Effect of Rituximab on the Incidence of GVHD in Lymphoma Patients who Received the BEAM-Conditioning and an Allogeneic Stem Cell Transplantation.

Abstract It has been postulated that B cells functioning as antigen-presenting cells may have an important role in the pathogenesis of GVHD. Depletion of donor cells from B-cells resulted in a low incidence of GVHD in mouse model (Schultz et al. BMT1995:16:289–289). More recently, we observed a lower incidence of chronic (and to a lesser extent acute GVHD) in patients with CLL who received an allogeneic stem cell transplantation after a non-myeloablative conditioning regimen containing rituximab (Exp Hematol32:28–35, 2004). The purpose of this study is to investigate the effect of rituximab on GVHD in the setting of a more intense chemotherapy with BEAM, in patients who received an allogeneic peripheral blood stem cell from HLA-identical siblings. To test this hypothesis, we retrospectively studied 11 consecutive patients with non-Hodgkin’s lymphoma who received BEAM/Rituximab at the M. D. Anderson Cancer Center. We attempted to match these patients by age, donor-recipient gender, and donor-recipient CMV reactivity to a historical control of 44 patients with lymphoma, who received BEAM alone as a conditioning regimen, without the Rituximab. Tacrolimus and methotrexate were used for GVHD prophylaxis in both groups. A total of 10 patients in the study group, could be matched with 19 patients in the control group and were included in the final analysis. The outcome of the 2 groups is shown below: Rituximab-Study Group Control Group -value P No. of patients 10 19 Median age 41 44 0.4 (range) (19–55) (19–60) Patient-Donor sex-matched 9(82%) 18(95%) 0.6 Median # CD34 + cells infused (106/kg) 5.1 4.73 0.1 Patient or Donor CMV+ 9(82%) 18(95%) 0.6 Patient and Donor CMV − 1(10%) 1(5%) Median # prior chemoregimens 3 3 0.9 range (1–8) (1–9) Median follow-up 17 38 range (8–48) (27–77) Acute GVHD 2–4 (n,%) 5(50%) 7(37%) 0.5 Acute GVHD 3–4 (n,%) 3(30%) 5(26%) 0.6 Chronic GVHD (n, % cumulative incidence) 8 (90% + 15) 10 (53% + 12 0.01 Our data suggest that the described protective effect of Rituximab against GVHD in mouse models or in the setting of non-myeloablative allogeneic transplantation, may be overcome by the BEAM. This more intense conditioning regimen may induce more GVHD by enhancing T-cell cytokines release and by causing more gastrointestinal toxicity, thus allowing for a greater antigen presentation.

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Ursodeoxycholic acid for the prevention of hepatic complications in allogeneic stem cell transplantation

Blood ◽

10.1182/blood-2001-12-0159 ◽

2002 ◽

Vol 100 (6) ◽

pp. 1977-1983 ◽

Cited By ~ 159

Author(s):

Tapani Ruutu ◽

Britta Eriksson ◽

Kari Remes ◽

Eeva Juvonen ◽

Liisa Volin ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Ursodeoxycholic Acid ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Treated Group ◽

Control Group ◽

To Receive

Abstract The role of ursodeoxycholic acid (UDCA) in the prevention of hepatic complications after allogeneic stem cell transplantation was studied in a prospective randomized open-label multicenter trial. A total of 242 patients were allocated to receive (n = 123) or not to receive (n = 119) UDCA in the dose of 12 mg/kg/d orally from the day preceding the conditioning until day 90 after transplantation. In the UDCA-treated group a significantly smaller proportion of patients developed a serum bilirubin level exceeding 50 μM (18 of 123 versus 31 of 119, P = .04), and similarly a smaller proportion of patients exceeded the alanine aminotransferase level of 100 U/L. There was no difference in the incidence of veno-occlusive disease of the liver. Compared to the control group, in the UDCA-treated group there was a nonsignificant trend toward a lower overall incidence of acute graft-versus-host disease (GVHD) and a significantly lower incidence of grade III to IV acute GVHD (5 of 123 versus 17 of 119,P = .01), stage II to IV liver and intestinal GVHD, and stage III to IV skin GVHD. There was no difference in the incidence of chronic GVHD or in the relapse rate. Among the patients given UDCA, the survival at 1 year was significantly better, 71% versus 55% (P = .02), and the nonrelapse mortality rate was lower, 19% versus 34% (P = .01), than in the control group. There were significantly more deaths in GVHD in the control group. In conclusion, UDCA administration reduced hepatic problems and severe acute GVHD and improved survival. These results suggest a role for UDCA in the prevention of transplant-related complications in allogeneic transplantation.

