Hodgkin's Lymphoma

Question 1

What age does Hodgkin Lymphoma (HL) most commonly occur?

Answer 1

HL has a bimodal peak with peaks at age 15–35 yrs and over age 50.

Question 2

Broad histologic categories of HL:

Answer 2

1. Classical (more common: 95%)

2. Nodular lymphocyte predominant Hodgkin lymphoma (NLPHL: 5%)

Question 3

What are the subtypes of classical HL, and which is most common in the United States?

Answer 3

Subtypes of classical HL:

1. Nodular sclerosis (most common in the United States)
2. Mixed cellularity
3. Lymphocyte depleted
4. Lymphocyte rich

Question 4

What are the 2 most commonly involved LN regions at the initial Dx of classical HL?

Answer 4

Most commonly involved LN regions at initial Dx of HL:
1. Cervical chains
2. Mediastinum
90% of pts have contiguous nodes.

Question 5

Pts who present with mediastinal LAD are most likely to have which subtype of HL?

Answer 5

Pts who present with mediastinal LAD are most likely to have nodular sclerosis HL.

Question 6

In classical HL, what is the most common pathologic feature and CD15, -30, -45, and -20 staining pattern?

Answer 6

Classical HL is characterized by Reed–Sternberg cells in an inflammatory background. In classical HL, tumors are typically CD15+ and 30+ but CD45- and 20-.

Question 7

In NLPHL, what is the common pathologic feature and CD15, -30, -45, and -20 staining pattern?

Answer 7

NLPHL is characterized by lymphocyte-predominant cells, previously called “popcorn” cells. In NLPHL, tumors are typically CD15- and 30- but CD45+ and 20+ (i.e., the reverse of classic HL).

Question 8

Which classical HL subtype has the best prognosis?

Answer 8

Lymphocyte-rich HL has the best prognosis.

Question 9

Which HL subtype has the worst prognosis?

Answer 9

Lymphocyte-depleted HL has the worst prognosis.

Question 10

Which HL subtype is associated with older age or HIV+ pts?

Answer 10

Lymphocyte-depleted HL is associated with older age and HIV+ pts.

Question 11

Pts with which subtype of HL are at greatest risk of developing a subsequent NHL?

Answer 11

Pts with NLPHL are at greatest risk of developing a subsequent NHL.

Question 12

What are the “B Sx” of lymphoma?

Answer 12

B Sx include:

1. Unexplained fevers >38°C (100.4°F)
2. 10% body weight loss in 6 mos
3. Drenching night sweats

Question 13

How is bulky mediastinal Dz commonly defined?

Answer 13

Bulky mediastinal Dz is commonly defined as a mass greater than one third of the intrathoracic diameter on an upright PA film. In the CT era, the definition of >10 cm has been used.

Question 14

How is bulky Dz defined outside of the mediastinum?

Answer 14

Outside of the mediastinum, bulky Dz is variably defined in clinical trials, but most often is any mass >10 cm.

Question 15

What kind of Bx is preferred for Dx of HL and why?

Answer 15

Excisional Bx is preferred for the Dx of lymphomas b/c it shows LN architecture.

Question 16

What imaging studies are typically ordered as part of the workup of HL?

Answer 16

An integrated PET/CT is commonly used in the workup imaging for HL.

Question 17

What lab work is required as part of the workup of HL?

Answer 17

The following labs have prognostic implications: ESR, CBC, albumin, and LDH. Labs necessary for Tx planning are BUN, Cr, and a pregnancy test in women of childbearing age.

Question 18

How is HL staged?

Answer 18

HL is staged using the Ann Arbor system:
Stage I: involvement of 1 LN region or localized involvement of a single extralymphatic organ or site (IE)
Stage II: involvement of ≥2 LN regions on same side of diaphragm or localized involvement of a single associated extralymphatic organ or site and its regional LN with or without involvement of other LN regions on same side of diaphragm (IIE)
Stage III: involvement of LN regions on both sides of diaphragm
Stage IV: multifocal involvement of ≥1 extralymphatic organ, with or without associated LN involvement, or isolated extralymphatic organ involvement with distant nodal involvement.

Question 19

Involvement of which sites is considered stage IV Dz?

