Pharmacotherapy of lymphoma

1
 objectives
Differentiate the pathologic findings of Hodgkin lymphoma and non-
Hodgkin lymphoma.
Describe the general staging criteria for the lymphomas and how it
relates to prognosis.
Compare and contrast the treatment algorithms for early and
advanced stage disease for HL.
 Delineate the clinical course of follicular indolent and diffuse
aggressive NHL and the implications for disease classification
schemes and treatment goals.
 Outline the general treatment approach to follicular indolent and 2

diffuse aggressive NHL for localized and advanced disease

 Introduction: lymphoma
The malignant lymphomas are a clonal disorder of hematopoiesis
with the primary malignant cells consisting of lymphocytes of B-, T-,
or natural killer cell origin.
Lymphoma cells predominate in the lymph nodes; however, they can
infiltrate lymphoid and non lymphoid tissues, such as the bone
marrow, central nervous system, gastrointestinal tract, liver,
mediastinum, skin, and spleen
There are two broad classifications of lymphoma,
◦ Hodgkin lymphoma (HL) 3

◦ non-Hodgkin lymphoma (NHL)

HODGKIN LYMPHOMA

4
 Introduction: HL
A neoplastic transformation of lymphocytes particularly in
lymph nodes.
Characterized by:
1) the presence of Reed-Sternberg cells on histology
2) spreading in an orderly fashion to contagious lymph nodes
( For example, Hodgkin lymphoma that starts in the
cervical lymph nodes may spread first to the
5
supraclavicular nodes then to the axillary nodes )
Introduction: HL cont…

6
 Classification of :HL
HL is classified into disease subtypes based on the number
and morphologic appearance of RS cells and the
background cellular milieu
Nodular lymphocyte-predominant HL
Classical HL
 Nodular sclerosis HL
 Lymphocyte-rich classical HL
 Mixed cellularity HL
7
 Lymphocyte depletion HL
EPIDEMIOLOGY
Hodgkin lymphoma represents less than 1% of
all known cancers in the United States.
 It is estimated that 8,500 new cases of Hodgkin
lymphoma will be diagnosed in the United States
in 2016, and there were 1,150 deaths associated
with Hodgkin lymphoma during this same
period. 8
 etiology

 The precise cause of HL is unknown,

 certain associations have been reported

 Epstein-Barr virus has been associated with HL,

◦ its viral genome is detected in Reed-Sternberg cells in up to 40%
of cases in developed countries.

 Other viruses (cytomegalovirus, human herpes viruses, HIV, and

adenoviruses) have been associated with HL;

 however, data is conflicting.

 Other possible risk factors identified include woodworking and 9a

familial history of HL.

etiology cont…
Weakened immune system:
 inherited condition
 certain drugs used after an organ transplant
o Age:
 Hodgkin lymphoma is most common among teens and adults
aged 15 to 35 years and adults aged 55 years and older.
o Family history:
 Family members, especially brothers and sisters, of a person
with Hodgkin lymphoma or other lymphomas may have an
increased chance of developing this disease.
10
 pathophysiology
The pathophysiology of HL is defined by the presence
of the RS cell in a grouping of lymph nodes.
The RS cell is a morphologically large cell with a
multinucleated structure possessing pronounced
eosinophilic nucleoli, thought to be B- cell in origin.
 In the affected lymph nodes, the RS cells are
contained within an inflammatory background that is
believed to be essential for their survival. 11
 Pathophysiology cont…
RS cells have lost the expression of most B-cell markers.
 Common cell-surface antigens expressed by RS cells include
CD30 and CD15, but other common B-cell antigens, such as
CD20 are inconsistently expressed.
The Janus kinase-signal transduction and signaling pathway has
also been found to be active in HL.
Additionally, the overexpression of nuclear factor kappa-B a
proliferative and antiapoptotic transcription factor nuclear factor
is believed to contribute to the expansion and survival of RS cells.
12
Clinical presentation
Enlarged, painless, rubbery, non erythematous, non tender lymph nodes are
the hallmark of the disease.
May become painful after drinking alcohol
 Patients may develop ‘’B’’ symptoms which are:
◦ Drenching night sweats
◦ 10% weight loss
◦ Fever

o 25% have ''B'' symptoms

Although pruritus is common in the disease it is not one of the
‘’B’’symptoms.
Cervical, supraclavicular and axillary lymphadenopathy are the most
13

common initial signs of the disease.

