Hodgkin lymphoma presentation

Lymphoma ???

Hetrogenous group of lymphoproliferative malignancies.

It results from clonal expansion from B, T, or NKcells .

85-90% derived from B-cell.

Variable clinical presentation (asymptomatic→medical emergency).

Hodgkin Lymphoma ???

It is the most commen childhood cancer (15-19 Y).

It was named after Thomas hodgkin (1832).

Incidence Hodgkin Lymphoma

The incidence of HL varies by

Age

Sex

Race

Rare in infants. 1st peak 15- to 19-year-old age group. 2nd peak older than 50 years.



Age

Sex

Race

In adolescents is greater in females than in males.Under age 15 boys have higher incidence than girls.



Age

Sex

Race

Younger than 10 years the incidence of HL is similar among white and African American children. Older than 10 years is increased among white children (ratio of 1.4:1).


Familial HL

It has been estimated to represent 4.5 % of all cases of HL.

This familial association may include:

Shared environmental factors,

Exposure to viruses, and

Genetic including inherited immunodeficiency states.

Histology HL

WHO classify HL into classic HL & Nodular lymphocytic predominant HL

Classic NLP% 90-59 % 5-10 %

Diagnostic cell Hodgkin/Reed-Sternberg

“L & H or popcorn”

Fibrosis Commen Rare

PatternDiffuse, inter-

follicular & nodular

Diffuse

CD 15 & CD30 +ve - veCD 45 & EMA - ve + ve

Histology HL

WHO classify HL into classic HL & Nodular lymphocytic predominant HL

Histology HL

Subtypes of classic HL & Nodular lymphocytic predominant HL

NS MC LR LD NLP

% 40-60% 30% 5% <1% 10-15%

CellHRS (may be

a variant Laccunar)

R-S R-S L & H or popcorn

EBV less frequently 75% 100% rare

Sex & Age

mostlyAdult & male < 10 Y 30

Y

Rare in children

Relapsing HIV +ve

Young female

Site

Supra-diaphragmatic

Mainly mediastinal

Advanced Etra nodal

Extensive Supra,

infra, BM &bone

Indolent course Sparing

mediastinal

CD 15 & 30 +ve -ve

Factors suggesting association with HL ?

HL & EBV

Post BMT

Immunosuppression

nNucleic acids and proteins from EBV are detected in the malignant cells.

The peak incidence of HL is ≥ 4 years.

An increased incidence is observed in HIV patients.


HL & EBV

Nucleic acids and proteins from EBV are detected in HL cells:

20 to 50 % of cases of classical HL

> 50 % of mixed cellularity and lymphocyte depleted HL cases.

Less frequently with nodular sclerosis HL.

EBV infected tumour cells express a subset of EBV genes including:

Latent membrane protein 1(LMP1)

Latent membrane protein 2a (LMP2a)

EBV nuclear antigen 1 (EBNA1)


HL & EBV

Through the activation of nuclear factor kappa B (NF-kB).Up-regulation bcl-2 & MHC-I (anti apoptotic factors).

produces a tonic survival signal

Prevent apoptosis of pre-B cells that fail to express Ig molecules.

Integral membrane protein

Expression is required for the replication and maintenance of the viral genome in proliferating cell.

Biology of HL

Hodgkin/Reed-Sternberg (HRS) cells is the malignant cells of HL.

HRS cells are germinal center B cells.

Most patients with nodular sclerosis HL, have a clonal

rearrangement of the V, D, and J segments of the immunoglobulin

(Ig) heavy chain locus in the HRS.

