Management of acute lymphoblatic leukemia with light on etiology, clinical features, diagnosis and different aspects of management including chemotherapy and radiation therapy

1. MANAGEMENT OF
ACUTE LYMPHOBLASTIC LEUKEMIA(ALL)
DR. ABHISHEK SONI
CLINICAL AND RADIATION ONCOLOGIST

2. ALL
• A neoplastic disease that results from multistep somatic
mutations in a single lymphoid progenitor cell at one of
several discrete stages of development.
• Originates in a single B or T lymphocyte progenitor.

5. Incidence
• Most common malignancy diagnosed in <15 years.
( 23 percent of all cancers and 76 percent of all leukemias)
• Only 20 percent of adult acute leukemias are ALL.
• Bimodal peak
– 2 to 4 years
– sixth decade.
• Males : females =1.3:1

6. Statistics
HEMATO ONCOLOGY, PGIMS 2008-10
ALL% CLL AML CML
Male 60.0 89.3 66.7 62.2
Female 40.0 10.7 33.3 37.8
Total 16.5 16.9 23.5 43.1
TOTAL MALES FEMALES
New cases 5,730 3,320 2,410
Deaths 1,420 780 640
USA – 2010-11

7. Etiology
 Precise etiology is unknown
 Risk factors
• Genetic Syndrome
– Ataxia-telangiectasia : 70 X
– Bloom syndrome
– Downs syndrome: 10 – 30 X
• Environmental Factors
– Radiation exposure
– Smoking
– Pesticide
• Chemotherapeutic agents
– Alkylating agents
– Epipodophyllotoxins
– Topoisomerase II inhibitors
– Anthracyclines

8. Clinical Features
 Due to marrow failure :
Proliferation and accumulation of blast cells → suppression of
hematopoiesis:
Anemia, thrombocytopenia, neutropenia.
 Due to extramedullary spread:
(Lymphoblasts can accumulate in various extramedullary sites)
Meninges, gonads, thymus, liver, spleen, and lymph nodes.

9. Clinical Features contd.….
Nonspecific (common)
• Fever
• Bleeding
• bone pain
• Presence of Petechiae
Musculoskeletal pain
• – Limp/Refusal to bear weight
• – Bone pain

10. Clinical Features contd….
• Lymphadenopathy (~50% on presentation)
• Organomegaly
Liver, spleen, and lymph nodes are the most common sites of extramedullary
involvement
• CNS symptoms
o Headache
o Increased ICP
o Vomiting
o Lethargy
o Papilloedema
o Nuchal rigidity
o Cranial nerve abnormalities

11. Clinical Features contd….
• Testicular involvement
Painless enlargement of the scrotum
• Mediastinal mass
o Tracheal compression
o Associated pleural effusions
o Superior vena cava syndrome
Pain
Dysphagia
Dyspnea
Swelling of the neck, face, and upper limbsface, limbs

12. DIAGNOSIS
• Peripheral blood :
• Leukocyte counts : range widely, from 0.1 to 1500 x 109/liter (median 10–
12 x 109/liter).
• Hyperleukocytosis (>100 x 109/liter) is seen in 10 to 16 percent of patients.
• 90% patients have circulating leukemic blast cells.
• Hypereosinophilia, generally reactive, may precede the diagnosis by
several months.

13. • Anemia, neutropenia, and thrombocytopenia are common in patients with
newly diagnosed ALL
• Hemoglobin :Occasionally, a child with ALL has a level as low as 1 g/dl.
• Profound neutropenia (<0.5 x 109/liter) is found in 20 to 40 percent of
patients.
• Decreased platelet counts often are seen at diagnosis (median, 48–52 x
109/liter).
Occasional patients, principally male, present with thrombocytosis (>400 x
109/liter).

14. • Serum lactate dehydrogenase (LDH), uric acid is increased.
• Rarely, patients present with hypercalcemia resulting from release of
parathyroid hormone-like protein from lymphoblasts and leukemic
infiltration of bone.
• Liver dysfunction as a result of leukemic infiltration occurs in 10 to 20
percent of patients, usually is mild.

15. BONE MARROW examination:
• Examination of bone marrow aspirate is preferable
o 10 percent of patients lack circulating blasts at the time of diagnosis
o bone marrow cells are better than blood cells for genetic studies.
• Bone marrow aspiration - >30% blasts present in bone marrow will result
in definitive diagnosis .

