Acute Lymphoblastic Lymphoma

Betemeba
H20, ESMO 2021 and uptodate 2022

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 Introduction
• Acute lymphoblastic leukemia (ALL) is a neoplastic disease that
results from multistep somatic mutations in a single lymphoid
progenitor cell at one of several discrete stages of development.
• Leukemic cells divide more slowly and require more time to
synthesize DNA than do normal hematopoietic counterparts.
• However, leukemic cells accumulate relentlessly because of
their altered response to growth and antigrowth signals.
• They compete successfully with normal hematopoietic cells,
resulting in anemia, thrombocytopenia, and neutropenia.
• At diagnosis, leukemic cells not only have replaced normal
marrow cells but also have disseminated to various
extramedullary sites.
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 Introduction

• The malignant clone arises from hematopoietic

progenitors in the bone marrow or lymphatic
system resulting in an increase of immature
nonfunctioning leukemic cells
• The frequency of immunological, cytogenetic,
and genetic subtypes changes with age
The immunological markers are the major criteria to subdivide ALL into B-cell
lineage or T-cell lineage (T-ALL) leukemias.
Cytogenetic and molecular evaluation provide further identification of ALL
subgroups

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 Incidence
• Peak in • Median age at diagnosis= 14
– Ages of 2 and 4 • 60% occur in those <
– Sixth decade and 20years age
reaches a second, • 24% diagnosed at
– Smaller peak in the >45years
elderly. • 11% diagnosed at
– Trimodal distribution of >65years
age 2-4 years, 15-24 and • Represents
> 65 years. – 75-80% of childhood
• M> F leukemias
• European > African descent, – 20% of adult leukemias
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 Overall Survival
Age Range 5 year survival Rate
Infants <60%
Children 86-89%
AYA (Adolescent and Young 42-63%
Adults)- 15-39yrs
Older Adults (40-59yrs) 24.1%
60-69yrs 17.7%

The prognosis among AYA is lower than that of children because favorable
cytogenetics like hyperploidy and TEL-AML1 occur less commonly than that of
children and the frequency of less favorable cytogenetics like BCR-ABL are
higher.
Same principle holds true for adults as well

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 Etiology & Pathogenesis
• Initiation and progression of ALL is driven by successive
mutations that alter cellular functions, including
–
An enhanced ability of self-renewal
–
A subversion of control of normal proliferation
–
A block in differentiation
–
An increased resistance to death signals (apoptosis).
• Environmental agents, such as ionizing radiation and chemical
mutagens, have been implicated in the induction of ALL in some
patients.
• However, in most cases, no etiologic factors are discernible.
– Favored theory: Leukemogenesis reflects the interaction between
host pharmacogenetics (susceptibility) and environmental factors*

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 Risk Factors
 Genetic Syndromes
◦ Only a minority (5%) of cases are associated with inherited, predisposing
genetic syndromes.
◦ Down’s Syndrome
 10 to 30 times greater risk of leukemia
 Autosomal recessive genetic diseases: Klinefelter’s syndrome, Fanconi’s anemia,
Bloom’s syndrome, ataxia telangiectasia, and neurofibromatosis
 Environmental Factors
◦ In utero radiation exposure
◦ Pesticide exposure
◦ Parental cigarette smoking before or during pregnancy have been
suggested causes of childhood ALL
◦ Infectious agents
In ALL, inheritance of certain diseases and exposure to ionizing radiation or to chemicals,
including prior chemotherapy, are associated with an increased risk of developing
leukemia, but less than in acute myeloid leukemia (AML)

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 Risk Factors
Infectious agents associated with lymphoid malignancies
Infectious Agent Lymphoid Malignancy
Epstein-Barr virus Burkitt's lymphoma
Post–organ transplant lymphoma
Primary CNS diffuse large B cell lymphoma
Hodgkin's disease
Extranodal NK/T cell lymphoma, nasal type

