Transcript ALL.4.2014

ACUTE LEUKEMIA
Definition
PB and/or BM blasts > 20 % of nucleated cell (NC) count
Acute lymphoblastic
leukemia (ALL)
 Clonal proliferation and accumulation of
blast cells in blood, bone marrow and
other organs
 Disorder originates in single B or T
lymphocyte progenitor
 Heterogenous disease with different
biological subtypes
 Incidence in adults : 20% of acute
leukemias
 Etiology - unknown
clinical features
1. Bleeding
2. Fever/infection
3. Bone/joint pain
4. Hepatomegaly
5. Splenomegaly
6. Lymphadenopathy
7. CNS involvement
Patients with very high WBC counts (>
100,000/mm3) are at higher risk for tumor
lysis syndrome and leukostasis, both of which
are considered oncologic emergencies and
require prompt recognition and management.
Tumor lysis syndrome can be due to
spontaneous or treatment-mediated cell
destruction and is characterized by
hyperuricemia, renal failure, acidosis,
hypocalcemia, and hyperphosphatemia.[Jabbour
2005b
• Manifestations of leukostasis include
dyspnea, chest pain, headache, altered
mental status, cranial nerve palsies,
and/or priapism.
laboratory findings
1. Blood examination
- anemia,
- thrombocytopenia,
- variable leukocyte count, usually
increased,
- blood morphology: presence of blast
cells
2. Bone marrow morphology
- presence of blast cells,
- suppression of normal hematopoiesis
Laboratory findings
3. Cytochemical stains
4. Immunophenotyping
5. Cytogenetics
6. Molecular studies
FAB Classification of ALL (1976)
L1: small monomorphic
L2: large,
heterogeneous
L3: Burkitt cell-type
ACUTE LEUKEMIA
Cytochemistry
Precursor
B-ALL
T-ALL
AML
Myeloperoxidase
-
-
+
Sudan black
-
-
+
Nonspecific
esterase (NSE)
-
-
+ with
• Na fluoride inhibition  M5
• No Na fluoride inhibition  M4
Periodic acidSchiff (PAS)
+++
(coarse)
-
-ve to diffuse fine +
Acid
phosphatase
-
+
-
Acute leukemia
Mixed lineage Vs biphenotypic
• Mixed lineage leukemia:
Two different blast populations
ALL
AML
• Biphenotypic leukemia:
The same blast population
and lymphatic markers
both myeloid
EGIL* scoring system for biphenotypic leukemia
*European Group for the Immunological characterization of Leukemia
Score
B-lineage
T-lineage
Myeloid lineage
2
CD 79a
Cy IgM
Cy CD22
CD 3 (cy/m)
Anti-TCR
Anti-MPO
Anti-lysozyme
1
CD 19
CD 10
CD 20
CD 2
CD 5
CD 8
CD 10
CD 13
CD 33
CD w65
TdT
CD 24
TdT
CD 7
CD 1a
CD 14
CD 15
CD 64
CD 117
0.5
To diagnose biphenotypic leukemia, the score should be at least:
2 in the myeloid lineage + 2 in the lymphatic lineage
Acute leukemia
ALL with myeloid coexpression
Myeloid coexpression = at least 20
% of blasts + ve for at least one
marker of:
CD13, CD33, CD65s.
AL: Immunophenotyping
ALL
B-ALL (incidence = 76%)
Subtype
Pro-B
C-ALL
Pre-B
B-cell
TdT
+
+
+
-
CD 19
+
+
+
+
CD 10 Cy IgM
+
+
+
+
+
S Ig
+
AL: Immunophenotyping
ALL
T-ALL (incidence =24%)
Compartment
T-cell type
Positive markers
Pro-T
CD 7
Compartment I
(early T)
Pre-T
CD 2 and/or
CD 5 and/or
CD 8
Compartment II
Thymic T
CD 1a
Compartment III
Mature T
sCD 3
Acute leukemia
WHO Classification of ALL (1999)
(1) Precursor B-cell ALL (pro-B, C-ALL, pre-B):
Ch abn.