Mechanism of tumorigensis EBV infected B-cells express LMP that

Upregulation NF-kB (transcription factor for activating lymphocytes)

Leads to excessive B-cell proliferation/protection of B-cell from proapoptotic

Increased number of B-cell

Mutation in immunoglobulin gene of B-cell

Production of Reed-sternberg cells

Mutation in negative regulators of NF-kB

Mechanism of tumorigensis 1. Activation of nuclear factor kappa B

2. Consequences of constitutive NF-kB activation

3. Interleukin-13 signaling pathway

4. NOTCH signaling pathway

- - Apoptosis+ + Proliferation

- - Apoptosis

+ + Proliferation

Mechanism of tumorigensis

5. Genomic alterations affecting HRS cell survival and immunoevasion

6. Mutations in HLA-associated genes

7. CIITA

8. Beta-2-microglobulin

Gene amplificationinvolving 9p

Loss of HLA espechially EBV -ve

Regulates MHC IIexpresion

Mutation→ loss MHC I expresion

80 to 85 % of pediatric HL patients (stage I to III) The remaining are stage IV.

Lymphadenopathy

Symptoms & signs

Mediastinal mass Systemic symptoms

S & S

Lymphadenopathy

Symptoms & signs

• Painless lymphadenopathy in most of cases (80%),

• Usually cervical, supraclavicular, axillary,

• Less often, inguinal.

• Lymph nodes feel rubbery and more firm than inflammatory adenopathy.

• Bulky lymphadenopathy→ (aggregates of lymph nodes 4 to 6 cm)

are considered in the risk-stratification for therapy.

Mediastinal mass

• At the time of presentation present in 75% of cases.

• They are more common among children >12 years of age.

• Bulky mediastinal disease {masses greater than one-third the

diameter of the intrathoracic cavity} may cause dysphagia,

dyspnea, cough, stridor, or the superior vena cava (SVC)

syndrome.

Symptoms & signs

Mediastinal mass

Symptoms & signs

Symptoms & signs

Bulky disease defintion

Lugano classification A nodal mass of 10 cm or > one-third of the transthoracic diameter at any level of thoracic vertebrae as determined by CT.

Stanford V protocolDefined as ≥5 cm, required the use of involved field irradiation following completion of chemotherapy.

Ann Arbor Staging system1. An abdominal node or nodal mass that is ≥10 cm in largest dimension as determined by CT, MRI, or ultrasound.2. A mediastinal mass which has a maximum width ≥ 1/3 of the internal transverse diameter of the thorax (at the pleural surfaces) at the level of T5/6 as determined on a posteroanterior chest radiograph.

• Obstruction of blood flow through the SVC.

• Caused by:

→Invasion or external compression of the SVC.

→Thrombosis of blood within the SVC.

• Symptoms of SVC syndrome within weeks because rapid

tumor growth.

Symptoms & signs

Superior vena cava syndrome

Dyspnea is the most common symptom,

Dysphagia,

Cough,

Chest pain,

Facial swelling, Fullness of face, Arm swelling,

Patients with cerebral edema may have headaches,

confusion, or possibly coma,

Symptoms & signs


Symptoms & signs


Systemic symptoms

Symptoms & signs

Non specific

Specific

Adults

Fatigue and anorexia

Fever (>38.0°C) during the previous month,

Drenching night sweats during the previous month,

Weight loss (≥10 % loss within 6 months before

diagnosis),

B symptoms

B symptoms correlate with:Advanced stage,Bulky disease,Worse prognosis.

Systemic symptoms

Symptoms & signs

Non specific

Specific

Adults

Fatigue and anorexia

Fever (>38.0°C) during the previous month,

Drenching night sweats during the previous month,

Weight loss (≥10 % loss within 6 months before

diagnosis),

B symptoms

Pruritus and alcohol-induced pain, which typically resolve with TTT

Symptoms & signs

S & S

Autoimmune disorders such as: (after diagnosis or after remission)

Autoimmune hemolytic anemia, thrombocytopenia, or

neutropenia.

Nephropathy.

Hypertrophic osteoarthropathy:

Children & intrathoracic HL may rarely present with this.

Characterized by digital clubbing and painful periostosis of tubular bones.

