Background In 2016, results from the first URD SCT for SCD (the SCURT Trial) revealed a 2-year ov... more Background In 2016, results from the first URD SCT for SCD (the SCURT Trial) revealed a 2-year overall survival (OS) and event-free survival (EFS) of 79% (95% CI 59-90) and 69% (95% CI, 48-82) respectively following reduced intensity conditioning (RIC).1 Though the RIC approach provided successful engraftment in the majority, the transplant approach was not considered safe for widespread adoption due to high rates of graft-versus-host disease (GVHD) especially in children >13 years, a predominant cause of mortality. Strategies to minimize GVHD were essential if URD SCT was to be considered with curative intent in SCD. Aim/Method Multicenter trial (NCT03128996) with the primary objective of determining EFS in non-malignant disorders at one-year was amended as follows. The phase I SCD cohort included conditioning with hydroxyurea, proximal alemtuzumab, fludarabine, and melphalan in patients with 8/8 HLA-matched URD (-A, -B, - C and -DRB1).1 Thiotepa (8 mg/kg) was added in 7/8 HLA-m...
Background SCD is a chronic debilitating disease secondary to frequent veno-occlusive events resu... more Background SCD is a chronic debilitating disease secondary to frequent veno-occlusive events resulting in chronic organ damage, including cerebral vasculopathy, acute chest syndrome (ACS), pulmonary hypertension and a significantly shortened life-span (Bunn et al, NEJM, 1997; Lanzkron et al, PHR, 2013; Platt et al, NEJM, 1994). Importantly, SCD survivors also develop significant defects in neurocognition, especially processing speed and have a poor HRQL (Stotesbury et al, Neurology, 2018); Vichinsky et al, JAMA, 2010; Panepinto et al, BJH, 2005). To date the only cure for SCD patients has been HLA matched sibling AlloSCT following either myeloablative (MAC) or reduced toxicity conditioning (RTC), (Walters et al, NEJM, 1996; Bhatia/Cairo et al, BMT, 2014; Talano/Cairo et al, EJH, 2015; Gluckman et al, Blood, 2017). Unfortunately, only approximately 15% of patients have an unaffected HLA matched sibling donor (Mentzer et al, AJPHO, 1994). We previously demonstrated the safety and effi...
The Journal of allergy and clinical immunology, Jan 4, 2018
In a 250 patient cohort from the US and Canada in the current era (2010-2018), we show that over ... more In a 250 patient cohort from the US and Canada in the current era (2010-2018), we show that over 90% of patients with severe combined immunodeficiency (SCID) can be genetically-characterized.
Allogeneic hematopoietic cell transplantation (HCT) with myeloablative conditioning for disorders... more Allogeneic hematopoietic cell transplantation (HCT) with myeloablative conditioning for disorders associated with excessive inflammation such as hemophagocytic lymphohistiocytosis (HLH) is associated with early mortality. A multicenter prospective phase 2 trial of reduced intensity conditioning with melphalan, fludarabine and intermediate-timing alemtuzumab was conducted for HLA matched or single HLA-locus mismatched related or unrelated donor HCT in a largely pediatric cohort. Graft-versus-host disease (GVHD) prophylaxis was cyclosporine with methylprednisolone. The primary endpoint was 1-year overall survival (OS). Thirty-four patients with HLH and 12 with other primary immune deficiencies were transplanted. With a median follow up of 20 months, the one-year OS for transplanted patients was 80.4% (90% CI: 68.6 - 88.2). Five additional deaths by 16 months yielded an 18-month OS probability of 66.7% (90% CI: 52.9 - 77.3). Two patients experienced primary graft failure and 18 patient...
