Acute Lymphoblastic Leukemia in Adults

Acute Lymphoblastic Leukemia in Adults

Steven E. Coutre

Acute lymphoblastic leukemia (ALL) is a neoplastic disorder that is rapidly fatal if untreated. In children, ALL is the most common malignancy, and considerable advances have led to the cure of most children with the disease. Historically, treatment outcomes in adults have not been as favorable. Although improved prognostic stratification has led to a better understanding of the biologic heterogeneity of the disease, targeted therapies exploiting these differences have not yet emerged as part of standard therapy for most patients. However, dramatic advances in whole genome sequencing as well as the development of novel immunotherapies promises to improve both the fundamental understanding of the biology of the disease and treatment outcomes.

The clinical onset of ALL is rarely insidious, and presenting signs and symptoms reflect bone marrow as well as extramedullary involvement by leukemia. Examination of the peripheral blood smear is often sufficient to establish the diagnosis of ALL, but additional clinical and laboratory tests are essential for formulating a treatment plan and provide important prognostic information. Current therapy for adults involves a scheduled sequence that starts with remission induction chemotherapy, followed by one or more cycles of intensification, prophylaxis of the central nervous system (CNS), and prolonged maintenance lasting 2 to 3 years. With this multiagent, multicycle approach, between 25% and 40% of adults with ALL are cured of their disease. Modifications to this general scheme, based on an appreciation of the high risk for disease relapse, have improved outcome for adult ALL patients who have the mature B-cell phenotype as well as those with the Philadelphia (Ph) chromosome. Age remains a significant limitation to treatment intensity as one third of adults with ALL are over the age of 60 years.

Most adult patients with ALL experience relapse of their disease. Successful treatment options for relapsed or refractory ALL are few.


Only a few decades ago, ALL was an incurable disease in all but a small minority of patients. Progress in the treatment of pediatric ALL has been substantial. This is clearly illustrated in the results reported from a series of successive clinical protocols from St. Jude Children’s Research Hospital.1,2,3 Sequential treatment modifications in successive cohorts of children show a steady improvement in survival outcome as shown in Figure 74.1A. The initial clinical trials from 1962 to 1969 introduced multiagent chemotherapy regimens into pediatric ALL therapy. This proved superior to single-agent therapy, but, still, few children experienced long-term survival. The next era, from 1967 to 1979, saw effective prevention of leukemia relapse in sanctuary sites in the CNS through the use of cranial irradiation and intrathecal chemotherapy. Intensification of post-remission therapy with administration of non-cross-resistant drugs was responsible for improving survival in subsequent cohorts. With further refinements, as well as general improvement in supportive care, approximately 85% of children with ALL are now cured of the disease (Chapter 76).

The success demonstrated in the pediatric ALL trials led to similar approaches in the treatment of adults. As shown in Figure 74.1B, outcomes in consecutive cohorts of adults with ALL treated by the United Kingdom Acute Lymphoblastic Leukemia (UKALL) collaborative study group gradually improved as treatment was intensified and extended. Compared with the success in treating childhood ALL, however, the degree of improvement was only modest. The British Medical Research Council initiated the UKALL trials in 1971.4 The first trial, UKALL I, evaluated CNS prophylaxis but only enrolled 16 adults. Subsequent trials examined both the addition of active agents and more sustained intensive post-remission therapy, and participation of adult patients progressively expanded. Survival for adults with ALL was still only 20% at the time the UKALL IX trial opened for patient accrual in 1980. It was the first trial in the series to enroll adults separately from children. UKALL IX and the subsequent trial, UKALL XA, saw further, although minor, incremental improvement in the survival rate but provided important systematic analyses of prognostic indicators based on clinical, immunophenotypic, and cytogenetic characteristics.5 The subsequent study, UKALL XII/ECOG 2993, was the largest treatment study of newly diagnosed ALL in adults. It compared post-remission chemotherapy with autologous or related donor transplant. The complete remission (CR) rate was 90% in the 1,646 Philadelphia chromosome negative patients; overall survival at 5 years was 43% and 39% if all 1,913 eligible patients were included.6 Patients up to age 50 were eligible for allogeneic hematopoietic stem cell transplantation (HSCT). Survival at 5 years was 54% for all Philadelphia chromosome-negative patients with a donor, versus 44% for those without (P = 0.007) and 63% versus 52% for standard risk patients (P = 0.02). There was no benefit to allogeneic transplant for high-risk Philadelphia chromosome-negative patients. Patients without a donor who underwent autologous transplant did no better than those who received chemotherapy alone. These series of studies, along with other national cooperative group studies have led to remarkably similar long-term survival rates among adults who receive chemotherapy without transplant. These outcomes are distinctly inferior to those achieved in the pediatric age group.7, 8, 9 and 10


