eha-tsh hematology tutorial on lymphoma · epidemiology new cases 2.4.-2.5/100,000 persons (eu and...
TRANSCRIPT
Hodgkin Lymphoma: Diagnosis
and Treatment (First Line and
Relapsed Disease
Speaker: Pervin Topcuoglu
EHA-TSH Hematology Tutorial
on Lymphoma
İzmir, Turkey
April 6-7, 2019
I have no actual or potential conflict of interest
in relation to this presentation
Learning Objectives
‒ the morphological and clinical features
‒ the staging work-up and apply the Lugano
classification to patients with Hodgkin lymphoma.
‒ the risk stratification prior to the treatment
‒ the treatment in patients with newly diagnosed HL
and in those with relapse/refractory HL
Content
‒ History
‒ Definition
‒ Epidemiology
‒ Subtypes
‒ Etiology
‒ Presentation
‒ Diagnosis
‒ Management
‒ Follow-up
‒ Summary and Future
History
History
Definition ‒ A type of malignant
lymphoma
‒ Germinal B center or Post-GBC
‒ Dorothy Reed and Carl Sternberg first described the malignant cells of HL-called as Reed Sternberg cells -Owl
Eyes appearance
‒ The first cancer could be successfully treated by radiation therapy and also combination with chemotherapy (ChT)
Epidemiology
New cases 2.4.-2.5/100,000 persons (EU and US data) male, 2.9; female, 2.2
HL most frequently diagnosed in patients 20-34 yrs of age, older than 55 yrs of age
Increased incidence in industrialized countries
Nodular sclerosis subtype associated with high standard of living
Hodgkin Lymphoma Cancer Stat Facts. 2018. https://seer.cancer.gov/statfacts/html/hodg.html.
Median age at
diagnosis
39
0%
10%
20%
30%
40%
<20
20-3
4
35-4
4
45-5
4
55-6
4
65-7
4
75-8
4
>84
Perc
ent
o D
eath
s
Age
Median age at death
67
Estimated New Cases in 2018 8,500
% of All New Cancer Cases 0.5%
Estimated Death in 2018 1,050
% of All Cancer Deaths 0.2 %
Percent Surviving 5
years
86.6 %
2008-2014
0,00
0,50
1,00
1,50
2,00
2,50
3,00
1992
1993
1994
1995
1996
1997
1998
1999
2000
2001
2002
2003
2004
2005
2006
2007
2008
2009
2010
2011
2012
2013
2014
2015N
um
ber
Per
100,0
00
Pers
ons
Years New Cases Death-US
Epidemiology
Hodgkin Lymphoma Cancer Stat Facts. 2018.
https://seer.cancer.gov/statfacts/html/hodg.html.
Histological Subtypes as
WHO classification
Type Proportion of All HL
Classical HL Nodular sclerosis classical HL
Mixed cellularity classical HL
Lymphocyte rich classical HL
Lymphocyte depletion HL
95 % 70 %
20-25 %
5 %
1-2 %
Lymphocyte predominant nodular,
HL 5 %
Swerdlow, SH IARC Press. 2008. Swerdlow, SH, et al. Blood.
2016;127(20):2375-2390 Teras. CA Cancer J Clin. 2016.
Risk Factors
‒ High socioeconomical status: NS type
‒ Low socioeconomical status: MC and LD
‒ EBV: MC ve LD
‒ HIV and other immunosupresive situation
‒ Familial history: 3-5 fold
Presentation
‒ Supradiaphragmatic LAP
• Cervical
• Anterior mediastinal
• Supraclavicular
• Axillary: 10-20 %
‒ Inguinal LAP (less) 6-12 %
Painless LAP: 70 %
60-80%
Presentation
‒ 1/3rd of the patients:
• Fever
• Drenching night sweats
• Weight loss (more than 10 % of BW within 6 months)
‒ Fatigue
‒ Chronic pruritus which may be early sign (15 %)
‒ Pain localized to the site of involved LAP that is precipitated by the consumption of alcohol.
