Meeting NewsPerspective

Consolidative transplant after CAR T-cell therapy may benefit certain patients with acute lymphoblastic leukemia

SAN DIEGO — Consolidative hematopoietic stem cell transplant after CD19-directed chimeric antigen receptor T-cell therapy prolonged leukemia-free survival for certain pediatric and young adult patients with relapsed or refractory CD19-positive acute lymphoblastic leukemia, according to results of the PLAT-02 trial presented at ASH Annual Meeting and Exposition.

Patients who attained complete remission after CAR T-cell therapy but remained at risk for relapse with a short term B-cell aplasia derived particular benefit.

However, investigators observed no significant difference in OS between patients who underwent consolidative HSCT and those who did not. This could be due to response to salvage therapy, according to researcher Corinne Summers, MD, principal investigator at Ben Towne Center for Childhood Cancer Research at Seattle Children’s Research Institute, research associate at Fred Hutchinson Cancer Research Center and acting instructor at University of Washington.

“Longer-term follow-up is needed, and I suspect that we may see a spread from those two lines eventually,” Summers told HemOnc Today. “I’m happy that a lot of these patients who relapse after CAR T-cell therapy are salvageable with other therapies, but these are still very high-risk patients and we just need more time and more subjects under our belt.”

CD19-directed CAR T-cell therapy has induced robust responses among patients with relapsed or refractory CD19-positive ALL.

In a phase 1 trial, 93% of patients achieved minimal residual disease-negative complete remission after infusion with SCRI-CAR19v1, a CD19-specific CAR T-cell therapy developed at Seattle Children’s Research Institute.

However, approximately half of patients who achieve remission experience recurrence, and the role of HSCT after CD19 CAR T-cell therapy remains controversial.

The institutional recommendation at Seattle Cancer Care Alliance suggests patients with relapsed or refractory disease who have no history of allogeneic HSCT undergo transplant if they achieve remission after SCRI-CAR19v1 infusion.

The institutional recommendation also suggests HSCT for patients who have a short duration of persistence of SCRI-CAR19v1 in vivo regardless of whether they underwent prior HSCT.

At ASH, Summers presented leukemia-free survival data for patients who achieved remission after SCRI-CAR19v1 infusion and proceeded to HSCT.

The retrospective analysis included 50 patients enrolled on the phase 1/phase 2 PLAT-02 trial. Eligibility criteria included age older than 12 months up to 27 years; relapsed or refractory CD19-poisitive B-ALL, no active graft-versus-host disease, and absolute lymphocyte count of at least 100/µl.

Of these 50 patients 32 were included in the phase 1 dose-finding segment of the study. The other 18 were treated on the phase 2 portion at a dose of 1 x 106 cells/kg.

All patients were followed for at least 1 year. Thirty-three (66%) had undergone at least one prior HSCT.

Objectives included evaluation of the role of allogeneic HSCT for maintaining leukemia-free survival and OS for patients who had sustained leukemic remission for more than 63 days after CD19 CAR T-cell therapy.

Results showed patients who underwent HSCT after CAR T-cell therapy infusion achieved longer leukemia-free survival; however, the difference did not reach statistical significance. Investigators observed no OS difference between groups.

Researchers also observed a trend toward improved leukemia-free survival among patients who underwent first HSCT after CAR T-cell therapy infusion but, again, the difference did not reach statistical significance.

Of the 17 patients who had no HSCT history, three did not undergo HSCT after CAR T-cell therapy. One relapsed at 6 months with CD19-positive disease, one relapsed at 7 months with CD19-negative disease, and one remained in remission at 28 months.

Two of the 14 patients who underwent first HSCT after SCRI-CAR19v1 infusion relapsed after transplant. One of those had minimal residual disease detected by flow cytometry at the time of transplant and the other developed CD19-negative disease.

Among the 33 patients who had a history of HSCT, 10 underwent second HSCT after CAR T-cell therapy infusion. Five remained in remission at data cutoff. Eight of the 23 patients who did not undergo second HSCT remained in remission.

Prior results revealed patients with a short duration of B-cell aplasia within 63 days of SCRI-CAR19v1 infusion demonstrated increased relapse risk.

Long-term follow-up showed patients with short duration of B-cell aplasia who achieved complete remission and did not relapse prior to day 63 derived clear leukemia-free survival benefit from consolidative HSCT (P = 0.007).

Fifteen patients had short duration of B-cell aplasia. All six who did not undergo HSCT developed disease recurrence; these included five with CD19-positive disease and one with CD19-negative disease.

