Reduced-dose chemotherapy and blinatumomab as induction treatment for newly diagnosed Ph-negative B-cell precursor acute lymphoblastic leukemia: a phase 2 trial.

Blinatumomab has emerged as a promising component of first-line therapy for acute B-cell precursor lymphoblastic leukemia (BCP-ALL), bolstering treatment efficacy. To mitigate CD19 selection pressure and reduce the incidence of blinatumomab-associated toxicities, pre-treatment chemotherapy is recommended before administering blinatumomab. From September 2022 to December 2023, we conducted a single-arm, multicenter, phase 2 trial (NCT05557110) in newly diagnosed Philadelphia chromosome-negative BCP-ALL (Ph-negative BCP-ALL) patients. Participants received induction treatment with reduced-dose chemotherapy (RDC), comprising idarubicin, vindesine, and dexamethasone over 7 days, followed by 2 weeks of blinatumomab. Those failing to achieve composite complete remission (CRc) received an additional 2 weeks of blinatumomab. The primary endpoint was the CRc rate post initial induction treatment. Of the 35 enrolled patients, 33 (94%) achieved CRc after 2 weeks of blinatumomab, with 30 (86%) achieving measurable residual disease (MRD) negativity. Two patients extended blinatumomab to 4 weeks. With either 2 or 4 weeks of blinatumomab treatment, all patients achieved CR (35/35) and 89% (31/35) were MRD negativity. The median time to CR was 22 days. Immune effector cell-associated neurotoxicity syndrome was limited (14%, all grade 1). Non-hematological adverse events of grade 3 or higher included pneumonia (17%), sepsis (6%), and cytokine release syndrome (9%). With a median follow-up of 11.5 months, estimated 1-year overall survival and 1-year progression-free survival rates were 97.1% and 82.2%, respectively. These findings affirm that RDC followed by blinatumomab is an effective and well-tolerated induction regimen for newly diagnosed Ph-negative BCP-ALL, supporting a shift towards less intensive and more targeted therapeutic approaches. Trial registration: https://www.clinicaltrials.Gov . Identifier NCT05557110.

The combination of a tyrosine kinase inhibitor and blinatumomab in patients with Philadelphia chromosome-positive acute lymphoblastic leukemia or Philadelphia chromosome-like acute lymphoblastic leukemia.

Tyrosine kinase inhibitors (TKIs) have revolutionized Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) treatment. The combination of blinatumomab and a TKI in the frontline setting has shown the safety and efficacy of the chemotherapy-free treatment approach in patients with Ph + ALL. This retrospective analysis included 19 patients with Ph + ALL and Ph-like ALL treated with the combination of blinatumomab and a TKI. Of the 14 newly diagnosed patients, the overall response, complete remission (CR), and molecular response (CMR) rates after one cycle of blinatumomab were 100% (10/10), 90% (9/10), and 57% (8/14), respectively. Of the five relapsed patients, the CR and CMR rates were 50% (2/4) and 40% (2/5). Blinatumomab in combination with TKIs is safe and effective and hence this combination therapy could be a viable therapeutic option in front-line treatment of patients with Ph + ALL.

A Quality Approach to Blinatumomab Delivery in Pediatric Oncology: A Children's Oncology Group Study.

Background: Blinatumomab is a promising immunotherapy agent that has been shown to improve survival outcomes in children diagnosed with relapsed B-lineage acute lymphoblastic leukemia. Expanded use of blinatumomab in the treatment of childhood cancer is expected; however, clinician perspectives regarding administering this agent in healthcare and home settings have not been explored. Method: Semistructured interviews were conducted with clinicians (N = 13) from pediatric institutions across the United States and Canada. Qualitative data were analyzed using a constant comparative analysis three-stage method. Results: Participants were primarily nurses (92%), female (77%), and had greater than 10 years of pediatric oncology experience. The selective code and overarching theme identified was "A quality approach to blinatumomab delivery in pediatric oncology." Clinicians described detailed processes that were created and implemented to promote a common goal of safe blinatumomab administration across the continuum of care. Clinicians shared how they engaged in planning activities and considered a variety of factors prior to and during blinatumomab administration. Clinicians also expressed a need to reflect and evaluate on previous patient experiences to create new or revise existing processes and workflows. Communication was also central to clinicians' work. Clinicians provided recommendations to assist others with blinatumomab administration and offered suggestions for items that could help with implementing future clinical trials containing similar agents. Discussion: Findings suggest nurses are pivotal to establishing processes which support safe administration of immunotherapies, such as blinatumomab, while also considering patient-specific needs and promoting quality of life.

