Haploidentical transplantation: selecting optimal conditioning regimen and stem cell source

Abstract CsA is widely used as the backbone immunosuppressive agent for GVHD prevention after allo-SCT. Previous studies have demonstrated that the immunosuppressive effects of CsA (eg. inhibition of calcineurine in lymphocytes) may be correlated with CsA blood concentration, especially in the context of solid organ transplantation. This report aimed to investigate the impact of CsA concentrations in the early post allo- SCT period, on the incidence of severe acute GVHD, in 85 consecutive patients treated in a single centre between Jan. 2006 and Jan. 2008, and for whom CsA concentrations in the blood were monitored weekly after the start of infusion. 85 patients (45 males) received CsA (usually at 3 mg/Kg/d, 2 or 3 days prior to graft infusion) as a 24-h continuous infusion until hematopoietic recovery and switch to oral formulation. Dose modifications of CsA were performed to maintain adequate trough blood levels and to prevent nephrotoxicity. Patients’ and donors characteristics were as follow: median age: 51 (range, 18–67), 46 (54%) female donors, 33 (39%) myeloid malignancies, 49 (58%) lymphoid malignancies, and 3 cases of SAA. The stem cell source was PBSC in 66 (78%) patients, while bone marrow was used in 19 (22%) patients. 37 (43.5%) were transplanted from a matched related donor, and 48 (56.5%) from a matched unrelated donor. A myeloablative conditioning regimen was used in 24 (28%) patients, and 61 (72%) received a reduced intensity regimen. The median concentrations of CsA in the blood at 1, 2, 3 and 4 weeks after allo-SCT were 348 (range, 172–733), 284 (range, 137–535), 274 (range, 107–649), and 247 (37–695) ng/mL respectively. All patients engrafted at a median of 17 (range, 0–42) days after allo-SCT. With a median follow-up of 16 (range, 5–29) months, grade 2–4 acute GVHD occurred in 36 patients (42%) at a median of 29 (range, 6–100) days after allo-SCT. The incidence of severe grade 3–4 acute GVHD was 23% (95%CI, 14–32%). In this cohort, all acute GVHD risk factors (age, donor-recipient gender, CMV serostatus, ABO compatibility, diagnosis, disease status, stem cell source, donor type, conditioning regimen type, GVHD prophylaxis regimen, CsA concentrations) were assessed. In multivariate analysis, we found that higher whole-blood CsA concentration in the first week following graft infusion, and before onset of acute GVHD was the strongest parameter significantly associated with a reduced the risk of severe grade 3–4 acute GVHD (P=0.01; RR=0.24; 95%CI, 0.08–0.73). Despite its retrospective nature, these data strongly indicate a close relationship between CsA trough blood concentration during the early post allo-SCT period and the severity of acute GVHD. Inadequate or insufficient early exposures of CsA can be a serious risk for developing severe acute GVHD. Therefore, precise monitoring of CsA concentrations and achievement of a high CsA target concentration may be an effective tool to prevent the onset of severe acute GVHD.

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Cyclophosphamide-Busulfan Instead of Busulfan-Cyclophosphamide for Conditioning in Allogeneic Hematopoietic Stem Cell Transplantation.

Blood ◽

10.1182/blood.v114.22.2268.2268 ◽

2009 ◽

Vol 114 (22) ◽

pp. 2268-2268

Author(s):

Nathan Cantoni ◽

Sabine Gerull ◽

Dominik Heim ◽

Joerg Halter ◽

Dimitrios Tsakiris ◽

...

Keyword(s):

