Is Hematopoietic Stem Cell the only APDS Option?

Is Hematopoietic Stem Cell the only APDS Option?

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APDS or activated PI3KK delta syndrome is a relatively new disease that was only fully characterized in 2013. It is a primary immune dysregulatory disorder which means it is a rare genetic disorder that involves both immune deficiency which shows up as frequent infections and immune dysregulation which can involve things like autoimmunity lymphoproliferation symptoms can vary widely from person to person and in general it's a progressive disease and can lead to end organ damage as well as malignancies including lymphomas in multiple family members before we get to challenge of treating a disease rare orphan disease like this I would like to also point out that a challenge in primary immunoregulatory dysregulatory disorders is or what we in the vernacular call inbound errors of immunity is diagnosis so more of these genetic diseases are being discovered and genetic testing is becoming more accessible at least in Europe and North America these patients experience a protracted diagnostic odyssey for patients with APDS and most inborn errors of immunity the median time to diagnosis with from the onset of symptoms in infancy or early childhood can be seven to eight years as we have seen in the natural history studies problems with treating any disease of this nature is that in order to treat the dysregulation we usually use immunosuppressive agents but because this patient population is already susceptible to infections we have to be very careful about suppressing the immune system further in other words they often need several types of medications including immunoglobulin supplementation and immunomodulators like rapamycin and mycophenolate mofetil or some other agent or rituximab some of which have opposing actions this is further complicated if the patient has lymphoma and there are no approved therapies for treatment of APDS as yet with the exception of hemopoietic stem cell transplantation the existing therapies do not treat the root cause of the disease which is a hyperactive enzyme found in the immune cell known as p110 delta even with a hematopoietic stem cell transplant there appears to be non-immune mediated problems including kidney disease which do not get better and there are problems related to graft acceptance by the host and the rationale for using linealism in the treatment of people with APDS is directly biased is because it directly targets the hyperactive enzyme p110 delta and inhibits it that is why it is called PI3K kinase inhibitor and there are a class of these drugs which are in clinical use in oncology hematology and but linealism is a medication that has been developed by the sponsor for specifically for this rare inherited genetic disorder what we are seeing today so far is that this affects the immune cells and allows them to develop correctly this particular medication which may have implications both for the deficiency and dysregulation aspects of the disease for example we have recently presented data in that in 12 weeks the linear recipe reduces the size of patients swollen lymph nodes and spleens which becomes they usually become swollen because of chronic inflammation infection as well as b and t cell dysregulation and we are excited to present the long-term outcome in fall at European society of immunodeficiency which is another meeting coming up in October so the aims and design of this phase 3 study that was presented at European hematology association or is to it was a randomized placebo-controlled trial to further investigate what we observed in the phase 2 dose escalation trial that we already published in 2017 using the same medication the crow primary endpoints were interesting because they addressed two large components of the disease the naive b cell replenishment lets us know that eventually we may see better antibody production and infection fighting in these patients as we use this medication longer term and early indication that was seen in in the published phase two long-term study was where three of the original six patients were able to stop the immunoglobulin replacement therapy was presented at ash meeting in 2018. the design was typical for a randomized control trial wherein 31 patients were randomized two is to one in a placebo-controlled design 21 of them received linearly say but a dose of 70 milligram orally twice a day and what is unusual though is that the length of time we have been followed following these patients who rolled over to a long-term extension study and these patients have been followed some of these patients have been followed for the long term in the sense about three to four years from now and eligibility was interesting in the sense it included patients from ages of 12 to 75 but the weight criteria of greater than equal to 45 kilograms made recruitment of younger patients rather challenging and we presented safety as well as reduction in lymphadenopathy reduction in splenomegaly as well as swollen or what is known as swollen spillings increasing the knife b cells and improvement in cytopenia’s at the European hematology association meeting and at EAACI another colleague of mine Dr. Virgil Dam has presented results related to lymphocyte subsets and further illustrate the reconstitution of the immune system so the finding of this study data and what are the implications for clinical practice uh the answer to this is complex um we I’m not sure we can make uh too much kind of implication because we haven't published data though we have it and we are going to be discussing it in various meetings coming forward in the near future remember what I presented at European hematology association is only 85 days or 12-week data of this use of this medication so the findings from recently completed studies have been presented at scientific congresses as you know and the product is still investigational and sponsor of the product is working closely with the regulatory authorities around the world seeking its approval the full implications will be realized when approved product is available for APDS patient populations worldwide and what the questions that remain unanswered are the pediatric population under the age of 12 years because this particular data is I’m showing you I have shown you in years yeah as well as we will be showing in future is limited to patients that are 12 years and older there are currently two studies planned in younger pediatric population at multiple centers in united states north America as well as in Europe and the first study is scheduled to start sometime this year and the in the field of inborn errors of immunity or Iei is growing and APDS is no exception we do not have a complete understanding of the genetic penetrance why symptoms vary so widely even sometimes within the same family we also hope to learn more about the natural history of this disease and non-immune mediated parts of the disease which may impact kidney central nervous system and other body organs are there other kind of uses of this kind of approach in for medical oncologists and hematologists I will say the hematologist should consider using PI3KK is modulation in other hematological conditions and oncologists are already using this class of drugs with some serious side effect concerns in lymphoma patients and what are the most common questions our colleagues have asked so far is any adverse side effects and we have not seen any serious adverse side effects that required stoppage of medication in any of the 31 patients that are being reported in this clinical trial and all six patients that we have published continue to be on this medication for more than five years now so people have asked us about improvement in infection rates and other comorbidities and that data will be presented with long-term follow-up of these patients in future so we are very excited to present the long-term outcome in the fall as well as in winter in various scientific meetings as we so stay tuned.