 Clinical presentation cont…
Extra lymphatic sites may be involved such as:
◦ Spleen
◦ Liver
◦ Bone marrow
◦ Lung
◦ CNS
Extra lymphatic involvement is more common with
non hodgkin lymphoma.
Emergency presentation:
◦ Infections
◦ SVC obstruction ( facial edema, increased JVP and
Dyspnea) 14
 Diagnosis
An excisional lymph node biopsy is the essential first
step in diagnosis.
A biopsy is the only sure way to diagnose Hodgkin
lymphoma.
The biopsy can be:
 Excisional biopsy
 Incisional biopsy

 Fine needle aspiration usually cannot remove a large enough15

sample for the pathologist to diagnose Hodgkin lymphoma
 Diagnosis cont…
Chest x-ray
CT

 MRI
 LP for CSF cytology if any CNS signs
 A bone marrow biopsy is used when :
 B symptoms
16
 Stage3 or 4
Diagnosis cont…
CBC: anemia and high WBC
( Eosinophilia is common)
LDH

ESR

LFTs

17
staging

18
Prognostic factors

19
TREATMENT OF HL

20
 Treatment cont…

Desired Outcome
The principal goal in treating HL is
◦ to cure the patient of the primary malignancy.

Other goals during treatment include:

◦ Complete resolution of disease symptoms

◦ Incorporation of supportive care measures to optimize quality

21
of life during therapy
 Non pharmacologic Therapy

Radiation therapy is effective in the treatment of HL and has

cured patients of their disease.
patients with favorable early stage I/II disease were treated with
radiation alone.
long-term toxicities associated with this practice have precluded
this approach.
Current treatment strategies combine radiation with
chemotherapy.
This has been reported to reduce the irradiated volume and dose 22
as well as the number of cycles of chemotherapy.
Radiation therapy cont…
Historically in the treatment of HL, the radiation fields were
large and often included the lungs, liver, heart, and breast.
Today, the use of involved-field radiotherapy limits radiation
to the involved area.
Inaddition to the smaller radiation volumes, other organs
such as the breast, heart, and lungs have reduced exposure.
Treatment with radiotherapy produces significant toxicity of
acute and delayed onset.
Acute effects of irradiation include
◦ nausea, vomiting
◦ anorexia, xerostomia, pharyngitis, 23

◦ dry cough, fatigue, diarrhea, and rash.

Radiation therapy cont…
Delayed effects from radiotherapy are.
◦ Pneumonitis
◦ pericarditis

◦ hypothyroidism

◦ infertility (with pelvic field irradiation)

◦ coronary artery disease

◦ deformities in bone and muscle growth in children

◦ herpes zoster reactivation

◦ increased risk for new cancers of the breast, lung, and stomach, as 24

well as melanoma and new NHL, depending on the radiation field.

 Pharmacologic Therapy

Early Stage Disease

Initial treatment of HL includes combination chemotherapy,
these regimens are effective and have acceptable long-term
toxicities.
Combined modality therapy of two to four cycles ABVD
(doxorubicin, bleomycin, vinblastine, and dacarbazine) plus 20
to 30 Gy (Gray, the absorbed radiation dose) of IFRT or two
cycles Stanford V chemotherapy plus 30 Gy of IRFT is the
preferred treatment of patients with favorable stage I/II HL. 25
 Early Stage Disease cont…

Patients with favorable disease have:

 an erythrocyte sedimentation rate less than 50 mm/hour, no extralymphatic lesions,
and one or two lymph nodes involved.

Restaging should occur after a minimum of two cycles of

chemotherapy.
IFRT should be initiated within 3 weeks for patients who
achieve a complete response or a partial response .
After completion of IFRT, no further treatment is necessary
for patients with a CR, further restaging is required for 26

patients with PR to therapy.

