signaling pathways provides opportunity to improve the standard treatment paradigm of intensive cytotoxic chemotherapy. Farnesyltransferase inhibitors (FTIs) show potential to fill this niche. The preclinical concept of farnesyltransferase blockade as a targeted therapy against oncogenic Ras has clearly evolved with the recognition that many proteins involved signaling pathways in tumor cells undergo farnesylation. Phase I/II trials of FTI monotherapy in AML demonstrate encouraging responses and good tolerability. The FTI tipifarnib (R115777, Zarnestra; Johnson & Johnson, Titusville, NJ) has advanced the furthest in clinical trials, with the most promising activity in previously untreated, high-risk AML patients. A major emphasis of current clinical studies has been to analyze potential candidate genes and signaling pathways modified by FTIs in order to identify mechanisms of response and resistance. Preclinical concepts related to the development of FTIs, the rationale for their use in AML, and efficacy and safety results from recent clinical trials are evaluated in this paper.     

The EORTC trials for acute myelogenous leukemia

Since the early 80s, the EORTC Leukemia Group has included 3947 patients in 8 consecutive phase III studies on acute myelogenous leukemia, with stratification according to the age groups. Some of these patients were included by other cooperative groups (GIMEMA, HOVON), within intergroup studies. The main hypotheses tested by randomization were intensive chemotherapy consolidation, allogeneic and autologous bone marrow transplantation in the younger patients. In patients aged 60 years or more, a wait and see policy followed by a palliative chemotherapy was compared to an immediate conventional induction treatment, mitoxantrone was compared to daunorubicin, and, during remission, a low dose Ara-C maintenance treatment to no maintenance. The main results can be summarized as follows: Allogeneic BMT, and, relatively, autologous BMT do better than intensive chemotherapy consolidation with regards to the disease-free survival, but not for the overall survival after remission. In the elderly, an immediate induction and a low-dose Ara-C maintenance treatment are preferable to the other options tested. Mainly in patients aged more than 45, the supplementary toxicity of more intensive chemotherapy consolidation, with high dose Ara-C, counter balanced the increased anti-leukemic effect. Finally the trials randomizing GM-CSF during induction yielded disappointing results. The EORTC LCG is currently studying the relative value of various intercalating agents during induction, and of the G-CSF as well, and, during remission the autologous peripheral stem cells compared to bone marrow transplantation.     

The EORTC trials for acute myelogenous leukemia

Since the early 80s, the EORTC Leukemia Group has included 3947 patients in 8 consecutive phase III studies on acute myelogenous leukemia, with stratification according to the age groups. Some of these patients were included by other cooperative groups (GIMEMA, HOVON), within intergroup studies. The main hypotheses tested by randomization were intensive chemotherapy consolidation, allogeneic and autologous bone marrow transplantation in the younger patients. In patients aged 60 years or more, a wait and see policy followed by a palliative chemotherapy was compared to an immediate conventional induction treatment, mitoxantrone was compared to daunorubicin, and, during remission, a low dose Ara-C maintenance treatment to no maintenance. The main results can be summarized as follows: Allogeneic BMT, and, relatively, autologous BMT do better than intensive chemotherapy consolidation with regards to the disease-free survival, but not for the overall survival after remission. In the elderly, an immediate induction and a low-dose Ara-C maintenance treatment are preferable to the other options tested. Mainly in patients aged more than 45, the supplementary toxicity of more intensive chemotherapy consolidation, with high dose Ara-C, counter balanced the increased anti-leukemic effect. Finally the trials randomizing GM-CSF during induction yielded disappointing results. The EORTC LCG is currently studying the relative value of various intercalating agents during induction, and of the G-CSF as well, and, during remission the autologous peripheral stem cells compared to bone marrow transplantation.European Organisation of Research and Treatment of Cancer