pr christian gisselbrecht hpital saint louis paris

Treatment options for relapsed patients unsuitable for aggressive therapy

Pr Christian GisselbrechtHôpital Saint Louis

Paris

LYON 23 FEBRUARY 2013

Primary refractory not achieving 1st line CR

Relapse Second-line therapy

Second-line therapy

Investigationalor BSC HDT/SCT

Investigationalor BSC

CR/PR

NR

NR

R-CHOP or R-ACVBP

CR

Cure

What is the standard of carefor relapsed DLBCL

Cure?

CR PR

TAKE HOME MESSAGES FROM RANDOMIZED STUDIES WITH TRANSPLANTATION: CORAL/NCIC

Survival according to second line treatment is similar with ICE= R DHAP= R GDP New drugs are mandatory for optimal salvage combination.

R-GDP is less intensive and less toxic than RDHAP.

Maintenance with rituximab not recommended. Other drugs to be studied

Clinical prognostic factors affecting response and survival remain very important:

relapse < 12 months, secondary aaIPI>1, prior rituximab exposure:

POOR RESULTS : RESPONSE RATE 50% PFS 30%

BEST RESULTS : RESPONSE RATE 80% PFS 60%

Importance of realizing molecular characterization in DLBCL for a rational development of treatment. ABC subtype.

When intensive treatment is not a solution: efficacy, toxicity.

• Age:• Performance status• Comorbidities: Score• Relapse in very old patient• Relapse post transplantation• Failure to first or second line treatment.

FACTORS AFFECTINGDECISION FOR INTENSIVE TREATMENT

Coiffier at al Blood 2010

CHOP/R-CHOP Study 10 years follow upIn elderly patients 60-80 yr. with Diffuse Large B-Cell Lymphoma: Impact

of salvage by chemotherapy alone on survival.

Relapse rate40-60%

Very few patientsAre transplanted After 65yr

Survival after first progression

Low risk patients* High risk patients*

* Risk is defined by the aaIPI score

CORAL: outcomes of 220 refractory to salvage and post ASCT relapsed patients

• Patients refractory or relapsed post ASCT:220 pts median 15 mo. Not affected by the type of new chemo.

• Patients refractory to intensive salvage :145 pts; median 14mo

• Patients relapsing after ASCT:75pts; median 27mo.

N=75pts

N=145ptsN=220pts

P=0.02

Personal communication Nicolas Mounier, Eric Van den Neste

Do we have a standard for second-line therapy in NHL

in older patients or relapses post ASCT?Looking for a less toxic regimen:

- Combination - Single agent

Regimen Disease status n ORR/CR Survival ReferenceR-GEM High grade B-NHL

(64–78 years)7 71%/29% median PFS and OS,

10 and 11 months, (Wenger et al, 2005)

R-GEMOX

Aggressive NHL 46 74%/72% 2-year EFS 43%, 2-year OS 66%

(El Gnaoui et al, 2007)

R-GIFOX Aggressive NHL 13 77%/54% median FFS 80% (Corazzelli et al, 2006)

GaRD Aggressive NHL 19 79%/42% (Cabanillas et al, 2006)

GaRD Aggressive B-NHL 22 55%/27% (CR/CRu)

(Smith et al, 2006)

R + E DLBCL 6 67%/50% (Leonard et al, 2005)

R + E DLBCL 15 47%/33% (CR/CRu)

median PFS 6 months

(Strauss et al, 2006)

R-CMD DLBCL (65–79 years)

30 74%/57% (CR/CRu)

2-year OS 45%, PFS 37%

(Niitsu et al, 2006)

R-TTP Aggressive NHL 71 (32 primary

refractory)

70%25%primary refractory

median DR 21 months

(Younes et al, 2005)

R-TTP B-cell lymphoma 10 60%/30% (Canales et al, 2005)

R-ADOX DLBCL (heavily pre-treated)

20 70%/25% Median OS 11 mos (Woehrer et al, 2005)

Rituximab and other salvage regimens

CMD: irinotecan, mitoxantrone, dexamethasone TTP: paclitaxel, topotecan E: epratuzumab Gisselbrecht C. B J H:2008 143, 607–621

