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Information from PDQ -- for Health Professionals
Chronic myelogenous leukemia
208/01031
** 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 or immunotherapy. Allogeneic bone marrow transplantation from
related or unrelated donors is the only known curative therapy.[1] Survival
after development of an accelerated phase is usually less than 1 year and after
blastic transformation is only a few months.[2]
Other related entities include polycythemia vera, myelofibrosis, and essential
thrombocythemia. CML is a clonal disorder that is usually easily diagnosed
because the leukemic cells of more than 95% of patients have a distinctive
cytogenetic abnormality, the Philadelphia (Ph) chromosome.[3] The Ph
chromosome results from a reciprocal translocation between the long arms of
chromosomes 9 and 22 and is demonstrable in all hematopoietic precursors.[3]
This translocation results in the transfer of the Abelson (abl) oncogene to an
area of chromosome 22 termed the breakpoint cluster region (bcr).[3] This in
turn results in a fused bcr-abl gene and in the production of an abnormal
tyrosine kinase protein that causes 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.[4,5] 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 Ph chromosome. However, patients who are
bcr-abl-negative by RT-PCR have a clinical course more consistent with chronic
myelomonocytic leukemia, a distinct clinical entity related to myelodysplastic
syndrome.[4,6,7]
The median age of patients with Ph+ CML is 67 years of age.[1] Median survival
is 4 to 6 years, with a range of less than 1 year to more than 10 years.
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.[8]
References:
1. Lee SJ, Anasetti C, Horowitz MM, et al.: Initial therapy for chronic
myelogenous leukemia: playing the odds. Journal of Clinical Oncology
16(9): 2897-2903, 1998.
2. Sawyers CL: Chronic myeloid leukemia. New England Journal of Medicine
340(17): 1330-1340, 1999.
3. Deininger MW, Goldman JM, Melo JV: The molecular biology of chronic
myeloid leukemia. Blood 96(10): 3343-3356, 2000.
4. 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.
5. Cortes JE, Talpaz M, Beran M, et al.: Philadelphia chromosome-negative
chronic myelogenous leukemia with rearrangement of the breakpoint
cluster region: long term follow-up results. Cancer 75(2): 464-470,
1995.
6. Oscier DG: Atypical chronic myeloid leukemia, a distinct clinical entity
related to the myelodysplastic syndrome? British Journal of Haematology
92(3): 582-586, 1996.
7. Kuzrock R, Bueso-Ramos CE, Kantarjian H, et al.: BCR
rearrangement-negative chronic myelogenous leukemia revisited. Journal
of Clinical Oncology 19(11): 2915-2926, 2001.
8. 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. Quantitative Southern blot analysis of blood samples for
breakpoint cluster region gene rearrangement may substitute for bone marrow
sampling to monitor response to therapy.[1]
The most common finding on physical examination at diagnosis is
splenomegaly.[2] 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.
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.[2]
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"). The annual rate of progression from chronic phase
to blast crisis is 5% to 10% in the first 2 years and 20% in subsequent
years.[3,4] 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.[2,5,6]
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, older age, male sex, elevated serum lactate
dehydrogenase, cytogenetic abnormalities in addition to the Ph chromosome, a
higher proportion of marrow or peripheral blood blasts, basophilia,
eosinophilia, thrombocytosis, and anemia predicted for a shorter chronic phase.
Predictive models using multivariate analysis have been derived.[3,4,7-10] It
should be noted that transplant centers performing 5 or fewer transplants
annually usually have poorer results than larger centers.[11]
-- 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.[5,6]
References:
1. Stock W, Westbrook CA, Peterson B, et al.: Value of molecular monitoring
during the treatment of chronic myeloid leukemia: a Cancer and Leukemia
Group B study. Journal of Clinical Oncology 15(1): 26-36, 1997.
2. Sawyers CL: Chronic myeloid leukemia. New England Journal of Medicine
340(17): 1330-1340, 1999.
3. Sokal JE, Cox EB, Baccarani M, et al.: Prognostic discrimination in
"good-risk" chronic granulocytic leukemia. Blood 63(4): 789-799, 1984.
4. Sokal JE, Baccarani M, Russo D, et al.: Staging and prognosis in chronic
myelogenous leukemia. Seminars in Hematology 25(1): 49-61, 1988.
5. 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.
6. 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.
7. 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.
8. Sacchi S, Kantarjian HM, Smith TL, et al.: Early treatment decisions with
interferon-alfa therapy in early chronic-phase chronic myelogenous
leukemia. Journal of Clinical Oncology 16(3): 882-889, 1998.
