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Ask NOAH About: Cancer
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Chronic myelogenous leukemia
208/01031
CancerNet: National Cancer Institute
PDQ Information for Health Care Professionals [for patients]
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Choose one of the following options to see the information directly:
* GENERAL INFORMATION
* STAGE INFORMATION
* TREATMENT OPTION OVERVIEW
* CHRONIC PHASE CHRONIC MYELOGENOUS LEUKEMIA
* ACCELERATED PHASE CHRONIC MYELOGENOUS LEUKEMIA
* BLASTIC PHASE CHRONIC MYELOGENOUS LEUKEMIA
* MENINGEAL CHRONIC MYELOGENOUS LEUKEMIA
* REFRACTORY CHRONIC MYELOGENOUS LEUKEMIA
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This information is intended for use by doctors and other health care
professionals. If you are a cancer patient, your doctor can explain how it
applies to you, or you can call the Cancer Information Service at
1-800-422-6237. CancerNet also contains PDQ information for patients; see
the CancerNet Contents List for PDQ for more information.
--------------------------------------
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GENERAL INFORMATION
Chronic myelogenous leukemia (CML) is one of a group of diseases called the
myeloproliferative disorders. CML is not currently curable with conventional
chemotherapy; the average survival is 42 months. Survival after development
of an accelerated phase is usually less than 1 year and after blastic
transformation is only a few months, although patients with lymphoblastic
transformation may live longer with appropriate treatment.[1,2]
Other related entities include polycythemia vera, myelofibrosis, and
essential thrombocythemia. CML is a clonal disorder that is usually easily
recognized because the leukemic cells of more than 95% of patients have a
distinctive cytogenetic abnormality, the Philadelphia (Ph) chromosome.[3,4]
The Ph chromosome results from a reciprocal translocation between the long
arms of chromosomes 9 and 22 and is demonstrable in all hematopoietic
precursors.[4] This translocation results in the transfer of the Abelson
(abl) oncogene to an area of chromosome 22 termed the breakpoint cluster
region (bcr).[5] This in turn results in a fused bcr-abl gene and in the
production of an abnormal tyrosine kinase protein that may be related to the
disordered myelopoiesis found in CML. Furthermore, these molecular
techniques can now be used to supplement cytogenetic studies to detect the
presence of the 9;22 translocation in patients without a visible Ph
chromosome (Ph-). Ph- CML is a poorly defined entity that is less clearly
distinguished from other myeloproliferative syndromes. Patients with Ph- CML
generally have a poorer response to treatment and shorter survival than Ph+
patients. However, Ph- patients who have bcr-abl gene rearrangement
detectable by Southern blot analysis have prognoses equivalent to Ph+
patients.[6,7] A small subset of patients have bcr-abl detectable only by
reverse transcription-polymerase chain reaction (RT-PCR), which is the most
sensitive technique currently available. Patients with RT- PCR evidence of
the bcr-abl fusion gene appear clinically and prognostically identical to
patients with a classic Philadelphia chromosome. However, patients who are
bcr-abl-negative by RT-PCR have a clinical course more consistent with
chronic myelomonocytic leukemia.[6] Some authorities suggest that a subset
of these patients may represent a distinct clinical entity related to
myelodysplastic syndrome.[8]
The median age of patients with Ph+ CML is 40-45 years. Median survival is
3-4 years, with a range of less than 1 year to more than 10 years. Median
age for patients who are Ph- is 60-65 years, and median survival is about 18
months.
CML can occur in children (2%-3% of all childhood leukemias are CML), but if
Ph+, the prognosis for children may be better than that for adults.[9]
References:
1. Champlin RE, Golde DW: Chronic myelogenous leukemia: recent advances.
Blood 65(5): 1039-1047, 1985.
2. Silver RT: Chronic myeloid leukemia: a perspective of the clinical and
biologic issues of the chronic phase. Hematology/Oncology Clinics of
North America 4(2): 319-335, 1990.
3. Fialkow PJ, Jacobson RJ, Papayannopoulou T: Chronic myelocytic
leukemia: clonal origin in a stem cell common to the granulocyte,
erythrocyte, platelet and monocyte macrophage. American Journal of
Medicine 63(1): 125-130, 1977.
4. Rowley JD: Molecular cytogenetics: Rosetta stone for understanding
cancer - Twenty-ninth G.H.A. Clowes Memorial Award Lecture. Cancer
Research 50(13): 3816-3825, 1990.