Another long listNo randomized study

Rituximab, Dexa Aracytine Oxaliplatin (R-DHAOX)

Rituximab: 375 mg/m² d1 Dexamethasone: 40mg d1-

d4 Aracytine: 2g/m²/12h d2 Oxaliplatin: 100 mg/m² d1

d1 = d21

Toxicitygrade 3-4 % of cycles

neutropenia 44thrombocytopenia 47infection 4

neurologic, 3renal 0

91 PTS/ 42 DLBCLORR 75% CR 57%

Lignon et al clinical lymphoma myeloma 2010

Rituximab: 375 mg/m² d1 Gemcitabine: 1000 mg/m² d2 followed by Oxaliplatin: 100 mg/m² d2 Toxicity:

d1 = d15

Rituximab, Gemcitabine and Oxaliplatin (R-GEMOX)

grade 3-4 % of cycles

neutropenia 36

thrombocytopenia 22

infection 4

neurologic, renal 1

49 PTSORR 60% CR 44%Median FU 41 m.

El Gnaoui et a, ASCO 2010

Months60 12 18 24 30 36 42 48 54 60

0.8

0.6

0.4

0.2

0

1

Surv

ival

pro

babi

lity

Progression - Free Survival

3 - year PFS rate 20.1% [ 9.8 - 32.4 % ]Median PFS (months) 5.3 [ 2.6 - 9.6 % ]

Median follow-up: 41 months

Anthracyclines: a cornerstone in the

management of DLBCL

• Dose limiting cumulative cardiotoxicity

• Alternative: – Liposomal doxorubicin– Aza-Anthracenedione

Pixantrone, a novel aza-anthracenedione: mode of action (1)

Like anthracyclines, pixantrone has a multimodal mode of action – DNA alkylation (pixantrone–DNA adducts formed preventing normal

replication)– High-affinity binding to DNA through intercalation, with consequent blockade

of replication– Weak inhibition of topoisomerase II (breaking of strands)

The structural modifications in pixantrone increase the stability of DNA adduct formation, reducing reactive oxygen species (ROS) formation and suppressing toxic drug–metal complexes

0.5

Preclinical cardiotoxicity with either doxorubicin, mitoxantrone or pixantrone

Cavalletti et al. Invest New Drugs 2007;25:187.

Morphologic evaluation of cardiac lesions in mice following repeated treatment cycles of either doxorubicin, mitoxantrone or pixantrone

Week 8 Week 14 Week 16 Week 220.0

2.5

5.0

7.5

10.0

0.2

5.4

6.4*

***

0.40.1

0.5

7.7*

***8.0

0.1

0.5

Pixantrone 27 mg/kgDoxorubicin 7.5 mg/kgMitoxantrone 3 mg/kg

Vehicle

*p < 0.05***p < 0.001

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Phase III PIX301: study design

Pixantrone base(50 mg/m2 Days 1,8,15)**

Comparator (physician’s choice)*

Treatment(28 days/cycle, ≤ 6 cycles)

Follow-up(18 months)

≥ 3rd-line treatment of

relapsed aggressive

NHLn = 140

Inclusion criteria•Histologically-confirmed aggressive NHL•Relapse after ≥ 2 prior chemotherapy regimens•ECOG PS 0–2•Prior cumulative dose of doxorubicin < 450 mg/m2 or baseline LVEF < 50%•No clinically significant CV abnormalities

Exclusion criteria•Prior exposure to doxorubicin > 450 mg/m2

•Myocardial infarction within previous 6 months

Pettengell et al. Lancet Oncol 2012;13:696. Engert et al. Clin Lymphoma Myeloma 2006;7:152.

*Choice of comparators included vinorelbine, oxaliplatin, ifosfamide, etoposide, mitoxantrone, gemcitabine or rituximab**Clinical trials were based on pixantrone dimaleate 85 mg/m2, equivalent to 50 mg/m2 pixantrone base, the EU approved dose

Phase III PIX301:baseline characteristics

Pettengell et al. Lancet Oncol 2012;13:696.

