HODGKIN LYMPHOMA IN CHILDREN Dr.M.Shamvil Ashraf Children Cancer Hospital, Karachi.

HODGKIN LYMPHOMA IN HODGKIN LYMPHOMA IN CHILDRENCHILDREN

Dr.M.Shamvil AshrafDr.M.Shamvil Ashraf

Children Cancer Hospital,Children Cancer Hospital,

Karachi. Karachi.

Hodgkin LymphomaHodgkin Lymphoma

One of the most curable cancer in childrenOne of the most curable cancer in children There are different effective treatment There are different effective treatment

approachesapproaches Can be cured with limited resourcesCan be cured with limited resources

EpidemiologyEpidemiology

Developed CountriesDeveloped Countries 5 - 6% of childhood cancers5 - 6% of childhood cancers

Male:Female 3-4:1 in <10yMale:Female 3-4:1 in <10y

Male:Female 1.3:1 in >10yMale:Female 1.3:1 in >10y

Bimodal age peak- Bimodal age peak-

adolescent/young adult, adolescent/young adult,

50yo50yo

Uncommon in <10 yrs Uncommon in <10 yrs

Karachi DataKarachi Data 10% of childhood cancers10% of childhood cancers

Male:Female 4.7:1 in <10yMale:Female 4.7:1 in <10y

Male:Female 1.7:1 in >10yMale:Female 1.7:1 in >10y

> 5 years 24%> 5 years 24%

>10years 62%>10years 62%

BiologyBiology

Inflammatory milieu with rare multinucleated Inflammatory milieu with rare multinucleated giant cells (Reed-Sternberg cells) or large giant cells (Reed-Sternberg cells) or large mononuclear cell variants (Hodgkin’s or mononuclear cell variants (Hodgkin’s or lacunar cells)lacunar cells)

R-S cell appears to arise from preapoptotic R-S cell appears to arise from preapoptotic germinal center B cells (no Ig production), germinal center B cells (no Ig production), although rarely may arise from T cellsalthough rarely may arise from T cells

RS cellsRS cells

Lacunar CellsLacunar Cells

Cellular ClassificationCellular Classification

Classical HL (CD15, CD30 +, B cell markers )Classical HL (CD15, CD30 +, B cell markers ) nodular sclerosis (50-60%)nodular sclerosis (50-60%) mixed-cellularity (20-30%)mixed-cellularity (20-30%) lymphocyte rich (<5%)lymphocyte rich (<5%) lymphocyte depleted (5-15%)lymphocyte depleted (5-15%)

Nodular Lymphocyte Predominant HL (5%) Nodular Lymphocyte Predominant HL (5%) (CD15 -, CD30 +/-, B cell markers +)(CD15 -, CD30 +/-, B cell markers +)

MC

NS

NLPHL

not specified

44 (55%)21 (26%)

2 (2.5%)

13 (16.2%)

Pathological Subtypes; Karachi DataPathological Subtypes; Karachi Data

Clinical PresentationClinical Presentation

Painless adenopathy (80%)Painless adenopathy (80%) B symptoms (25-30%)B symptoms (25-30%)

fever >38fever >3800C x 3 daysC x 3 days wt loss >10% of body wt. over 6 mowt loss >10% of body wt. over 6 mo drenching night sweatsdrenching night sweats

Bulky disease (20%)Bulky disease (20%) med mass >1/3 of internal thoracic diametermed mass >1/3 of internal thoracic diameter node/nodal aggregate >6 cmnode/nodal aggregate >6 cm

Clinical PresentationClinical Presentation

15% to 20% of patients will have 15% to 20% of patients will have noncontiguous extranodal involvement noncontiguous extranodal involvement

The most common sites of extranodal The most common sites of extranodal involvement are the lung, liver, bones, and involvement are the lung, liver, bones, and bone marrow bone marrow

Hodgkin vs TBHodgkin vs TB

Most common differential especially if limited Most common differential especially if limited to cervicalto cervical

Often put on ATT without definitive diagnosisOften put on ATT without definitive diagnosis Biopsy is essentialBiopsy is essential

DiagnosisDiagnosis

Excision Biopsy of NodeExcision Biopsy of Node Needle Biopsy of mass if excision not possible Needle Biopsy of mass if excision not possible FNAC is not recommended in childrenFNAC is not recommended in children

