Long-Term Remission in T315I+ Relapsed Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia with Blinatumomab and Allogeneic Stem Cell Transplantation: Two Case Studies

Introduction

Acute lymphoblastic leukemia (ALL) in adult patients is associated with high relapse rates and a low overall response rate. Patients with relapsed/refractory (R/R) ALL have a complete remission (CR) rate of 30% to 40% with the first salvage regimen and 10% to 20% with the second salvage regimen [1], and the 5-year survival rate is <12% [2]. Philadelphia chromosome-positive ALL (Ph+ ALL) constitutes about 20% to 30% of the total ALL cases and is associated with a poor prognosis, poor induction rate of remission, challenging minimal residual disease (MRD) conversion, high recurrence rate, and short overall survival (OS) period [3]. Tyrosine kinase inhibitors (TKIs) in combination with chemotherapy are the first-line treatment option for patients with Ph+ ALL [1]. Sequential treatment of TKI combined with chemotherapy and allogeneic hematopoietic stem cell transplantation (allo-HSCT) after remission is the standard therapy for patients with Ph+ ALL but is associated with a high relapse rate. T315I mutation has been reported to be a major cause of relapse in patients with Ph+ ALL [4]. Hence, there remains a high unmet need for the development of novel therapies to improve outcomes in adult patients with R/R Ph+ ALL by overcoming the resistance caused by T315I.

Blinatumomab is the first bispecific T-cell-engaging immunooncology molecule that redirects endogenous T cells to cell-surface antigen-expressing cancer cells by its dual specificity for CD19+ and CD3+ cells [5]. In the ALCANTARA study, among adult patients with R/R Ph+ ALL treated with single-agent blinatumomab, 35.6% of patients achieved CR or CR with partial hematologic recovery, and the response continued for the long term [5,6].

Here, we report 2 cases of R/R Ph+ ALL with T315I treated with the combination of blinatumomab and allo-HSCT and the potential efficacy of the therapeutic combination in this difficult-to-treat disease. Written informed consent was obtained from the patients for publication of the details of their medical case in this article.

Case Reports

PATIENT 1:

Patient 1 was a 48-year-old woman with a skin petechiae for 3 days and fever for 1 day. She had no family history of cancer but had increased leukocytes in her peripheral blood cells, with 90% abnormal cells and a decreased platelet count. Bone marrow (BM) smear showed 95% blasts, while immunophenotype on BM was consistent with ALL. Ph+ ALL was diagnosed based on the results of chromosomal and gene analyses (Table 1). We treated the patient with long-term flumatinib-targeted therapy after induction chemotherapy with the vincristine, cyclophosphamide, and prednisone regimen for 1 cycle in August 2021. After 2 months of treatment, the patient had a negative BCR: : ABL gene mutation, normal karyotype, and 1.5% BM-naïve cells, and was in CR status. After 3 months of treatment, the patient’s BM biopsy showed 73% naïve cells, and the level of BCR: : ABL p190 transcript was 35.29%, indicating the recurrence of ALL in November 2021. As a next therapeutic option, the venetoclax- and flumatinib-targeted therapy combined with homoharringtonine, ara-C, vincristine, and prednisone was administered for 1 cycle [7,8]. In December 2021, BM morphology showed 54% naïve cells, with an abnormal karyotype (46,XX, t(8;9)(q11.2;p22),t(9;22)(q34;q11,2)). In addition, the presence of Ph-like fusion genes, IKZF1 and ABL T315I mutation, suggested the ineffectiveness of the treatment. Hence, we opted to use olverembatinib, which is a third-generation BCR: : ABL TKI that was recently approved in China. The patient received olverembatinib 40 mg every other day, and after 1 month of treatment, in January 2022, the patient had a normal karyotype. The BM morphology showed the absence of abnormal cells, an MRD of 0.3%, with BCR: : ABL p190 transcript level of 0.22%, suggesting a complete disease remission. To attain deeper remission and relief, the patient received blinatumomab that was continuously infused for 4 weeks (9 μg/day for the first 7 days and 28 μg/day thereafter). Consequently, the patient achieved CR, as determined by BM examination. In March 2022, the patient underwent subsequent allo-HSCT grafting (stem cells of a haploidentical donor were infused [patient’s brother]: HLA typing 5/10, donor blood group B Rh positive, recipient blood group A Rh-positive, CD34+ cell count of 5.51.03×106/kg) with a condition regimen of BU 0.8 mg/kg/every 6 h for 4 days, CY 60 mg/kg/day for 2 days, and ATG 2.5 mg/kg/day for 4 days, granule implantation +14 days, and meganucleus implantation +20 days. From May 2022 to February 2023, the patient remained in the state of CR, with persistent negative MRD, BCR: : ABL p190, and ABL kinase mutation, as determined by multiple repeat BM smears and flow cytometry analyses. Regrettably, the patient was admitted to the Intensive Care Unit in February 2023 with severe pneumonia due to a SARS-CoV-2 infection and ultimately died of acute respiratory distress syndrome. The patient’s leukemia had been in remission prior to death.

