Beyond Therapeutic Advances, Elimination of MRD and Less Toxic Regimens Needed in AYA Patients With ALL

Wendy Stock, MD

The adoption of intensive pediatric treatment regimens has resulted in improved survival for adolescents and young adults (AYA) with acute lymphoblastic leukemia (ALL) over the past decade, said Wendy Stock, MD, at the 2018 SOHO Annual Meeting.

The next steps, she said, including eliminating minimal residual disease (MRD) early in treatment, minimizing toxicity, delivering treatment to high-risk subgroups, and addressing the unique psychosocial and economic challenges facing this often-overlooked patient population.

Stock, the Anjuli Seth Nayak Professor of Leukemia at the University of Chicago Medicine and co-leader of the Hematopoiesis and Hematological Malignancies program, University of Chicago Cancer Research Center. She was named the SOHO 2018 Distinguished Lecturer and delivered the keynote address at this year’s meeting.

Stock said that survival improved dramatically for AYA patients over the past decade when physicians adopted intensive pediatric regimens, rather than treating these patients with adult regimens. Previously, this population experienced the “AYA Survival Cliff,” where survival nosedived for patients aged 16 to 22 years. Results of an analysis of trials conducted by the Children's Cancer Group (CCG) or the Cancer and Leukemia Group B (CALGB) from 1988 to 2001 showed that AYA patients did better on pediatric regimens.¹

Complete response rates were 90% for AYAs treated in both CCG and CALGB trials, but 7-year event-free survival (EFS; relative HR, 63% vs 34%;P<.001) and overall survival (OS; 67% vs 46%; relative HR, 1.9;P<.001) favored CCG patients. Seven-year EFS for CALGB AYAs aged 16 to 17 years old was 55%, similar to all CCG AYAs, but the EFS for 18- to 20-year-old CALGB patients was only 29%.

&ldquo;We demonstrated a significant difference in outcomes for young adults treated with pediatric versus adult ALL regimens that was confirmed in multiple studies all over the world,&rdquo; Stock said. &ldquo;This challenged us to begin to address the idea of: could we improve outcomes if we actually treated young adults the same way that the pediatricians had so successfully treated children with ALL?

&ldquo;So, there has been this tremendous progress that we&rsquo;re all very excited about. We have so many new tools to improve those outcomes.&rdquo;

Stock is part of the research team that conducted the C10403 trial, which showed that a pediatric regimen improved survival in AYA patients aged up to 39 years compared with patients treated with an adult regimen. The 3-year EFS was 60% compared with 34% previously with an adult regimen and 3-year OS was 73% compared with 46%. Results from that trial are under publication review.

Investigators in the NOPHO ALL2008 trial found that a pediatric regimen improved survival for patients up to age 45. At a median 4.6-year follow-up, EFS was 74% for patients aged 18 to 45 years, 80% for those aged 10 to 17 years, and 89% for those aged 1 to 9 years.²

&ldquo;This study is a wonderful example of how risk stratification based on biology of the disease can be used in all ages to improve outcomes,&rdquo; Stock said. &ldquo;You can see outstanding survival for patients, even up to the age of 45 years, using the identical regimen but with different dose intensifications based on biology.&rdquo;

Data from COG ALL0434 presented at the 2018 ASCO Annual Meeting showed a 4-year DFS rate of 91% for patients with T-ALL and T-cell lymphoblastic lymphoma treated with a select nelarabine (Arranon) regimen.³

Patients were randomly assigned to escalating-dose methotrexate without leucovorin rescue plus pegaspargase (C-MTX) or high-dose MTX (HDMTX) plus leucovorin rescue. Intermediate- and high-risk patients were randomized to receive six 5-day courses of 650 mg/m²of daily nelarabine or no nelarabine.

The study included 3 other treatment arms comprising C-MTX alone, HD-MTX alone, or HD-MTX plus nelarabine. All patients initially received the COG augmented Berlin-Frankfurt-Munster multidrug chemotherapy regimen.

The 4-year DFS rates were 88% among patients receiving a nelarabine combination versus 83% for patients receiving HD-MTX or C-MTX alone. The 4-year OS rate was 90.2% among 1545 evaluable patients, and the 4-year EFS rate was 84.1%. Additionally, the number of central nervous system relapses was lower among patients receiving nelarabine, and there was no difference in neurotoxicities between treatment arms.

Rituximab (Rituxan) has also demonstrated efficacy in this population. In data from the phase III GRAALL-R 2005 study published in 2015, investigators demonstrated that adding rituximab to conventional chemotherapy improved EFS for patients aged 18 to 59 years with newly diagnosed, CD20-positive, Philadelphia chromosome-negative, B-cell precursor ALL. Two-year EFS increased from 52% with conventional therapy to 65% with rituximab.⁴

The 13% absolute difference in EFS translated into a 34% reduction in the hazard ratio in favor of rituximab (HR, 0.66;P= .038). An OS analysis demonstrated a trend in favor of rituximab (71% vs 64%), but the difference did not achieve statistical significance (HR, 0.70;P= .095).

With survival improvements in this population, Stock said investigators and physicians can turn their attention to eradicating MRD, thereby preventing the emergence of treatment-resistant clones. She added that MRD eradiation with additional treatment such as inotuzumab ozogamicin (Besponsa) and blinatumomab (Blincyto) must begin early in treatment, before such clones can develop.

&ldquo;We also need to focus and minimize toxicity,&rdquo; she said. &ldquo;Clearly, the toxicities of these pediatric regimens are more intense in the young adult population.&rdquo;

References:

1. Stock W, La M, Sanford B, et al. 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.
2. Toft N, Birgens H, Abrahamsson J, et al. Results of NOPHO ALL2008 treatment for patients aged 1—45 years with acute lymphoblastic leukemia.Leukemia. 2018;32(3):606-615. doi: 10.1038/leu.2017.265.
3. Dunsmore KP, Winter SS, Devidas M, et al. COG AALL0434: A randomized trial testing nelarabine in newly diagnosed t-cell malignancy.J Clin Oncol. 2018;36(suppl; abstr 10500).
4. Maury S, Chevret S, Thomas X, et al. Rituximab in B-lineage adult acute lymphoblastic leukemia.N Engl J Med. 2016;375:1044-1053. doi: 10.1056/NEJMoa1605085.