16. CSF examination :
Lumbar puncture
• If there is a risk of bleeding due to a very low platelet count or of blast cell
contamination due to a high leukemic blast content in the peripheral blood,
lumbar puncture should be postponed.
• CNS leukemia is:
• Presence of at least five leukocytes per microliter of CSF and the
detection of leukemic blast cells.
• Presence of cranial nerve palsy.

17. Flow Cytometry:
(Whole blood/ Bone Marrow)
Immunophenotyping
• Pan –B cell marker: CD 19,CD 22,CD 79
• B cell maturity marker: Surface IgM
• Pre –B cell ALL prognostic marker: Cytoplasmic IgM
• Precursor cell markers: CD 34, TdT
• Leukocyte common antigen(LCA): CD 45
• Pan-T cell marker : CD 3 ,CD 7
• T cell marker: CD 5

18. • CYTOGENETIC STUDY:
Karyotyping (specific reciprocal translocations.)
MOLECULAR ANALYSIS:
• Fluorescence in situ hybridization (FISH)
• Reverse transcriptase polymerase chain reaction (RT-PCR) assays.
( Can identify several important submicroscopic genetic alterations not
visible by standard karyotyping procedures, such as the TEL-AML1 fusion)

19. CLASSIFICATION OF ALL
• Morphologic and Cytochemical (FAB)
• Immunological
• Genetic

20. Morphologic and Cytochemical Classification:
FAB Classification of ALL

21. Immunologic Classification
World Health Organization
(WHO)classification (modified)

22. Genetic Classification

23. Classification of Acute Lymphoblastic Leukemia

24. Prognostic Factors
Risk classification of childhood ALL
St. Jude Total Therapy Study XV

25. • ADVERSE PROGNOSTIC FACTORS IN ADULT ALL
• Age :>50yrs
• High WBC count : >30000/mm3 (B lineage ALL)
>100000/mm3 (T lineage ALL)
• Cytogenetics : Hypodiploid , t(9;22) , t(4;11) , t(1;19)
• Immunophenotype: mature B cell ALL
• Response to treatment: Time for CR>4 weeks, persistence of blasts in PB at
day 7and BM at day 14

26. TREATMENT:
• Supportive Care
– Metabolic Complications
– Leukostasis
– Infection Control
– Hematologic Support

27. Metabolic Complications
• Hyperuricemia, hyperphosphatemia, 20 hypocalcemia
• Especially with B cell or T cell ALL or B cell precursor leukemia with high
leukemic cell burden
• Management :
– Hyperuricemia :
• IV fluids
• Allopurinol or rasburicase (recombinant urate oxidase) .
– Hyperphosphatemia :
• Phosphate binder, such as aluminum hydroxide
• Calcium carbonate (if the serum calcium concentration is low)
• Sevelamer .

28. Leukostasis
• Occurs with elevated blast count (25% of patients have WBC>50000/mm3 )
• Symptoms result from capillary plugging by leukemic cells.
Dyspnea,headache,confusion and hypoxia
Management :
• Leukapheresis and aggressive hydration is repeated daily in conjunction
with chemotherapy (eg.,oral hydroxyurea or intravenous
cyclophosphamide) until blast count is<50000.
•

29. Infection Control
Infection can be
• Due to neutropenia
Management:
– broad-spectrum antibiotic until fever is controlled.
• Due to Remission induction therapy
By exacerbating myelosuppression, immunosuppression, and mucosal
breakdown. (50 percent of patients )

30. Infection Control contd…..
• Care during remission induction therapy:
1. Reverse protective isolation and air filtration
2. Elimination of contact with people with infections
3. Refraining from eating certain food products, such as raw cheese, uncooked
vegetables, or unpeeled fruits
4. Use of antiseptic mouthwash or sitz baths, especially for patients with
mucositis.
5. Administration of granulocyte colony stimulating factor can hasten
recovery .

31. Infection Control contd…..
• Due to early intensification of therapy,
(especially in combination with dexamethasone)
• resulted in an increased risk of disseminated fungal infection.
• Management:
– Trimethoprim-sulfamethoxazole,
• 2 to 3 days per week
• 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.
– Alternatives - aerosolized pentamidine, dapsone, and atovaquone.

32. Hematologic Support
• ALL or its treatment ( induction treatment including L-asparaginase and a
glucocorticoid ) can lead to thrombocytopenia.
Hemorrhagic manifestations are common
Management:
Platelet transfusions :
• Overt bleeding
• Platelet counts < 10 x 109/liter.
Packed red cells transfusions :
• Anemia and marrow suppression
(should be delayed until the leukocyte count is reduced in patients with
extreme hyperleukocytosis)

33. Specific
• B Cell Precursor and T Cell ALL
Treatment consists of three standard phases:
• Remission induction
• Intensification (consolidation)
• Prolonged continuation therapy
• CNS-directed therapy
Started early and is given for different lengths of time, depending on the
patient's risk of relapse and the intensity of the primary systemic regimen.

