Chapter 104. Acute and Chronic Myeloid Leukemia (Part 16) pptx

Chapter 104. Acute and Chronic
Myeloid Leukemia
(Part 16)

Interferon
Before imatinib, when allogeneic SCT was not feasible, IFN-α therapy was
the treatment of choice. Only longer follow-up of patients treated with imatinib
will prove whether IFN-α will still have a role in the treatment of CML. Its
mode(s) of action in CML is still unknown.
Chemotherapy
Initial management of patients with chemotherapy is currently reserved for
rapid lowering of WBCs, reduction of symptoms, and reversal of symptomatic
splenomegaly. Hydroxyurea, a ribonucleotide reductase inhibitor, induces rapid
disease control. The initial dose is 1–4 g/d; the dose should be halved with each
50% reduction of the leukocyte count. Unfortunately, cytogenetic remissions with
hydroxyurea are uncommon. Busulphan, an alkylating agent that acts on early
progenitor cells, has a more prolonged effect. However, we do not recommend its
use because of its serious side effects, which include unexpected, and occasionally
fatal, myelosuppression in 5–10% of patients; pulmonary, endocardial, and
marrow fibrosis; and an Addison-like wasting syndrome.
Autologous SCT
Autologous SCT could potentially cure CML if a means to select the
residual normal progenitors, which coexist with their malignant counterparts,
could be developed. As a source of autologous hematopoietic stem cells for
transplantation, blood offers certain advantages over marrow (e.g., faster
engraftment for the patient and no general anesthesia for the donor). Normal
hematopoietic stem cells appear with increased frequency in the blood of patients
with CML during the recovery phase after chemotherapy and G-CSF. A role for
imatinib before stem cell collection to achieve minimal residual disease and
following transplantation to maintain this status is currently being investigated.
Specifically, several groups store peripheral blood stem cells from patients in

major or complete molecular remissions. However, only a few cases have been
transplanted following imatinib therapy. Therefore, such approaches should be
performed only in clinical trials.
Leukapheresis and Splenectomy
Intensive leukapheresis may control the blood counts in chronic-phase
CML; however, it is expensive and cumbersome. It is useful in emergencies where
leukostasis-related complications such as pulmonary failure or cerebrovascular
accidents are likely. It may also have a role in the treatment of pregnant women in
whom it is important to avoid potentially teratogenic drugs.
Splenectomy was used in CML in the past because of the suggestion that
evolution to the acute phase might occur in the spleen. However, this does not
appear to be the case, and splenectomy is now reserved for symptomatic relief of
painful splenomegaly unresponsive to imatinib or chemotherapy, or for significant
anemia or thrombocytopenia associated with hypersplenism. Splenic radiation is
used rarely to reduce the size of the spleen.
Minimal Residual Disease
The kinetics of BCR/ABL transcript elimination are currently replacing
qualitative detection of the BCR/ABL message, in spite of a lack of standard
acceptable methodology. A consensus panel has proposed ways to harmonize the
different methods and to use a conversion factor so that individual laboratories
will be able to express BCR/ABL transcript levels on an agreed upon scale.
Slow reduction of BCR/ABL transcripts following SCT correlates with the
possibility of hematologic relapse. However, the definition of "slow reduction"
depends on the preparative regimen (reduced-intensity versus fully myeloablative)
and the selection of time-points to measure the transcript levels. While persistent
RT-PCR positivity at 6 months was regarded as an indication for additional
therapy in the past, current studies utilize periods between engraftment and day
100 for evaluating the clearance rate of BCR/ABL transcripts and recommending
additional therapies. Large trials with longer follow-up are needed to establish
consensus guidelines.

The randomized trial of imatinib versus IFN-α and cytarabine was the first
to establish the concept of log
10
reduction of BCR/ABL transcript from a
standardized baseline for untreated patients. This measurement unit was developed
instead of either the transcript numbers expressed per µg of leukocyte RNA or the
ratio of BCR/ABL to a housekeeping gene on a log scale. In this randomized trial,
patients who achieved ≥3 log reduction of BCR/ABL message had an extremely
low probability of relapse, with a median follow-up of 60 months. It is unclear
whether achieving complete molecular remission should still be the goal of
treatment in this disease.
These studies also established the value and convenience of using
peripheral blood instead of bone marrow testing as a means to assess disease status
in patients who achieve complete cytogenetic responses. However, one still needs
to consider following CML patients in complete cytogenetic remission and at least
major molecular remission with annual cytogenetic bone marrow testing, as these
patients are at risk of developing cytogenetic aberrations in t(9;22)-negative cells
and secondary MDS/AML. These aberrations in the t(9;22)-negative cells are
frequently transient, and their clinical significance is unclear. Such aberrations
may occur in 7–10% of imatinib-treated patients. Development of MDS/AML is
rare.
Treatment of Blast Crisis
Treatments for primary blast crisis, including imatinib, are generally
ineffective. Only 52% of patients treated with imatinib achieved hematologic
remission (21% complete hematologic remission), and the median overall survival
was 6.6 months. Patients who achieve complete hematologic remission or whose
disease returns to a second chronic phase should be considered for allogeneic
SCT. Other approaches include induction chemotherapy tailored to the phenotype
of the blast cell followed by imatinib, with or without additional chemotherapy
and SCT. Blast crisis following initial therapy with imatinib carries a dismal

prognosis even if treated with dasatinib or nilotinib.
Further Readings
AML
Frohling S et al: Genetics of myeloid malignancies: Pathogenetic and
clinical implications. J Clin Oncol 23:6285, 2005 [PMID: 16155011]
National Comprehensive Cancer Network: Acute myeloid leukemia.
Clinical Pra
ctice Guidelines in Oncology, Version 1. 2006.

Sanz MA et al: Tricks of the trade for the appropriate management of newly
diagnosed acute promyelocytic leukemia. Blood 105:3019, 2005 [PMID:
15604216]
Tallman MS et al: Drug therapy for acu
te myeloid leukemia. Blood
106:1154, 2005 [PMID: 15870183]
CML
Cortes J, Kantarjian H: New targeted approaches in chronic myeloid
leukemia. J Clin Oncol 23:6316, 2005 [PMID: 16155014]
Hughes TP et al: Monitoring CML patients responding to treatment wit
h
tyrosine kinase inhibitors. Review and recommendations for 'harmonizing' current
methodology for detecting BCR-
ABL transcripts and kinase domain mutations
and for expressing results. Blood 108:28, 2006 [PMID: 16522812]
National Comprehensive Cancer Net
work: Chronic myelogenous leukemia.
Clinical Practice Guidelines in Oncology, Version 1. 2007.