Leukemia : ALL, AML, CML and JMML Prognosis, Treatment
LEUKEMIA (BLOOD CANCER)
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Last Updated : 2/8/2010
Bharat R Agarwal
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ALL- Prognostic Features
Age at diagnosis
- Infants with ALL especially young infants of less than 6 months have a high risk of treatment failure. The poor outcome for infants with ALL is strongly associated with the presence of t (4,11) translocation involving the MLL gene.
- Young children (1-9 years) have a favourable outcome as compared to older children or infants.

WBC count at diagnosis
Patients with high WBC counts at diagnosis (> 50,000/cu mm) have a poorer prognosis.

Gender
Girls have a slightly better prognosis. One reason for better prognosis in girls is the occurrence of testicular relapses among boys. Also boys are at higher risk for bone marrow relapse.

Cellular morphology
In the past, ALL was classified into 3 types - L1, L2 & L3 using the FAB criteria for prognosis. However this classification is no longer applied. However molecular and biologic characteristics are used for determining the outcome.
Immunophenotype:
- B cell precursor ALL: Represents 80-85% of childhood ALL. Approximately 80% of B-cell precursor ALL express the CALLA, CD 10 antigen. The lack of cALLA is associated with a worse prognosis.
- Stage of B cell maturation: Patients with early pre B phenotype have the best prognosis, pre B phenotype have an intermediate prognosis and B-cell type have the worst prognosis.
- T-cell ALL: Approximately 15% of children with ALL have a T-cell phenotype. In patients with T-cell ALL, CD2 has a favourable prognosis, whereas CD7 +, CD2- and CD5- immunophenotype has a worse prognosis.

Chromosome number:
- Hyperdiploidy (> 50 chromosomes per cell or DNA index > 1.16) have favourable prognosis. Hyperdiploid leukemic cells are susceptible to undergoing apoptosis.
- Trisomy 4 and 10 are associated with favorable prognosis. Hypodiploidy (<45 chromosomes per cell) have a high risk of treatment failure.
Chromosomal translocations: t(8;14), t(9;22), t(4;11) and t(1;19) are associated with unfavorable prognosis. t(12;21) has a favourable prognosis.

Rapidity of leukemic cytoreduction following onset of treatment
- Patients who have a rapid reduction in the leukemic cells in the bone marrow within 7-14 days following multiagent chemotherapy have a better prognosis.

CNS disease at presentation
- Patients with CNS manifestations at onset have an unfavourable prognosis.

Mediastinal mass
Patients with a mediastinal mass at onset have a favourable prognosis.

CCG divided patients into "standard risk" or "high risk" based on age and WBC criteria. Standard risk patients are patients between 1-9 years and those who have WBC count <50,000 / cu mm at diagnosis. The remaining patients are classified as high-risk ALL. The "very high risk" category includes -presence of t (9;22); M3 marrow on day 29 or M2 or M3 marrow on day 43; or hypodiploidy (DNA index <0.95). Infants with ALL are considered "high risk" and have special chemotherapy protocols.

Treatment of ALL
Successful treatment of children with ALL requires the control of systemic disease (marrow, liver, spleen, lymph nodes, etc) as well as the treatment (or prevention) of extramedullary disease in sanctuary sites like the CNS and the testicular region.

Only 3% of patients have detectable CNS involvement at diagnosis (> 5 WBC/ cu mm with presence of lymphoblasts), however, unless specific therapy is directed toward the CNS, 50% or more children will eventually develop overt CNS leukemia. Hence, all children with ALL should receive some form of CNS prophylaxis.

Treatment of ALL is divided into stages:
- Remission induction
- Consolidation or intensification
- Maintenance therapy.
CNS sanctuary therapy is given at each stage.

