Alignment of a Ritchey-Chrétien telescope with primary mirror figure error guided by the rapid measurement of binodal astigmatism.

Introduction

Hereditary hemorrhagic telangiectasia (HHT; Osler-Weber-Rendu disease) is an autosomal dominant vascular bleeding disorder affecting 1 in 5000 people, making it the second most common inherited bleeding disorder. 1 In HHT, pathogenic mutations in the ALK1/BMPRII signaling pathway cause dysregulated angiogenesis, which leads to formation of fragile, bleeding telangiectasias on nasal and gastrointestinal mucosae and arteriovenous malformations (AVMs) in central nervous system and visceral organs. 2 Nasal mucocutaneous telangiectasias and gastrointestinal AVMs result in recurrent, often severe epistaxis, chronic gastrointestinal bleeding, and chronic and recurrent iron deficiency anemia that may be severe and result in dependence on IV iron infusions and/or red cell transfusions. 3 , 4 Most patients also develop AVMs in at least one solid organ that can cause numerous morbid and potentially fatal bleeding and nonbleeding complications. 2 Despite the morbidity of solid organ AVMs, patients and caregivers clearly identify mucosal bleeding as the most important clinical manifestation. 5 Bleeding in HHT reduces health-related quality of life and has been demonstrated to result in diagnosable psychiatric comorbidities in nearly half of patients. 6 , 7 Patients with HHT have reduced survival compared with the general population and recent evidence suggests that HHT may be the most morbid inherited bleeding disorder of women. 8 , 9 , 10

Despite the considerable morbidity and relative commonality of HHT among inherited bleeding disorders, there remain no licensed therapies to treat it worldwide. 11 , 12 Treatment of bleeding in HHT is currently limited to off-label use of antifibrinolytics, antiangiogenic agents, and temporizing invasive procedures. 13 , 14 , 15 , 16 , 17 , 18 , 19 However, the first large, double-blind, multicenter, placebo-controlled, US National Institutes of Health–sponsored clinical trial of a disease-modifying antiangiogenic therapeutic in HHT, the PATH-HHT study, was completed and its primary results published in 2024. 16 PATH-HHT enrolled 144 participants with moderate-to-severe HHT-associated bleeding and randomized participants to receive the immunomodulatory imide drug pomalidomide or placebo for 6 months of treatment. Immunomodulatory imide drugs have been shown to have antiangiogenic properties, reducing vascular endothelial growth factor and basic fibroblast growth factor, and have demonstrated favorable vascular remodeling potential in patients with HHT. 20 , 21 PATH-HHT was successful, meeting its primary end point of significant improvement in the epistaxis severity score (ESS) in the pomalidomide group vs the placebo group. These results created a great deal of interest in the use of pomalidomide for HHT. 22 However, many critical questions regarding pomalidomide in HHT remain to be answered, including the long-term effectiveness of the drug to treat epistaxis, the effect of the drug on gastrointestinal bleeding, and the long-term safety of the drug. Pomalidomide has a known thromboembolic and infection risk in patients with multiple myeloma, among other potential toxicities, 23 and the dosing intensity evaluated in PATH-HHT was 33% greater than in myeloma.

Because the PATH-HHT study was funded by the National Institutes of Health and was not a pharmaceutical industry–sponsored study, a formal prospective open-label long-term extension component of the study was not possible due to funding limitations. However, Bristol Myers Squibb, the manufacturer of pomalidomide in the United States, made available a pomalidomide poststudy drug access program to participants completing PATH-HHT. For patients under the care of principal investigators willing to use high-intensity pomalidomide treatment off-label outside of the bounds of the trial, this provided pomalidomide access to participants who desired to continue treatment (if they had been randomized to pomalidomide) or initiate it (if they had been randomized to placebo). Because pomalidomide in the United States has a US Food and Drug Administration–mandated risk evaluation and mitigation strategy program requiring monthly monitoring of patients receiving the drug by prescribing providers, a structured monthly monitoring plan was required after study that was nearly identical to the protocoled monitoring during the double-blind study. Therefore, the PATH-HHT after trial longitudinal assessment study (ATLAS; ClinicalTrials.gov identifier: NCT07018401 ) was initiated as a separate, successor study to rigorously evaluate the long-term safety and effectiveness of pomalidomide to treat bleeding in HHT.