B symptoms
Presentation
‒ Most commonly EN involvement:
• Spleen
• Lungs
• Liver
• Bone marrow
Other Presentations
‒ Skin lesions: • Ichthyosis, acrokeratosis, urticaria, erythema multiforme,
erythema nodosum, necrotizing lesions, hyperpigmentation, skin
infiltration
‒ CNS involvement is rare, but paraneoplastic
neurological syndroms such as cerebellar
degeneration
‒ Nephrotic syndrome
‒ Hypercalcemia
‒ Anemia, thrombocytopenia, leukocytosis
‒ Chest pain, bronchial obstruction, abdominal pain,
spinal cord compression, and peripheral edema
Diagnosis
‒ Excisional LN biopsy
‒ If excision not feasible core-needle biopsy may
suffice
‒ FNA is inadequate for initial diagnosis
Histological and IHC
Features ‒ HL originated from GCB or post-GBC cells
‒ Classical HL includes Reed-Sternberg Cells(RS) (CD30+, CD15+ variable, PAX5+)
• RS cells: Large binucleated or
multinucleated cells with pale chromatin, distinct nuclear membrane, single prominent eosinophilic, inclusion-like nucleolus in each nuclear lobe, and abundant amphophilic cytoplasm
‒ Surrounding inflammatory cells
RS cells 0.1-2% of
total tumor cells
Nodular Lymphocyte-Predominant Hodgkin Lymphoma ‒ Macronodular proliferation are
composed of scattered neoplastic cells: lymphocyte- predominant (LP) cells.
‒ IHC pattern: CD20+, PAX-5+, and CD79a+
‒ In contrast to RS cells, CD15- and CD30-, but OCT-2+ and BOB.1+ .
‒ The origin is GBC: BCL-6+ but usually CD10neg
‒ 50% of the pts are EMA+, variably express IRF4/MUM1.
‒ EBERneg and LMP-1neg
Evaluation and Staging
‒ WBC
‒ RFT, albumin and LFT
‒ ESR and C-RP
‒ PA X-Ray
‒ Hepatitis tests (B and C) and HIV screening
‒ PET/CT*
‒ BM biopsy is no longer indicated in PET/CT
available
‒ MRI and PET/MRI in selected patients
*Prior to ChT or surgery, gross tumor volume and planning target volume should be defined.
tRoutine BM bx is not required if the PET scan (-) or displays homogenous pattern of BM
uptake. BM may be assumed to be involved if the PET scan displays multifocal (≥3) skeletal
lesions
Evaluation and Staging
‒ Prior to treatment: • Cardiac evaluation (ECO or MUGA)
• If necessary, Pulmonary function tests
• Thyroid tests
• Reproductive counseling, and serum pregnancy
testing
How can we stage a patient with
lymphoma?
1971 Ann Arbor
Classification 1988 Cotswolds modification
1999 NCI criteria
2007 IWG revised guidelines
2011 workshop at 11-ICML
2013 2nd workshop at 12-ICML
2014 Lugano classification
Lugano Classification (Derived from Ann-Arbor Staging with Cotswolds- Modification)
Stage I Involvement of a single lymph node ((LN) region (eg, cervical, axillary, inguinal,
mediastinal) or lymphoid structure such as the spleen, thymus, or Waldeyer's ring.
Stage II Involvement of two or more LN regions or LN structures on the same side of the
diaphragm. Hilar nodes should be considered to be "lateralized" and when involved on
both sides, constitute stage II disease.
For the purpose of defining the number of anatomic regions, all nodal disease within
the mediastinum is considered to be a single LN region, and hilar involvement
constitutes an additional site of involvement. The number of anatomic regions should
be indicated by a subscript (eg, II-3).
Stage III Involvement of LN regions or lymphoid structures on both sides of the diaphragm. This
may be subdivided stage III-1 or III-2: stage III-1 is used for patients with involvement of
the spleen or splenic hilar, celiac, or portal nodes; and stage III-2 is used for patients
with involvement of the paraaortic, iliac, inguinal, or mesenteric nodes.
Stage IV Diffuse or disseminated involvement of one or more extranodal organs or tissue beyond
that designated E, with or without associated lymph node involvement.
Cheson BD, et al. J Clin Oncol 2014; 32: 3059-3068
Lugano Classification (Derived from Ann-Arbor Staging with Cotswolds- Modification)
Addendum A B symptoms are absent.
Addendum B B symptoms are present: fever (temperature >38ºC), drenching night sweats, and/or
unexplained loss of >10% of body weight within the preceding 6 months.
