nhl for pediatrics2011

Pediatric Lymphomas2011

• NHL of childhood is one of the major success stories of pediatric oncology

Introduction Lymphomas

• Account for 10% to 15% of malignancies in pediatric patients(third most frequent ) – 3% for children younger than 5 years old – 24% for 15- to 19-year-olds. In

• The most common subtypes are Hodgkin lymphoma (HL)and non-Hodgkin Lymphoma (NHL)– Younger children NHL more frequent

– Adolescents HL more common

• The most “curable” forms of pediatric cancer

Hodgkin Lymphoma

• is rare in children under 5 years of age

• Sex predilection– under age 10,more common in boys– Equally affected among adolescents and

young adults

Clinical Presentation

• Indolent, painless lymphadenopathy – the lower cervical and supraclavicular

regions in majority – the size of these nodes may appear to

fluctuate over time – mediastinal involvement in 60% of patients– inguinal lymph nodes in less than 5%

Clinical Presentation

• Constitutional (“B”) symptoms– In up to 25% – are associated with more aggressive

disease

• Bone marrow involvement at diagnosis– is rare (2% of patients)– confined exclusively to those with

advanced disease

Pathology and Prognostic Factors

WHO classification system separates

HL into 2 distinct entities:– classical Hodgkin lymphoma-4 subtypes

• the nodular sclerosis

• mixed cellularity

• lymphocyte-rich

• lymphocyte-depleted subtypes

– the nodular lymphocyte-predominant variant. The former

• includes. According to the National Cancer Institute’s• Surveillance, Epidemiology, and End Results database, the frequency• of nodular sclerosis in children is 70%; mixed cellularity, 16%; lymphocyterich,• 7%; and cases not otherwise specified, 6%. The lymphocyte-depleted• subtype is very rare, constituting less than 2% of all cases. It should• be noted that the mixed cellularity subtype has been reported in up to• 30% of pediatric patients in series outside the United States. The nodularPathology and

Prognostic Factors


• lymphocyte-predominant variant is very rare. It tends to be localized, and• it exhibits a slowly progressive course.• The diagnosis of classical Hodgkin lymphoma requires evidence of• Reed-Sternberg cells, which are derived from B lymphocytes and are positive• for CD15 and CD30. There is also evidence of immunoglobulin gene• rearrangement. Lymphocytic and histiocytic cells are found in the nodular• lymphocyte-predominant variant of Hodgkin lymphoma. These cells• express CD20 and other B-cell antigens but are negative for CD15 and• CD30. Late relapses are more common in this variant than in the classical• subtypes, and some cases of the nodular lymphocyte-predominant variant• may progress to large B-cell non-Hodgkin lymphoma.

• Several prognostic factors have been identified in pediatric Hodgkin• lymphoma. Most studies have shown that clinical features such as advanced• stage (IIIB and IV); bulky mediastinal adenopathy; nodular• sclerosis; B symptomatology, such as fever and weight loss; and laboratory• abnormalities, including anemia, leukocytosis, and hypoalbuminemia,• adversely affect treatment outcome. Prognostic indexes using• a combination of these factors have been proposed, but they have not• been validated in prospective clinical trials. It should also be remembered• that the predictive value of the prognostic factors is decreased by effective• therapy.

Diagnosis and Staging . . .• Diagnosis and Staging• A detailed history should be taken to quantify signs and symptoms related• to lymphadenopathy. Despite the size of mediastinal involvement,• respiratory compromise is rare. It is also important to elicit evidence of• B symptomatology. Studies should then be performed to establish a diagnosis,• to investigate the extent of disease, to assess the prognosis, and• to establish baseline organ functions. The required laboratory and radiographic• tests are excisional biopsy of primary site, complete blood cell• count, sedimentation rate, serum ferritin level, albumin level, liver and• renal profiles, bilateral marrow biopsies (may be reserved for advanced• stages with constitutional symptoms), computed tomography (CT) scans,• bone scans, gallium scan by single photon-emission computed tomography,• echocardiogram, and pulmonary function studies. Recent reports• show that metabolic function studies using whole-body positron-emission• tomography (PET) may detect more disease sites than CT or gallium scans.• Lymphangiography, although sensitive, has been abandoned in favor of• the more sophisticated modalities. It is useful to obtain baseline hormone• profiles. Sperm banking should be discussed with adolescent boys before• the start of chemotherapy.• Clinical staging, according to the Ann Arbor classification system, is still• used in pediatric Hodgkin lymphoma. This system is being combined with• other clinical and laboratory parameters to develop various prognostic

