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H. Al-Samkari et al.
overall bevacizumab dose intensity used in continuous maintenance) resulted in significantly lower mean hemoglo- bin and higher mean ESS than continuous maintenance (Online Supplementary Table S4). This is not unexpected given that recurrence of bleeding and/or anemia are the triggers for re-treatment with an intermittent maintenance approach. It is unclear whether the financial savings of administering less drug in the intermittent maintenance approach offsets the potential disadvantages. Additionally, although patients in this study were treated for up to 8 years without any com- plications specifically attributed to extended-duration treat- ment, the impact of indefinite bevacizumab exposure in HHT (either positive or negative) is not known. How main- tenance strategy and overall dose intensity could affect this impact is therefore also unknown.
Bevacizumab was well-tolerated overall, with hyperten- sion, proteinuria, fatigue, and myalgia/arthralgia being the most common TEAE, consistent with prior reports in HHT patients.23-27,39-42 Only 5% of patients discontinued treatment because of adverse events. An understanding of the adverse event profile of single-agent systemic bevacizumab in HHT patients is critical, given that the vast majority of prior beva- cizumab studies added bevacizumab (typically at 2-3 times the common 5 mg/kg dose used in this study) to multiagent cytotoxic chemotherapy regimens and administered this combination to patients with metastatic cancer. Therefore, the adverse event rates described in the prescribing infor- mation, such as the relatively high rates of serious events including VTE or intestinal perforation, are not reflective of single-agent bevacizumab use in HHT patients. This point is highlighted by the VTE rate in this study of 2%, with a median duration of bevacizumab exposure considerably longer than that of most cancer studies finding VTE rates in the 5-10% range. Furthermore, two out of five of the VTE observed were provoked events immediately following major joint replacement surgery (Online Supplementary Table S6). We observed no central nervous system bleeding, hemoptysis, pulmonary hemorrhage, or intestinal perfora- tion. Additionally, while anticoagulation in HHT patients can be very challenging and dramatically exacerbate bleed- ing, patients with VTE in this study receiving anticoagula- tion did well with concurrent bevacizumab treatment with- out significantly increased bleeding (Online Supplementary Table S6).
Our study has several limitations consistent with its retrospective nature. These include center variability in the management of HHT and variability in the use and availability of adjunctive measures to control bleeding. The lack of randomization allows for the presence of con- founding factors that could have resulted in clinical improvement independent of bevacizumab use. However, the fact that significant improvements in all outcome measures occurred following initiation of beva- cizumab treatment increases our confidence that beva- cizumab was the cause of the clinical improvements. Additionally, we analyzed known confounders such as concurrent use of antifibrinolytics and receipt of local hemostatic procedures and found no significant differ- ence in outcomes between the two groups. To minimize the impact of patient heterogeneity in this disease, we employed a pre/post-treatment analytical design with paired analyses such that each patient served as his or her own internal control in our effectiveness analyses.
Adverse event reporting was limited by the retrospective design, but we expect it is unlikely that any serious adverse events would not have been appropriately docu- mented. Finally, our study evaluated number of iron infu- sion events, not exact milligrams of elemental iron infused. Although less precise, we believe that the observed reduction in iron infusions to be valid for two reasons: the median number of iron infusions went from six before treatment to zero after treatment (and the amount of elemental iron in 0 iron infusions is none) and more importantly, the reduction in iron infusions paral- leled the dramatic reduction in RBC transfusions.
In conclusion, we observed that systemic bevacizumab was effective in the management of severe HHT-related epistaxis and gastrointestinal bleeding in a cohort of 238 HHT patients. While data from large, randomized prospective studies are needed to confirm these findings, in this large observational study, bevacizumab was associ- ated with significant improvements in hemoglobin and ESS, along with significant reductions in the need for RBC transfusion and intravenous iron infusion. Improvement was similar regardless of the underlying pathogenic muta- tion. Following an initial sequence of induction treat- ments, continuous scheduled maintenance therapy and intermittent as-needed maintenance therapy were both reasonable to maintain treatment effect. Hypertension, fatigue, proteinuria, and myalgia/arthralgia were the most common TEAE; VTE and treatment discontinuation for adverse events were rare, occurring in 2% and 5% of patients, respectively.
Disclosures
HA-S has provided consultancy services for Agios, Argenx, Rigel, Sobi, and Dova, and received research funding from Agios, Dova and Amgen. CRW has acted as a consultant for Medtronic and BTG/BSCI; and has received grant support from Medtronic, BTG/BSCI and Siemens Healthcare. MC: has provided consul- tancy services for Medtronic. DJK has received research funding from Protalex, Bristol-Myers Squibb, Rigel, Bioverativ, Agios, Syntimmune, Principia and Alnylam); and has acted as a consult- ant for ONO, Pfizer, 3SBios, Eisai, GlaxoSmithKline, Genzyme, Shire, Amgen, Shionogi, Rigel, Syntimmune, MedImmune, Novartis, Alexion, Bioverativ, Argenx, Zafgen, Fujifilm, Principia, Kyowa Kirin, Takeda and the Platelet Disorders Support Group. RSK, JGP, HAA, YAA, CV, MMS, SD-G, CBW, JPM, EHF, JRG, VNI, MAL, AI, MM-Z, MEM and JR-L have no conflicts of interest to disclose.
Contributions
HA-S wrote the first draft of the manuscript and contributed to the study design, data collection, data analysis, creation of tables and figures, critical revision of the manuscript, and its final approval; VNI contributed to the study design, data collection, crit- ical revision of the manuscript, and its final approval; JGP, HAA, YAA, CV, MMS, SD-G, CBW, JPM, EHF, JRG, CBW, MAL, AI, MM-Z, MEM, MC, JR-L, DJK and RSK contributed to data collection, critical revision of the manuscript, and its final approval.
Acknowledgments
HA-S is the recipient of the National Hemophilia Foundation- Shire Clinical Fellowship Award, the Harvard KL2/Catalyst Medical Research Investigator Training Award, and the American Society of Hematology Scholar Award.
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haematologica | 2021; 106(8)