5. Kurzrock R, Gutterman JU, Talpaz M: The molecular genetics of
Philadelphia chromosome-positive leukemias. New England Journal of
Medicine 319(15): 990-998, 1988.
6. Martiat P, Michaux JL, Rodhain J: Philadelphia-negative (Ph-) chronic
myeloid leukemia (CML): comparison with Ph+ CML and chronic
myelomonocytic leukemia. Blood 78(1): 205-211, 1991.
7. Cortes JE, Talpaz M, Beran M, et al.: Philadephia chromosome-negative
chronic myelogenous leukemia with rearrangement of the breakpoint
cluster region: long term follow-up results. Cancer 75(2): 464-470,
1995.
8. Oscier DG: Atypical chronic myeloid leukemia, a distinct clinical
entity related to the myelodysplastic syndrome? British Journal of
Haematology 92(3): 582-586, 1996.
9. Castro-Malaspina H, Schaison G, Briere J, et al.: Philadelphia
chromosome-positive chronic myelocytic leukemia in children: survival
and prognostic factors. Cancer 52(4): 721-727, 1983.
----------------------------------------------
STAGE INFORMATION
Bone marrow sampling is done to assess cellularity, fibrosis, and
cytogenetics. The Philadelphia (Ph) chromosome is usually more readily
apparent in marrow metaphases than in peripheral blood metaphases; in some
cases, it may be "mashed" and molecular studies are necessary to demonstrate
the 9;22 translocation.
The most common finding on physical examination at diagnosis is
splenomegaly. The spleen may be enormous, filling most of the abdomen and
presenting a significant clinical problem, or the spleen may be only
minimally enlarged. In about 10% of patients, the spleen is neither palpable
nor enlarged on splenic scan.[1]
Histopathologic examination of bone marrow aspirate demonstrates a shift in
the myeloid series to immature forms that increase in number as patients
progress to the blastic phase of the disease. The marrow is hypercellular,
and differential counts of both marrow and blood show a spectrum of mature
and immature granulocytes similar to that found in normal marrow. Increased
numbers of eosinophils or basophils are often present, and sometimes
monocytosis is seen. Increased megakaryocytes are often found in the marrow,
and sometimes fragments of megakaryocytic nuclei are present in the blood,
especially when the platelet count is very high. The percentage of
lymphocytes is reduced in both the marrow and blood in comparison with
normal subjects, and the myeloid/erythroid ratio in the marrow is usually
greatly elevated. The leukocyte alkaline phosphatase enzyme is either absent
or markedly reduced in the neutrophils of patients with chronic myelogenous
leukemia.[1]
Transition from the chronic phase to the accelerated and later the blastic
phase may occur gradually over a period of 1 year or more, or it may appear
abruptly ("blast crisis"). Signs and symptoms commonly heralding such a
change are progressive leukocytosis, thrombocytosis or thrombocytopenia,
anemia, increasing and painful splenomegaly or hepatomegaly, fever, bone
pain, development of destructive bone lesions, and thrombotic or bleeding
complications. In the accelerated phase, differentiated cells persist,
although they often show increasing morphologic abnormalities, and
increasing anemia and thrombocytopenia and marrow fibrosis are
apparent.[1-3]
Studies have suggested that certain presenting features have prognostic
significance and may help in identifying patients in whom bone marrow
transplantation should be considered earlier in the course of the disease.
Increased splenomegaly, male sex, elevated serum lactate dehydrogenase,
cytogenetic abnormalities in addition to the Ph chromosome, a higher
proportion of marrow or peripheral blood blasts and/or basophils, and anemia
predicted for a shorter chronic phase. Predictive models using multivariate
analysis have been derived.[4-6] It should be noted that transplant centers
performing five or fewer transplants annually usually have poorer results
than larger centers.[7]
Chronic phase
Chronic phase: bone marrow and cytogenetic findings as described above with
less than 5% blasts and promyelocytes in the peripheral blood and bone
marrow.
Accelerated phase
Accelerated phase: greater than 5% in either the peripheral blood or bone
marrow but less than 30% blasts in both the peripheral blood and bone
marrow.
Blastic phase
Blastic phase: greater than 30% blasts in the peripheral blood or bone
marrow.
When greater than 30% blasts are present in the face of fever, malaise, and
progressive splenomegaly, the patient has entered blast crisis, and survival
is on the order of a few months.[2,3]
Meningeal
Meningeal leukemia is diagnosed by morphologic examination of the
cerebrospinal fluid and the identification of blasts in the fluid.
