Drugs Used for Leukocyte Stimulation and Treatment (Stewart)

Treatment of Leukocyte, Lymphocyte and Platelet Disorders

Neutropenia
Thrombocytopenia
Leukemia
Lymphoma
Hematopoietic Growth Factors
Glycoproteins that regulate proliferation and differentiation of
hematopoietic progenitor cells in the bone marrow
Include:
o Erythropoietin
o Granulocyte colony stimulating factor (G-CSF)
o Granulocyte macrophage colony stimulating factor (GMCSF)
o Interleukins (IL-1 through IL-18)
o Thrombopoietin
Mechanism of action
o Many activate type I cytokine receptors
o Regulate gene expression via the JAK/STAT pathway
o Also stimulate activation of PI3K and Ras/MAPK pathways
Neutropenia
Caused by:
o Bone marrow disorders
o Peripheral disorders
o Infection of gram
positive or gram
negative bacteria or
fungi
o Drugs
Treatment:
o Discontinue causative
drugs
o Infections are treated
with broad spectrum
antibiotics or antifungal
agents
Antibiotics:
Quinolones

(levofloxacin)
Cephalosporins (cefepime)
Antifungal agents

Drugs Used for Leukocyte Stimulation and Treatment (Stewart)

Voriconazole
o Administration of myeloid growth factors (GM-CSF, GCSF)
GM-CSF/G-SCF increase neutrophils decrease
infections

G-CSF
Preparations
o Filgrastim (recombinant human G-CSF)
Prepared in bacterial expression system
Half life 2-7 hrs
o Pegfilgrastim (neulasta) (only have to give once)
Polyetehylene glycol conjugate of filgrastim
Longer half life than filgrastim
Route of administration:
o IV or SC
Mechanism of action
o Activates G-CSF receptors
o Increase proliferation and differentiation of neutrophil
progenitors
o Increase phagocytic activity of mature neutrophils
o Increase neutrophil survival
o Mobilize hematopoietic stem cells
Clinical uses
o Neutropenia
Congenital neutropenia
Cyclic neutropenia
Chemotherapy induced neutropenia
Myelodysplasisa
Aplastic anemia
o Neutrophil recovery following steam cell transplantation
o Mobilization of PBSCs (stem cell transplantation)
G-CSF has best mobilization of PBSCs
Side effects
o Bone pain
o Splenic rupture (rare)
GM-CSF
Preparations
o Sargramostim (recombinant human GM-CSF)

Drugs Used for Leukocyte Stimulation and Treatment (Stewart)

Prepared in yeast expression system

Serum half life of 2-7 yrs
Route of administrations:
o IV or SC
Mechanism of Action/biological effects
o Stimulates proliferation and differentiation of
granulocytic, erythroid and megakaryocyte progenitors
o Stimulates phagocytic activity of mature neutrophils
o Increases neutrophil survival
o Stimulate T cell proliferation (with IL-2)
Clinical uses (same as G-CSF)
o Neutropenia
Congenital neutropenia
Cyclic neutropenia
Chemotherapy induced neutropenia
Myelodysplasisa
Aplastic anemia
o Neutrophil recovery following steam cell transplantation
o Mobilization of PBSCs (stem cell transplantation)
Doesnt work as well as G-CSF and has greater
side effects
Side effects:
o Fever
o Malaise
o Arthralgias
o Myalgia
o Capillary leak syndrome

Thrombocytopenia
Treatment:
o Platelet transfusion
Can cause adverse reaction in patients
Doesnt increase platelet count in all patients

Drugs Used for Leukocyte Stimulation and Treatment (Stewart)

Not the best way
o Administration of
recombinant IL-11
(oprelvekin) or
thrombopoietin receptor
agonists (romiplostim)
Better plan
o Administration of IL-11 or
thrombopoietin receptor
agonist (romiplostim)
Promote production of
platelets
Recombinant human
thrombopoietin
induces formation of
autoantibodies
IL-11
Endogenous form made in bone marrow by fibroblast and
stromal cells
Recombinant form is Oprelvekin
o Produced in E.coli expression system
o Half life is 7-8hrs (subcutaneously)
Route of administration: SC
Mechanism of Action
o Activates IL-11 receptor
o Stimulates growth of megakaryocytic progenitors
o Increases circulating platelets
Clinical Uses
o Prevent thrombocytopenia in patients receiving
chemotherapy (nonmyeloid cancers)
Side effects:
o Fatigue
o Headache
o Dizziness
o Cardiovascular effects (anemia, dyspnea, transient atrial
arrhythmias)
IL-2
Endogenous IL-2 made by activated T- cells
Recombinant form known as aldesleukin
Mechanism of action
o Induces T cell proliferation and differentiation
o Increases NK cells
Clinical uses

Drugs Used for Leukocyte Stimulation and Treatment (Stewart)

o Renal cell cancer
o Metastatic melanoma
Leukemia (Acute and
Chronic)
ALL treatment Strategy
Induction therapy
o Vincristine
o Prednisone
o L-asparaginase with
or without an
anthracycline
o Supportive care
blood and platelet
transfusions,
antibiotics,
filgrastim

