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.     

Reduced intensity conditioning (RIC) haematopoietic cell transplants in elderly patients with AML

Reduced intensity conditioning (RIC) transplants were first developed almost a decade ago to reduce the transplant-related mortality (TRM) of allogeneic haematopoietic cell transplantation (HCT) and to make the graft-versus-leukaemia effect accessible to patients otherwise ineligible for HCT. Acute myelogenous leukaemia (AML) in elderly patients is now a frequent indication for RIC-HCT. The major reasons for these rapid developments have been on the one hand the high median age of patients with AML coupled with the unsatisfactory results with conventional chemotherapy, and on the other hand with the promising results already reported for RIC-HCT. Using RIC-HCT, overall survival rates at 2 years of 45-50% have been observed in patients with AML. This compares favourably with overall survival rates of 10-15% under chemotherapy in AML CR1, or no long-term survivors in patients >CR2. From the available data we conclude that RIC-HCT is a promising treatment for elderly patients with AML. However, phase-III studies with unrelated donors will have to be done in order to formally prove its superiority in comparison to conventional chemotherapy.     

Molecularly targeted therapies in myelodysplastic syndromes and acute myeloid leukemias

Although there has been significant progress in acute myeloid leukemia (AML) treatment in younger adults during the last decade, standard induction therapy still fails to induce remission in up to 40% of AML patients. Additionally, relapses are common in 50–70% of patients who achieve a complete remission, and only 20–30% of patients enjoy long-term disease-free survival. The natural history of myelodysplastic syndrome (MDS) is variable, with about half of the patients dying from cytopenic complications, and an additional 20–30% transforming to AML. The advanced age of the majority of MDS patients limits the therapeutic strategies often to supportive care. To address these shortcomings, much effort has been directed toward the development of novel treatment strategies that target the evolution and proliferation of malignant clones. Presented here is an overview of molecularly targeted therapies currently being tested in AML and MDS patients, with a focus on FMS-like tyrosine kinase 3 inhibitors, farnesyltransferase inhibitors, antiangiogenesis agents, DNA hypomethylation agents, and histone deacetylase inhibitors.     

Implications of somatic mutations in the AML1 gene in radiation-associated and therapy-related myelodysplastic syndrome/acute myeloid leukemia

Somatically acquired point mutations of AML1/RUNX1 gene have been recently identified in rare cases of acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS). Moreover, germ line mutations of AML1 were found in an autosomal dominant disease, familial platelet disorder with predisposition to AML (FPD/AML), suggesting that AML1 mutants, as well as AML1 chimeras, contribute to the transformation of hematopoietic progenitors. In this report, we showed that AML1 point mutations were found in 6 (46%) of 13 MDS patients among atomic bomb (A-bomb) survivors in Hiroshima. Unlike acute or chronic leukemia patients among A-bomb survivors, MDS patients exposed relatively low-dose radiation and developed the disease after a long latency period. AML1 mutations also were found in 5 (38%) of 13 therapy-related AML/MDS patients who were treated with alkylating agents with or without local radiation therapy. In contrast, frequency of AML1 mutation in sporadic MDS patients was 2.7% (2 of 74). Among AML1 mutations identified in this study, truncated-type mutants lost DNA binding potential and trans-activation activity. All missense mutations with one exception (Gly42Arg) lacked DNA binding ability and down-regulated the trans-activation potential of wild-type AML1 in a dominant-negative fashion. The Gly42Arg mutation that was shared by 2 patients bound DNA even more avidly than wild-type AML1 and enhanced the trans-activation potential of normal AML1. These results suggest that AML1 point mutations are related to low-dose radiation or alkylating agents and play a role distinct from that of leukemogenic chimeras as a result of chromosomal translocations caused by sublethal radiation or topoisomerase II inhibitors.     

Therapy-related myeloid neoplasms in lymphoma survivors: Reducing risks

Treatment for Hodgkin (HL) and non-Hodgkin's lymphoma (NHL) has changed dramatically in the last fifty years. While there are increasing numbers of long-term survivors, there has been increasing recognition of the long-term toxicities of treatments, particularly therapy-related myelodysplastic syndrome and acute myeloid leukemia (t-MDS/AML). The survival for t-MDS/AML is extremely poor. Multiple heterogeneous retrospective studies have reported risk factors for the development of t-MDS/AML. Chemotherapy and radiation therapy have been most closely examined as possible t-MDS/AML risk factors. In this paper, we will review the risks of t-MDS/AML for HL and NHL patients as reported in the literature and assess for any changes over time. In HL patients, the incidence of t-MDS/AML has decreased with a reduction in alkylating agents. In indolent NHL patients, we anticipate decreased incidence of t-MDS/AML as targeted therapies begin to replace cytotoxic chemotherapy.     

