CD7 CAR-T Cell as Bridging Therapy for Successful Allogeneic Hematopoietic Stem Cell Transplantation in Relapsed/Refractory T Lymphoblastic Leukemia/Lymphoma: A Case Report and Literature Review

Introduction

T-cell acute lymphoblastic leukemia/lymphoma (T-ALL/LBL) is a highly aggressive malignancy originating from immature T cell precursors, characterized by the abnormal proliferation and infiltration of lymphocytes in the bone marrow, peripheral blood, or extramedullary sites [1].

Although the incidence in adult is relatively low, patients with relapsed / refractory (R/R) T-ALL/LBL face a dismal prognosis. Following failure of standard chemotherapy, the 5-year overall survival (OS) rate is less than 20%. Minimal residual disease (MRD) status is a critical prognostic factor in ALL. Among patients who achieve complete remission (CR) after intensive chemotherapy, persistent MRD is observed in approximately 30% to 50% of cases and is the leading determinant of relapse [2]. For patients with R/R T-ALL/LBL, salvage treatment options remain limited. Nelarabine, the approved agent for this population, yields an overall response rate (ORR) of 50% and a complete remission (CR) rate of 36% in real-world studies, with 40% of patients subsequently undergoing allogeneic hematopoietic stem cell transplantation (allo-HSCT). After transplant, the 2-year and 5-year OS rates are 46% and 38%, respectively, whereas patients who do not undergo transplantation have a dismal 5-year OS of less than 10% [3]. More recently, BCL-2 inhibitors such as venetoclax have shown promise in combination regimens, achieving MRD-negative CR in selected R/R T-ALL/LBL cases. However, despite these encouraging results, the overall response rate for R/R T-ALL/LBL patients remains suboptimal, with reported CR rates ranging from 20% to 40% in this challenging population, and many responders eventually experience relapse, underscoring the limited durability of even novel targeted combination strategies 4]. Given these limitations, CD7-targeted chimeric antigen receptor T-cell (CAR-T) therapy specifically targets T-ALL/LBL cells and is a promising therapeutic avenue. CD7 is expressed on approximately 95% of T-cell leukemias and a subset of peripheral T-cell lymphomas, establishing it as an important target for CAR-T therapy in T-ALL/LBL. Reports on donor-derived CD7 CAR-T therapy as a bridge to allo-HSCT for R/R T-ALL/LBL are scarce. We retrospectively analyzed the case of a patient with R/R T-ALL/LBL who achieved MRD negativity following donor-derived CD7 CAR-T therapy, successfully bridged to allo-HSCT, and attained sustained remission. A review of the relevant literature is also provided. We present this article in accordance with the CARE reporting checklist.

Case Report

A 51-year-old man was hospitalized in Jining No. 1 People’s Hospital on June 6, 2024, due to a right neck mass persisting for 1 month. The patient denied any significant past medical, family, or psychosocial history. No pertinent genetic history was noted. His past surgical and interventional history was noncontributory. Physical examination revealed multiple enlarged lymph nodes in the bilateral cervical, axillary, and inguinal regions, the largest measuring approximately 3 × 2 cm. An excisional biopsy of a right axillary lymph node was performed. Immunohistochemistry results were as follows: CD7(+), TDT(+); CD10(+), CD20(−), CD21(FDC+), CD23(FDC+), CD3(+), CD43(+), CD5(+), BCL-2(+), Bcl-6(−), CyclinD1(−), SOX-11(−), CD19(−), CD79a(−), LEF-1(+), CD4(−), CD8(−), CD56(−), CXCL-13(−), MPO(−), PD-1(−), granzyme B(−), TIA-1(−), CD2(partial+), CD34(partial+), CD117(−), CD30(−), ALK(−), and Ki67(~ 90%); in situ hybridization for EBER was negative. The histopathological findings were consistent with T lymphoblastic lymphoma (T-LBL). Bone marrow morphology revealed slightly decreased trilineage hematopoiesis, with immature lymphocytes accounting for 3%. Immunophenotyping by flow cytometry identified an abnormal population of precursor T lymphocytes comprising 44.57% of nucleated cells. These cells strongly expressed CD38m, CD3, cCD3, CD99, and CD7; partially expressed CD34 and CD2; weakly expressed CD10, CD5, and TDT; and were negative for CD117, CD33, CD14, CD19, CD16, CD13, CD1b, HLA-DR, CD71, CD36, CD11c, CD123, CD4, CD56, CD64, CD8, CD20, and CD1a. The immunophenotype supported a diagnosis of acute T lymphoblastic leukemia (T-ALL). Bone marrow biopsy showed approximately 50% cellularity, normal granulocyte-to-erythroid ratio, adequate megakaryocytes, increased lymphocytes, and myelofibrosis grade MF-1. Fusion gene screening was negative, and chromosomal karyotype analysis revealed no clonal abnormalities. PET-CT indicated metabolically active lymphadenopathy above and below the diaphragm, along with diffusely increased bone marrow metabolism, suggestive of lymphomatous involvement (Figure 1A). A final diagnosis of T-ALL/LBL was established.

