Clonal Hematopoietic Disorders
1
Management of AL, MDS & MPD
MANAGEMENT OF ACUTE LEUKEMIA,
MYELODYSPLASTIC SYNDROME, AND
MYELOPROLIFERATIVE DISORDERS
MANAGEMENT OF ACUTE LEUKEMIA:
The approach to a patient with suspected acute leukemia must begin with a clinical
history, physical examination, a complete blood count with differential, and review of a
peripheral blood smear. Many patients present with signs of bone marrow failure such as
weakness and pallor resulting from anemia; infections secondary to neutropenia; and,
bleeding because of low platelet counts. A CBC often shows a high white cell count with
increased blasts in the peripheral blood. Some patients, however, present with
unexplained cytopenias and little or no circulating blasts. These cases are often referred
to as aleukemic leukemia. Physical examination may reveal splenomegaly,
lymphadenopathy, or evidence of other tissue infiltration by blasts such as leukemia cutis
or gum hypertrophy.
PRETREATMENT WORKUP:
Patients with suspected acute leukemia undergo a ritual of pretreatment workup that
include the following measures:
1. Laboratory tests, imaging studies and other general measures:
(a) Complete pretreatment blood count with manual differential.
(b) Blood chemistry tests – electrolytes, serum creatinine, liver enzymes,
bilirubin, blood urea nitrogen (BUN), serum calcium, phosphorus, serum
LDH, amylase, and serum lipase.
(c) Blood coagulation studies – PT, aPTT, Fibrinogen, and D-dimer levels.
(d) Viral serologies – CMV, HSV-1, Varicella zoster
(e) RBC type and screen
(f) HLA-typing of the patient followed at some other point by HLA-typing of
siblings, and parents for potential stem cell transplant
(g) Bone marrow aspiration and core biopsy for (i) morphologic evaluation,
(ii) histochemical analysis of blasts for expression of myeloperoxidase,
and non-specific esterase, (iii) immunophenotyping of blasts by flow
cytometry or immunohistochemistry, and, (iv) cytogenetics and/or
molecular evaluation for specific aberrations.
(h) Cryopreservation of viable leukemia cells for potential future studies
(i) Baseline echocardiogram for cardiovascular functional status
(j) Baseline chest radiographs
(k) Placement of central venous catheter
(l) Counseling for all patients
2. Specific tests and measures may be performed depending on each case such as
(a) Lumber puncture in patients suspected of CNS involvement
(b) Screening spine MRI for patients with back problems
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material for teaching purposes only. No commercial incentives are sought or intended.
Clonal Hematopoietic Disorders
2
Management of AL, MDS & MPD
TREATMENT PLANS:
SUPPORTIVE THERAPY:
If the blasts count is too high (>200,000/L), immediate treatment might include
cytopheresis/leukapheresis (removal of blast cells from circulation by a pheresis
machine) and hydration to avoid acute renal failure due to high uric acid formation and
deposition in the kidneys by cytoreductive chemotherapy. Pre-induction therapy with
low-dose glucocorticoid with or without other agents may be used in treating
hyperleukocytosis. The metabolic complications of hyperleukocytosis should be managed
aggressively by intravenous hydration, sodium bicarbonate to alkalinize the urine,
allopurinol to treat hyperuricemia, and phosphate binder agent to treat
hyperphosphatemia. Blood and platelet transfusions are often required in some patients.
SPECIFIC ANTI-LEUKEMIC THERAPY:
Not all patients are candidates for an aggressive chemotherapy or bone marrow
transplantation and a subset of patients opt not to be treated. For most other patients
specific treatment plans exist.
The contemporary treatment plans require that acute leukemia must first be categorized
as either:
1. Acute myeloid leukemia (AML), or
2. Acute lymphoblastic leukemia (ALL)
An acute myelogenous leukemia need be further differentiated as
1. Acute promyelocytic leukemia (APL/AML-M3 subtype), or
2. Non-APL AML subtypes (AML-M0, M1/M2, M4, M5, M6, M7), and
An Acute lymphoblastic leukemia need be further differentiated as
1. Precursor B-cell and T-cell ALL
(a) Low-risk
(b) Standard-risk
(c) High-risk
2. Mature B-cell ALL (Burkitt cell leukemia)
Specific treatment protocols may vary from one institution to another, and change over
time based on results of research studies. Also, a variety of prognostic factors, including
age, and specific chromosomal changes, dictate what specific treatment should be
instituted. However, same basic strategies are followed for both AML and ALL
throughout institutions. These include a stepwise treatment plan
1. Induction of remission
2. Consolidation/Intensification of treatment
3. Maintenance/Continuation of treatment
4. Treatment of relapsed leukemia with standard regimens
5. Option to treat refractory leukemia with investigational protocols and agents
Several patients also undergo
1. CNS treatment or prophylaxis.
2. Allogeneic or autologous bone marrow transplantation for curative treatment
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material for teaching purposes only. No commercial incentives are sought or intended.
