Dr Jabbour on Frontline Treatment Considerations in ALL

"Every patient should have a full profile from the biology point of view. [If I have a patient who is] Philadelphia chromosome [Ph]–positive, they have a specific treatment. Then I move to [determine if patients in the] frontline [have] Ph-negative B-cell, T-cell, Burkitt lymphoma, or Ph-like ALL…and then all other patients."

Elias Jabbour, MD, professor, Department of Leukemia, Division of Cancer Medicine, The University of Texas MD Anderson Cancer Center, discusses important frontline treatment considerations in newly diagnosed acute lymphocytic leukemia (ALL).

Treatment decisions for ALL are influenced by several critical factors, including patient age, immune phenotype, and disease biology, Jabbour begins. These factors guide initial therapy and help determine subsequent strategies such as transplantation or CAR T-cell therapy.

Patient age is a key consideration, as younger individuals generally tolerate intensive therapies better than older patients, Jabbour states. Older adults often have comorbidities and reduced tolerance to aggressive chemotherapy, necessitating tailored approaches to improve outcomes and minimize toxicity.

The immune phenotype, specifically whether the disease is B-cell or T-cell ALL, also dictates treatment strategies, he continues. Philadelphia chromosome (Ph)–positive ALL, for instance, requires TKIs such as imatinib (Gleevec) or dasatinib (Sprycel) combined with either chemotherapy or immunotherapy, Jabbour details. Conversely, patients with Ph-like or Ph-negative ALL follow distinct treatment pathways, emphasizing the need for comprehensive diagnostic profiling, he says.

Biological characteristics of the leukemia, such as hypodiploidy or other high-risk features, play a crucial role in planning post-remission therapy, Jabbour notes. For example, patients with hypodiploidy or other aggressive markers may benefit from frontline immunotherapy trials, yet they are likely candidates for subsequent transplantation to achieve durable remission, he explains. Similarly, patients with Burkitt's lymphoma or double-negative lineage ALL require unique therapeutic approaches, Jabbour adds.

Although up-front induction therapy may not always be heavily influenced by specific biological markers, these factors are critical for long-term treatment decisions, such as whether to pursue transplant as consolidation, Jabbour concludes.

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Elias Jabbour, MD, discusses frontline treatment considerations in newly diagnosed acute lymphocytic leukemia.

 of obecabtagene autoleucel (obe-cel; Aucatzyl) has added another treatment options for patients with acute lymphoblastic leukemia (ALL) in the relapsed/refractory setting, contributing to the growing number of options for patients with this disease.

 In light of the growing number of treatments, molecular testing will be a key factor in determining which therapy is right for a given patient, according to Elias Jabbour, MD.

“We’re witnessing a revolution in ALL management, and it relies on a better understanding of ALL physiopathology [in order to] be able to discern different subsets molecularly and different [disease] entities, and as a result [determine] our therapy accordingly,” Jabbour, a professor in the Department of Leukemia, Division of Cancer Medicine, at The University of Texas MD Anderson Cancer Center in Houston, said in an interview with 

. “[It’s also] very important is to assess the depth of response [to frontline therapy] as early as possible and tailor the treatment according to the response. It’s time to personalize our therapy based on a molecular profile of a patient and a second [therapy] on a molecular response to treatment.”

In recent years, investigators have made great advancements in using gene expression data to molecularly and cytogenetically classify ALL subtypes.

 Established B-cell ALL entities include Philadelphia chromosome (Ph)–positive and –negative ALL, as well as ALL with 

 rearrangement, high hyperdiploidy, hypodiploidy, 

 rearrangement, and iAMP21. Novel entities added in recent years include B-cell ALL with 

High-risk cytogenetic characteristics in ALL include 

 rearrangements, complex cytogenetics, and low hypodiploidy or near haploidy.

 are also associated with a poor prognosis.

Blinatumomab Makes Its Mark in Frontline ALL

In the first line of therapy, the standard of care for adult patients with ALL is chemotherapy, often with hyper-cyclophosphamide-vincristine-doxorubicin-dexamethasone.

 Although optimized frontline chemotherapy approaches have displayed impressive results in pediatric patients, they have been less effective in older patients and are often accompanied by higher rates of toxicity.

“Older patients have a very poor tolerance to chemotherapy, [as well as those] with more aggressive disease biology; they need to be treated differently than younger patients,” Jabbour said.

