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Recent treatment strategies for adult acute lymphoblastic leukemia (ALL) have resulted in improved complete remission (CR) rates of 80-90% [1-3]. However, longterm disease-free survival (DFS) rates have remained disappointingly low at 30-40%. Current research efforts are focused on an improved understanding of the biology of the disease, and innovative postremission strategies that will prolong disease-free duration. Stem cell transplantation (SCT) is one strategy that may improve disease outcome. Allogeneic SCT has been demonstrated to improve DFS in high-risk ALL patients in multiple large series. High risk is defined by specific biologic and clinical features that have been noted to consistently influence the outcome of adult ALL (Table 18.1). Age greater than 60 years, an elevated white blood cell count at presentation, failure to achieve clinical remission within the first 4 weeks of treatment, and specific recurring cytogenetic abnormalities are all considered adverse clinical features. In a multivariate analysis of risk factors in adult ALL, karyotype was identified as the most important factor for DFS [4]. [ABSTRACT FROM AUTHOR]

Adult patients with acute lymphoblastic leukemia (ALL) can now achieve complete remission (CR) rates of 80-90% [1-3]. However, only 25-50% of these patients achieve long-term, disease-free survival. Current research efforts are focused on innovative postremission strategies with the goal of improving disease-free (DFS) and overall survival (OS). The identification of different prognostic groups based on the biology of the malignant clone and prognostic factors allows for risk-adapted therapy. Multiple randomized trials have demonstrated that hematopoietic stem cell transplantation (SCT) improves the outcome of patients with high-risk ALL. In this chapter, we will define the different disease risk groups, the clinical outcomes of major transplant trials for ALL, and the therapeutic factors that affect outcome after SCT. [ABSTRACT FROM AUTHOR]

The clinical presentation of acute lymphoblastic leukemia (ALL) may range from nonspecific symptoms such as progressive malaise, fever, and fatigue to severe life-threatening manifestations, requiring immediate medical intervention. [ABSTRACT FROM AUTHOR]

Treatment of acute lymphoblastic leukemia in children is one of the great success stories of combination chemotherapy. Unfortunately, adults fare much worse and the majority of adult patients ultimately fail their initial treatment program. Most current induction regimens obtain complete responses (CRs) in 65-90% of newly diagnosed adult patients with acute lymphoblastic leukemia (ALL). Early deaths account for some of the induction failures, but in most studies 10-25% of patients have disease resistant to vincristine/prednisone-based regimens. In addition to these primary refractory patients, 60-70% of patients who achieve a CR relapse. Treatment of relapsed and refractory patients is therefore an important and common problem. Numerous regimens have been reported in the setting of relapsed ALL. There are two widely tested approaches to reinduction therapy for adult patients with recurrent or refractory ALL. One option is to treat the patient with a regimen that is similar to their original induction therapy (this strategy is obviously not used for primary refractory patients). [ABSTRACT FROM AUTHOR]

Central nervous system (CNS) involvement is identified at the time of diagnosis in less than 5% of children with acute lymphoblastic leukemia (ALL) [1]. However, prior to the institution of adequate CNS prophylaxis, it was a major obstacle to cure in childhood ALL as 50-75% of patients would eventually relapse in the CNS [1, 2]. The routine use of CNS prophylaxis has improved the long-termprognosis of patients, and CNS relapse occurs in less than 10% of patients treated with contemporary protocols [3]. Effective means of CNS prophylaxis include cranial irradiation, intrathecal chemotherapy (IT), and high-dose systemic chemotherapy (HDCT) with agents that can cross the blood-brain barrier [4]. A risk-oriented approach has been developed for childhood CNS prophylaxis, in an attempt to reduce the occurrence of CNS relapse while minimizing the potentially serious adverse effects of radiotherapy and chemotherapy [4]. [ABSTRACT FROM AUTHOR]

