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1040 Part VII Hematologic Malignancies

A B C
Fig. 66.7 CEREBROSPINAL FLUID AND CENTRAL NERVOUS SYSTEM DISEASE. Blasts in the
cerebrospinal fluid can be identified on a cytospin preparation. (A) They have similar cytologic features as the
blasts in the blood or bone marrow aspirate. Histologic section of the brain is illustrated from a patient with
acute lymphoblastic leukemia and leukemic meningitis. (B) The sections show blasts within the leptomeninges
(higher power, C).

approximately 30% to 50%, depending on risk factors and treatment the CNS prophylaxis is omitted. Now with the universal adoption of
approach. Notably, adults older than the age of 60 years have uni- CNS prophylaxis in the treatment regimens, the rates of CNS relapse
formly fared poorly with an OS below 10%. Table 66.6 summarizes have decreased substantially. CNS prophylaxis is typically adminis-
the major treatment questions, therapeutic approach, and results of tered by multiple rounds of intrathecal chemotherapy that are stag-
several of the recent large prospective cooperative group trials in the gered over the entire treatment duration. In addition, the use of
United States and Europe. high-dose methotrexate and cytarabine also provides for CNS pro-
phylaxis because both agents penetrate the blood–brain barrier. The
CENTRAL NERVOUS SYSTEM DISEASE: PROPHYLAXIS intensive use of high-dose systemic methotrexate and frequent intra-
thecal therapy has often replaced the more traditional combination
AND TREATMENT of CNS irradiation and intrathecal therapy that were the hallmarks
of the earlier ALL regimens. This non–radiation-containing approach
Involvement of the CNS (Fig. 66.7) is uncommon at the time of has resulted in effective CNS protection, with rates of CNS relapse
diagnosis, with most series reporting it at less than 10%. However, now routinely reported as occurring in fewer than 5% to 10% of
because many patients with CNS involvement may not be referred for cases. Adolescents and young adults (AYAs) treated on pediatric regi-
clinical trial enrollment, this may be an underestimate of the true rate. mens with more intensive CNS prophylaxis have reported CNS
In the MRC UKALL XII/ECOG E2993 trial, of the 1508 eligible relapse rates as low as 1%. The omission of cranial irradiation may
patients, 77 (5%) had CNS involvement at diagnosis. Similarly, the prevent neurocognitive damage in adults. Although this has not been
French group reported a 7% (104 out of 1493 patients) incidence of demonstrated in adult studies, definitive evidence from pediatric
CNS disease at diagnosis. Risk factors for CNS disease at diagnosis studies indicates that avoidance of cranial irradiation may prevent
have varied in different studies. In the French trial (LALA-87 and declines in cognitive function.
LALA-94), risk factors included mediastinal mass associated with
precursor T-cell immunophenotype, lymphadenopathy, higher
hemoglobin level, and absence of the Philadelphia chromosome. In MAINTENANCE THERAPY
the MRC trial, the risk factors included a higher WBC count, precur-
sor T-cell immunophenotype, and mediastinal mass. The presence of The goal of maintenance treatment is to prevent disease relapse by
CNS disease at diagnosis has been shown not to affect the CR rate. elimination of leukemia clones by long-term exposure to cytotoxic
The French group also reported no significant difference in the OS drugs. One of the commonly used regimens uses daily 6-mercaptopurine
in patients with and without CNS disease at diagnosis. However, in and weekly oral methotrexate with monthly vincristine and predni-
the MRC trial, the OS at 5 years was lower in the CNS disease group sone (POMP regimen). Some groups replaced prednisone with
(29% versus 38%; p = .03), and they also reported that patients with dexamethasone. The duration of maintenance treatment is generally
CNS disease at diagnosis were twice as likely to relapse in the CNS. 2–3 years (2 years for women and 3 years for men). Similar to the
In the French study, younger age (<30 years), male gender, absence other components of adult ALL regimens, the adoption of long-term
of the Ph chromosome, achievement of CR with one course, and use maintenance therapy is based upon the benefit of maintenance
of transplant as postremission therapy had favorable impact on OS therapy that has been demonstrated in pediatric trials.
for patients presenting with CNS disease at diagnosis. Although the benefit of maintenance therapy in adult trials has
Induction therapy of ALL usually includes lumbar punctures with not been demonstrated in randomized trials, it has been shown that
introduction of intrathecal chemotherapy during the first weeks of omission of maintenance treatment leads to worse clinical outcomes.
therapy. For those presenting with CNS disease at diagnosis or in In a CALGB study, 164 newly diagnosed ALL patients were random-
whom CNS disease develops later in the course of the treatment, ized to receive daunorubicin or mitoxantrone during induction fol-
immediate intensified CNS treatment is imperative. These patients lowed by four cycles of consolidation. No maintenance therapy was
should receive intrathecal chemotherapy (intrathecal methotrexate planned. There were significantly more relapses noted in this study,
alone or together with cytarabine and steroid [triple intrathecal with median remission duration of only 10–12 months. The study
therapy]) twice weekly until clearing of cerebrospinal fluid along with was stopped earlier than planned because remission duration was
initiation of systemic chemotherapy. Cranial irradiation (1800 cGy shorter than in historical control participants who had received
given in 10 daily fractions of 180 cGy per fraction) is considered maintenance therapy. Similar results were obtained by the Dutch–
necessary for the successful treatment of CNS disease with cranial Belgian Haemato-Oncology Cooperative Group (HOVON), which
nerve involvement. treated 130 ALL patients with induction followed by three cycles of
CNS prophylaxis is an essential component of therapy for all consolidation. No maintenance therapy was given. The estimated
patients given the high incidence (30% to 40%) of CNS relapse if 5-year OS and DFS were only 22% and 28%, respectively. Pediatric