Bruce D. Cheson, MD, FACP, FAAAS, FASCO
In the December 10, 2017, issue of The ASCO Post, I authored an article in which I raised the possibility of curing follicular lymphoma without the dreaded chemotherapy. Clearly, no good deed goes unpunished: My good friend and The ASCO Post’s editor Jim Armitage, MD, challenged me to defend that position in the current issue of the same publication.
So, where to start the saga? I would set the WABAC machine to more than a century ago, to the time of Paul Ehrlich, the founder of modern immunology. Professor Ehrlich conceptualized the “magic bullet,” which would specifically target organisms or tumor cells, sparing the remainder of the body substances. The sketches in his monograph bore an uncanny resemblance to what we now recognize as the structure of monoclonal antibodies.1
Historical Look at Lymphoma Chemotherapy
‘Twas not until the year I was brought unto this earth that the first paper was published on the successful use of a systemic treatment of patients with lymphosarcoma, the disorder we now call non-Hodgkin lymphoma.2 The agent was nitrogen mustard, an alkylating agent, a derivative of the mustard gas dumped on the Allied soldiers during World War II, leading to skin ulcerations, blindness, and secondary malignancies, among other unpleasantries. However, exposure also resulted in lymphopenia and atrophic lymph nodes. The list of authors of this manuscript read like a hematologist’s version of Marvel superheroes—Goodman and Gilman (we have all used their pharmacology text), Max Wintrobe and William Dameshek, the latter two considered the founders of modern hematology. This class of drugs has formed the foundation of almost all of our current lymphoma chemotherapy regimens, including drugs such as cyclophosphamide and bendamustine. But then we were totally sidetracked for decades with the mixing and matching of various chemotherapy agents, creating naught but chaos, and continued exposure of our patients to noxious substances.
Birth of Monoclonal Antibodies and Targeted Agents
It would be a long time before Ehrlich’s vision could be realized by identifying the appropriate tumor target3 and developing the capacity to manufacture therapeutic antibodies.4 The initial result was rituximab (Rituxan), a chimeric monoclonal antibody that forever (perhaps too strong a word) altered the follicular lymphoma landscape by prolonging the survival of patients with follicular lymphoma, regardless of the chemotherapy backbone. Nonetheless, the cure rate for follicular lymphoma remained disappointingly low.
Abandoning a Frankenstein-like undertaking for rationally devised, individualized treatments relying solely on targeted agents will eventually breathe life into the cure of follicular lymphoma.— Bruce D. Cheson, MD, FACP, FAAAS, FASCO
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In 2004, given the encouraging results with a single antibody, investigators from the Cancer and Leukemia Group B were the first to eschew alkylating-based regimens for combinations of biologic agents, first with doublets of monoclonal antibodies,5,6 and then with rituximab and the immunomodulatory agent lenalidomide (Revlimid).7,8 When introduced as initial therapy, each of these regimens produced response rates of 85% to 95%, at least consistent with those achievable with multiagent chemoimmunotherapy combinations, often with responses ongoing for many years.
A new wave of novel targeted agents has rekindled interest in clinical research: antibodies and antibody-drug conjugates, those that interfere with intracellular pathways, and others that are directed at the microenvironment. A number of them appear to be superior to chemotherapy in a variety of clinical situations: for example, idelalisib (Zydelig)9 or copanlisib (Aliqopa)10 in second or greater relapsed follicular lymphoma. Logically, combinations should certainly lead us to our goal!
The Frankenstein Principle
Unfortunately, the current development of targeted regimens mostly adheres to what I call the Frankenstein principle: Lovely nose from here, great heart from there, sturdy arms from elsewhere, decent torso, very good brain. But, when you stitch them all together, the result is reminiscent of a line by Dr. Victor Frankenstein from the classic eponymous novel: “How can I describe my emotions at this catastrophe, or how delineate the wretch whom with such infinite pains and care I had endeavoured to form?”11
I submit we are already curing a substantial fraction of patients with follicular lymphoma despite its reputation as being incurable.— Bruce D. Cheson, MD, FACP, FAAAS, FASCO
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Countless trials have focused on the empiric mixing and matching various generations of phosphatidylinositol 3-kinase, Bruton’s tyrosine kinase, or bcl-2 inhibitors with type I or type II anti-CD20s, programmed cell death protein 1 and programmed cell death ligand 1 inhibitors. In many circumstances, the creation was no grander than the sum of its parts.12 In others, regimens were abandoned because of unexpected and disastrous consequences.13
Nonetheless, can one or more of these agents or combinations achieve biologic cure in patients with lymphoma? I submit we are already curing a substantial fraction of patients with follicular lymphoma despite its reputation as being incurable. Indeed, in my clinic, I am following scores of patients with follicular lymphoma who are alive and disease-free for up to a decade or longer, some having received chemoimmunotherapy, but others only doublets of biologic agents, and in the relapsed as well as front-line settings. We are currently conducting experiments using clonotypic next-generation sequencing to confirm my belief that their disease is forever gone.
