Current Management of Acute Lymphoblastic Leukemia in Adults

Intensive remission chemotherapy followed by post-remission consolidation and maintenance therapies has achieved complete remission rates of 75% to 90% and 3-year survival rates of 25% to 50% in adults with acute lymphoblastic leukemia (ALL). These results, although promising, are still less favorable than those achieved in childhood ALL. However, various novel experimental and clinical approaches show promise for improving cure rates. Also, specific therapies directed at high-risk subgroups with ALL are beginning to emerge. Detection of specific chromosomal abnormalities at diagnosis identifies patients who are at risk of failing to achieve remission, as well as those who are likely to have short, intermediate, or prolonged disease-free intervals after successful remission induction. Such prognostic information may, ultimately, be used to assign risk categories and to individualize post-remission therapy.

Introduction

Acute lymphoblastic leukemia (ALL) accounts for 20% of all acute leukemias seen in patients over 20 years of age, and affects approximately 2 persons per 100,000 in the United States annually. Despite its relative rarity, ALL continues to generate considerable interest because of its high mortality when untreated, and because of the biologic and therapeutic lessons learned from studying this disease.

The success of therapy in childhood ALL has also fueled a quest for similar cure rates in adults, using intensive remission induction chemotherapy and the concepts of post-remission consolidation and maintenance therapies. So far, treatment for adult ALL has yielded inferior, but increasingly promising, complete remission rates of 75% to 90% and 3-year survival rates of 25% to 50%.1 Moreover, recent studies have contributed to an understanding of the biology of ALL and its prognostic factors [2-4]. Importantly, specific therapies directed at relatively homogeneous subgroups of ALL are now emerging. Parallel improvements in supportive care, such as antibiotic prophylaxis, the appropriate use of bone marrow transplantation, and perhaps the use of hematopoietic growth factors have also contributed to better survival rates.

Diagnosis and Classification

The diagnosis of ALL continues to rely on morphology and cytochemistry. However, with the increasing availability of immunophenotyping by flow cytometry, this technique has become an important part of the diagnostic evaluation (Table 1). Thus, in the initial assessment of the acute leukemia patient, a relatively limited panel of monoclonal antibodies will allow patients to be divided into those with ALL derived from either B lymphocytes (B-lineage) or T lymphocytes (T-lineage) and those with acute myeloid leukemia (AML). The distinction between ALL and AML is the critical first step in the selection of therapy, and when this division is not correctly made, poor results are common.

Differential Diagnosis

Other diseases may be confused with ALL, the most common of which are listed in Table 2. Minimally differentiated AML (MO by the French-American-British Cooperative Group [FAB] criteria) and acute undifferentiated leukemia lack lymphoid surface markers, and are rarely cured with typical ALL treatment.

The diagnosis of AML-MO is often difficult to make, as it relies on morphology, cytochemistry, and immunophenotyping. These cells usually have FAB-L2 morphology and are negative for myeloperoxidase or Sudan Black B reactivity. Thus, patients with AML-MO are often mistakenly entered into ALL clinical trials, where their outcome has been poor. However, these cases, by definition, do not express lymphoid-specific markers. They may be positive for terminal deoxynucleotidyl transferase (TdT) reactivity and CD7 expression, but these markers are not specific for lymphoblasts. In contrast, AML-MO cells are positive for CD13, CD33, or other myeloid markers, suggesting a minimal level of differentiation along the granulocytic pathway.

Occasional patients may have hybrid acute leukemia, wherein the blast cells express both myeloid and lymphoid surface markers. They may be either bilineal, when such features are seen in separate cell populations, or biphenotypic, when they are seen on the same cell. In the former case, therapy is usually based on the dominant pattern.

In approximately 20% of cases of typical ALL in adults, the individual lymphoblasts express both myeloid and lymphoid antigens. These cases are more commonly B-lineage than T-lineage in origin. The myeloid antigen-positive ALL immunophenotype does not appear to be associated with a poor outcome in children, but the data are less clear in adults [5]. However, recent improvements in treatment may have overcome the poor prognosis formerly associated with myeloid antigen expression in adult ALL [4,6].