Methods

Patients and study design

This study was approved by the Mass General Brigham institutional review board. Adult patients were eligible for inclusion into the PATH-HHT ATLAS if they had previously enrolled on, and completed, the PATH-HHT study. The complete eligibility criteria for PATH-HHT are listed in the supplemental Appendix . In brief, patients qualified for PATH-HHT if they had a definite diagnosis of HHT as defined by the Curacao criteria or molecular testing, moderate-to-severe bleeding in HHT as defined by an ESS of ≥3 with concurrent hematologic compromise (anemia or a requirement for IV iron infusion and/or red cell transfusion in the preceding 6 months), and no contraindication to receiving pomalidomide. 16 The ESS is a longitudinal, well-validated HHT-specific bleeding assessment tool with scores ranging from 0 (no epistaxis) to 10 (worst epistaxis) over a specified time period. 24 The minimal clinically important difference (MCID) of the ESS is a change of 0.71 points. 25

Although this study was observational with data collected retrospectively, all investigators followed the PATH-HHT study protocol’s monthly assessment and laboratory monitoring for each patient treated with pomalidomide after completion of PATH-HHT as well as the US Food and Drug Administration–mandated risk evaluation and mitigation strategy program requirements requiring monthly assessment by a provider and completion of a provider survey. 16 This included monthly patient assessment, complete blood count with white cell differential, comprehensive metabolic panel, and iron studies (serum ferritin, serum iron, and total iron binding capacity). The date of database lock for this study was 31 May 2025.

All patients in this study (PATH-HHT ATLAS) previously enrolled on the PATH-HHT study, in which they were randomized to pomalidomide or placebo, and after the study they continued on pomalidomide via a poststudy drug access program. All patients were unblinded at the close of the PATH-HHT study, so their treatment assignment during that study was known. If a patient was randomized to pomalidomide, the 6 months that they received pomalidomide on the randomized trial is included in this analysis (safety and effectiveness). If they were randomized to placebo, the 6 months of placebo was not included in this analysis, and the patient’s baseline characteristics were taken with initiation of poststudy of pomalidomide as their time zero.

Pomalidomide was initiated at 4 mg daily in all patients in accordance with the PATH-HHT protocol. Investigators followed the PATH-HHT protocol for dose modification, treatment holds, and treatment discontinuation 16 but could deviate from the protocol if felt to be in the best interest of the patient. All dose modifications and treatment discontinuations, and their reasons, were recorded.

This study was conducted in accordance with the Declaration of Helsinki.

Outcomes

The primary outcome was the change from baseline in the ESS. A 1-month ESS was assessed at baseline before pomalidomide initiation (for patients randomized to pomalidomide in the PATH-HHT trial, this was the baseline assessment as part of the trial before initiating pomalidomide, and for those randomized to placebo, it was the baseline assessment before initiating pomalidomide after PATH-HHT completion) and throughout treatment with pomalidomide. For patients randomized to pomalidomide on PATH-HHT who continued it after study, the first 6 months of their pomalidomide treatment (while on PATH-HHT) are included in outcome assessments (both safety and effectiveness) in PATH-HHT ATLAS.

Secondary outcomes included the hematologic support score, 26 a composite hematologic end point for chronic bleeding disorders integrating milligrams of IV iron infused as well as units of red cells transfused into a single outcome measured in red blood cell unit equivalents (RUEs; 1 RUE = 1 red blood cell unit or 250 mg IV elemental iron); hemoglobin; milligrams IV iron infused; red cell units transfused; and safety. The hematologic support score was used as a composite hematologic end point in accordance with recommendations from the International Consensus Report on the Standardization of Terminology, Definitions, and Outcome Criteria in HHT. 27 All hematologic support administered in the study was per investigator, without any protocolized thresholds for administration (as was the case in the PATH-HHT parent study).

Effect on epistaxis was primarily evaluated using the ESS. Patients with known gastrointestinal bleeding at baseline and those previously receiving systemic bevacizumab were evaluated in descriptive subgroup analyses. Effect on gastrointestinal bleeding was primarily judged based on impact on hematologic support requirements.