Evaluation

Goal

Extent of disease (stage)

Risk stratification

Prognosis

Intensity of treatment

Evaluation

History

B symptoms

Previuos infection

Exposure to toxins

Immune deficiencies

Familial

Evaluation

Examination

Lymph node "size & location"

Liver & spleen "size"

Pulmonary findings

Skin infiltration

Neurological signs

Evaluation

Laboratory

CBC with differential count

Liver and renal functions

HIV serology

ESR & LDH

Immunologic evaluation if....Pregnancy test if ♀ married

Evaluation

Imaging

CT with contrast "neck, chest, abdomen, pelvis"

Echo

PET-CT "after pathological confirmation"

Pulmonary function if patient >6 Y

Evaluation

PET-CT

It is the examination of choice for detecting disease activity during and after treatment.

PET/CT scanning distinguish between active tumour and necrosis or fibrosis in residual masses.

The negative predictive value of PET-CT averages 80-90%.

The positive predictive value of PET-CT averages 65%.

Evaluation

PET-CT

Up to 40% of patients with positive PET-CT will not relapse.

Poor tumour shrinkage and Positive PET-CT after chemotherapy have a higher risk of relapse or progression despite the use of RTH.

The causes of false positive PET-CT: Post-inflammatory changes after chemotherapy and RTH, Rebound thymic hyperplasia, Infectious and inflammatory processes, Brown fat (neck muscles).

So tissue biopsy is must prior to giving more therapy.

Evaluation

Tissue biopsy

Excisional biopsy "not FNAC"

Why excisional biopsy not FNAC ???

Fine needle aspirates do not provide adequate amounts of material for proper histologic classification nor for molecular studies needed in the evaluation. Subclassification of HL depends upon whether the tumoral architecture is nodular, diffuse, or both, and whether "classic" or variant Reed-Sternberg cells are present, as well as the composition of the cellular infiltrate (eg, non-neoplastic small lymphocytes, eosinophils, plasma cells, fibroblasts, histiocytes, neutrophils, and collagen fibers).

Evaluation

Tissue biopsy

BMA & BMB

Excisional biopsy "not FNAC"

Should we do BMA & BMB for every case ???

BMA & BMB are recommended only for patients with:Advanced stage disease (stage III, IV), B symptoms, or Any abnormality on CBC that is suspicious for bone marrow involvement (anaemia).

Evaluation

Fertility counseling

Options for women are limited. Men can often participate in sperm banking.

Evaluation

Differential diagnosis

Malignant

Infectious

Inflammatory

Non-Hodgkin lymphoma, Metastatic adenopathy from other primary tumors (eg, nasopharyngeal carcinoma, soft tissue sarcoma). Toxoplasmosis, Typical and atypical mycobacterium infections, EBV infection.

Systemic lupus erythematosus.

HL starts at a single site within the lymphatic system, usually a lymph node, and then progresses to adjacent lymph nodes via lymphatic channels before disseminating to distant non-adjacent sites and organs.

Based on laparotomy and lymphangiogram.

1974

Ann Arbor staging system

Cotswold modifications added valuable information regarding the presence of bulky disease and the efficacy of imaging for staging.

1988

The Lugano classification proposed further revisions to clarify the role of PET and better define extranodal involvement.

2014

Ann Arbor staging with Cotswolds modifications for Hodgkin lymphoma

Involvement of a single lymph node region (eg, cervical, axillary, inguinal, mediastinal) or Lymphoid structure such as the spleen, thymus, or Waldeyer's ring.Involvement of 2≥ lymph node regions or lymph node structures on the same side of the diaphragm.All nodal disease within the mediastinum is considered to be a single lymph node region.Hilar involvement constitutes an additional site of involvement.

Stage I

Stage II

Involvement of lymph node regions or lymphoid structures on both sides of the diaphragm.

stage III-1: with involvement of the spleen or splenic hilar, celiac, or portal nodes.

stage III-2: with involvement of the paraaortic, iliac, inguinal, or mesenteric nodes.

Stage III

Diffuse or disseminated involvement of one or more non-contiguous extranodal organs

or tissue, with or without associated lymph node involvement.

