Article

Frontline Setting Boasts Multiple Treatment Options for Patients With ALL

Author(s):

Clinicians treating patients with newly diagnosed acute lymphocytic leukemia now have multiple options at their disposal, including tyrosine kinase inhibitors, blinatumomab, and multiagent chemotherapy-based regimens, with more options aiming to enter the treatment paradigm.

Jae H. Park, MD

Jae H. Park, MD

Clinicians treating patients with newly diagnosed acute lymphocytic leukemia (ALL) now have multiple options at their disposal, including tyrosine kinase inhibitors (TKIs), blinatumomab (Blincyto), and multiagent chemotherapy-based regimens, with more options aiming to enter the treatment paradigm, according to Jae H. Park, MD.1

“The biggest impact that we have made is in Ph [Philadelphia chromosome]–positive B-cell ALL. We not only have effective therapy [but] survival in these patients has clearly improved compared with traditionally what we have considered to be high-risk disease,” Park said during a presentation at the 40th Annual CFS®. “In adolescent and young adults and older adults, the trend is the incorporation of blinatumomab and inotuzumab ozogamicin [Besponsa]—that will make a big difference. There is also a COG [Children’s Oncology Group] study incorporating chimeric antigen receptor T cells in younger adults with ALL [who are] very high-risk patients. We also anticipate the results of those. There is a lot is happening.” Park is director of the Adult ALL Clinical Program and acting chief of the Cellular Therapeutics Service at Memorial Sloan Kettering Cancer Center in New York, New York.

Ph-positive Disease Has Multiple Effective Avenues

For patients with Ph-positive ALL, there are multiple combination strategies available. The TKI ponatinib (Iclusig) plus hyper-CVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone) has shown promising response rates in this patient population.

Findings from a clinical trial showed that patients with Ph-positive disease (n=68) achieved a complete response (CR) rate of 100%. Overall minimal residual disease (MRD) responses included complete molecular remission (CMR; 86%), major molecular response (MMR; 9%), and no MMR (6%).2

There were 11 relapses reported; 3 of these patients were taking ponatinib at the time of relapse, 6 were taking other TKIs, and 2 were not taking a TKI. The median time to relapse was 21 months (range, 5-80).

“[These are] somewhat old data, but [they are] kind of the latest,” Park said. “At 3 months, the overall response rate [ORR] didn’t really increase. [At] 3 months, most patients achieved this deep response.”

Longer term follow-up showed that the 3-year and 5-year overall survival (OS) rates among 86 treated patients were 80% and 76%, respectively. The 3-year and 5-year event-free survival (EFS) rates were 76% and 71%, respectively. The median age of patients in this analysis was 47 years (range, 39-61), and the median follow-up was 48 months (range, 10-100).

Additionally, blinatumomab can be used as a component of multiple combination regimens for patients with Ph-positive disease. In a phase 2 trial (NCT02744768), the agent was added to the TKI dasatinib (Sprycel). Patients received dasatinib induction at a dose of 140 mg per day up to day 84, after which they received 28 µg of blinatumomab per day intravenously for at least 2 cycles and a maximum of 5 cycles. Eligible patients had Ph-positive ALL and an ECOG performance status of 1 or 0.3

The primary end points were CMR and MRD negativity after 2 cycles. Secondary end points included CMR after dasatinib induction, CMR duration, and OS.

Findings from the study showed that at day 85 the overall molecular response rate was 29% among 59 efficacy-evaluable patients. However, overall molecular response rates after 2 (n=55), 3 (n=40), and 4 (n=36) cycles of blinatumomab increased to 60%, 70%, and 81%, respectively.

At a median follow-up of 14.3 months, the OS rate was 95.2% among 63 patients. The disease-free survival (DFS) rate was 89.7%. Twenty-four patients eventually had allogeneic hematopoietic stem cell transplantation (HSCT).

Another approach for patients with Ph-positive ALL involves the TKI ponatinib combined with blinatumomab. In a phase 2 trial (NCT03263572), investigators are evaluating the combination in patients with newly diagnosed or relapsed/refractory Ph-positive ALL. Ponatinib is given daily at a dose of 30 mg during cycle 1 then is decreased to 15 mg daily if a CMR is achieved.4

Early findings from the trial showed that at a median follow-up of 10 months (range, 1-41), 1-year OS rate in the overall cohort (n=50) was 93%. The 2-year OS rate was 79%.

Ph-negative Adolescents and Young Adults

As he transitioned into discussing treatment options for patients with Ph-negative disease, Park quickly highlighted the prognostic implication of MRD.

“There is a very clear distinction [in terms of] EFS- and OS-based MRD status,” Park said. “One of the more significant MRD time points is at the end of consolidation or induction, around 3 or 4 months. That is the time that we often switch therapy if they do have persistent MRD.”