34. Remission Induction
• Aim : To rapidly kill most tumor cells and get the patient into
remission.
• Clinical Remission:
Presence of less than 5% leukemic blasts in the bone marrow, normal blood
cells and absence of tumor cells from blood, and absence of other signs and
symptoms of the disease.
• Central nervous system (CNS) prophylaxis should begin during this phase
of treatment and continue during the consolidation/intensification period.

35. • Combination of Prednisolone or dexamethasone, vincristine, asparaginase
(better tolerance in pediatric patients), and daunorubicin (used in Adult
ALL) is used to induce remission.

36. Intensification (Consolidation) Therapy
• Aim: To further reduce tumor burden .
• When normal hematopoiesis is restored, patients in remission become
candidates for intensification therapy
• High doses of multiple agents not used during the induction phase or
readministration of the induction regimen.

37. • Vincristine , cyclophosphamide, cytarabine, daunorubicin, etoposide,
thioguanine or mercaptopurine in different combinations.
• CNS protection
Intrathecal methotrexate or cytarabine is usually used combined with or
without cranio-spinal irradiation (the use of radiation therapy to the head
and spine).

38. • Continuation Therapy
• Aim: To kill any residual cell that was not killed by remission
induction, and intensification regimens.
• Long-term drug exposure or the host immune system is needed to kill
residual, slowly dividing leukemic cells or to suppress their growth and
thus allow programmed cell death to occur.
• total duration of 2 to 2.5 years

39. • Daily oral mercaptopurine, once weekly oral methotrexate, once monthly
5-day course of intravenous vincristine and oral corticosteroids are usually
used.
• Another integral component of many protocols is reinduction
therapy after the first remission.
– This treatment, which relies on the same drugs used during the initial
phase of induction therapy, has improved outcomes for children and
adults with ALL.

40. Various Regimens:
• Berlin-Frankfurt-Munro regimen
(BFM): CCG
• Larson Regimen
(Cancer and leukemia Gp B :CALGB)
• Hyper CVAD and MTX/HIDAC REGIMEN:
MD Anderson Cancer Center
• MCP 841 Protocol
(Tata memorial,Mumbai)

41. Berlin-Frankfurt-Munro regimen
(BFM)
Early Intensification
Induction:
• Vincristine:1.5mg/m2 i.v on d1,8,15,22
• Daunorubicin:25mg/m2 i.v on d1,8,15,22
• Prednisolone PO on d 1-28 then taper
• L-asparginase-6000IU/m2 i.m on days 1-14
Consolidation:(9 weeks)
• Cyclophosphamide -650mg/m2 (max 1gm)i.v on d 29,43,57
• Cytarabine: 75mg/m2 i.v on d 31-34,38-41,45-48,52-55
• 6 –MP:60mg/m2 i.v on d 29-57.
• Vincristine:1.5mg/m2 i.v d 14,21,42,49
• L-asparginase-6000IU/m2 i.m d 14,16,18,21,23,25,42,44,46,49,51,53
CCG (Childrens Cancer Group)

42. CNS prophylaxis
• IT Methotrexate:10mg on d 31,38,45,52
• Cranial irradiation:1800cGy (for no CNS disease at diagnosis)
Interim maintenance:
• Vincristine: 1.5mg/m2 i.v d 0,10,20,30,40
• Methotrexate:100mg/m2 i.v d o,10,20,30,40
• L-asparginase:150000U/m2 i.m d 1,11,21,31,41
Delayed intensification (8 weeks)
Reinduction(4 weeks)
• Vincristine:1.5mg/m2 i.v on d1,14,21
• Daunorubicin:25mg/m2 i.von d1,7,14
• Dexamethasone:10mg/m2 PO q.d.d-0-20 then taper for 7 days.
• L-asparginase-6000IU/m2 i.m d-3,5,7,10,12,14

43. Reconsolidation:(4 weeks)
• Cyclophosphamide -650mg/m2 (max 1gm) i.v d-28
• Cytarabine: 60mg/m2 i.v /sc on d-29-32,36-39
• 6 –TG:60mg/m2 po d-28-41
• Vincristine:1.5mg/m2 i.v d 42,49
• L-asparginase-6000IU/m2 i.m d 42,44,46,51,53
• IT methotrexate: days 29, 36
• Interim Maintenance II (same as interim maintenance I except IT
methotrexate on d-0,20,40)
• Delayed intensification II (Same as I)
• Maintenance (12 week cycle)
• Vincristine: 1.5mg/m2 i.v d 0,28,56
• Prednisolone:60mg/m2 po qd d0-4,28-32,56-60
• 6MP : 75mg/m2 p.o qd d 0-83
• Methotrexate: 20mg/m2 p.o d 7,14,21,28,35,42,56,63,70,77
• IT Methotrexate: d 0

