Cases exploring the many facets of MCL

Dr Pam McKay

This medical education meeting was organised and funded by Janssen-Cilag Ltd. EM-14633 | July 2019

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MCL workshop

Dr Pam McKay

Consultant Haematologist

Beatson Cancer Centre

Glasgow

February 2019

This meeting was organised and funded by Janssen

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for the Pharmaceutical Industry

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Conflicts of interest

Honoraria received from:

• Epizyme

• Gilead

• Janssen

• Roche

• Takeda

MCL

• Male predominance1

• >90% present with advanced stage disease2

• Widespread lymphadenopathy, splenomegaly, BM and peripheral blood involvement2

• EN involvement common, e.g. gut, breast, lung, skin, salivary gland, lacrimal gland3

– 30–50% have ≥2 EN sites

• B symptoms and bulk uncommon4

BM: bone marrow; EN: extranodal;

MCL: mantle cell lymphoma.

1. WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues. Revised 4th Edition. Volume 2. 2008. Swerdlow SH, et al (Ed.); 2. Martins C, et al. Rev Bras Hematol Hemoter. 2017; 39:73–6; 3. Jares P, Campo E. Br J Haematol. 2008; 142:149–65; 4. McKay P, et al. Br J Haematol. 2018; 182:46–62.

Adapted from Haematological Malignancy Research Network. Incidence. [Accessed: July 2019]. Available at: www.hmrn.org/statistics/incidence

Median age in the UK is 73 years

Incidence of haematological neoplasms

Clinical course and outcome

• Heterogeneous course:– Indolent: splenomegaly and

per blood → 5 to 12-year survival (SOX11 negative)

– Aggressive: blastoid

• Incurable

• Relapse → resistance

• Median OS: 4 to 5 years

• OS increased in younger, fitter patients who can tolerate intensive therapy

Proposed model of molecular pathogenesis in the development and progression of major subtypes of MCL

Cheah CY, et al. J Clin Oncol. 2016; 34:1256–69.IG: immunoglobulin;

OS: overall survival; PB: peripheral blood.

Case 1

• 64-year-old man, presented in 2010

• Deaf (R ear)

• Nasal blockage

• Swelling at back of throat (R side)

• MRI: large R post-nasal space mass (4.7 x 5.8 x 3.4 cm)

• Biopsy: MCL, Ki67 30%

Case 1

• Well, PS=0, no B symptoms

• No comorbidities; no medication

• Non-smoker; >20 units alcohol/week

• Hb 160; WCC 5.2 (lymph 0.8); platelets 221

• LDH 244 (ULN 240)

• CT scan: nasopharyngeal mass; bilateral cervical LNs

• BM: minor infiltrationHb: haemoglobin; LDH: lactate dehydrogenase; LNs: lymph nodes;

PS: performance status; ULN: upper limit of normal; WCC: white cell count.

Case 1

• Stage IVA

• MIPI score = 3 (low risk)

• What treatment?

• Rituximab + HD cytarabine

HD: high dose; MIPI: mantle cell lymphoma international prognostic score.

Which cytarabine-containing regimen?

• Hyper-CVAD– CR rates of 87%1 and 92%2 in a single centre

– ~40% cannot complete treatment in the multicentre setting3,4

• Nordic MCL2 study

• European MCL Network study, MCL Younger

• GELA/Lysa study

• LyMa study

• British-Nordic MCL5 study

CR: complete response; CVAD: cyclophosphamide, vincristine, doxorubicin,

dexamethasone, methotrexate, cytarabine.

1. Romaguera JE, et al. Br J Haematol. 2010; 150:200–8; 2. Ritchie DS, et al. Ann Hematol. 2007; 86:101–5; 3. Merli F, et al. Br J Haematol. 2012; 156:346–53; 4. Bernstein SH, et al. Ann Oncol. 2013; 24:1587–93.

Nordic MCL2 2000–2006

No. Eval. CR/CRu ORR

160 54% 96%

0.0 2.5 5.0 7.5 10.0 12.50.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

Survival (53 deaths)

MCL2 Update 2010:- Overall and Event-freeSurvival.- Response Duration

EFS (79 events)RD (145, 54 progressions)

Years

Fra

cti

on

su

rviv

al

Predicted 10-year EFS: 43%, OS: 58%

Geisler CH, et al. Br J Haematol. 2012; 158:355–62.