Fusion gene
t (9;22)
BCR/ABL
t (V;11)
e.g. t (4;11)
MLL rearranged
e.g. MLL/AF4
t (1;19)
E2A/PBX1
t (12;21)
Tel/AML1
(2) Burkitt–cell (mature B-cell) ALL:
(3) Precursor T-cell ALL:
(4) Mature T-cell ALL:
Cytogenetic classification of ALL
Bad Prognosis
• Ph-chromosome
t(9;22)
*30% of adult ALL
*3% of pediatric ALL
• Hypoploidy
(DNA index < 1.12)
• t(4;11)
Good Prognosis
• t(12;21)
(Tel/AML1)
*30% of pediatric ALL
• Hyperploidy
(DNA index =1.12-1.6)
Algorithm for diagnosis of AL
Clinically suspected + blasts in PB
Lymphoblastic
lymphoma
Morphology + cytochemistry of
PB + BM
< 20% blasts
in BM
ALL (L1, L2)
ALL (L3)
AML
< 20% blasts
in BM
Burkitt
lymphoma
Immunophenotyping
B-lineage
Pro-B
C-ALL
Pre-B
T-lineage
Mature B
Early
Thymic
Cytogenetics / Molecular genetics
t (4;11)
ALL1/AF4
t (9;22)
BCR/ABL
Mature
Acute Lymphoblastic Leukemia
Outcome
• High remission rates possible in adults and
children
• Leukemia-free survival in children 2-10 years of
age: 80% Most adults experience relapse
Complete
LeukemiaRemission Free Survival
Adults
Children (2-10
yrs of age)
80% to 90%
35%
97%
80%
Pui CH, et al. N Engl J Med. 2006;354:166-178.
ALL: Typical Treatment
• Induction, consolidation, maintenance phases
– CNS prophylaxis with IT-MTX
CNS Prophylaxis (IT-MTX)
Induction
3/26/2016
Consolidation
Maintenance
Over a period
of months
2-3 years
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• ALL therapy is one of the most complex types of
anticancer programs. Multiple drugs are
combined into regimen-specific sequences of
various doses and durations.
• The backbone of ALL induction regimens is a
combination of vincristine, corticosteroids, and
anthracyclines. This combination achieves
complete remission rates of 72% to 92% with a
median remission duration of approximately 18
months
Adult ALL: Large Clinical Trials
Clinical
Trials
N
Age
Treatment
CR, %
DFS, %
GMALL 02/84
562
28
BFM
75
39
GMALL 05/93
1163
35
BFM, HD-ARA-C,
HD-MTX
87
35-40
CALGB 8811
198
35
BFM, ↑ Cy, ↑ ASP
85
36
CALGB 19802
163
41
BFM, ↑ Cy , ↑ DNR
78
35
GIMEMA
778
28
BFM ± Cy
82
29
MRC-UKALL
XA
618
> 15
BFM + early
intensification
89
--
MRC/ECOG
1521
BFM + HD-MTX ± SCT
91
38
UCSF 8707
84
27
BFM intensified
93
52
288
Cy, D, AD, HD-MTX, HD40 Free Template from
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92
23
38
3/26/2016
Hyper-CVAD
Prognostic factors in adult ALL
(1) At diagnosis
Favorable
Unfavorable
Age
15-20 yrs
>50 yrs
WBC (B-lineage)
<30 000/µL
>30 000/µL
• Pro B-ALL
• Early T-ALL
• Mature T-ALL
Immunophenotype
Thymic T-ALL
Cytogenetics &
Molecular genetics
•Normal diploid • T(9;22)/BCR-ABL
karyotype (?)
• T(4;11)/ALL1-AF4
•Hyperdiploid
karyotype (?)
3/26/2016
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Prognostic factors in adult ALL
(2) Response to treatment
Favorable
Time to CR
MRD after
induction
MRD during
consolidation
3/26/2016
Unfavorable
CR in 2-4 ws
CR >4 ws
<10-3
>10-3
<10-4 or
negative
>10-4 or
increasing
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Risk-adapted treatment of ALL
Risk
Standard
risk
High risk
Mature
B-cell
3/26/2016
Age
<50 yrs
50-60 yrs
>60 yrs
Standard-risk protocol 
•No further treatment or
•Maintenance X 2-3 yr or
•Allogeneic BMT
Standard-risk protocol 
• No further treatment or
• Maintenance X 2-3 yr
• No BMT
COAP
only
High-risk protocol
6 full blocks i.e.
