Table of Contents Purpose of This PDQ Summary General Information Cellular Classification Stage Information Treatment Option Overview Untreated Adult Acute Lymphoblastic Leukemia
Adult Acute Lymphoblastic Leukemia in Remission Recurrent Adult Acute Lymphoblastic Leukemia Get More Information From NCI Changes to This Summary (09/25/2008) More Information
Purpose of This PDQ Summary
This PDQ cancer information summary for health professionals provides comprehensive, peer-reviewed, evidence-based information about the treatment of adult acute lymphoblastic leukemia. This summary is reviewed regularly and updated as necessary by the PDQ Adult Treatment Editorial Board 1.
Information about the following is included in this summary:
- Prognostic factors.
- Cellular classification.
- Staging.
- Treatment options by cancer stage.
This summary is intended as a resource to inform and assist clinicians who care for cancer patients. It does not provide formal guidelines or recommendations for making health care decisions.
Some of the reference citations in the summary are accompanied by a level-of-evidence designation. These designations are intended to help readers assess the strength of the evidence supporting the use of specific interventions or approaches. The PDQ Adult Treatment Editorial Board uses a formal evidence ranking system 2 in developing its level-of-evidence designations. Based on the strength of the available evidence, treatment options are described as either “standard” or “under clinical evaluation.” These classifications should not be used as a basis for reimbursement determinations.
This summary is available in a patient version 3, written in less technical language, and in Spanish 4. General Information
Note: Estimated new cases and deaths from acute lymphoblastic leukemia (ALL; also called acute lymphocytic leukemia) in the United States in 2008:[1]
- New cases: 5,430.
- Deaths: 1,460
Sixty percent to 80% of adults with ALL can be
expected to attain complete remission status following appropriate induction
therapy. Approximately 35% to 40% of adults with ALL can be expected to
survive 2 years with aggressive induction combination chemotherapy and
effective supportive care during induction therapy (appropriate early treatment
of infection, hyperuricemia, and bleeding). A few studies, including a Cancer and Leukemia Group B study (CALGB-8811 5), that use intensive
multiagent approaches suggest that a 50% 3-year survival is achievable in
selected patients, but these results must be verified by other
investigators.[2-5]
As in childhood ALL, adult patients with ALL are at risk of developing central
nervous system (CNS) involvement during the course of their disease. This is
particularly true for patients with L3 histology.[6] Both treatment and
prognosis are influenced by this complication. The examination of bone marrow
aspirates and/or biopsy specimens should be done by an experienced oncologist,
hematologist, hematopathologist, or general pathologist who is capable of
interpreting conventional and specially stained specimens. Diagnostic
confusion with acute myelocytic leukemia (AML), hairy-cell leukemia, and
malignant lymphoma is not uncommon. Proper diagnosis is crucial because of the
difference in prognosis and treatment of ALL and AML. Immunophenotypic
analysis is essential because leukemias that do not express myeloperoxidase
include M0 and M7 AML as well as ALL.
Appropriate initial treatment, usually consisting of a regimen that includes
the combination of vincristine, prednisone, and anthracycline, with or without
asparaginase, results in a complete remission rate of up to 80%. Median
remission duration for the complete responders is approximately 15 months.
Entry into a clinical trial is highly desirable to assure adequate patient
treatment and also maximal information retrieval from the treatment of this
highly responsive, but usually fatal, disease. Patients who experience a
relapse after remission can be expected to succumb within 1 year, even if a
second complete remission is achieved. If there are appropriate available
donors and if the patient is younger than 55 years of age, bone marrow
transplantation may be a consideration in the management of this disease.[7]
Transplant centers performing five or fewer transplants annually usually have
poorer results than larger centers.[8] If allogeneic transplant is considered,
transfusions with blood products from a potential donor should be avoided if
possible.[5,9-14]
Patients with L3 morphology have improved outcomes, as evidenced in a Cancer and Leukemia Group B study (CALGB-9251 6), when treated according to
specific treatment algorithms.[15,16] Age, which is a significant factor in
childhood ALL and in AML, may also be an important prognostic factor in adult
ALL. In one study, overall the prognosis was better in patients younger than
25 years; another study found a better prognosis in those younger than 35
years. These findings may, in part, be related to the increased incidence of
the Philadelphia chromosome (Ph1) in older ALL patients, a subgroup associated
with poor prognosis.[2,3] Elevated B2-microglobulin is associated with a poor
prognosis in adults as evidenced by lower response rate, increased incidence of
CNS involvement, and significantly worse survival.[17] Patients with Ph1-positive ALL are rarely cured with chemotherapy. Many patients who
have molecular evidence of the bcr-abl fusion gene, which characterizes the Ph1
, have no evidence of the abnormal chromosome by cytogenetics.
Because many patients have a different fusion protein from the one found in
chronic myelogenous leukemia (p190 vs. p210), the bcr-abl fusion gene may be
detectable only by pulsed-field gel electrophoresis or reverse-transcriptase
polymerase chain reaction (RT-PCR). These tests should be performed whenever
possible in patients with ALL, especially those with B-cell lineage disease.
Two other chromosomal abnormalities with poor prognoses are t(4;11), which is
characterized by rearrangements of the MLL gene and may be rearranged despite
normal cytogenetics, and t(9;22). In addition to t(9;22) and t(4;11), patients
with deletion of chromosome 7 or trisomy 8 have been reported to have a lower
probability of survival at 5 years compared to patients with a normal
karyotype.[18] L3 ALL is associated with a variety of translocations that
involve translocation of the c-myc proto-oncogene to the immunoglobulin gene
locus: t(2;8), t(8;12), and t(8;22).
Long-term follow-up of 30 patients with ALL in remission for at least 10 years has demonstrated 10 cases of secondary malignancies. Of 31 long-term female survivors of ALL or acute myeloid leukemia under 40 years of age, 26 resumed normal menstruation following completion of therapy. Among 36 live offspring of survivors, two congenital problems occurred.[19]
References
-
American Cancer Society.: Cancer Facts and Figures 2008. Atlanta, Ga: American Cancer Society, 2008. Also available online. 7 Last accessed October 1, 2008.