Although the clinical presentation is variable and may develop insidiously, virtually all adults diagnosed with ALL present with symptoms of only a few weeks duration. The symptoms generally reflect bone marrow failure or involvement of extramedullary sites by leukemia (Table 74.1). Up to one-half of patients with ALL have fever or documented infections. One third have bleeding symptoms at diagnosis, which is less frequent than in patients presenting with acute myeloid leukemia. Severe hemorrhage is uncommon.34 Fatigue, lethargy, dizziness, or even dyspnea and cardiac angina may reflect anemia in adults with ALL. Marrow expansion by
leukemic blasts may produce bone pain and arthralgias, but marrow necrosis is much less frequently found in adults as compared with children who have ALL.35 Approximately one half of adult patients have hepatomegaly, splenomegaly, or lymphadenopathy at diagnosis that can be appreciated on physical examination. Mediastinal masses are detected by chest radiographs or computed tomography scans primarily in patients with T-lineage ALL, who also frequently have pleural involvement and may complain of chest pain.36 The fewer than 10% of ALL patients who have CNS involvement infrequently present with referable symptoms, such as headache, vomiting, neck stiffness, alteration in mental status, and focal neurologic abnormalities. Other sites of extramedullary involvement include testis, retina, and skin, although virtually any organ can be infiltrated by leukemic blast cells.



Patients (%)














Mediastinal mass


Central nervous system leukemia


Other organ involvement













Data are based on collaborative trials reported by the CALGB,7 MRC,8 GIMEMA,9 and GMALL.10


In addition to a complete medical history and physical examination, patients with ALL should have a battery of diagnostic laboratory tests to confirm the diagnosis, subcategorize the patient’s disease for prognostic classification, and plan for appropriate therapy (Table 74.2). These studies include a complete blood count with examination of the peripheral blood smear, electrolyte measurements, creatinine, hepatic enzymes, uric acid, calcium, and albumin. Therapy-related declines in anticoagulation factors, including fibrinogen, occur with L-asparaginase, a drug commonly used in the treatment of ALL, and baseline levels should therefore be obtained. A mediastinal mass may be detected with a chest radiograph. A lumbar puncture for examination of the CSF to assess for leukemic involvement should be performed if patients present with neurologic symptoms. A bone marrow examination is mandatory and should include a complete cytogenetic assessment and immunologic phenotyping. Morphologic, cytogenetic, and immunophenotypic characteristics of ALL are detailed in Chapter 73. This section emphasizes features pertinent to adults diagnosed with the disease.

Routine Laboratory Evaluation

Routine laboratory evaluation reveals that a substantial number of adult patients with ALL have normal or only modestly elevated white blood cell (WBC) counts at the time of diagnosis (Table 74.3). Hyperleukocytosis (>100 × 109/L) occurs in approximately 15% of patients and may exceed 200 × 109/L. Some degree of anemia is present in the majority of adults. Approximately one third of patients have a platelet count less than 25 × 109/L, which is approximately the same proportion that present with bleeding symptoms. Circulating leukemic blasts may not be evident on examination of the peripheral smear in a significant number of patients. Coagulation parameters are typically normal, and disseminated intravascular coagulation is rarely observed.37 Metabolic abnormalities, including hyperuricemia, can occur, especially in patients with rapidly dividing leukemia cells and high tumor burden.


Medical history

Physical examination

Laboratory studies

Complete blood count, peripheral smear, coagulation studies, fibrinogen level, serum chemistry (renal and hepatic function, electrolytes, calcium, phosphate, uric acid, LDH), ABO and Rh blood group, HLA typing Appropriate cultures in the setting of fever

Chest radiograph or computed tomography

Cardiac assessment

(EKG, ECHOcardiogram or MUGA)

Lumbar puncture

Bone marrow aspiration and biopsy

Immunophenotype analysis (± cytochemical stains); cytogenetic analysis (FISH probes for specific genes, translocations, and/or chromosome abnormalities); BCR-ABL molecular analysis (p190 and p210); minimal residual disease markers (by flow cytometry or PCR)

Pregnancy test

Information about fertility


Laboratory Finding

Patients (%)

White blood cell count (×109/L)











Hemoglobin (g/g/L)







Platelet (×109/L)









Blast cells in peripheral blood





Blast cells in bone marrow (%)







Note: Data are based on collaborative trials reported by the CALGB,7 MRC,8 GIMEMA,9 and GMALL.10

Lumbar Puncture

A lumbar puncture is often performed at the time of diagnosis to examine the cerebrospinal fluid (CSF). CNS involvement is traditionally defined as greater than 5 WBC/µl of CSF with morphologically unequivocal leukemic blasts on the cytocentrifuged specimen.38 Patients at risk for bleeding complications due to thrombocytopenia should be transfused to an adequate platelet count before the procedure. Whether to perform a lumbar puncture in patients with a high circulating blast count is controversial. This is due to concerns of iatrogenic “seeding” of the CNS with leukemic cells. Studies in pediatric ALL have shown that when the procedure is complicated by a traumatic tap, the finding of blast cells in the CSF occurs more frequently in children with higher presenting WBC count.39 Among the patients who had traumatic lumbar punctures, those with leukemic blasts in the CSF were more likely to have subsequent CNS relapse.