Blinatumomab in the Therapy of Acute B-Lymphoid Leukemia.

Blinatumomab, a CD19-CD3 bispecific T cell engager (BiTE), has two recombinant single-chain variable fragments that temporarily link CD3+ T cells and CD19+ B cells, leading to the T cell-mediated lysis of neoplastic B cells. Improved minimal residual disease (MRD)-negative response rates and long-term overall survival have been observed in B-ALL patients who received this drug. These therapeutic successes have led to FDA approval for refractory/relapsed and MRD-positive B-ALL patients. Furthermore, recent studies in newly diagnosed B-ALL patients have led in Philadelphia chromosome-positive patients to the development of chemotherapy-free regimens based on tyrosine kinase inhibitors plus Blinatumomab and in Philadelphia chromosome-negative patients to improvement in outcomes using chemotherapy regimens that have incorporated Blinatumomab in the consolidation phase of treatment.

Prediction of Response to FDA-Approved Targeted Therapy and Immunotherapy in Acute Lymphoblastic Leukemia (ALL).

OPINION STATEMENT: Acute lymphoblastic leukemia (ALL) represents the predominant cancer in pediatric populations, though its occurrence in adults is relatively rare. Pre-treatment risk stratification is crucial for predicting prognosis. Important factors for assessment include patient age, white blood cell (WBC) count at diagnosis, extramedullary involvement, immunophenotype, and cytogenetic aberrations. Minimal residual disease (MRD), primarily assessed by flow cytometry following remission, plays a substantial role in guiding management plans. Over the past decade, significant advancements in ALL outcomes have been witnessed. Conventional chemotherapy has remarkably reduced mortality rates; however, its intensive nature raises safety concerns and has led to the emergence of treatment-resistant cases with recurrence of relapses. Consequently, The U.S. Food and Drug Administration (FDA) has approved several novel treatments for relapsed/refractory ALL due to their demonstrated efficacy, as indicated by improved complete remission and survival rates. These treatments include tyrosine kinase inhibitors (TKIs), the anti-CD19 monoclonal antibody blinatumomab, anti-CD22 inotuzumab ozogamicin, anti-CD20 rituximab, and chimeric antigen receptor (CAR) T-cell therapy. Identifying the variables that influence treatment decisions is a pressing necessity for tailoring therapy based on heterogeneous patient characteristics. Key predictive factors identified in various observational studies and clinical trials include prelymphodepletion disease burden, complex genetic abnormalities, and MRD. Furthermore, the development of serious adverse events following treatment could be anticipated through predictive models, allowing for appropriate prophylactic measures to be considered. The ultimate aim is to incorporate the concept of precision medicine in the field of ALL through valid prediction platform to facilitate the selection of the most suitable treatment approach.

Cost-effectiveness of blinatumomab for the treatment of B­precursor acute lymphoblastic leukemia pediatric patients with high­risk first­relapse in Mexico.