HTLV-I Adult T cell leukemia/lymphoma

HIV Diffuse large B cell lymphoma
Burkitt's lymphoma

Hepatitis C virus Lymphoplasmacytic lymphoma

Helicobacter pylori Gastric MALT lymphoma
Human herpesvirus 8 Primary effusion lymphoma
Multicentric Castleman's disease
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 Risk Factors
• Host Susceptibility
– Multiple, subtle genetic polymorphisms of xenobiotic-metabolizing enzymes
may interact with environmental, dietary, maternal, and other external factors,
thus affecting the development of ALL
– However, all these associations must be confirmed by larger studies
• In utero development of ALL
– Retrospective identification of leukemia-specific fusion genes ( e.g., MLL-AF4,
TEL-AML1 ) in the neonatal blood spots and development of concordant
leukemia in identical twins indicate some leukemias have a prenatal origin
– Some researchers believe "delayed" exposures to common infections at a time
of increased lymphoid cell proliferation serve as the postnatal instigating events
• Acquired Genetic cases
– In almost all cases of ALL, lymphoblasts have acquired genetic changes, three
fourths of which have prognostic and therapeutic relevance
– Changes include abnormalities in the number (ploidy) and structure of
chromosomes.
• The latter comprise translocations (the most frequent abnormality),
inversions, deletions, point mutations, and amplifications 9
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 Abnormality Children Adults
Hyperdiploidy (>50 chromosomes) 23–26% 6–7%
Hypodiploidy (<45 chromosomes) 1% 2%
t(1;19)(q23;p13.3) 3% in white, 11% in 2–3%
black
t(9;22)(q34;q11.2) 3% 25–30%
t(4;11)(q21;q23) 2% 3–7%
t(8;14)(q23;q32.3) 2% 4%
TEL-AML1 fusion 20–25% 0–3%
HOX11L2 overexpressiona 2–3% 1%
LYL1 overexpressiona 1.5% 2.5%
TAL1 overexpressiona 3–7% 12%
HOX11 overexpressiona 0.7% 8%
MLL-ENL fusion 0.3% 0.5%
Abnormal 9p 7–11% 6–30%
Abnormal 12p 7–9% 4–6%
del(7p)/del(7q)/monosomy 7 4% 6–11%
+802/29/2024 Betemeba 2% 10–12% 10
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 Clinical Features
• Symptoms
– Symptoms may appear insidiously or acutely
– Fever: ~50% of patients
• Often is induced by pyrogenic cytokines (e.g., IL-1, IL-6, and
TNF) released from leukemic cells
• In these patients, fever resolves within 72 hours after the
start of antileukemic therapy.
– Fatigue, lethargy, dyspnea, angina, and dizziness: due to
Anemia
– Limping, bone pain, arthralgia, or an unwillingness to walk:
• Because of leukemic infiltration of the periosteum, bone, or
joint or because of expansion of the marrow cavity by
leukemic cells
• Arthralgia and bone pain are less severe in adults 12
 Could ALL be asymptomatic?

• Symptoms ctd
– Less common signs and symptoms include headache,
vomiting, altered mental function, oliguria, and anuria
– Occasionally, patients present with a life-threatening
infection or bleeding (e.g., intracranial hematoma).
– Usually, intracranial hemorrhage occurs mainly in
patients with an initial WBC count> 400 x 109/liter.
– Very rarely, ALL produces no signs or symptoms and is
detected during routine examination.

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 Clinical Features
• Signs
– Common: pallor, petechiae, and ecchymosis in the skin and
mucous membranes and bone tenderness
• The latter is as a result of leukemic infiltration, microvascular
obstruction with infarction or hemorrhage that stretches the
periosteum
– Liver, spleen, and lymph nodes are the most common sites
of extramedullary involvement
• ~50% of adults (NCCN 2014: in only 20% of patients)
• The degree of organomegaly is more pronounced in children than in
adults.
– An anterior mediastinal (thymic) mass is present in 7 to 10
% of childhood cases and 15 % of adult cases*
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• More commonly seen T cellBetemeba
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• Signs ctd
• Painless scrotal swelling
• Can be due to testicular leukemia or hydrocele
• The latter resulting from lymphatic obstruction
• Overt testicular disease is relatively rare, generally seen in infants or patients with T
cell leukemia with hyperleukocytosis, and does not require radiation therapy

Chest x-ray film of a 12-year-old black male with T cell ALL and an anterior mediastinal mass

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 Clinical Features

• Signs ctd
– Other uncommon presenting features include
• Ocular involvement (leukemic infiltration of the orbit, optic
nerve, retina, iris, cornea, or conjunctiva),
• Subcutaneous nodules (leukemia cutis),
• Enlarged salivary glands (Mikulicz syndrome),
• Cranial nerve palsy, and
• Priapism (resulting from leukostasis of the corpora
cavernosa and dorsal veins or sacral nerve involvement).
• Epidural spinal cord compression

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 Diagnosis
• The initial diagnostic work-up must be carried out
expeditiously and before any chemotherapy (within 1–2
working days) to
– Confirm ALL diagnosis
– Distinguish B-cell precursor (BCP) ALL from T-cell ALL (TALL)
– Distinguish Burkitt leukaemia (B-ALL) from BCP-ALL (different
treatment required)
– Distinguish Philadelphia (Ph) chromosome-positive (Ph+) ALL
from Ph-negative (Ph−) ALL (different treatment required)
– Shorten time to treatment start.