(A1B1A2B2A3B3)
+ BMT
• High-risk protocol
with ABMT arm
• No allo BMT
COAP
only
4 incomplete blocks (without
HD MTX) i.e. a1b1a2b2
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Risk-adapted treatment procedure for adult ALL
(other than mature B-ALL)
Induction (phase I & II)
CR
Standard risk
High risk
Consolidation
(phase I &II)
MRD<10-4
Donor
No donor
MRD >10-4
HAM
Donor
End of
therapy
3/26/2016
Allo BMT
No donor
Maintenance
XFree
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Allo BMT
Auto BMT
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2
Treatment of
standard-risk group
3/26/2016
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Treatment of standard-risk group
Induction (phase I & II)
CR
Consolidation
(phase I &II)
MRD>10-4
MRD<10-4
Donor
End of
therapy
3/26/2016
Allo BMT
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No donor
Maintenance
X 2-3 yrs
29
Induction treatment of standard-risk group
L-Asparaginase 5000U/ m2
30 min inf on saline
MTX 15 mg
ITH inj
24 Gy
DNR 45 mg/m2
VCR 2 mg I.v.
Pred 60 mg / m2 P.O. D1-28
VCR/Pred
1
7
Prephase
3/26/2016
1
8
15
22
28
Days
Induction treatment Phase I
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Details of induction treatment of standard-risk group
Prephase
If TLC >25000 and/or marked organomegaly
• VCR : 2 mg I.V. …………………….… D1
• Pred: 60 mg / m2 P.O. ……………….. D1-7
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Details of induction treatment of standard-risk group
Phase I induction
• VCR: 2 mg I.V. ………………..... D1, 8, 15, 22
• DNR: 45 mg/m2 (30 min. inf.) ..... D1, 8, 15, 22
• L-Asp: 5000 U/m2 ………………. D15–28
• Prednisone: 60 mg /m2 P.O. ...... D1-28 followed
by dose reduction in 3 phases of 3 days each:
1/2  1/4  1/8 of the dose then stop.
• MTX: 15 mg intrathecal …..……. D1
3/26/2016
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L-asparaginase in ALL
• Used only in ALL
• Enzyme that depletes serum L-asparagine
• Activity related to serum L-asparagine
depletion
• No myelosuppression
• No late effects
• Unique adverse effects
3/26/2016
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L-asparaginase: Toxicity
• Hypersensitivity
– Neutralizing antibodies
• Liver dysfunction
– Liver enzymes, bilirubin, low albumin
• Hemostasis
– Bleeding: low clotting factors
– Clotting: low antithrombin III, protein S
• Pancreatitis, diabetes mellitus, CNS effects (lethargy,
somnolence)
3/26/2016
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There are three formulations of asparaginase available:
Asparaginase (L-asparaginase isolated from E.coli )
Erwinia asparaginase (L-asparaginase isolated from Erwinia
chrysanthemi, previously called Erwinia carotova6)7
Pegaspargase (L-asparaginase isolated from E.coli and
attached to polyethylene glycol)
Erwinia asparaginase is serologically and biochemically
distinct from asparaginase, although the antineoplastic
activity and toxicity is similar. Pegaspargase has a longer
half-life and decreased toxicity.
Details of induction treatment of standard-risk group
L-Asparginase
• Give Erwina-Asp if possible (less adverse reactions)
• Check Fibrinogen before giving L-Asp. :
 If < 100 mg/dl give FFP 15 ml/kg or 2 gm fibrinogen for
correction but continue therapy.
 If < 50 mg /dl or prothrombin conc. falls to < 30%  stop
L-Asp and substitute as above.
• Check blood sugar & amylase during L-asp. treatment (3
times / week) and correct hyperglycemia.
• The half-life of fibrinogen is 96 hrs.
Daunorubicin
• DNR dose of day 15 may be omitted if the counts are very low
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Details of induction treatment of standard-risk group
Cranial prophylaxis
• All standard-risk patients receive 24 Gy cranial
irradiation
• During cranial irradiation, MTX 15 mg intrathecal
is given as 4 doses ( twice / week)
3/26/2016
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Although central nervous system
(CNS) disease is uncommon at
diagnosis (< 10%) in patients with
acute lymphoblastic leukemia
(ALL), it can increase to as high as
50% to 75% of patients at 1 year
without central nervous system
(CNS)–directed therapy.
In the absence of IT therapy, isolated CNS
recurrence can account for 10% to 16% of
relapses, warranting the inclusion of IT
chemotherapy in CNS prophylactic regimens.
In a study, the use of IT chemotherapy in
combination with the hyper-CVAD regimen
(hyperfractionated cyclophosphamide,
vincristine, doxorubicin, dexamrthasone
alternating with methotrexate and high-dose
cytarabine) reduced the incidence of CNS
relapse to 4%.[Kantarjian 2000]
Details of induction treatment of standard-risk group
Phase II induction
To be started when neutrophils rise to >1500 /µL
and platelets >100 000 / µL.
