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Home , B symptoms, Hodgkin lymphoma, Plasmacytoma

Hematologic Malignancies: … A Guide to the ILROG Guidelines

John P. Plastaras, MD, PhD Associate Professor

February 27, 2020 Disclosures

 Steering Committee of ILROG, and chair the Education Committee  Co-chair of the Committee for the American Board of Radiology  ASTRO Scientific Committee (Heme, Vice-Chair)  My wife is on ASTRO Board of Directors, ACGME, RRC

 I am receiving support from Merck (free drug) for a clinical trial we are doing at Penn

 Unfortunately, no financial disclosures

2 Outline

 What ILROG guidelines are out there?  Solitary and  Low-Grade  Insights into “Involved Site” Radiotherapy (ISRT)  Treating the  DLBCL

3 Who is making guidelines currently?

 National Comprehensive Network (NCCN)  European Society for Medical (ESMO)  Children’s Oncology Group (COG)  American Radium Society (ARS) adopted the Appropriateness Criteria program from the American College of Radiology (ACR)

 International Lymphoma Radiation Oncology Group (ILROG)

4 ESMO Guidelines: Medical Oncology

5 ESMO Guidelines: Hematologic Diseases  Waldenstrom's macroglobulinaemia  Chronic myeloid leukaemia  Newly diagnosed and relapsed  Multiple myeloma  Newly diagnosed and relapsed  Extranodal diffuse large B-cell lymphoma and primary mediastinal B-cell lymphoma  Acute lymphoblastic leukaemia  Peripheral T-cell lymphomas  Diffuse large lymphoma  Chronic lymphocytic leukaemia  Hairy cell leukaemia  Philadelphia chromosome-negative chronic myeloproliferative  Myelodysplastic syndromes  Hodgkin lymphoma  Primary cutaneous lymphoma  Acute myeloblastic leukaemia in adult patients  Gastric marginal zone lymphoma of MALT type 6 NCCN Guidelines for Hematologic Diseases

 Acute Lymphoblastic  Acute Myeloid Leukemia  Chronic Lymphocytic Leukemia/Small Lymphocytic Lymphoma  Chronic Myeloid Leukemia   Hodgkin lymphoma  Multiple Myeloma  Waldenström's / Lymphoplasmacytic Lymphoma  Myelodysplastic Syndromes  Myeloproliferative Neoplasms  B-cell Lymphomas  Primary Cutaneous Lymphomas  T-Cell Lymphomas

7 Guidelines for Supportive Care

 ESMO: • and radiotherapy-induced nausea and vomiting • Oral and gastrointestinal mucosal injury • Management of refractory symptoms at the end of life and the use of palliative sedation • Advanced care planning in palliative care • Bone health in cancer patients • Cancer, fertility and pregnancy • Cardiovascular toxicity induced by chemotherapy, targeted agents and radiotherapy

 NCCN: • Survivorship • Palliative Care • others

8 Current ILROG Guidelines  2014:  2020: • Nodal non-Hodgkin lymphoma • ISRT Mini-Atlas • Hodgkin lymphoma • “Making Every Single Gray Count: Involved  2015: Site Radiation • Primary cutaneous lymphomas Therapy Delineation • Extranodal lymphomas Guidelines for • Pediatric Hodgkin lymphoma Hematological Malignancies”  2018: • Not exactly a • Lymphoblastic Lymphoma guideline, but a • Central Nervous System Leukemia supplementary • Extramedullary Leukemia/Chloroma resource • Total Body Irradiation • Solitary Plasmacytoma and Multiple Myeloma • Relapsed/Refractory Hodgkin Lymphoma • Relapsed/Refractory Diffuse Large B-Cell Lymphoma • Proton therapy for adults with mediastinal lymphomas  2019: • Optimal use of imaging

9 ILROG.org Easy Links to All the Guidelines

Major Limitation of ILROG Guidelines: No current mechanism to maintain “evergreen” status, so they are aging quickly.

10 Diseases: Picking Dose

 61 M with newly diagnosed multiple  62 M with solitary plasmacytoma of the myeloma with a path comp fx at T11. nasopharyngeal wall, < 1 cm, resected T9 infiltrated as well. .

Treatment Approach?

2.5 Gy x 8 = 20 Gy 1.8 Gy x 22 = 39.6 Gy

11 Plasma Cell Disease Guidelines

 Solitary BONY : • SBPs <5 cm: total dose 35 to 40 Gy – for small SBPs it is acceptable to prescribe 35 Gy, which has differed from NCCN • SBPs >/= 5 cm: total dose 40 to 50 Gy  Solitary EXTRAMEDULLARY plasmacytomas • SEPs: total dose 40 to 50 Gy (if small, well-defined, or post-excision with positive margins, 40 Gy is acceptable.)