Long-Term Survival in Acute Leukemia

ABSTRACT. An intermittent combination chemotherapy program was initiated in 1971–79 in 172 patients, aged 15–59 years, with acute leukemia (131 myelogenous (AML) and 41 lymphoblastic (ALL)). Sixteen patients with AML and 6 with ALL have survived for more than 5 years. These long-term survivors represent 24% of AML and 18% of ALL patients who obtained complete remission. Twelve patients (10 AML and 2 ALL) are in continuous first remission 5.5–13.5 years after diagnosis. Occasional late relapses up to 9 years after diagnosis make it impossible to declare any individual patient cured.     

Long-term outcome after intensive therapy with etoposide, melphalan, total body irradiation and autotransplant for acute myeloid leukemia

Intensive therapy and autologous blood and marrow transplantation (ABMT) is an established post-remission treatment for acute myeloid leukemia (AML), although its exact role remains controversial and few data are available regarding longer-term outcomes. We examined the long-term outcome of patients with AML transplanted at a single center using uniform intensive therapy consisting of etoposide, melphalan and TBI. In all, 145 patients with AML underwent ABMT: 117 in first remission, 21 in second remission and seven beyond second remission. EFS and OS were significantly predicted by remission status (P<0.0001). For transplantation in first remission, 8 year EFS and OS were 55% (95% CI, 44-64%) and 62% (95% CI, 50-72%), respectively. By multivariate analysis, only age (P=0.04) and cytogenetic risk group (P=0.006) influenced OS. For patients transplanted in second remission, 8 year EFS and OS were 30% (95% CI, 9-55%) and 36% (95% CI, 13-60%), respectively. No pre-transplant variables significantly predicted outcome. None of the seven patients who underwent ABMT beyond second remission or in early relapse were long-term survivors. ABMT can provide long-term antileukemic control for patients with AML in first remission. For patients in second remission approximately 30% can achieve cure with ABMT, and this option may be preferable to alternate donor allogeneic stem cell transplantation.     

Acute myeloid leukemia treatment in patients over 60 years of age. Comparison of symptomatic, palliative, and aggressive therapy

State-of-art of aggressive treatment of acute myeloid leukemia (AML) in patients older than 60 years is one of the least satisfactory topics of present-day hematology. This fact led us to ask the following questions: Does it make sense to administer aggressive treatment to older patients with AML? Could it be that we only complicate the rest of the life of these older patients with AML, by using aggressive treatment? Would they not benefit more from palliative or symptomatic therapy? What is the quality of life of older patients with AML like? Therefore, to try to answer these questions, we performed the next analysis. A retrospective analysis was performed including (without any selection) all consecutive patients over 60 years of age who were treated with AML in our centre from 1998 till 2003. We have analyzed data from 137 elderly patients who were diagnosed with AML (excluding acute promyelocytic leukemia). Median survival from diagnosis in the aggressive (curative) therapy group was 4 months, in palliative therapy group 2 months and in symptomatic therapy group 0.8 months. Patients receiving curative therapy spent in a hospital (in-patient stay) 70% (median) of their life after diagnosis of AML, patients receiving palliative treatment 64% (median) of their life after diagnosis, and patients receiving symptomatic treatment 100% (median), respectively. Only marginal advantage in the median overall survival is observed in the group of aggressively treated patients.     

Long-term survival in myelomatosis; A REPORT TO THE MRC WORKING PARTY ON LEUKAEMIA IN ADULTS

S ummary . The patients entered into the Medical Research Council's First Myelomatosis Trial (MRC I) have been followed up for a minimum of 12 years, and an attempt has been made to define features recorded at presentation that might predict long-term survival and to estimate the risk of acute myeloid leukaemia (AML) induced by treatment with either of the alkylating agents, melphalan or cyclophosphamide. In this series, the chance of a patient surviving 5 years was strongly related to the haemoglobin, blood urea concentration (BUC) and performance status at presentation. Other features, including paraprotein levels, type of heavy or light chain, bone lesions and recovery of polyclonal immunoglobulin added little useful information. Six patients died of AML, all after more than 4 years in the trial; the incidence of AML among 4-year survivors was 10%. All six patients had been treated with continuous melphalan and the implications of this for future chemotherapy for myelomatosis are discussed.     