Together, the use of morphology, cytochemical stains, immunophenotyping, and electron microscopy can reliably differentiate between AML and ALL in more than 95% of patients. Most cases of ALL are strongly positive for terminal deoxynucleotidyl transferase. Lymphoblasts that are negative for terminal deoxynucleotidyl transferase often have FAB-L3 morphology, and correspond to mature B-cell ALL. Such cases are sometimes called Burkitt cell ALL, because of their similarities with Burkitt's lymphoma. The lymphoblasts of these patients generally express surface membrane immunoglobulins, and the 8;14 translocation or one of its variants [t(2;8) or t(8;22)] is usually present.

Cytogenetic Evaluation

Cytogenetic evaluation has become a critical part of the pretreatment evaluation of patients with ALL [7]. Indeed, the most predictable clinical outcomes occur when patients are classified according to recurring cytogenetic abnormal- ities.4 The most common of these involves the Philadelphia chromosome [3]. Originally described in chronic myelogenous leukemia, this rearrangement involves the translocation of the ABL proto-oncogene from chromosome 9 to the breakpoint cluster region (BCR) gene on chromosome 22: t(9;22)(q34;q11). In chronic myelogenous leukemia, this results in the production of the hybrid protein p210, but in Philadelphia-positive ALL, either a p210 or a smaller p190 protein results.

The importance of recognizing this subgroup lies in the considerably shorter survival observed in both childhood and adult Phildelphia-positive ALL cases. Although fewer than 5% of childhood ALL cases are positive for this chromosome, the frequency of positivity increases steadily with age, and approximately 30% of adults with ALL have Philadelphia-positive disease [3,8]. Indeed, the poorer prognosis of adult ALL overall may be due, in part, to the proportionately higher number of Philadelphia-positive cases seen among adults.

Other karyotypes that occur in ALL and have important prognostic significance include t(8;14), t(4;11), and t(1;19). The poorer prognosis associated with certain karyotypes has dictated that different approaches be taken with these patients, as discussed below.

Prognostic Factors

Table 3 lists the adverse prognostic factors that have a major influence on complete remission rates, remission duration, and survival in patients with ALL [1,4]. In multivariate analyses, patients presenting with white blood cell counts > 30,000/µL have had a significantly shorter duration of remission than patients with lower leukocyte counts. However, among patients with T-cell ALL, extreme leukocytosis does not negatively affect outcome [4].

Older age (> 60 years) is another adverse characteristic. Remission duration and overall survival have decreased in almost every adult ALL trial as the ages of the patient groups have increased. Minor prognostic factors, or those that have had some significance with certain treatment regimens, are the percentage of circulating blast cells; the degree of bone marrow involvement; the presence of hepatomegaly, splenomegaly, or lymphadenopathy; lactate dehydrogenase levels; central nervous system (CNS) involvement at presentation; and the time required to achieve complete remission (eg, > 4 to 6 weeks).

Principles of Therapy

Modern ALL treatment regimens have three basic aims:

1) The rapid restoration of bone marrow function, using multiple chemotherapeutic drugs at acceptable toxicities, so as to prevent the emergence of resistant subclones;

2) Adequate prophylactic treatment of sanctuary sites, such as the CNS; and

3) The use of post-remission consolidation therapies to eliminate minimal (undetectable) residual disease. (Post-remission therapy has traditionally been categorized as intensification, or consolidation, and prolonged maintenance therapies.)

Table 4 depicts a typical treatment schema for adult ALL. Four or five drugs are usually used for remission induction, followed by similar agents plus antimetabolites for remission consolidation treatment. Data suggest that high doses of cytarabine or cyclophosphamide (Cytoxan, Neosar) may be particularly beneficial in patients with T-cell ALL and some high-risk subsets, and that high-dose methotrexate may be particularly useful in individuals with B-lineage ALL.

Central nervous system prophylaxis most often consists of intrathecal methotrexate plus either systemic methotrexate or cranial irradiation. Since some of the agents used systemically in the more intensive remission induction and consolidation programs do penetrate the leptomeninges, the need for additional CNS treatment may have diminished. The likelihood of an isolated CNS relapse for adults with ALL appears to be about 5%.

For late intensification therapy, virtually every chemotherapeutic agent and treatment modality has been used, including bone marrow transplantation. Some period of maintenance chemotherapy has traditionally been given
for 1 to 3 years, using mercaptopurine (Purinethol) and methotrexate, often with monthly pulses of vincristine and prednisone.

