[Show abstract][Hide abstract] ABSTRACT: We have previously shown that serum VEGF-D is elevated at baseline, correlates with kidney angiomyolipoma size at baseline and 12 months, and decreases with sirolimus treatment in adults with tuberous sclerosis complex (TSC). To further investigate the utility of serum VEGF-D for longer term monitoring of TSC kidney disease, we present VEGF-D level results with 24 month follow-up.
To compare 24 month VEGF-D levels in two subgroups of sirolimus treated patients (OFF SIROLIMUS AFTER 12 MONTHS or ON SIROLIMUS AFTER 12 MONTHS). DESIGN AND INTERVENTION(S): Serum VEGF-D was measured in samples collected from subjects enrolled in a phase 2 multicenter trial evaluating sirolimus for the treatment of kidney angiomyolipomas associated with TSC or TSC/LAM. All participants were treated with sirolimus from 0-12 months. During months 12-24, sirolimus was discontinued in one subgroup. The other subgroup was treated with additional sirolimus.
Adult TSC participants were recruited from six clinical sites in the United States (comprehensive TSC clinics, 5; urology clinic, 1).
There were 28 TSC patients who completed all 24 months of the study and serum samples were available at 24 months from 18/28 patients.
We compared the percent change in VEGF-D levels (baseline to 24 months) in patients from the two treatment subgroups.
At 24 months, VEGF-D levels decreased by 67% compared with baseline (to 787±426 pg/ml) in the ON SIROLIMUS AFTER 12 MONTHS group versus a 13% decrease (to 2971±4014 pg/ml) in the OFF SIROLIMUS AFTER 12 MONTHS group (p = 0.013, Mann-Whitney test). A similar trend was observed in kidney angiomyolipoma size but not in pulmonary function tests. Conclusions Serum VEGF-D may be useful for monitoring response to treatment with sirolimus and kidney angiomyolipoma size in patients with TSC, but confirmation is needed.
Clinical trials.gov NCT00126672.
[Show abstract][Hide abstract] ABSTRACT: Kidney function before and after sirolimus treatment. Almost all those enrolled had good renal function with a normal creatinine and BUN at baseline. There were only 6 with a creatinine ≥1.5 mg/dL at study entry. The average creatinine at study entry was 1.10±0.40 mg/dL (range 0.7–2.6, n = 36). The average blood urea nitrogen (BUN) at study entry was 17.75±10.70 mg/dL (range 8–70, n = 36). Sirolimus was not nephrotoxic in this population. Based on creatinine and BUN data at study entry and week 52, there was no significant difference after 52 weeks of drug treatment. For the 28 participants who completed 52 weeks of treatment, the average creatinine was 1.01±0.27 mg/dL at week 0 and 1.01±0.33 mg/dL at week 52. Similarly, the average BUN was 15.82±5.70 mg/dL at week 0 and 15.48±5.80 mg/dL at week 52 (see details in table below).
[Show abstract][Hide abstract] ABSTRACT: TSC skin manifestations before and after sirolimus treatment. These observations indicate that TSC related skin lesions seem to improve in some individuals after 52 weeks of sirolimus treatment. It is particularly encouraging that improvement was reported for facial angiofibromas in 57% of participants. Although the subjective nature of the assessment is a limitation of this data, these findings are consistent with a recent case report on the efficacy of systemic sirolimus for the treatment of TSC skin lesions . Topical sirolimus is also of therapeutic interest because it has anti-tumor activity in a mouse model for TSC related tumors  and there is also a recent case report on the potential utility of topical sirolimus for the treatment of TSC skin lesions . Overall, the exploratory results on TSC skin lesions indicate that additional clinical trials evaluating systemic or topical sirolimus for the treatment of TSC related skin disease could lead to new therapeutic options for these problems.
[Show abstract][Hide abstract] ABSTRACT: Tuberous sclerosis (TSC) related tumors are characterized by constitutively activated mTOR signaling due to mutations in TSC1 or TSC2.
We completed a phase 2 multicenter trial to evaluate the efficacy and tolerability of the mTOR inhibitor, sirolimus, for the treatment of kidney angiomyolipomas.
36 adults with TSC or TSC/LAM were enrolled and started on daily sirolimus. The overall response rate was 44.4% (95% confidence intervals [CI] 28 to 61); 16/36 had a partial response. The remainder had stable disease (47.2%, 17/36), or were unevaluable (8.3%, 3/36). The mean decrease in kidney tumor size (sum of the longest diameters [sum LD]) was 29.9% (95% CI, 22 to 37; n = 28 at week 52). Drug related grade 1-2 toxicities that occurred with a frequency of >20% included: stomatitis, hypertriglyceridemia, hypercholesterolemia, bone marrow suppression (anemia, mild neutropenia, leucopenia), proteinuria, and joint pain. There were three drug related grade 3 events: lymphopenia, headache, weight gain. Kidney angiomyolipomas regrew when sirolimus was discontinued but responses tended to persist if treatment was continued after week 52. We observed regression of brain tumors (SEGAs) in 7/11 cases (26% mean decrease in diameter), regression of liver angiomyolipomas in 4/5 cases (32.1% mean decrease in longest diameter), subjective improvement in facial angiofibromas in 57%, and stable lung function in women with TSC/LAM (n = 15). A correlative biomarker study showed that serum VEGF-D levels are elevated at baseline, decrease with sirolimus treatment, and correlate with kidney angiomyolipoma size (Spearman correlation coefficient 0.54, p = 0.001, at baseline).
