CANINE LYMPHOMA THERAPY

Chiara Leo, DVM, MSc, Dipl. ACVIM (Oncology)

Oncology service
Istituto Veterinario di Novara
chiara.leo@istitutoveterinarionovara.it

LYMPHOMA TREATMENT’S GOAL

Survival time
relapse relapse relapse

remission remission remission

inducction rescue rescue RIP

Drug sensitivity / Resistance

Courtesy Dr. Ana Lara

MONOCHEMOTHERAPY POLICHEMOTHERAPY

Low cost Higher costs

Less toxicity More toxicity
Rarely hospitalisation Sometimes hospitalisation
less effective More effective
> Chemoresistance < Chemoresistance
 MONOCHEMOTHERAPY
No treatment < 1 month
Only steroids 2-4 months* ADRIAMYCINE
DOXORUBICINE (monotherapy) (30 mg/m2
iv every 2-3 weeks):
80% remissions for B-cell lymphoma
50% remission for T-cell lymphoma
MST 6-8 months

LOMUSTINE: probably best mono therapy

choice for T-cell lymphoma (75%
remissions)

POLICHEMOTHERAPY

COP, CHOP, COAP, VELCAP-L, VELCAP-S, COPLA/LVP, CaVP, ACOPA-I, ACOPA-II, VCAA, AMC,
PVAC3, Madison-Wisconsin (12, 19 OR 25 WEEKS)

L-ASPARAGINASE CYCLOPHOSPHAMIDE

CHOP
PREDNISONE
DOXORUBICINE

VINCRISTINE/VINBLASTINE

POLICHEMOTHERAPY

LOPP, LPP, LOMUSTINE+L-ASP

L-ASPARAGINASE PROCARBAZINE

LOPP
PREDNISONE
LOMUSTINE

VINCRISTINE/VINBLASTINE
Diffuse Large B-cell Multicentric Lymphoma
Most common type (50-60% of cases) +++

Response rate to combination chemotherapy with COP (vincristine,

cyclophosphamide, prednisolone) or CHOP protocols (vincristine,
cyclophosphamide, doxorubicin, prednisolone) is close to 100%.

Median remission periods will be longer with CHOP (9-10 months) than
with COP induction protocols (4-5 months)

Use of rescue therapy at relapse and use of doxorubicin at rescue if COP

was used at induction will improve median survival times which will vary
between 9-13 months.

COP

CHOP
Remission rate 80-95%
First remission median duration 7-10m
median survival percentage 30-50%
More intense protocols?
Adding CCNU & MOPP:
PFI 298 vs 317d
35% survival @ 2y
Longer remission for patients with dose delays

NO STUDIES WITH STANDARDISED PATIENTS’

GROUPS
 INDUCTION PROTOCOLS

COAP VS. WISCONSIN-MADISON

COAP
Wisconsin-Madison n=30

(Hosoya et al. 2007, JVIM) n=71

Length of protocol 56 d (2m) 133 d (4.5m)

Remission rate 92% 100%
Median remission time 94 d (3m) 174 d (5.8m)
Median survival time 309 d 275 d
Survival rate at 1 year 32% 45%
Survival rate at 2 years 0% 17%
 High grade multicentric T-cell Lymphoma
It is a rapidly progressing lymphoma. It seems to have
Inherent resistance to doxorubicin so remission periods
with CHOP protocols are short (around 3 months)

Longer remission is seen with protocols like MOPP, LOPP

and VELCAP-TSC including alkylating agents like lomustine,
merchloretamine, procarbazine and/or dacarbazine

The most feasible protocol of these in practice is LOPP

(vincristine, procarbazine, lomustine and prednisolone)
97% response rates are observed with median time to
progression close to 6 months and median survival time of
11 months

96% ORR
88% CR
Median duration 100 days

(JAVMA, 2010)
 Courtesy Dr. Ana Lara

(Rebhun et al., 2011)

Alkylating based protocols for T-cell LSA

n PFS ST Response
MOPP+elspar
189d
RR 98%
(Brodsky, 50
CR 939d 270d CR78%
2009)
LOPP/LOP
173d
TR 87%

15 211d
(Stell, 2013) CR 231d RC 40%

(Mercloretamine / Lomustine, procarbazine, vincristine, prednisolone)

Treatment on a budget: what should I invest in?