Answer 19

Pts with involvement of extralymphatic structures, such as the BM, liver, and lung, have stage IV Dz.

Question 20

Name the 14 distinct LN regions as per the Rye classification.

Answer 20

LN regions per the Rye classification:

1. Waldeyer ring
2. Occipital, cervical, preauricular, and SCV
3. Infraclavicular
4. Axillary
5. Epitrochlear
6. Mediastinum
7. Right hilum
8. Left hilum
9. P-A
10. Spleen
11. Mesenteric
12. Iliac
13. Inguinofemoral
14. Popliteal

Question 21

Is involvement of the Waldeyer ring, thymus, or spleen considered extranodal?

Answer 21

No. Waldeyer ring, thymus, and spleen are typically considered nodal sites.

Question 22

What does the Waldeyer ring include?

Answer 22

The Waldeyer ring includes:

1. Pharyngeal tonsil (adenoids)
2. Palatine tonsil
3. Lingual tonsil (base of tongue)

Question 23

What are unfavorable factors for early HL?

Answer 23

Risk factors used to stratify early-stage HL in clinical trials vary. Unfavorable
factors for early HL:
1. Age ≥50 yrs
2. Bulky Dz (at least one-third max T diameter by the German Hodgkin Study
Group [GHSG] or >10 cm by Stanford or NCCN guidelines)
3. ≥4 sites (≥3 sites by GHSG)
4. ESR >50 if no B Sx or >30 if B Sx
5. Presence of extranodal sites
6. Mixed-cellularity or lymphocyte-depleted histology

Question 24

What are unfavorable factors for advanced HL used in the International Prognostic Score (IPS)?

Answer 24

Unfavorable factors for advanced HL used in the IPS:
WBC ≥15 × 109 cells/L
Albumin <4 g/dL
Lymphocytes (ANC) <600 or <8%
Stage IV
Hgb <10.5 g/dL
Age ≥45 yrs
Male
(Mnemonic: WALSH AM)

Question 25

In the pre-PET era, what % of pts with favorable early-stage HL had occult splenic involvement?

Answer 25

In the pre-PET era, 30% of pts with favorable early-stage HL had occult splenic involvement. (Carde P et al., JCO 1993)

Question 26

How many times are HL pts assessed by PET/CT?

Answer 26

HL pts should have a PET-CT performed at the time of Dx for upfront staging. Then, PET-CT scans are performed to assess Tx response. Often, a PET-CT will be performed after 2 cycles of chemo and at the completion of upfront chemo.

Question 27

What are the 3 most common multiagent chemo regimens used for HL?

Answer 27

Most common chemo regimens used for HL:

1. ABVD
2. Stanford V
3. Dose-escalated BEACOPP

Question 28

What agents are included in ABVD chemo for HL?

Answer 28

ABVD includes:

1. Adriamycin
2. Bleomycin
3. Vinblastine
4. Dacarbazine

Question 29

What agents are included in the Stanford V regimen for HL?

Answer 29

There are 7 drugs in the Stanford V regimen (MOPE-ABV), listed below. Although ABVD is sometimes used without consolidation RT, the Stanford V regimen requires consolidation RT to sites originally ≥5 cm and/or to macroscopic splenic Dz. The Stanford V protocol dictates that RT should be administered 2–4 wks after chemo.

1. Mechlorethamine
2. Vincristine
3. Prednisone
4. Etoposide
5. Adriamycin
6. Bleomycin
7. Vinblastine

Question 30

What agents are included in BEACOPP?

Answer 30

There are 7 agents included in the BEACOPP regimen, as listed below. Escalated-dose BEACOPP is typically used for advanced-stage HL with poor prognostic factors. It is more commonly used in Europe than in the United States.

1. Bleomycin
2. Etoposide
3. Adriamycin
4. Cyclophosphamide
5. Vincristine
6. Procarbazine
7. Prednisone

Question 31

What is the common Tx strategy for stages I–II classic HL?

Answer 31

Chemo f/b consolidation RT. Pts with favorable risk Dz according to the GHSG criteria are generally treated with ABVD × 2 cycles f/b 20 Gy ISRT according to the HL10 study. Long-term f/u from this study has shown 10-yr PFS of 87% and OS of 94%. (Sasse S et al., JCO 2017) Pts with unfavorable risk Dz according to the GHSG criteria are generally treated with ABVD × 4
cycles f/b 30 Gy ISRT according to the HL11 study.

