Stem cell transplant after CAR T-cell therapy reduces relapses in acute lymphocytic leukaemia

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Published: 1 Dec 2018
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Dr Corinne Summers - Seattle Children's Hospital, Seattle, USA

Dr Corinne Summers gives a press conference at ASH 2018 about the benefits of a stem cell transplant after CAR T-cell therapy.

Watch her interview with ecancer here.

Read the article about this work here.

 

I’d like to thank the committee for selecting our abstract which focusses on our work evaluating the role of transplant for patients that achieve a sustained remission following CD19 CAR T-cell therapy in our Seattle Children’s PLAT-02 trial.
Our CD19 CAR T-cell trial is a phase I/II study in paediatric and young adults with B-cell leukaemia. The study objectives include determining manufacturing feasibility of the CAR product as well as determining the safety of the product infusion as well as the product’s toxicity profile. On the phase II portion of the trial we are additionally evaluating the efficacy of the product. The study’s eligibility criteria include age greater than 12 months and less than 27 years, subjects with relapsed or refractory CD19 positive leukaemia, subjects with a history of bone marrow transplant could not have active graft versus host disease and subjects also needed an absolute lymphocyte count greater than 100 cells per microlitre.

We treated 43 subjects on the phase I portion of the trial which has been previously described. One million CAR T-cells per kilogram was determined to be the maximum tolerated dose and this was the cell dose used for the phase II portion of the trial. The first 21 subjects treated on the phase II portion of the trial are described in abstract 4012.

The one year leukaemia free survival for the subjects evaluated is 76%, however, we continue to see late relapses including CD19 positive relapses at 22 and 27 months as well as CD19 negative relapse at 37 and 41 months from CAR T-cell infusion. Therefore, we aimed to evaluate the role of bone marrow transplant in maintaining leukaemia free survival and overall survival for subjects with sustained leukemic remission for greater than 63 days following CD19 CAR T-cell therapy. We retrospectively analysed 50 subjects, 32 were treated on the phase I dose finding portion of the trial, the remaining 18 were treated on the initial phase II cohort. We excluded subjects who did not have an opportunity to undergo transplant and this included four subjects that did not respond to their CAR T-cells, nine that had an early relapse prior to day 63 and one subject that died from toxicity. We compared leukaemia free survival and overall survival between subjects with regards to the receipt of bone marrow transplant.

On looking at leukaemia free survival for the subjects that did or did not receive a transplant, transplant appears to improve leukaemia free survival. We did not observe a difference in overall survival for the two groups and we hypothesised this is due to continued responsiveness to therapy following post-CAR relapse though more follow-up is needed. We then evaluated subjects without a history of transplant. It seems much of the transplant benefit observed on the previous graph stems from the population that received their first transplant. Here the blue line represents subjects that received their first transplant following CAR therapy, the grey represents those that did not pursue a transplant. Of those subjects two relapsed, only one subject that received a transplant has relapsed. Though they are a small number of subjects, the data is suggestive of a leukaemia free survival benefit for those without a history of transplant who pursue a transplant once in remission following CAR T-cell therapy. Again, we did not observe a difference in overall survival.

Evaluating only the subjects with a history of transplant prior to CAR T-cell therapy there does not appear to be a clear benefit to pursuing a transplant following CAR T-cells. The blue line above represents subjects that received a second transplant. Of the ten, one subject died from transplant complications and four subjects have relapsed. Of the 24 subjects that did not receive a transplant 17 have relapsed. Overall survival between the two groups did not differ.

Lastly, we evaluated only the subjects with short functional CD19 CAR T-cell persistence, demonstrated by return of CD19 positive cells by day 63 following cell infusion. Comparing subjects that did and did not receive a transplant there appears to be a benefit to transplant for these subjects. As shown in grey, all subjects that did not receive a transplant ultimately experienced a relapse. Of the subjects that received a transplant shown in blue only two have relapsed. One subject died due to transplant complications following their second transplant. Again, here overall survival was not statistically different.
In conclusion, despite initial remissions late leukaemia relapse remains a barrier to long-term efficacy following CAR T-cell therapy for B-cell leukaemia. Patients without a history of transplant who achieve a remission following CD19 CAR T-cell therapy may benefit from transplant. The role of transplant following CD19 CAR therapy for patients that have a history of transplant is unclear and larger studies are needed. Transplant may abrogate the increased risk of relapse due to early loss of the CD19 CAR T-cell persistence and overall survival differences were not observed, perhaps due to response to salvage therapy though longer follow-up is needed.