allo-SCT and CAR-T in Lymphoid Neoplasms: History
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Contributor:
Massimo Martino
,
Filippo Antonio Canale
,
Virginia Naso
,
Gaetana Porto
,
Demetrio Gerace
,
Alessandro Allegra

Allogeneic stem cell transplantation (allo-SCT) represented the first immunotherapy to treat hematologic malignancies: it has been considered as a cure for the disease and never as an approach to extend the life of patients. The success of allo-SCT derives both from the ability to treat patients with intensive chemoradiotherapy and from the potent graft-versus-leukemia effects mediated by donor immunity. The treatment of hematologic malignancies, particularly acute lymphoblastic leukemia and certain forms of lymphomas, has been revolutionized by the commercial introduction of genetically modified autologous T-lymphocyte therapy (CAR-T). 

  • allogeneic stem cell transplantation
  • autologous stem cell transplantation
  • CAR-T treatment

1. R/R DLBCL

allo-SCT has been considered a curative treatment option for patients with DLBCL who relapse or progress after auto-SCT [1]. A registry study reported results on 101 patients who received an allo-SCT for DLBCL between 1997 and 2006 [2]. Three-year non-relapse mortality (NRM), relapse rate (RR), progression free survival (PFS), and overall survival (OS) were 28.2%, 30.1%, 41.7%, and 53.8%, respectively. No statistically significant differences were seen between patients transplanted after a myeloablative (MAC) or a reduced-intensity conditioning (RIC), or patients transplanted from mismatched related or matched unrelated donors. A prospective randomized clinical trial compared GVHD prophylaxis including rituximab, after allo-SCT [3]. At a median follow-up of 4.0 years, no significant difference was found between patients receiving or not receiving rituximab in addition to standard GVHD prophylaxis. In all patients, the 1-year OS rate was 52%, with significant differences between patients transplanted from matched family donors or unrelated donors not receiving or receiving anti-thymocyte globulin for GVHD prophylaxis, where the OS was 64.7%.
A study evaluated 121 patients with R/R B cell lymphomas who underwent an allo-SCT after an RIC regimen [4]. All the patients had failed a previous auto-SCT. At a median follow-up of 41 months, the 3-year PFS and OS were 50% and 61%, respectively. Long-term outcome was also evaluated with the composite endpoint of GVHD-free and relapse-free survival (GRFS). The 1-year and 3-year GVHD-free and GRFS were 40% and 34%, respectively. The conclusions were that allo-SCT could cure a fraction of these patients.
The Center for International Blood and Marrow Transplant Research (CIBMTR) performed a registry analysis of DLBCL patients undergoing allo-SCT after a failed prior auto-SCT [5]. The results were as follows: NRM was 23% and 30% at 1 and 3 years respectively; MAC provided no benefit; and GVHD increased the risk of non-relapse and overall mortality without reducing the risk of relapse/progression. The authors indicated a prognostic model to predict PFS after allo-SCT, with 5 points for chemoresistance, 4 points for a Karnofsky performance score <80, and 2 points for patients who went from auto-SCT to allo-SCT in less than one year. The 3-year OS was 43% in patients with 0 points (low risk), 39% in those with 2–5 points (intermediate risk), and 19% and 11% in those with 6–9 points (high risk), and 11 points (very high risk), respectively.
These data show that allo-SCT is a valid alternative to any other treatment for patients relapsing after failure from auto-SCT, and allo-SCT should be considered for patients with early relapse after first-line chemotherapy [1].
Auto-SCT remains the standard of care in a late chemosensitive relapse of DLBCL [1][6]. CAR-T is currently considered the standard of care in the third line, according to clinical trial and real-world date results where axicabtagene ciloleucel, tisagenlecleucel, and lisocabtagene maraleucel have produced significant rates of overall response rate (ORR) and complete remission (CR) [7][8][9][10] (Table 1).
Table 1. Pivotal Anti-CD19 CAR T-Cell Therapy Trials: DLBCL.
JULIET ZUMA-1 TRANSCEND NHL 001
CAR T-cell agent Tisa-cel Axi-cel Liso-cel
Patient population Adults with R/R DLBCL post/ineligible for Auto-SCT Adults with R/R DLBCL Adults with R/R DLBCL
Patients apheresed/treated, n 165/111 111/101 344/269
ORR, %
CR, %		 52%
40%		 82%
54%		 73%
53%
Survival 12-mo PFS 65%
12-mo OS 49%		 PFS 5.8 mo
18-mo OS 52%		 12-mo RFS 44%
12-mo OS 58%
Legend: diffuse large B-cell lymphoma = DLBC; relapsed/refractory = R/R.
In patients who are refractory or at high risk of relapse, the debate is wide open as to whether the treatment of choice should be CAR-T. High-risk relapse of DLBCL has been defined as a remission duration of <12 months after first-line therapy [1]. The new European Society for Blood and Marrow Transplantation (EBMT) guidelines indicate CAR-T as the therapy of choice in this category of patients [1] based on the results of two recent phase III clinical studies [11][12]. Due to the unique characteristics of the study design, the chemosensitivity of the patients in the CAR-T arms was unknown. The EBMT guidelines introduced a category defined as untested relapse; for this situation, the results of CAR-T therapy have been considered superior to those of standard chemotherapy followed by auto-SCT. For patients with high-risk R/R LBCL and unknown chemosensitivity, anti-CD19 CAR-T should replace auto-SCT as the standard care. Figure 1 summarizes the inclusion of CAR-T cell therapy in the current treatment paradigms for DLBCL.
Figure 1. Fitting CAR-T Cell Therapy Into Current Treatment Paradigms in DLBCL.
The role of allo-SCT appears to be significantly reduced, at least in patients with refractory, high-risk, or relapsed disease after auto-SCT [13]. Moreover, comparing CAR-T cell therapy to allo-SCT using the CIBMTR prognostic tool, the probability of a better PFS was higher for CAR T-cell therapy [14]. A multivariate evaluation of chemoresistance before transplant and its impact on outcomes showed that patients with chemo-resistant disease had a higher risk of NRM, progression, and relapse. Patients with a Karnofsky performance status <80 and chemo-resistant condition had inferior OS outcomes.
Limited data exist to document the safety and efficacy of allo-SCT after CAR-T therapy, and most of the evidence has come from a small patient series. Zurko et al. [15] presented data for patients treated at 18 US academic medical centers. The 88 patients included in the analysis had a median age of 54. About half the patients were in CR before allo-SCT, and a fourth had partial response (PR). The median duration from CAR-T failure to allo-SCT was 8.4 months. The 1-year NRM, PFS, and OS were 22%, 45%, and 59%, respectively. By multivariate analysis, patients in CR at allo-SCT had better OS than patients in PR. The investigators found no predictors of PFS, NRM, or progression/relapse. Additionally, patients who had received fewer than two lines of therapy between CAR-T failure and allo-SCT fared better than those who received two or more intervening lines of treatment.
Based on these findings, in patients with DLBCL treated with CAR-T cells and in whom this therapy has failed, allo-SCT may be an option, at least for those who achieve a CR after CAR-T failure. The data may help inform decisions related to one of the critical challenges of CAR T-cell therapy. Although the treatment produces response rates as high as 83% in R/R LBCL [7][8][9][10], responses are durable in only 30–40% of cases and the median OS after CAR-T failure is poor [16][17].

