scholarly journals Fanconi Anemia: Hematopoietic Stem Cell Transplant or Gene Therapy?

2021 ◽  
Author(s):  
Parisa Naji ◽  
Maryam Behfar ◽  
Arefeh Jafarian ◽  
Amir Ali Hamidieh
Keyword(s):  
Conditioning Regimen ◽  
Cell Transplant ◽  
Hematopoietic Growth Factors ◽  
Hematopoietic Stem ◽  
Advantages And Disadvantages ◽  
Electronic Search ◽  
Mesh Terms ◽  
Good Potential ◽  
Or Gene ◽  
Citation Databases

FA is a rare, multi-organ cancer-prone IBMFS associated with hematological malignancies and STs. The androgen therapy, hematopoietic growth factors, HSCT, and GT, still in the clinical trial, are various treatments for this disease. Here, we aimed to compare the advantages and disadvantages of HSCT and GT in FA cures. We perform an advanced electronic search of “FA” AND (genetics OR treatment OR HSCT OR GT OR Mosaicism), and “Allo-HSCT” AND (conditioning regimen OR complications OR GvHD OR infection OR cost) MeSH terms in non-citation and citation databases. Besides, the gray literature was searched too. This article will provide a summary of the advantages and disadvantages of HSCT and GT of FA disease. Our results show that GT has a good potential in FA treatments in the future. Furthermore, it has higher advantages and fewer disadvantages in comparison with HSCT. Systematic Review Registration: CRD42021247364 ID on PROSPERO database.

scholarly journals Fanconi Anemia: Hematopoietic Stem Cell Transplant or Gene Therapy?

2021 ◽  
Author(s):  
Parisa Naji ◽  
Maryam Behfar ◽  
Arefeh Jafarian ◽  
Amir Ali Hamidieh
Keyword(s):  
Conditioning Regimen ◽  
Cell Transplant ◽  
Hematopoietic Growth Factors ◽  
Hematopoietic Stem ◽  
Advantages And Disadvantages ◽  
Electronic Search ◽  
Mesh Terms ◽  
Good Potential ◽  
Or Gene ◽  
Citation Databases

FA is a rare, multi-organ cancer-prone IBMFS associated with hematological malignancies and STs. The androgen therapy, hematopoietic growth factors, HSCT, and GT, still in the clinical trial, are various treatments for this disease. Here, we aimed to compare the advantages and disadvantages of HSCT and GT in FA cures. We perform an advanced electronic search of “FA” AND (genetics OR treatment OR HSCT OR GT OR Mosaicism), and “Allo-HSCT” AND (conditioning regimen OR complications OR GvHD OR infection OR cost) MeSH terms in non-citation and citation databases. Besides, the gray literature was searched too. This article will provide a summary of the advantages and disadvantages of HSCT and GT of FA disease. Our results show that GT has a good potential in FA treatments in the future. Furthermore, it has higher advantages and fewer disadvantages in comparison with HSCT. Systematic Review Registration: CRD42021247364 ID on PROSPERO database.

scholarly journals Outcome of Severe Aplastic Anemia Post Allogenic Stem Cell Transplant with Mycophenolate and Calcineurin Inhibitor for Graft Versus Host Disease Prophylaxis

Blood ◽  
2021 ◽  
Vol 138 (Supplement 1) ◽  
pp. 4879-4879
Author(s):  
Omar Albanyan ◽  
Hyejeong Jang ◽  
Seongho Kim ◽  
Andrew Kin ◽  
Asif Alavi ◽  
...  
Keyword(s):  
Stem Cells ◽  
Stem Cell ◽  
Conditioning Regimen ◽  
Unrelated Donor ◽  
Cell Transplant ◽  
Advisory Committees ◽  
Hematopoietic Stem ◽  
Gvhd Prophylaxis ◽  
Grade Ii ◽  
Matched Donor