Must is…..
To have a defined diagnosis and have spent the less possible in
diagnostics and staging
If we have a multicentric low grade lymphoma
No treatment or oral chlorambucil and prednisolone
If we have a multicentric high grade lymphoma
Multiagent protocols = longer remissions (consider the cheapest option)
Single agent protocols = effective though shorter remissions

RESCUE PROTOCOLS
 Rescue protocols re-induce remission in
patients that have relapsed after receiving an
induction protocol

Reported mean remission response between 40%

and 90%
Median remission time of 1.5-2.5 months
INDEPENDENTLY OF THE PROTOCOL
<20% of animals have long remissions
No strong literature
THE CHOICE OF A RESCUE PROTOCOL SHOULD BE
BASED ON DIFFERENT FACTORS, INCLUDING COSTS,
COMMITMENT, EFFICACY, TOXICIY AND EXPERIENCE
OF THE CLINICIAN
AS LONG AS QUALITY OF LIFE IS GUARANTEED,
SEQUENTIAL USE OF RESCUE PROTOCOLS CAN
EXTEND THE LENGHT OF LIFE OF VARIOUS MONTHS

DRUG % ORR M REMISSION T Ref

Lomustina 28% 86 giorni Moore et al 1999
Dacarbazina 35% 43 giorni Griessmayr at al 2009
D-Actinomicina 41% 129 giorni Bannink et al 2008
MOPP 65% 60 Rassnik et al 2002
MPP 34% 56 Northrup et al 2008
DMAC 72%% 61 Alvarez et al 2008
Lomustine + DTIC 35% 62 Flory et al 2008
Doxo +
Temozolomide 72% 40 Dervisis et al 2007

Doxo + DTIC 71% 50 Dervisis et al 2007

 WHY LYMPHOMAS RELAPSE?

Suggested reasons:

(1) Inadequate scheduled intensity

(2) Use of steroids before or after chemotherapy*
(3) Ineffective drug penetration for some localisation (es. SNC)
(4) Multi-drug resistance development
(5) Emerging naturally resistant clone
 Chemio

MDR clone

DIMINISHED/INCREASED/ALTERED
DECREASED ABSORBTION
TARGET ENZYMES LEVELS

INCREASED EXCRETION

DECREASED APOPTOTIC
MECHANISMS

DECREASED DRUG ACTIVATION DRUG INACTIVATION

INCREASED CATABOLISM AINCREASED DNA REPAIR ABILITY

 LINDA
B- cell lymphoma stage IV sub-stage A

18/02/2016: COP + LP maintenance

20/07/2016: relapse
CHOP (12 weeks)
28/03/2017: relapse
COP (2) + maintenance
vincristine/cyclophosphamide

1 year with only 4 drugs

LUCKY
B- cell lymphoma stage IV sub-stage A

3/10/16: Vincristine, Cyckophosphamide

17/10/16: Vincristine
24/10/16: Vincristine
31/10/16: Doxo
7/11/16: Lomustine
21/11/16: Vincristine
28/11/16: Chlorambucile
5/12/16: Doxo 09/03/17: Vinblastine
12/12/16: Lomustine 16/03/17: Vinblastine
02/01/17: Doxo 23/03/17: RELAPSE
30/03/17: L-asp-cytarab
09/01/17: RELAPSE L-asp 04/04/17: Vinbla + Temozolomide SID x 5 days
16/01/17: D-act, Cortis, Cytarab 11/04/17: Vinbla + Temozolomide SID x 5 days
27/01/17: Melphalan 19/04/17: Vinbla + Temozolomide SID x 5 days
6/02/17: D-act, Cortis, Cytarab 30/04 PD
20/02/17: RELAPSE Lomustina 06/05 DEAD (7 months)

THE QUESTION OF WHEN SHOULD WE START WITH A

RESCUE PROTOCOL?