All effectiveness end points were evaluated during the first year of pomalidomide treatment, and safety was evaluated during the entire treatment duration. Treatment-emergent adverse events (TEAEs) were defined according to Common Terminology Criteria for Adverse Events version 5.0 (National Cancer Institute). Patients were evaluated for TEAEs by the treating physician monthly at assessments, and TEAEs were adjudicated by the treating investigator as related or unrelated to pomalidomide. Receipt of pomalidomide for at least 1 treatment cycle (28 days) was required for inclusion in effectiveness analyses. All pomalidomide discontinuations, along with the reason(s) for discontinuation, were collected.

Statistical analysis

Linear mixed-effects models (mixed models for repeated measures [MMRM]) with restricted maximum likelihood and a Geissler-Greenhouse correction were used to evaluate the ESS, hematologic support score, hemoglobin, elemental iron infused, and units of red cells transfused at baseline through specified time points during the first year on treatment. Time was a fixed effect in each model. The mean ESS over time in patients requiring dose reduction in the first year of treatment vs those who did not was compared using the extra-sum-of-squares F test.

Results

Patients and treatment exposure

Between 8 October 2020 and 16 April 2024, 62 patients who initially enrolled in PATH-HHT initiated (n = 23) or continued (n = 39) treatment with pomalidomide after completion of PATH-HHT and were included in this study ( Table 1 ); all of these patients were either randomized to pomalidomide and continued it after trial or initiated pomalidomide after trial after initial randomization to placebo. Of 144 patients initially enrolling in PATH-HHT, 113 completed the trial protocol or were actively receiving study drug when the trial was halted early at interim analysis after meeting a prespecified threshold for efficacy; all 62 patients in PATH-HHT ATLAS were from this group of 113 patients. The disposition of all 62 patients is shown in Figure 1 . The mean duration of pomalidomide treatment in this study was 1.7 years per patient (range, 4 days to 4.4 years). Eight patients (13%) discontinued pomalidomide treatment early (within the first 90 days of treatment): 4 due to pomalidomide hypersensitivity rash, 1 due to development of grade 2 fatigue, 2 due to nonmedical logistical reasons (moving to a new state, insurance difficulties), and 1 due to progression of HHT liver disease and transition to hospice. After the first 90 days of treatment, 13 patients (21%) discontinued pomalidomide due to AEs and 9 patients (15%) discontinued due to secondary loss of response (after achieving initial response) after a mean treatment duration of 1.2 years (range, 5.9 months to 2.3 years). At the last follow-up assessment, 22 patients (36%) with a mean treatment duration of 2.9 years (range, 1.4-4.4) remained on long-term pomalidomide treatment with ongoing good clinical response. The total duration of pomalidomide treatment exposure in the cohort is 105.2 patient-years.

All patients began pomalidomide at 4 mg daily. Over the course of treatment, 31 patients (50%) underwent permanent dose reductions during the course of treatment (20 to 3 mg, 8 to 2 mg, and 3 to 1 mg), primarily due to grade 2 or 3 neutropenia (20 patients). Reasons for dose reductions are given in Table 2 . The median time from pomalidomide initiation to first dose reduction was 5.3 months (range, 24 days to 3.6 years), and 25 patients (81%) underwent first dose reduction during the first year of treatment. Of 31 patients who underwent permanent dose reduction, 5 ultimately discontinued pomalidomide due to inadequate treatment effect.

A total of 60 patients (97%) received at least 1 cycle of pomalidomide of 28 days and were evaluable for effectiveness. All 62 patients were evaluable for safety.

Primary outcome

The mean ESS was significantly improved over the course of treatment, decreasing from 5.55 (95% confidence interval [CI], 5.08-6.02) points at baseline to 2.80 (95% CI, 2.26-3.34) points at month 12 (MMRM F [3.30, 142.9], 44.94; P < .0001; Figure 2 A). The mean ESS was 2.26, 2.37, 2.54, and 2.75 points lower at 3, 6, 9, and 12 months, respectively, relative with baseline. During the first year of pomalidomide therapy, 54 patients (90%) achieved an improvement of ≥0.71 points (the MCID), 49 patients (82%) achieved an improvement of ≥1.42 points (twice the MCID), and 33 patients (55%) achieved an improvement of ≥2.13 points (3 times the MCID).