Critical appraisal of the impact on disease-free survival of each component of post-remission therapy used in any given trial is difficult for many reasons. Few well-controlled randomized studies have analyzed the importance of individual treatment com- ponents on outcome. Also, changes in treatment protocols have rarely been made in a stepwise fashion. Rather, alterations in post-remission therapy have often been made simultaneously with new induction regimens.

New drugs have been introduced along with other changes, making their impact on outcome difficult to discern. At present, the benefit of such newer drugs as etoposide (VePesid), teniposide (Vumon), high-dose cytarabine, and mitoxantrone (Novantrone) cannot be critically evaluated. Table 5 summarizes the large clinical trials using intensive induction and post-remission therapies [4,9-15].

Remission Induction

The use of vincristine and corticosteroids (prednisone or dexamethasone) plus an anthracycline (either doxorubicin or daunorubicin [Cerubidine]) forms the cornerstone of most modern induction regimens. The further benefit of adding daunorubicin to vincristine, prednisone, and asparaginase (Elspar) was proven in a randomized trial conducted by the Cancer and Leukemia Group B (CALGB study 7612). In this study, patients who received daunorubicin had a complete remission rate of 83% vs 47% for those who did not [16].

Asparaginase improves the complete remission rate when added as a third drug to vincristine and prednisone, but its value in improving either the complete remission or disease-free survival rate when daunorubicin is included in the induction regimen is unclear. In childhood ALL, asparaginase appears to prolong disease-free survival when given during consolidation therapy.

Other agents that have been incorporated into induction regimens include cyclophosphamide, conventional and high-dose cytarabine, mercaptopurine, conventional and high-dose methotrexate, and mitoxantrone [1]. The relative importance of individual drugs and drug schedules is difficult to discern, given the lack of randomized comparative trials. As yet, none of the modifications involving the addition of a fourth or fifth drug to a three-drug regimen has demonstrated reliably higher cure rates, although some such modifications may produce considerable benefit in certain subsets of patients.

Remission Consolidation

Post-remission consolidation therapy is designed to eradicate the rapidly proliferating neoplastic cells that are thought to be responsible for early relapses. In general, drugs given during this period are cell-cycle phase specific. However, unlike the necessity for remission induction therapy, the need for intensive consolidation therapy in achieving cure is controversial [17]. The relative benefit of any particular consolidation therapy is likely to be inversely proportional to the intensity of the initial induction therapy and its efficacy in rapidly reducing the leukemia cell mass.

Maintenance Therapy

Remission maintenance therapy-ie, a prolonged period of treatment with low doses of chemotherapy drugs-is still a standard component of the management of ALL. This approach stands in marked contrast to most other "curable cancers," such as Hodgkin's disease, large-cell lymphoma, and testicular cancer, in which cure follows the initial intensive cytoreductive therapy and low-dose maintenance chemotherapy provides no additional benefit. The necessity for prolonged maintenance therapy in adults with ALL may also be a function of the intensity and the success of initial chemotherapy. As yet, the need for maintenance therapy has not been proven in adults.

The experience in childhood ALL has led to the use of methotrexate and mercaptopurine in most maintenance regimens in adults, either alone or in combination with other agents. The duration of therapy has been derived empirically, and programs lasting 1 to 3 years are commonly used.

The uncertainties regarding the duration of, and even the necessity for, maintenance therapy are due, in part, to our lack of knowledge about its mechanism of benefit. The continuous presence of low doses of antimetabolite drugs may kill drug-resistant or slowly dividing leukemia cells. Alternatively, maintenance therapy may modify the host immune response so that it may destroy residual leukemia cells. A third possibility is that maintenance treatment may suppress the proliferation of residual leukemia cells until senescence or apoptosis occurs, ie, until the normal regulation of lymphocyte survival is restored. One or more of these mechanisms may be active in any individual patient. Clearly, much additional work remains to be done in this area.

Two trials in which maintenance therapy was omitted after the completion of consolidation therapy demonstrated high relapse rates. In CALGB study 8513, all therapy ended after 29 weeks [18]. Unfortunately, the median remission duration was found to be significantly shorter than in the preceding trial, which used 3 years of therapy (11 vs 21 months) [17]. Median survival duration in trial 8513 was 19 months, however, compared to 16 months in the earlier trial. In a pilot study conducted by the Eastern Cooperative Oncology Group (ECOG 2483) in which no maintenance therapy was employed after an intensive consolidation treatment regimen lasting approximately 12 months, median disease-free survival was 10 months, and the 4-year disease-free survival rate was only 13% [13].