MCL2 update (all patients):OS and EFS

Response duration

BEAM/C: BCNU, AraC, etoposide, melphalan, cyclophosphamide; CHOP: cyclophosphamide,

doxorubicin, vincristine, prednisone; CRu: unconfirmed complete response;

EFS: event-free survival; ORR: overall response rate;

R: rituximab; RD: residual disease.

15-year follow-up of the Nordic MCL2 trial

• Median follow-up: 11.4 years; PFS: 8.5 years; OS: 12.7 years

• Despite long-term responses, late relapses still occur

• On-going relapses >10 years out

MIPI– High: PFS 2.5 years; OS 4 years

– Int: PFS 8 years; OS 11 years

– Low: PFS 12.8 years; OS NR

Low/int group: 40% in first CR >12 years

Eskelund CW, et al. Br J Haematol. 2016; 175:410–18. Int: intermediate; NR: not reached; PFS: progression-free survival.

PBSCT

3 x R-CHOP3 x R-DHAPalternating

PBSCT

TBI 10 GrayAra-C 4 x 1.5 g/m2

Melphalan 140 mg/m2

6 x R-CHOP

DexaBEAM(stem cell mobilisation)

MCL younger

Cyclo/TBI

Hermine O, et al. Lancet. 2016; 388:565–75.

497 patients

R-DHAP: rituximab, dexamethasone, cytarabine, cisplatin; PBSCT: peripheral blood stem cell transplant; TBI: total body irradiation.

TTF, stratified by MIPIBenefit across all MIPI and Ki67 groups

TTF in primary analysis and OSTTF: median 9.1 years vs 3.9 years

65% at 5 years vs 40%

OS not significantly different at time of analysis

Graphs adapted from: Hermine O, et al. Lancet. 2016; 388:565–75. CI: confidence interval; HR: hazard ratio; TTF: time to treatment failure.

LyMa trial2

• Phase 3

• R-DHAP x 4 (+ R-CHOP x 4 if not in CR/PR)→ ASCT →maintenance R or observation

• ORR: 94% (CR/CRu: 77%)

• 4-year PFS: 68%; OS: 78%

1. Delarue R, et al. Blood. 2013; 121:48–53; 2. Le Gouill S, et al. N Engl J Med. 2017; 377:1250–60. ASCT: autologous stem cell transplantation; PR: partial response.

LYSA (GELA)1

• Phase 2

• CHOP x 2; R-CHOP x 1; R-DHAP x 3 then ASCT

• ORR: 95% (CR: 57%)

• Median EFS: 83 months

• 5-year OS: 75%

R-HD cytarabine +/- dexamethasone

• 18 patients

• 72% int (61%) or high (11%) MIPI

• Cytarabine: 3 g/m2 IV bd D1–2 (2 g/m2 IV bd if age ≥60 years)

• Rituximab: 375 mg/m2 IV D1

• Dexamethasone: 40 mg OD D1–4 (optional)

• Repeat every 21 days to a maximum of six cycles, then transplant

• Number of patients completing planned therapy: 16 (88.9%)

• Median number of total cycles (range): 5 (4–6)

• Reasons for not completing therapy:

– Disease progression (1)

– Treatment toxicity (1)

Forbes A, et al. Leuk Lymphoma. 2013; 54:2303–05. bd: twice daily; D: day; IV: intravenous; OD: once daily.

Update at BSH 20161

• 45 transplant-eligible patients

• Four UK centres

• 2010–2015

• Median age: 60 years (56–58 in other major studies)

• Nine patients (20%) progressed on HDAC– Three patients (33%) responded to second-line

therapy, with two subsequently dying of PD

• 69% had transplant (62% ASCT)

• ORR 78% (+/- ASCT), 67% CR

• Median PFS and OS not reached (median follow-up of 38 months)

• 61% PFS and 78% OS at four years

• Post-induction CR of 67% compares favourably to:

– Geisler 54%2

– DeLarue 57%3

– Hermine 54%4

– Le Gouill 77%5

• Conclusions:– Well tolerated, effective– Avoids excess toxicity from

additional drugs– Greater range of therapies for relapse

1. Burrows S, et al. Presentation at BSH 2016. Abstract E970; 2. Geisler CH, et al. Br J Haematol. 2012; 158:355–62; 3. Delarue R, et al. Blood. 2013; 121:48–53; 4. Hermine O, et al. Lancet. 2016; 388:565–75; 5. Le Gouill S, et al. N Engl J Med. 2017; 377:1250–60.