BACKGROUND: Blinatumomab is a CD3/CD19-directed bispecific T-cell engager molecule that engages T cells to lyse CD19-expressing B cells. Based on a multicenter, open-label, phase 3, randomized clinical trial (Clinical Trials ID: NCT02393859), we aimed to evaluate the cost-effectiveness (CE) of blinatumomab compared to standard consolidation chemotherapy (SC) for the treatment of pediatric patients with high-risk first-relapsed Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia (B-ALL) from a Mexico healthcare payer perspective. METHODS: A decision-analytic model, a partitioned survival model, was used to estimate the life-years (LYs) and costs over a lifetime horizon. We assumed that patients who remained alive beyond a 5-year period were cured. To account for the lingering impacts of cancer treatment, an excess mortality rate was incorporated into the model. Event-free survival (EFS) and overall survival (OS) were estimated by fitting mixture-cure and standard parametric survival distributions to the time-to-event data from the phase 3 trial. The model accounted for treatment costs, adverse event costs, follow-up costs, subsequent allogeneic hematopoietic stem cell transplantation (alloHSCT) costs, and subsequent treatment costs. RESULTS: Blinatumomab was associated with a lifetime gained of 5.11 years at an incremental cost of $621,111 MXN, relative to SC. The ICER for blinatumomab vs Standard of care was estimated to be $121,526 MXN/LY gained in the base case. Cost-effectiveness was sensitive to varying the time horizon. Blinatumomab had a probability of 99 % of being cost-effective, relative to SC, at the willingness to pay threshold defined in Mexico. LIMITATIONS: Health-related quality of life values were not included in the analysis and therefore we did not estimate the quality-adjusted life-years gained. CONCLUSIONS: Blinatumomab was associated with greater benefit in terms of OS and EFS relative to SC. Probabilistic, deterministic, and scenario analyses indicate that blinatumomab represents the best value for money. Therefore, blinatumomab administered as part of consolidation therapy in B-ALL pediatric patients with high-risk first relapse is a cost-effective option.

The characterization and the impact of CSF pleocytosis during blinatumomab therapy for adult acute lymphoblastic leukemia.

Reactive pleocytosis in the CSF has been observed with blinatumomab but has not been well-described. We performed a retrospective study of 88 patients who received intrathecal chemotherapy (IT) while on blinatumomab with CSF analyzed to determine if pleocytosis had an impact efficacy and safety. Blinatumomab was used for relapsed/refractory 62.5%, MRD-positive 31.8%, and consolidation in MRD-negative 5.7%. The incidence of pleocytosis in CSF was 51% and was more frequent after day 15 (55.8% vs. 18.2%, p = 0.025). Pleocytosis did not impact CR, clearance of MRD positivity, PFS and OS rates. Lower incidence of non-CNS extramedullary relapse was seen (3.7% vs. 30.8%, p = 0.011) with pleocytosis in CSF. Analysis of CSF by flow cytometry showed median CD4:CD8 ratio of 1.34. In conclusion, CSF pleocytosis is prevalent with blinatumomab but only demonstrated lower rates of non-CNS extramedullary relapse but no impact on CNS relapse or neurotoxicity.

Novel Treatment Modality for Chimeric Antigen Receptor T-cell Therapy Complications: A Case Report.

Immune cell-associated neurotoxicity syndrome (ICANS) and cytokine release syndrome (CRS) are both common adverse effects of chimeric antigen receptor (CAR) T-cell therapy. Blinatumomab is a commonly used CAR T-cell treatment in patients with B-cell acute lymphoblastic leukemia (B-ALL). Our patient presented with an extensive past medical history, including refractory B-ALL, and developed CRS and ICANS following treatment with blinatumomab CAR-T cell therapy. Early clinical detection of ICANS, monitoring using immune effector cell encephalopathy scores, following the appropriate protocol for ICANS grade, and adding anakinra (IL-1 receptor antagonist) were crucial steps in managing his condition. The approach to managing and monitoring this patient was unique in that we added anakinra to the standard treatment regimen. With this report, we emphasize the need for further research regarding CAR T-cell therapeutic regimens and how to decrease the morbidity and mortality of its adverse effects.

Effective treatment of relapsed/refractory CD19-positive B/T-type mixed-phenotype acute leukemia with blinatumomab: A case report.

A 26-year-old man was diagnosed with B/T-type mixed-phenotype acute leukemia (MPAL-B/T) based on blasts being positive for CD19, cytoplasmic CD3, and cyCD79a, but negative for myeloperoxidase. Acute lymphoblastic leukemia-based chemotherapy was started, but the leukemia was refractory. He underwent cord blood transplantation with the conditioning regimen of total body irradiation plus cyclophosphamide and cytarabine with granulocyte-colony stimulating factor priming. Prophylaxis for graft versus host disease was performed with short-term methotrexate and cyclosporin. The leukemia relapsed in bone marrow 20 months later. At that time, he was treated with inotuzumab ozogamicin because the blasts expressed CD22 (75.4%), but this was ineffective. He was next administered blinatumomab with dexamethasone pretreatment, resulting in a complete remission (CR). He subsequently underwent human leukocyte antigen-haploidentical peripheral blood stem cell transplantation. He has still maintained a CR for 12 months. Blinatumomab might be a promising treatment and a bridge to stem cell transplantation even in relapsed/refractory CD19-expressing MPAL-B/T.