V. Koneti Rao, MD, FRCPA, Senior Research Physician, Primary Immune Deficiency Clinic (ALPS Clinic) at the National Institute of Allergy and Infectious Disease (NIH). In this video, he speaks about the EHA 2022 abstract - Hematological Outcomes From A Phase 3, Placebo-Controlled, Randomized Clinical Trial Of PI3K Delta Inhibitor Leniolisib In Patients With Activated PI3K Delta Syndrome.


Pathogenic mutations in the PIK3CD or PIK3R1 genes that cause kinase hyperactivity can result in activated PI3K syndrome (APDS) or PASLI, a primary immunodeficiency. APDS patients have dysregulated B and T cells, which results in lymphoproliferation, autoimmunity, immunodeficiency, and a higher risk of cancer. The majority of current treatments are empirical.


We previously reported the use of molecularly targeted inhibition of hyperactive PI3K signaling with the investigational drug leniolisib (CDZ173) in 6 patients with APDS in a 12-week open-label, within-subject dose-escalation Phase 2/3 clinical trial (Part 1 of NCT02435173; Rao VK, et al. Blood. 2017;130(21):2307-2316), as well as an interim analysis of the open- We present the findings of a randomized 2:1, placebo-controlled, triple-blind, fixed-dose research (Part 2 of NCT02435173).


Thirty-one patients aged 12 were enrolled worldwide. We acquired informed consent. Change from baseline in log10 transformed sum of product of diameters in index lymph nodes and change from baseline in percentage of naive B cells out of total B cells were co-primary outcomes at 12 weeks. Changes in the size of non-index lymph nodes and the spleen were also observed. Cytopenias were also assessed.


Primary effectiveness objectives for lymph node and naive B cells were fulfilled (p=0.0012 and p0.0001, respectively). From baseline to day 85 (D85; p=0.0011), leniolisib reduced the log10 transformed 3D volume in non-index lymph nodes. Several patient accounts reported that decreased lymphoproliferation reduced neck discomfort and difficulties swallowing. Analyses of the change in 3D volume and bi-dimensional spleen size from baseline at D85 revealed that leniolisib reduced spleen size (p=0.0009 and p=0.0079, respectively). Table 1 describes the many types of cytopenias. In patients receiving leniolisib, 82 percent of cytopenias improved, compared to 60 percent in individuals getting placebo.

Leniolisib was well tolerated; 23.8 percent of leniolisib AEs and 30.0 percent of placebo AEs were due to study therapy. There were no AEs that caused the study treatment to be discontinued. None of the significant adverse events were thought to be related to the treatment. 4 of 21 individuals (all of whom were 18 years old) in the leniolisib arm developed moderate neutropenia by D85, which was not clinically significant. These patients' neutrophil counts (x 109/L) at baseline, D15, D29, D57, and D85 are as follows:

* 8001002 patient: 1.83, 1.06, 0.79, 1.97, 1.11

* 4001003 patient: 2.90, 1.80, 2.60, 3.10, 0.90

* 5001002 patient: 2.55, 1.20, 2.30, 1.70, 1.20

* 1001006 patient: 2.35, 1.30, 2.80, 2.10, 1.30

At D85, the mean neutrophil level in all 21 patients receiving leniolisib was 2.94 x 109/L. By D85, two patients had developed lymphopenia. By D85, one patient in the placebo arm had developed lymphopenia and another had moderate neutropenia, both of which were not clinically significant.


In patients with APDS, leniolisib was well tolerated and met both primary efficacy objectives. Changes in other crucial parameters were discovered through additional observations.