HDAC: histone deacetylase; PD: progressive disease.

R

British-Nordic MCL5 protocol

BEAM

H D-ARA-C: 3 g/m2 (>60 years: 2g/m2) four infusions/cycle

RH

D-A

RA

-C

DDDD

DDDD: dexamethasone p.o. 40 mg D1–4

R: rituximab 375 mg/m2 D1

Protocol: Phase 2, historic control (MCL2 and 3)Inclusion criteria:

• Nordic: untreated MCL s-MIPI-B high-risk• British: all patients in need of treatment• Below 66 years of age

ASCT

MRD monitoringand pre-emptiverituximab at molecular relapse

Stage Restage 1 Restage 2 Restage 3Harvest Reinfusion

Stem cell:

R

H D

-AR

A-C

DDDD

R

H D

-AR

A-C

DDDD

R

H D

-AR

A-C

DDDD

R

H D

-AR

A-C

DDDD

R

H D

-AR

A-C

DDDD

CycleWeek

11

24

37

410

513

616 19 20 28

MRD: minimal residual disease; p.o.: by mouth.Adapted from: Nordic-lymphoma. A Nordic Lymphoma Group Phase 2 Trial. Available at: www.nordic-lymphoma.org/wp-content/uploads/2016/11/MCL5_final_04-11-2011.pdf [accessed July 2019].

Nordic MCL5

• Restricted to high-risk MIPIB (high Ki67)

• Low- and int-risk groups: 70% 10-year survival in the MCL2 and MCL3 trials

• Five patients:– Two responded after three cycles,

with one subsequently progressing– Three non-responders

• Trial stopped

• Patients salvaged with mega-CHOP

“High-dose cytarabine with rituximab is not enough in first-line treatment of mantle cell lymphoma with high proliferation: early closure

of the Nordic Lymphoma Group Mantle Cell Lymphoma 5 trial”

Laurell A, et al. Leuk Lymphoma. 2014; 55:1206–08.

RB/RC induction chemotherapy for transplant-eligible patients with uMCL

• Pooled analysis: two phase 2 trials + off-trial results; 86 patients1

• DFCI trial: RB x 3 followed by RC x 3

– B 90 mg/m2 D1–2; C 3 g/m2 bd D1–2

– Preliminary results2

→ SOC

• WUSTL trial: alternating RB/RC x 6

– ORR 98% (CR 92%); 85% → ASCT

– PFS 88% at two years; 80% at four years; OS 96%; 92%

– Efficacy similar; delayed platelet engraftment with sequential regimen and C >2 g/m2

1. Merryman R, et al. Presentation at ASH 2018. Abstract 0145; 2. Armand P, et al. Br J Haematol. 2016; 173:89–95.

RB/RC: rituximab/bendamustine, rituximab/cytarabine; SOC: standard of care; uMCL: untreated mantle cell lymphoma.

Trial ORR CR/Cru

NORDIC MCL21 96% 54%

MCL Younger:2

- alt R-CHOP/R-DHAP 95% 54%

- R-CHOP 90% 40%

Lysa3 95% 57%

LyMa4 94% 77%

R-HD Ara-C5 78% 67%

R-hyperCVAD*6 94% 41%

RB*6 86% 43%

*SWOG S1106 phase 2 inter-group trial.1. Geisler CH, et al. Br J Haematol. 2012; 158:355–62; 2. Hermine O, et al. Lancet. 2016; 388:565–75; 3. Delarue R, et al. Blood. 2013; 121:48–53; 4. Le Gouill S, et al. N Engl J Med. 2017; 377:1250–60; 5. Burrows S, et al. Presentation at BSH 2016. Abstract E970; 6. Chen RW, et al. Br J Haematol. 2017;176:759–69.

HD-cytarabine regimens

alt: alternating.

HD-cytarabine trial outcomes

Trial PFS OS

NORDIC MCL21 8.5 years (median) 12.7 years (median)

MCL younger2 65% (5 years) 76% (5 years)

Lysa3 64% (5 years) 75% (5 years)

LyMa4 68% (4 years) 78% (4 years)

R-HD Ara-C5 61% (4 years) 78% (4 years)

1. Geisler CH, et al. Br J Haematol. 2012; 158:355–62; 2. Hermine O, et al. Lancet. 2016; 388:565–75; 3. Delarue R, et al. Blood. 2013; 121:48–53; 4. Le Gouill S, et al. N Engl J Med. 2017; 377:1250–60; 5. Burrows S, et al. Presentation at BSH 2016. Abstract E970.