Stem Cell ◽

Cumulative Incidence ◽

Liver Toxicity ◽

Conditioning Regimen ◽

Hematopoietic Stem ◽

Allogeneic Hsct ◽

Stem Cell Source ◽

Cell Source ◽

Donor Type ◽

Total Body

Abstract Abstract 2268 Poster Board II-245 Busulfan-cyclophosphamide (BU-CY) is the established non total body irradiation based myeloablative conditioning regimen for allogeneic hematopoietic stem cell transplantation (HSCT). The introduction of intravenous busulfan has facilitated its application and reduced toxicity. Theoretical considerations and pharmacological data indicate that previous application of busulfan may trigger liver toxicity of subsequent cyclophosphamide. A reverse order of cyclophosphamide-busulfan (CY-BU) would be preferable. Recent animal data confirmed this hypothesis, showing less liver toxicity and better outcomes in mice treated with CY-BU. While CY-BU was not feasible in patients with oral busulfan, it has become a possibility with the introduction of i.v. busulfan. We were therefore interested in exploring this concept and changed the order of drug application to CY-BU in 2003 in those patients not on a multicentre standardized BU-CY protocol. We now retrospectively analyzed in this single centre cohort study liver toxicity and transplantation outcome in patients receiving BU and CY as conditioning regimen for allogeneic HSCT. We analyzed 93 consecutive patients between 1993 and 2008, 52 male (55.9%), median age 46 years (range 16 to 70) with hematological malignancies (AML 41 [44.1%], ALL 11 [11.8%], CML 12 [12.9%], myelodysplastic syndrome and myeloproliferative neoplasia 22 [23.7%], lymphoproliferative disorders 4 [4.3%]) or other diseases (3 [3.2%]), receiving an allogeneic HSCT from an HLA- identical sibling (52 [55.9%]), other family member (3 [3.2%]) or a matched unrelated donor (38 [40.9%]) after conditioning regimen with BU-CY (34 patients; 18 patients with oral, 16 patients since 2003 with i.v. busulfan) or CY-BU (59 patients). Outcomes were analyzed using a Cox regression model, adjusting for disease, stage, donor type, stem cell source, previous total body irradiation (TBI) and busulfan administration (oral vs. intravenous). Pretransplant patient characteristics were comparable in the two cohorts for age, gender, underlying disease, stem cell source, donor type and EBMT risk score, but differed in stage (advanced disease BU-CY 28 [84,8%] vs. CY-BU 40 [66.7%]) and previous TBI (BU-CY 16 [48.5%] vs. CY-BU 9 [15.0%]). Liver function as measured by levels of bilirubin and liver enzymes (aspartate amino transferase [AST], alanine amino transferase [ALT], gamma glutamyl transpeptidase [GGT] and alkaline phosphatase [AP]) was not different between the groups before starting conditioning regimen. In contrast liver function differed significantly at day 20, with higher levels of ALT (median 51.0 vs 27.0 IU/l; p=0.012) and a higher incidence of veno-occlusive disease (VOD) (5/34 vs. 1/59, p=0.036) in the BU-CY group (Figure 1A). The cumulative incidence of transplant-related mortality (TRM) at 2 years was significantly higher in patients receiving BU-CY (BU-CY 0.48, CY-BU 0.24, p=0.024; hazard ratio 4.594 for BU-CY, 95% CI 1.382-15.268, p=0.013) (Figure 1B). The cumulative incidence of TRM with BU i.v.-CY was lower (0.44) than with BU oral-CY (0.56) but still higher than CY-BU. This did translate into a higher overall survival in patients after conditioning regimen with CY-BU (hazard ratio for mortality 0.426 for CY-BU, 95% CI 0.184-0.987, p=0.047). Time to engraftment (BU-CY median 13 days vs. CY-BU median 14 days), cumulative incidence of acute GVHD and relapse were similar between patients receiving BU-CY or CY-BU. These data support the concepts derived from Sadeghi et al in their mouse model in favor of CY-BU compared to the traditional BU-CY. They form the basis for prospective controlled studies. Disclosures: No relevant conflicts of interest to declare.

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Allogeneic Stem Cell Transplantation (allo-SCT) in 192 Acute Myeloid Leukemias (AML): A Single Center Experience From 1982 to 2010

Blood ◽

10.1182/blood.v118.21.4498.4498 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4498-4498

Author(s):

Carmen Montes-Gaisan ◽

Jorge Monge ◽

Clara Martin ◽

Zurie Diez ◽

Johny Alberto Hinostroza ◽

...

