In this issue of the e-news


CONTENTS:

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Due to the global pandemic, the 63rd ASH Annual Meeting and Exposition was a hybrid event, held in-person in Atlanta, GA and virtually, December 11-14, 2021. The meeting attracted thousands of clinicians, scientists, trainees, and pharmaceutical company personnel worldwide to share ground-breaking research in the field of hematology.

In conjunction with the ASH meeting, PDSA hosted virtually the annual Friday Morning ITP Breakfast, coordinated by PDSA and Medical Advisors, James Bussel, MD, Nichola Cooper, MD, Michele Lambert, MD and John Semple, PhD. Thirteen hematology experts presented their leading-edge ITP research and.the prestigious Robert McMillan, MD ITP award was initiated to honor a person who has made a significant difference in the lives of many with ITP. The PDSA Medical Advisory Board unanimously chose PDSA President and CEO Caroline Kruse as the first recipient of the Robert McMillian, MD award.

In this issue of the e-news, we report on new therapies and combination strategies for treating ITP. Watch for additional ASH reports in the 2022 winter issue of The Platelet News, the PDSA quarterly newsletter.



All-Trans Retinoic Acid Plus Low-Dose Rituximab vs Low-Dose Rituximab in Corticosteroid-Resistant or Relapsed ITP

Previous studies have suggested that a low dose of rituximab (LD-RTX) may be as efficient as the standard dose in treating ITP, which is helpful given the costs for treatment. All-trans retinoic acid (ATRA) is synthesized from vitamin A to treat a variety of conditions including acne and specific forms of leukemia. ATRA impacts megakaryocyte maturation and has an immunomodulation effect, which is one reason why it is now being investigated as a possible ITP therapy. In this study the benefits of using ATRA plus LD-RTX (combination therapy) versus using LD-RTX alone (monotherapy) are compared in adult ITP patients who were either corticosteroid resistant, or who relapsed following corticosteroid use.

There were 168 adult participants recruited from seven different medical centers in China. One hundred and twelve were given combination therapy, while 56 were given monotherapy. Similar clinical and age characteristics between both groups. Primary outcome (referred to as the overall response) was defined as achieving a platelet count over 30,000 µL, doubling of baseline count, and with no bleeding events.

Although individuals receiving combination therapy seemed to meet the primary outcome more and seemed more likely to have a sustained response (how long the effect of the drug lasts), comparisons of both between the two treatment groups was not significantly different. That means using a combination of ATRA plus LD-RTX did not offer additional clinical benefit compared to using LD-RTX alone. More adverse effects were reported in the combination group; however, they were mild and included dry skin, headaches, and dizziness. There was no difference in response time between the two treatment groups.

Overall, it appears treating ITP with either a combination of ATRA plus LD-RTX or using LD-RTX alone can reduce thrombocytopenia and risks for bleeding in a subgroup of adult ITP patients who fail to respond to steroids, or who are steroid-dependent.

https://ash.confex.com/ash/2021/webprogram/Paper149527.html

Comments from PDSA’s Medical Advisors:

On the one hand this is a novel approach to management of ITP. Given that combination treatments may be the wave of the future if affordable, it is appropriate to investigate combinations. This study was done in the ideal fashion by comparing treatment A (in this case rituximab) to treatment A plus the experimental treatment B (in this case ATRA). The results did not demonstrate a significant difference in the 2 approaches meaning that there is a less than 1 in 20 chance that the combination is better than just low dose rituximab alone. There of course may be advantages to the combination but they are not very striking. Ideally, if the authors or others feel strongly about the benefits of ATRA (as demonstrated previously with danazol in ITP) then a repeated and perhaps even larger study would be needed.


Tacrolimus Plus High-Dose Dexamethasone Vs High-Dose Dexamethasone alone as First Line Treatment for Adult ITP (Results from the Target Trial)

Tacrolimus is a non-steroid immunosuppressant that is used as a treatment in many immune conditions and has been shown to improve anti-platelet antibody mediated thrombocytopenia in mice. As a result, it is now being investigated as a possible new therapy for ITP. This study summarizes the results from a phase two, open-label, clinical trial comparing the effectiveness of using Tacrolimus with high-dose dexamethasone (combination therapy) vs using high-dose dexamethasone alone (monotherapy).

A total of 140 participants were recruited into this study; 72 received combination therapy, while 69 received monotherapy. There was a slight female predominance (52%) with a median participant age of 33 years. Combination therapy use significantly increased the chance for a sustained response six months into the study (63% vs 43%) in addition to increasing the chance for clinical remission within two weeks (76.4%). Combination therapy had significantly less treatment failures, less bleeding events, and was associated with a lower bleeding score. There wasn’t a significant difference between the two treatment groups regarding side effects, adverse events, and the need for rescue therapy.

Overall, researchers concluded that Tacrolimus plus high-dose dexamethasone is an effective treatment and may benefit those who are unable to access more expensive second-line therapies.

https://ash.confex.com/ash/2021/webprogram/Paper152111.html

Comments from PDSA’s Medical Advisors:

This is an interesting study of the effect of tacrolimus in ITP. Tacrolimus is primarily used to prevent graft rejection when the grafts are solid organs such as heart, lungs, liver, and/or small intestine. It may also be used for kidney transplantation. This is of interest because in these settings the immune reaction being prevented is alloimmune (directed again something foreign to one’s body) not immune as in ITP in which the immune reaction attacks one’s own platelets. However, the precursor drug (it allowed the initial solid organ transplantations to be possible before tacrolimus came into use) cyclosporin has been used in difficult cases of ITP for many years. The mechanisms of tacrolimus and cyclosporin are somewhat similar but tacrolimus has is used more widely because it is thought to be less toxic than cyclosporin. Therefore, it is not surprising for tacrolimus to be tried in ITP. This combination study (both arms received high dose dexamethasone for 4 days and only 1 arm also received tacrolimus) demonstrated a substantial and significant improvement in platelet response in the combination arm. The more intensive immunosuppression induced by the two agents combined is not only effective but did not result in increased serious infections, always the concern with intensified immunosuppression. Of course, these results need to be reproduced in other studies. Future studies may demonstrate additional combinations or dosing strategies to optimize the use of tacrolimus. Another approach might involve focussing on which patients would do best if treated with tacrolimus as part of their initial therapy.

 

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