Letter to the Editor: In Response to Stopping Imatinib in CML

In Dr. Andrew Roberts’ review of the article by Dr. Amy Hughes and colleagues¹ in the May/June issue (Stopping Imatinib in CML: Safe in the Long Term for Deep Molecular Responders As the Immune System Steps Up. The Hematologist. 2017;14[3]:9), he writes, “Patients who achieve a deep molecular response to imatinib (and other TKIs [tyrosine kinase inhibitors]) have a normalization of key aspects of their innate and adaptive immune systems that can be maintained without ongoing TKI therapy. But whether re-establishment of immunity is central to the ability to stop imatinib successfully is unknown.”

Quite right. However, the title offers a rather different implication: A step up in the immune system is how CML therapy-free remission is achieved. The study by Dr. Hughes et al also implies this: “Immunological control may contribute to achievement of deep molecular response in chronic myeloid leukemia (CML) patients on tyrosine kinase inhibitor (TKI) therapy and may promote treatment-free remission.”¹  However, studies like this cannot, of course, distinguish cause and effect. It only seems logical if you get rid of a lot of CML cells your immunity will improve, but this does not mean this is why CML does not recur after stopping TKI-therapy. To address the question of whether immune surveillance is important in controlling CML, we used several strategies. We found no increase in CML incidence in persons with hereditary, congenital, or acquired immune deficiencies. We also found only 25 excess cases of CML amongst 441,232 recipients of solid organ transplants receiving intense immune suppression with 2 million person-years at-risk observation.

These data and others suggest immune surveillance is a rather unlikely explanation of why some persons stopping TKI-therapy do not relapse. More generally, the immune system is often invoked to explain seemingly mysterious events in medicine and biology. However, several other explanations such as measurement error and chance (concepts anathema to most scientists and physicians) are an equal or more likely explanation of therapy-free remission in CML. Let’s give immune surveillance a break; it’s tired.

— Robert Peter Gale, MD, PhD, DSc(hc), FACP, FRSM, from Imperial College London, London, United Kingdom

— Gerhard Opelz, MD, from University of Heidelberg, Heidelberg, Germany

Reply: The critique of Drs. Gale and Opelz is welcome, and their data highlight that immune suppression per se does not predispose to CML. For clarity though, the title that has troubled them identified an association, without implying cause and effect. Further, the experience with allogeneic stem cell transplantation and donor lymphocyte infusion as curative therapies for CML provides prime facie evidence of a role for the immune system in controlling established disease. It all highlights the need for more research into the mechanisms underpinning long-term remissions post TKI withdrawal.

— Andrew Roberts, MBBS, PhD, FRACP, FRCPA, from Metcalf Chair of Leukaemia Research, Melbourne, Australia