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Doing the same thing over and over again but expecting different results: It’s time to move on
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A publication in Journal of Clinical Oncology reports the results of a randomized trial that compared rituximab, cyclophosphamide, doxorubicin, vincristine and prednisone, or R-CHOP, to high-dose sequential chemotherapy with autologous stem cell transplantation as first-line therapy in patients with poor-risk diffuse large B-cell lymphoma.
The trial, analyzed by intent to treat, showed no difference in EFS, PFS or OS associated with the transplant regimen.
As I read this study, I could not help but think of the famous quote in the title of this editorial, which is often — and possibly mistakenly — attributed to Albert Einstein.
I certainly mean no disrespect to the researchers, who have executed a well-conducted study with a conclusive result, confirmatory of many previous trials. But I must question why the subject of “upfront” transplant in aggressive lymphomas still merits investigation after almost exclusively negative results from clinical trials over 2 decades.
In fairness to the researchers, their study opened in 2005, when this arguably was still an open question. But let’s hope that this study will close the door on the evaluation of early transplant in this disease, and that we can move on to explore other strategies.
Parma and beyond
The use of upfront transplant was catalyzed in the 1990s following the publication of results from the Parma trial.
This landmark trial established high-dose therapy and autologous stem cell transplantation as the standard of care for patients with relapsed, aggressive lymphomas — a standard that has remained for more than 21 years.
As someone who entered patients onto this study, I recognize its importance but also its limitations in today’s context.
The trial began in 1987 and was completed in 1994. The study predated WHO classification of lymphoid neoplasms, so multiple histologic subtypes — almost certainly including T-cell lymphomas — were included. Rituximab (Rituxan; Genentech, Biogen) was not available at that time and peripheral blood stem cell transplantation was in its infancy, so all patients had bone marrow transplants. The upper age limit of the study was 60 years, and patients with marrow involvement at the time of relapse were excluded.
All patients received two cycles of therapy with rituximab plus cisplatin, cytarabine, and dexamethasone (DHAP), and responding patients then were randomly assigned to receive two more cycles of DHAP, or high-dose therapy with autologous stem cell transplantation.
Of the 215 patients entered onto the study, only 64% had a response to DHAP, and ultimately only 109 patients were randomly assigned to subsequent therapy.
There was a significant improvement in PFS and OS in favor of transplant, calculated from the date of transplantation. No intent-to-treat analysis was performed.
In summary, this relatively small, underpowered study — with no long-term follow-up, inclusion criteria that are questionable in 2016 and uncertain relevance to modern treatment paradigms in diffuse large B-cell lymphoma (DLBCL) — has defined the unchallenged standard of care for patients with chemotherapy-sensitive relapsed DLBCL.
Following the Parma study, the use of upfront consolidative transplant was appropriately investigated in multiple subsequent studies. Three independent systematic reviews and meta-analyses have been conducted using data from these studies, and they concluded there is no benefit to early transplant in this disease.
The Southwest Oncology Group-9704 trial showed a similar result, concluding there was no PFS or OS benefit, but with two caveats — first, that an exploratory analysis showed a possible benefit for patients with high-risk International Prognostic Index scores, and second, that the lack of OS benefit might be explained by the use of salvage transplants in patients who relapsed on the conventional-dose arm.
It is noteworthy that, in the eyes of some oncologists, the use of early transplant is still regularly considered in patients regarded as high risk. I still see patients in my clinic for second opinions, for whom upfront transplant has been recommended. The preponderance of evidence from randomized trials should convince everybody that stem cell transplantation should not be a part of first-line therapy for patients with poor-risk DLBCL.
The use of stem cell transplantation in the relapsed and refractory setting also is becoming less well defined. The introduction of rituximab-containing first-line therapy has resulted in significant improvements in PFS and OS in aggressive non-Hodgkin lymphoma, and the use of transplantation in the salvage setting, therefore, has declined.
Intuitively, it seems likely that patients who relapse from a rituximab-based regimen might be more difficult to salvage with a transplant strategy than those not previously exposed to this drug. Results are conflicting with respect to this question, although the so-called CORAL trial showed that patients exposed to a rituximab-based regimen within 1 year of relapse had a poorer outcome with a rituximab-based cytoreductive regimen followed by autologous transplant.
It seems clear that patients who relapse after R-CHOP or similar regimens appear to have a higher frequency of poor-risk features. As an example, two studies suggest that patients with highly proliferative subtypes of DLBCL — including MYC–positive, as well as double-hit and double-expressing DLBCL — are overrepresented in the group of relapsing patients. Further, these studies show apparently low response rates to second-line cytoreductive therapy and poor outcomes after autologous transplant. In a study from Herrera and colleagues, patients with rearranged MYC and Bcl-2 by fluorescence in situ hybridization — known as double hit — have 3-year posttransplant OS of only around 20%.
Time to move on
These data suggest that patients with DLBCL who relapse today likely represent a very different group from those who relapsed in the early 1990s and were entered onto the Parma protocol.
In my own practice, I have taken care of a 70-year-old man who presented in spring 2015 with a bulky retroperitoneal mass and widespread bone disease. A biopsy showed a double-hit lymphoma with an almost 100% proliferation fraction.
We treated him with dose-adjusted R-EPOCH (rituximab, etoposide phosphate, prednisone, vincristine sulfate, cyclophosphamide and doxorubicin hydrochloride) and he achieved a complete radiologic and metabolic remission, but he relapsed 1 year out from completion of treatment.
After extensive discussion with the patient — and in the absence of many published data — we agreed to treat him with rituximab, ifosfamide, carboplatin and etoposide (R-ICE) salvage, followed by high-dose therapy and stem cell transplantation. He has achieved a partial response to R-ICE and now is undergoing his transplant. Data suggest that his chances for cure with this approach are low.
Twenty-one years after the then-definitive study of stem cell transplantation in lymphoma, it is truly time to move on.
In the frontline setting, trials incorporating new agents in combination with R-CHOP — such as lenalidomide (Revlimid, Celgene) — are underway.
In the salvage setting, the identification of biological factors — that not only predict for poor outcome, but that may be potential therapeutic targets — is ongoing. Examples include inhibitors of Bcl-2, and of MYC and its target genes.
There no doubt will be a role for stem cell transplantation for some relapsing patients for many years to come — the study by Herrera and colleagues showed a 3-year PFS of about 70% for patients with relapsed DLBCL who were neither double hit or double expressers. So, transplant still has a role, but that is likely to diminish.
It is time to move on and start asking new questions.
References:
Cortelazzo S, et al. J Clin Oncol. 2016;doi:10.1200/JCO.2016.67.2980.
Cuccuini W, et al. Blood. 2012;doi:10.1182/blood-2012-01-406033.
Gisselbrecht C, et al. J Clin Oncol. 2010;doi:10.1200/JCO.2010.28.1618.
Herrera AF, et al. J Clin Oncol. 2016;doi:10.1200/JCO.2016.68.2740.
Philip T, et al. New Engl J Med. 1995;doi:10.1056/NEJM199512073332305.
Stiff PJ, et al. New Engl J Med. 2013;doi:10.1056/NEJMoa1301077.
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John Sweetenham, MD, is HemOnc Today’s Chief Medical Editor for Hematology. He also is senior director of clinical affairs and executive medical director of Huntsman Cancer Institute at University of Utah. He can be reached at john.sweetenham@hci.utah.edu.
Disclosure: Sweetenham reports no relevant financial disclosures.