Browse the corpus

Pomalidomide for Epistaxis in Hereditary Hemorrhagic Telangiectasia. BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is characterized by extensive telangiectasias and arteriovenous malformations. The primary clinical manifestation is epistaxis that results in iron-deficiency anemia and reduced health-related quality of life. METHODS: We conducted a randomized, placebo-controlled trial to evaluate the safety and efficacy of pomalidomide for the treatment of HHT. We randomly assigned patients, in a 2:1 ratio, to receive pomalidomide at a dose of 4 mg daily or matching placebo for 24 weeks. The primary outcome was the change from baseline through week 24 in the Epistaxis Severity Score (a validated bleeding score in HHT; range, 0 to 10, with higher scores indicating worse bleeding). A reduction of 0.71 points or more is considered clinically significant. A key secondary outcome was the HHT-specific quality-of-life score (range, 0 to 16, with higher scores indicating more limitations). RESULTS: The trial was closed to enrollment in June 2023 after a planned interim analysis met a prespecified threshold for efficacy. A total of 144 patients underwent randomization; 95 patients were assigned to receive pomalidomide and 49 to receive placebo. The baseline mean (±SD) Epistaxis Severity Score was 5.0±1.5, a finding consistent with moderate-to-severe epistaxis. At 24 weeks, the mean difference between the pomalidomide group and the placebo group in the change from baseline in the Epistaxis Severity Score was -0.94 points (95% confidence interval [CI], -1.57 to -0.31; P = 0.004). The mean difference in the changes in the HHT-specific quality-of-life score between the groups was -1.4 points (95% CI, -2.6 to -0.3). Adverse events that were more common in the pomalidomide group than in the placebo group included neutropenia, constipation, and rash. CONCLUSIONS: Among patients with HHT, pomalidomide treatment resulted in a significant, clinically relevant reduction in epistaxis severity. No unexpected safety signals were identified. (Funded by the National Heart, Lung, and Blood Institute; PATH-HHT Clinicaltrials.gov number, NCT03910244).

Affecting approximately 1 in 3800 persons,1 hereditary hemorrhagic telangiectasia (HHT) is the second most common inherited bleeding disorder.2 HHT is an autosomal dominant vasculopathy caused by mutations affecting transforming growth factor-β (TGF-β)/BMP signaling, resulting in fragile mucocutaneous telangiectasias and visceral arteriovenous malformations.2, 3 Over 95% of patients develop recurrent epistaxis, with frequent psychiatric comorbidity (depression and post-traumatic stress disorder) and reduction in health-related quality of life (HRQoL).4–7 One-third of patients exhibit gastrointestinal bleeding, and most develop iron deficiency anemia.8, 9 HHT-associated bleeding usually worsens over the lifespan and results in a requirement for frequent iron infusions and/or red blood cell (RBC) transfusions.5 Visceral arteriovenous malformations also occur in the lung (~50%), liver (~70%), and brain (~20%)5 andmay result in embolic stroke, pulmonary hemorrhage, tissue or brain abscesses, high output heart failure, hepatic disease, hemorrhagic stroke, and epilepsy.2, 3 Despite the morbidity of visceral arteriovenous malformations, patients distinctly identify bleeding as their most important disease manifestation.10 Patients with HHT may have reduced overall survival relative to the general population.11

igh output heart failure, hepatic disease, hemorrhagic stroke, and epilepsy.2, 3 Despite the morbidity of visceral arteriovenous malformations, patients distinctly identify bleeding as their most important disease manifestation.10 Patients with HHT may have reduced overall survival relative to the general population.11 No treatments for HHT are approved by the U.S. Food and Drug Administration (FDA) or European Medicines Agency. Management of bleeding involves temporizing ablative procedures on telangiectasias in the nose and gastrointestinal tract, off-label use of antifibrinolytic drugs,5 and potentially more aggressive surgery (e.g., surgical closure of the nares). However, given the systemic angiogenic dysregulation inherent to HHT, repurposing systemic antiangiogenic agents for its treatment has been explored.12–14 Non-randomized and/or underpowered studies with bevacizumab or thalidomide suggest some effectiveness in treating HHT-associated bleeding.15–17 Thalidomide, an immunomodulatory imide drug (IMiD), is the only antiangiogenic agent with positive prospective efficacy in HHT, demonstrated in a 31-patient study.17 However, thalidomide is associated with serious toxicities, such as thromboembolism and irreversible peripheral neuropathy.18 We wished to determine whether pomalidomide, a thalidomide derivative, may have efficacy in treating HHT with a more favorable toxicity profile. IMiDs such as pomalidomide may be disease-modifying in HHT, improving the integrity of fragile telangiectasias and exerting an antiangiogenic effect.19, 20