Risk Categories of Hodgkin Lymphoma in Pediatric

Patients

Treatment• Treatment• The management of Hodgkin lymphoma in pediatric patients has evolved• over the past 4 decades. Accumulated experience from clinical trials has• provided the following information.• When radiotherapy is used alone, relatively high doses and large• fields are required. The local control rate of early-stage Hodgkin• lymphoma is lower with radiotherapy alone than with radiotherapy• plus chemotherapy, but the overall survival rate resulting from• these 2 treatment approaches is about the same.• Multiagent chemotherapy allows lower doses and smaller fields of• irradiation to be used, limiting the treated volume to areas of known• involvement rather than extending fields to cover nearbylymphnode• groups.• Involved field (IF) radiotherapy (less than 25 Gy) combined with• chemotherapy improves the event-free survival rate compared with• chemotherapy alone in advanced Hodgkin lymphoma (Children’s• Cancer Group study 5942 and Pediatric Oncology Group study 8725).• However, the overall survival rates of these 2 treatment options are• similar.• It is not necessary to prolong therapy after complete remission is• achieved.• The gonadotoxic and leukemogenic potentials of alkylating agents• led to attempts to modify chemotherapy. Mechlorethamine and procarbazine• have now been replaced by less toxic drugs.• Because of the possibility of late relapses and the confounding effects• of late complications, reports with a median follow-up of less than• 5 years from diagnosis should be interpreted with caution.• Although conventional chemotherapy with or without radiotherapy• produces excellent results for the majority of patients with Hodgkin• lymphoma, hematopoietic stem cell transplantation (HSCT) can play

• an important role in the management of patients for whom frontline

• therapy fails to produce a response

Therapy for Primary Disease

• Therapy for Primary Disease

• The current treatment approach for children with Hodgkin lymphoma involves• risk-adapted, combined-modality therapy. A dose-intense strategy

• is also being investigated and is aimed at reducing the duration of therapy• and lowering the cumulative doses of individual chemotherapeutic agents.

• In ongoing clinical trials, therapy is determined on the basis of tumor• response at the end of the second or third cycle of chemotherapy.With this• response-based strategy, the dose of subsequent radiotherapy, subsequent• chemotherapy, or the combination of these is determined by the result of• a disease evaluation at that point in time. Patients with 70% or greater

• reduction in tumor burden are considered rapid early responders (RERs),• and patients with less reduction in tumor burden are considered slow early

• responders (SERs)

• An increase in the intensity of induction chemotherapy appears to improve• treatment outcome in adults with advanced-stage Hodgkin lymphoma.• In the current North American pediatric trial (not yet published),• patients receive 2 cycles of dose- and time-intensive chemotherapy. After• disease evaluation, RERs receive further therapy; the strategy for the• supplemental therapy is sex specific. Girls receive 4 additional cycles of• maintenance chemotherapy, but radiotherapy is omitted. This approach is• designed to avoid the high incidence of breast cancer among girls given• mediastinal irradiation. Boys receive a nonalkylator chemotherapy regimen• that includes doxorubicin, bleomycin, vincristine, and dacarbazine• (ABVD) plus IF irradiation. The goal of this treatment is to preserve fertility.• SERs continue receiving 4 additional cycles of induction chemotherapy• along with IF irradiation. For intermediate-risk Hodgkin lymphoma,• RERs are randomly assigned to receive or not receive IF irradiation. All• SERs receive radiotherapy, and half of them are treated with augmented• chemotherapy.• The nodular lymphocyte-predominant variant of Hodgkin lymphoma• is usually localized and runs an indolent course. Treatment with rituximab• alone produces a high response rate, but the durability of the remission is• not known

