Page 1178 - Hematology_ Basic Principles and Practice ( PDFDrive )

1026 Part VII Hematologic Malignancies

observation is consistent with the finding that T-lineage blast cells is undetectable prior to transplantation, and worsens with increasing
accumulate methotrexate polyglutamates less avidly than do B-lineage MRD levels at time of transplant. Whether CAR T-cell therapy can
blast cells. The increased ability of hyperdiploid ALL blasts cells to replace transplantation in selected patients will need to be tested in
accumulate methotrexate polyglutamate could partially explain the prospective clinical trials.
excellent outcome of children with hyperdiploid >50 ALL treated on Treatment approaches for adolescents and young adults with
regimens based on low-intensity antimetabolites. Leucovorin rescue ALL have evolved considerably with the widespread adoption
is necessary after treatment with high-dose methotrexate; however, of pediatric-based protocols that appears to have significantly
overzealous rescue might counteract the antileukemic activity of improved survival and decreased the need for transplantation in
methotrexate. While the intensive asparaginase and high-dose metho- this age group. The benefit of allogeneic transplantation in infants
trexate treatment has significantly improved the outcome for patients with t(4;11) ALL remains controversial, and should be evaluated in
with T-cell ALL, the emergence of specific therapy like the purine the context of emerging molecular therapies such as FLT3, DNA
nucleoside analog nelarabine will likely increase the tendency to methyltransferase, proteasome, and histone deacetylase inhibitors.
assign patients with T-cell ALL to a specific treatment protocol or Patients with the recently identified ETP ALL and Ph-like ALL may
stratum. benefit from molecularly targeted therapy that will improve their
About 10% of the population inherit one wild-type gene encoding outcome without relying on transplantation. Matched unrelated-
thiopurine methyltransferase (TPMT) and one nonfunctional variant donor or cord blood transplantation has yielded outcomes compa-
allele, resulting in intermediate enzyme activity, while 1 in 300 people rable to those obtained with matched related-donor transplantation,
inherit two nonfunctional variant alleles and are completely deficient and should be considered reasonable alternatives if a matched
of this enzyme that catalyzes the S-methylation of mercaptopurine donor is not available. Many advances have been made in stem
to its inactive metabolite. Patients with heterozygous and especially cell transplantation, such as prevention of graft-versus-host disease,
homozygous deficiency of TPMT are at high risk of severe myelosup- expansion of the pool of suitable unrelated or related donors,
pression. Patients with poor tolerance to antimetabolite treatment donor selection and tissue typing, acceleration of engraftment,
should be tested for TPMT genotype or activity for selective dose enhancement of the graft-versus-leukemia effect, and supportive
reduction of mercaptopurine. Recently, NUDT15 polymorphism care. Because improvements in transplantation tend to parallel
was found to account for the poor tolerance of Asian and to a those in chemotherapy, the indications for transplantation in newly
lesser degree Hispanic populations to mercaptopurine. Substituting diagnosed and relapsed patients should be re-evaluated periodically.
thioguanine for mercaptopurine during continuation therapy was For example, the presence of the Philadelphia chromosome is no
associated with a high incidence of profound thrombocytopenia and longer a clear indication for transplantation with the advent of ABL
hepatic venoocclusive disease. Thioguanine use has therefore been tyrosine kinase inhibitors.
limited to short pulses administered during consolidation therapy in
some trials, and some patients who develop mercaptopurine-induced
pancreatitis. ACUTE LYMPHOBLASTIC LEUKEMIA RELAPSE
As optimizing the administration of existing therapies is reaching
its limit, further improvements in outcome will require the develop- Most relapses occur during treatment or within the first 2 years after
ment of therapeutic approaches directed against rational therapeutic its completion, although relapses have been reported as late as 10
targets. The expanded understanding of the biologic, immunologic, years after initial ALL diagnosis. The most common site of relapse is
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and genetic heterogeneity of ALL has enabled development of several the BM. Relapse in extramedullary sites, such as the CNS and testes,
novel therapeutic strategies. Various monoclonal antibodies, bispecific has decreased to less than 3% and 1%, respectively. Leukemia relapse
T-cell engager antibody (blinatumomab), and autologous CD19 occasionally occurs at other sites, including the eye, ovary, uterus,
chimeric antigen receptor (CAR) T cells are showing promise in early bone, muscle, tonsil, kidney, mediastinum, pleura, and paranasal
clinical trials and may be incorporated into ALL regimens in the sinus. Extramedullary relapse in children with ALL frequently pre-
future. 22 sents as an isolated clinical finding. However, in studies that included
Autologous transplantation has failed to improve the outcome in the MRD assay, many extramedullary recurrences were associated
ALL. Comparisons between allogeneic hematopoietic cell transplan- with MRD in the BM. A small fraction of patients experience a
tation and intensive chemotherapy for high-risk patients have yielded recurrence of acute leukemia with an immunophenotype different
inconsistent results due to the small number of patients studied and from that determined at diagnosis. Some of the cases represent relapse
differences in case selection criteria. It is generally accepted that of original leukemic clones with a shift in immunophenotype, but
allogeneic transplantation is a treatment modality for patients with others are secondary malignancies caused by the mutagenic effects of
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ALL who are predicted to respond poorly to intensive chemotherapy. leukemia treatment, especially from epipodophyllotoxin. Patients
At present, patients with refractory leukemia (failure to enter mor- with isolated BM relapse generally fare worse than those with isolated
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phologic remission after 4 to 6 weeks of induction therapy), high extramedullary relapse or combined BM and extramedullary relapse.
level of MRD (>1%) after remission induction, persistent MRD after Factors indicating an especially poor prognosis are short initial remis-
consolidation treatment, and early hematologic relapse are candidates sion and T-cell immunophenotype. The presence of MRD at the end
for allogeneic transplantation. It is crucial to reduce residual disease of second remission induction is also a strong adverse prognostic
to, or close to, undetectable levels as the outcome is superior if MRD indicator. While chemotherapy may secure a prolonged second remis-
sion in children with ALL who experience late relapse (defined as
more than 6 months after cessation of therapy), allogeneic transplan-
tation is the treatment of choice for patients who experience
Dose Schedule
The biologically equivalent doses among the different formulations
of corticosteroids, thiopurines, and asparaginase are not clear. Trials
comparing such agents should be cautiously interpreted taking into Therapeutic Innovations Being Incorporated Into Contemporary
account the dose schedule and route of administration, and the effect Personalized ALL Therapy
of variability in the pharmacokinetic profile and potency among the
agents involved. Simple modification of dose, schedule, or route of 1. Targeting genetic alterations that drive high-risk Ph-like ALL with
administration may result in significant differences in efficacy and toxic- ABL tyrosine kinase inhibitors and JAK inhibitors
ity. Also, when comparing regimens containing high-dose intravenous 2. Immunotherapeutic approaches with bispecific T-cell engager
methotrexate, the dose schedule of leucovorin rescue should not be antibodies and chimeric antigen receptor (CAR) T cells
ignored as it plays a crucial role in modulating the activity and toxicity 3. Proteasome inhibitors
of methotrexate. 4. Histone deacetylase inhibitors