Adult patients with definite HHT defined by the Curacao criteria21 with an Epistaxis Severity Score of at least 3 over the three months before screening, and who had anemia at screening and/or received iron infusions or red blood cell (RBC) transfusions in the prior 6 months were eligible (Table S1.1). The Epistaxis Severity Score is a validated HHT-specific bleeding assessment tool with scores between 0 (no epistaxis) and 10 (worst epistaxis) over a period of time (Table S2.2).22 The protocol was approved by an independent Data and Safety Monitoring Board and the institutional review board at Cleveland Clinic. Trial activities and oversight were conducted in accordance with FDA regulatory requirements. All participants provided written informed consent upon entry.

period of time (Table S2.2).22 The protocol was approved by an independent Data and Safety Monitoring Board and the institutional review board at Cleveland Clinic. Trial activities and oversight were conducted in accordance with FDA regulatory requirements. All participants provided written informed consent upon entry. This double-blind randomized trial conducted at 11 U.S. sites compared epistaxis and HRQoL outcomes every 4 weeks during 24 weeks of treatment with pomalidomide or placebo, and at 4 weeks post-treatment. Participants were randomized 2:1: to pomalidomide 4 mg daily or matching placebo using permuted blocks with random sizes of 3 and 6, stratified by site and implemented within the electronic data management system. Participants and study staff were blinded to treatment assignment except for one statistician (BAC) who provided emergency unblinding and interim analyses. Dose reductions to 3 mg or 2 mg were allowed for toxicity. Any clinically indicated interventional treatments were recorded. Oral antifibrinolytic agents taken at a stable dose at study entry could be continued. Participants were managed in accordance with the FDA-mandated risk evaluation and mitigation strategy program for pomalidomide.23 The protocol and statistical analysis plan are available with this article at NEJM.org. The authors vouch for the data and adherence to the protocol. The manuscript was written without assistance from contract science writers.

nce with the FDA-mandated risk evaluation and mitigation strategy program for pomalidomide.23 The protocol and statistical analysis plan are available with this article at NEJM.org. The authors vouch for the data and adherence to the protocol. The manuscript was written without assistance from contract science writers. The primary outcome was the Epistaxis Severity Score change from baseline at 24 weeks. Epistaxis Severity Score was assessed for the prior 4 weeks at baseline and each 4-week visit. Key secondary outcomes, also assessed at 24 weeks were: 1) HHT-specific HRQoL (HHT-QoL) score,6 which measures the impact of HHT manifestations on HRQoL in the preceding 4 weeks and ranges from 0 (none) to 16 (worst); 2) daily self-reported epistaxis duration recorded via smartphone diary, averaged over 28 days; 3) number of units of packed red blood cells transfused through 24 weeks; 4) amount of parenteral iron (mg) infused through 24 weeks; and 5) Neuro-QoL™ Satisfaction with Social Roles and Activities T-score,24, 25 which is evaluated over the preceding week and is scored relative to a normal population. Other secondary outcomes included changes in levels of hemoglobin, hematocrit, mean corpuscular volume (MCV), mean cellular hemoglobin concentration (MCHC), ferritin, transferrin saturation, individual items of the Epistaxis Severity Score, endoscopic interventions, and PROMIS Depression and Fatigue T-scores.26, 27 Oral iron preparations, but not dietary iron, were also recorded.