Clonal Hematopoietic Disorders
3
Management of AL, MDS & MPD
PROGNOSTIC FACTORS IN ACUTE LEUKEMIA:
ACUTE MYELOGENOUS LEUKEMIA:
A variety of prognostic factors have been associated with acute myelogenous leukemia
and include the following:
BETTER PROGNOSIS THAN AVERAGE OF ALL PATIENTS:
1. Certain chromosomal abnormalities
(a) t(15;17) or its variants
(b) t(8;21) without del(9q) or complex karyotypes
(c) inv(16)/t(16;16)/del(16q) with any other abnormality
2. Residual normal metaphases admixed with clonal cytogenetic abnormalities
3. Absence of overt and exaggerated myelodysplasia in remaining marrow cells
POORER PROGNOSIS THAN AVERAGE OF ALL PATIENTS:
1. Certain chromosomal abnormalities
(a) -5, -7, del(5q), del(7q)
(b) Involvement of MLL gene (11q23 region) such as t(9;11)
(c) t(9;22)(q34;q11) – Philadelphia chromosome involvement
(d) Complex karyotypes (> 3 abnormalities)
(e) t(6;9)
2. Older age (>60 years) or infants
3. Multi drug resistance phenotype – Blasts expressing P-glycoprotein
4. AML arising from prior myelodysplastic syndrome and showing dysmyelopoiesis
in remaining cells
5. Secondary acute myeloid leukemias (secondary to chemotherapy for other
malignancies)
6. Higher WBC (>30,000/L)
7. Very low platelet count (30,000/L)
8. Poor performance status
ACUTE LYMPHOBLASTIC LEUKEMIA:
Age, WBC count at presentation, specific chromosomal abnormalities, and response to
standard treatment are the most important prognostic factors for ALL. For treatment
purposes these patients can be categorized into the following prognostic groups
1. Low-risk ALL
(a) Precursor B-cell type with age 1-9 years & presenting WBC <50 x 109/L
(b) Hyperdiploidy (>50 chromosomes) and/or ETV6-CBFA2 fusion
(c) Must not have the following: CNS leukemia, testicular leukemia, t(9;22),
t(1;19), involvement of MLL gene, hypodiploidy, or poor early response
2. Standard-risk ALL
(a) T-cell ALL & all cases of precursor B-ALL not meeting the criteria for
low-risk or high-risk ALL
3. High-risk ALL
(a) t(9;22), involvemnt of MLL gene [t(4;11)], poor early treatment response
The contents & pictures in this handout are derived from various sources including books, journal articles and patient
material for teaching purposes only. No commercial incentives are sought or intended.
Clonal Hematopoietic Disorders
4
Management of AL, MDS & MPD
TREATMENT OF ACUTE PROMYELOCYTIC LEUKEMIA (APL):
Acute promyelocytic leukemia (APL) is the most curable subtype of AML mainly
because of treatment with all-trans Retinoid acid (ATRA), which induces differentiation
in malignant promyelocytes. As you may recall these leukemias rearrange retinoic acid
receptor gene on chromosome 17 in balanced translocations with other partner genes such
as t(15;17). Treatment with ATRA leads to maturation in malignant promyelocytes. The
current standard of therapy is with an anthracycline (daunorubicin or idarubicin):
Induction
ATRA + anthracycline-based chemotherapy
Anthracycline alone, if cannot give ATRA
Consolidation
Anthracycline-based chemotherapy x 1-2 cycles
Maintenance
ATRA + low dose chemotherapy
Treatment of relapsed leukemia:
With arsenic trioxide
Bone marrow transplantation:
No role of Allo-BMT in first remission
Special problems:
ATRA resistance (20-30% patients)
Retinoic acid syndrome in ~15% patients treated with ATRA alone
TREATMENT OF NON-APL ACUTE MYELOID LEUKEMIA:
The treatment of non-APL AMLs is more complex than APL and a variety of protocols
have been used. However, some basic strategies remain the same including the most
commonly used 3+7 induction protocol. The 3+7 induction protocol derives its name
because anthracycline (daunorubicin or idarubicin) is given for the first 3 days only in
conjunction with the use of ara-C (cytarabine) for the first 7 days. Numerous variations
on this theme have been tried with similar results.
Induction
Idarubincin or Daunorubicin for day 1-3
Ara-C (Cytarabine) for day 1-7
Post-remission
Depends on cytogenetic prognostic groups; favorable [t(8;21)],
intermediate (+8, normal karyotype) or unfavorable [-5, -7, other].
