2. DEFINITION
ā¢ The leukemias are a group of neoplastic disorders of the
hematopoietic system, characterized by aberrant or arrested
differentiation.
ā¢ Involve: Bone marrow, spleen, lymphatic system
3. LEUKEMIC STEM CELL
ā¢ In normal hematopoietic development ļ myeloid or lymphoid
progenitors ļ do not have self-renewal capacity ļ mature into
normal terminally differentiated cells in the peripheral blood.
ā¢ But, leukemic stem cell ļ has limitless self-renewal capacity ļ
gives rise to clonogenic leukemic progenitors ļ do not have self-
renewal capacity + incapable of normal hematopoietic
differentiation.
ā¢ The bulk of leukemic cells ļ differentiated progeny that undergo
limited maturation along the myeloid or lymphoid lineage.
4.
5.
6. ā¢ Childhood ALL ļ cured in 80% to 89% of cases, initial remissions in about
90%.
ā¢ In adults, initial remission rates are generally equally high, but cure rates
are only in the 30% to 45% range.
ā¢ Pediatric AML - 60% cure rates, a marked improvement since the 1970s
when cure rates were roughly 20%.
ā¢ Adult AML cures are less frequent, principally afflicts older individuals.
ā¢ CML and CLL are primarily diseases of adults and have natural histories
measured in years to decades.
7. ACUTE LEUKEMIA
ā¢ Acute leukemias are characterized by aberrant differentiation and
maturation of the malignant cells, with a maturation arrest and
accumulation of leukemic blasts in the bone marrow.
ā¢ Acute leukemias are categorized according to their differentiation
along the myeloid or lymphoid lineage.
ā¢ In 10% to 20% of patients, the leukemic cells have characteristics of
both myeloid and lymphoid cells.
8. CAUSE?
ā¢ Unknown - clear cause can be found in only a minority of patients
ā¢ Malignant transformation is likely caused by the culmination of multiple
processes that produce genetic damage secondary to physical or chemical
exposure in susceptible progenitor cells.
ā¢ Following CT/RT given for another malignancy ļ secondary leukemias have
a poor prognosis.
9. ā¢ Inherited genetic abnormalities :
- ataxia telangiectasia,
- Down syndrome,
- and certain polymorphisms in MTHFR (a gene involved in the folate
metabolism).
ā¢ Alkylating agents and topoisomerase II inhibitors - most commonly a/w
therapy-related leukemias -myeloid leukemias.
ā¢ EBV ļ mature B-cell or Burkittās ALL.
ā¢ Finally, many environmental toxins have been implicated, but only exposure
to nuclear or atomic agents have been clearly demonstrated to be involved in
the development of ALL.
10. CHROMOSOMAL ABNORMALITIES IN ACUTE
LEUKEMIA
ā¢ Nonrandom chromosomal abnormalities ļ detected in majority of
cases:
1. Chromosomal translocations ļ t(8;21)(q22;q22) or
t(15;17)(q22;q21);
2. Internal deletions of single chromosomes ļ 5q- or 7q-;
3. Gain or loss of whole chromosomes (+8 or ā7);
4. Chromosome inversions ļ inv(3), inv(16), or inv(8)
5. Certain genomic loci are a/w specific subtypes of leukemia
11. ā¢ For eg,
- MLL gene locus on chromosome 11q23 ļ myelomonocytic or monocytic
AML phenotype.
- the retinoic acid receptor alpha locus (RAR-Ī±)ļ acute promyelocytic
leukemia (APL) phenotype.
6. Transcription factors
ā¢ For example, translocations t(8;21) or inv(16), , target the core-binding
factor (CBF) ļ expression of dominant negative inhibitors of normal CBF
function ļ impaired hematopoietic differentiation.
ā¢ (CBF)ārelated AMLs have the most favorable prognosis and constitute
10% to 15% of cases in patients under age 60
13. ā¢ CNS involvement is more common in ALL than in AML.
ā¢ Bone and testicular involvement - ALL, and most commonly in children
rather than adults.
On physical examination
ā¢ signs associated with thrombocytopenia ļ pallor, gingival bleeding,
epistaxis, petechiae, ecchymoses, or fundal hemorrhages.
