1. Lymphoma is cancer of the lymphatic system and lymphocytes. It is divided into Hodgkin's lymphoma (HL) and non-Hodgkin's lymphoma (NHL), with NHL being more common.
2. HL is characterized by the presence of Reed-Sternberg cells and usually presents with enlarged lymph nodes. Stages range from I to IV. Treatment involves chemotherapy such as ABVD plus radiation therapy.
3. NHL encompasses a group of cancers of lymphocytes. It has a higher incidence than HL and can involve extralymphatic sites. Treatment depends on the subtype but may include chemoimmunotherapy and radiation.
2. LearningObjectives
By the end of the session, you should be
able to:
1. What is Lymphoma?
2. Types of lymphoma? HL,NHL
3. Subtypes
4. Epidemiology
5. Stages of the disease
6. Sign and symptoms
7. Diagnosis
8. Treatment protocols
9. Side effects
10. Prognosis
3.
4. Lymphoma: a cancer of blood cells (immune cells) called
lymphocytes.
Cancer of LNs /lymphatic system
May arise within single or multiple LNs
Arise from malignant transformation of lymphocytes
Cell of origin: B‐cell, T-cell
Lymphomas divided into 2 main types:
Hodgkin’s Lymphoma (HL) 15%
Non- Hodgkin’s Lymphoma (NHL) 85%
6. M > F (1.2:1)
Disease of the young (commonly)
Bimodal age of distribution
–First peak in 20s /30s
–Second peak > age 50 (less common)
Arise in single L.N or chain nodes:
HL appears to follow a predictable pattern of nodal
spread that is not seen with the NHLs
Spread to 1st anatomically contiguous nodes (orderly)
Typically from B-cell line
7. Most case curable (Cure rate 80-90%)
5-year overall survival for all stages of HL is about 85%
Unknown aetiology:
Studies suggested an increased risk of H.L in patients:
Who have been infected with the Epstein-Barr’s virus
(EBV)40%
Immunosuppressed individuals (HIV)
Genetic factors
F.H
Pathophysiology
The malignant cell in
H.L is known as the
Reed–Sternberg cell (RSC)
8.
9. WHO classification
Nodular Lymphocyte predominant NLPHL (5%)
Best prognosis. (cure 95%)
Express CD20 antigen. (Cellular marker CD 20 +ve)
More indolent in nature (Slow growing)
Classical HL (95%)
1. Nodular Sclerosis –good prognosis (most common type,
2/3 cases)
2. Mixed Cellularity -2nd most common type (15-30%)
3. Lymhocyte depleted (worst prognosis)- common HIV+
4. Lymphocyte rich HL -uncommon (good-excellent
prognosis)
10. STAGE DISCRIPTION
Stage I Involve 1- lymphoid site (I) or single extranodal
site(IE)
Stage II 2 ≥ lymphoid site either above or bellow
diaphragm (II) or localized involvement of an
contiguous extranodal organ/site(IIE)
Stage III 2 ≥ lymphoid site above and bellow diaphragm
(III) or localized involvement of an
extralymphatic organ/site(IIIE)
Stage IV Extralymphoid tissue (B.M, liver)
11.
12. Most patients present with a painless, rubbery, enlarged
lymph node (lymphadenopathy)
LN. above diaphragm:
Cervical/supraclavicular, mediastinal, axillary L.Ns
LN. below diaphragm:
Mesenteric LNs, inguinal LNs.
L.Ns pain after alcohol
Asymptomatic
B-symptoms:
Fever (>38 C)
Excessive sweeting (night)
Loss of weight (>10% within 6 month)
13. 25% of patients present with the 3 B symptoms
Some pts. Present with B-symptoms before they discover
any LNs enlargement.
B-symptoms incidence increase in advance disease (50%)
B symptoms associated with poorer prognosis
Other symptoms:
Cough, SOB, itching (25%), flushing in face, fatigue,
weakness, pruritus.
Each stage is then divided into 2 categories A & B
A: Absence of B symptoms
B: Presence of B symptoms
15. Prognosis:
Patients with early-stage disease (stages I to II) have a
90% to 95% cure rate
Those with advanced disease (stages III to IV) have only a
60% to 80% cure rate
Patients with Hodgkin lymphoma can be categorized into
4 prognostic groups:
1. Early favorable disease.
2. Early unfavorable disease.
3. Advanced favorable disease.
4. Advanced unfavorable disease.
Unfavorable factors in early stage:
Large mediastinal mass (bulky), high ESR ≥50,
extranodal disease, or ≥3 nodal sites, B-symptoms.