Pixantrone (n = 70) Comparator (n = 70)

Median age, years 60 (18–80) 58 (26–82)

Females (%) 24 (34) 30 (43)

ECOG grade 1 and 2 (%) 44 (63) 46 (66)

IPI score, n (%)0–12≥ 3

21 (30)25 (36)24 (34)

17 (24)27 (39)25 (36)

Ann Arbor stage, n (%)I/IIIII/IV

19 (27.1)51 (72.9)

14 (20.0)56 (80.0)

Median NHL duration, months*

32.0 31.6

> 1 extranodal sites, n (%) 34 (49) 33 (47)

*calculated by time from primary diagnosis of NHL to first dose of study treatment

PIX301 Prior TherapyPatients, n (%)

Pixantrone N = 70

ComparatorN = 70

Median prior chemotherapy regimens, (range)

3 (2-9) 3 (2-9)

Median doxorubicin dose equivalent, mg/m2, (range) 293 (51-472) 316 (15 - 681)

First-line CHOP+/-R, n (%) 63 (90) 60 (86)

Prior Rituximab, n (%) 38 (54) 39 (57)

Prior platinate based regimen (ICE,DHAP,ESHAP+/-R)Second-line 40 (57) 36 (51)

Third-line 21 (30) 21 (30)

Prior SCT, n (%) 11 (16) 10 (14)19

Pettengell et al. Lancet Oncol. 2012 Jul;13(7):696-706.

Phase III PIX301: tumor response rate

Pixantrone (n = 70) Comparator (n = 70) p

End of treatment, n (%)CR/CRuORR

14 (20.0)26 (37.1)

4 (5.7)10 (14.3)

0.0210.003

End of study, n (%)CR/CRuORR

17 (24.3)28 (40.0)

5 (7.1)10 (14.3)

0.0090.001

CR/CRu rate: 20% vs 5.7%Median duration CR/CRu: 9.6 vs 4.0 months

(pixantrone vs comparator)3/17 who had CR/CRu at end of study had

> 1 year continuous remission


Duration of Best Response (days)* Continuing response at last follow-up

PIX301 Duration of CR/CRu

Pettengell et al. Lancet Oncol. 2012 Jul;13(7):696-706.

Phase III PIX301: PFS


Time from randomization (months)0

0.2

0.3

0.6

0.9

Prog

ress

ion-

free

sur

viva

l pro

babi

lity

0.1

0.0

0.4

0.5

1.0

0.8

0.7

6 12 18 24

Pixantrone

Comparator

Pixantron

en = 70

Comparator

n = 70

Event (PD or death), n (%) 58 (83%) 64 (91%)

Median PFS, months (95% CI) 5.3 (2.3, 6.2)

2.6 (1.9, 3.5)

p = 0.005

HR = 0.60 (95% CI: 0.42, 0.86)

Phase III PIX301: overall survival


Time from randomization (months)0

0.2

0.3

0.6

0.9

Ove

rall

surv

ival

pro

babi

lity

0.1

0.0

0.4

0.5

1.0

0.8

0.7

6 12 18 24

Pixantrone

Comparator

Pixantronen = 70

Comparatorn = 70

Event (death), n (%) 47 (67%) 52 (74%)

Median OS, months (95% CI) 10.2 (6.4, 15.7) 7.6 (5.4, 9.3)

Log rank p-value = 0.251

HR = 0.79 (95% CI: 0.53, 1.18)

Positive trends in OS in favor of pixantrone

Phase III PIX301: subanalysis

Previous rituximab No previous rituximab

Pixantrone (n = 38) Comparator (n = 39) Pixantrone (n = 32) Comparator (n = 31)

No. of previous chemo regimens

2 (n = 10)

3 (n = 15)

≥ 4 (n = 13)

2 (n = 9)

3 (n = 16)

≥ 4 (n = 14)

2 (n = 22)

3 (n = 9)

≥ 4 (n = 1)

2 (n = 15)

3 (n = 16)

≥ 4 (n = 0)

CR/CRu, n (%)

3 (30.0)

3 (20.0)

1 (7.7)

0 (0.0)

1 (6.3)

3 (21.4)

8 (36.4)

2 (22.2)

0 (0.0)