Neither the CALGB nor ECOG trial used a randomized design to assess the value of maintenance chemotherapy. Also, both trials have been criticized for employing inadequate initial induction and consolidation therapies.

CNS Prophylaxis

The CNS is an important site of involvement by ALL. Although infrequently found at diagnosis, CNS involvement is common at the time of relapse. The meninges may harbor leukemia cells, and the blood-brain barrier may shelter them from systemic chemotherapy. Recurrence within the CNS usually coincides with systemic relapse.

Preventive treatment of the CNS during post-remission therapy has become an integral part of virtually all current adult ALL treatment protocols. Although the true value of CNS prophylaxis in adults is controversial, studies in which adult patients either refused or could not receive CNS prophylaxis have demonstrated a higher rate of CNS relapse than was seen in patients receiving such treatment.

Central nervous system leukemia is more easily prevented than treated. Once overt CNS leukemia has developed, there is a high likelihood of subsequent CNS relapse despite treatment.

Prophylaxis of the CNS typically consists of cranial irradiation plus intrathecal methotrexate. Cytarabine and hydrocortisone are occasionally added to methotrexate for "triple intrathecal therapy." Some investigators have substituted high-dose systemic chemotherapy with either methotrexate or cytarabine, since therapeutic levels of these drugs can be achieved in the cerebrospinal fluid when they are administered intravenously in high doses. The overall superiority of any one prophylactic therapy has not been established.

Modern Multiagent Clinical Trials

What is the expected outcome for patients with ALL treated with one of the modern multiagent chemotherapy regimens? A review of several large clinical trials of these regimens provides the best answer to this question.

CALGB Trials

The CALGB recently reported on its 8811 trial, which evaluated a dose-intense, multicourse, 2-year treatment program in 197 adults ages 16 to 80 years (median, 32 years) [4]. The complete remission rate was 85%, the median remission duration was 29 months, and the median survival overall was 36 months. The five-drug induction regimen consisted of a single dose of cyclophosphamide, 3 days of daunorubicin, and 4 weeks of vincristine, prednisone, and asparaginase. The two myelosuppressive drugs were given within the first 3 days, and the doses were reduced by one-third in patients over the age of 60 years.

This induction regimen was followed by early and late intensification courses. The early intensification program included 2 months of treatment with cyclophosphamide, intrathecal methotrexate, subcutaneous cytarabine, oral mercaptopurine, intravenous vincristine, and additional asparaginase. Central nervous system prophylaxis was then completed with cranial irradiation and five weekly doses of intrathecal methotrexate together with daily mercaptopurine. The late intensification course lasted 6 weeks and was followed by prolonged maintenance treatment with daily mercaptopurine and weekly oral methotrexate plus monthly pulses of vincristine and prednisone until 2 years after diagnosis.

Value of Adding G-CSF--More recently, the CALGB completed another trial (study 9111) using the same chemotherapy program, but randomizing patients in a double-blind fashion to receive either filgrastim (granulocyte-colony stimulating factor [G-CSF]; Neupogen) or placebo during the induction and early intensification courses.19 The complete remission rate among the patients who received G-CSF was 91%, compared with 80% in the placebo group, but this difference was not statistically significant. Among the patients treated with G-CSF, the time to recover > 1,000 neutrophils/mL during the induction course was significantly decreased, from 22 to 16 days. This shortened duration of neutropenia was more apparent in patients > 60 years old (16 days with G-CSF vs 29 days with placebo).

Data from two other randomized trials suggest that concurrent use of G-CSF may improve the ability to deliver intensive chemotherapy more safely [20,21]. The follow-up periods for these trials are still short, however, and the full impact of the use of G-CSF during the treatment of adults with ALL remains to be determined.

GIMEMA Trial

The GIMEMA ALL 0288 trial is one of the largest randomized trials in adults to date [14]. In this multicenter Italian trial, 541 patients between the ages of 12 and 65 years were given an induction regimen consisting of daunorubicin, vincristine, prednisone, and asparaginase, and, in addition, were randomized to either a single dose of cyclosphosphamide or no cyclophos- phamide. Once in remission, patients were further randomized to both consolidation and maintenance therapies or maintenance therapy alone.

