APPROACH TO CHILDHOOD NON-HODGKINS

LYMPHOMA
Dr Sanjaykumar Yadav
SR Paed Onco

Moderator
Dr.Farooq Aziz
 Flow of today's presentation
• Introduction to Childhood lymphoma
• Epidemiology
• Clinical features
• Staging
• Risk stratification
• Treatment protocols
• Prognosis
• Salvage therapy
 What is lymphoma?

• Def: Clonal proliferation of Lymphocytes

• Diff from Leukaemia?
• Leukaemia arise from clonal proliferation of myeloid or lymphoid progenitor of
BM

• Lymphoma arise from clonal proliferation of lymphoid cells Lymphoreticular

system outside BM
 Epidemiology
• Lymphomas are 3rd MC malignancy in children & adolescent, after leukaemia & brain
tumour
 60% NHL Reported incidence of lymphomas in India varies from
 40% HL 12-25% of all childhood cancers Cf. 7-10% in west
• Lymphomas are uncommon below 5yrs of age & incidence increases with age
• Both major lymphomas subtypes are distinct in origin/ CF/biology/treatment
approaches/outcome
• Between 1975 and 2010, 5-year survival rate has increased from 45% to 87% in children
younger than 15 years and from 48% to 82% for adolescents aged 15 to 19 years
Incidence of Common NHL types in
India
Lymphoma registry
TMH in 2001

B-cell lymphomas T-cell lymphomas

48.1% 44.3%

DLBCL (22.9%) LL (31.5%)

BL (15.3%) ALCL (11.1%)
 Classification
Sub -classification of Lymphoma
(2008 WHO Classification of Lymphoid neoplasm
Hodgkin Classical Hodgkin Lymphoma Nodular lymphocyte
lymphoma predominant Hodgkin
lymphoma(NLPHL)
Nodular Mixed LP LD
sclerosis cellularity
Non-Hodgkin Burkitts T B ALCL Rare variety:
Lymphoma Lymphoma Lymphoblastic Lymphoblast Paediatric follicular lymphoma
lymphoma ic Mucosa-associated lymphoid
DLBCL lymphoma tissue (MALT) lymphoma
Primary central nervous
system (CNS) lymphoma
Peripheral T-cell lymphoma
Cutaneous T-cell lymphoma
DISTRIBUTION OF NON-HODGKIN LYMPHOMA
SUBTYPES BY AGE
 Inherited Immunodeficiency Syndromes A/w Lymphoma in Children
Syndrome Genetics/Pathogenesis Immune Defect Malignancy

Ataxia telangiectasia ATM; impaired DNA repair Progressive decline in T cells, T-cell ALL and T-cell LL,
abnormal immunoglobulins CHL, BL, DLBCL

Wiskott-Aldrich syndrome WASP; abnormal Defects in T cells, B cells, EBV-associated DLBCL,

(WAS) cytoskeletal architecture
of hematopoietic cells
Severe combined X-linked: gamma chain
immunodeficiency (SCID) mutations with defective
IL signaling; ADA:defective adenosine
Deaminase
neutrophils, macrophages
low or absent
T and NK cells,
nonfunctional B cells
Hodgkin, lymphomatoid
granulomatosis
EBV-associated lesions

X-linked lymphoproliferative SH2D1A; SAP, which Defective EBV-specific T and EBV-associated

disease (XLP) modulates B- and T-cell NK cells HLH
interactions B-cell lymphoproliferative disease

Autoimmune Defects in FAS-mediated Increased CD4 and CD8 T LPHL, CHL, DLBCL, BL
lymphoproliferative apoptosis pathway cells
syndrome (ALPS)
Common variable Defects in genes encoding Low IgG and IgA, EBV-associated lesions,
immunodeficiency (CVID) ICOS, CD19, BAFFR Decreased B cells DLBCL, Hodgkin
X-linked CD40L mutation Low or absent IgG and IgA, EBV-associated lesions,
HyperIGM leading to defective B cells variable T-cell defects DLBCL, Hodgkin
syndrome
Pathology
 Clinical Differenece between HL NHL
• Hodgkin Lymphoma
• Lymph node enlargement –
(Cervical, Axillary, Abdominal)
• Fever
• Weight loss
• Night sweats
• Anemia
• Hepatosplenomegaly
Non-Hodgkin Lymphoma

