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. Author manuscript; available in PMC: 2020 Nov 10.
Published in final edited form as: Bone Marrow Transplant. 2020 May 10;55(11):2160–2169. doi: 10.1038/s41409-020-0926-1

Low Toxicity and Favorable Overall Survival in Relapsed/Refractory B-ALL following CAR T cells and CD34-selected T Cell Depleted Allogeneic Hematopoietic Cell Transplant.

Vanessa A Fabrizio 1,2, Nancy A Kernan 1,2,3, Farid Boulad 1,2,3, Maria Cancio 1,2, Jennifer Allen 1, Meghan Higman 4, Steven P Margossian 5,6, Audrey Mauguen 7, Susan Prockop 1,2, Andromachi Scaradavou 1,2, Niketa Shah 8, Barbara Spitzer 1,2, Elliot Stieglitz 9, Nicholas Yeager 10, Richard J O’Reilly 1,2,3, Renier J Brentjens 3,11, Jaap Jan Boelens 1, Kevin J Curran 1,2,3
PMCID: PMC7606268  NIHMSID: NIHMS1587859  PMID: 32390002

Abstract

To define the tolerability and outcome of allogeneic hematopoietic stem cell transplant (allo-HSCT) following CAR T cell therapy, we retrospectively reviewed pediatric/young adult patients with relapsed/refractory B-ALL who underwent this treatment. Fifteen patients (median age 13 years; range 1–20 years) with a median potential follow up of 39 months demonstrated 24-month cumulative incidence of relapse, cumulative incidence of TRM, and OS of 16% (95% CI: 0–37%), 20% (95% CI: 0–40%), and 80% (95% CI: 60–100%), respectively. Severe toxicity following CAR T cells did not impact OS (p=0.27) while greater time from CAR T cells to allo-HSCT (>80 days) was associated with a decrease in OS. In comparing CD34-selected T cell depleted (TCD; n=9) versus unmodified (n=6) allo-HSCT, the cumulative incidence of relapse, TRM, and OS at 24-months was 22% (95% CI: 0–49%) vs 0% (p=0.14), 0% vs. 50% [95% CI: 10–90%] (p = 0.02) and 100% vs. 50% [95% CI: 10–90%] (p=0.02). In this small cohort of patients, CAR T cells followed by a CD34-selected TCD allo-HSCT appears to result in less TRM and favorable OS when compared to unmodified allo-HSCT. There was no evidence that disease control was impacted by the type of consolidative allo-HSCT, which demonstrates the feasibility of this approach.

INTRODUCTION

Acute lymphoblastic leukemia (ALL) is the most common malignancy occurring in children, and survival with risk-stratified therapy for B-cell ALL (B-ALL) approaches ≥90%.1–3 However, for pediatric/young adult patients with relapsed or refractory (R/R) disease the prognosis remains dismal.4–6 Traditionally patients with R/R disease have required allogeneic hematopoietic stem cell transplantation (allo-HSCT) for cure. The necessity of achieving minimal residual disease negative complete response (MRD-negative/CR) prior to allo-HSCT has precluded a large number of patients with R/R B-ALL from undergoing allo-HSCT.7–9 Several groups initiated investigation of CD19-specific CAR T cells as a potential therapeutic option for patients with R/R B-ALL.10–17 This led to the approval by the Food and Drug Administration of CD19-specific CAR T cells for R/R B-ALL in patients <26 years old.10–16 Despite this success, the incidence of relapse following treatment with CAR T cells in all patients with R/R B-ALL is unknown and has been reported to exceed 50% in some series, demonstrating a need to improve therapy.11–13, 16

The tolerability and outcome of allo-HSCT following CAR T cell therapy in pediatric/young adult patients is undefined and the use of allo-HSCT as consolidative therapy may reduce the incidence of disease relapse and improve overall survival (OS). Reported outcomes for adult B-ALL patients (age 26–74 years) who underwent allo-HSCT following CAR T cell therapy failed to demonstrate superior results as compared to patients who received CAR T cells alone.16 Additionally, in a cohort of adult patients with B-ALL, longer duration between CAR T cell therapy and allo-HSCT (≥80 days) was associated with higher risk of death and non-relapse mortality.18 Herein we report the results of a cohort of pediatric and young adult patients with B-ALL who received CAR T cells followed by allo-HSCT and describe that allo-HSCT as consolidative therapy following CAR T cells is well tolerated and CD34-selected T cell depleted (TCD) allo-HSCT has a low incidence of toxicity.