ā¢ Less commonly, generalized lymphadenopathy, hepatosplenomegaly, or
dermal involvement
ā¢ T-lineage ALL may commonly present with a mediastinal mass.
14. DIAGNOSIS
ā¢ Identification of malignant blasts in ļ
- peripheral blood and bone marrow aspirate smears,
- phenotypic analysis of the blasts by cytochemical studies and flow
cytometry,
- IHC
ā¢ Cytospin slides from CSF ļ CNS involvement.
ā¢ The current definition of CNS involvement used by the Childrenās
Cancer Group (CCG) is >5 WBC/microliter of CSF + unequivocal blasts
identified on the cytospin.
15. CLASSIFICATION
ā¢ Acute leukemias have traditionally been classified using the French-
American-British (FAB) morphologic criteria
- the presence of Auer rods,
- staining for myeloperoxidase or monocyte-associated esterases
17. Replaced by WHO classification
ā¢ the classification uses all available information - morphology,
cytochemistry, immunophenotype, genetics, and clinical
ā¢ In addition, in the WHO scheme, the number of blasts in the blood or
bone marrow required to confirm a diagnosis of AML is 20%, instead
of the 30% specified by the older FAB criteria.
18.
19. FAB classification for ALL
ā¢ 3 subtypes based on morphology, which is largely of historical
interest.
1. L1 - predominant type in 85% of childhood ALL. Characterized by
small cells with scanty cytoplasm and inconspicuous nucleoli.
2. L2 - common in ALL of adults and is identified morphologically by
blasts that show prominent nucleoli, abundant cytoplasm, and
more variability in size.
3. L3 - lymphoblasts are large cells with cytoplasmic basophilia and
vacuolization, similar to Burkittās lymphoma cells.
21. ā¢ 85% ALL ļ B-cell lineage ļ most common form precursor-B ļ
express a B-cell immunophenotype (CD19, CD22), TdT, cytoplasmic
CD79A, CD34, CD10 (CALLA)
ā¢ It is found frequently in patients with the Philadelphia chromosome,
t(9;22) (q34;q11).
ā¢ T-lineage ALL ļ 15% to 20% of cases ļ expresses pan T-cell markers,
CD2, cytoplasmic CD3 (cCD3), CD7, CD5, and coexpression of CD4 and
CD8 and expression of CD1a.
22. FREQUENCY AND DISEASE CONTROL ASSOCIATED
WITH IMMUNOPHENOTYPES AND CYTOGENETIC
ABNORMALITIES AND SURVIVAL IN ALL
23. National Cancer Instituteās (NCI) risk classification
scheme
1. Standard risk
ā¢ 2/3rd of pediatric B-cell ALL patients ļ age at diagnosis is 1 - 10 years +
presenting leukocyte count of <50,000/Ī¼L, in the absence of CNS
involvement, ļ 80% 4-year disease-free survival.
2. High-risk patients
ā¢ high WBC count + age below 1 year or above 10 years, or CNS
involvement at diagnosisāhad a corresponding 65% 4-year disease-free
survival.
24. ā¢ T-cell phenotype occurs in 12% to 15% of pediatric ALL cases ļ poor
prognosis ļ due to :-
ā¢ older age,
ā¢ male sex,
ā¢ elevated WBC count,
ā¢ extensive extramedullary disease - mediastinal and peripheral
adenopathy or hepatosplenomegaly,
ā¢ and a higher tendency for relapse in the CNS and testes in males.
25. ā¢ Current clinical practice is for T-cell leukemias to be treated on different
protocols than B-lineage ALL
ā¢ B-cell ALL - low, standard, and high risk.
ā¢ Low-risk patients/standard risk features ļ rapid early response to
induction chemotherapy. Age is also an important prognostic factor.
ā¢ Intensity of the treatment program is of importance as shown by the
fact that adolescents treated on pediatric leukemia regimens have had
better outcomes than those treated on adult programs.
26. ā¢ The response to induction chemotherapy ļ extremely important
prognostic category.
ā¢ In pediatric ALL ļ minimal residual disease (MRD) ļ detected by flow
cytometry of post induction peripheral blood or marrow aspirates.
