Update in Pediatric Hodgkin Lymphoma

Transcription

1 Update in Pediatric Hodgkin Lymphoma Jeff Deyo, MD, PhD Medical Director, Baton Rouge Affiliate St Jude Children s Research Hospital Our Lady of the Lake Children s Hospital Acadiana Potpourri, August 19, 2017

2 Disclosure Statement Unfortunately I have nothing to disclose No lucrative contracts No endorsement deals No payment for patient recruitment

3 Outline Background including Epidemiology, Pathology and Biology Staging and Diagnostic Workup Treatment advances emphasizing the importance of Clinical Trial participation Conclusions Future Directions 3

4 Major Take Home Points of Discussion Advances in diagnosis and staging Use of PET CT for metabolic-based disease evaluation Standardization efforts in staging patients to allow for more reliable comparisons between treatment regimens Advances in Therapy Radiation Therapy (RT) reduction for select patients to reduce late effects Upfront targeted therapy

5 Hodgkin Lymphoma Sir Thomas Hodgkin is credited with the initial description of the clinical disorder that bears his name in 1832 Today, HL represents 6-7% of Childhood cancers, 1% of childhood cancer deaths Approximately 1,180 children and adolescents each year are diagnosed with Hodgkin lymphoma in the United States Virtually unknown in infants, #1 pediatric cancer in 15-19yo adolescents High survival rates 5 year overall survival (OS) rate for early stage disease exceeds 90% - regardless of the therapeutic regimen chosen Even high risk disease has cure rates > 85% with modern therapy, unfortunately with increased risk of late effects Research now is largely aimed at long term toxicity reduction through improved risk stratification, response-adapted therapy and novel, less toxic frontline and salvage agents

6 Late Effects of Therapy Involved organ Agents Side effects Cardiac Pulmonary Gonadal Bone Second malignancies Thyroid Anthracyclines Radiotherapy Bleomycin Radiotherapy Alkylating agents Radiotherapy Steroids Radiotherapy Alkylating agents Topoisomerase II inhibitors Radiotherapy Radiotherapy Cardiomyopathy Arrythmias Pericarditis Coronary artery disease Fibrosis Delayed puberty Azoospermia Hypogonadism Osteopenia Osteonecrosis Hypoplasia Leukemia Sarcomas Breast cancer Hypothyroidism Thyroid cancer 6

7 Context of Leukemia - Lymphoma UptoDate 2005 UpToDate

8 Epidemiology M>F M>F Childhood cases associated with primary EBV infection (developing countries) peak < 10 years of age. Young adult age group, associated with delayed primary EBV-infection peak years of age. Older adult group, accounts for most cases over 55 years. Non-EBV-associated Hodgkin lymphoma is the largest group and accounts for the young adult peak in developed countries. Macsween et al. The Lancet Infectious Disease 2003 Jarrett et al. Ann Oncol

9 Distribution of Common Pediatric Malignancies About 1 in 300 boys and 1 in 333 girls will develop cancer before their 20 th birthdate ,569 American Childhood Cancer Statistics 2012

10 df Population of Louisiana Total Number Potential HL cases All ages 4,468, Ages 0-19 yo 1,368,029 16

11 Pathology and Biology classical HL Nodular Sclerosing Mixed cellularity Lymphocyte rich Lymphocyte depleted 60-80% of cases 15-30% of cases 4% of cases < 1% of cases Equal age distribution Most common in < 10y/o age More common in the elderly Found in HIV+ and elderly pts Supradiaphragmatic disease Abdomen and spleen Limited stages Advanced stages 11

12 Pathology and Biology - LPHL Lymphocyte predominant Unimodal age distribution (median 30 y/o) Localized presentation 2-3% risk of NHL transformation 12

13 Immunohistochemistry chl Reed Sternberg cells nlphl Lymphocyte and histiocytic popcorn cells CD 20 Negative (80%) Usually + CD 45 Negative Positive + CD 15 Usually + Negative - CD BCL6 expression absent present EBV In 80% of mixed cellularity Rarely (<1%) 13

14 Hodgkin-Reed-Sternberg (HRS) Cell The clonal malignant cell of HL Pre-apototic germinal center B cell Due to deregulation of several signal transduction pathways, these cells no longer express antibodies like normal B cells HRS cells are characterized by the expression of aberrant proteins from other cell lineages such as T cells, dendritic cells even myeloid cells Known mutations in NFκB and JAK-STAT signal transduction pathways

15 B symptoms Persistent (painless) lymphadenopathy Constitutional symptoms: Clinical Presentation Unexplained fever Night sweats Weight loss (> 10%) Itching

