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

the drugs be used? Should they only be started in cases of molecular TABLE 89–7. Chronic Myelogenous Leukemia: 5-Year
relapse? How can they be best combined with DLI in cases of relapse?
Period Relative Survival Rates (2004–2012) by Age at
Diagnosis
IMMUNOTHERAPY: ADOPTIVE CELL THERAPY
FOR POSTTRANSPLANTATION RELAPSE Age (years) Percent of Patients*
86
<45
Substantial evidence indicates that the effectiveness of allografting in
CML does not result solely from the eradication of the leukemic clone 45–54 82
with high-dose chemoradiotherapy conditioning regimens, but also 55–64 70
from adoptive immunotherapy provided by lymphocytes in the allog- 65–74 51
raft, the graft-versus-leukemia effect (see “Myeloablative Allogeneic
707
Transplants” above). This phenomenon has been recreated to produce <75 27
a therapeutic response by infusing the lymphocytes from the stem cell *Percent rounded to nearest whole number.
donor after a relapse following allogeneic stem cell transplantation. 708,709
The overall response rate to DLI is approximately 75 percent. The Data from Surveillance, Epidemiology, End Results Cancer Statistics:
5-Year Survival Rates, Table 13.6, All Races and Sexes. National Cancer
response rate is higher when this approach is used early after detecting Institute, Washington, DC. Available at http://www.seer.cancer.gov.
710
a relapse by PCR, compared to use after a hematologic or cytogenetic
relapse. Patients with a short interval between transplantation and DLI
have a higher probability of response than patients with longer inter-
711
vals. Responses are the same with related versus unrelated donors. molecular response, progression-free, and overall survival to those who
724
Some patients show a very rapid decline of BCR-ABL1 transcript levels achieve a cytogenetic remission sooner. In patients with failure to
(<6 months after DLI), whereas other patients demonstrate PCR nega- respond or intolerance to imatinib the estimated 3-year survival rate
tivity only over a longer period. The responses to DLI can be durable. was approximately 70 percent for patients in chronic phase. Survival
713
712
Molecular responses can occur in up to two-thirds of patients. 714 in chronic phase was better when subsequent therapy was nilotinib or
The main toxicities of DLI have been the induction of GVHD dasatinib as compared to allogeneic hematopoietic stem cell transplan-
and myelosuppression. Chronic GVHD can occur in up to 60 percent tation or to others agents. This result was at a median followup of 2
725
715
of cases. Attempts to diminish these toxicities have included use of years. Older patients have lower response rates when treated in late
CD8-depleted DLIs and infusion of smaller numbers of T cells. 716,717 chronic phase, but if they attain a CCyR, no difference was found in the
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Lower initial cell dose is associated with less myelosuppression, the level of molecular response. Table 89–7 shows the most recent 5-year
same response rate, better survival, and less DLI-related mortality, lead- relative survival data by age at diagnosis in the United States.
8
ing to suggestions that the initial dose should not exceed 0.2 × 10 mono- The introduction of imatinib has minimized the impact of prog-
726
718
nuclear cells/kg. The initial doses should be lower when matched nostic factors at diagnosis of chronic phase CML. Several prognostic
unrelated donors are used. Immune suppression should first be tapered scales have been proposed in CML, including the Sokal and Hasford
before DLIs are administered. As noted above, imatinib may synergize systems for patients at the time of diagnosis (Table 89–8). The European
with DLI to foster rapid molecular responses after relapse. 719 Bone Marrow Transplantation Consortium Risk Score was introduced
COURSE AND PROGNOSIS TABLE 89–8. The Variables Used to Calculate the Risk
Imatinib was first used experimentally for CML treatment in June 1998. Group (High, Intermediate, Low) at Diagnosis in Patients
Although it has completely altered the treatment approach to CML, its with Chronic Phase Chronic Myelogenous Leukemia to
use has raised several questions. Studies require long-term followup of Estimate Prognosis
survival, but the degree of cytogenetic response, and degree of molec- The Sokal score, which is a hazard ratio, is calculated using the
ular response can be used as surrogate end points. The durability of following formula based on age, spleen size, platelet count,
cytogenetic and molecular responses in the face of persistent mini- and blood percent blast cells: exp (0.0116 × (age [years]−43.4))
mal residual disease during imatinib therapy require longer followup + (0.0345 × (spleen size [cm] − 7.51) + (0.188 × ((platelets
9
of larger numbers of patients, as more than 95 percent of cases have [10 /L]/700)^2 − 0.563)) + (0.0887 × (blasts [%] − 2.10)). There are
molecular evidence of disease at 2 years. three risk groups: low-risk (Sokal score <0.8), intermediate-risk
With the advent of TKI treatment, median survival in chronic (Sokal score 0.8–1.2), and high-risk (Sokal score >1.2).
phase CML is estimated to be 25 to 30 years. The prevalence of CML in The Hasford score (or Euro score) is calculated using the following
the TKI era is estimated to reach a plateau 35 times the annual incidence formula based on the four Sokal variables plus percent eosino-
with plateau estimated to occur in 2050. Therefore, the prevalence of phils and basophils in the blood: (0.6666 × age [0 when age
CML is predicted to increase by a factor of 10. Using the Swedish <50 years; 1 otherwise]) + (0.0420 × spleen size [cm]) + (0.0584 ×
720
Cancer Registry over a 36-year period, relative survival rates compared blasts [%]) + (0.0413 × eosinophils [%]) + (0.2039 × basophils
with the total population for CML improved from 0.21 in 1973 to 1979 [0 when basophils <3%; 1 otherwise]) + (1.0956 × platelet count
9
to 0.80 for 2001 to 2008; imatinib was introduced in Sweden in 2001. [0 when platelets <1500 × 10 /L; 1 otherwise]) × 1000). Three risk
721
Another study from the Swedish CML registry of 779 patients showed groups are: low-risk (score ≤780, 40.6% of patients), intermedi-
ate-risk (score 781–1480, 44.7% of patients), and high-risk (score
that the mean survival ratio at 5 years was close to 1.0 for those younger ≥1481, 14.6% of patients).
than 60 years old and 0.9 for those 60 to 80 years old. Only 3 percent had
722
progressed to accelerated or blast phase at 12 months. Resistance rates These scores may be calculated electronically by insertion of the
decline with each passing year, and adverse effects have not emerged individual variables, such as age, spleen size, blood blast percent-
age, etc. at the following website. http://bloodref.com/myeloid/
723
over time. Those who require 1 year or more of imatinib therapy cml/sokal-hasford.
to attain a complete cytogenetic remission have comparable rates of

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