ā¢ Even up to 0.01% blasts from day 8 post induction mononuclear
peripheral blood cells conferred a poorer prognosis
27. ā¢ Assessment of CNS involvement
ā¢ CNS -1 - defined as no blast cells on CSF cytology
ā¢ CNS - 2 - <5 WBC/Ī¼L with blast cells present
ā¢ CNS - 3 - a CSF leukocyte count of ā„5 WBC/Ī¼L +
either blast cells on cytospin or the presence of cranial nerve palsy.
ā¢ Patients with CNS-3 ļ intensive chemotherapy along with cranial
radiation within the first year of therapy have similar event-free survival
as CNS-2 patients.
28. Radiotherapeutic Emergencies
ā¢ Mediastinal adenopathy ļ airway compression/spinal cord
compression from epidural disease ļ 1.5- to 2.0-Gy/# x 1-3 while the
diagnosis is being established and systemic therapy is being initiated.
ā¢ Glucocorticoids in CNS RT can produce rapid lysis of some
lymphoblastic lymphomas/leukemia ļ hamper diagnostic evaluation.
ā¢ In the presence of cranial nerve palsies at diagnosis, 10 to 15 Gy to
the base of skull early in the treatment course
29. ā¢ Extreme leukocytosis with blast counts over 75,000 to 100,000/Ī¼L is a
concern with myeloid leukemia
ā¢ RT directed at the whole brain was employed using low doses on the
order of 6 to 10 Gy in various fractionations.
ā¢ RT considered when leukophoresis or exchange transfusion is
contraindicated or unavailable.
30. Treatment of Acute Myeloid Leukemias
ā¢ Classical induction therapy for AML is an anthracycline on days 1 to
3 with cytarabine for 7 days.
ā¢ APML - exception ļ a combination of anthracycline and all-trans-
retinoic acid or single-agent arsenic trioxide.
ā¢ Daunorubicin and idarubicin are the anthracyclines most commonly
used
ā¢ Meta-analysis of multiple trials suggested that idarubicin has a higher
(CR) rate and survival over daunomycin, more recent data suggest
that when equivalently dosed, responses are similar.
31. ā¢ Remission rates vary from 50% to 80% dependant on patient age,
karyotype, and subtype of AML.
ā¢ Patients younger than age 60 ļ CR 70% to 80%, older patients tend to
have lower CR 50% to 60%.
ā¢ Patients who develop secondary AML following chemotherapy for other
cancers have CR 40% to 60% range.
ā¢ Adding other chemotherapy drugs to anthracycline and cytarabine has
yet to be shown to produce a convincing survival benefit for AML
induction in adults.
ā¢ >60 years of age who are not candidates for hematopoietic stem cell
transplantation ļ treatment with low-intensity palliative therapies such
as low-dose subcutaneous cytarabine, azacitidine, or decitabine.
32. ā¢ Postremission consolidative therapy begins with high-dose ara-C for
up to four cycles.
ā¢ Alternatively, additional cycles of anthracycline for 2 days along with
conventional-dose cytarabine for 5 days has been used in both
younger and older individuals with AML.
33. ā¢ Role of CNS prophylaxis is not well defined because CNS relapse
rates are relatively infrequent (at roughly 5% to 10%).
ā¢ Some studies show no difference in relapse rates with cranial
radiation.
ā¢ Patients with a high WBC count at diagnosis or monocytic variants of
AML ļ have a higher risk for CNS relapse, which may justify both IT
chemotherapy and cranial radiation in this setting.
34. TREATMENT of Myeloid or Granulocytic
Sarcoma
ā¢ Also called a chloroma
ā¢ Solid masses of leukemic infiltrates
ā¢ Occur in all varieties of extramedullary sites including periosteum,
skin, soft tissues, gastrointestinal tract, the spine, and in epidural
spaces or meninges.
ā¢ symptomatic problems from chloromas may be readily relieved with
doses of 10 to 20 Gy.
35. Treatment of Acute Lymphoblastic Leukemia
ā¢ The four components of specific ALL therapy are:
(i) induction of remission,
(ii) intensification and/or consolidation
(iii) maintenance therapy
(iv) CNS prophylaxis.