2. MCL

The survival of patients with MCL has improved since the introduction of rituximab and other novel agents, such as BTK inhibitors, in the overall treatment landscape [18][19]. For younger MCL patients, various intensive chemotherapy regimens incorporating rituximab and high-dose cytarabine are optimal, and auto-SCT remains a highly efficacious initial therapy [20]. Unfortunately, most patients with MCL relapse even after achieving a CR to first-line therapy. In the relapsed setting, the first-line treatment of choice is usually a BTK inhibitor [19]. BTK inhibitors work very well in relapsed MCL with high response rates and good tolerability profiles. However, the length of remission for patients receiving BTK inhibitors tends to be approximately 1.5–2.0 years [21]. The available evidence does not suggest a benefit of allo-SCT in CR1, and upfront allo-SCT, outside of clinical trials, is not recommended [22] (Figure 2).
Figure 2. Fitting CAR T-Cell Therapy Into Current Treatment Paradigms in MCL.
CAR T-cell therapy could be a major breakthrough in MCL. The EMA recently approved brexucabtagene autoleucel for third-line treatment, which is a CAR T-cell therapy directed against CD19, for R/R MCL based on data from the ZUMA-2 trial [23]. The ORR was 92%, and 67% at a median 17.5-month follow-up. However, the researchers need longer follow-up to know what the longer-term efficacy is with this agent. As with all CAR T-cell therapy, brexucabtagene autoleucel is associated with the risk for cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS), so treatment with this agent is not without some risk. However, relapsed MCL has historically been a difficult disease to manage, and therefore, the researchers can accept a certain amount of toxicity for an agent with good efficacy.