Keyword(s):

Stem Cell ◽

Median Time ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Multivariable Analysis ◽

The Other ◽

Univariable Analysis ◽

Stem Cell Source ◽

Significant Difference ◽

Cell Source

Abstract Abstract 4498 Background: Giving the fact that allo- SCT currently offers patients with high risk AML the best chance of cure, we`ve aimed to investigate the outcome of AML patients who have undergone allo-SCT in our center, considered as one of spanish reference hospital in SCT, and the parameters that have been able to influence in relapse rate (RR), overall survival (OS) and relapse free survival (RFS). Methods: Retrospective study in 192 AML patients who have undergone allo-SCT between 1982 and 2010. The analysis has been performed in 171 patients (85 male and 86 female) by excluding 21 acute promyelocitic leukemias (APL): 65 patients until 1999 and 106 since 2000. Median age was 37 1874 and median lecocyte count, \batchmode \documentclass[fleqn,10pt,legalpaper]{article} \usepackage{amssymb} \usepackage{amsfonts} \usepackage{amsmath} \pagestyle{empty} \begin{document} \(13400/\hbox{ L }\frac{470}{250000}\) \end{document}. 82 were de novo AML and 87 were in morfologic complete remission (70 in first CR). 14 patients had received a previous SCT. Cytogenetic risk was as follows: 55 intermediate, 34 high and 11 low. Conditioning regimen was ablative in 162 patients: CyTBI (36), BuCy (31), BuFlu (30) and others (3). 130 patients (76) underwent a related allo-SCT (95 of them were matched) and 41 patients (24), an unrelated allo-SCT (64 of them were matched). Stem cell source was bone marrow (BM) in 146 patients (85) and only 3 patients received umbilical cord (UC). Graft versus host disease (GvHD) prophilaxis was based on Ciclosporine in 150 patients (88). Median time from last treatment was 73 days 12268. Results: The median follow-up of this study was 61 months 1317. OS at 1, 3 and 5 years were 57, 44 and 40. RFS at 1, 3 and 5 years were 62, 50 and 45. Early mortality (before day 100) was 26 (43 until 1999 and 15 since 2000, p0,0001): 18 patients because of infections, 10 because of toxicity, 9 because of disease and 7 because of EICH. Late mortality was 27 (more than the half because of relapse, with no significant difference between 19881999 and 20002010). Cumulative relapse incidence at 5 years was 35, with a median time of relapse of 4 months. Secondary malignancies incidence was 5. Multivariable analysis showed that Transplantation Related Mortality (TRM) was influenced by: year of allo-SCT (OS at 5 years of 49 if 20002010 vs 28 if 19821999, p0,0001), late engraftment (p0,002) and severe acute GvHD (OS at 5 years of 45 if no evidence/grade I-II vs 25 if grade III-IV, p0,071). The other important parameters which lost its univariable analysis significance were donor type, recipient age and conditioning regimen. No difference was found in case of HLA and ABO discordance or donor/recipient CMV status. Multivariable analysis also showed that RR and RFS at 5 years was influenced by: disease status at allo-SCT (50 if 1CR vs 0 if 2CR/PR/refractory disease, p0,002), chronic GvHD (67 if present vs 41 if absent, p0,035) and leucocyte count at diagnosis (54 if 20000/ L vs 37 if 20000/ L, p0,038). The other important parameters which lost its univariable analysis significance were cytogenetic risk, initial induction response and positive minimal residual disease (MRD) before allo-SCT. No diference was found in case of ethiologic classification or stem cell source. Conclusions: Allo-SCT is a curative procedure in AML patients (global RFS of 50 at 3 years), specially when disease is under control and patient develops chronic GvHD. In the last decade, there have been important improvements in the procedure which have led to a significant decrease in TRM, and consequently, a significant increase in OS. Disclosures: No relevant conflicts of interest to declare.

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Novel Conditioning Regimen for Haploidentical Hematopoietic Cell Transplant for Severe Aplastic Anemia in Children

Blood ◽

10.1182/blood-2019-126620 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 5651-5651 ◽

Cited By ~ 1

Author(s):

Hasan Hashem ◽

Rawad Rihani ◽

Eman Khattab ◽

Mayada Abu Shanap ◽

Abdelghani Tbakhi ◽

...