Occasionally patients will have cranial nerve palsies due to leukemic
involvement without clearly abnormal spinal fluid on examination.
References:
1. Clarkson B: The chronic leukemias. In: Wyngaarden JB, Smith LJ, Eds.:
Cecil Textbook of Medicine. Philadelphia: WB Saunders, 18th ed., 1988,
pp 988-1001.
2. Kantarjian HM, Keating MJ, Talpaz M, et al.: Chronic myelogenous
leukemia in blast crisis: analysis of 242 patients. American Journal of
Medicine 83(3): 445-454, 1987.
3. Cervantes F, Rozman M, Rosell J, et al.: A study of prognostic factors
in blast crisis of Philadelphia chromosome-positive chronic myelogenous
leukaemia. British Journal of Haematology 76(1): 27-32, 1990.
4. Sokal JE, Cox EB, Baccarani M, et al.: Prognostic discrimination in
"good-risk" chronic granulocytic leukemia. Blood 63(4): 789-799, 1984.
5. Kantarjian HM, Smith TL, McCredie KB, et al.: Chronic myelogenous
leukemia: a multivariate analysis of the associations of patient
characteristics and therapy with survival. Blood 66(6): 1326-1335,
1985.
6. Sokal JE, Baccarani M, Russo D, et al.: Staging and prognosis in
chronic myelogenous leukemia. Seminars in Hematology 25(1): 49-61,
1988.
7. Horowitz MM, Przepiorka D, Champlin RE, et al.: Should HLA-identical
sibling bone marrow transplants for leukemia be restricted to large
centers? Blood 79(10): 2771-2774, 1992.
----------------------------------------------
TREATMENT OPTION OVERVIEW
Treatment of chronic myelogenous leukemia (CML) is usually initiated when
the diagnosis is established, which is done by the presence of an elevated
white blood cell (WBC) count, thrombocytosis, Philadelphia (Ph) chromosome,
and splenomegaly. At initial diagnosis, consideration should be given to
referral of patients younger than age 60 years to centers exploring
potentially curative therapy with bone marrow transplantation when
appropriate donors are available (identical twin, HLA-identical family
member, or HLA-identical non-family donor).[1] Interferon alfa may produce
partial or complete remissions in chronic phase CML. Cytogenetic responses
have been reported in up to 20% of patients, with delay of disease
progression and prolongation of overall survival.[2] Standard drug therapy
is administered to diminish WBC count to approximately 10,000 per cubic
millimeter without producing marrow hypoplasia. Before chemotherapy, early
deaths occurred in patients left with extremely high WBC and platelet
counts. Leukapheresis and platelet pheresis can also be used to rapidly
lower these counts although this is only of temporary benefit and is rarely
required in adults in chronic phase.
When blast crisis supervenes (as evidenced by fever, progressive
splenomegaly, and increased blast cells in the peripheral blood), minimally
satisfactory remission-induction treatment appears to be available only to a
group of patients whose cells are positive for the enzyme terminal
deoxynucleotidyl transferase (TdT).[3] In these patients survival can be
extended 4-8 months using simple treatment with combinations of drugs
including vincristine and prednisone, usually given in the treatment of
acute lymphocytic leukemia. In addition intensive chemotherapy/radiation
therapy followed by reinfusion of marrow or peripheral blood or both
collected and frozen during the chronic phase has also been used regardless
of TdT status.[1,3-7] However, in most patients early relapse of blast
crisis has developed. Intensive combination chemotherapy for juvenile CML
may be more effective in producing long-term disease-free survivors.[8]
Allogeneic bone marrow transplantation in the chronic phase is the only
therapy known to cure CML. Other state-of-the-art treatment of CML does not
cure the disease, prevent blastic crisis, or prolong the average survival
time. Thus, all newly diagnosed patients should be considered appropriate
candidates for clinical trials exploring new therapeutic approaches,
including bone marrow transplantation, biologic response modifiers, and
combination chemotherapy.
It has been recognized for many years that some patients presenting with
acute leukemia may have a cytogenetic abnormality that is morphologically
indistinguishable from the Ph chromosome.[9] In typical Ph+ CML or CML
presenting de novo in blast crisis without a recognizable preceding chronic
phase, the breakpoints in chromosome 22 occur either between the second and
third or between the third and fourth exon of the bcr region. This results
in the two common variants of the fused bcr-abl gene seen typically in Ph+
CML, both of which are associated with the expression of a p210 bcr-abl
hybrid protein.[2,10,11]
The designations in PDQ that treatments are "standard" or "under clinical
evaluation" are not to be used as a basis for reimbursement determinations.