• Cyclophosphamide:
650 mg/m2 I.V. short inf. …….… D 1, 14, 28
• ARA-C:
75 mg/m2 short inf. ……………. D 3, 4 , 5 , 6
D 9, 10, 11, 12
D 16, 17, 18, 19
3/26/2016
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D 23, 24. 25, 26 44
Details of induction treatment of standard-risk group
Phase II induction
In this phase marked neutropenia usually
occurs after the 2nd cycle of ARA-C:
 As the patient is in CR it is allowed to stop
therapy in between cycles until hematological
recovery occurs.
 Do not reduce doses or leave out cycles
3/26/2016
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Consolidation treatment of standard-risk group
Phase I consolidation
Triple ITH
injection
ADR 25 mg/m2
VCR 2 mg I.V.
Pred 60 mg / m2 P.O. D1-28
1
3/26/2016
8
15
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22
28
Days
46
Consolidation treatment of standard-risk group
Phase I consolidation
• VCR 2 mg I.V. …………….
• ADR 25 mg/m2 I.V. ……….
• Pred 60 mg / m2 P.O. …….
reduced as previously)
• Triple intrathecal ………….
D1, 8, 15, 22
D1, 8, 15, 22
D1-28 (then
D1
» ARA-C 40 mg
» MTX 15 mg
» Dexamethasone 4 mg
3/26/2016
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Consolidation treatment of standard-risk group
Phase II consolidation
• Cyclophosphamide: 650 mg/m2 short inf. .... D1
• ARA-C: 75 mg /m2 short infusion …………… D 3, 4, 5, 6
9,10,11,12
100 mg /m2 …………………………..... D 25, 26, 27, 30
• VP16: 100 mg /m2 short infusion ……........... D 25, 26, 27, 30
• Triple intrathecal ………………………………... D1
ARA-C 40 mg
MTX 15 mg
Dexamethasone 4 mg
3/26/2016
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Consolidation treatment of standard-risk group
Maintenance therapy
Duration: 2-3 years (depending on MRD study)
• 6-MP: 60 mg/m2 P.O. in the morning before breakfast
• MTX: 20 mg /m2 I.V. (obligatory) once weekly.
CBC should be checked on a weekly basis.
3/26/2016
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Adult ALL: Maintenance Therapy
• Weekly methotrexate + daily 6-mercaptopurine
•
•
•
•
Duration: 2-3 years
Appropriate for all cases except B-cell and Ph+ ALL
Poor outcome if omitted
No randomized trials in adults
3/26/2016
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• No maintenance therapy is given in
mature B-cell ALL as these patients have
a high cure rate with short-term doseintense regimens, and relapses beyond
the first year in remission are rare.
• The best maintenance therapy for
patients with Ph-positive ALL remains
disputed, but should incorporate effective
BCR-ABL (breakpoint cluster region–
Abelson) tyrosine kinase inhibitors.
Adult ALL: Maintenance Therapy
(cont’d)
• 6-mercaptopurine dose varies
– Higher sensitivity in patients with inherited
deficiency of thiopurine methyltransferase
• Elevation of liver enzyme
– Recovery after discontinuation of therapy
– No need to withhold or reduce dose in absence of
severe liver toxicity
3/26/2016
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Consolidation treatment of standard-risk group
Maintenance therapy
Dose reduction:
TLC
PLT
2 000 - 3 000
100-150 X 106
2/3
1 500 – 3 000
50-100 X 106
1/2
< 1 500
< 50 X 106
3/26/2016
Dose of MTX and 6-MP
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No treatment
53
Consolidation treatment of standard-risk group
Maintenance therapy
Triple intrathecal prophylaxis:
Intrathecal
•MTX
15 mg
•ARA-C 40 mg
•Dexa
4 mg.
every 2
months till
end of
maintenance
3/26/2016
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3
Treatment of
high-risk group
3/26/2016
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Treatment of high-risk group
Induction (phase I & II)
CR
Donor
No donor
HAM
Allo BMT
3/26/2016
Auto BMT
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Treatment of high-risk group
For this group 1 cycle of HAM is added after induction
and before ABMT for patients who have no donor :
- ARA-C: 1 gm/m2 (3hr inf / 12hr) …………. D 1-3.
