Preparing for ASH 2020| Advances in ctDNA for lymphoma prognosis

The Lymphoma Hub is looking forward to attending the 62nd American Society of Hematology (ASH) Annual Meeting & Exposition, which will take place in a virtual format on December 5–8, 2020. Here, we provide a recap of the developments in prognostic methods discussed during last year’s meeting, and explore the emerging role of liquid biopsy and circulating tumor (ct)DNA, which looks set to make an impact at the 2020 meeting.

Ensure that you stay up to date with ASH by following our Twitter @lymphomahub and #ASH20. The Lymphoma Hub will be providing live coverage, articles on key sessions, and interviews with leaders in the field.

2019/2020 roundup

Lymphomas are aggressive cancers with a high risk of relapse. Although many screening tests exist, such as IGH-PCR and PET-CT, disease progression may not be picked up early enough for changes in treatment regimens to have a significant effect on survival. Monitoring disease progression through cell free (cf)DNA or ctDNA could represent a valuable new tool in the clinician’s armamentarium without the need for invasive procedures. Prognostic factors and liquid biopsies have been explored on the Lymphoma Hub over the past year and a summary of this can be found below.

Following the 15th International Congress on Malignant Lymphoma (15-ICML) last year, Dipti Talaulikar talked with the Lymphoma Hub about the role of liquid biopsy in non-Hodgkin lymphoma and its potential use in the clinic. Dipti Talaulikar advocates for the use of ctDNA not only as a screening tool for diagnosis and prognosis but also as a monitoring tool by assessing measurable residual disease (MRD) status following treatment. The video can be found below.

The subject of ctDNA also came up as part of our practice-changing abstract series from ASH 2019. Ulrich Jäger recommended an article by Ehsan Tabari and colleagues concerning ctDNA published in Blood.¹

In this study, 310 patients with diffuse large B-cell lymphoma (DLBCL) enrolled in the GOYA study (NCT01287741) were sampled for ctDNA measurement using next-generation sequencing (NGS). In each sample the number of tumor genome copies per mL of plasma (MMPM) was measured, which acts as a measurement of tumor burden. PET measurement of total metabolic tumor volume was significantly correlated with baseline MMPM (p < 0.001) and the sum product of diameters (SPD; p = 0.022). In addition, increased MMPM was correlated with the following:

• Increased International Prognostic Index scores (p < 0.001)
• Increased risk of bulky disease (p = 0.019)
• Reduced progression-free survival (HR, 1.46; p = 0.0006).

In a multivariate model accounting for MMPM and SPD, both were independently prognostic (MMPM, p = 0.010; SPD, p = 0.0046). MMPM was also significantly correlated with progression-free survival when International Prognostic Index and cell of origin were accounted for following analysis (HR, 1.23; p = 0.079).

In addition to these articles, the Lymphoma Hub explored the educational theme of prognostic factors in lymphoma in 2019 and this summary article can be found here.

ASH 2020: What to look out for

The program for ASH 2020 looks set to be as busy as ever. Using liquid biopsy to measure cfDNA and ctDNA appears to be a hot topic, with multiple abstracts being presented on these subjects. The Lymphoma Hub is happy to summarize the ones to look out for here.

Prognostic value of ctDNA in patients with DLBCL

Patients with de novo DLBCL are at a high risk of relapse or may be refractory to R-CHOP treatment, the current standard of care. Identifying what patients would benefit from improved therapies could reduce the current relapse rate, which is between 30 and 45%. In a phase Ib/II study (NCT02596971) that will be presented by Aparna Raval et al., patients with de novo DLBCL were treated with an initial R-CHOP cycle followed by R-CHOP and atezolizumab.² ctDNA analysis was performed on 26 patients, both before and during treatment, using CAncer Personalized Profiling by deep Sequencing (CAPP-Seq) technology for NGS, to determine whether these measurements could be a marker of high relapse risk in DLBCL.