Addendum E The designation "E" refers to extranodal contiguous extension (ie, proximal or
contiguous extranodal disease) that can be encompassed within an irradiation field
appropriate for nodal disease of the same anatomic extent. More extensive extranodal
disease is designated stage IV.
Bulky disease A single nodal mass, in contrast to multiple smaller nodes, of 10 cm or ≥⅓ of the
transthoracic diameter at any level of thoracic vertebrae as determined by CT; record
the longest measurement by CT scan. The term "X" (used in the Ann Arbor staging
system) is no longer necessary.
Subscript "RS" is used to designate the stage at the time of relapse.
Patients can be clinically or pathologically staged. Splenectomy, liver biopsy, lymph
node biopsy, and/or bone marrow biopsy are mandatory for the establishment of
pathological stage. The pathologic stage at a given site is denoted by a subscript (eg, M
= bone marrow, H = liver, L = lung, O = bone, P = pleura, and D = skin).
Cheson BD, et al. J Clin Oncol 2014; 32: 3059-3068
Lymph Node Regions
Diaphragm
Supra
Infra
Ann Arbor EORTC GHSG
R Cervical/SCL
R ICL/Subpec
R axilla
L Cervical/SCL
L ICL/Subpec
L axilla
Mediastinum
R Hilum
L Hilum
Total 9 5 5
EORTC includes to combine the ICL/subpec area with axilla:
GHSG includes to combine the cervical/SCL and subpec
GHSG combined the mediastinum and bilaterally hila
Practical Staging
Criteria of Involvement
Sites Tissue site Clinical Type Test Positive finding
Lymph nodes Palpable
FDG-avid
PET-CT
Increased FDG uptake
Non-avid
CT
Unexplained node enlargement
Spleen Palpable
FDG-avid PET-CT Diffuse uptake, solitary mass,
military lesion, nodules
Non-avid CT > 13 cm in vertical length, mass,
nodules
Liver Palpable FDG-avid
PET-CT
Diffuse uptake, mass, nodules
Non-avid CT Mass, nodules
Cheson BD, et al. J Clin Oncol 2014; 32: 3059-3067
Criteria of Involvement
Sites Tissue site Clinical Type Test Positive finding
CNS Sign,
symptom
CT scan
Mass lesion(s)
MRI Leptomeningeal infiltration,
mass lesions
CSF
assessment
Cytology, flow cytometry
Other
(e.g., skin,
lung, GI tract,
bone, BM)
Site
dependent
PET/CT,
biopsy
Lymphoma involvement
Cheson BD, et al. J Clin Oncol 2014; 32: 3059-3067
Treatment of
Classical Hodgkin
Lymphoma
Prognostic Factor, Risk
Stratification, and Treatment Groups Treatment Group EORTC/LYSA GHSG
Early Stage CSI-II without risk factors
(supradiaphragmatic)
CI-II without risk factors
Intermediate stage CSI-II with ≥1 risk factors
(supradiaphragmatic)
CSI, IIa with ≥ risk factors;
CSIIB with risk factors C
and/or D, but not A/B
Advanced Stage CSIII-IV CSIIB with risk factors A and/or
B, CS III/IV
Early stage
Favorable
Unfavorable
A. Large Mediastinal mass: mediastinum-thorax ratio ≥0.35 (EORTC/LYSA), mediastinal larger than 1/3 of the
maximum thoracic width (GHSG)
B. EN disease
C. Elevated ESR: > 50 mm/h wo B symptoms, > 30 mm/h w (B symptoms; fever, night sweat, unexplained
weight loss > 10 % over 6 months