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BMA will selfies unless it is insufficient

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 Laboratory Features
• Cytopenia are common in patients with newly
diagnosed ALL b/c of the compitition
– Hyperleukocytosis (>100 x 109/liter) is seen in 10 to
16 % of patients.
– Profound neutropenia (<0.5 x 109/liter) is found in
20 to 40 % of patients, rendering them at high risk
for infection.
• In patients with anemia, a strong inverse
relationship exists between the hemoglobin
level and age at diagnosis
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 Laboratory Features
• Most patients have circulating leukemic blast cells.
• Hypereosinophilia, generally reactive, may precede the
diagnosis of ALL by several months
• Severe bleeding is uncommon, even when platelet counts are as
low as 20 x 109/liter, provided infection and fever are absent.
• Occasional patients, principally male, present with
thrombocytosis (>400 x 109/liter).
• Spontaneous recovery of cytopenia may precede the diagnosis of
ALL in rare cases.
• Coagulopathy, usually mild, can be seen in 3 to 5 % of patients,
most of whom have T cell ALL, and is only rarely associated with
clinical bleeding

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 What is the role of LDH?
• Serum LDH and uric acid
– Correlated with the size of the leukemic infiltrate.
• Renal involvement
– Increased levels of creatinine, urea nitrogen, uric acid, and phosphorus.
– Urine may show microscopic hematuria
– Occasionally, patients with T cell ALL present with acute renal failure, despite a
relatively small leukemic infiltrate.
• Hypercalcemia
– Parathyroid hormone-like protein from lymphoblasts and leukemic infiltration
of bone
• Liver involvement
– From leukemic infiltration in 10-20% of the case
– Usually mild with no prognostic importance
• Ig
– Serum IgA and IgM will decrease
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 Imaging
 Mediastinal masses are detected by chest radiographs or
computed tomography scans primarily in patients with T-
lineage ALL, who also frequently have pleural involvement
and may complain of chest pain
◦ So Chest CT scans are warranted in cases of T cell ALL
 Chest radiography is needed to detect enlargement of the
thymus or mediastinal nodes, with or without pleural effusion.
◦ Although bony abnormalities, such as metaphyseal banding,
periosteal reactions, osteolysis, osteosclerosis, and osteopenia, can
be found in 50 % of patients, especially children with low leukocyte
counts at presentation, skeletal roentgenography is not necessary for
case management.
 Spinal roentgenography is useful in patients with suspected
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vertebral collapse.
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 Diagnosis
• The diagnosis of precursor B-lymphoblastic leukemia/lymphoma is
made based upon the results of a bone marrow aspirate with or
without biopsy, and aspirate with or without biopsy of other
involved tissues, such as lymph nodes or skin.
• In addition to histological analysis, portions of the aspirated material
should be sent for flow cytometry and cytogenetic evaluation.
WHO 2008
 The term ALL is used if there are >20 % bone marrow blasts, with or
without a mass lesion.
 For cases with a mass lesion and less than 20 % bone marrow
involvement, the term lymphoblastic lymphoma is used.
 Hematopathology studies should include
◦ Morphologic examination
◦ Immunophenotyping with flow cytometry
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◦ Cytogenetic studies
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 Diagnostic creteira
• PM
– Leukemic blast cells (LBC) in the peripheral blood are
largely responsible for the rise in white blood cell count,
but it is noteworthy that in 8% of the ALL patients, no
circulating leukemic blast cells are observed.
• BM
– The bone marrow is usually heavily packed with leukemic
blast cells comprising >90% of the nucleated cells in ~70%
of patients.
– A biopsy of the bone marrow will further demonstrate
marked hypercellularity with replacement of fat spaces
and normal elements by infiltration with leukemic cells
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 …
• Why does high blood count a CI for LP?
• LP
– The timing of LP is controversial b/c doing before treatment will result in iatrogenic
metastasis so this group will wait till remission
– Early identification will result in better out come
– In any case prophylaxitic intrathecal metotrexate should be given in the first LP
– Adequate platelet count (>20 × 109 /L), an absence of manifest clinical hemorrhage,
and without a high white blood cell count.
– Cytology and flow cytometry from the CSF might be diagnostic
• Morphologic subtype in all
– Distinguished by the French-American-British classification.
– L1 and L2 morphology has no clinical consequences, the detection of L3 ALL is of
clinical and prognostic relevance.
– It is observed in up to 5% of adult patients and should be distinguished as it is
indicative of mature B-ALL, usually termed Burkitt’s leukemia, with distinct
treatment options.
– A surface marker confirmation should be obtained.
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 Diagnosis & Cell Classification

• Examination of the cerebrospinal fluid (CSF) is an

essential diagnostic procedure.
– Leukemic blasts can be identified in as many as one third of
pediatric patients at diagnosis of ALL; most of these patients
lack neurologic symptoms.
• Traditionally, CNS leukemia is defined by the presence of at
least five leukocytes per microliter of CSF (with leukemic blast
cells apparent in a cytocentrifuged sample) or by the presence
of cranial nerve palsies.
– The presence of any leukemic blast cells in the CSF is
associated with increased risk of CNS relapse and is an
indication to intensify intrathecal therapy
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 Diagnosis & Cell Classification
• Diagnosis: begins with morphologic analysis of Romanowsky -
stained (Wright - Giemsa or May- Grünwald-Giemsa ) bone
marrow films.
• Lymphoblasts: relatively small (ranging from the same size to
twice the size of small lymphocytes) with scanty, often light-blue
cytoplasm; a round, cleft, or slightly indented nucleus; fine to
slightly coarse and clumped chromatin; and inconspicuous
nucleoli
• In some cases, the lymphoblasts are large, with prominent
nucleoli, moderate amounts of cytoplasm, and an admixture of
smaller blasts.
• Cytoplasmic granules are found in the lymphoblasts of some
patients with ALL.
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 Diagnosis & Cell Classification