In 2018, the FDA granted accelerated approval to blinatumomab for the treatment of adult and pediatric patients with B-cell ALL in first or second complete remission with MRD greater than or equal to 0.1%.5

The approval was based on findings from the phase 2 BLAST trial (NCT01207388), which enrolled patients with B-cell ALL after first CR or later and treated them with blinatumomab monotherapy. Patients also needed to have a persistent or recurrent MRD of at least 10–3 after a minimum of 3 blocks of intense chemotherapy. The primary end point was MRD-CR after cycle 1.6

Findings from the trial showed that the MRD-CR rate at cycle 1 was 80% (95% CI, 71%-87%) among 103 efficacy-evaluable patients. The median relapse-free survival, a key secondary end point, was 18.9 months (95% CI, 12.3-35.2) among 110 patients. Most patients (70%) proceeded to allogeneic HSCT.

There are multiple clinical trials underway examining therapeutic strategies for adolescents and young adults with Ph-negative ALL. In the phase 3 A041501 trial (NCT03150693), the monoclonal antibody inotuzumab ozogamicin is being added to a pediatric frontline chemotherapy regimen in young adults (aged 18-39 years). In the phase 3 trial E1910 (NCT02003222), combination chemotherapy is being evaluated with and without the use of blinatumomab as consolidation therapy.7,8

Treatment Options Continue to Expand for Ph-negative Older Adults

Blinatumomab monotherapy also is under evaluation as an initial therapy for adults 65 years or older with Ph-positive disease. In the phase 2 SWOG 1318 trial (NCT02143414). Among 29 eligible patients, the CR plus CR with incomplete hematologic recovery (CRi) rate was 66% (95% CI, 46%-82%). Additionally, the 1-year OS rate was 65% and no induction deaths were reported within the first 28 days.9

Another strategy for older patients involves combining inotuzumab ozogamicin with mini–hyper-CVD (a lower intensity version of hyper-CVAD). In a phase 2 study (NCT01371630), 52 patients with a median age of 68 years (range, 64-72) achieved an ORR of 98% and a CR rate of 85%. The median progression-free survival (PFS) was 35 months. The 2-year PFS and 2-year OS rates were 59% and 66%, respectively. The 3-year rates were 49% and 56%, respectively.10

Treatment with venetoclax (Venclexta) also has been making an impact among older patients with treatment-naïve ALL. In a phase 1 trial, investigators combined venetoclax with mini-hyper-CVD in patients 60 years and older with untreated Ph-negative ALL. The trial was later expanded to include adult patients with relapsed/refractory ALL.11

Among patients with de novo ALL (n=10), 9 patients achieved a CR and 1 patient experienced a partial response. Additionally, 9 patients were MRD negative.

The median age was 65 years (range, 23-82). Six of the patients with de novo disease went on to receive posttreatment allogeneic HSCT. Regarding safety, among all patients (n=18), grade 3 adverse events (AEs) included febrile neutropenia (39%), hyperglycemia (17%), and hypocalcemia (11%). Grade 4 pneumonia (11%) and sepsis (11%) were also present. There were no grade 5 AEs.

“This is ongoing, [these are] preliminary data,” Park said. “The response rates are quite good at over 90% CR rate but, again, it is only 10 patients. [Additionally], some of these responses to appear to be durable.”

There are also multiple ongoing clinical trials examining combination therapy approaches in older patients with ALL.

In the upcoming phase 2 A042001 trial (NCT05303792), investigators will be comparing the safety and efficacy of inotuzumab ozogamicin plus chemotherapy with that of usual chemotherapy in older adult patients with treatment-naïve B-cell ALL or B-cell lymphoblastic lymphoma. Eligible patients must be at least 50 years old; have Ph-negative, CD22-positive disease; and have an ECOG performance status of 2 or less. An ECOG performance status of 3 will be permitted if it is related to disease.12

Patients with uncontrolled infections, cardiac disease, central nervous system involvement, and/or other cancers will not be eligible for the trial. Qualified patients will be randomly assigned via parallel assignment to receive either inotuzumab ozogamicin plus mini–hyper-CVD followed by maintenance POMP (prednisone, vincristine, 6-mercaptopurine, and methotrexate) or dose adjusted hyper-CVAD followed by maintenance POMP. Patients will be stratified by age (< or ≥70 years) and CD20 status (positive or negative).

The primary end point of the trial is EFS after cycle 2. Secondary end points include DFS, OS, ORR, and the rate of grade 3 to 5 adverse events. The accrual goal of the trial is 80 patients, and it is not yet recruiting.