36. ā¢ In the 1960s, CNS recurrence was addressed with CNS radiation and
IT chemotherapy.
ā¢ The late sequela of 24-Gy cranial irradiation were recognized in the
1980s and 1990s, leading to the elimination of cranial RT in favor of
intermediate- or high-dose MTX in all but high-risk patients or those
with CNS-3 disease.
37. Induction therapy for ALL :
ā¢ Dexamethasone + vincristine + L-asparaginase.
ā¢ Higher-risk patients often receive additional drugs such as an
anthracycline, especially for adult ALL.
Intensification therapies :
ā¢ MTX, ara-C, or L-asparaginase. Additional anthracycline therapy is
beneficial in high-risk patients. It is believed that high-dose MTX helps
control CNS disease, which has allowed for less use of cranial radiation
in some pediatric programs.
Maintenance treatment:
ā¢ In all but mature B-cell ALL, maintenance therapy over 2 to 3 years with
agents such as weekly low-dose MTX and mercaptopurine
38. CNS Prophylaxis of Acute Leukemia and the Role of
Cranial Radiotherapy
ā¢ Historically, as multiagent chemotherapy proved to be highly
effective in producing remissions in childhood ALL, numerous
investigators noted a significant increase in CNS relapses.
ā¢ The CNS protected from chemotherapy by the bloodābrain barrier.
ā¢ CNS recurrences invariably led to systemic recurrence suggesting that
CNS disease was capable of reseeding the blood and marrow.
ā¢ This observation led to a long series of CNS preventative therapy
trials, which initially utilized craniospinal irradiation (CSI).
39. ā¢ Studies V and VI in 1962ā1967 from SJCRH established that CSI to 24 Gy
in 15 to 16 #s reduced the isolated CNS relapse rate from 67% to 4%.
ā¢ Concerns ļ acute myelosuppression, late musculoskeletal hypoplasia,
as well as the technical difficulties of CSI
ā¢ In SJCRH study VIII (1972ā1975), all patients received 24-Gy cranial
radiation plus IT MTX
ā¢ The incidence of CNS relapse was 5.0%, 1.5%, 20%, and 11.4%,
respectively.
40. ā¢ Some patients developed leukoencephalopathy ļ syndrome of lethargy,
seizures, spasticity, paresis, and ataxia.
ā¢ Thus, standard maintenance with oral MTX and mercaptopurine
following cranial radiation along with IT MTX to treat the spinal
subarachnoid space ļ lowest CNS relapse rate and the least toxicity.
41. ā¢ In the 1970s and 1980s, additional phase III trials further defined
appropriate preventative CNS therapy for childhood ALL.
ā¢ The Childrenās Cancer Study Group (CCSG) trial #101 compared:
ā¢ (i) 24-Gy CSI + EFRT encompassing the liver, spleen, and gonads;
ā¢ (ii) 24-Gy CSI alone;
ā¢ (iii) 24-Gy cranial RT plus IT MTX;
ā¢ iv) IT MTX alone.
ā¢ Overall, the different radiation regimens were comparable in preventing
CNS relapse while statistically superior to IT chemotherapy alone.
42. ā¢ The CCSG further compared cranial RT plus IT MTX with CSI in high-
risk patients, defined by a WBC at diagnosis of >50,000/Ī¼L; ļ
significantly superior with respect to both CNS and systemic relapse
rates.
ā¢ Patients with low- or standard-risk ALL (e.g., age 3 to 6 years and
WBC count <10,000/Ī¼L)
ā¢ ļ managed without cranial radiation by substituting IT MTX
throughout induction, consolidation, and maintenance therapy
ā¢ ļ CNS relapse rates 5% or less
43. ā¢ In CCG-105, 1,388 patients ļ randomly assigned to receive either IT MTX alone
or cranial radiation for CNS treatment.
ā¢ A secondary complex randomization scheme allocated patients to standard or
intensive chemotherapy.
ā¢ Intensive chemotherapy included either more drugs for induction or the
addition of a delayed intensification chemotherapy phase after consolidative
and CNS therapies.
