Outcomes of patients with myelodysplastic syndromes ( MDS ) after hypomethylating agent ( HMA ) failure remain poor. Improving the response and survival of patients with higher-risk myelodysplastic syndromes and developing treatments for patients after hypomethylating agent failure is needed.
Upregulation of PD-1, PD-L1 and CTLA-4 in CD34+ cells after exposure and loss of response to hypomethylating agent have been reported ( Yang, Leukemia 2014 ).
Nivolumab ( Opdivo ) and Ipilimumab ( Yervoy ) are monoclonal antibodies targeting PD-1 and CTLA-4, respectively, with clinical activity in solid tumors.
Researchers have hypothesized that use of these drugs after HMA failure or in combination with Azacitidine ( Vidaza ) in the frontline setting may improve treatment outcomes of patients with myelodysplastic syndromes.
A phase II study of Nivolumab or Ipilimumab in monotherapy or combination for patients with myelodysplastic syndromes was designed.
Patients with prior therapy with hypomethylating agent were to be treated in one of 3 consecutive cohorts: cohort #1: Nivolumab 3mg/kg iv days 1 and 15 of a 28 day cycle; cohort #2: Ipilimumab 3mg/kg iv on day 1 of a 21 day cycle; cohort #3: Nivolumab 3 mg/kg iv on days 1 and 15 + Ipilimumab 3 mg/kg iv on day 1 of a 28 day cycle.
The study design allowed for Azacitidine add-back after 6 cycles of therapy if there was no response or progression.
Patients with previously untreated myelodysplastic syndromes were to be treated in one of 3 consecutive cohorts combining Azacitidine 75mg/m2 iv daily days 1-5 of a 28 day cycle in each cohort with: cohort #4: Nivolumab 3mg/kg iv on days 6 and 20; cohort #5: Ipilimumab 3mg/kg iv on day 6; and cohort #6: Nivolumab 3 mg/kg iv on days 6 and 20 + Ipilimumab 3 mg/kg iv on day 6.
The maximum size per cohort is 20 patients.
The primary endpoint was to determine the safety of Nivolumab or Ipilimumab as single agents or in combination with Azacitidine. Secondary objectives included overall response rate ( ORR ) and assessment of biological activity.
Responses were evaluated following the revised 2006 International Working Group ( IWG ) criteria.
The study included stopping rules for response and toxicity.
Adverse events were assessed and graded according to the CTCAE v4 criteria.
A total of 39 patients were registered between September 2015 and July 2016, with 2 enrollment failures, 13 ( 35% ) treated with frontline Azacitidine + Nivolumab, and 15 ( 41% ) and 9 ( 24% ) with Nivolumab or Ipilimumab after HMA failure, respectively.
Thirty-five pts ( 95% ) were evaluable for toxicity and 33 ( 89% ) for response at the time of analysis.
The median number of treatment cycles was 4 ( range 2-11 ) in patients treated with Azacitidine + Nivolumab, 3 ( 1-8 ) in the Nivolumab cohort, and 3 ( 2-4 ) in the Ipilimumab cohort.
A total of 25 ( 71% ) patients experienced at least one adverse effect during therapy, with 3 ( 27% ) patients in the Azacitidine + Nivolumab cohort, 6 ( 40% ) in the Nivolumab cohort, and 3 ( 33% ) in the Ipilimumab cohort having related grade greater than or equal to 3 non-hematologic adverse effects.
Therefore, the stopping rule for toxicity was not met in any of the cohorts.
Delays of therapy due to adverse effects were required in 9 patients due to: rash ( n=1 ), adrenal insufficiency ( n=1 ), colitis ( n=1 ), thyroiditis ( n=2 ), pneumonitis ( n=3 ), and nephritis ( n=1 ).
Early 8-week mortality occurred in 1 patient due to a non-related intracranial hemorrhage.
The ORR was 69% ( 6/11 ) in the Azacitidine + Nivolumab cohort including 2 CR [ complete response ], 5 mCR [ major cytogenetic response ] + HI [ hematological improvement ], and 2 HI.
The ORR was 0% and 22% ( 2/9 ) in the Nivolumab and Ipilimumab arms, respectively ( p=0.156 ).
Therefore, the stopping rule for response was met on the Nivolumab arm, and enrollment after patient 15 was stopped.
A total of 4 and 1 patients required addition of Azacitidine due to lack of response on the Nivolumab and Ipilimumab arms, respectively.
At the present time of follow up, 18 ( 49% ) patients remain on study, with 3 having been taken off study due to death ( all in the Nivolumab arm ), 3 due to no response (Azacitidine + Nivolumab: 1; Nivolumab: 2 ), 6 due to progression to acute leukemia (Azacitidine + Nivolumab: 1; Nivolumab: 4; Ipilimumab: 1 ), 1 due to transplant, and 1 due to side effects from therapy in the Ipilimumab arm.
Immunophenotypic analysis of stem cell and progenitor compartments was performed in 27 patients, including PD-1 and PD-L1 expression analysis in 16 patients.
Increased PD-1 and PD-L1 expression on progenitor and stem cell compartments was observed in 3 and 4 patients, respectively.
Treatment with PD-1 inhibitors could not overcome the aberrant differentiation patterns. No differences in response were observed based on PD-1 bone marrow expression.
In conclusion, preliminary results have indicated that PD-1 blockade with Nivolumab in combination with Azacitidine in untreated higher-risk patients with myelodysplastic syndromes is associated with a tolerable safety profile and clinical activity.
Single-agent Ipilimumab is capable of inducing responses in previously treated patients with myelodysplastic syndromes.
Single-agent Nivolumab did not show clinical activity.
Further follow-up is needed to update efficacy and safety data. ( Xagena )
Garcia-Manero G et al, ASH ( American Society of Hematology ) Meeting, 2016