Keyword(s):

Stem Cell ◽

Peripheral Blood ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Cell Transplant ◽

Hematopoietic Cell Transplant ◽

Stem Cell Source ◽

Cell Source

New hematopoietic cell transplant (HCT) approaches are urgently needed for patients with severe aplastic anemia (SAA) who lack an HLA-identical donor. Haploidentical HCT with post transplant cyclophosphamide (PTCy) represent a potential universal available option for almost all children with SAA. We present a novel conditioning regimen for haploidentical HCT in children with SAA in a center where horse ATG is not available. Conditioning regimen consists of rabbit ATG 2.5 mg/kg/day from day -9 to -7, Fludarabine 30 mg/kg/day from day -6 to -2, Cyclophosphamide 14.5 mg/kg/day from day -6 to -5, Thiotepa 5 mg/kg/day from day -4 to -3, and 4 Gy TBI on day -1 in in two fractions. GvHD prophylaxis consist of PTCy 50 mg/kg/day on days +3 and +4 along with Cyclosporine A and Mycophenolate mofetil (MMF) starting on day +5. Four consecutive children with SAA referred to our center for haploidentical HCT starting in 2018. Median age at HCT was 9 years (5-16) with 3 males and 1 female. All patients were heavily transfused with both blood and platelets prior to referral for HCT. Two patients had strong and one had weak positive anti-HLA antibodies (DSAs) and received desensitization with IVIG, Rituximab and plasmapheresis. One patient received buffy coat infusion on day -1 due to persistent strong DSAs despite desensitization. Median CD34+ dose received was 12 x 10e6, and median CD3+ dose was 29 x 10e6. Donors were all same blood group to patients. All patients successfully engrafted neutrophils at median of 13 days (12-14). Platelets engraftment in 3/4 patients at median of 7 days (5-10). All patients received peripheral blood as stem cell source. Three of four patients survived and doing well at last follow up. One patient had toxic death on day +38 due to chemotherapy related toxicity causing multi-organ failure. Chimerism analysis was full donor in all four patients at median follow up time of 11 months (2-12). Patients were sent home at median of 24 days post HCT. None developed grade 2-4 acute GvHD nor chronic GvHD. Acute GvHD of skin grade 1 stage 1 developed in 2 patient and managed with topical steroids. Viral reactivations consisted of CMV viremia and BK hemorrhagic cystitis in all patients, and have all resolved. No post transplant autoimmune complications. Haploidentical HCT with PTCy represents a quick and first line approach in heavily transfused children with SAA. Although yet limited number of patients, this regimen is feasible and appears to be safe. A great advantage of this regimen is the rapid engraftment of both neutrophils and platelets. Moreover, although using peripheral blood as a stem cell source, there was no severe acute or chronic GvHD. Disclosures No relevant conflicts of interest to declare.

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Peripheral Blood Stem Cell (PBSC) Haploidentical Transplantation Using a Reduced Intensity Conditioning (RIC), T Cell Replete Approach Proves Both Efficacious and Well Tolerated In a Range of Haematological Malignancies.

Blood ◽

10.1182/blood.v116.21.4584.4584 ◽

2010 ◽

Vol 116 (21) ◽

pp. 4584-4584

Author(s):

John Laurie ◽

Andrew Hodson ◽

Tamara Elston ◽

Carol Black ◽

Ophelia Manwaring ◽

...

Keyword(s):