References:
1. Wagner JE, Zahurak M, Piantadosi S, et al.: Bone marrow transplantation
of chronic myelogenous leukemia in chronic phase: evaluation of risks
and benefits. Journal of Clinical Oncology 10(5): 779-789, 1992.
2. Kurzrock R, Gutterman JU, Talpaz M: The molecular genetics of
Philadelphia chromosome-positive leukemias. New England Journal of
Medicine 319(15): 990-998, 1988.
3. Marks SM, Baltimore D, McCaffrey R: Terminal transferase as a predictor
of initial responsiveness to vincristine and prednisone in blastic
chronic myelogenous leukemia: a co-operative study. New England Journal
of Medicine 298(15): 812-814, 1978.
4. Goldman JM, Gale RP, Horowitz MM, et al.: Bone marrow transplantation
for chronic myelogenous leukemia in chronic phase: increased risk for
relapse associated with T-cell depletion. Annals of Internal Medicine
108(6): 806-814, 1988.
5. Thomas ED, Clift RA: Indications for marrow transplantation in chronic
myelogenous leukemia. Blood 73(4): 861-864, 1989.
6. McGlave P: Bone marrow transplants in chronic myelogenous leukemia: an
overview of determinants of survival. Seminars in Hematology 27(3,
Suppl 4): 23-30, 1990.
7. Reiffers J, Trouette R, Marit G, et al.: Autologous blood stem cell
transplantation for chronic granulocytic leukaemia in transformation: a
report of 47 cases. British Journal of Haematology 77(3): 339-345,
1991.
8. Chan HS, Estrov Z, Weitzman SS, et al.: The value of intensive
combination chemotherapy for juvenile chronic myelogenous leukemia.
Journal of Clinical Oncology 5(12): 1960-1967, 1987.
9. Peterson LC, Bloomfield CD, Brunning RD: Blast crisis as an initial or
terminal manifestation of chronic myeloid leukemia: a study of 28
patients. American Journal of Medicine 60(2): 209-220, 1976.
10. Goldman JM, Grosveld G, Baltimore D, et al.: Chronic myelogenous
leukemia - the unfolding saga. Leukemia 4(3): 163-167, 1990.
11. Dreazen O, Canaani E, Gale RP: Molecular biology of chronic myelogenous
leukemia. Seminars in Hematology 25(1): 35-49, 1988.
----------------------------------------------
CHRONIC PHASE CHRONIC MYELOGENOUS LEUKEMIA
Treatment options for chronic phase:
Average overall duration of therapy is 3 years; in many patients
therapy can be administered intermittently.[1,2]
1. The only consistently successful curative treatment for chronic
myelogenous leukemia (CML) has been high-dose chemotherapy and
total-body irradiation followed by rescue with transplantation of
syngeneic or allogeneic bone marrow. All patients younger than 55 years
old with an identical twin or with HLA-identical siblings should be
considered for bone marrow transplantation early in the chronic phase.
Although the procedure is associated with considerable acute morbidity
and mortality, in several large series, 50%-70% of patients
transplanted in the chronic phase survived 2-3 years, with the results
better in younger patients (especially those younger than age 20 years)
and progressively worse in the accelerated and blastic phases of the
disease.[3-5] It is not yet certain how many patients are cured by bone
marrow transplantation because many of the survivors have persistent
Philadelphia-positive (Ph+) cells in the marrow, and it is possible
that late relapses will occur. Immunologic mechanisms mediated by donor
cells (sometimes occurring with graft- versus-host disease) are
associated with long-term remissions after allogeneic bone marrow
transplantation.[6]
About 60% of otherwise eligible CML patients lack a suitably matched
sibling donor. HLA-matched unrelated donors or donors mismatched at one
HLA antigen can be found for about 20% of eligible participants through
the National Marrow Donor Program. However, there are still major
obstacles in using unrelated donors, especially in older patients, and
this approach must still be considered under evaluation.[7,8]
* Patients ineligible for syngeneic or allogeneic transplantation should
receive interferon alfa. In two trials comparing interferon alfa with
conventional chemotherapy (hydroxyurea or busulfan), patients in chronic
phase who received interferon alfa had more karyotypic responses, more delay
of disease progression, and prolonged overall survival.[9,10] Another
randomized study confirmed the advantage of interferon (median survival 5.5
years) over busulfan (median survival 3.8 years), but it did not detect a
significant difference between interferon and hydroxyurea (median survival