16 Clinical Sites of Disease 76% Lung 15% BM 5% 24% 22% 24% 60% 26% 7%

17 Current Imaging Staging Approach CXR Study Assessment Advantage Disadvantage Mediastinal bulk M:T 33% CT scan To assess intrathoracic, abdominal and pelvic nodal groups. Lung parenchyma, pericardium, pleura, and the chest wall. MRI Intrathoracic and abdominal structures Easy means to assess bulk of disease Very good for pulmonary structures Better evaluation of fat enclosed retroperitoneal LN compared to CT. Limited capability to assess mediastinal and nodal sites involvement. Not good enough for lung. Not very sensitive in little kids. Requires a lot of oral and iv contrast. Not good for pulmonary parenchyma PETscan Functional activity 1-day procedure with higher resolution, better dosimetry, and less intestinal activity Extreme sensitivity thymic rebound after therapy, high false positive findings

18 Mediastinal Bulk A A:B 33% B

19 Current Imaging Staging Approach CXR Study Assessment Advantage Disadvantage Mediastinal bulk M:T 33% CT scan To assess intrathoracic, abdominal and pelvic nodal groups. Lung parenchyma, pericardium, pleura, and the chest wall. MRI Intrathoracic and abdominal structures Easy means to assess bulk of disease Very good for pulmonary structures Better evaluation of fat enclosed retroperitoneal LN compared to CT. Limited capability to assess mediastinal and nodal sites involvement. Not good enough for lung. Not very sensitive in little kids. Requires a lot of oral and iv contrast. Not good for pulmonary parenchyma PETscan Functional activity 1-day procedure with higher resolution, better dosimetry, and less intestinal activity Extreme sensitivity thymic rebound after therapy, high false positive findings

20 CT Scan

21 Current Imaging Staging Approach CXR Study Assessment Advantage Disadvantage Mediastinal bulk M:T 33% CT scan To assess intrathoracic, abdominal and pelvic nodal groups. Lung parenchyma, pericardium, pleura, and the chest wall. MRI Intrathoracic and abdominal structures Easy means to assess bulk of disease Very good for pulmonary structures Better evaluation of fat enclosed retroperitoneal LN compared to CT. Limited capability to assess mediastinal and nodal sites involvement. Not good enough for lung. Not very sensitive in little kids. Requires a lot of oral and iv contrast. Not good for pulmonary parenchyma PET scan Functional activity High resolution mild intestinal activity Extreme sensitivity thymic rebound after therapy, high false positive findings

22 Positron Emission Tomography Computerized Tomography (PET CT) 18-fluoro-2-deoxyglucose (FDG) Uptake in to cells suggests higher metabolic rate Benign causes of signal include infection and inflammatory disease

23 Staging and Diagnostic Work up Ann Arbor Staging Classification image.slidesharecdn.com/hodgkinslymphoma A= no B symptoms B= fever (>38⁰C), unexplained weight loss (>10%), drenching night sweats E= extranodal extension S= splenic involvement 23

24 Other Tests used Routinely Test Indication Comments Bone Marrow Biopsy To assess bone marrow involvement Usually performed in all patients with B symptoms and any stage III and IV Bone scan Bone involvement When ALP is elevated, or patient has bone pain

25 PET for the Assessment of Bone Marrow Involvement 25

26 Low Risk Pediatric HL Trials Group n Stage SMC/SJCRH /DFCI SMC/SJCRH /DFCI CCG I/IIA Chemotherapy 4 VAMP 88 IA/IIA 4 VAMP Radiation (Gy) Field If CR 15, IF < CR 25.5 IF If CR no RT < CR 25.5 IF Survival (%) DFS, EFS, OS or RFS Follow-up (Year) 109 IA/B, 21 IF x COPP/ABV 106 IIA R None Comment 10 Reduction/Elimination of RT is safe in very low risk patients that achieve a CR after 2 5 VAMP IFRT lead to improved EFS (p=0.004) but not OS (p=0.5) 81 I-IIIA 1 2MOPP/2ABVD 25.5 IF IFRT did not improve survival. Patients with early CR fared better than those that did not. POG 8625 CR at end of therapy was not prognostic. R Early responders did significantly better (EFS 78 I-IIIA 1 3MOPP/3ABVD None %) versus non-early responders (EFS 77%). POG I-IIIA 4 ABVE 25.5 IF Evaluation of safety and efficacy of ABVE POG I-IIIA if CR 2 ABVE 4 ABVE AHOD IA/IIA 3 AV-PC R 22.5 IF If CR no RT < CR 21 IF Safe to reduce therapy in patients that achieve a CR after 2 ABVE CR after 3 cycles is not optimal, about ½ patients did not receive RT. PET (-) after 1 cycle was very predictive 65% vs 87% EFS. 26

