Sickle Cell Disease Advisory Committee Minutes

Video conference


Dr. Keith Hoots, the Division Director at the Division of Blood Diseases and Resources (DBDR) opened the meeting by greeting the Sickle Cell Disease Advisory committee (SCDAC) members. He reminded everyone in attendance that the committee follows the regulations set forth by the Federal Advisory Committee Act (FACA).

Dr. Nahed El Kassar, medical officer within the DBDR ,welcomed everyone and thanked the new members for going through the onboarding process. After reading a disclosure in accordance with the legal requirements of FACA, the committee chair Dr. Allison King took the lead.

After general introduction of each committee member, speaker and NHLBI member, Dr. Asif Rizwan from DBDR presented the HEAL initiative RFAs: HEAL Non-addictive Analgesic Therapeutics Development to Treat Pain (R61, U19, UG3/UH3) Secondary NHLBI sign-on.

The second presentation was by Dr. Courtney Fitzhugh, M.D, Lasker Clinical Research Scholar, Laboratory of Early Sickle Mortality Prevention on the NIH Experience in Nonmyeloablative Allogeneic Transplant for SCD.

SCD leads to debilitating painful episodes as well as subclinical and overt organ damage. In a publication on 225 patients, primarily with Hb SS disease, data shows that even though 60% of patients were taking hydroxyurea, the median survival age was only 48 years. Thus patients with SCD continue to experience early mortality (DeBaun M et al. Blood, 2019. 133(6): 615-617). In another paper, the cumulative survival in 150 adults was followed from 2003 to 2016 and patients were screened for heart, lung, and kidney disease. They found that survival was significantly higher in patients who had < 1 organ involved with a mean time to death of 14.0 years as compared to those who had more than 1 organ involved with a mean time to death of 7.8 years. (Chaturvedi S et al. American Journal of Hematology, 2018. 93(9): 1153-1160).

In 1999 there were 2 major obstacles for curing adults with sickle cell disease. The first step was to provide a curative option for the majority of adults with SCD that are not eligible for the standard transplant because of age and co-morbidities including heart, lung, and kidney disease. Dr. Fitzhugh and her colleagues therefore sought to develop a less toxic (or nonmyeloablative) regimen which focused on drugs not only to suppress the immune system but also to re-educate the immune system, leading to immunologic tolerance, so that donor and recipient cells would no longer recognize each other as foreign, therefore decreasing the incidence of graft rejection and graft versus host disease (Hsieh MM, Kang E, Fitzhugh CD, et al. NEJM, 2009. 361(24): 2309-2317). The second obstacle was the availability of transplant donors. While the HLA-matched sibling protocol was very successful, <15% of patients with SCD have an HLA-matched sibling donor. Therefore, the goal was to develop a nonmyeloablative haploidentical (or half-matched) protocol for adults with severe SCD. Using mice models, Dr. Fitzhugh et al showed for the first time that sirolimus and post-transplant cyclophosphamide work synergistically to induce tolerance (Fitzhugh CD et al. Bone Marrow Transplantation, 2013. 48(10): 1335-1341).

Between 2009 and 2017, results translated into a phase I-II trial for adults with severe SCD not eligible for other curative therapies and with severe organ damage. The study contained 3 cohorts. Patients in the first cohort did not receive post-transplant (PT)-cyclophosphamide (Cy) and 3 patients were transplanted. One of the 3 patients engrafted but lost the graft at 7 months post-transplant. Stopping rules were built into the study so that if too many patients either rejected their grafts or developed moderate to severe GVHD, the study would move to the 2nd cohort. Based on the three patients losing their grafts, stopping rules were met and the study moved to the 2nd cohort where 1 dose of Cy was given at 50mg/kg on day 3 post-transplant. Eight patients were transplanted in the 2nd cohort. Five of eight patients engrafted and only two remain free of SCD. When stopping rules were again met, the study advanced to the third cohort which included 100mg/kg Cy in divided doses on days 3 and 4 post-transplant. Ten of twelve patients engrafted, but only six remain free of SCD. The study met stopping rules and closed to accrual. Despite enrolling such sick patients, none died before 100 days post-transplant. One patient in the third cohort died as a result of the transplant at 6 months post-transplant. Four other patients died after rejecting their grafts between 3 and 8 years post-transplant. The major problem was that either patients failed to engraft, or they engrafted and then subsequently acutely rejected their graft between days 60 and 100 post-transplant. Because no significant GVHD developed, the investigators concluded that additional upfront immunosuppression would decrease the graft rejection rate while avoiding unacceptable GVHD or viral disease.