9. Hasford J, Pfirrmann M, et al, for the Collaborative CML Prognostic
Factors Project Group: A new prognostic score for survival of patients
with chronic myeloid leukemia treated with interferon alfa. Journal of
the National Cancer Institute 90(11): 850-858, 1998.
10. Kvasnicka HM, Thiele J, Schmitt-Graeff A, et al.: Bone marrow features
improve prognostic efficiency in multivariate risk classification of
chronic-phase Ph1+ chronic myelogenous leukemia: a multicenter trial.
Journal of Clinical Oncology 19(12): 2994-3009, 2001.
11. 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 **
Note: Some citations in the text of this section are followed by a level of
evidence. The PDQ editorial boards use a formal ranking system to help the
reader judge the strength of evidence linked to the reported results of a
therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more
information.)
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.[1] 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.[2] Many patients will not be young or healthy enough to tolerate
transplantation; those who can are likely to find a histocompatible related
donor 30% of the time and a suitable unrelated donor 50% of the time.[2]
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.[3] 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.
Since tyrosine kinase activity is required for the transforming function of the
bcr-abl fusion protein, a specific inhibitor of the kinase could be an
effective treatment for patients with CML.[4,5] Imatinib mesylate (STI571)
competitively blocks the ATP-binding site of the abl kinase; the kinase
activity of the stem-cell-receptor factor (c-KIT) and platelet-derived growth
factor receptors are also blocked.[6-8] Imatinib mesylate specifically
inhibits the proliferation of CML-derived cell-lines and the clonogenic growth
of cells from the bone marrow of patients with CML. CML proliferation in nude
mice was also eradicated. In the preliminary results of 2 phase I trials,
imatinib mesylate induced hematologic remission in almost all patients with
interferon-resistant chronic phase CML; with a median duration of therapy less
than 1 year, 45% to 54% showed some degree of cytogenetic response.[5][Level of
evidence: 3iiiDiii];[9] Responses were also seen in patients with myeloid and
lymphoid blast crises, although the responses appear more durable for the
myeloid blast phenotype.[10][Level of evidence: 3iiiDiii] These preliminary
results demonstrate activity which appears greater than that of any other agent
used in treatment of CML. However, the follow-up of treated patients is short
(median follow-up was 265 days). Results are expected from a multicenter
prospective trial randomizing untreated patients to interferon plus cytarabine
or imatinib mesylate.[11] The outcome of this trial will be critical in
helping to determine whether imatinib mesylate should be used as first-line
therapy or reserved for patients who do not develop cytogenetic responses to
interferon. For a relatively young patient for whom cure is the primary goal,
allogeneic stem cell transplantation must remain the first option until it is
clear that imatinib can cure most patients or prolong life more than interferon
alfa.[12]
In patients with blast crisis who have relapsed following treatment with
imatinib mesylate, imatinib resistance was associated with reactivation of bcr-
abl signal transduction. In 6 of 9 patients studied, this was associated with
a mutation in the abl kinase domain which forms a critical hydrogen bond with
the drug. In 3 patients, resistance was associated with progressive gene
amplification of bcr-abl.[13]
Allogeneic bone marrow transplantation in the chronic phase is the only therapy
known to cure CML. Most transplant series suggest improved survival when the
procedure is performed within 1 year of diagnosis.[14][Level of evidence:
3iiiA];[15][Level of evidence: 3iiiA];[16][Level of evidence: 3iiiA] However,
the data supporting early transplant have never been confirmed in controlled
trials. Other treatment of CML does not cure the disease. 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.[17] 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 breakpoint cluster region
(bcr). This results in the 2 common variants of the fused bcr-Abelson (abl)
gene seen typically in Ph+ CML, both of which are associated with the
expression of a p210 bcr-abl hybrid protein.[3,18,19]
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. Sawyers CL: Chronic myeloid leukemia. New England Journal of Medicine
340(17): 1330-1340, 1999.
2. Lee SJ, Anasetti C, Horowitz MM, et al.: Initial therapy for chronic
myelogenous leukemia: playing the odds. Journal of Clinical Oncology
16(9): 2897-2903, 1998.
3. Kurzrock R, Gutterman JU, Talpaz M: The molecular genetics of
Philadelphia chromosome-positive leukemias. New England Journal of
Medicine 319(15): 990-998, 1988.