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Gaynor J, Chapman D, Little C, et al.: A cause-specific hazard rate analysis of prognostic factors among 199 adults with acute lymphoblastic leukemia: the Memorial Hospital experience since 1969. J Clin Oncol 6 (6): 1014-30, 1988.
[PUBMED Abstract]
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Hoelzer D, Thiel E, Löffler H, et al.: Prognostic factors in a multicenter study for treatment of acute lymphoblastic leukemia in adults. Blood 71 (1): 123-31, 1988.
[PUBMED Abstract]
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Zhang MJ, Hoelzer D, Horowitz MM, et al.: Long-term follow-up of adults with acute lymphoblastic leukemia in first remission treated with chemotherapy or bone marrow transplantation. The Acute Lymphoblastic Leukemia Working Committee. Ann Intern Med 123 (6): 428-31, 1995.
[PUBMED Abstract]
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Larson RA, Dodge RK, Burns CP, et al.: A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811. Blood 85 (8): 2025-37, 1995.
[PUBMED Abstract]
-
Kantarjian HM, Walters RS, Smith TL, et al.: Identification of risk groups for development of central nervous system leukemia in adults with acute lymphocytic leukemia. Blood 72 (5): 1784-9, 1988.
[PUBMED Abstract]
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Bortin MM, Horowitz MM, Gale RP, et al.: Changing trends in allogeneic bone marrow transplantation for leukemia in the 1980s. JAMA 268 (5): 607-12, 1992.
[PUBMED Abstract]
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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): 2771-4, 1992.
[PUBMED Abstract]
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Linker CA, Levitt LJ, O'Donnell M, et al.: Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report. Blood 78 (11): 2814-22, 1991.
[PUBMED Abstract]
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Barrett AJ, Horowitz MM, Gale RP, et al.: Marrow transplantation for acute lymphoblastic leukemia: factors affecting relapse and survival. Blood 74 (2): 862-71, 1989.
[PUBMED Abstract]
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Dinsmore R, Kirkpatrick D, Flomenberg N, et al.: Allogeneic bone marrow transplantation for patients with acute lymphoblastic leukemia. Blood 62 (2): 381-8, 1983.
[PUBMED Abstract]
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Jacobs AD, Gale RP: Recent advances in the biology and treatment of acute lymphoblastic leukemia in adults. N Engl J Med 311 (19): 1219-31, 1984.
[PUBMED Abstract]
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Doney K, Buckner CD, Kopecky KJ, et al.: Marrow transplantation for patients with acute lymphoblastic leukemia in first marrow remission. Bone Marrow Transplant 2 (4): 355-63, 1987.
[PUBMED Abstract]
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Vernant JP, Marit G, Maraninchi D, et al.: Allogeneic bone marrow transplantation in adults with acute lymphoblastic leukemia in first complete remission. J Clin Oncol 6 (2): 227-31, 1988.
[PUBMED Abstract]
-
Lee EJ, Petroni GR, Schiffer CA, et al.: Brief-duration high-intensity chemotherapy for patients with small noncleaved-cell lymphoma or FAB L3 acute lymphocytic leukemia: results of cancer and leukemia group B study 9251. J Clin Oncol 19 (20): 4014-22, 2001.
[PUBMED Abstract]
-
Hoelzer D, Ludwig WD, Thiel E, et al.: Improved outcome in adult B-cell acute lymphoblastic leukemia. Blood 87 (2): 495-508, 1996.
[PUBMED Abstract]
-
Kantarjian HM, Smith T, Estey E, et al.: Prognostic significance of elevated serum beta 2-microglobulin levels in adult acute lymphocytic leukemia. Am J Med 93 (6): 599-604, 1992.
[PUBMED Abstract]
-
Wetzler M, Dodge RK, Mrózek K, et al.: Prospective karyotype analysis in adult acute lymphoblastic leukemia: the cancer and leukemia Group B experience. Blood 93 (11): 3983-93, 1999.
[PUBMED Abstract]
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Micallef IN, Rohatiner AZ, Carter M, et al.: Long-term outcome of patients surviving for more than ten years following treatment for acute leukaemia. Br J Haematol 113 (2): 443-5, 2001.
[PUBMED Abstract]
Cellular Classification
Leukemic cell characteristics including morphological features, cytochemistry,
immunologic cell surface and biochemical markers, and cytogenetic
characteristics are important. In adults, FAB L1 morphology (more mature
appearing lymphoblasts) is present in fewer than 50% of patients and L2
histology (more immature and pleomorphic) predominates.[1] Chromosomal
abnormalities including aneuploidy and translocations have been described and
may correlate with prognosis.[2] In particular, patients with Philadelphia
chromosome (Ph1)-positive t(9;22) acute lymphoblastic leukemia (ALL) have a
poor prognosis and represent more than 30% of adult cases. The bcr-abl fusion
gene resulting from the breakpoint in the Ph1 may, on occasion, be
detectable only by pulse-field gel electrophoresis or reverse-transcriptase
polymerase chain reaction. Bcr-abl-rearranged leukemias that do not
demonstrate the classical Ph1 carry a poor prognosis that is similar
to those that are Ph1-positive.
Using heteroantisera and monoclonal antibodies, ALL cells can be divided into
early B-cell lineage (80% approximate frequency), T cells (10%–15% approximate
frequency), B cells (with surface immunoglobulins), (<5% approximate
frequency), and CALLA+ (common ALL antigen), 50% approximate frequency.[1,3-5]
About 95% of all types of ALL except B cell, which usually has an L3 morphology
by the FAB classification, have elevated terminal deoxynucleotidyl transferase
(TdT) expression. This elevation is extremely useful in diagnosis; if
concentrations of the enzyme are not elevated, the diagnosis of ALL is suspect.