Bone Marrow Evaluation

All patients with ALL should undergo a bone marrow aspiration and core biopsy procedure. The specimens must be submitted for histologic, cytogenetic, and immunophenotypic analysis. Morphologically, the marrow space is usually densely packed with leukemic blasts, which account for greater than 90% of nucleated cells in many adult ALL patients. As a result, the marrow biopsy sections are generally hypercellular, and, in 7% of adult patients with ALL, the normal marrow is completely replaced by leukemic blasts. This may prevent a successful aspiration, and a touch imprint of the biopsy tissue then becomes useful in evaluating cytologic features. Although increased reticulin deposits are common, marrow fibrosis is rarely present.40,41


Historically, poor chromosomal morphology in ALL made banding studies challenging, and karyotypic abnormalities were not reliably detected in early studies.42 The implementation of modern metaphase spreading, banding, and molecular cytogenetic techniques now reveals prognostically significant abnormal karyotypes in the majority of adult patients with ALL.43 These molecular techniques include fluorescent in situ hybridization using chromosome- and gene-specific probes for gene rearrangements that are difficult to identify, such as the t(12;21) chromosomal translocation.44 Application of these sensitive methods has revealed, for instance, that the t(12;21) translocation is much less common in adults with ALL than in children.45,46 Other age-related differences include fewer occurrences of numerical chromosome abnormalities and a higher incidence of the Ph chromosome in adults (Table 74.4).

Because of the profound prognostic implication of the Ph chromosome, molecular testing for the BCRABL gene rearrangement should be performed for all patients diagnosed with ALL. The Ph chromosome was originally identified in a patient with chronic myeloid leukemia (CML), in whom the BCR and ABL genes juxtaposed within the so-called major breakpoint region.24 This transcribes a 7-kb messenger RNA that is expressed as a 210-kd fusion protein, or p210BCR-ABL. In ALL, a variant breakpoint location, which results in the smaller p190BCR-ABL oncoprotein, is commonly found.47 A polymerase chain reaction (PCR) -based laboratory test capable of detecting both the p210BCR-ABL and p190BCR-ABL gene transcripts is now readily available to most clinicians and should always be performed in all newly diagnosed patients.


Patients (%)

Chromosomal Abnormalities



Normal karyotype



Numerical abnormalities







(>50 chromosomes)

Structural abnormalities (abn)


12p abnormal



9p abnormal




6q abnormal



Pre-B-Lineage (e.g.,)

t(1;19) (q23; p13)




t(4;11) (q21; q23)




t(9;22) (q34; q11)




t(12;21) (p13; q22)




T-Lineage (e.g.,)

t(1;14) (p32; q11)




t(5;14) (q35; q32)




t(7;7) or inv7(p15; q34)




t(10;14) (q24; q11)




Mature B

t(8;14) (q24; q32)




t(2;8) (p12; q24)



t(8;22) (q24; q11)




The primary basis of initial treatment strategies for ALL depends on antigenic parameters, and, hence, all patients should have their leukemic blasts characterized by immunophenotypic analysis. By current World Health Organization classification, the majority of adult ALL cases involve the precursor lymphoid neoplasms.48 Approximately 70% of cases are B-cell ALL, and 25% are T-cell ALL. The remaining 5% are a mature B-cell neoplasm, Burkitt leukemia.49 Compared with adults, children less often present with T-lineage ALL. There is also a slightly higher incidence of myeloid antigen expression in adult ALL patients, with reported incidences ranging from 15% to 54% compared with 4% to 35% in children.50,51 Commonly detected myeloid antigens include CD13, CD15, and CD33.

Rare cases with co-expression of multiple lymphoid and myeloid antigens may be considered acute biphenotypic leukemia according to criteria suggested by a European group.52 The clinical course appears to be poor; however, there is no uniform consensus on whether to manage these cases as acute myeloid or lymphoid leukemia.53 The Royal Marsden Hospital group identified 25 acute biphenotypic leukemia patients whom they treated over a 7-year period.54,55 The patients variably underwent remission induction with ALL-like regimens, AML-like regimens, or hybrid regimens containing elements of both with equal success, except for an excess of treatment-related mortality with the combined regimen. Overall survival was 39.4% at 2 years. They observed a high incidence of the Ph chromosome (41%) that partially accounted for the unfavorable outcome and emphasized the importance of aggressive risk-adapted therapy for these cases.


Many clinical and biologic characteristics previously identified as prognostic factors for adult patients with ALL have lost predictive value as therapy has evolved and become more intensive. In contrast, age, WBC count at presentation, and immunophenotype remain strong predictors of disease-free and overall survival for Ph-negative patients.61 (Table 74.5). More sophisticated assessment of the response to therapy, such as molecular detection of minimal residual disease (MRD), is becoming increasingly important in the management of adult ALL patients. The German Multicenter Study Group for Adult ALL (GMALL) prospectively assessed MRD evaluation in two consecutive trials.62 The complete response rate was 89% after induction, but the molecular CR rate was only 70% in 580 evaluable patients. After consolidation molecular CR was highly predictive of continuous complete remission (CCR; 74% vs. 35%; P < 0.0001) and of overall survival (80% vs. 42%; P = 0.0001) compared with patients with molecular persistence. These results justify the routine assessment of MRD in the treatment of adult ALL and define a new high-risk group based on molecular persistence of disease.63