SUBJECTS AND METHODS

Study Design

We conducted a retrospective analysis of pediatric and young adult patients with B-ALL who received CAR T cells followed by an allo-HSCT. Patients received CAR T cells on an investigator-initiated protocol NCT01860937 or experimental CAR T cells at referring institutions. Allo-HSCT occurred at both our institution and five collaborating institutions. Only patients who achieved MRD-negative/CR proceeded to allo-HSCT based on treating physician preference and institutional guidelines. Timing, preperative regimen, and graft manipulation of allo-HSCT were determined by the treating physician. Data was captured as part of an IRB approved protocol (NCT01860937) or retrospective waiver for research. Informed consent was obtained from all subjects taking part in the IRB approved protocol (NCT01860937).

Outcomes of Interest

The main outcomes of interest were OS, transplant-related mortality (TRM), and relapse. Other outcomes of interest were neutrophil engraftment, platelet engraftment, occurrence of graft vs host disease (GVHD), occurrence of veno-occlusive disease (VOD), CD19-positive B cell recovery and donor chimerism. Relapse was defined as any (medullary or extramedullary) evidence of hematologic, cytogenetic, and/or molecular recurrence of primary disease. Late relapse was defined as relapse ≥12 months after allo-HSCT. Neutrophil engraftment was defined as the first of 3 consecutive days of an absolute neutrophil count >0.5 ×109/L. Platelet engraftment was defined as a platelet count of >20 ×109/L for 7 days without transfusion. GVHD was diagnosed and scored based on the Center for International Blood and Marrow Transplant Research criteria for acute GVHD (aGVHD)19 and National Institute of Health consensus criteria for chronic GVHD (cGVHD).20 VOD was defined according to the modified Seattle criteria.21 Regimen-related toxicities were graded according to the standard National Cancer Institute Common Terminology Criteria for Adverse Events (CTCAE) version 5.0. CD19-positive B cell recovery was defined as any detectable CD19-positive B cells (>0 cell/mcL) on a peripheral blood lymphocyte flow cytometry panel. Chimerism was obtained on bone marrow samples (bulk population short tandem repeat (STR) analysis) and peripheral blood (American Red Cross (ARC), lineage specific donor chimerism) and was considered all donor if ≥95% donor chimerism was reported in the bulk population (bone marrow sample) or 100% was reported in the myeloid population (peripheral blood sample).

Statistical Analysis

For all analyses, transplantation date was considered time 0, with a data cutoff of Nov 1, 2019. The median potential follow-up was calculated using the reverse Kaplan-Meier method. OS was defined as the time from transplant to death from all causes. Patients alive were censored at their last follow-up date. Time-to-relapse was defined as the time from the date of transplantation to the date of disease relapse. Patients alive without disease relapse were censored at their date of last follow-up and deaths without disease relapse were considered as competing events. Finally, TRM is defined as the time from transplant to death related to transplant. Kaplan-Meier analysis was used to estimate OS while an Aalen-Johansen estimator was used for the cumulative incidence of relapse and TRM. A comparative analysis was performed between CD34-selected TCD versus unmodified allo-HSCT on fifteen patients. Differences in survival endpoints between groups was tested using a log-rank test or Gray’s test for cumulative incidences.

RESULTS

Patient Characteristics

Between February 3, 2014 and June 8, 2018 fifteen pediatric/young adult patients with R/R B-ALL were treated with CAR T cells followed by an allo-HSCT. All fifteen patients received CD19-specific CAR T cells including fourteen who received 19–28z CAR T cell (NCT01860937) and one patient who received 19-BBz CAR T cells (NCT03792633). Baseline characteristics and toxicity following CAR T cell therapy are shown in Table 1.