- Mitoxantrone: 12 mg/m2 (30 min iv inf) … D 3-5.
On day 3 mitoxantrone should be given before the
morning dose of ARA-C
Dexamethasone eye drops should be given every
6hrs on day 1-7
3/26/2016
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Treatment of high-risk group
Induction
Regimen:
Induction by high risk protocol as Hyper-CVAD Regimen
Overall, 92% of patients obtained a CR.
The 5-year survival and percentage of patients in CR at 5
years were both 38%.
Patients with Ph+ ALL had a 92% CR rate but only a 12% 5year survival.
Patients with T-cell ALL had a 75% CR rate and a 48% 5year survival
Patients with Burkitt ALL had a 93% CR rate and a 67% 5year survival.
Hyper-CVAD Regimen
• Part A
– Dexamethasone, vincristine, doxorubicin,
cyclophosphamide
• Part B (after WBC recovery)
– High-dose MTX, high-dose cytarabine
– No asparaginase
• Parts A and B repeated 4 times
3/26/2016
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Hyper-CVAD Regimen
3/26/2016
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Stem Cell Transplantation (SCT):
• First CR
– Allo SCT or MUD in high-risk patients
– Role in standard-risk patients unclear but not
recommended
– Auto SCT: no benefit over chemotherapy
• Second CR
– Allo SCT
3/26/2016
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Allo BMT vs Auto BMT in Patients
With Ph- ALL: MRC UKALL XII/ECOG
E2993
High-Dose
Methotrexate
(3 doses)
Patients with
Ph- ALL aged < 55 yrs
in complete remission after
induction therapy
Sibling Allo BMT
(n = 389)
Yes
HLA-matched sibling
donor available?
(N = 919)
No
High-Dose
Methotrexate
(3 doses)
3/26/2016
Rowe JM, et al. ASH 2006. Abstract 2.
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Auto BMT
(n = 530)
Consolidation/Maintenance
Chemotherapy:
2.5 years
62
Allo BMT vs Auto BMT in Patients With PhALL: 5-Year Results
• Improved OS with allo BMT vs auto BMT or
postinduction chemotherapy in standard-risk Phpatients
Outcome by Risk
Group, %
Donor
(n = 389)
No Donor
(n = 530)
P Value
Overall 5-yr survival
53
45
.02
• High risk
40
36
.50
• Standard risk
63
51
.01
39
62
< .0001
10-yr relapse rate
• High risk
3/26/2016
• Standard risk
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63
50
< .0001
Allo BMT vs Auto BMT in Patients With
Ph- ALL: 5-Year Results (cont’d)
• Better EFS, OS with consolidation/maintenance
chemotherapy vs auto BMT
– No role for auto BMT in postremission Phnegative ALL
» Allo BMT treatment of choice in
standard-risk patients
Outcome by Risk
Group, %
Overall 5-yr survival
Chemother
apy
47
• High risk
• Standard risk
3/26/2016
Overall
EFS
40
49
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Auto BMT
P Value
37
32
41
33
.06
.2
.2
.02
64
Rowe JM, et al. ASH 2006. Abstract 2.
Philadelphia Chromosome (Ph+)
ALL
• t(9;22) bcr/abl translocation
• Precursor B cell
• Incidence continuously increasing with age
– Rare in children; 50% incidence in ALL patients
older than 55 years of age
• Associated with very poor outcome
– No cure with intensive ALL chemotherapy (all
ages)
– Cure with SCT
• Lower cure rate than other ALL subtypes
3/26/2016
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Imatinib in Ph+ ALL
• Induces high response rate as single agent
– Response generally not durable
• In combination with ALL chemotherapy
– Higher CR rate: 90% to 97% and improved
outcome compared with chemotherapy alone[1,2]
– Increased access to transplantation for more
patients[3]
– Improves outcome of subsequent SCT[3]
– Concurrent administration of imatinib +
chemotherapy superior to alternating schedule[4]
1. Thomas DA, et al. Blood. 2004;103:4396-4407. 2. Yanada M, et al. J Clin
Oncol.
2006;24:460-464. 3. Lee S, et al. Blood.
3/26/2016
Free2005;105:3449-3457.
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4. Wassmann B, et al. Blood. 2006;108:14691477.
