Allogeneic Stem Cell Transplantation for Sickle Cell Disease in Brazil: The Time Is Now!

Blood ◽  
2011 ◽  
Vol 118 (21) ◽  
pp. 1064-1064
Author(s):  
Belinda Pinto Simoes ◽  
George B Navarro ◽  
Fabiano Pieroni ◽  
Luiz G Darrigo ◽  
Daniela Moraes ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Stem Cell ◽  
Sickle Cell ◽  
Neonatal Screening ◽  
Graft Failure ◽  
Sickle Cell Trait ◽  
Screening Program ◽  
Primary Graft Failure ◽  
Neonatal Screening Program

Abstract Abstract 1064 Introduction: Sickle Cell Diseases (SCD) are the most frequent inherited monogenic diseases worldwide. Data from the neonatal screening program showed that about 4% of the brazilian population harbors the sickle cell trait, reaching until 10% in the afro-brazilians. In the northern states of Brazil this frequency is much higher, as an example in Bahia 1/17 births are of children with sickle cell trait. The neonatal screening program doesn't cover the whole country so the estimate of about 3500 newborns with SCD per year in Brazil is certainly underestimated. Nevertheless the first official document regarding the treatment of these patients was published by the brazilian ministry of health only in 2004. Hydroxiurea (HU) is already used in more severe forms of SCD by the public health system since several years but is not available for all patients yet. In a recent publication Machado et al (ASH 2010 #843) demonstrated for the first time that HU can prolong survival in SCD, although the mortality rate for this disease is still high in Brazil. Stem Cell Transplanation (SCT) is the only available curative treatment for the inherited hemoglobinopathies, in spite of this there is no such program for SCD in Brazil. Here we describe the first brazilian cases transplanted in 5 brazilian centers of severely affected patients with no other treatment options not responding to HU. Patients and Methods: Sixtheen patients (15 HbSS, 1 case Sbeta thalassemia), median age 16 years (3–39), all except for one with HLA identical sibling donors (3 donors with sickle cell trait)received a alo SCT. Indications consisted mainly of severe acute chest syndrome, priapism, alloimunization and silent cerebral infarctions and overt previous stroke. One patient transplanted because of advanced Hodgkin's disease. The conditioning consisted of BuCy or FluBu with ATG in all but 3 patients who received FluCy and ATG. The decision was based on the age of one of the patients (39 years old and grade IV liver fibrosis) and 2 patients with previous stroke. Results: Primary graft failure occurred only with the unrelated donor. All other patients engrafted, but one patient conditioned with FluCy lost the graft about 100 days after transplant. She received a second transplant 3 years after with BuCy from the same donor, had a 100% engraftment without any sign of GVHD but unfortunately died 3 years later in remission from a SNC bleeding caused by her acquired vascular abnormality. Median follow up for all surviving patients is 2 years (152 days – 12,2 years). Overall survival is 13/16. Death occurred in 3 cases (1 primary graft failure and sepsis, 1 Hodgkin disease, 1 hemorrhagic stroke in a patient with severe cerebral vasculopathy with MoyaMoya). No veno-occlusive disease was observed. Acute GVHD grade II were observed in 4 patients (gut and skin) easily treated with short time prednisone. All surviving patients but one are full chimeras and the 39 years old patient remain a stable mixed chimera 6 years after transplant. Quality of life has improved in all patients considerably referring extremely grateful to be free of pain. Conclusion: Different from thalassemia SCT can be offered safely for older patients with SCD in our opinion. Our data confirm the curative potential of SCT in SCD and reinforce us to offer this curative approach to patients not responding to HU. A prospective trial is planned in Brazil who should address also long term toxicities and quality of life. Disclosures: No relevant conflicts of interest to declare.

scholarly journals The Neonatal Screening Program in Brazil, Focus on Sickle Cell Disease (SCD)

2019 ◽  
Vol 5 (1) ◽  
pp. 11 ◽  
Author(s):  
Ana Silva-Pinto ◽  
Maria Alencar de Queiroz ◽  
Paula Antoniazzo Zamaro ◽  
Miranete Arruda ◽  
Helena Pimentel dos Santos
Keyword(s):  
Sickle Cell Disease ◽  
Sickle Cell ◽  
Health Care Professionals ◽  
Neonatal Screening ◽  
Screening Program ◽  
Cell Disease ◽  
Ministry Of Health ◽  
Basic Care ◽  
Main Challenge ◽  
Neonatal Screening Program