Stage I & II
16. Unfavorable factors in advanced stage
International Prognostic Score (IPS) for Advanced HL
Age ≥ 45
Gender Male
Serum Albumin <40g/dl
Haemoglobin <10.5g/dl
Stage 4
WBC ≥15,000 cells/mm3
(≥15x109/l)
Lymphocytes
(Lymphocytopenia)
<600 cells/mm3
(<0.6x109/l)
18. Advanced-stage patients ≤ 3 poor prognostic factors
are considered to have favorable disease
Advanced-stage patients with ≥ 4 poor prognostic
factors are considered to have unfavorable disease
Therapy response:
Complete remission (90% of pts. will achieve it)
Partial remission
Resistance disease/ 5-10% refractory to initial regimen
Relapsed disease after complete/partial remission
(relapse rate can vary from 5% for early-stage disease
to 35% for advanced disease)
20. Early disease
(Stage I & IIA)
Chemotherapy (2-4 cycles) +
radiotherapy
Early disease
(unfavourable)
Chemotherapy (4-6 cycles) +
radiotherapy
Advanced disease
Stage (III & IV) (IIB –
IV).
Chemotherapy(6-8 cycles) ±
radiotherapy (residual area, bulky)
Refractory/resistance
disease
Salvage chemotherapy (Treatment
given after cancer not responded to
other treatments) (MOPP/ABVD) or
Stanford V or BEACOPP
Relapsed disease Salvage chemotherapy or high dose
chemotherapy with Stem cell support
23. ABVD is the preferred treatment compared with
MOPP
MOPP vs. ABVD: ABVD has been shown to have an
improved OS & lower risk of both short- and long-term
toxicities (myelosuppression, infertility, & 2ndry leukemia)
ABVD standard treatment in early disease
Stanford V regimen is acceptable option
Safety precautions with ABVD:
Cardiac function EF (Adiamycin)
Pulmonary function test (bleomycin)
Patients receiving ABVD are at high risk for
neutropenia (Dacarbazine & vinblastine) increased
risk of infections.
Stage IIB (large mediastinal/extranodal) can treated as
advanced disease (some guidelines).
24. Advanced disease treatment:
ABVD (still treatment of choice).
Stanford-V
MOPP
ABVD was less toxic (leukemia, sterility,
myelosuppression) & provided similar/better
outcomes than MOPP it eventually replaced MOPP
as the standard regimen for advanced-stage HL.
More aggressive regimen: BEACOPP
Hybride-regimen MOPP/ABV (was superior to MOPP
but not ABVD)
BEACOPP superior to ABVD in high risk pts. (however,
more neutropenia, severe infection).
BEACOPP not encouraged to be given to elderly.
25. Escalated-dose BEACOPP for unfavourable disease, for
relapsed disease.
Escalated BEACOPP higher risk of neutropenia (37%vs.19%)
and leukaemia as compared to normal BEACOPP dose.
Patients who do not achieve a complete remission with the
initial regimen are considered to have primary refractory
disease Salvage chemotherapy or high dose
chemotherapy + autologous HSCT (hematopoietic stem cell
transplantation)
Patients who have an early relapse (<1 year) generally
respond poorly to standard-dose salvage chemotherapy
(high dose chemotherapy + HSCT) or salvage
Late relapse (>1-year) same regimen, different regimen,
high dose chemotherapy+ HSCT
If relapse after HSCT Limited treatment Options
26. ABVD (repeated every 28 days)
Doxorubicin
(adriamycin)