However, 20% of cases of acute myeloid leukemia (AML) may express TdT;
therefore, its usefulness as a lineage marker is limited. Because B-cell
leukemias are treated according to different algorithms, it is important to
specifically identify these cases prospectively by their L3 morphology, absence
of TdT, and expression of surface immunoglobulin. These patients will
typically have one of three chromosomal translocations: t(8;14), t(2;8), or t(8;22).
References
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Brearley RL, Johnson SA, Lister TA: Acute lymphoblastic leukaemia in adults: clinicopathological correlations with the French-American-British (FAB) co-operative group classification. Eur J Cancer 15 (6): 909-14, 1979.
[PUBMED Abstract]
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Chromosomal abnormalities and their clinical significance in acute lymphoblastic leukemia. Third International Workshop on Chromosomes in Leukemia. Cancer Res 43 (2): 868-73, 1983.
[PUBMED Abstract]
-
Hoelzer D, Thiel E, Löffler H, et al.: Prognostic factors in a multicenter study for treatment of acute lymphoblastic leukemia in adults. Blood 71 (1): 123-31, 1988.
[PUBMED Abstract]
-
Sobol RE, Royston I, LeBien TW, et al.: Adult acute lymphoblastic leukemia phenotypes defined by monoclonal antibodies. Blood 65 (3): 730-5, 1985.
[PUBMED Abstract]
-
Foon KA, Billing RJ, Terasaki PI, et al.: Immunologic classification of acute lymphoblastic leukemia. Implications for normal lymphoid differentiation. Blood 56 (6): 1120-6, 1980.
[PUBMED Abstract]
Stage Information
There is no clear-cut staging system for this disease.
Untreated
For a newly diagnosed patient with no prior treatment, untreated adult acute
lymphoblastic leukemia (ALL) is defined as an abnormal white blood cell count
and differential, abnormal hematocrit/hemoglobin and platelet counts, abnormal
bone marrow with more than 5% blasts, and signs and symptoms of the disease.
In remission
A patient who has received remission-induction treatment of ALL is in remission
if the bone marrow is normocellular with less than 5% blasts, there are no
signs or symptoms of the disease, no signs or symptoms of central nervous
system leukemia or other extramedullary infiltration, and all of the following
laboratory values are within normal limits: white blood cell count and
differential, hematocrit/hemoglobin level, and platelet count.
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 2 for more
information.)
Successful treatment of acute lymphoblastic leukemia (ALL) consists of the
control of bone marrow and systemic disease as well as the treatment (or
prevention) of sanctuary-site disease, particularly the central nervous system
(CNS).[1,2] The cornerstone of this strategy includes systemically
administered combination chemotherapy with CNS preventive therapy. CNS
prophylaxis is achieved with chemotherapy (intrathecal and/or high-dose
systemic) and, in some cases, cranial radiation therapy.
Treatment is divided into three phases: remission induction, CNS prophylaxis, and
remission continuation or maintenance. The average length of treatment of ALL
varies between 1.5 and 3 years in the effort to eradicate the leukemic cell
population. Younger adults with ALL may be eligible for selected clinical
trials for childhood ALL.
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 Philadelphia chromosome (Ph1).[3] The Ph1 occurs in only 1% to 2% of patients with acute myelocytic leukemia, but it occurs in about 20% of
adults and a small percentage of children with ALL.[4] In the majority of
children and in more than one half of adults with Ph1-positive
ALL, the molecular abnormality is different from that in Ph1-positive chronic
myelogenous leukemia (CML).
Ph1-positive ALL has a worse prognosis than most other types of ALL, though many
children and some adults with Ph1-positive ALL may have complete remissions following
intensive ALL treatment clinical trials. Imatinib mesylate, an orally available inhibitor of the BCR-ABL tyrosine kinase, has been shown to have clinical activity as a single agent in this disease.[5,6][Level of evidence: 3iiiDiv] In one study, 10 patients with Ph1-positive ALL and 10 patients with CML lymphoid blast crisis were treated with doses of imatinib ranging from 300 mg to 1000 mg per day.[5] Of these 20 patients, 4 had complete hematologic remission and 10 had marrow responses. Responses were short lived, with the majority of these patients relapsing at a median of 58 days after the start of therapy. In another study, 48 patients with Ph1-positive ALL were treated with 400 mg to 800 mg of imatinib per day.[6] The overall response rate was 60%, with 9 out of 48 patients (19%) achieving a complete remission. The responses again were short, with a median duration of 2.2 months. While there are no randomized clinical trials comparing chemotherapy with or without imatinib for this disease, because of the responses observed in monotherapy trials, imatinib is generally incorporated into the treatment of patients with Ph1-positive ALL. If a suitable donor is available,
allogeneic bone marrow transplantation should be considered because remissions
are generally short with conventional ALL chemotherapy clinical trials. Many
patients who have molecular evidence of the bcr-abl fusion gene, which
characterizes the Ph1, have no evidence of the abnormal chromosome by
cytogenetics. Because many patients have a different fusion protein from the
one found in CML (p190 vs. p210), the bcr-abl fusion gene may be detectable
only by pulsed-field gel electrophoresis or reverse-transcriptase polymerase
chain reaction (RT-PCR). These tests should be performed whenever possible in
patients with ALL, especially those with B-cell lineage disease. Two other
chromosomal abnormalities with poor prognosis are t(4;11), which is
characterized by rearrangements of the MLL gene and may be rearranged despite
normal cytogenetics, and t(9;22). In addition to t(9;22) and t(4;11), patients
with deletion of chromosome 7 or trisomy 8 have been reported to have a lower
probability of survival at 5 years compared to patients with a normal
karyotype. In multivariate analysis, karyotype was the most important
predictor of disease-free survival.[7][Level of evidence: 3iiDii] L3 ALL is
associated with a variety of translocations which involve translocation of the
c-myc proto-oncogene to the immunoglobulin gene locus (t(2;8), t(8;12), and
t(8;22)). Unlike bcr-abl-positive ALL and t(4;11) ALL, there is some evidence such as was found in a Cancer and Leukemia Group B study (CALGB-9251 6) that L3 leukemia can be cured with aggressive, rapidly cycling lymphoma-like
chemotherapy regimens.[8-10]
References
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Clarkson BD, Gee T, Arlin ZA, et al.: Current status of treatment of acute leukemia in adults: an overview of the Memorial experience and review of literature. Crit Rev Oncol Hematol 4 (3): 221-48, 1986.