A case of posttransplant isolated extramedullary relapse of acute lymphoblastic leukemia achieving durable treatment-free remission with blinatumomab and donor lymphocyte infusion.

Acute lymphoblastic leukemia (ALL) relapsed after allogeneic hematopoietic cell transplantation (allo-HCT) has a catastrophic prognosis. Blinatumomab, a CD3/CD19-directed bispecific T cell engager, is reportedly effective for advanced B-cell ALL (B-ALL), even after allo-HCT. However, the efficacy of blinatumomab in extramedullary relapse (EMR) is controversial. Donor lymphocyte infusion (DLI) is another immunological treatment worth considering for ALL relapsed after allo-HCT. We report the case of a 56-year-old woman with B-ALL. Allo-HCT was performed during the second complete remission (CR). Thirteen months after allo-HCT, isolated EMR (iEMR) of B-ALL developed without bone marrow lesions. A third CR was achieved with 2 cycles of blinatumomab. An additional four cycles each of blinatumomab and DLI were then administered. The patient did not develop graft-versus-host disease and has confirmed 2-year treatment-free remission without a second allo-HCT. Therefore, blinatumomab was considered an effective salvage therapy for iEMR of B-ALL after allo-HCT, because iEMR could have a lower tumor burden than that seen in systemic relapse, and low tumor burden was a prognostic factor for response to blinatumomab. Furthermore, immunological consolidation therapies could only provoke graft-versus-leukemia effects if the imbalanced effector/target ratio was restored and the tumor burden was lowered through immunosurveillance.

Efficacy of Chemotherapy-Free Regimens in the Treatment of Philadelphia Chromosome-Positive Acute Lymphoblastic Leukemia: A Systematic Review and Meta-Analysis.

INTRODUCTION: The historical standard of care for Ph+ ALL is chemotherapy plus a tyrosine kinase inhibitor (TKI). Recently chemotherapy-free regimens have shown promising efficacy. We performed a meta-analysis to compare the efficacy of chemotherapy-free regimens for Ph+ ALL. METHODS: We searched PubMed and Embase for chemotherapy-free regimens for Ph+ ALL published between January 2000 and October 2023. Of the 5,348 articles screened, 9 nonrandomized clinical trials enrolling 413 patients were included. Two trials (N = 117) included treatment with 3 agents (blinatumomab, TKI, and steroid) and 7 trials (N = 248) included treatment with 2 agents (TKI and steroids). R software was used to conduct the meta-analysis (PROSPERO registration no. CRD42023482439). RESULTS: The pooled complete molecular response (CMR) rate of patients receiving a TKI, blinatumomab, and steroids was 81% (95%CI, 69%-89%). TKIs plus blinatumomab were nearly 6 times as likely to have CMR (odds ratio [OR], 5.98; 95%CI, 2.99-11.96) and more than 5 times as likely to be alive at 1-year (OR, 5.1; 95%CI, 1.74-14.9) as compared to TKIs alone. Patients receiving ponatinib were about twice as likely as those receiving dasatinib to achieve CMR (OR, 2.51; 95%CI, 0.72-8.72). CONCLUSION: Adding blinatumomab to TKIs and steroids significantly improved Ph+ ALL patients' response and survival rates. Regimens with ponatinib elicited higher molecular response rates than those with other TKIs. The high response and survival rates achieved with blinatumomab plus TKIs and steroids suggest that further studies are required to assess the need for intensive treatments such as chemotherapy or stem cell transplant in these patients.

Blinatumomab infusion interruptions in pediatric patients rarely lead to readmission.

Blinatumomab is a bispecific T-cell engager administered as a 28-day continuous infusion. Infusions can be associated with interruptions requiring support from clinical staff, but the frequency of interventions with outpatient blinatumomab has not been characterized. This study is a single-center, retrospective review of patients who received blinatumomab between December 3, 2014 and October 31, 2021 to determine frequency and type of interventions. Forty patients received blinatumomab for 69 cycles. Clinical staff intervention was required in 31 (45%) cycles, only six (8.7%) cycles needed readmission. Management of outpatient blinatumomab infusions requires education and training of clinical staff and caregivers to quickly troubleshoot interruptions.

