Alessandro LevisHaematology - Alessandria - Italy

Is still ABVD the best chemotherapy regimen in Hodgkin’s lymphoma ?

Data from the GHSG HD9 trial in advanced stage HL(from Engert et al JCO 27, 4548, 2009)

4 COPP-ABVD (ABVD-like)

8 BEACOPP escalated

The superiority of BEACOPP in terms of disease control has been confirmed also over ABVD and not

only over COPP-ABVD

(Gianni et al ASCO 2008; abstract 8506) Folluw up updated to June 2010

personal communication

7-years progression free survival

(Federico et al JCO 2009; 27: 805-811)

5-years progression free survival

BEACOPP escalated is superior to ABVD in terms of progression free survival

ABVD

BEACOPP

Not always the most powerful tool is safe and it is the best choice in order to reach long term results

Acute toxicity • Haematological• Infections • Toxic deaths in older patients

Late toxicity• Secondary MDS/AML• Infertility

The problem of toxicity

Even the baseline version of BEACOPP is highly toxic over 65 years of age

data from HD9elderly study of the GHSG

COPP-ABVD BEACOPP

N° of patients 26 42

Grade IV leucopaenia 40 % 87 %

Grade IV any toxicity 44 % 87 %

Toxic deaths 8 % 21 %

(from Ballova et al Ann Oncol 16, 124131, 2005)

Data from the GHSG HD9 in advanced stages

Arm A: COPP-ABVDArm B : BEACOPP baselineArm C BEACOPP escalated

(Engert et al JCO 27, 4548, 2009)

Secondary cancers

MDS - AML

Male infertility is a problem after both baseline and escalated BEACOPP chemotherapy

(from Sieniawski et al Blood 111, 71-76, 2008)

% %

Male infertility is a minimal problem with ABVD as compared to COPP-ABVD

(from Kulkarni et al Am J Clin Oncol 20, 354-357, 1997)

% %

Male infertility evaluated by high FSH levels is highly dependent on alkyilating agents

(from van der Kaaij et al JCO 25, 2825-2832, 2007)

Rate of FSH abnormal level

Rt only 21 %

ABVD/EBVP 26 %

Alkylating T. 82 %

Amenorrhea is a major problem with BEACOPP escalated treatment

(Berhinger et al JCO 23, 7555-7564, 2005) (Bonadonna et al JCO 22, 2835-2841, 2004)

% %

Pregnancy rate is not compromised by ABVD chemotherapy

(from Hodgson et al Hematol Oncol 25, 11-15, 2007)

1-year pregnancy rate

HL survivors 70 %Control women 75 %

Canadian survey on women who tried to become pregnant

ABVD

Early stage (IA and IIA) without any unfavourable factors (bulky disease, more than 3 sites… )

Early stage (IA and IIA) with one or more unfavourable factors

Advanced stage (IIB-IV)

Different conditions

Early favourable stages: data from the HD10 GHSG trial

(Engert et al NEJM 2010,363: 640-652)

random

2 ABVD+

Rt IF 30 Gy

2 ABVD+

Rt IF 20 Gy

4 ABVD+

Rt IF 20 Gy

4 ABVD+

Rt IF 30 Gy

No reasons to shift from ABVD to BEACOPP in favourable early stages

Early stage (IA and IIA) with one or more unfavourable factors

Advanced stage (IIB-IV)

Different conditions

Early unfavourable stages: data from the HD11 GHSG trial

(Borchman et al ASH 2009, Abs 717)

random

4 ABVD+

Rt IF 30 Gy

4 ABVD+

Rt IF 20 Gy

4 BEACOPP b+

Rt IF 20 Gy

4 BEACOPP b+

Rt IF 30 Gy

30 Gy

ABVD vs. BEACOPP b - 1,6 % (Cl -3,6; 6,9)

20 Gy

ABVD vs. BEACOPP b- 5,7 % (Cl 0,1;11,3)

5 y.FFTF

More toxicLess effective

No reasons to shift from ABVD to BEACOPP in favourable early stages

What strategy is the less toxic between [4 ABVD + 30 Gy I.F. Radiotherapy] and[4 BEACOPPb + 20 Gy I.F. Radiotherapy] ?

Advanced stage (IIB-IV)

Different conditions

Data from the GHSG HD9 in advanced stages

Arm A: COPP-ABVDArm B : BEACOPP baselineArm C BEACOPP escalated

(Engert et al JCO 27, 4548, 2009)

Superiority of BEACOPP escalated over COPP-ABVD

in terms of both FFTF and OS

Superiority of BEACOPP over ABVD in terms of FFS but not in terms of OS (Italian IIL study)

(Gianni et al ASCO 2008; abstract 8506) Folluw up updated to June 2010: personal communication

7-years progression free survival 7-years overall survival

Superiority of BEACOPP over ABVD in terms of FFTF and PFS but not in terms of OS (Italian GISL study)

(Federico et al JCO 2009; 27: 805-811)

The advantage of BEACOPP over ABVD in terms of PFS seems to be significant only in the unfavourable group of

IPS 3-7 patients (Italian GISL study)

(Federico et al JCO 2009; 27: 805-811)

A new hypothesis: a BEACOPP strategy limited to patients candidate to become ABVD poor-responders

(Federico et al JCO 2009; 27: 805-811)

70 % of patients cured with minimal toxicity with 6 ABVD only

20% ABVD failures that can benefit from

BEACOPP

(Gallamini et al. JCO 25, 3746-3752, 2007)

A new hypothesis: a strategy based on chemo-sentivity evaluated according to early PET results

?

+

random

Rt bulky No Rt

stage IIB-IV

Staging including PET scan

2 ABVD

- PET

2 ABVD

Salvage IGEV + ASCT

- CT + PET +

2 ABVD

Advanced stage Hodgkin lymphoma

IIL-HD0801 protocol

 

ABVD x2

escalated BEACOPP x4ABVD x4

High-risk HL

PET-2

standard BEACOPP x4

End-therapy PET

PET-2 +ve HL PET-2 -ve HL

IIB-IVB orIIA with more than 3 nodal sites, ESR > 50, bulky lesion

Ongoing GITIL study

PET-0

Consolidation RxT Consolidation RxT

By courtesy of Gallamini (ASCO 2010)

FFS according to PET-2 results reported by the local PET centers.

Cohort of 158 patients correctly treated

Subgroup of 141 patients withstage IIB-IVB disease

All patients PET-2 negative PET-2 positive

Ongoing GITIL study

By courtesy of Gallamini (ASCO 2010)

No reasons to shift from ABVD to BEACOPP in favourable early stages

What strategy is the less toxic between [4 ABVD + 30 Gy I.F. Radiotherapy] and[4 BEACOPPb + 20 Gy I.F. Radiotherapy] ?

BEACOPP is more effective than ABVD in terms of PFS, but not OS, and front line ABVD escalated strategies have to be considered for the future.

Conclusions

Acknowledgments to all centres and groups cooperating to the studies of the

Intergruppo Italiano Linfomi