D. Nodal areas: Involvement of 4 out 5 supradiaphragmatic nodal areas (EROTC/LYSA), involvement of 3 out
of 11 nodal areas on both sides of the diaphragm (GHSG)
Eichenauer DA, et al. HemaSPhere 2018; 2: 5(e149)
Prognostic Factor, Risk Stratification, and Treatment Groups
Bröckelmann PJ, et al. Blood 2018; 131(15):1666-1678
* Elevated ESR: > 50 mm/h wo B symptoms, > 30 mm/h w (B symptoms; fever, night sweat, unexplained weight loss > 10 % over 6
months t Large Mediastinal mass: mediastinum-thorax ratio ≥0.35 (EORTC/LYSA), mediastinal larger than 1/3 of the maximum thoracic width
(GHSG)
Stage IIB with the respective RF considered advanced-stage disaese by the GHSG
Nodal areas: Involvement of 4 out 5 supradiaphragmatic nodal areas (EROTC/LYSA), involvement of 3 out of 11 nodal areas on both
sides of the diaphragm (GHSG)
Early-Stage: Favorable
2xABVD
PET-adapted Non-PET-adapted
PET-pos PET-neg
1xABVD
20 Gy-ISRT
2xBEACOPPesc
30 Gy-ISRT
EORTC/LYSA/FIL H10 study
GHSG
HD10 study
20 Gy-ISRT
ESMO Guideline
Eichenauer DA, et al. Annals of
Oncology, 2018; 29 (Suppl 4): iv19-
iv29
5 ys PFS: 87 %
10 ys OS: 94 %
5 ys PFS: 99 %
5 ys OS: 96 %
5 ys PFS: 91 %
5 ys OS: 96 %
5-point scale (Deauville Criteria)
Score 18-FDG uptake
1 No uptake
2 ≤ Mediastinal blood pool
3 > Mediastinum and ≤ liver
4 Moderately > liver at any site
5 Markedly1 > liver at any site and/or new sites of disease
X New areas of uptake unlikely to be related to lymphoma
1. i.e., maximum standardized uptake value (SUVmax) of the lesion > 2xliver uptake
Barrington SF, et al. Eur J Nucl Med Mol Imaging 2010; 37: 1824
CMR
Residual
MR
Possible
CMR
FDG uptake
Early-Stage: Favorable
2xABVD
PET-adapted
Deauville 1-3 Deauville 5
2xABVD
Refractory
disease
Biopsy
NCCN Recommendation V3.2018
20 Gy-ISRT
Deauville 4
PET/CT
20 Gy-ISRT
Neg Pos
Modified
from GHSG
HD10 study OR
or
Early-Stage: Favorable
3xABVD
PET-adapted
Deauville 1-2 Deauville 5
1xABVD
plus
30 Gy-ISRT
Refractory
disease
Biopsy
NCCN Recommendation V3.2018
Observe
Deauville 3-4
PET/CT
Neg Pos
Modified from
RAPID,
EORTC H10
and Stanford
G4 trial
OR
1xABVD
Early-Stage: Favorable
2xABVD
PET-adapted
Deauville 1-2 Deauville 5
2xABVD (Deauville 3)
Refractory
disease
Biopsy
NCCN Recomendation V3.2018
Deauville 3-4
PET/CT Neg Pos
Modified from
RAPID,
EORTC H10
and Stanford
G4 trial
OR
1xABVD
plus
30 Gy-ISRT
2xBEACOPPe
sc (Deauville 4-5)
30 Gy-ISRT
3 ys PFS: 91 %
3 ys OS: 97 % 3 ys PFS: 95 %
3 ys OS: 99 %
Early-Stage: Favorable
Stanford Vx8weeks
PET-adapted
Deauville 1-4 Deauville 5
Refractory
disease
Biopsy
NCCN Recommendation V3.2018
Neg Pos
Modified from
RAPID,
EORTC H10
and Stanford
G4 trial
30 Gy-IFRT
Median FU: 10.6 ys
FFP 94%
DSS 94%
OS 99%
Standard Treatment Summary in
Early Stage with Favorable
Treatment
Chemotherapy x 2 cycles + IFRT, or
Chemotherapy x 2 (3) cycles, then
– If PET neg → Observe or chemotherapy x 0-2 cycles
and/or IFRT (ISRT)
– If PET pos → IFRT (ISRT) and/or chemotherapy
(consider biopsy if high Deauville)
Chemotherapy = ABVD or BEACOPPesc.