Lymphoblastic lymphoma (LBL) is a rare entity of non-Hodgkin's lymphoma (NHL) with an incidence of less than 2% (1.7% for T- and less than 1% for B-lymphoblastic lymphoma) within all NHL [1]. In the USA, the population-based incidence was 0.2/100 000 in males and 0.1/100 000 in females between 1978 and 1995. The age distribution is bimodal with higher rates in individuals younger than 20 and in those older than 50 years [ABSTRACT FROM AUTHOR]

Considerable progress has been made in the treatment of both childhood and adult acute lymphoblastic leukemia (ALL) during the past two decades. The majority of both children and adults achieve a complete remission (CR) while the majority of children are now cured with current therapies, most adults will ultimately experience a relapse and die of their leukemia. The ability to distinguish good-risk patients who are likely to be cured with conventional chemotherapy from those who are likely to relapse has important clinical implications. [ABSTRACT FROM AUTHOR]

Although prognosis of adult ALL has improved over the last few decades, still only 30-40% of patients achieve long-term, disease-free survival and can be considered cured [1, 2]. The remainder will eventually relapse and die from disease progression or other ALL-related consequences. New strategies, refinements of old ones, and novel agents are therefore needed. How modifications of induction regimens can positively impact the outcome in subsets of the disease is exemplified in mature B-cell ALL where short, dose-intensive chemotherapy leads to survival of 50-70% of the patients and T-cell ALL in which addition of cyclophosphamide, high-dose methotrexate and cytarabine in the induction and consolidation sequence is associated with similar survival rates [3]. Other subgroups such as Philadelphia chromosome-(Ph) positive ALL are still largely incurable with chemotherapy alone although the combination of BCR-ABL tyrosine kinase inhibitors with intensive chemotherapy is showing promising leads in this group of patients as well. [ABSTRACT FROM AUTHOR]

Accounting for 1-3% of all cases of acute lymphoblastic leukemias (ALL), Burkitt cell ALL (L3ALL) is characterized by the morphology of blast cells, the presence of monoclonal surface immunoglobulins (sIg), and by chromosomal translocations, usually t(8;14) (q24;q32) and less commonly its variants t(2;8) (p12;q24) or t(8;22) (q24;q11) [1-4]. These translocations lead to rearrangements of the protooncogene c-myc, located at band 8q24 [5]. Recently, the World Health Organization (WHO) classification of lymphoid diseases recognized the Burkitt lymphoma and the L3ALL as a single entity; a mature B-cell neoplasm with an oncogenic c-myc overexpression [6]. [ABSTRACT FROM AUTHOR]

Since 1978 more than 4500 adult ALL patients have been treated according to the protocols of the German Multicenter Study Group for Adult Acute Lymphoblastic Leukemia (GMALL). GMALL protocols are administered in hospitals all over Germany and the number of participating centers in Germany increased from 25 in 1981 to 120 in the most recent trial. Up to now seven consecutive trials for adult de novo ALL have been conducted. The major aim of all trials was the improvement of remission duration and survival of adult ALL patients, detailed diagnostic characterization, the development of prognostic models and the evaluation of risk-adapted, individualized and targeted treatment strategies. The time-periods and further aims of these studies are briefly summarized in Table 13.1. [ABSTRACT FROM AUTHOR]

The Philadelphia chromosome (Ph) is the shortened chromosome 22 resulting from the reciprocal translocation between 5′ part of the BCR gene from chromosome 22 combines with the 3′ part of the ABL gene, resulting in an chimeric BCR-ABL tyrosine kinase that is constitutively activated and oncogenic. The Ph is the genetic hallmark of chronic myeloid leukemia (CML), and it is also the most frequent cytogenetic abnormality in adult acute lymphoblastic leukemia (Ph+ ALL), where it is present in roughly 25% of cases. The Ph occurs less often in pediatric ALL, with a prevalence of <5%. In both age groups the Ph chromosome describes a subgroup of ALL with a poor prognosis. Thus, patients with Ph+ ALL are usually offered a hematopoietic stem cell transplant if a suitable donor is available. The tyrosine kinase inhibitor, imatinib mesylate, has been found to block the activity of the BCR-ABL tyrosine kinase and has made an impact in the short-term management of Ph+ ALL. Unfortunately the effect of Imatinib monotherapy tends to be short-lived in Ph+ ALL, and it is by no means curative. [ABSTRACT FROM AUTHOR]