StagingStaging

Ann Arbor staging system I-IVAnn Arbor staging system I-IV ““A” vs “B”A” vs “B” ““E”- extralymphatic disease resulting from E”- extralymphatic disease resulting from

direct extension of involved LN regiondirect extension of involved LN region ““S”- splenic diseaseS”- splenic disease ideally want pathologic confirmation of ideally want pathologic confirmation of

noncontiguous extralymphatic involvement noncontiguous extralymphatic involvement (Stage IV disease)(Stage IV disease)

Ann Arbor StagingAnn Arbor Staging Stage I:Stage I: Involvement of single lymph node region (I) or localized involvement of a single Involvement of single lymph node region (I) or localized involvement of a single

extralymphatic organ or site (Iextralymphatic organ or site (IEE))

Stage II:Stage II: Involvement of two or more lymph node regions on the same side of the diaphragm Involvement of two or more lymph node regions on the same side of the diaphragm (II) or localized involvement of a single extralymphatic organ or site and its regional lymph (II) or localized involvement of a single extralymphatic organ or site and its regional lymph node(s) with involvement of one or more lymph regions on the same side of the diaphragm node(s) with involvement of one or more lymph regions on the same side of the diaphragm (II(IIEE))

Stage III:Stage III: Involvement of lymph node regions on both sides of the diaphragm (III), which Involvement of lymph node regions on both sides of the diaphragm (III), which may also be accompanied by localized involvement of an extralymphatic organ or site (IIImay also be accompanied by localized involvement of an extralymphatic organ or site (IIIEE), ),

by involvement of the spleen (IIby involvement of the spleen (IISS), or both (III ), or both (III E+SE+S))

Stage IV:Stage IV: Disseminated (multifocal) involvement of one or more extralymphatic organs or Disseminated (multifocal) involvement of one or more extralymphatic organs or tissues, with or without associated lymph node involvement, or isolated extralymphatic organ tissues, with or without associated lymph node involvement, or isolated extralymphatic organ involvement with distant (non-regional) nodal involvement.involvement with distant (non-regional) nodal involvement.

Staging WorkupStaging WorkupImagingImaging CXRCXR U/SoundU/Sound CT scan of neck, chest, abdomen and pelvisCT scan of neck, chest, abdomen and pelvis GalliumGallium PET ScanPET ScanOther TestsOther Tests Bone marrow aspirate and trephine only in Bone marrow aspirate and trephine only in

Patients with stage II B or morePatients with stage II B or more Bone scan only in stage III or moreBone scan only in stage III or more Blood testsBlood tests

CBCCBC LDHLDH Urea, Cr, electrolytes, Ca, Mg, LFTsUrea, Cr, electrolytes, Ca, Mg, LFTs Hepatitis screeningHepatitis screening

Therapy: History

XRT alone cured early stage disease 1960s- MOPP 1970s- ABVD Combined modality therapy (CMT)

Chemotherapy and radiation

Therapy HistoryTherapy History

Good results were obtained but at the cost of Good results were obtained but at the cost of severe late toxicitiessevere late toxicities

XRT ; profound musculoskeletal growth XRT ; profound musculoskeletal growth retardation and increase the risk for retardation and increase the risk for cardiovascular disease and secondary solid cardiovascular disease and secondary solid malignancies in children malignancies in children

Chemotherapy induced gonadal Chemotherapy induced gonadal injury,cardiovascular disease and SMNinjury,cardiovascular disease and SMN

Combination Chemotherapy Regimens Commonly Used for Combination Chemotherapy Regimens Commonly Used for Children and Young Adults with Hodgkin LymphomaChildren and Young Adults with Hodgkin Lymphoma

ABVDABVD doxorubicin (Adriamycin), bleomycin, vinblastine, dacarbazinedoxorubicin (Adriamycin), bleomycin, vinblastine, dacarbazine

ABVEABVE doxorubicin (Adriamycin), bleomycin, vincristine, etoposidedoxorubicin (Adriamycin), bleomycin, vincristine, etoposide

VAMPVAMP vincristine, doxorubicin (Adriamycin), methotrexate, vincristine, doxorubicin (Adriamycin), methotrexate, prednisoneprednisone

OPPA +/- OPPA +/- COPPCOPP

vincristine, prednisone, procarbazine, doxorubicin, vincristine, prednisone, procarbazine, doxorubicin, cyclophosphamide, vincristine (Oncovin), prednisone, cyclophosphamide, vincristine (Oncovin), prednisone, procarbazineprocarbazine