The contents & pictures in this handout are derived from various sources including books, journal articles and patient
material for teaching purposes only. No commercial incentives are sought or intended.
Clonal Hematopoietic Disorders
5
Management of AL, MDS & MPD
Treatment of relapsed leukemia:
Ara-C (Cytarabine) based or non-Ara-C based
Prognosis very poor
Bone marrow transplantation:
Allo-BMT in first remission if donor available
Auto-BMT if HLA-matched donor unavailable
Special problems:
Treatment of older patients – high mortality
Treatment in patients <2 years of age – Marrow transplant
Secondary acute myeloid leukemia – poor response
TREATMENT OF PRECURSOR B OR T-CELL ACUTE LEUKEMIA
Acute lymphoblastic leukemia as a group, in general, has a better prognosis than AMLs.
The treatment in both children and adults follow similar protocols and drugs.
Induction
For Children:
Glucocorticoid + vincristine + L-asparaginase (+ Anthracycline)
For adults:
Glucocorticoid + vincristine + Anthracycline (+ L-asparaginase)
Consolidation
For Children:
Methotrexate + 6-mercaptopurine; other regimens
For adults:
Treatment effectiveness less clear; several protocols
Maintenance
For Children:
Methotrexate (weekly) + 6-mercaptopurine (daily)
For adults:
Treatment effectiveness less clear; several protocols
Treatment of CNS disease
Started after the remission induction phase with
intrathecal methotrexatae + cranial irradiation
Treatment of relapsed leukemia
Second induction of remission with chemotherapy
Bone marrow transplantation
Special problems:
Secondary AMLs with very poor prognosis
TREATMENT OF MATURE B-CELL ACUTE LEUKEMIA
Treatment of mature B-cell (Burkitt cell/FAB-L3) type comprises regimens including
cyclophosphamide, high-dose methotrexate, and other agents. CNS treatment is an
essential component of the treatment.
The contents & pictures in this handout are derived from various sources including books, journal articles and patient
material for teaching purposes only. No commercial incentives are sought or intended.
Clonal Hematopoietic Disorders
6
Management of AL, MDS & MPD
MANAGEMENT OF CHRONIC MYELOID LEUKEMIA
PRETREATMENT WORKUP:
Patients with suspected chronic myelogenous leukemia (CML) also undergo a ritual of
pretreatment workup similar to patients with acute leukemia that include the following
measures:
3. Laboratory tests, imaging studies and other general measures:
(a) Complete pretreatment blood count with manual differential.
(b) Blood chemistry tests – electrolytes, serum creatinine, liver enzymes,
bilirubin, blood urea nitrogen (BUN), serum calcium, phosphorus, and
serum LDH.
(c) Leukocyte alkaline phosphatase levels (LAP score)
(d) Serum vitamin B-12-binding proteins and vitamin B-12
(e) Blood coagulation studies – PT, aPTT, Fibrinogen, and D-dimer levels.
(f) Viral serologies – CMV, HSV-1, Varicella zoster
(g) RBC type and screen
(h) HLA-typing of the patient followed at some other point by HLA-typing of
siblings, and parents for potential stem cell transplant
(i) Bone marrow aspiration and core biopsy for (i) morphologic evaluation,
(ii) histochemical analysis of blasts for expression of myeloperoxidase,
and non-specific esterase, (iii) immunophenotyping of blasts by flow
cytometry or immunohistochemistry, and, (iv) cytogenetics and/or
molecular evaluation for specific aberrations.
(j) Peripheral blood and/or bone for routine cytogenetics, PCR and FISH for
bcr-abl fusion transcript.
(k) Cryopreservation of viable leukemia cells for potential future studies
(l) Baseline echocardiogram for cardiovascular functional status
(m) Baseline chest radiographs
(n) Placement of central venous catheter
(o) Counseling for all patients
4. Specific tests and measures may be performed depending on each case such as
(a) Screening spine MRI for patients with back problems
TREATMENT PLANS:
SUPPORTIVE THERAPY:
If the blasts count is too high (>200,000/L), immediate treatment might include
cytopheresis/leukapheresis (removal of white blood cells from circulation by a pheresis
machine) and hydration to avoid acute renal failure due to high uric acid formation and
deposition in the kidneys. Another indication of leukapheresis is a pregnant patient with
CML in whom chemotherapy is avoided during the early months or in some cases
throughout the pregnancy. The metabolic complications of hyperleukocytosis should be
managed aggressively by intravenous hydration, sodium bicarbonate to alkalinize the
urine, allopurinol to treat hyperuricemia, and phosphate binder agent to treat
hyperphosphatemia. Blood and platelet transfusions may be required in some patients.