[Clinical efficacy and safety of blinatumomab bridging CAR-T cell therapy in the treatment of patients with adult acute B-cell lymphoblastic leukemia].

Objective: Exploring the efficacy and safety of bridging blinatumomab (BiTE) in combination with chimeric antigen receptor T (CAR-T) cell therapy for the treatment of adult patients with acute B-cell lymphoblastic leukemia (B-ALL) . Methods: Clinical data from 36 adult B-ALL patients treated at the First Affiliated Hospital of Suzhou University from August 2018 to May 2023 were retrospectively analyzed. A total of 36 cases were included: 18 men and 18 women. The median age was 43.5 years (21-72 years). Moreover, 21 cases of Philadelphia chromosome-positive acute lymphoblastic leukemia were reported, and 16 of these cases were relapsed or refractory. Eighteen patients underwent blinatumomab bridging followed by CAR-T cell therapy, and 18 patients received CAR-T cell therapy. This study analyzed the efficacy and safety of treatment in two groups of patients. Results: In the BiTE bridge-to-CAR-T group, 16 patients achieved complete remission (CR) after BiTE immunotherapy, with a CR rate of 88.9%. One month after bridging CAR-T therapy, bone marrow examination showed a CR rate of 100.0%, and the minimal residual disease (MRD) negativity rate was higher than the nonbridging therapy group (94.4% vs. 61.1%, Fisher, P=0.041). The incidence of cytokine release syndrome and other adverse reactions in the BiTE bridge-to-CAR-T group was lower than that in the nonbridging therapy group (11.1% vs. 50.0%, Fisher, P=0.027). The follow-up reveals that 13 patients continued to maintain MRD negativity, and five patients experienced relapse 8.40 months (2.57-10.20 months) after treatment. Two of five patients with relapse achieved CR after receiving the second CAR-T cell therapy. In the nonbridging therapy group, 10 patients maintained continuous MRD negativity, 7 experienced relapse, and 6 died. The 1 year overall survival rate in the BiTE bridge-to-CAR-T group was higher than that in the nonbridging therapy group, with a statistically significant difference at the 0.1 level (88.9%±10.5% vs. 66.7%±10.9%, P=0.091) . Conclusion: BiTE bridging CAR-T cell therapy demonstrates excellent efficacy in adult B-ALL treatment, with a low recent recurrence rate and ongoing assessment of long-term efficacy during follow-up.

Blinatumomab Maintenance Therapy Following Bone Marrow Transplantation for Early Relapsed Pediatric B-cell Precursor Acute Lymphoblastic Leukemia and Analysis of Lymphocyte Subset Changes.

Blinatumomab, a CD19/CD3 bispecific T-cell engager, is recognized as an effective immunotherapy for relapsed B-cell precursor acute lymphoblastic leukemia (BCP-ALL). However, the efficacy and safety of blinatumomab in post-hematopoietic stem cell transplantation (HSCT) maintenance therapy has not been established. A 5-year-old male patient with BCP-ALL suffered a relapse in his bone marrow during maintenance therapy. After re-induction therapy with UK-R3 regimen, 2.3% of the blasts remained. Then the blinatumomab was administered, and he achieved minimal residual disease (MRD)-negative complete remission (CR). After two cycles of blinatumomab, he underwent allogeneic bone marrow transplantation (BMT) from his human leukocyte antigen (HLA)-matched sibling, following conditioning with total body irradiation, etoposide, and cyclophosphamide. Two cycles of blinatumomab maintenance therapy were initiated to prevent relapse. There was no exacerbation of graft-versus-host disease (GVHD) or other severe adverse events. CR was maintained for >22 months after BMT. A t-distributed symmetric neighbor embedding (tSNE) analysis revealed that blinatumomab altered the CD8+ population, as with pre-HSCT use, and markedly reduced the CD8+19dim+/CD8+CD19- ratio (i.e., naïve lymphocyte predominance). Blinatumomab maintenance therapy after HSCT may be considered a safe treatment.

Blinatumomab in Children with MRD-Positive B-Cell Precursor Acute Lymphoblastic Leukemia: A Report of 11 Cases.

