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1466 Part X: Malignant Myeloid Diseases Chapter 89: Chronic Myelogenous Leukemia and Related Disorders 1467

The enzyme is present in normal immature thymocytes and in the blast including promyelocytic blast crisis, can occur during imatinib ther-
886
cells of nearly all patients with acute lymphoblastic leukemia. Rare apy. Compared to historical controls in which various combinations of
patients have blasts with a T-lymphocyte phenotype. 835,836,860–862 Some chemotherapy were utilized, imatinib used alone results in compara-
cases are biphenotypic; the blasts have both lymphoid and myeloid ble outcomes (6-month median survival of patients in blast crisis).
887
markers. 841,863–865 Some cases may have myeloperoxidase activity in blast Although dasatinib therapy can result in CCyRs in 29 percent of blast
cells and express CD33 or CD13. Myeloid to lymphoid clonal succession crisis CML, and nilotinib can result in CCyRs in 27 percent of myeloid
following autologous transplantation in the second chronic phase has blast crisis and in 43 percent of lymphoid blast crisis, these responses
866
been described. Patients with lymphoid blast crisis seldom have an are rarely durable, so in a patient of appropriate age with an accept-
intermediate accelerated phase, have less splenomegaly and basophilia, able donor, transplantation options should be considered with the
and usually have a higher degree of marrow blast infiltration. With second-line TKIs used as a bridge to transplantation therapy. 888,889 The
non-TKI therapy, remission rate and survival were somewhat longer in choice of TKI in accelerated phase is based on prior therapy and/or
cases of lymphoid than in myeloid blast crisis. 867 mutational status. If response to TKI therapy is inadequate in acceler-
ated phase, allogeneic hematopoietic stem cell transplantation should
be considered. In lymphoid or myeloid blast phase, allogeneic hemato-
CYTOGENETIC STUDIES poietic stem cell transplantation is recommended if there is a suitable
Most large studies have shown seven recurrent changes in patients’ donor. Omacetaxine has shown activity in patients with disease pro-
417
cells prior to, or during, the accelerated phase: trisomy 8 (33 percent gression to accelerated phase CML after prior TKI use. 890
of cases), additional 22q− (30 percent of cases), isochromosome 17
(20 percent of cases), trisomy 19 (12 percent of cases), loss of Y chromo-
some (8 percent of males), trisomy 21 (7 percent of cases), and mono- Chemotherapy
somy 7 (5 percent of cases). 867–870 In addition, a large number of other The treatment approach is predicated on the phenotype of the blast cells
chromosome abnormalities have been described. 871–875 In one study, in CML patients with blast crisis and is rarely used in accelerated phase.
46 (63 percent) of 73 blast crisis patients had secondary cytogenetic In patients with myeloid phenotypes, the approach has been similar to
abnormalities. These abnormalities were more common in myeloid that used for AML: combinations of an anthracycline antibiotic, such
blast crisis and were associated with shorter remission. The changes as idarubicin or daunorubicin, with cytosine arabinoside and some-
788
891
may be features of myeloid blast crisis compared to lymphoid cri- times etoposide. Because this approach produces few remissions
sis. 869,874 Some abnormalities, such as inv16, are associated with early that are of short duration (median survival approximately 6 months),
transformation to AML. 870,874–877 A significant proportion (50 percent) a variety of other drug combinations have been used, but with no sig-
887
of patients in the accelerated phase or blast crisis have no additional nificant improvement in outcome. Complete hematologic response is
cytogenetic abnormalities beyond t(9;22)(q34;q11) after banding and observed in only a quarter to a third of patients with this approach. 2
multicolor FISH analysis. In cases where the blastic transformation is In patients with lymphoid phenotypes, vincristine sulfate 1.4 mg/m
876
in extramedullary sites, such as lymph nodes or spleen, the additional (not to exceed 2 mg/dose) given intravenously once per week and pred-
2
cytogenetic abnormalities may be in the cells at those sites but not in nisone 60 mg/m per day given orally are the mainstay of treatment. A
cells in the blood or marrow. 878 minimum of two cycles of treatment (2 weeks) should be given to judge
responsivity. Other more intense ALL-type regimens, such as Hyper-
CVAD (cyclophosphamide, vincristine, doxorubicin, and dexametha-
TREATMENT sone), have also been used. Approximately one-third of patients with
892
Optimal treatment is allogeneic stem cell transplantation if the patient lymphoid blast transformation reenter the chronic phase after such
treatment. However, because only about one-third of patients have lym-
is eligible based upon patient’s age and donor availability. The role of phoid blasts, this number represents a remission rate of only approxi-
stem cell transplantation is also evolving as TKI use in these phases mately 10 percent of patients who enter blast crisis using this approach.
of diseases becomes better defined. Thus far, treatment with TKIs has The benefit of intensive chemotherapy has been small because remis-
improved survival only modestly in blast crisis, and most long-term sion durations have been modest. TdT-positive, CD10 (CALLA)-posi-
survivors have been transplanted. At present, it is recommended that tive lymphoblasts may be the lymphoblast phenotype most responsive
patients in blast crisis be treated with TKIs with or without chemother- to vincristine and prednisone. mTOR inhibitors may be useful in lym-
855
apy to a second chronic phase and proceed to stem cell transplant as phoid blast crisis. 897
soon as possible once a donor is identified. One of the major goals of
treatment of chronic phase CML is the prevention of evolution to accel-
erated or blast phases of the disease. Use of Chemotherapy with Tyrosine Kinase Inhibitors in
Accelerated Phase or Blast Crisis
Tyrosine Kinase Inhibitors in Accelerated and Blast Crisis Imatinib has been successfully combined with decitabine, low-dose
The initial dose of imatinib in accelerated phase is 600 mg/day. Ima- cytarabine, and standard anthracycline plus cytarabine (“7 + 3”) where
879
tinib, dasatinib 140 mg/day, and nilotinib 400 mg BID, bosutinib 500 complete remission can be as high as 75 percent. Median time to relapse
815
mg daily, and ponatinib 45 mg/day have been used as bridging therapies and overall survival are brief, however. Imatinib and dasatinib have
to permit allogeneic stem cell transplantation in accelerated phase. been combined with HyperCVAD in lymphoid blast crisis. 892,893
880
Dasatinib and nilotinib can achieve a better molecular response, and
thus the role for and timing of transplantation in accelerated phase Allogeneic Hematopoietic Stem Cell Transplantation
CML is being redefined, Imatinib can be combined with an anthracy- Stem cell transplantation from an appropriately HLA-matched donor
cline plus cytarabine for patients in myeloid blast crisis. Imatinib has has been used in some patients after entry into the blastic crisis. Occa-
881
produced complete hematologic remissions in approximately 20 per- sional patients have had long-term survival. The 3-year survival rate
cent of patients. 882,883 However, CCyRs are uncommon. Central nervous is approximately 15 to 20 percent, 894–896 unlike transplantation in the
system and other extramedullary blast crisis can occur during imatinib chronic phase, in which the 3-year survival rate is 50 to 60 percent.
therapy for accelerated phase disease, 884,885 and all types of blast crisis, However, for patients who present in blast crisis, who develop blast

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