12 Myeloma Palliation Doses:

 For bony sites, where the goal is limited to symptom relief: 8-30 Gy (8 Gy x 1, 20 Gy in 5, 30 Gy in 10). • 8 Gy x1 preferred for bone disease with poor predicted survival • 20 to 30 Gy in 10 to 15 preferred RT volumes are large or retreatment  For epidural disease with , or bulky mass, when durable local control is desired: 30 Gy in 10 to 15 • consider glucocorticoids to prevent pain flare

 Trend: lowered doses overall to mitigate marrow toxicity • Active trial (Leslie Ballas is PI) for 2 Gy x 2. • 2.5 x 10 for cord compression? • 2.5 Gy x 8, 4 Gy x 5, 8 Gy x 1. • “New Paradigm for Radiation in Multiple Myeloma: lower yet effective dose to avoid radiation toxicity.” Elhammali A, et al. Haematologica. 2020 Jan 9.

13 Limited Stage Low Grade Lymphomas

 31 M with left submandibular gland mass, FNA showed “may be compatible with a CD5+ mature B Cell ”  Underwent TORS excision, piecemeal resection (3 chunks). Left him with speech defect, tongue and facial numbness, but a diagnosis of marginal zone lymphoma. Margins? Treatment Approach?

14 ISRT Volumes Without Chemo?

 “…in clinical situations that require RT as the primary modality…the CTV should be more generous in this clinical situation and also encompass lymph nodes in the vicinity that, although of normal size, might contain microscopic disease that will not be treated when no chemotherapy is given.”  RT Alone is used with CURATIVE intent in: • Stage I/II follicular lymphoma • Stage IE marginal zone lymphoma • Stage I/II Nodular Predominant Hodgkin Lymphoma • Relapsed/refractory HL or NHL

15 ISRT with RT Alone: How Much Margin?

 British Columbia retrospective of limited stage follicular lymphoma defined “Involved Site” RT as 5 cm margin or less • Adjust according to what toxicities worry you • I will add 2-5 cm of nodal volume depending on what is adjacent (e.g. parotid)

 Bonus planning tip: • is the most important OAR given future systemic therapies once these patients relapse and need treatment

16 Non-Nodal NHL: Extranodal and Skin

 pCNS, Orbital, Head & Neck (incl thyroid), NK/T-cell, Breast, Lung, Testicular, bone, abdomen/Pelvis, bowel

17 Dose Considerations for Indolent NHL

 Indolent nodal lymphomas, stage I/II with curative intent: • 24-30 Gy in 12-15 fx

 Marginal zone lymphomas with curative intent: • Salivary: 24 Gy • Gastric: 30 Gy (but maybe 24 Gy?) • Orbit: 24 Gy (but maybe 4 Gy?) • Other sites (thyroid, cutaneous, pulmonary): 24-30 Gy

 Advanced stage or palliative intent indolent B-cell NHL: • 2 Gy x 2, but realize that local control may not be as durable

 Palliation of cutaneous T-cell lymphoma: • 4 Gy x 2 or 8 Gy x 1 for localized CTCL/MF • 12 Gy for total skin electron treatment

18 Basics of Hodgkin Lymphoma Treatment

 Early stage, favorable: EORTC H10 Style: • ABVD x 2 + 20 Gy IFRT (HD10) - 2 vs. 3 sites of disease can be F  Early stage, unfavorable: - ABVD x 3 for F • ABVD x 4 + 30 Gy IFRT (HD11) - 30 Gy regardless U/F  Advanced stage (IIB bulky, III/IV): - BEACOPP escalation for DS3-4 • ABVD x 6 (or BEACOPP in Europe) after PET2 • RT for partial response, bulky disease  Relapsed/refractory: • 2nd line chemo +/- RT +/- transplant • Brentuximab (CD30 ADC) and PD1 inhibitors  Palliation

19 Relevant Guidelines: Hodgkin Lymphoma

2019

20 Early Stage Mediastinal Hodgkin

 25-year old woman received ABVD x 4 for an unfavorable risk, Stage IIA classic Hodgkin lymphoma of the mediastinum.  Pre-chemotherapy PET/CT (fused to planning CT), in DIBH  What ISRT Volume would you use?

Post Chemo Mass

21 A B

C D

22 ISRT with Combined Modality Treatment  Contour the post-chemotherapy tissue volume, which contained the initially involved lymphoma tissue, taking into account tumor shrinkage, respecting normal structures that were never involved by lymphoma (lungs, chest wall, muscles, esophagus)  Be a bit more generous when in doubt  Connect CTV’s when nodal volumes are less than 5 cm apart

23 Minimizing Dose to OARs: Mediastinum

 21 F with unfavorable risk classic Hodgkin lymphoma (per GHSG criteria – 3 sites of disease, non-bulky, ESR <50, no extranodal sites). Upper mediastinum and bilateral SCV. • ABVD x 2 → Deauville (5PS) 2. AVD x 2 more (4 cycles total)

Treatment Approach?

Free Breathing Deep Inspiratory Breath Hold

 Decreases dose to lungs and heart  Requires confirmatory method to ensure breath hold position is reproducible

24 DIBH and Protons: Which has more value?

Rechner LA et al. Radiother Oncol. 2017 Oct;125(1):41-47. Life years lost attributable to late effects after radiotherapy for early stage Hodgkin lymphoma: The impact of proton therapy and/or deep inspiration breath hold.

