Allogeneic Hematopoietic Stem Cell Transplant Versus Gene Therapy in Sickle Cell Disease: A Systematic Review

BACKGROUND: Despite advancements in medical therapy and supportive care for sickle cell disease (SCD) over the last several decades, disease morbidity and mortality remain unacceptably high. Allogeneic hematopoietic stem cell transplant (HSCT) is a curative therapy for SCD, but is associated with significant risks: conditioning regimen toxicity, graft failure, graft-versus-host disease (GVHD), and death are all potential sequelae, particularly when hematopoietic stem cells (HSC) originate from sources other than HLA-matched related donors (MRD). Gene therapy (GT), which involves ex vivo gene addition or editing of autologous HSCs, has recently emerged as an alternative curative approach for SCD. While GT still carries the risk of conditioning regimen-associated toxicity, the use of autologous over allogeneic HSCT eliminates the risk of GVHD as well as the need for an available HLA-matched donor. Both allogeneic HSCT and GT have demonstrated efficacy against SCD in clinical trials, yet these curative strategies have never been compared. Here, we present preliminary data from a systematic review comparing allogeneic HSCT and GT outcomes in SCD. METHODS: We searched the MEDLINE and EMBASE databases (including American Society of Hematology and European Hematology Association meeting abstracts) for studies evaluating outcomes following allogeneic HSCT and GT in SCD. The references of included studies were screened for additional relevant studies. We included phase I, II, and III clinical trials, retrospective reviews, case reports, and case series involving SCD patients of all ages undergoing allogeneic HSCT or GT. All HSC donor sources (MRD, matched unrelated donors (MUD), haploidentical, autologous) and conditioning regimens were included. Case reports with <2 SCD patients, non-English studies, and pre-clinical studies were excluded. Studies including both SCD and thalassemia patients were included if SCD outcomes were reported separately. We assessed the primary outcomes of overall survival (OS) and event-free survival (EFS)-defined as stable donor erythropoiesis or transgene expression, absence of new or worsening SCD complications, graft rejection, GVHD, or graft failure-at 2 and 5 years post-transplant. All titles and abstracts were screened for full text retrieval. Data on study characteristics, quality, and effects were extracted and analyzed using descriptive statistics. Risk of bias was assessed using the Newcastle-Ottawa Scale. Heterogeneity of outcomes was assessed using sensitivity and subgroup analyses, and publication bias was assessed using funnel plot, where applicable. RESULTS: We identified 828 titles through database searching and 9 titles from references of included studies (Figure). Following removal of duplicate citations (n=142), exclusion of records not meeting eligibility criteria (n=605), and merging 38 studies with their primary article, 52 unique studies were included for data extraction. Of these 52 studies, 49 reported outcomes for allogeneic HSCT and 3 reported outcomes for GT, representing 1026 and 19 unique patients, respectively. Donor HSC source was MRD (n=24), MUD (n=5), haploidentical (n=5), or a combination thereof (n=10) in 44/49 allogeneic HSCT studies which reported these data. Length of follow-up was 3249.5 patient-years in the allogeneic HSCT group versus 24 patient-years in the GT group. Transplant-related mortality was 60/1026 (5.8%) and 0/19 in the allogeneic HSCT and GT groups, respectively. Graft failure was 83/1026 (8.1%) for allogeneic HSCT patients. In the GT group, 1/19 (5.3%) failed to achieve clinically significant anti-sickling globin levels. OS for allogeneic HSCT patients at 2 years was 91% among 158 patients from 8 studies, and 93% at 5 years among 162 patients from 4 studies. EFS for allogeneic HSCT patients at 2 years was 86% among 126 patients from 6 studies, and 89% at 5 years among 192 patients from 5 studies. OS and EFS were not reported for GT studies. Rates of GVHD could not be calculated due to heterogeneity of reporting. CONCLUSIONS: Although data for both allogeneic HSCT and GT in SCD are encouraging, longer follow-up is needed for GT patients in order to better assess regimen efficacy. Furthermore, outcomes reporting is highly heterogeneous both within and between treatment groups, underscoring the need for standardized reporting. Additional outcomes will be reported during the meeting. Disclosures Kuo: Agios: Consultancy; Alexion: Consultancy, Honoraria; Apellis: Consultancy; Bioverativ: Other: Data Safety Monitoring Board; Bluebird Bio: Consultancy; Celgene: Consultancy; Novartis: Consultancy, Honoraria; Pfizer: Consultancy.