4. Deininger MW, Goldman JM, Melo JV: The molecular biology of chronic
myeloid leukemia. Blood 96(10): 3343-3356, 2000.
5. Druker BJ, Talpaz M, Resta DJ, et al.: Efficacy and safety of a specific
inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia.
New England Journal of Medicine 344(14): 1031-1037, 2001.
6. Goldman JM: Tyrosine-kinase inhibition in treatment of chronic myeloid
leukaemia. Lancet 355(9209): 1031-1032, 2000.
7. Druker BJ, Tamura S, Buchdunger E, et al.: Effects of a selective
inhibitor of the Abl tyrosine kinase on the growth of Bcr-Abl positive
cells. Nature Medicine 2(5): 561-566, 1996.
8. Deininger MW, Goldman JM, Lydon N, et al.: The tyrosine kinase inhibitor
CGP57148B selectively inhibits the growth of BCR-ABL-positive cells.
Blood 90(9): 3691-3698, 1997.
9. le Coutre P, Mologni L, Cleris L, et al.: In vivo eradication of human
BCR/ABL-positive leukemia cells with an ABL kinase inhibitor. Journal
of the National Cancer Institute 91(2): 163-168, 1999.
10. Druker BJ, Sawyers CL, Kantarjian H, et al.: Activity of a specific
inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic
myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia
chromosome. New England Journal of Medicine 344(14): 1038-1042, 2001.
11. Clinical Trial Line NO, Novartis Pharmaceuticals Corporation: Phase III
Randomized Study of STI571 vs Interferon Alfa and Cytarabine in Patients
With Newly Diagnosed, Previously Untreated, Philadelphia Chromosome
Positive, Chronic Phase Chronic Myelogenous Leukemia (Summary Last
Modified 02/2001), NOVARTIS-CSTI5710106, clinical trial, closed,
01/16/2001.
12. Goldman JM, Melo JV: Targeting the BCR-ABL tyrosine kinase in chronic
myeloid leukemia. New England Journal of Medicine 344(14): 1084-1086,
2001.
13. Gorre ME, Mohammed M, Ellwood K, et al.: Clinical resistance to STI-571
cancer therapy caused by BCR-ABL gene mutation or amplification.
Science 293(5531): 876-880, 2001.
14. Goldman JM, Szydlo R, Horowitz MM, et al.: Choice of pretransplant
treatment and timing of transplants for chronic myelogenous leukemia in
chronic phase. Blood 82(7): 2235-2238, 1993.
15. Clift RA, Appelbaum FR, Thomas ED: Treatment of chronic myeloid leukemia
by marrow transplantation. Blood 82(7): 1954-1956, 1993.
16. Hansen JA, Gooley TA, Martin PJ, et al.: Bone marrow transplants from
unrelated donors for patients with chronic myeloid leukemia. New
England Journal of Medicine 338(14): 962-968, 1998.
17. 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.
18. Goldman JM, Grosveld G, Baltimore D, et al.: Chronic myelogenous leukemia
- the unfolding saga. Leukemia 4(3): 163-167, 1990.
19. 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 **
Note: Some citations in the text of this section are followed by a level of
evidence. The PDQ editorial boards use a formal ranking system to help the
reader judge the strength of evidence linked to the reported results of a
therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more
information.)
The choice of initial therapy for patients with chronic phase chronic
myelogenous leukemia (CML) is complicated. Allogeneic transplantation offers
the only prospect of cure, but the morbidity and mortality are high. For
patients younger than 40 years of age, allogeneic transplantation with a
related or unrelated donor is the highest priority and should be considered
within the first year following diagnosis.[1-3] Patients older than 40 years
of age who have a related donor should strongly consider allogeneic
transplantation, although morbidity and mortality of the procedure rise with
increased age. Because of the increased morbidity and mortality from unrelated
donors in patients over 40 years of age, a trial of interferon with or without
cytarabine is recommended.[4] Patients without a major cytogenetic response
would then proceed to transplantation when feasible.