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, Jan 19, 2018
We enrolled 150 patients in a prospective multi-center study of children with acute myeloid leuke... more We enrolled 150 patients in a prospective multi-center study of children with acute myeloid leukemia undergoing hematopoietic stem cell transplant (HSCT) comparing detection of measurable residual (MRD) disease by a "Difference from Normal" flow cytometry (ΔN) approach with assessment of Wilms tumor 1 (WT-1) gene expression without access to the diagnostic specimen. Prospective analysis of the specimens using this approach showed that 23% of patients being screened for HSCT had detectable residual disease by ΔN (0.04-53%). Of those patients who proceeded to transplant as being in morphologic remission, 10 had detectable disease (0.04-14%) by ΔN. The disease free survival of this group was 10% (0-35%), compared to 55% (46-64; <0.001) for those without disease. The ΔN assay was validated using the post-HSCT specimen by sorting the abnormal or suspicious cells to confirm recipient or donor origin by chimerism studies. All 15 of the patients who had confirmation of tumor de...
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, Jan 10, 2018
Allogeneic hematopoietic cell transplantation (HCT) can halt organ damage and eliminate symptoms ... more Allogeneic hematopoietic cell transplantation (HCT) can halt organ damage and eliminate symptoms in hemoglobin disorders, including sickle cell disease (SCD) and thalassemia major. Managing the residual manifestations of pre-HCT disease complications and the long-term effects of HCT requires systematic monitoring, follow-up and intervention when indicated. Late complications vary with age and disease status at HCT and with transplant variables such as preparative regimen, donor source and compatibility, and immune reconstitution. An international consensus conference sponsored by the Pediatric Blood and Marrow Transplant Consortium in May 2016 entitled "Late Effects Screening and Recommendations Following HCT for Immune Deficiency and Nonmalignant Hematologic Disorders" focused on follow-up after HCT for hemoglobinopathy. An earlier publication from experts who participated in this session described the pathophysiology and spectrum of complications that HCT recipients expe...
Alemtuzumab is a humanized mAb targeted to CD52. Alemtuzumab is highly immunosuppressive with the... more Alemtuzumab is a humanized mAb targeted to CD52. Alemtuzumab is highly immunosuppressive with the ability to deplete T and B cells (in addition to other immune cell lines). A growing understanding of the PKs, dosing, and timing of administration of alemtuzumab has allowed for the study of its use as a conditioning agent for allogeneic HCT. The highly immunosuppressive properties of the drug are particularly appealing in the setting of non-malignant HCT, where GVHD provides no clinical benefit and relapse of malignancy is not applicable. In addition, the degree of immune suppression achieved with alemtuzumab has allowed for a reduction in the intensity of myeloablative cytotoxic agents included in some HCT conditioning regimens, allowing for fewer acute and late toxicities. This review paper will provide a comprehensive summary of the mechanism of action, PKs, dosing, and timing of alemtuzumab, a brief description of its use in various allogeneic HCT protocols for non-malignant condi...
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, Jan 31, 2018
Allogeneic hematopoietic stem cell transplantation (HSCT) can cure transfusion-dependent thalasse... more Allogeneic hematopoietic stem cell transplantation (HSCT) can cure transfusion-dependent thalassemia (TDT). In a multicenter trial we investigated the efficacy of reduced-intensity conditioning (RIC) before unrelated donor (URD) HSCT in children with TDT. Thirty-three children, ages 1 to 17 years, received bone marrow (BM) or umbilical cord blood (UCB) allografts. Median time to neutrophil engraftment was 13 days (range, 10 to 25) and 24 days (range, 18 to 49) and platelet engraftment 23 days (range, 12 to 46) and 50 days (range, 31 to 234) after BM and UCB allografts, respectively. With a median follow-up of 58 months (range, 7 to 79), overall and thalassemia-free survival was 82% (95% CI, .64% to .92%) and 79% (95% CI, .6% to .9%), respectively. The cumulative incidence of grades II to IV acute graft-versus-host disease (GVHD) after BM and UCB allografts was 24% and 44%; the 2-year cumulative incidence of chronic extensive GVHD was 29% and 21%, respectively; 71% of BM and 91% of U...