Pentostatin and cyclophosphamide were shown in a mismatched murine model and in humans to deplete lymphocytes and promote stable mixed chimerism. In 2017, the same group designed a phase I-II nonmyeloablative haploidentical trial which included pentostatin and Cy preconditioning starting at -21 days before transplant with the goal of decreasing the incidence of graft rejection. Alemtuzumab starts at -7 days before transplant followed by 400cGy TBI in divided doses. Patients also receive sirolimus starting at 4 days post-transplant. The study is currently ongoing.

From previously reported 67 patients with SCD who underwent nonmyeloablative transplant at the NIH and were prospectively followed, Dr. Fitzhugh et al. evaluated the percentage of donor myeloid chimerism (DMC) sufficient to reverse sickle cell disease. They were most interested in donor myeloid chimerism because it tracks the percentage of donor erythroid chimerism in the bone marrow. Three patients whose donors had sickle cell trait initially achieved high donor myeloid chimerism levels, but they slowly fell over time. As long as the DMC was at least 20%, the patients HbS was close to their donors’ HbS at <50%. As the DMC decreased below 20%, HbS rose above 50%, and all three patients had return of their SCD. A mathematical model was developed which showed the reason only 20% DMC is necessary is due to the vast differences in RBC survival of 3 months for donor RBCs and only 5 to 20 days for RBCs in patients with SCD.

In conclusion, in the HLA-matched sibling setting, myeloablative conditioning has high efficacy in children. Non-myeloablative conditioning aimed at tolerance induction has a lower rate of GVHD despite the use of PBSCs, but appears to have a higher rate of graft rejection. Newer studies are being developed in an attempt to decrease the graft rejection rate. With haploidentical HSCT, recent published studies including PT-Cy have event free survival (EFS), GVHD, and mortality rates similar to the HLA-matched sibling setting. As tricuspid regurgitation velocity (TRV), (a biomarker that when elevated is associated with early mortality), decreases after non-myeloablative allo-HSCT (results presented by Dr. Fitzhugh at ASH in Dec 2021), this approach may positively impact survival. And finally, long-term follow-up is critical to assess late effects of curative therapies for patients with SCD.

The third presentation was by Dr. Phuong Vo, Assistant Professor of Medicine University of Washington, Clinical Research Division, Fred Hutch presented Radioimmunotherapy (RIT)-based conditioning regimen to reduce toxicity post-transplant for nonmalignant hematologic disorders, research funded by NHLBI and NCI. She presented on behalf of Dr. Sandmaier.

Dr. Vo started with a background explaining that the ideal conditioning regimen enables engraftment with limited early toxicity and decreased late effects. The basic elements of RIT are 1-the use of a specific antigen: expressed on the target cell surface and not expressed on non-hematopoietic normal tissues; 2-the radioisotope selection and its interaction with tumor cells. The main advantage of RIT is reduction of late toxicity. It is selected based on different properties including its half life and its interaction with specific tumor cells. Radioisotopes used are: Iodine 131 with 8.07 days half-life; Yttrium-90 β with 2.7 days half-life and Astatine-211 α with7.2 hours half-life. The antigen used by Fred Hutch team is CD45, a tyrosine phosphatase expressed on virtually all leukocytes. Targeting CD45 contributes significant lympho-myelosuppression that necessitates HCT to reconstitute hematopoiesis.