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Nonmyeloablative Versus Myeloablative Allogeneic Hematopoietic Stem Cell Transplant for GATA2 Deficiency

Blood ◽

10.1182/blood.v124.21.1247.1247 ◽

2014 ◽

Vol 124 (21) ◽

pp. 1247-1247 ◽

Cited By ~ 2

Author(s):

Jennifer Cuellar-Rodriguez ◽

Dennis D. Hickstein ◽

Jennifer K. Grossman ◽

Mark Parta ◽

Juan Gea-Banacloche ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell Transplant ◽

Stem Cell Transplant ◽

Conditioning Regimen ◽

Cell Transplant ◽

Hematopoietic Stem ◽

Allogeneic Hsct ◽

Gata2 Deficiency ◽

Related Donor

Abstract Background: Mutations in the zinc finger transcription factor GATA2 are responsible for: MonoMAC, monocytopenia with nontuberculous mycobacterial (NTM) infections; DCML, dendritic cell, monocyte and lymphoid cell deficiency; Emberger's syndrome with lymphedema and monosomy 7; and familial myelodysplastic syndrome (MDS)/acute myelogenous leukemia (AML). Allogeneic hematopoietic stem cell transplant (HSCT) is the only definitive therapy for GATA2 deficiency. Methods: We used matched related donors (MRD), matched unrelated donors (URD), umbilical cord blood (UCB), and haploidentical related donors in allogeneic HSCT for GATA2 deficiency. Fourteen patients received a nonmyeloablative conditioning regimen (4 MRD, 4 URD, 4 UCB, and 2 haplo donors). Five patients received a myeloablative conditioning regimen (1 MRD, 2 URD, and 2 haplo donors). In the nonmyeloablative group, MRD and MUD recipients received fludarabine and 200cGy of total body irradiation (TBI), UCB recipients received cyclophosphamide 50mg/kg, fludarabine 150 mg/m2, and 200cGy of TBI, and haploidentical related donor recipients received cyclophosphamide 29 mg/kg, fludarabine 150 mg/m2, and 200 cGy TBI. In the myeloablative group, MRD and URD received busulfan 12.8 mg/kg and fludarabine 160 mg/m2, and haploidentical related donors received the same regimen as in the nonmyeloablative regimen except for the addition of two days of busulfan 6.4 mg/kg total dose. Nonmyeloablative MRD and URD recipients received tacrolimus and sirolimus post-transplant, and myeloablative MRD and URD recipients received tacrolimus and short course methotrexate post-transplant. All haploidentical related donor recipients received cyclophosphamide 50 mg/kg/day on days + 3 and +4 followed by tacrolimus and mycophenolate mofetil. Three patients in the nonmyeloablative cohort required one or more rounds of pre-transplant chemotherapy because of an increased number of blasts, whereas none of the 5 patients in the myeloablative arm required pre-transplant chemotherapy. Results: In the nonmyeloablative cohort, 8 of 14 (57%) of patients are alive at a median follow-up of 3.7 years (range 12 months to 5 years). One MRD recipient died of GVHD and one relapsed, one URD recipient rejected the donor stem cells and died, three UCB recipient died (one rejection, one early death, and one donor cell leukemia), and one haploidentical recipient died from regimen-related toxicity. All 5 patients (100%) in the myeloablative group, including two recipients of haploidentical related donors, are alive at a median follow-up of 9.2 months (range 6 to 12 months). All patients who survived had complete reconstitution of the monocyte, NK, and B-lymphocyte compartments, the three cell compartments that were severely deficient pre-transplant, and all had reversal of the infection susceptibility phenotype, characteristic of the disease. In particular, there were no recurrences of non-tuberculous mycobacterial (NTM) infections. Conclusions: Nonmyeloablative HSCT results in reversal of the hematologic and clinical manifestations of GATA2 deficiency. However, a more intensive conditioning regimen with busulfan resulted in more uniform engraftment, a reduced risk of relapse, avoidance of pre-transplant chemotherapy, and a low regimen-related toxicity. We anticipate that with the use of a high-dose regimen with busulfan, the replacement of UCB with haploidentical related donors, and HSCT earlier in the clinical course, before significant organ damage or clonal evolution of MDS to AML or CMML, the outcome of allogeneic HSCT in patients with GATA2 deficiency will continue to improve. Disclosures No relevant conflicts of interest to declare.

