1. ACUTE LEUKEMIA Definition
PB and/or BM blasts > 20 % of nucleated cell (NC) count

2. 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

3. clinical features 1. Bleeding 2. Fever/infection 3. Bone/joint pain
4. Hepatomegaly
5. Splenomegaly
6. Lymphadenopathy
7. CNS involvement

4. 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

5. Manifestations of leukostasis include dyspnea, chest pain, headache, altered mental status, cranial nerve palsies, and/or priapism.

6. 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

7. Laboratory findings 3. Cytochemical stains 4. Immunophenotyping
5. Cytogenetics
6. Molecular studies

8. FAB Classification of ALL (1976)
L1: small monomorphic
L2: large, heterogeneous
L3: Burkitt cell-type

9. ACUTE LEUKEMIA Cytochemistry - + + with -ve to diffuse fine +
Precursor B-ALL
T-ALL
AML
Myeloperoxidase - +
Sudan black
Nonspecific esterase (NSE)
+ with
Na fluoride inhibition  M5
No Na fluoride inhibition  M4
Periodic acid-Schiff (PAS)
+++ (coarse)
-ve to diffuse fine +
Acid phosphatase

10. Mixed lineage Vs biphenotypic
Acute leukemia
Mixed lineage Vs biphenotypic
Mixed lineage leukemia:
Two different blast populations
Biphenotypic leukemia:
The same blast population both myeloid and lymphatic markers
AML
ALL

11. 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 13
CD 33
CD w65
0.5
TdT
CD 24
CD 7
CD 1a
CD 14
CD 15
CD 64
CD 117
To diagnose biphenotypic leukemia, the score should be at least:
2 in the myeloid lineage + 2 in the lymphatic lineage

12. ALL with myeloid coexpression
Acute leukemia
ALL with myeloid coexpression
Myeloid coexpression = at least 20 % of blasts + ve for at least one marker of:
CD13, CD33, CD65s.

13. AL: Immunophenotyping
ALL
B-ALL (incidence = 76%)
Subtype
TdT
CD 19
CD 10
Cy IgM
S Ig
Pro-B +
C-ALL
Pre-B
B-cell -

14. AL: Immunophenotyping
ALL
T-ALL (incidence =24%)
Compartment
T-cell type
Positive markers
Compartment I (early T)
Pro-T
CD 7
Pre-T
CD 2 and/or
CD 5 and/or
CD 8
Compartment II
Thymic T
CD 1a
Compartment III
Mature T
sCD 3

15. WHO Classification of ALL (1999)
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:

16. Cytogenetic classification of ALL
Bad Prognosis
Good Prognosis
Ph-chromosome t(9;22)
*30% of adult ALL
*3% of pediatric ALL
Hypoploidy
(DNA index < 1.12)
t(4;11)
t(12;21)
(Tel/AML1)
*30% of pediatric ALL
Hyperploidy
(DNA index = )

18. Immunophenotyping Cytogenetics / Molecular genetics
Algorithm for diagnosis of AL
Clinically suspected + blasts in PB
Morphology + cytochemistry of PB + BM
AML
Lymphoblastic lymphoma
< 20% blasts in BM
< 20% blasts in BM
Burkitt lymphoma
ALL (L1, L2)
ALL (L3)
Immunophenotyping
B-lineage
T-lineage
Pro-B
C-ALL
Pre-B
Mature B
Early
Thymic
Mature
Cytogenetics / Molecular genetics
t (4;11)
ALL1/AF4
t (9;22)
BCR/ABL

20. 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 Remission
Leukemia-Free Survival
Adults
80% to 90%
35%
Children (2-10 yrs of age)
97%
80%
Pui CH, et al. N Engl J Med. 2006;354:

21. ALL: Typical Treatment
Induction, consolidation, maintenance phases
CNS prophylaxis with IT-MTX
CNS Prophylaxis (IT-MTX)
IT-MTX, intrathecal methotrexate
Induction
Consolidation
Maintenance
Over a period of months
2-3 years
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22. ALL therapy is one of the most complex types of anticancer programs
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