The GET-LALA (Groupe d‘Etude et de Traitement de la Leucémie Aiguë Lymphoblastique de l'Adulte) group has performed a series of studies evaluating different aspects of remission induction and postremission treatment in adults with acute lymphoblastic leukemia (ALL). The LALA group was formed by interested hematologists, physicians, and statisticians in the beginning of the 1980s. The first working party was set up in 1982 with Professor Denis Fiere as chairman of the Steering Committee, and the first randomized trial involving multiple French centers was started in 1983. Since then several other trials have been opened to persons over 15 years of age. In recent years, clinical trials have been supplemented by systematic morphologic, immunophenotyping, cytogenetic, and molecular genetic studies leading to the identification of different risk groups of patients who may warrant individualized treatments. With the development of data managing and the establishment of a large network of collaborating physicians and biologists, the later trials became larger, and reporting was more reliable. [ABSTRACT FROM AUTHOR]

Prognosis of adult ALL has improved over the last few decades. Following the lead from the pediatric experience, dose-intense multiagent regimens now achieve remission rates exceeding 80% with 5-year survival probabilities of around 40%. In addition, ALL is more and more recognized as a heterogeneous group of diseases. Definition of subgroups based on cytogenetic-molecular markers has important practical implications including better delineation of prognostic groups, design of risk-adapted therapies, and eventually integration of novel agents into existing therapies that target pathways relevant for ALL pathophysiology. The hyper-CVAD program is one example of a regimen that has been successfully patterned after a previous pediatric regimen and that has developed along advances based on better understanding of ALL biology and availability of new drugs with activity in ALL. This article summarizes the rationale for the development of hyper-CVAD, experience with this regimen in adult ALL, and recent modifications and subtype-specific approaches. [ABSTRACT FROM AUTHOR]

The Cancer and Leukemia Group B (CALGB) has performed a series of studies evaluating different aspects of induction and postremission treatment in adults with acute lymphoblastic leukemia (ALL). In recent years, these clinical trials have been supplemented by systematic morphologic, immunophenotyping, cytogenetic and molecular genetic studies, leading to the identification of different risk groups of patients who may warrant individualized treatments. Importantly, these protocols have enrolled all adult patients older than 15 years with ALL without an upper age restriction and did not exclude Philadelphia (Ph) chromosome positive patients. [ABSTRACT FROM AUTHOR]

Remarkable progress has been made in the treatment and outcome of adult acute lymphoblastic leukemia (ALL) over the past 3 decades. This progress is the result of an accumulation of a mosaic of knowledge and experience, which have led to a more profound understanding of the biology of the disease, and at the same time the development of new drugs and treatment strategies. Advances in the understanding of the biology has highlighted significant differences between childhood and adult ALL (e.g., high frequency of Philadelphia-positive ALL and low incidence of TEL-AML1-positive disease in adults) and thus explains at least partly the divergence of outcomes that is still observed between children and adults. Moreover, ALL is increasingly recognized as a group of heterogeneous disease entities with unique responses to therapy and prognosis. The combination of further cytogenetic-molecular dissection of ALL subtypes with the emergence of new and targeted therapies will thus continue to constitute the fundament upon which further progress will hopefully occur in adult ALL. [ABSTRACT FROM AUTHOR]

Acute lymphoblastic leukemia (ALL) is characterized by distinctive morphologic, cytogenetic, and molecular genetic features, some of which have important clinical implications for both diagnosis and predicting response to specific treatment regimens, while the role of others is yet to be defined. This chapter will describe the cytogenetic and molecular aberrations in ALL. [ABSTRACT FROM AUTHOR]

Acute lymphoblastic leukemia (ALL) is a malignant neoplasm of lymphocytes characterized by the clonal accumulation of immature blood cells in the bone marrow. These abnormal cells are arrested in the lymphoblast stage of the normal maturation pathway. Aberrations in proliferation and differentiation of these cells are common, and normal hematopoiesis is suppressed. Symptoms result from varying degrees of anemia, neutropenia, and thrombocytopenia or from infiltration of ALL cells into tissues. Although virtually any organ system may become involved, once leukemia cells enter the peripheral blood, the lymph nodes, spleen, liver, central nervous system (CNS), and skin are the most common sites detected clinically. [ABSTRACT FROM AUTHOR]