Standard treatment options:
1. The only consistently successful curative treatment of CML has been high-
dose therapy followed by allogeneic bone marrow transplantation.[5] All
patients younger than 60 years of age with an identical twin or with
HLA-identical siblings should be considered for bone marrow transplantation
(BMT) early in the chronic phase. Although the procedure is associated with
considerable acute morbidity and mortality, in several large series, 50% to 70%
of patients transplanted in the chronic phase survived 2 to 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.[6-9] Most transplant series suggest improved survival when the
procedure is performed within 1 year of diagnosis.[1][Level of evidence:
3iiiA];[2][Level of evidence: 3iiiA];[3][Level of evidence: 3iiiA] However,
the data supporting early transplant have never been confirmed in controlled
trials. In a randomized clinical trial, disease-free and overall survival were
comparable when allogeneic transplantation followed preparative therapy with
cyclophosphamide and total body irradiation (TBI) or busulfan and
cyclophosphamide without TBI. The latter regimen was associated with less
graft-versus-host disease and fewer fevers, hospitalizations, and hospital
days.[10][Level of evidence: 1iiA]
About 20% of otherwise eligible CML patients lack a suitably matched sibling
donor.[4] HLA-matched unrelated donors or donors mismatched at 1 HLA antigen
can be found for about 50% of eligible participants through the National Marrow
Donor Program.[4] However, there are still major obstacles in using unrelated
donors, especially in older patients. Two retrospective series following
allogeneic BMT from an HLA-matched unrelated donor showed a 5-year relapse rate
of 3% to 10% and a 5-year overall survival rate of 31% to 57% (most deaths were
treatment-related).[9][Level of evidence: 3iiiA];[11] Patients with unrelated
donor transplants were generally younger and had a longer interval from
diagnosis to transplant. While the majority of relapses occur within 5 years
of transplantation, relapses have occurred as long as 9 years following BMT.
The risk of relapse appears to be less in patients transplanted early in
disease, and in patients who develop chronic graft-versus-host disease.[9,12]
BMT from an unrelated donor is associated with a higher risk of post-transplant
graft failure and infection (viral and fungal). The incidence of relapse is
lower with BMT from unrelated donors than it is from sibling donors.
Interferon alfa, hydroxyurea, or both, are standard treatments used to
stabilize patients prior to BMT. Early studies also suggested that prior
interferon exposure had an adverse effect on outcome following subsequent
allogeneic BMT.[13,14] However, subsequent studies have not confirmed these
observations.[15,16] Retrospective studies suggest that the potential negative
impact of interferon on transplant outcome appears to be limited to patients
receiving transplantation from a matched, unrelated donor, and may be
ameliorated by withdrawal of interferon for at least 90 days prior to
transplantation.[17,15,16]
2. Patients ineligible for syngeneic or allogeneic transplantation should
receive interferon alfa. A meta-analysis of 7 trials that randomized patients
to receive interferon or conventional chemotherapy (hydroxyurea or busulfan)
demonstrated a 30% reduction in the annual death rate for patients who received
interferon (P<.00001). The annual death rate was reduced by 26% in the trials
of interferon versus hydroxyurea (P=.001) and 36% in the trials of interferon
versus busulfan (P=.00007). Median survival was prolonged by 1 to 2 years; 5-
year survival rate was 57% for patients treated with interferon, and 42% for
patients treated with chemotherapy (P<.00001). Further analysis of the 2
trials, which included a 3-way randomization between interferon, hydroxyurea,
and busulfan, showed hydroxyurea to be superior to busulfan, decreasing the
proportional odds of death by 24% (P=.02).[18] About 20% of the chronic-phase
patients treated with interferon alfa have complete 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.[19-21] These data
have only been published in the context of a review article, rather than a
peer-reviewed research manuscript.[21] Long-term follow-up of the interferon-
treated patients from a randomized trial comparing interferon with chemotherapy
showed that the median survival had not been reached at 10 years for patients
who had complete or major cytogenetic responses to interferon.[22] Seventy-
four percent of patients with complete cytogenetic responses and 55% of
patients with major cytogenetic responses were alive and had shown no disease
progression at date of publication (median follow-up time was not provided).
