Update on long-term outcomes of a cohort of patients with TCF3::HLF-positive acute lymphoblastic leukemia treated with blinatumomab and stem cell transplantation

TCF3::HLF rearranged B-cell acute lymphoblastic leukemia (B-ALL) is a rare and highly aggressive subtype of B-ALL.^1-3 It is characterized by high rates of chemotherapy resistance, treatment failure, and early relapse. These patients are typically unsalvageable with standard chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT), resulting in a dismal prognosis.^2,4,5

However, due to the almost universally CD19-positive immunophenotype the emerging CD19-directed immunotherapies, such as the bispecific T-cell engager antibody blinatumomab or chimeric antibody receptor T cells (CAR T) have become viable therapeutic options, which may improve the long-term outcomes of these patients.^6-8 Nonetheless, because of the rarity of TCF3-HLF B-ALL, these approaches have not yet been widely evaluated.

Here we report the outcomes of a cohort of 17 pediatric and two adult patients with TCF3-HLF B-ALL, who received an early intervention with blinatumomab as a bridge to HSCT. The patients were treated between 2015 and early 2024 by members of the international AEIOP- Berlin-Frankfurt-Münster (BFM), ALLtogether, and GRAALL study groups. The initial outcomes and acute toxicity data for patients 1-9 have been previously reported in 2019.⁶ We now update these outcomes with a longer follow-up and report on ten additional, similarly treated patients (patients 10-19). This restrospective study has been approved by the Cantonal Ethics Committee of Zurich.

Minimal residual disease (MRD) assessment were performed according to the EuroMRD Guidelines,⁹ used in the AEIOP-BFM Study group and MRD negativity was defined as non-detectable disease using molecular MRD.

A summary of demographic data and treatment is shown in Table 1. The median age of the patients was 10 years (range, 3-52) and only three had extramedullary disease. Seventeen patients achieved MRD negativity either before or with blinatumomab treatment. In most cases, one blinatumomab cycle was sufficient for this. Patient 16 additionally received venetoclax and dexamethasone between the two cycles of blinatumomab, after already achieving MRD negativity.

Patients 13 and 19 failed to attain MRD negativity with blinatumomab. In both cases it was subsequently achieved with CD19-directed CAR T-cell therapy, followed by a planned HSCT in patient 19 and HSCT due to loss of CAR T-cell persistence in patients 13.

All but two patients underwent a HSCT. Patient 5 had an early CD19-negative relapse before reaching HSCT. This patient subsequently died from a severe infectious complication during relapse therapy. Patient 18 likewise suffered a relapse after receiving three cycles of blinatumomab and received HSCT in the second remission after CAR T-cell therapy.

Patient outcomes are depicted in Table 2, Figure 1 and Online Supplementary Figure S1. The median follow-up from the start of blinatumomab treatment for the complete cohort was 25 months (range, 2-104). Ten of 19 patients (2, 3, 7, 10, 11, 13, 14, 16, 17, 19) are alive after a median follow-up of 42 months (range, 8-104). Eight patients (patients 2, 3, 7, 10, 13, 16, 17 and 19) remain MRD-negative after a median follow-up of 53 months (range, 25-104). This corresponds to 2-year overall survival (OS) and 2-year event-free survival (EFS) of 63.1% and 52.6% respectively (Online Supplementary Figure S1). Two patients received additional prophylactic blinatumomab cycles after HSCT as an attempt to further consolidate the MRD-negative remission (patients 2 and 3). Patient 4 received additional courses of blinatumomab after a relapse post-HSCT and achieved MRD negativity but succumbed to an infectious complication after the second HSCT.

Five patients died from infectious complications, three while in remission (patients 4, 8, and 15), and two following relapse (patients 5 and 6). Four patients died due to disease progression or non-infectious treatment-related mortality during relapse (patients 1, 9, 18, and 12 respectively).

Seven patients relapsed post-blinatumomab-HSCT (patients 1, 4, 6, 9, 11, 12 and 14). The majority of relapses were CD19-positive. Five of seven relapses occurred within 1 year post-transplantation (patients 4, 6, 9, 11 and 14). Most post-relapse salvage therapies were unsuccessful. Two patients underwent a second HSCT, with one later dying from an infectious complication, and the second due to a subsequent relapse (patients 4 and 1, respectively). Two patients are still undergoing treatment following a second relapse (patients 11 and 14).