Since 2001, the Brazilian Ministry of Health has been coordinating a National Neonatal Screening Program (NNSP) that now covers all the 26 states and the Federal District of the Brazilian Republic and targets six diseases including sickle cell disease (SCD) and other hemoglobinopathies. In 2005, the program coverage reached 80% of the total live births. Since then, it has oscillated between 80% and 84% globally with disparities from one state to another (>95% in São Paulo State). The Ministry of Health has also published several Guidelines for clinical follow-up and treatment for the diseases comprised by the neonatal screening program. The main challenge was, and still is, to organize the public health network (SUS), from diagnosis and basic care to reference centers in order to provide comprehensive care for patients diagnosed by neonatal screening, especially for SCD patients. Considerable gains have already been achieved, including the implementation of a network within SUS and the addition of scientific and technological progress to treatment protocols. The goals for the care of SCD patients are the intensification of information provided to health care professionals and patients, measures to prevent complications, and care and health promotion, considering these patients in a global and integrated way, to reduce mortality and enhance their quality of life.

The Experience and Health-Related Quality of Life after Haploidentical Stem Cell Transplantation for Adults with Sickle Cell Disease

2019 ◽  
Vol 41 (12) ◽  
pp. 1829-1844 ◽  
Author(s):  
Brooklyn Hastings ◽  
Crystal Patil ◽  
Agatha M. Gallo
Keyword(s):  
Quality Of Life ◽  
Stem Cell ◽  
Sickle Cell Disease ◽  
Stem Cell Transplantation ◽  
Sickle Cell ◽  
Health Related Quality ◽  
Cell Disease ◽  
Related Quality ◽  
Health Related

Haploidentical hematopoietic stem cell transplantation (HSCT) from partially matched first-degree relatives (e.g., parent, sibling, child) is the newest therapy available to reverse symptoms of adults with sickle cell disease. Because of this innovation, little is known about the recipients’ transplant experiences and how this type of transplant affects their quality of life. We describe the experiences and health-related quality of life (HRQOL) of five (3 female, 2 male) of nine eligible adults with sickle cell disease who received HSCT. Participants completed a brief demographics form, an HRQOL survey, and a 90-minute audio-recorded interview. We produced a series of matrices and summaries for our content analysis in addition to descriptive statistics. We report on recipients’ perspectives about the process, outcomes, personal life goals, and how their experience relates to their HRQOL scores. Participants’ impressions of their experience varied, but their HRQOL scores paralleled their complications. Those with successful transplants and minimal complications scored highest. Those with successful transplants but significant complications scored in the middle and the individual with an unsuccessful transplant scored the lowest. The four with successful transplants remarked that their health had improved and expressed optimism. We identified three themes: (a) the relief of being pain free, (b) new availability of opportunities, and (c) no regrets about undergoing the transplant. These results delve into the complex factors affecting health and the success of adults with SCD who have a haploidentical HSCT.

scholarly journals A Cost-Effectiveness Analysis of a Pilot Neonatal Screening Program for Sickle Cell Anemia in the Republic of Angola

2015 ◽  
Vol 167 (6) ◽  
pp. 1314-1319 ◽  
Author(s):  
Patrick T. McGann ◽  
Scott D. Grosse ◽  
Brigida Santos ◽  
Vysolela de Oliveira ◽  
Luis Bernardino ◽  
...  
Keyword(s):  
Cost Effectiveness ◽  
Sickle Cell ◽  
Sickle Cell Anemia ◽  
Neonatal Screening ◽  
Screening Program ◽  
Cost Effectiveness Analysis ◽  
Effectiveness Analysis ◽  
Neonatal Screening Program ◽  
The Republic

scholarly journals Nonmyeloablative HLA-Identical Sibling Donor Transplantation for Children and Young Adults with Sickle Cell Disease: Interim Results of the SUN Multicenter Phase II Trial

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 1799-1799
Author(s):  
Robert Sheppard Nickel ◽  
KY Chiang ◽  
Steven J. Hardy ◽  
Hemalatha G Rangarajan ◽  
Sonali Chaudhury ◽  
...  
Keyword(s):  
Quality Of Life ◽  
Sickle Cell ◽  
Research Funding ◽  
Graft Failure ◽  
Cell Transplant ◽  
Cell Disease ◽  
Free Survival ◽  
Children And Young Adults ◽  
Median Change