Consolidation/intensification therapy
o Cyclophosphamide
o Cytararbine
o 6-mercaptopurine
Maintenance therapy
o methotrexate
o 6-mercaptopurine
CNS prophylaxis (intrathecal methotrexate)
AML Treatment Strategy
Induction Chemotherapy
o Cytarabine + an anthracyclin (idarubicin or daunorubicin)
Supportive care- platelet transfusions, filgrastim,
and antibiotics
Intrathecal chemotherapy (cytarabine or
methotrexate)
Consolidation chemotrheapy
o Once remission achieved
o Involving cytabarine
Allogenic bone marrow transplantation
o <55 years old
CML Treatment Strategy

Drugs Used for Leukocyte Stimulation and Treatment (Stewart)

First line therapy include tyrosine kinase inhibitors that target

Bcr-Abl:
Imatinib (targets Bcr-Abl, c-kit and PDGFR)
Dasatinib (targets Bcr-Abl, Src, c-kit and PDGFR- )
Nilotinib (targets Bcr-Abl, c-kit and PDGFR- )
o Route of administration oral
o Side effects:
Nausea
Vomiting
Fluid retention
Diarrhea
Myalgias
Congestive heart failure
Additional CML treatment options include:
o Interferon
o Busulfan
o Hydroxurea
o Cytarabine (high dose)
o Vincristine and prednisone -/+ anthrracycline
Choice of therapy depends on disease pahse
Only consistently curative option is allogenic bone marrow
transplantation or stem cell transplantation

CLL Treatment Strategy (Stages I-IV)

Watchful waiting (asymptomatic)
Alkylating agents
o Chlorambucil (in combination with prednisone)
o Cyclophosphamide (in COP or CHOP)
o Bendamustine
Purine analogs
o Fludarabine
Monoclonal antibody targeted therapies
o Rituximab
Mechanism of action
Binds to CD20 on malignant B lymphocytes
Stimulates cell death
Route of administration intravenous
Side effects hypersensitivity, myelosuppresion
Can be combined with other drugs (CHOP,
fludarabine)
o Alemtuzumab
Humanized mAb that targets CD52

Drugs Used for Leukocyte Stimulation and Treatment (Stewart)

Treatment fro B cell CLL that is refractory to

alkylating agents or fludarabine
Mechanism of action- antibody driven cell
lysis/death

Treatment Strategy for Hodgkins Lymphoma

Stage I and IIa disease
o Combination chemotherapy (ABVD)+
involved filed radiation therapy
Stage III and IV disease
o 4 cycles of ABVD or 12 weeks of Stanford V
o Radiation therapy may follow Stanford V

Treatment Strategy for Recurrent Hodgkins Lymphoma

Recurrence following radiation chemotherapy

Recurrence following chemotherapy stem cell transplant

Treatment Strategy for Indolent Non- Hodgkins Lymphoma

(Follicular)
Disease Stage
Indolent Stage I and Contiguous
Stage II

Treatment Options
1. Radiation Therapy
2. Rituximab (-/+ chemotherapy)
3. Watchful waiting

Drugs Used for Leukocyte Stimulation and Treatment (Stewart)

Indolent, Noncontinguous Stage
II/III/IV

1. Watchful waiting
2. Rituximab
3. Purine Nucleoside analogs
(Fludarabine)
4. Alkylating Agents (-/+
prenisone)
5. Combination chemotherapy
6. Ibritumomab tiuxetan and
tositumomab
1. Chemotherpay
2. Rituximab
3. Lenalidomide
4. Ibritumomab tiuxetan and
tositumomab
5. Palliative radiation therapy

Indolent Recurrent

Ibritumomab tiuxetan
Mouse mAB against CD20
Labeled with Yttrium-90
Tositumomab
Mouse mAb against CD20
Labeled with iodine 131

Treatment Strategy for Aggressive Non-Hodgkins Lymphoma

(Diffuse)
Disease Stage

Treatment Options

Aggressive Stage I and Contiguous

Stage II
Aggressive Noncontinguous Stage
II/III/IV

R-CHOP (-/+ radiation therapy)

Aggressive Recurrent

Types of Stem Cell Transplantation

1. R-CHOP
2. Combination chemotherapy
(CHOP and others)
1. bone marrow or stem cell
transplantation
2. Retreatment with rituximab,
ibritumomab tiuxetan and
tositumomab
3. palliative radiation therapy

Drugs Used for Leukocyte Stimulation and Treatment (Stewart)

Autologous
o hematopoietic stem cells from patients peripheral blood
o mobilized using G-CSF (filgrastim)
o isolated by centrifugation and cryopreserved
Allogenic
o Hematopoietic stem cells from appropriate donor
o Donor must be matched with patient at HLA locus

Immunosuppressive Drugs
Used to reduce
occurrence or impact of

exaggerated/inappropriate immune responses

Common clinical uses are for solid organ and bone marrow
transplantation and autoimmune disorders

Immunosuppression in patients with aplastic anemia

Immunosuppressive drugs reduce T cell driven immune
response
Used in patients that cannot undergo bone or blood marrow
transplant
Option1 anti-thymocyte globulin +cyclosporine
o Cyclosporine inhibits calcineurin
reduces the production of IL-2 and IFN by
activated cells
Option 2- cyclophosphamide
o Alkylating agent that destroys proliferating lymphoid cells

Drugs Used for Leukocyte Stimulation and Treatment (Stewart)

Drugs Used for Leukocyte Stimulation and Treatment (Stewart)