Nine patients with short duration of B-cell aplasia underwent HSCT. One died of treatment-related causes. Two others — one of whom was minimal residual disease positive prior to HSCT — relapsed after transplant.

All events among patients who underwent consolidative HSCT occurred by 20 months after CAR T-cell therapy infusion.

Late relapses continue to be observed among patients who did not proceed to HSCT. Three relapses occurred after 2 years. These included one case of CD19-positive disease at 27 months, one patient with lineage switch AML at 38 months, and one who developed CD19-negative disease at 41 months.

More research is necessary to understand the continued long-term risk for relapse after CD19-directed CAR T-cell therapy, as well as the potential role and timing for consolidative HSCT for patients who underwent prior HSCT, Summers and colleagues wrote.

“The benefit of second HSCT following CD19 CAR T-cell therapy is unclear and may be restricted to those [who] have short functional persistence of SCRI-CAR19v1,” researchers wrote. “Late relapses after SCRI-CAR19v1 have only occurred [among] those without consolidative HSCT, but longer follow-up is needed to confirm these findings.” – by Mark Leiser

Reference:

Summers C, et al. Abstract 967. Presented at: ASH Annual Meeting and Exposition; Dec. 1-4, 2018; San Diego.

Disclosure: Summers reports no relevant financial disclosures. One other author reports research funding from, consultant roles with and patents/royalties with Juno Therapeutics.

SAN DIEGO — Consolidative hematopoietic stem cell transplant after CD19-directed chimeric antigen receptor T-cell therapy prolonged leukemia-free survival for certain pediatric and young adult patients with relapsed or refractory CD19-positive acute lymphoblastic leukemia, according to results of the PLAT-02 trial presented at ASH Annual Meeting and Exposition.

Patients who attained complete remission after CAR T-cell therapy but remained at risk for relapse with a short term B-cell aplasia derived particular benefit.

However, investigators observed no significant difference in OS between patients who underwent consolidative HSCT and those who did not. This could be due to response to salvage therapy, according to researcher Corinne Summers, MD, principal investigator at Ben Towne Center for Childhood Cancer Research at Seattle Children’s Research Institute, research associate at Fred Hutchinson Cancer Research Center and acting instructor at University of Washington.

“Longer-term follow-up is needed, and I suspect that we may see a spread from those two lines eventually,” Summers told HemOnc Today. “I’m happy that a lot of these patients who relapse after CAR T-cell therapy are salvageable with other therapies, but these are still very high-risk patients and we just need more time and more subjects under our belt.”

CD19-directed CAR T-cell therapy has induced robust responses among patients with relapsed or refractory CD19-positive ALL.

In a phase 1 trial, 93% of patients achieved minimal residual disease-negative complete remission after infusion with SCRI-CAR19v1, a CD19-specific CAR T-cell therapy developed at Seattle Children’s Research Institute.

However, approximately half of patients who achieve remission experience recurrence, and the role of HSCT after CD19 CAR T-cell therapy remains controversial.

The institutional recommendation at Seattle Cancer Care Alliance suggests patients with relapsed or refractory disease who have no history of allogeneic HSCT undergo transplant if they achieve remission after SCRI-CAR19v1 infusion.

The institutional recommendation also suggests HSCT for patients who have a short duration of persistence of SCRI-CAR19v1 in vivo regardless of whether they underwent prior HSCT.

At ASH, Summers presented leukemia-free survival data for patients who achieved remission after SCRI-CAR19v1 infusion and proceeded to HSCT.

The retrospective analysis included 50 patients enrolled on the phase 1/phase 2 PLAT-02 trial. Eligibility criteria included age older than 12 months up to 27 years; relapsed or refractory CD19-poisitive B-ALL, no active graft-versus-host disease, and absolute lymphocyte count of at least 100/µl.

Of these 50 patients 32 were included in the phase 1 dose-finding segment of the study. The other 18 were treated on the phase 2 portion at a dose of 1 x 106 cells/kg.

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All patients were followed for at least 1 year. Thirty-three (66%) had undergone at least one prior HSCT.

Objectives included evaluation of the role of allogeneic HSCT for maintaining leukemia-free survival and OS for patients who had sustained leukemic remission for more than 63 days after CD19 CAR T-cell therapy.

Results showed patients who underwent HSCT after CAR T-cell therapy infusion achieved longer leukemia-free survival; however, the difference did not reach statistical significance. Investigators observed no OS difference between groups.

Researchers also observed a trend toward improved leukemia-free survival among patients who underwent first HSCT after CAR T-cell therapy infusion but, again, the difference did not reach statistical significance.