4.7 years).[11] About 20% of the chronic-phase patients treated with
interferon alfa have significant cytogenetic remissions with temporary
disappearance of Ph+ cells in the marrow, and in about 10% of the patients
these cytogenetic responses are quite long-lasting.[12,13] However, using
molecular methods of analysis, small numbers of Ph+ cells can still be
detected in the majority of patients having long-term cytogenetic
remissions, and longer follow-up will be required to ascertain whether the
disease will recur. Patients older than 60 years with chronic phase CML have
a hematologic and cytogenetic response rate and duration of cytogenetic
response similar to that in younger patients; however, the incidence of
complications is greater in elderly patients.[14] Interferon alfa has
significant toxic effects that can result in dosage modification or
discontinuation of therapy in many cases. Common side effects include
influenza-like syndrome, nausea, anorexia, and weight loss. Immune- mediated
complications, such as hyperthyroidism, hemolysis, and connective tissue
diseases may occur rarely after long-term treatment.[15] Interferon alfa is
quite costly, and daily subcutaneous injections can be troublesome. The
combination of interferon alfa and low-dose cytarabine may be more effective
than standard therapy in late chronic phase.[16] Interferon alfa is also
effective for patients who have relapsed after allogeneic bone marrow
transplantation.[17,18]
* Hydroxyurea is given daily by mouth (1-3 g/day as a single dose on an
empty stomach). Hydroxyurea is superior to busulfan in the chronic phase of
CML, with significantly longer median survival and significantly fewer
severe adverse effects.[19] A dose of 40 milligrams per kilogram per day is
often used initially and frequently results in a rapid reduction of the
white blood cell (WBC) count. When the WBC count drops below 20,000 per
cubic millimeter, the hydroxyurea is often reduced and titrated to maintain
a WBC count between 5,000 and 20,000. However, in a randomized trial in
which the hydroxyurea dose was adjusted to normalize the WBC count, no
difference in survival was seen between a group treated with hydroxyurea and
a group treated with interferon alfa, suggesting that a more aggressive
application of hydroxyurea may lead to additional benefits. This finding
requires confirmation.[11] Because of its lower toxicity, hydroxyurea is the
drug of choice for patients who are candidates for bone marrow
transplantation.
* Busulfan (Myleran) is given orally, either daily (4-8 milligrams per day)
or in 2-week courses. Busulfan is associated with unpredictable prolonged
myelosuppression, pulmonary fibrosis, and Addison's-like disease. A dose of
0.1 milligrams per kilogram per day is often used initially. The dose is
halved as the WBC count drops by one half and is discontinued when the WBC
count drops below 20,000.
* Splenectomy may be required and useful in patients having hematologic
problems and physical discomfort from a massive spleen.
* The possibility of eradicating the leukemic cell population during the
chronic phase by intensive treatment followed by rescue with autologous
marrow or peripheral blood stem cells has also been considered.[20] Various
methods have been tried to eliminate or reduce residual leukemic cells in
the autografts, including ex vivo treatment with cytotoxic drugs and various
immunologic or biologic purging methods. While some of the early reports
appear promising, they are based on relatively small numbers of selected
patients, and the follow-up period is too short to be sure late relapses
will not occur.
References:
1. Clarkson B: The chronic leukemias. In: Wyngaarden JB, Smith LJ, Eds.:
Cecil Textbook of Medicine. Philadelphia: WB Saunders, 18th ed., 1988,
pp 988-1001.
2. Silver RT: Chronic myeloid leukemia: a perspective of the clinical and
biologic issues of the chronic phase. Hematology/Oncology Clinics of
North America 4(2): 319-335, 1990.
3. Thomas ED, Clift RA: Indications for marrow transplantation in chronic
myelogenous leukemia. Blood 73(4): 861-864, 1989.
4. McGlave P: Bone marrow transplants in chronic myelogenous leukemia: an
overview of determinants of survival. Seminars in Hematology 27(3,
Suppl 4): 23-30, 1990.
5. Wagner JE, Zahurak M, Piantadosi S, et al.: Bone marrow transplantation
of chronic myelogenous leukemia in chronic phase: evaluation of risks
and benefits. Journal of Clinical Oncology 10(5): 779-789, 1992.