Therapy for Recurrent Disease

• Therapy for Recurrent Disease• Patients with primary treatment failure (defined as either disease progression• or incomplete response to initial therapy, unequivocal radiographic• disease progression after achievement of a partial response, or presence• of biopsy-documented residual Hodgkin lymphoma after primary treatment)• and those with a brief initial remission (less than 12 months) have a• particularly poor prognosis. Single-center studies have shown that highdose• chemotherapy followed by autologous stem cell rescue can improveTherapy for Recurrent

Disease• Patients with primary treatment failure (defined as either disease progression• or incomplete response to initial therapy, unequivocal radiographic• disease progression after achievement of a partial response, or presence• of biopsy-documented residual Hodgkin lymphoma after primary treatment)• and those with a brief initial remission (less than 12 months) have a• particularly poor prognosis. Single-center studies have shown that highdose• chemotherapy followed by autologous stem cell rescue can improve

• these patients’ long-term disease-free survival rate. Overall, 31% to 67%• of patients remain disease-free after HSCT; therefore, it is considered the• treatment of choice for these patients.• Children with recurrent or relapsed Hodgkin lymphoma should first• receive re-induction chemotherapy. The regimens usually consist of noncross-• resistant agents such as cisplatin, cytosine arabinoside, and ifosfamide.• Newer agents, including gemcitabine and vinorelbine, when given• individually or in combination often produce a good response. We have• also included rituximab, an anti-CD20 antibody, in our regimen. Rituximab• has been shown to produce some response, although most cases of• Hodgkin lymphoma are CD20 negative. The positive effect of rituximab is• thought to relate to its effect on the cellular milieu surrounding the lymphoma• cells. At M. D. Anderson, we are also testing the activity of the• anti-CD30 monoclonal antibody in refractory Hodgkin lymphoma. PET• can be used to decide metabolic activity in any residual lesions detected• on CT or magnetic resonance imaging scan. PET is often used to decide the• optimal time to begin the transplant phase of treatment

• The conditioning regimen most commonly used in the Division of• Pediatrics at M. D. Anderson consists of carmustine (or BCNU), etoposide,• cytosine arabinoside, and melphalan (BEAM). Following hematologic recovery,• we administer interferon alfa as maintenance therapy. The starting• dose is 0.5 million units/m2 given subcutaneously 3 times a week, which• is increased gradually to 1 to 1.5 million units/m2 5 times a week. This• treatment is continued for 1 year after the transplant. Early results suggest• that this approach results in an increased disease-free survival rate. Additionally,• local radiotherapy to sites of previous disease involvement is• recommended.• Patients whose recurrent Hodgkin lymphomas do not respond completely• (incomplete response) after reinduction chemotherapy and patients• with marrow involvement have a very grave prognosis, even after autologous• HSCT. Allogeneic HSCT with conventional myeloablative conditioning• is associated with a very high transplant-related mortality rate. Any• potential benefit from a graft-versus-lymphoma effect may be negated.• More recently, a reduced-intensity preparative regimen based on fludarabine• in combination with melphalan or cyclophosphamide has been used.• Preliminary results have shown regular donor-cell engraftment and encouraging• short-term outcome.

Long-Term Side Effects

• Long-Term Side Effects• Because most children with Hodgkin lymphoma have an excellent

outcome,• the mortality rate associated with complications of therapy is about• the same as the mortality rate associated with the primary tumor.