Early Stage Disease cont…

ABVD or Stanford V followed by IFRT is recommended for

patients with unfavorable, bulky disease.
Four cycles of ABVD are given before restaging.
For patients with a CR, IFRT is administered alone or in
combination with two more cycles of ABVD.
Patients with a PR will receive two additional cycles of
chemotherapy.
If there is response, patients then receive IFRT followed by
27
end of treatment assessment to determine disease response.
Early Stage Disease cont…

Patients with unfavorable, nonbulky disease receive

ABVD for two cycles followed by interim staging.
Two to four more cycles are recommended guided
by the response to chemotherapy.
The use of the Stanford V regimen should be
considered for patients with mediastinal disease,
bulky disease, B symptoms, or unfavorable
nonbulky disease 28
 Advanced Disease treatment
Patients with advanced disease can be further
classified into two groups based on IPS.
Patients with three or fewer poor prognostic factors
are considered to have favorable disease while
 patients with four or more factors have unfavorable
disease.
Patients who have at least four of the criteria may
29

warrant more aggressive treatment

 Advanced Disease treatment cont…
there are several approaches to the initial
treatment of stages III and IV Hodgkin
lymphoma.
A standard treatment of advanced-stage
favorable Hodgkin lymphoma is to administer
two cycles of ABVD chemotherapy followed by
a restaging CT. 30
 Advanced Disease treatment cont…
If the Stanford V regimen is selected for initial therapy, then the
full 12 weeks of planned chemotherapy would be given before
the restaging CT.
Escalated-dose BEACOPP for 6 cycles should be considered
for patients with unfavorable disease
No further treatment is needed for patients who achieve a
complete remission with chemotherapy alone.
Patients who achieve a partial remission should be considered
for consolidative radiation to residual sites of disease 31
Treatment cont…
 Common Treatment
Regimens in HL
MOPP—Every 28 Days
◦ Mechlorethamine 6 m/m2 IV × 1, days 1 and 8
◦ Vincristine 1.4 mg/m2 IV × 1, days 1 and 8
◦ Procarbazine 100 mg/day po, days 1–14
◦ Prednisone 40 mg/day po, days 1–14
ABVD—Every 28 Days
◦ Doxorubicin 25 mg/m2 IV × 1, days 1 and 15
◦ Bleomycin 10 units IV × 1, days 1 and 15
◦ Vinblastine 6 mg/m2 × 1, days 1 and 15 32

◦ Dacarbazine 375 mg/m2 IV × 1, days 1 and 15

 Common Treatment Regimens in HL cont…
Stanford V
◦ Doxorubicin 25 mg/m2 IV weeks 1, 3, 5, 7, 9, and 11
◦ Vinblastine 6 mg/m2 IV weeks 1, 3, 5, 7, 9, and 11
◦ Mechlorethamine 6 mg/m2 IV weeks 1, 5, and 9
◦ Etoposide 60 mg/m2 IV weeks 3, 7, and 11
◦ Vincristine 1.4 mg/m2 IV weeks 2, 4, 6, 8, 10, and 12
◦ Bleomycin 5 mg/m2 IV weeks 2, 4, 6, and 8
◦ Prednisone 40 mg po every other day for 12 weeks, start taper at week 10
BEACOPP (Escalated)—Every 21 Days
◦ Bleomycin 10 mg/m2 IV, day 8
◦ Etoposide 200 mg/m2 IV daily × days 1–3
◦ Doxorubicin 35 mg/m2, day 1
◦ Cyclophosphamide 1200 mg/m2 IV, day 1
◦ Vincristine 1.4 mg/m2 IV, day 8
◦ Procarbazine 100 mg/m2 po daily, days 1–7
33
◦ Prednisone 40 mg po daily, days 1–14
34
 Treatment of Refractory or Relapsed Disease

 For healthy patients, the definitive therapy after relapse is

high-dose chemotherapy with autologous stem cell
transplantation
This treatment offers a cure rate of approximately 40%
Patients who are not candidates for autologous SCT may
receive standard salvage chemotherapy, such as etoposide,
methylprednisolone, cytarabine, and cisplatin (ESHAP) or
dexamethasone, cytarabine, and cisplatin (DHAP). 35
 Treatment of Refractory or Relapsed Disease cont…