6. Pichert G, Roy DC, Gonin R, et al.: Distinct patterns of minimal
residual disease associated with graft-versus-host disease after
allogeneic bone marrow transplantation for chronic myelogenous
leukemia. Journal of Clinical Oncology 13(7): 1704-1713, 1995.
7. Mackinnon S, Hows JM, Goldman JM, et al.: Bone marrow transplantation
for chronic myeloid leukemia: the use of histocompatible unrelated
volunteer donors. Experimental Hematology 18(5): 421-425, 1990.
8. McGlave PB, Beatty P, Ash R, et al.: Therapy for chronic myelogenous
leukemia with unrelated donor bone marrow transplantation: results in
9. cases. Blood 75(8): 1728-1732, 1990.
10. The Italian Cooperative Study Group on Chronic Myeloid Leukemia:
Interferon alfa-2a as compared with conventional chemotherapy for the
treatment of chronic myeloid leukemia. New England Journal of Medicine
330(12): 820-825, 1994.
11. Allan NC, Richards SM, Shepherd PC, et al.: UK Medical Research Council
randomised, multicentre trial of interferon-alpha n1 for chronic
myeloid leukaemia: improved survival irrespective of cytogenetic
response. Lancet 345(8962): 1392-1397, 1995.
12. Hehlmann R, Heimpel H, Hasford J, et al.: Randomized comparison of
interferon-alfa with busulfan and hydroxyurea in chronic myelogenous
leukemia. Blood 84(12): 4064-4077, 1994.
13. Ozer H, George SL, Schiffer CA, et al.: Prolonged subcutaneous
administration of recombinant alpha 2b interferon in patients with
previously untreated Philadelphia chromosome-positive chronic-phase
chronic myelogenous leukemia: effect on remission duration and
survival: Cancer and Leukemia Group B study 8583. Blood 82(10):
2975-2984, 1993.
14. Kantarjian HM, Smith TL, O'Brien S, et al.: Prolonged survival in
chronic myelogenous leukemia after cytogenetic response to
interferon-alpha therapy. Annals of Internal Medicine 122(4): 254-261,
1995.
15. Cortes J, Kantarjian H, O'Brien S, et al.: Results of interferon-alpha
therapy in patients with chronic myelogenous leukemia 60 years of age
and older. American Journal of Medicine 100: 452-455, 1996.
16. Sacchi S, Kantarjian H, O'Brien S, et al.: Immune-mediated and unusual
complications during interferon alfa therapy in chronic myelogenous
leukemia. Journal of Clinical Oncology 13(9): 2401-2407, 1995.
17. Kantarjian HM, Keating MJ, Estey EH, et al.: Treatment of advanced
stages of Philadelphia chromosome-positive chronic myelogenous leukemia
with interferon-a and low-dose cytarabine. Journal of Clinical Oncology
10(5): 772-778, 1992.
18. Higano CS, Raskind WH, Singer JW: Use of alpha interferon for the
treatment of relapse of chronic myelogenous leukemia in chronic phase
after allogeneic bone marrow transplantation. Blood 80(6): 1437-1442,
1992.
19. Arcese W, Goldman JM, D'Arcangelo E, et al.: Outcome for patients who
relapse after allogeneic bone marrow transplantation for chronic
myeloid leukemia. Blood 82(10): 3211-3219, 1993.
20. Hehlmann R, Heimpel H, Hasford J, et al.: Randomized comparison of
busulfan and hydroxyurea in chronic myelogenous leukemia: prolongation
of survival by hydroxyurea. Blood 82(2): 398-407, 1993.
21. O'Brien SG, Goldman JM: Current approaches to hematopoietic stem-cell
purging in chronic myeloid leukemia. Journal of Clinical Oncology
13(3): 541-546, 1995.
22. Ozer H: Biotherapy of chronic myelogenous leukemia with interferon.
Seminars in Oncology 15(5, Suppl 5): 14-20, 1988.
23. Talpaz M, Kantarjian H, Kurzrock R, et al.: Update on therapeutic
options for chronic myelogenous leukemia. Seminars in Hematology 27(3,
Suppl 4): 31-36, 1990.
----------------------------------------------
ACCELERATED PHASE CHRONIC MYELOGENOUS LEUKEMIA
Treatment options for accelerated phase:
1. Bone marrow transplantation. Autologous marrow transplantation may
return the patient to a chronic phase, which may be durable. Allogeneic
marrow transplantation has the potential for cure, although results to
date are poor.[1-4]
* High-dose cytarabine.[5]
* Hydroxyurea.
* Busulfan.