bin, hematocrit, mean corpuscular volume (MCV), mean cellular hemoglobin concentration (MCHC), ferritin, transferrin saturation, individual items of the Epistaxis Severity Score, endoscopic interventions, and PROMIS Depression and Fatigue T-scores.26, 27 Oral iron preparations, but not dietary iron, were also recorded. We planned to randomize 159 participants to obtain 90% power to identify a treatment difference in Epistaxis Severity Score change from baseline at 24 weeks of 1.0, assuming a standard deviation of 1.7 and discontinuation rate of 10%. Efficacy outcomes were analyzed for all randomized and treated participants with post-baseline data (modified intent-to-treat mITT population). A supportive pre-specified per-protocol analysis excluded early discontinuations and participants with treatment compliance less than 80%. Safety outcomes were analyzed for all randomized and treated participants. Epistaxis Severity Score change at 24 weeks was evaluated for statistical significance at p<0.0425 accounting for two planned interim analyses. Five key secondary outcomes were assessed for statistical significance at p<0.01 with adjustment for multiple comparisons (Supplemental Methods).. All treatment group comparisons include an estimated difference with 95% confidence interval. Widths of the confidence intervals have not been adjusted for multiplicity and should not be used for hypothesis testing. All other p-values are for descriptive purposes.

tment for multiple comparisons (Supplemental Methods).. All treatment group comparisons include an estimated difference with 95% confidence interval. Widths of the confidence intervals have not been adjusted for multiplicity and should not be used for hypothesis testing. All other p-values are for descriptive purposes. Changes from baseline outcomes were analyzed with a repeated measures linear model or generalized logistic model which accounts for correlation of measurements over time, with adjustment for baseline value and clinical site.28 Missed visits after discontinuations are assumed missing at random. Supportive analyses of the primary outcome included evaluation on the per-protocol population and pre-specified subgroups. Sensitivity to the missing at random assumption was assessed with control-based and tipping-point multiple imputation (Supplemental Methods).29–31 Non-normally distributed outcomes were analyzed with rank analysis of covariance by visit.32 Analyses were based on a statistical plan prepared by a masked statistician and performed using SAS, version 9.4.33

This double-blind randomized trial conducted at 11 U.S. sites compared epistaxis and HRQoL outcomes every 4 weeks during 24 weeks of treatment with pomalidomide or placebo, and at 4 weeks post-treatment. Participants were randomized 2:1: to pomalidomide 4 mg daily or matching placebo using permuted blocks with random sizes of 3 and 6, stratified by site and implemented within the electronic data management system. Participants and study staff were blinded to treatment assignment except for one statistician (BAC) who provided emergency unblinding and interim analyses. Dose reductions to 3 mg or 2 mg were allowed for toxicity. Any clinically indicated interventional treatments were recorded. Oral antifibrinolytic agents taken at a stable dose at study entry could be continued. Participants were managed in accordance with the FDA-mandated risk evaluation and mitigation strategy program for pomalidomide.23 The protocol and statistical analysis plan are available with this article at NEJM.org. The authors vouch for the data and adherence to the protocol. The manuscript was written without assistance from contract science writers.

The primary outcome was the Epistaxis Severity Score change from baseline at 24 weeks. Epistaxis Severity Score was assessed for the prior 4 weeks at baseline and each 4-week visit. Key secondary outcomes, also assessed at 24 weeks were: 1) HHT-specific HRQoL (HHT-QoL) score,6 which measures the impact of HHT manifestations on HRQoL in the preceding 4 weeks and ranges from 0 (none) to 16 (worst); 2) daily self-reported epistaxis duration recorded via smartphone diary, averaged over 28 days; 3) number of units of packed red blood cells transfused through 24 weeks; 4) amount of parenteral iron (mg) infused through 24 weeks; and 5) Neuro-QoL™ Satisfaction with Social Roles and Activities T-score,24, 25 which is evaluated over the preceding week and is scored relative to a normal population. Other secondary outcomes included changes in levels of hemoglobin, hematocrit, mean corpuscular volume (MCV), mean cellular hemoglobin concentration (MCHC), ferritin, transferrin saturation, individual items of the Epistaxis Severity Score, endoscopic interventions, and PROMIS Depression and Fatigue T-scores.26, 27 Oral iron preparations, but not dietary iron, were also recorded.

We planned to randomize 159 participants to obtain 90% power to identify a treatment difference in Epistaxis Severity Score change from baseline at 24 weeks of 1.0, assuming a standard deviation of 1.7 and discontinuation rate of 10%. Efficacy outcomes were analyzed for all randomized and treated participants with post-baseline data (modified intent-to-treat mITT population). A supportive pre-specified per-protocol analysis excluded early discontinuations and participants with treatment compliance less than 80%. Safety outcomes were analyzed for all randomized and treated participants. Epistaxis Severity Score change at 24 weeks was evaluated for statistical significance at p<0.0425 accounting for two planned interim analyses. Five key secondary outcomes were assessed for statistical significance at p<0.01 with adjustment for multiple comparisons (Supplemental Methods).. All treatment group comparisons include an estimated difference with 95% confidence interval. Widths of the confidence intervals have not been adjusted for multiplicity and should not be used for hypothesis testing. All other p-values are for descriptive purposes.

