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ctDNA surveillance to detect early relapse in patients with large B-cell lymphoma

Aug 27, 2021
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Treatment with axicabtagene ciloleucel (axi-cel) has been beneficial to many patients with relapsed/ refractory large B-cell lymphoma (LBCL); however, many patients do not achieve durable remission. Early identification of patients that are likely to progress earlier could allow for more successful interventions. The current method relies on positron emission tomography-computed tomography (PET-CT) serial imaging; however, circulating tumor DNA (ctDNA) has been identified as having potential as a marker of disease progression. Recombination in variable, diversity, and joining gene segments of immunoglobulin genes results in unique markers of clonality, which can be used to monitor B-cell malignancies through cell-free DNA using next generation sequencing.

In a prospective study by Frank, et al. the value of ctDNA monitoring in patients with LBCL was investigated.1

The Lymphoma Hub recently ran an educational theme investigating the use of ctDNA, the first article can be found here.

Study design

This study included 72 patients and assessed the value of ctDNA analysis before and after treatment with axi-cel.

Eligibility criteria for the study included adults ≥18 years of age who had been:

  • diagnosed with diffuse LBCL, transformed follicular lymphoma or primary mediastinal B-cell lymphoma,
  • enrolled prior to lymphodepleting (LD) chemotherapy,
  • had histology samples available for clonotype identification; and,
  • had disease measurable by PET-CT.

The primary endpoints were:

  • To assess the ability of pre-lymphodepletion (pre-LD) ctDNA in predicting the progression free survival (PFS) of axi-cel treated patients with LBCL, with ≥6 months follow-up.
  • To investigate the association of ctDNA and minimal residual disease (MRD) on Day 28 to predict PFS of patients with LBCL being treated with axi-cel.

The baseline patient characteristics of the 72 patients included in this study are shown in Table 1. Most of the patients included were diagnosed with diffuse LBCL (68%). The median age of those enrolled was 62 years, 35% of patients were ≥65 years, and 60% of patients were male. Patients had received a median of 3 lines of therapy, and 51% had elevated lactate dehydrogenase (LDH).

Table 1. Patient demographics*

Demographics, % (unless otherwise stated)

Enrolled patients
(N = 72)

Primary analysis
(n = 64)

Durable responders
(n = 33)

Progressors
(n = 31)

p value

Subtype

 

 

 

 

 

              DLBCL

68

67

70

65

              TFL

24

25

18

32

              PBMCL

8

8

12

3

Median age (range), years

62 (19–79)

59 (19–76)

61 (19–76)

53 (29–73)

0.0175

              ≥65 years

35

31

48

13

0.0029

Sex, male

60

56

45

68

0.0841

Disease characteristics and risk factors

 

 

 

 

 

              Stage III or IV

72

72

66

77

0.4104

              Elevated LDH

51

52

27

77

0.0001

              Bulky

18

19

15

23

0.5307

              Double hit

22

20

18

23

0.7606

Lines of therapy

 

 

 

 

 

              Median (range),               n

3 (1–7)

3 (1–7)

3 (1–6)

3 (2–7)

              ≥3

60

58

55

61

0.621

              Auto

11

11

9

13

0.7039

              Allo

3

3

3

3

>0.9999

Allo, allogeneic; auto, autologous; DLBCL, diffuse large B-cell lymphoma; LDH, lactate dehydrogenase; PBMCL, primary mediastinal B-cell lymphoma; TFL, transformed follicular lymphoma.
Adapted from Frank, et al.1

Results                                                                                                                 

Survival outcomes and adverse events

The overall response rate was 84.7% and the complete response rate was 63.9%. Median PFS was 10.3 months, median duration of response was 79.5% at one year, and median overall survival was 71.2% at one year.

Recorded adverse events included any grade cytokine release syndrome (CRS) (91.7%) vs Grade ≥3 CRS (5.6%), and any grade immune effector cell-associated neurotoxicity syndrome (ICANS) (55.6%) vs Grade ≥3 ICANS (27.7%). Of the 72 patients included in the study, 96% had sufficient formalin-fixed paraffin-embedded (FFPE) samples for tumor clonotype tracking. Clonotypes were identified from FFPE in 93%, while 7% ultimately required the use of initial plasma samples when clonotypes could not be identified using FFPE tissue.

ctDNA analysis

A significant association was found between elevated LDH levels and high pre-LD ctDNA concentration as compared with normal LDH (p < 0.001). In addition, an International Prognostic Index score of ≥3 vs a score of 0–2 (p = 0.0143) and stage III−IV vs stage I or II disease were also associated with elevated pre-LD ctDNA (p = 0.0196; Table 2).

