ASH Clinical News July 2016 | Page 43

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tions had the smallest increase in elongation , the authors noted .

Of patients evaluable for hematologic response , 79 percent ( 19 / 24 ) experienced a hematologic response at three months , 81 percent ( 17 / 21 ) at six months , 78 percent ( 14 / 18 ) at 12 months , and 83 percent ( 10 / 12 ) at 24 months .

“ To our knowledge , this is the first drug capable of preserving telomeres in humans with a genetic impairment involving telomere maintenance ,” Dr . Townsley told ASH Clinical News . “ These findings suggest that androgens could be studied in other disorders where telomere shortening is pathologic . For example , they could be used following chemotherapy where proliferative stress drives telomere shortening .”

Of the 13 transfusion-dependent patients at baseline , only one patient continued to require regular transfusions after danazol treatment . Patients with hemoglobin levels < 9.5 g / dL at baseline saw mean increases of 3.3 g / dL ( 95 % CI 2.1-4.4 ) of hemoglobin and 41,300 / mm 3 in their ( 95 % CI 25,320-57,280 ) absolute reticulocyte count . Neutrophil counts increased by a mean of 300 / mm 3 ( 95 % CI 124-476 ) and platelet counts increased by 14,250 / mm 3 ( 95 % CI 4,880-23,620 ).

The most common treatment-related AEs included increased liver enzyme levels ( 41 %), muscle cramps ( 33 %), edema ( 26 %), and lipid abnormalities ( 26 %). One patient died of an acute exacerbation of pulmonary failure associated with viral pneumonia .

Three patients experienced disease progression while receiving danazol . Marrow cytogenetic abnormalities appeared in two patients , without morphologic evidence of MDS . “ Lower doses of danazol or other hormone formulations are likely to have better side effect profiles ,” the authors wrote .

The small patient population and mutations not always being identified in patients are limitations of this study . The researchers also suggested that a longer observation period prior to the start of danazol treatment could have provided a better baseline to assess treatment effects .

TABLE 2 . Change in Telomere Length During Study Course

Time after Treatment Initiation

Number of Patients

Mean Change in Telomere Length ( bp )

Patients with Increase in Telomere Length

76 % ( 95 % CI 56-96 )

89 % ( 95 % CI 73-100 )

92 % ( 95 % CI 73-100 )

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Patients ’ blood counts and liver function were evaluated at baseline and monthly after the initiation of danazol treatment .

The primary efficacy endpoint was biologic response at 24 months ( defined as a reduction in the telomere length attrition rate to ≤96 bp per year ), while the primary safety endpoint was toxic AEs during the 24-month treatment period . Secondary endpoints included : relapse ; development of myelodysplastic syndromes ( MDS ) or acute myeloid leukemia ( AML ); progression of pulmonary fibrosis ; survival ; and hematologic response ( defined as an increase in hemoglobin level of ≥1.5 g / dL or no further need for transfusions or a > 50 % reduction in transfusions , a ≥20,000 / mm 3 increase in platelet count , or a ≥500 / mm 3 increase in neutrophil count ).

Of the 27 patients enrolled , 10 had mutations in TERT , seven had mutations in TERC , three had mutations in DKC1 , and one had a mutation in RTEL1 . Most patients ( 85 %) had a family history of telomere disease .

As of April 2015 , 11 of the first 12 patients evaluated at 24 months had consistent telomere elongation , prompting the NHLBI to close the study early . All patients met the primary efficacy endpoint , and in the intention-to-treat analysis , the response rate was 44 percent ( n = 12 / 27 ; 95 % CI 26-64 ).

Telomere elongation was noted at all time points during danazol treatment ( TABLE 2 ). Patients with TERT mutation had greater telomere elongation compared with those with unidentified mutations , while those with TERC and DKC1 muta-

“ Patients now have more options other than just transplant , and danazol may ameliorate failure of other organs , as it appeared to stabilize liver and lung disease ,” Dr . Townsley said . “ To adequately assess this theory , we need follow-up studies powered to investigate these endpoints .” ●

REFERENCE

Townsley DM , Dumitrui B , Liu D , et al . Danazol treatment for telomere diseases . N Engl J Med . 2016 ; 374 ; 1922-32 .

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