Sirolimus treatment for 52 weeks induced regression of kidney angiomyolipomas, SEGAs, and liver angiomyolipomas. Serum VEGF-D may be a useful biomarker for monitoring kidney angiomyolipoma size. Future studies are needed to determine benefits and risks of longer duration treatment in adults and children with TSC.
[Show abstract][Hide abstract] ABSTRACT: MR images of SEGA (brain tumor) before and after sirolimus treatment. T1 post gadolinium MR images demonstrate a SEGA that measured 2.03 cm at baseline and 1.68 cm at week 52.
[Show abstract][Hide abstract] ABSTRACT: Percent change in kidney angiomyolipomas size at 12 and 24 months for individual subjects. A) Subjects from the ON SIROLIMUS AFTER 12 MONTHS subgroup (n = 6); B) Subjects from the OFF SIROLIMUS AFTER 12 MONTHS subgroup (n = 12). The blue bars show the percent change in kidney tumor size at 12 months. The red bars show year 2 measurements of kidney tumors in treatment subsets (24 months). Arrows indicate return to baseline (0% change). Note: the subject with the tumor size increase of ∼60% had a single small tumor at baseline. In this case, the tumor diameter was 2.2 cm at baseline, 3.2 cm at 4 months, 2.9 cm at 8 months, 1.8 cm at 12 months, 3.5 cm at 18 months, and 3.5 cm at 24 months. Because of the small size of the tumor, we suspect that the changes noted during our study may be in part due to imaging slightly different tumor cross sections at different time points. All details regarding timing of response, number of tumors per subject, and kidney tumor size have been published in reference 19 (Table S1).
[Show abstract][Hide abstract] ABSTRACT: TSC gene mutations. TSC gene mutation testing is now commercially available so we collected this data in our study subjects (see Table below). There were 18 cases that underwent mutation testing, 15 that were not tested, and 3 for whom testing status is unknown. In the 18 cases that were tested, 14 had TSC2 gene mutations, 0 had TSC1 mutations, and no mutation was identified in 4 cases. The TSC2 mutation spectrum included 3 missense, 3 in frame deletions, 1 frame shift deletion, 3 nonsense, 1 splice, 1 large deletion, 1 inversion, and 1 unknown mutation type. When we compare this data (14 TSC2 mutations, 0 TSC1 mutations, 3 with no mutations identified ) to previously published genotype-phenotype data it appears that there may be a slightly higher frequency of TSC2 mutations in the participants of this study (14/18, 78%) compared with the TSC populations from two genotype-phenotype studies where the frequency of TSC2 mutations was 66–70% , . There were a number of subjects for whom testing was not done (15/36, 42%), which suggests that mutaton testing is not considered critical and while mutaton testing can be very helpful for genetic counseling purposes, the expense may be a barrier for many, and testing is not considered critical for management decisions in this group.
[Show abstract][Hide abstract] ABSTRACT: Summary of hematuria data. Hematuria was not common, but was observed in 4 participants at study entry. In all 4 cases, baseline hematuria was minimal (up to 20 RBCs/high powered field (hpf)). As shown in the table below, at each time point there were 3–4 participants with minimal to mild hematuria (up to 10,000 RBCs/hpf). There were no cases of moderate/severe hematuria (>10,000 RBCs/hpf) at any time during this study. Interestingly, minimal to mild hematuria seemed to come and go in different participants over time. There were a total of 14 subjects who had minimal to mild hematuria at one of these time points (but not others) and 1 subject who had mild hematuria at 2 time points. Hematuria was clinically insignificant, remained infrequent, and generally did not persist so does not appear to be related to treatment with sirolimus.
[Show abstract][Hide abstract] ABSTRACT: Summary of proteinuria data. At study entry, proteinuria was not common but was noted in 4 subjects (31 with no proteinuria, 1-unknown). Of the 4 with proteinuria, according to urine dipstick testing, there were 2 with trace to 1+ proteinuria, 1 with 2+ proteinuria, and 1 with 3+ proteinuria. We did observe an increased frequency of proteinuria with sirolimus treatment, but in most cases proteinuria was trace to 1+. More severe (3+) proteinuria was less common but was observed in 2/28 (7.1%) subjects at week 52. In one case, the 3+ proteinuria prompted a sirolimus dose reduction and treatment with lisinopril. The data is summarized in the table below. There were 2 cases that had no proteinuria at baseline, but had 2+ or 3+ proteinuria at week 52. There were also 2 cases that had 2+ to 3+ proteinuria at baseline but had improvement at the week 104 visit. At week 52 there were 10 cases with proteinuria, at week 78 there were 6 cases with proteinuria, and at week 104 there were 11 cases with proteinuria. Almost all of these cases had only mild (trace to 1+) proteinuria. Of the 11 cases with trace to 1+ proteinuria at week 104, 7 were taking sirolimus according to the amended version of the protocol. Our data shows that an increased frequency of mild proteinuria may be a side effect of sirolimus treatment in this study population, which is consistent with the known toxicities of sirolimus in the kidney transplant population (Rapamune product information). It is important to note that severe proteinuria was infrequent and in 2 cases proteinuria improved during sirolimus treatment.
[Show abstract][Hide abstract] ABSTRACT: MR images of kidney angiomyolipoma before and after sirolimus treatment. Post contrast MR images demonstrate an angiomyolipoma (arrow) in the right kidney measuring 3.62 cm maximal diameter at baseline, and 2.26 cm maximal diameter at week 52.