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, Jan 16, 2017
Relapse remains the major cause of mortality post hematopoietic cell transplantation (HCT) for pe... more Relapse remains the major cause of mortality post hematopoietic cell transplantation (HCT) for pediatric acute leukemia. Previous research suggests that reducing the intensity of calcineurin inhibitor based graft versus host disease (GVHD) prophylaxis may be an effective strategy in abrogating the risk of relapse in pediatric patients undergoing matched sibling donor (MSD) HCT. We reasoned that benefits of this strategy could be maximized by selectively applying it to those patients least likely to develop GVHD. We conducted a study of risk for GVHD, to risk stratify patients based on age. Patients <18 years with leukemia who received myeloablative, T cell-replete MSD bone marrow transplantation and calcineurin inhibitor based GVHD prophylaxis between 2000-2013 entered into the Center for International Blood and Marrow Transplant Research registry were included. Cumulative incidence of grade 2-4 acute GVHD was 19%, grade 3-4 acute GVHD 7%, and chronic GVHD 16%. Compared to age 13...
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2017
Allogeneic hematopoietic cell transplantation (HCT) is curative in patients with β-thalassemia ma... more Allogeneic hematopoietic cell transplantation (HCT) is curative in patients with β-thalassemia major. However, most reports on HCT outcomes lack long-term follow-up data with the exception of single-center reports. An international multicenter retrospective data collection and analysis was conducted in 176 β-thalassemia patients who were 1 year or beyond after first HCT to evaluate follow-up methods and outcomes at 7 centers. Median age at HCT was 5.5 years (range, .6 to 18.5), and median follow-up was 7 years (range, 1 to 20). HCT was predominantly from HLA-matched related donors (91%) with bone marrow as stem cell source (91%) and myeloablative conditioning regimens (88%). Late mortality or persistent chronic graft-versus-host disease (GVHD) was rare (<2%). Graft rejection was reported in 23% (24% of these occurred beyond 1 year) post-HCT. Of 119 patients with donor chimerism results available for ≥4 years post-HCT, 50% had >95%, 22% had 50% to 95%, 7% had 20% to 50% and 25 ...
Background In 2016, results from the first URD SCT for SCD (the SCURT Trial) revealed a 2-year ov... more Background In 2016, results from the first URD SCT for SCD (the SCURT Trial) revealed a 2-year overall survival (OS) and event-free survival (EFS) of 79% (95% CI 59-90) and 69% (95% CI, 48-82) respectively following reduced intensity conditioning (RIC).1 Though the RIC approach provided successful engraftment in the majority, the transplant approach was not considered safe for widespread adoption due to high rates of graft-versus-host disease (GVHD) especially in children >13 years, a predominant cause of mortality. Strategies to minimize GVHD were essential if URD SCT was to be considered with curative intent in SCD. Aim/Method Multicenter trial (NCT03128996) with the primary objective of determining EFS in non-malignant disorders at one-year was amended as follows. The phase I SCD cohort included conditioning with hydroxyurea, proximal alemtuzumab, fludarabine, and melphalan in patients with 8/8 HLA-matched URD (-A, -B, - C and -DRB1).1 Thiotepa (8 mg/kg) was added in 7/8 HLA-m...
Background SCD is a chronic debilitating disease secondary to frequent veno-occlusive events resu... more Background SCD is a chronic debilitating disease secondary to frequent veno-occlusive events resulting in chronic organ damage, including cerebral vasculopathy, acute chest syndrome (ACS), pulmonary hypertension and a significantly shortened life-span (Bunn et al, NEJM, 1997; Lanzkron et al, PHR, 2013; Platt et al, NEJM, 1994). Importantly, SCD survivors also develop significant defects in neurocognition, especially processing speed and have a poor HRQL (Stotesbury et al, Neurology, 2018); Vichinsky et al, JAMA, 2010; Panepinto et al, BJH, 2005). To date the only cure for SCD patients has been HLA matched sibling AlloSCT following either myeloablative (MAC) or reduced toxicity conditioning (RTC), (Walters et al, NEJM, 1996; Bhatia/Cairo et al, BMT, 2014; Talano/Cairo et al, EJH, 2015; Gluckman et al, Blood, 2017). Unfortunately, only approximately 15% of patients have an unaffected HLA matched sibling donor (Mentzer et al, AJPHO, 1994). We previously demonstrated the safety and effi...
