Genetic Mutations, Changes in Circulating Tumor DNA Levels Predict Early Response to Panobinostat for Patients with Diffuse Large B-Cell Lymphoma

Treatment with panobinostat, an oral pan-histone deacetylase inhibitor (HDI), led to durable responses in a subset of patients with diffuse large B-cell lymphoma (DLBCL), according to results from a randomized, phase II study published in Blood. The study authors, led by Sarit Assouline, MDCM, MSc, from the Jewish General Hospital at McGill University in Canada, were also able to identify certain genetic markers that could predict early response to treatment.

Dr. Assouline and authors evaluated the response rate and toxicity of panobinostat, with or without rituximab, in 40 patients with relapsed/refractory transformed or de novo DLBCL, as well as the association between HME mutations and response to treatment.

All patients in the study received 30 mg of panobinostat administered orally three days a week (every Monday, Wednesday, and Friday), and 19 patients also received 375 mg/m2 of rituximab administered intravenously every three weeks.

Adult patients were enrolled from four Canadian sites between December 2010 and December 2013; all patients had relapsed/refractory DLBCL for which no curative therapy was available, a platelet count ≥100×1012/L, adequate hepatic and renal function, an Eastern Cooperative Oncology Group performance status of 0-2, and measureable disease (≥1.5 cm) by computed tomography (CT) scan. Patients were excluded from the study if they had received rituximab within 84 days of enrollment or other prior therapies within 28 days. CT scans were performed at baseline and at every other cycle to assess response. Treatment continued for at least six cycles or until unacceptable toxicity or disease progression.

The median patient age was 59.8 years (range = 28.9-78.6 years), and the median number of prior therapies was three (range = 1-9 therapies). Thirteen patients had follicular lymphoma that had transformed to DLBCL.

The overall response rate (the study’s primary endpoint) was 29 percent (95% CI 11.3-52.2) for patients receiving panobinostat alone and 26 percent (95% CI 9.2-51.2) for patients receiving panobinostat plus rituximab. Rituximab, therefore, did not appear to improve response in patients with DLBCL, despite preclinical models suggesting that panobinostat’s effect could be augmented by rituximab, the authors observed.

Seven patients experienced a complete response (CR) and four had a partial response (PR). All other patients progressed on treatment. The median time to response was 42 days (range = 21-231 days), and the median duration of response was 14.5 months (95% CI 9.4 – not reached), with the longest response ongoing at 43.2 months. The overall median progression-free survival (PFS; a secondary endpoint of the study) was less than three months, with a median PFS of 14.5 months for those who responded to treatment (95% CI 9.4 – not reached).

Among the 11 responding patients, a median of six treatment cycles were administered (range = 4-50 cycles). Five responding patients had progressed at the time of study analysis.

“The response rate observed [in this study] was appreciably higher than previous studies of HDI in DLBCL, which may be due to the purported greater potency of panobinostat relative to other HDIs,” the authors wrote. See TABLE for a complete comparison of treatment efficacy.

The most common grade ≥3 adverse events associated with panobinostat with or without rituximab were thrombocytopenia and neutropenia. Toxicity-related dose reductions and dose interruptions or delays were required in 58 percent (n=23) and 55 percent of patients (n=22), respectively. “As expected, panobinostat was associated with thrombocytopenia and neutropenia, which required dose reductions in a large number of patients,” Dr. Assouline and authors wrote. “Overall, a lower dose of panobinostat, such as 20 mg three times per week, and possibly a two-week-on/one-week-off regimen should be considered in subsequent trials to allow more continuous therapy.”

To help identify patients who are most likely to respond to HDI treatment, the authors compared circulating tumor DNA (ctDNA) analysis and tissue biopsies before treatment and at day 15 of panobinostat treatment. Biopsy samples were assessed for mutations commonly associated with DLBCL (including HME genes) and for COO, MYC, and BCL2 expression.

Twenty-three biopsies were obtained prior to panobinostat treatment; the remaining patients underwent targeted gene sequencing.

Patients with MEF2 tumor mutations (representing 15.4% of patients tested) were more likely to respond to panobinostat, with a likelihood ratio of 3.67 for achieving a CR or PR (95% CI 1.46-9.19). The authors noted that this raises “the possibility that these mutations are associated with greater sensitivity to HDI.”

Early changes in ctDNA levels (measured in 25 patients via lymphoma-related gene-sequencing and digital polymerase chain reaction) appeared to be a strong predictor of changes in tumor burden. Levels differed substantially from baseline to day 15 of panobinostat treatment in the majority of patients (n=20/25), and 10 patients had increased ctDNA levels at this time.

“Changes in ctDNA after only 15 days of therapy [demonstrated a] very high specificity and positive predictive value,” the authors explained. “No patients with an increase in ctDNA at 15 days responded to treatment, while all patients who eventually responded had a significant drop in ctDNA after 15 days of therapy. Overall survival and PFS were also significantly associated with a decrease in ctDNA.”

Though the study was limited by its small sample size and unblinded design, the results “promote sequence-based analysis of ctDNA as a powerful and promising tool for gleaning early signals of response, while possibly affording opportunity to detect ongoing clonal evolution, a known feature of DLBCL,” the authors concluded.


Reference

Assouline SE, Nielsen TH, Yu S, et al. Phase 2 study of panobinostat +/- rituximab in relapsed diffuse large B cell lymphoma and biomarkers predictive of response. Blood. 2016 May 10. [Epub ahead of print]

TABLE. Comparison of Treatment Efficacy
  Panobinostat

(n=21)

Panobinostat plus Rituximab

(n=19)

Overall

(n=40)

Best response
n Percentage (95% CI) n Percentage (95% CI) n Percentage (95% CI)
ORR (CR + PR) 6 29%

(95% CI 11.3-52.2)

5

 

26%

(95% CI 9.2-51.2)

11

 

28%

(95% CI 14.6-43.9)

CR 5 24% 2 11% 7 18%
PR 1 5% 3 16% 4 10%
SD 0 0% 1 5% 1 3%
PD 15 71% 13 68% 28 70%
Time to response
Median days 73 21 42
Range (days) 23-209 21-231 21-231
Duration of response
Median months Not reached 9.4

(95% CI 4.3-not reached)

14.5

(95% CI 9.4-not reached)

Range (months) 6.2-43.2 1.6-40.5 1.6-43.2
Number progressed 2 3 5
ORR = overall response rate; CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease

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