Abstract Introduction: Severe aplastic anemia (SAA) is a rare hematopoietic stem cell disorder characterized by hypocellular marrow and pancytopenia. Multiple factors play an important role in treatment approach include age, comorbidities, degree of pancytopenia and availability of stem cell donor to either immunosuppression irrespective (IST) or allogenic hematopoietic stem cell transplant (alloSCT). The use of nonmyeloablative conditioning regimen has improved the outcomes, however the choice for post-transplant GVHD prophylaxis remain a topic of debate. The use of mycophenolate mofetil (MMF) has been used as an alternative for methotrexate (MTX) as has shown to be associated with lower incidence of mucositis and shorter time to engraftment. Methods: We retrospectively evaluated consecutive adult patients with SAA who underwent alloSCT at Karmanoc Cancer Institute. All patients received fludarabine, cyclophosphamide and antithymocyte globulin for conditioning regimen with calcineurin inhibitors (CNI) and MMF for GVHD prophylaxis. MMF was started at day -3 at 15 mg/kg three times daily and stopped at day +30 in the absence of active GVHD. The primary objectives were to estimate cumulative incidence of acute (aGVHD) and chronic GVHD (cGVHD) and overall survival (OS). Secondary objectives were to evaluate time to engraftment, days of hospitalization and incidence of mucositis. Results: From January 2005 and May 2019, 33 patients with SAA underwent alloSCT. Patient characteristics are detailed in Table 1. Median age was 36 years (range, 18-71). Twenty-seven patients received bone marrow stem cells (82%) and six patients received peripheral blood stem cells (18%). Thirty patients (91%) received 8/8 HLA matched donor and three patients (9%) received 7/8 HLA matched donor. Sixteen patients (48%) received stem cells from sibling donor and 17 patients (52%) received stem cells from unrelated donor. Thirteen patients (39%) had received IST prior to alloSCT, and 20 patients (61%) received upfront alloSCT. For GVHD prophylaxis all patients received MMF and CNI (tacrolimus=32, and cyclosporine=1). Median time from diagnosis to transplant was 15.8 months for patients who received IST prior to alloSCT and 2 months for patients who received upfront alloSCT. Median time to platelet engraftment was 13.5 days and neutrophil engraftment was 12 days, while one patient experienced graft failure. The median number of days for hospital stay were 25 days. Four patients (11%) developed grade I-II mucositis, no grade III-IV mucositis was observed in the first 30 days and 6 patients had CMV reactivation. The 100-day cumulative incidence rate of grade II-IV aGVHD was 21.2% (95% CI, 9.2 - 36.5), grade III-IV aGVHD was 9.1% (2.3-21.9) and 1-year CIR of cGVHD was 21.2% (95% CI, 9.2-36.5). Comparing patients who received IST prior to alloSCT versus upfront alloSCT, the 100-day CIR of grade II-IV aGVHD was 30.8% (95% CI, 8.2 - 56.5) and 15% (95% CI, 3.6 - 34.0), respectively, (Gray p=0.26) and the 3-year CIR of cGVHD was 39.6% (95% CI, 13.1 - 65.5) and 27.8% (95% CI, 9.2 - 50.3), respectively, (Gray p=0.37). Comparing patients who received alloSCT from related versus unrelated donor, 100-day CIR of II-IV aGVHD was 12.5% (95% CI, 1.9 - 33.6) and 29.4% (95% CI, 10.2 - 51.9), respectively, (Gray p=0.26), and the 3-year CIR of cGVHD was 34.2% (95% CI, 11.4 - 58.9) and 29.4% (95% CI, 10.1 - 52.0), respectively (Gray p=0.90). Median follow up of surviving patient was 5 years (95% CI, 3.1-6.8). Three-year OS was 87% (95% CI, 75.7- 99.9) and median OS was not reached. Six patients died by the time of the analysis, one patient died from graft failure (86 days after transplant from 8/8 HLA MUD), two patients died due infectious complications (808 days and 1637 days after transplant), three patients died due to multiorgan failure (215, 297 and 1097 days after transplant). Conclusion: Our data with use of CNI and MMF for GVHD prophylaxis for SAA following alloSCT with nonmyeloablative conditioning regimen showed that the rate of mucositis was low, engraftment time was rapid, and hospitalization was short, while OS, rates of acute and chronic GVDH were comparable to previously published rates with CNI and MTX-based GVHD prophylaxis. Figure 1 Figure 1. Disclosures Modi: Genentech: Research Funding; Seagen: Membership on an entity's Board of Directors or advisory committees; MorphoSys: Membership on an entity's Board of Directors or advisory committees. Deol: Kite, a Gilead Company: Consultancy.