Abstract Background: HLA-identical sibling hematopoietic stem cell transplant (HSCT) using myeloablative chemotherapy conditioning is a proven cure for sickle cell disease (SCD), but is associated with serious short and long-term toxicities. Additionally graft versus host disease (GVHD) can complicate care post-HSCT and contribute to mortality. Given these concerns many pediatric hematologists and families are reluctant to pursue HSCT for SCD. Nonmyeloablative HSCT resulting in stable mixed chimerism has been demonstrated to abrogate the SCD phenotype in adults. Data on outcomes of this approach to decrease toxicities and achieve cure in children remains scarce. Objective: To evaluate event-free survival (EFS), toxicity, health-related quality of life (HRQL), and transfusion burden among pediatric patients with SCD using a chemotherapy-free nonmyeloablative regimen. Methods/design: Children and young adults with SCD were prospectively enrolled in the Sickle transplant Using a Nonmyeloablative approach (SUN) multicenter clinical trial (NCT03587272). Six Sickle Cell Transplant Advocacy and Research Alliance (STAR) sites in the United States and Canada enrolled patients. The conditioning regimen consisted of alemtuzumab IV (0.03mg/kg on Day -7, 0.1mg/kg on Day -6, 0.3mg/kg on Days -5 to -3), low-dose total body irradiation with gonadal shielding (300 cGY on day -2), peripheral blood stem cells from an HLA-identical sibling, and sirolimus for at least one year. Baseline HRQL was compared with scores at day +30 and day +100 post-HSCT using the PedsQL and PROMIS measures. EFS was defined by any of the following events: death, graft failure (myeloid donor chimerism <10%), or GVHD. Results: All 30 of the patients planned for the primary endpoint of EFS have been enrolled. As of 7/20/2021, 24 patients are greater than 100 days post-HSCT with a median follow-up of 365 days (range 189-1105). The median age of this group at time of transplant was 13.5 years (range 2-22). All patients had neutrophil recovery (ANC >500/ul x 3 days) at a median of 21.5 days (range 0-29). Eleven patients (46%) did not require any platelet transfusions. Median transplant hospitalization was 16.5 days (range 14-43). Seven patients (29%) were again hospitalized (median 4 days, range 1-26). Three patients had secondary graft rejection at Day +71, +91, and +92 with no major complications and autologous recovery resulting in an EFS of 87.5% (Figure 1). Three additional patients have stable low donor chimerism (myeloid chimerism 11%, 38%, and 47%). The remaining 18 patients (75%) are disease-free and have robust donor engraftment (72-100% myeloid chimerism). Nine of these patients are >1 year post-HSCT and off sirolimus. Overall survival is 100% with no acute or chronic GVHD. Figure 2 shows total PedsQL scores during the peri-transplant time period. The median change in day +30 scores compared to baseline was 0 (IQR -7, +10), p=0.66. The median change in day +100 scores compared to baseline was +5 (IQR 0, +10), p=0.02. Conclusions: Outcomes of pediatric nonmyeloablative HLA-identical sibling HSCT for SCD appear similar to the larger adult experience with a GVHD-free, rejection-free survival of >80%. Importantly, patients have no worsening of their quality of life in the first month post-HSCT and already an improvement at day +100, suggesting that the short-term toxicities experienced by patients transplanted with this regimen are minimal. The majority of patients achieve disease resolution with no GVHD, but graft failure incidence appears higher than with myeloablative HSCT. Given the low intensity of this approach, a reasonable strategy may be to reserve myeloablation for a second transplant in the minority of patients who experience graft failure. Figure 1 Figure 1. Disclosures Rangarajan: Medexus (Treosulfan): Consultancy, Honoraria. Guilcher: BlueBirdBio: Research Funding; Project Sickle Cure Study: Other: Principal Investigator, Research Funding. OffLabel Disclosure: alemtuzumab and sirolimus were used off-label as part of the studied transplant regimen

A Pilot Study of Reduced Toxicity Conditioning (RTC) with Busulfan (Bu), Fludarabine (Flu), and Alemtuzumab Followed by Allogeneic Stem Cell Transplantation (AlloSCT) to Induce Sustained Mixed Donor Chimerism In Patients with Symptomatic Sickle Cell Disease (SCD)

