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1452 Part X: Malignant Myeloid Diseases Chapter 89: Chronic Myelogenous Leukemia and Related Disorders 1453

421
TABLE 89–3. Definition of a Treatment Response to a of patients had undetectable BCR-ABL1 blood levels. In one trial,
major molecular remission (MMR) at 12 and 24 months was higher in
Tyrosine Kinase Inhibitor
422
those receiving doses of imatinib greater than 600 mg/day. In another
Complete hematologic White cell count <10 × 10 /L, trial, patients receiving 400 mg twice per day had a MCyR of 90 and
9
response (CHR) platelet count <450 × 10 /L, no 96 percent at 12 and 18 months, respectively. MMR rates were 48 per-
9
immature myeloid cells in the cent and 54 percent at 6 and 12 months, respectively. These results
blood, and disappearance of all compared favorably to historical data in the IRIS (International Ran-
signs and symptoms related to domized Study of Interferon) trial studying 400 mg/day of imatinib, but
leukemia (including palpable
splenomegaly) lasting for at myelosuppression, rash, fatigue, and musculoskeletal symptoms were
least 4 weeks. greater with these higher doses. Responses were, also, more rapid with
the higher doses. More edema, gastrointestinal symptoms, rash, and
Minor cytogenetic response >35% of cell metaphases are myelosuppression occurred at the higher doses. Despite these reports
423
(mCyR) Philadelphia (Ph) chromo-
some–positive by cytogenetic the current starting dose is customarily 400 mg/day, balancing both
analysis of marrow cells. effectiveness and tolerability in newly diagnosed patients. Moreover, the
more rapid response with higher doses of imatinib may not translate
Partial cytogenetic response 1–35% of cell metaphases are into better long-term results. 424,425 For example, in another trial, MMR
(pCyR) Ph chromosome–positive by and CCyR at 12 months were not significantly different between stan-
cytogenetic analysis of marrow
cells. dard and high-dose patients, although patients in higher-risk catego-
ries based on Sokal scores, fared better with high-dose imatinib. (See
424
Major cytogenetic response <35% of cell metaphases con- “Course and Prognosis” below for an explanation of the Sokal Score.)
(MCyR) tain the Ph chromosome by Doses of imatinib lower than 400 mg/day result in fewer CCyR
cytogenetic analysis of marrow and a shorter duration of that response. Patients who are older and who
cells.
have lower body weight may only tolerate a lower dose, but they are
Complete cytogenetic response No cells containing the Ph chro- less likely to achieve a CCyR. If however, a patient is on a lower dose
426
(CCyR) mosome by cytogenetic analy- (e.g., 300 mg/day) for a special reason (body size or tolerance level) and
sis of marrow cells.
achieves a complete hematologic response (CHR) and CCyR within
Major molecular response BCR-ABL1/ABL1 ratio <0.1% or 12 months of onset of therapy, acceptable outcomes without excess tox-
(MMR) a 3-log reduction in quantita- icity can result. 427
tive polymerase chain reac- Some patients have been followed for up to 8 years on imatinib in
tion (qPCR) signal from mean the IRIS trial (IFN vs. STI571). With median followup of 60 months,
428
pretreatment baseline value, the best observed MCyR and CCyR rates were 89 percent and 82 per-
if International Standard (IS)-
based PCR not available. cent, respectively. Only 7 percent had progressed to accelerated or blast
phase, and overall survival rate was 89 percent. The best MMR rate was
Complete molecular response BCR-ABL1 mRNA levels unde- 86 percent during the 8-year followup. No patient with an MMR at
(CMR) tectable by qPCR with assay 12 months progressed to accelerated or blast phase. By 8 years of follow
sensitivity at least 4.5 logs up on the IRIS trial, 22 percent of patients had discontinued imatinib
below baseline (IS).
treatment because of an unsatisfactory response or toxicity, and only
55 percent remained on study. The 5-year probability of remaining in
MCyR while receiving imatinib was approximately 60 percent. Achiev-
ing a CCyR correlated with progression-free survival, but achieving a
a maximal effect is variable, but as long as a patient is having a con- MMR conferred no further survival benefit. 429
tinued reduction in the size of the leukemic clone as judged by cyto-
genetic or PCR measurements, and has met response benchmarks, the Use of Imatinib in Patients with Variant Chromosomal
drug is continued at 400 mg/day. If the patient stops responding before Translocations or Breakpoints
a complete cytogenetic remission or complete molecular remission is Patients with variant Ph chromosome translocations have a similar
achieved, the dose can be increased to 600 mg/day or to 800 mg/day prognosis to that of patients with classic Ph chromosome translocations
430
(400 mg every 12 hours), if tolerated. Alternatively, another TKI can be who are treated with imatinib. (See Fig. 89–3 for a diagram of break-
used. About two-thirds of patients who do not have a significant hema- points.) Patients with the e13a2, p210BCR-ABL translocation respond
431
tologic response or who relapse while receiving imatinib at a dose of well to imatinib, with similar rates of complete cytogenetic remission.
400 mg/day achieve a complete or partial hematologic response with The e13a2 transcript may be more sensitive to imatinib than the e14a2
432
higher doses, but few cytogenetic responses occur. Some patients transcript. In a patient with both e1a2 and e14a2 fusion transcripts,
418
without a cytogenetic response can enter a partial or complete cytoge- only the p210 e14a2 transcript disappeared, whereas the e1a2 transcript
netic response(CCyR) with higher doses of imatinib. Unfortunately, the persisted during progression to blast phase. No mutation in the kinase
433
responses to higher doses of imatinib in patients lacking a hematologic domain of ABL1 was found. Thus, different clones in a patient may
or cytogenetic response at 400 mg/day usually are transient. 419,420 have a different sensitivity to imatinib. Deletions of the derivative chro-
Several studies have examined use of imatinib at doses higher than mosome 9 do not influence the response and outcomes in CML chronic
400 mg/day. Patients with newly diagnosed chronic phase CML treated phase when using imatinib. 434
with imatinib, 800 mg/day, administered in two 400-mg doses, every
12 hours, had a frequency of 90 percent CCyR, and 96 percent had at Response to Imatinib in Children and Older Patients
least a major cytogenetic response (MCyR). At a median of 15 months, More than 80 percent of children with chronic phase CML who are
no patients had progressed and 63 percent showed blood BCR-ABL1/ treated with imatinib, 260 to 570 mg/m , enter a complete cytogenetic
2
ABL1 percentage ratios of less than 0.05 percent. Twenty-eight percent remission. Imatinib is now approved for use in pediatric patients.

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