Glomerular Filtration rate and its determinants.pptx
acute and chronic Leukemia therapy by irfan hamid
1. Presented to:
Prof. Dr. Khalid Hussain Janbaz
Dean, Faculty of Pharmacy
B. Z. University Multan.
Presented by:
Irfan Hamid
Ph.D. Pharmacology
2nd Semester
Roll No. 05-PhDL-12
Acute &
Chronic
Leukemia
Therapy
2.
3. Leukemia
Group of malignant disorders of the
hematopoietic tissues characteristically
associated with increased numbers of white cells
in the bone marrow and / or peripheral blood
4. Development of Leukemia in the
Bloodstream
Stage 1- Normal
Stage 2- Symptoms
Stage 3- Diagnosis
Legend
White Cell
Red Cell
Platelet
Blast
Germ
Stage 5a- Anemia
Stage 4- Worsening
Stage 5b- Infection
7. Myeloid vs Lymphoid
Any
disease that arises from the myeloid
elements (white cell, red cell, platelets) is a
myeloid disease
….. AML, CML
Any
disease that arises from the lymphoid
elements is a lymphoid disease
….. ALL, CLL
8. Acute vs. chronic leukemia
Leukemias are classified
Lymphoid cells
ALL - lymphoblasts
CLL – mature appearing lymphocytes
Myeloid cells
AML – myeloblasts
CML – mature appearing neutrophils
On a CBC, if you see:
Predominance of blasts
according to cell of origin:
in blood
consider an acute leukemia
Leukocytosis with mature lymphocytosis
consider CLL
Leukocytosis with mature neutrophilia
consider CML
9. Chronic and Acute
Chronic Leukemia:
accumulation of mature granulocytes or lymphocytes
longer
Progress
Not
clinical course (several to many years)
slowly (runs a slow course)
immediately fatal.
Acute Leukemia:
excess
short
clinical course (weeks to months)
Progress
Life
myeloblasts or lymphoblasts
rapidly (runs a fast course)
expectancy short without treatment.
10. Acute leukemias
Definition: Malignancies of immature
hematopoietic cells.
(> 20% blast cells in the bone marrow)
Types:
Acute Myeloid Leukemia
(AML)
Acute Lymphoblastic leukemia
Groups:
Childhood (< 15)
Adult
(> 15)
(ALL)
> 80% ALL
> 80% AML
11. Chronic Myeloid Leukaemia
The
myeloproliferative diseases (MPDs)
are clonal stem cell disorders
characterised by leukocytosis,
thrombocytosis, erythrocytosis,
splenomegaly, and bone marrow
hypercelularity
12. 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
Incidence in adults : 20% of acute
leukemias
18. Differentiation between AML
and ALL
Age
Blood
AML - anemia, neutropenia, thrombocytopenia, myeloblasts and
promyelocytes
ALL - anemia, neutropenia, thrombocytopenia, lymphoblasts and
prolymphocytes
Morphology
AML - mainly in adults
ALL - common in children
AML - blasts are medium to large with more cytoplasm which may
contain granules, Auer rods, fine nuclear chromatin, distinct
nucleoli
ALL - blasts are small to medium with scarce cytoplasm, no
granules, fine nuclear chromatin and indistinct nucleoli
Cytochemistry
AML - positive peroxidase and Sudan black, negative TdT
ALL - negative peroxidase and Sudan black, positive TdT
22. AML:
FAB classification
French
American British classification
M0-M7
based on morphology, and
special cytochemical studies
Historically,
distinguishing AML M0 from
ALL was a major clinical problem
23. AML
FAB classification
M0,M1,
M2: Myeloblasts with no, little or
some granulocytic maturation
M3: Promyelocytic leukemia
M4: Myelomonocytic or eosinophilic
M5: Monocytic
M6: Erythroleukemia
M7: Megakaryoblastic
Not all that useful except for M3
24. AML – M1
Note
the myeloblasts and the auer rod:
25. AML – M2
Note
myeloblasts and hypogranulated
PMNs:
30. Morphologic subtypes of
acute lymphoblastic
leukemias (FAB
classification
Subtype
L1
L2
L3
Morphology
Occurrence (%)
Small round blasts
75
clumped chromatin
Pleomorphic larger blasts
20
clefted nuclei, fine chromatin
Large blasts, nucleoli,
05
vacuolated cytoplasm
31. FAB Classification
L1
Small, uniform lymphoblasts
Scant cytoplasm, indistinct nucleoli,
occassional clefting of nucleus, chromatin is
clumped
Affects primarily children
32. FAB Classification: L2
L2
Large, pleomorphic lymphoblasts
Abundant cytoplasm, predominant nucleoli,
nuclear clefting and indentation
Affects adults
33. FAB Classification: L3
L3: Burkitt’s type
Uniform population of large lymphoblasts with
deeply basophilic cytoplasm, vacuoles,
round to oval nuclei without indentation
Affects adults and children
36. CHRONIC LYMPHOCYTIC
LEUKAEMIA (CLL)
Neoplastic proliferations of mature
lymphocytes.
