Recap: Fellows at MSK and Moffitt ‘Face Off’ to Discuss Treatment Strategies in Older Patients With ALL

As part of its inaugural Face-Off program, CancerNetwork^® hosted fellows from the Moffitt Cancer Center in Tampa, Florida, and from Memorial Sloan Kettering Cancer Center (MSK) in New York to compete in discussing treatment strategies for patients with acute lymphoblastic leukemia (ALL). The Moffitt and MSK teams were led, respectively, by Bijal D. Shah, MD, associate member, Department of Malignant Hematology, and Anthony Mato, MD, MSCE, director, Chronic Lymphocytic Leukemia Program.

The fellows on each institution’s team reviewed information from recent clinical studies, which were met by challenging questions from the opposition. After both teams were given a chance to defend their presentations, a live virtual audience rated their performance to determine a winner.

Moffitt Challenges

Nikesh Shah, MD, a third-year fellow in hematology and oncology at Moffitt, started the discussion by outlining a phase 1/2 trial (NCT01371630) with results presented by Hagop Kantarjian, MD, and colleagues in 2018 in Lancet Oncology. The combination of inotuzumab ozogamicin (Besponsa) plus lower-intensity hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with methotrexate and high-dose cytarabine (mini–hyper-CVD) was shown to be safe and effective in the first-line treatment of older patients with newly diagnosed, Philadelphia chromosome (Ph)–negative ALL.¹

In the trial, the patients’ median age was 68 years, and the primary end point was progression-free survival (PFS): median, 35 months (95% CI, 16.3 months to not reached [NR]); 2-year PFS, 59% (95% CI, 43%-72%); and 3-year PFS, 49% (95% CI, 32%-64%). Safety concerns included hepatic adverse events, which occurred in 100% of patients, and veno-occlusive disease (VOD), which affected 8%.

Mato asked Nikesh Shah if the results warrant use of the regimen despite lack of phase 3 randomized data.

“The challenging thing now is that [since] the publication of the trial in 2018, [we’ve seen] so many more advances in the frontline setting,” said Nikesh Shah. “It’s tough to sell frontline inotuzumab ozogamicin in the context of hepatotoxicity and VOD as well. Subsequent lowering of the inotuzumab dose reduced VOD, but that’s still something you’ll [need to] be
worried about.”

Next, Reem Akel, MD, a Moffitt first-year fellow, discussed a study examining pediatric-inspired regimens to treat adolescents and young adults (AYAs) with ALL. Results showed that despite evidence supporting the use of these regimens, adult oncologists had not widely adopted their use in this patient population.²

“We know that retrospective analyses and historical comparators have suggested that AYAs with ALL have superior outcomes when treated with pediatric treatment protocols. We also know that the pediatric ALL regimens are more intensive and highly regimented than adult regimens. The objective of this study was to provide a population-based description of the ALL treatment patterns in these AYA individuals,” Akel said.

The study, conducted using data from 2004 to 2014, showed that no patients treated by oncologists who typically treat adult patients before 2008 received a pediatric-inspired regimen. Further, while the US Adult Intergroup Cancer and Leukemia Group B (CALGB) 10403 study (NCT00558519) examining a pediatric-inspired ALL protocol was open to accrual from 2008 to 2012, only 31% of AYAs treated by adult oncologists in these years received a pediatric regimen. The rate dropped further, to 21%, in 2013 and 2014.

When questioned about these low rates, Akel said, “Pediatric-inspired regimens come with a lot of toxicity, particularly due to the asparaginase, and they are very regimented. There could be social barriers as well as toxicities that [prevent AYAs from receiving] all these cycles. These are among the biggest barriers that [clinicians] would [point to], compared with the adult regimens.”

In a follow-up question, the Moffitt team was asked about the data that would be necessary to help those oncologists who deal mostly with adult patients to decide between treatment with a regimen based on a hyperfractionated CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone) regimen vs a pediatric-inspired regimen. All in attendance agreed that a major challenge lies in deciding which situation is preferable: that a clinician is familiar with a regimen, it may not be as optimal in the given setting, use of a pediatric-based protocol, with no first-hand knowledge of treatment toxicities.

MSK Rebuttals

Varun Narendra, MD, a third-year fellow at MSK, presented the results of the CALGB 10403 trial published in Blood by Wendy Stock, MD, of the University of Chicago Comprehensive Cancer Center, and colleagues.³

The study’s motivation, said Narendra, was that several “retrospective analyses [indicated] that patients of equivalent age, or age-matched cohorts of patients, who had been enrolled on clinical trials as part of pediatric vs adult cooperative group studies had markedly different outcomes.”