COPP/ABVCOPP/ABV cyclophosphamide, vincristine (Oncovin), prednisone, cyclophosphamide, vincristine (Oncovin), prednisone, procarbazine, doxorubicin (Adriamycin), bleomycin, procarbazine, doxorubicin (Adriamycin), bleomycin, vinblastinevinblastine

BEACOPPBEACOPP bleomycin, etoposide, doxorubicin (Adriamycin), bleomycin, etoposide, doxorubicin (Adriamycin), cyclophosphamide, vincristine (Oncovin), prednisone, cyclophosphamide, vincristine (Oncovin), prednisone, procarbazineprocarbazine

Hodgkins Therapy in 90`sHodgkins Therapy in 90`s

Prognostic factors and risk grouping concept Prognostic factors and risk grouping concept introducedintroduced

Radiation dose and field were reducedRadiation dose and field were reduced Involved Field Radiotherapy introducedInvolved Field Radiotherapy introduced Chemotherapy regimen were manipulatedChemotherapy regimen were manipulated

to reduce cumulative dose and avoid long term to reduce cumulative dose and avoid long term toxicitiestoxicities

Determining Risk Assignment

I

Chemotherapy Options

Current ApproachesCurrent Approaches

Current approaches use chemotherapy with or Current approaches use chemotherapy with or without LD-IFRTwithout LD-IFRT

An exception to this general approach is selected An exception to this general approach is selected patients with stage I, completely resected, nodular patients with stage I, completely resected, nodular lymphocyte-predominant Hodgkin lymphoma, whose lymphocyte-predominant Hodgkin lymphoma, whose initial treatment may be surgery alone. initial treatment may be surgery alone.

The number of cycles and intensity of chemotherapy The number of cycles and intensity of chemotherapy may be determined by the rapidity and degree of may be determined by the rapidity and degree of response, as is the radiation dose and volume.response, as is the radiation dose and volume.

Approach for Developing CountriesApproach for Developing Countries

Chemotherapy AloneChemotherapy Alone If radiotherapy is not availableIf radiotherapy is not available Pediatric radiotherapy service is not developedPediatric radiotherapy service is not developed Good result (up to 80% survival) can be obtained Good result (up to 80% survival) can be obtained

as shown by Indian Experienceas shown by Indian Experience

(Arya et al)(Arya et al)

Approach for Developing CountriesApproach for Developing Countries

Chemotherapy with Radiotherapy only for Chemotherapy with Radiotherapy only for bulky residual diseasebulky residual disease

Excellent result can be achieved with this Excellent result can be achieved with this approach as shown by our experience at approach as shown by our experience at Children Cancer HospitalChildren Cancer Hospital

CCH DataCCH Data Retrospective studyRetrospective study From Aug 2000 - 2007All the patients with From Aug 2000 - 2007All the patients with

histopathological diagnosis of Hodgkin histopathological diagnosis of Hodgkin Lymphoma, up to 20 years of age were Lymphoma, up to 20 years of age were includedincluded

Mean age: 9.9 yrsMean age: 9.9 yrs Pts. included in the study – 80Pts. included in the study – 80

Treatment Strategy At CCHTreatment Strategy At CCH Chemotherapy used was alternating courses of Chemotherapy used was alternating courses of

ABVD (adriamycin, bleomycin, vincristine and ABVD (adriamycin, bleomycin, vincristine and dacarbazine) dacarbazine)

COPDAC (cyclophophamide, vincristine, COPDAC (cyclophophamide, vincristine, prednisolone and dacarbazine)prednisolone and dacarbazine)

Radiotherapy was reserved only for the pts. Radiotherapy was reserved only for the pts. with significant residual disease at the end of with significant residual disease at the end of chemotherapychemotherapy

Response AssessmentResponse Assessment

CT scan of all the sites positive on pre CT scan of all the sites positive on pre treatment scan was repeated after 2 cyclestreatment scan was repeated after 2 cycles

Bone marrow or bone scan was repeated only Bone marrow or bone scan was repeated only if it was positive initiallyif it was positive initially

For good responder CT was repeated after 6 For good responder CT was repeated after 6 cyclescycles

PET scan could not be performed because of PET scan could not be performed because of non-availabilitynon-availability

Response Assessment CriteriaResponse Assessment Criteria

CR was taken as complete resolution of all CR was taken as complete resolution of all measurable disease, clinically and radiologicallymeasurable disease, clinically and radiologically