Case 1

• Started R-HD Ara-C

• C1D6 – chest pain

• Large inferoposterior MI → stent– Echo: normal LV function

– Aspirin and clopidogrel for three months

– Culture-negative neutropenic sepsis

• What now?

LV: left ventricular; MI: myocardial infarction.

Case 1

• Received R-HD Ara-C x 4 → CR

• What now?

• ASCT (BEAM), August 2010

Transplant – ASCT

• Only one prospective study comparing the outcome of ASCT with non-SCT strategies for first-line consolidation1

– CHOP-based induction then HDT + ASCT or IFN

– PFS: 39 months vs 17 months; no OS advantage

• Several phase 2 studies – difficult to separate the effects of intensive induction and consolidation HDT

– 4 to 5-year PFS: 56–73%; OS: 64–81% → SOC

Dreyling M, et al. Blood. 2005; 105:2677–84. HDT: high-dose therapy; IFN: interferon.

Prognostic factors for favourable outcome of first-line consolidation HDT

• Low or intermediate MIPI

• Achievement of MRD-negative state

• Disease status at transplantation

Dr Pam McKay personal communication

Allogeneic SCT1

• Limited data

• Heterogenous populations– First-line, relapse, +/- previous ASCT

• Substantial toxicity– Non-relapse mortality rates 9–25% at 1 year2–6

• cGVHD in 40–50%7

• Relapse rate: 15–38%3,6,8

• Suggestion of a plateau after four years

cGVHD: chronic graft vs host disease.

1. McKay, et al. Br J Haematol. 2018; 182:46–62; 2. Maris MB, et al. Blood. 2004;104:3535–42; 3. Tam CS, et al. Blood. 2009; 113:4144–52; 4. Cook G, et al. Biol Blood Marrow Transplant. 2010; 16:1419–27; 5. Le Gouill S, et al. Ann Oncol. 2012; 23:2695–703; 6. Fenske TS, et al. J Clin Oncol. 2014; 32:273–81; 7. Jagasia M, et al. Blood. 2012;119(1):296–307. 8. Robinson. Bone Marrow Transplant. 2017; 52:S17–155.

Rituximab maintenance after SCT

• Previously untreated MCL <66 years, 53% MIPI low-risk

• R-DHAP x 4 (+ R-CHOP14 in NR), R-BEAM auto-SCT

• 299 enrolled, 240 randomised post-SCT to observation vs MR, once every two months for three years

• Four-year PFS: 83% MR vs 64% observation

• Four-year OS: 89% MR vs 80% observation

Conclusion: MR prolongs survival in younger MCL patients post-ASCT

Le Gouill S, et al. N Engl J Med. 2017; 377:1250–60. MR: maintenance rituximab; NR: non-responders

Case 1

• Prostate cancer, March 2014

• Relapsed MCL (biopsy confirmed, Ki67 15–20%), November 2014

• CT scan: localised to L neck

• Management?

• Watch and wait

Case 1

• November 2017 (three years later)

• CT scan showed progressive, widespread LNs

• Well; remained on watch and wait

• No cardiac issues; on aspirin

• February 2018: cervical LNs ~4 cm; LDH normal; platelets 87

• Management?

Case 1

• January 2018: commenced ibrutinib

• Continued on aspirin

• February 2018: attended GP with sore throat and lymphadenopathy– Lymph 23.8

• Action?

• November 2018: no palpable LNs; normal LDH

Management of the relapsed patient

DrugNo. pts

Median prior lines

ORR (CR) %Median DOR

(months)Median PFS

(months)Median OS (months)

Trial

Temsirolimus 54** 3 22 (2) 7.1 4.8 12.8OPTIMAL1

Chemotherapy 53 4 2 (0) NA 1.9 9.7

Lenalidomide 170 2 40 (5) 16 8.7 27.8SPRINT2

Chemotherapy 84 2 11 (0) 10.4 5.2 21.2

Ibrutinib 139 2 72 (19) NR 14.6 NRRAY3

Temsirolimus 141 2 40 (1) 7 6.2 21.3

BR* 24* 1 71 (38) 17.6 35.3STiL4

FR* 23* 1 26 (13) 4.7 20.9

*results shown for subset with MCL; **results shown for 175/75 mg dose group. SPRINT trial single agent chemotherapy = rituximab, gemcitabine, fludarabine, chlorambucil, or cytarabine; OPTIMAL trial single agent chemotherapy = gemcitabine, fludarabine, chlorambucil, cladribine, etoposide, cyclophosphamide, thalidomide, vinblastine. Medianfollow-up: OPTIMAL trial = not reported, SPRINT trial = 15.9 months, RAY trial = 20 months, STiL trial = 96 months.