•Abdominal mass
•Mediastinal mass
•Jaw swelling
•Fever
•Weight loss
•Anemia
HODGKIN LYMPHOMA NONHODGKIN LYMPHOMA

Peripheral LAD Abdomen/ jaw /LN/visceral /extranodal

Contigous involvement LN Non-contiguous

Less aggressive course Life-threating and aggressive course

Less systemic sign More systemic sign

Rare Present with Oncologic emergencies

Excellent prongnosis >95% Poor prognosis in advanced disease

 Pathology
sheets of rapidly
dividing, abundant cytoplasm and
intermediate- horseshoe-shaped nucleus
sized known as Hallmark cells
lymphocytes
with basophilic
cytoplasm
“classic starry-sky
pattern”

Burkitt lymphoma ALCL

Cells are typically

very large with
more cytoplasm
than in BL

Diffuse large B-cell lymphoma. Precursor B cell lymphoma

 Clinical features
• NHL in children is high grade and extranodal (mediastinum/abd/head and neck) presents as aggressive disseminated disease

• Most common symptom of childhood NHL is painless lymphadenopathy

• Intrathoracic NHL most often T cell – may have features of SMS/SVCS

• Associated pleural/pericardial effusion

• Cervical adenopathy

• Abdominal pain, ascites, palpable abdominal mass intestinal obstruction or intussception

• CNS- Cranial nerve palsy , increased intracranial pressure

• Bone or Jaw swelling, cytopenia with BM involvement

• Renal involvement, TLS

 Diagnostic workup for Suspected NHL
1 History and physical exam Symptomatic large mediastinal masses, epidural or paraspinal tumors, should be recognized on
examination

2 Laboratory Complete Blood Count , Renal function test, Liver function test, LDH*, Coagulation profile
Uric acid, Calcium, Phosphate, Electrolytes(TLS Parameters)
Bilateral bone marrow aspirate & trephine biopsy
Lumbar puncture

3 Imaging CXR
Ultrasound for certain intra-abdominal masses
CT scan neck chest abdomen and pelvis
OR
PET scan whole body
Magnetic Resonance Imaging (MRI): It can be done in children having a mass in paraspinal area
Echocardiogram to assess cardiac function and measure shortening fraction and ejection fraction

4 Tissue diagnosis Biopsy (open/image guided) is planned depending on the site of involvement (abdominal mass,
extranodal site, lymph node,skin)

5 Molecular diagnosis Immunophenotype, flow cytometry/cytogenetics

 STAGING
Murphys St Jude’s staging system for childhood NHL

Stage Definition
I Single Tumour (extranodal)
Single anatomic area (nodal) excluding mediastinum or abdomen

II Single tumor (extranodal) with regional node involvement

Primary gastrointestinal tumor with or without involvement of mesenteric node only.
On same side of diaphragm:
two or more nodal areas
two single extranodal tumors with or without regional node involvement

III All primary intra-thoracic tumors.

All extensive primary intra-abdominal disease
Two or more nodal or extranodal areas on both sides of diaphragm

IV Any of the above with CNS or bone marrow involvement

More than 25% blasts in the marrow is considered leukemic disease. Any identifiable
tumor cell in the CSF constitutes CNS disease
 Revised International Paediatric Non-Hodgkin Lymphoma
Staging System (IPNHLSS)
Stage I Single tumour with exclusion of mediastinum and abdomen

Stage II Single EN tumour with regional node involvement

Two or more N areas on same side of the diaphragm
Primary GI tract tumour (usually in ileocaecal area) +/- involvement of associated mesenteric nodes, that
is completely resectable
(if malignant ascites or extension of tumour to adjacent organs, it should be regarded as stage III)
Stage III ≥2 EN tumours (including EN-B or EN-S) above and/or below diaphragm
≥2 N areas above and below diaphragm
Any intrathoracic tumour (mediastinal, hilar, pulmonary, pleural or thymic)
Intra-abdominal and retroperitoneal disease including liver, spleen, kidney and/or ovary localisations,
regardless of degree of resection
Any paraspinal or epidural tumour, regardless of whether other sites involved
Single B lesion with concomitant involvement of EN and/or nonregional N sites
Stage IV Any of the above findings with initial involvement of CNS (stage IV CNS),
BM (stage IV BM),
or both (stage IV combined)
 Mature B-Cell Neoplasms -Burkitt Lymphoma