ā¢ CNS recurrence rates - 5% to 7% except in those patients receiving standard
chemotherapy without cranial radiation, where the CNS recurrence was 20%
ā¢ Compared different doses of radiation (generally 18 to 21 Gy versus 24 Gy).
ā¢ There were no differences in CNS or non-CNS relapse rates that could be
discerned
44. Use of cranial RT in pediatric ALL
ā¢ The European BFM-ALL trials since 1990 have reduced the cranial
radiation dose to 12 Gy,
ā¢ Those with CNS-3 disease received 24 Gy in their BFM-90 trial and 18 Gy
in the more recent BFM-95 trial.
ā¢ To reduce the toxicity of PCI ļ 18 Gy in 9 or 10 fractions along with IT
MTX yields (comparable disease control rates as 24 Gy) ļ Protocol for
pediatric ALL
45. ā¢ Most T-cell ALL patients are at increased risk for CNS relapse ļ receive
cranial irradiation.
ā¢ Patients being treated with BFM-type chemotherapy - 12 Gy.
ā¢ For adults with ALL, various protocols have used 24 Gy, whereas others
employ 18 Gy.
46. Meningeal Leukemia at Diagnosis
ā¢ At the time of diagnosis of ALL, approximately 3% to 5% of patients ļ
CNS-3 disease ļ managed as high-risk leukemia with cranial RT.
ā¢ CT ļ intensive therapy with agents that penetrate the bloodābrain
barrier + IT therapy.
ā¢ Cranial radiation doses may vary from 18 to 25 Gy.
47. ā¢ Delay in RT up to 12 months ā safe - as long as intensive CT is being
given first ļ avoids the marrow compromise that could potentially
occur with early spine irradiation.
ā¢ <16 Gy to the spine, myelosuppression has not been a major problem.
ā¢ The sequencing of RT after rather than before potentially neurotoxic
drug therapy such as MTX may theoretically result in a lower incidence
of cognitive dysfunction or encephalopathy.
ā¢ ALL-BFM 90 protocol, which utilizes cranial rather than CSI, avoids any
RT for those younger than 1 year of age, 18 Gy for ages 1 to 2 years, and
24 Gy for older patients.
48. IRRADIATION TECHNIQUES
ā¢ Cranial Radiation
The volume of treatment must include the subarachnoid space within
the cranial vault.
The inferior margin ļ extended to the bottom of either the first or
second cervical vertebra and includes the whole vertebral body.
SCALP ļ flash.
The posterior globe of the eye is typically included given concerns of
leukemic relapse in the posterior retina near where there is
subarachnoid space extending alone the optic nerves.
49. Therapeutic CNS Irradiation for Meningeal
Relapse
ā¢ Relapse rates are typically <10% - RT has a central role.
ā¢ 5-year survivals of 50% to 70%.
ā¢ Almost all trials have employed RT
ā¢ the debate has been between cranial RT alone or CSI.
ā¢ Most comparisons have not been randomized, but superior outcomes
seem to be achieved with CSI
ā¢ Radiation doses for overt CNS leukemia are 18 to 30 Gy to the cranium
in 1.5- to 1.8-Gy fractions.
50. ā¢ Maximum beam energy of 6 MV is recommended.
ā¢ Rare that overt CNS leukemia for children or adults be treated with
craniospinal fields
ā¢ In such cases ļ IT chemotherapy, the spine may be treated to total
doses of 6 to 15 Gy depending on individual circumstances.
ā¢ TBI must be taken into account IF allogeneic transplant can be
conceptualized as being in part CNS therapy.
51. Testicular Relapse
ā¢ In boys with ALL, particularly those with T-cell subtype, testicular involvement was
once a common problem.
ā¢ 2% of males with ALL, poor prognostic situation. ļ intermediate- to high-dose
MTX, this is now rare.
ā¢ In cases of testicular relapse, systemic and/or CNS relapse usually follows.
ā¢ Both intensive systemic therapy and local RT are indicated.
ā¢ Doses of 24 to 26 Gy/ 1.5- to 2.0-Gy fractions over 2.5 to 3.5 weeks are considered
standard.
ā¢ When testicular boost is given in conjunction with TBI for HCT, the dose is either 4
Gy / 1 fraction or 2 Gy x 2 fractions.