Between November 5, 2019 and June 27, 2023, 177 patients were screened, and 144 meeting eligibility criteria were randomized (95 pomalidomide, 49 placebo), Figure 1. The study was closed to enrollment after the second planned interim analysis due to meeting pre-specified efficacy criteria. Eleven ongoing participants were terminated after completing at least 12 weeks of treatment. Twenty-seven percent (26/95) of participants in the pomalidomide group discontinued, including 15 (16%) for adverse events, compared to 10% (5/49) in the placebo group. Demographic and clinical characteristics were similar between groups (Table 1). Participants included 48% females, 11% race other than white, 3% Hispanic/Latino ethnicity; mean (± standard deviation) age was 58.8 ± 12.2 years. Though extensive demographic data on HHT is not available, our study population appears consistent with previous U.S. studies.34 (Table S1.2) However, Blacks were underrepresented. The mean Epistaxis Severity Score was 5.0 ± 1.5 (moderate severity) and the mean HHT-QoL score was 6.3 ± 3.1 (Figure S1). At baseline, 99 (69%) had anemia. In the 6 months before screening, 121 (84%) received intravenous iron and 28 (19%) received RBC transfusion.

.34 (Table S1.2) However, Blacks were underrepresented. The mean Epistaxis Severity Score was 5.0 ± 1.5 (moderate severity) and the mean HHT-QoL score was 6.3 ± 3.1 (Figure S1). At baseline, 99 (69%) had anemia. In the 6 months before screening, 121 (84%) received intravenous iron and 28 (19%) received RBC transfusion. The reduction in the Epistaxis Severity Score at 24 weeks was significantly greater in the pomalidomide compared to the placebo group (−1.84 [95% confidence interval (CI), −2.25 to −1.43] versus −0.90 [95% CI −1.39 to −0.40]; mean difference, −0.94 [95% CI, −1.57 to −0.31], p=0.004) (Table 2, Figure 2A, Table S2.1, Table S2.2). This difference is larger than the minimally important difference of 0.71.35 Cohen’s D (a statistical measure of effect size generated by comparing the means of two groups) was 0.57, indicating a medium effect size. The difference between pomalidomide and placebo became apparent at week 12 (−0.52; 95% CI, −1.04 to −0.01) and was consistent from week 16 (−0.95; 95% CI, −1.56 to −0.34) through the remainder of the study including 4 weeks post-treatment (Week 28) (−1.03; 95% CI, −1.62 to −0.44). Results were consistent across supportive analyses in the per-protocol population (Table-Figure S2.3), in pre-defined and exploratory subgroups including participants with ENG or ACVRL1 mutations, and those with Epistaxis Severity Score baseline scores <6 vs >=6 (Table-Figure S2.4). Efficacy of pomalidomide was also evident in participants with dose reduction at any timepoint (Table-Figure S2.5), and with control-based multiple imputation (Table S2.6) and tipping point sensitivity analyses (Table S2.7).

tations, and those with Epistaxis Severity Score baseline scores <6 vs >=6 (Table-Figure S2.4). Efficacy of pomalidomide was also evident in participants with dose reduction at any timepoint (Table-Figure S2.5), and with control-based multiple imputation (Table S2.6) and tipping point sensitivity analyses (Table S2.7). The incidence of relapse of the Epistaxis Severity Score to the baseline value or greater at the 4-week post-treatment visit was substantially lower in the pomalidomide group (21%) compared with the placebo group (39%) (relative risk, 0.46; 95% CI, 0.15 to 0.77), Table S2.8. Responses to individual items of the Epistaxis Severity Score are shown in Tables and Figures S2.9–S2.11. Acute visceral bleeds, categorized as serious adverse events, occurred in 6% of participants receiving pomalidomide and 10% receiving placebo (Table 3).