• First human tumor to be associated with a virus

• First to be associated with recurrent chromosomal translocations

• First reported to be associated with HIV infection

• Classified as endemic, sporadic (the type found in nonmalarial areas), or Immunodeficiency

• Dysregulation of MYC appears essential for the development of BL

• Mechanism of lymphomagenesis -abnormal proliferation rather than defective apoptosis (Cf:adult)

• EBV infection is present in 90% of endemic BL cases, 20% of sporadic BL, 40% of HIV-associated BL
 Clinical Features BL

Endemic BL Sporadic

Peak: 6–12 years

Peak: 4–7 years Males > Females
Males > Females
Jaw involvement
Involves the mesentery & omentum, more MC Abdominal mass with massive disease,
than ileum & caecum Surgical debulking is neither feasible nor
appropriate

malnourished at presentation Head and neck region is the 2nd MC site of

disease

Jaw involvement fewer than 10%

BM infiltration at diagnosis & at relapse is
uncommon
Bone marrow
CNS disease in almost one-third of patients involvement occurs in approximately 20%
Comparison of Endemic and Sporadic Burkitt Lymphoma
Feature Endemic Sporadic
Most common distribution Malaria Belt: Equatorial Africa, New North America, Europe
of disease Guinea, Amazonian Brazil most common
Common tumour sites Jaw, abdomen, central nervous system, Abdomen, bone
cerebrospinal fluid marrow, lymph nodes,
ovaries

Presence of Epstein–Barr 95% 15%

virus DNA in tumor cells

Endemic BL Sporadic BL BL Histology

Histology Immunology Clinical Features Translocations’ Remarks

Burkitt and Burkitt-like Mature B cell Abdominal masses, head neck, GIT t(8;14)(q24;q32) India: Sporadic form
(Surface IgG± IgM) tumors, Waldeyer's ring t(2;8)(p11;q24) common
50% NHL CD 10,19.20: t(8;22)(q24;q11)
Kappa & lambda Less common CNS/testis/Marrow BCL2 –ve Africa: endemic form
Ki-67 proliferation(MIB-1) common with jaw mass
index is very high and approaches Types of NHL overexpression of the MYC
100%. oncogene

Diffuse large B-cell Mature B-cells Node, Abdominal masses, bone t(8;14)(q24;q32) 20% present as
(DLBCL) CD 19,20,22,38,79a t(2;17)(p23;q23) Mediastinal mass: Poor
Ki-67 proliferation index will be Less common: CNS, Mediastinum, prognosis
20% NHL elevated, Cf:BL Marrow BCL2+(40%)

PMBL CD30, Cf:diagnosis of nodular adolescent females gains in chromosome 9p with EFS of 81% using
sclerosis cHL amplification of the REL gene EPOCH-R.
presents with a slow-growing
lacks cell-surface mediastinal mass
immunoglobulin
PD-L1/L2 inhibitors have
CD23 is useful in distinguishing been conditionally
PMBCL from other approved by Food and
types of large BCL Drug Administration

Large BCL MUM1 is strongly positive typically occurs in children as a IRF4 rearrangement
diffuse or follicular lesion in
pattern Waldeyer ring
Histology Immunology Clinical Features Translocations’ Remarks

Lymphoblastic Pre T-cell 70% Mediastinal, BM, skin, t (1;14) (p32;q11) Majority 70%
Lymphoma (immaturity markers, bone t (11;14) (p13;q11) T-LINEAGE with
20% NHL such as TdT or CD34) t (10;14) (q24;q11) Mediatinal mass
t (7;19) (q35;p13)
Pre B cell >25% blasts as
30% leukaemia

ALCL T-cell, null cell or NK cell mean age 12 years t (2;5) (p23;q35) fusion Varied presentation
(CD30+) B symptom+ of NPM1 and ALK genes Extranodal +
15%NHL ALK, Systemic sym+
CD3,CD20,CD45RO t (1;2) (q21;p23) concomitant HLH (10–
EMA Skin, nodes, bone, Lung t (2;3) (p23;q21) 12%)

Paediatric-type follicular mutations in mass in the head and rare

lymphoma (PTFL) TNFRSF14 neck
CD10, CD20, and
surface
immunoglobulin
 Clinic-pathological differences between diffuse large B-cell lymphoma and Burkitt lymphoma