Stem Cell ◽

T Cell ◽

Graft Failure ◽

Chronic Gvhd ◽

Viral Loads ◽

Haploidentical Transplantation ◽

Stem Cell Source ◽

Cell Source ◽

Relapse Rates ◽

Grade Iii

Abstract Abstract 4584 Haploidentical transplantation is an option for patients who do not have a timely identifiable sibling or volunteer unrelated donor (VUD). Benefits of this stem cell source include donor availability, highly motivated donors and the ability to select the best donor from several relatives taking: age/fitness, cytomegalovirus (CMV) status, ABO group and natural killer cell alloreactivity into account. Historically the high level of human leukocyte antigen (HLA) disparity led to increased graft failure and high rates of acute and chronic graft versus host disease (GVHD). Luznik et al (Blood 2001) demonstrated that the use of post stem cell return cyclophosphamide in RIC haploidentical transplantation (using bone marrow as a stem cell source) reduced acute and chronic GVHD to acceptable levels, but at the expense of higher relapse rates in their cohort. We postulated that the use of PBSC's with their inherently higher T cell complement would reduce relapse rates compared to bone marrow, whilst post cell return cyclophosphamide would reduce acute and chronic GVHD. We present 5 patients treated at our centre using a RIC T cell replete haploidentical transplant protocol utilising PBSC's and post cell return cyclophosphamide. The patients, (median age 51; range 44–58), were treated for: relapsed follicular non Hodgkin's lymphoma (NHL), secondary acute myeloid leukaemia, Mycosis Fungoides and Adult T-Cell Leukaemia/Lymphoma (ATLL). Four patients had received 1st line chemotherapy only and remained chemotherapy sensitive, 3 of whom were in complete remission, one in a partial response. None had undergone a previous transplant. The NHL patient was chemotherapy insensitive following 4 previous lines of chemotherapy, a splenectomy and 2 rejected sibling allografts. Three patients were a major ABO mismatch, the remaining 2 fully matched. Four patients were CMV +/+ and 1 mismatched. HLA disparity ranged from 2–5 alleles (2 and 3 patients respectively). Median CD34+ cell dose returned was 6.98×106 cells/kg (range 4.81–8.00), with a median CD3+ cell dose of 2.36×108 cells/kg (range 1.19–2.97). The conditioning regime used was that of Luznik et al's (Blood 2001) phase I trial: Fludarabine 30mg/m2 day -6 to -2, cyclophosphamide 14.5mg/kg day -6 to -5, total body irradiation 2 Gray day -1, post stem cell cyclophosphamide 50mg/kg day +3 to +4, tacrolimus 1mg IV day +5 onwards, mycophenolate mofetil 15mg/kg TDS day +5 to +35. Outcomes: Four of 5 (80%) patients were fully donor chimeric by day 28 however graft failure with autologous reconstitution due to previously undetected HLA antibodies occurred in 1 patient. This patient reconstituted autologous neutrophils and platelets at 15 and 26 days respectively. Median time to neutrophil and platelet engraftment was 16.5 days (range 14–17) and 12 days (range 11–14) respectively. All 5 patients reactivated CMV (the latest at day 112). With pre-emptive treatment however none developed CMV disease. The incidence of acute GVHD grade II – IV and grade III - IV by day 100 was 40% and 20% respectively. Limited chronic GVHD was seen in 3 patients. 2 were assessed as grade I-II and 1 patient grade III. All cases of acute and chronic GVHD were steroid responsive. In both ATLL patients a sustained suppression of human T-lymphotropic virus (HTLV) viral loads was observed post transplant. One patient subsequently died of sepsis at day 113, the patient who had rejected their graft went on to relapse. The remaining 3 patients continue in CR, performance status 0, currently at day 245, 280 and 438. This data shows that RIC T cell replete haploidentical transplantation using PBSC's is well tolerated and enables both early engraftment and full donor chimerism. The rates of acute and chronic GVHD (40 and 60%) are comparable to sibling and fully matched unrelated donors. All of which has resulted in 60% of patients remaining in CR, including both ATLL patients who have gone on to fully suppress their HTLV viral loads. Disclosures: No relevant conflicts of interest to declare.

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Influence of the hematopoietic stem cell source on early immunohematologic reconstitution after allogeneic transplantation

Blood ◽

10.1182/blood.v97.9.2580 ◽

2001 ◽

Vol 97 (9) ◽

pp. 2580-2586 ◽

Cited By ~ 27

Author(s):

Valérie Lapierre ◽

Nadia Oubouzar ◽

Anne Aupérin ◽

Dominique Tramalloni ◽

Hakim Tayebi ◽

...

Keyword(s):

Stem Cell ◽

Hematopoietic Stem Cell ◽

Conditioning Regimen ◽

Allogeneic Transplantation ◽

Phase Iii ◽

Hematopoietic Stem ◽

Stem Cell Source ◽

Cell Source ◽

A Minor ◽

Stimulating Factor

Abstract Several acute hemolysis episodes, sometimes lethal, have been recently described after transplantation of allogeneic peripheral blood hematopoietic stem cells (PBHSCs). Hemolysis resulted from the production of donor-derived antibodies (Abs) directed at ABO antigens (Ags) present on recipient red blood cells (RBCs). A multicenter randomized phase III clinical study comparing allogeneic PBHSC transplantation (PBHSCT) versus bone marrow hematopoietic stem cell transplantation (BMHSCT) has been conducted in France. In the course of this study, serum anti-A and/or anti-B Ab titers were compared before the conditioning regimen and on day +30 after transplantation in 49 consecutive evaluable PBHSCT (n = 21) or BMHSCT (n = 28) recipients. PBHSCT resulted in a higher frequency of increased anti-A and/or anti-B Ab titers 30 days after transplantation as compared to BMHSCT: 8 (38%) of 21 versus 3 (11%) of 28 (P = .04). In PBHSCT recipients, increased titers were observed mostly after receiving a minor ABO mismatch transplant: 5 of 7 versus 3 of 14 in the absence of any minor ABO mismatch (P = .05), whereas this was not the case after BMHSCT: 1 of 8 versus 2 of 20. Anti-A and/or anti-B serum Abs detectable at day +30 after PBHSCT were always directed against A and/or B Ags absent both on donor and recipient RBCs. Finally, 3 of 21 PBHSCT versus 0 of 28 BMHSCT recipients developed anti-allogeneic RBC Abs other than ABO (P = .07). Overall, the data strongly suggest that immunohematologic reconstitution differs significantly after granulocyte colony-stimulating factor–mobilized PBHSCT when compared to BMHSCT. Such a difference could contribute to the acute hemolysis described after PBHSCT as well as to distinct alloreactivity after PBHSCT.