25mg/m2 IV Days 1 + 15
Bleomycin 10mg/m2 IV Days 1 + 15
Vinblastine 6mg/m2 IV Days 1 + 15
Dacarbazine 375mg/m2 IV Days 1 + 15
27. BEACOPP (Recycle: day 22.)
Bleomycin 10 mg/m2 IV Day 8
Etoposide 100mg/m2 IV Days 1-3
Adriamycin 25 mg/m2 IV Days 1
cyclophosphamide 650 mg/m2 IV Days 1
Vincristine (Oncovin) 2 mg/m2 IV Days 8
Procarbazine 100mg/m2 oral Days 1-7
Prednisolone 40mg/m2 Oral Days 1-14
28. Escalated BEACOPP: (Recycle day 22)
Bleomycin 10 mg/m2 i.v. Day 8
Etoposide 200 mg/m2 i.v. Days 1–3
Adriamycin 35 mg/m2 i.v. Day 1
Cyclophosphamide 1250 mg/m2 i.v. Day 1
Oncovin 2 mg/m2, max. 2 mg i.v. Day 8
Procarbazine 100 mg/m2 p.o. Day 1–7
Prednisone 40 mg/m2 p.o. Day 1–14
Granulocyte-colony stimulating factor (G-CSF s.c. From
day 8 = Filgrastim (Neupogen®)
29. The more commonly used regimens for
relapsed/refractory HL include the platinum-based
regimens:
ESHAP (etoposide, methylprednisolone, high-
dose cytarabine, and cisplatin)
ASHAP (doxorubicin, solumedrol, high-dose
cytarabine, and cisplatin)
DHAP (cisplatin, cytarabine, and dexamethasone)
ifosfamide-containing regimen ICE (infused
ifosfamide, carboplatin, and etoposide)
30. NLPHL treatment :Nodular lymphocyte predominant:
Radiation (early stage without R.F) pts. Cannot tolerate chemo.
Or pt. choose to omit chemo., not affect survival).
Disadvantage of radiation alone high relapse rate (20-25%)
Rituximab alone (overexpress CD20) if localized
Dose: 375 mg/m2 weekly for 4 weeks
Treat with R-ABVD or R-CHOP (advance stage/standard) with
/without radiation.
Most pts. Receive chemo + radio (residual/bulky area)
Can be treated as other HL
If relapse new biopsy (exclude NHL)
Salvage
Follow –up for HL
Every 3 months for 1st year, then every 6 months until the 4 year, then
once a year after that.
TSH function (yearly at least 5-years)
31.
32. Short term S.E:
N, V, D
Loss of appetite
Hair loss (transient)
Fatigue
Neutropenia
(dacarbazine,
vinblastine)
Febrile neut.
Infections
Tumour Lysis
Syndrome (TLS)
Long term S.E
Gonadal dysfunction:
Infertility, Hypothyroidism
For men, even a single dose
of nitrogen mustard
or chlorambucil can cause sterility,
so if fertility is a major
concern, ABVD may be the best
alternative)
Cardio-toxicity (5-10 y)
Pulmonary dysfunction.
2ndry Malignancy (↑3-fold).
MOPP, high dose E,
+radiotherapy, Chemo+HSCT,
alkylating agents
34. Incidence NHL>HD
Males > females
Incidence increasing with age (occur in any age)
Commonly diagnosed at 60s (Median age of
presentation is 65-70 years)
5th most common cause of newly diagnosed cancer in
the U.S.
About 19,000 deaths each year in the U.S.
Lymphoma without of Reed‐Sternberg cell (RSC)
Extranodal involvement more common than HL
Cell of origin: B-cell-85% ; T-cell-15% (poor prognosis)
35. Proliferation of either malignant B or T lymphocytes
and their precursors
Un known aetiology
Risk increase with:
Genetics
Certain Infection:
EBV Burkitt’s lymphoma
H-pylori infection MALT lymphoma (mucosa
associated lymphoid tissue)
Immunodeficiency disorder (HIV)/ immunesuppressive
medications
Auto-immune disease: R.A, SLE
Hepatitis B,C
Occupational reason/environment: herbicide/pesticide
37. Comparison HL vs. NHL
Hodgkin’s Lymphoma Non-Hodgkin’s Lymphoma
Incidence Less than NHL More than HL
Cell of origin-
(B or T cell)
B-cells B or T cells
Type of Cell RSC No characteristic cells
Age of
Occurrence
Commonly young adults Older adults
L.N spread Contagious (orderly) Sporadic
B-symptoms Common less common (>20% of
patients)
Extranodal Less common More common
Cure Most Some (based on score and type of
lymphoma – aggressive/not)
38. 1. Indolent (low-grade)
Slow-growing
Waxing & waning symptoms
25-40% of NHL (2nd common type)
Good prognosis (median survival 10 y)/long survival
Not curable
B-cells
Common among older adults (female slight more)
B-symptoms, bulky disease, extranodal uncommon
Can transform to aggressive form /unpredictable
eg: Follicular lymphoma (70%)
39. 2. Aggressive (high-grade)
Fast-growing
60-75% of NHL
Cure in 30%-60% of patents
Short survival
B or T Cells
All ages, mostly 70s
Extranodal is common
eg: Diffuse large B-cell lymphoma (DLBCL) B-cell
neoplasm, mantle cell lymphoma, Richter syndrome.