Self-reported fertility in long-term survivors of acute myeloid leukemia

Acute myeloid leukemia (AML) survival rates in younger patients have improved considerably since the 1970s. In order to evaluate the impact of AML and its treatment on fertility and family situation in adult long-term survivors, we used the Swedish population-based registries to identify 161 adult patients diagnosed with AML within the Leukemia Group of Middle Sweden (LGMS) 1973–2003, who survived for more than 5 years and were alive in 2010. Ninety-eight patients (61 %) completed a questionnaire including items on reproductive concerns, family situation, and infertility-related distress. After excluding women >45 years and/or postmenopausal women and men >55 years, 22 women and 38 men were included in the final analysis. Nine of the women (41 %) tried to conceive after treatment, but only three succeeded. Five (83 %) of the unwillingly childless women reported “a moderate” or “a lot” of distress caused by this. Among men in the same age group, all six who wanted children after treatment succeeded. None of the men 46–55 years old cryopreserved their sperm or tried to father a child. Among patients who wanted children after AML treatment, 46 % of the women and 40 % of the younger men reported that they were not, or not fully, informed about fertility-related issues. In contrast, among men 46–55 years, none reported they would have wanted more information. Infertility among young female AML survivors thus remains an important clinical issue, and there is a need for improved clinical counseling and education in this area.     

Current strategies in the treatment of advanced stage mantle cell lymphoma

Advanced stage mantle cell lymphoma (MCL) with a median survival of only three years and virtually no long-term survivors represents the lymphoma subtype with the poorest prognosis and remains incurable with conventional chemotherapy. Recently two randomized trials of the German Low Grade Lymphoma Study Group (GLSG) demonstrated the superiority of a combined immunochemotherapy with the anti-CD20 antibody rituximab in first-line therapy (R-CHOP) as well as in relapsed disease (R-FCM). In addition, in a trial of the European MCL Network, intensified-consolidation with high-dose radiochemotherapy followed by autologous stem cell transplantation significantly improved the progression-free survival in patients up to 65 years of age. However, the vast majority of patients with MCL will eventually relapse. Thus, new strategies such as allogenic transplantation after dose-reduced conditioning or novel molecular targeting agents (e. g. proteasome inhibitors or radiolabeled antibodies) are urgently warranted to further improve the long-term outcome of MCL.     

Long-term survival and late relapses in acute leukaemia in adults

34 out of 403 apparently unselected adult patients with acute leukaemia referred to a single department from 1970 through 1989 survived more than 3 years. The cumulative rate of relapse after 3 years was 39% in patients with acute myeloblastic leukaemia (AML) and 74% in patients with acute lymphoblastic leukaemia (ALL). The latest relapse was observed 75 months after diagnosis in AML and 98 months after diagnosis in ALL. 65% of the long-term survivors were able to undertake normal physical activity, 26% had decreased activity, and 9% were unable to work. 5-year survival for all patients, whether treated or not, during two successive decades was 16% versus 18% and 5% versus 6%, respectively, for ALL and AML. The departmental results were identical with population-based national results. Only in patients 15-49 years of age with AML was there evidence that more intensive treatment had led to better survival.     

Choosing induction chemotherapy in therapy-related acute myeloid leukemia

Patients with AML that develops after cytotoxic therapy (tAML) have overall inferior outcomes relative to de novo AML due to both patient-related factors and the intrinsic biology of the disease. Treatment of patients with tAML is challenging. The key initial clinical decision is whether a patient is a candidate for or likely to benefit from intensive induction chemotherapy, a determination which we argue should not be predicated on chronologic age alone. For those determined likely to tolerate intensive induction chemotherapy, CPX-351 is likely superior to conventional induction with cytarabine and daunorubicin. For those deemed inappropriate for intensive induction, hypomethylating agents have the strongest evidence base in elderly adults with AML, and are an attractive option in tAML. This is particularly true in patients with TP53 mutations who are less likely to respond to conventional induction chemotherapy. Exciting options on the therapeutic horizon for tAML include combination therapies incorporating BCL2 inhibitors, Hedgehog pathway inhibitors, and isocitrate dehydrogenase inhibitors.     

