“We do not think that TKIs have any role in increasing CD86 on pDCs, simply because we have analyzed over 200 untreated CML patients before TKI exposure and they also have a similar pattern of CD86 positivity,” Dr Burchert told Cancer Therapy Advisor.

Patients from EURO-SKI TKI who maintained TFR within the first 12 months of discontinuing TKI therapy had a significantly lower median frequency of CD86-positive pDCS at baseline compared with patients who relapsed (P = .0144). The absolute CD86-positive pDC counts were significantly higher at baseline in patients who relapsed, with a median of 86.1 compared with 50.6 in normal donors (P = .0147).

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Dr Burchert said that more studies are needed, but if these findings are confirmed it would indicate that “patients with high CD86+ pDC counts have a much lower probability of TFR.”

In an interim analysis of EURO-SKI, patients with 95 or fewer CD86-positive pDCs demonstrated significantly prolonged relapse-free survival (RFS) if they received TKI treatment for at least 8 years (hazard ratio [HR], 0.3; 95% CI, 0.1-0.8; P = .0263).

RFS was significantly lower for patients with more than 95 CD86-positive pDCs vs those with 95 or fewer CD86-positive pDCs treated for at least 8 years (HR, 10.155; 95% CI, 3.179-38.229). Patients treated with a TKI for up to 8 years with high levels of CD86-positive pDCs maintained an increased risk of relapse, suggesting that the risk of relapse was independent of treatment duration in patients with high counts.

Dr Burchert noted that longer TKI-pretreatment duration increases the chance of TFR only in patients with low CD86-positive pDC counts. “This means that if you measure a patient with low, but not high, CD86-positive pDCs you can tell them, ‘if you stay on a TKI a bit longer before stopping, your chance of TFR rises,’” he said.

CD86-positive pDCs and T cell Exhaustion

T cell expression of PD-1 can indicate T cell exhaustion. The study found that CD86-positive pDC counts greater than 95 were associated with greater levels of PD-1-positive CD8-positive T cells. “Our data suggest that pDCs control T cell activation and risk of relapse,” said Dr Burchert. He suggested that stimulating the immune system with immune checkpoint inhibitors or interferon may improve TFR after TKI discontinuation.

Future Studies Planned

Dr Burchert told Cancer Therapy Advisor that his group has several more studies planned to further evaluate the role of CD86-positive pDCs in CML relapse.

RELATED: CML: First-line Generic Imatinib May Be Inferior to Branded Imatinib

The multicenter, randomized ENDURE trial will evaluate patients in deep MR who discontinue TKI therapy vs those who discontinue TKI treatment but receive maintenance therapy with ROG peginterferon for 15 months. The primary endpoint will be RFS after 6 months of TKI discontinuation and the secondary endpoints will include RFS at 12 and 24 months.

A similar trial, called INCEPTION, is planned later in 2017 and will use immune checkpoint inhibitors as maintenance therapy.

References

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  3. Imagawa J, Tanaka H, Okada M, et al. Discontinuation of dasatinib in patients with chronic myeloid leukemia who have maintained deep molecular response for longer than 1 year (DADI trial): a multicentre phase 2 trial. Lancet Haematol. 2015;2:e528-35. doi: 10.1016/S2352-3026(15)00196-9
  4. Rea D, Nicolini FE, Tulliez M, et al. Discontinuation of dasatinib or nilotinib in chronic myeloid leukemia: interim analysis of the STOP 2G-TKI study. Blood. 2017;129:846-54. doi: 10.1182/blood- 2016-09-742205
  5. Mahon FX, Rea D, Guilhot J, et al. Discontinuation of imatinib in patients with chronic myeloid leukaemia who have maintained complete molecular remission for at least 2 years: the prospective, multicentre Stop Imatinib (STIM) trial. Lancet Oncol. 2010;11:1029-35. doi: 10.1016/S1470-2045(10)70233-3
  6. Schutz C, Inselmann S, Sausslele S, et al. Expression of CTLA-4 ligand CD86 on plasmacytoid dendritic cells (pDC) predicts risk of disease recurrence after treatment discontinuation in CML. Leukemia. 2017 Jan 27. doi: 10.1038/leu.2017.9 [Epub ahead of print]

Topics:

Chronic Myeloid Leukemia Hematologic Cancers Leukemia