25 Minimizing Dose to OARs: Mediastinum

 21 F with unfavorable risk classic Hodgkin lymphoma (per GHSG criteria – 3 sites of disease, non-bulky, ESR <50, no extranodal sites) • ABVD x 2 → Deauville (5PS) 2. AVD x 2 more (4 cycles total)

Deep breath hold? 3D? IMRT? Proton? Dose constraints for substructures?

26 27 New Era: Stricter Dose Requirements

 Continued controversial role of RT in combination with chemo, so pressure is on to make RT safe  Era of ISRT has allowed very conformal techniques to prioritize certain OAR’s over others  Many new technological options to achieve lower dose constraints • 3D, IMRT (fixed/VMAT), protons • Positioning: special angle board, DIBH  Selective use of combined modality vs. chemo only when options exists and RT plan looks like it will be ugly • Cardiophrenic disease (breath hold may make it worse) • Use the aortic valve/LAD take off as a discussion point with med oncs

28 Case: Advanced Stage DLBCL

 49 yo M with Stage IVB DLBCL s/p R-CHOP x 6 with complete metabolic response. Both skeletal involvement (T5) and bulky retroperitoneal/mesenteric adenopathy (mesentery, paracaval, interaortocaval, para-aortic regions, total diameter 9.4 x 4.1) Treatment Approach?

29 Relevant Guidelines: Aggressive NHL

2019

30 Basics of Aggressive NHL (DLBCL)

 Limited Stage (I/II) • R-CHOP x 6, radiate partial response, bulk (>7.5 cm), or skeletal dz • or R-CHOP x 3-4 + consolidative radiation (30-40 Gy)  Advanced Stage (III/IV) • Indications for RT after R-CHOP x 6 – radiate partial response – bulk (>7.5 cm) – skeletal dz (30-36 Gy)  Relapsed/Refractory • 2nd line chemo +/- RT +/- transplant  Palliation • RT for symptom control, local control, oligoprogression, bridge to next systemic therapy

31 Aggressive NHL Dose Considerations

 Upfront DLBCL after chemo: 30-40 Gy • 30 Gy if DS 1-3 • Boost to higher doses for DS4  Upfront Double Hit DLBCL (myc/bcl2 or ) • Correct dose is unknown, but I tend to lean toward higher end of dose spectrum when consolidating  Upfront Primary Mediastinal Large B-cell lymphoma (PMBCL) • Avoid radiation if given DA-R-EPOCH if possible • After R-CHOP x 6: 30-40 Gy depending on PET response  Relapsed/Refractory DLBCL • DS1-3 with salvage chemo and ASCT: 30-36 Gy • Transplant ineligible, curative intent: 45-55 Gy • Palliative intent with limited life expectancy: hypofractionated schedule of 8-30 Gy

32 Advanced Stage DLBCL: Bulk and Skeletal

 49 yo M with Stage IVB DLBCL s/p R-CHOP x 6 with complete metabolic response. He is eferred for consideration of consolidative RT to sites of skeletal involvement (T5).

33 Relapsed/Refractory DLBCL

 57F p/w and CD10+ B-cell lymphoma in December, Stage IVB at dx • R-EPOCH x6c completed • 1 month later, progressed in PA nodes • 1 cycle R-DHAP with stable to progressive disease • Recommended for CAR T-cell therapy (Kymriah) and started systemic bridging venetoclax  Referred for “bridging” to painful, “chemorefractory” mesenteric nodal conglomerate, measuring 6.2 x 5.8 cm

Pre-bridging-RT PET/CT

34 Combining with Biologics: Guidelines?

 4DCT sim fused to PET-CT scan  PTV = GTV + 7mm  20 fraction SIB volumetric arc plan • 220cGy / fx to GTV (4400 cGy) • 180 cGy / fx to PTV (3600 cGy)

 Acute toxicity: G1 nausea

35 Biologic Explosion in Lymphomas

 Hodgkin Lymphoma: • Brentuximab-vedotin – Anti-CD30 with microtubule disrupting agent • PD1 Blockade • CART therapies?

 Non-Hodgkin Lymphoma: • CD20 agents (, ofatumumab, obinutuzumab, etc.) • PI3K/MTOR • Proteasome inhibitors • BTK inhibitors (ibrutinib) • BITEs (bispecific T-cell engager antibody, CD19/CD3) (blinatumomab) • Immunomodulators: Revlimid, PD1 Blockade, CART 19

36 Future of ILROG Guidelines

 Mechanism to update aging guidelines  Make them easier to reference at point of care  Potential unmet needs: • Palliation? • Indolent Lymphomas? • Extranodal expansion? • Combination with biologic agents?  Stay tuned for more help with contouring • ILROG Education Committee: Terezakis, Hoppe, Gunther – eContour and EduCase collaborations  Learning heme radiation 1 tweet at a time: • @ILROGTeam  ILROG Sponsored ACGME Resident Away Rotation • AROPC, application on ILROG.org

37 Conclusions

 ILROG Guidelines should help us move RT for hematologic malignancies into modern era, using contour-based planning  Trends in heme radiation community move fast, so guidelines are aging  Please join ILROG, use the website which is new and improved!  Good luck on the SA-CME  Now for more contouring…

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