Dr. Vo presented Phase 1 trial of 131I-anti-CD45 Ab for older AML and MDS patients results published in Blood 2009; 58 patients- Median age 63, range (50-74 years) 86% with refractory/active disease. Results were encouraging with 38% 3-year DFS. Dr. Vo et al also published in Haematologica, 2019 the results of their CT 90Y-anti-CD45 Ab followed by RIC-HCT for high risk MDS/AML patients (NCT01300572) . The 1-year estimate of relapse was 41% in 15 patients treated in this protocol.

Alpha-emitters have favorable qualities compared to β particles: Short path length, high linear energy transfer (LET) and short half-life. This was the reason for switching the Astatin 211At, conjugated to anti-CD45 to induce myelosuppression at Fred Hutch; results in mouse models were published in Cancer Res 2009, then in Canine models in Blood 2012 where in these models there was achievement of rapid and stable donor engrafment. Eight dogs conditioned with a dose range 155-625 uCi/kg achieved rapid and stable donor engraftment. In research published by Aya Nakaya et al.,Transplantation and Cellular Therapy 2021, authors found that 211At-Anti-CD45 RIT conditioning overcomes graft rejection pre-sensitization model in a canine model.

Finally, Dr. Vo presented protocol 9595 (NCT 03128034) funded by NCI and published in Sandmaier, et al. TCT 2021: Phase I/II 211At-BC8-B10 Before Donor Stem Cell Transplant in Treating Patients With High-Risk Acute Myeloid Leukemia, Acute Lymphoblastic Leukemia, Myelodysplastic Syndrome, or Mixed-Phenotype Acute Leukemia. Patients received 211At-BC8-B10 intravenously (IV) over 6-8 hours on day -7 and fludarabine phosphate IV over 30 minutes on days -4, -3 and -2; then they underwent TBI and peripheral blood stem cell transplant (PBSC) on day 0; received cyclosporine orally or IV every 12 hours on days -3 to 56 and then tapered to day 180, or continuing to day 96 and then tapered to day 150; patients also received mycophenolate mofetil PO or IV (first dose to occur 4-6 hours after PBSC infusion) every 12 hours on days 0-27, or every 8 hours on day 0 and then reduced to every 12 hours on days 30-40. Patients with HLA-matched unrelated donors received sirolimus PO once daily (QD) on days -3 to 150 and then tapered to day 180. After completion of study treatment, patients were followed up at 100 days and then at 6, 9, 12, 18 and 24 months. With a median follow-up of one year, 35% of these high risk patients remain in relapse free survival.

This protocol has inspired protocol FH 9524 211At-Anti-CD45 for nonmalignant hematologic disorders (NCT 04083183), funded by the NHLBI, with the goal of developing a safe and effective regimen that enables stable engraftment without increasing the risk for early toxicities, such as GVHD and late effects secondary to TBI. Arm A (HLA-MRD, -MURD, or an URD with a single HLA-class-1 allele MM or DQB1 antigen or allele MM) endpoint will be graft rejection, defined as the establishment of <5% donor CD3 and CD33 chimerism at day 80-100. Arm B (HLA-haploidentical or an URD MM for a single HLA-class 1 antigen or a single HLA-DRB1 allele MM) endpoint will be Graft rejection, defined as the establishment of <5% donor CD3 and CD33 chimerism at day 80-100. This protocol is open for enrollment.

The last talk was by Lydia Pecker, MD., Director, Young Adult Clinic, Johns Hopkins Sickle Cell Center for Adults and Assistant Professor of Medicine. Dr. Pecker presented a thorough talk on reproductive health in SCD women. She started by reminding stigma on black women being described as hyper-fertile. She also mentioned that several fertility problems are also encountered by boys and men with SCD; those include vaso-occlusive complications such as priapism, but also fertility problems secondary to blood and marrow transplant (BMT).

