An opinionated take on NEJM highlights for January-February 2021

Gene therapy in beta-thalassemia and sickle cell anemia

Beta-thalassemia and sickle cell anemia are common genetic diseases of hemoglobin (Hb) which manifest themselves in the former through transfusion dependence, in the latter through painful vaso-occlusive crises that frequently land patients in the hospital in a pitiful state. BlueBird’s lentiglobin therapy is an ex-vivo gene therapy in which autologous stem cells are harvested, transfected with new HbA gene, and then returned to the patient. Because the HbA is slightly modified via a single amino-acid substitution (HbAT87Q), expression is trackable.  Now in back-to-back issues, we have results for both conditions showing how post engraftment, the HbAT87Q becomes the dominant form of hemoglobin, how most beta-thalassemia patients become transfusion independent, and how sickle-cell patients stop having sickle cell crises. How long this will be sustained remains to be seen, but the beta-thalassemia trial had up to 4 years of follow-up with no noticeable drop off.  This is about as good as can be imagined for these severe conditions which deeply affect children and shorten adult lives.  A shadow on an otherwise bright picture is that two patients from earlier cohorts developed a leukemia. The first did not have HbAT87Q in the tumor clone, but the second did; though a very detailed analysis shows evidence against the lentiviral insertion being the culprit. Beyond that, one wonders if this new data will reopen conversations with European payers after Bluebird’s decision to pull out given lack of agreement on pricing. Betibeglogene Autotemcel Gene Therapy for Non–β0/β0 Genotype β-Thalassemia; Biologic and Clinical Efficacy of LentiGlobin for Sickle Cell DiseaseAcute Myeloid Leukemia Case after Gene Therapy for Sickle Cell Disease


Risks of JAK vs TNF inhibitors

JAK and TNF inhibitors are powerful immunomodulatory agents that have changed the face of autoimmune disease none more so than rheumatoid arthritis (RA) – but their very power comes with well-known drawbacks: classically immunosuppression increasing risks, for instance, reactivation of tuberculosis. There have also been indications that the use of JAK inhibitors might increase cancer and cardiovascular event rates and this is why the FDA required Pfizer to conduct a head-to-head safety trial comparing tofacitinib (Xeljanz) to older generation TNF inhibitors (i.e., etanercept and adalimumab). This study involving 1,455 subjects followed for 4 years is now in and the results are that tofacitinib statistically significantly increases the risk of cancer (HR 1.48) and non-statistically significantly for cardiovascular events (HR 1.33). How will this impact practice? Clearly it will impact how new patients are steered to treatment, but it is a real question mark on how many current patients on a JAK oral therapy will be interested in switching to an injectable. Cardiovascular and Cancer Risk with Tofacitinib in Rheumatoid Arthritis; Risks and Benefits of Janus Kinase Inhibitors in Rheumatoid Arthritis — Past, Present, and Future


Go easy on the chips, eat your bananas

An association between sodium and potassium intake and cardiovascular risk has been well documented, but so far it has been poorly quantified. This study of more than 10,000 individuals relied on 24-hour urinary sodium and potassium measurements (based on the principle that “what comes in must come out”) and followed the subjects for about 9 years. The results show a remarkably strong dependence of serious cardiac events on intake: an incremental gram/day of sodium increases risk by 18% while an incremental gram/day of potassium decreases it by a symmetric amount of 18%. 24-Hour Urinary Sodium and Potassium Excretion and Cardiovascular Risk


The New England Journal of Medicine is a premier weekly medical journal covering many topics of interest to the health sector. In this monthly series we offer an opinionated perspective on selected highlights that might be of interest to our clients and others.

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