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The Impact of Methylenetetrahydrofolate Reductase C677T Gene Polymorphism on Engraftment after Allogeneic Hematopoetic Cell Transplantation.

Blood ◽

10.1182/blood.v106.11.5318.5318 ◽

2005 ◽

Vol 106 (11) ◽

pp. 5318-5318

Author(s):

Ender A. Soydan ◽

Pervin Topcuoglu ◽

Muhit Ozcan ◽

Onder Arslan ◽

Gunhan Gurman ◽

...

Keyword(s):

Stem Cell ◽

Gene Polymorphism ◽

Cell Transplantation ◽

Conditioning Regimen ◽

Mthfr Gene ◽

Stem Cell Source ◽

Gvhd Prophylaxis ◽

Mthfr Gene Polymorphism ◽

Cell Source ◽

The Impact

Abstract Methotrexate (MTX) is an antifolate agent used to prevent graft versus host disease (GVHD) in allogeneic hemapoietic cell transplantation (AHCT). The effectiveness of MTX is largely attributable to its role of MTHR and its gene polymorphism is a common (10–12% homozygote and 40% heterozygote) variation in the population. It was shown by Ulrich et al that C677T polymorphism leads to variations in toxicities. Depending on to this finding, we investigated whether methylenetetrahyrofolate reductase (MTHFR) C677T gene polymorphism has any affect on engraftment kinetics of patients undergoing AHCT. We retrospectively analyzed our cohort of 82 allogeneic stem cell recipients whose MTHFR gene polymorphism of C677T region was analyzed by RQ-PCR for the pretransplant evaluation of hereditary thrombophilia. The patient’s median age was 31 (range, 14–50) years, with a M/F: 50/32 and diagnosis; 35 AML, 26 CML, 12 ALL and 9 other. Nearly all the patients received ablative conditioning regimen (BU-CY) or CY-TBI. All the patients received CSA and short term MTX for GVHD prophylaxis. Stem cell source was bone marrow (BM) in 23 and peripheral blood (PB) in 59. MTHFR gene polymorphism was detected in 32 (39%) of all patients, whose 90% were heterozygote (MTHFR HeZ). When we compared the engraftment kinetics, granulocyte engraftment was found to be late in MTHFR HeZ group (neutrophil 1000 median 19 vs 17 d; p=0.01) but no difference in platelet engraftment. In order to eliminate the effect of stem cell source on engraftment kinetics we have done the same analysis for BM and PB group separately. We have observed that MTHFR gene polymorphism had a prominent effect on BM recipients, as both neutrophil 500 and 1000 and also platelet engraftments were affected (granulocyte 500 median 21 vs 15 p=0.005; granulocyte 1000 median 22.5 vs 17 p=0.0001 and plt 20 median 27 vs 21 p=0.03) significantly. On the contrary, there was no difference in the PB group. There was no difference in acute GVHD incidence. Our knowledge on epigenetic data will help us on tailoring the chemotherapy regimen for conditioning and GvHD prophylaxis in transplant recipients. Our data on a limited patient size suggests that the presence of MTHFR HeZ may have an impact on allo HCT recipients’ engraftment kinetics while using MTX for GVHD prophylaxis and BM as stem cell source.

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Results of Haematopoietic Stem Cell Transplantation (HSCT) for Hurler’s Syndrome: European Experience 1994–2004.