On June 18, 2024, pre-phase therapy with the CP regimen (cyclophosphamide [CTX] 200 mg/m2and prednisone [Pre] 1 mg/kg for 5 days) was administered to reduce tumor burden. The HyperCVAD-A regimen was then initiated: CTX 200 mg/m2 every 12 hours on days 1 to 3; vincristine (VDS) 4 mg on days 4 and 11; Epirubicin (EPI) 70 mg/m2 on day 4; and dexamethasone (Dex) 40 mg on days 1 to 4 and 11 to 14. Bone marrow re-evaluation on July 21 showed trilineage hematopoiesis with immature lymphocytes at 28.0%. MRD analysis revealed 22.90% abnormal precursor T cells. On July 22, the HyperCVAD-B regimen was administered with methotrexate (MTX) 1g/m2 on day 1 and cytarabine (Ara-c) 3g/m2 every 12 hours on days 2 and 3. Bone marrow examination on August 24 demonstrated trilineage hematopoiesis with 5% immature lymphocytes; MRD decreased to 6.79%. Subsequently, the MA regimen combined with venetoclax (Ven) regimen was given: MTX 1g/m2 on day 1; Ara-c 2.5g/m2 every 12 hours on days 2 and 3; Ven 100 mg on day 1, 200 mg on day 2, and 400 mg on days 3 to 14. On September 26, bone marrow was hypercellular with trilineage hematopoiesis; MRD was 8.61%. Due to persistent MRD positivity, the regimen was adjusted on September 27 to HyperCVD combined with azacitidine (AZA) and Ven chemotherapy: CTX 200 mg/m2 every 12 hours on days 1 to 3, VDS 4 mg on days 4 and 11; Dex 40 mg on days 1 to 4 and 11 to 14, AZA 100 mg on days 4 to 10, and Ven 400 mg on days 1 to 7. Bone marrow assessment on October 30 showed trilineage hematopoiesis with 2% immature lymphocytes; MRD decreased to 4.31%. The MA plus Ven regimen was repeated. On December 4, bone marrow exhibited decreased cellularity with 1% immature lymphocytes; MRD further declined to 1.45%. On December 8, therapy was intensified to HyperCVD combined with AZA, Ven, and chidamide (Chi): CTX 200 mg/m2 every 12 hours on days 1 to 3, VDS 4 mg on days 4 and 11, Dex 40 mg on days 1 to 4 and 11 to 14, AZA 100 mg on days 4 to 10, Ven 400 mg on days 1 to 7, and Chi 10 mg orally twice weekly for 2 weeks. On January 3, 2025, bone marrow showed 1% immature lymphocytes, but MRD increased to 6.32%. Given persistent MRD positivity, the regimen was changed on January 5 to GDP combined Ven and Chi: Gemcitabine 1 g/m2 and cisplatin 75 mg/m2 on day 1, Dex 40 mg on days 1 to 4, Ven 200mg on days 1 to 7, and Chi 10 mg orally twice weekly for 2 weeks. Bone marrow biopsy on February 5 revealed active trilineage hematopoiesis; MRD decreased to 3.04%. On February 8, the GDP combined with Ven and Chi regimen was repeated. On March 9, bone marrow examination revealed occasional naive lymphocytes. MRD increased to 11.35%. The failure of multiple intensive chemotherapy regimens combined with targeted agents to achieve MRD negativity indicated a poor prognosis. Salvage therapy with CD7 CAR-T cells followed by bridging to allo-HSCT was recommended. After obtaining informed consent, a reduced-dose GDP regimen combined with Ven and Selinexor was administered for tumor reduction treatment on March 11: Gemcitabine 0.6 g and Cisplatin 50 mg on day 1, Dex 20 mg on days 1 to 4, Ven 200mg on days 1 to 5, and Selinexor 20 mg orally