DLBCL with less than PR to second line therapy…

Correcting a Misconception….

Koen van Besien, MDWeill Cornell Medical College, NY

TRM CCR CR PR NR

Sensitive Relapse

44 10 19 19 2 3

Relapse –PD at TX

22 4 10 3 5

Never in CR-PD at TX

34 7 9 15 10

High Dose Chemotherapy not all that useful for patients with progressive disease…

High-Dose Chemotherapy With ABMTIs Effective in Relapsed Chemosensitive DLBCL: Parma

Study

• 215 patients treated with 2 cycles of DHAP • 109 patients showed CR or PR and were randomized to

– Conventional treatment: 4 more cycles of DHAP (n = 54)– High-dose treatment: BEAC (carmustine, etoposide, cytarabine,

cyclophosphamide, and mesna) + ABMT (n = 55)

Philip T, et al. N Engl J Med. 1995;333:1540–1545.

100

80

60

40

20

00 15 30 45 60 75 90

Transplantation

Conventional treatmentP = 0.038

Transplantation(n = 49)

Conventional treatment(n = 54)

P = 0.001

Months after randomization

100

80

60

40

20

00 15 30 45 60 75 90

Event-free survival Overall survival

Survival (%)

Misconception….

• High dose chemotherapy is not effective in those with progressive disease (NEJM 1987)

• Limit studies to those with CR/PR to salvage (PARMA)

• It does not work in those excluded from PARMA study

• They should be offered investigational therapies (drugs or medical procedures that are under investigation in clinical trials regarding their safety and efficacy)

What are the Data?

Two studies…

CIBMTRVose et al, J Clin Oncol 19: 406-413, 2001

Disease Free survival in monthsC

umul

ativ

e P

ropo

rtio

n S

urvi

ving

Fre

e of

Dis

ease

0.0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1.0

1.1

0 12 24 36 48 60 72 84 96

Remission (n=15)

Stage I-III (n=52)

Stage IV (n=22)

P=0.007

Figure 1C

MDACCPopat et al, J Clin Oncol 16: 63-69, 1998

Outcome Of Autologous Transplant In Patients Never Achieving Remission

CIBMTRVose et al, J Clin Oncol 19: 406-413, 2001

Outcome of autologous transplant relates to remission status

Popat et al, J Clin Oncol 16: 63-69, 1998

Di se a se Fre e su rvi va l i n m o n th s

Cu

mu

lativ

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rop

ort

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0 1 2 2 4 3 6 4 8 6 0 7 2 8 4 9 60 .0

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P rim a ry m e d i a sti n a l l ym p h o m a (n =3 1 )

O th e r B -ce l l d i ffu se l a rg e ce l l l ym p h o m a (n =5 9 )

P = 0 .0 7

Fig u re 1 DDi se a se Fre e su rvi va l i n m o n th s

Cu

mu

lativ

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rop

ort

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Fre

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Re m issio n (n = 1 5 )

S ta g e I-III (n =5 2 )

S ta g e IV (n =2 2 )

P = 0 .0 0 7

Fig u re 1 C

Can we identify predictors???

Vose et al, J Clin Oncol 19: 406-413, 2001

There is a cure rate for pts never achieving remission# prior therapiesKSAgeRole of prior XRT

Outcome of autologous transplant relates to remission status

Popat et al, J Clin Oncol 16: 63-69, 1998

Di se a se Fre e su rvi va l i n m o n th s

Cu

mu

lativ

e P

rop

ort

ion

Su

rviv

ing

Fre

e o

f D

ise

ase

0 1 2 2 4 3 6 4 8 6 0 7 2 8 4 9 60 .0

0 .1

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0 .5

0 .6

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0 .8

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1 .0

P rim a ry m e d i a sti n a l l ym p h o m a (n =3 1 )

O th e r B -ce l l d i ffu se l a rg e ce l l l ym p h o m a (n =5 9 )

P = 0 .0 7

Fig u re 1 DDi se a se Fre e su rvi va l i n m o n th s

Cu

mu

lativ

e P

rop

ort

ion

Su

rviv

ing

Fre

e o

f D

ise

ase

0 1 2 2 4 3 6 4 8 6 0 7 2 8 4 9 60 .0

0 .1

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0 .6

0 .7

0 .8

0 .9

1 .0

Re m issio n (n = 1 5 )

S ta g e I-III (n =5 2 )

S ta g e IV (n =2 2 )

P = 0 .0 0 7

Fig u re 1 C

Di se a se Fre e su rvi va l i n m o n th s

Cu

mu

lativ

e P

rop

ort

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Su

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ing

Fre

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0 1 2 2 4 3 6 4 8 6 0 7 2 8 4 9 60 .0

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1 .0

L DH e le va te d (n =3 3 )

L DH n o rm a l (n = 5 7 )

P = 0 .0 2

Fig u re 1 B

Is Allogeneic Transplant Preferable?

Pro• GVL effects…• Tumor Free Grafts• Everybody has a donor…• Age limit’s don’t apply

Probability Of Relapse After Syngeneic Transplantation

PR

OB

AB

ILIT

Y, %

YEARS

ASC01_9.ppt

Allo T-deplete

Auto unpurged

Allo T-replete

0

20

40

60

80

100

0 1 2 3 54

Auto purged

Syngeneic

P < 0.01

89 patients syngeneic transplant. 30 intermediate grade lymphoma

Bierman et al, J Clin Oncol 21, 3744, 2003

Allogeneic after Failure of Autologous in DLBCL

Kim et al, Ann Hematol. 2014 Aug;93(8):1345-51.

Rigacci et al, Ann Hematol. 2012 Jun;91(6):931-9

Everybody has a donor….

O S A M L /M DS HC vs M UD > 5 0

0 1 2 2 4 3 6 4 8 6 0 7 2 8 4 9 6

M o n th s

0 .0

0 .1

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HC M UD

Survival in Patients over age 50 URD vs. HC

Haplo Cord for Lymphoma22

Age 54 (24-72)

Diagnosis

HL 5

CLL 5 (1 Richter)

MCL 3 (2 Blastoid)

DLBCL (MYC) 2

FL Transformed 1

MF 2

PTCL 4 (ALCL, AngImm, HS)

Chemo Response

Refractory (less than PR)

11

Chemo Sensitive 11

MFU Survivors: 11 months (2-71)

Is Allogeneic Transplant Preferable?

Pro• GVL effects…• Tumor Free Grafts• Everybody has a donor…• Age limit’s don’t apply

Con• Still a much more complex

procedure • The same prognostic factors

apply…

Role of PET scanning after allogeneic SCT for NHL

Kenkre et al, Leukemia and Lymphoma, 52, 214, 2011

Lambert et al, Blood 115, 2010

Role of LDH after allogeneic SCT for NHL

Kenkre et al, Leukemia and Lymphoma, 52, 214, 2011 Armand et al, BBMT 14: 418, 2008

Misconcep·tion

• Many with less than partial responses to salvage therapy will achieve durable remissions from high dose chemotherapy and autologous or allogeneic transplant.

• Delays in treatment from investigational treatments may adversely affect long-term outcome….

The future… combination

Refractory Lymphoma: Benda Bridge to TX

Dubovsky et al, JCI, 2014