Table 1:

Characteristics all Entire Cohort, CD34-Selected TCD Cohort, and Unmodified Cohort

CAR + HSCT Entire Cohort N=15 CAR + CD34-Selected HSCT Cohort N=9 CAR + Unmodified HSCT Cohort N=6 p-value*
Median Age (range, years) 13 (1–20) 13 (1–20) 12.5 (4–20) 0.81
Median time from CAR T cell therapy to allo-HSCT (range, days) 57 (30–135) 46 (30–135) 65 (55–95) 0.09
Lymphodepleting regimen pre-CAR T cell therapy
 Cyclophosphamide/Fludarabine
 Cyclophosphamide
6
9
4
5
2
4		 >0.99
CRS grade
 0
 1
 2
 3
 4
2
6
5
1
1
2
4
2
0
1
0
2
3
1
0		 >0.99
(0/1/2
vs 3/4)
ICANS grade
 0
 1
 2
 3
 4
2
4
5
3
1
2
2
3
1
1
0
2
2
2
0		 >0.99
(0/1/2
vs 3/4)
Disease Status
 CR1
 CR2
 CR3
 CR4
6
5
3
1
5
2
2
0
1
3
1
1		 0.29
(CR1 vs ≥CR2)
Conditioning Regimen
 TBI-based
  1500 cGy
  1200–1440 cGy
  unknown
 Chemotherapy only
  clo/mel/thio**
  flu/mel/thio***
12
8
3
1
3
2
1
7
7
0
0
2
2
0
5
1
3
1
1
0
1		 >0.99
HLA
 Matched
 Mismatched
 Related
 Unrelated
10
5
8
7
6
3
4
5
4
2
4
2
>0.99

0.61
Graft Source
 BM
 PBSC
7
8
1
8
6
0		 n/a
GVHD prophylaxis
 CD34+ selected
 CNI plus MTX
 CNI plus MMF
 Post HSCT Cyclophosphamide
9
4
1
1
9
0
0
0
0
4
1
1		 n/a
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CAR, chimeric antigen receptor; HSCT, hematopoietic stem cell transplantation; CRS, cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome; CR, complete remission; TBI, total body irradiation; BM, bone marrow; PBSC, peripheral blood stem cell; GVHD, graft-vs-host disease; CNI, calcineurin inhibitor; MTX, methotrexate; n/a, not applicable for statistical analysis because graft source and GVHD prophylaxis is dependent on the graft manipulation cohort.

*

p-values from Mann-Whitney-Wilcoxon rank test or Fisher’s exact test.

**

clofarabine (150 mg/m2), melphalan (140 mg/m2), and thiotepa (10mg/kg).

***

fludarabine (120 mg/m2), melphalan (140 mg/m2), and thiotepa (10 mg/kg).

All patients received lymphodepleting chemotherapy prior to CAR T cell therapy including: cyclophosphamide (3000 mg/m2) and fludarabine (75 mg/m2) (n=5), cyclophosphamide (500 mg/m2) and fludarabine (120 mg/m2) (n=1), cyclophosphamide (3000 mg/m2) alone (n=8), and cyclophosphamide (750 mg/m2) alone (n=1). Lymphodepleting chemotherapy regimens were determined based on CAR specific protocol guidelines and have been previously described.15 Cytokine release syndrome (CRS) and severe CRS were observed in 87% (13/15 patients) and 13% (2/15 patients) respectively. Immune effector cell-associated neurotoxicity syndrome (ICANS) and severe ICANS were observed in 87% (13/15 patients) and 27% (4/15 patients). Severe toxicity (grade 3/4 CRS or ICANS) following CAR T cell therapy occurred in 27% (4/15 patients). Eleven patients underwent allo-HSCT at MSKCC and four were transplanted in one of the four referring institutions after receiving CAR T cells.