Randomised trials in relapsed/refractory MCL

DOR: duration of response; FR: fludarabine and rituximab;

mo: months; NA: not available. 1. Hess G, et al. J Clin Oncol. 2009; 27:3822–9; 2. Trneny M, et al. Lancet Oncol. 2016; 17:319–31; 3. Dreyling M, et al. Lancet. 2016; 287:770–8; 4. Rummel M, et al. Lancet Oncol. 2016; 17:57–66.

1. Rule S, et al. Presentation at ASH 2015. Abstract 469.

High response rates for ibrutinib, irrespective of line of therapy

CR

PR

Number of prior lines of therapy

RAY trial: ORR by number of prior linesO

RR

1 2 ≥3

Ibr Tem Ibr Tem Ibr Tem

ibrutinib

Graph adapted from: Rule S, et al. 2015.1

1. Rule S, et al. Presentation at ASH 2015. Abstract 469. 36

Ibr ≥2 prior

0 3 6 129 15

Months

18 21 24

0

30

10

20

40

50

60

70

80

90

100

% a

live

wit

ho

ut

pro

gre

ssio

n

Patients at risk

Ibr 1 prior 57 47 43 39 37 21 19 3 2

Tem 1 prior 50 33 24 13 11 6 4 0 0

82 67 58 44 40 24 15 5 3

91 60 45 32 22 13 7 3 1

Temsirolimus prior line 1

Ibrutinib prior line 1

Tem ≥2 prior

Ibrutinib prior line ≥ 2

Temsirolimus prior line ≥ 2

RAY trial: PFS by line of therapy

However, best outcomes for ibrutinib in second-line

Graph adapted from: Rule S, et al. 2015.1

PFS and OS by prior line of therapy; 3.5-year follow-up of ibrutinib-treated relapsed/refractory mantle cell lymphoma patients: pooled analysis

Median PFS was just over two years in patients with one prior line of therapy

Patients censored from OS analysis upon study discontinuation. 1. Rule S, et al. Presentation at the 2018 Korean Society of Hematology Conference and 59th Annual Meeting. Abstract 57.

OS

Median NR (36.0–NE)

Median 22.5 mo(16.2–26.7)

PFS

Median 25.4 mo(17.5–57.5)

Median 10.3 mo(8.1–12.5)

Median PFS overall (95% CI): 12.5 (9.8–16.6) months Median OS overall (95% CI): 26.7 (22.5–38.4) months

Patients at risk

1 prior

> 1 prior

99

271

81

193

66

147

61

117

55

97

51

79

47

67

38

60

36

54

31

47

27

43

16

30

12

22

5

12

3

5

2

2

2

1

2

1

0

0

Patients at risk

1 prior

> 1 prior

99

271

88

227

81

186

70

158

66

139

66

122

59

103

50

83

46

68

41

59

36

50

20

37

15

29

8

16

4

8

3

3

3

2

2

2

0

1

0

0

NE: not estimable.

Graphs adapted from: Rule S, et al. 2018.1

• Ibrutinib had improved tolerability vs temsirolimus

– Fewer Grade ≥3 TEAEs: 68% vs 87%– Fewer discontinuations of study medication due to AEs:

6% vs 26%

• Most common side effects with ibrutinib were diarrhoea, fatigue, cough, thrombocytopenia and anaemia

• Grade ≥3 atrial fibrillation: 4% ibrutinib vs 1% tem

• Major bleeding: 10% ibrutinib vs 6% tem

• In the phase 1 trial (PCYC 1123), the prevalence of infection, diarrhoea, and bleeding was highest for the first six months of therapy and less thereafter2

1. Dreyling M, et al. Lancet. 2016; 287:770–8; 2. Wang ML, et al. N Engl J Med. 2013; 369:507–16.

Ibrutinib safety

AEs: adverse events; TEAEs: treatment-emergent adverse events.