23. Adult ALL: Large Clinical Trials
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
BFM, ↑ Cy, ↑ ASP 85 36
CALGB 19802
163 41
BFM, ↑ Cy , ↑ DNR 78
GIMEMA
778
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
Hyper-CVAD
288 40
Cy, D, AD, HD-MTX, HD-ARA-C 92
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24. 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
Immunophenotype
Thymic T-ALL
Pro B-ALL
Early T-ALL
Mature T-ALL
Cytogenetics &
Molecular genetics
Normal diploid karyotype (?)
Hyperdiploid karyotype (?)
T(9;22)/BCR-ABL
T(4;11)/ALL1-AF4
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25. Prognostic factors in adult ALL
(2) Response to treatment
Favorable
Unfavorable
Time to CR
CR in 2-4 ws
CR >4 ws
MRD after induction
<10-3
>10-3
MRD during consolidation
<10-4 or negative
>10-4 or increasing
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26. Risk-adapted treatment of ALL
Age
<50 yrs
50-60 yrs
>60 yrs
Standard risk
Standard-risk protocol 
No further treatment or
Maintenance X 2-3 yr or
Allogeneic BMT
Maintenance X 2-3 yr
No BMT
COAP only
High risk
High-risk protocol
High-risk protocol with ABMT arm
No allo BMT
Mature B-cell
6 full blocks i.e. (A1B1A2B2A3B3)
+ BMT
4 incomplete blocks (without HD MTX) i.e. a1b1a2b2
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27. Induction (phase I & II) Consolidation (phase I &II)
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)
Donor
No donor
MRD<10-4
MRD >10-4
HAM
Donor
No donor
Allo BMT
Auto BMT
End of therapy
Allo BMT
Maintenance X 2-3 yrs
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28. Treatment of standard-risk group2
Treatment of standard-risk group
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29. Treatment of standard-risk group
Induction (phase I & II) CR
Consolidation (phase I &II)
MRD>10-4
MRD<10-4
Donor
No donor
End of therapy
Allo BMT
Maintenance X 2-3 yrs
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31. Induction treatment of standard-risk group Induction treatment Phase I
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.
VCR/Pred
Pred 60 mg / m2 P.O. D1-28
Days
Prephase
Induction treatment Phase I
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32. 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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33. 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: 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
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34. Free Template from www.brainybetty.com
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
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35. 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)
CNS, central nervous system
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36. 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.

37. 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 (with no blasts in BM)
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40. 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)
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42. 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.

43. 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]

44. Details of induction treatment of standard-risk group
Phase II induction
To be started when neutrophils rise to >1500 /µL and platelets > / 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
D 23, , 26
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45. 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
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46. 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
Days
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47. Consolidation treatment of standard-risk group
Phase I consolidation
VCR 2 mg I.V. ……………. D1, 8, 15, 22
ADR 25 mg/m2 I.V. ………. D1, 8, 15, 22
Pred 60 mg / m2 P.O. ……. D1-28 (then reduced as previously)
Triple intrathecal …………. D1
ARA-C 40 mg
MTX 15 mg
Dexamethasone 4 mg
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48. 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
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49. 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.
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50. 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
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51. No maintenance therapy is given in mature B-cell ALL as these patients have a high cure rate with short-term dose-intense 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.

52. 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
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53. Consolidation treatment of standard-risk group
Maintenance therapy
Dose reduction:
TLC
PLT
Dose of MTX and 6-MP
X 106
2/3
1 500 – 3 000
X 106
1/2
< 1 500
< 50 X 106
No treatment
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54. Consolidation treatment of standard-risk group
Maintenance therapy
Triple intrathecal prophylaxis:
Intrathecal
every 2
months till
end of
maintenance
MTX mg
ARA-C 40 mg
Dexa mg.
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55. Treatment of high-risk group3
Treatment of high-risk group
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56. Treatment of high-risk group Induction (phase I & II)CR
Donor
No donor
HAM
Allo BMT
Auto BMT
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57. 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
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58. 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% 5-year survival.
Patients with T-cell ALL had a 75% CR rate and a 48% 5-year survival
Patients with Burkitt ALL had a 93% CR rate and a 67% 5-year survival.