However, partially due to the advances in molecular subtype classification in ALL, investigators have been able to develop the CD19- and CD3-directed T-cell engager blinatumomab (Blincyto) to augment traditional chemotherapy. 

, blinatumomab was approved by the FDA for the treatment of adult and pediatric patients aged 1 month or older with CD19-positive, Ph-negative B-cell precursor ALL in the consolidation phase.

 The regulatory decision was supported by findings from the phase 3 ECOG-ACRIN E1910 study (NCT02003222).

Findings from ECOG-ACRIN E1910 demonstrated that patients who received blinatumomab in addition to multiphase consolidation chemotherapy (n = 112) achieved a 3-year overall survival (OS) rate of 84.8% (95% CI, 76.3%-90.4%) compared with 69% (95% CI, 58.7%-77.2%) among patients who received consolidation chemotherapy alone (n = 112; HR, 0.42; 95% CI, 0.24-0.75; 

 At a median follow-up of 4.5 years, the 5-year OS rates were 82.4% (95% CI, 73.7%-88.4%) and 62.5% (95% CI, 52.0%-71.3%), respectively (HR, 0.44; 95% CI, 0.23-0.76).

The efficacy of blinatumomab monotherapy was evaluated vs IntReALLHR2010 HC3 intensive combination chemotherapy as the third consolidation cycle in the phase 3 Study 20120215 (NCT02393859). Patients who received blinatumomab (n = 54) achieved a 5-year OS rate of 78.4% (95% CI, 64.2%-87.4%) vs 41.4% (95% CI, 26.3%-55.9%) among patients who received chemotherapy (n = 57; HR, 0.35; 95% CI, 0.17-0.70). The 5-year relapse-free survival rates were 61.1% (95% CI, 46.3%-72.9%) and 27.6% (95% CI, 16.2%-40.3%), respectively (HR, 0.38; 95% CI, 0.22-0.66). ˙

In the safety population of ECOG-ACRIN E1910, the most common any-grade adverse effects (AEs) that occurred in the blinatumomab arm (n = 111) included neutropenia (82%) thrombocytopenia (75%), anemia (59%), leukopenia (43%), and lymphopenia (32%). These events occurred in the chemotherapy arm at respective rates of 89%, 75%, 50%, 57%, and 25%. Fatal AEs were reported in 2 patients in the blinatumomab arm; patients in this arm also experienced dose interruptions (5%) and reductions (28%), and 2% were forced to discontinue treatment due to AEs.

Recent FDA Approvals Add Options in Relapsed/Refractory ALL

The most recent FDA approval in the relapsed/refractory ALL space was the CD19-directed genetically modified autologous T-cell immunotherapy obe-cel.

 The agent earned an indication for the treatment of adult patients with relapsed or refractory B-cell precursor ALL. The regulatory decision was supported by findings from the phase 1/2 FELIX trial (NCT04404660).

“[Although] the approval is for [relapsed]/refractory ALL, [obe-cel] will [eventually] be used earlier in the disease stage of ALL, [including] in [minimal residual disease] MRD–negative patients and frontline patients,” Jabbour noted.

Data from FELIX demonstrated that efficacy-evaluable patients (n = 65) achieved a complete remission (CR) rate within 3 months of 42% (95% CI, 29%-54%).

 Notably, the median duration of CR among these responders was 14.1 months (95% CI, 6.1-not reached [NR]). The overall CR rate was 63% (95% CI, 50%-75%) with a median duration of CR of 14.1 months (95% CI, 6.2-NR).

Obe-cel is unique among cellular therapies in that it is administered via split dosing, allowing for a higher dose (100 × 10

 CAR T cells) to be given on day 1 in patients with a low tumor burden (bone marrow blasts ≤ 20%) or at a lower dose (10 × 10

 CAR T cells) in patients with a high tumor burden (bone marrow blasts > 20%). Patients with a low tumor burden receive 310 x 10

 CAR T cells on day 10 if they did not experience grade 3 or higher cytokine release syndrome (CRS) or any-grade immune effector cell–associated neurotoxicity syndrome (ICANS); patients with high tumor burden receive 400 x 10

 CAR T cells on day 10 if they did not experience grade 3 or higher CRS or any-grade ICANS. In terms of safety, any-grade CRS occurred at a rate of 75% and at a rate of 3% for grade 3 events. Any-grade ICANS was reported in 24% of patients and 7% of patients had grade 3 or greater ICANS.