[PUBMED Abstract]
-
Hoelzer D, Gale RP: Acute lymphoblastic leukemia in adults: recent progress, future directions. Semin Hematol 24 (1): 27-39, 1987.
[PUBMED Abstract]
-
Peterson LC, Bloomfield CD, Brunning RD: Blast crisis as an initial or terminal manifestation of chronic myeloid leukemia: a study of 28 patients. Am J Med 60(2): 209-220, 1976.
-
Secker-Walker LM, Cooke HM, Browett PJ, et al.: Variable Philadelphia breakpoints and potential lineage restriction of bcr rearrangement in acute lymphoblastic leukemia. Blood 72 (2): 784-91, 1988.
[PUBMED Abstract]
-
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. N Engl J Med 344 (14): 1038-42, 2001.
[PUBMED Abstract]
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Ottmann OG, Druker BJ, Sawyers CL, et al.: A phase 2 study of imatinib in patients with relapsed or refractory Philadelphia chromosome-positive acute lymphoid leukemias. Blood 100 (6): 1965-71, 2002.
[PUBMED Abstract]
-
Wetzler M, Dodge RK, Mrózek K, et al.: Prospective karyotype analysis in adult acute lymphoblastic leukemia: the cancer and leukemia Group B experience. Blood 93 (11): 3983-93, 1999.
[PUBMED Abstract]
-
Fenaux P, Lai JL, Miaux O, et al.: Burkitt cell acute leukaemia (L3 ALL) in adults: a report of 18 cases. Br J Haematol 71 (3): 371-6, 1989.
[PUBMED Abstract]
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Reiter A, Schrappe M, Ludwig WD, et al.: Favorable outcome of B-cell acute lymphoblastic leukemia in childhood: a report of three consecutive studies of the BFM group. Blood 80 (10): 2471-8, 1992.
[PUBMED Abstract]
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Lee EJ, Petroni GR, Schiffer CA, et al.: Brief-duration high-intensity chemotherapy for patients with small noncleaved-cell lymphoma or FAB L3 acute lymphocytic leukemia: results of cancer and leukemia group B study 9251. J Clin Oncol 19 (20): 4014-22, 2001.
[PUBMED Abstract]
Untreated Adult Acute Lymphoblastic Leukemia
Standard treatment options for remission induction therapy:
Most current induction regimens for patients with adult acute lymphoblastic leukemia (ALL)
include prednisone, vincristine, and an anthracycline. Some regimens, including a Cancer and Leukemia Group B study (CALGB-8811 5), also add
other drugs, such as asparaginase or cyclophosphamide. Current multiagent
induction regimens result in complete response rates that range from 60% to
90%.[1-3]
Imatinib mesylate is often incorporated into the therapeutic plan for patients with Ph1-positive ALL. Several studies have suggested that the addition of imatinib results in complete response rates, event-free survival rates, and overall survival rates that are higher than those in historical controls. In each of these studies, common toxicities were nausea and liver enzyme abnormalities necessitating interruption and/or dose reduction of imatinib. (For more information on nausea, refer to the PDQ summary on Nausea and Vomiting 8.) Subsequent allogeneic transplant does not appear to be adversely affected by the addition of imatinib to the treatment regimen. At the present time, no conclusions can be drawn from these studies regarding which imatinib dose or schedule should be used.[4-6]
Two additional subtypes of adult ALL require special consideration. B-cell ALL [which
expresses surface immunoglobulin and cytogenetic abnormalities such as t(8;14),
t(2;8), and t(8;22)] is not usually cured with typical ALL regimens.
Aggressive brief duration high-intensity regimens, as evidenced in the Cancer and Leukemia Group B study (CALGB-9251 6), similar to those used in
aggressive non-Hodgkin lymphoma have shown high response rates and cure rates
(75% complete remission; 40% failure-free survival).[7,8] T-cell ALL,
including lymphoblastic lymphoma, similarly has shown high cure rates when
treated with cyclophosphamide-containing regimens.[3] Whenever possible, such
patients should be entered in clinical trials designed to improve the outcomes
in these subsets. (Refer to the B cell (Burkitt) lymphoma and T cell (lymphoblastic) lymphoma sections in the PDQ summary on Adult Non-Hodgkin Lymphoma
Treatment 9 for more information.)
Since myelosuppression is an anticipated consequence of both the leukemia and
its treatment with chemotherapy, patients must be closely monitored during
remission induction treatment. Facilities must be available for hematological
support as well as for the treatment of infectious complications.
Supportive care during remission induction treatment should routinely include
red blood cell and platelet transfusions when appropriate.[9,10] Randomized
trials have shown similar outcomes for patients who received prophylactic
platelet transfusions at a level of 10,000/mm3 rather than
20,000/mm3.[11] The incidence of platelet alloimmunization was
similar among groups randomly assigned to receive pooled platelet concentrates
from random donors; filtered, pooled platelet concentrates from random donors;
ultraviolet B-irradiated, pooled platelet concentrates from random donors; or
filtered platelets obtained by apheresis from single random donors.[12]
Empiric broad spectrum antimicrobial therapy is an absolute necessity for
febrile patients who are profoundly neutropenic.[13,14] Careful instruction in
personal hygiene, dental care, and recognition of early signs of infection are
appropriate in all patients. Elaborate isolation facilities, including
filtered air, sterile food, and gut flora sterilization are not routinely
indicated but may benefit transplant patients.[15,16] Rapid marrow ablation
with consequent earlier marrow regeneration decreases morbidity and mortality.