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.[23] 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,
weight loss, and neuropsychiatric symptoms, all of which are completely
reversible with cessation of therapy.[24] Immune -mediated complications, such
as hyperthyroidism, hemolysis, and connective tissue diseases may occur rarely
after long-term treatment.[25] Interferon alfa is quite costly, and daily
subcutaneous injections can be troublesome. Patients who achieve cytogenetic
remission should continue therapy (3-5 million units per meter squared daily)
for at least 2 to 3 years beyond remission, and perhaps indefinitely, as
suggested by some investigators. Partially responding patients (<35%
Philadelphia chromosome) should continue taking interferon until loss of
response unless a suitable transplant donor can be found (if applicable).[26]
The French Chronic Myeloid Leukemia Study Group randomized 721 patients to
interferon and cytarabine versus interferon alone.[27][Level of evidence: 1iiA]
Patients who received the combination had significantly more major cytogenetic
responses (41% versus 24%, p<.001) and improved 3-year survival (86% versus
80%). All patients initially received hydroxyurea until complete hematologic
remission was attained; many clinicians use hydroxyurea to normalize the
leukocytosis when starting interferon. The improved efficacy of this
combination of interferon and cytarabine must be balanced against the increased
toxic effects.[27] For patients who have adequate performance status, yet are
not candidates for transplantation, this combination is a reasonable
option.[28] Interferon alfa is also effective for patients who have relapsed
after allogeneic bone marrow transplantation.[29,30]
3. Since tyrosine kinase activity is required for the transforming function of
the bcr-abl fusion protein, a specific inhibitor of the kinase could be an
effective treatment for patients with CML.[31,32] Imatinib mesylate (STI-571)
is a compound which inhibits the bcr-abl oncoprotein which is pathogenic in
CML. In the preliminary results of 2 phase I trials, imatinib mesylate induced
hematologic remission in almost all patients with interferon-resistant chronic
phase CML; with a median duration of therapy less than 1 year, 45% to 54%
showed some degree of cytogenetic response.[32][Level of evidence:
3iiiDiii];[33] Responses were also seen in patients with myeloid and lymphoid
blast crises, although the responses appear more durable for the myeloid blast
phenotype.[34][Level of evidence: 3iiiDiii] These preliminary results
demonstrate activity which appears greater than that of any other agent used in
treatment of CML. However, the follow-up of treated patients is short (median
follow-up was 265 days). Results are expected from a multicenter prospective
trial randomizing untreated patients to interferon plus cytarabine or imatinib
mesylate.[35] The outcome of this trial will be critical in helping to
determine whether imatinib mesylate should be used as first line therapy or
reserved for patients who do not develop cytogenetic responses to
interferon.[32] For a relatively young patient for whom cure is the primary
goal, allogeneic stem cell transplantation must remain the first option until
it is clear that imatinib can cure most patients or prolong life more than
interferon alfa.[36]
In patients with blast crisis who have relapsed following treatment with
imatinib mesylate, imatinib resistance was associated with reactivation of bcr-
abl signal transduction. In 6 of 9 patients studied, this was associated with
a mutation in the abl kinase domain which forms a critical hydrogen bond with
the drug. In 3 patients, resistance was associated with progressive gene
amplification of bcr-abl.[37]
4. Hydroxyurea is given daily by mouth (1-3 grams per 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.[38] 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.[39] Hydroxyurea is
currently used primarily to stabilize patients with hyperleukocytosis, or as
palliative therapy for patients for whom other therapies have failed.
5. Busulfan (Myleran), which is rarely used, 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.
6. Splenectomy may be required and useful in patients having hematologic
problems and physical discomfort from a massive spleen.
7. 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.[40,41] 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. Goldman JM, Szydlo R, Horowitz MM, et al.: Choice of pretransplant
treatment and timing of transplants for chronic myelogenous leukemia in
chronic phase. Blood 82(7): 2235-2238, 1993.
2. Clift RA, Appelbaum FR, Thomas ED: Treatment of chronic myeloid leukemia
by marrow transplantation. Blood 82(7): 1954-1956, 1993.
3. Hansen JA, Gooley TA, Martin PJ, et al.: Bone marrow transplants from
unrelated donors for patients with chronic myeloid leukemia. New
England Journal of Medicine 338(14): 962-968, 1998.
4. Lee SJ, Anasetti C, Horowitz MM, et al.: Initial therapy for chronic
myelogenous leukemia: playing the odds. Journal of Clinical Oncology
16(9): 2897-2903, 1998.
5. Gratwohl A, Hermans J: Allogeneic bone marrow transplantation for chronic
myeloid leukemia. Bone Marrow Transplantation 17(Suppl 3): S7-S9, 1996.
6. Thomas ED, Clift RA: Indications for marrow transplantation in chronic
myelogenous leukemia. Blood 73(4): 861-864, 1989.
7. 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.
8. 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.
9. Enright H, Davies SM, DeFor T, et al.: Relapse after non-T-cell-depleted
allogeneic bone marrow transplantation for chronic myelogenous leukemia:
early transplantation, use of an unrelated donor, and chronic
graft-versus-host disease are protective. Blood 88(2): 714-720, 1996.