Early-Stage: Unfavorable
2xABVD
PET-adapted Non-PET-adapted
PET-pos PET-neg
2xABVD
30 Gy-ISRT
2xBEACOPPesc
30 Gy-ISRT
EORTC/LYSA/FIL H10 study
GHSG
HD14 study
30 Gy-ISRT
ESMO Guideline
2xBEACOPPesc plus
2xABVD
or 4xABVD
Eichenauer DA, et al. Annals of
Oncology, 2018; 29 (Suppl 4): iv19-
iv29
5 ys PFS: 91 %
5 ys OS: 97 %
5 ys PFS: 92 %
5 ys OS: 97 %
5 ys PFS: 92 %
5 ys OS 96 %
Early-Stage: Unfavorable
2xBEACOPPesc plus 2xABVD
PET-adapted
Biopsy
Modified
GHSG
HD14
study
NCCN Recommendation V3.2018
ISRT
Deauville 5
Refractory
disease
Neg
Pos
Deauville 1-4
Standard Treatment Summary in
Early Stage with unfavorable
Treatment
Chemotherapy x 4 cycles + IFRT (ISRT), or
Chemotherapy x 2 cycles, then
– If PET neg → chemotherapy x 2 cycles and IFRT (ISRT)
– If PET pos → intensive chemotherapy x 2 cycles and
IFRT (ISRT)
– (or accepted as refractory disease in Deauville 5)
Chemotherapy = ABVD or BEACOPPesc.
Advanced Stage cHL
‒ International Prognostic Score
• Age ≥45 ys
• Male gender
• Stage IV disease
• Albumin level < 4g/dL
• Hemoglobin Level < 10.5 g/dL
• Leukocytosis (WBC > 15,000/uL)
• Lymphopenia (lymphocyte count < 8 % of the
WBC and/or lymphocyte count <600/uL)
Hasenclever D, et al. NEJM 1998; 339: 1506-1514
Advanced Stage: III-IV
2xABVD
PET-adapted Non-PET-adapted
GHSG HD18
study Localized RT to
residual ≥2.5 cm
ESMO Guideline
6xBEACOPPesc
or
6xABVD
2xBEACOPPesc
RATHL
study
Eichenauer DA, et al. Annals of
Oncology, 2018; 29 (Suppl 4): iv19-iv29
Advanced Stage: III-IV
2xBEACOPPesc
PET-adapted
PET-pos PET-neg
2xBEACOPPesc
Observe
4xBEACOPPesc
Localized RT to residual ≥2.5 cm
ESMO Guideline
PET-scan
PET-pos PET-neg
GHSG
HD18 study
Advanced Stage: III-IV
2xABVD
PET-adapted
PET-pos PET-neg
4xAVD
Observe
4xBEACOPPesc or
4xABVD
Localized RT to residual ≥2.5 cm
ESMO Guideline
PET-scan
PET-pos PET-neg
RATHL
study
Merging of different risk-adapted approaches.
Sean H. Lim, and Peter W. M. Johnson Blood 2018;131:1679-1688
RATHL/AHL2011 Lysa approaches
<60y BV-AVD x2
FDG-PET
AVD X4 BV-AVDX4
89% -
12 ms PFS: 95 vs 85%
Younes A et al. Lancet Oncol. 2013; 14(13):1348-56
ECHELON-1
study
Advanced Stage: III-IV
2xBVxAVD
PET-adapted
Deauville 1-4 Deauville 5
4xBV+AVD or
Alternative treatment
Refr disease
4xBV+AVD
Observe
NCCN Recommendation V3.2018
PET-scan
Deauville 1-2 Deuville 5 Deauville 3-4
Observe or
RT to PET+
Standard Treatment Summary in
Advanced Stage
Treatment
Chemotherapy x 6 cycles or BV plus ChT x 6 cyles, then
– If CR by CT → stop
– If PR by CT and PET neg → stop
– If PR by CT and PET pos, then
• Can receive radiotherapy → IFRT
Chemotherapy = ABVD or BEACOPPesc.
Treatment of
Relapse/Refractory
HL
Prognostic Factors
in R/R HL as the LYSA study
High Risk
Primary refractory disease1 or relapse with two poor
prognosis factors (early relapse2 and stage III/IV
at relapse)
Intermediate Risk
Relapse with only one poor prognostic factor
(early relapse or stage III/IV at relapse)
Standart Risk
Relapse without risk factor (relapse > 12 months after
end of treatment and stage I/II disease)
Van Den Neste E, et al. Haematologica 2013; 98: 1185-1195
1Defined either by progression at any time during chemotherapy and up to 3 months after end of chemotherapy, or by failure to achieve at least PR with first-line therapy, or by persistence of significant (score 4 or 5/5) residual FDG metabolic activity using the quantitative 5-point scale Deauville score (DS). 2Defined by time to treatment failure > 3 months but < 12 months after end of first-line therapy.