Distinguished from ALL by
A.
B.
C.
D.
Morphology of cells.
Degree of maturation of cells.
Immunologically immature blasts in
ALL.
CLL affects mainly elderly.
37. SYMPTOMS of CLL
Weakness, fatigue, vague sense of
being ill
Night sweat
Infections esp pneumonia
38. TREATMENT OF CLL
Observation
Chemotherapy.
Oral chlorambucil
Fludarabine,
Immunotherapy
Anti-CD 20 (rituximab),
Anti-CD 52 (Alemtuzumab)
Indications for starting chemotherapy
a. Progressive Symptoms
b. Progressive Anemia or Thrombocytopenia
c. Bulky LN, large spleen
d. Recurrent Infections
39. CHRONIC MYELOID
LEUKEMIA
CML is a clonal stem cell disorder
characterised by increased proliferation
of myeloid elements at all stages of
differentiation.
Incidence increases with age, M > F.
40. CML is characterised by 3
distinct phases
a)
Chronic Phase:Proliferation of
myeloid cells, which show a full
range of maturation.
b)
Accelerated Phase decrease in
myeloid differentiation occurs.
c)
Blast crisis (acute leukemia)
42. CYTOGENETICS OF CML
Philadelphia (Ph) chromosome is an
acquired cytogenetic abnormality in all
leukaemia cells in CML
Reciprocal translocation of
chromosomal material between
chromosome 22 and chromosome 9.
t(9;22)
45. ACUTE LYMPHOBLASTIC
LEUKEMIA ( ALL)
DOSE
ROUTE REGIMEN
Induction ( 4 weeks)
Vincristin
Prednisolone
L- Asparaginase
Daunorubicin
1.5 mg/m2
40mg/m2
6000u/m2
45mg/m2
I.V
Oral
I.M
I.V
Weekly for 4 weeks
Daily for 4 weeks
3xWeekly for 3
weeks
Daily for 2 days
Intensification(1 week)
Vincristin
Daunorubicin
Prednisolone
Etoposide
Cytarabine
Thioguanine
1.5mg/m2
45mg/m2
40mg/m2
100mg/m2
100mg/m2
80mg/m2
I.V
I.V
Oral
I.V
I.V
Oral
1 dose
Daily for 2 days
Daily for 5 days
Daily for 5 days
2x daily for 5 days
Daily for 5 days
CNS Prophylaxis( 3 weeks)
Cranial irradiation
Methotrexate
24 Gy
I.T weekly for 3 weeks
Oral
Oral
Oral
I.V
Weekly
Daily
5days/ Month
Monthly
Maintenance Therapy ( 2
years)
Methotrexate
6-Mercaptopurine
Prednisolone
vincristine
20mg/m2
75mg/m2
40mg/m2
1.5mg/m2
46. (Treatment of acute
leukemias)Induction
Obtained by using high doses of chemotherapy
1 Severe bone marrow hypoplasia
2 Allowing regrowth of normal residual stem cells to
regrow faster than leukemic cells.
Remission
Normal neutrophil count
Normal platelet count
Normal hemoglobin level
Remission defined as < 5% blast in the bone marrow
47. (Treatment of acute leukemia)
Consolidation
•
Different or same drugs to those used during
induction
•
Higher doses of chemotherapy
•
Advantage: Delays relapse and
survival
improved
48. (Treatment of acute leukemias)
Maintenance
•
Smaller doses for longer period
•
Produce low neutrophil counts & platelet
counts
•
Objective is to eradicate progressively any
remaining leukemic cells.
49. (Treatment of acute leukemias)
Supportive Care
Vascular access (Central line)
Prevention of vomiting
Blood products (Anemia, ↓Plat)
Prevention & treatment of infections
(antibiotics)
Management of metabolic
complications
50. ALL vs AML
ALL
AML
Induction
Induction
Consolidation
Consolidation
Maintenance
No maintenance
CNS prophylaxis all
CNS – Selected
group only
patients
52. DRUGS USED TO TREAT ACUTE
MYELOBLASTIC LEUKEMIA (
AML)
TOPOISOMERASE
INHIBITORS
ETOPOSIDE
TOPOTECAN
DNA DAMAGING
( ALKYLATING AGENT)
o
CYCLOPHOSPHAMIDE
CARBOPLATIN
TEMOZOLOMIDE
CELL MATURING AGENT
ALL-TRANS RETIONIC ACID
(ATRA)
ARSENIC TRIOXIDE
o
HYPOMETHYLATING
AGENT
AZACITIDINE
DECITABINE
53. Treatment of Chronic
Lymphoblastic Leukemia (CLL)
Alkylating
agents :
Chlorambucil intermittently (10 mg/m2 x 7
days, monthly ) or continously ( 5 -10 mg /
day )
Combinations :
COP : Cyclophosphamide, Oncovin,
Prednisolone( 5 day – monthly course )
Chlorambucil + Epirubicin
CHOP : COP + Doxorubicin
54. Treatment of Chronic
Lymphoblastic Leukemia (CLL)
Corticosteroids :
Prednisolone : 30 mg / m2 for 3 weeks + 1 week tailing
off for initial treatment of pts with Stage C disease.