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Relapsed Follicular Lymphoma Treatment - with or without Hematopoietic Stem Cell Transplant?

Blood ◽

10.1182/blood.v124.21.5893.5893 ◽

2014 ◽

Vol 124 (21) ◽

pp. 5893-5893

Author(s):

Dulcineia Pereira ◽

Carolina Teixeira ◽

Sofia Ramalheira ◽

Patricia Rocha ◽

Claudia Moreira ◽

...

Keyword(s):

Stem Cell ◽

Treatment Strategy ◽

Hematopoietic Stem Cell Transplant ◽

Stem Cell Transplant ◽

Histological Grade ◽

Cell Transplant ◽

Hematopoietic Stem ◽

Allogeneic Hsct ◽

Autologous Hsct

Abstract BACKGROUND: The best treatment strategy in patients with relapsed Follicular Lymphoma (FL) remains controversial. The incorporation of rituximab (R) in the 1st line chemotherapy (CT) regimen and in treatment relapse resulted in better progression-free survival (PFS) but the benefit in overall survival (OS) was observed in only one trial (Hiddemann W. et al, Blood 2006). Hematopoietic stem cell transplant (HSCT) is the only treatment potentially curative, although the ideal time for its implementation remains undefined. AIM: Evaluation of the best treatment strategy and the impact of HSCT in PFS and OS in patients with relapsed FL. METHODS: Retrospective study including 85 patients with relapsed FL followed at a cancer care center between 2000-2012. Selection criteria: treatment naïve patients with the diagnosis of FL; absence of histological transformation at diagnosis and/or during the 1st line treatment. Survival analysis using the Kaplan-Meier method. Type of response defined according to NCCN criteria. RESULTS: Median follow-up of 64 months [4-158]. Disease progression after the 1st line CT was documented in 85 patients (median age 51 years [28-78], 42.4% male). 64 of the 85 patients had an Ann Arbor stage III-IV, of which 85.9% with follicular pattern, 95.3% grade 1/2 and 43.8% FLIPI ≥ 3. All patients underwent one or more CT regimens containing R, except in one case. In this study, 27.1% (n = 23) patients with age ≤ 60 years were submitted to HSCT (52.2% allogeneic HSCT from a related donor versus 47.8% autologous HSCT), almost all with ≥ 2 prior lines of CT (95.6%, n = 22). 78.3% (n = 18) had a CR or PR> 75% at the time of HSCT, and one death related to graft versus host disease was registered. Patients undergoing HSCT had a better PFS than those not transplanted (p = 0.022). A significant improvement in OS was observed in the HSCT subgroup (p = 0.007), especially in those with stage III-IV (p = 0.006). The type of HSCT had no impact on PFS and OS (p> 0.05), perhaps due to the small number of patients and short follow-up. By univariate Cox regression analysis, the number of regimens of CT before HSCT and the histological grade were independent predictors of PFS (p <0.05). The age and the histological grade were independent predictors of OS (p <0.05). CONCLUSION: In this study, HSCT improved PFS and also OS in patients with relapsed FL, especially in patients receiving less than 3 CT regimen, highlighting the importance of completing the HSCT earlier, during the disease’s chemosensitive phase. Our data suggest the curative potential of HSCT in these patients, due to the GVL effect in allogeneic HSCT and/or intensive high-dose CT in autologous HSCT. More studies are needed to validate these observations. Disclosures No relevant conflicts of interest to declare.

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