Page 1223 - Hematology_ Basic Principles and Practice ( PDFDrive )

Chapter 67 Chronic Myeloid Leukemia 1069

front-line therapy for CML with excellent outcomes on long-term Management of the Newly Diagnosed Chronic Myeloid Leukemia
follow-up, the number of patients undergoing allogeneic transplanta- Patient
tion has declined dramatically. Currently, allogeneic transplantation
is a preferred treatment for patients in whom a second-generation What should be the initial management for CML patients? After years
TKI has failed, patients with TKI-resistant mutations such as T315I, of clinical research, we know (A) imatinib is remarkably effective for
and patients in AP or blast phase CML. The MD Anderson Cancer patients treated in CP, because more than 85% of patients obtain a
Center group reported outcomes of imatinib-resistant CML patients CCR and approximately 70% of cases remain in CCR at 5 years of
(CP, n = 34; AP, n = 9; and BC, n = 4) who underwent allogeneic follow-up; (B) second-generation TKIs, dasatinib and nilotinib, used as
transplantation. Nineteen patients (40%) had BCR-ABL mutations, first-line treatment for CP CML, may be even more effective, resulting in
15 of whom had advanced disease. Thirty two patients (68%) had a faster and more profound reduction in BCR-ABL levels; (C) allogeneic
MMR after transplantation, with a 2-year EFS of 36% and 58% for transplantation is generally associated with 10-year survival rates of
70% or better for younger patients in early CP; and (D) outcome
the mutant and nonmutant groups, and a 2-year OS of 44% and for patients receiving TKI treatment can be effectively monitored by
76%, respectively. These results confirm the effectiveness of trans- sensitive RT-PCR assays.
29
plantation as salvage treatment for TKI-resistant patients. Since Imatinib has become the initial treatment of choice for patients with
patients with mutations are more likely to develop advanced disease CML. For patients diagnosed during CP, imatinib is a reasonable first
and have worse outcomes after transplantation, this procedure should choice of therapy. However, in view of the association between cytoge-
be considered early for patients with poor response to a second- netic and molecular responses on imatinib and survival, it is reasonable
generation TKI. Major or CCR to TKI therapy was associated with to suggest that the faster and deeper reduction in disease burden using
better posttransplant outcome, supporting the use of TKIs to reduce the second-generation agents may reduce the risk for progression
disease burden before allogenic HCT for AP and BC CML. when compared with imatinib. The tolerability of the newer agents
appears to be comparable with imatinib, although long-term effects
of treatment are a potential concern. It is notable that differences in
overall survival have not been observed as yet. In addition, low-risk
Autologous Transplantation CP patients demonstrate excellent survival with imatinib, and imatinib
is considerably less expensive than the newer agents and a generic
The rationale for autologous transplantation in CML was provided form will soon be available, reducing costs further. Careful monitoring
by experimental and clinical evidence for persistence of polyclonal of imatinib response could potentially identify the subset of patients
−
Ph progenitors capable of reconstituting hematopoiesis in CML who will benefit from second-generation TKI treatment. An alternative
patients. This is most dramatically demonstrated by the high rate of strategy to universal first-line use of second-generation TKIs was tested
cytogenetic and molecular response in CML patients treated with in the Australian Therapeutic Intensification in De Novo Leukemia II
study, which used imatinib to treat CML first-line, with selective nilotinib
TKIs. Furthermore, it was shown that transplantation of autologous switching based on failure to achieve targeted reduction in BCR-ABL
cells may allow restoration of Ph hematopoiesis. Initial studies carried levels at designated time points. This approach was associated with
out using unmanipulated autologous marrow or blood cells indicated excellent molecular response and survival, supporting the feasibility
that autologous transplantation could reestablish CP in patients with of this approach. At present, the choice of first-line TKI is dependent
advanced disease and induce cytogenetic responses in a small propor- on individual preference based on risk group, toxicity profile, dosing
tion of CML CP patients. Subsequent studies indicated that depletion schedule, and economic factors.
+
of Ph progenitors by ex vivo graft manipulation was associated with For patients with CP disease, tyrosine kinase treatment can be initi-
cytogenetic remission posttransplant. Another approach to depleting ated with simultaneous workup of family donors and unrelated donors.
malignant cells from the graft was to treat patients before harvesting Criteria for failure or suboptimal response have been developed. Cer-
tainly, the failure of imatinib treatment to achieve a CHR at 3 months
marrow or peripheral blood for transplantation, also called in vivo of treatment, lack of any cytogenetic response by 6 months, or lack of
purging. However, remissions following autologous transplantation a major cytogenetic response by 12 months is an indication to switch
were usually of short duration. In addition, the procedure was often therapy. By a conservative approach, patients should achieve a CCR
associated with significant toxicity and delayed recovery. Although by 18 months of therapy. Similarly, BCR-ABL mRNA levels greater
the compiled results of 200 autologous transplants at eight different than 10% at 6 months and greater than 1% at 12 months (using
centers in Europe and North America indicated a possibility of the international scale) are indicators to switch treatment. Patients
improved survival, it is not possible to make any definite conclusions who relapse after a CCR, especially those with ABL point mutations,
in the absence of controlled clinical trials. A meta-analysis of six trials should consider alternative therapy, including transplant. For patients
in which patients were randomly allocated to receive autologous diagnosed in accelerated phase or in blast crisis, initial treatment with
dasatinib results in better responses than those seen with imatinib, but
HCT or an IFN-based regimen did not show an advantage for HCT. in general these responses tend to be short-lived; thus advanced-phase
Autologous HCT fell out of favor in view of the excellent results patients should consider transplantation as soon as possible.
of TKI treatment in CML patients. Collection of peripheral blood
stem cells from patients responsive to TKIs may form the framework
of any future attempts to perform autologous transplantation in
CML, and is well tolerated and results in more consistent achieve- the type of BC (myeloid or lymphoid), and whether or not HCT is
−
ment of Ph collections. However, additional strategies are needed to possible. Allogeneic HCT remains the only curative option for
further deplete leukemia cells and to improve therapy for residual patients with available matched donors who are able to tolerate the
disease posttransplant. At this point, autologous HCT for CML procedure. The best results are achieved if the patient returns to CP,
should be limited to investigational trials for patients who lack allo- especially with significant cytogenetic or molecular improvement
geneic donors and for those in whom TKIs have failed. prior to transplant. All TKIs except nilotinib are approved for the
treatment of BC. Hematologic and cytogenetic responses with single-
TREATMENT OF CML PATIENTS WITH agent TKIs are achieved in about 50% and 12%, respectively, the
1-year overall response ranges from 25% to 49%, and median survival
ADVANCED DISEASE from 6 to 11.8 months. The combination of dasatinib and the
+
hyperCVAD regimen has shown efficacy in relapsed Ph ALL or
The incidence of BC has been significantly reduced following the lymphoid BC of CML (CML-LB). The overall response rate was
advent of TKI treatment compared with the pre-TKI era. The 91%, with 71% of patients achieving CR, and 21% CR with incom-
German CML study IV, a five-arm study of imatinib-based treat- plete platelet recovery. Grades 3 and 4 toxicities included hemorrhage,
ments, reported an 8-year cumulative BC incidence of 5.6 % com- pleural and pericardial effusions, and infections. The 3-year OS of
pared with 12% to 62% in studies preceding the TKI era. The highest patients with CML-LB was 70%, with 68% remaining in CR at 3
incidence of BC occurs in the first year after diagnosis. Treatment of years. Therefore long-term leukemia-free survival is possible in
CML patients with advanced disease depends on previous therapy, CML-LB patients even without allogeneic HCT.