Table 2. ctDNA concentration association with clinical characteristics*

 

Median Pre-LD ctDNA concentration
(range), LG/ml

p value

IPI 0–2

14 (0–3,200)

0.0143

IPI ≥3

187 (0–17,903)

Stage I–II disease

5 (0–3,200)

0.0196

Stage III–IV disease

133 (0–17,903)

Normal LDH

7 (0–13,270)

<0.0001

Elevated LDH

529 (1–17,903)

Received bridging therapy

187 (0–17,903)

0.0310

Did not receive bridging
therapy

14 (0–2,032)

ctDNA, circulating tumor DNA; IPI, international prognostic index; LD, lymphodepletion; LDH, lactate dehydrogenase; LG, lymphoma genomes.
Data from Frank, et al.1

ctDNA was measured until the patient experienced disease progression, died, or reached one year after therapy. Patients that showed a durable response had a decreased level of pre-LD ctDNA compared with progressing patients (8 [0–1,327] LG/mL vs 581 [0–17,903] LG/mL, p < 0.0001). In total, 70% of responding patients had no measurable ctDNA by Day 7, which became 100% after Day 90.

For most patients experiencing disease progression, there was an initial decrease which reached its lowest point by Day 28 at 6 (0–2,945) LG/ml, this was followed by a subsequent increase. A 1-log reduction in ctDNA concentration was seen in 77% of patients experiencing disease progression, while 52% showed a 2-log reduction at the lowest point compared with baseline. Notably, 39% of progressing patients had at least one sample with undetectable ctDNA levels between Days 7 and 21.

There was a group of nine durable responders and three patients experiencing disease progression that had no detectable ctDNA despite having PET-avid disease when they were enrolled. For the three patients with disease progression, ctDNA became measurable after Days 0, 7, and 90, respectively. For the durable responders, ctDNA levels remained undetectable during the study period.

Risk of relapse and pre-LD ctDNA concentration

The association of the pre-LD ctDNA with risk of relapse or progression was investigated and it was found that ctDNA concentrations >100 LG/ml had an increased risk (Table 3).

Table 3. Correlation of pre-LD ctDNA concentration with survival outcomes*

Pre-LD ctDNA, LG/ml

1-year PFS, %

1-year OS, %

ctDNA <10

78

90

ctDNA 10–100

77

91

 

Median PFS

Median OS

ctDNA 100–1,000

3

19

ctDNA >1,000

3

7.4

ctDNA, circulating tumor DNA; LD, lymphodepletion; LG, lymphoma genomes; OS, overall survival; PFS, progression free survival.
Data from Frank, et al.1

The association between the risk of developing CRS and ICANS and pre-LD ctDNA concentration was also analyzed. Patients with low grade or no CRS had significantly decreased median ctDNA concentration compared with Grade ≥3 (p = 0.0485). For no or Grade 2 ICANS vs Grade ≥2 ICANS a similar trend was seen (p = 0.0340).

ctDNA surveillance and MRD

On Day 28, ctDNA was measured—along with clinical and radiographic staging—to assess for MRD; detection of any amount of ctDNA was recorded as MRD positive. Of the 72 patients, 60 had samples available for analysis; 50% were durable responders and the other 50% were patients experiencing disease progression. Of the durable responders, 83% were MRD negative. Of the patients experiencing disease progression, 73% were MRD positive.

At least one MRD positive sample was recorded prior to relapse for all 30 of the patients in which the disease progressed.

MRD status was also compared with response measured by PET-CT on Day 28. The four patients who had progressive disease on Day 28 were all MRD positive and had a median OS of 3.2 months. Once these patients were excluded, a significant difference was found between median PFS and OS for MRD negative patients vs MRD positive or those with PET-avid disease (Table 4). Results for patients achieving a complete response were similar to the outcomes for MRD negative patients.

Table 4. MRD status on Day 28 and survival outcomes*

 

Median PFS,
months

p value

Median OS,
months

p value

MRD positive

3.03

<0.0001

19.0

0.008

MRD negative

NR

NR

PR or SD

3.1

0.0018

19.0

0.0033

Achieved CR

NR

NR

CR, complete response; MRD, measurable residual disease; NR, not reached; OS, overall survival; PFS, progression free survival; PR, partial response; SD, stable disease.
Data from Frank, et al.1

Conclusion

ctDNA shows promise as an early marker for relapse and progression in LBCL patients treated with axi-cel alongside PET-CT evaluation. ctDNA monitoring also has the advantage of being non-invasive. A total of 97% of patients experiencing disease progression had detectable ctDNA levels at the same time they were found to be progressing. In addition, almost all patients became MRD positive prior to relapse, demonstrating that serial ctDNA measurements may be a valuable tool in asymptomatic patients.

  1. Frank MJ, Hossain NM, Bukhari A, et al. Monitoring of circulating tumor DNA improves early relapse detection after axicabtagene ciloleucel infusion in large B-cell lymphoma: results of a prospective multi-institutional trial. J Clin Oncol. 2021. Online ahead of print. DOI: 1200/JCO.21.00377

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