Question 32

In early-stage HL, which factors are considered “unfavorable” according to the GHSG criteria?

Answer 32

Early-stage HL is considered “unfavorable” in the presence of 1 or more of the following:
3 or more sites of involvement based on the GHSG definition of sites (i.e., 5 “sites” above the diaphragm: R neck, L neck, mediastinum, R axilla, Laxilla)
Bulk, defined as a mediastinal-mass ratio >1/3, the ratio of the max width of the mass and the max intrathoracic diameter. ESR >50, or ESR >30 in the presence of B Sx
Extranodal Dz
(Mnemonic: 3-BEE)

Question 33

What are common Tx strategies for stages III–IV classic HL?

Answer 33

1. ABVD × 6 cycles +/– ISRT to initial bulky Dz and/or residual PET+ sites at restaging
2. Stanford V + ISRT to initial bulky Dz and residual PET+ sites
3. Escalated-dose BEACOPP +/– ISRT to initial bulky Dz and residual PET+ sites

Question 34

What is the Tx paradigm for stages I–II NLPHL?

Answer 34

Stages I–II NLPHL Tx paradigm: Tx is similar to Tx for a low-grade NHL.
Stage I and contiguous stage II NLPHL can be treated with RT alone (“generous” ISRT) or chemo + ISRT (if bulk or B Sx are present).

Question 35

What is the Tx paradigm for stages III–IV NLPHL?

Answer 35

Stages III–IV NLPHL is treated with chemo + rituximab +/– ISRT, or rituximab alone, or local RT for palliation.

Question 36

What are the commonly used RT doses in HL after initial chemo?

Answer 36

Sites without bulky Dz are typically treated to 20–30 Gy after chemo. Sites of initial bulky Dz are typically treated to 30–36 Gy after chemo.

Question 37

Describe the evidence that suggests improved outcomes with CRT c/w RT alone in early-stage favorable HL.

Answer 37

In the 1990s, CRT vs. RT alone was evaluated in at least 4 major randomized trials, listed below. Although the chemo and RT techniques varied in these studies, long-term relapse rates consistently favored the CRT arms. The conclusion of these studies was that CRT is associated with improved Dz control, when compared to RT alone. In EORTC H8 F, 10-yr OS was significantly improved with CRT (97% vs. 92%), but long-term OS was not significantly different in the other studies.

1. EORTC H7 F (Noordijk EM et al., JCO 2006)
2. EORTC H8 F (Ferme C et al., NEJM 2007)
3. German HL7 (Engert A et al., JCO 2007)
4. SWOG S9133 (Press OW et al., JCO 2001)

Question 38

Summarize the evidence for and against the elimination of consolidative RT in pts who achieve a CR after chemo in early-stage HL.

EORTC GELA H9 F

Answer 38

Randomized favorable stages I–II HL pts with a CR after epirubicin/bleomycin/vinblastine/prednisone (EBVP) × 6 cycles to 36 Gy IFRT vs. 20 Gy IFRT vs. no RT. 5-yr EFS was similar b/t the 36 Gy and 20 Gy arms (89% vs. 84%, respectively) but was significantly lower in the no-IFRT arm (70%). (Thomas TM et al., IJROBP 2018)

Question 39

Summarize the evidence for and against the elimination of consolidative RT in pts who achieve a CR after chemo in early-stage HL.

EORTC H10

Answer 39

Compared outcomes of early-stage HL pts treated with (i) ABVD + INRT vs. (ii) ABVD alone (more cycles) without RT for pts with a negative PET after ABVD × 2. Risk of early relapse in nonirradiated pts was significantly higher than in standard combined modality treated pts,
even in this selected group of pts with an early negative PET. (Raemakers JM, JCO 2014)

Question 40

Summarize the evidence for and against the elimination of consolidative RT in pts who achieve a CR after chemo in early-stage HL.