The median age at time of allo-HSCT was 13 years (range 1–20 years). All patients achieved MRD-negative/CR confirmed by flow cytometry following CAR T cells and prior to allo-HSCT. The median time from last MRD testing prior to the start of conditioning was 14 days (range 6–53). The median time from CAR T cell infusion to allo-HSCT was 57 days (range 30 –135). Median time from CAR T cell infusion to allo-HSCT in patients with severe toxicity (n=4) vs without severe toxicity (n=11) was 56 days (range 39–65) vs 57 days (range 30–135) respectively (p=0.56). Two patients had prior allo-HSCT before CAR T cell therapy and subsequently underwent a second allo-HSCT at 24 (CD34-selected TCD cohort) and 39 months (unmodified cohort) from the first allo-HSCT. Conditioning regimens and allo-HSCT graft source/manipulation was determined by each transplant center. Conditioning regimens were myeloablative (total body irradiation (TBI)-based n=12 or chemotherapy only n=3). Individual characteristics for each patient are listed in Table 2.

Table 2:

Individual Characteristics of Patients Who Received allo-HSCT after CAR T cells

Age at HSCT Prior allo-HSCT Disease status Conditioning Regimen Time from CAR T cells to allo-HSCT Graft Source Graft manipulation Donor GVHD ppx Neutrophil engraftment Platelet engraftment Relapse Cause of Death Transplant Complications
1 13 no CR2 TBI/thio/cy 39 BM CD34+ Unrelated 9/10 TCD 14 215 No NA aGVHD
(grade 2)
2 16 yes CR3 TBI/thio/cy 57 PBSC CD34+ Related 10/10 TCD 11 16 Yes NA None
3 12 no CR2 TBI/cy 57 BM Unmodified Related Tacro/MMF 16 26 No NA aGVHD (grade 2), cGVHD (*)
4 1 no CR1 Clo/mel/thio 30 PBSC CD34+ Unrelated 9/10 TCD 12 34 No NA None
5 4 no CR1 TBI/thio/cy 46 PBSC CD34+ Unrelated 9/10 TCD 15 217 No NA cGVHD
(score 3)
6 11 no CR1 TBI/thio/cy 57 PBSC CD34+ Unrelated 10/10 TCD 11 34 No NA cGVHD
(score 1)
7 4 no CR2 TBI/thio/cy 55 BM Unmodified Related 10/10 Tacro/MTX 13 32 No NA None
8 8 no CR2 TBI/thio/cy 66 BM Unmodified Related 10/10 Tacro/MTX 13 30 No NA None
9 20 no CR3 TBI/cy 81 BM Unmodified Unrelated 10/10 CSA/MTX 23 265 No GVHD aGVHD (grade 3), cGVHD (score 3)
10 5 no CR1 TBI/thio/cy 44 PBSC CD34+ Unrelated 10/10 TCD 11 16 Yes NA None
11 13 no CR1 TBI/flu/cy 64 BM Unmodified Related haplo Post-cy
Tacro/MMF		 29 NA No VOD, MSOF aGVHD (grade 4), VOD
12 15 no CR2 Clo/mel/thio 45 PBSC CD34+ Related 10/10 TCD 11 17 No NA None
13 20 no CR1 TBI/thio/cy 135 PBSC CD34+ Related 10/10 TCD 9 17 Yes NA aGVHD
(grade 2)
14 18 yes CR4 Flu/mel/thio 95 BM Unmodified Unrelated 10/10 Tacro/MTX 22 NA No VOD, MSOF VOD
15 15 no CR3 TBI/thio/cy 65 PBSC CD34+ Related 10/10 TCD 10 26 No NA None
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CAR, chimeric antigen receptor; allo-HSCT, allogeneic hematopoietic stem cell transplantation; CR, complete remission; TBI, total body irradiation; flu, fludarabine; cy, cyclophosphamide; mel, melphalan; thio, thiotepa; clo, clofarabine; BM, bone marrow; PBSC, peripheral blood stem cell; GVHD, graft-vs-host disease; CSA, cyclosporine; MTX, methotrexate; TCD, T cell depleted; tacro, tacrolimus; MMF, mycophenolate mofetil; post cy, post-transplant cyclophosphamide; VOD, veno-occlusive disease; MSOF, multi-system organ failure; aGVHD, acute graft-vs-host disease; cGVHD, chronic graft-vs-host disease.

*

information not available

The median potential follow-up after allo-HSCT was 39 months (range 1–48 months). The median CD34+ dose was 6.9 ×106/kg (range 1.98–11.9 × 106/kg; n=15) and the median CD3+ dose was 4.7 ×103/kg (range 0.36–37,590 ×103/kg; n=14). All fifteen patients achieved neutrophil engraftment and thirteen achieved platelet engraftment. The median time to neutrophil engraftment was 13 days (range 9–29). The median time to platelet engraftment was 30 days (range 16–265).