Preliminary results show no significant differences in the complete remission rates between patients who received cyclophosphamide and those who did not (80% on each arm). These findings call into question the benefit of adding cyclophosphamide to the four-drug regimen of daunorubicin, vincristine, prednisone, and asparaginase. It is possible, however, that cyclophosphamide will exert its beneficial effects on long-term relapse-free survival. As yet, the results of the second part of the study have not been reported, but hopefully it will shed light on the necessity for a consolidation phase once adequate intensive induction therapy has been given.

Seven-Drug Induction Regimen

The German ALL Group enrolled 368 patients (median age, 25 years) into a multicenter study [9] over a 5-year period from 1978 to 1983. The remission induction treatment consisted of vincristine, prednisone, daunorubicin, and asparaginase during the first 4 weeks, and then cyclophosphamide, cytarabine, and mercaptopurine during the next 4 weeks. The complete remission rate was 74%, median remission duration was 24 months, and the rate of disease-free survival was 35% at 10 years.

Favorable outcomes were observed in patients under 35 years old, those with T-ALL, and those with white blood cell counts < 30,000/ml. In addition, this study found that delayed achievement of a complete remission (> 4 weeks) was predictive of a shortened remission duration. Only one of the four patients with mature B-ALL achieved a complete remission. Of interest, CNS involvement at presentation did not predict an adverse outcome, perhaps because effective therapy against CNS relapse (intrathecal methotrexate until the disappearance of all blast cells plus 3,000 cGy of irradiation to the skull and neuraxis) was given.

Multiple Courses of Eight Drugs

At the Memorial Sloan-Kettering Cancer Center in New York, multiple courses of eight drugs were used in various combinations in the L-10 and L-10M protocols [22]. A complete remission rate of 85% was reported among 72 patients. The median remission duration was 51 months, and disease-free survival at 5 years was estimated to be 45%. However, when the same chemotherapy program was evaluated in a Southwest Oncology Group multi-institutional trial of 168 patients, the complete remission rate was only 68% and the median remission duration was 23 months [11].

A similar chemotherapy program was evaluated at the University of Iowa [10]. The HOP-L regimen produced a complete remission rate of 75% in 59 patients. The median remission duration was about 50 months, and 15 patients (34%) remained in continuous complete remission for more than 5 years. In contrast to other recent trials, patients with T-ALL had a poor outcome with this regimen.

Intensive Consolidation Regimens

An intensive consolidation chemotherapy program for adults with ALL has been evaluated by investigators at the University of California in San Francisco [12]. After remission induction with daunorubicin, vincristine, prednisone, and asparaginase, cyclic courses of reinduction therapy, followed by cytarabine plus teniposide, and then high-dose methotrexate were given to 109 patients less than 50 years old. Patients then received maintenance therapy until they were in continuous complete remission for 2½ years.

The rate of disease-free survival for all patients was 35%, and 42% of those who achieved complete remission were projected to remain disease-free at 5 years. Failure to achieve remission within 4 weeks and the presence of the Philadelphia chromosome were associated with a 100% risk of relapse. After achieving complete remission, 59% of patients with T-ALL remained disease-free, as compared with 31% of patients with the common ALL antigen (CD10).

In another trial using an intensive consolidation regimen, ECOG investigators gave high-dose cytarabine followed by several courses of MACHO (methotrexate, Ara-C, cyclophosphamide, doxorubicin, and Oncovin). No maintenance therapy was given. The leukemia-free survival rate was only 13% at 4 years [13].

M.D. Anderson Trial of VAD

A trial conducted at the M.D. Anderson Cancer Center using vincristine, Adriamycin, and dexamethasone (VAD) is notable for its low morbidity and mortality during the remission induction phase [15]. Only 3% of the 105 patients died during induction, and only half of the patients required more than 1 week of hospitalization or prolonged use of intravenous antibiotics. The complete remission rate was 84%, and the median duration of remission was 22 months.

Treatment of High-Risk Patients

Various high-risk subsets of adults with ALL warrant special attention with regard to treatment approaches.

Burkitt Cell ALL

One such high-risk subset, Burkitt cell ALL (also known as FAB L3 or mature B-cell ALL), constitutes 3% to 5% of adult ALL case. Its ubiquitous biologic features are the presence of monoclonal surface immunoglobulin and the 8;14 translocation or one of its two variants.