twice weekly for 2 weeks. Concurrently, peripheral blood mononuclear cells were collected from the patient’s son for the manufacture of donor-derived CD7 CAR-T cells. High-resolution HLA genotyping by polymerase chain reaction-sequence-based typing (PCR-SBT) revealed that the related donor (son) was a 9/10 HLA-matched donor (GVH and HVG direction) with a single allelic mismatch at HLA-B (donor B*15: 18 vs patient B*15: 01) and complete matching at HLA-A, C, DQB1, and DRB1. From March 31, an intensified lymphodepleting regimen consisting of fludarabine (30 mg/m2), CTX (300 mg/m2), and etoposide (100 mg) was administered for 5 consecutive days. The patient received infusions of donor-derived CD7 CAR-T cells (3.0 × 106/kg in total) on April 7th and 8th. On day 3 after infusion, the patient developed grade 3 cytokine release syndrome (CRS), which gradually improved after treatment with tocilizumab, Dex, and Dopamine to manage symptoms. No immune effector cell-associated neurotoxicity syndrome (ICANS) was observed. Bone marrow evaluation performed on day 15 after infusion demonstrated reduced cellularity with no evidence of abnormal blasts; MRD was negative (< 0.01%). The PET-CT reexamination on day 16 after infusion revealed decreased size and metabolic activity in the supra- and infradiaphragmatic lymph node lesions relative to previous studies, with a Deauville score of 4 (Figure 1B). Repeat bone marrow on day 39 after infusion confirmed complete morphological remission (CR) and sustained MRD negativity. No infections, clinically significant persistent cytopenias beyond the expected post-lymphodepletion nadir, or graft-versus-host disease (GVHD) were observed during the CAR-T cell treatment phase. On May 23, following myeloablative conditioning with busulfan (3.2 mg/kg/day, days -9 to -7), cyclophosphamide (40 mg/kg/day, days -6 to -5), and fludarabine (30 mg/m2/day) plus cytarabine (1 g/m2/day, both days -4 to -2), the patient underwent haploidentical related-donor hematopoietic stem cell transplantation. Graft-versus-host disease (GVHD) prophylaxis consisted of rabbit anti-human thymocyte immunoglobulin (150 mg/day, days -4 to -2), cyclosporine in combination with mycophenolate mofetil (0.5 g/day, days +1 to +30), and short-course methotrexate (26 mg on day +1 and 17 mg on days +3, +6, and +11). Neutrophil engraftment was achieved on day +14 after transplantation, whereas platelet engraftment was delayed until day +45. Bone marrow evaluation on day +26 after HSCT showed donor-derived trilineage hematopoiesis with few megakaryocytes; MRD remained negative, and donor chimerism was 93.33%. Serial monitoring of blood counts (Figure 2A, 2B) and CAR-T cell expansion (Figure 2C, 2D) was performed. All assessments at days +60, +90, +120, and +150 after transplantation indicated sustained remission. PET-CT at day +90 after HSCT demonstrated a complete metabolic response (CMR), with a Deauville score of 2 (Figure 1C). The patient tolerated the procedure well and demonstrated excellent adherence. He had no major adverse events and remains under close follow-up. The disease treatment process is shown in Figure 3.