Common TEAEs (20% or more of patients) in the safety population

Learning points from case 1

• Management of the younger, fitter patient– Cytarabine-containing regimen

o Unclear which is best

– Role of ASCT

– Maintenance rituximab

• Management of relapse– Role of observation

– Ibrutinib vs second-line chemotherapy

Adapted from: Haematological Malignancy Research Network. Incidence. [Accessed: July 2019]. Available at: www.hmrn.org/statistics/incidence

Median age in the UK is 73 years

>50% ‘too old’

Incidence of haematological neoplasms

Case 2

• 74-year-old man, presented December 2017

• R cervical LN mass, ~6 x 4 cm; abdominal LNs, splenomegaly, BM infiltration

• Stage IVA

• MIPIc = 6.4 (intermediate-risk, median OS: 58 months)

• No comorbidities (aneurysm noted on CT scan)

• How would you manage him?

Options

No standard of care– R-CHOP

– R-bendamustine

– VR-CAP

– R-chlorambucil

• Maintenance R

VR-CAP: bortezomib, rituximab, cyclophosphamide, doxorubicin, prednisone.

Adapted from: Kluin-Nelemans HC, et al. N Engl J Med. 2012; 367:520–31.

R-CHOP vs FCR followed by IFN vs maintenance REuropean MCL elderly trial

Maintenance continued until progression

N=560 patients

FCR: fludarabine, cyclophosphamide, rituximab; Peg: pegylated.

R

A

N

D

O

M

I

S

E

D

R

A

N

D

O

M

I

S

E

D

Improved results with maintenance R vs IFNα(R-CHOP patients)

• Median PFS NR for R-CHOP + R at a median follow-up of 36 monthsMedian survival not reached at median follow-up of 36 months

Improved results with R-CHOP vs FCR• Comparable response• Less haem toxicity• Fewer progressions (5% vs 14%)• Longer four-year survival (62% vs 47%)

Results favour R-CHOP followed by maintenance REuropean MCL Elderly Trial: Final results

1. Kluin-Nelemans HC, et al. N Engl J Med. 2012; 367:520–31.

OS, patients assigned to R-CHOP

Time since start of induction (months)

OS

(p

rob

ab

ility

)

Median follow-up: 36 months

P=0.0023

FCR, median: 36 months

R-CHOP, median: 77 months

Graphs adapted from: Kluin-Nelemans HC, et al. 2012.1

• B-R vs R-CHOP (no maintenance)

• n=514 analysed (94 MCL)

• Non-inferiority margin 10%

• Comparable response rates

• PFS at 45 months= 35 months (B-R) vs 22 months (R-CHOP)

Data shown are for MCL subgroup.1. Rummel MJ, et al. Lancet. 2013; 381:1203–10.

Is R-bendamustine better than R-CHOP?

STiL NHL 1-2003 trial

B-R: bendamustine, rituximab; IQR: interquartile range.

Time (months)

Pro

bab

ility

PFS in histological subtypes of MCL

0 12 24 36 48 60 72 84 96

Graph adapted from: Rummel MJ, et al. 2013.1

• BR vs R-CHOP and BR vs R-CVP; non-inferiority design

• n=447 randomised (74 MCL)

• R-CVP least effective overall

• BR non-inferior: ORR 97% (BR) and 91% (R-CVP/R-CHOP); p=0.0102

• PFS/OS not reported

Data shown are for MCL subgroup.1. Flinn IW, et al. Blood. 2014; 123:2944–52.

Is R-bendamustine better than R-CHOP?BRIGHT trial

R-CVP: rituximab, cyclophosphamide, vincristine, prednisone; SD: stable disease.

Table adapted from: Flinn IW, et al. 2014.1

BR R-CHOP

How well tolerated is R-bendamustine?

BRIGHT trial2

STiL NHL 1-2003 trial1

• Less Grade 3–4 neutropenia for BR vs R-CHOP (39% vs 87%)

• More Grade 3–5 infection for BR vs R-CHOP (12% vs 5%)

• More opportunistic infection (all grades) for BR vs R-CHOP (10% vs 7%)

§p<0.0001, Pearson’s χ-square test.1. Rummel MJ, et al. Lancet. 2013; 381:1203–10; 2. Flinn IW, et al. Blood. 2014; 123:2944–52.

Tables adapted from: Rummel MJ, et al. 2013;1

Flinn IW, et al. 2014.2

Is there a role for maintenance rituximab after R-bendamustine?

