Page 1484 - Williams Hematology ( PDFDrive )

1458 Part X: Malignant Myeloid Diseases Chapter 89: Chronic Myelogenous Leukemia and Related Disorders 1459

Rising BCR-ABL1 levels may be associated with an ABL1 mutation will have the most utility for in vitro purging of CML marrow cells
or relapse of disease. Those with more than a twofold rise in BCR-ABL1 before autotransplantation. 616,617
596
are more likely to have a mutation. A serial rise in the BCR-ABL1 level
may also indicate loss of response to therapy. 415
RADIOTHERAPY
OTHER AGENTS USED IN TREATMENT OF Palliative splenic irradiation may be useful occasionally in subjects who
have entered the accelerated or advanced chronic phase and are trou-
CHRONIC PHASE bled with extreme splenomegaly with splenic pain, perisplenitis, and
Interferon-α encroachment of the spleen on the gastrointestinal tract. Splenic irra-
618
619
IFN-α, formerly the most effective agent, is rarely used in the treatment diation may palliate symptoms for a short time. Spleen size associated
of CML. A CCyR with IFN-α was uncommon (13 percent), but 10-year with chronic phase disease usually is decreased with TKI therapy.
597
survival rates in responders were approximately 70 percent. CCyRs to Palliative radiotherapy may be useful for extramedullary myeloid
IFN-α were stable and durable. Approximately 50 percent of complete sarcomas, which may occur occasionally in bone or soft tissue during
598
responders become long-term survivors. Common toxicities of IFN- the late chronic or accelerated phase.
α use include fatigue, low-grade fever, weight loss, liver function test
abnormalities, hematologic changes, and neuropsychiatric symptoms.
Overall survival is improved in imatinib-treated patients compared SPLENECTOMY
599
with patients treated with IFN-α or IFN-α plus cytarabine. Neverthe- Splenectomy does not prolong the chronic phase of CML, delay the
less, among all patients who attained a major or CCyR at 12 months, onset of the accelerated phase, enhance sensitivity to TKIs or chemo-
the survival rate was comparable in either case. IFN-α has also been therapy, or prolong survival of patients. In carefully selected patients
620
proposed as an immune stimulant to consolidate imatinib remissions with symptomatic thrombocytopenia unresponsive to therapy, mechan-
because additive effects have been noted. 600,601 Conversely, those treated ical discomfort, hypercatabolic symptoms, and portal hypertension,
initially with INF-α who achieve a CCyR have an improved molecular splenectomy may be useful. Postoperative morbidity from infection,
response with imatinib. 602,603 Some patients intolerant to a TKI may be thrombosis, or hemorrhage has been high, with mortality rates up to 10
treated successfully with INF-α. percent reported. Splenectomy performed before allografting has not
621
been found to influence the severity of graft-versus-host disease (GVHD)
Use of Other Chemotherapeutic Agents in Chronic Phase or survival after allogeneic hematopoietic stem cell transplantation. 622
Hydroxyurea The major side effect of hydroxyurea is an extension of
its pharmacologic effect, that is, reversible suppression of hematopoie-
sis, often with megaloblastic erythropoiesis. The median survival of TREATMENT OF CHRONIC PHASE CHRONIC
patients with CML treated with hydroxyurea alone is approximately 5 MYELOGENOUS LEUKEMIA DURING
years. Studies with high-dose hydroxyurea indicate that marrow meta-
phase cells in some patients lose the Ph chromosome either partially PREGNANCY
604
or completely after such therapy. Hydroxyurea often is used for ini- Treatment of chronic phase CML during pregnancy is sometimes needed
tial cytoreduction, but it has few other indications in the TKI era of to prevent placental insufficiency from hyperleukocytosis. Imatinib may
CML therapeutics. Chronic use of hydroxyurea is associated with leg be teratogenic. Normal newborns have been delivered by patients who
ulcers. 605 conceived and ingested imatinib during early pregnancy. 623–626 In 125
2
Cytarabine IFN-α combined with cytarabine (20 mg/m per women exposed to imatinib during pregnancy, 50 percent delivered
2b
day for 10 days per month) in the chronic phase was associated with normal infants, and 25 percent underwent elective terminations, three
a greater proportion of MCyRs at 12 months and with greater survival of the latter following the identification of fetal abnormalities. Twelve
606
627
prolongation than was IFN alone. Toxicities with these drug combi- other infants had abnormalities. The majority of patients who dis-
nations were greater, and this combination has been replaced by TKI continue imatinib during pregnancy lose their complete hematologic
628
therapy and is rarely used. remission and their cytogenetic responses. One fetal fatality during
Busulfan Once the mainstay of treatment for the chronic phase, pregnancy as a result of a meningocele has been reported. Males treated
629
607
busulfan usage now is rare. It is used primarily as part of the prepara- with imatinib have fathered healthy infants. Current recommenda-
tive regimen for allografting or autografting. It may be used occasionally tions are to practice contraception during treatment with any TKI, or,
in older patients who do not tolerate TKIs. if pregnant, at the onset of the disease, to consider IFN treatment until
Other Cytotoxic Agents Intensive multidrug regimens have been delivery. 626,630 Imatinib does appear in breast milk. 631
used in an attempt to eradicate the Ph chromosome–positive clone and, IFN can be used during pregnancy with minimum risk of terato-
occasionally, have led to prolongation of remission or cure of the dis- genicity. Eight patients treated with IFN from the first trimester have
ease. This approach did not significantly increase population survival. 608 been described, and each of these pregnancies resulted in normal infants,
Other Potential Therapeutic Agents in Chronic Phase Chronic except for one with mild neonatal thrombocytopenia. All infants had
632
Myelogenous Leukemia The farnesyltransferase inhibitors lonafarnib normal growth patterns. Hydroxyurea may be useful during the sec-
and tipifarnib have been combined with imatinib and have activity after ond and third trimester but should be avoided in the first trimester. 626,633
imatinib failure. 609,610 The hypomethylation agent decitabine has activity Leukapheresis in the first trimester (or longer) also can be used to
in imatinib refractory CML. INNO-406, a dual BCR-ABL/LYN inhibi- avoid fetal drug exposure early in pregnancy (see “Leukapheresis”
611
tor, suppresses the growth of CML cells in the central nervous system. above). It is important to use a TKI after delivery to achieve the best
MicroRNA approaches may eventually play a role in CML treatment, outcome. Further observation may show it to be safe later in pregnancy.
612
and synthetic BCR-ABL1 small interfering ribonucleic acid (siRNA) has Although controversial, stopping and later restarting TKI therapy may
been used in a patient with resistant CML, postallografting with inhi- not result in as favorable an outcome of therapy as use of IFN or other
613
bition of BCR-ABL1 noted. Ribozymes targeting BCR-ABL1 mRNA approaches, initially. If conception is desired, attaining a MMR before
626
have been used as CML treatment, 614,615 and these approaches probably the TKI therapy is discontinued and a 3-month washout period are

Kaushansky_chapter 89_p1437-1490.indd 1459 9/18/15 3:42 PM