Clinical Features

Advanced age and high WBC count at the time of diagnosis have held up as significant adverse prognostic factors in all modern adult ALL multicenter collaborative trials.5,7, 8 and 9,61,64,65, 66, 67, 68, 69, 70, 71, 72 and 73 Both advanced age and high WBC count were inversely correlated with more frequent occurrences of CR, longer duration of CR, or better overall survival in either the majority or all of the collaborative studies. Advanced age was variably defined as greater than 30 or 35 years. When included in multivariate analysis as a continuous variable, increasing age predicted worse outcome across the entire age range, making it difficult to choose a cut-off separating standard-risk from high-risk patients. The cut-off for high WBC count was either 30 × 109/L or 50 × 109/L. In the trial conducted by the CALGB study group, patients with advanced age (30 to 59 years) and high WBC count had an overall survival of 39% and 34%, respectively, compared with 69% and 59% for patients without these adverse prognostic factors.7


Patient Features

Prognostic Factor

Age (y)

<25, <35


>35, >55, >70


White blood cell count (×109/L)



≥30 (≥100 for T cell)



Thymic T


Early T (CD1a-, SCD3-)


Mature T (CD1a-, SCD3+)


Pro B (CD10-)


Cytogenetics/Molecular genetics/gene expression profiles

Hyperdiploidy >50

Intermediate to favorable

Hypodiploidy <44


9p abnormality

Intermediate to favorable

deletion 6q




Complex (≥ 5 abnormalities)


B Lineage (e.g.,)

t(12;21) (p13; q22) (ETV6-RUNX1)


t(4;11) (q21; q23) (MLL-AFF1)


t(1;19) (q23;p13) (TCF3-PBX1)


t(9;22) (q34; q11) (BCR-ABL1)


IKZF1 deletions/mutations


T Lineage (e.g.,)

NOTCH1/FBXW7 mutations


TLX1 or t(10;14) (q24; q11) (TLX1-TCRA/D)


t(10;11) (p13; q14) (PICALM-MLLT10)


t(5;14) (q35; q32) (TLX3BCL11B)


Response to therapy

Complete remission within 4 wk


Persistent minimal residual disease


a Improved prognosis with tyrosine kinase inhibitors.

Laboratory Features


The major immunophenotypic subgroup with prognostic value and therapeutic importance is the mature B-cell neoplasm, Burkitt leukemia. Burkitt leukemia is characterized by strong expression of surface immunoglobulin in addition to other markers common to B-lineage ALL, including CD10, CD19, CD20, and CD22.52 These patients respond poorly to standard ALL therapy, and outcome was dismal until brief, dose-intensified treatment programs were established as standard therapy.74,75,76 The substantial improvement in survival that resulted has negated the adverse prognostic value of this feature if patients are optimally managed.

T-cell ALL is another formerly unfavorable prognostic subgroup that, due to changes in treatment approach, is no longer a poor risk feature.77 In fact, with many modern treatment programs, the T-cell immunophenotype has become prognostically favorable.7,68,78 High WBC count does not adversely affect survival in T-cell ALL unless the WBC is >100 × 109/L.66,67,79 In addition, more detailed examination of prospective immunophenotypic data collected by the CALGB identified a subset characterized by expression of fewer than three T-cell markers that had an unfavorable prognosis.80 Leukemic blasts from these patients also infrequently expressed mature T-cell surface markers such as CD1a, CD2, CD3, CD4, and CD8, and, hence, would be consistent with the “early” T-cell ALL immunophenotype also reported to be unfavorable by the GMALL.81,82 The distinction between early T-ALL (sCD3-, CD1a-), thymic T-ALL (sCD3-/+, CD1a+), and mature T-ALL (sCD3+, CD1a-) described by GMALL may serve as an example of a clinically significant, risk-adapted treatment stratification.83

Other immunophenotypic markers have variably been shown to have prognostic value but are less well established. CD34 is expressed more frequently in adults with B-lineage ALL and was reported to affect outcome by the CALGB adversely.80 However, CD34 expression overlapped with both a high WBC and the presence of the Ph chromosome, and findings from other smaller series have yielded conflicting results.84, 85, 86, 87 and 88 Expression of myeloid antigen markers was slightly more frequent in B-lineage ALL than in T-lineage ALL but had no prognostic value in either instance.64,80,89


Unfavorable cytogenetic abnormalities in adult ALL include t(9;22) [BCR-ABL], observed in up to 30% of cases, t(4;11)(q21;q23)[MLL-AFF1], rare in adult ALL, t(1;19)(q23;p13)[TCF3-PBX1], also rare, and a hypodiploid karyotype, seen in 5% to 6%. Translocations involving chromosomal band 14q11 and abnormalities of the short arm of chromosome 12, including t(12;21)[ETV6-RUNX1], observed in 3% of cases, are favorable cytogenetic abnormalities. Results from collaborative studies providing karyotypic data generally indicate disease-free survival rates less than 25% for
patients with unfavorable abnormalities, as opposed to greater than 75% for those with favorable cytogenetic findings.60,65,90, 91, 92, 93 and 94 Additional reports from single institutions have provided similar outcome data.95,96 Cytogenetic findings commonly identified in adult ALL with an intermediate prognosis include normal karyotype, hyperdiploidy, and abnormalities at 6q or 9p. The t(8;14) (q24;q32)[MYC-IGH] and other MYC gene rearrangements are associated with the Burkitt leukemia subtype and are not prognostically unfavorable markers with optimal treatment.