The incidence of relapse of the Epistaxis Severity Score to the baseline value or greater at the 4-week post-treatment visit was substantially lower in the pomalidomide group (21%) compared with the placebo group (39%) (relative risk, 0.46; 95% CI, 0.15 to 0.77), Table S2.8. Responses to individual items of the Epistaxis Severity Score are shown in Tables and Figures S2.9–S2.11. Acute visceral bleeds, categorized as serious adverse events, occurred in 6% of participants receiving pomalidomide and 10% receiving placebo (Table 3). Improvement in the HHT-QoL score was substantially greater at 24 weeks in the pomalidomide compared to the placebo group (−2.7 [95% CI −3.4 to −1.9] versus −1.2 [95% CI, −2.1 to −0.3]; mean difference, −1.4 [95% CI, −2.6 to −0.3]). This improvement was maintained through the 4-week post treatment visit (Table 2, Figure 2B, Tables S3.1 and S3.2). The remaining key secondary outcomes showed greater improvement in the pomalidomide group at 24 weeks (Table 2). Daily self-reported epistaxis duration, reported for 82% (87/106) of active participants at 24 weeks, was highly variable with no treatment group differences noted (Table 2, Table-Figure S4.1). However, post-hoc analyses that weighted bleeding duration by the reported intensity (Supplemental Methods) identified reduced weighted bleeding duration in pomalidomide-treated participants across all time points: at 24 weeks: −12.2 weighted intensity-minutes [95% CI −17.1 to −7.3] versus −3.3 [95% CI, −9.5 to 2.8], mean difference −8.9 [95% CI, −16.5 to −1.2]), Table 2, Table-Figure S4.2. Group differences in red blood cell transfusions and iron infusions were most apparent in a post-hoc evaluation encompassing weeks 12–24 of treatment: RBC transfusions were administered to 9% of participants in the pomalidomide group compared to 18% in the placebo group, and the median amount of iron infused (mg per 4 weeks) was 0 (IQR 0–340) in the pomalidomide group and 333 mg (IQR 0–500) in the placebo group (Table 2, Table S5). The Neuro-QoL Satisfaction with Social Roles and Activities score demonstrated the greatest improvement in the pomalidomide compared to the placebo group at the 4-week post-treatment visit (mean difference, 2.6 [95% CI, 0.1 to 5.2], Table 2, Tables S6.1 and 6.2–Figure S6.

–500) in the placebo group (Table 2, Table S5). The Neuro-QoL Satisfaction with Social Roles and Activities score demonstrated the greatest improvement in the pomalidomide compared to the placebo group at the 4-week post-treatment visit (mean difference, 2.6 [95% CI, 0.1 to 5.2], Table 2, Tables S6.1 and 6.2–Figure S6. Other secondary efficacy outcomes are described in Table 2 and Tables-Figures S7–S15. Most did not demonstrate a notable treatment group difference at 24 weeks, but several had a strong treatment group difference at 4 weeks post-treatment, as follows: PROMIS Fatigue score (mean difference, −5.5 [95% CI, −8.7 to −2.3], Tables S8.1 and S8.2–Figure S8), hemoglobin (mean difference, 1.09 [95% CI, 0.38 to 1.80] g/dL, Table-Figure S10), hematocrit (mean difference, 2.41% [95% CI, 0.51% to 4.32%], Table-Figure S11). Proportional changes in MCV (Table-Figure S13), and MCHC (Table-Figure S14) were also observed. No differences were seen in use of concomitant medications (e.g., tranexamic acid or epsilon-aminocaproic acid) or interventional procedures between the pomalidomide and placebo groups (Tables 2, S15).