Induction chemotherapy: Three drug induction therapy using vincristine, prednisolone/ dexamethasone, L-asparaginase in conjunction with intrathecal therapy results in complete remission rate of greater than 95%. For patients with high risk, an anthracycline (daunorubicin) may be included. The aim of induction phase is to induce remission. In general, patients will achieve complete remission within the first 4 weeks. Patients who require more than 4 weeks to achieve remission or those who demonstrate more than 25% blasts in the bone marrow or have persistent blasts in the peripheral blood after 1 week of intensive induction therapy have a poor prognosis. (A bone marrow is done at the end of induction to establish remission status).

CNS Prophylaxis - Intrathecal (IT) : Chemotherapy with IT methotrexate with or without systemic methotrexate is used for CNS prophylaxis. For patients at high risk of CNS relapse (e.g. age > 10 years, presence of hyperleukocytosis or T cell ALL), use of cranial irradiation is controversial.

Consolidation / Intensification: It is given to consolidate the remission achieved during induction phase. It may involve the use of intermediate or high dose methotrexate, same drugs as used in induction, other drug combinations, extended use of high dose L-asparaginase or combinations of above.

Maintenance: Most protocols include daily oral mercaptopurine and weekly oral methotrexate. If the patient has not had cranial irradiation, intrathecal chemotherapy for CNS prophylaxis is continued in the maintenance phase.

Monthly pulses of vincristine and prednisolone/dexamethasone are often added to the standard maintenance regimen. Maintenance chemotherapy is generally given for 2 to 3 years to achieve complete remission.

AML- Prognostic Features
The various unfavorable factors are:
- Hyperleukocytosis (WBC count > 1,00,000/cu mm)
- Secondary AML/MDS
- Monosomy 7 or 7q-
- Aneuploidy
- Trisomy 8
- Abnormalities of Chromosome 11 at band q23
- FAB type M7

The favorable factors include:
- FAB type M2 ,M3 , M4
- Inversion of chromosome 16
- Reactivity with CD2 (T1)
- t(8;21) and t(15;17) abnormality

AML- Treatment
Between 75 - 85% can achieve a complete remission following appropriate induction chemotherapy. The mainstay of treatment is systemically administered chemotherapy. Treatment of the CNS is essential in AML, but has not yet shown to have an effect on survival.

Treatment is usually divided into
- Induction (to achieve remission)
- Consolidation
- Past remission intensification (optional).
Maintenance therapy does not appear to have any value.

Treatment of AML is usually associated with severe and protracted myelosuppression and other complications. Children who receive intensive chemotherapy (including anthracyclines) should be periodically assessed for cardiac, renal and auditory function.

Induction chemotherapy
The 2 most effective drugs used to induce remission include cytarabine (Ara-C) and an anthracycline. Usually 70 -85% of children achieve remission with these drugs. Children with M3 sub-type should be induced with all-trans retinoic acid.
Complete response (remission) is defined as the following for at least 4 weeks:
- Restoration of normal blood counts.
- Maturation of all hematopoietic cell lines.
- Less than 5% blasts on a normocellular bone marrow.

Consolidation
The aim is to prolong the duration of the initial remission with either additional chemotherapy or bone marrow transplantation (BMT). Survival with chemotherapy alone is 35-40%. Hence BMT is indicated in most patients. However, in absence of a suitable marrow donor, intensive chemotherapy is given e.g. VAPA and epipodophyllotoxin based regimes.

In Down's children, chemotherapy usually cures AML and BMT is not indicated in 1st remission.

Various clinical trials are trying newer methods of therapy like:
- Monoclonal antibodies to optimize graft Vs leukemia effect.
- Agents to overcome multidrug resistance.
- Other anti neoplastic agents to improve remission duration (e.g. Etoposide).
Thus, in future, various novel and effective treatments may be available for AML.

