Page 1488 - Williams Hematology ( PDFDrive )

1462 Part X: Malignant Myeloid Diseases Chapter 89: Chronic Myelogenous Leukemia and Related Disorders 1463

TABLE 89–7. Chronic Myelogenous Leukemia: 5-Year for patients undergoing allogeneic hematopoietic stem cell transplan- response at the time of a CCyR or a 3-log response anytime thereafter
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is an independent prognostic marker of progression-free survival.
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tation, in which performance status is added to five variables (age,
Period Relative Survival Rates (2004–2012) by Age at spleen size, blood blast cell count, basophil and eosinophil count, and Other studies, however, show that patients who achieve CCyR do not
Diagnosis platelet count [Hasford score]), and has been validated with good dis- derive additional benefit from a CMR. The treatment response, to
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Age (years) Percent of Patients* crimination for survival. The Sokal score based on age, spleen size, imatinib, nilotinib, or dasatinib showed the 3-year event-free survival
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<45 86 platelet count, and percent blasts was developed much earlier during was 95 percent for those with BCR-ABL1 transcripts of 1 percent or less
the busulfan era of treatment and was less accurate in patients treated at 3 months, 98 percent for greater than 1 percent to 10 percent, and
45–54 82 with IFN. The European Treatment and Outcome Study (EUTOS) score 61 percent for greater than 10 percent. These 3-month responses trans-
55–64 70 uses basophils and spleen size but has not been well-validated. A simple lated into overall survival of 98, 96, and 92 percent, respectively. 750
65–74 51 prognostic scale that includes donor type, stage of disease at time of Interphase FISH is not standardized, but a large number of cells can
transplantation, age of recipient, sex of donor and recipient, and inter- be rapidly analyzed (100 to 500). Fixation, specimen preparation, and
<75 27 val between diagnosis and transplantation has been proposed to predict hybridization conditions may account for differing false-positive ranges
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*Percent rounded to nearest whole number. outcome of allogeneic hematopoietic stem cell transplantation. These and scoring criteria. In CML patients treated with imatinib, FISH for
Data from Surveillance, Epidemiology, End Results Cancer Statistics: prognostic scales require revalidation given the dramatic impact of con- BCR-ABL1 on interphase blood neutrophils, but not unselected white
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cells, correlates with marrow cytogenetics. FISH and RT-PCR can be
version to TKI therapy. There is evidence that a patient with chronic
5-Year Survival Rates, Table 13.6, All Races and Sexes. National Cancer 753
Institute, Washington, DC. Available at http://www.seer.cancer.gov. phase CML and a favorable Sokal Score at the time of diagnosis has a useful complementary techniques, but FISH is generally not suitable
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higher proportion of CHR and CCyR than other patients. Cytogenetic for monitoring minimal residual disease. 754
response and molecular response as a surrogate marker for survival is For patients who are undergoing allogeneic hematopoietic stem
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useful in patients undergoing TKI therapy. The score of a patient may cell transplantation, the kinetics of minimal residual disease in either
be calculated, easily, using an online website (Table 89–8). Studies sug- standard or nonmyeloablative transplants differ. BCR-ABL1/ABL1
gest that in certain healthcare systems, healthcare setting may influence ratios were 0.2 percent with reduced-intensity transplants versus 0.01
survival time, especially for those in advanced phases of the disease. 732 percent in transplantation patients with traditional conditioning reg-
Outcomes after allogenic hematopoietic stem cell transplantation imens in the first 3 months. By 12 months, however, 20 percent of
have also improved in the imatinib era, but those in chronic phase have patients who received standard transplants and 50 percent of patients
better 3-year survival rates than those in advanced phases (91 percent vs. who received reduced-intensity transplants had reached a level less than
59 percent, respectively). There is favorable long-term survival after 5 0.01 percent, supporting the concept of different kinetics of disease
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years free of relapse after allogeneic hematopoietic stem cell transplan- eradication between the two transplantation modalities. Patients who
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tation. Prognostic factors in the TKI era for allogeneic transplantation relapse after allografting have reappearance and/or rising levels of BCR-