Follicular and DLBCl lymphoma as the most common
subtypes NHL
40. Highly aggressive lymphoma
Potentially curable
Progress very rapidly
Commonly metastasize to CNS
High risk of TLS (allopurinol, IV hydration, electrolytes)
Example 1: Burkitt’s lymphoma
50% pts. < 45 years (children, young adults)
Endemic form (malaria region)
<2% (rare) most common in African
Example 2: lymphoblastic lymphoma ( ALL)
Treat as leukaemia
41. Classification Aggressive Indolent
Exemple DLBCL Follicular lymphoma
Cell types B or T cells B-cells
Presentation Rapid onset of
symptoms
Insidious onset
Natural history
(growth rate)
Rapidly growing
(fatal if untreated)
Slow growing
(treatment not always required
at time of diagnosis)
Sensitivity to
Chemotherapy
(Cure)
Potentially curable Responses seen with
chemotherapy but rarely
curable
42. Indolent
Watch- and -wait (asymptomatic patients)
Median time to need treatment 3-5 years
20% will not need treatment for 10 years
If symptomatic:
Stage I & II : Teat with radiation therapy
Chemotherapy may be useful in high risk stage II
disease (bulky, multiple sites involvement)
Single agent therapy/Rituximab
Stage III &VI:
1. Oral therapy (alkylating agent +/- Prednisone)
Prednisolone + Cyclophosphamide
43. • Prednisolone + Chrolambucil no hair loss, little
nausea, minimum myelosuppression recommended
for older pts., comorbidities.
• Complete response occur more rapidly with combination
chemotherapy
2. IV chemotherapy:
• CVP : Cyclophosphamide+ Vincristine + Prednisone
check baseline peripheral neuropathy
• CHOP: CVP+ Doxorubicine (if rapid response is more
necessary) check EF, baseline peripheral neuropathy
Note:
• Antiemetic, bowel regimen/stool softener (prevent
constipation).
• G-CSF prophylaxis for high risk patients (febrile
neutropenia).
44. 2. Immunotherapy
MoAB against CD20
Rituximab (MabThera)
Dose: 375mg/m2 weekly for 4 wks.
Increase overall response
infusion related rxn (fever, chills, rigor ( more
common), headache, fatigue during infusion.
45. Respiratory symptoms (bronchospasm), urticaria, pruritus,
angioedema, hypotension ) Occur mostly within 30
minutes - 2 hrs.
Particularly after 1st infusion (slow/interrupt infusion)
Premedication- 30 minutes before infusion:
Paracetamol & 50mg Diphenhydramine
Infusion rate may take 4-5 hr
If tolerate 1st infusion infused over 90 minutes
Hep.B testing before MabThera (patients testing positive should
receive empiric antiviral therapy during chemotherapy treatment to
prevent hepatitis reactivation. )
FDA approve CVP + Rituximab as 1st line follicular
lymphoma (R-CVP).
R-CHOP acceptable option
46. 4. Purine analogs (Fludrabine)
Don’t cause N, V, hair loss
Associated with cumulative myelosuppression infection
risk
Can be used in refractory/relapse advanced follicular
lymphoma
Can be used alone or with mitoxantrone &
dexamethasone
Impair stem cell collection not recommended for pts.
Candidate HSCT
4. Radiotherapy also can be used in relapse
5. Salvage
Multiple relapses can occur in Indolent form
Guidelines listed maintenance therapy Rituximab (every 2
months for 2 years) after 1st line therapy
47. Aggressive lymphoma
R-CHOP (6 cycles) +/- radiotherapy
The current standard for stage I & 2 3-6 cycle R-
CHOP + involved field radiation (IFR).