1 (6.7)

0 (0.0)

–

ORR,n (%)

5 (50.0)

6 (40.0)

1(7.7)

0 (0.0)

3 (18.8)

4 (28.6)

11 (50.0)

4 (44.4)

1 (100.0)

2 (13.3)

1 (6.3)

–

Median PFS, months (range)

5.7 (1.1–14.6)

3.3 (1.1–6.7)

– 2.8 (0.7–4.3)

2.8 (1.4–7.8)

– 5.7 (2.0–9.0)

6.5 (1.9–NA)

– 1.9 (0.8–4.9)

3.4 (1.3–4.1)

–

Response rates were consistent for patients in the pixantrone group, and appeared more affected by number of previous chemotherapy regimens than

whether the patient had previously received rituximab


Phase III PIX301: adverse events of interest

All grades Grades 3 or 4Pixantrone

(n = 68) n (%)

Comparator(n = 67)

n (%)

Pixantrone(n = 68)

n (%)

Comparator(n = 67)n (%)

Hematologic Anemia 21(30.9) 22 (32.8) 4 (5.9) 9 (13.4)

Neutropenia 34 (50.0) 16 (23.9) 28 (41.2) 13 (19.4)

Febrile neutropenia 6 (8.8) 2 (3.0) 5 (7.4) 2 (3.0)

Leukopenia 17 (25.0) 7 (10.4) 16 (23.5) 5 (7.5)

Non-hematologic Abdominal pain 11 (16.2) 7 (10.4) 5 (7.4) 3 (4.5)

Pyrexia 16 (23.5) 16 (23.9) 3 (4.4) 6 (9.0)

Pneumonia 5 (7.4) 4 (6.0) 4 (5.9) 3 (4.5)

Dyspnea 9 (13.2) 9 (13.4) 4 (5.9) 3 (4.5)


Phase III PIX301: Grade 3 or 4 adverse events (2)Adverse event Pixantrone (n=68) n, (%) Comparator (n=67) n, (%)

Infections and infestations

Pneumonia 4 (5.9) 3 (4.5)

Cellulitis 2 (2.9) 2 (3.0)

Investigations

Ejection fraction decreased 2 (2,9) 0 (0.0)

Neutrophil count decreased 3 (4.4) 0 (0.0)

Platelet count decreased 2 (2.9) 2 (3.0)

Weight decreased 1 (1.5) 2 (3.0)

Metabolism and nutrition disorders

Anorexia 2 (2.9) 1 (1.5)

Dehydration 3 (4.4) 0 (0.0)

Hypokalaemia 2 (2.9) 1 (1.5)

Hyponatraemia 1 (1.5) 2 (3.0)

Metabolic acidosis 2 (2.9) 0 (0.0)

Neoplasms (benign, malignant and unspecificed)

Malignant neoplasm progression 0 (0.0) 1 (1.5)

Pyschiatric disorders

Depression 2 (2.9) 1 (1.5)

Renal and urinary disorders

Renal failure 0 (0.0) 3 (4.5)Data presented are AEs that occurred at grade 3 or 4 in more than 2% of patients in either groupPettengell et al. Lancet Oncol 2012;13:696.

Phase III PIX301: overall summary Patients with relapsed/refractory aggressive NHL who were treated with

pixantrone compared to other chemotherapies achieved– Superior CR/CRu rate– Superior ORR– Superior PFS– A positive trend in OS

Pixantrone was well tolerated and toxicities were readily manageable– The higher frequency of cardiac AEs in the pixantrone arm may have been due to

patient history of cardiac disease

‘Because no combination or single-agent therapy is considered the standard of care for patients with relapsed or refractory NHL, and

palliative care or clinical trials are often the only remaining treatment options, an effective salvage therapy is needed for these patients.

Our study suggests that pixantrone is an effective single-agent treatment for patients with aggressive NHL and that it could fill the need for a

standard salvage therapy that leads to improved outcomes with manageable toxicities’


Larger comparative study such as R Pixantrone versus R « Gemcitabine ?» is warranted to better define the efficacy and prognostic parameters.

pr christian gisselbrecht hpital saint louis paris

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