“This [dosing] strategy is safe and effective, but the [CAR T] cells are persistent,” Jabbour explained. “The advantage [of obe-cel] is that it is safe, effective, and leads to a persistent response and a plateau that will make this a viable option to be a finite therapy, where patients will have durable control of the disease with no concerns whatsoever. [These characteristics] will allow obe-cel to move to the frontline, or early on, in the treatment strategy compared with other CAR [T-cell agents].”

Beyond obe-cel, there are 2 other cellular therapies approved by the FDA for the treatment of patients with relapsed/refractory ALL: the CAR T-cell agents tisagenlecleucel (tisa-cel; Kymriah) and brexucabtagene autoleucel (brexu-cel; Tecartus).

 Tisa-cel was approved in August 2017 for the treatment of patients up to 25 years of age with B-cell precursor ALL that is refractory or in second or later relapse.

 In October 2021, brexu-cel earned FDA approval in adult patients with relapsed/refractory B-cell precursor ALL.

The FDA approval of tisa-cel was supported by findings from the phase 2 ELIANA trial (NCT02435849), which demonstrated that patients who received tisa-cel (n = 63) achieved a CR/CR with incomplete count recovery (CR/CRi) rate of 83% (95% CI, 71%-91%); the median duration of remission was NR (95% CI, 7.5-not evaluable).

 Additionally, 83% of patients (95% CI, 71%-91%) achieved a CR/CRi with MRD-negative bone marrow. Tisa-cel was the first CAR T-cell agent to earn FDA approval.

Data from the phase 1/2 ZUMA-3 study (NCT02614066) supported the approval of brexu-cel and showed that efficacy-evaluable patients (n = 54) achieved a CR/CRi rate of 64.8% (95% CI, 51%-77%), including a CR rate of 51.9% (95% CI, 37.8%-65.7%).

 The median duration of remission was 13.6 months (95% CI, 9.4-NE) and the median duration of remission among patients who experienced a CR was NR (95% CI, 9.6-NE). 

Outside of cellular therapies, the FDA has also recently approved the CD22-directed antibody-drug conjugate inotuzumab ozogamicin (Besponsa) for the treatment of pediatric patients at least 1 year of age with relapsed/refractory CD22-postive B-cell precursor ALL.

 was supported by findings from the phase 2 Study WI203581 (ITCC-059; NCT02981628).

Data from Study WI203581 demonstrated that the CR rate among all patients who received inotuzumab ozogamicin (n = 53) was 42% (95% CI, 28.1%-55.9%), with a median duration of CR of 8.2 months (95% CI, 2.6-NE).

 Most patients (95.5% [95% CI, 77.2%-99.9%]) achieved MRD negativity via flow cytometry and 86.4% (95% CI, 65.1%-97.1%) experienced MRD negativity by RQ-PCR.

In terms of safety, 21% of patients discontinued treatment with inotuzumab ozogamicin and 11% experienced dose interruptions. Any-grade AEs included pyrexia (49%), anemia (45%), and vomiting (45%). Grade 3 or higher AEs included anemia (38%), febrile neutropenia (28%), and infection (23%).

NCCN ALL Guidelines Continue to Evolve in 2024

Over the course of 2024 there were several notable updates to the National Comprehensive Cancer Network (NCCN) Clinical Practice Guidelines in Oncology for ALL.

 Notable updates in version 1.2024 of the guidelines from version 4.2023 included modifying T-cell ALL to include adding T-cell ALL, not otherwise specified, cortical type, mature type, and early T-cell precursor ALL. The guideline panel also noted that early T-cell precursor ALL usually lacks expression of CD5, CD8, and CD1a, as well as expression of at least 1 myeloid/stem cell marker.

In terms of treatment updates to the guidelines, blinatumomab in combination with a TKI was added as a new therapy option for adolescent and young adult patients, as well as patients who are less than 65 years old without substantial comorbidities, during the induction phase. This combination was also added as a new therapy option for adult patients who are at least 65 years old or with substantial comorbidities.