10. Clift RA, Buckner CD, Thomas ED, et al.: Marrow transplantation for
chronic myeloid leukemia: a randomized study comparing cyclophosphamide
and total body irradiation with busulfan and cyclophosphamide. Blood
84(6): 2036-2043, 1994.
11. Hansen JA, Gooley TA, Martin PJ, et al.: Bone marrow transplants from
unrelated donors for patients with chronic myeloid leukemia. New
England Journal of Medicine 338(14): 962-968, 1998.
12. 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.
13. Beelen DW, Graeven U, Elmaagacli AH, et al.: Prolonged administration of
interferon-alpha in patients with chronic-phase Philadelphia
chromosome-positive chronic myelogenous leukemia before allogeneic bone
marrow transplantation may adversely affect transplant outcome. Blood
85(10): 2981-2990, 1995.
14. Giralt SA, Kantarjian HM, Talpaz M, et al.: Effect of prior interferon
alfa therapy on the outcome of allogeneic bone marrow transplantation
for chronic myelogenous leukemia. Journal of Clinical Oncology 11(6):
1055-1061, 1993.
15. Giralt S, Szydlo R, Goldman JM, et al.: Effect of short-term interferon
therapy on the outcome of subsequent HLA-identical sibling bone marrow
transplantation for chronic myelogenous leukemia: an analysis from the
International Bone Marrow Transplant Registry. Blood 95(2): 410-415,
2000.
16. Hehlmann R, Hochhaus A, et al. for the German CML-Study Group and the
SAKK: Interferon-alfa before allogeneic bone marrow transplantation in
chronic myelogenous leukemia does not affect outcome adversely, provided
it is discontinued at least 90 days before the procedure. Blood 94(11):
3668-3677, 1999.
17. Morton AJ, Gooley T, Hansen JA, et al.: Association between pretransplant
interferon-alpha and outcome after unrelated donor marrow
transplantation for chronic myelogenous leukemia in chronic phase.
Blood 92(2): 394-401, 1998.
18. Interferon alfa versus chemotherapy for chronic myeloid leukemia: a
meta-analysis of seven randomized trials: Chronic Myeloid Leukemia
Trialists' Collaborative Group. Journal of the National Cancer
Institute 89(21): 1616-1620, 1997.
19. 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.
20. 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.
21. Kantarjian HM, Deisseroth A, Kurzrock R, et al.: Chronic myelogenous
leukemia: a concise update. Blood 82(3): 691-703, 1993.
22. Long-term follow-up of the Italian trial of interferon-alfa versus
conventional chemotherapy in chronic myeloid leukemia. The Italian
Cooperative Study Group on Chronic Myeloid Leukemia. Blood 92(5):
1541-1548, 1998.
23. 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.
24. Hensley ML, Peterson B, Silver RT, et al.: Risk factors for severe
neuropsychiatric toxicity in patients receiving interferon alfa-2b and
low-dose cytarabine for chronic myelogenous leukemia: analysis of Cancer
and Leukemia Group B 9013. Journal of Clinical Oncology 18(6):
1301-1308, 2000.
25. 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.
26. Jankovic GM, Colovic MD: International conference on chronic myelocytic
leukemia: biology and treatment organised by the Scientific Committee of
The Israel Society of Hematology, Jerusalem, Israel, 28-31 January 1996.
Leukemia 10(10): 1667-1670, 1996.
27. Guilhot F, Chastang C, et al, for the French Chronic Myeloid Leukemia
Study Group: Interferon alfa-2b combined with cytarabine versus
interferon alone in chronic myelogenous leukemia. New England Journal
of Medicine 337(4): 223-229, 1997.
28. Goldman JM: Optimizing treatment for chronic myeloid leukemia. New
England Journal of Medicine 337(4): 270-271, 1997.
29. 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.
30. 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.
31. Deininger MW, Goldman JM, Melo JV: The molecular biology of chronic
myeloid leukemia. Blood 96(10): 3343-3356, 2000.
32. Druker BJ, Talpaz M, Resta DJ, et al.: Efficacy and safety of a specific
inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia.
New England Journal of Medicine 344(14): 1031-1037, 2001.
33. le Coutre P, Mologni L, Cleris L, et al.: In vivo eradication of human
BCR/ABL-positive leukemia cells with an ABL kinase inhibitor. Journal
of the National Cancer Institute 91(2): 163-168, 1999.
34. Druker BJ, Sawyers CL, Kantarjian H, et al.: Activity of a specific
inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic
myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia
chromosome. New England Journal of Medicine 344(14): 1038-1042, 2001.