She focused on reproductive health problems in girls and women with SCD.

- Delayed menstruation, also pain during menstruation that ends by missing school due to hospitalization. In addition, two major complications can be encountered: opioid addiction and treatment by contraceptives that can increase the pre-existing risk of thrombo-embolism.

- Later on, there is lack of family planning and genetic counseling or even sometimes a wrong interpretation of the partner genetic testing (with a HbC considered as normal) could lead to having kids with SCD. Genetic counseling and considering IVF is the solution of choice for most of couples when the right testing and counseling are done.

-Another major reproductive problem is the acceleration in decline of ovarian reserve. It seems that this is the reason for the high risk of miscarriage in SCD women. Of course, the major complications are decreased fertility and early menopause. This latter complication is a major problem especially because it causes early osteoporosis which will add to the risk of hip fracture in SCD patients (due to avascular osteonecrosis). The pathophysiology for the early decline in ovarian reserve in unclear and one publication suggested that HU could add to this risk. It is also unclear if there is a pituitary-hypothalamic component.

-BMT is indicated when there is a matched related sibling and age is <13 years which is the case in 10% of cases. Transplant represents a threat for gonadal fertility. Cryo-tissue preservation is only offered at the NIH and covered by insurance only in Illinois. This represents an important gap in reproductive treatment of women with SCD.

-Maternal morbidity and mortality of SCD patients is high and 70% is attributable to SCD complications.

-Those complications are preventable.

- Four drugs are approved for SCD but none during pregnancy. Transfusion is safe for the mother, but safety is unclear for the baby.

- Thinking beyond survival: Could reducing anemia and opioid exposure (with chronic transfusion) affect neurodevelopmental outcomes in children born to women with SCD.

There is high disparity in parents whose life is affected by having kids with SCD that Dr. Pecker mentioned at the beginning of her talk.

Finally, Dr. Pecker underlined the low funding rate for key words with ovary, fertility and reproductive health. She also emphasized that it is time to move the mean age of lifespan of SCD patients above the age of 40 y at which we have been immobilized. This requires a multi-disciplinary effort of hematologists, Ob/Gyn specialists, reproductive endocrinologists, neonatologists, maternal fetal medicine doctors and funding agencies.

Questions and answers followed each presentation. In addition, a general discussion took place at the end of all presentations.

The HEAL initiative was very well received by outside investigators since addiction was unfortunately often associated with pain in SCD.

Studies focused on chimerism are important for gene therapy, thalassemia, in addition to SCD transplant to study late effects and cure therapies.

In terms of SCD, creating silos of funding are not necessarily good solutions and opening doors of funding such as having “pain” as focus, or “cure for SCD”, or “behavioral science”, or “implementation science”.

A question might be “can the clinical trial for transplant cover for the basics such as pain and other problems in the patient?” Dr. Hoots answered that there are ongoing discussions with CMS based on data that are currently gathered for our CTs (evidence generation) to answer these kind of questions; the objective is to have the basic care covered by CMS while the research part covered by the NIH or Pharma.

Regarding fertility, we need basic science and clinical science to stratify the risk for SCD (males and females) because we don’t really have data. There is iron overload in the pituitary gland in half of chronically transfused patients. In a patient with a detectable cardiac iron overload, we should assume that there is a central component. Otherwise, the fertility problem is primarily due to ovarian failure.

Messaging to the communities was a recurrent theme; in addition to the need for the knowledge-base how to package and deliver the message are of equal importance in order to not to add/create inequities; how to engage stakeholders through implementation science, creating consortia, engaging patients families and different providers in important topics such as fertility were discussed.

At the end of the meeting, Dr Hoots announced that he was retiring from his position as DBDR director. He thanked the SCDAC for their continuous commitment and he was thanked in return for his outstanding dedication to the SCD mission as the DBDR direction.