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 (GM-

CSF) 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 Voriconazole

Drugs Used for Leukocyte Stimulation and Treatment (Stewart)

o Administration of myeloid growth factors (GM-CSF, G-CSF)

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 actiono Activates G-CSF receptors o Increase proliferation and differentiation of neutrophil

progenitorso 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) Prepared in yeast expression system Serum half life of 2-7 yrs

Route of administrations:

Drugs Used for Leukocyte Stimulation and Treatment (Stewart)

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)

Doesn’t work as well as G-CSF and has greater side effects

Side effects:o Fever o Malaise o Arthralgia’s o Myalgia o Capillary leak syndrome

Thrombocytopenia Treatment:

o Platelet transfusion Can cause adverse reaction in patients Doesn’t increase

platelet count in all patients

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

Drugs Used for Leukocyte Stimulation and Treatment (Stewart)

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 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

Drugs Used for Leukocyte Stimulation and Treatment (Stewart)

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 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- α) Nilotinib (targets Bcr-Abl, c-kit and PDGFR- β)

o Route of administration – oral o Side effects:

Nausea Vomiting Fluid retention Diarrhea Myalgias Congestive heart failure

Additional CML treatment options include:o Interferon αo Busulfan o Hydroxureao Cytarabine (high dose) o Vincristine and prednisone -/+ anthrracycline

Drugs Used for Leukocyte Stimulation and Treatment (Stewart)

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 Treatment fro B cell CLL that is refractory to

alkylating agents or fludarabine Mechanism of action- antibody driven cell

lysis/death

Treatment Strategy for Hodgkin’s 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

Drugs Used for Leukocyte Stimulation and Treatment (Stewart)

Treatment Strategy for Recurrent Hodgkin’s Lymphoma

Recurrence following radiation chemotherapy Recurrence following chemotherapy stem cell transplant

Treatment Strategy for Indolent Non- Hodgkin’s Lymphoma (Follicular)

Disease Stage Treatment Options

Indolent Stage I and Contiguous Stage II

1. Radiation Therapy2. Rituximab (-/+ chemotherapy)3. Watchful waiting

Indolent, Noncontinguous Stage II/III/IV

1. Watchful waiting2. Rituximab3. Purine Nucleoside analogs

(Fludarabine)4. Alkylating Agents (-/+

prenisone)5. Combination chemotherapy6. Ibritumomab tiuxetan and

tositumomabIndolent Recurrent 1. Chemotherpay

2. Rituximab3. Lenalidomide4. Ibritumomab tiuxetan and

tositumomab5. Palliative radiation therapy

Ibritumomab tiuxetan Mouse mAB against CD20 Labeled with Yttrium-90

Tositumomab Mouse mAb against CD20 Labeled with iodine 131

Drugs Used for Leukocyte Stimulation and Treatment (Stewart)

Treatment Strategy for Aggressive Non-Hodgkin’s Lymphoma (Diffuse)

Disease Stage Treatment Options

Aggressive Stage I and Contiguous Stage II

R-CHOP (-/+ radiation therapy)

Aggressive Noncontinguous Stage II/III/IV

1. R-CHOP2. Combination chemotherapy

(CHOP and others)Aggressive Recurrent 1. bone marrow or stem cell

transplantation2. Retreatment with rituximab,

ibritumomab tiuxetan and tositumomab

3. palliative radiation therapy

Types of Stem Cell Transplantation

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

Drugs Used for Leukocyte Stimulation and Treatment (Stewart)

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 IFNγ by

activated cells Option 2- cyclophosphamide

o Alkylating agent that destroys proliferating lymphoid cells

Drugs Used for Leukocyte Stimulation and Treatment (Stewart)