• The granules usually are amphophilic (which stain fuchsia),

readily distinguishable from the primary myeloid granules
(which stain deep purple), and demonstrated to be mitochondria
in some cases by electron microscopy.
• B cell blasts in ALL are characterized by intensely basophilic
cytoplasm, regular cellular features, prominent nucleoli, and
cytoplasmic vacuolation
• Analysis of only a Romanowsky-stained film is not sufficient to
differentiate ALL and acute myelogenous leukemia.
• The cytochemical stains needed to discriminate between the
two leukemias are the Sudan black stain and the stains for
myeloperoxidase and the nonspecific esterases, including α-
naphthyl butyrate and α- naphthyl acetate esterase.
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 Diagnosis & Cell Classification
• Stains for these esterases generally do not react with leukemic
lymphoblasts.
• Occasionally, a low level of myeloperoxidase is detected in bone
marrow samples from ALL patients because of the presence of
residual normal myeloid precursors
• Staining with periodic acid–Schiff reagent is positive in more than 70
% of ALL cases, whereas acid phosphatase reactivity can be
demonstrated in approximately 70 % of cases with a T cell
immunophenotype.
• However, neither stain reacts exclusively with leukemic lymphoid cells
• FAB classification of ALL
– L1, L2, L3
– Based on the morphology of lymphoblasts
– Less relevant in predicting outcome
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 L1 - lymphoblasts are small cells with scant cytoplasm, condensed nuclear
chromatin, and indistinct nucleoli.
◦ Accounts for 85-89% of ALL in children

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 L2--- the most common accounting 60%
Lymphoblasts are larger cells with a moderate amount of cytoplasm, dispersed
chromatin, and multiple nucleoli.
In some studies, L2 has been associated with worse prognosis than has L1
However, when patients are stratified according to age, sex, and initial WBC, differences
in prognosis between L1 and L2 are no longer observed
Accounts for 11-14% of all in children

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• L3 - Burkitt’s leukemia
• Lymphoblasts have deep cytoplasmic basophilia with prominent cytoplasmic
vacuolation
• It correlates with a more guarded prognosis.
• The L3 cell usually has mature B-cell characteristics and often is treated using
drugs effective for highly aggressive B-cell lymphoma variants.
• Accounts for <1% of ALL in children

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 Diagnosis & Cell Classification
• Immunophenotyping….
– ALL can be further subclassified according to the recognized
steps of normal maturation within the B lineage (early pre-B,
pre-B, transitional pre-B, and mature B) or T lineage (early,
mid, and late thymocyte) pathways
– However, the only distinctions of therapeutic importance are
those between T cell, mature B, and other B lineage (B cell
precursor) immunophenotypes.
– Among children B-cell lineage ALL constitute 88% of cases
– In adults
• Sub types of B-cell ALL - 75%
– Including mature B cell which accounts for 5%
• T-cell ALL - 25%

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 Diagnosis & Cell Classification
• Cytogenetic studies
– Approximately 75% of adult and childhood cases can be readily
classified into prognostically or therapeutically relevant subgroups
based on
• The modal chromosome number (or DNA content estimated by flow
cytometry)
• Specific chromosomal rearrangements
• Molecular genetic changes
– The frequency certain subtypes differ among children and adults, which
partially explains the differences in outcomes between the two patient
populations
• Hyperdiploidy (25% in children vs 7%) ---- Favorable
• TEL- AML1 (22% in children vs 2% in adults) --- Favorable
• BCR-ABL (3% in children vs 25% in adults) ---- Unfavorable
– In addition children (1-9yrs) with Philadelphia positive ALL have a better
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prognosis than Adolescents with
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 Minimal residual disease (MRD)

• MRD is the detection of residual leukemic cells, not

recognizable by light microscopy.
• Methods for determining MRD are based on the detection of
leukemia-specific
– Aberrant immunophenotypes by flow cytometry
– Rearranged immunoglobulin or T-cell receptor sequences
by real-time quantitative polymerase chain reaction
– Detection of fusion genes associated with chromosomal
abnormalities (e.g., BCR-ABL, MLL-AF4).
• The phenotypic aberrations are unique to each patient with
ALL and can be detected in up to 95% of individuals.