The Role of Stem Cell Mobilization Regimen on Lymphocyte Collection Yield and Survival after Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1174-1174 ◽  
Author(s):  
Luis F. Porrata ◽  
Suzanne R. Hayman ◽  
Morie A. Gertz ◽  
Martha Q. Lacy ◽  
Angela Dispenzieri ◽  
...  
Keyword(s):  
Multivariate Analysis ◽  
Stem Cell ◽  
Peripheral Blood ◽  
Plasma Cells ◽  
Conditioning Regimen ◽  
Stem Cell Mobilization ◽  
Cell Labeling ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Cell Mobilization

Abstract We previously have reported that autograft absolute lymphocyte count (A-ALC) is a possible prognostic factor for survival after autologous peripheral blood stem cell transplant (ASCT) for myeloma (MM). Factors affecting A-ALC in MM are unknown. We hypothesize that method of stem cell mobilization, hematopoietic growth factor (HGF) vs. HGF+Cytoxan chemotherapy (C+HGF), directly affects A-ALC collection. 191 consecutive MM patients between 1994 and 2004 were analyzed retrospectively. Patients generally were mobilized with C+HGF prior to 2003. Thereafter, C+HGF was reserved largely for those with ≥4% circulating peripheral blood plasma cells (PC), a negative prognostic indicator. No patients were transplanted in disease relapse or refractory disease. Patients also were matched for age, sex, β2-microglobulin, conventional cytogenetics, LDH, c-reactive protein, number of prior therapies, plasma cell labeling index (PCLI), pre-mobilization ALC, and % bone marrow (BM) PC. The groups HGF (n=80) and C+HGF (n=111) differed with respect to the conditioning regimen (p < 0.0001), and presence of (≥4%) circulating peripheral blood PC (p<0.005). The primary end-point of the study was to assess the correlation between HGF vs C+HGF, and A-ALC. The secondary endpoint was to determine if HGF vs C+HGF affected survival post-ASCT. Patients mobilized with HGF had a higher A-ALC compared to those mobilized with C+HGF [0.764 x 109 lymphocytes/kg (range: 0.146–1.803) vs. 0.212 (range: 0.016–1.26), p<0.0001]. No association was identified between A-ALC and conditioning regimens (p = 0.19) and PC (p = 0.31). Median overall survival (OS) and progression-free survival (PFS) were longer in those mobilized with HGF vs. C+HGF (not reached vs. 48 months, p<0.0150; not reached vs. 21 months, p<0.007, respectively). Multivariate analysis demonstrated that age ≥50 vs age ≤50 (p<0.05) and A-ALC ≥0.5 vs <0.5x109 lymphocytes/kg (p<0.0397) were independent predictors of OS. Factors influencing PFS in the multivariate analysis included circulating PC ≥4% vs <4% (p<0.0157), PCLI ≥ 1% vs PCLI ≤ 1% (p<0.0107), and A-ALC ≥0.5 vs <0.5x109 lymphocytes/kg (p<0.0042). On multivariate analysis, the method of stem cell mobilization and the conditioning regimen did not have a statistically significant effect on either OS or PFS. We hypothesize that the differences in PFS and OS seen between the HGF vs C+HGF mobilization groups are mediated through the A-ALC. These data suggest that mobilization regimens should not only collect CD34+ stem cells, but also be optimized to collect an A-ALC target which may impact on PFS and OS post-ASCT.