52. ā¢ Both gonads and the scrotum can be irradiated with either electrons or
photons.
ā¢ With the patient in a āfrog-legā position and the penile shaft taped onto
the abdomen, an anterior inferior oblique photon field works well.
ā¢ For MV photon beams, bolus may be required to avoid superficial
underdosing.
ā¢ In young boys where the scrotum/testes thickness is under 2 cm, 250-kV
orthovoltage x-rays may also be used. Alternatively, direct en face
electron beams of appropriate energy work adequately..
53. Chronic Myelogenous Leukemia
ā¢ It involves myeloid, erythroid, megakaryocytic, and sometimes
lymphoid elements.
ā¢ Male preponderance
ā¢ The only established risk factor is exposure to ionizing radiation ļ
survivors of the nuclear explosions in Japan and patients exposed to
thorotrast or radiotherapy.
54. Pathogenesis
ā¢ In 1973, Janet Rowley discovered that Ph is in fact the result of a
reciprocal translocation between chromosomes 9 and 22 [t(9;22)
(q34;q11)].
ā¢ The genes juxtaposed by the translocation ļ ABL (Abelson) on 9q34
and breakpoint cluster region (BCR) on chromosome 22q11
ā¢ Tyrosine kinase activity of BCR-ABL is required for cellular
transformation
ā¢ According to WHO the presence is diagnostic of CML, although the
translocation is also found in ALL and rare cases of AML.
55.
56. Clinically:
ā¢ an initial chronic indolent phase of 3 to 4 years ļ accelerated phase ļ
acute transformation to blast phase with a survival of 3 to 6 months
ā¢ Accelerated phase is characterized by:
- increasing difficulty in controlling the peripheral WBC count,
-increasing splenomegaly,
-increasing blasts in the peripheral blood and bone marrow,
-basophilia and eosinophilia.
ā¢ The blast crisis ļ >30% blasts in blood or bone marrow with symptoms
such as bone pain, sweats, fever, anorexia, or weight loss, Anemia,
thrombopenia, and extramedullary disease involving bones, skin, CNS,
and lymph.
57. ā¢ Poor prognosis factors :
- age >60 years,
- spleen >l0 cm below the costal margin,
- blasts >3% in blood or marrow,
- basophilia >7% in blood or marrow, and platelets >700,000/Ī¼L.
- poor response to therapy
59. 2. Cytogenetics
ļ standard method to detect the Ph chromosome
3. Molecular Testing
- BCR-ABL fusion gene detectable by FISH / RT-PCR.
- Ph chromosomeānegative and BCR-ABLā negative ļ more
aggressive clinical course.
61. RT IN CML
ā¢ RT to the spleen and sometimes the liver
ā¢ Today, used in a palliative ļ painful splenomegaly or other
extramedullary sites when indicated with doses in the 10- to 20-Gy.
ā¢ Extreme radiosensitivity of the malignant stem cells in CML ļ very
low doses per fraction (25 to 100 cGy) once or twice a week with
close monitoring of blood counts
ā¢ In some centers, TBI plays an important role in allogeneic
transplantation.
62. CHEMOTHERAPY IN CML
ā¢ Imatinib is a relatively nontoxic oral medication effective in both
chronic and accelerated phase.
ā¢ For those who do not respond adequately/lose response ļ
allogeneic transplantation.
ā¢ About 70% of good-risk patients achieve long-term disease-free
survival.
63. Chronic Lymphocytic Leukemia
ā¢ of B-cell origin.
ā¢ Many patients live a normal lifespan, never require therapy, and die
of unrelated causes. Others progress within a few years despite
treatment.
ā¢ Gradual progression - no significant physical findings ļ
lymphadenopathy, gradual increase in peripheral blood lymphocyte
count, and increasing splenomegaly, sometimes massive in size.
ā¢ Advanced stage ļ Nonlymphoid organ involvement, anemia and
thrombocytopenia .
64. ā¢ Occasionally ļ transformation to an aggressive large B-cell lymphoma
referred to as Richterās syndrome ļ abrupt onset of asymmetric
adenopathy, fever, and elevated LDH.