* Supportive transfusion therapy.
References:
1. Martin PJ, Clift RA, Fisher LD, et al.: HLA-identical marrow
transplantation during accelerated-phase chronic myelogenous leukemia:
analysis of survival and remission duration. Blood 72(6): 1978-1984,
1988.
2. Copelan EA, Grever MR, Kapoor N, et al.: Marrow transplantation
following busulfan and cyclophosphamide for chronic myelogenous
leukaemia in accelerated or blastic phase. British Journal of
Haematology 71(4): 487-491, 1989.
3. Reiffers J, Trouette R, Marit G, et al.: Autologous blood stem cell
transplantation for chronic granulocytic leukaemia in transformation: a
report of 47 cases. British Journal of Haematology 77(3): 339-345,
1991.
4. Thomas ED, Clift RA: Indications for marrow transplantation in chronic
myelogenous leukemia. Blood 73(4): 861-864, 1989.
5. Kantarjian HM, Talpaz M, Kontoyiannis D, et al.: Treatment of chronic
myelogenous leukemia in accelerated and blastic phases with
daunorubicin, high-dose cytarabine, and granulocyte-macrophage
colony-stimulating factor. Journal of Clinical Oncology 10(3): 398-405,
1992.
----------------------------------------------
BLASTIC PHASE CHRONIC MYELOGENOUS LEUKEMIA
Treatment options for blastic phase:
1. Vincristine and prednisone with or without an anthracycline (for the
approximately 25% of patients with terminal deoxynucleotidyl
transferase- positive cells and lymphoblastic transformation).[1,2]
* Allogeneic bone marrow transplantation is successful in less than 10% of
patients because of complications of transplantation and recurrent
leukemia.[3,4] If available, this represents the only potentially curative
approach in such patients.
* Autologous marrow transplantation may return the patient to a chronic
phase, which may be durable.[5]
* Clinical trials exploring combination chemotherapy or new chemotherapeutic
agents. Drugs such as 5-azacytidine and mitoxantrone alone or in combination
have been associated with a 20% response rate.[6]
* Hydroxyurea (palliative).
* Radiation therapy to lytic bone lesions.
* High-dose cytarabine.[7,8]
The prognosis for any treated cancer patient with progressing, recurring, or
relapsing disease is poor, regardless of cell type or stage.[3] The question
and selection of further treatment depends on many factors, including the
specific cancer, previous treatment, site of recurrence, and individual
patient considerations. Because of the extremely poor results with standard
therapy of blast crisis, clinical trials are particularly appropriate and
should be considered when possible.[3,4,9,10]
References:
1. Preti HA, O'Brien S, Giralt S, et al.: Philadelphia-chromosome-positive
adult acute lymphocytic leukemia: characteristics, treatment results,
and prognosis in 41 patients. American Journal of Medicine 97: 60-65,
1994.
2. Walters RS, Kantarjian HM, Keating MJ, et al.: Therapy of lymphoid and
undifferentiated chronic myelogenous leukemia in blast crisis with
continuous vincristine and adriamycin infusions plus high-dose
decadron. Cancer 60(8): 1708-1712, 1987.
3. Copelan EA, Grever MR, Kapoor N, et al.: Marrow transplantation
following busulfan and cyclophosphamide for chronic myelogenous
leukaemia in accelerated or blastic phase. British Journal of
Haematology 71(4): 487-491, 1989.
4. Martin PJ, Clift RA, Fisher LD, et al.: HLA-identical marrow
transplantation during accelerated-phase chronic myelogenous leukemia:
analysis of survival and remission duration. Blood 72(6): 1978-1984,
1988.
5. Reiffers J, Trouette R, Marit G, et al.: Autologous blood stem cell
transplantation for chronic granulocytic leukaemia in transformation: a
report of 47 cases. British Journal of Haematology 77(3): 339-345,
1991.
6. Dutcher JP, Eudey L, Wiernik PH, et al.: Phase II study of mitoxantrone
and 5-azacytidine for accelerated and blast crisis of chronic
myelogenous leukemia: a study of the Eastern Cooperative Oncology
Group. Leukemia 6(8): 770-775, 1992.
7. Kantarjian HM, Walters RS, Keating MJ, et al.: Treatment of the blastic
phase of chronic myelogenous leukemia with mitoxantrone and high-dose
cytosine arabinoside. Cancer 62(4): 672-676, 1988.