Intravenous Busulfan: Pharmacokinetic Disposition and Clinical Outcomes in Children Undergoing Hematopoietic Stem Cell Transplant.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 1760-1760
Author(s):  
Tal Schechter ◽  
Yaron Finkelstein ◽  
John Doyle ◽  
Zulfikaral Verjee ◽  
Gideon Koren ◽  
...  
Keyword(s):  
Stem Cell ◽  
Oral Administration ◽  
Hematopoietic Stem Cell ◽  
Conditioning Regimen ◽  
Significant Proportion ◽  
Pharmacokinetic Parameters ◽  
Cell Transplant ◽  
Older Children ◽  
Hematopoietic Stem ◽  
The Mean

Abstract Background: Conditioning regimens preceding hematopoietic stem cell transplantation (HSCT) for various malignant and non-malignant diseases in children often include busulfan. Busulfan administration may be complicated by hepatic veno-occlusive disease (HVOD). A relationship has been described between high systemic exposure to busulfan after oral administration, as measured by area under the curve (Bu-AUC) and HVOD. Recently, IV busulfan (IV Bu) administration has been reported to be associated with a much lower incidence of HVOD than oral administration in adults. Objectives: To describe the pharmacokinetics of IVBu in infants (<1 year of age) and children. To determine the incidence of HVOD in children undergoing conditioning with IV Bu, and to correlate IV Bu AUC with the development of HVOD and neutrophil engraftment. Methods: Twenty-four children who underwent HSCT at The Hospital for Sick Children between April 2003 and September 2004 and received IV Bu as part of their conditioning regimen were included in this retrospective study. Diagnoses included: AML (6), metabolic storage disease (6), immune deficiency syndromes (4), histiocytosis (2), beta-thalassemia (2), WAS (1), MDS (1), CML (1), relapsed meduloblastoma (1). Initial IV Bu doses were based on actual patient weight: <9kg =0.95mg/kg/dose; 9–16kg =1.2mg/kg/dose; 16–23kg =1.1mg/kg/dose; 24–34kg =0.95mg/kg/dose; >34kg =0.8mg/kg/dose. Seven blood samples were drawn after the first IV Bu dose for determination of plasma busulfan concentrations. Pharmacokinetic parameters were calculated using 1-compartment analysis (WinNonLin 4.1). The third and subsequent IV Bu doses were adjusted to achieve an AUC of 900–1500μMol•min. HVOD (modified Baltimore criteria) and engraftment (ANC > 0.5 x 109/L) were evaluated. Results: The median patient age was 3.5 years (range 3mo–16.9yrs), including 9 infants. Mean IV Bu pharmacokinetic parameters were: Cmax=4.7±0.9μMol; Vss=0.70±0.22L/kg; ke=0.005±0.001min−1; AUC=1256±320μMol•min. The mean IV Bu AUC of infants was not different from older children (1164μ±331Mol•min vs. 1311±311μMol•min; p=0.35). The mean Vss was higher in infants than older children (0.84±0.29L/kg vs. 0.62±0.10L/kg; p=0.025), but the mean clearance was not different when corrected for body weight. Twenty-three patients (95.8%) engrafted between day +10 to +27. HVOD was diagnosed in 6 patients (25%), including 3 infants. Five patients had moderate HVOD and one had fatal HVOD. Mean IV Bu AUC was 1317±310μMol•min and 1074±299μMol•min in the non- HVOD vs. the HVOD group, respectively (p=0.10). The number of children who did not engraft precluded assessment of the relationship between IV Bu AUC and engraftment. Conclusions: Busulfan Vss differs significantly between infants and older children. A significant proportion of patients developed HVOD. No association was observed between IV Bu AUC and the development of HVOD in children where busulfan doses are adjusted to achieve a target IV Bu AUC.