Newer regimens such as

GVD (gemcitabine, vinorelbine, and pegylated liposomal
doxorubicin),
IGEV (ifosfamide, gemcitabine, and vinorelbine) and
GCD (gemcitabine,carboplatin, and dexamethasone) have
also been effective for relapsed refractory HL
Brentuximab vedotin is a monoclonal antibody approved
36
for the treatment of relapsed or refractory HL
 OUTCOME EVALUATION
Integrated PET–computed tomography scanning is
recommended as part of the initial workup and to
evaluate for residual disease at the end of treatment

Long-term follow-up monitors patients for continued

disease remission or relapse with careful examination
of the original areas of involvement and imaging
studies including chest x-rays and CT scans to detect
recurrence.

Patients also require long term monitoring for toxicities

of their treatment 37
 OUTCOME EVALUATION cont…
Most patients treated for lymphoma with chemotherapy or
radiation notice a regression of palpable lymphadenopathy
within days.
 This necessitates implementation of tumor lysis syndrome precautions
with aggressive intravenous hydration and allopurinol.
 Rasburicase should be considered for patients with moderate to high
tumor burdens.

Most chemotherapy treatments for lymphoma have a significant

risk of infectious complications.
 Consideration must be given to supportive care with prophylactic antibiotics and 38

CSFs
 OUTCOME EVALUATION cont…
Most chemotherapy regimens discussed in this
section are highly emetogenic.
◦ Antiemetic regimens are available to control chemotherapy-induced
nausea and vomiting well for most standard-dose regimens

Identification of long-term complications of

lymphoma therapy is vital to patient follow up
 Two leading causes of death associated with lymphoma
treatment are secondary malignancies and cardiovascular 39

disease
Thank you!!!

40
Non Hodgkin lymphoma
 Introduction :NHL
 are a heterogeneous group of lymphoproliferative disorders
originating in B-lymphocytes, T-lymphocytes or natural
killer (NK) cells.
 NHL causes the accumulation of neoplastic cells in both the
lymph nodes as well as more often diffusely in
extralymphatic organs and the bloodstream.
 Absent reed-Sternberg cells.
 Introduction :NHL cont…
 Classification schemes such as the Working Formulation
categorize disease on aggressiveness into three categories:
 low grade—survival estimated in years without
treatment
 intermediate grade—survival estimated in months
without treatment,
 high grade—survival measured in days to weeks for
untreated
 Introduction :NHL cont…
The nodal presentation of NHL is divided into two
main categories:
follicular, corresponding to low-grade disease,
◦ A follicular disease pattern in the inspected lymph node is
indicative of a more indolent or low-grade progression that
has survival measured in years if left untreated.
◦ Follicular NHL is the most common indolent subtype,
comprising 22% of NHL
diffuse, corresponding to aggressive disease.
◦ a diffuse pattern of lymph node infiltration is a marker of
highly aggressive disease, resulting in death within weeks
to months if untreated.
◦ Diffuse, large B-cell lymphoma is the most common
aggressive histology, comprising 31% of NHL
Introduction :NHL cont…
 Epidemiology
Non-Hodgkin lymphoma is the fifth most common cause of
newly diagnosed cancer in the United States and accounts for
about 4% of all cancers.
An estimated 72,580 new cases will be diagnosed in 2016,
and it is estimated that 19,020 people will die from NHL
during this same period.
 Although the average age of patients at the time of diagnosis
is about 67 years, NHL can occur at any age.
The incidence rate generally increases with age, and is higher
in men than in women and in whites than in blacks.5
etiology
The etiology of certain aggressive NHL subtypes is
related to specific endemic geographic factors.
 Follicular or low-grade lymphoma is more common in the
US and Europe and is relatively uncommon in the Far
East, Middle East, or Africa.
Environmental factors
◦ occupations such as
 wood and forestry workers,
 butchers, exterminators, grain millers,
 machinists, mechanics, painters, printers, and industrial
workers have a higher prevalence of disease.
◦ Industrial chemicals such as
 pesticides, herbicides, organic chemicals (eg, benzene)
 solvents, and wood preservatives
 Etiology cont…
INFECTIONS:
◦ Human immunodeficiency virus
◦ Epstein-Barr virus : linked to Burkitt lymphoma.
◦ Helicobacter pylori: Extranodal tissues generating
lymphoma include Mucosa associated lymphoid tissue
◦ Human T-cell leukemia/lymphoma virus( HTLV-1)
◦ Hepatitis C virus
Age:
 Most people with non-Hodgkin lymphoma are older than
60

 high intake of meats and dietary fats.