TRM and Overall Survival

Post transplantation outcomes for all patients are shown in Table 3. The cumulative incidence of TRM for the entire cohort at 12 months and 24 months was 13% (95% CI: 0–31%) and 20% (95% CI: 0–40%) respectively (Figure 1A). Three patients in the unmodified cohort died due to TRM, including veno-occlusive disease (multi-organ failure/infection) (n=2) and GVHD (n=1). The cumulative incidence of TRM for the unmodified cohort (n=6) at 12-months and 24-months was 33% (95% CI: 0–71%) and 50% (95% CI: 10–90%) respectively, while TRM was absent in the CD34-selected TCD cohort (n=9) (p=0.02) (Figure 1B). OS at 12-months and 24-months for the entire cohort was 87% (95% CI: 69–100%) and 80% (95% CI: 60–100%) respectively (Figure 2A), with a median potential follow-up of 39 months. Three patients (unmodified cohort only) died during follow up and the 12-month and 24-month OS probabilities for the unmodified and CD34-selected TCD allo-HSCT cohorts were 67% (95% CI: 29–100%) and 50% (95% CI: 10–90%) vs 100% respectively (p=0.02, Figure 2B). The 12-month and 24-month OS in patients who underwent allo-HSCT >80 days vs ≤80 days after receiving CAR T cell therapy was 67% (95% CI: 13–100%) and 33% (95% CI: 0–87%) vs 92% (95% CI: 76–100%) and 92% (95% CI: 76–100%) respectively (Figure 3). Peripheral blood counts prior to allo-HSCT between these two groups are noted in supplementary table 1. The 12-month and 24-month OS in patients with severe toxicity following CAR T cells (grade 3 or 4 CRS or ICANS) vs without severe toxicity was 100%vs 82% (95% CI: 59–100%) and 73% (95% CI: 46–99%) respectively (p=0.27).

Table 3:

Post Transplantation Outcomes of Entire Cohort, CD34-selected Cohort, and Unmodified Cohort

CAR + HSCT Entire Cohort N=15 CAR + CD34-Selected HSCT Cohort N=9 CAR + Unmodified HSCT Cohort N=6
Relapse 3 3 0
TRM 3 0 3
GVHD
 Acute
 Chronic
5
4
2
2
3
2
Viral Infections
 Adenovirus
 CMV
 BK
 EBV
 HHV-6
 Toxoplasmosis
4
4
4
1
2
1
3
3
2
1
0
1
1
1
2
0
2
0
Bacterial Infections
 CONS
 Klebsiella
 C. Difficile
1
2
4
1
2
4
0
0
0
Death
 VOD/MSOF
 GVHD
2
1
0
0
2
1
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CAR, chimeric antigen receptor; HSCT, hematopoietic stem cell transplantation; TRM, transplant-related mortality; GVHD, graft-vs-host disease; CMV, cytomegalovirus; EBV, Epstein-Barr virus; HHV-6, human herpesvirus 6; CONS, coagulase negative staphylococci; VOD, veno-occlusive disease; MSOF, multi-system organ failure.

Figure 1.

Figure 1.

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(A) Cumulative incidence of treatment-related mortality in entire cohort and (B) cumulative incidence of treatment-related mortality in CD34-selected TCD allo-HSCT cohort and unmodified cohort (p=0.02).

Figure 2.

Figure 2.

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(A) Overall survival of entire cohort and (B) overall survival of CD34-selected TCD allo-HSCT cohort and unmodified cohort (p=0.02).

Figure 3.

Figure 3.

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Overall survival of patients who went to allo-HSCT less than 80 days from CAR T cell therapy compared to patients who went to allo-HSCT >80 days from CAR T cell therapy.