Lymphoma type Burkitt lymphoma Diffuse large B-cell lymphoma

Clinical Children > adults Adults > children
Extranodal (abdominal) > nodal Nodal or extranodal
Bulky, rapidly growing masses Sometimes large mass lesions, often localized
Commonly go into tumor lysis TLS less common
syndrome (TLS)
Histological Medium sized cells Large oval cells
Cytoplasmic vacuolation Irregular nuclei, scant cytoplasm
Starry-sky pattern common Sometimes starry sky
Immunohistochemistry Ki67~100% Ki67~90– 95%
CD20+, CD10+, Bcl-6+, sIg+ CD20+, CD10−/+, Bcl-6+/−, Bcl-2+/−, sIg+/−
Bcl-2−, CD5−, TdT−,
Molecular t(8;14), t(2;8), or t(8;22) (myc and IgH bcl-2 and bcl-6 abnormalities common, myc
or IgL) abnormal
No bcl-2 or bcl-6 translocation in a minority
 Management of NHL in children

• Principles of management
1. Extremely chemosensitive tumors.
2. Surgery plays a very limited role, mainly for arriving at a diagnosis or for emergency management of obstruction or perforation.
3. Localized abdominal tumors diagnosed at the time of emergency laparotomy are often easily resected, and the prognosis is
excellent with a short course (6 weeks) of chemotherapy
4. Radiation of primary sites is used very rarely in emergency situations such as a large mediastinal mass causing airway
obstruction.
5. Multi-agent chemotherapy directed to the histologic subtype
6. Stage of the disease remains the cornerstone of therapy.
• Emergency management:two potentially life-threatening clinical situations at presentation
1. Superior Vena Cava syndrome (or mediastinal tumor with airway obstruction), most often seen in LL
2. TLS, most often seen in LL and BL
 Superior vena cava syndrome(SVC/SMS)
• Clinical features of SMS/SVC syndrome

Structure Signs and symptoms

compressed
Tracheobronchial Cough, dyspnoea, orthopnoea, stridor, wheezing, suprasternal/subcostal
tree retractions
Oesophagus Dysphagia
Recurrent Hoarseness of voice
laryngeal nerve
Superior vena Edema of head, neck and upper limb, plethora, cyanosis, conjunctival
cava congestion, neck engorgement & dilated veins over neck and chest
Other CNS symptoms, Pleural and pericardial effusion ,oncological emergencies
• Most common causes : Compression by malignant mediastinal mass, viz., leukemia/lymphoma,
germ cell tumour (GCT), neuroblastoma, sarcoma [Ewing's sarcoma (EWS),
rhabdomyosarcoma(RMS)]
• Venous thrombosis caused by central venous catheter or cardiac surgery
• Management of SVC:
• Steroids: Steroids are the first-line agents to be initiated for initial stabilization of children
presenting with SMS/SVCS. Dexamethasone (5-10mg/m2),Methylprednisolone(1mkdo Q 6H)
Hydrocortisone(5mkdo Q 6H)
• Cytotoxic chemotherapy: At times, the steroids alone may not be effective, Chemotherapeutic
agents commonly used along with steroids include cyclophosphamide (200 mg/m2), vincristine (1–
1.5 mg/m2), and anthracyclines(doxorubicin/daunorubicin: 25–50 mg/m2)
• Radiotherapy: Role of emergent radiotherapy is obsolete
 Tumor lysis syndrome (TLS)
• Constellation of metabolic derangements (↑K,↑UA↑P, ↓Ca) due to rapid breakdown of malignant cells
• Usually occurs after initiation of cytotoxic chemotherapy or spontaneously in tumors with high proliferative rate
Patients are classified into three risk groups
• Identification of patient at-risk and prevention of TLS by adequate prophylaxis is the best
management
• Continuous monitoring: urine output, serum electrolytes urea, creatinine,& uric acid q 6–8 hrly
• Hydration:Hyperhydration is the cornerstone of both prevention and treatment of TLS,
3 L/m2/day to achieve a target UO >3 mL/kg/hr, either oral or intravenous (IV)
hydration
• Diuresis: Fluid overload or urine output is suboptimal despite adequate hydration
contraindicated when the child has obstructive uropathy or hypovolemia
• Alkalinization of urine
• Uric acid lowering agents
 Supportive care & Initial Stabilization
• Present in advanced stages, high disease burden, metabolic complications & comorbidities
• Following precautions should be taken during treatment
1. Sick children should be initially cared for in intensive care , timely intervention in case of complications
2. Stabilized first, especially with aggressive tumor lysis prevention & management
3. Aggressive nutrition support enteral/parenteral nutrition, especially in children with moderate to severe malnutrition and/or
gut involvement is critical
4. Clinically unresected disease (group B & C) especially bulky tumors should receive COP pro-phase for gradual cytoreduction
COP pro-phase may be repeated in children with persistent poor general condition
5. Dose modification
6. Children with transmural gut involvement
Pediatric B-NHL: Current Risk Grouping
RISK STRATIFICATION
Protocol Group Definition