Blood ◽

10.1182/blood.v106.11.402.402 ◽

2005 ◽

Vol 106 (11) ◽

pp. 402-402 ◽

Cited By ~ 1

Author(s):

Jaap Jan Boelens ◽

R. Wynn ◽

A. O’Mearra ◽

P. Veys ◽

M. Cavazzana-Calvo ◽

...

Keyword(s):

Stem Cell ◽

T Cell ◽

Conditioning Regimen ◽

Unrelated Donor ◽

Donor Chimerism ◽

Stem Cell Source ◽

Cell Source ◽

Conditioning Regimens ◽

Hurler’S Syndrome

Abstract Worldwide more than 400 patients with Hurler’s syndrome (HS), characterized by severe neurodegeneration, cardiac disease, skeletal abnormalities and death in early childhood, have undergone allogeneic-HSCT since 1980. Although, long term follow up of successfully transplanted children is very encouraging, the engraftment and survival results are very variable between the various studies, ranging from less than 25% up to more than 85%. We retrospectively analyzed the results of 146 patients transplanted in Europe from 1994–2004, to assess: 1) the effect of conditioning regimen and grafts (-manipulation) used on the “alive and engrafted” rate and 2) the transplantation-related morbidity/mortality. HSCT with a family donor was performed in 52 patients. An unrelated donor was used in 94 patients. The majority of patients received marrow (n=103). The rest received cordblood (n=23) or peripheral blood (n=20). Twenty-eight patients received a T-cell depleted (TCD) graft. Conditioning regimens used were grouped as follows: busulfan-cyclofosfamide 200mg/kg (n=68), busulfan- with high dose cyclofosfamide (either 240mg/kg or 260mg/kg; n=41), fludarabine-based myelo-ablative (n=19) and reduced intensity conditioning regimens (RIC: n=18). Fourteen patients received dose-adjusted busulfan. Engrafted was defined as a donor chimerism of more than 10%, and an alpha-L-iduronidase level of more than the lower limit of normal for the heterozygote individuals (>4.5 nmol/hr/mg). The “alive and engrafted” rate after first transplantation and overall “alive and engrafted” rate after one to three transplantations was 83/146 (57%) and 111/146 (76%), respectively. The median follow up was 39 mth (5–120mths). Multivariate analysis (confounders: age, sex, heterozygote donor, unrelated donor, stem cell source, HLA-disparity, conditioning regimen, TCD and busulfan targeting) on the primary endpoint “alive and engrafted” showed that RIC (RR 13,4: 2,6–67,1) and TCD (RR 5,7: 1,14–28,4) are individual risk factor for graft failure. Busulfan targeting suggests to be an individual protective factor (RR 0,27; 0,04–1,8); 12/14 (86%) were “alive and engrafted” after 1st HSCT. Thirthy three patients received a 2nd graft, of whom 26/33 (82%) are alive and engrafted: 16/21 using the same, 10/12 using a different donor, and 16/19 after myeloabaltive, 10/14 after RIC. Two of the 3rd HSCTs were successful. After 1st HSCT moderate to severe aGvHD (grade ≥2) occurred in 23/146 (16%) patients. Extensive cGvHD was seen in 2/114 (1.4%) patients, only. IPS/DAH was seen in 4/134 (2.3%) patients and VOD in 12/134 (9%) patients. Main cause of death (n=28) was infectious (n=15: mainly viral). Other causes of death: GvHD (n=3), Cardiac ECI (n=2), VOD (n=2), DAH (n=1), unknown (n=1), Hurler (n=4). The majority of the “alive and engrafted” patients have a donor chimerism of >95% (91/111; 82%), 11/111 (9,9%) between 75–95%, 6/111 (5,4%) between 50–75% and 3/111 (2.7%) between 10–50%. In summary, no stem cell source (BM, cordblood and PBSC) is superior and no conditioning regimen used is superior. RIC and TCD results in inferior engraftment rates. Second HSCTs are successful in more than 80%. Relatively low morbidity rates are seen. The engraftment of HSCT for HS can be optimized by avoiding T-cell depletion, RIC and probably by busulfan-targeting.

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Risk Factors for Acute Graft-Versus-Host Disease (GvHD) after Related Donor HLA-Matched Myeloablative Allogeneic Hematopoietic Stem Cell Transplantation (HSCT) for Adult Leukemia: Identification of Modifiable and Non-Modifiable Factors. A CIBMTR Study.