Background/Objectives: Relapsed B-cell acute lymphoblastic leukemia (B-ALL) remains an unresolved matter of concern regarding adverse outcomes. This case study aimed to evaluate the effectiveness of blinatumomab, with or without door lymphocyte infusion (DLI), in treating measurable residual disease (MRD)-positive B-ALL. Methods: All patients who received blinatumomab salvage therapy were included in this study. Eleven patients were included in the study. All patients were evaluated for MRD-negativity. Results: Before starting blinatumomab therapy, seven patients tested positive for MRD, three tested negative, and one had refractory disease. Hematopoietic cell transplantation (HCT) was reserved for five patients with persistent MRD. Six patients became MRD-negative and subsequent HCT was not performed. Only two patients relapsed; one patient died of relapse, and the other one received carfilzomib-based therapy and was MRD-negative thereafter. Nine patients were MRD-negative at a median follow-up of 28 months (15-52 months). Two of three MRD-positive post-transplant patients remained in complete molecular remission after preemptive DLI at the last follow-up date. In the first salvage, blinatumomab may achieve complete remission and bridging to HCT in pediatric patients with end-of-induction MRD-positive B-cell precursor ALL. Conclusions: The decision on how to treat post-transplant relapse continues to affect survival outcomes. Blinatumomab combined with DLI may extend the armamentarium of release options for high-risk pediatric patients. This approach is encouraging for high-risk ALL patients who are MRD-positive post-transplantation.

Treatment of Relapsed Acute Lymphocytic Leukemia in Adult Patients.

OPINION STATEMENT: For adult patients diagnosed with relapsed B cell-ALL (B-ALL), there have been significant improvements in available treatment options following the FDA approval of novel cellular and immunotherapy approaches - blinatumomab, chimeric antigen receptor (CAR) T therapy, and inotuzumab. For the last several years, research has focused on gaining a better understanding of the effects of specific disease and patient characteristics on long-term outcomes with each of the FDA-approved agents. In combination with the better prevention and management of unique, treatment-specific toxicities, providers can now select the best available treatment option for each individual patient diagnosed with relapsed, adult B-ALL needing therapy. This has allowed more patients to proceed to consolidative hematopoietic stem cell transplant (HSCT), and long-term data has even brought into question the need for HSCT for long-term durable remission for all patients. However, with the adoption of blinatumomab, CAR T therapy, and inotuzumab in front-line treatment regimens, it remains unclear what effects this will have on patients with relapsed B-ALL following exposure to these novel cellular and immunotherapy therapies. Unlike B-ALL, similar advances have unfortunately not yet been realized in T cell-ALL (T-ALL). Currently, new therapeutic approaches are underway to utilize similar targeting strategies that have been successful in B-ALL - monoclonal antibodies, bispecific T-cell engagers (BiTE), and CAR T therapy. Like B-ALL, the only existing approved therapy for relapsed T-ALL, nelarabine, is now used in the upfront treatment setting potentially limiting its utility in relapsed disease. Over the next several years, the hope is for patients diagnosed with T-ALL to experience the drastic improvement in outcomes as has been seen for patients diagnosed with B-ALL over the last decade.

Advances in the treatment of adults with newly diagnosed B-cell acute lymphoblastic leukemia: the role of frontline immunotherapy-based regimens.

Blinatumomab and inotuzumab ozogamicin (INO) are both active in relapsed/refractory B-cell acute lymphoblastic leukemia (ALL) and improve outcomes compared with conventional chemotherapy in this setting. Several prospective clinical trials have explored the use of these agents in adults with newly diagnosed B-cell ALL, with promising outcomes observed in younger and older adults and in both Philadelphia chromosome (Ph)-positive and Ph-negative ALL. These novel regimens result in high rates of deep measurable residual disease (MRD) negativity and may improve survival compared with chemotherapy-only approaches, allowing for less reliance on intensive chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT). This review discusses novel approaches to integrating INO and/or blinatumomab into frontline ALL regimens, including the potential role of chemotherapy-free regimens in some subgroups. The role of MRD monitoring is also discussed, including how this can inform decisions for consolidative allogeneic HSCT or investigational approaches with CD19 CAR T-cells.