 PATHOPHYSIOLOGY

The pathophysiology of NHL is governed

by numerous environmental and genetic
events culminating with a monoclonal
population of malignant lymphocytes.
B cells represent the cells of origin in
excess of 90% of cases
 PATHOPHYSIOLOGY
Evolving data are correlating chromosomal mutations with specific
disease subtypes.
Cytogenetic abnormalities involving translocations of antigen
receptor genes are prevalent in NHL.
These include T-cell receptor genes in T-cell lymphomas and
immunoglobulin genes in B-cell lymphomas.
The principal defect appears to be an error in the assembly of the
regulatory gene segment of an antigen receptor gene, resulting in
inappropriate binding to an oncogene.
This results in dysregulation of cell growth and proliferation,
leading to the malignant clone of lymphocytes
 Clinical Presentation: NHL
 Patients with NHL present with a wide variety of
symptoms, depending on the site of involvement and
whether tumor involvement is nodal or extranodal.
 Symptoms
 About 40% of patients present with fever, night sweats,
and weight loss (ie, B symptoms).
 Fatigue, malaise, and pruritus.
 Signs
◦ More than two-thirds of patients present with peripheral
lymphadenopathy.
◦ CNS involvement is more common with NHL.
 HIV positive patients often have CNS involvement
 diagnosis
physical examination
biopsy (preferably an excisional biopsy) of the enlarged node
 complete blood count
complete metabolic panel to assess renal and hepatic function
 lactate dehydrogenase
 erythrocyte sedimentation rate
 will be helpful in treatment planning and aid in prognosis.
Computed tomography
Pregnancy test and HIV status should be assessed.
STAGING
 Grades

 NHL divided into Low or high grade

 A high grade lymphoma has cells which look quite different
from normal cells.
 They tend to grow fast (aggressive).
 usually look follicular
 Incurable.
 Wider dissemination at presentation.
 Low grade lymphomas have cells which look much like
normal cells and multiply slowly(indolent).
 usually look diffuse.
 Long term treatment maybe achievable.
Prognostic factors
TREATMENT OF NHL
 TREATMENT OF NHL cont…
 Treatment of NHL depends primarily

◦ on histologic subtype (follicular low grade versus diffuse

aggressive)

◦ staging (local stage I/II versus advanced stage III/IV) to

guide treatment with
 observation
 chemotherapy
 radiation
 chemotherapy and radiation
TREATMENT OF NHL cont…
Desired Outcome
 The treatment goals for low-grade NHL include:
◦ Observation of the disease until the patient exhibits obvious
progression that limits functional capacity or is life threatening

◦ Treatment that induces remission with manageable

toxicity

◦ Judicious selection of treatment options to avoid long-

term Toxicity

◦ Prevention of infectious complications

 The intent of treatment for patients with aggressive
histologies is
 cure of the malignancy
For patients with low-grade follicular NHL, deferring initiation
of therapy until progression of disease is a standard approach.
The median survival time is 6 to 10 years.
Some patients may be asymptomatic for several years after
initial diagnosis, making observation a reasonable approach.
Radiation therapy has a limited role in NHL relative to HL.
NHL is more often a systemic disease, and radiation typically
has been reserved for consolidation after chemotherapy in
patients presenting with a large extranodal mass.
However, IFRT without systemic therapy is a treatment option
for patients with stage I/II follicular lymphoma.
For early-stage diffuse, aggressive NHL, combined-modality
therapy was tested versus a longer course of chemotherapy.
Overall survival favored the CHOP–radiation arm for 5 years
(82% vs 72%).
Nonpharmacologic Therapy
For patients with low-grade follicular NHL, deferring initiation
of therapy until progression of disease is a standard approach.
The median survival time is 6 to 10 years.
Some patients may be asymptomatic for several years after
initial diagnosis, making observation a reasonable approach.
Radiation therapy has a limited role in NHL relative to HL.
NHL is more often a systemic disease, and radiation typically
has been reserved for consolidation after chemotherapy in
patients presenting with a large extranodal mass.
However, IFRT without systemic therapy is a treatment option
for patients with stage I/II follicular lymphoma.
For early-stage diffuse, aggressive NHL, combined-modality
therapy was tested versus a longer course of chemotherapy.
Overall survival favored the CHOP–radiation arm for 5 years
(82% vs 72%).
Pharmacologic Therapy

