Chemotherapy in lymphoma: Questions and currently available evidence

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1 Chemotherapy in lymphoma: Questions and currently available evidence Prof. Dr. Peter Borchmann 1st Department of Internal Medicine University of Cologne

2 Evidence? Cochrane! Yang K, Tan J, Wu T. Alkylating agents for Waldenstrom's macroglobulinaemia. Cochrane Database of Systematic Reviews 2009, Issue 1. Art. No.: CD DOI: / CD pub3 Greb A, Bohlius J, Schiefer D, Schwarzer G, Schulz H, Engert A. High-dose chemotherapy with autologous stem cell transplantation in the first line treatment of aggressive Non-Hodgkin Lymphoma (NHL) in adults. Cochrane Database of Systematic Reviews 2008, Issue 1. Art. No.: CD DOI: / CD pub2

3 Is there a controlled randomized trial comparing chemo with no-chemo? Follicular lymphoma, first diagnosis Ardeshna et al., Lancet, 2003

4 If there is no evidence, why are we then using chemotherapy in lymphoma? Because we do see an obvious benefit!

5 A tribut to our pioneers: Louis S. Goodman and Alfred Gilman Nitrogen mustard therapy; use of methyl-bis (betachloroethyl) amine hydrochloride and tris (beta-chloroethyl) amine hydrochloride for Hodgkin's disease, lymphosarcoma, leukemia and certain allied and miscellaneous disorders Goodman, J Am Med Assoc, 1946

6 How to use chemotherapy? 1/2 Skipper and Schabel (1964): - Doubling time of proliferating cancer cells is constant - Cell kill by chemotherapy follows first-order kinetics (% of cells killed at a given dose is constant, regardless of tumor size): Ctx A (90%) + Ctx B (90%) = 99% cell kill (2log)

7 Development of polychemotherapy: MOPP, CHOP, and ABVD in the 60ies and 70ies MOPP: DeVita, V. T., Serpick, A. A., and Carbone, P. P.: Combination chemotherapy of advanced Hodgkin s disease: The NCI Program, a progress report. Proc. Amer. Ass. Cancer Res. 10:19, CHOP: Gottlieb, Jeffrey A., Jordan U. Gutterman, Kenneth B. McCredie, Victorio Rodriguez, and Emil Frei: Chemotherapy of Malignant Lymphoma with Adriamycin. Cancer Res. 33, , November 1973 ABVD: Bonadonna, G., Zucali, R., Monfardini, S., De Lena, M, Uslenghi, C.: Combination chemotherapy of Hodgkin's disease with adriamycin, bleomycin, vinblastine, and imidazole carboxamide versus MOPP. Br J Cancer Jul;36(1):

8 How to use chemotherapy? 2/2 Goldie and Coldman (1976): - assumptions: Tumors have an inherently higher mutation rate vs. normal cells and with progression, there appears to be an increase in mutation rate - Probability of resistance cells depends on tumor size Based on size of detectable tumors (10 9 ) and mutation frequency (10-5 ) ~ 10 4 resistant cells at time of diagnosis Use multiple agents in short intervals to avoid resistance: Alternating schedules of the 80ies

9 Chemotherapy of Advanced Hodgkin's Disease with MOPP, ABVD, or MOPP Alternating with ABVD George P. Canellos, M.D., James R. Anderson, Ph.D., Kathleen J. Propert, Sc.D., Nis Nissen, M.D., M. Robert Cooper, M.D., Edward S. Henderson, M.D., Mark R. Green, M.D., Arlan Gottlieb, M.D., and Bruce A. Peterson, M.D. N Engl J Med 1992; 327:

10 Survival (%) Applied theory in aggressive B-NHL: Improving CHOP by adding drugs N Death Estimate 5-Year CHOP % MACOP-B % ProMACE-CytaBOM % m-bacod % Years after registration Updated from Fisher RI et al. N Engl J Med 1993;328:1002

11 G-CSF and Dose Intensification, the 90ies Conventional therapy i.e. 8 x ABVD weeks BEACOPP escalated weeks

12 SURVIVAL COPP/ABVD versus BEACOPP: Proof of principle in advanced HL % The GHSG HD9 trial p <0.001 COPP/ABVD BEACOPPbase BEACOPPesc A (75%) B (80%) C (86%) Years The GHSG HD9 study, Engert et al., J Clin Oncol, 2010, 27:

13 Limits of intensification in lymphoma therapy: The HDR2 trial 2x DHAP + G-CSF PR or CR: continue Single agent HD Ctx - Cyclophosphamide - Mtx, Vcr - Etoposide BEAM + APBSCT

14 probability HDR2: Increase of toxicity overcomes efficacy p = Intensified (at 3y: 67%) Standard (at 3y: 72%) Time [months] Pts. at Risk Standard Intensified Josting et al., 2010 Dec 1;28(34):

15 Where to go from here?

16 First of all: Understanding Malignancy From Hanahan and Weinberg, Cell, Vol. 100, 57 70, January 7, 2000

17 Hallmarks of Malignancy From Hanahan and Weinberg, Cell, 2011

18 HL and the Hodgkin Reed Sternberg (HRS) cell A B-cell without B-cell receptor: why can it survive? Surrounded by cells of the immune system: why is it not being attacked?

19 Antibody therapy: the revolution From Paul Ehrlich, 1900 to therapeutics, 100 years later From Schulman et al., 2001

20 How do antibodies work in contrast to chemotherapy? CDC (complement dependent cytotoxicity) tumor cell effector cell (NK / T tox ) ADCC (antibody dependent cellular cytotoxicity) Signal transduction (induction of apoptosis) indirect: inhibition of proproliferative factors or angiogenesis

21 Rituximab: the billion dollar antibody Do we have evidence? No clear phase I result: optimal dose and schedule are unknown No proven concept of its complex mechanism of action, however, CD20 positive B-cells are depleted Single agent activity in B-NHL is modest ( 50% drug ), even in indolent lymphoma therefore, it is not being used frequently in its first approved indication Is this a case for Dr. Cochrane?

22 Meta-analysis of overall survival among patients who received rituximab with chemotherapy (Rchemo) or chemotherapy alone. Schulz H et al. JNCI J Natl Cancer Inst 2007;99: The Author Published by Oxford University Press

23 Spreading of Rituximab in lymphoma since 1998 Approved as single agent in patients In relapsed or resistant follicular lymphoma patients In combination with chemotherapy in patients with untreated follicular NHL, stage III-IV CD20 positive untreated diffuse large B-cell lymphoma (CHOP) Untreated or relapsed or refractory chronic lymphocytic leukemia As maintenance therapy after response to first line therapy response to second line therapy

24 Beyond naked antibodies: Magic bullets!? Antibody drug conjkugate Brentuximab vedotin monomethyl auristatin E (MMAE), potent antitubulin agent protease-cleavable linker anti-cd30 monoclonal antibody ADC binds to CD30 ADC-CD30 complex traffics to lysosome MMAE is released MMAE disrupts Microtubule network G2/M cell cycle arrest Apoptosis

25 Tumour size (% change from baseline) Brentuximab Vedotin (SGN-35): dramatic response rate in relapsed HL (phase II) 100 Complete remission by PET % (96 of 102) of patients achieved tumour reduction Individual patients (n=98) Chen et al ASCO 2011

26 Hallmarks of Malignancy From Hanahan and Weinberg, Cell, 2011

27 Understanding malignancy becomes more and more sophisticated From Hanahan and Weinberg, Cell, 2011

28 Targeted therapy in lymphoma 2011 Bcl-2-targeted drugs m-tor inhibitors Akt inhibitors PI3-K inhibitors HDAC inhibtors

29 Perspectives of systemic therapy in malignant lymphoma Likelihood of cure?

30 Currently available evidence of chemotherapy in lymphoma? The golden era of chemotherapy has passed by, however, cytotoxic chemotherapy obviously cures lymphoma patients and will remain the comparator and the backbone for any new development

31 Questions concerning systemic therapy in lymphoma? To do s for lymphomaniacs in 2011 (first 5/1 Mio): 1. To restrict the burden of chemotherapy to those being in need of it 2. To refine our understanding of the immune system and the microenvironment of tumors 3. To keep academic independence 4. To implement molecular diagnostics into the selection process for therapeutic developments and interventions 5. To perform high quality studies allowing the CHMG to easily perform high quality meta-analyses

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33 The ABC rule for an obvious benefit A benefit that clearly outweighs all possible adverse effects (whether frequent and mild, or rare and severe); A benefit that could not be explained by bias; and An intervention that is obviously beneficial in all contexts in which it will be applied Reeves, BMJ, 2006 Oct 14;333(7572):807; discussion