UK RAPID

Answer 40

randomized pts with negative PET after 3 cycles of ABVD to IFRT vs. no further Tx. 3-yr PFS was 94.6% in the RT group and 90.8% in the no-RT group. This was designed as a noninferiority study and failed to
meet this endpoint. (Radford J et al., NEJM 2015)

Question 41

Summarize the evidence for and against the elimination of consolidative RT in pts who achieve a CR after chemo in early-stage HL.

Blank O et al., Cochrane Database of Systematic Reviews 2017

Answer 41

A recent Cochrane library meta-analysis included RCTs comparing chemo alone with chemo + RT in pts with early-stage HL. For the comparison with the same numbers of chemo cycles in both arms, there was moderate quality evidence that PFS is sup in pts receiving chemo + RT than in those receiving chemo alone. The addition of RT to chemo resulted in little or no difference in OS. However, a sensitivity analysis without the trials with potential high risk of bias showed that chemo + RT is associated with improved OS compared to chemo alone.

Question 42

Summarize the evidence to support the use of IFRT instead of more extensive RT fields in HL pts receiving CRT.

Answer 42

At least 4 RCTs have compared IFRT to more extensive RT fields in HL pts receiving CRT, as listed below:
1. Groupe Pierre-et-Marie-Curie (GPMC) (Zittoun R et al., JCO 1985)
2. German HL8 (Klimm B et al., Ann Oncol 2007)
3. Milan study (Bonadonna G et al., JCO 2004)
4. EORTC H8-U (Ferme C et al., NEJM 2007)
The 5–12-yr OS outcomes were similar in all studies

Question 43

Summarize the evidence to support the use of IFRT at 20 Gy after induction chemo in favorable stages I–II HL pts.

Answer 43

The use of <30 Gy in favorable stage I–II HL pts after initial chemo has been studied in at least 2 RCTs:
1. HL10 from the GHSG randomized pts to 2 vs. 4 cycles of ABVD f/b 20 Gy vs. 30 Gy IFRT (2 × 2 factorial design). 10-yr PFS, FFTF, and OS were similar b/t the chemo comparison and the RT dose comparison. This study supports the use of ABVD × 2 + 20 Gy in pts with early-stage, favorable HL according to the GHSG criteria. (Engert A et al., NEJM 2010; Sasse S
et al., JCO 2017)
2. EORTC GELA H9 F (see above)

Question 44

Summarize the evidence to support the use of consolidative RT in advanced-stage HL to treat sites that responded only partially to chemo.

Answer 44

1. Aleman et al. randomized pts with stages III–IV HL who achieved a CR after 4 or 6 cycles of MOPP-ABV to IFRT or observation. Pts with PR after 6 cycles rcvd IFRT to 30 Gy with a 4–10 Gy boost. Rates of EFS and OS in
   a pt with PR who rcvd IFRT were similar to those of pts in CR. In pts with CR, there was no difference in 8-yr EFS (observation, 77% vs. IFRT, 73%) or 8-yr OS (observation, 85% vs. IFRT, 78%). (IJROBP 2007)
2. HL12 randomized pts to 2 BEACOPP regimens and pts with initial bulky Dz or a PR to chemo to consolidative RT to 30 Gy vs. no consolidative RT.
   RT improved FFTF in pts with residual Dz after chemo but ot in pts with initially bulky Dz with a CR. (Borchmann P, JCO 2011)

Question 45

What are the historic fields used to treat HL?

Answer 45

The mantle field is a classic comprehensive field including major nodal regions above the diaphragm. TLI treats a mantle field and “inverted Y” to include the P-A LNs, pelvic LNs, and spleen. Sub-Total Lymphoid
Irradiation excludes the pelvic LNs.

Question 46

What is the difference b/t IFRT vs. RFRT vs. INRT vs. ISRT?