ā¢ Its incidence ranges from 3% to 5% of CLL cases.
ā¢ It may arise in active disease or during a CR.
65. DIAGNOSIS
ā¢ National Cancer Institute Working Group 1996 guidelines for
diagnostic criteria and treatment for CLL
1. A peripheral blood B lymphocyte count >5 Ć 109/L, with less than
55% of the cells being atypical (prolymphocytes).
2. The lymphocytes should be monoclonal B lymphocytes expressing
B-cell surface antigens (CD19, CD20, CD23), low-density surface
immunoglobulin (M or D), and CD5.
67. TREATMENT
ā¢ Asymptomatic early-stage patients may be followed without therapy.
ā¢ About 20% will have an indolent course indefinitely. For the
remaining ļ NCI has established guidelines:
1. Symptomatic lymphadenopathy and/or hepatosplenomegaly,
2. Lymphocyte doubling time <6 months,
3. anemia (hemoglobin <10 g/dL),
4. Thrombocytopenia (platelets <100,000/Ī¼L)
5. The absolute lymphocyte count ļ not an indication for treatment,
as symptoms associated with marked lymphocytoses do not
typically occur in CLL.
68. ROLE OF RT
ā¢ Management of painful splenomegaly or occasionally for cytopenias
associated with splenomegaly when splenectomy is not an option.
ā¢ Unresponsive disease
ā¢ Fractionated doses up to 20 Gy.
69. Splenic Irradiation
ā¢ Anterior and posterior opposed portals for photon treatments
ā¢ Standard practice ļ whole spleen in 0.25- to 1.0-Gy fractions either
daily or 2-3 times a week with doses titrated to response and
hematologic tolerance.
ā¢ As the spleen responds ļ shrink the treatment fields accordingly.
ā¢ Blood counts monitored several times a week.
ā¢ Total doses ļ 4 to 10 Gy with usually no more than 20 Gy required.
70. ā¢ In patients with extramedullary hematopoiesis ļ chanes of severe
neutropenia or thrombocytopenia is very high
ā¢ Dose per fraction may need to be as low as 0.1 to 0.5 Gy
ā¢ Another strategy ļ treat only half of the spleen.
ā¢ For myelodysplastic conditions or extramedullary/intrasplenic
hematopoiesis ļ
total doses of 1 to 9 Gy are usually adequate.
71. ā¢ nausea is uncommon with these low-dose fractions but can be
readily managed with antiemetics if necessary.
ā¢ As there can be rapid cell lysis, allopurinol to prevent uric acid
nephropathy is advised.
ā¢ Cumulative dose to the left kidney should be monitored, especially as
retreatment in the future may be required, but it is rare for doses
beyond 20 Gy to be required.
72. CHEMOTHERAPY
ā¢ Previously standard treatment ļ single-agent chlorambucil +/-
prednisone.
ā¢ Newer purine analog ļ fludarabine - high response rate ļ
standard therapy for CLL.
ā¢ CR ļ chlorambucil was 4% ; fludarabine 20%.
ā¢ ORRļ 37% with chlorambucil and 63% with fludarabine.
ā¢ MSļ 66 months (fludarabine) versus 56 months.
ā¢ More recently, a combination of fludarabine,
cyclophosphamide, and rituximab ļ high complete remission
rate of 70%, with a median time to progression of 80 months.
73. ā¢ Allogeneic transplantation employed with increasing frequency in the
past decade
ā¢ Indications:
- early relapse following chemoimmunotherapy,
- resistance to fludarabine,
- chromosome 17p deletion,
- Richterās transformation.
74. Newer approaches
ā¢ The anti-CD52 antibody, alemtuzumab ļ single-agent activity in
patients refractory to fludarabine and appears effective in patients
harboring chromosome 17p deletions.
ā¢ alkylating agent bendamustine
ā¢ new humanized anti-CD20 monoclonal antibody, ofatumumab.
ā¢ The immunomodulatory drug, lenalidomide
Though there are considerable dose inhomogeneities in treating such a curved surface with electrons, the relatively low doses employed in this setting translates into relatively low risks related to skin and subcutaneous soft tissue reactions