There was no significant difference in mean ESS over time between patients undergoing dose reduction during the first year and those who did not ( Figure 3 ).

Secondary effectiveness outcomes

Hematologic support score

The mean hematologic support score was significantly improved over the course of treatment, going from 9.11 RUEs (95% CI, 6.35-11.87) during the 6 months pretreatment to 5.73 RUEs (95% CI, 3.22-8.24) at months 7 through 12 of treatment (MMRM F [1.48, 74.12], 6.54; P = .0056; Figure 2 B). The mean hematologic support score was 2.14 RUEs lower during months 1 through 6 of treatment and 3.38 RUEs lower during months 7 through 12 of treatment relative with 6 months pretreatment.

Hemoglobin

The mean hemoglobin was not significantly different over the course of treatment, going from 11.3 g/dL (95% CI, 10.7-11.8) at baseline to 11.8 g/dL (95% CI, 11.0-12.7) at month 12 (MMRM F [2.19, 101.7], 0.76; P = .48; Figure 2 C).

Elemental iron infused

The mean quantity of elemental iron infused was significantly improved over the course of treatment, going from 1909 mg (95% CI, 1357-2461) during the 6 months pretreatment to 1166 mg (95% CI, 729-1604) at months 7 through 12 of treatment (MMRM F [1.42, 69.52], 5.74; P = .011; Figure 2 D). The mean quantity of elemental iron infused was 439 mg lower during months 1 through 6 of treatment and 743 mg lower during months 7 through 12 of treatment relative with 6 months pretreatment.

Red cell units transfused

The mean number of units of red cells transfused was not significantly different over the course of treatment, going from 1.5 units (95% CI, 0.4-2.5) during the 6 months before treatment to 0.9 units (95% CI, ˗0.2 to 2.0) at months 7 through 12 of treatment (MMRM F [1.76, 91.43], 1.64; P = .20; Figure 2 E). Sixteen patients (27%) required red cell transfusion during the 6 months before treatment, compared with 11 patients (18%) during months 1 through 6 of treatment and 4 patients during months 7 through 12 of treatment (8% of 48 patients evaluable during months 7 through 12 of treatment).

Patients with active chronic gastrointestinal bleeding at pomalidomide initiation

Of 24 patients with active chronic gastrointestinal bleeding at pomalidomide initiation, treatment was discontinued in 16 (67%) patients (5 [21%] for AEs, 10 [42%] for inadequate effectiveness in treating gastrointestinal bleeding or patient decision, and 1 due to progression of HHT liver disease and death). Eight (33%) patients remain on pomalidomide therapy, doing well. Of 6 patients requiring red cell transfusion in the 6 months before pomalidomide initiation (mean, 7.2 units [range, 1-26]), who received pomalidomide for a mean duration of 2.1 years, only patients requiring 1 or 2 units in the 6 months before pomalidomide initiation (patients who were not transfusion dependent) remain on pomalidomide; all 3 patients with more severe gastrointestinal bleeding, manifested by higher red cell transfusion requirements (mean pomalidomide treatment duration, 1.1 years), ultimately discontinued treatment due to inadequate effectiveness.

Patients previously treated with systemic bevacizumab

A total of 14 patients (23%) had previously received systemic bevacizumab; 7 of whom had a history of gastrointestinal bleeding and 6 of whom had active gastrointestinal bleeding at pomalidomide initiation. This group had a mean baseline ESS of 5.52, and a mean ESS on treatment as follows: 4.57 at month 3 (n = 14), 4.54 at month 6 (n = 11), 4.34 at month 9 (n = 5), and 3.11 at month 12 (n = 3). The attrition of this group was substantial, and ultimately only 2 of 14 patients remained on pomalidomide (mean treatment duration, 1.7 years) with good response on the date of database lock.