Relapse

A total of three patients relapsed following consolidative allo-HSCT, all in the CD34-selected cohort. One patient experienced an antigen negative relapse (CD19-negative n=1) following targeting of that antigen by CAR T cells. The 12-month and 24-month cumulative incidence of relapse for the entire cohort was 0% and 16% (95% CI: 0–37%) respectively. In the comparative analysis, 24-month cumulative incidence of relapse was 22% (95% CI: 0–49%) in the CD34-selected TCD allo-HSCT cohort (n=9), versus 0% in the unmodified allo-HSCT (n=6; p=0.14) respectively.

All three of the patients in the CD34-selected TCD cohort who relapsed experienced late relapse (range 16.1–24.4 months). All three patients with relapsed disease were successfully re-treated with subsequent CAR T cell therapy (CD19-specific n=2; CD22-specific n=1) (Supplementary Table 2). The time from allo-HSCT to leukapheresis ranged from 16.4 to 41.5 months and the time from relapse to infusion of second CAR T cell product ranged from 2.4 to 3.4 months. All three patients achieved MRD-negative/CR following CAR T cell infusion and remain alive without disease. Follow up since second CAR T cell infusion ranges between 1.3 and 16.6 months.

GVHD and Organ Toxicity

aGVHD occurred in 33% (5/15) of patients after allo-HSCT including two patients in the CD34-selected TCD cohort and 3 patients in the unmodified cohort (Table 2). cGVHD was seen in 27% (4/15) of patients after allo-HSCT including two patients in the CD34-selected TCD cohort and two patients in the unmodified graft cohorts (Table 2). Donor lymphocyte infusion for persistent adenovirus infection contributed to cGVHD for one patient (CD34-selected TCD cohort). Death from cGVHD (TRM) was seen in one patient with skin cGVHD and a late flair of GI cGVHD (unmodified cohort).

VOD did not occur in the CD34-selected cohort, while two patients developed VOD in the unmodified cohort. These patients with VOD ultimately died secondary to VOD and related complications, including one patient with a history of prior allo-HSCT. No post-transplant lymphoproliferative disease was seen in either cohort. No death secondary to infections occurred and pattern of infection was typical for this patient population (Table 3).

B cell Reconstitution and Donor Chimerism

Lymphocyte subset flow cytometry panel data for CD19-positive B cell recovery and chimerism data was available for eleven patients, nine in the CD34-selected cohort and two in the unmodified cohort. All measured patients had evidence of CD19-positive B cell recovery with a median time of 56 days (range 36–117 days). IVIG replacement was not standardized across the cohort, however twelve patients, nine in the CD34-selected cohort and three in the unmodified cohort, received IVIG replacement following allo-HSCT.

Chimerism data were available for eleven patients (CD34-selected cohort, n=9; unmodified cohort n=2). Bone marrow donor chimerism (median sample number 4, range 2–17)) demonstrated complete donor chimerism in 82% (9/11) of patients with median time of 51.5 days (19–158 days). Peripheral blood lineage specific donor chimerism (median number of samples 5, range 1–11) was obtained for the same eleven patients. Complete myeloid chimerism was achieved in 91% (10/11) of patients with a median time of 109.5 days (range 44–221 days). One patient (CD34-selected TCD cohort) who received a chemotherapy only conditioning regimen failed to achieve full donor chimerism (both BM/PB samples) and another patient (CD34-selected TCD cohort) is doing well with mostly host chimerism (both BM/PB samples) after losing his myeloid chimerism.

DISCUSSION

Allo-HSCT is the standard of care for patients with R/R B-ALL who achieve MRD-negative remission.22–26 The use of CAR T cells in R/R B-ALL has enabled chemotherapy refractory patients to achieve MRD-neg/CR however, the durability of this response is untested. Management of pediatric/young adult patients post CAR T cell therapy and the role of allo-HSCT as consolidative therapy is yet to be defined. This is in part due to the paucity of data on the tolerability and outcomes of patients who undergo allo-HSCT following CAR T cells. Our institution commonly offers allo-HSCT with particular focus on donor options and disease response after CAR T cell therapy (Figure 4). This report presents the outcomes of a cohort of patients who received CAR T cells followed by allo-HSCT and demonstrates the feasibility of this approach. In this small cohort of patients it appears that CD34-selected T cell depleted (TCD) allo-HSCT as compared to unmodified allo-HSCT is well tolerated with a low incidence of toxicity and favorable OS.