All procedures performed in this study were in accordance with the ethical standards of the institutional and/or national research committee(s) and with the Helsinki Declaration. Written informed consent for publication of this case report was not obtained from the patient or the relatives after all possible attempts were made.

Discussion

T-ALL/LBL is a highly aggressive and heterogeneous malignancy derived from immature T-cell precursors, frequently associated with chemotherapy resistance and poor outcomes. T-ALL accounts for 20% to 30% of adult ALL, while T-LBL accounts for 3% to 4% of adult non-Hodgkin lymphomas. Currently, T-ALL and T-LBL are considered the same disease with different clinical manifestations and at different stages of progression [5]. Conventional chemotherapy forms the mainstay of initial treatment; however, sustained remission rates are low [6]. Achieving early MRD negativity is a critical prognostic factor, with recurrence rates escalating when MRD levels exceed ≥ 10−4 [7]. Allo-HSCT remains the only potentially curative treatment for R/R T-ALL/LBL, although outcomes remain suboptimal in a subset of patients; early transplantation during remission is recommended for eligible individuals with high-risk features [8,9]. For R/R T-ALL/LBL, salvage multi-agent chemotherapy offers limited benefit, underscoring the urgent need for more effective therapies [10].

Therapeutic advances for R/R T-ALL/LBL have been modest. Investigational agents include histone deacetylase (HDAC) inhibitors, EZH1/2 inhibitors, Bcl-2 inhibitors, NOTCH1 inhibitors, CD38 monoclonal antibodies, and Cladribine, yet none have yielded transformative improvements [11,12]. Inspired by the success of CAR-T therapy in B-cell malignancies, CD7-targeted CAR-T therapy has emerged as a promising strategy for T-cell malignancies, given the high prevalence of CD7 expression [13,14]. Studies have shown that CD7 CAR-T cell therapy has significant clinical advantages in the treatment of R/R T-ALL/LBL. CD7 CAR-T cells exhibit a high response rate in eliminating tumor cells, with a complete remission rate reaching 90% to 95% [15,16]. Compared to conventional chemotherapy, it offers superior efficacy and serves as an effective bridge to subsequent allo-HSCT, potentially reducing relapse risk and improving long-term survival. However, in the application of CD7 CAR-T therapy, CRS and other immune related adverse effects need to be recognized and managed promptly [17,18].

Our patient presented with widespread lymphadenopathy and high tumor burden. After initial combination chemotherapy, MRD remained > 10−4, indicating poor response to conventional agents. Subsequent regimens incorporating venetoclax, azacitidine, and chidamide-selected based on BCL-2 overexpression and epigenetic regulatory changes in T-ALL [19–26] also failed to achieve MRD negativity. Given the critical importance of MRD-negative status prior to transplantation, immunotherapy was pursued. Tumor cells expressed CD7, prompting the use of donor-derived CD7 CAR-T cells [27]. Crucially, post-CAR-T bone marrow evaluation confirmed sustained MRD negativity with complete remission—a deep response unattainable with prior therapies. This enabled successful bridging allo-HSCT after myeloablative conditioning. After transplant, the patient achieved sustained donor chimerism and remained in remission throughout follow-up. This sequential strategy underscores the unique ability of CD7 CAR-T therapy to convert MRD-positive refractory disease to a transplant-eligible state. Prospective trials across the Asia-Pacific region and Western countries confirm that CD7 CAR-T therapy achieves high rates of MRD-negative remission in R/R T-ALL/LBL, and consolidative allo-HSCT substantially improves survival. A phase II donor-derived CD7 CAR-T trial reported an 89% best overall response rate and superior long-term outcomes in transplanted patients [28]. Similarly, the NS7CAR trial achieved a 94.4% deep bone marrow complete remission rate, with a 1-year PFS of 67.2% versus 15.0% in transplanted versus non-transplanted responders [29]. A Western phase I/II trial of off-the-shelf WU-CART-007 demonstrated an 72.7% composite complete remission rate [30]. These data collectively support CD7 CAR-T followed by consolidative HSCT as a viable therapeutic strategy for high-risk T-ALL/LBL.

T-ALL has multiple antigens co-expressed by tumor cells and normal T cells, which may lead to a “fratricide” phenomenon where CAR-T cells attack each other during the manufacturing process, thus limiting the therapeutic effect [31]. Researchers have developed various anti-CD7 CAR-T cell products to address this challenge. Oh et al [32] used an anti-CD7 protein expression blocker (PEBL) to inhibit CAR-T cell fratricide, enabling patients to achieve a high remission rate quickly, with strong antitumor activity and good safety. Zhang et al [33] utilized nanobody-derived CD7 CAR-T cells that persisted in the body for up to 270 days and showed significant efficacy, indicating a lasting therapeutic effect. Although CAR-T cell therapy shows good efficacy, safety issues cannot be ignored. Ma [34] pointed out that severe immune deficiency and hematotoxicity after CD7 CAR-T cell therapy were the major adverse events, and were accompanied by difficulties in immune reconstitution. The vast majority of R/R T-ALL patients should undergo bridging transplantation as soon as possible after CAR-T treatment because tumor and normal T cells are cleared after CAR-T cells infusion, leaving patients in an immunodeficient state. Timely bridging transplantation after disease remission can rebuild hematopoietic and immune function and effectively eliminate CAR-T cells, avoiding the occurrence of long-term immune deficiency.

Conclusions

This case demonstrates that donor-derived CD7 CAR-T therapy effectively induces deep remission—specifically converting MRD-positive refractory disease to sustained MRD negativity—and serves as a successful bridge to allo-HSCT in R/R T-ALL/LBL. These findings provide important evidence supporting the clinical application of CD7 CAR-T therapy, highlight its unique role in achieving MRD clearance that is unattainable with conventional regimens, and underscore the necessity of integrating immunotherapy with subsequent transplantation. Despite favorable outcomes, risks such as CRS, ICANS, immune dysfunction, and prolonged cytopenias require careful management. Larger, multicenter studies are warranted to optimize protocols and explore personalized strategies.