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Molecular response can be evaluated only for patients in complete cytological remission,
with one marker or more for MRD analysis and

• Prognostic factors
• Patient Age
• WBC count
• Immunophenotypi
ng/Cytogenetics
• Response to
Induction therapy

Achievement of molecular complete response/molecular remission is the most relevant independent

prognostic factor for disease-free survival and overall survival.
Patients with molecular complete remission after induction therapy had significantly superior outcome
in several studies, with a disease-free survival of 54–74%, compared to 17–40% for MRD-positive
patients.
Patients with molecular failure after induction therapy should proceed to a targeted therapy to reduce
the tumor load, to be followed by immediate allogeneic hematopoietic stem cell transplant.
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 Prognostic Factors and Risk Stratification
Risk Group Feature
Standard B cell precursor phenotype in patients aged 1–9 years with a
presenting leukocyte count <50 x 109/liter, TEL-AML1 fusion, or
hyperdiploidy (>50 chromosomes or DNA index >1.16)

Achieve molecular remission (about 90–95%)

Must not have CNS leukemia (CNS-3 status), testicular leukemia, t(9;22),
t(1;19), rearranged MLL gene, hypodiploidy, or 0.01% leukemia cells in
marrow after 6-week remission induction

High T cell ALL and all cases of B cell precursor ALL that do not meet
the criteria for standard or very-high-risk ALL
Very high Age<1yr
t(9;22)/BCR-ABL, High risk and very high risk
MLL subtype patients are candidate for HSCT
Initial induction failure, or
1% leukemic cells in bone marrow after 6-week remission
induction

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 Does HSCT indicated in complete remission?
• Thereby defined standard-risk patients who are highly likely to achieve
molecular remission (about 90–95%) will remain as standard-risk patients,
whereas those who are MRD-positive will be defined accordingly as high-risk
patients.
• Clinically defined high-risk patients are potential candidates for a stem cell
transplant in first complete remission.
• However, it is not clear how to proceed if they achieve a complete molecular
remission, since some studies suggest a lack of benefit from transplant in
those who are MRD negative.
• If MRD information is not available, the risk stratification should rely on
clinical risk factors evaluated at diagnosis.
• Unfortunately, 20–30% of adult ALL patients who are MRD-negative after
induction will relapse.
• Why does relapse occur after complete remission?
– Potential reasons include loss of sensitivity, evolution of leukemic subclones, and
extramedullary origin of disease.
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 NCCN Recommendation on risk assessments

• High risk
• Low risk( standard risk
– Hypodiploidy ( < 44 chromosomes – Absence of all high
) risk feature
– MLL rearrangement
– Complex Karyotypes ( >5 – No CNS involvement
chromosomal abnormality) – t(12;21)(
– Age <1 or >10
– WBC count (>30,000 for B cell or
p13;q22)/TEL-AML1 +
>100,000 for T cell) ALL (rare in adults)
– Age<1yr and hyperdiploid ALL,
– t(9;22)/BCR-ABL and NOTCH-1/FBXW7-
– Initial induction failure
mutated T-ALL
– 1% leukemic cells in bone marrow
after 6-week remission induction
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 Therapy
• Goal of therapy
– Achievement of a complete remission, or even better, a
molecular complete remission
– Evaluated within 6–16 weeks of starting chemotherapy.
– With current regimens the complete remission rate has
increased to 80–90%, being higher for standard-risk
patients (≥90%), and lower for high-risk patients
(~80%).
– Outcome is strictly related to the age of the patient,
and treatment protocols considering the age of an
individual patient have emerged
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 Pre-phase therapy
• The aim is to reduce tumor burden with low risk of TLS
• It will be given while the cytogenetics and ICH is processing
• Response to pre-phase therapy had prognostic importance.
• The pre-phase therapy allows a safe tumour reduction,
avoiding in most cases a tumour lysis syndrome (TLS)
• Pre-phase therapy include 5-7 days of
– Hydration
– Allopurinol (rasburicase if WBC> 100,000) but if insufficient
leukapheresis can be used
• PO or IV dexamethasone with vincristine and cyclophosphamide
Dexamethasone is often preferred to prednisone, since it penetrates the
blood–brain barrier and also acts on resting leukaemic blast cells (LBCs).
– 1st does of CNS prophylaxis with methotrexate

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 What to do for leukostasis?
• Hyperleukocytosis
– For patients with extreme leukocytosis (leukocyte count >400 x
109/liter), either leukapheresis or exchange transfusion (in small
children) can be used to reduce the burden of leukemic cells
– Pre-induction therapy with low-dose glucocorticoids, with addition
of vincristine and cyclophosphamide in cases of B cell ALL, is a
favored means of ameliorating hyperleukocytosis
• Infection control
– Infections are common in febrile patients with newly diagnosed ALL.
– Broad-spectrum antibiotics until infection is excluded.
– Remission induction therapy can increase susceptibility to infection
by exacerbating myelosuppression, immunosuppression, and
mucosal breakdown.