Stage III-IV & bulky stage II: 6-8 cycles R-CHOP
If refractory or relapse Salvage chemotherapy:
DHAP: dexamethasone, cytarabine, cisplatin
MINE: mesna, Ifosfamide, mitoxantrone, etoposide
ICE: Ifosfomide, carboplatin, etoposide
Combined with Rituximab followed by HSCT
48. Highly aggressive lymphoma,:
Regimen should include CNS prophylaxis intrathecal
methotrexate/ cytarabine.
R-CHOP may not enough intensive treatment
Best treatment:
(cyclophosphamide, vincristine, doxorubicin,
dexamethasone) or (high dose methotrexate &
cytarabine), CNS prophylaxis
49. CHOP (Recycle: day 22.)
cyclophosphamide 750mg/m2 IV Days 1
Doxorubicin 50mg/m2 IV Days 1
Vincristine 2 mg/m2 IV Days 1
Prednisone 100 mg/m2 O Days 1 -5
51. Tumour Lysis Syndrome: (TLS)
Life threatening complication of cancer therapy.
Common in lymphoma & acute leukaemia (most
frequently associate with aggressive NHL/ Burkitt and ALL).
TLS occurs when tumour cells release their contents
into the bloodstream, either spontaneously or in
response to therapy, leading to metabolic
abnormalities (electrolytes abnormalities & renal
failure).
Can happen spontaneously or within 48-72 hrs after
therapy (can 24 hr ).
1. Metabolic abnormalities ( ARF)
↑K, ↑ U.A, ↑ PO4, 2ndry ↓ Ca
U.A crystals obstruction of renal tubules
Ca-PO4 crystals precipitation
52.
53. 2. Cardiac arrhythmia ↑K, ↓ Ca: ECG changes
↑K :Can lead to peak T wave, prolong PR interval, ……)
↓ Ca : QT interval lengthen
3. Metabolic acidosis
Hyperkalaemia often first sign of this abnormality.
High risk pts should have lab monitoring: BUN, creatinine,
phosphate, uric acid, LDH, Calcium) prior therapy and 48-72
hrs after treatment. (4-6 hrs daily)
ECG monitoring
TLS Manifestations:
Hyperuricemia appears 48-72 hours after chemotherapy
Hyperkalemia appears 6-72 hours after chemotherapy
Hyperphosphatemia appears 24-48 hours after
chemotherapy
Hypocalcemia
Increased S.Cr and decreased urine output
54. Start preventative strategies 24-48 hours prior to
treatment,
Identify patients who are at risk
Strategies for management :
1. Hyper-hydration
2. Urinary alkalinisation
3. Uricosuric agent
4. Correction of electrolytes abnormalities
5. Dialysis
55. To Control UA Allopurinol (xanthine oxidase
inhibitor): 600mg/d orally for prophylaxis, 600-900
mg/d for treatment
Will NOT decrease present levels of uric acid
Rasburicase (recombinant urate oxidase Converts uric
acid to allantoin) , rapid onset of action.
For volume depletion and electrolytes disturbance :
Aggressive hydration Start 24hr before chemo
Goal Fluid Rate: ~3L/m2/day (usually NS or D5W ½ NS),
continue for up to 72 hours after completion of
chemotherapy
56. For hyperkalaemia:
i. Discontinue all K+ supplements, ACE-I, ARB,
aldosterone antagonist
ii. Loop diuretics + hydration
iii. Sodium polystyrene sulfonate (Kayexalate®)
iv. Calcium gluconate 10% 100-200mg/kg by slow IV
infusion for life-threatening arrhythmias
v. Insulin 0.1U/kg IV) and D50 (2mL/kg) IV
vi. Sodium Bicarbonate 1-2 mEq/kg IV push) can be given
to induce influx of potassium into cells. However,
sodium bicarbonate and calcium should NOT be
administered through the same line
vii. Dialysis
57. For Hyperphosphatemia
i. Aluminum hydroxide, sevelamer, calcium carbonate
(only treat if Phos ≥ 6 mg/dL)
For Hypocalcemia
i. IV calcium supplementation (only if symptomatic – ie.
Seizures, tetany)
Acute Renal Failure
i. Consider dialysis