White blood cell transfusions can be beneficial in selected patients with
aplastic marrow and serious infections that are not responding to
antibiotics.[17] Prophylactic oral antibiotics may be appropriate in patients
with expected prolonged, profound granulocytopenia (<100/mm3
for 2 weeks), though further studies are necessary.[18] To detect the
presence or acquisition of resistant organisms, serial surveillance cultures
may be helpful in such patients. As evidenced in a Cancer and Leukemia Group B study (CALGB-9111 10), the use of myeloid growth factors during
remission induction therapy appears to decrease the time to hematopoietic
reconstitution.[19,20]
Treatment options for remission induction therapy under clinical evaluation:
- Clinical trials are ongoing, and patients should be considered for these
studies.
Standard treatment options for central nervous system (CNS) prophylaxis:
The early institution of CNS prophylaxis is critical to achieve control of
sanctuary disease.
- Cranial radiation therapy plus intrathecal (IT) methotrexate.
- High-dose systemic methotrexate and IT methotrexate without cranial
therapy radiation.
- IT chemotherapy alone.
Current Clinical Trials
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with untreated adult acute lymphoblastic leukemia 11. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site 12.
References
-
Hoelzer D, Thiel E, Löffler H, et al.: Prognostic factors in a multicenter study for treatment of acute lymphoblastic leukemia in adults. Blood 71 (1): 123-31, 1988.
[PUBMED Abstract]
-
Linker CA, Levitt LJ, O'Donnell M, et al.: Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report. Blood 78 (11): 2814-22, 1991.
[PUBMED Abstract]
-
Larson RA, Dodge RK, Burns CP, et al.: A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811. Blood 85 (8): 2025-37, 1995.
[PUBMED Abstract]
-
Thomas DA, Faderl S, Cortes J, et al.: Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood 103 (12): 4396-407, 2004.
[PUBMED Abstract]
-
Yanada M, Takeuchi J, Sugiura I, et al.: High complete remission rate and promising outcome by combination of imatinib and chemotherapy for newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia: a phase II study by the Japan Adult Leukemia Study Group. J Clin Oncol 24 (3): 460-6, 2006.
[PUBMED Abstract]
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Wassmann B, Pfeifer H, Goekbuget N, et al.: Alternating versus concurrent schedules of imatinib and chemotherapy as front-line therapy for Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Blood 108 (5): 1469-77, 2006.
[PUBMED Abstract]
-
Hoelzer D, Ludwig WD, Thiel E, et al.: Improved outcome in adult B-cell acute lymphoblastic leukemia. Blood 87 (2): 495-508, 1996.
[PUBMED Abstract]
-
Lee EJ, Petroni GR, Schiffer CA, et al.: Brief-duration high-intensity chemotherapy for patients with small noncleaved-cell lymphoma or FAB L3 acute lymphocytic leukemia: results of cancer and leukemia group B study 9251. J Clin Oncol 19 (20): 4014-22, 2001.
[PUBMED Abstract]
-
Slichter SJ: Controversies in platelet transfusion therapy. Annu Rev Med 31: 509-40, 1980.
[PUBMED Abstract]
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Murphy MF, Metcalfe P, Thomas H, et al.: Use of leucocyte-poor blood components and HLA-matched-platelet donors to prevent HLA alloimmunization. Br J Haematol 62 (3): 529-34, 1986.
[PUBMED Abstract]
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Rebulla P, Finazzi G, Marangoni F, et al.: The threshold for prophylactic platelet transfusions in adults with acute myeloid leukemia. Gruppo Italiano Malattie Ematologiche Maligne dell'Adulto. N Engl J Med 337 (26): 1870-5, 1997.
[PUBMED Abstract]
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Leukocyte reduction and ultraviolet B irradiation of platelets to prevent alloimmunization and refractoriness to platelet transfusions. The Trial to Reduce Alloimmunization to Platelets Study Group. N Engl J Med 337 (26): 1861-9, 1997.
[PUBMED Abstract]
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Hughes WT, Armstrong D, Bodey GP, et al.: From the Infectious Diseases Society of America. Guidelines for the use of antimicrobial agents in neutropenic patients with unexplained fever. J Infect Dis 161 (3): 381-96, 1990.
[PUBMED Abstract]
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Rubin M, Hathorn JW, Pizzo PA: Controversies in the management of febrile neutropenic cancer patients. Cancer Invest 6 (2): 167-84, 1988.
[PUBMED Abstract]
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Armstrong D: Symposium on infectious complications of neoplastic disease (Part II). Protected environments are discomforting and expensive and do not offer meaningful protection. Am J Med 76 (4): 685-9, 1984.
[PUBMED Abstract]
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Sherertz RJ, Belani A, Kramer BS, et al.: Impact of air filtration on nosocomial Aspergillus infections. Unique risk of bone marrow transplant recipients. Am J Med 83 (4): 709-18, 1987.
[PUBMED Abstract]
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Schiffer CA: Granulocyte transfusions: an overlooked therapeutic modality. Transfus Med Rev 4 (1): 2-7, 1990.
[PUBMED Abstract]
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Wade JC, Schimpff SC, Hargadon MT, et al.: A comparison of trimethoprim-sulfamethoxazole plus nystatin with gentamicin plus nystatin in the prevention of infections in acute leukemia. N Engl J Med 304 (18): 1057-62, 1981.
[PUBMED Abstract]
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Scherrer R, Geissler K, Kyrle PA, et al.: Granulocyte colony-stimulating factor (G-CSF) as an adjunct to induction chemotherapy of adult acute lymphoblastic leukemia (ALL). Ann Hematol 66 (6): 283-9, 1993.