>80% response was taken as good response>80% response was taken as good response 60 to 80% was taken as partial response60 to 80% was taken as partial response <60% was taken as poor response or stable disease<60% was taken as poor response or stable disease Any increase in the size of an existing lesion or Any increase in the size of an existing lesion or

appearance of any new lesion during treatment was appearance of any new lesion during treatment was taken as progressive diseasetaken as progressive disease

Response Adapted TherapyResponse Adapted Therapy

Low risk patients with CR after 2 courses Low risk patients with CR after 2 courses received 4 coursesreceived 4 courses

All other pts were given 6 – 8 courses All other pts were given 6 – 8 courses depending upon the response (CR + 2 courses)depending upon the response (CR + 2 courses)

11(13.7%) pts received 4 courses11(13.7%) pts received 4 courses Majority of pts 56 (70%) received 6 coursesMajority of pts 56 (70%) received 6 courses

Radiation TherapyRadiation Therapy Radiation therapy was reserved only for the Radiation therapy was reserved only for the

pts with residual disease at the end of chemopts with residual disease at the end of chemo only 8 (10%) needed radiationonly 8 (10%) needed radiation

Stage II A – 1 ptStage II A – 1 pt Stage II B – 1 ptStage II B – 1 pt Stage III B – 3 ptsStage III B – 3 pts Stage III BS – 1 ptStage III BS – 1 pt Stage IV – 2 ptsStage IV – 2 pts

Results Results

74 (92%) pts achieved first remission (CR) 74 (92%) pts achieved first remission (CR) after 2 courses of chemotherapyafter 2 courses of chemotherapy

Only one pt. died during chemotherapy due to Only one pt. died during chemotherapy due to meningitismeningitis

One pt. relapsed on treatment and was One pt. relapsed on treatment and was switched to second line treatment switched to second line treatment

4 (5%) pts relapsed 2 – 12 months after 4 (5%) pts relapsed 2 – 12 months after completion of chemotherapycompletion of chemotherapy

3 yrs OS 98% and EFS 92%3 yrs OS 98% and EFS 92%

Progressive/Relapsed Ds

• Prognostic factors: – progressive ds or relapse at <1y from end of treatment

– B symptoms

– extranodal ds

– response to salvage therapy

Chemotherapy OptionsChemotherapy Options Salvage therapies (with harvest)Salvage therapies (with harvest)

ICE, EPIC,mini-BEAM, DHAP, ASHAP, ICE, EPIC,mini-BEAM, DHAP, ASHAP, bortezomibbortezomib//ifos/vinorelbine (AHOD 0521)ifos/vinorelbine (AHOD 0521), GDP (PMH), GDP (PMH)

Autologous transplantAutologous transplant conditioning: conditioning: CBVCBV, BEAM, VP16/melphalan, BEAM, VP16/melphalan BEAM plus immunomodulation (AHOD 0121)BEAM plus immunomodulation (AHOD 0121)- closed- closed

Refractory Disease

• Gemcitabine/Vinorelbine AHOD 0321- closed

– eligibility: >/= 2 prior regimens– beware non-cardiogenic pulmonary edema– may require 4-6 cycles to see response

• Vinblastine, lomustine, VP16

• New agents/targeted therapies

Late EffectsLate Effects

Cardiotoxicity and Musculoskeletal problems Cardiotoxicity and Musculoskeletal problems are now rare are now rare

EndocrineEndocrine Thyroid ; HypothyroidismThyroid ; Hypothyroidism Fertility; Fertility;

Increased risk of ovarian failure in womenIncreased risk of ovarian failure in women Oligospermia and sterility in menOligospermia and sterility in men

Second Malignant NeoplasmSecond Malignant Neoplasm

Conclusion Conclusion Chemotherapy alone in majority of patients with Chemotherapy alone in majority of patients with

Hodgkin Lymphoma can yield excellent outcomeHodgkin Lymphoma can yield excellent outcome

Most of Hodgkin Disease pts can be managed without Most of Hodgkin Disease pts can be managed without

the use of radiotherapy, thereby minimizing the the use of radiotherapy, thereby minimizing the

adversity associated with radiation, specially in adversity associated with radiation, specially in

young childrenyoung children

Hodgkin Lymphoma can be cured within limited Hodgkin Lymphoma can be cured within limited

resourcesresources

Monitoring for late effects is importantMonitoring for late effects is important