In the UKALL XII/ECOG 2993 trial, 41 patients (5%), without an established translocation, had a complex karyotype with 5 or more chromosomal abnormalities. Four patients were primary induction failures and 19 of 37 CR patients relapsed. All but 3 of these 19 patients relapsed within 2 years of diagnosis and 17 of the 19 died. EFS and OS were significantly inferior in this group. These results established complex karyotype as a poor prognostic indicator.97

Adult Ph-positive patients achieve CR rates comparable to Ph-negative ALL patients, but the remissions are short and survival poor with standard therapy. The most frequent translocation in adults involving the MLL gene, located at chromosome band 11q23, is t(4;11) and is also associated with poor survival.94 The t(1;19) translocation results in the TCF3PBX gene rearrangement, and patients with this abnormality were found to have a 3-year disease-free survival rate of only 20%.92 Patients with hypodiploidy ranging from 30 to 39 chromosomes have a disease-free interval of only 2 to 4 months from the start of treatment.92

Deletions and translocations involving 12p include the ETV6-RUNX1 gene rearrangement. ETV6 gene rearrangements are much less frequent in adults than in children but are prognostically favorable in both. Translocations involving the TCR-α/β loci at chromosome 14q11 most frequently result in rearrangement with the TLX1 (HOX1) gene at 10q24.98 Adult ALL patients with t(10;14)(q24;q11) experience long survival, but this may reflect an association with T-cell ALL subtypes.65,92


The absence of chromosomal abnormalities does not preclude the less conspicuous presence of aberrantly expressed oncogenes that promote leukemogenesis. Oligonucleotide microarrays, and more recently, next-generation sequencing technologies have led to a revolution in analysis of the leukemia genome and will undoubtedly add to cytogenetic profiling in the risk stratification of ALL. These are discussed in detail in Chapter 72. Using oligonucleotide microarrays, Ferrando et al. identified T-cell oncogenes—TLX1, TLX3, TAL1, and LYL1—that may have prognostic relevance in T-cell ALL.99 These genes normally function as a homeobox gene (TLX1) or encode developmentally essential transcription factors (TAL1, LYL1) in normal thymocyte maturation. Their dysregulated expression is thought to foster leukemogenicity and can be detected as a signature genetic profile, which not only has the ability to provide insight into their pathogenetic heterogeneity, but also render important prognostic information. Overexpression of TLX1, present in approximately 30% of adult T-ALL cases, has been associated with a favorable prognosis, and in one study, demonstrated a leukemia-specific survival rate of 88% in TLX1-positive patients compared with 56% in TLX1-negative patients at a median follow-up of 4.7 years.100 In contrast, the overexpression of TAL1 or LYL1 has been linked to poor response to treatment, and the predictive value of TLX3, another homeobox factor related to TLX1, is conflicting.101,102

Another mechanism for ALL leukemogenesis is the constitutive activation of tyrosine kinase via the NUP214-ABL1 fusion episome. The juxtaposition of the two oncogenes leads to the familiar amplification of ABL1 on the chromosome band 9q34. However, the NUP214-ABL1 fusion escapes detection by conventional cytogenetics by virtue of its extrachromosomal position and requires molecular analysis for delineation. The fusion episome has been detected in approximately 6% of individuals with T-ALL.103 Because of its sensitivity to abl tyrosine kinase inhibitors, the subset of T-ALL patients with this molecular feature is predicted to benefit from early identification.104 The known presence of TLX1 or TLX3 may also merit exploration for the NUP214-ABL1 fusion given their tendency for co-expression.105

Response to Therapy

Response to therapy can be assessed by determination of time to attainment of CR, quantitation of early leukemic blast clearance, or detection of MRD. These measurements provide a direct assessment of biologic susceptibility to antileukemic agents, and, as such, prognostic factors based on them have inherently high heuristic power. In addition, prospective evaluation of their utility as predictors of outcome in clinical trials has established that they also have high explanatory power. However, until recently, virtually all of the clinical studies measuring these outcomes have been performed in pediatric ALL. Assessments of response to therapy have become crucial prognostic factors in adult ALL, but remain underutilized in clinical practice. These should aid in refining prognostic models with the goal of improving outcome with ris-kadapted therapy.