The major• late effects of radiotherapy include atherosclerotic heart disease,

thyroid• dysfunction, soft-tissue hypoplasia, and retardation of bone

growth.• The most devastating complication is the incidence of second

malignant

• neoplasms, which continues to increase with extended follow-up. The risk• for breast cancer in girls who receive thoracic irradiation is high, and we• recommend that annual mammography begin 10 years after treatment.• Breast self-examination should be practiced once the girl reaches puberty.• The incidence of late effects, especially second malignant neoplasms, following• treatment with low-dose IF irradiation is yet unknown, but it is• expected to be lower than that associated with higher doses of irradiation.• Serious late effects can also be caused by certain chemotherapy• drugs (for example, sterility can result from alkylating agents, secondary• leukemia from alkylating agents and etoposide, pulmonary fibrosis from• bleomycin, and cardiomyopathy fromanthracyclines). It should be emphasized,• however, that the treatment of relapse can itself increase the risk for• a second malignancy; therefore, the danger of inadequate frontline therapy• cannot be ignored

Non-Hodgkin Lymphoma

Clinical Presentation .

Diagnosis and Staging

Treatment . .

Therapy for Primary Disease

Therapy for Recurrent Disease

Key Practice Points

WHO classification- Lymphoid neoplasmsDLBCL Mycosis fungoides/Sezary

Marginal zone lymphoma Peripheral T-cell lymphoma

Follicular lymphoma -Anaplastic large cell lymphoma

CLL/SLL -peripheral T lymphoma NOS

Mantle cell lymphoma -T/NK cell lymphoma

Burkitt lymphoma/leukemia -γδ lymphomas

Plasma cell neoplasms Lymphoblastic lymphomas

Multiple myeloma -T-precursor leukemia/lymphoma

Plasma cell leukemia -B-precursor Leukemia/lymphoma

Plasmacytoma Angioimmunoblastic lymphoma

Hairy cell leukemia

Lymphoplasmacytic lymphoma

Waldenstrom macroglobulinemia

B-cell lymphoid neoplasms, NOS

Pediatric NHLn=2174 registered on BFM studies (Burkhardt B, Zimmermann M, Oschlies I et al.2005)

Burkitts Lymphoblastic Large cell

52% 23% 25%

B-cell large cell (DBCLC) 11%

Anaplastic(ALCL) 14% ( Non-ALCL peripheral T-cell (rare) e.g mycosis

fungoides)

Pediatric NHL-what cell line are they?

Burkitts Lymphoblastic Large cell 52% 23% 25%

B-cell large cell (DBCLC) 11% Anaplastic(ALCL) 14%

Mature B-cell immature -T cell 85% Mature T cell immature -B-cell 15% Non-ALCL peripheral T-cell

B-cell development

Tdt TdtTdt

HLA-DR

Ig genesgermline

HLA-DR

CD10

CD19

CD22CD22

HLA-DR

CD19CD10

cIG

SIg

CD20CD20

CD22 CD138

→

Pro B Early B Pre-B Mature B Plasma cell

B-lineage lymphoblastic leukemia/lymphoma

Burkitts B-ALLLarge B-cell

Myeloma

CD79a

CD10

→ → →

Rearranging immunoglobulin genes

Stem cell

CD34

T-cell development

Tdt TdtTdt

CD7 CD7

CD2

CD7

CD2cCD3

CD3CD7

CD4 CD8

CD4

CD8

Early thymocyte

Commonthymocyte

Mature thymocyte

MaturePeripheralT cell

Immature T-Lymphoblastic leukemia/ lymphoma

CD3CD7

CD7

CD3

TCR

TCR

ALCL

CD5 helper T

suppressor

Rearranging T-cell receptor genes

Childhood NHL

• Is it important to distinguish the different pediatric lymphomas?

• The results of lymphoma therapy depend on giving the correct type of therapy for that type of lymphoma

• What can you do when you cannot get cell typing?

• Use clinical features

Clinically can usually distinguish Burkitts from lymphoblastic

QuickTime™ and a decompressor

are needed to see this picture.

Where does Burkitts lymphoma arise?