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Impact of Age on Hospitalization and Readmission on Post Allogeneic Stem Cell Transplantation Outcome, Single Center Experience

Blood ◽

10.1182/blood-2021-146275 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 4122-4122

Author(s):

Eshrak Al-Shaibani ◽

Shiyi Chen ◽

Wilson Lam ◽

Arjun Law ◽

Ivan Pasic ◽

...

Keyword(s):

Risk Factors ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Research Funding ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Hospitalization Period

Abstract Background: Recent advances and improvement of supportive care allowed allogeneic stem cell transplantation (HCT) to be offered to selected older patients. However, data regarding outcome and factors affecting the outcomes are limited. Method: We retrospective analyzed the outcome in 332 patients, median age 65 years (60-76), who underwent HLA-matched related (n=85), matched unrelated (n=205) and haploidentical donor (n=42) HCT, between January 2014 to December 2019. Of these 60% were male. Diagnosis was leukemia: 193, MDS: 76, MF: 46 and others: 17. Graft source was PBSC in 98%. Reduce-intensity conditioning regimen was used in 95%, and in vivo T-cell depleted in 89% of patients. We categorized them to 3 age-groups (G): G1 60-65y, (n=175), G2 >65-70y (n=127), and G3 >70y (n=30).Cox models were used to compare the rates of overall survival (OS), non-relapse mortality( NRM), event free-survival (EFS), length of hospitalization for HCT, GVHD and reasons of re-hospitalization during the first year post HCT. Results: The median follow up was 14 months (range: 1-123 months). Median days of hospitalization during HCT period were 30-days (range: 20-132 days), with trend towards significance when stratified by age group (p=0.049). HCT-CI scores were 0-1 (n=143), 2-3 (n=107) and >3 (n=70). The cumulative incidences of grade II-IV acute-GVHD was 38.3% and 16.3% for grades III-IV. Moderate-severe chronic-GVHD was 23.7%. Increasing age was not associated with increases in acute GVHD (p=0.86) or chronic-GVHD (p= 0.6). Overall, 188 (56%) patients were re-hospitalized within the first 6-month of HCT, and 61 (18%) in the second 6-month period. The 2-year OS rate (Fig 1) were 56% in G1, 53% in G2 and 34% in G3 (p=0.05). The 2-year EFS rate (Fig 2) were 54% for G1, 49% for G2, and 31% for G3 (P=0.04). Cumulative incidence of NRM at 2-year (Fig 3) were 25% in G1, 36% in G2 and 52% in G3 (p=0.008). Further results are illustrated in Table 1. Risk factors such as age, KPS, HCT-CI, donor-type, readmission and GVHD were analyzed for their associations with outcomes using univariate analyses, those with significant results entered in multivariate-analysis Table 2. Patients aged 60-≤65 had significantly better EFS (p=0.04) and associated with a border line significant trend for lower NRM (p=0.05) than those aged >70. Re-admission in the first 6-month post HCT had a significant impact on the OS, EFS and NRM. HCT-CI >3 had significant impact on NRM. Conclusion: Age had a significant impact on hospitalization period during HCT. Age >70 had significant impact on EFS and trend toward higher NRM. HCT-CI, acute and chronic-GVHD and readmission in first 6-month post-HCT were significant risk factors. Readmission in the first 6 months correlated with lower OS, EFS and higher NRM. Acute GVHD III-IV or moderate-severe chronic GVHD associated with poor outcomes. Selecting patients based on HCT-CI, and good management of GVHD and post-HCT complication may improve the clinical outcome. Figure 1 Figure 1. Disclosures Law: Novartis: Consultancy; Actinium Pharmaceuticals: Research Funding. Kim: Bristol-Meier Squibb: Research Funding; Pfizer: Honoraria; Paladin: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding. Lipton: Bristol Myers Squibb, Ariad, Pfizer, Novartis: Consultancy, Research Funding.