Malignancy: Current Clinical Practice: Current Therapeutic Options in Myelodysplastic Syndromes

Myelodysplastic syndromes (MDS) are characterized initially by ineffective hematopoiesis and subsequently the frequent development of acute myelogenous leukemias (AML). During the last 15 years, important progress has been made in the understanding of the biology and prognosis of myelodysplastic syndromes. Risk-adapted treatment strategies were established due to the high median age (60-75 years) of MDS-patients and the individual history of the disease (number of cytopenias, cytogenetical changes, transfusion requirements). The use of allogeneic bone marrow transplantation for MDS patients currently offers the only potentially curative treatment, but this treatment modality is not available for the most of the "typical" MDS-patients aged >60 years. Based on in-vitro findings analyzing the potential of several agents to differentiate or to stimulate hematopoietic progenitor cells a number of therapeutic options were evaluated in clinical trials: hematopoietic growth factors (e.g. erythropoietin, G-CSF), differentiation inducers (e.g. retinoids), or cytoprotective substances (amifostine). The role of immunsuppressive agents (antithymocyte globulin, cyclosporine A) either alone or in combination is being actively investigated. Using intensive cytotoxic treatment in patients with advanced MDS or AML after MDS complete remission rates comparable with those known from the treatment of de novo AML were reported. The therapy related toxicity (early death rate <10%) was reduced by using G-CSF given prior ("Priming") and/or after the cytotoxic treatment.     

Treatment of older patients with AML

Undertreatment of the older patients with AML can explain, in part, their inferior outcome when compared with that in younger patients. In analogy to the benefit of patients under the age of 60 years from high-dose AraC there are dosage related therapeutic effects in the patients over 60 years in particular for daunorubicin in the induction treatment, and for maintenance versus no maintenance in the post-remission treatment. Utilizing these effects can partly overcome the mostly unfavorable disease biology in older age AML, whereas the role of risk factors involved is not completely understood and the concept of dose-response needs to be requestioned. We recommend an adequate dosage of 60 mg/(m2day) daunorubicin for 3 days in a combination with standard dose AraC and 6-thioguanine given for induction and consolidation and followed by a prolonged monthly maintenance chemotherapy. Further improvements in supportive care may help delivering additional anti-leukemic cytotoxicity. As a novel approach, reduced toxicity preparative regimens may open up allogeneic transplantation for older patients with AML. Other new options like MDR modulators, antibody targeted therapies and tyrosine kinase inhibitors are under clinical investigation. A questionnaire study in patients with AML showed that according to patients' self-assessment intensive and prolonged treatment did not result in decreasing quality of life. This finding did not vary by age under or above 60 years. Given the actual median age in this disease being more than 60 years the adequate management of older age AML remains as the major challenge.     

Acute myelogenous leukaemia in the elderly: retrospective study of 235 consecutive patients

A retrospective analysis was performed on 235 elderly acute myelogenous leukaemia (AML) patients aged 60 years or more, consecutively admitted to a single haematological department during a 10-year period from 1980 to 1989. 46% of patients received only conventional induction chemotherapy. The rate of inclusion in EORTC cooperative clinical trials was significantly lower than for younger patients despite specific protocols proposed for the elderly since 1983, thus confirming the important selection bias of most published series on elderly AML patients. Compared with treatment results in patients <60 years. complete remission (CR) rate was lower (33·3% v 65·4%, P <0·0001), with a marked drop in patients older than 70, and induction death rate was higher (21·3% v 12·5%, P = 0·04). Intrinsic characteristics of leukaemic cells, especially expression of the MDR1 gene, in vitro growth of the leukaemic clonogenic cells and sensitivity to daunorubicin+cytosine arabinoside, did not differ according to age, except that there was a higher incidence of previous myelodysplastic syndromes and a lower incidence of good prognostic cytogenetics in the elderly patients. Thus, treatment failure in elderly AML patients appears to be mainly due to host-related factors (especially performance status and age < or ±70 years), and to inadequate treatments. Some elderly patients may have been undertreated because of the planned anthracycline dose reduction, resulting in a higher rate of 'resistant'AML, i.e. patients surviving the induction period without entering into CR, than in younger patients (45·4% v 22·1%, P <0·0001). 11 patients (4·7%) with untreated or 'resistant'AML survived more than 1 year, while receiving only supportive care. These slowly progressive AML patients were characterized by a good performance status, and lower circulating blast cells and bone marrow blast counts.     