 Follicular Low-Grade NHL

 The management of low-grade lymphomas is an area of controversy,

especially in patients presenting with early stage disease

 Typical indications for treatment include

 Cytopenias
 recurrent infections
 threatened end-organ function
 disease progression over at least 6 months
 patient preference.
 In these patients, chemotherapy such as fludarabine or bendamustine is

typically offered initially.

Pharmacologic Therapy

In patients in whom a more rapid response is

desired, multiagent chemotherapy such as CVP
(cyclophosphamide, vincristine, and prednisone)
or CHOP may be used
 Treatment
 Diffuse, Aggressive NHL
 The mainstay of therapy for diffuse, aggressive NHL has
been anthracycline-based combination chemotherapy,
generally consisting of four or more drugs.
 Therapy options for intermediate- and high-grade NHL
generally are segregated between localized (stage I/II) and
advanced (stage III/IV) disease.
 Combined-modality therapy with an abbreviated course of
CHOP and local radiation is considered a standard of care for
stage I/II disease.
 Treatment Diffuse, Aggressive NHL

 The standard therapy for disseminated disease has been

CHOP
 Rituximab is also routinely used to treat diffuse, aggressive
NHL.
 Another study randomized patients 60 to 80 years of age with
newly diagnosed disease to either CHOP for eight cycles or
CHOP plus rituximab for eight cycles.
 Two-year follow up showed rituximab improved CR (76%
vs 63%) and median event-free survival (57% vs 38%) and
long-term follow-up confirmed benefit was with an increase
in 10-year survival (43% vs 27.6%).
 Similar findings have been reported in younger patients,
making CHOP plus rituximab first-line therapy for advanced
stage diffuse, aggressive NHL
 Treatment Diffuse, Aggressive NHL

 There are histologic subtypes of diffuse, aggressive NHL

that respond less well to treatment with conventional
regimens such as CHOP.
 Burkitt lymphoma, lymphoblastic lymphoma, mantle cell
lymphoma, and primary CNS lymphoma are examples of
disease that benefit from more intensive therapy.

Regimens such as hyper-CVAD, which alternate cycles of

hyperfractionated cyclophosphamide, doxorubicin,
vincristine, and dexamethasone with high-dose cytarabine
and methotrexate, may be substituted for CHOP
Patients with CNS NHL have disease that is poorly
responsive to therapy
 because of inadequate penetration of standard doses of chemotherapy
across the blood–brain barrier.

High-dose methotrexate, ranging from 2500 to 8000 mg/m2

is a mainstay of therapy.
Treatment may also include intrathecal chemotherapy.
Drugs that are commonly instilled intrathecally include
 methotrexate

 cytarabine (conventional formulation and liposomal products),

 corticosteroids
 The recent appreciation of H. pylori colonization and
MALT has spurred the more aggressive treatment of this
organism with antibiotics.
 In patients with localized disease, aggressive, combination
therapy for H. pylori has been shown to induce MALT
remission.
 Patients with advanced disease may require
 combination chemotherapy, such as CHOP
 OUTCOME EVALUATION
 Integrated PET–computed tomography scanning is
recommended as part of the initial workup and to evaluate
for residual disease at the end of treatment

 Long-term follow-up monitors patients for continued

disease remission or relapse with careful examination of
the original areas of involvement and imaging studies
including chest x-rays and CT scans to detect recurrence.

 Patients also require long term monitoring for toxicities of

their treatment