The diagnosis of acute lymphoblastic leukemia (ALL) is dependent on the identification and characterization of blast cells in peripheral blood or bone marrow. Although it is not clear why blasts have a tendency to circulate in some patients and not in others, ALL can be reliably diagnosed using peripheral blood or bone marrow blasts when blasts are in circulation [79]. However, distinguishing blasts from activated lymphocytes is difficult in some patients, particularly children. Standard care and thorough evaluation of patients with ALL thus require good bone marrow aspiration, with high-quality smears and bone marrow biopsy specimens. When bone marrow biopsy specimens are available, touch imprints should be made [1]. [ABSTRACT FROM AUTHOR]

Acute lymphoblastic leukemia (ALL), also known as acute lymphocytic leukemia, is a malignant neoplasm of the lymphocyte precursor cells, or lymphoblasts, that occurs annually in nearly 4000 people in the US [51]. Leukemic lymphoblasts have exaggerated and uncontrolled growth, fail to mount a normal immune response, and cause a drop in production of normal bone marrow cells that leads to a deficiency of circulating red cells (anemia), platelets (thrombocytopenia), and white cells other than lymphocytes (especially neutrophils, or neutropenia) [146]. Both T-cell and B-cell precursors can give rise to ALL; B-cell ALL represents about 88% of all cases. [ABSTRACT FROM AUTHOR]

Despite effective initial therapy, the majority of adults with acute myeloid leukemia (AML) who achieve a complete remission (CR) eventually relapse and usually within 2 years. Furthermore, approximately 20% of patients never achieve first complete remission (CR1). In these settings, alternative treatment strategies have limited efficacy and allogeneic hematopoietic stem cell transplantation (HSCT), with generation of the potent immunologic reaction graft-vs.-leukemia (GVL) effect, is considered the best curative strategy. However, many patients do not have a suitable donor or are not candidates for transplantation. Therefore, the treatment of patients who relapse or are refractory to conventional initial therapy is challenging. The definition of refractory AML includes patients who fail conventional induction chemotherapy, those with a short (less than 6-12 months) CR1 duration, and patients who have relapsed twice or more [1]. This definition has been useful in defining relatively uniform populations of patients for clinical trials. [ABSTRACT FROM AUTHOR]

Although acute leukemias are infrequent diseases, they are highly malignant neoplasms responsible for a large number of cancer-related deaths. Acute myeloid leukemia (AML) is the most common type of leukemia in adults, yet continues to have the lowest survival rate of all leukemias. While results of treatment have improved steadily in younger adults over the past 20 years, there have been limited changes in survival among individuals of age >60 years [1, 2]. [ABSTRACT FROM AUTHOR]

The Acute Myeloid Leukemias (AML) are a diverse set of phenotypically similar diseases whose classification has been the source of some controversy in recent years. In this chapter we discuss the best current clinically and biologically relevant classification of these diseases, including appropriate laboratory studies for accurate diagnosis and subclassification. Understanding the basis for current classification of AML requires additional knowledge of the Myelodysplastic Syndromes (MDS) and their relationship to a subset of AML, which will also be discussed. Finally, some attention will be devoted to monitoring AML during treatment. [ABSTRACT FROM AUTHOR]

As with any disease, there are three general options for treatment of AML: supportive care only, standard therapy, and investigational therapy. Although, as discussed below, there are instances where the first option is preferable, the natural history of AML typically mitigates against it [1]. Since by definition there is much more information available about standard than about investigational therapy, most patients prefer the former, provided outcome with it is satisfactory. Hence, this review will begin by describing standard therapy, with emphasis on the factors that predict success following its use. Subsequent discussion will focus on investigational options of potential use for patients in whom results with standard therapy are poor. [ABSTRACT FROM AUTHOR]