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• Imatinib mesylate, in combination with
hyper-CVAD in a phase II study of newly
diagnosed Ph-positive ALL patients
• In the overall study population, the 3-year
CR duration was 68% vs 24% for hyperCVAD alone, and the 3-year overall
survival rate was 54% vs 15% for hyperCVAD alone. Similar results have been
reported with other studies of Imatinib and
dose-intensive chemotherapy programs.
ALL in Older Adults
•
•
•
•
•
Low CR and survival rates
Lower rate of T-cell ALL
High rate of Ph-positive ALL
Often excluded from clinical trials
Often receive attenuated chemotherapy
3/26/2016
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Complications Observed in Older Adults
With ALL
• Comorbid conditions
• More severe mucositis related to pain medications
• Events associated with specific chemotherapies
– Vincristine: neuropathy, constipation
– Steroids: hyperglycemia, infections
– L-asparaginase: encephalopathy (lethargy and
somnolence)
• Low marrow reserve
– Adding G-CSF improves CR rate
3/26/2016
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1
Treatment of Mature
B-cell Type
3/26/2016
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B-Cell ALL (FAB L3): Burkitt’s
Leukemia
• Rapid cell proliferation and very high LDH
• t(8;14), t(2;8), t(8;22)
– Rearrangement of myc protooncogene (ch 8) with
Ig heavy chains (ch 14) or light chains (ch 2 or 22)
• Short intensive chemotherapy
– High-dose MTX and cyclophosphamide
• Intensive CNS prophylaxis
• No maintenance
• Cure rate: 60%; relapse rare 6 months after CR
3/26/2016
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Treatment of mature B-cell type
(1) Patients < 50 yrs
Give 2 full blocks
(A1+B1)
CR
No CR
Low-risk
High-risk
Continue for another 4 blocks
Continue for another 4
blocks till CR
A2+B2 +A3 + B3
A2+B2 +A3 + B3
HLA identical donor
Then stop treatment
3/26/2016
Available
Allo
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BMT
Not available
Auto BMT
74
Treatment of mature B-cell type
Prephase
– Cyclophosphamide: 200 mg/m2 (1 hr inf.)---- D1-5
– Prednisone:
60 mg /m2 P.O. ..……………. D1-5
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75
Treatment of mature B-cell type
Block A







VCR: 2 mg I.V………………………….. D1
MTX: 3 gm /m2 ( over 24 hrs)……….. D1
Ifosphamide: 800 mg/m2 (1hr inf.)……. D1-5
VP16 or vumon : 100 mg/m2 (1hr inf.).. D4, 5
ARA-C: 150 mg/m2 1hr inf/12hr……... D4, 5
Dexamethasone :
10 mg/m2 I.V. … D1-5
Triple intrathecal : …………………….... D1& 5
MTX 15 mg
ARA-c 40 mg
Dexamethasone 4 mg
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76
Treatment of mature B-cell type
Block B






after 2 weeks give block B
VCR: 2 mg I.V. …………………………….... D1
MTX: 3 gm /m2 ( over 24 hrs)………….…… D1
Cyclophosphamide: 200 mg/m2 (1 hr inf.)... D1-5
Doxorubicin: 25 mg/m2(short infusion)…… D4, 5
Dexamethasone :
10 mg/m2 I.V. ……… D1-5
Triple intrathecal : …………………………... D1& 5
MTX 15 mg
ARA-c 40 mg
Dexamethasone 4 mg
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77
Treatment of mature B-cell type
How to administer HD MTX (3 gm/m2)
• Route:
10% of the dose short infusion over ½ hr
90% of the dose  continuous I.V. infusion over 23½ hr
• Hydration:3L / m2 glucose/saline
Add to each bottle: 20 mEq NaHCo3 & 10 mEq Kcl
40 mg Lasix given at 6; 12 hrs after start of MTX.
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Treatment of mature B-cell type
How to administer HD MTX (3 gm/m2)
• Start leucovorin rescue: 1 hr infusion in at
least 150 ml solvent (high Ca content):
At hr 42  30 mg/m2
At hr 48  15 mg/m2
At hr 54  15 mg/m2
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79
Treatment of mature B-cell type
(2) Patients > 50 yrs
Give 4 incomplete blocks (without HD MTX)
a1 + b1 + a2 + b2
CR
No further
therapy
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80
Treatment of ALL
The sanctuaries
(CNS and testis)
(1) CNS leukemia
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81
CNS leukemia
Diagnosis
CNS Leukemia is diagnosed by at least one of the following criteria:
CSF
•Leukocytic Cell count > 5/l + morphological
evidence of blasts in the cytospin (fresh
within 10 minutes of sampling) .