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3504-3504
Author(s):  
Monica Bhatia ◽  
Mark B Geyer ◽  
Courtney Baker ◽  
Erin Morris ◽  
Deirdre Duffy ◽  
...  
Keyword(s):  
Median Time ◽  
Sickle Cell ◽  
Graft Failure ◽  
Sickle Cell Trait ◽  
Donor Chimerism ◽  
Kaplan Meier ◽  
Primary Graft Failure ◽  
Reduced Toxicity ◽  
Neutrophil Engraftment

Abstract Abstract 3504 The only known curative therapy for patients with SCD is a matched family donor AlloSCT (Walters et al, NEJM, 1996). Complications after myeloablative AlloSCT are numerous and include death, graft versus host disease (GVHD), and infections, making reduced toxicity conditioning regimens more appealing. A major obstacle allowing most SCD patients to undergo SCT is the lack of an unaffected, HLA-matched identical sibling (Bhatia et al, BMT, 2008). Umbilical cord blood (UCB) has been proven to be an excellent alternate donor source that can safely reconstitute hematopoiesis after AlloSCT in pediatric recipients with non-malignant conditions (Cairo et al, BBMT, 2008). In this study, we report the results of a RTC regimen followed by an AlloSCT from matched family and unrelated UCB donors in selected patients with symptomatic SCD. Between August 27, 2004 and March 2, 2010, 18 patients (14M:2F) with symptomatic SCD (HbSS=10, HbSC=4, HbSßThal=4) underwent an AlloSCT. Indications for SCT included: ACS (n=8), CVA (n=2), multiple VOC (n=9), splenic sequestration (n=6) and retinopathy (n=1). Conditioning was Bu (4mg/kg × 4d < 4 yrs and 12.8mg/kg × 4d > 4 yrs), Flu (30mg/m2 × 6d), and Alemtuzumab (2mg/m2 × 1d, 6mg/m2 × 2d, and 20mg/m2 × 2d). Median age was 6.29 yrs(1.3–19.2). Median follow-up was 26 months. Donor sources: 8-6/6 HLA-matched sibling bone marrow (BM), 2–6/6 sibling UCB, 1–6/6, 4–5/6 and 3–4/6 unrelated UCB. Donors were HbAA (n=13), HbAC (n=1), HbAS(n=3), or ßThal trait (n=1). Sibling BM recipients received a median total nucleated cell (TNC) dose/kg of 7.16 × 108 (range 2.27–11.31) and a median CD34 cell dose/kg of 5.38 × 106 (range 1.50–6.83). Recipients of related or unrelated UCB received a median TNC dose/kg of 4.35 × 107 (range 3.40–9.10) and a median CD34 cell dose/kg of 2.21 × 105 (range 0.60–7.94). All received tacrolimus and mycophenolate mofetil as GVHD prophylaxis (Bhatia/Cairo et al, BBMT, 2009) and phenytoin or keppra as seizure prophylaxis for 180 days post SCT. Patients receiving sibling donor AlloSCT had a median time to neutrophil engraftment of 16 days (range 13–41). Among evaluable unrelated UCBT recipients, median time to neutrophil engraftment was 34 days (range 27–47). Four patients (all unrelated UCBT) experienced primary graft failure at day +60 post-SCT secondary to CMV (n=2), adenovirus, and low Bu Css levels with early withdrawal of MMF. Patients with sibling donors had a median time to platelet engraftment of 26 days (range 17–75). Of evaluable unrelated UCB recipients, median time to platelet engraftment was 54 days (range 43–70). Patients achieved mean whole blood donor chimerism of 71.0, 79.6, 85.7, 92.9, 90.7% and 93.2% at days 30, 60, 100, 180, 365 and 730 post-transplant, respectively. Mean erythroid (CD71) donor chimerism at these time points was 78.1, 81.1, 86.6, 90.5, 87.9% and 94.0%, respectively. Patients with non-sickle cell trait donors had median HbS levels of 0% at 1 yr (n=8) and 2 yrs (n=3) post-SCT; those with sickle cell trait donors had median HbS levels of 38.3% at 1 yr (n=3) and 39% at 2yrs (n=3) post-SCT. Among evaluable patients, the Kaplan-Meier probability of grade II-IV acute GVHD is 33.3% and of chronic GVHD is 8.3%. Among the ten donor-recipient pairs in which at least one member of the pair had CMV positivity, four experienced CMV reactivation on days +13, +26, +30 and +32 (BM: n=2, unrelated UCB: n=2). Of the four patients with primary graft failure (all unrelated UCBT recipients), one resumed chronic transfusions, two died of complications from disseminated CMV and adenoviral infections, and one received a second myeloablative SCT 1 yr after initial SCT and died of fungal sepsis. Among all patients, the Kaplan-Meier probability of OS is 81.8% (100% with sibling donors, 62.5% with UCB donors) and of EFS is 77.8% (100% with sibling donors, 50% with UCB donors) with none of these patients showing any evidence of SCD symptomatology post-SCT. The longest follow-up is 2134 days. In summary, we report the largest experience of RTC and matched family AlloSCT in selected children with symptomatic SCD with persistent long-term donor chimerism and absence of SCD symptoms or progression of disease. However, with the high incidence of viral infections and toxic deaths following unrelated UCBT, it is too premature to extend this treatment option to those SCD patients lacking a sibling donor. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Haemoglobinopathies care and cure: Have we reached the end?