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Non-Myeloablative Allogeneic Stem Cell Transplantation in 154 Patients (pts) with Chronic Myeloid Leukaemia (CML).

Blood ◽

10.1182/blood.v110.11.4975.4975 ◽

2007 ◽

Vol 110 (11) ◽

pp. 4975-4975

Author(s):

Malek Benakli ◽

Rose-Marie Hamladji ◽

Redhouane Ahmed Nacer ◽

Amina Talbi ◽

Farih Mehdid ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Median Time ◽

Allogeneic Stem Cell Transplantation ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Chronic Phase ◽

Transfusion Requirements

Abstract Background: Allogeneic stem cell transplantation using a reduced intensity or nonmyeloablative conditioning (NSCT) represents an attractive treatment modality in CML. The rationale behind such approach is to decrease toxicity while inducing the graft-versus-leukemia (GVL) effect. Because of its significantly lower cost in comparison to Imatinib mesylate, NSCT may be considered an early treatment option in countries where limited resources. Material and Methods: Between April 2001 and December 2006, we treated 154 CML patients (131 in first chronic phase, 23 in accelerated phase) with NSCT from an HLA-identical family donor. The majority of pts has a Gratwohl score <2 prior to NSCT (n=115; 74,6%). The conditioning regimen included Fludarabine 150 mg/m2 and oral Busulfan 8 mg /kg (139 pts). GVHD prophylaxis consisted of association ciclosporine (CSA)-Mycophenolate (MMF). 15 pts received an additional prophylaxis with antithymocyte globulin (ATG). Median age was 35 (range, 18–55) years, and the sex-ratio (M/F) 0,87. The median time from diagnosis to NSCT was 11 (range, 4–50) months. All pts received G-CSF mobilised peripheral blood stem cells, median CD34+ cells count: 7,02.106/kg (range, 1,28–44,9). Results: Leucopenia is found almost at 71 pts (46,1%). The median time to achieve ANC >500. 109/l granulocytes was 14 (range, 7–24) days, and median time of aplasia was 7 (range, 2–19) days. Transfusion requirements were significantly reduced, only 3 pts (1,9%) required red blood cells transfusions. Only 15 pts (9,7%) needed platelets transfusions. Acute GVHD was seen in 65 cases (43,6%) including 26 (17,4%) cases of grade III–IV and 32 cases (21%) of late onset acute GVHD occurring after day 100 post-NSCT. 93 pts (67,3%) had chronic GVHD, of whom 58 with an extensive form. 23 pts (15,4%) had CMV reactivation. 24 pts (16,1%) relapsed (15 in chronic phase, 7 in blast crisis and 2 with a molecular relapse), but 11 pts could be salvaged and are currently in remission (7 after immunosupression discontinuation, one after DLI and 3 after a second conventional allograft). The chimerism of donor origin (STR-PCR method) of patients in remission was at an average of 74% at day 30, 80% at d100, 93% at 6 months, 97% at 1 year, and 99% at 2 years. Fifty pts (33,5%) have died, of whom 39 (22,1%) from GVHD and 10 (6,7%) from disease relapse. Transplant Related Mortality (TRM) at 100 days was 6%, but rose to 31,5% at 3 years. At last follow-up (median, 32 (range 6–68) months), 99 pts (66,4%) are still alive, 97 (65,1%) pts in hematologic remission; of whom 76 (78,3%) in complete molecular remission evaluated by RT-PCR. Overall survival and progression-free survival at 5 years are 61% and 51,6% respectively. Conclusion. The study demonstrates a relatively low rate of short-term toxicities after NSCT. However, long-term TRM is still high because of the GVHD. The GVL effect is well admited. The relapse can be often controled by immunomodulation (stoppage of immunosuppression, DLI) and eventually by second myeloablative allograft.