PATIENT 2:

A 20-year-old man was referred to our center in December 2015. Peripheral blood showed leukocytosis with thrombocytopenia, while all other parameters were normal (Table 1). BM aspirate showed 98% immature granulocytes/blasts. Immunophenotypic observations on BM were consistent with the presence of ALL. The gene rearrangement and karyotyping results confirmed the diagnosis of Ph+ ALL. An initial treatment consisted of imatinib followed by the vincristine, idarubicin, cyclophosphamide, and prednisone regimen for 3 cycles until March 2016, with the patient achieving CR status in the second cycle. Subsequent imatinib maintenance therapy was continued until allo-HSCT in July 2016. The patient was followed up and had BM examinations regularly after transplantation (BUCY, HLA typing 7/10, father to son) and continued in CR status until July 2019. Although the blasts in BM were still <5%, the level of BCR: : ABL p190 transcript was >3% at 2 time points (3.34% and 8.15%). Reinitiating imatinib in September 2019 did not achieve rewarding efficacy, and the level of BCR: : ABL p190 transcript persistently remained positive for the next 3 times, until January 2020 (0.04%, 0.04%, and 0.48%). Therefore, we switched to dasatinib-targeted therapy in February 2020. Although the patient reached CR rapidly after 2 months of treatment with dasatinib, the gene rearrangement of BCR: : ABL P190 reappeared along with the T315I mutation, indicating disease relapse in May 2020. Therefore, the patient received ponatinib in June 2020, which helped the patient to achieve CR after 1 month of treatment, which was continued for the next 11 months. Unfortunately, the recurrence of ALL was observed in August 2021, with 11% blasts in BM, 7.1% MRD, 12.37% BCR: : ABL p190, and the presence of T315I mutation. Interferon peginterferon-α-2 was introduced along with ponatinib, but the combination regimen failed to achieve any therapeutic effect. Moreover, BM aspirate showed 47% blasts in October 2021. After the failure of multiple TKIs, leading to disease recurrence, we introduced blinatumomab as the salvage regimen in October 2021, which was given for 4 weeks (9 μg/day for the first 7 days and 28 μg/day thereafter) resulting in CR. Similar to patient 1, subsequent allo-HSCT was smooth, (stem cells of haploidentical donor were infused [patient’s sister]: HLA typing 6/10, donor blood group B Rh positive, recipient blood group O Rh-positive, CD34+ cell count of 6.68×106/kg) with a condition regimen of BU 0.8 mg/kg/every 6 h for 3 days, Flu 30 mg/kg/day for 4 days, Tt 5 mg/kg/every 12 h for 2 days and ATG 5 mg/kg/day for 4 days) granule implantation +11 days, and meganucleus implantation +14 days after graft. This patient remained in CR until February 2023. Regrettably, the patient also died of severe pneumonia due to COVID-19. He also had been in remission status for leukemia.