FAB-LMB-96 A Completely resected stage-1 & abdominal stage-2

B Multiple extra-abdominal sites

Non-resected stages I and II, III (Normal LDH)
Stage III (elevated LDH), marrow <25% blasts,
no CNS disease
C Mature B-ALL > 25% Blast &/or CNS +ve
NHL-(BFM-95) R1 Completely resected stage I and abdominal stage II

R2 Stage 1& II Unresected, Stage III with LDH < 500U/L

R3 Stage III with LDH 500–999 IU/L,

Stage IV,
B-cell ALL (>25% blasts), and LDH <1,000 IU/L
No CNS disease

R4 Unresected & LDH > 1000U/L and/or CNS +ve

 DEFINITIVE MANAGEMENT

FABLMB 96
Group A: COPAD 2 x COPAD at 21-day intervals
Vincristine 2.0 mg/m2 (max dose 2 mg) as IV bolus

Cyclophosphamide 250 mg/m2/dose every 12 hours as

an infusion over 15 mins on Days 1-3 (total of 6 doses).
Continue hydration according to local practice at a rate of
3000 ml/m2/day until 12 hours after the last dose of
cyclophosphamide.

Prednisolone 60 mg/m2/day (divided into two doses)

orally on Days 1-5 inclusive and then reduced to zero over
3 days. Methylprednisolone IV may be used at the same
G-CSF 5 mcg/kg/day subcutaneously on Day 7 -21 inclusive. dose of prednisolone if unable to take orally or GI
absorption affected.

Doxorubicin 60 mg/m2/day in 1 hour infusion on Day 1.

 Group B (COPInductionConsolidation)

Pre-phase COP
Vincristine 1.0 mg/m2 (max single dose
2.0 mg)
Cyclophosphamide 300 mg/m2
Prednis(ol)one 60 mg/m2 /day
Methotrexate 8 - 15 mg by IT injection
Hydrocortisone 8 - 15 mg by IT
injection
Evaluation of tumour response should be performed on day 7,
<20% reduction should be treated according to Group C
 Vincristine 2.0 mg/m2
Group B: Induction: COPADM
Prednisolone 60 mg/m2 /day
Methotrexate 3000 mg/m2 over 3hr
Folinic acid 15 mg/m2 orally every 6
hours for a total of 12 doses
Cyclophosphamide (500 mg/m2
/day)
Doxorubicin 60 mg/m2 as a 6 hour
infusion, after first dose of
cyclophosphamide.
IT drugs Methotrexate &
G-CSF 5 mcg/kg/day by subcutaneous injection on Days 7 -21 inclusive.
Hydrocortisone 8 - 15 mg by IT
injection

COPADM2 receives 1000mg/m2/day of Cyclophospamide

 Group B: CONSOLIDATION: 2 x CYM = Course n°3 and course n°4
Methotrexate 3 g/m2 in fluids
iV infusion over 3 hours
Folinic acid 15 mg/m2 orally/IV
every 6 hours
Cytarabine 100 mg/m2 in
glucose 5% & sodium chloride
0.9%. IV infusion over 24 hours.
Repeat daily from day 2-6

Cytarabine 100 mg/m2 G-CSF There is no need to give G-CSF after the CYM courses.