Results Of The Large Prospective Study On The Use Of Defibrotide (DF) In The Treatment Of Hepatic Veno-Occlusive Disease (VOD) In Hematopoietic Stem Cell Transplant (HSCT). Early Intervention Improves Outcome - Updated Results Of a Treatment IND (T-IND) Expanded Access Protocol

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 700-700 ◽  
Author(s):  
Paul G. Richardson ◽  
Angela R. Smith ◽  
Brandon M. Triplett ◽  
Nancy A. Kernan ◽  
Stephan A Grupp ◽  
...  
Keyword(s):  
Early Intervention ◽  
Conditioning Regimen ◽  
Chemotherapeutic Agents ◽  
Study Entry ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Allogeneic Hsct ◽  
Kaplan Meier ◽  
Common Diagnosis ◽  
Improved Outcome

Abstract Background Given the life-threatening nature of severe VOD (sVOD) and associated multi-organ failure (MOF), the absence of other approved therapies for this complication in the USA, and the promising results to date with DF in this setting, DF has been made available since 2007 through a prospective T-IND. The aim of the T-IND is to gather additional data on safety and response to DF in a broader patient (pt) population, including those with sVOD/MOF and those with non-severe VOD. Thus far, this is the largest prospective evaluation of DF for the treatment of sVOD/MOF in pts undergoing HSCT, and in pts who developed VOD following chemotherapy (non-HSCT pts). Here we provide an update on the efficacy and safety of DF in HSCT and non-HSCT pts, together with analysis of other clinical features of interest, including GvHD. Methods The original T-IND protocol required pts to have a diagnosis of VOD by Baltimore criteria (total bilirubin ≥2.0 mg/dL with ≥2 of the following: hepatomegaly, ascites or 5% weight gain) with MOF (either renal and/or pulmonary failure) following HSCT, and was amended to allow inclusion of pts with non-severe VOD (defined as no MOF) occurring either post-HSCT and post-chemotherapy. Key exclusion criteria included clinically significant bleeding or the need for >1 vasopressor. Complete response (CR) was defined as bilirubin <2 mg/dL plus resolution of MOF (if applicable). Mortality was assessed at Day +100 (D+100) in all pts. DF was given at 6.25 mg/kg IV q6h (25 mg/kg/d) with recommended treatment duration of at least 21 days (d). Results The current interim analysis is based on 470 VOD pts enrolled between December 2007 and December 2012 at 75 centers, 45 of which developed VOD following chemotherapy and 425 had undergone HSCT (376 allogeneic HSCT, 89%). In HSCT patients, median age was 15 yrs (range 0.1–70), 55% were male and 18% had undergone multiple HSCTs (>1 HSCT); 284 pts had severe disease at study entry. The most common diagnosis was leukemia (29% AML; 22% ALL; 6% other). Conditioning regimen included CY (66%), BU (50%) and TBI (36%). Median onset of VOD was 15 d post-HSCT. Of HSCT pts, 35% (147/425) achieved CR and 55% (Kaplan-Meier estimate) survived to D+100. In pts with sVOD, CR was 29% and D+100 survival was 48%. For pts with non-severe VOD, CR and D+100 survival was 47% and 69%, respectively. In all HSCT pts, delay of >2 d (vs ≤2 d) in the start of DF after VOD diagnosis resulted in reduced CR (25% vs 39%, p=0.0052) and survival (Kaplan-Meier estimate) (38% vs 61%, p<0.0001). Children (≤16 years) as compared to adults had higher CR rates (41% vs 27%, p=0.0038) and better survival (60% vs 49%, p=0.0203). In the 45 non-HSCT patients, median age was 8 yrs (range 0.1–63), and 53% were male; the most common diagnosis was ALL (33%) and AML (22%). Cyclophosphamide (49%), vincristine (44%) and cytarabine (33%) were the most frequent chemotherapeutic agents associated with VOD. Median onset of VOD after chemotherapy was 14 d, and sVOD was present in 53% of pts at study entry. Of non-HSCT pts, 40% (18/45) achieved CR and 62% were alive at D+100. Toxicity proved generally manageable: 23% of pts experienced at least one related AE, primarily consisting of hemorrhage including pulmonary bleeding (6%), GI hemorrhage (7%), epistaxis (3%), hematuria (2%), and hypotension (4%). Similar to the observation of decreased GvHD in other studies, the incidence of all grade GvHD in the allogeneic HSCT pts was low at 11%. Conclusions DF therapy in sVOD/MOF pts achieved significantly improved outcome compared to that expected based upon historical data. Given the results of this large cohort of pts, early treatment with DF (i.e. within 2 d of VOD diagnosis) is recommended, and consistently improved outcome was seen in pts who have not yet progressed to sVOD. Generally, DF was well-tolerated and as with prior studies, there was a low incidence of DF-associated toxicities. These results confirm the findings of previous trials and strongly support early intervention with DF once the diagnosis of VOD is made after HSCT, which also reinforces the validity of positive studies in prophylaxis to date and suggests further trials in prevention are warranted. Outcomes in children appear to be better than in adults, supporting the importance of this agent in the pediatric population in particular. In addition, low rates of GvHD were seen and this is an important area in which further studies are planned. Enrollment to the T-IND study continues. Disclosures: Richardson: Gentium : Membership on an entity’s Board of Directors or advisory committees. Hannah:Gentium: Consultancy. Hume:Gentium: Employment. Bandiera:Gentium: Employment. Heringa:Gentium: Employment. Study Group:Gentium: Employment.