The trial results showed manageable safety for pediatric regimens, with treatment-related mortality occurring in 3% of the 319 enrolled patients. Among 295 patients who were evaluable for response, median event-free survival (EFS) was 78.1 months (95% CI, 41.8-NR) at a median follow-up of 64 months for all surviving patients, more than double the EFS length of the historical controls. Median overall survival (OS) was NR, with a 3-year OS rate of 73% (95% CI, 68%-78%).

Narendra also presented data of a phase 2 trial (NCT01920737) that explored a pediatric-inspired chemotherapy regimen, incorporating pegaspargase, in adults aged less than 60 years with Ph-negative ALL. Investigators on that trial concluded that pegaspargase can be administered with intensive multiagent chemotherapy with a manageable safety profile, and that the regimen could serve as an effective backbone for novel agents going forward.⁴

Narendra was asked how he thought the 2 presented regimens compared in terms of safety and efficacy, and he replied that it all depends on the individual clinician’s definition of “tolerable.”

“Mortality was quite low across both studies, and efficacy was in the 70-plus-percent range. Many toxicities were significant, but whether they were truly symptomatic and whether [these events] led to worse outcomes is the most important thing to focus on. And that didn’t seem to be the case,” Narendra said. “Whether or not somebody got 3 or 6 doses of pegaspargase, per protocol, is less relevant than how they did in the long term. My sense was, in terms of severe morbidity from things like elevated bilirubin levels or elevated triglycerides, it was uncommon with both regimens to see symptomatic [events] or morbidity associated with the treatment.”

The final study was a retrospective comparison of baseline characteristics, treatment strategies, and outcomes from 321 AYAs aged 16 to 20 years with newly diagnosed ALL who participated in multiple trials; it was presented by Xiaoli Mi, MD, a first-year fellow at MSK.⁵ The 7-year EFS rates were 63% for the patients who were enrolled in the Children’s Cancer Group (CCG) trials vs 34% for those in the adult CALGB trials (relative HR, 2.2; P <.001).

Bijal Shah questioned Mi about an interesting finding: Whereas younger AYAs treated in the CALGB trials had similar outcomes to all patients treated in CCG, older AYAs (aged 18-20 years) who were treated with a CALGB protocol experienced a significantly worse 7-year EFS rate, at 29%.

“The [retrospective study’s authors] seemed to favor an extrinsic explanation, focused primarily on reduced adherence to the strict protocols by both patients and physicians who are in adult practices,” Mi responded. “The [authors] suggest that patients in adult practices may be emancipated adults who are under less parental supervision, and that may lead to [lower] adherence. Since ALL protocols are so complex and require a lot of oral administration at home, perhaps the younger adults who still live with their parents and go to pediatric practices may be adhering to those protocols better.”

Mi noted that the investigators tried to verify this possibility by examining the time to maintenance therapy initiation following complete remission, which was more rapid in those on pediatric vs adult trials. “But then they didn’t find a significant difference in EFS for those who reached maintenance therapy on time vs those who were delayed,” said Mi, leading her to wonder if the reasons could potentially be intrinsic. “Maybe [certain] disease characteristics in older patients, [such as] different molecular features and transcriptional differences, lead to worse outcomes,” Mi stated, adding that such characteristics weren’t explored in the study.

Face Off Winners

Based on a survey administered to a live virtual audience, the MSK team led by Mato finished in first place with 4.85 points, followed closely by the Moffitt team with 4.70 points.

References

1. 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
2. Muffly L, Lichtensztajn D, Shiraz P, et al. Adoption of pediatric-inspired acute lymphoblastic leukemia regimens by adult oncologists treating adolescents and young adults: a population-based study. Cancer. 2017;123(1):122-130. doi:10.1002/cncr.30322
3. Stock W, Luger SM, Advani AS, et al. A pediatric regimen for older adolescents and young adults with acute lymphoblastic leukemia: results of CALGB 10403. Blood. 2019;133(14):1548-1559. doi:10.1182/blood-2018-10-881961
4. Geyer MB, Ritchie EK, Rao AV, et al. Pediatric-inspired chemotherapy incorporating pegaspargase is safe and results in high rates of minimal residual disease negativity in adults up to age 60 with Philadelphia chromosome-negative acute lymphoblastic leukemia. Haematologica. 2021;106(8):2086-2094. doi:10.3324/haematol.2020.251686
5. Stock W, La M, Sanford B, et al; Children’s Cancer Group; Cancer and Leukemia Group B Studies. What determines the outcomes for adolescents and young adults with acute lymphoblastic leukemia treated on cooperative group protocols? a comparison of Children’s Cancer Group and Cancer and Leukemia Group B studies. Blood. 2008;112(5):1646-1654. doi:10.1182/blood-2008-01-130237