44. Comparison:
Clinical
Remission
(CR)
Overall
Survival
5yr Disease
free
survival
CCG
(BFM
regimen)
96% 67% 65%
CALGB
Regimen
(Protocol
9111)
87% 43% 41%
Hyper –
CVAD
regimen
91% 38% 38%
MCP 841 87.8% 60.34% 56%

45. B Cell ALL
• Mature B-cell ALL is the leukemic equivalent of
Burkitt’s lymphoma .
Have poor prognosis
• CR remission rates : 40%
• Remission duration :11 months
Treatment for mature B-cell ALL differs from that for other types of ALL :
• Short cycles at frequent intervals over a period of 6 months.

46. • 2% to 4% cases
associated with HIV syndrome.
• Characteristic clinical features include frequent CNS involvement,
lymphadenopathy, splenomegaly, and high serum LDH levels.
Management :
o Hyper-CVAD therapy
o HIV testing and CNS prophylaxis
• CR : 90% and cure rate : 70%
Rituximab(anti-CD20 antibody ) with Hyper-CVAD :R-Hyper-CVAD
• CR : 86%
• OS :89%

47. Hyper CVAD and MTX/HIDAC REGIMEN:
Cycle 1,3,5,7
• Cyclophoshamide 300mg/m2 i.v over 3hr q12hr Day 1-3(six doses)
• (a/w Mesna 600mg/m2/d as continuous infusion Day 1-3
• Vincristine 2mg i.v Day 4,11
• Doxorubicin 50mg/m2 i.v Day 4
• Dexamethasone 40mg PO daily 1-4 and 11-14
• G-CSF 10ug/kg/d SQ starting after chemotherapy
Cycle 2,4,6,8
• Methotrexate 200mg/m2 i.v over 2 hr on Day1 ,followed by
• Methotrexate 800mg/m2 i.v over 22hr on Day 1
• Leucovorin 50mg starting 12hr after Mtx completed ,followed by leucovorin 15mg
every 6h x eight doses(dose adjusted on the basis of mtx levels)
• Cytarabine 3gm/m2 i.v. over 2hr every 12 hr on Day 2 and 3( four doses)
• Methylprednisolone 50mg i.v twice daily Day 1-3
• G-CSF 10ug/kg/d SQ starting after chemotherapy
Kantarjian and colleagues at MD Anderson
Cancer Center

48. CNS prophylaxis
• Methotrexate 12mg intrathecal (IT) on Day 2
• Cytarabine 100mg IT on Day 8
Maintenance therapy(POMP) x 2yrs
• Mercaptopurine 50mg PO three times daily
• Methotrexate 20mg/m2 PO,weekly
• Vincristine 2mg i.v monthly
• Prednisone 200mg/d for 5 days each month.
• Note: in case of CD 20+ (>20% cases) :addition of Rituximab should be
considered

49. Philadelphia Chromosome Positive Acute Lymphoblastic
Leukemia
• Patients with Ph+ ALL have a poor prognosis.
• Long-term DFS rate of 10% to 20%.
• Allogeneic transplantation from a related or unrelated donor has been
widely used for consolidation.
( 27% to 65% long-term survival : in first complete remission)
• Beyond first remission,
DFS : 5% to 17%.

50. • Imatinib mesylate has demonstrated significant activity in patients with
Ph+ALL.
• Remission induction rates : 95%.
• 50% to 70% : achieve molecular negativity.
• Second-generation TK inhibitors such as dasatinib and nilotinib in relapse
and refractory Ph+leukemias

51. Prevention and Treatment of Central
Nervous System Leukemia
• 6% of patients at diagnosis present with CNS leukemia.
• Higher incidence in T-cell ALL (8%) and mature B-cell ALL (13%).
• Risk factors:
 High-risk genetic features
 Large leukemic cell burden
 T-lineage ALL
 Leukemic cells in the CSF (even if iatrogenic from a traumatic lumbar
puncture) .

