Page 1426 - Williams Hematology ( PDFDrive )

1400 Part X: Malignant Myeloid Diseases Chapter 88: Acute Myelogenous Leukemia 1401

new remission upon withdrawal of immune suppression. Patients who patients who relapse more than 1 year after the first remission, the orig-
enter remission by donor lymphocyte infusion or cessation of immu- inal remission-induction regimen can be readministered or a combi-
nosuppressive agents have a better survival than those who entered nation salvage chemotherapy regimen can be administered. At relapse,
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remission with chemotherapy alone or after a second transplantation. cell lineage trees suggest that the leukemic cell sustaining the relapse
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Unrelated donor-leukocyte infusions can be used to treat relapsed leu- resembles the leukemic stem cell of origin. When primary tumor
760
kemia after unrelated donor stem cell transplantation. Approximately and relapse genomes are compared, two primary patterns of relapse are
40 percent of AML patients enter remission with this treatment. G-CSF discerned: gain of mutations in a founding clone that evolved into the
has been used as an alternative to donor leukocyte infusions after AML relapse clone or a subclone of the founding clone that survived induc-
relapse posttransplantation. Donor blood stem cells can be combined tion, gained mutations, and gained ascendancy to become the dominant
761
with chemotherapy for early relapse of AML after allogeneic stem cell clone at relapse. 771
762
transplantation. Strategies with donor leukocyte infusions are antici- Refractory leukemia is defined as leukemia that does not respond
pated to become more effective once the effector cells are identified and to initial induction chemotherapy with cytarabine and an anthracy-
the tumor target antigens better understood. 763 cline antibiotic or anthraquinone. Patients with refractory disease are
Other Modalities to Decrease or Treat Relapse after more likely to have disease with adverse cytogenetic findings, a history
Transplant. Killer-cell immunoglobulin-like receptor (KIR) genes of antecedent clonal myeloid disease, adverse immunophenotypic fea-
among HLA-matched potential donors can point to donors with donor tures, and expression of MDR. 772
764
KIR genotype that are associated with enhanced disease-free survival. Relapsed leukemia is leukemia that recurs following a remission.
Early cytomegalovirus replication after transplantation is also associ- The duration of remission greatly affects the patient’s prognosis and
ated with decreased relapse risk, possibly because of a virus-versus- response to additional treatment. The wide range of response rates
leukemia effect in AML. Hypomethylating agents have been used for may not only reflect the regimen used but may also reflect variability in
765
the treatment of relapse after allogeneic transplantation with some suc- patient selection, age, and other prognostic factors. 772,773
cess and with induction of T-regulatory cells. 766,767 Extramedullary sites Chemotherapy regimens can be divided into cytarabine-based,
of relapse are more common after transplant. 767 noncytarabine-based, and timed sequential therapy with growth factors
Recurrent Leukemia in Donor Cells or New Leukemia in Recip- and cytotoxic drugs. Table 88–6 lists regimens and their response rates;
ient Cells Recurrence of AML in donor cells has been reported in the duration of response usually is measured in months, and, therefore,
patients who received transplants from healthy siblings. These recur- clinical trials are also recommended for this patient group. The duration
rences in donor cells occurred in approximately one in 18 relapsed of response is difficult to define because many patients go on to other
patients who received marrow from a donor of the opposite sex. A therapies, including allogeneic stem cell transplantation.
768
similar frequency of relapsed AML is observed in recipient cells but In a large patient cohort treated on successive Medical Research
with a different clonal cytogenetic abnormality, suggesting a “new” Council trials, of those patients who relapsed after first remission,
768
leukemia. The frequencies are dependent on the sensitivity and spec- 55 percent entered a second remission. For those with favorable cyto-
ificity of cytogenetic techniques, which have been challenged. AML genetics, 5-year survival was 32 percent; for those with intermediate
developing in a stem cell recipient but of donor cell origin long after cytogenetics, 5-year survival was 17 percent; and for those with adverse
transplantation has been documented in rare cases. 768,769 cytogenetic patterns, 5-year survival was 7 percent. In those in a sec-
Summary of Postremission Therapy In younger patients with ond remission who underwent transplant, 42 as compared to 16 per-
favorable cytogenetics (CBF with no mutation of KIT) or with NPM1 cent survived 5 years. Results from therapy were better in younger
774
or double CEBPα mutations in the absence of a FLT3 mutation, there patients, and in those with longer first remissions, longer durations
is no advantage to do an allograft in first remission and four cycles of since last chemotherapy, and better general health. The probability of
high-dose cytarabine is appropriate treatment. Another option would a second remission is approximately 40 percent in younger (ages 15 to
be two cycles of high-dose cytarabine followed by autografting, an 60 years) and approximately 25 percent in older (ages 60 to 80 years)
approach often favored in Europe. In those with intermediate-risk cyto- patients, but the duration of remission is nearly always much shorter
genetics, an allograft should be considered as consolidation, and three than the first remission. An eventual fatal outcome is nearly certain
to four cycles of high-dose cytarabine could be offered if a transplant unless allogeneic HSC transplantation can be performed. Rare patients
donor cannot be found. Those with poor-risk cytogenetics or a FLT3- may have a third (or more) relapse followed by a remission when treated
ITD mutation should be considered for an allograft in first complete with cytotoxic drugs, but each remission is shorter than the preceding
remission. These recommendations may change as transplant mortality one and usually is measured in weeks. For those who have favorable or
improves and subclasses of the “normal” cytogenetics group are better normal karyotype, long second remission, and no previous stem cell
defined such that targeted agents might have an impact on relapse rates. transplantation, intensive chemotherapy can be useful. In one study,
775
After patients complete consolidation therapy, they are generally fol- 21 (approximately 17 percent) of 124 patients had a second remission
776
lowed with blood counts every 3 months for 2 years, and then every 3 to duration at least 2 months longer than the first remission. In patients
6 months for 5 years. Marrow examination is done to confirm continued in relapse treated with the sequential high-dose cytosine arabinoside
remission after consolidation is completed but is rarely pursued regu- and mitoxantrone (S-HAM) regimen, the duration of the first remis-
larly thereafter unless blood counts change. sion was the only factor associated with a successful outcome, and
unfavorable karyotype was the only factor related to duration of sur-
777
vival. Patients who relapse less than 1 year from remission should be
TREATMENT OF RELAPSED OR treated with investigational agents, whereas patients who relapse more
778
REFRACTORY PATIENTS than 1 year later may benefit from standard reinduction therapy. No
standard chemotherapy regimen provides a durable remission of AML
Chemotherapy patients who relapse (Table 88–7), 779–789 and all such patients should be
Patients who relapse after remission-induction and postinduction ther- considered for clinical trials if available. For patients not fit for intensive
apy have a decreased probability of entering a subsequent remission, salvage regimens, low-dose cytarabine, hypomethylating agents, or sup-
and the duration of any remission that occurs is usually shorter. In portive or palliative care can be offered.

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