Secondary neutropenia (SN) after autologous hematopoietic stem cell transplantation (AHSCT) in patients (pts) with lymphoma.

2012 ◽  
Vol 30 (15_suppl) ◽  
pp. 6552-6552
Author(s):  
Sunita Nathan ◽  
John Joseph Maciejewski ◽  
Elizabeth Shima Rich ◽  
Parameswaran Venugopal ◽  
Kent W. Christopherson ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplant ◽  
Conditioning Regimen ◽  
Stage Iv ◽  
Autologous Stem Cell Transplant ◽  
Cell Transplant ◽  
Hematopoietic Stem ◽  
Post Transplant ◽  
Cd34 Cells ◽  
Transplant Complications

6552 Background: Plerixafor for mobilization of autologous stem cells (ASC) has increased the yield of transplanted ASC and is evolving as an important option for mobilization. A prior study reported a 10% incidence of SN after AHSCT (BMT 2009 Aug; 44(3): 175-83). Incidence and outcome of SN in the setting of Plerixafor/G-CSF (P/G), is unknown. We report the incidence and possible etiology for the development of SN in pts undergoing AHSCT for lymphoma at our institution. Methods: Data from 80 consecutive AHSCT pts over a 2 year period were reviewed. All pts were mobilized using P/G. Demographics, AHSCT indication, prior therapies (Rx), conditioning regimen (CR), engraftment and post-transplant complications were identified and collected. SN was defined as ANC <1000 after initial engraftment. Results: 80 pts underwent an AHSCT for lymphoma from 2009-11. 70 pts had evaluable data. 37 (52.86%) pts (average age 55.4 yrs) were male and 33 (47.14%) pts (average age 48.3 yrs) female. 25 (35.7%) pts had ≥2 comorbidities. Indications included relapsed/ refractory B-NHL, T-NHL and HL. 47 (67%) pts had Stage IV ds, 48.9% with BM involvement. 17 (24.3%) pts had >2 Rx, 18 (25.7%) with loco-regional XRT and 3 (4.3%) with RIT. CR included BEAM, BEC and Benda-EAM +/- Rituxan. # of CD34+ cells given ranged; 1.77-19.99 x 10^6/kg. Neutrophil engraftment occurred at a median of 11 days. 26 (37.14%) pts developed SN possibly from PCP prophylactic antibiotics and infections. Prior BM involvement, Rx or XRT had no role. 5 (45.4%) pts with Benda-EAM CR had SN. Associated morbidity/mortality were not noted. Conclusions: We conclude that secondary neutropenia is common after autologous stem cell transplant using the Plerixafor/GCSF combination for mobilization and is higher than reported in the literature (37% vs 10%). Patients who received this combination for mobilization should be followed up closely in the post-transplant period for secondary neutropenia. About half the patients who received the Benda-EAM conditioning regimen developed secondary neutropenia warranting its use with caution outside of a clinical trial.

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