are also being defined, and in addition to disease phase, donor-match, ABL1 transcripts. Use of quantitative RT-PCR early (3 to 5 months)
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age, sex, and calculated comorbidity indices are of importance. 735 after stem cell transplantation can project long-term outcomes. When
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RT-PCR was negative, the 3-year risk of relapse was 16.7 percent; when
RT-PCR was positive at a ratio of less than 0.02 percent, the relapse rate
DETECTION OF MINIMAL RESIDUAL DISEASE was 42.9 percent; and when RT-PCR was positive at a level greater than
Detection of minimal residual disease by molecular probes makes pos- 0.02 percent, the relapse rate was 86.5 percent. Another group found
sible the identification of approximately one cell in 1,000,000 that is that detection of blood BCR-ABL1 at 18 or more months after trans-
derived from the CML clone. Techniques used to monitor residual plantation was associated with a highly significant risk of relapse and
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disease have been reviewed. 737,738 PCR permits observation of regression that patients who had a positive test result but failed to relapse generally
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or persistence of subclinical disease following therapy and of progres- had only one positive test result at a low copy number. Performance of
sion of subclinical disease prior to the disease becoming overt, and it is quantitative PCR (qPCR) at regular intervals after allogeneic transplant
therefore critical for monitoring responses to CML treatment. 739,740 The (every 2 to 4 months in the first year and every 6 months thereafter) is
stable persistence of subclinical disease does not invariably predict early appropriate. If the PCR results are persistently positive or become posi-
relapse. 741,742 tive, qPCR should be performed at monthly or shorter intervals. Molec-
Efforts are underway to standardize the technique for measur- ular relapse is defined as a 10-fold increase of PCR positivity without
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ing and reporting real-time RT-PCR, and serial measurements are any signs of cytogenetic relapse. Detection of increasing recipient chi-
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required for treatment decisions based on increases in transcript num- merism by FISH for the male chromosome in sex-mismatched donor–
bers. Some studies show that marrow values tend to be higher than recipient pairs or variable number of tandem repeats after allogeneic
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blood in real-time RT-PCR assays, but both follow a similar trend dur- transplantation or after DLI infusion also is usually associated with a
ing treatment. Interchanging these may lead to misinterpretation of relapse. 760
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disease status. In patients on imatinib, who have MMR, confirmed by In an imatinib-treated patient, the absence of BCR-ABL1 tran-
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real-time quantitative PCR, no marrow cell cytogenetic abnormalities scripts should not be interpreted as an absence of the leukemic clone.
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were found, indicating that patients with MMR do not require regu- In terms of response to second-generation TKIs, there was no difference
lar marrow examinations for cytogenetics. The International Standard in event-free survival and CCyR duration between patients with CCyR
uses baseline diagnosis levels in the IRIS study as 100 percent and fixes with and without MMR up to 18 months with followup at 3-month
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a 3-log reduction from a standardized baseline (MMR) at 0.1 percent. intervals. One study examined 116 patients with durable cytogenetic
Widespread use of the International Standard will require laboratories responses on imatinib who had increased PCR levels on at least two
to send in specimens for analysis, 743,746 but is a priority in order to ascer- occasions. Only 9 percent of those had CML progression. Ten patients
tain response to therapy accurately and to be able to analyze responses had lost MMR or had never had it, and all of these had more than 1-log
among treatment centers. increase in qPCR. With second-generation TKI, the BCR-ABL1 tran-
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Patients who achieve a MMR (expressed as a 3-log reduction from script levels at 3 months are also correlated with CCyR and MMR by 24
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median baseline value) at the time of achieving a CCyR have been found months, with levels less than 10 percent at 3 months being optimal.
to have longer cytogenetic remissions than those without this magni- The European Leukemia Net criteria for failure or suboptimal response
tude of molecular response. The achievement of a 2-log molecular may also identify CML in early chronic phase treated with imatinib
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