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Sirolimus and Thrombotic Microangiopathy after Allogeneic Stem Cell Transplantation.

Blood ◽

10.1182/blood.v104.11.1834.1834 ◽

2004 ◽

Vol 104 (11) ◽

pp. 1834-1834 ◽

Cited By ~ 1

Author(s):

N. Lynn Henry ◽

Shuli Li ◽

Haesook T. Kim ◽

Colm Magee ◽

Edwin Alyea ◽

...

Keyword(s):

Overall Survival ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Thrombotic Microangiopathy ◽

Simultaneous Occurrence ◽

Control Group ◽

Study Group ◽

Gvhd Prophylaxis

Abstract Sirolimus (SRL) is a novel immunosuppressive agent that has been demonstrated to reduce GVHD and minimize morbidity after allogeneic stem cell transplantation (alloSCT). We have described a syndrome of thrombotic microangiopathy (TMA), characterized by microangiopathic hemolysis, thrombocytopenia, and renal dysfunction, whose incidence is increased when SRL is used in association with calcineurin inhibitors (CIs) but not with SRL monotherapy. To determine if SRL use potentiates the effects of CIs on TMA incidence and risk factors, we performed a retrospective cohort analysis of subjects who underwent alloSCT between 1997 and 2003. Methods: Subjects who received a SRL-containing GVHD prophylaxis after a myeloablative preparative regimen were compared with a cohort who received a non-SRL regimen. All subjects received CIs. Diagnosis of TMA required the simultaneous occurrence of: (1) creatinine elevation >2 mg/dL or >50% above baseline, (2) schistocytosis, (3) elevated LDH, and (4) no laboratory evidence of disseminated intravascular coagulopathy. Results: 111 patients who received SRL were compared with 216 patients who received no SRL during the first 100 days after alloSCT. The two groups of patients were balanced for demographic parameters; however, more patients in the SRL group received peripheral blood stem cells (50.5 vs. 18.1%, p<0.01) and had unrelated donors (58.6 vs. 42.6%, p<0.01). The incidence of TMA in the SRL group was 10.8% in comparison with an incidence of 4.2% in the non-SRL group (OR 2.57, p=0.03). Patients who received SRL developed TMA earlier than those who did not receive SRL (median 25 vs. 58 days, p=0.04). At the time of TMA diagnosis, median blood levels of immunosuppressive medications were in their respective therapeutic ranges: SRL (study group) 6.1 ng/ml, tacrolimus (study group) 9.9 ng/ml, tacrolimus (control group) 9.1 ng/ml; cyclosporine (control group) 418 ng/ml. In a multivariable logistic regression model, only the use of SRL (Adjusted Exact OR 3.49, p =0.02) and grade II-IV acute GVHD (Adjusted Exact OR 6.60, p = 0.0002) predicted the occurrence of TMA. Treatment of TMA consisted of discontinuation or dose adjustment of CIs. SRL was discontinued or dosed according to serum level. Two subjects in each group required temporary hemodialysis, and 3 subjects (1 SRL, 2 non-SRL) underwent plasmapheresis. 78% of surviving SRL-treated subjects regained normal renal function. No subject had a TMA recurrence if SRL was reintroduced. Overall survival after TMA diagnosis was better for SRL patients than non-SRL patients (58.3 vs. 11.1%, log rank p=0.02). Conclusion: SRL use is associated with an increased risk of TMA after alloSCT and may act by potentiating the effects of CIs. TMA associated with SRL appears reversible and does not affect overall survival after alloSCT. A careful monitoring strategy for TMA should be employed as part of a SRL-containing GVHD prophylaxis regimen.

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Durable Remission after Prophylactic Donor Lymphocyte Transfusion Following Allogeneic Stem Cell Transplantation with Reduced Conditioning for High-Risk AML and MDS.