Similarly, Reid Merryman and colleagues will be presenting an analysis of ctDNA in apheresis stem cell samples and post-transplant peripheral blood samples to determine whether this marker could predict relapse after autologous stem cell transplant in patients with DLBCL.³ In addition, Alex Herrera et al. will be reporting on whether using ctDNA can predict a higher risk of relapse in a phase Ib/II study (NCT02257567) of patients with relapsed/refractory DLBCL treated with bendamustine and rituximab +/− polatuzumab.⁴

Anthony Cutts and colleagues will state the results of their investigation of ctDNA, as well as total cfDNA, in the plasma using NGS by CAPP-seq in the ACCEPT phase Ib/II study (NCT03571308).⁵ In this study, patients with DLBCL received first-line treatment with R-CHOP and acalabrutinib. Samples were taken at four different time points (at baseline and prior to each cycle of chemotherapy) and data were available for 15 patients overall.

Using ctDNA to predict relapse of primary mediastinal B-cell lymphoma (PMBCL)

The prognosis for patients with PMBCL lymphoma following relapse is very poor. Therefore, being able to identify the patients at risk using ctDNA would be very valuable. Diwen Pang and colleagues,⁶ will be announcing their results from 38 patients with PMBCL that were retrospectively analyzed using NGS to measure ctDNA.

ctDNA-based MRD assessment in mantle cell lymphoma

A detailed assessment of MRD using ctDNA was performed in a study of ibrutinib plus rituximab followed by short course R-Hypercvad/MTX therapy in 161 patients with untreated mantle cell lymphoma. The results will be reported by Michael Wang at ASH 2020.⁷

Monitoring treatment responses using cfDNA

T-cell receptor (TCR) changes during antitumor immune responses are important for understanding the host’s reaction to disease. In a study that will be reported on by Navika Shukla and colleagues, cfDNA samples were used to profile the changes in TCR diversity in patients with T-cell lymphomas and patients with B-cell lymphomas treated with chimeric antigen receptor (CAR) T-cell therapy.⁸ A technique called Sequence Affinity capture & analysis By Enumeration of cell-free Receptors (SABER) was used to monitor TCR rearrangements in cfDNA along with CAPP-seq. Samples were taken from 75 patients with lymphoma and 18 healthy controls.

Response to CAR T-cell therapy was monitored using genome-wide sequencing of cfDNA in patients with DLBCL in a study that will be presented by Aaron Goodman et al.⁹ A median of ten blood samples per patient were taken from 12 cases and analyzed by NGS. Changes in copy number were quantified using the genomic instability number.

Liquid biopsies of the cerebrospinal fluid (CSF)

Central nervous system (CNS) involvement in patients with lymphoma is associated with dismal prognosis. Traditionally, cytology and flow cytometry have been used to monitor changes in the CSF, but the sensitivity of these methods is suboptimal. Liquid biopsies can be used to measure cfDNA and ctDNA in the CSF of patients with lymphoma to check for signs of CNS progression. Two abstracts to be presented at ASH 2020 describe the techniques used to analyze these prognostic factors.

Firstly, a study by Xiaoxiao Wang and colleagues measured ctDNA in the plasma and CSF of 67 patients with DLBCL at high risk of CNS relapse to evaluate the association between CSF ctDNA and high-risk CNS involvement.¹⁰

Secondly, Adam Olszewski et al. will be presenting their work on the use of tumor-specific CSF cfDNA, analyzed with NGS and PCR, to predict CNS involvement and relapse.¹¹ In this study, CSF samples were taken from six patients with lymphomas that had been diagnosed with parenchymal or leptomeningeal CNS invasion. Historical samples of eight patients who were negative for CNS involvement through conventional screening with IGH-PCR but who were subsequently found to have CNS lymphoma were also included. In addition, 19 newly diagnosed patients with high-risk lymphoma without known CNS involvement were prospectively enrolled in the study to assess the prognostic value of cfDNA measurement.

Conclusion

The use of liquid biopsy to measure cfDNA and ctDNA offers a noninvasive method to predict relapse in patients with lymphoma. This technique shows promise to be more sensitive than many conventional screening methods. The Lymphoma Hub is looking forward to hearing the full results of these exciting studies at ASH 2020. Please keep an eye on the Lymphoma Hub for further ASH coverage that will be coming soon!