CML- Poor Prognostic Markers
Clinical
- Older age
Symptoms at diagnosis
- Significant weight loss
- Hepatomegaly
- Splenomegaly
- Poor performance
- Black race
Laboratory
- Anemia
- Thrombocytosis,thrombocytopenia, megakaryocytopenia
- Increased blasts or blasts and promyelocytes in blood or marrow
- Increased basophils in blood or marrow
- Collagen or reticulin fibrosis grades 3-4
Treatment associated
- Longer time to achieve hematologic remission with busulfan chemotherapy
- Short remission duration
- Total dose of busulfan or hydroxyurea therapy required in the first year to control the disease
- Lack of significant suppression of Ph-positive metaphases with intensive chemotherapy or alpha-interferon therapy
- Poor initial response to alpha-interferon therapy

CML- Treatment
Figure 1: Proposed treatment approach in patients with CML




Allogenic bone marrow transplantation, if a suitably matched family donor is available, should be carried out in all patients during the early chronic phase.

Conventional Single-Agent Chemotherapy
Hydroxyurea, as a single agent, is indicated for all patients for symptomatic relief and also for patients presenting with leukocytosis for rapid cytoreduction (before starting treatment with alpha-interferon with or without Ara-C). Hydroxyurea 20-30 mg/kg per day continuously or 80 mg/kg per day 2-3 times per week intermittently is the drug of choice. It is used either in intermittent schedules to maintain a WBC count between 10,000 and 50,000/mm3 or in continuous schedules to control the WBC count at a range of 2000 to 5000/mm3. Hydroxyurea does not induce cytogenetic remission.

Before starting any specific antileukemic therapy, the patient should be treated for metabolic complications, hyperleukocytosis, and its complications.

Alpha-Interferon: This treatment results in a median survival of 60-65 months with 25% of patients in durable cytogenetic remission. Alpha Interferon therapy appears to be superior to conventional therapy; as evaluated by cytogenetic response and survival, and may be preferable to allogeneic BMT in the absence of an HLA-identical sibling match.

Treatment of Ph1 Chronic Myelogenous Leukemia with Alpha-Interferon
Alpha-Interferon: 5 x 106 units/m2 IM or SC per day for 9-15 months. This dose is reduced by 50% if any of the following indications of toxicity are observed:
- Development of neurologic symptoms of Parkinsonism, memory change, reduced attention span.
- Increase in liver enzymes to more than 5 times the normal values
- Increase in serum creatinine to 2.5 mg/dl or more
- Decline in performance status to 80% or less of the Karnofsky scale
Discontinue Alpha -Interferon when the ANC in less than 750/mm3 or the platelet count is less than 40,000/mm3.
Early flu-like side effects (fever, chills, anorexia, postnasal drip) are minimized by starting alpha-interferon at 50% of dose for the first week of treatment).

Alpha Interferon with hydroxyurea: This regimen provides rapid disease control, decreases the incidence of side effects attributable to leukocytosis (fever, chills, musculoskeletal syndrome), and provides longer duration of disease control. However, it does not improve the cytogenetic response rates.

Alpha Interferon with low dose Ara-C: Similar results as with alpha-interferon with hydroxyurea can be obtained with this regimen.

Management of Blastic Phase
Treatment of myeloid blastic phase: Treatment with standard anti-AML chemotherapy is disappointing.

Treatment of lymphoid blastic phase: This can be treated with vincristine and prednisone. Approximately 50-60% of patients attain remission and may revert to chronic phase.

JMML- Treatment
Prognosis
The prognosis is poor. The median survival is less than 9 months.

Treatment
High dose of an alkylating agent, total-body irradiation, and BMT is the only treatment with potential for cure and is the treatment of choice when a suitable donor is available. Chemotherapy is of limited value. Temporary improvement in clinical status may be achieved with the use of VP16 alone, standard AML therapy, or treatment with 13-cis-retinoic acid (100 mg/m2/day for infants less than 1 year of age). Expected complete response from 13-cis-retinoic acid is 25%.



Contributor Information and Disclosures

Bharat R Agarwal
Pediatric Hematologist- Oncologist, Division of Pediatric Hem-Onco, B.J. Wadia Hospital for Children, Mumbai, India


First Created : 2/2/2001
Last Updated : 2/8/2010

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