2018 ◽  
Vol 8 (1) ◽  
Author(s):  
John Porter
Keyword(s):  
Quality Of Life ◽  
Gene Therapy ◽  
Stem Cell ◽  
Blood Transfusion ◽  
Stem Cell Transplantation ◽  
Iron Overload ◽  
Sickle Cell ◽  
Sickle Cell Disorders ◽  
The Cost

Recent years have seen accelerating advances in the treatment, monitoring and potential cures for haemoglobin disorders, as the interaction between basic science, pharmaceutical research, and practical medicine intensifies. In order to appreciate how close to the end we may have reached, it is helpful to consider the journey thus far. For thalassaemia syndromes, advances with non-curative treatment began with the establishment of the principles of blood transfusion and their application in the 1950s both to treat anaemia and suppress erythropoietic expansion. The consequences of transfusional iron overload soon became a problem however, with patients dying in their late teens and early 20s, typically with cardiomyopathy. The introduction of desferrioxamine infusions in the 1970s, led to gradual improvement in outcome and the subsequent introduction and licensing of orally active chelation has contributed to improved treatment adherence and improved survival. Morbidity from iron overload, particularly hypogonadotrophic hypogonadism remains a serious issue and emergence of new pathologies in older patients, such as in the liver, is a cause for concern. Curative treatment with allogeneic stem cell transplantation was introduced in the 1980s but is only available to a minority of patients and is still associated with significant morbidity and mortality. Novel approaches aimed at decreasing transfusion requirements by improving the efficiency of erythropoiesis, such as with activin receptor traps, may prove useful in both transfusion dependent and non-transfusion dependent thalassaemias. Gene therapy is now a reality for a small number of patients and has the potential for application to many patients in whom allogeneic transplant was precluded by lack of a suitable donors, or was too risky for other reasons such increasing as age. For sickle cell disorders, advances have included the setting up of specialist clinics, pneumococcal septicaemia prevention programs, the application of blood transfusion for the prevention and treatment of disease complications, the use of hydroxyurea for prevention of painful crises and chest syndrome and allogeneic transplantation for carefully selected patients. New pharmacological agents with novel mechanisms of action are being evaluated at a hitherto unprecidented rate. However thus far, the impact of these advances on survival and quality of life in patients as a whole often lags somewhat behind those of thalassaemia. Disease prevention is a key element to management of both sickle and thalassaemia syndromes but implementation has been highly variable both geographically and even between these conditions at a local level. Prevention of births with sickle cell disorders have been less effective than for thalassaemia, even in countries such as the UK which share the same prevention programs for these conditions. The perceived variability and unpredictability of sickle cell disease is part of the reason for this: if all patients had a uniformly fatal outcome without transfusion, blood transfusion would be more uniformly applied, as with TDT , from an early age with perhaps better overall quality of life and survival. In order approach “the end,’’ advances in therapy will need to be more affordable and deliverable to populations where the conditions are most prevalent. It is anticipated in the next decade that blood transfusion safety will improve, the cost of chelation will fall, the safety and applicability of allogeneic stem cell transplantation with increase, and with further scientific advances such as CRISPR technology, the cost of gene therapy fall. In the meantime, to paraphrase a well-known quotation, “this is not the end, it is not even at the beginning of the end, but it is perhaps the end of the beginning”.

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