So, what are the remaining obstacles to surmount to cure the rest of the patients? First, we need to better understand what molecular or genetic features distinguish those who are cured. Comparing responders with nonresponders using next-generation sequencing and other technologies into our prospective trials may generate enlightening hypotheses.
Next, how can we efficiently study combinations of the burgeoning number of agents and next generations of those agents directed at a variety of targets? If we were limited to only 8 agents, the number of potential doublets to test would be 36, and the number of triplets would be a staggering 84. The solution requires novel statistical designs for clinical trials and reliable surrogate markers to facilitate their completion. The latter might include assessment of minimal residual disease by polymerase chain reaction14 or a more sensitive clonotypic assay.15 Most important is the need to identify biomarkers not only for response and toxicity, but also for mechanisms of resistance, as seen in other lymphoid malignancies.16
These factors will provide the template for assembling the parts together into an effective and tolerable creation. Abandoning a Frankenstein-like undertaking for rationally devised, individualized treatments relying solely on targeted agents will eventually breathe life into the cure of follicular lymphoma. ■
Dr. Cheson is Professor of Medicine; Head of Hematology and Cellular Therapy; Deputy Chief, Division of Hematology-Oncology; Fellowship Program Director, Georgetown University Hospital, Lombardi Comprehensive Cancer Center, Washington, DC.
DISCLOSURE: Dr. Cheson reported no conflicts of interest.
Disclaimer: This commentary represents the views of the author and may not necessarily reflect the views of ASCO or The ASCO Post.
1. Ehrlich P: On immunity with special reference to the cell of life. Proc Royal Soc London 66:424-448, 1900.
2. Goodman LS, Wintrobe MM, Dameshek W, et al: Landmark article Sept. 21, 1946: Nitrogen mustard therapy. Use of methyl-bis(beta-chloroethyl)amine hydrochloride and tris(beta-chloroethyl)amine hydrochloride for Hodgkin’s disease, lymphosarcoma, leukemia and certain allied and miscellaneous disorders. By Louis S. Goodman, Maxwell M. Wintrobe, William Dameshek, Morton J. Goodman, Alfred Gilman and Margaret T. McLennan. JAMA 251:2255-2261, 1984.
3. Nadler LM, Ritz J, Hardy R, et al: A unique cell surface antigen identifying lymphoid malignancies of B cell origin. J Clin Invest 67:134-140, 1981.
4. Köhler G, Milstein C: Continuous cultures of fused cells secreting antibody of predefined specificity. Nature 256:495-497, 1975.
5. Czuczman MS, Leonard JP, Jung S, et al: Phase II trial of galiximab (anti-CD80 monoclonal antibody) plus rituximab (CALGB 50402): Follicular Lymphoma International Prognostic Index (FLIPI) score is predictive of upfront immunotherapy responsiveness. Ann Oncol 23:2356-2362, 2012.
6. Grant BW, Jung SH, Johnson JL, et al: A phase 2 trial of extended induction epratuzumab and rituximab for previously untreated follicular lymphoma: CALGB 50701. Cancer 119:3797-3804, 2013.
7. Leonard JP, Jung SH, Johnson J, et al: Randomized trial of lenalidomide alone versus lenalidomide plus rituximab in patients with recurrent follicular lymphoma: CALGB 50401 (Alliance). J Clin Oncol 33:3635-3640, 2015.
8. Martin P, Jung SH, Pitcher B, et al: A phase II trial of lenalidomide plus -rituximab in previously untreated -follicular non-Hodgkin’s lymphoma: CALGB 50803 (Alliance). Ann Oncol 28:2806-2812, 2017.
9. Gopal AK, Kahl BS, de Vos S, et al: PI3Kδ inhibition by idelalisib in patients with relapsed indolent lymphoma. N Engl J Med 370:1008-1018, 2014.
10. Dreyling M, Santoro A, Mollica L, et al: Phosphatidylinositol 3-kinase inhibition by copanlisib in relapsed or refractory indolent lymphoma. J Clin Oncol 35:3898-3905, 2017.
12. Ujjani CS, Jung SH, Pitcher B, et al: Phase 1 trial of rituximab, lenalidomide, and ibrutinib in previously untreated follicular lymphoma: Alliance A051103. Blood 128:2510-2516, 2016.
13. Cheson BD: Speed bumps on the road to a chemotherapy-free world for lymphoma patients. Blood 128:325-330, 2016.
14. Cheson BD, Trneny M, Bouabdallah K, et al: Obinutuzumab plus bendamustine followed by obinutuzumab maintenance prolongs overall survival compared with bendamustine alone in patients with rituximab-refractory indolent non-Hodgkin lymphoma: Updated results of the GADOLIN study. 2016 ASH Annual Meeting. Abstract 615. Presented December 3, 2016.
15. Roschewski M, Dunleavy K, Pittaluga S, et al: Circulating tumour DNA and CT monitoring in patients with untreated diffuse large B-cell lymphoma: A correlative biomarker study. Lancet Oncol 16:541-549, 2015.
16. Woyach JA, Ruppert AS, Guinn D, et al: BTK(C481S)-mediated resistance to ibrutinib in chronic lymphocytic leukemia. J Clin Oncol 35:1437-1443, 2017.