SPECIFIC ANTI-LEUKEMIC THERAPY:
The contents & pictures in this handout are derived from various sources including books, journal articles and patient
material for teaching purposes only. No commercial incentives are sought or intended.
Clonal Hematopoietic Disorders
7
Management of AL, MDS & MPD
The treatment plans are evolving rapidly as new therapeutic agents and improved BMT
protocols are available so any one current protocol may not be the protocol of choice for
all patients at all the centers. The control of high white cell count can be done with
hydroxyurea with or without leukapheresis. One of the current protocols for initiation of
definitive treatment for chronic phase CML is following:
OPTION 1:
Treat every patient with STI571 (tyrosine kinase inhibitor) or IFN- or a combination.
Patients who “fail” the above treatment and who have HLA-identical siblings or HLAmatched other donors may undergo allogeneic stem cell transplantation.
OPTION 2:
A/G
PEG-IFN
Allo-SCT
= Autografting of bone marrow stem cells
= Pegylated Interferon alpha
= Allogeneic stem cell transplant
MANAGEMENT OF ESSENTIAL THROMBOCYTOSIS
Patients with ET are at increased risk for thrombotic and hemostatic complications.
Symptomatic patients with a high platelet count must be treated whereas in asymptomatic
individuals the guidelines are unsettled. If symptoms warrant immediate reduction in the
platelet count, cytopheresis may be employed. Hydroxyurea is highly effective as initial
therapy for ET. Blood counts should be checked within 7 days of initiating therapy and
monitored frequently thereafter, since bone marrow suppression can occur with this
treatment. Anarrelide is effective in platelet reduction and serves as the first-line
alternative treatment. Antiplatelet drugs may be used to prevent thrombosis.
MANAGEMENT OF POLYCYTHEMIA VERA
The contents & pictures in this handout are derived from various sources including books, journal articles and patient
material for teaching purposes only. No commercial incentives are sought or intended.
Clonal Hematopoietic Disorders
8
Management of AL, MDS & MPD
Polycythemia vera shows two phases of the disease. In the initial “plethoric” phase the
marrow is hypercellular and high cell counts are the features whereas in the later “spent”
phase the marrow starts showing fibrosis with decreasing counts. The goal is to treat the
symptoms and also the disease itself. The initial treatment for most symptomatic patients
is repeated phlebotomy. The hematocrit may be reduced to normal or near-normal values
by removing 450 – 500 ml of blood at intervals of about 2 – 4 days. Other intervals are
set depending on the hematocrit, symptomatology and patients weight. Treatment with
myelosuppressive agents may be required if the platelet count is too high to pose risk of
thrombosis or bleeding. Hydroxyurea is the most commonly employed agent for that
purpose, although a few other agents including Busulfan may be used. Myelosuppressive
treatment is associated with a slight increased risk for transformation to acute leukemia.
MANAGEMENT OF IDIOPATHIC MYELOFIBROSIS
Most of these patients remain cytopenic for prolonged periods and many are
asymptomatic and do not require any specific treatment. Severe anemia may improve
with androgen therapy in some patients. Cytotoxic agents may be used in patients with
massive splenomegaly, thrombocytosis and constitutional symptoms. Hydroxyurea is the
most commonly used drug in that regard. Splenectomy is an important option in the
management of these patients. The major indication for splenectomy include: (1) painful
enlargement of the spleen, (2) excessive transfusion requirements or refractory hemolytic
anemia, (3) severe thrombocytopenia, and, (4) portal hypertension. Radiation therapy is
also an important treatment modality in these patients. Treatment with radiotherapy may
be instituted in the following situations: (1) severe splenic pain, (2) massive splenic
enlargement with a contraindication to splenectomy (such as extreme thrombocytosis),
(3) ascites resulting from myeloid metaplasia of the peritoneum, (4) focal areas of severe
bone pain, and, (5) extramedullary hematopoietic tumors such as in the epidural space.
MANAGEMENT OF MYELODYSPLASTIC DISORDER
A patient with a diagnosis of myelodysplastic syndrome is further categorized into
various subtypes and managed appropriately. In patients whose cytopenia are mild to
moderate without any complications may not need any treatment at all. In other patients,
supportive therapy with transfusion with packed red cells or platelets may be necessary.
Treatment with erythropoietin and growth factors (G-CSF) may also be used. Still in
other patients with progressive disease and increasing blasts, cytotoxic chemotherapy
may be employed. In younger patients with symptomatic MDS bone marrow
transplantation may be indicated.
The contents & pictures in this handout are derived from various sources including books, journal articles and patient
material for teaching purposes only. No commercial incentives are sought or intended.