The Journal of allergy and clinical immunology, Jan 4, 2018
In a 250 patient cohort from the US and Canada in the current era (2010-2018), we show that over ... more In a 250 patient cohort from the US and Canada in the current era (2010-2018), we show that over 90% of patients with severe combined immunodeficiency (SCID) can be genetically-characterized.
Allogeneic hematopoietic cell transplantation (HCT) with myeloablative conditioning for disorders... more Allogeneic hematopoietic cell transplantation (HCT) with myeloablative conditioning for disorders associated with excessive inflammation such as hemophagocytic lymphohistiocytosis (HLH) is associated with early mortality. A multicenter prospective phase 2 trial of reduced intensity conditioning with melphalan, fludarabine and intermediate-timing alemtuzumab was conducted for HLA matched or single HLA-locus mismatched related or unrelated donor HCT in a largely pediatric cohort. Graft-versus-host disease (GVHD) prophylaxis was cyclosporine with methylprednisolone. The primary endpoint was 1-year overall survival (OS). Thirty-four patients with HLH and 12 with other primary immune deficiencies were transplanted. With a median follow up of 20 months, the one-year OS for transplanted patients was 80.4% (90% CI: 68.6 - 88.2). Five additional deaths by 16 months yielded an 18-month OS probability of 66.7% (90% CI: 52.9 - 77.3). Two patients experienced primary graft failure and 18 patient...
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, Jan 19, 2018
We enrolled 150 patients in a prospective multi-center study of children with acute myeloid leuke... more We enrolled 150 patients in a prospective multi-center study of children with acute myeloid leukemia undergoing hematopoietic stem cell transplant (HSCT) comparing detection of measurable residual (MRD) disease by a "Difference from Normal" flow cytometry (ΔN) approach with assessment of Wilms tumor 1 (WT-1) gene expression without access to the diagnostic specimen. Prospective analysis of the specimens using this approach showed that 23% of patients being screened for HSCT had detectable residual disease by ΔN (0.04-53%). Of those patients who proceeded to transplant as being in morphologic remission, 10 had detectable disease (0.04-14%) by ΔN. The disease free survival of this group was 10% (0-35%), compared to 55% (46-64; <0.001) for those without disease. The ΔN assay was validated using the post-HSCT specimen by sorting the abnormal or suspicious cells to confirm recipient or donor origin by chimerism studies. All 15 of the patients who had confirmation of tumor de...
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, Jan 10, 2018
Allogeneic hematopoietic cell transplantation (HCT) can halt organ damage and eliminate symptoms ... more Allogeneic hematopoietic cell transplantation (HCT) can halt organ damage and eliminate symptoms in hemoglobin disorders, including sickle cell disease (SCD) and thalassemia major. Managing the residual manifestations of pre-HCT disease complications and the long-term effects of HCT requires systematic monitoring, follow-up and intervention when indicated. Late complications vary with age and disease status at HCT and with transplant variables such as preparative regimen, donor source and compatibility, and immune reconstitution. An international consensus conference sponsored by the Pediatric Blood and Marrow Transplant Consortium in May 2016 entitled "Late Effects Screening and Recommendations Following HCT for Immune Deficiency and Nonmalignant Hematologic Disorders" focused on follow-up after HCT for hemoglobinopathy. An earlier publication from experts who participated in this session described the pathophysiology and spectrum of complications that HCT recipients expe...