Other secondary efficacy outcomes are described in Table 2 and Tables-Figures S7–S15. Most did not demonstrate a notable treatment group difference at 24 weeks, but several had a strong treatment group difference at 4 weeks post-treatment, as follows: PROMIS Fatigue score (mean difference, −5.5 [95% CI, −8.7 to −2.3], Tables S8.1 and S8.2–Figure S8), hemoglobin (mean difference, 1.09 [95% CI, 0.38 to 1.80] g/dL, Table-Figure S10), hematocrit (mean difference, 2.41% [95% CI, 0.51% to 4.32%], Table-Figure S11). Proportional changes in MCV (Table-Figure S13), and MCHC (Table-Figure S14) were also observed. No differences were seen in use of concomitant medications (e.g., tranexamic acid or epsilon-aminocaproic acid) or interventional procedures between the pomalidomide and placebo groups (Tables 2, S15). Drug doses were reduced to 3 mg or 2 mg in 37% of pomalidomide participants versus 4% of placebo (Table-Figure S16). The major toxicity was neutropenia (44% in the pomalidomide group vs 10% in the placebo group, p<0.001, Tables 3, Table-Figure S17.1, Tables S18.1–S18.7). The mean change in absolute neutrophil count (ANC) from baseline to week 24 was −1710 (95% CI −2030 to −1390) /μL in the pomalidomide group compared to −20 (95% CI −420, 380) /μL in the placebo group (P<0.001, Table-Figure S17.1). Three pomalidomide participants (3%) developed an ANC <500/μl; none were associated with infection. Neutropenia was reversible with dose reduction or temporary discontinuation of pomalidomide. No significant difference in platelet counts was noted in pomalidomide versus placebo treated patients (Table S17.2). Other adverse events more common in the pomalidomide group included constipation (47% vs 18%) and rash (35% vs 10%). Adverse events of grade 3 (severe) or higher occurred more often in the pomalidomide group (47% vs 24%). Four venous thromboembolic events (4%) occurred in the pomalidomide group (2 provoked distal DVT, 2 unprovoked subsegmental pulmonary emboli) versus 1 venous thromboembolic event (2%) in the placebo group (portal vein thrombosis) (Table S18.3). Participants with drug permanently stopped due to adverse events, interrupted but not stopped, and dose reduced but not interrupted in the pomalidomide group compared to placebo were 16% vs 2% (p=0.01), 40% vs 14% (p=0.002) and 13% vs 0 (p=0.01) respectively (Tables 3, S18.4–S18.6).

The reduction in the Epistaxis Severity Score at 24 weeks was significantly greater in the pomalidomide compared to the placebo group (−1.84 [95% confidence interval (CI), −2.25 to −1.43] versus −0.90 [95% CI −1.39 to −0.40]; mean difference, −0.94 [95% CI, −1.57 to −0.31], p=0.004) (Table 2, Figure 2A, Table S2.1, Table S2.2). This difference is larger than the minimally important difference of 0.71.35 Cohen’s D (a statistical measure of effect size generated by comparing the means of two groups) was 0.57, indicating a medium effect size. The difference between pomalidomide and placebo became apparent at week 12 (−0.52; 95% CI, −1.04 to −0.01) and was consistent from week 16 (−0.95; 95% CI, −1.56 to −0.34) through the remainder of the study including 4 weeks post-treatment (Week 28) (−1.03; 95% CI, −1.62 to −0.44). Results were consistent across supportive analyses in the per-protocol population (Table-Figure S2.3), in pre-defined and exploratory subgroups including participants with ENG or ACVRL1 mutations, and those with Epistaxis Severity Score baseline scores <6 vs >=6 (Table-Figure S2.4). Efficacy of pomalidomide was also evident in participants with dose reduction at any timepoint (Table-Figure S2.5), and with control-based multiple imputation (Table S2.6) and tipping point sensitivity analyses (Table S2.7).

Improvement in the HHT-QoL score was substantially greater at 24 weeks in the pomalidomide compared to the placebo group (−2.7 [95% CI −3.4 to −1.9] versus −1.2 [95% CI, −2.1 to −0.3]; mean difference, −1.4 [95% CI, −2.6 to −0.3]). This improvement was maintained through the 4-week post treatment visit (Table 2, Figure 2B, Tables S3.1 and S3.2). The remaining key secondary outcomes showed greater improvement in the pomalidomide group at 24 weeks (Table 2). Daily self-reported epistaxis duration, reported for 82% (87/106) of active participants at 24 weeks, was highly variable with no treatment group differences noted (Table 2, Table-Figure S4.1). However, post-hoc analyses that weighted bleeding duration by the reported intensity (Supplemental Methods) identified reduced weighted bleeding duration in pomalidomide-treated participants across all time points: at 24 weeks: −12.2 weighted intensity-minutes [95% CI −17.1 to −7.3] versus −3.3 [95% CI, −9.5 to 2.8], mean difference −8.9 [95% CI, −16.5 to −1.2]), Table 2, Table-Figure S4.2. Group differences in red blood cell transfusions and iron infusions were most apparent in a post-hoc evaluation encompassing weeks 12–24 of treatment: RBC transfusions were administered to 9% of participants in the pomalidomide group compared to 18% in the placebo group, and the median amount of iron infused (mg per 4 weeks) was 0 (IQR 0–340) in the pomalidomide group and 333 mg (IQR 0–500) in the placebo group (Table 2, Table S5). The Neuro-QoL Satisfaction with Social Roles and Activities score demonstrated the greatest improvement in the pomalidomide compared to the placebo group at the 4-week post-treatment visit (mean difference, 2.6 [95% CI, 0.1 to 5.2], Table 2, Tables S6.1 and 6.2–Figure S6.

