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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
Cha
nges
in m
ean
tota
l sco
re (M
TS)
afte
r 1 a
nd 2
cyc
les
of s
tudy
dru
g
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
Pettengell et al. Lancet Oncol 2012;13:696.
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
Pettengell et al. Lancet Oncol 2012;13:696.
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
Pettengell et al. Lancet Oncol 2012;13:696.
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
Pettengell et al. Lancet Oncol 2012;13:696.
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)
Pettengell et al. Lancet Oncol 2012;13:696.
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’
Pettengell et al. Lancet Oncol 2012;13:696.
Larger comparative study such as R Pixantrone versus R « Gemcitabine ?» is warranted to better define the efficacy and prognostic parameters.