OS in R/R HL according to
risk groups
(n=258)
47%
74%
51%
43%
Sibon D, et al. Haematologica 2016; 101: 474-481
Primary Refractory cHL/cHL in 1st relapse
2nd and 3rd line ChT to test chemosensivity
ASCT
Disease relapse after ASCT
Prior BV therapy or BV resistant disease
No Yes
BV CPIs or
Clinical trial
No response
Conventional salvage or
Clinical trial Consider Allo-tx
Observe
Consider Allo-tx
Sureda A&Martinez C.
EBMT Handbook 2019
HDT/ASCT Eligibility
‒ Relapsed/refractory to induction therapy • 20% to 30% of patients with Hodgkin lymphoma are relapsed/refractory to
induction regimen of ABVD
‒ Standard of care: combination chemotherapy followed by ASCT • Long-term PFS: ~ 50% of patients
‒ 70 yrs of age or younger
‒ Adequate organ function testing
‒ Able to auto collect 2 x 106 CD34+ cells
‒ Chemosensitive disease
Josting. A, et al. Ann Oncol. 2005;16:1359-65. Moskowitz
CH, et al. Blood. 2001;97:616-23; Santoro A, et al.
Haematologica 2007;92:35-41; Bartlett NL, et al. Ann Oncol.
2007;18:1071-9.
85 %
72 %
Relapsed/Refractory HL: Prognosis and Response to
Salvage Chemotherapy Before ASCT
‒ CR status at ASCT is predictive of outcome (5-yr EFS: 75% vs 31%)[1]
‒ Extranodal disease and primary refractory or relapsed disease within 1 yr are also risk factors[2]
Salvage
Regimen N ORR, % CR, %
ICE[3] 65 88 26
DHAP[4] 102 89 21
GVD[5] 91 70 19
GDP[6] 34 62 10
ICE/aug ICE[2] 97 60 (by PET)
IGEV[7] 91 81.3 53.8 (by PET)
1. Moskowitz. Blood. 2010;116:4934. 2. Moskowitz. Blood. 2012;119:1665. 3. Moskowitz. Blood. 2001;97:616. 4. Josting. Ann Oncol. 2005;16:116. 5. Bartlett. Ann Oncol. 2007;18:1071. 6. Kuruvilla. Cancer. 2006;106:353. 7. Santoro. Haematologica. 2007;92:35.
EFS by PET Status Pre-ASCT[1]
1.0
0.8
0.6
0.4
0.2
0
Yrs 0 2 4 6 8 10 12 14
Cu
mu
lati
ve E
FS
P < .0001
PET negative
PET positive
Slide credit: clinicaloptions.com
Novel Salvage Regimens for Patients
With Relapsed/Refractory HL Before
ASCT
Salvage Regimen N ORR, % CR by PET, %
BV + ICE (sequential)[1] 37 89 65
BV + augICE (sequential)[2] 45 96 76
BV + Bendamustine[3] 55 93 74
BV + ESHAP (BRESHAP)[4] 66 96 70
BV + ICE (concurrent)[5] 16 94 69
BeGEV[6] 59 83 73
1. Chen. Biol Blood Marrow Transplant. 2015;21:2136. 2. Moskowitz. Lancet Oncol. 2015;16:284. 3. LaCase. ASH 2015. Abstr 3982. 4. Garcia-Sanz. ASH 2016. Abstr 1109. 5. Cassaday. ASH 2016. Abstr 1834. 6. Santoro A. J Clin Oncol. 2016;34:3293.
Slide credit: clinicaloptions.com
Survival in Patients With HL
Relapsing After HDT/ASCT Database analysis from 5 institutions on patients with recurrent HL and
at least 1 yr of follow-up after transplantation
Arai. Leuk Lymphoma. 2013;54:2531. Slide credit: clinicaloptions.com
Agent Indications
Nivolumab
Adult patients with relapsed/refractory disease after
ASCT and brentuximab vedotin
Adult patients with relapsed/refractory disease after
≥ 3 lines of systemic therapy including ASCT Dosing: 240 mg Q2W or 480 mg Q4W
Pembrolizumab
Adult or pediatric patients with refractory disease or
who have relapsed after ≥ 3 lines of therapy
Dosing: 200 mg Q3W (adults) or 2 mg/kg Q3W (pediatric)
Slide credit: clinicaloptions.com
Current Approved Indications for PD-1
Inhibitors in Relapsed/Refractory HL
Anti-PD-1
Blokage
Phase Ib
Nivolumab Pembrolizumab
Tumoral reduction: 87 % Tumoral reduction: 65 %
17%
70%
13%
CR PR Stabil
R/R HL
Ansell S, et al NEJM 2015; Armand P, et al. 2016
16%
48%
23%
13%
CR PR Stabil Progr.