Blood ◽

10.1182/blood.v110.11.1069.1069 ◽

2007 ◽

Vol 110 (11) ◽

pp. 1069-1069

Author(s):

Theresa Hahn ◽

Philip L. McCarthy ◽

Dan Wang ◽

Mei-Jie Zhang ◽

Mukta Aurora ◽

...

Keyword(s):

Risk Factors ◽

Stem Cell ◽

Univariate Analysis ◽

Conditioning Regimen ◽

Modifiable Risk Factors ◽

Graft Versus Host ◽

Stem Cell Source ◽

Cell Source ◽

Grade Ii ◽

Cmv Status

Abstract Allogeneic HSCT is a curative therapy for leukemia and other hematologic malignancies and disorders. Acute Graft-versus-Host Disease (aGvHD) is a significant cause of morbidity and mortality that limits the success of HSCT. No large analysis of this complication has been recently performed. Risk factors for aGvHD after HLA-matched sibling myeloablative unmanipulated HSCT were analyzed in 1960 adult (≥18 yrs) patients treated for AML (n=761), ALL (n=303), or CML (n=896) and reported to the CIBMTR registry from 1995–2002 by 226 centers worldwide. All patients received cyclosporine+methotrexate (CSA+MTX) alone (85%) or CSA+MTX+other agents (15%) for aGvHD prophylaxis. 635 (32%) patients developed grade II-IV aGvHD before day +100 post–HSCT. Outcome was measured as time from HSCT to onset of aGvHD Grade II-IV with death as a competing risk. Statistically significant risk factors for aGvHD in the univariate analysis were: Age ≥ 40 vs < 40 at HSCT, RR (95% CI, P) =1.35 (1.16–1.58, P=0.0001); Race, White/Black vs. Asian/Hispanic, RR=1.65 (1.31–2.08, P<0.0001); Recipient Gender, Female vs Male RR=0.83 (0.71–0.98, P=0.025); Stem Cell Source, Peripheral Blood (PB) vs. Bone Marrow (BM), RR=0.76 (0.65–0.89, P=0.0008); Disease, CML vs. AML, RR=1.26 (1.06–1.5, P=0.008), and ALL vs AML, RR=1.12 (0.88–1.42, P=0.37); Disease Status at HSCT, Not in Remission vs. Remission, RR=1.29 (1.03–1.62, P=0.029); Conditioning Regimen, CyTBI vs. BuCy, RR=1.39 (1.18–1.62, P<0.0001); KPS at HSCT, ≤ 80 vs > 80, RR=1.34 (1.12–1.60, P=0.0016); and Donor ever Pregnant, Yes vs No/Male, RR=1.21 (1.10–1.43, P=0.034). Other factors not significant in the univariate analysis were year of HSCT (1995–1998 vs. 1999–2002), recipient/donor sex-matching, time from diagnosis to HSCT, recipient/donor CMV status, donor gender, ABO compatibility, and planned G-CSF use post-HSCT. Multivariate analysis of time to onset of aGvHD Grade II-IV was performed by using a Cox proportional hazards model with backwards step-wise selection and P > 0.05 to remove each clinical factor from the model. Significant independent predictors of aGvHD Grade II-IV risk were: Conditioning Regimen, CyTBI vs BuCy, RR (95% CI, P) RR=1.4, (1.2–1.7, P<0.0001); PB vs BM in Patients 18–39 yrs at HSCT, RR=1.4 (1.1–1.8, P=0.0023); Disease, CML vs. AML/ALL, RR=1.3 (1.1–1.6, P=0.0003); Race, White/Black vs. Asian/Hispanic, RR=1.5 (1.2–1.9, P=0.0003); KPS, ≤ 80 vs > 80, RR=1.3 (1.05–1.5, P=0.014) and recipient/donor CMV status, at least one + vs −/ −, RR=0.8 (0.7–0.99, P=0.04). For pts ≥ 40 yrs at BMT, PB was not an independent risk factor for aGvHD Grade II-IV. There are modifiable risk factors for aGvHD Grade II-IV which include conditioning regimen, stem cell source (in younger patients) and CMV negative donors for CMV negative recipients. There are non-modifiable risk factors such as recipient age, race and gender and underlying diagnosis. Identifying patients at high risk for aGvHD Grade II-IV may allow for individualized risk modification and result in altering treatment strategies.

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