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1518 Part XI: Malignant Lymphoid Diseases Chapter 91: Acute Lymphoblastic Leukemia 1519

stem cell transplantation is feasible and beneficial for adults with Phila- Marrow relapse, with or without extramedullary involvement,
delphia chromosome–positive ALL who achieve a molecular remission portends a poor outcome for most patients. 231,232 Factors indicating
after combined chemotherapy and imatinib. 208,209 an especially poor prognosis include relapse while on therapy or
Targeted Therapies The best example of targeted therapy is the after a short initial remission, T-cell immunophenotype, the pres-
use of the tyrosine kinase inhibitors imatinib or dasatinib in Philadel- ence of the Philadelphia chromosome, and an isolated hematologic
phia chromosome–positive ALL. 21,113,114,210 Used as single agents or with relapse. 232–234 Prolonged second remissions (>3 years) can be achieved
a glucocorticoid, they can induce complete remission in older patients with chemotherapy in as many as half of patients with late relapses
where this subset of ALL is more common. 114,210,211 In combination with (i.e., >6 months after cessation of therapy) but in only approximately
chemotherapy, they not only induce a higher complete remission rate 10 percent of those with early relapse. The persistence of minimal
but also a high rate of molecular remission in children and adults. 200,201,212–216 residual disease after reinduction treatment also portends a very poor
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The duration of these remissions is uncertain, but some have been quite prognosis. In patients who develop hematologic relapse while on
long after additional chemotherapy. Although the need for early trans- therapy or shortly thereafter, and in those with residual disease after
plantation in childhood cases is uncertain, this treatment modality is remission induction for relapse, allogeneic hematopoietic stem cell
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still a standard for adult cases. 206,217 The use of imatinib or dasatinib transplantation is the treatment of choice. Autologous transplanta-
yields a higher proportion of adult cases suitable for transplantation. tion as postinduction treatment offers no substantial advantage over
The outcome depends on minimal residual disease before and after chemotherapy. 190,192,237 For patients without histocompatible related
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transplantation. In patients with residual disease after transplantation, donors, transplantation of stem cells from cord blood or marrow
rapid response to imatinib was associated with a superior survival. from matched unrelated donors is recommended. 201,238–241 For patients
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It is uncertain whether and when to discontinue imatinib or dasatinib with ALL that has relapsed after allogeneic transplantation, a second
after the patient is treated with chemotherapy or transplantation. transplant or donor T-lymphocyte infusion occasionally results in
Surface expression of CD20 by leukemia cells is associated with sustained remission. 242
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an inferior outcome in adult, but not childhood, ALL. Chemo-
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therapy trials incorporating rituximab, an anti-CD20 antibody, have Central Nervous System Relapse
yielded promising results in adults with CD20-positive B-cell precursor Although extramedullary relapse is frequently an isolated clinical finding,
ALL. 150,222 Other monoclonal antibodies that bind CD22 and CD19 are many occurrences are associated with recurrent disease detectable in the
in late-stage clinical development. Nelarabine is an approved antime- marrow. CNS relapses are associated with higher level of minimal residual
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tabolite drug that has shown considerable activity in T-cell ALL, both disease in the marrow than testicular relapses. Submicroscopic marrow
243
alone and in combination with other chemotherapy. 224–226 involvement at a level of 10 or higher at the time of overt extramedullary
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relapse confers a very poor outcome. Hence, patients with extramedul-
243
COURSE AND PROGNOSIS lary relapse and detectable disease in marrow require intensive systemic
treatment to prevent subsequent hematologic relapse. The efficacy of sal-
RELAPSE vage therapy in children with an isolated CNS relapse depends partly on
Relapse is defined as the reappearance of leukemia cells at any site in the duration of first complete remission and partly on whether CNS irradia-
body. Most relapses occur during treatment or within the first 2 years tion was previously performed. The strategy of delaying cranial or crani-
after its completion, although initial relapses have been observed 10 or ospinal irradiation for 6 to 12 months to allow initial intensification with
more years after diagnosis. Molecular studies suggest that in some systemic chemotherapy has yielded long-term second EFS of 70 to 80 per-
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cases, especially those with the ETV6-RUNX1 fusion, subsequent muta- cent in children with isolated CNS relapse. 244,245 In one study, 12 months
tions of the residual preleukemic clone that were not eradicated during of intensive systemic chemotherapy and reduced-dose cranial irradiation
initial treatment account for the “late relapse.” The marrow remains the (18 Gy) resulted in an excellent 4-year EFS rate among children with pre-
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most common site of relapse in ALL. Anemia, leukocytosis or leukopenia, cursor B-cell ALL who had not received cranial irradiation during initial
thrombocytopenia, enlargement of the liver or spleen, bone pain, fever, or treatment and who had an initial remission duration of 18 months or
246
a sudden decrease in tolerance to continuation chemotherapy may signal more. Notably, in this study, a favorable age group of 1 to 9.9 years plus
9
the onset of marrow relapse. In contemporary treatment programs for a low presenting leukocyte count (<50 × 10 /L) at diagnosis of ALL was
childhood ALL, the rates of CNS and testicular relapse have decreased an independent favorable prognostic factor. For patients, especially those
to 3 percent or less. 190,192 Leukemic relapse occasionally occurs at other with T-cell ALL, in whom relapse develops during therapy and who had
extramedullary sites, including the eye, ear, ovary, uterus, bone, muscle, previously undergone cranial irradiation, the remission rate generally does
tonsil, kidney, mediastinum, pleura, and paranasal sinus. not exceed 30 percent. 244,245 Adults with isolated CNS relapse fare much
For ALL patients who have received a modern, intensive multi- more poorly than children. However, the recommended treatment strat-
agent treatment regimen, with delayed intensification and prolonged egy remains the same–combining CNS-directed treatment with additional
continuation therapy, a relapse of disease portends a very poor survival. systemic chemotherapy.
Although some individuals can be rescued with additional chemother-
apy alone, in general, only allogeneic hematopoietic stem cell transplan- Testicular Relapse
tation offers a reasonable chance for cure and long-term survival. Thus, One-third of patients with early testicular relapse and two-thirds of
treatment for relapse is often considered as “a bridge to transplant.” Two patients with late testicular recurrence became long-term survivors
new drugs, clofarabine and liposomal vincristine, were approved as sin- after salvage chemotherapy and testicular irradiation. 232,247,248 In one
gle agents in large part based upon their ability to enable patients with study, some patients with late isolated testicular relapses were suc-
relapsed ALL to proceed to a transplant. 229,230 Because the outcome of cessfully treated with chemotherapy that included very high-dose
249
allogeneic transplantation is poor in the presence of overt ALL, reinduc- methotrexate, without the addition of radiation therapy. The optimal
tion therapy aims for rapid cytoreduction of lymphoblasts while efforts treatment and prognosis for patients with relapse at unusual extramed-
proceed concurrently to identify an HLA-matched donor. The optimal ullary sites are unclear. However, the same principles that apply to the
pretransplant conditioning regimen then depends largely on the age clinical management of CNS or testicular relapse probably apply to this
and medical condition of the patient. subgroup.

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