[PUBMED Abstract]
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Larson RA, Dodge RK, Linker CA, et al.: A randomized controlled trial of filgrastim during remission induction and consolidation chemotherapy for adults with acute lymphoblastic leukemia: CALGB study 9111. Blood 92 (5): 1556-64, 1998.
[PUBMED Abstract]
Adult Acute Lymphoblastic Leukemia in Remission
Current approaches to postremission therapy for adult acute lymphoblastic
leukemia (ALL) include short-term, relatively intensive chemotherapy followed
by longer-term therapy at lower doses (maintenance), high-dose marrow-ablative
chemotherapy or chemoradiation therapy with allogeneic stem cell rescue (alloBMT),
and high-dose therapy with autologous stem cell rescue (autoBMT). Several
trials, including a Cancer and Leukemia Group B study (CALGB-8811 5), of aggressive postremission chemotherapy for adult ALL now confirm a
long-term disease-free survival rate of approximately 40%.[1-5] In the latter
two series, especially good prognoses were found for patients with T-cell lineage
ALL, with disease-free survival rates of 50% to 70% for patients receiving
postremission therapy. These series represent a significant improvement in
disease-free survival rates over previous, less intensive chemotherapeutic
approaches. In contrast, poor cure rates were demonstrated in patients with
Philadelphia chromosome (Ph1)-positive ALL, B-cell lineage ALL with an L3
phenotype (surface immunoglobulin positive), and B-cell lineage ALL
characterized by t(4;11). Administration of the newer dose-intensive schedules
can be difficult and should be performed by physicians experienced in these
regimens at centers equipped to deal with potential complications. Studies in
which continuation or maintenance chemotherapy were eliminated had outcomes
inferior to those with extended treatment durations.[6,7]
Imatinib has been incorporated into maintenance regimens in patients with Ph1-postive ALL.[8-10]
AlloBMT results in the lowest incidence of leukemic relapse, even when compared
with a bone marrow transplant from an identical twin (syngeneic BMT). This
finding has led to the concept of an immunologic graft-versus-leukemia effect
similar to graft-versus-host disease (GVHD). The improvement in disease-free
survival in patients undergoing alloBMT as primary postremission therapy is
offset, in part, by the increased morbidity and mortality from GVHD,
veno-occlusive disease of the liver, and interstitial pneumonitis.[11]
The results of a series of retrospective and prospective studies published between 1987 and 1994 suggest that alloBMT or autoBMT as postremission therapy offer no survival advantage over intensive chemotherapy, except perhaps for patients with high risk or Ph1 positive ALL.[12-15] The use of alloBMT as primary postremission therapy is limited by both the need for an HLA-matched sibling donor and the increased mortality from alloBMT in patients in their fifth or sixth decades. The mortality from alloBMT using an HLA-matched sibling donor in these studies ranged from 20% to 40%.
Following on the results of these earlier studies, the International ALL Trial (ECOG-2993 13) was launched as an attempt to examine the role of transplant as postremission therapy for ALL more definitively and accrued patients from 1993 to 2006.[16] Patients with Ph1 negative ALL between the ages of 15 to 59 received identical multiagent induction therapy resembling previously published regimens.[1-3] Patients in remission were then eligible for HLA typing; patients with a fully matched sibling donor underwent alloBMT as consolidation. Those patients lacking a donor were randomly assigned to receive either an autoBMT or maintenance chemotherapy. The primary outcome measured was overall survival (OS), with event-free survival, relapse rate, and nonrelapse mortality as secondary endpoints. A total of 1,929 patients were registered and stratified according to age, white blood cell count, and time-to-remission. High-risk patients were defined as those having a high white blood cell count at presentation or those older than age 35. Ninety percent of patients in this study achieved remission after induction therapy. Of these patients, 443 were found to have an HLA-identical sibling, 310 of whom underwent alloBMT. For the 456 patients in remission who were eligible for transplant but lacked a donor, 227 received chemotherapy alone, while 229 underwent an autoBMT. By donor-to-no-donor analysis, standard risk ALL patients with an HLA-identical sibling had a 5-year OS of 53% compared with 45% for patients lacking a donor (P = .01). In subgroup analysis, the advantage for patients with donors remained significant for patients with standard risk ALL (OS = 62% vs. 52%; P = .02). For patients with high-risk disease (age older than 35 or high white blood cell count), the difference in OS was 41% versus 35% (donor vs. no donor), but was not significant (P = .2). Relapse rates were significantly lower (P < .00005) for both standard and high-risk patients with HLA-matched donors. In contrast to alloBMT, autoBMT was less effective than maintenance chemotherapy as postremission treatment (5-year OS = 46% for chemotherapy vs. 37% for autoBMT; P = .03). The results of this trial seem to confirm the existence of a graft versus leukemia effect for adult Ph1 negative ALL and support the use of sibling donor alloBMT as the consolidation therapy providing the greatest chance for long term survival for standard risk adult ALL in first remission.[16][Level of evidence: 2A] The results also suggest that in the absence of a sibling donor, maintenance chemotherapy is preferable to autoBMT as postremission therapy.[16][Level of evidence: 2A]
The use of alloBMT as primary postremission therapy is limited
both by the need for an HLA-matched sibling donor and by the increased
mortality from alloBMT in patients in their fifth or sixth decade. The mortality
from alloBMT using an HLA-matched sibling donor ranges from 20% to 40%,
depending on the study. The use of matched unrelated donors for alloBMT is
currently under evaluation but, because of its current high treatment-related
morbidity and mortality, is reserved for patients in second remission or
beyond. The dose of total body radiation therapy administered is associated with the
incidence of acute and chronic GVHD and may be an independent predictor of
leukemia-free survival.[17][Level of evidence: 3iiB]
Aggressive cyclophosphamide-based regimens similar to those used in aggressive
non-Hodgkin lymphoma have shown improved outcome of prolonged disease-free
status for patients with B-cell ALL (L3 morphology, surface immunoglobulin
positive).[18] Retrospectively reviewing three sequential cooperative group trials
from Germany, Hoelzer and colleagues found a marked improvement in survival,
from zero survivors in a 1981 study that used standard pediatric therapy and
lasted 2.5 years, to a 50% survival rate in two subsequent trials that used
rapidly alternating lymphoma-like chemotherapy and were completed within 6
months. Aggressive CNS prophylaxis remains a prominent component of treatment.