Arise in relatively mature B lymphocytes

80% Peyers patches ie Abdominal mass

20% Waldeyer’s ring (tonsil and adenoid)

Endemic -jaw --often localized

Burkitts Lymphoma localized abdominal where Peyers patches are

most dense

>>ileocaecal area• often lead point for intussusception or • diagnosed during surgery for appendicitis

Complete excision and 6 weeks chemoRx >95% cured

Advanced Burkitt’s abdomen

Burkitts lymphoma Advanced disease: abdominal in endemic and sporadic formsAbdominal painAbdominal DistentionAscites Right pleural effusion (but not lung)Commonly involves kidneyCommonly spreads to CNS and bone marrow --

less in endemic Endemic more paraspinal (epidural) --

paraplegia

Burkitts

• Differences endemic /sporadic Burkitts?

Burkitts lymphoma

Sporadic Endemic

0.2/10,000 10/100,000

Abd mass Abd mass

Jaw occ Jaw 70%

Leptomeningeal Extradural- paraplegia

t(8;14) t(8;14) diff

breakpoint in the Ig gene

EBV 15% EBV 95%

Burkitts lymphomaOrem et al, African Health Sciences 2007

Endemic Sporadic HIV-assocAge 2-9 yrs any age 10-19(any)

Area Malaria none Africa

EBV 100% 30% Africa yes other no Cure poor 90% good if HIV low and CD4 OK

Burkitts lessons

• Early diagnosis --- keep high index suspicion –highly treatable condition

• Intussusception in a child >2 years of age

think about lymphoma

Burkitt’s- lessons

• Back pain • Back tenderness ---In a patient with possible malignancy spinal cord SPINAL CORD! SPINAL CORD!!!

MRI or contrast CT same day!!No spinal tap until MRI spine reported

What about therapy?

• Localized vs advanced stage disease

Lessons learned from trials in African Burkitts lymphoma

• Single agent Cyclophosphamide results in approx 48% survival in Burkitts (Malawi and French trials).

Summary Localized B-NHL and ALCL

• tumor lysis or severe malnutrition or dehydration -- correct hydration and electrolytes and start with a low dose COP prephase

Advanced B-NHL

• LMB studies (SFOP)1974-1980 COPAD EFS stage III 42% IV 32%

1981-1996 LMB EFS stage III 91% IV 87%

How did they do this?

Burkitt’s lymphoma

• >95% cells in cycle

• Doubling time 17-72 hours

• High spontaneous cell death rate –up to 70% in big tumors

• N.B. tumor lysis syndrome!!

• Early and rapid diagnosis and therapy

Why discuss growth rate?

For advanced disease need Cytotoxic blood and CSF levels for at least 72 hours

• LMB Cyclo 250mg/m2 q12h x 6 covering the 72 hours

• BFM Cyclophosphamide 500mg/m2/d x 5

• POG 9317 --72 hours Cyclo 500mg/m2 bid

• CSF also: Intrathecal chemo day 1, 3 and 5 or day 1

and 5

Endemic Burkitts• Same high growth rate

• Same risk of tumor lysis and kidney failure

• African Trials summarized by Magrath I Current Opinion in Oncol 2009

• Simultaneous drug combinations from beginning better

• Need effective CNS preventive therapy Intrathecal therapy over several cycles

Lymphoblastic lymphoma ~25% of NHL

• How does it present?

• T-cell 85% -thymus

--Majority present with an anterior mediastinal mass

--infrequently only with neck/axillary nodes

• B-cell 15% --anywhere -Rx like ALL

Lymphoblastic lymphoma

90% advanced stage

• Mediastinal mass always stage III

• Bone marrow

• CNS

• 10% localized to lymph nodes

Lymphoblastic lymphoma

• Basically leukemia (ALL) type therapy

• 24 months duration

• No cranial radiation if CNS negative

ALCL

• 14% of childhood NHL

• Any site

• Lymphoma in unusual sites –skin, bone, lung -usually large cell

ALCL

• Adenopathy may be tender• Nodes may fluctuate for a while before increasing• May present with systemic symptoms---fever, night

sweats, weight loss, neutrophilia• In differential diagnosis of fever and tender

adenopathy• Often involves skin, nodes and bone• May produce diffuse pulmonary disease

ALCL

Diagnosis made on immunostains

CD30 pos

t(2;5) NPM-ALK

ALK pos

If not available --? Suggested at least on morphology?

