Page 1058 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 59 Clinical Manifestations and Treatment of Acute Myeloid Leukemia 941

into a durable molecular (PCR-negative) response and maintain PCR
negativity throughout. For patients who are treated with an ATRA/
chemotherapy combination, common practice is to give another two
or three anthracycline-based cycles. Addition of ATO to a standard
consolidation has significantly improved EFS and disease-free survival
28
in a large randomized United States Intergroup study. For ATRA/
ATO-treated patients, the combination is continued throughout
consolidation. Following consolidation, maintenance therapy for 1
to 2 years with ATRA ± mercaptopurine and methotrexate has been
recommended. There is debate as to the benefit of maintenance and
it is very likely that the impact of maintenance on overall outcome
will change now that ATRA and ATO are a standard treatment for
lower risk patients during induction. High-dose ara-C and
mercaptopurine-methotrexate maintenance may not add benefit in
the context of optimal novel therapies using ATRA-ATO with or
without anthracyclines or GO. PCR testing is essential in the
follow-up of patients with APL. In no other leukemia, with the
possible exception of chronic myeloid leukemia and emerging in CBF A B
leukemias, does molecular testing play such a critical role and influ-
ences clinical decision-making processes. Patients who do not achieve Fig. 59.17 HYPERLEUKOCYTOSIS IN ACUTE MYELOID LEUKE-
a molecular response by the end of the consolidation (usually 3 MIA. The patient was a 23-year-old man who presented with several weeks
months into CR) have a poorer prognosis with a higher likelihood of abdominal pain, weight loss, and fatigue. He was found to have a marked
of relapse. Furthermore, these patients have a better survival with leukocytosis of 165,300/µL composed of mostly blasts ([A] and higher power
early intervention at the time of molecular rather than morphologic [B]), which were shown to be myeloblasts by flow immunophenotyping. The
relapse. Whereas no further monitoring may be necessary for molecu- patient developed some shortness of breath and hypoxia, and underwent two
lar responders with low-risk disease because of the very low relapse cycles of leukapheresis and hydroxyurea before induction. Molecular analysis
likelihood, monitoring should take place every 3 months for 2 years revealed the leukemia to have an FLT3-ITD mutation.
for patients with high-risk disease, those older than 60 years, and
patients for whom treatment delays occurred during consolidation.
Positive PCR test results should be confirmed by a second PCR test triggering inflammatory responses. It is therefore imperative that
within 1 to 4 weeks. If the repeat test results are negative, no further efforts be undertaken to reduce the blast burden as soon as possible.
action is necessary; however, close prospective monitoring should be Because red blood cell transfusions increase the viscosity of blood
applied. flow, they should be used judiciously or if possible avoided as long
ATO is effective therapy for patients with relapsed APL, including as the WBC remains high. Leukapheresis is a fast and effective
those with persistent PCR-positive disease. Morphologic remissions method for WBC reduction. Although it has an immediate effect in
are achieved in up to 90% and molecular remissions in 70% to 80% reducing early mortality, there has been no impact on survival.
of patients, respectively. Three-year survival rates are between 50% Leukapheresis does not affect cellular plugs that are already formed
and 70%. Addition of ATRA to ATO may provide little further in a vascular territory, nor does it abate inflammatory reactions in
benefit if ATRA was already part of the induction/consolidation, tissues infiltrated by blasts. Rapid administration of cytotoxic chemo-
which is the case most of the time. HSCT should follow achievement therapy with or without leukapheresis therefore plays an important
of a second remission. Autologous HSCT is recommended for role. The most effective drug is cytarabine. Hydroxyurea is an oral
patients who have again achieved a molecular response. For those alternative that is well tolerated and easy to administer. However,
whose PCR results remain positive despite ATO-based therapy, hydroxyurea does not effectively infiltrate tissues and thus may not
allogeneic HSCT is favored. CNS involvement at the time of relapse reach extravascular blast infiltrates. Care must be taken to avoid
is rare, so that there is no commonly agreed-upon strategy of CNS tumor lysis syndrome, using adequate hydration and uricosuric
prophylaxis. Whereas some groups such as the National Comprehen- agents, and to meticulously follow electrolyte levels and renal
sive Cancer Network advocate prophylactic intrathecal therapy for function.
patients in second morphologic remission, the Spanish PETHEMA
group showed that two independent risk factors for CNS disease are
a WBC >10,000/µL and occurrence of CNS hemorrhage during Myeloid Sarcoma
induction. Under those circumstances the incidence of CNS involve-
ment has been as high as 5.5%, but it was not higher than 1.2% at Myeloid sarcoma (granulocytic sarcoma, chloroma) is an extramedul-
5 years for the remainder of the patients. lary myeloid tumor composed of myeloid blasts. Myeloid sarcomas
can occur in any tissue but most commonly present in the skin
(leukemia cutis), lymph nodes, gastrointestinal tract, testes, CNS, soft
ADDITIONAL ISSUES IN ACUTE MYELOID LEUKEMIA tissue, and bones. They can easily be confused with lymphomas and
soft-tissue sarcomas. Myeloid sarcomas can be isolated, occur together
Hyperleukocytosis with marrow involvement, or precede it. In a few instances they may
be the relapse manifestation of patients who have been treated for
Hyperleukocytosis is often understood as a WBC >100,000/µL (Fig. AML in the past, particularly following allogeneic stem cell trans-
59.17), although this definition is not always followed very closely in plantation. In the context of chronic myeloid malignancies (e.g.,
clinical practice. It should be noted that lesser degrees of hyperleu- MDS, myeloproliferative neoplasms, chronic myeloid leukemia,
kocytosis can have grave consequences dependent on the biologic chronic myelomonocytic leukemia), their appearance represents
properties of the blasts. Myeloid blasts are less deformable than progression to a blast phase. Even when isolated, myeloid sarcoma
normal myeloid cells or even lymphoid blasts, and adhere to vessel should be treated systemically with chemotherapy, as for any other
walls and extramedullary tissues due to a complex array of adhesion AML. Radiation therapy may be of help to optimize local control in
molecules. Hyperleukocytosis is a medical emergency with a high challenging anatomic compartments. However, in the absence of
mortality rate, mainly due to pulmonary and CNS complications systemic therapy, subsequent progression to systemic AML is very
from bleeding (intravascular sludging, anatomic disruption of the likely. There is controversy over whether patients with myeloid
endothelium, DIC, or a combination) and direct tissue infiltration sarcoma do better or worse than those with AML. The majority of