Other secondary efficacy outcomes are described in Table 2 and Tables-Figures S7–S15. Most did not demonstrate a notable treatment group difference at 24 weeks, but several had a strong treatment group difference at 4 weeks post-treatment, as follows: PROMIS Fatigue score (mean difference, −5.5 [95% CI, −8.7 to −2.3], Tables S8.1 and S8.2–Figure S8), hemoglobin (mean difference, 1.09 [95% CI, 0.38 to 1.80] g/dL, Table-Figure S10), hematocrit (mean difference, 2.41% [95% CI, 0.51% to 4.32%], Table-Figure S11). Proportional changes in MCV (Table-Figure S13), and MCHC (Table-Figure S14) were also observed. No differences were seen in use of concomitant medications (e.g., tranexamic acid or epsilon-aminocaproic acid) or interventional procedures between the pomalidomide and placebo groups (Tables 2, S15).

Drug doses were reduced to 3 mg or 2 mg in 37% of pomalidomide participants versus 4% of placebo (Table-Figure S16). The major toxicity was neutropenia (44% in the pomalidomide group vs 10% in the placebo group, p<0.001, Tables 3, Table-Figure S17.1, Tables S18.1–S18.7). The mean change in absolute neutrophil count (ANC) from baseline to week 24 was −1710 (95% CI −2030 to −1390) /μL in the pomalidomide group compared to −20 (95% CI −420, 380) /μL in the placebo group (P<0.001, Table-Figure S17.1). Three pomalidomide participants (3%) developed an ANC <500/μl; none were associated with infection. Neutropenia was reversible with dose reduction or temporary discontinuation of pomalidomide. No significant difference in platelet counts was noted in pomalidomide versus placebo treated patients (Table S17.2). Other adverse events more common in the pomalidomide group included constipation (47% vs 18%) and rash (35% vs 10%). Adverse events of grade 3 (severe) or higher occurred more often in the pomalidomide group (47% vs 24%). Four venous thromboembolic events (4%) occurred in the pomalidomide group (2 provoked distal DVT, 2 unprovoked subsegmental pulmonary emboli) versus 1 venous thromboembolic event (2%) in the placebo group (portal vein thrombosis) (Table S18.3). Participants with drug permanently stopped due to adverse events, interrupted but not stopped, and dose reduced but not interrupted in the pomalidomide group compared to placebo were 16% vs 2% (p=0.01), 40% vs 14% (p=0.002) and 13% vs 0 (p=0.01) respectively (Tables 3, S18.4–S18.6).

This randomized double-blind trial demonstrated that pomalidomide resulted in a significant improvement in the epistaxis severity score and substantially improved disease specific HRQoL.6 These improvements occurred despite a strong placebo effect that dissipated following discontinuation of blinded study drug. Additional objective measures, including incidence of blood transfusion, quantity of infused iron, hemoglobin, hematocrit, MCV and MCHC were all directionally consistent with these outcomes. The benefits of pomalidomide were most apparent over the second twelve weeks of the study, not dependent on HHT genotype or epistaxis severity and persisted during the four weeks after treatment discontinuation. Pomalidomide is structurally related to other IMiD family drugs, particularly thalidomide. These agents share similar properties, including therapeutic efficacy in multiple myeloma. Compared to thalidomide, however, pomalidomide displays an improved safety profile, with a lower incidence of cytopenias and peripheral neuropathy.36 Given that fatigue and thrombosis have been observed in populations with multiple myeloma receiving IMiDs and are relevant in HHT, the low and similar rates of these adverse events in treatment and placebo arms suggest feasibility for the use of pomalidomide in HHT.