27 Intermediate and High Risk HL Trials Group N Stage Chemotherapy POG 8726 CCG 5942 Radiation (Gy), Field Survival (%) DFS, EFS OS or RFS Follow-up (Year) Comment 80 IIB, IIIA 2, 21 EF IFRT does not improve survival after so 4 MOPP/4 ABVD IIIB, IV R 81 None intense CT IF IIB, III 6 x COPP/ABV R 10 IFRT did not improve survival in 110 None patients that achieved CR at the end of IV R 10 chemotherapy POG CCG AHOD SMC/ SJCRH/ DFCI IB, IIA/IIIA 1 with mx or IIIA 2, IIB/IIIB/IVB IIB or IIIB X or IV IAE or X, IB, IIAE or X, IIB, IIIA, and IVA COPP/ABV + CHOP + Ara-C/VP-16 RER: 3 ABVE-PC SER: 5 ABVE-PC All: 4 BEACOPP (1) RER: Female: 4 COPP/ABV (2) RER: Male: 2 ABVD (3) SER: 4 BEACOPP RER: 4 ABVE-PC R SER : 4 ABVE-PC 4 ABVE-PC + 2 DECA 132 IIB, IIIB, IV Stanford V R 21 IF None 21 IF 21 IF (1) None (2) 21 IF (3) 21 IF 21 IF None IF 95 If CR 15, IF < CR 25.5 IF ABVE-PC is a dose dense regimen that provides good outcome in early response-adapted therapy. There were no disease progressions, but 2 secondary leukemias. Early intensification followed by less intense response-based therapy for RER patients is effective for children with high-risk HL. 4 IFRT did not improve survival. 4 Augmentation with DECA did not improve survival in SER This risk-adapted, combined-modality therapy is well tolerated with manageable acute toxicities. 27

28 Evolution of the DAL/GPOH-HD Studies Study Induction Consolidation RT (Gy) DAL-HD 78 2 x OPPA 4-6 x COPP EF 5-yr EFS (%) Comment DAL-HD 82 2 x OPPA TG1 --- TG2 2 x COPP TG3 4 x COPP 35 IF 30 IF 25 IF TG1: stages I and IIA TG2: stages IE, IIB, IIAE and IIIA TG3: stages IIBE, IIIB and IV DAL-HD 85 2 x OPA (0-4) x COMP same 85, Elimination of procarbazine and/or substitution with methotrexate was detrimental. DAL-HD 87 2 x OPA (0-4) x COPP 30 IF 25 IF 20 IF DAL-HD 90 GPOH- HD 95 GPOH- HD x OPPA 2 x OEPA 2 x OPPA 2 x OEPA 2 x OPPA 2 x OE*PA (0-4) x COPP TG1 25 IF 91 OPPA 89 OEPA (0-4) x COPP CR no RT < CR 20 IF (0-4) COPP (0-4) COPDac TG1 CR no RT TG1 < CR 20 IF TG2/3 20 IF TG1 RT vs no RT 94 vs 97 TG2/3 RT vs no RT 91 vs Gender adapted therapy introduced to maintain male fertility TG2/3 patients in CR at the end of CT fared much worse if no RT was given. TG1 patients did not. 5-yr OS 97. Patients in TG2/3 treated with OEPA/COPDac fared as well as those treated with OPPA/COPP. (GPOH-HD=DAL group + NOPHO group + Dutch COG) 28

29 Variation in Risk Stratification TG1 TG2 TG3 E = Extranodal extension X = Bulky disease (peripheral > 6cm and mediastinal); mx = mediastinal bulk RF= ESR 30 mm/hour and/or bulk 200 ml 29

30 S.E.A.R.C.H. Staging Evaluation and Response Criteria Harmonization (SEARCH) for pediatric Hodgkin lymphomas is an international effort that will help compare trials and foster intergroup collaborations This harmonization effort will provide a framework to expedite identification of effective therapies by allowing for enhanced comparisons of cooperative group trials and aid in the approval process for new agents by regulatory agencies. Independent nodal region definitions exact definitions of nodal groups Staging criteria definitions standardized language and exact definitions Response criteria what constitutes complete response v partial response and gradiations of partial response Modalities used in staging and response evaluations balancing ultrasound, MRI, CT, and FDG-PET/CT or PET/MRI

31 Advances in Radiation Therapy for HL radiation techniques suitable for adults produced significant morbidities in children affecting musculoskeletal development, increasing risk for secondary malignant neoplasms, hypothyroidism, cerebrovascular accidents and cardiopulmonary toxicities Goals have been exposure reduction to normal tissues thru reduced field applications and novel RT modalities