AEs (safety)

TEAEs, and the strongest action taken with pomalidomide in response to a TEAE per patient, are listed in Table 3 . Fifty-nine patients (95%) experienced at least 1 TEAE, 17 patients (27%) experienced a grade ≥3 hematologic TEAE (all neutropenia), and 7 patients (17%) experienced a grade ≥3 nonhematologic TEAE. Doses were reduced to 3 mg, 2 mg, or 1 mg daily in 22 patients (36%), and 18 patients (29%) discontinued pomalidomide due to TEAEs. The most common TEAEs observed were neutropenia, occurring in 33 patients (52%); constipation, occurring in 24 patients (38%); and rash, occurring in 23 patients (37%). Four patients (7%) developed a pomalidomide hypersensitivity rash necessitating permanent drug discontinuation. No patient developed peripheral neuropathy.

Venous thromboembolism was observed in 1 patient (2%, a pulmonary embolism) and arterial thromboembolism was observed in 1 patient (2%, an ischemic stroke). Grade ≥2 infection-related TEAEs potentially related to pomalidomide were observed in 5 patients (8%), including 3 patients with deep-seated tissue infections. All of these infection-related TEAEs were grade 3 and required hospitalization and included 1 case each of community-acquired pneumonia, Pneumocystis jirovecii pneumonia, septic arthritis, paraspinal abscess (methicillin-sensitive Staphylococcus aureus ), and hepatic abscess (methicillin-sensitive S aureus ). Of these 5 patients, 4 also had neutropenia (grade 3 in 3 patients, and grade 2 in 1 patient). The case of P jirovecii pneumonia occurred in a 78-year-old woman with no known immunocompromise aside from drug-related grade 3 neutropenia who had received continuous pomalidomide for 4 years with good treatment effect and was not receiving Pneumocystis prophylaxis.

Discussion

In this longitudinal assessment study conducted in patients enrolling on the randomized, placebo-controlled PATH-HHT study, pomalidomide was highly effective in treating the recurrent and often severe epistaxis of HHT, the manifestation of HHT that most significantly affects the quality of life of this population. The population of PATH-HHT ATLAS comprised patients with moderate-to-severe HHT-associated epistaxis and/or gastrointestinal bleeding and carried a high burden of morbidity from HHT. Improvements in epistaxis were deep, significant, and largely durable, as demonstrated by a mean improvement in the ESS of >3-times the MCID of this well-validated disease-specific bleeding scale and loss of response in a minority of patients. Along with the improvement in epistaxis, significant improvements in total hematologic support as demonstrated by the hematologic support score were observed, driven primarily by a significant improvement in quantity of elemental iron infused. Improvements in these outcomes deepened with longer treatment duration. Patients with significant red cell transfusion burden or frank transfusion dependence due to concomitant ongoing chronic gastrointestinal bleeding, however, did not experience adequate improvement in their transfusion requirements. Although a fraction of patients with more modest ongoing gastrointestinal bleeding did improve, pomalidomide appears to be less effective in the management of gastrointestinal bleeding than epistaxis in HHT.

The benefits of pomalidomide in improving HHT-associated bleeding, however, did come with a notable burden of TEAEs, primarily neutropenia in approximately half of patients, constipation in approximately one-third, and transient drug rash in approximately one-quarter of patients. In most cases, neutropenia resolved or became mild with dose reduction to 3 or 2 mg daily. These findings are consistent with the PATH-HHT trial; however, with much longer durations of pomalidomide treatment of HHT in PATH-HHT ATLAS (1.7 years per patient on average, and up to 4.4 years), approximately half of patients underwent pomalidomide dose reduction from the starting dose of 4 mg daily due to TEAEs (primarily neutropenia) and ultimately approximately one-quarter of patients discontinued pomalidomide due to TEAEs. Notably, only 5 of 31 patients undergoing permanent dose reduction discontinued treatment due to inadequate treatment effectiveness, and a direct comparison of patients requiring dose reduction during the first year of treatment demonstrated similar improvement in ESS as those who did not require dose reduction. These data strongly suggest that the 4 mg pomalidomide continuous daily dosing used in PATH-HHT and PATH-HHT ATLAS, which was selected empirically and is more intensive than the dosing of pomalidomide in multiple myeloma, is likely higher than what is necessary or optimal for most patients. A lower daily dose of 3 mg or 2 mg appears to be similarly effective in reducing bleeding with a better tolerability profile (and, in particular, much less clinically relevant neutropenia). A less intensive initial approach to dosing may also avoid early discontinuation prompted by TEAEs in some patients. Notably, a small number of patients did develop a pomalidomide hypersensitivity rash, which, in contrast to the transient benign drug rash experienced by approximately a quarter of patients, does not alleviate unless the drug is discontinued. Formal drug desensitization to pomalidomide hypersensitivity reactions has been described 28 but was not undertaken in any of the patients in this study. Critically, the most insidious and feared toxicity that limits long-term thalidomide treatment, peripheral neuropathy, was not observed in any patients treated with long-term pomalidomide, a reassuring finding.