Of the 17 patients who had no HSCT history, three did not undergo HSCT after CAR T-cell therapy. One relapsed at 6 months with CD19-positive disease, one relapsed at 7 months with CD19-negative disease, and one remained in remission at 28 months.

Two of the 14 patients who underwent first HSCT after SCRI-CAR19v1 infusion relapsed after transplant. One of those had minimal residual disease detected by flow cytometry at the time of transplant and the other developed CD19-negative disease.

Among the 33 patients who had a history of HSCT, 10 underwent second HSCT after CAR T-cell therapy infusion. Five remained in remission at data cutoff. Eight of the 23 patients who did not undergo second HSCT remained in remission.

Prior results revealed patients with a short duration of B-cell aplasia within 63 days of SCRI-CAR19v1 infusion demonstrated increased relapse risk.

Long-term follow-up showed patients with short duration of B-cell aplasia who achieved complete remission and did not relapse prior to day 63 derived clear leukemia-free survival benefit from consolidative HSCT (P = 0.007).

Fifteen patients had short duration of B-cell aplasia. All six who did not undergo HSCT developed disease recurrence; these included five with CD19-positive disease and one with CD19-negative disease.

Nine patients with short duration of B-cell aplasia underwent HSCT. One died of treatment-related causes. Two others — one of whom was minimal residual disease positive prior to HSCT — relapsed after transplant.

All events among patients who underwent consolidative HSCT occurred by 20 months after CAR T-cell therapy infusion.

Late relapses continue to be observed among patients who did not proceed to HSCT. Three relapses occurred after 2 years. These included one case of CD19-positive disease at 27 months, one patient with lineage switch AML at 38 months, and one who developed CD19-negative disease at 41 months.

PAGE BREAK

More research is necessary to understand the continued long-term risk for relapse after CD19-directed CAR T-cell therapy, as well as the potential role and timing for consolidative HSCT for patients who underwent prior HSCT, Summers and colleagues wrote.

“The benefit of second HSCT following CD19 CAR T-cell therapy is unclear and may be restricted to those [who] have short functional persistence of SCRI-CAR19v1,” researchers wrote. “Late relapses after SCRI-CAR19v1 have only occurred [among] those without consolidative HSCT, but longer follow-up is needed to confirm these findings.” – by Mark Leiser

Reference:

Summers C, et al. Abstract 967. Presented at: ASH Annual Meeting and Exposition; Dec. 1-4, 2018; San Diego.

Disclosure: Summers reports no relevant financial disclosures. One other author reports research funding from, consultant roles with and patents/royalties with Juno Therapeutics.

    Perspective

    There are limited options for patients who have refractory acute lymphocytic leukemia. Many times, allogeneic stem cell transplant is the only potential curative treatment for these patients, but outcomes often are still very poor. If conventional chemotherapy is used to try to get patients into remission, but they are not in remission when they go for allogeneic transplant, most patients will fail.

    That’s why there is so much excitement surrounding CAR T-cell therapy. There is a very high rate of response and favorable results regarding minimal residual disease, which predict improved outcome.

    I was very hopeful when I saw the high rate of remission, because that is the first step toward cure. But then people started relapsing, and also some of the T cells are not persistent.

    When you look at this abstract and long-term follow-up for the CAR T, there is no plateau. They are continually relapsing. We don’t know the exact reason for that yet, but it may be related to the disappearance of the CAR T cells. When a patient gets an allogeneic bone marrow transplant when they get into remission, they have a much longer leukemia-free survival.

    It could be that outcomes for patients who achieve complete remission prior to transplant are always excellent. Or, because the graft-versus-leukemia effect with transplant sometimes takes too long to develop, maybe they do much better by getting them into remission with CAR T-cell therapy.

    This is not a randomized study but, by looking at the survival curves, it appears there is a very promising trend that suggests it make sense to get them into remission and then consolidate them with an allogeneic transplant.

    Of course, financial toxicity has to be a consideration. Allogeneic transplant is costly and, when you add CAR T-cell therapy, it becomes extremely expensive. This study had a small number of patients, but these are long-term follow-up data, and they show CAR T-cell therapy plus allogeneic transplant can lead to a potential cure. Can you really put a dollar figure on how much that is worth?

    With such a small number of patients, it is difficult to demonstrate an OS benefit, but the goal of therapy is cure. In that context, leukemia-free survival is very important. At the end of 5 years, maybe the same number of patients in each group are alive, but the ones who went on to transplant don’t have any disease and don’t need further treatment. Which one is better?


    • Henry Chi Hang Fung, MD, FACP, FRCPE
    • Fox Chase Cancer Center

    Disclosures: Fung reports no relevant financial disclosures.

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