Early Complete Remission

Failure to achieve CR within 4 weeks of starting treatment or after one course of induction chemotherapy has been considered an independent unfavorable prognostic factor, confirmed in most adult ALL studies.7,73 An exception is the international, multicenter UKALL XII/ECOG E2993 trial, which could not confirm its importance in its 1,500 patient cohort.61 When significant, early CR held predictive value for standard ALL programs as well as for newer, dose-intensified treatment protocols.5,67,78,106,107,108 Patients requiring greater than 4 weeks to achieve CR were at least twice as likely to relapse, depending on the study. In one study, patients who did not achieve CR by week 4 of induction had a 5-year disease-free survival of 0% as compared with 46% for the remainder of the complete responders.78 In this study, the number of weeks required to achieve CR was only marginally worse than the Ph chromosome as an unfavorable variable.

Early Leukemic Blast Clearance

Evaluation for persistence of leukemic blasts at even earlier time-points, between days 7 and 21 of induction, has been firmly established as an important prognostic indicator for outcome in pediatric ALL.109, 110 and 111 Early persistence of leukemic blasts at 7 days after starting induction is thought to represent corticosteroid resistance.112 In contrast, persistence at time-points after 21 days is considered a reflection of cytotoxic chemotherapy resistance. Numerous prospective studies in pediatric ALL have shown that a substantial unfavorable influence on outcome is associated with the morphologic detection of blood or marrow leukemic blasts persisting during induction therapy at day 7, day 21, or at other time-points in between. Persistence of leukemia was usually defined as the finding of greater than 1 × 109/L blast cells in a peripheral blood sample or leukemic blasts greater than 5% of normal cells in a marrow specimen.

Although pediatric protocols already incorporate early treatment response assessment by a day 7 or day 14 bone marrow examination into risk classification, similar data in adult ALL are limited.113 Results from the few reported studies agree with findings from the pediatric experience. Sebban et al. prospectively evaluated persistence of marrow blasts, defined as greater than 5% of nucleated cells, at day 15 of induction for influence on outcome.107 Among 437 adult ALL patients, one third were found
to have persistent blast cells. These patients were less likely to achieve CR after 4 weeks of therapy. Even among only the patients who achieved CR within 4 weeks, an otherwise favorable feature, those who had persistent blasts at day 15 fared significantly worse. Among all complete remitters, the 5-year disease-free survival was 34% for those who cleared marrow blasts at day 15, compared with 19% for those who did not. Annino et al. and the Italian collaborative study group evaluated the early corticosteroid response by giving a 7-day course of prednisone immediately before induction.9 The pre-induction response was previously shown to have strong prognostic value in pediatric ALL.114,115 In the adult ALL study, prednisone response was defined by reduction of peripheral blood blasts to less than or equal to 1 × 109/L. Lack of a prednisone response was found to affect overall survival negatively, as it did in the pediatric ALL studies, and, among CR patients, it also adversely influenced remission duration.

Minimal Residual Disease

MRD refers to the post-remission persistence of leukemia that cannot be detected by histomorphologic assessment. Immunophenotypic, cytogenetic, or molecular techniques can be used to detect MRD.116 Samples from peripheral blood are generally one log10 less sensitive than bone marrow, perhaps as post-treatment BCR-ABL transcripts from peripheral blood clear more rapidly,117 but may have comparable sensitivity in T-lineage ALL.118,119,120 Fluorescence in situ hybridization is better than conventional banding analysis for detecting chromosomal translocations and numerical abnormalities, but both techniques are limited by low sensitivity.121, 122, 123 and 124 Flow cytometry, used in four or more color combinations and taking advantage of new reagents, detects aberrant antigen expression on leukemic cells and can unambiguously distinguish one leukemic blast among more than 104 normal cells in 90% of all patients.125,126 This level of sensitivity is sufficient for prognostically significant MRD detection.127 Additionally, flow cytometry is rapid, reliable, and allows accurate quantitation, and the technical requirements for the assay are already in place at most centers, making it an attractive diagnostic tool. The most sensitive assays for detecting MRD, however, are based on PCR techniques, which can detect one leukemic blast in up to 106 normal cells. PCR targets using fusion gene transcripts such as BCR-ABL, ETV6-RUNX1, AFF1MLL, and E2A-PBX are relatively standardized, but each alone can only be used for patient subsets.128, 129 and 130 PCR targets based on immunoglobulin and T-cell receptor gene rearrangements can be used to detect MRD in theoretically all patients, but lose sensitivity if consensus rather than patient-specific primers are used.128,131 On the other hand, generating patient allele-specific primers requires DNA sequencing capability. Although a number of clinical studies have suggested the prognostic significance of threshold values of MRD,132,133 early experience with accurate quantitation of leukemia-specific residual disease with the PCR assay was fraught with technical challenges, and standardization of assay sensitivity among testing facilities was of major concern.130 Where available, however, real-time quantitative PCR technology utilizing newer automated methods has proven to be technically simple, yielding precise and consistent quantitation of residual leukemic clones, and is gaining widespread acceptance.134,135 Information from pediatric ALL trials using PCR and flow cytometry in tandem may help determine more definitively the role of each for evaluating MRD.136