Stage IV

Prognostic factors

Patients with stage III or IV disease are → advanced stage.

Patients with stage I or II disease are → early (limited) stage.

Early stages are further stratified for treatment purposes into

favorable and unfavorable prognosis varies by region.

It is based upon the presence or absence of certain clinical

features.

Prognostic factors

Age ≥ 45 years

Male

Hb ≤ 10.5 gm/dl

ESR > 50 mm/h

B symptoms

Extranodal disease

Mixed cellularity "NCIC"

Large mediastinal adenopathy

Involvment of ≥4 sites "NCIC"

Risk stratification

Stratification of children and adolescents based upon:

Stage

The presence or absence of bulky disease

Low risk disease:

Stage IA or IIA disease (Non-bulky).

Intermediate risk disease: Stage IB or IIB disease.

Stage IA or IIA disease (Bulky).

Stage IIIA or IVA disease (regardless of bulk).

High risk disease: Stage IIIB or stage IVB disease.

EFS 92% & OS 98%

EFS 85% & OS 93%

EFS 83% & OS 94%

Response assessment

Complete remissionNo clinical evidence of disease or disease-related symptoms.

The post-treatment PET is negative (residual mass of any size is permitted).

Spleen and liver must be non-palpable and without nodules.

If a pre-treatment bone marrow biopsy was positive, an adequate bone

marrow biopsy from the same site must be cleared of infiltrate; if this

is indeterminate by morphology, immunohistochemistry should be

negative.

Response assessmentPartial remission

A decrease by at least 50 % in the sum of the products of the largest

perpendicular diameters (SPD) of up to six of the largest measurable

lesions.

Splenic or hepatic nodules must decrease by at least 50 % in the

SPD or in the greatest transverse diameter for single nodules).

The post-treatment PET should be positive in at least one previously

involved site.

There is no increase in the size of other nodes, liver, or spleen.

No new areas of disease.

Bone marrow biopsy results are not useful in determining PR.

Response assessment

Stable disease Failure to attain a CR or PR.

No evidence of progressive disease. The post-treatment PET should be positive at prior sites of disease.

No new sites should be present on PET or CT.

Response assessment

Progressive diseaseDevelopment of a new lesion is defined by the appearance of

Any new lesion >1.5 cm in long axis.

If the long axis diameter is from 1.1 to 1.5 cm, the lesion

should only be considered abnormal if its short axis is > 1.0 cm.

Progressive disease is also defined as an increase of at least

50 % in the longest diameter of a previously identified node.

Lesions should be PET positive unless they are below a

detectable size (ie, <1.5 cm in long axis by CT).

Response assessment

Rapid early responders: patients who achieved ≥ 60 % reduction

in node diameters by CT scan post two cycles of chemotherapy.

Slow early responders: patients who achieved < 40 % reduction

in node diameters by CT scan post two cycles of chemotherapy.

Response assessment

Refractory (resistant) HL: is a failure to achieve a complete

or partial response. Primary :failure to respond to initial therapy

(eg, chemotherapy ± RTH)

Secondary: initial response but failure to respond after

disease relapse.

Relapsed HL is the reappearance of disease in sites of prior

disease and/or in new sites after initial therapy and attainment

of complete response (CR).

A combination of chemotherapy and radiotherapy

Non-cross resistant: different mechanism of

action for each drug.

Non-dependant: each drug is individually

active.

No toxicity overlap: to allow full dose of each

drug.

Rules for combination TTT

Commonly used regimens

ABV (doxorubicin, bleomycin, vinblastine)

ABVE (doxorubicin, bleomycin, vinblastine, etoposide)

ABVD (doxorubicin, bleomycin, vinblastine, DTC)

VAMP (vinblastine, doxorubicin, methotrexate, prednisone)

MOPP (mechlorethamin, vincristine, procarbazine, prednisone)

COPP (cyclophosphamide, vincristine, procarbazine, prednisone)

OEPA (vincristine, etoposide, prednisone, doxorubicin; for ♂)

OPPA (vincristine, procarbazine, prednisone, doxorubicin; for ♀)

AVPC (doxorubicin, vincristine, prednisone, cyclophosphamide)


Several paediatric study groups have evaluated treatment de-escalation in an attempt to avoid toxicities that can be associated with treatment. As examples COG trial observed 52 children with stage IA:

* Non-bulky single node disease &* A negative PET/CT scan after complete resection.