Alemtuzumab is a humanized mAb targeted to CD52. Alemtuzumab is highly immunosuppressive with the... more Alemtuzumab is a humanized mAb targeted to CD52. Alemtuzumab is highly immunosuppressive with the ability to deplete T and B cells (in addition to other immune cell lines). A growing understanding of the PKs, dosing, and timing of administration of alemtuzumab has allowed for the study of its use as a conditioning agent for allogeneic HCT. The highly immunosuppressive properties of the drug are particularly appealing in the setting of non-malignant HCT, where GVHD provides no clinical benefit and relapse of malignancy is not applicable. In addition, the degree of immune suppression achieved with alemtuzumab has allowed for a reduction in the intensity of myeloablative cytotoxic agents included in some HCT conditioning regimens, allowing for fewer acute and late toxicities. This review paper will provide a comprehensive summary of the mechanism of action, PKs, dosing, and timing of alemtuzumab, a brief description of its use in various allogeneic HCT protocols for non-malignant condi...
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, Jan 31, 2018
Allogeneic hematopoietic stem cell transplantation (HSCT) can cure transfusion-dependent thalasse... more Allogeneic hematopoietic stem cell transplantation (HSCT) can cure transfusion-dependent thalassemia (TDT). In a multicenter trial we investigated the efficacy of reduced-intensity conditioning (RIC) before unrelated donor (URD) HSCT in children with TDT. Thirty-three children, ages 1 to 17 years, received bone marrow (BM) or umbilical cord blood (UCB) allografts. Median time to neutrophil engraftment was 13 days (range, 10 to 25) and 24 days (range, 18 to 49) and platelet engraftment 23 days (range, 12 to 46) and 50 days (range, 31 to 234) after BM and UCB allografts, respectively. With a median follow-up of 58 months (range, 7 to 79), overall and thalassemia-free survival was 82% (95% CI, .64% to .92%) and 79% (95% CI, .6% to .9%), respectively. The cumulative incidence of grades II to IV acute graft-versus-host disease (GVHD) after BM and UCB allografts was 24% and 44%; the 2-year cumulative incidence of chronic extensive GVHD was 29% and 21%, respectively; 71% of BM and 91% of U...
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, Jan 16, 2017
Relapse remains the major cause of mortality post hematopoietic cell transplantation (HCT) for pe... more Relapse remains the major cause of mortality post hematopoietic cell transplantation (HCT) for pediatric acute leukemia. Previous research suggests that reducing the intensity of calcineurin inhibitor based graft versus host disease (GVHD) prophylaxis may be an effective strategy in abrogating the risk of relapse in pediatric patients undergoing matched sibling donor (MSD) HCT. We reasoned that benefits of this strategy could be maximized by selectively applying it to those patients least likely to develop GVHD. We conducted a study of risk for GVHD, to risk stratify patients based on age. Patients <18 years with leukemia who received myeloablative, T cell-replete MSD bone marrow transplantation and calcineurin inhibitor based GVHD prophylaxis between 2000-2013 entered into the Center for International Blood and Marrow Transplant Research registry were included. Cumulative incidence of grade 2-4 acute GVHD was 19%, grade 3-4 acute GVHD 7%, and chronic GVHD 16%. Compared to age 13...
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation, 2017
Allogeneic hematopoietic cell transplantation (HCT) is curative in patients with β-thalassemia ma... more Allogeneic hematopoietic cell transplantation (HCT) is curative in patients with β-thalassemia major. However, most reports on HCT outcomes lack long-term follow-up data with the exception of single-center reports. An international multicenter retrospective data collection and analysis was conducted in 176 β-thalassemia patients who were 1 year or beyond after first HCT to evaluate follow-up methods and outcomes at 7 centers. Median age at HCT was 5.5 years (range, .6 to 18.5), and median follow-up was 7 years (range, 1 to 20). HCT was predominantly from HLA-matched related donors (91%) with bone marrow as stem cell source (91%) and myeloablative conditioning regimens (88%). Late mortality or persistent chronic graft-versus-host disease (GVHD) was rare (<2%). Graft rejection was reported in 23% (24% of these occurred beyond 1 year) post-HCT. Of 119 patients with donor chimerism results available for ≥4 years post-HCT, 50% had >95%, 22% had 50% to 95%, 7% had 20% to 50% and 25 ...
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Papers by Shalini Shenoy