In summary, this case series confirms the profound resistance of this ALL subtype to chemotherapy, as the most common indication for blinatumomab therapy was MRD persistence after conventional consolidation therapy. Only two patients achieved MRD negativity before receiving blinatumomab therapy, one of whom also received venetoclax as part of a clinical trial (patient 15). The data also show an excellent response to CD19-directed immunotherapy with most other patients achieving MRD negativity after blinatumomab therapy. Furthermore, eight patients achieved sustained molecular remissions after consolidation with HSCT post-blinatumomab. One of those patients (19) required CAR T-cell therapy as a bridge to transplant due to poor response to blinatumomab. Patient 4 also demonstrates that blinatumomab is a therapeutic option for relapse post-HSCT.

Table 1.Demographic data and treatment details of the patients treated with blinatumomab and hematopoietic stem cell transplantation.

Table 2.Long-term outcomes of the patients treated with blinatumomab and hematopoietic stem cell transplantation.

We could not identify any clinical markers or characteristics to predict relapse in this cohort, as nearly all patients responded to blinatumomab quickly and the time to relapse varied greatly among the patients. However, in contrast to pre-immunotherapy era, we documented several late relapses. Further research into molecular characteristics is warranted to answer this question.

Five patients also received CAR T-cell therapy, either as therapy of relapse after blinatumomab-HSCT (patients 1 and 11) or before HSCT due to non-response to or early relapse after blinatumomab (patients 13, 19 and 18 respectively). These findings indicate that CD19-directed CAR T-cell therapy remains a feasible treatment option even following post-blinatumomab.

Since our initial report on the blinatumomab-based approach to TCF3::HLF B-ALL, other investigators have also reported a limited number of cases where sustained remissions had been achieved using CD19- and CD22-directed CAR T-cell therapy.^2,7,8 Several European patients also underwent therapy with CD19-directed CAR T-cell therapy in the meantime, but their outcomes have not yet been reported (personal communication). It is therefore yet to be determined how CAR T-cell therapy will compare to blinatumomab and HSCT. For patients with TCF3::HLF-B-ALL experts may recommend consolidation with HSCT even after CAR T-cell therapy.¹⁰ The role of additional blinatumomab cycles post-transplantation remains unclear.

An alternative bridging therapy, based on drug resistance profiles from preclinical models, was reported using the combination of the CD22 antibody-drug conjugate inotuzumab ozogamicin with BCL2-inhibitors, demonstrating the still largely untapped potential of combination therapies.^4,11 Other rationales for biologically driven treatments include MEK inhibition, SRC family kinase inhibition, and Aurora kinase inhibition, but no clinical data on the effectiveness of such therapeutic agents have been reported to date.^4,12 Our case series suggests that a long-term cure for TCF3::HLF B-ALL, which is considered incurable by conventional therapy, may be achieved with CD19-directed immunotherapy. Since our initial publication⁶ there has been a shift towards using more immunotherapy and our updated data further reinforces the recommendation that this approach should be integrated early into frontline treatment strategies for TCF3::HLF B-ALL. In general, we recommend the addition of venetoclax in combination with induction chemotherapy and a rapid bridge to CD19-directed immunotherapy. As first choice we bridge these patients as early as possible with blinatumomab to HSCT at first diagnosis already. This approach is recommended in treatment protocol by the AIOEP-BFM-ALL study group. We plan a retrospective international study of the experience with CAR T-cell therapy before providing a guideline. Prospective studies should evaluate the optimal bridge to CAR T-cell therapy without HSCT and more efforts are needed to understand the underlying functional dependencies of this rare but fatal leukemia subtype in order to further improve the outcome of patients with TCF3::HLF-positive ALL.

Figure 1.Swimmer’s plot depicting the disease course of patients with TCF3::HLF-positive B-acute lymphoblastic leukemia. MRD: minimal residual disease; HSCT: hematopoietic stem cell transplantation; CAR T cell: chimeric antibody T cell.

Footnotes

• Received November 9, 2024
• Accepted January 28, 2025

Correspondence

J-P. BOURQUIN - Jean-Pierre.Bourquin@kispi.uzh.ch

Disclosures

No conflicts of interest to disclose.

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