incidence of cytopenias and peripheral neuropathy.36 Given that fatigue and thrombosis have been observed in populations with multiple myeloma receiving IMiDs and are relevant in HHT, the low and similar rates of these adverse events in treatment and placebo arms suggest feasibility for the use of pomalidomide in HHT. Pomalidomide was generally associated with low grade toxicities. The most notable adverse event was neutropenia that was generally mild, not associated with opportunistic infections, and promptly reversible with dose modification. We observed no reduction in efficacy in patients in whom the pomalidomide dose was decreased, suggesting that, as with thalidomide, lower doses of pomalidomide may be similarly efficacious in HHT with fewer adverse events.17 HHT is characterized by mutations in ENG, ACVRL1 or SMAD4 in more than 90% of patients. These genes encode proteins involved in signaling through the TGF-β/BMP pathway and the beneficial effects of pomalidomide in HHT might reflect reversal of angiogenic dysregulation by bypassing or reversing abnormalities in TGF-β/BMP signaling. We found that the Epistaxis Severity Score improved similarly in patients with either ENG or ACVRL1 mutations. In a seven patient pilot study, participants treated with thalidomide underwent biopsy of nasal telangiectasia before and after treatment. Examination of post-treatment biopsies did not demonstrate inhibition of endothelial cell proliferation, but rather enhanced mural cell coverage of the vasculature.20

RL1 mutations. In a seven patient pilot study, participants treated with thalidomide underwent biopsy of nasal telangiectasia before and after treatment. Examination of post-treatment biopsies did not demonstrate inhibition of endothelial cell proliferation, but rather enhanced mural cell coverage of the vasculature.20 Participants treated with pomalidomide demonstrated increases in hemoglobin and hematocrit. These occurred despite a substantial decrease in intravenous iron infusions and red cell transfusions. We observed a persistent reduction in the Epistaxis Severity Score below baseline in the four weeks following pomalidomide treatment, accompanied by further improvement in the HHT-specific quality-of-life score, hemoglobin, and hematocrit. These results suggest that pomalidomide effects may extend beyond the duration of treatment in HHT, and that the failure to more substantially increase hemoglobin levels during treatment may represent a component of bone marrow suppression by pomalidomide at the 4 mg daily dosing regimen used in this study.

hematocrit. These results suggest that pomalidomide effects may extend beyond the duration of treatment in HHT, and that the failure to more substantially increase hemoglobin levels during treatment may represent a component of bone marrow suppression by pomalidomide at the 4 mg daily dosing regimen used in this study. The efficacy of pomalidomide compared to bevacizumab in HHT can only be discerned by head-to-head trials. Retrospective reports of intravenous bevacizumab enrolled patients with a higher mean Epistaxis Severity Score than our study, though the reduction in Epistaxis Severity Score in pomalidomide treated patients with Epistaxis Severity Score ≥ 6 compared to those in series of bevacizumab is similar.15 An advantage of pomalidomide, unlike bevacizumab, is that it is an oral medication and might be more convenient for patients without access to infusion centers. Whether pomalidomide or bevacizumab are more effective in patients with different types of bleeding or sites of arteriovenous malformations is uncertain and will need to be determined in future studies. Since pomalidomide and bevacizumab may have different mechanisms of action, they may have additive or synergistic activity in severe cases of HHT.

izumab are more effective in patients with different types of bleeding or sites of arteriovenous malformations is uncertain and will need to be determined in future studies. Since pomalidomide and bevacizumab may have different mechanisms of action, they may have additive or synergistic activity in severe cases of HHT. Strengths of this study include double-blind treatment, adequate power for the primary outcome, broad inclusion criteria, and thorough collection of secondary outcomes. Evidence of efficacy based on changes in the Epistaxis Severity Score led to early study termination, resulting in reduction from the planned sample size, thus impacting power for secondary outcome analyses. A potential weakness of the study is that similar efficacy might have been observed with lower doses of pomalidomide with less toxicity. In addition, Black patients were underrepresented. Though our study provides evidence of efficacy and safety of pomalidomide for HHT-related epistaxis, whether similar effects are evident in patients with GI bleeding, or pulmonary, liver or brain arteriovenous malformations is uncertain. Moreover, defining mechanisms of action of pomalidomide in HHT will require additional studies. Most importantly, however, PATH-HHT demonstrates efficacy of a new agent for HHT that may provide improved quality of life for this population for whom no approved therapies exist.