Burkitt cell ALL is relatively easily recognized at diagnosis from the characteristic clinical findings of hepatosplenomegaly and lymphadenopathy. Lactate dehydrogenase and uric acid levels are usually markedly elevated, and there is often leptomeningeal involvement. In the past, few if any of these patients survived following treatment with the standard ALL regimens described above.

More recently, there have been several reports of high complete remission rates and a survival plateau in the range of 30% to 40% with the use of short intensive chemotherapy programs for B-cell ALL [23-25]. These regimens, which may require as few as 16 to 18 weeks of treatment, use high doses of methotrexate, cytarabine, and cyclophosphamide or ifosfamide (Ifex), together with other ALL drugs. Additional trials are underway to confirm these encouraging results.

Elderly Patients With ALL

The treatment of ALL in elderly patients remains a difficult problem. A review of the annual age-specific leukemia incidence in the United States underscores the observation that ALL is relatively uncommon in the middle adult years, but increases rapidly in incidence over age 60. Elderly patients with ALL have only rarely been included in clinical trials, and as yet, no optimal treatment programs are available for this age group (Table 6).

In a recent report from the northern counties of England [26], approximately one-third of adult ALL cases occurred in patients over age 60. Various treatment approaches were taken in this elderly group of patients, but outcomes were uniformly poor.

Investigators at M.D. Anderson Cancer Center described 52 elderly patients treated with infusional VAD. This regimen produced a high complete remission rate with relatively low toxicity [27].

In the most recent CALGB trials, we observed a complete remission rate of 65% in patients 60 to 80 years old (median age, 65). Nevertheless, the 3-year survival in all three of these reports was quite poor. The low tolerance of elderly patients for intensive chemotherapy remains one of the obstacles to increasing the cure rate in adults with ALL.

Philadelphia Chromosome-Positive ALL

Philadelphia chromosome-positive ALL also has proved difficult to treat, although some progress has been made. This disease has a high initial response rate, but a short duration of remission [4]. At present, Philadelphia-positive ALL represents the major challenge in curing ALL, since it makes up approximately one-third of all adult cases and perhaps one-half of all cases of B-lineage ALL [3].

Shown in Table 7 are the outcomes of a group of 30 patients prospectively identified in a CALGB study (8811) as having a t(9;22) or the BCR/ABL rearrangement, compared to outcomes of 83 patients who did not have this genetic mutation. Although the complete remission rates were similar (70% vs 84%, P = 0.11), the remission duration was markedly shorter in the Phildelphia-positive than in the Philadelphia-negative cases (median, 7 vs > 33 months; P < 0.001). This was also reflected in the median survival of the two groups, which was 11 vs 44 months (P < 0.001). As yet, no chemotherapy regimen, by itself, appears to have the potential to cure this group of patients.

In contrast, the International Bone Marrow Transplant Registry has reported on the outcome after HLA-identical sibling marrow transplants among patients with Philadelphia-positive ALL, either in first complete remission or with more advanced disease, and for a small number of Philadelphia-positive ALL patients with primary induction failure [28]. The leukemia-free survival was approximately 35% for all three groups. The probability of relapse after transplantation was approximately 30% to 50% for the group overall, attesting, in part, to the treatment-resistant nature of this disease.

Thus, at this time, the treatment for Phildelphia-positive ALL should include an intensive remission induction chemotherapy program, followed by allogeneic bone marrow transplantation during the first complete remission if a donor is available. Alternatively, intensive post-remission chemotherapy is being explored, using high-dose cytarabine or methotrexate.

Preliminary data suggest a possible benefit from the use of alpha-interferon during maintenance therapy. There is considerable interest in the investigation of new agents, including immunotoxins, modulators of multi-drug resistance, and antisense molecules in this high-risk group of patients.

Detection of Minimal Residual Disease

The sometimes difficult decision of whom to recommend for bone marrow transplantation (BMT) vs continued chemotherapy has fostered considerable interest in the detection of subclinical or minimal residual disease while patients are still in remission. The laboratory techniques currently under investigation for this purpose include multichannel flow cytometry, in vitro cloning assays, molecular analyses of clonal gene rearrangements (using either Southern analyses or the polymerase chain reaction), and fluorescence in situ hybridization.