Blood ◽

10.1182/blood.v104.11.299.299 ◽

2004 ◽

Vol 104 (11) ◽

pp. 299-299

Author(s):

Michael Schleuning ◽

Christoph Schmid ◽

Georg Ledderose ◽

Johanna Tischer ◽

Meike Humann ◽

...

Keyword(s):

Stem Cell ◽

High Risk ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Acute Gvhd ◽

Chronic Gvhd ◽

Allogeneic Transplantation ◽

Chronic Infections ◽

Term Survival

Abstract Prophylactic transfusion of donor lymphocytes (pDLT) is an attractive form of maintenance therapy after allogeneic stem cell transplantation in patients with high risk of relapse. However, clinical experience is limited, and disease response is often achieved at the expense of severe graft-versus-host disease (GvHD). We here report our data on pDLT in high-risk AML and MDS. Cells were given within a prospective protocol that contained a sequence of chemotherapy, reduced intensity conditioning for allogeneic transplantation, and pDLT (FLAMSA-regimen). For pDLT, patients had to be in CR at least 120 days from transplantation, off immunosuppression for 30 days, and free of GvHD. 22/86 patients alive at day +120 fulfilled the criteria for pDLT. They had been transplanted for refractory or relapsed leukemia (n=9 each) or in CR1 because of unfavorable cytogenetics (n=4). 14 patients had an unfavorable karyotype, 8 with complex aberrations. Reasons for withholding pDLT in 64 patients included cGvHD or prolonged immunosuppression (n=38), refractory or relapsed leukemia (n=15), refusal of patient or donor (n=4 each), a history of grade IV acute GvHD (n=2), and chronic infections (n=3). The median time from transplant to first pDLT was 167 days (range 120–297). Median follow up of transfused patients is 696 days (range 209–1341). Ten patients received 1, 6 patients received 2, and 6 patients received 3 transfusions in escalating doses, containing a median of 1x106, 5x106 and 1x107 CD3+ cells/kg at pDLT 1, 2 and 3, respectively. Reasons for giving less than 3 transfusions were GvHD, relapse or refusal of the patient. Induction of GvHD was the main complication; grade III acute GvHD developed in 1, and chronic GvHD in 7 patients. So far, 5 patients have relapsed despite pDLT. One died of refractory leukemia, whereas 2 achieved secondary CR following adoptive immunotherapy. Two patients are currently under treatment. At present, 18/22 patients are alive and in CR at a median of 423 days post DLT. The current leukemia free survival at two years from first pDLT is 79%. Nineteen patients were complete chimeras at time of pDLT. pDLT converted mixed into complete bone marrow chimerism in 1, but failed in 2 cases. In our experience, pDLT is safe after allogeneic transplantation for high risk AML, when given at low doses and to a selected group of patients. Results are encouraging, and long term survival can be achieved. However, further studies need to define more precisely the contribution of pDLT to the therapeutic effect of the entire procedure.

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No Direct Effect of NOD2/CARD15 Variants On Clinical Outcome After Non-Myeloablative Allogeneic Stem Cell Transplantation.

Blood ◽

10.1182/blood.v114.22.4322.4322 ◽

2009 ◽

Vol 114 (22) ◽

pp. 4322-4322

Author(s):

Hanneke M. van der Straaten ◽

Martine M. Paquay ◽

Marcel G.J. Tilanus ◽

Leo F. Verdonck ◽

Cynthia Huisman

Keyword(s):

Stem Cell ◽

Clinical Outcome ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Haematopoietic Stem Cell ◽

