Transplantation and Cellular Therapy 28 (2022) 1 2
Transplantation and
Cellular Therapy
journal homepage: www.tctjournal.org
The Bottom Line
Should CD19 CAR-T Cells for ALL be Followed by Allogeneic Stem Cell
Transplant?
Carlos A. Ramos
Center for Cell and Gene Therapy, Houston Methodist Hospital, Texas Children's Hospital and Baylor College of Medicine, Hematology-Oncology Section, Department of
Medicine, Baylor College of Medicine, Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, Texas, USA
T cells expressing chimeric antigen receptors (CARs) targeting
CD19 (CD19-CARTs) have shown remarkable activity in B-cell
acute lymphoblastic leukemia (B-ALL), with reported complete
remission (CR) rates ranging from 61 to 93%, even in patients
with multiply relapsed disease.1-7 This success allowed one
such product (tisagenlecleucel) to be the first CAR-T cell ther-
apy approved by the FDA for any indication (in August 2017).
A second autologous CD19-CART product approval (brexucab-
tagene autoleucel) for relapsed or refractory B-ALL has fol-
lowed. Despite these impressive CR rates, unfortunately nearly
half of patients who enter remission after CD19-CART relapse
within 12 months. In this issue of TCT, Summers et al. examine
whether these outcomes can be improved by following “suc-
cessful” CD19-CART therapy by consolidation with an alloge-
neic hematopoietic stem cell transplant (allo-HSCT).8
Previous protocols combining CD19-CART and allo-HSCT
provided conflicting results, with some studies failing to dem-
onstrate a benefit of allo-HSCT over observation, while others
hinting otherwise. Moreover, many patients who received
allo-HSCT after being treated with CD19-CARTs have lacked
systematic follow-up. The obvious concern about introducing
allo-HSCT routinely after CD19-CART therapy is that any
potential benefits may be offset by toxicities, physical, psycho-
social, and financial. Since a subset of patients entering remis-
sion after CD19-CART therapy are evidently cured,
recommendation for allo-HSCT should ideally be confined to
only the most at-risk group.
Summers et al. report the results of their early phase clini-
cal trial investigating the safety and efficacy of an autologous
CD19-CART product manufactured at the Seattle’s Children’s
Research Institute (SCRI) in the treatment of children and
young adults ( 27 years of age) with relapsed or refractory B-
cell ALL. The SCRI CD19-CAR product is transduced with a len-
tivirus encoding a CAR that contains the FMC63 scFv (the CD19
binding moiety used in the majority of CD19-CART products
tested in clinic to date) and a 4-1BB costimulatory domain;
and the CD4 and CD8 T cell components are grown and trans-
duced independently, before being combined at a 1:1 ratio
into the final product for infusion. While all subjects initially
treated on protocol had to have disease that had relapsed after
an allo-HSCT, in a later phase of the trial a cohort of patients
without previous allo-HSCT was included. Individuals who
https://doi.org/10.1016/j.jtct.2021.12.002
2666-6367/© 2019 Published by Elsevier Inc. on behalf of The American Society for Transplantation and Cellular Therapy.
were in CR (negative for measurable residual disease) after
CD19-CART administration could proceed to allo-HSCT at the
discretion of the treating physician, presumably based on their
medical fitness and donor availability, with the intensity of the
conditioning regimen also determined by the treating institu-
tion. Of the 50 evaluable patients who achieved CR, 27 under-
went allo-HSCT.
Survival analysis suggests an improvement in leukemia free
survival (LFS), but not overall survival (OS), in patients who
undergo consolidative allo-HSCT versus observation. The LFS
improvement was most evident in patients who have early
loss (within 63 days of CART infusion) of B-cell aplasia (BCA). It
should be noted that BCA has not been defined uniformly
among different protocols. In this study, the authors define it
as the presence of less than 1% of B cells in total peripheral
blood lymphocytes as assessed by flow cytometry. Notably, no
excess transplant related mortality over expected was appar-
ent after CART therapy. These findings are consistent with
those of a recent study employing CD28-containing CD19-
CARTs.9 The absence of benefit to OS could be attributable to
the short follow-up or the availability of novel therapies for
patients with disease relapsed after CART therapy.
As acknowledged by the authors, receipt of allo-HSCT
under their clinical trial was not randomized. As expected,
patients for whom allo-HSCT had not previously failed had
lower relapse risk and transplant related mortality (TRM) than
those for whom it had. Such transplant-naive patients were
both more likely to be offered it and to receive a more inten-
sive preparative regimen, which has been associated with
decreased risk of relapse compared to less intensive regi-
mens.10 Additionally, it is hard to gauge how generalizable the
results observed with this CD19-CART will be, since currently
available CD19-CART products are protean regarding binding,
co-stimulatory and structural domains, as well as manufacture
specifics;11 all these variables may influence their activity in
comparable disease settings. Furthermore, some previous
reports that contradict the current analysis5 pertain to studies
that enrolled patients with different demographics (such as
age) than those treated by Summers et al.
The above limitations notwithstanding, results from this
study suggest that (young) patients who achieve complete
remission after treatment with lymphodepleting chemotherapy
2 C.A. Ramos / Transplantation and Cellular Therapy 28 (2022) 1 2
(including fludarabine) and CD19-CARTs should be considered
for allo-HSCT, in particular when loss of functionality of the
CD19-CARTs (i.e., loss of BCA) is detected within 2 months of
treatment. Following B cell counts in the peripheral blood of
these patients during this critical period may be warranted. Fur-
ther studies would be needed to fully validate these approaches.
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