3. The Rationale for Clinical Development of CAR T-Cell Therapy in ALL

Most adults with ALL who achieve CR will relapse, and the prognosis of these patients is poor [24]. However, treatment options for patients with R/R ALL are rapidly expanding with the advent of promising immunotherapy. Inotuzomab ozogamicin is a humanized monoclonal antibody targeting CD22 that is conjugated to calicheamicin, a cytotoxic compound that binds to the minor groove of DNA and causes double-stranded DNA breaks. Inotuzumab has been studied for the treatment of ALL in R/R disease in the upfront setting [25]. The drug is well tolerated with easy administration and a CR rate of 80%. A potential disadvantage is the increased risk of sinusoidal obstruction syndrome (VOD) in prior allo-SCT and liver disease, and that most data are from the s1/2 setting only.
Blinatumomab is a bispecific T cell-engaging antibody drug that redirects cytotoxic T cells to cells expressing CD19 and is approved for R/R ALL [26]. The antibody itself contains the variable domains of CD19 and CD3, which are linked together. Once bound to CD19 as part of the antibody complex, cytotoxic T cells induce cell death via the perforin system. Blinatumomab is manageable, with reversible AEs, and a CR rate between 40% and 50%; moreover, it is highly effective in a minimal residual disease (MRD) + setting, with a CR rate of 80%. However, the drug is less effective with high bone marrow blasts, and the need for a continuous infusion/pump is a disadvantage. Despite blinatumomab and inotuzumab treatment, the median OS for R/R B-ALL remains low at 7–8 months [27][28].
Anti-CD19 CAR-T cell therapy is approved for patients up to 25 years of age based on the ELIANA study [29] and, more recently, for adult ALL based on the ZUMA-3 trial [30].
ELIANA was an international, open-label, single-arm phase II study that enrolled 92 patients aged 3–21 years with R/R B-cell ALL. After tisagenlecleucel infusion, ORR at 3 months was 81%, and EFS and OS at 6 and 12 months were 73%, 50%, 90%, and 76%, respectively.
Zuma-3 was a multicenter, open-label phase I/II trial that enrolled adult patients with R/R B-cell ALL. After a lymphodepletion with fludarabine + cyclophosphamide, 55 patients received Brexucabtagene autoleucel at a dose of 1 × 106 cells/kg. The ORR was 70.9% and the CR rate was 56.4%. At the median follow-up of 16.4 months, 39 patients had CR or CR with incomplete hematological recovery. The median duration of remission, RFS and OS were 12.8, 11.6 and 18.2 months, respectively. The median OS was not reached among responders, and 38 (97%) patients had MRD negativity.
Most trials of CAR-T cells in R/R ALL demonstrate impressive response rates, with >70% of patients achieving CR regardless of cytogenetic background, prior therapies, or age [31]. Prognostic factors associated with higher remission rates and better outcomes in adult ALL include lower disease burden (assessed by bone marrow blast count), lower LDH, and higher platelet count before lymphodepletion, whereas TP53 mutations are associated with worse outcomes [32][33]. CD19 CAR T-cells can induce high CR rates, even in patients with blinatumomab/inotuzumab failure and with multiple prior treatments [31][32][33]. The potential disadvantages are the need for bridging time during cell manufacturing, CRS and ICANS. The early trials showed that a subset of patients could be cured with no additional therapy, but relapse after CD19 CAR T-cell therapy remains challenging and a clinically unmet need.
In a pediatric single-center study, patients in MRD-negative CR after CAR-T and who underwent a subsequent allo-SCT showed better EFS and OS [34]. Another single-center study in adults found no difference in outcomes for patients bridged to allo-SCT versus observation [35]. Most pediatric patients treated with tisagenlecleucel were not bridged to allo-SCT, and a subset had durable remissions that correlate with in vivo functional persistence. However, the outcomes of initial bridge to allo-SCT versus observation are unknown [29].
In Figure 3, the researchers postulate the introduction of CAR T-Cell therapy into current treatment paradigms in ALL.
Figure 3. Fitting CAR T-Cell Therapy Into Current Treatment Paradigms in ALL.

This entry is adapted from the peer-reviewed paper 10.3390/ijms24021045

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