The HHT population treated with pomalidomide in this study had high rates of comorbidity at baseline directly relevant to pomalidomide treatment, including baseline fatigue in nearly half of patients and previous thromboembolism in one-fifth. A very concerning theoretical toxicity of pomalidomide use in a bleeding disorder is thromboembolism, and with >100 patient-years of exposure in the PATH-HHT ATLAS among a population highly enriched for previous thromboembolism, only a single venous thromboembolic event (a pulmonary embolism) and a single arterial thromboembolic event (a stroke) were observed, the former during an inpatient hospitalization and the latter in a patient with a known history of pulmonary AVMs. Infection is another recognized risk of pomalidomide and the risk of deep-seated tissue infection and severe bacterial infection is well recognized in HHT. Three patients developed deep-seated tissue infections but given the relatively common incidence of these infections in patients with HHT (∼14% in the largest study published to date), 29 the incidence in this study is not excessive. One late elderly (aged ≥75 years) patient, however, developed Pneumocystis jirovecii pneumonia in the setting of prolonged grade 3 pomalidomide-induced neutropenia, a clear opportunistic infection for which she had no recognized preexisting risk factors. Pneumocystis pneumonia has previously been reported in patients with multiple myeloma receiving pomalidomide treatment. 30

Given that HHT remains without licensed therapies, taken together with the findings from PATH-HHT, the findings of this study support the routine use of pomalidomide to treat moderate-to-severe bleeding in certain patients with HHT. Only 2 other medical treatments, oral tranexamic acid and IV bevacizumab, have adequate published data to support their routine use for this indication. 14 , 22 , 31 , 32 As a once-daily oral medication, pomalidomide has obvious convenience and adherence-related advantages to these medications, avoiding the need for regular infusions, high pill burden, or thrice-daily dosing. However, as this study demonstrates, pomalidomide may not be ideal for some patient subgroups, including older patients, those with known immunosuppression or severe constipation at baseline, and those with severe gastrointestinal bleeding. In the case of the latter, published data suggest that systemic bevacizumab may be more likely to be effective. 14 , 33 Additionally, the monitoring requirements of pomalidomide (risk evaluation and mitigation programs), given its known teratogenicity, must be considered.

Our study has many notable strengths. It is, to our knowledge, the largest study of both safety and effectiveness of an immunomodulatory imide drug (IMiD) treatment of HHT by patient number (excepting only the parent PATH-HHT study) and longitudinal cumulative drug exposure duration (which was much greater than in PATH-HHT). This includes all previously published studies of thalidomide in HHT. Despite being an observational study due to a lack of continued government funding to support formal prospective data collection, the investigators on this study followed the established PATH-HHT protocol in monitoring patients and recording detailed effectiveness and safety data in the medical record, resulting in data fidelity and completeness that reasonably rivals that of a prospective open-label extension study. This is particularly evident in the quality of the AE reporting, which included investigator-determined Common Terminology Criteria for Adverse Events grade and attribution. However, our study also has a number of important limitations. Although AE reporting was comprehensive for an observational study, data collection was retrospective. Although the longitudinal cumulative drug exposure duration was long relative to published studies of antiangiogenics in HHT, there are potential adverse effects of IMiD therapy that could appear much later in the course of treatment. The lack of a formal open-label extension and requirement for patients to apply to a drug access program from the manufacturer meant that many of the 113 patients eligible for PATH-HHT ATLAS, including numerous patients who responded well to pomalidomide on PATH-HHT, did not continue pomalidomide treatment after PATH-HHT completion for a variety of reasons. Many of the HHT Center Director principal investigators in PATH-HHT were not hematologists and had not used pomalidomide or any immunomodulatory imide drug in clinical practice before this trial, which may have resulted in reluctance to administer this antineoplastic therapy (off-label at higher intensity than its labeled cancer indication) outside of the formal oversight of a clinical trial. Many patients of limited financial means lived a great distance from their study site and the financial support offered to cover travel and lodging costs provided by the Cure HHT Foundation for PATH-HHT study visits was not available to support continued treatment after the study. The drug manufacturer’s pomalidomide access program application was logistically complex, requiring support from financial assistance staff variably available at study sites, and required disclosure of personal information including detailed household income information, all barriers that prevented some patients from proceeding to treatment with off-label drug. Given these logistical barriers and access limitations, we expect that the number of patients that would have crossed over to a formal open-label extension would have been significantly closer to the 113 patients who would have been eligible to do so. Additionally, the PATH-HHT ATLAS cohort may include a population with greater motivation to continue or initiate pomalidomide, possibly due to a heavier symptom burden or a particularly favorable response to pomalidomide in the parent trial, than the overall population of the parent trial. Nevertheless, the inclusion of 62 patients from 7 sites was still a large cohort for an immunomodulatory imide drug in HHT and adequate for the PATH-HHT ATLAS to answer the questions it set out to evaluate.