Following recovery from 1st CYM a full assessment of response should be carried out
Residual masses must be biopsied/resected unless <2cm or surgically inaccessible.
If histology negative Continue with CYM 2
If histology positive (even if completely resected) Change to Arm C1 starting with CYVE
 GROUP B: MAINTENANCE COURSE

Vincristine 2.0 mg/m2

Prednis(ol)one 60 mg/m2 /day
Cyclophosphamide 500 mg/m2 /day
Methotrexate 3000 mg/m2
Folinic acid 15 mg/m2
Doxorubicin 60 mg/m2
IT Methotrexate 8 - 15 mg IT Hydrocortisone 8 - 15 mg
LMB-89/96Protocol for Burkitt's Lymphoma (Group C) Reduction Phase : COP

Evaluation of tumour response on day 7 to ascertain at least

an incomplete response to COP before proceeding with
COPADM1
Non-responding  Treat with Group C Arm C1
Group C Induction Phase: COPADM 1

Vincristine 2.0 mg/m2 (max dose 2

mg)
Prednisolone 60 mg/m2/day (divided
into two doses) orally on Days 1 - 5

Methotrexate HD 8000 mg/m2 in 500

mls/m2 dextrose 5% IV infusion over
4 hours

Folinic acid 15 mg/m2 orally/IV every

6 hours for a total of 12 doses

Cyclophosphamide 500mg/m2/day

Group C Induction (Continued): COPADM 2

Cyclophosphamide 1000mg/m2/day
 Group C (Cns -Ve) Consolidation: CYVE 1 & 2

Cytarabine 50 mg/m2 by continuous

infusion over 12 hours in dextrose saline.
Ara-C HD 3000 mg/m2 in 375 mls/m2
dextrose saline as IV infusion over 3hrs
Etoposide 200 mg/m2 in 500 mls/m2 CYVE 2 is same as CYVE1
dextrose saline as IV infusion over 2 hours
daily
G-CSF 5 mcg/kg/day
Following recovery from CYVE2 a full assessment of response should be
carried out
Group C (Cns -Ve) Consolidation: Mini CYVE1 Arm C2

Cytarabine 50 mg/m2 by continuous

infusion over 12 hours in dextrose saline.
Ara-C HD 2000 mg/m2 in 375 mls/m2
dextrose saline as IV infusion over 3hrs
Etoposide 100 mg/m2 in 500 mls/m2
dextrose saline as IV infusion over 2 hours
daily
G-CSF 5 mcg/kg/day

Mini-CYVE 2 same as Mini CYVE 1

Group C (CNS +Ve) Consolidation: CYVE 1(+MTX) & 2
Methotrexate HD Around day 18 , 8000 mg/m2 in 500 mls/m2 5% dextrose as
infusion over 4 hrs
Triple IT drugs Should be given before folinic acid is started
Folinic acid 15 mg/m2 orally
Double IT drugs Hydrocortisone and
methotrexate
NB No intrathecal Ara-C is given.
Cytarabine 50 mg/m2 Days 1-5 continuous
infusion over 12 hours in dextrose saline
Ara-C HD 3000 mg/m2 (days 2-5 only) in
375 mls/m2 dextrose saline as IV infusion
over 3 hours
Etoposide 200 mg/m2 (days 2-5 inclusive) in
500 mls/m2 dextrose saline as IV infusion
over 2 hours. Starts 3 hours after high dose
cytarabine (Ara-C HD)
G-CSF 5 mcg/kg/day
Group C (CNS +Ve) Consolidation: Mini-CYVE 1(Mtx)& 2 Arm C2
Methotrexate HD Around day 18 , 8000 mg/m2
in 500 mls/m2 5% dextrose as infusion over 4
hrs
Triple IT drugs Should be given before folinic acid
is started
Folinic acid 15 mg/m2 orally
Double IT drugs Hydrocortisone and
methotrexate
NB No intrathecal Ara-C is given.
Cytarabine 50 mg/m2 Days 1-5 continuous
infusion over 12 hours in dextrose saline
Ara-C HD 2000 mg/m2 (days 2-5 only) in 375
mls/m2 dextrose saline as IV infusion over 2
hours
Etoposide 100 mg/m2 (days 2-5 inclusive) in 500
mls/m2 dextrose saline as IV infusion over 1
hours. Starts 3 hours after high dose cytarabine
(Ara-C HD)
G-CSF 5 mcg/kg/day
Mini-CYVE 2 (no MTX) starts 1 week after HD MTX
 Group C Maintenance Course M1 (Both Arms C1 & C2)

Vincristine 2.0 mg/m2 (max dose 2 mg)

Prednis(ol)one 60 mg/m2 /day (divided into bid doses
Cyclophosphamide 500 mg/m2 /day given
Methotrexate HD 8000 mg/m2 in 500 mls/m2 dextrose 5%
Folinic acid 15 mg/m2 orally
Doxorubicin 60 mg/m2 as a 6 hour infusion, after first dose
of cyclophosphamide.
Triple IT drugs By IT injection on Day 2
Maintenance course 2
& 4 are same

