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PET in DLBCL | Interim PET as a biomarker for response and PET-directed therapy for limited stage DLBCL

Feb 6, 2020
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18F-FDG positron emission tomography (PET) is widely used in the treatment of patients with diffuse large B-cell lymphoma (DLBCL) and is commonly used for disease staging or response assessment following treatment.1 However, 18F-FDG PET can also be used during treatment (interim PET [iPET]) to determine early response and may have a role in guiding treatment.1,2 Two abstracts were presented during the 61st American Society of Hematology (ASH) Annual Meeting & Exposition focusing on the potential of PET in patients with DLBCL. The first was a retrospective study presented by Corinne Eertink, Amsterdam University Medical Center (UMC), Amsterdam, NL, which aimed to answer the question: can 18F-FDG PET be used as an early biomarker for response?1 The second presentation was given by Daniel O. Persky, University of Arizona, Arizona, US, and addressed the question: can we use PET-directed therapy to cure limited stage DLBCL?2 Both of these presentations are summarized below, though data in this article may supersede that in the published abstracts.

18F-FDG PET as an early biomarker for response1

Corinne Eertink and colleagues conducted a retrospective meta-analysis of individual patient data from the PETRA database, to determine if iPET could be used as an early biomarker of response to treatment in patients with DLBCL. This study included patients (N= 1,840) with DLBCL who were treated with rituximab + cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) or dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, doxorubicin, and rituximab (DA-EPOCH-R) for whom iPET scans following 1–4 cycles of treatment, and survival data were available.

Criteria for response

iPET scans were scored using the Deauville scoring system (1–5) where a score of 1–3 is generally considered negative. An adapted version of the Deauville system was used, as shown in Table 1, using two cut-offs to define a positive Deauville score (DS): 4–5 (DS4–5) and 5 (DS5).

Table 1. Adapted Deauville score

Score

Definition

1

No uptake

2

Uptake ≤ mediastinum

3

Uptake > mediastinum but ≤ liver

4

Increased uptake compared to liver

5

Uptake ≥ 3x liver and/or new lesions

A standardized uptake value (ΔSUV) was also used to determine response (radioactivity concentration divided by administered dose per kg weight). Measuring ΔSUV at baseline and at iPET allowed a calculation of reduction in uptake. After 1–3 cycles of therapy, the iPET was considered negative if there was a ≥ 66% reduction, and after four cycles of therapy the cut-off was ≥ 70%.

Patients included in this analysis were treated on nine different studies, with iPET conducted typically at only one timepoint. The outcomes of these patients in relation to progression-free survival (PFS) significantly varied between studies, however this was predominantly due to the difference in enrolment criteria (high-risk vs low-risk patients). When PFS curves were corrected for International Prognostic Index (IPI) score, the outcomes were similar and so all patient data was used for the analysis.

Optimal timing

Using DS4–5 or DS5 as a positive iPET cut-off, the hazard ratios (HRs) for the two-year PFS increases as the timing of iPET increases (Table 2). This is also true when using the ΔSUV score. These results appear to indicate that iPET after one cycle is too soon to discriminate between responders and non-responders. After three cycles iPET is discriminative but due to the large confidence intervals (CIs), the investigators focused on responses after two or four cycles of therapy.  

Table 2. HRs at different timepoints by each criteria system
CI, confidence interval; DS, Deauville score; ΔSUV, standardized uptake value

Cycles of therapy

N

HR with DS4–5

95% CI

HR with DS5

95% CI

ΔSUV

95% CI

1

61

1.12

0.42–2.98

2.51

0.94–6.69

1.47

0.45–4.81

2

1,233

1.82

1.40–2.38

5.47

3.84–7.77

3.19

2.37–4.30

3

64

3.20

1.16–8.82

4.90

1.58–15.24

2.49

0.79–7.81

4

482

3.26

2.14–4.96

7.01

4.07–12.07

5.00

2.91–8.58

Survival

  • Positive iPET with DS4–5: survival probability, stratified by IPI score, showed iPET was prognostic for survival and was able to discriminate between responders and non-responders. iPET after four cycles of therapy had the highest discriminatory power
  • Positive iPET with DS5: patients with DS5 had a particularly poor response, and this was independent of timing. iPET was clearly prognostic in this group
  • Positive iPET by ΔSUV: iPET was prognostic across all IPI groups and iPET after four cycles had a slightly higher discriminatory power than after two cycles

Diagnostic accuracy

  • Negative predictive values (NPVs) were higher (> 80%), irrespective of iPET criteria or number of cycles of therapy (Table 3)
  • Positive predictive values (PPVs) were lower than NPVs, particularly with DS4–5, and were highest with DS5. ΔSUV PPV was highest after four cycles
Table 3. Two-year PFS PPVs and NPVs by criteria and timing of iPET

CI, confidence interval; DS, Deauville score; NPV, negative predictive value; PPV, positive predictive value; ΔSUV, standardized uptake value

Cycles of therapy and iPET positive criteria

PPV (95% CI)

NPV (95% CI)

Two cycles

 

 

DS4–5

28.9 (26.1–31.8)

83.5 (81.4–85.3)

DS5

64.6 (52.8–74.9)

80.9 (80.2–81.7)

ΔSUV

42.1 (35.2–49.3)

81.3 (80.2–82.3)

Four cycles

 

 

DS4–5

41.2 (33.5–49.3)