Drug therapy for acute myeloid leukemia

Although improvement in outcomes has occurred in younger adults with acute myeloid leukemia (AML) during the past 4 decades, progress in older adults has been much less conspicuous, if at all. Approximately 50% to 75% of adults with AML achieve complete remission (CR) with cytarabine and an anthracycline such as daunorubicin or idarubicin or the anthracenedione mitoxantrone. However, only approximately 20% to 30% of the patients enjoy long-term disease survival. Various postremission strategies have been explored to eliminate minimal residual disease. The optimal dose, schedule, and number of cycles of postremission chemotherapy for most patients are not known. A variety of prognostic factors can predict outcome and include the karyotype of the leukemic cells and the presence of transmembrane transporter proteins, which extrude certain chemotherapy agents from the cell and confer multidrug resistance and mutations in or over expressions of specific genes such as WT1, CEBPA, BAX and the ratio of BCL2 to BAX, BAALC, EVI1, KIT, and FLT3. Most recently, insights into the molecular pathogenesis of AML have led to the development of more specific targeted agents and have ushered in an exciting new era of antileukemia therapy. Such agents include the immunoconjugate gemtuzumab ozogamicin, multidrug resistance inhibitors, farnesyl transferase inhibitors, histone deacetylase and proteosome inhibitors, antiangiogenesis agents, Fms-like tyrosine kinase 3 (FLT3) inhibitors, and apoptosis inhibitors.     

Single-agent lenalidomide induces complete remission of acute myeloid leukemia in patients with isolated trisomy 13

Patients with acute myeloid leukemia (AML) frequently fail chemotherapy due to refractory disease, relapse, or toxicity. Among older AML patients (age > 60 years), there are few long-term survivors. Lenalidomide is a candidate for study in AML based on its clinical activity in a related disorder, myelodysplastic syndrome (MDS), with the 5q- chromosomal abnormality. We report induction of sustained morphologic and cytogenetic complete remission in 2 older AML patients treated with high-dose, single-agent lenalidomide; each patient had trisomy 13 as the sole cytogenetic abnormality. We show for the first time that lenalidomide has clinical activity in this poor-risk cytogenetic subset of AML. The clinical trials described in this paper have been registered with www.clinicaltrials.gov under identifiers NCT00466895 and NCT00546897.     

The role of intensive remission induction and consolidation therapy in patients with acute myeloid leukaemia

Sixty-one patients with AML, 59 adults and two children, were treated with intensive remission induction and consolidation therapy. The median age was 36 years. Forty-four (72%) patients entered complete remission (CR); 11 patients received a bone marrow transplantation. The median survival of complete remitters was 26.5 months; the probability of remaining in CR at respectively 1 and 2 years was 75% and 62%. The only factor significantly correlated with the outcome of remission induction, survival and duration of CR was age. Patients less than 30 years fared significantly better than those 30 years or older; no difference in outcome was observed between patients aged 30-50 and those over 50 years. In patients less than 30 years the CR rate was 95%; 75% of them were still alive at 2 years and only one (5%) has relapsed. In contrast, in patients 30 years or older the CR rate was 60% and the median survival only 11.5 months, 50% of the complete remitters in this age group have relapsed. Morbidity from intensive consolidation therapy was considerable; more than 50% of consolidation courses were complicated by high fever, needing urgent admission; only four (3%) courses had a fatal event. It is concluded that intensive consolidation therapy may be considered as a major advance in the treatment of younger patients with AML, while its role in older individuals remains questionable. A possible explanation for the completely different outcome in younger and older patients with AML is discussed.     

Venetoclax-based therapies for acute myeloid leukemia

The prognosis of adult acute myeloid leukemia (AML) remains poor, with the long-term survival rate less than 50%. However, the current paradigms of treatment are changing through a better understanding of the disease genetics and pathophysiology. Since 2017, eight new drugs have been approved by the U.S. Food and Drug Administration for the treatment of AML, including the FLT3 inhibitors midostaurin and gilteritinib, the IDH inhibitors ivosidenib and enasidenib, the anti-CD33 monoclonal antibody gemtuzumab ozogamicin, liposomal daunorubicin and cytarabine, the hedgehog pathway inhibitor glasdegib and the BCL-2 inhibitor venetoclax. Preclinical data demonstrated the anti-leukemic efficacy of venetoclax in AML and its synergy when combined with hypomethylating agents or chemotherapy agents. Clinical trials have demonstrated the clinical benefit of venetoclax-based therapies in newly diagnosed AML, leading to the recent FDA approval of venetoclax in combination with hypomethylating agents or low-dose cytarabine for older adults with newly diagnosed AML. Herein, we focus on the role of single-agent BCL-2 inhibition in AML and review the clinical studies of venetoclax-based combination regimens and the evolving mechanisms of resistance.