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 Treatment- Supportive Care
• Infection control
– At least 50 % of patients undergoing induction therapy experience
infections.
– Special precautions to reduce infection risk:
• Reverse protective isolation and air filtration;
• Elimination of contact with people with infections;
• Refraining from eating certain food products, such as raw
cheese, uncooked vegetables, or unpeeled fruits; and
• Use of antiseptic mouthwash or sitz baths, especially for
patients with mucositis.
– Administration of granulocyte colony stimulating factor can
hasten recovery from neutropenia and reduce the complications
of intensive chemotherapy but does not improve the event-free
survival rate for children or adults
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 What is the indication for infection prophylaxis?

• Prophylactic antibiotic
– Antibacterial prophylaxis should be given when duration
of neutropenia (<500/micL) is prolonged (>7days)
• Preferred agents: Fluoroquinolones
• Antiviral (acyclovir or vancyclovir)
– Seropositive for HSV or VZV
– Should continue till WBC normalized or mucositis improved
which ever comes later
• Can be prolonged to one year in
– Recurrent VZV
– GVHD
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 Treatment---Supportive Care
• Infection control ctd
– Usually, all patients with ALL are given trimethoprim-
sulfamethoxazole, 2 to 3 days per week, as prophylactic
therapy for Pneumocystis carinii (Pneumocytis jiroveci)
pneumonia.
• Prophylaxis is started after 2 weeks of remission induction
and continues until 6 weeks after completion of all
chemotherapy.
• Alternative treatments for patients who cannot tolerate
trimethoprim-sulfamethoxazole include aerosolized
pentamidine, dapsone, and atovaquone.

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 Treatment- Supportive Care

• Prevention of HBV flare

– Patients receiving chemotherapy who have a history
of previous hepatitis B virus infection are at risk of
reactivation with a flare of hepatitis that may
potentially result in hepatic failure
– Antiviral will be started 1 week prior to initiation and
discontinued after 4 weeks of completion
• Nutritional support- NCCN 2014
– For patients with a 10% or more weight loss, enteral
or parenteral nutritional support should be
considered
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 …
• Hematologic support---Coagulopathies
– ALL or its treatment can lead to thrombocytopenia.
– Hemorrhagic manifestations are common but usually are limited to
the skin and mucous membranes.
– Patients with extremely high leukocyte counts (>400 x 109/liter) at
diagnosis are more likely to develop such complications
– Coagulopathy attributable to disseminated intravascular coagulation,
hepatic dysfunction, or chemotherapy usually is mild.
– Patients receiving induction treatment, including L-asparaginase and
a glucocorticoid, generally are in a hypercoagulable state
– Platelet transfusions should be given therapeutically for overt
bleeding and may be indicated when platelet counts are less than 10
x 109/liter.

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 Treatment- Supportive Care
• Hematologic support ctd
• Anemia
• Transfusion of packed red cells is indicated in patients with anemia
and marrow suppression but should be delayed until the leukocyte
count is reduced in patients with extreme hyperleukocytosis.
• Transfusion should be given slowly in patients with profound but
chronic anemia to prevent development of congestive heart failure
• Neutropenia
– Granulocyte transfusions are needed only rarely for patients with
absolute neutropenia and documented gram-negative septicemia or
disseminated fungal infection, which responds poorly to antimicrobial
treatment.
• All blood products should be irradiated to prevent graft-versus-host
disease (NCCN 2014)
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 …

Using current approaches, the CR rate had increased to 80%–90%, higher for SR patients at
≥90%, and less in HR patients at ∼75%.
There is only one randomised study for induction therapy; this compares prednisone to
dexamethasone [38], demonstrating equal outcome [I, C].
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 Induction and Consolidation
• The goal of induction therapy is the achievement of a CR, or even
better, a molCR/good molecular response, usually evaluated within
6–16 weeks from start of chemotherapy, after which time the
achievement of molCR is rather uncommon.
• L-Asparaginase is the only ALL-specific drug that depletes the
asparagine levels and has been particularly explored in paediatric
trials. It is now more intensively used in adults.
• Accounting for a total of eight cycles, such as the
– Hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone)
protocol, preferentially used in the United Stat
• Post remission consolidation
– 6–8 courses which contain either HD methotrexate or HD cytarabine ±
asparaginase.
– HD cytarabine is usually administered for 4–12 doses at 1–3 g/m2 and
methotrexate at 1–1.5 g/m2 and up to 3 g/m2 .
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 Maintenance therapy
• Usually consists of daily 6-mercaptopurine and weekly
methotrexate.
• Repeated cycles of vincristine, dexamethasone or other
drugs in monthly or longer intervals are given. In one
randomised study, the maintenance arm with
reinforcement cycles was not superior to conventional
maintenance therapy (37% versus 38% at 8 years).
• A treatment duration of 2.5–3 years is optimal and is
usually recommended.
• Omission of maintenance worsens outcome significantly in
BCP-ALL, but less so in T-ALL and not in B-ALL
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 CNS prophylaxis
• Without some form of prophylactic CNS-directed therapy, in very
early studies without any intensive systemic chemotherapy,
around 30% of adults with ALL developed CNS leukemia.
• Prophylactic CNS therapy in ALL is essential for several reasons
– CNS leukemia is more easily prevented than treated
– Once CNS leukemia has developed, it is generally followed by
systemic relapse shortly after
– Effective CNS prophylaxis also prevents systemic relapse.
• For how long we continue the prophylaxis?
– For 812 cycle during induction and then will continue for
consolidation but not during maintenance