In the consolidation phase, patients with persistent or rising MRD gained inotuzumab ozogamicin with or without a TKI as a new therapy option. Additionally, the top treatment pathway was modified to consider allogeneic hematopoietic cell transplantation for these patients. Blinatumomab plus a TKI was noted as the preferred regimen in consolidation regardless of MRD status for the treatment of patients who are blinatumomab naive.

“We’re making significant progress towards curing ALL in adult patients, [in addition to] pediatric [patients]; it is going to happen in our lifetime,” Jabbour said in conclusion.

FDA approves obecabtagene autoleucel for adults with relapsed or refractory B-cell precursor acute lymphoblastic leukemia. FDA. November 8, 2024. Accessed December 4, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-obecabtagene-autoleucel-adults-relapsed-or-refractory-b-cell-precursor-acute

Davis K, Sheikh T, Aggarwal N. Emerging molecular subtypes and therapies in acute lymphoblastic leukemia. 

. 2023;40(3):202-215. doi:10.1053/j.semdp.2023.04.003

Jabbour E, Short NJ, Jain N, et al. The evolution of acute lymphoblastic leukemia research and therapy at MD Anderson over four decades. 

. 2023;16(1):22. doi:10.1186/s13045-023-01409-5

Aldoss I, Roboz GJ, Bassan R, et al. Frontline treatment of adults with newly diagnosed B-cell acute lymphoblastic leukaemia. 

. 2024;11(12):E959-E970. doi:10.1016/S2352-3026(24)00285-0

FDA approves blinatumomab as consolidation for CD19-positive Philadelphia chromosome-negative B-cell precursor acute lymphoblastic leukemia. FDA. June 14, 2024. Accessed December 4, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-blinatumomab-consolidation-cd19-positive-philadelphia-chromosome-negative-b-cell

Blincyto. Prescribing information. Amgen; 2024. Accessed December 4, 2024. https://www.pi.amgen.com/-/media/Project/Amgen/Repository/pi-amgen-com/Blincyto/blincyto_pi_hcp_english.pdf

Aucatzyl. Prescribing information. Autolus, Inc; 2024. Accessed December 4, 2024. https://www.fda.gov/media/183463/download?attachment

FDA approves tisagenlecleucel for B-cell ALL and tocilizumab for cytokine release syndrome. FDA. Updated September 7, 2017. Accessed December 4, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-tisagenlecleucel-b-cell-all-and-tocilizumab-cytokine-release-syndrome

FDA approves brexucabtagene autoleucel for relapsed or refractory B-cell precursor acute lymphoblastic leukemia. FDA. October 1, 2021. Accessed December 4, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-brexucabtagene-autoleucel-relapsed-or-refractory-b-cell-precursor-acute-lymphoblastic

Kymriah. Prescribing information. Novartis; 2017. Accessed December 4, 2024. https://www.fda.gov/media/107296/download

Tecartus. Prescribing information. Kite Pharma Inc; 2020. Accessed December 4, 2024. https://www.fda.gov/media/140409/download

FDA approves inotuzumab ozogamicin for pediatric patients with acute lymphoblastic leukemia. FDA. March 6, 2024. Accessed December 4, 2024. https://www.fda.gov/drugs/resources-information-approved-drugs/fda-approves-inotuzumab-ozogamicin-pediatric-patients-acute-lymphoblastic-leukemia

Besponsa. Prescribing information. Pfizer, Inc; 2024. Accessed December 4, 2024. https://www.accessdata.fda.gov/drugsatfda_docs/label/2024/761040s003lbl.pdf

NCCN. Clinical Practice Guidelines in Oncology. Acute lymphoblastic leukemia, version 2.2024. Accessed December 4, 2024. https://www.nccn.org/professionals/physician_gls/pdf/all.pdf

Articles

Recent advancements in the treatment of acute lymphoblastic leukemia (ALL) have been marked by the approval of several novel therapies, including CAR T-cell therapies and monoclonal antibodies. These therapies target specific molecular subtypes, offering personalized treatment options for patients with relapsed or refractory B-cell precursor ALL. The FDA has approved drugs like obecabtagene autoleucel, blinatumomab, and inotuzumab ozogamicin, reflecting a shift towards targeted therapies. These developments underscore the importance of molecular profiling in guiding treatment decisions and improving patient outcomes in ALL.

The therapeutic arsenal for patients with ALL in the first line and beyond is expanding beyond traditional approaches, enabling better outcomes for patients.

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