High – dose Methylprednisolone IV at 1 g/m2 ( 5-day
monthly course )
Nucleoside analogues :
Fludarabine ( 25 mg / m2 IV daily as 30 min infusion for
5 days every 28 days )
Fludarabine + Cyclophosphamide
Pentostatin ( 2 mg/m2/day IV for 5 days every 28
days)
Cladribine ( IV infusion over 2 hrs dose of 0.12
mg/kg/day for 5 consecutive days )
55. Nucleoside analogues
Studies
have shown FLUDARABINE
superior to Chlorambucil in CLL with
higher clinical response rates, superior
time to treatment failure, better tolerance
in pts > 65 yrs.
FLUDARABINE – Currently 1st line of
treatment in CLL
56. Monoclonal Antibodies
Alemtuzumab
( monoclonal antibody directed at
CD 52 ) :
1st line agent
For salvage in pts with fludarabine refractory
disease
Effective in CLL with p53 mutations
Very effective in clearing Bone Marrow disease
Limited activity in clearing bulky
lymphadenopathy
Has role in consolidation therapy for elimination of
minimal residual disease.
57. Monoclonal Antibodies
Anti-viral prophylaxis and prophylactic antibiotics for
Pneumocystis carnii are recommended for pts
receiving Alemtuzumab and for 2 – 4 months after
treatment
Rituximab – (monoclonal antibody specific for CD 20)
used extensively in combination with chemotherapy.
Fludarabine combined with Rituximab – shown higher
clinical remission rates than fludarabine alone .
FCR – ( Fludarabine, Cyclophosphamide, Rituximab )
– shown clinical response rates of 76% in trials.
CFAR – ( Cyclophosphamide, Fludarabine,
Alemtuzumab, Rituximab ) still under trials
58. Monoclonal Antibodies
LENALIDOMIDE
: An immunomodulatory
drug currently approved for use in
Multiple Myeloma and MDS with deletion
of Chr 5q .
Studies have shown response rates of 47 –
38 % with complete response rates of 9 %
and elimination MRD have been
reported.
59. Bone Marrow Transplantation
Allogenic
bone marrow transplantation is
the only known curative therapy.
Addition
of ALEMTUZUMAB to pts receiving
hematopoetic stem cell transplantation
aids in elimination of MRD ( Minimal
Residual Disease )
60. Radiotherapy
For many decades, irradiation of spleen was primary
treatment of CLL.
Useful in pts with bulky lymph nodes compressing nerves
/ other organs & massive / painful splenomegaly.
IRRADIATION of mediastinum, extracorporeal irradiation
of blood and total body irradiation – may reduce the
peripheral blood lymphocyte counts and size of lymph
node, spleen and liver.
Total body irradiation plus cyclophosphamide &
prednisolone had higher response to those treated with
TBI alone.
61. Supportive therapy
Hypogammaglobulinemia : IV Immunoglobulins
Prednisolone - useful against autoimmune manifestations of
disease.
Rituximab alone / in combination : effective in eliminating the B
cell clone inducing autoimmune disorders, particularly
autoimmune thrombocytopenia
Leukapheresis : removal of leukemic cells reduces tumor load and
leukostasis.
Long term antibiotics
66. TREATMENT OF CML
Tyrosine kinase inhibitor (TKI) Imatinib (Glivec) is
the first line treatment
In resistent cases 2nd line TKIs (Nilotinib,
Dasatinib, Bosutinib) very useful
Allogenic bone marrow trasnsplantation can
be curative in pts resisrant to TKIs but has
significant complications & mortality
Accelerated and blast phase
Treat like AML or ALL followed by BMT
67. Bone marrow or PBSC
transplantation in leukemias
1.
2.
Types of transplant
Autologous transplant
Allogeneic Transplant
Purpose of transplant
Autologous
-To deliver a high dose of chemo to kill any
residual cancer
(lymphoma, multiple myeloma)
Allogeneic
-To eradicate residual leukemia cells
-Graft vs leukemia effect