59. Free Template from www.brainybetty.com
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
MTX, methotrexate; WBC, white blood cell count
4/28/2017
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Kantarjian H, et al. J Clin Oncol. 2000;18:

60. Free Template from www.brainybetty.com
Hyper-CVAD Regimen
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61. 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
Allo SCT, allogeneic stem cell transplant; Auto SCT, autologous stem cell transplant; CIBMTR, Center for International Blood and Marrow Transplant Research; LFS, leukemia free survival; CR, complete remission; MUD, matched unrelated donor
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Hahn T, et al. Biol Blood Marrow Transplant. 2006;12:1-30.

62. HLA-matched sibling donor available?
Allo BMT vs Auto BMT in Patients With Ph- ALL: MRC UKALL XII/ECOG E2993
Patients with Ph- ALL aged < 55 yrs
in complete remission after induction therapy
(N = 919)
Sibling Allo BMT
(n = 389)
High-Dose Methotrexate (3 doses)
HLA-matched sibling donor available?
Yes
Auto BMT
Consolidation/Maintenance Chemotherapy: 2.5 years
(n = 530) No
ALL, acute lymphoblastic leukemia; Allo, allogeneic; Auto, autologous; BMT, bone marrow transplantation; HLA, human leukocyte antigen; MRC, Medical Research Council; Ph-, Philadelphia chromosome negative; ECOG, Eastern Cooperative Oncology Group
4/28/2017
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Rowe JM, et al. ASH Abstract 2.

63. Allo BMT vs Auto BMT in Patients With Ph- ALL: 5-Year Results
Improved OS with allo BMT vs auto BMT or postinduction chemotherapy in standard-risk Ph- patients
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
10-yr relapse rate 39 62
< .0001 27 50
OS, overall survival; WBC, white blood cell count
4/28/2017
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Rowe JM, et al. ASH Abstract 2.

64. 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 Ph-negative ALL
Allo BMT treatment of choice in standard-risk patients
Outcome by Risk Group, %
Chemotherapy
Auto BMT
P Value
Overall 5-yr survival 47 37
.06
High risk 40 32 .2
Standard risk 49 41
Overall EFS 42 33
.02
EFS, event-free survival; OS, overall survival
4/28/2017
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Rowe JM, et al. ASH Abstract 2.

65. 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
SCT, stem cell transplant
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66. Free Template from www.brainybetty.com
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]
CR, complete remission; SCT stem cell transplant
1. Thomas DA, et al. Blood. 2004;103: Yanada M, et al. J Clin Oncol. 2006;24: Lee S, et al. Blood. 2005;105: Wassmann B, et al. Blood. 2006;108:
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67. 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 hyper-CVAD alone, and the 3-year overall survival rate was 54% vs 15% for hyper-CVAD alone. Similar results have been reported with other studies of Imatinib and dose-intensive chemotherapy programs.