Does diagnosis matter?

Not as much as lymphoblastic

• ALCL99 -based on BFM Low risk B-cell protocol

4 courses for intermediate risk

6 courses for high risk ( stage IV)

ALCL –outcome by therapyALCL –outcome by therapy

no. Duration EFS OSno. Duration EFS OS

ALCL99 99-2006 352 4.5-12mo 74ALCL99 99-2006 352 4.5-12mo 744% 924% 923 %3 %

POG9315 94-2000 86 12mo 71POG9315 94-2000 86 12mo 716% 866% 864%4%

CCG5941 96-2001 86 48wk 70CCG5941 96-2001 86 48wk 7010% 8010% 807%7%

ALCL

• Because difficult to diagnose without special studies

• Suggest use same protocol as for B-cell NHL rather than T-NHL

Summary

• In absence of special stains and genetics need to try to make a clinical distinction between lymphoblastic lymphoma and the others

• Lymphoblastic localized and advanced needs ALL type therapy for 18-24 months

• B-NHL and ALCL can be treated on the same protocols -but different intensity and duration for localized and advanced stage disease

Pediatric lymphoma

• One of great success stories in developed countries

• Improving in developing countries• Certain principles of therapy that can be

applied • Others may prove to be too toxic but are

worth trying in this setting of academic pediatrics --but expense needs to be considered

Characteristics of pediatric NHL Burkitt Lymphoblastic DLBCL ALCL 52% 25% 11% 14% mature B immature T (80%) mature B mature T

Abd chest any any

t(8;14) Notch1, t(2;5)(ALK) others

Rx 3-6mo 24mo 3-6mo 4-12mo

EFS 90% 85% 90% 76%

Possible adjusted COMP • Cyclophosphamide 250mg/m2/d x 3 • Methotrexate 300mg/m2 d 1• Vincristine 1.5mg/m2 d 1• Prednisone 60mg/m2 /day x 5• Double IT chemo x 2 doses day 1 and day

5

Repeat courses every 3 weeks or as soon as count recovery to neutrophils 750 and platelets 75,000 and patient well.

If patient tolerates well consider increasing cyclo dose to 250mg/m2 x 5 days per course

Mature from Immature lymphocytes?

• Presence of the enzyme terminal deoxytransferase (TDT) means cell is immature i.e lymphoblast

e.g. pleural fluid or pericardial fluid in a patient with a mediastinal mass

? Infiltration with lymphoma and therefore useful for diagnosis e.g T-cell lymphoblastic lymphoma?

or ? Fluid due to compression by the mass and the cells in

the fluid are normal small lymphocytes e.g Hodgkins disease

Mature vs immature lymphocytes?

Normal lymphocytes in pleural or pericardial fluid can look like lymphoblasts ( thoracic duct thymocytes) and therefore morphology can be misleading.

Use TdT ( chemical stain) to differentiateTdT pos = immature cell =lymphoblastic lymphoma -

don’t need biopsyTdT neg =mature lymphocyte =something else- ?

Hodgkins? --need biopsy

• Bigger problem with large cell=the big mimickers

but Burkitts and Large B-cell lymphoma is treated

with the same protocols

Although not ideal --Anaplastic large cell could be suspected morphologically

In practical terms

• Important to distinguish the Lymphoblastic lymphomas

• The remainder could be treated on the same B-cell protocol

• With any protocol watch response and change if not good--all lymphomas should be in remission by 9 weeks

nhl for pediatrics2011

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