35. Clinical Trial Line NO, Novartis Pharmaceuticals Corporation: Phase III
Randomized Study of STI571 vs Interferon Alfa and Cytarabine in Patients
With Newly Diagnosed, Previously Untreated, Philadelphia Chromosome
Positive, Chronic Phase Chronic Myelogenous Leukemia (Summary Last
Modified 02/2001), NOVARTIS-CSTI5710106, clinical trial, closed,
01/16/2001.
36. Goldman JM, Melo JV: Targeting the BCR-ABL tyrosine kinase in chronic
myeloid leukemia. New England Journal of Medicine 344(14): 1084-1086,
2001.
37. Gorre ME, Mohammed M, Ellwood K, et al.: Clinical resistance to STI-571
cancer therapy caused by BCR-ABL gene mutation or amplification.
Science 293(5531): 876-880, 2001.
38. 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.
39. 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.
40. 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.
41. Carella AM, Simonsson B, Link H, et al.: Mobilization of
Philadelphia-negative peripheral blood progenitor cells with
chemotherapy and rhuG-CSF in chronic myelogenous leukaemia patients with
a poor response to interferon-alpha. British Journal of Haematology
101(1): 111-118, 1998.
** ACCELERATED PHASE CHRONIC MYELOGENOUS LEUKEMIA **
Note: Some citations in the text of this section are followed by a level of
evidence. The PDQ editorial boards use a formal ranking system to help the
reader judge the strength of evidence linked to the reported results of a
therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more
information.)
Standard treatment options:
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]
2. Imatinib mesylate (STI571). Nineteen patients treated on the phase I trial
of imatinib mesylate for patients failing to respond to alpha interferon had
features of accelerated disease. The data have not been presented in such a way
to estimate response rate for this sub-group of patients. However, given the
activity of this compound in blast crisis (see below), it is highly likely that
activity is maintained for some patients in accelerated phase.[5]
3. Interferon alfa.[6] Although the response rate is lower for accelerated
phase disease than it is for chronic phase disease, durable responses and
suppression of cytogenetic clonal evolution have been reported.[6,7] When
cytarabine was added to interferon alfa, in comparison to historical controls
of interferon alone, the response rate and 3-year survival appeared to be
improved in late-stage patients.[7][Level of evidence: 3iiiA]
4. High-dose cytarabine.[8]
5. Hydroxyurea.
6. Busulfan.
7. 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. Druker BJ, Talpaz M, Resta DJ, et al.: Efficacy and safety of a specific
inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia.
New England Journal of Medicine 344(14): 1031-1037, 2001.
6. Cortes J, Talpaz M, O'Brien S, et al.: Suppression of cytogenetic clonal
evolution with interferon alfa therapy in patients with Philadelphia
chromosome-positive chronic myelogenous leukemia. Journal of Clinical
Oncology 16(10): 3279-3285, 1998.
7. Kantarjian HM, Keating MJ, Estey EH, et al.: Treatment of advanced stages
of Philadelphia chromosome-positive chronic myelogenous leukemia with
interferon-alfa and low-dose cytarabine. Journal of Clinical Oncology
10(5): 772-778, 1992.
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.
** BLASTIC PHASE CHRONIC MYELOGENOUS LEUKEMIA **
Standard treatment options:
1. Imatinib mesylate (STI571) has demonstrated marked activity in patients with
myeloid blast crisis and in patients with lymphoid blast crisis or Philadelphia
chromosome-positive acute lymphoblastic leukemia. In a phase I trial, 4 of 38
patients with myeloid blast crisis had a complete hematologic remission and 17
had a decrease in blasts in the marrow to 15% or less.[1] Of the 20 patients in
the lymphoid cohort, 4 had a complete hematologic response and 10 had a
decrease in blasts in the marrow to 15 percent or less. Unfortunately, these
responses have not been durable. Of 21 responding patients with myeloid blast
crisis, 9 relapsed between 42 and 194 days; of the 14 responding patients with
lymphoid disease, 12 relapsed with a median duration of time to relapse of 58
days. Seven of the 21 responding patients with myeloid blast crisis continue
in remission with longest follow up of 349 days. These response data are the
highest single agent responses in this disease.[1]
2. Vincristine and prednisone with or without an anthracycline (for the
approximately 25% of patients with terminal deoxynucleotidyl transferase-
positive cells and lymphoblastic transformation).[2,3]
3. Allogeneic bone marrow transplantation is successful in less than 10% of
patients because of complications of transplantation and recurrent
leukemia.[4] If available, this represents the only potentially curative
approach in such patients. Allogeneic transplantation is more effective in
patients induced into a second chronic phase, with long-term disease-free
survival approximating 20%.[5]
4. Hydroxyurea (palliative).
5. High-dose cytarabine.[6]
The prognosis for any treated cancer patient with progressing, recurring, or
relapsing disease is poor, regardless of cell type or stage.[4] 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.[4,7,8]
References:
1. Druker BJ, Sawyers CL, Kantarjian H, et al.: Activity of a specific
inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic
myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia
chromosome. New England Journal of Medicine 344(14): 1038-1042, 2001.