84.7 (82.4–86.8)

DS5

66.7 (46.8–82.0)

81.7 (80.3–82.9)

ΔSUV

52.8 (38.0–67.1)

82.3 (80.2–84.2)

Conclusion

  • iPET is prognostic for outcome, independent of IPI score
  • Patients with a DS5 have the poorest outcomes
  • The optimal timing of iPET depends on patient selection and the authors recommend:
    • Treatment de-escalation: iPET after two cycles
    • Treatment escalation:
      • DS5 patients: iPET after two cycles
      • DS4 patients and ΔSUV: iPET after four cycles

PET-directed therapy for limited stage DLBCL2

Daniel O. Persky presented the results of the Intergroup NCTN Study S1001 on behalf of the Southwest Oncology Group (SWOG) alliance. This abstract focused on PET-directed therapy for patients with DLBCL. The aim of the S1001 study was to cure limited-stage DLBCL (> 90% PFS at five-years) using the hypothesis that PET-directed therapy can guide the intensity of treatment (increase for high-risk [HR] and reduce for low-risk [LR]).

Study design

Patients with newly diagnosed non-bulky stage I/II DLBCL, with measurable or evaluable disease were enrolled (N= 159). Patients who were stage III/IV by PET received six cycles of R-CHOP (n= 1), whilst patients who were stage I/II by both computerized tomography (CT) and PET scans received three cycles of R-CHOP (n= 132). Twenty-six patients who were enrolled were subsequently considered ineligible, predominantly due to incorrect histology. Four patients who received three cycles of R-CHOP did not have an iPET. The remaining 128 patients were assessed for response after three cycles of R-CHOP (between Days 15–18 of Cycle 3). Of these, 110 were iPET-negative and 18 were iPET-positive. Four patients who were classed as iPET-positive had a DS of X and were treated as iPET negative, two patients refused further treatment, and one patient died. The results of iPET assessment dictated subsequent therapy, as below:

  • DS1–3: iPET-negative (n= 113):
    • One round of R-CHOP between Days 21-35 of Cycle 3
  • DS4–5: iPET-positive (n= 12):
    • 36–45 Gy involved-field radiation therapy (IFRT) starting between Days 21–35 of Cycle 3 of R-CHOP followed by ibritumomab tiuxetan starting between Days 21–42 after IFRT

The primary endpoint was five-year PFS and secondary endpoints were PFS by PET-positive and PET-negative subgroups, toxicity of PET-directed therapy, response and overall survival (OS) probability.

Patient characteristics (n= 132)

  • The median patient age was 62 years (range, 18–86) with 54% of patients > 60 years old
  • Most patients had a performance status of 0 (67%) and stage I disease (62%)
  • Extranodal involvement was noted in 43% of patients
  • Stage modified (Miller) IPI (smIPI, 0 vs 1 vs 2 vs 3): 27% vs 42% vs 28% vs 4%
  • Most patients were diagnosed with DLBCL not otherwise specified: 74%
  • The cell of origin was germinal center in 68% of patients (59/87)

Outcomes

  • Median follow-up: 4.5 years (range, 1.1–7.5)
  • Progression: five patients progressed
    • Three patients progressed after four cycles of R-CHOP
    • One patient was iPET-positive but declined radiation
    • One patient went off-treatment after one cycle of R-CHOP
  • Deaths:
    • Two patients died from lymphoma
    • Eleven patients died from non-lymphoma causes
  • Five-year PFS and OS rates are shown in Table 4
    • PFS rates were similar between iPET-positive and iPET-negative patients
  • A competing risk model was made:
    • Risk of progression or death by lymphoma at five-years: 4.3%
    • Risk of death by other causes at five-years: 10.8%
Table 4. PFS and OS for total cohort and by subgroup
OS, overall survival; PFS, progression-free survival

 

Total cohort

iPET-positive

iPET-negative

Five-year PFS

87%

86%

88%

Five-year OS

90%

93%

91%

Conclusion

The S1001 study is the largest study of limited DLBCL in the rituximab era. In total, 11% of patients were iPET-positive and received radiation therapy, but their outcomes were similar to patients who were iPET-negative. Most deaths were non-lymphoma-related, and due to a small number of lymphoma events, it was not possible to draw concrete conclusions on the prognostic ability of these variables. The authors concluded that R-CHOP for four cycles should be standard of care for limited stage disease in the majority of patients.

Future directions

These abstracts presented at the 61st ASH Annual Meeting & Exposition highlight the important role of PET in the treatment of lymphomas such as DLBCL. These studies have demonstrated iPET may be able to predict response, though the optimal timing is dependent upon the patient setting, and that iPET can guide the intensity of treatment without impacting outcomes in patients with limited DLBCL. 

To read the Lymphoma Hub Steering Committee’s opinions on these practice-changing abstracts, click here.

  1. Eertink C. et al., The Optimal Timing of Interim 18F-FDG PET in Diffuse Large B-Cell Lymphoma: An Individual Patient Data Meta-Analysis By the Petra Consortium. Blood.2019; 134 (supplement_1): 487. DOI: 10.1182/blood-2019-122298
  2. Persky D.O. et al., PET-Directed Therapy for Patients with Limited-Stage Diffuse Large B-Cell Lymphoma - Results of Intergroup Nctn Study S1001. Blood.2019; 134 (supplement_1): 349. DOI: 10.1182/blood-2019-123871
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