Check Point Inhibitors-Phase Ib
CheckMate-205
Total
(n=210)
n (%)
ORR 143 (68,1)
CR 63 (30,0)
PR 80 (38,1)
Stabile 40 (19,0)
Progresive 23 (11,0)
Undetermined 4 (1,9)
KEYNOTE-087
J Clin Oncol 2018; 36:1428-1439 J Clin Oncol 2017; 35:2125-2132
Total
(n=210)
N (%)
ORR 168 (69)
CR 40 (16)
PR 128 (53)
Stabile 47 (19)
Progresive 23 (9)
Undetermined 5 (2)
Check Point Inhibitors-Phase II
Mechanism Agent(s)
Antibody–drug conjugate CD25 ADC
IMiD Lenalidomide
Transcriptional pathways HDAC inhib, PIK3 inhib, mTOR inhib, BTK, Jak/STAT,
PIM kinases, galectin-1
Antibody/receptor cell therapy Anti-CD30 CAR T; CD123 (dendritic) CAR T;
bispecific Ab (CD30/CD16)
EBV-directed therapy EBV-cytotoxic T-cells, LMP-2A inhibition
Other immunotherapy (including TME) PD-L1 inhibitors; CD47-SIRP-α signaling; CSF-1 inhibitors
(macrophage)
Antiapoptotic molecules Proteasome pathway inhibition, XIAP; arsenic trioxide (restore B-cell
phenotype)
Additional approaches Adenoviral vector-transduced dendritic cells with LMP1 and LMP2
construct for latency II , CD30-targeted oncolytic viruses
Slide credit: clinicaloptions.com
A Snapshot of the Current Investigational
Therapeutic Landscape for cHL
Treatment of Elderly Patients with
cHL
NCNN guideline
Stage I/II favorable Stage I/II (unfavorable) or Stage III/IV
2xA(B)VD±2xAVD+ISRT (preferred)
VEPEMB*±ISRT
2xA(B)VD±4x AVD
6xVEPEMB*±ISRT
• Poor outcome
•B symptoms
•Poor PS
•MC type
•EBV+
•Medical comorbidities
*VEPEMB: vinblastine, cyclophosphamide, procarbazine, prednisone, etoposide, mitoxantrone,
bleomycin
Treatment of NLPHL
ILROG Guideline
and NCNN
guideline
Stage IA or IIA wo RFs Other Stage
ISRT Chemotherapy plus anti-
CD20 ±ISRT
Initial Treatment
Refractory/Relapsed Disease
Biopsy
NLPHL
Localized disease
Anti-CD20
Disseminated and/or poor risk
Salvage ChT
Follow-Up After Completion
Therapy ‒ PET/CT within completion therapy
‒ Until 5 years
• History&Physical Examination: 3-6 ms for 1-2 ys, then
every 6-12 ms until year 3, then annually
• Laboratory Examination
• CBC, ESR, BFT and LFT
• TSH annually if RT to neck
• CT for neck/chest/abdomen/pelvis scan with contrast at
6, 12 and 24 mo or as indicated
• Annual influenza vaccines
Follow-Up After Completion
Therapy ‒ After 5 years
• History&Physical Examination annually
• Laboratory Examination
• Vaccines for pneumococcus, meningococcus and
H-flu if pt was treated with splenic RT or
splenectomy
• Annual influenza vaccine
• Screening for secondary neoplasia
• Cardiovascular function
• Carotis doppler (especially neck radiotherapy)
Summary in HL
‒ HL is successful story among hematological
malignancy.
‒ Today, treatment modalities and approaches are
controversial.
‒ iPET might refine the treatment (esc- or des).
‒ Incorporation of the novel agents to 1st line setting
‒ Allo-tx is still an option in highly selected patients with
relapse/refractory HL after ASCT.