32 Evolution of RT Fields

33 Potential for Proton beam therapy 3D Conformal RT IMRT Proton beam

34 What About Targeted Therapy in Frontline Pediatric Trials? Search for targeted therapies driven by desire to salvage more high risk patients and reduce toxicity Brentuximab targeted to microtubules Nivolumab check point inhibition

35 Brentuximab vedotin adcetrispro.com

36 Brentuximab vedotin Excellent response rates in relapsed/refractory HL (40-50% ORR) Frontline combination with AVD in adults 95% CR Ongoing adult trial comparing BEACOPP with BvEACOP ADECTRIS

37 multicenter pilot study assessed the safety and efficacy of brentuximab vedotin (BV) and AVD (adriamycin, vinblastine, and dacarbazine) followed by 30 Gy involved site radiation therapy (ISRT) Patients with newly diagnosed, early stage classical Hodgkin lymphoma (HL) with unfavorable-risk features were treated with 4 cycles of BV and AVD. After 2 and 4 cycles of BV / AVD, 90% (26 of 29) and 93% (27 or 29) of patients respectively achieved a negative PET scan All 25 patients who completed BV / AVD / ISRT achieved a complete response. With a median follow-up of 18.8 months, by intent to treat, the 1-year progression-free survival is 93.3% (95% confidence interval, ) CONCLUSION - Overall, the treatment was well-tolerated with no evidence of significant pulmonary toxicity. The majority of patients ( 90%) achieved negative interim PET scans after 2 and 4 cycles ofbv1avd. Excluding 2 primary refractory patients, all patients are disease free, suggesting that this is a highly active treatment program even in patients with substantial disease bulk.

38 St Jude / Stanford / Dana Farber Stages IIB, IIIB and IV Consortium HLHR13 Nodal sites that are in CR 2 x AEPA RA 4 x CAPDac Nodal sites that are not in CR RT 25 Gy Adcetris substitutes the vincristine in the well established EuroNet-PHL OEPA-COPDac Regimen. 38

39 Nivolumab Cancer cells have been shown to escape immune surveillance by up-regulating surface molecules that directly induce T-cell suppression. These mechanisms are known as immune checkpoint pathways. Inhibiting this inhibition or blockade can restore immune surveillance and toxicity

40 Normal Immune Response

41 Checkpoint inhibition

42 Blocking inhibition

43 23 study patients 78% were enrolled in the study after a relapse following autologous stem-cell transplantation / brentuximab vedotin. An objective response was reported in 20 patients (87%) 17% with a complete response 70% with a partial response the remaining 3 patients (13%) had stable disease. The rate of progression-free survival at 24 weeks was 86% On May 17, 2016, the U. S. Food and Drug Administration granted accelerated approval to nivolumab (Opdivo, marketed by Bristol-Myers Squibb) for the treatment of patients with classical Hodgkin lymphoma (chl) that has relapsed or progressed after autologous hematopoietic stem cell transplantation (HSCT) and posttransplantation brentuximab vedotin (Adcetris). CONCLUSIONS - Nivolumab had substantial therapeutic activity and an acceptable safety profile in patients with previously heavily treated relapsed or refractory Hodgkin s lymphoma.

44 Conclusions Pediatric HL has a very good prognosis with combined modality therapies Most pediatric cooperative groups strive to identify a favorable group of patients in whom therapy can safely be reduced through risk stratification and early response to therapy Effective use of PET CT for staging Staging Evaluation and Response Criteria Harmonization (SEARCH) Refined RT fields with no loss of effectiveness, Proton therapy Targeted therapies have made their way into pediatric front line trials, Brentuximab Nivolumab 44

45 Future Directions Proton therapy for pediatric HL Late effects of therapy need to be considered in the selection of therapy Biology of HL needs to be further explored and incorporated into clinical trials are there other unique targets to be exploited? Activated growth signal transduction pathways? 45

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48 References Donaldson et al J Clin Oncol 2007 Metzger et al JAMA 2012 Wolden et al J Clin Oncol 2012 Kung et al J Ped Hematol 2006 Tebbi et al Ped Blood Cancer 2012 Tebbi et al Ped Blood Cancer 2006 Keller et al ASH, Abstract Hall et al Br J Haematol 2007 Weiner et al J Clin Oncol 1997 Wolden J Clin Oncol 2012 Schwartz Blood 2009 Kelly et al Blood 2011 Friedman et al J Clin Oncol 2014 Metzger et al ASCO 2012 Mauz-Körholz et al J Clin Oncol 2015 Mauz-Körholz et al Cancer 2007 Appel et al ASCO 2012, Abstract