52. PREVENTION
In the hyper-CVAD regimen,
• High risk disease : 8 prophylactic IT treatments
• Low risk disease : 6 prophylactic IT treatments.
• Mature –B cell : 16 IT therapies.
• Prophylactic CNS irradiation is administered.
TREATMENT
• Intrathecal (IT) methotrexate or cytarabine (Ara-C) ,often alternating
.Given twice weekly until disease clears ,then weekly for 4 weeks ,and then
resume prophylaxis schedule.
• Radiation (2400-3000cGy) can also be considered.

53. CNS relapse rate with various treatments:
CNS relapse rate
No treatment 30%
Intrathecal Chemotherapy 13%
Intravenous +Intrathecal
Chemotherapy
7%
Additional CNS irradiation 6%

54. Cranial Irradiation
• Prophylactic cranial irradiation
• Indication
• In all adults with ALL
• High and very high risk group(children)
• Prophylactic Dose:
• 18 Gy in 9 or 10 fractions
• Therapeutic dose:
• 24Gy in 12 fractions.
.

55. • Include the subarachnoid space
within the cranial vault.
• Inferior margin : cribriform plate,
middle cranial fossa, lower border
C2 .
• The posterior globe of the eye is
included.
• SHIELD: anterior half eye

56. Testicular Relapse
• Commonly in T cell subtype
• Approx 2% of males .
• Poor prognostic indicator.
• Systemic and/or CNS relapse usually follows .
• Both intensive systemic therapy and local radiotherapy are indicated.

57. • Unilateral irradiation or orchiectomy: significant risk of contralateral
testicular relapse
• Treatment of both testes: infertility.
• CCG and POG studies :
( Children’s Cancer Group & pediatric oncology group )
Local irradiation and intensive systemic therapy :
Event-free survival : 50% to 65% .
• Dose: 24 to 26 Gy in 1.5- to 2.0-Gy fractions.

58. Testicular Irradiation
Technique
• Patient in a frog-leg position
• Penile shaft taped onto the abdomen .
• Check the cremaster reflex and potential ascent of the testes into the
inguinal canal.
• For megavoltage photon beams, bolus may be required to avoid superficial
underdosing.
• In young boys in whom the scrotum/testes thickness is under 2 cm, 250 kV
orthovoltage x-rays may also be used.

59. Allogeneic Stem Cell Transplantation
INDICATIONS:
All patients with relapsed or refractory disease
Overall Survival:
– <35% in relapsed disease
– < 10% in refractory disease.
After first CR or early in the course for those patients with poor risk
cytogenetics, t(9;21)
– Overall survival is 50%
Long-term event-free survival rates range from
• 30 to 40 percent with chemotherapy alone
• 40 to 60 percent with allogeneic transplantation

60. Autologous Transplant
• Minimal benefit in CR1
• Can be considered in patients achieving CR2,without the availability of an
allogenic donar
• It may be performed in older patients >60yrs
• Higher rate of morbidity and mortality
Estimated 5-Year Survival Rates Following Transplantation:
Allogeneic,% Autologous,%
First remission 50 40
Second remission 40 30

61. 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
• Early Relapse:<during treatment
• Late Relapse: >6 months after cessation of therapy
• Marrow is 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 .

62. • Extramedullary sites : CNS , testes and eye.
Marrow relapse, with or without extramedullary involvement, is a poor
outcome .
• Late relapse : reinduction with the original regimen.
• Early relapse or refractory disease : Transplantation or changing treatment
plan.
• For patients who receive only chemotherapy, a second course of CNS-
directed treatment is needed to prevent subsequent CNS relapse

63. Options:
• High dose cytarabine with idarubicin,mitoxantrone or fludarabine
• Methotrexate,vincristine,asparginase,steroids(MOAD)
• Imatinib,dasatinib or nilotinib(if Ph positive)
• Hyper-CVAD ,if not given initially
• Vinorelbine with mitoxantrone, fludarabine, steroids or rituximab
• Nelarabine
• Clofarabine

64. Side Effects Associated with Antileukemic
Therapy
Acute complications Delayed complications

65. Side Effects Associated with Antileukemic Therapy contd….
Acute complications Delayed complications

66. Newer drugs in ALL:
Role in relapsed or refractory cases.
Antimetabolites(Purine nucleoside analogues):
o Clofarabine
o Nelarabine T cell ALL
o Forodesine
 Overall response rates : 33% to 60%
 Overall survival rate : 28%
o Alemtuzumab (Anti-CD 52)
o Gemtuzumab ,Ozogamicin (anti-CD33)
o Epratuzumab (anti-CD22)
o Blinatumomab(new class of drug which uses T cell to exert its action)
 Overall survival rate: 75%