8. Kantarjian HM, Talpaz M, Kontoyiannis D, et al.: Treatment of chronic
myelogenous leukemia in accelerated and blastic phases with
daunorubicin, high-dose cytarabine, and granulocyte-macrophage
colony-stimulating factor. Journal of Clinical Oncology 10(3): 398-405,
1992.
9. Silver RT: Chronic myeloid leukemia: a perspective of the clinical and
biologic issues of the chronic phase. Hematology/Oncology Clinics of
North America 4(2): 319-335, 1990.
10. Kantarjian HM, Keating MJ, Talpaz M, et al.: Chronic myelogenous
leukemia in blast crisis: analysis of 242 patients. American Journal of
Medicine 83(3): 445-454, 1987.
----------------------------------------------
MENINGEAL CHRONIC MYELOGENOUS LEUKEMIA
Treatment options for meningeal chronic myelogenous leukemia:
1. Intrathecal methotrexate.
* Intrathecal cytarabine.
* Cranial irradiation.
----------------------------------------------
REFRACTORY CHRONIC MYELOGENOUS LEUKEMIA
The prognosis for any treated cancer patient with progressing, recurring, or
relapsing disease is poor, regardless of cell type or stage.[1] The question
and selection of further treatment depends on many factors, including the
specific cancer, previous treatment, and site of recurrence, as well as
individual patient considerations. Because of the extremely poor results
with standard therapy of blast crisis, clinical trials are particularly
appropriate and should be considered when possible.[2-5] After relapse from
allogeneic bone marrow transplantation, some patients will respond to
interferon alfa.[6]
Infusions of buffy coat leukocytes or isolated T cells obtained by pheresis
from the bone marrow transplant donor have induced long-term remissions in
more than 50% of patients who relapse following allogeneic transplant. The
efficacy of this treatment is thought to be due to an immunologic
graft-versus-leukemia effect. This treatment is most effective for patients
whose relapse is detectable only by cytogenetics and is associated with
significant graft- versus-host disease.[7-10]
References:
1. Cervantes F, Rozman M, Rosell J, et al.: A study of prognostic factors
in blast crisis of Philadelphia chromosome-positive chronic myelogenous
leukaemia. British Journal of Haematology 76(1): 27-32, 1990.
2. Silver RT: Chronic myeloid leukemia: a perspective of the clinical and
biologic issues of the chronic phase. Hematology/Oncology Clinics of
North America 4(2): 319-335, 1990.
3. Kantarjian HM, Keating MJ, Talpaz M, et al.: Chronic myelogenous
leukemia in blast crisis: analysis of 242 patients. American Journal of
Medicine 83(3): 445-454, 1987.
4. Copelan EA, Grever MR, Kapoor N, et al.: Marrow transplantation
following busulfan and cyclophosphamide for chronic myelogenous
leukaemia in accelerated or blastic phase. British Journal of
Haematology 71(4): 487-491, 1989.
5. Martin PJ, Clift RA, Fisher LD, et al.: HLA-identical marrow
transplantation during accelerated-phase chronic myelogenous leukemia:
analysis of survival and remission duration. Blood 72(6): 1978-1984,
1988.
6. Pigneux A, Devergie A, Pochitaloff M, et al.: Recombinant
alpha-interferon as treatment for chronic myelogenous leukemia in
relapse after allogeneic bone marrow transplantation: a report from the
Societe Francaise de Greffe de Moelle. Bone Marrow Transplantation
15(6): 819-824, 1995.
7. Mackinnon S, Papadopoulos EB, Carabasi MH, et al.: Adoptive
immunotherapy evaluating escalating doses of donor leukocytes for
relapse of chronic myeloid leukemia after bone marrow transplantation:
separation of graft-versus-leukemia responses from graft-versus-host
disease. Blood 86(4): 1261-1268, 1995.
8. Bar BM, Schattenberg A, Mensink EJ, et al.: Donor leukocyte infusions
for chronic myeloid leukemia relapsed after allogeneic bone marrow
transplantation. Journal of Clinical Oncology 11(3): 513-519, 1993.
9. Porter DL, Roth MS, McGarigle C, et al.: Induction of graft-versus-host
disease as immunotherapy for relapsed chronic myeloid leukemia. New
England Journal of Medicine 330(2): 100-106, 1994.
10. Kolb HJ, Schattenberg A, Goldman JM, et al.: Graft-versus-leukemia
effect of donor lymphocyte transfusions in marrow grafted patients.
Blood 86(5): 2041-2050, 1995.
Date Last Modified: 03/97
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