•
CT
CP
protein ,
glucose .
Evidence of leptomeningeal infiltration.
Headache
Vomiting
Visual disturbances
Cranial nerve palsies especially VII
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Seizures
82
CNS leukemia
Fundus ex.
Look for:
1) Papilloedema
2) Hemorrhage
3) Fungal infection (opaque vitreous)
4) CMV ( pale optic disc )
5) Leukemic infiltration
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83
Treatment of CNS leukemia
A) Patients with initial CNS presentation
• Are not regarded as high-risk based on this
presentation alone.
• If such patients receive adequate therapy,
their prognosis is not worse.
• These patients should be stratified
according to other known risk factors and
treated in their group according to the
previous plan.
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84
Treatment of CNS leukemia
A) Patients with initial CNS presentation
• However these patients should receive triple
intrathecal therapy (and not MTX alone as usual)
- MTX
15 mg
- ARA-c 40 mg
- Dexa
Trendelnberg
position X 2 hrs.
4 mg
• To be started in the prephase and repeated 2 times /
week until CSF is free and then 5 more doses are
given (twice/week).
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85
A) Patients with initial CNS presentation
Further therapy
Standard-risk pts
High-risk pts
Craniospinal irradiation after phase
II of induction (in this situation, the
irradiation is given as prophylaxis
against recurrence. Patients are
usually already free after ITH therapy)
Triple intrathecal injections are
given every 2 months for 2 years
Patients will
receive allo or
auto BMT i.e.
No CNS
irradiation
(irrespective whether maintenance
treatment is indicated or not)
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86
B) Patients with CNS relapse (± BM relapse)
Triple ITH twice/week
till CSF is clear
+
Concomitant systemic
treatment e.g. HAM
5 more doses
Allo or auto
BMT if possible
If allo or auto BMT are not possible
(such patients usually had cranial
prophylaxis 24 Gy before)
Complete 30 Gy on the cranium and add
24 Gy on the spine followed by triple ITH
every 2 months for at least 24 months
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No consolidation or maintenance treatment
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from .
is effective in Free
such
patients
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87
Treatment of ALL
The sanctuaries
(CNS and testis)
(2) Testicular relapse
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Testicular relapse
•Either isolated or accompanied by BM relapse
US guided biopsy
Diagnosis
Management
Orchiectomy
Or
30 Gy irradiation
on both testes
(even if one only
is affected)
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+
One course of
HAM
concomitantly
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Immediate
allo or
auto BMT
(if eligible)
89
Treatment of primary refractory ALL
•Patients who do not enter into CR after induction (phase I & II)
One course of HAM
If no response
Ida FLAG
If no response
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Palliative
treatment
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90
•(irrespective of risk group)
Treatment of BM Relapse
BM Relapse
>1 yr after induction treatment
≤1 yr after induction treatment
Re-induction with the same protocol
CR2
Available
donor
No available
donor
Allo BMT
One course
of HAM
Salvage Course
HAM not given
before
HAM given
before
HAM
FLAG or AVVV
CR2
Available
donor
Discontinue
treatment
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Allo BMT
No available
donor
Discontinue
treatment
91
No consolidation or maintenance
treatment is effective in such patients
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Treatment of BM Relapse
In both groups
CNS-directed triple intrathecal
injections should be given every
two months for 24 months
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93
New Chemotherapies
•
•
•
•
•
•
•
RituximabAnti-CD20 May potentiate
chemotherapy in B-cell malignancies .
AlemtuzumabAnti-CD52.
Liposomal encapsulated drugs:
Liposomal vincristine
diminished
neurotoxicity
Liposomal daunorubicin
diminished
cardiotoxicity
Pegylated asparaginase
Long half-life
(6 days)
Cytarabine
liposome
(IT)
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94
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New Chemotherapies
• Antimetabolites
– Nelarabine (relapsed T-ALL) Pro-drug of
ara-G.Effective in T-ALL Inhibits purine
nucleoside phosphorylase (PNP).
– Clofarabine (Nucleoside analog ); inhibits
ribonucleotide reductase and DNA
polymeraseApproved for relapsed
childhood ALL .
– Trimetrexate (dihydrofolate reductase
inhibitor)
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Pegylated Asparaginase
• In children
– More rapid reduction
in marrow blasts
during induction
– Lower incidence of
neutralizing
antibodies
– Similar safety profile
as native form
• In adults
– Similar toxicity to
native form after
Avramis
VI, et al. Blood. 2002;99:1986-1994.