STiL NHL7-2008 trial1

NCT00877214 N=122 of 168 (73%)

European MCL Elderly2

NCT00209209 N=184 of 280 (66%)

RB RB + R R-CHOP + INF R-CHOP + R

DoRMedian since randomisation 57 months 68 months* 23 months NR

Rate at six years 49% 40% 12% 50%

OSMedian since randomisation NR NR 64 months NR

Rate at six years 70% 66% 50% 71%

*p=0.341. Rummel MJ, et al. Presentation at ASCO 2016. Abstract 7503; 2. Kluin-Nelemans HC, et al. N Engl J Med. 2012; 367:520–31.

STiL NHL7-2008 trial (MAINTAIN) Subgroup analysis1

Eligibility criteria • Patients with MCL• Not eligible for ASCT

PR

Rituximab every two months for two years (N=60)

RB

Up to six cycles

N=122

Cross-study comparison

Observation (N=62)

At this time (4.5 year follow-up) there is no PFS benefit for

maintenance R after first-line RB

1. Robak T, et al. N Engl J Med. 2015; 372:944–53.

Is VR-CAP better than R-CHOP?• VR-CAP (LYM-3002 trial)

• Untreated MCL unsuitable for transplant

• No maintenance rituximab

bortezomib

Diagram adapted from: Robak T, et al. 2015.1

1. Robak T, et al. N Engl J Med. 2015; 372:944–53; 2. NICE. Technology appraisal 370. [Published: October 2015], [Accessed July 2019]. Available at: www.nice.org.uk/guidance/ta370.

VR-CAP leads to longer PFS than R-CHOP1

• N=487 patients

• ORR 92% vs 89%

• VR-CAP superior for CR rate (53% vs 42%) and PFS (25 vs 14 months)

• But more toxic…

• SAEs 38% vs 30% – Peripheral neuropathy 30% vs 27%– Thrombocytopenia 57% vs 6%– Neutropenia 85% vs 67%– Infections 21% vs 14%

NICE approval: December 2015 as option for first-line treatment for adult patients unfit for transplant2

ITT: intent-to-treat; SAEs: serious adverse events.

PFS according to independent review (ITT population)

Graph adapted from: Robak T, et al. 2015.1

• CGA ‘fit’ patents aged 61–80 years with untreated MCL

Induction phase x 6 cycles q3 weeks

rituximab(375 mg/m2)

bendamustine(70 mg/m2)

cytarabine

(500 mg/m2)*

Day 1 2 3 4*Former 800 mg dose too toxic.Visco C, et al. Lancet Haematol. 2017; 4:e15–23

Does cytarabine improve survival when added to R-B?

FIL phase 2 trial of RBAC-500

Does cytarabine improve survival in elderly MCL?• n=57 evaluable, median age 71 years

(range: 61–79)• 91% advanced stage disease • 45% high MIPI• 9% blastoid

Efficacy:• ORR 96% (CMR 93%)• MRD-negative: 76% blood, 55% marrow • Two-year PFS 81 +/- 5%

Toxicity:• ~50% Grade 3–4 neutropenia

and thrombocytopenia• 6% febrile neutropenia• 26% stopped due to toxicity

FIL phase 2 trial of RBAC-500

Improved two-year PFS, randomised data needed to establish a PFS or survival advantage for addition of cytarabine

Median 5.3 cycles delivered/patient. Median follow-up of 34 months.1. Visco C, et al. Lancet Haematol. 2017; 4:e15–23. CMR: complete molecular response.

Graph adapted from: Visco C, et al. 2017.1

Case 2 management

• Patient received R-bendamustine on clinical trial

• Achieved CR after six cycles

• On maintenance R for two years

Learning points from case 2

• Multiple options for first-line treatment of patients“unsuitable” for HDT and transplant

• Influenced by:– Age

– Fitness

– Comorbidities

Case 3

• WF, 65-year-old female

• Previously fit and well, ECOG 0

• Presented in April 2017 with fatigue, weight loss and enlarging neck nodes

• CT scan: bilateral neck, axillae, mediastinal, abdominal, retroperitoneal, groin nodes. Spleen 16.9 cm

• Core biopsy neck node:– MCL: CD20, CD5, cyclin D1 and SOX11 positive. Ki67 40–50%;

Classical MCL

ECOG: Eastern Cooperative Oncology Group.