At a median follow-up of 39 months: * Nine patients (17 %) relapsed. * All of these patients attained CR after three cycles of AV-PC. * No patients required radiation therapy.

The 3-year estimated PFS & OS rates were 82 & 100%, respectively.


Several paediatric study groups have evaluated treatment de-escalation in an attempt to avoid toxicities that can be associated with treatment. As examples COG trial evaluate use 3 cycles AV-PC 137 children with:

* Stage IA or IIA non-bulky single node disease.

Folowing chemotherapy alone: * 126 patients (92 %) CR. * 11 children had PR that was successfully converted to CR after IFRT.

The 4-year estimated PFS & OS rates were 88 & 100%, respectively.

Radiotherapy

Volume

Dose

Involved field radiation therapy (LD-IFRT).

Depth of radiation varied according different trials.

Mainly on areas of bulky disease or those with poor

response to chemotherapy.

Ranging from 15-25 Gy / 10-15 fraction

Radiotherapy


Radiotherapy

COG trial investigated whether (AVPC) without radiotherapy would be curative in patients with CR at end of therapy.

Though preliminary data in those patients with PET-avid disease after one cycle of therapy and who did not receive radiotherapy due to complete remission at end of treatment.

→ showed two-year OS & EFS 100 %, 65 % respectivelly.


Risk adapted treatment

WHY?

Standard RTH & Alkylating-CHT→Significant toxicity. So tailor amount & intensitiy of treatmnt to severity of disease.

Low-Risk adapted treatment

Four cycles followed by LD-IFRT.

{VAMP or COPP or ABVE or OEPA or OPPA}

A non-randomized prospective international trial (GPOH-HD95)

suggested that omission of radiation did not compromise survival

rates among children with early stage HL who attained a CR on

CT or MRI following initial treatment with OEPA or OPPA.

Intermediate-Risk adapted treatment

Six cycles COPP or 5 cycles ABVE-PC plus LD-IFRT.

PC = (prednisone,cyclophosphamide) Results from the COG AHOD0031 trial suggest that therapy may be

modified (escalated or deescalated) based on initial response to ABVE-PC:

The omission of IFRT in rapid early responders (60 %reduction

in node diameters by CT scan post two cycles) who achieve PET-

negative CR after four cycles of ABVE-PC.

The escalation of therapy in slow early responders with PET +ve

disease.EFS 85%OS 93%

High-Risk adapted treatment

Most protocols incorporate high intensity combination

chemotherapy + low dose or standard dose IFRD

Six cycles ABVE-PC or

Two cycles of OEPA for ♂, followed by four cycles of

COPDAC.

Two cycles of OPPA for ♀, followed by four cycles of COPP.

6 cycles+LD or SD-RTH

EFS 83% OS 94%

Low-Risk adapted treatment

Intermediate-Risk adapted treatment

High-Risk adapted treatment

EFS 85%OS 93%

6 cycles+LD or SD-RTH

EFS 83% OS 94%

Treatment of Nodular lymphocyte-predominant HL

NLPHL represents a more indolent disease than classical HL. Patients with stage III/IV are treated in a similar fashion to patients with classical HL. In contrast, patients with stage I/II NLPHL without B symptoms are treated with less intensive therapy than patients with classical

HL. Small studies have evaluated the use of in stage I/II NLPHL:Chemotherapy alone.Observation without treatment following excision.

The current strategies for treating NLPHL in children areModest intensity chemotherapy regimens, Some without anthracyclines, With or without involved field radiation.

Favourable outcome

Progression of disease after a partial initial response was seen in 10-15 %.