The prognostic utility of MRD detection was first described in studies conducted on children with ALL.109,128,137 Three of the pediatric studies stand out for having large patient numbers, inclusion of both B- and T-lineage ALL, and for including patients with poor risk features.127,132,133 The European studies were multicentered and used PCR detection of patient-specific antigen receptor gene rearrangement, whereas Coustan-Smith et al. used multicolor flow cytometry in an unselected patient cohort treated at the St. Jude Children’s Research Hospital. MRD was determined at the end of induction and at various time-points thereafter. The testing was technically challenging, as 1,254 of 1,914 (66%) combined patients treated during the study period did not have suitable PCR targets, serial PCR performed, or an immunophenotype suitable for MRD assessment. Nonetheless, all three studies demonstrated an unfavorable influence of persistent MRD on relapse-free survival. By multivariate analyses in the St. Jude study, sequential detection of persistent MRD remained a poor prognostic marker after controlling for age, WBC count, and adverse cytogenetics including the Ph chromosome and MLL gene rearrangement.127 Detection of MRD during maintenance therapy tended to have the strongest positive predictive value for relapse. Conversely, absence of MRD at the end of induction negated the unfavorable influence of persistent leukemic blasts at day 7 as a prognostic factor.

Studies assessing the predictive value of MRD in adult ALL have generally echoed findings of pediatric studies.138, 139 and 140 Mortuza et al. reported results for 66 Ph-negative adult B-lineage ALL patients treated at a single institution, for whom MRD was assessed with PCR using consensus immunoglobulin heavy chain gene primers.138 Detection of residual leukemia at the 10-3 level, the limit of sensitivity of the assay, independently correlated with inferior disease-free survival when measured 3 to 5 months after induction therapy. The kinetics of MRD clearance has also gained much attention with respect to predicting relapse risk. Among the 196 standard-risk ALL patients monitored by quantitative PCR during their first year of treatment in the German Multicenter Acute Lymphoblastic Leukemia (GMALL) study, the 3-year relapse rate was 0% if MRD declined rapidly to lower than 10-4 at day 11, or below detection threshold at day 24, compared with a relapse rate of 94% if the MRD was at a level of 10-4 or higher until week 16.141 Based on these results, they defined three risk groups based on MRD assessment in this otherwise homogeneous standard risk group. Scheuring et al. suggested that the magnitude and rate of BCR-ABL increase, as well as the absolute number of transcripts, could predict relapse within 2 months.142 Another large cooperative group study reported that a 2-log reduction of MRD after induction, and a greater than 3-log reduction after consolidation therapy were associated with a 2-year actuarial probability of overall, disease-free, and relapse-free survival of 48%, 27%, and 38%, respectively, compared with 0% survival with smaller reductions.143 The increasingly recognized prognostic significance of MRD has prompted a large cooperative group study to evaluate prospectively the utility of MRD in selecting patients for stem cell transplantation in first CR as a model for risk-adapted treatment strategy.144


Current management strategies for adult patients with ALL require a careful assessment of relapse risk at the time treatment is initiated. Most adult ALL patients have the precursor B-cell or T-cell subtype and can be managed with established treatment programs that start with remission induction, followed by blocks of intensification, CNS relapse prophylaxis, and prolonged maintenance therapy. With modern multiagent regimens, up to 90% of patients achieve CR, and 25% to 40% can be cured. The disease-free survival figure obviously needs improvement, and, hence, therapy should be tailored for patients who have an adverse prognostic profile. Risk-adapted therapy has proven remarkably effective for certain poor-risk groups, such as brief dose-intensive protocols for adult patients with Burkitt leukemia. Other patient groups known to have high risk for disease relapse should undergo allogeneic stem cell transplantation
(SCT) in first remission, given an available donor and eligibility status. Considerable clinical data suggest that this strategy has been effective, particularly with Ph+ patients. The ECOG/MRCXII trial also demonstrated the benefit of transplant in standard risk patients under age 50. Elderly ALL patients pose special treatment considerations that are discussed in this chapter. General issues relating to supportive care of the patient with leukemia are discussed in Chapter 69.

General Principles

On presentation, certain pre-treatment considerations should be addressed before initiating therapy. Leukemia therapy is guided by an estimate of relapse risk, although there is no formal risk assessment tool for adult ALL. In reviewing the list of agents used to induce remission and protect against relapse, it can be appreciated that the individual superiority of one drug over another in many instances has not been established. Complicating management decisions are similarly conflicting outcome results for SCT in first remission for high-risk patients, although the general consensus is that allogeneic SCT from a sibling donor is best therapy.