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96
Panosyan EH, et al. J Pediatr Hematol Oncol. 2004;26:217-226. single and multiple
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• Pegylated E. coli
L-asparaginase
• Less immunogenic
• Long half-life
– Less frequent dosing
– Continuous
asparagine depletion
T-Cell ALL: Gamma Secretase
Inhibitor MK 0752
• NOTCH 1 gain-of-function mutations in 50% of T-ALL
• Gamma secretase inhibitors abrogate(inhibit)
stimulatory effects of NOTCH 1
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DeAngelo D, et al. ASCO 2006. Abstract 6585.
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97
Common cytogenetic abnormalities in T-ALL
Chromosomal translocation of NOTCH1
causes T cell leukaemia
The t(7:9) chromosomal translocation in T-ALL patients is characterised by the
juxtaposition of the 3’ part of the human Notch1 gene into the T cell receptor β
locus. This leads to expression of truncated Notch1 transcripts from the TCR?
promoter, causing T cell leukaemia (T-ALL).
ALL: Targeted Treatments
• Targets include BCR/ABL, CD 20, and FLT3
overexpression, among others
ALL Subtype
Target
Treatment
Ph+
BCR/ABL
Imatinib, dasatinib, nilotinib
T cell
NUP214-ABL1
NOTCH1 mutation
Imatinib, dasatinib, nilotinib
Gamma secretase inhibitor
Mature B cell
CD20
Rituximab
Precursor B cell
CD20
Rituximab
All subtypes
CD52
Alemtuzumab
FLT3 overexpression
CEP701, PKC 212
MLL and hyperdiploidly
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ALL: Novel Management
Approaches
• Minimal residual disease evaluation
– Define prognostic groups for treatment selection
• Microarray analysis (gene expression profiles)
– Prognosis
– Identify new targets
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• Measurement of MRD in patients with
acute lymphoblastic leukemia (ALL) has
become an increasingly important
prognostic factor for assessing risk of
patient relapse.
• Persistence of MRD early in complete
remission typically does not have the
same significance as detection of residual
disease in later stages of therapy.
• A recent study suggested that detection of
MRD by flow cytometry at the time of
allogeneic hematopoietic stem cell
transplantation in either adult or children
with ALL was predictive for decreased
overall survival, leukemia-free survival,
and event-free survival after transplant
[Sanchez-Garcia 2013]
Minimal Residual Disease
• Methods
– Multicolor flow cytometry or PCR
– Prognostic levels defined for children; prognostic
time points and levels yet to determined for adults
Time of Evaluation
Prognosis
Minimum Residual
Disease
Children
• At CR
< 0.01%
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> 0.1%
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• After CR
Excellent outcome
High relapse risk
105
Minimal Residual Disease and
Prognosis in ALL
• 4730 patients on AIEOP-BFM ALL 2000 (pediatric)
•
MRD measured by RT-qPCR at Days 33 and 77
5-Yr EFS by MRD-D33/77, %
Pre B-ALL (Day 33/Day
77)
T-ALL (Day 33/Day
77)
Neg
92/88
94/92
≤ 10-4
82/69
91/77
10-3
66/56
75/50
MRD Levels
≥10-2
53/38
60/33
• MRD more + in T-ALL on D33 (84% vs 56%) and D77 (52% vs
22%)
• High MRD predictive of poorer survival for both disease types
• D33 measurement more predictive of 5-year EFS > 90%
Minimal Residual Disease and
Prognosis in ALL
• Separate study tested MRD at 0.1% level in 165 patients with ALL
with CR (85.5%) following induction and consolidation therapy
• Patients assigned to standard-risk (23%) or high-risk (77%)
groups
• MRD only significant predictive factor in multivariate analysis for
– Relapse incidence (HR: 2.5; P = .006)
– Leukemia-free survival (HR: 2.1; P = .01)
Parameter, %
MRD+
MRD-
P Value
MRD evaluated after induction (37% MRD+)
82
29
.00007
MRD evaluated after consolidation (26% MRD+)
62
41
.05
3-yr leukemia-free survival
26
65
.008
Overall relapse incidence
73
28
.004
• Standard-risk group
92
20
.01
3-yr relapse incidence
• High-risk group
Holowiecki J, et70
al. ASH 2007.
33 Abstract
.05 2821.