Relapse rates range from:

10 to 20 % in favorable prognosis localized (stage I-II) disease.

30 to 40 % in patients with more advanced disease (stages IIB-IV).

Failed induction therapy (resistant disease) (relapse in 30- 40 %),

Relapsed <12 months after having obtained a CR (relapse 27-

38%),

Relapsed > one year after attaining a CR (relapse in 24-40%).

%

The most favourable for successful salvage

The majority of relapses following an apparent CR will occur:

Within the first 12 months in 42%Within one to three years in 24% Late relapses (ie, >3 years following treatment) occur at the rate of

a few %/ year, extending up to 12 years post-treatment.

Time

Site

Relapse will more likely occur in previously uninvolved nodal regions or extranodal sites such as the liver or lungs.

Confirmation of relapse

Diagnosis of recurrence is generally made with biopsy of a mass.

This is especially true in case of late relapse, since there is

a significant risk for second cancers (non-Hodgkin lymphoma

or solid tumours) in these patients.

Evaluation of relapse

PET scans have added considerably to the assessment of

remission or persistent disease following salvage therapy prior to

high-dose chemotherapy and HCT.

Residual fibrotic, necrotic masses on CT scan suggest incomplete

response.

However, case series have demonstrated a relapse rate of only:

20 % if the PET scan is negative prior to HCT.

76 % if the PET scan is positive prior to HCT.

Goal of treatment

The goal of therapy is to attain a second complete response

(as defined by CT/PET negative) or an unconfirmed complete

response (as defined by CT) prior to autologous HCT.

Salvage therapy with second (or third) line regimens can

achieve responses in approximately 50 % of these

patients.

The decision to use a more aggressive treatment

approach in relapsed or refractory HL is typically based

on the presence of predictors of poor outcome.

Treatment

Predictors of better outcome in Relapsed patients:

Relapse >12 months from the end of initial TTT or

Patients who had reduced dose chemotherapy and no

RTH.

Predictors of poor outcome in Relapsed patients:

B symptoms,

Relapse between 3-12 months from the end of TTT.

Poor response to second-line therapy.

Treatment

Chemotherapy regimens

At a median follow-up of 45 months, patients with none of these

factors had a freedom from second progression of 48 % as

compared with 17 % for patients with three factors:Short time to relapse (≤12 months from end of primary TTT).

Clinical stage III or IV at relapse.

Anemia.

Algorithm in recurrent HL

Late relapse (>1year) & Early stage & No B symptoms & was treated with chemotherapy alone.

Chemotherapy + IFRTH

Early relapse (<1 year) or Induction failure or 2nd relapse

Advanced stage (even relapse >12 m)

High dose Chemotherapy + Auto BMT

Chemotherapy regimens

ICE (ifosfamide, carboplatin, and etoposide)

GDP (gemcitabine, dexamethasone, cisplatin)

DHAP (dexamethasone, high dose cytarabine, cisplatin)

Ifosfamide and vinorelbine

Vinorelbine and gemcitabine

MIED (high-dose methotrexate, ifosfamide, etoposide, and dexa)

Biologic therapy:

Immunotherapy,

Immunotoxins, and

Adoptive immunotherapy.

Auto BMT

Disease status at time transplantation is an important predictor

of survival and time to treatment failure.

Case series have demonstrated a relapse rate of only: 20 % if the PET scan is negative prior to HCT.

76 % if the PET scan is positive prior to HCT.

Auto BMT

Disease status at time transplantation is an important predictor

of survival and time to treatment failure.

Preparative regimen: we use CMV

CBV (cyclophosphamide, BCNU [carmustine], etoposide [VP-16]).

BEAM (BCNU, etoposide, cytarabine [Ara-C], and melphalan).

Adjuvant involved-field radiation therapy (IFRT).

What about relapse post Auto BMT ???

Other options include the use of :

Brentuximab vedotin,bendamustine,

Mtor inhibitors (eg, everolimus, gemcitabine, vinorelbine),

Immunomodulators (eg, lenalidomide),

Local regional irradiation,

Allogeneic HCT,

■ Anti PD-1 antibody nivolumab.