These assays for minimal residual disease are still technically difficult and are not widely available. Also, their predictive value remains to be proven. Occasionally, there may be clonal evolution with new genetic mutations or the appearance of malignant subclones with variant expression of surface markers. In addition, the genotype and phenotype of the residual clonogenic malignant cells may differ from those of the majority of their malignant progeny that were initially evaluated at diagnosis. Finally, uncertainty exists over whether complete eradication of neoplastic cells is required for cure, ie, for prolonged disease-free survival. Several cases of clonal remission have been observed in other neoplastic diseases.

Bone Marrow Transplantation

The role of allogeneic BMT in the treatment of adult ALL patients in first remission is controversial. Disease-free survival rates for ALL patients who underwent transplantation during first remission range from 30% to 50%, depending on patient characteristics at entry as well as certain supportive care measures [29]. When various prognostic characteristics are considered, it is not clear whether allogeneic transplantation offers a survival advantage over conventional chemotherapy for patients with a "favorable" prognosis.

The International Bone Marrow Transplant Registry performed a retrospective review of the results of BMT vs intensive consolidation chemotherapy in adults with ALL in first remission [30]. While relapse rates were lower among those who received transplants, this advantage was offset by a high rate of transplant-related mortality. Thus, overall disease-free survival was comparable in the two groups. Many of the factors that predicted poor outcome with conventional chemotherapy also adversely affected outcome after BMT.

One shortcoming of this study was the failure to evaluate cytogenetic subgroups adequately. Given the very poor outcome for Philadelphia-positive ALL patients following standard chemotherapy, and the encouraging results of BMT in such patients, it would appear that most of these patients who have a suitable marrow donor should undergo BMT while in first remission.

Data from several transplant centers have reported disease-free survival rates of about 30% at 3 years for selected ALL patients who underwent BMT early in the second remission. In general, results of marrow transplantation in patients with refractory ALL have been worse, although a recent report by the International Bone Marrow Transplant Registry suggests that over 20% of such patients may become long-term survivors following BMT [29]. Adult patients with refractory or relapsed ALL who are young and have a suitable donor should undergo allogeneic BMT.

High-dose chemotherapy followed by autologous bone marrow reinfusion or blood stem-cell transplantation may be considered for patients too old to tolerate an allogeneic transplant, or for those who lack an HLA-compatible donor (see Table 8) [31]. As in AML, a major concern in ALL remains the high likelihood of residual leukemia cells within the harvested, cryopreserved remission marrow or stem-cell fraction. In general, results with autologous transplantation in ALL have been inferior to those in AML. For young adult ALL patients in first remission who have high-risk features, high-dose chemotherapy and HLA-matched unrelated donor marrow transplantation should be considered.

Relapsed/Refractory ALL

Despite the use of modern chemotherapy, more than half of adult patients with ALL relapse, most often within the first 2 years. Over 80% of relapses occur first in the bone marrow, while the remainder develop in extramedullary sites, primarily the CNS. Relapses in other sites, such as the lymph nodes, skin, and testes, occur much less frequently. Since patients with an isolated extramedullary relapse have a very high risk for subsequent bone marrow relapse, they should receive systemic chemotherapy following local treatment.

Various treatment protocols have been employed in patients with relapsed or refractory ALL. High-dose cytarabine, with or without additional agents, produces complete remissions in about 50% of adult patients [32]. However, in almost every instance, the median remission duration has been < 6 months, and only a small fraction of these patients have survived over the long term. The best results for such patients have been obtained with allogeneic BMT during second remission.

Future Directions

Despite major advances in the treatment of adult patients with ALL over the past decade, many patients continue to die either from the disease itself or the complications of treatment. However, a number of novel experimental and clinical approaches hold promise for improving cure rates.

In recent years, the biologic heterogeneity of ALL has been further defined. Various clinical and laboratory parameters have been reported to convey useful prognostic information. For patients with ALL, however, the most consistently observed prognostic factors have been age and karyotype.

Currently, detection of chromosomal abnormalities at the time of initial diagnosis provides the most useful means of identifying patients at risk of failing induction therapy, as well as those likely to have short, intermediate, or prolonged remissions after achieving complete remission. In the future, such prognostic information will become valuable for assigning risk categories and for individualizing post-remission therapy.

Application of modern molecular technologies designed to detect minimal residual leukemia may aid clinicians in monitoring disease during and after chemotherapy, and could result in the early detection of patients likely to relapse, in whom further therapy may be necessary.

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