This report, which requires confirmation in other cooperative group settings,
is encouraging for patients with L3 ALL. Patients with surface immunoglobulin
but L1 or L2 morphology did not benefit from this regimen. Similarly, patients
with L3 morphology and immunophenotype but unusual cytogenetic features were
not cured with this approach. A white blood cell count of less than 50,000 per
microliter predicted improved leukemia-free survival in univariate analysis.
Because the optimal postremission therapy for patients with ALL is still
unclear, participation in clinical trials should be considered. (Refer to the
B-cell (Burkitt) lymphoma section in the PDQ summary on Adult Non-Hodgkin Lymphoma Treatment 9 for more information.)
Standard treatment options for central nervous system (CNS) prophylaxis:
The early institution of CNS prophylaxis is critical to achieve control of
sanctuary disease. Some authors have suggested that there is a subgroup of
patients at low-risk for CNS relapse for whom CNS prophylaxis may not be
necessary. However, this concept has not been tested prospectively.[19]
- Cranial radiation therapy plus intrathecal (IT) methotrexate.
- High-dose systemic methotrexate and IT methotrexate without cranial
radiation therapy.
- IT chemotherapy alone.
Current Clinical Trials
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with adult acute lymphoblastic leukemia in remission 14. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site 12.
References
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Gaynor J, Chapman D, Little C, et al.: A cause-specific hazard rate analysis of prognostic factors among 199 adults with acute lymphoblastic leukemia: the Memorial Hospital experience since 1969. J Clin Oncol 6 (6): 1014-30, 1988.
[PUBMED Abstract]
-
Hoelzer D, Thiel E, Löffler H, et al.: Prognostic factors in a multicenter study for treatment of acute lymphoblastic leukemia in adults. Blood 71 (1): 123-31, 1988.
[PUBMED Abstract]
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Linker CA, Levitt LJ, O'Donnell M, et al.: Treatment of adult acute lymphoblastic leukemia with intensive cyclical chemotherapy: a follow-up report. Blood 78 (11): 2814-22, 1991.
[PUBMED Abstract]
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Zhang MJ, Hoelzer D, Horowitz MM, et al.: Long-term follow-up of adults with acute lymphoblastic leukemia in first remission treated with chemotherapy or bone marrow transplantation. The Acute Lymphoblastic Leukemia Working Committee. Ann Intern Med 123 (6): 428-31, 1995.
[PUBMED Abstract]
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Larson RA, Dodge RK, Burns CP, et al.: A five-drug remission induction regimen with intensive consolidation for adults with acute lymphoblastic leukemia: cancer and leukemia group B study 8811. Blood 85 (8): 2025-37, 1995.
[PUBMED Abstract]
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Cuttner J, Mick R, Budman DR, et al.: Phase III trial of brief intensive treatment of adult acute lymphocytic leukemia comparing daunorubicin and mitoxantrone: a CALGB Study. Leukemia 5 (5): 425-31, 1991.
[PUBMED Abstract]
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Dekker AW, van't Veer MB, Sizoo W, et al.: Intensive postremission chemotherapy without maintenance therapy in adults with acute lymphoblastic leukemia. Dutch Hemato-Oncology Research Group. J Clin Oncol 15 (2): 476-82, 1997.
[PUBMED Abstract]
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Thomas DA, Faderl S, Cortes J, et al.: Treatment of Philadelphia chromosome-positive acute lymphocytic leukemia with hyper-CVAD and imatinib mesylate. Blood 103 (12): 4396-407, 2004.
[PUBMED Abstract]
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Yanada M, Takeuchi J, Sugiura I, et al.: High complete remission rate and promising outcome by combination of imatinib and chemotherapy for newly diagnosed BCR-ABL-positive acute lymphoblastic leukemia: a phase II study by the Japan Adult Leukemia Study Group. J Clin Oncol 24 (3): 460-6, 2006.
[PUBMED Abstract]
-
Wassmann B, Pfeifer H, Goekbuget N, et al.: Alternating versus concurrent schedules of imatinib and chemotherapy as front-line therapy for Philadelphia-positive acute lymphoblastic leukemia (Ph+ ALL). Blood 108 (5): 1469-77, 2006.
[PUBMED Abstract]
-
Finiewicz KJ, Larson RA: Dose-intensive therapy for adult acute lymphoblastic leukemia. Semin Oncol 26 (1): 6-20, 1999.
[PUBMED Abstract]
-
Horowitz MM, Messerer D, Hoelzer D, et al.: Chemotherapy compared with bone marrow transplantation for adults with acute lymphoblastic leukemia in first remission. Ann Intern Med 115 (1): 13-8, 1991.
[PUBMED Abstract]
-
Sebban C, Lepage E, Vernant JP, et al.: Allogeneic bone marrow transplantation in adult acute lymphoblastic leukemia in first complete remission: a comparative study. French Group of Therapy of Adult Acute Lymphoblastic Leukemia. J Clin Oncol 12 (12): 2580-7, 1994.
[PUBMED Abstract]
-
Forman SJ, O'Donnell MR, Nademanee AP, et al.: Bone marrow transplantation for patients with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood 70 (2): 587-8, 1987.
[PUBMED Abstract]
-
Fière D, Lepage E, Sebban C, et al.: Adult acute lymphoblastic leukemia: a multicentric randomized trial testing bone marrow transplantation as postremission therapy. The French Group on Therapy for Adult Acute Lymphoblastic Leukemia. J Clin Oncol 11 (10): 1990-2001, 1993.