58
 CNS prophylaxis
• The route of application is generally lumbar puncture.
• CRT (18–24 Gy in 12 fractions >16 days) may be administered with or
without parallel intrathecal therapy.
• Systemic high-dose chemotherapy may include methotrexate or
cytosine arabinoside since both drugs reach cytotoxic drug levels in the
cerebrospinal fluid (CSF) and showed efficacy in overt CNS leukemia.
• A liposomal preparation of cytosine arabinoside has been introduced
for the treatment of CNS in patients with ALL or lymphoma; this
formulation is more effective since it has a half-life of >2 weeks,
compared to only a few hours for the other used intrathecal drugs.
Treatment modalities of CNS prophylaxis are
CNS irradiation
Intra-thecal (i.th.) methotrexate, mono- or i.th. triple (usually methotrexate,
steroids, cytarabine)
Systemic HD therapy with either methotrexate and/or cytarabine.
With a combination of these CNS prophylactic measures, the CNS relapse rate in
recent adult ALL trials could be reduced from 10% to <5%.
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 Therapy of CNS disease
• About 5–10% of adult patients present with manifestations of
CNS leukemia.
• The incidence is correlated with the immunological subtype
and is higher in mature B-ALL up to 10–15% and in T-ALL up
to 10%.
• For the treatment of CNS leukemia, the same treatment
measures as those used for CNS prophylaxis are employed,
either intrathecal MTX alone or in combination with cytosine
arabinoside or hydrocortisone.
• The intrathecal therapy is given 2–3 times per week,
continued for >2 or 3 weeks until two consecutive CSF
examinations show no evidence of leukemic infiltration.
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 …
• When adult ALL patients with initial CNS leukemia are
treated adequately, leukemia-free survival and CNS
relapse rate are not inferior to those without CNS
involvement.
• Relapse in the CNS is difficult to treat.
• Mostly it occurs synchronously with bone marrow relapse,
and if leukemic blasts are not seen morphologically, MRD
is positive in nearly all cases.
• This requires a local as well as a systemic therapy.
• The outcome after CNS relapse is still dismal, and an
allogeneic stem cell transplantation is the most promising
option to achieve a remission. 61
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 Targeted therapy
• Anti-CD 20
– For Burkitt leukemia and lymphoma
– Intensive chemotherapy with rituximab increased OS
from 62% to 83%
• Monoclonal antibodies directed against CD22,
linked to cytotoxic agents, either to calicheamicin
(Inotuzumab ozogamicin) or to plant or bacterial
toxins (epratuzumab), are explored in
refractory/relapsed childhood and adult ALL

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 …
• Targeting CD19 is of great interest, as it is expressed in all B-
lineage cells, most likely including early lymphoid precursor cells.
• The bispecific antibody Blinatumomab combines single chain
antibodies to CD19 and CD3, and thereby T cells lyse the CD19-
bearing B cells.
– It is effective in patients with positive MRD or
refractory/relapsed ALL
– The CD19 antigen is also the target for a promising new
approach, the use of chimaeric antigen receptor-modified T
cells (CAR T cells).
• In T-ALL, specific antibodies as in B-lineage ALL are not available.

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 Targeted therapy
• TKI therapy
– Initiated in frontline therapy
together with the first
chemotherapy cycle.
– A continuous TKI exposure
should be favoured, even if a
few weeks off may be needed
to limit myelosuppression
– Can also be used for Ph-like
ALL
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GRAAPH-2005 trial
Compared
Hyper-CVAD/imatinib Vs reduce
chemotherapy + imatinib
Combination of TKIs with dose-
reduced chemotherapy should
probably be preferred,
compared with standard
intensive chemotherapy/TKI
combinations
Had low early mortality + high
CR
64
 Targeted therapy

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 ESMO 2021 TKI recommendation

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 Stem cell transplantation
• The recommendation is not clear for low risk patients
• Had higher over all survival in high risk patients done after 1 st
cure
• What to transplant?
– Recent studies have shown that SCT offers better results than
chemotherapy in patients with high MRD levels after consolidation,
regardless of the conventional risk factors at baseline
– Increasing evidence that sibling and very well matched, unrelated
donors (MUD) SCT can be considered equivalent options in terms of
results
With what to do conditioning?
There is no standard MAC regimen
Total body irradiation-based regimens seem to have better anti-leukaemic activity
than busulfan-based preparative regimens

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 What to transplant?