Answer 46

IFRT covers the involved lymphoid region defined by the Rye classification, and field borders are based upon bony anatomy as defined by Yahalom et al.
(Ann Oncol 2002). RFRT covers the involved regions + the immediately adjacent LN regions. ISRT covers only the prechemo tumor volume, accounting for uncertainties in imaging and changes in anatomy that occur with chemo (e.g., in the mediastinum, normal lung tissue is omitted from the Tx volume, b/c the tumor that once pushed into the lung has regressed with
chemo). ISRT is the current standard of care and is an adaptation of INRT in situations where adequate prechemo imaging is not available. INRT relies on
ideal prechemo imaging with PET/CT in the Tx planning position, while ISRT is used when this ideal prechemo imaging is not available. For this reason, the CTV cannot be reduced to the same extent with ISRT as with
INRT; therefore, clinical judgment is used along with imaging to create a larger CTV in order to accommodate for these uncertainties. (Specht L et al., IJROBP 2014)

Question 47

Describe INRT.

Answer 47

INRT relies on ideal prechemo imaging. The prechemo PET/CT is fused with the postchemo RT planning CT. The prechemo GTV (based on prechemo CT and PET imaging) is drawn. The CTV is then created by modifying the prechemo GTV based on the postchemo CT scan to exclude normal structures that were never involved by lymphoma. For details regarding INRT as well as ISRT, see S Specht L et al. (IJROBP 2014)

Question 48

According to Children’s Oncology Group AHOD0031, where do pts tend to relapse after chemo and RT?

Answer 48

The mediastinum was the most common site of relapse. Relapses typically involved sites that had been involved at the time of initial Dx +/– new sites, but they rarely involved new sites only. Relapses occurred at both initially bulky and nonbulky Dz sites. (Dharmarajan KV et al., IJROBP 2015)

Question 49

In pts treated for HL, what is the RR for a 2nd solid malignancy after 30 yrs?

Answer 49

In pts who survived >5 yrs, the 30-yr cumulative risk of a second cancer for men and women diagnosed with HL at 30 yrs of age were 18% and 26%, respectively, c/w 7% and 9%, respectively, in the general population
(Hodgson DC et al., JCO 2007). In another population study, the 30-yr cumulative incidence of breast cancer in women diagnosed with HL at younger than 35 yrs of age was 13.8%. (Sud A et al., JCO 2017)

Question 50

Which type of secondary cancer occurs sooner after HL Tx: leukemias or solid malignancies?

Answer 50

Leukemias tend to occur <5 yrs after Tx, whereas solid malignancies typically occur >7 yrs after Tx.

Question 51

What is the impact of family Hx of cancer on secondary malignancies in HL survivors?

Answer 51

The risk of all second cancers is 1.3-fold higher for HL survivors with a 1st degree relative with cancer (p < .001), with a 3.3-fold difference for lung cancer, a 2.1-fold difference for colorectal cancer, and a 1.8-fold difference
for breast cancer. (Sud A et al., JCO 2017)

Question 52

What are the long-term neurocognitive effects in adult survivors of childhood HL?

Answer 52

HL survivors demonstrate lower performance on sustained attention, short term memory, long-term memory, working memory, naming speed, and
cognitive fluency. MRI revealed leukoencephalopathy in 53% of survivors and 37% had evidence of cerebrovascular injury. (Krull KR et al., JCO 2012)

Question 53

What phase II data exists for the use of pembrolizumab in relapsed/refractory HL?

Answer 53

The KEYNOTE-087 trial was a single-arm phase II study of pembrolizumab in pts with relapsed/refractory HL. It showed an ORR of 69% and a CRR of 22.4%. (Chen R et al., JCO 2017)

Question 54

What data exists for the use of brentuximab vedotin in relapsed/refractory HL?

Answer 54

In a single-center, phase II study, brentuximab vedotin f/b augmented ICE resulted in 76% of pts with relapsed/refractory HL achieving PET negativity prior to ASCT. (Moskowitz AJ et al., Lancet Oncol 2015)
The AETHERA study was a phase III trial randomizing pts with unfavorable risk, relapsed/refractory HL to early consolidation with maintenance BV or no maintenance BV. PFS was 42.9 mos for pts with maintenance BV and
24.1 mos in the placebo group, p = 0.0013. (Moskowitz CH et al., Lancet 2016)

Question 55

Why is bleomycin omitted when combined with brentuximab vedotin?

Answer 55

During a phase I, dose-escalation study comparing BV combined with ABVD or AVD, there was unacceptable grade 3 or worse pulmonary toxicity in the BV and ABVD group observed in 24% of pts. (Younes A et al., Lancet Oncol 2013)