Pre-treatment Considerations

Attention should be paid to metabolic, infectious, and hematologic issues before starting leukemia-specific therapy. Hyperuricemia, hyperphosphatemia, and secondary hypocalcemia may be pronounced with high leukemic cell burden and require intravenous hydration, alkalinization, and administration of allopurinol. In addition to myelosuppression during intensive treatment blocks, ALL therapy suppresses cell-mediated immunity, and some protocols have provisions for prophylaxis against herpes simplex virus and Pneumocystis jiroveci infections.106 The clinical consequences of hyperleukocytosis (≥100 × 109/L) in adult ALL patients are not well understood. Patients with MLL gene rearrangements and Burkitt leukemia are at higher risk for hyperleukocytosis at presentation.60 In children, pronounced hyperleukocytosis involving lymphoid blasts are better tolerated than myeloid blasts, as reflected by fewer complications attributable to leukostasis or hemorrhage.145 In one series, leukapheresis for pediatric ALL patients having blast counts greater than or equal to 2 × 109/L led to outcomes equivalent to those for children who did not have this degree of hyperleukocytosis.146 A similar policy is reasonable for adult ALL patients. Alternatively, immediate administration of prednisone or vincristine can rapidly reduce the circulating blast count. In an adult series, the WBC count dropped from greater than 100 × 109/L to less than 1 × 109 in 39% of patients given a 7-day course of prednisone immediately preceding remission induction chemotherapy.9

Risk Assessment Model

There are no useful clinical staging or prognostic scoring systems for adult ALL patients as there are for other hematologic malignancies, and there are no agreed-on uniform risk criteria as there are for pediatric ALL.147, 148, 149, 150 and 151 A prognostic model based on CALGB data suggested an additive effect of multiple adverse prognostic features on outcome, and, conversely, those without any poor prognostic factors did exceptionally well with few relapses.7 Others have described similar analyses.66,78 Based on these models and the current clinical evidence, a general framework for risk assessment may consider placing adults with ALL in different risk prognostic categories (Fig. 74.3). All patients with at least one established poor prognosis factor based on clinical, immunophenotypic, cytogenetic, or molecular features and response to induction therapy should be considered at high risk for relapse. Adding response to therapy, based on MRD detection, as a risk criterion for adapting therapy has been validated in several adult studies. In two consecutive GMALL trials (GMALL 06/99 and 07/03) involving 1,648 patients, prospective MRD evaluation was used at several time-points. MRD absence after consolidation therapy was highly predictive of continuous complete remission after 5 years (74% vs. 35%) as well as OS (80% vs. 42%). A multivariate analysis of prognostic factors, including age, immunophenotype, risk group, and MRD status after consolidation, found that only the MRD status was predictive of CCR after 5 years with a hazard ratio of 4.5 (P < 0.0001). Both age, with a hazard ratio of 1.3 (P = 0.0007), and MRD status, with a hazard ratio of 4.0 (P < 0.0001), influenced overall survival.62

In addition, patients with persistent MRD undergoing HSCT in first CR experienced higher rates of CCR than those without HSCT (66% vs. 11%), which led to better survival (54% vs. 32%). The Northern Italian Study Group also reported an advantage for patients positive for MRD treated with HSCT (n = 36) compared with non-HSCT (n = 18) with approximately 50% compared with 10% long-term disease-free survival.152

Remission Induction

The goal of remission induction therapy is hematologic complete remission (CR), as defined by the eradication of morphologically detectable leukemia cells in blood and bone marrow and the return of normal hematopoiesis. The importance of achieving CR after induction was highlighted in a study that demonstrated a 5-year overall survival rate of 45% in CR patients compared with 5% in patients who did not achieve CR.61 Remission induction chemotherapy for adults with ALL is most commonly built around a backbone of vincristine and prednisone. Remission induction with these two drugs in combination produces CR in approximately one half of patients with de novo ALL. The CR rate improves to 70% to 85% when an anthracycline is added, which was proven in a landmark CALGB trial to be superior to vincristine and prednisone alone.153 Induction failures are evenly divided between refractory disease and toxicity-related mortality.5,7,9,66,78 The efficacy of various anthracyclines in adults, including daunorubicin, doxorubicin, zorubicin, and mitoxantrone, has been similar.77,154, 155 and 156

Many alterations to the basic induction regimen have been evaluated.82,157, 158, 159 and 160 A critical evaluation of the individual merits of these modifications is challenging. Improvement to CR rates that already exceed 80% would be difficult to detect at a satisfactory level of significance. Modern treatment protocols are complex, and it is difficult to attribute outcome results to any one component or to make comparisons of significant findings between any two trials. For example, some modern induction protocols also incorporate L-asparaginase, cyclophosphamide, or both, although neither has been proven by controlled trials to be beneficial in adult ALL when added to standard three-drug induction regimens. The one randomized trial with L-asparaginase found no improvement in frequency or duration of CR with the addition of L-asparaginase to doxorubicin, vincristine, and prednisone during induction.161 Nonetheless, L-asparaginase has a mechanism of action that is close to being ALL-specific, causes minimal myelosuppression, and has been shown to be efficacious in pediatric ALL.162 An Italian Gruppo Italiano Malattie Ematologiche dell’ Adulto (GIMEMA) trial randomized adult ALL patients to induction with daunorubicin, vincristine, prednisone, and L-asparaginase with or without cyclophosphamide.9 The rate and durability of remission, as well as overall survival, did not differ between the two randomized treatment groups or for any subtype analyzed. In contrast, other studies have suggested a benefit with the inclusion of cyclophosphamide during induction, especially for patients with T-cell ALL, and, conversely, worse outcome with its omission.7,163

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Oct 21, 2016 | Posted by in HEMATOLOGY | Comments Off on Acute Lymphoblastic Leukemia in Adults

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