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 Course & Prognosis
• Relapse
– Relapse is defined as the reappearance of leukemic cells at
any site in the body.
– Most relapses occur during treatment or within the first 2
years after its completion, although initial relapses have
been observed 10 or more years after diagnosis
– The marrow remains the most common site of relapse in
ALL.
• Anemia, leukocytosis, leukopenia, thrombocytopenia,
enlargement of the liver or spleen, bone pain, fever, or a sudden
decrease in tolerance to chemotherapy may signal the onset of
marrow relapse.
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 Course & Prognosis
• Relapse
– In some contemporary programs of childhood ALL treatment,
the rates of CNS and testicular relapse have decreased to 2 %
or less.
– Leukemic relapse occasionally occurs at other extramedullary
sites, including the eye, ear, ovary, uterus, bone, muscle, tonsil,
kidney, mediastinum, pleura, and paranasal sinus.
– Marrow relapse, with or without extramedullary involvement,
portends a poor outcome for most patients.
• Factors indicating an especially POOR PROGNOSIS
• Relapse while on therapy or after a short initial remission
• T cell immunophenotype
• Presence of the Philadelphia chromosome
• An isolated hematologic relapse 71
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 Course & Prognosis
• Relapse ctd
– Prolonged second remissions ( > 3 years ) can be achieved
with chemotherapy in as many as half of patients with late
relapses ( i.e, > 6 months after cessation of therapy ) but in
only approximately 10 % of those with early relapse.
– In patients who develop hematologic relapse while on
therapy or shortly thereafter, allogeneic hematopoietic
stem cell transplantation is the treatment of choice.
– Hence, patients with extramedullary relapse require
intensive systemic treatment to prevent subsequent
hematologic relapse.

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 Course & Prognosis
• Relapse ctd
– Intensive chemotherapy and CNS irradiation are expected to
achieve long-term second remissions in at least half of the
previously unirradiated patients with ALL relapses after
completion of therapy.
– For patients in whom relapse develops during therapy and
who had previously undergone cranial irradiation, the
remission rate generally does not exceed 30%.
– Adults with isolated CNS relapse fare much more poorly
than children.
– The optimal treatment and prognosis for patients with
relapse at unusual extramedullary sites also are unclear.

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 Treatment of relapsed disease
• No consensus on the Rx of
relapse in adults
• Therpay related AML should be
excluded
• In the case of Ph+ ALL, BCR-ABL1
tyrosine kinase domain
mutations should be evaluated
• Disease-specific factors
– (BCP-ALL or T-ALL, BCRABL1
status)
– Patient factors
– Previous therapy
– Specific toxicities of prior
treatment
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• Treatment with a curative aim
involves achievement of CR
followed by allogeneic SCT
• Blinatumomab and Inotuzumab
have shown promising results in
phase II studies and are being
evaluated in randomised,
controlled trials where the
comparator arm is ‘standard of
care’ chemotherapy.
• A clinical trial involving
immunotherapy with CD19 CAR
T-cell therapy is also a
possibility
Betemeba 74
 …
• Chemotherapy for relapsed ALL.
– The most commonly used regimens fludarabine-
and anthracycline-containing regimens, for
example, FLAG-Ida (fludarabine, high-dose ara-C,
granulocyte colony-stimulating factor and
idarubicin).
– Liposomal vincristine is licensed for the treatment
of relapsed ALL.
– These standard chemotherapy approaches are
applicable in BCP-ALL as well as in T-ALL.
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 Role of MRD assessment
• Current MRD assays (flow cytometry or PCR) can detect leukemic
cells at a sensitivity threshold of 1x10-4 (<0.001%) bone marrow
nucleated cells
• Numerous studies in childhood and adult ALL has shown the
prognostic significance of post induction and/or post consolidation
MRD in predicting the likelihood of predicting disease relapse
– And its potential role in identifying patient subgroups who may
benefit from intensification of chemotherapy
• Timing of MRD
– After completion of initial induction therapy
– Additional time points for MRD may be useful depending on
the regimens used

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 ….
• Role of MRD assessment
– MRD assessment with multicolor flow cytometry
• BM mononuclear cells preferred to peripheral blood
• At least 1x106 MNC is required for analysis. i.e
– ~2ml of BM or 5-10ml of periheral blood provide sufficient amount for
multiple analysis
– MRD by high-sensitivity PCR
• Sampling of bone marrow is preferred
• 1x107 MNC are required for initial marker characterization and
generation of individual dilution series
• 1x106 MNC is enough for follow up analysis
• The minimal limit of assay to detect MRD negativity should be less
than 1x10-4 (0.001%)
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 Thank You!

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