Discussion

According to the existing treatment guidelines, allo-HSCT is the recommended therapy for patients with R/R ALL [9]. Multiple clinical studies have explored the combined application of blinatumomab and allo-HSCT in patients with R/R ALL, which can significantly increase the maintenance duration [10,11]. Achieving an MRD-negative state before allo-HSCT can significantly improve survival outcomes in patients with R/R ALL undergoing transplantation. However, for patients with R/R Ph+ ALL who relapse with a short remission duration, this is a big challenge. Although blinatumomab can be used as a salvage therapy to help patients achieve MRD-negative status before transplantation and attain a higher OS rate, a real-world study by the GRAALL showed that the OS and progression-free survival outcomes for patients with higher pre-blinatumomab MRD levels were not promising. Thus, pre-blinatumomab tumor burden could be used to design effective strategies in the treatment of patients with R/R ALL [12].

There is a lack research focusing on patients with R/R Ph+ ALL. One such study, ALCANTARA, reported that 35.6% of patients with R/R Ph+ ALL achieved CR/CR with partial hematologic recovery within the first 2 cycles of blinatumomab, and 87.5% achieved complete MRD response. In a subgroup of patients with BCR: : ABL1 mutations (n=17), the median OS was 6.5 months. The median OS was not estimable for 10 patients with T315I mutations and was 5.6 (95% CI, 0.8–12.1) months in 7 patients with mutations other than T315I. These data demonstrate the efficacy of blinatumomab as a single agent and in combination with other TKIs in R/R Ph+ ALL, suggesting a promising role of blinatumomab in this disease setting [5].

In a single-arm multicenter phase 2 trial, blinatumomab demonstrated safety and effectiveness in highly pretreated R/R Ph+ ALL patients. Among 45 treated patients, the CR/CRi rate was 36%, with 88% of responders reaching MRD negativity. Regardless of the T315I mutation status, responses showed that the median OS was 7.1 months, and half of the patients were able to get HSCT [4,6]. Combination therapy including inotuzumab ozogamicin has been a viable therapeutic option for relapsed/refractory acute lymphoblastic leukemia with the T315I mutation. For instance, in one study, blinatumomab and inotuzumab ozogamicin combination exhibited complete molecular remission and successfully aided in allo-SCT transplantations without veno-occlusive disease/sinusoidal obstruction syndrome [13]. Mutations in the BCR: ABL1 kinase domain, found in >80% of patients, are one of the major reasons for drug resistance and disease relapse in Ph+ ALL [14,15]. Although next-generation TKIs, including dasatinib and nilotinib, can overcome many of the mutations, treatment failure is common due to the gatekeeper T315I mutation [16]. While olverembatinib [17] and ponatinib [18] have shown an effect on this mutation in some patients, these TKIs were not effective in our patients. T315I mutation and other mutations, deletions, and alternations in the IKZF1 gene are strongly associated with drug resistance. In the newly diagnosed patients with Ph+ ALL in the GIMEMA trail, 29% of patients had a molecular response after dasatinib induction therapy; however, this effect was increased to 60% after treatment with blinatumomab. Among patients with alterations in the IKZF1 gene, the disease-free survival rate was lower, but these mutations were cleared by blinatumomab [19]. Therefore, owing to its TKI-independent mechanism of action, blinatumomab can direct immune-mediated cell death of Ph+ blasts by overcoming the T315I resistance mechanism.

Based on this scientific evidence, we selected blinatumomab as a salvage regimen, which helped our patients quickly achieve CR with MRD-negative status in one course. No patients had any serious adverse events. Subsequent allo-HSCT helped patients remain in CR status for a long period. Our report suggests that the combined therapy with blinatumomab and subsequent allo-HSCT could be a potentially effective therapeutic option for Ph+ ALL patients with T315I mutation.

Conclusions

Blinatumomab as a salvage therapy helped our patients quickly achieve CR with MRD negativity in one treatment course, with no serious adverse events. Subsequent allo-HSCT helped patients remain in CR status for a long period. Thus, our results suggest that the combined therapy with blinatumomab and allo-HSCT could be an effective therapeutic option for R/R Ph+ ALL patients with T315I mutation.