Once the patient achieves CR, each drug should be able to maintain the remission for 3-4
weeks. When the patient relapses, drugs used within 3-4 weeks are no longer effective.
Insure that all drugs in the initial protocol are no longer effective and then move on to rescue.
If the time interval between the last treatment and relapse was greater than 4 weeks,
re-induction with the same drugs used initially should be attempted first. If the re-induction
is successful, the protocol should be continued. If the re-induction fails, rescue protocols
should be started.

Pubmed: 0
Proceedings of the WSAVA Congress, Sydney, Australia 2007
Rescue Chemotherapy Protocols for Dogs with Lymphoma
Kenneth M. Rassnick, DVM, DACVIM (Oncology)

Cornell University College of Veterinary Medicine, Ithaca, New York, USA
 TO RE-CHOP OR NOT TO RE-CHOP?
Dogs that experiences relapsed AFTER HAVING
COMPLETED a CHOP protocol, can achieve a new
remission with a similar protocol
Reported 87% ORR at the second CHOP
Consider third CHOP (beware doxo cardiotoxicity:
Mitoxantrone or epirubicine)

CCNU

CCNU often used as first rescue after CHOP

CCNU = alkilating agent without cress-resistance with drugs

included in CHOP. NO P-Glycoprotein substrate

CCNU alone ORR 28% (Moore et al. 1999)

 57 dogs
4 weeks protocol 31 dogs
CCNU + Dacarbazine ORR 87% —> 52% CR
55% ORR —> 23% CR MTP 63 days
MRT 225 for CR Little toxicity
MRT 92 for PR

LOPP-FL
33 Cani
1° rescue
ORR 61% —> 32% CR
Low toxicity
Median Remission Time = 84 days
(10-308)

40 dogs
35% ORR —>PFI 43 days
Thrombocytopenia *
 88 dogs
ORR 51% —> 12% CR
T-cell ORR 55% 60 days
B-cell ORR 57% 81 days
OST 183 days

54 dogs
74% ORR —> 44% CR
Median remission duration: CR 112, PR 44, SD 27 days
56% thrombocytopenia
17% neutropenia

86 dogs
43% ORR —> 16% CR
PFS 24 days
Thrombocytopenia 41%
17% neutropenia
39 dogs
dose 1.7-2.8 mg/m2
7.7% CR, 18% PR, 46% SD
25% neutropenia
PFI: 29.5 days, MST 46 days

22 dogs
ORR 18% carboplatin alone
PFI 18 days (28 forresponders)
ORR carbo + cytarabine 28%
84% thrombocitopenia + neutropenia

WHAT I DO

INDUCTION PROTOCOL FOR B-Cell: COP/CHOP

1° rescue: COP/CHOP
2° rescue: CVP/CHVP (vinblastine)
3° rescue: Lomustine-based protocol
4° rescue: DMAC
5° rescue: Dacarbazine/temozolomide-based protocol
6° rescue: L-asparaginase, cytarabine … CHOP??
 WHAT I DO

INDUCTION PROTOCOL FOR T-Cell: LOPP

1° rescue: COP/CHOP
2° rescue: CVP/CHVP (vinblastine)
3° rescue: DMAC
4° rescue: Dacarbazina/temozolomide-based protocol
6° rescue: L-asparaginasi, citarabina … MASIVET?

CHOP

CHOP
CHOP L-ASP DMAC

CHOP

LYMPHOMA THERAPY
RADIATION FOR LYMPHOMA
 Courtesy of Julia Buchholz

BONE MARROW TRANSPLANTATION

• Myeloablative chemotherapy + total body RT(10Gy)
• Autologous transplant of BM stem cells
n=24 dogs with B-cel LSA
Only 30% MST >2 y
PFI 271d; MST 463d
16% Mortality for complications
Costs 16,000-25,000$
Available in 4 private practices and 1 USA university
Dr Steve Suter
Still need a better selection of patients
North Carolina University
Vet College
 n=30/38 (79%) ORR
23 RC (61%) 7 RP (18%)
n=17 NAIVE
N=21 relapsed (10 RC, 3 RP)
Median response duration 129d

IN EUROPE?

Conditionally approved by FDA (USA) in 2017 for

canine lymphoma “compassionate use”
Only specialists in oncology
Europe? Still need EMEA licence