In conclusion, we observed good effectiveness and durability of pomalidomide treatment effect on moderate-to-severe epistaxis in HHT for treatment durations exceeding 4 years, despite widespread dose reductions from the starting dose of 4 mg daily primarily due to neutropenia. Lower starting doses of 2 or 3 mg daily appear to largely approximate the effectiveness of 4 mg daily dosing with a better AE profile. Effects on gastrointestinal bleeding were much more modest, and pomalidomide was not ultimately effective in patients with very severe red cell transfusion–dependent gastrointestinal bleeding. Reassuringly, we did not observe increased risks of thromboembolism or peripheral neuropathy in patients with HHT receiving pomalidomide over extended durations of therapy. Considering the findings of PATH-HHT and PATH-HHT ATLAS, pomalidomide should be considered a routine antiangiogenic therapeutic option for certain patients with moderate-to-severe HHT-associated bleeding.

Conflict-of-interest disclosure: H.A.-S. reports grants or contracts (research funding to institution) from Agios, Sobi, Vaderis, Novartis, and Amgen; and reports consulting fees from Agios, Amgen, Alnylam, Alpine, Sobi, Takeda, Pharmacosmos, Novartis, and Sanofi. R.S.K. reports grants or contracts (research funding to institution) from the US Department of Defense and the US Health Resources and Services Administration; and reports consulting fees from Alnylam, Crosswalk, Pharmacosmos, and Tectonic. K.R.M. reports payment or honoraria for lectures/presentations/other from MD Anderson Cancer Center and University of Southern California; and reports participation in data safety monitoring board/advisory board for Alnylam. A.M.P. serves on the advisory board for BioMarin LLC; receives royalties from UpToDate; and reports grants or contracts (research funding to institution) from Novartis and Janssen Pharmaceuticals. The remaining authors declare no competing financial interests.

Acknowledgments

The authors thank Sonia M. Thomas for her critical review of the manuscript, as well as the patients with hereditary hemorrhagic telangiectasia who participated in the PATH-HHT clinical trial.

This study was supported by grants (UG3HL140097 [K.R.M.] and K23HL159313 [H.A.-S.]) from the National Heart, Lung, and Blood Institute.

Authorship

Contribution: E.Z. contributed to data collection, analysis and interpretation of the data, critical revision of the intellectual content, and final approval of the manuscript; H.A.-S. contributed to conception and design, data collection, analysis and interpretation of the data, writing the first draft of the manuscript, critical revision of the intellectual content, and final approval of the manuscript; and R.S.K., J.P., V.P., V.N.I., K.J.W., P.G.H., A.M.P., M.B.C., D.P., J.R.-L., and K.R.M. contributed to data collection, critical revision of the intellectual content, and final approval of the manuscript.

Footnotes

Data are available from the corresponding author, Hanny Al-Samkari ( hal-samkari@mgh.harvard.edu ), on request.

The full-text version of this article contains a data supplement.

Supplementary Material

Supplemental Table

References

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