Complete Remission (CR)
Complete disappearance of all measurable or
evaluable lesions (except bone), no L3 blasts
in the bone marrow nor in the CSF
CRb Resected residual mass that is
pathologically(morphologically)
negative for the disease
CRu Residual mass has no morphologic
evidence of disease from limited or
core biopsy,
no new lesions by imaging
BM and CSF morphologically free of
disease
Residual mass is negative by FDG-PET
Response Assessment Criteria in NHL
Partial response (PR)
50% decrease in SPD on CT or MRI;
FDG-PET may be positive (Deauville score of 4–5
with reduced uptake
compared with baseline) with no new and/or PD
Morphologic evidence of disease may be present in
BM or CSF if present at diagnosis; however, 50%
reduction in percentage of lymphoma cells
PD:
>25% increase in SPD on CT or MRI,
Deauville score 4 or 5 on FDG-PET with an increase
in lesional uptake from baseline
OR development of new morphologic evidence of
disease in BM or CSF
Minor response (MR)
Decrease in SPD > 25% but < 50% on CT
or MRI;
no new and/or PD
Morphologic evidence of disease may
be present in BM or CSF if present at
diagnosis; however, 25–50% reduction
in percentage of lymphoma cells
No Response (NR)
do not meet CR, PR, MR, or PD criteria
 Management of Relapsed B-NHL
ICE chemotherapy schedule
Days 1 2 3 6 10 17
Ifosfamide ● ● ●
Etoposide ● ● ●
Carboplatin ●
IT drugs ● (●) (●)
Start G-CSF ●
Ifosfamide 3 g/m2, IV over 2 hours on D1-3.
Ensure adequate pre-/post-hydration and administer prophylactic mesna, 3.6 g/m2/day.
Etoposide 100 mg/m2, IV over 1 hour on D1-3
Carboplatin 635 mg/m2, IV over 1 hour on D3 only
IT drugs Methotrexate and cytarabine are given on D3 of cycle 1 to all patients and
on D3 of cycle 2/3 to Burkitt lymphoma/leukaemia patients.
Only CNS positive patients receive IT drugs on D10 and D17
LYPMHOBLASTIC LYMPHOMA :PRINCIPLES OF MANAGEMENT

Treatment as per Pre B ALL

BFM 90 protocol

Tteatment as Pre B ALL

BFM 90 protocol
 CNS disease at presentation

• Cranial radiotherapy guidelines

• Children under 2years of age do not receive cranial irradiation
• Midplane dose 24 Gy in 15 fractions of 1.6 Gy each, in 15-21 days
• Treatment need not be interrupted for cytopenia unless the patient is unwell
• No further intrathecal methotrexatewill be replaced by once weekly oral methotrexate , 20 mg/m2 in the
week
• Testicular radiotherapy guidelines:
• dose will be 24 Gy in 12 daily fractions of2 Gy during weeks 14-16 (post Intentensification)
 Treatment Recommendations for India

• Most children in India with LL present in advanced stages with high disease burdens, metabolic complications, massive pleural
& pericardial effusions and comorbidities such as malnutrition and infections.
• Sick children, especially with SVCS/superior mediastinal syndrome should :intensive care/high-dependency unit in propped-up
lateral position
• Least invasive procedure should be used to establish the diagnosis of lymphoma such as blood smear/flow, pleural tap, BM
examination, a lymph node biopsy under local anesthesia in sitting/prone position.
• Aggressive tumor lysis prevention & management include proactive & timely use of low-dose rasburicase
• Pro-phase steroids should be used in children present in a poor general condition, with large disease burden and metabolic
obstructive complications.
• Patients should be followed for response ,those with no response to the 7-day pro-phase or presence of a residual mediastinal
mass at day 33 or at the end of induction (with less than 70% reduction) should preferably get intensified therapy
Risk Stratification of ALCL
 Management of ALCL
Modified MCP842 regimen

1. Multi-agent, short course, intensive

chemotherapy protocol
2. All patients received eight cycles of
chemotherapy (Cycles A and B)
irrespective of the stage
 Chemotherapy doses and schedule (Modified MCP842 regimen)

