An iatrogenic orphan?

In this issue of Blood, Wang and colleagues from the Mayo Clinic and the University of Iowa, describe the outcomes of patients diagnosed with diffuse large B-cell lymphoma (DLBCL) and treated in the era of rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) who are also found to have an underlying indolent lymphoma in the lymph nodes or the bone marrow.¹ 

This is not an uncommon scenario, because up to 15% of DLBCL patients fall into this category. One of the biggest challenges is determining what to call such patients. Do they have DLBCL? Transformed lymphoma? Composite lymphoma? Discordant lymphoma? The table provides the current definitions for these variations. Strictly speaking, the patients in this series have DLBCL with an underlying indolent component which can be classified as composite if the indolent component is found in same site (ie, same lymph node) and discordant of the indolent lymphoma is discovered in a site distinct from the DLBCL (ie, DCLBC in a lymph node and chronic lymphocytic leukemia in the bone marrow). Technically, they do not have transformed lymphoma (which requires a history of indolent lymphoma). The big question is How do these patients differ from those with de novo DLBCL? Do they present differently? Do they respond to treatment differently? Do they have different outcomes? Does the type of underlying indolent lymphoma matter? The historical literature regarding these questions is contradictory.^2-9  The Wang et al report presents the largest and most contemporary series to date on this topic.

The patient data (N = 1324) were derived from the Iowa-Mayo Molecular Epidemiologic Resource, and 12.9% (n = 171) of the patients were found to have an underlying indolent lymphoma. The patient data were collected between 2002 and 2015, so follow-up is more than adequate. Follicular lymphoma (FL) was the most common indolent lymphoma (8.2%) followed by small lymphocytic lymphoma (1.1%) and marginal-zone lymphoma (1.1%). Not surprisingly, patients with DLBCL with underlying FL almost always had germinal center B-cell-like (GCB) cells of origin. The event-free survival (EFS) and overall survival (OS) of GCB DLBCL compared with DLBCL with an underlying FL were virtually identical. DLBCL patients with an underlying non-FL indolent component tended to have marrow involvement with the indolent lymphoma, worse baseline characteristics, and higher International Prognostic Index (IPI) scores. However, after adjusting for IPI score, these patients also had similar EFS and OS when compared with de novo DLBCL.

Although this data set is incredibly valuable, several important questions remain. Should DLBCL patients with an underlying indolent component be observed and monitored differently? For example, many clinicians will discharge DLBCL patients from their practice after a continuous remission of 5 years, because they are highly likely to be cured. Can the same procedure be followed for those with an underlying indolent lymphoma? Or should those patients be observed indefinitely, like one might do for any FL patient?

What about clinical trial participation? Many first-line DLBCL trials will exclude patients with an underlying indolent component, creating “orphan” status for 13% of our patients. Is this rational? The Wang data suggest it is not. It may be time for large randomized phase 3 trials in DLBCL to be more inclusive in this regard, to better reflect the real-world DLBCL population.

Finally, data sets like these provide opportunities to clarify disease entities and simplify confusing nomenclature. Do we need all of these different terms like “transformed,” whose definition is influenced by the timing of the event, and “composite” vs “discordant,” whose definitions are based upon anatomic location? A better nomenclature would be biologically based, reserving the term transformed for clonally related lymphomas and composite for clonally unrelated lymphomas. Perhaps this is something the World Health Organization Classification can consider at a future update. In the meantime, Wang and colleagues have provided a valuable contribution to the lymphoma literature by helping to define the natural history of an orphan entity.