Biologic therapy

Immunotherapy & Immunotoxins & Adoptive immunotherapy Immunotherapy

Rituximab

It is a recombinant anti-CD20 antibody is used in the treatment of

many hematologic malignancies that express CD20.

It binds to antigen CD20 (antigen)→activating complement-dependent

B-cell cytotoxicity.

Biologic therapy


Biologic therapy


It is more useful in the TTT of nodular lymphocyte predominant HL.

The value of rituximab in classic HL is uncertain.

Alone or with other second-line chemotherapy.

Biologic therapy

Immunotherapy & Immunotoxins & Adoptive immunotherapy Immunotoxins

Brentuximab vedotin

It is an immunotoxin comprised of a CD-30 (commonly expressed on

Hodgkin/Reed-Sternberg cells) directed antibody linked to the antitubulin

agent monomethyl auristatin E (MMAE).

Biologic therapy

Immunotherapy & Immunotoxins & Adoptive immunotherapy Immunotoxins

A phase II trial of brentuximab in adults who had relapsed status post

autologous hematopoietic cell transplantation demonstrated a 75 % overall

response rate, with median progression-free survival of 5.6 months.

Pediatric phase I and II studies are ongoing, both with brentuximab as a

single agent and in combination with gemcitabine.

Brentuximab vedotin

It is an immunotoxin comprised of a CD-30 (commonly expressed on

Hodgkin/Reed-Sternberg cells) directed antibody linked to the antitubulin

agent monomethyl auristatin E (MMAE).

Biologic therapy

Immunotherapy & Immunotoxins & Adoptive immunotherapy Adoptive immunotherapy

Cytotoxic T lymphocytes (CTLs)Cytotoxic T lymphocytes (CTLs) has antitumor activity.

Cytotoxic T-lymphocytes that are specific for Epstein-Barr virus

latent antigens LMP1 and LMP2 or Reed-Sternberg cells.

Expanded clones of these cells may have a therapeutic role in those

patients with HL whose Reed-Sternberg cells express Epstein-Barr

viral antigens.

PD-1 blockade

Nivolumab, Pembrolizumab

Programmed death 1 (PD-1) is over-expressed in classical HL and

results in transient down-regulation of T cell function (T cell

exhaustion).

PD-1 blockade


Programmed death 1 (PD-1) is over-expressed in classical HL and

results in transient down-regulation of T cell function (T cell

exhaustion).

Small prospective studies have reported high response rates

with PD-1 inhibitors (eg, nivolumab, pembrolizumab).

Nivolumab (3 mg/kg) was administered

At week 1 and week 4, and

Then every two weeks

Until disease progression or complete response or for

a maximum of two years.

PD-1 blockade


The most common toxicities were:

Rash (22 %),

Thrombocytopenia (17 %),

Fatigue, pyrexia,diarrhea,nausea, and pruritus (13 %each)

Overall and complete response rates were 87 and 17 %,

respectively.

Further studies are needed to further define efficacy and

toxicity prior to their general clinical use in this setting.

Effects of treatment

Acute effects

1. Radiotherapy effects

2. Chemotherapy effects

Skin: redness & hyper-pigmentation & transient hair thinning in exposed fields.

GIT: Mild nausea and vomiting & dry mouth or mucositis or taste alterationHaematological : neutropenia & thrombocytopenia.

Nausea and vomiting.Reversible alopecia.Myelosuppression and immunosuppresion.Other specific for each drug (VCR→neurotoxicity).

Effects of treatment

Late effects

1. Impaired growth of soft tissue and bone.

2. Thyroid dysfunction

Many of these long-term effects were described initially following treatment regimens that are no longer used in children.

3. Gonadal dysfunction

4. Pulmonary toxicity

5. Cardiac toxicity

6. Secondary malignancies

Late effects

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Hodgkin lymphoma presentation

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