2. 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.
3. 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.
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. Gratwohl A, Hermans J, Niederwieser D, et al.: Bone marrow
transplantation for chronic myeloid leukemia: long-term results. Bone
Marrow Transplantation 12(5): 509-516, 1993.
6. 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.
7. 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.
8. 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.
** RELAPSING CHRONIC MYELOGENOUS LEUKEMIA **
Note: Some citations in the text of this section are followed by a level of
evidence. The PDQ editorial boards use a formal ranking system to help the
reader judge the strength of evidence linked to the reported results of a
therapeutic strategy. (Refer to the PDQ summary on Levels of Evidence for more
information.)
In the preliminary results of 2 phase I trials, imatinib mesylate (STI571)
induced hematologic remission in almost all patients with interferon-resistant
chronic phase CML; with a median duration of therapy less than 1 year, 45% to
54% showed some degree of cytogenetic response.[1];[2][Level of evidence:
3iiiDiii] Responses were also seen in patients with myeloid and lymphoid blast
crises, although the responses appear more durable for the myeloid blast
phenotype.[3][Level of evidence: 3iiiDiii] These preliminary results
demonstrate activity which appears greater than that of any other agent used in
treatment of CML. Results are expected from a multicenter prospective trial
randomizing untreated patients to interferon plus cytarabine or imatinib
mesylate.[4] For a relatively young patient for whom cure is the primary goal,
allogeneic stem cell transplantation must remain the first option until it is
clear that imatinib mesylate can cure most patients or prolong life more than
interferon alfa.[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 or molecular studies and is associated with
significant graft-versus-host disease.[7-11]
Combinations of chemotherapy are being evaluated for patients who relapse from
interferon or who cannot tolerate the side effects of interferon.[12]
References:
1. le Coutre P, Mologni L, Cleris L, et al.: In vivo eradication of human
BCR/ABL-positive leukemia cells with an ABL kinase inhibitor. Journal
of the National Cancer Institute 91(2): 163-168, 1999.
2. Druker BJ, Talpaz M, Resta DJ, et al.: Efficacy and safety of a specific
inhibitor of the BCR-ABL tyrosine kinase in chronic myeloid leukemia.
New England Journal of Medicine 344(14): 1031-1037, 2001.
3. Druker BJ, Sawyers CL, Kantarjian H, et al.: Activity of a specific
inhibitor of the BCR-ABL tyrosine kinase in the blast crisis of chronic
myeloid leukemia and acute lymphoblastic leukemia with the Philadelphia
chromosome. New England Journal of Medicine 344(14): 1038-1042, 2001.
4. Clinical Trial Line NO, Novartis Pharmaceuticals Corporation: Phase III
Randomized Study of STI571 vs Interferon Alfa and Cytarabine in Patients
With Newly Diagnosed, Previously Untreated, Philadelphia Chromosome
Positive, Chronic Phase Chronic Myelogenous Leukemia (Summary Last
Modified 02/2001), NOVARTIS-CSTI5710106, clinical trial, closed,
01/16/2001.
5. Goldman JM, Melo JV: Targeting the BCR-ABL tyrosine kinase in chronic
myeloid leukemia. New England Journal of Medicine 344(14): 1084-1086,
2001.
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.
11. van Rhee F, Savage D, Blackwell J, et al.: Adoptive immunotherapy for
relapse of chronic myeloid leukemia after allogeneic bone marrow
transplant: equal efficacy of lymphocytes from sibling and matched
unrelated donors. Bone Marrow Transplantation 21(10): 1055-1061, 1998.
12. Kantarjian HM, Talpaz M, Smith TL, et al.: Homoharringtonine and low-dose
cytarabine in the management of late chronic-phase chronic myelogenous
leukemia. Journal of Clinical Oncology 18(20): 3513-3521, 2000.
Date Last Modified: 09/2002
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