Significant Prognostic Factor ◽

Wild Type

Abstract Abstract 4322 Background Single nucleotide polymorphisms (SNPs) in the innate immunity receptor NOD2/CARD15 have been demonstrated to modulate the outcome of allogeneic haematopoietic stem cell transplantation. The effect of the NOD2/CARD15 polymorphism seems to be associated with donor source as well as type of conditioning regimen. Methods We reviewed NOD2/CARD15 mutations in all donor/recipient pairs of 192 consecutive patients who received non-myeloablative allogeneic stem cell transplantation(SCT) at our institution between 2002 and 2006. All patients were treated uniformly with fludarabine 30 mg/m2/day for 3 days followed by 200 cGy TBI (n=154) or TBI alone (n=38) and received grafts from HLA-matched related (n=132) or unrelated (n=60) donors. Results Mutated alleles were observed in 36 of 192 (19%) patients and in 35 of 192 (18%) donors. These SNPs, however, did not have a significant impact on clinical outcome data (P > 0.05, Kaplan Meier and Fine & Gray's test). Acute graft-versus-host disease (GVHD) occurred in 24 of 61 (39%) patients with the polymorphism and in 66 of 131 (50%) patients without the polymorphism. Chronic GVHD developed in 28 of 55 (51%) patients with SNP pairs and in 79 of 121 (65%) patients with the wild type. The incidence of transplant-related mortality was 21% in both groups, 13 of 61 patients in the group with the polymorphism and 27 of 131 without the polymorphism. Relapse was seen in 23 of 61 (38%) patients with the SNP pairs and in 48 of 131 (37%) wild type patients. Finally, overall survival was 43% (26/61) in patients with the polymorphism and 39% (51/131) in patients without the polymorphism. Conclusion These data indicate that mutations in the NOD2/CARD15 genes do not influence the clinical outcome of non-myeloablative allogeneic SCT directly. Since NOD2/CARD15 variants are not recognized as a single significant prognostic factor, screening for NOD2/CARD15 when selecting a donor does not seem to have additional value in patients undergoing non-myeloablative SCT. Disclosures: No relevant conflicts of interest to declare.

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High-Dose Rituximab in the Conditioning Regimen Before Allogeneic Stem Cell Transplantation Reduces the Incidence of Acute Gvhd in B-Cell Lymphomas

Blood ◽

10.1182/blood.v118.21.4546.4546 ◽

2011 ◽

Vol 118 (21) ◽

pp. 4546-4546

Author(s):

Paolo Corradini ◽

Barbara Sarina ◽

Cristiana Carniti ◽

Francesca Patriarca ◽

Angelo Michele Carella ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

B Cell ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Immune Reconstitution ◽