Case 3

• Stage IVB

• Hb 116, WCC 4.0, lymph 1.7

• LDH 423

• MIPI score 6.9 (high-risk)

• Rituximab and high-dose cytarabine 2 g/m2 (age >60 years)

• Completed six cycles and achieved VGPR

• BEAM-conditioned ASCT, November 2017

• Commenced maintenance R

• Day 100 assessment: VGPR. Largest node (periportal) 19x10 mm, spleen 10.9 cm, bone marrow clear

VGPR: very good partial response.

Case 3

• Remained well until August 2018

• Presented with fevers, sweats and fatigue (PS 3)

• Subsequently developed nausea, reduced appetite and headache

• Documented fevers to 39⁰C; blood cultures negative

• 22/8/18: Hb 140, platelets 145, WCC 5.0, neutrophils 3.8, lymph 0.5

• Cr 61, albumin 42, bilirubin 17, ALT 73, AST 32, ALP 70; LDH 277 – rose to 469 over two weeks, CRP <5

• CT NCAP: no LNs. Spleen 10.5 cm. No focus of infection

ALP: alkaline phosphatase; ALT: alanine aminotransferase; AST: aspartate aminotransferase; Cr: creatinine;

CRP: C-reactive protein; NCAP: neck-chest-abdomen-pelvis.

Case 3

• CT head: right frontal lobe lesion with surrounding oedema

• MRI brain: right frontal lobe mass involving the corpus callosum. Local mass effect. Possible additional mass in right temporal lobe

• Differential diagnosis: primary brain tumour or relapsed lymphoma

Case 3

• Biopsy frontal lobe tumour

• Cerebral involvement by MCL

• Positive: CD5, CD20, BCL2, cyclin D1, SOX11

• Ki67 proliferation 70%

• Thought to represent blastoid variation of MCL on this occasion

CNS involvement in MCL

• Rare at diagnosis

• 4.1–7.8%

• Median onset 15–20 months

• Ki-67 and blastoid histology

• >90% leptomeningeal

• Poor survival: 3–8 months

Cheah et a. J Clin Oncol. 2016; 34:1256–1269; Chihara et al. Annals Oncol. 2015; 26:966–973; Conconi et al. Leuk & Lymphoma. 2013; 54:1908–1914; Chea et al. Annals Oncol. 2013; 24:2119–2123.

Case 3

• Treatment options?– Ibrutinib single agent

• Patient 64 years old, but fit

• Started dexamethasone 8 mg bd post-biopsy

• Weaned quickly due to side effects (agitation)

• Ibrutinib started three weeks post-biopsy (8/10/18)

Case 3

Response:

• Fevers and sweats resolved within one week

• Nausea and headache also resolved quickly, 1–2 weeks

• LDH normalised

• Fatigue improving weekly

• No side effects from ibrutinib

• MRI of brain repeated post-five-week treatment with ibrutinib

MRI brain: five weeks post-treatment with ibrutinib

Comparison: pre- and post-ibrutinib (five weeks of treatment)

Case 3

As of 22/11/18:

• Seven weeks on ibrutinib

• Off dexamethasone

• Well

– No headache or nausea

– No B symptoms

• Energy improving – out to shops, travelling by train, etc.

BSH treatment algorithm for MCL

Diagram adapted from: McKay P, et al. Br J Haematol. 2018; 182:46–62.

Beatson Cancer Centre

Thank you for listening

TP53 mutations identify younger mantle cell lymphoma patients who do not benefit from intensive chemoimmunotherapy

• 183 patients on MCL2 and MCL3 studies

• Genomic studies on DNA from diagnostic BM

Inferior outcomes noted with mutations of:

– TP53 (11%)

– NOTCH1 (4%)

– delTP53 (16%)

– CDKN2A (20%)

• MIPI and MIPI-c

• Blastoid morphology

• Ki67 >30%

• TP53 mutation associated with Ki67 >30%, blastoid morphology, high-risk MIPI, inferior response to induction and HDT

• Multivariate analysis – only TP53 mutation retained prognostic impact on OS

• TP53 mutated patients:

– Median OS 1.8 years

– 50% relapsed at one year

• TP53 unmutated cases:

– Median OS not reached, p<.0001

Eskelund CW, et al. Blood. 2017; 130:1903–10.

Prognostic impact of TP53 mutations on OS in MCL

Graph adapted from: Cohen JC. Blood. 2017; 130:1876–77.

TP53-mutated patients

• Difficult not to offer HDT in younger patients

• Consider experimental front-line therapy with novel agents, e.g. R-I-Len

R-I-Len: rituximab, ifosfamide, lenalidomide.