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Chapter 66 Acute Lymphoblastic Leukemia in Adults 1037

MRD-positive patients to early intensification with aSCT to try to survival (DFS), and OS were similar in the two arms. Thomas and
improve survival for these patients at very HR for relapse. Recent colleagues randomized 236 ALL patients treated on the LALA-94
data from the ALL-SCT-BFM 2003 study showed that MRD can trial to receive G-CSF, GM-CSF, or no CSF. Use of G-CSF was
also be reliably assessed after aHSCT as a predictor for relapse. associated with a significant decrease in time to neutrophil recovery,
Further data from these studies will help elucidate the optimal timing duration of hospitalization, and infections that were grade 3 or
of MRD assessments and the appropriate management response. higher. Thus use of G-CSF can allow for faster hematopoietic recov-
ery, especially in older adult patients, and may decrease infectious
complications; however, the prophylactic use of G-CSF has not been
TREATMENT OF ACUTE LYMPHOBLASTIC LEUKEMIA uniformly adopted, and many studies simply follow standard guide-
lines for use of growth factors in the setting of neutropenic fever.
Combination chemotherapy is the cornerstone of ALL management. All patients should be monitored carefully for tumor lysis syn-
In the 1960s, investigators at the National Institutes of Health dromes, especially those with risk factors such as elevated WBC
designed multidrug chemotherapy regimens given over many differ- counts, renal dysfunction, and elevated LDH at presentation. Patients
ent courses for pediatric ALL patients. A similar approach was then must be provided adequate hydration and prophylaxis or treatment
introduced for adults with ALL. The Berlin–Frankfurt–Muenster for hyperuricemia with allopurinol for the first week of induction.
(BFM) group in the 1980s conducted pioneering studies and showed Rasburicase, a urate oxidase, can be considered for the treatment of
that an intensive multidrug induction and consolidation chemo- hyperuricemia in cases with high proliferation rates.
therapy followed by delayed intensification led to improvement in
survival in the majority of children. These regimens combine drugs
with varying mechanisms of action at different doses, often in REMISSION INDUCTION
complex schedules, which have largely evolved empirically. Only a
few of these drugs have been tested individually in randomized clini- The aim of induction therapy is to achieve maximal reduction of the
cal trials in adults with ALL; therefore, the relative contribution of leukemic burden to result in morphologic remission (<5% blasts with
each of the drugs in a multidrug regimen to the overall outcome is trilineage hematopoiesis) and normalization of the blood counts,
difficult to assess. Because there is an increased propensity for CNS with as little toxicity as possible. This is typically achieved using
involvement in ALL patients, all treatment regimens must also combination chemotherapy consisting of four or five systemically
include CNS prophylaxis with intrathecal chemotherapy with or administered drugs and intrathecal chemotherapy over a period of
without cranial radiation. approximately 3–4 weeks. Most current ALL induction regimens in
The therapy for ALL is typically divided into three phases: (1) the adults are modeled after pediatric regimens, and include a prolonged
remission induction phase, (2) remission consolidation or intensifica- course of oral corticosteroid (prednisone or dexamethasone), weekly
tion, and (3) the maintenance (or continuation) phase. The remission vincristine, and either weekly or pulsed anthracycline (doxorubicin,
induction and consolidation phases typically involve blocks of daunorubicin, or mitoxantrone). Many groups (CALGB, French
monthly treatment for 6–8 months followed by long-term mainte- Group for Research in Adult Acute Lymphoblastic Leukemia
nance, which is given for up to 3 years; thus the treatment of ALL is [GRAALL] 2003, and BFM) have also used twice-weekly
long and challenging, and requires tremendous attention to detail, L-asparaginase as part of induction therapy and some have added
compliance, and support. Because of these challenges and the relative cyclophosphamide (MD Anderson, GRAALL 2003, and GMALL
rarity and biologic heterogeneity of the disease, it is recommended 07/2003, CALGB 8811, and CALGB 19802). With the current
that patients are referred to larger academic centers for evaluation and treatment regimens, very high CR rates in adults with ALL have been
treatment to ensure the best possible survival rates. In the ensuing achieved in the range of 84% to 94% (Table 66.6). There have been
sections, the various components of treatment are reviewed. Special few randomized comparisons between these different induction regi-
attention to the treatment of certain disease subsets are addressed mens; therefore the choice of the regimen should depend on the
because treatment of ALL is becoming increasingly based on its treating physician’s experience with a particular regimen. Most ALL
heterogeneity and the ability to adapt therapy to each of these subsets. regimens are designed to optimally deliver a variety of chemothera-
Effective chemotherapy regimens must be supplemented with peutic agents; thus an entire treatment program should be selected at
adequate supportive care measures to obtain the best patient out- the time of diagnosis based on the patient’s performance status and
comes. Given the highly immunosuppressive nature of ALL treatment biologic risk factors. Whenever possible, these patients should be
regimens, prophylaxis for Pneumocystis carinii with trimethoprim– referred to centers that offer expertise in the treatment of ALL and
sulfamethoxazole should be initiated early during treatment and where enrollment into clinical trials is available. Once a specific
continue throughout the consolidation and maintenance phases of regimen has been selected, the goal (and challenge) is for both the
chemotherapy. It is also reasonable to consider antifungal and antiviral medical team and the patient to adhere to the recommended treat-
prophylaxis during periods of neutropenia. Consideration may be ments, which are arduous and lengthy in duration.
given to antibacterial prophylaxis during periods of neutropenia. Traditionally, prednisone was the corticosteroid of choice during
Fluoroquinolones such as levofloxacin are the preferred agent, induction therapy for ALL trials. Studies in pediatric patients have
although the optimal antibiotic choice should depend on local bacte- shown lower relapse rates but higher toxicity (more sepsis, higher
rial resistance patterns. Neutropenic fever in this group of patients incidence of osteonecrosis) with dexamethasone. Dexamethasone
must be treated as a medical emergency with immediate institution penetrates the blood–brain barrier effectively and therefore may offer
of intravenous (IV) antibiotics after obtaining the necessary more direct CNS protection than prednisone. Comparative studies
cultures. of prednisone versus dexamethasone have not been performed in
In an attempt to decrease the duration of neutropenia and improve adults, and some groups have incorporated prednisone (CALGB
remission rates, several groups have studied the role of granulocyte 10403, GRAALL 2003, and BFM); others have incorporated dexa-
colony-stimulating factor (G-CSF) or granulocyte-macrophage methasone (CALGB 10102, MD Anderson, and GMALL 07/2003)
colony-stimulating factor (GM-CSF) during induction therapy. In during the induction cycle. Anthracyclines form an important part
the CALGB 9111 trial, 198 adults with untreated ALL were random- of induction therapy. In an early trial from the CALGB (7612),
ized to receive G-CSF (beginning 4 days after the start of induction patients were randomized to receive vincristine, prednisone, and
until neutrophil recovery) versus placebo. The median time to neu- L-asparaginase with or without daunorubicin. Significant improve-
trophil recovery (≥1000/µL for 2 days) significantly shortened to 16 ments in CR rates and remission duration were noted with the
days in the G-CSF arm compared with 22 days in the placebo arm. addition of daunorubicin; anthracyclines have since become standard
The duration of hospitalization was also significantly shorter in the components of induction chemotherapy in adult and pediatric ALL.
G-CSF arm. There was a trend toward increased CR rate in the Different anthracyclines (doxorubicin, daunorubicin, and mitoxan-
G-CSF arm. However, the infectious complications, disease-free trone) are thought to be clinically equivalent and, to date, dose