Figure 4.

Figure 4.

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MSKCC institutional post-CAR T cell therapy treatment algorithm

The toxicities following allo-HSCT (VOD, organ dysfunction, GVHD) and CAR T cell therapy (CRS, ICANS, HLH) have been well described.11, 13, 15, 16, 19, 20, 27, 28 Severe toxicity following CAR T cell toxicity did not impact the timing of allo-HSCT in this cohort. Timing from CAR T cell therapy to allo-HSCT does appear to impact OS in this cohort (Figure 3), however the number of patients who received an allo-HSCT >80 days (n=3) is too small to discern statistical significance. This finding is consistent with a previous findings in a cohort of adult patients with worse outcomes if allo-HSCT was >80 days from CAR T cell therapy.18 The mechanism as to why a delay in allo-HSCT impacts OS remains speculative, however any delay was not related to the severity of CAR T cell toxicity in this cohort. Of note, the toxicity profile for the majority of patients included in this cohort has been previously reported and while not impacting the timing or outcome of allo-HSCT, the incidence of ICANS is different from the commercially approved CAR T cell product (Tisagenlecleucel).15 Prospective studies are needed to define the optimal the time between allo-HSCT and CAR T cell therapy but in cases where allo-HSCT is certain there should be minimal delay.

Overall survival for the entire cohort and particularly the CD34-selected TCD cohort was favorable. This included three patients in the CD34-TCD cohort that experienced a late relapse and achieved MRD-negative CR following a second CAR T cell infusion. The ability to salvage patients with re-collection (sufficient circulating lymphocytes) and use of a different CAR T cell product demonstrates that re-treatment with immunotherapies can provide benefit for select patients. TRM was notably absent in the CD34-seleted TCD cohort following CAR T cells whereas TRM complications (VOD and GVHD) impacted survival in the unmodified cohort. Improved tolerability in the CD34-selected cohort would be futile if disease control was not equivalent.

To this point, this limited cohort demonstrates no increased risk of relapse using a TCD graft compared to an unmodified graft despite the concern of the elimination of graft vs leukemia in a TCD graft.29–32 Additionally, Shalabi et al. have previously reported CAR T cell therapy as an effective bridge to allo-HSCT with a low incidence of relapse.33 Not included in this analysis are the consequences of any financial toxicity novel immunotherapies will have within our healthcare system.34 Regardless, a significant proportion of patients will experience disease relapse following CAR T cells therapy which requires further investigation to improve consolidative therapy and durability of response 11–13, 16.

In summary, CAR T cells, when followed by allo-HSCT, appears to be a tolerable option with favorable OS for patients. This retrospective study represents a heterogeneous group of patients with diverse transplant conditioning regimens and graft source/manipulation. This data suggests further research incorporating CAR T cell persistence, timing of allo-HSCT, ongoing post CAR T cell toxicity, likelihood of antigen negative disease escape, and donor transplant specific factors including graft manipulation is required to determine the optimal strategy for these patients. Once these questions are answered, a prospective study is needed to determine if consolidation with allo-HSCT should be the standard of care after CAR T cell therapy.

Supplementary Material

1

ACKNOWLEDGEMENTS

The authors thank the patients and families who participated in this trial; Georgia Flynn, and the Cellular Therapeutic Center at MSKCC for help with this study; Joseph Olechnowicz (Editor, Department of Pediatrics, Memorial Sloan-Kettering Cancer Center), for editorial assistance; and Audrey Mauguen (PhD) for biostatistical support.

This work was supported by the William Lawrence and Blanche Hughes Foundation (K.J.C.), St. Baldrick’s Foundation provided an A.V.M. Traders Scholar Award (K.J.C.), and National Institutes of Health (NIH), National Cancer Institute (NCI) Cancer Center Support Grant (P30CA008748).

Conflict of interest statement: KJC has received research support from Juno Therapeutics and Novartis; has consulted, participated in advisory boards, or participated in educational seminars for Juno Therapeutics, Novartis, and Mesoblast; SM has participated in advisory boards for Novartis; RJB is a co-founder and received royalties for Juno Therapeutics. The remaining authors declare no competing financial interests.

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