1. Prephase is given for

advance stage ALCL
(Stages III and IV) and
patients who are acutely
ill at the time of
presentation.
2. Ifosfamide given along
with Mesna,400 mg/m2
IV @ 0, 4, and 8 h
3. IT ARA-C and MTX
four cycles-> CNS-ve
eight cycles-> CNS+ve
 ALCL 99

• Treatment consists of a prephase followed by six alternating cycles of high-dose intensive

chemotherapy over a short period of time
• Total duration of therapy is around 4–5 months
• Study proved : intrathecal chemotherapy can be safely omitted
higher dose with shorter infusion duration (3 g/m2 over 3 hours)less
toxicity
ALCL 99
Prephase in all
patient
AM1 begins from D6
BMV
 Response assessment
• At the end of two cycles of chemotherapy (week 6) by either conventional CT scans or PET-CT scan

Complete response (CR) lesions decreased by >70% sum of the

products of the greatest perpendicular
diameters
Partial response (PR) <70% decrease sum of the products of the
greatest perpendicular diameters NO NEW
LESION
 PROGNOSTIC FACTORS IN ALCL

• Mediastinal, skin, and visceral (lung, liver, spleen) involvement

• Independent poor prognostic factor: target protein for detecting MDD (minimal disseminated
disease) NPM-ALK fusion protein by PCR
• Pediatric ALCL is a relatively chemosensitive tumor with high response rate, survival in ALCL is
slightly inferior to that of the mature B-NHL
• ALK-negative ALCL
• Histology: Noncommon variant remains a poor prognostic factor
 Management of Relapsed disease

• Single-agent Vinblastine weekly

• Future treatment options—ALK inhibitors, agents targeting CD30, immunotherapy
• Primary progressive Disease with
Very early relapse with TFI(<6months)  Counselled for Allogeneic stem-cell transplant (Allo-SCT)
• Late relapse (TFI >6 months) Salvage chemotherapy containing single-agent weekly

vinblastine + oral celecoxib 100 mg/m2 /d daily

& counselled for autologous transplant
NOVEL THERAPEUTIC APPROACHES

1. Antibody–drug conjugate that targets CD30-positive cells

2. Most common adverse events :fever (44%), nausea (36%), &
peripheral neuropathy 33%

• ALK Inhibitors: prevent the proliferation of cancer cells

Crizotinib
Alectinib
Ceritinib

• Nivolumab: blocks the ligand activation of the programmed

death-1 cell receptor (PD-1)
 Hematopoietic Stem Cell Transplantation

• CD3+ vs CD3-
• Early relapse vs late relapse
• Auto vs Allogenic ?
 Outcome of childhood NHL in India

• Disease-free-survival (DFS) 74.4%

• Event-free-survival (EFS) 60.7%.
• Treatment-related mortality (TRM) 14.3%
• Relapse/progression 14.5%
• Treatment abandonment 8.4%

• Bone marrow positivity, stage IV disease, and lactate dehydrogenase (LDH) > 2,000 U/l predicted inferior EFS

Ref: Rahiman EA, Bakhshi S, Deepam Pushpam, Ramamoorthy J, Das A, Ghara N, Kalra M, Kapoor G, Meena JP, Siddaigarhi S, Thulkar S, Sharma MC, Srinivasan R, Trehan A. Outcome and
prognostic factors in childhood B non-Hodgkin lymphoma from India: Report by the Indian Pediatric Oncology Group (InPOG-NHL-16-01 study). Pediatr Hematol Oncol. 2022 Aug;39(5):391-405.
doi: 10.1080/08880018.2021.2002485. Epub 2022 Jan 3. PMID: 34978257.
 Take home messages
• Childhood lymphomas form one of the most curable malignancies
• Risk stratification based on stage and unfavourable prognostic factors
• Treatment should be protocol specific
• Prompt Emergency management with high index of suspicion for TLS/SMS
• Chemotherapy forms mainstay of treatment
• Novel therapeutic drugs
 References

• Lanzowsky manual of hematology – 7th edition

• Pizzo and Poplack pediatric oncology- 8th edition
• Rahiman EA, Bakhshi S, Deepam Pushpam, Ramamoorthy J, Das A, Ghara N, Kalra M, Kapoor
G, Meena JP, Siddaigarhi S, Thulkar S, Sharma MC, Srinivasan R, Trehan A. Outcome and
prognostic factors in childhood B non-Hodgkin lymphoma from India: Report by the Indian
Pediatric Oncology Group (InPOG-NHL-16-01 study)
• Case based scenario Rachna seth