Inotuzumab ozogamicin is also being evaluated in older adult patients with B-cell ALL in another phase 2 trial, A041703 (NCT03739814), in this case in combination with blinatumomab. Patients must have had treatment-naïve, Ph-negative, CD22-positive disease to be included in the trial. Eligible patients also needed to be at least 60 years old, be ineligible for HSCT, and have no central nervous system disease.13

In cohort 1 of this trial, patients received 1 cycle of inotuzumab ozogamicin. Patients with no cytoreduction then were treated with blinatumomab for 4 to 5 cycles, then proceeded to follow-up. If adequate cytoreduction was observed after the first cycle of inotuzumab ozogamicin, patients received another cycle before moving on to blinatumomab and follow-up.

The primary end point was 1-year EFS, with a goal of at least 30%. Secondary end points included OS, MRD negativity, EFS, and ORR. The accrual goal of the trial was 29 patients and accrual was completed in June 2021.

References

  1. Park JH. Updates in newly diagnosed ALL. Presented at: 40th Annual CFS®: November 9-11, 2022; New York, NY, and virtual.
  2. Short NJ, Kantarjian HM, Ravandi F, et al. Long-term safety and efficacy of hyper-CVAD plus ponatinib as frontline therapy for adults with Philadelphia chromosome-positive acute lymphoblastic leukemia. Blood. 2019;134(suppl 1):283. doi:10.1182/blood-2019-125146
  3. Foà R, Bassan R, Vitale A, et al; for the GIMEMA Investigators. Dasatinib-blinatumomab for Ph-positive acute lymphoblastic leukemia in adults. N Engl J Med. 2020;383(17):1613-1623. doi:10.1056/NEJMoa2016272
  4. Short NJ, Kantarjian HM, Konopleva M, et al. Combination of ponatinib and blinatumomab in Philadelphia chromosome-positive acute lymphoblastic leukemia: early results from a phase II study. J Clin Oncol. 2021;39(suppl 15):7001. doi:10.1200/JCO.2021.39.15_suppl.7001
  5. FDA granted accelerated approval to blinatumomab (Blincyto, Amgen Inc.) for the treatment of adult and pediatric patients with B-cell precursor acute lymphoblastic leukemia. News release. FDA. March 29, 2018. Accessed November 9, 2022. bit.ly/2lc8EQR
  6. Gökbuget N, Dombret H, Bonifacio M, et al. Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia. Blood. 2018;131(14):1522-1531. doi:10.1182/blood-2017-08-798322
  7. Inotuzumab ozogamicin and frontline chemotherapy in treating young adults with newly diagnosed B acute lymphoblastic leukemia. ClinicalTrials.gov. Updated May 27, 2022. Accessed November 9, 2022. https://clinicaltrials.gov/ct2/show/NCT03150693
  8. Combination chemotherapy with or without blinatumomab in treating patients with newly diagnosed BCR-ABL-negative B lineage acute lymphoblastic leukemia. ClinicalTrials.gov. Updated September 16, 2022. Accessed November 9, 2022. https://clinicaltrials.gov/ct2/show/NCT02003222
  9. Advani AS, Moseley A, O’Dwyer KM, et al. SWOG 1318: a phase II trial of blinatumomab followed by POMP maintenance in older patients with newly diagnosed Philadelphia chromosome-negative B-cell acute lymphoblastic leukemia. J Clin Oncol. 2022;40(14):1574-1582. doi: 10.1200/JCO.21.01766
  10. Kantarjian H, Ravandi F, Short NJ, et al. Inotuzumab ozogamicin in combination with low-intensity chemotherapy for older patients with Philadelphia chromosome-negative acute lymphoblastic leukaemia: a single-arm, phase 2 study. Lancet Oncol. 2018;19(2):240-248. doi:10.1016/S1470-2045(18)30011-1
  11. Jain N, Stevenson KE, Winer ES. Et al. A multicenter phase I study combining venetoclax with mini-hyper-CVD in older adults with untreated and relapsed/refractory acute lymphoblastic leukemia. Blood. 2019;134(suppl 1):3867. doi:10.1182/blood-2019-129988
  12. Testing the combination of inotuzumab ozogamicin and lower dose chemotherapy compared to usual chemotherapy for adults with B-cell acute lymphoblastic leukemia or B-cell lymphoblastic lymphoma. ClinicalTrials.gov. Updated August 3, 2022. Accessed November 9, 2022. https://clinicaltrials.gov/ct2/show/NCT05303792
  13. Inotuzumab ozogamicin and blinatumomab in treating patients with newly diagnosed, recurrent, or refractory CD22-positive B-lineage acute lymphoblastic leukemia. ClinicalTrials.gov. Updated November 7, 2022. Accessed November 9, 2022. https://clinicaltrials.gov/ct2/show/NCT03739814
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