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Ibrutinib and Obinutuzumab in chronic lymphocytic leukemia: MRD responses sustained for several years with deepest MRD depletion in patients with more than 1 year prior Ibrutinib exposure


Ibrutinib ( Imbruvica ) inhibits chronic lymphocytic leukemia ( CLL ) proliferation and effects prolonged remission without eradicating disease.
Obinutuzumab ( Gazyvaro ) is an anti-CD20 monoclonal antibody that can effect depletion of measurable residual disease ( MRD ) below 0.01%.

In the IcICLLe study, 20 treatment-naïve CLL patients and 20 with relapsed / refractory ( R/R ) chronic lymphocytic leukemia received Ibrutinib until complete remission with less than 0.01% MRD in the bone marrow ( BM ) or disease progression.
The IcICLLe Extension Study examined the efficacy/safety of combining Ibrutinib & Obinutuzumab in 40 patients with R/R chronic lymphocytic leukemia and was open to the IcICLLe R/R cohort.
Initial results after 1 month of combination treatment have indicated that adding Obinutuzumab to Ibrutinib improved CLL depletion, and 3-5 year follow-up data is now available.

The aim of the study was to assess the long-term MRD response status for patients treated with Ibrutinib as a sole agent or in combination with Obinutuzumab.

Patients received continuous Ibrutinib ( 420mg OD ) with the addition of 6 cycles of Obinutuzumab given over 6 months in the extension study.
20 treatment-naive patients received Ibrutinib monotherapy; 20 R/R patients ( median 2 prior treatments, range 1-7 ) initiated Ibrutinib monotherapy of which 10/20 enrolled in the Extension study receiving Obinutuzumab after more than 1year of Ibrutinib monotherapy; and 30 Ibrutinib-naïve R/R ( median 1 prior treatment, range 1-3 ) started Obinutuzumab 24 hours after first Ibrutinib dose.
MRD assessment was performed according to ERIC guidelines with a maximum detection limit of 0.001%/10-5.

Ibrutinib monotherapy in treatment-naive patients was well tolerated with 18/20 patients alive and 13/20 remaining on Ibrutinib after median 4.9 years follow-up ( range 0-5.9 ).
Ibrutinib was stopped due to toxicity ( 3 ), progression/relapse ( 2 ) or other causes ( 2 ).
Ibrutinib-monotherapy resulted in median 0.65 log depletion per year in years 1-2, followed by relatively stable disease levels ( median 0.2 log depletion per year ) in the subsequent 3 years in 13/20 evaluable patients.
Only 1 patient showed more than 0.3log increase in peripheral blood MRD level and this preceded clinical progression.
No patients achieved an IWCLL CR/CRi and MRD was more than 0.01% in PB/ bone marrow in all patients at all time points.

In the R/R group initially receiving Ibrutinib-monotherapy, 11/20 patients remain alive and 3/20 remain on Ibrutinib after a median 3.9 years follow-up ( range 0.3-5.3 ).
In this heavily pre-treated group, 10 did not enrol on the Obinutuzumab Extension study ( 1 died, 1 progression/relapse, 4 ineligible/other causes, 4 patient preference ) with 10/20 receiving Obinutuzumab at median 16.2 months ( range 13-19 ) after starting Ibrutinib-monotherapy of which 7/10 had resolved any lymphadenopathy pre-Obinutuzumab.
2/10 achieved MRD-negative remission and stopped treatment, while 6/10 have since stopped Ibrutinib due to death ( 2 ), progression / relapse ( 3 ) or other causes ( 1 ).
30 R/R patients with no prior Ibrutinib exposure ( most in first relapse ) started Ibrutinib and Obinutuzumab at the same time: 26/30 remain alive and 18/30 remain on Ibrutinib after median 3.0 years follow-up ( range 0.8-4.2 ).
Ibrutinib was stopped in 2/30 patients achieving MRD-negative remission while 10 stopped Ibrutinib due to death ( 2 ), disease progression / transformation ( 3 ), toxicity ( 4 ), or patient decision ( 1 ).

There were no grade 5 adverse events related to Obinutuzumab.

3 months post-Obinutuzumab, patients with more than 1 year prior Ibrutinib-monotherapy achieved a higher response rate ( CR/CRi 50% vs 30% ), MRD response ( less than 0.01% bone marrow MRD in 50% vs 6% ) and a greater depth of remission ( 3.1 vs 1.5 log reduction ) compared to Ibrutinib-naive patients despite greater number of prior treatment lines.

The deepest peripheral blood MRD responses were observed 6-12 months after the last Obinutuzumab infusion.
MRD levels showed little change in the following year to month 24 ( median 0 log depletion, range 1.3 log depletion to 2.5 log increase ).

After 2 years of Ibrutinib exposure, the MRD levels shows a similar pattern to treatment-naive patients on Ibrutinib monotherapy, being generally very stable ( less than 0.3log increase ) except in 7 patients showing more than 0.3log increase at two sequential timepoints of which 4/7 have shown clinical disease progression and 3/7 still have low ( less than 1% ) but rising MRD levels.

In conclusion, the addition of Obinutuzumab to Ibrutinib may substantially improve depletion of CLL cells from the peripheral blood and bone marrow.
A greater impact in MRD response rate and depth was seen when Obinutuzumab was introduced after more than 1 year of Ibrutinib treatment and tumour bulk was low.
One fifth of patients maintain less than 0.01% MRD up to 3 years after combined Ibrutinib + Obinutuzumab, demonstrating that response improvements associated with Obinutuzumab are sustainable in some cases. ( Xagena )

Source: American Society of Hematology ( ASH ) Virtual Meeting, 2020

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