70. Free Template from www.brainybetty.com
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
CR, complete remission; Ph+, Philadelphia chromosome positive
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71. 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
CR, complete remission; G-CSF, granulocyte-colony stimulating factor
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72. Treatment of Mature B-cell Type1
Treatment of Mature B-cell Type
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73. 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
CNS, central nervous system; CR, complete remission; FAB, French-American-British; LDH, lactic dehydrogenase; MTX, methotrexate
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74. (A1+B1) 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 till CR
Continue for another 4 blocks
A2+B2 +A3 + B3
A2+B2 +A3 + B3
HLA identical donor
Then stop treatment
Not available
Available
Allo BMT
Auto BMT
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75. 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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76. 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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77. 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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78. 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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79. 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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80. 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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81. The sanctuaries (CNS and testis)
Treatment of ALL
The sanctuaries (CNS and testis)
(1) CNS leukemia
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82. Cranial nerve palsies especially VII
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) .
protein , glucose . CT
Evidence of leptomeningeal infiltration. CP
Headache
Vomiting
Visual disturbances
Cranial nerve palsies especially VII
Seizures
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83. Free Template from www.brainybetty.com
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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84. 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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85. 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 mg
- ARA-c 40 mg
- Dexa mg
Trendelnberg position X 2 hrs.
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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86. 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)
Patients will receive allo or auto BMT i.e.
No CNS irradiation
Triple intrathecal injections are given every 2 months for 2 years (irrespective whether maintenance treatment is indicated or not)
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87. + 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
No consolidation or maintenance treatment is effective in such patients .
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88. The sanctuaries (CNS and testis)
Treatment of ALL
The sanctuaries (CNS and testis)
(2) Testicular relapse
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89. + Or Testicular relapse Diagnosis US guided biopsy Management
Either isolated or accompanied by BM relapse
Diagnosis
US guided biopsy
Management
Orchiectomy
Immediate allo or auto BMT (if eligible) Or
One course of HAM concomitantly +
30 Gy irradiation on both testes (even if one only is affected)
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90. 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
Palliative treatment
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91. Treatment of BM Relapse
(irrespective of risk group)
BM Relapse
>1 yr after induction treatment
≤1 yr after induction treatment
Re-induction with the same protocol
Salvage Course
CR2
HAM not given before
HAM given before
Available donor
No available donor
HAM
FLAG or AVVV
CR2
Allo BMT
One course of HAM
Available donor
No available donor
Discontinue treatment
Discontinue treatment
Allo BMT
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No consolidation or maintenance treatment is effective in such patients

93. 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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94. Free Template from www.brainybetty.com
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 injection (IT)
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95. Free Template from www.brainybetty.com
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)
IT, intrathecal
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96. 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 single and multiple doses
Pegylated E. coli L-asparaginase
Less immunogenic
Long half-life
Less frequent dosing
Continuous asparagine depletion
Avramis VI, et al. Blood. 2002;99: Panosyan EH, et al. J Pediatr Hematol Oncol. 2004;26:
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97. 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 Abstract 6585.

98. Common cytogenetic abnormalities in T-ALL

99. 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).

100. 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
Gamma secretase inhibitor
Mature B cell
CD20
Rituximab
Precursor B cell
All subtypes
CD52
Alemtuzumab
MLL and hyperdiploidly
FLT3 overexpression
CEP701, PKC 212
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102. 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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103. 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.

104. 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]

105. 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
Minimum Residual Disease
Prognosis
Children
At CR
< 0.01%
Excellent outcome
After CR
> 0.1%
High relapse risk
CR, complete remission; PCR, polymerase chain reaction
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106. 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
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%
5-Yr EFS by MRD-D33/77, %
MRD Levels
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
≥10-2
53/38
60/33
ALL, acute lymphocytic leukemia; B-ALL, B-cell ALL; EFS, event-free survival; MRD, minimal residual disease; RT-qPCR, reverse transcriptase quantitative polymerase chain reaction; T-ALL, T-cell ALL.
The presence of minimal residual disease in ALL is increasingly important. This large German study enrolled 4730 pediatric patients, and PCR was used to detect minimal residual disease at Days 33 and 77. Unsurprisingly, patients who became PCR negative had the best 5‑year event‑free survival.
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107. 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
3-yr relapse incidence
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
High-risk group 70 33
ALL, acute lymphocytic leukemia; CR, complete response; HR, hazard ratio; MRD, minimal residual disease.
Another way to look at minimal residual disease in ALL is by using flow cytometry. This Polish Adult Leukemia Group study assigned ALL patients to typical high- and standard-risk groups based on age, cytogenetics, and number of cycles to achieve a complete response. By multivariate analysis, achieving negative minimal residual disease was the best predictor for good leukemia‑free survival.
Monitoring minimal residual disease is increasingly important in ALL, and patients will soon be treated based on those results, likely with newer targeted agents. Such monitoring could also be used to determine which patients should receive transplantation. For example, consider a patient who is in remission but still positive for minimal residual disease after 8 cycles of hyper‑CVAD. That patient might be a candidate for allogeneic transplantation in first remission.
Holowiecki J, et al. ASH Abstract 2821.
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