Successful treatment of two cases with Philadelphia-chromosome positive acute lymphoblastic leukemia who relapsed after allogeneic stem cell transplantation and the treatments with novel immunotherapies and ponatinib.

The outcomes of relapsed Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ALL) resistant to new drugs such as tyrosine kinase inhibitors, inotuzumab ozogamicin (InO) and blinatumomab are dismal. We treated two cases of Ph+ALL resistant to these drugs that achieved long-term survival after treatment with chimeric antigen receptor (CAR)-T cell therapy or a second allogeneic hematopoietic stem cell transplantation (HCT) with a sequential conditioning regimen. Case 1: A 15-year-old boy was diagnosed with Ph+ALL. Despite the second HCT after the treatment of ponatinib and blinatumomab, hematological relapse occurred. InO was ineffective and he was transferred to a CAR-T center. After the CAR-T cell therapy, negative measurable residual disease (MRD) was achieved and maintained for 38 months without maintenance therapy. Case 2: A 21-year-old man was diagnosed with Ph+ALL. Hematological relapse occurred after the first HCT. Despite of the treatment with InO, ponatinib, and blinatumomab, hematological remission was not achieved. The second HCT was performed using a sequential conditioning regimen with clofarabine. Negative MRD was subsequently achieved and maintained for 42 months without maintenance therapy. These strategies are suggestive and helpful to treat Ph+ALL resistant to multiple immunotherapies.

MRD in Philadelphia Chromosome-Positive ALL: Methodologies and Clinical Implications.

PURPOSE OF REVIEW: Measurable residual disease (MRD) is integral in the management of Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). This review discusses the current methods used to evaluate MRD as well as the interpretation, significance, and incorporation of MRD in current practice. RECENT FINDINGS: New molecular technologies have allowed the detection of MRD to levels as low as 10- 6. The most used techniques to evaluate MRD are multiparametric flow cytometry (MFC), quantitative reverse transcription polymerase chain reaction (RT-qPCR), and high-throughput next-generation sequencing (NGS). Each method varies in terms of advantages, disadvantages, and MRD sensitivity. MRD negativity after induction treatment and after allogeneic hematopoietic cell transplantation (HCT) is an important prognostic marker that has consistently been shown to be associated with improved outcomes. Blinatumomab, a new targeted therapy for Ph + ALL, demonstrates high efficacy in eradicating MRD and improving patient outcomes. In the relapsed/refractory setting, the use of inotuzumab ozogamicin and tisagenlecleucel has shown promise in eradicating MRD. The presence of MRD has become an important predictive measure in Ph + ALL. Current studies evaluate the use of MRD in treatment decisions, especially in expanding therapeutic options for Ph + ALL, including tyrosine kinase inhibitors, targeted antibody therapies, chimeric antigen receptor cell therapy, and HCT.

A Multicentre, Randomized Trial in Adults with de novo Philadelphia Chromosome-Positive Acute Lymphoblastic Leukaemia to Assess the Efficacy of Ponatinib versus Imatinib in Combination with Low-Intensity Chemotherapy, to Compare End of Therapy with Indication for Stem Cell Transplantation versus Tyrosine Kinase Inhibitor, Blinatumomab, and Chemotherapy in Optimal Responders, and to Evaluate Blinatumomab in Suboptimal Responders (GMALL-EVOLVE).

INTRODUCTION: Philadelphia chromosome-positive acute lymphoblastic leukaemia (Ph+ALL) is treated as standard of care (SoC) by imatinib-based treatment combined with induction and consolidation chemotherapy followed by allogeneic stem cell transplantation (SCT) in first remission. The German Multicenter ALL Study Group for Adult ALL (GMALL) reports about a trial to evaluate the impact of ponatinib-based therapy, blinatumomab treatment for suboptimal responders, and the possibility of omission of SoC Allo SCT in optimal responders entitled GMALL-EVOLVE. METHODS: Herein, imatinib is randomized versus ponatinib as frontline treatment combined with chemotherapy, optimal responders also get randomized between SCT and chemo-immunotherapy, and suboptimal responders receive immunotherapy before SCT. The trial is registered under the EudraCT number 2022-000760-21. CONCLUSION: This trial will answer several major questions in the treatment of Ph+ALL.