[PUBMED Abstract]
-
Goldstone AH, Richards SM, Lazarus HM, et al.: In adults with standard-risk acute lymphoblastic leukemia, the greatest benefit is achieved from a matched sibling allogeneic transplantation in first complete remission, and an autologous transplantation is less effective than conventional consolidation/maintenance chemotherapy in all patients: final results of the International ALL Trial (MRC UKALL XII/ECOG E2993). Blood 111 (4): 1827-33, 2008.
[PUBMED Abstract]
-
Corvò R, Paoli G, Barra S, et al.: Total body irradiation correlates with chronic graft versus host disease and affects prognosis of patients with acute lymphoblastic leukemia receiving an HLA identical allogeneic bone marrow transplant. Int J Radiat Oncol Biol Phys 43 (3): 497-503, 1999.
[PUBMED Abstract]
-
Hoelzer D, Ludwig WD, Thiel E, et al.: Improved outcome in adult B-cell acute lymphoblastic leukemia. Blood 87 (2): 495-508, 1996.
[PUBMED Abstract]
-
Kantarjian HM, Walters RS, Smith TL, et al.: Identification of risk groups for development of central nervous system leukemia in adults with acute lymphocytic leukemia. Blood 72 (5): 1784-9, 1988.
[PUBMED Abstract]
Recurrent Adult Acute Lymphoblastic Leukemia
Patients with acute lymphoblastic leukemia (ALL) who experience a relapse following chemotherapy and maintenance
therapy are unlikely to be cured by further chemotherapy alone. These patients
should be considered for reinduction chemotherapy followed by allogeneic bone
marrow transplantation. Patients for whom an HLA-matched donor is not
available are excellent candidates for enrollment in clinical trials that are
studying autologous transplantation, immunomodulation, and novel
chemotherapeutic or biological agents.[1-7] Low-dose palliative radiation
therapy may be considered in patients with symptomatic recurrence either within
or outside the central nervous system.[8]
Patients with Ph1-positive ALL will often be taking imatinib at the time of relapse and thus will have imatinib-resistant disease. Dasatinib, a novel tyrosine kinase inhibitor with efficacy against several different imatinib-resistant BCR/ABL mutants, has been approved for use in Ph1-positive ALL patients who are resistant to or intolerant of imatinib. The approval was based on a series of trials involving patients with chronic myelogenous leuekmia, one of which included small numbers of patients with lymphoid blast crisis or Ph1-positive ALL. In one study, 10 such patients were treated with dasatinib in a dose escalation study.[9] Seven of these patients had a complete hematologic response (<5% marrow blasts with normal peripheral blood counts), three of whom had a complete cytogenetic response. The common toxicities were reversible myelosuppression (89%) and pleural effusions (21%). Virtually all of these patients relapsed within 6 months of the start of treatment with dasatinib.
Current Clinical Trials
Check for U.S. clinical trials from NCI's PDQ Cancer Clinical Trials Registry that are now accepting patients with recurrent adult acute lymphoblastic leukemia 15. The list of clinical trials can be further narrowed by location, drug, intervention, and other criteria.
General information about clinical trials is also available from the NCI Web site 12.
References
-
Herzig RH, Bortin MM, Barrett AJ, et al.: Bone-marrow transplantation in high-risk acute lymphoblastic leukaemia in first and second remission. Lancet 1 (8536): 786-9, 1987.
[PUBMED Abstract]
-
Thomas ED, Sanders JE, Flournoy N, et al.: Marrow transplantation for patients with acute lymphoblastic leukemia: a long-term follow-up. Blood 62 (5): 1139-41, 1983.
[PUBMED Abstract]
-
Barrett AJ, Horowitz MM, Gale RP, et al.: Marrow transplantation for acute lymphoblastic leukemia: factors affecting relapse and survival. Blood 74 (2): 862-71, 1989.
[PUBMED Abstract]
-
Dinsmore R, Kirkpatrick D, Flomenberg N, et al.: Allogeneic bone marrow transplantation for patients with acute lymphoblastic leukemia. Blood 62 (2): 381-8, 1983.
[PUBMED Abstract]
-
Sallan SE, Niemeyer CM, Billett AL, et al.: Autologous bone marrow transplantation for acute lymphoblastic leukemia. J Clin Oncol 7 (11): 1594-601, 1989.
[PUBMED Abstract]
-
Paciucci PA, Keaveney C, Cuttner J, et al.: Mitoxantrone, vincristine, and prednisone in adults with relapsed or primarily refractory acute lymphocytic leukemia and terminal deoxynucleotidyl transferase positive blastic phase chronic myelocytic leukemia. Cancer Res 47 (19): 5234-7, 1987.
[PUBMED Abstract]
-
Biggs JC, Horowitz MM, Gale RP, et al.: Bone marrow transplants may cure patients with acute leukemia never achieving remission with chemotherapy. Blood 80 (4): 1090-3, 1992.
[PUBMED Abstract]
-
Gray JR, Wallner KE: Reversal of cranial nerve dysfunction with radiation therapy in adults with lymphoma and leukemia. Int J Radiat Oncol Biol Phys 19 (2): 439-44, 1990.
[PUBMED Abstract]
-
Talpaz M, Shah NP, Kantarjian H, et al.: Dasatinib in imatinib-resistant Philadelphia chromosome-positive leukemias. N Engl J Med 354 (24): 2531-41, 2006.
[PUBMED Abstract]
Get More Information From NCI
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For more information, U.S. residents may call the National Cancer Institute's (NCI's) Cancer Information Service toll-free at 1-800-4-CANCER (1-800-422-6237) Monday through Friday from 9:00 a.m. to 4:30 p.m. Deaf and hard-of-hearing callers with TTY equipment may call 1-800-332-8615. The call is free and a trained Cancer Information Specialist is available to answer your questions.
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Untreated Adult Acute Lymphoblastic Leukemia 19
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