Acute Gvhd ◽

Chronic Gvhd ◽

High Dose ◽

Unrelated Donors

Abstract Abstract 4546 Background: Reduced-intensity conditioning (RIC) followed by allogeneic stem cell transplantation (alloSCT) is an effective salvage therapy for relapsed lymphomas. The present GITMO study is a prospective multicenter phase II trial for patients affected by relapsed CD20 positive lymphomas. Compared with the previous thiotepa/fludarabine/cyclophosphamide GITMO protocol (Leukemia 2007), the thiotepa dose is increased, and high-dose Rituximab is included in the regimen to improve the outcome and possibly modulate the incidence of acute GVHD. Aims: Primary end-point was 1-year progression-free survival; secondary endpoints were non-relapse mortality and incidence of acute and chronic GVHD. Methods: Fifty-seven patients (pts) were enrolled so far in the study and 49 are evaluable for analysis. Treatment plan consisted of high-dose R (500 mg/ms on day -6) followed by thiotepa (12 mg/kg), fludarabine (60 mg/kg) and cyclophosphamide (60 mg/kg). Graft-versus-host disease (GVHD) prophylaxis included cyclosporine and mini-methotrexate; ATG (7.5 mk/kg) was only added for pts allografted from one antigen mismatched sibling or unrelated donors. Histopathological subtypes included 24 aggressive (HG) (n= 17 diffuse large B-cell lymphomas, n= 7 mantle cell lymphomas) and 25 indolent lymphomas (LG) (n= 13 follicular lymphomas, n= 12 small lymphocytic/chronic lymphocytic leukemia). Patients were allografted from related siblings (SIB) (n= 32 matched, n=1 one single mismatched) or unrelated donors (UD) (n=11 matched, n=5 mismatched). All the pts had chemosensitive disease (n=20, 41% in complete remission) and 26 (53%) came from a failed autoSCT. Results: At a median follow-up of 13 months (range, 5–44 months), 36 pts are alive [n=27 (75%) in CR] and 13 died from any cause [n=6 for non-relapse mortality (NRM), n=7 for disease progression]. All the patients engrafted (94% had full donor chimerism at 3 months). The cumulative incidence (CI) of NRM was 13% at 1 year: 9% vs 19% for SIB and MUD (p=0.3), and 9% versus 16% for for LG and HG (p=0.3), respectively. In total only 11 of 49 pts had acute GVHD (n=8 grade II, n=3 grade III) with an estimated CI of 21% at 100 days. In the previous GITMO study the incidence was 35% with SIB only. Forty pts are evaluable for chronic GVHD with an estimated CI of 41% and 47% at 1 and 2 year, respectively (n=11 limited, n=3 extensive). Infections after engraftment requiring hospitalization or intravenous treatment were evaluable in 46 pts (n=3 excluded for early death). The overall incidence of infections was 58% (n=27) including 5 pts experienced sepsis and 10 pts pneumonia. Preliminary data on immune-reconstitution at 1 year showed: 1) low number of circulating B cells (median CD19+/ul: 129/ul) with an expansion of naive cells (IgD+, CD27-); 2) the median value of IgM was 89 mg/dl whereas IgG and IgA remained at low levels. The CI of relapse was 26% and 37% at 1 year and 2 years, respectively. In the indolent and aggressive groups, OS estimates at 2 years were 79% (95%CI, 52%-91%) and 61% (95 CI, 38%-77%) and PFS estimates were 53% (95%CI, 23%-76%) and 48% (95% CI, 27%-66%), respectively. Conclusions: The present data suggest that the administration of high-dose R is feasible and causes an unexpected reduction of the incidence of acute GVHD without increasing the NRM and the incidence of severe infections complications. Complete data evaluating the effects of R on immune reconstitution are ongoing. Disclosures: No relevant conflicts of interest to declare.

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Allogeneic Stem Cell Transplantation For Patients With Adrenoleukodystrophy. Nationwide Retrospective Study In Japan

Blood ◽

10.1182/blood.v122.21.2148.2148 ◽

2013 ◽

Vol 122 (21) ◽

pp. 2148-2148

Author(s):

Koji Kato ◽

Hiromasa Yabe ◽

Shunichi Kato ◽

Souichi Adachi ◽

Yoshiko Hashii ◽

...

Keyword(s):

Bone Marrow ◽

Stem Cell ◽

Stem Cell Transplantation ◽

Cord Blood ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Low Dose ◽

Chronic Gvhd ◽

Conditioning Regimen ◽

Transplant Outcome

Abstract Introduction Adrenoleukodystrophy (ALD) is an autosomal recessive disorder with progressive neurodegeneration caused by the mutation of ABCD1 gene and allogeneic stem cell transplantation (SCT) at its early stage is recognized as the only effective treatment modality to control the neurological symptoms. But the transplant outcome according to the conditioning regimen is not well understood so far. Here we analyzed the transplant outcome of patients with ALD using the clinical data accumulated in the Japan Society of Hematopoietic Cell Transplantation and tried to find the favorable conditioning regimen. Methods From 1988 to 2010, 76 patients with ALD were transplanted and their age at transplant was 1-34 years old (median 8). Stem cell sources the patients received were bone marrow (sibling 26, non-sibling related donor 5, unrelated volunteer donor 17), and cord blood (sibling 1, unrelated 28). Conditioning regimen was classified into four categories of A: busulfan + cyclophosphamide +/- others, (n=25), B: melphalan + total lymphoid irradiation (TLI) / thoraco-abdominal irradiation (TAI) +/- fludarabine +/- anti-thymocyte globulin (n=23), C: fludarabine + melphalan +low dose total body irradiation (TBI) (n=18), and D: others (n=10). Results Sustained engraftment was obtained in 59 patients (77.8%) and it was significantly higher in bone marrow transplant (BMT) patients than cord blood transplant (CBT) patients (87.8% vs 60.7%, P=0.001). The incidence of acute graft-versus-host disease (GVHD), chronic GVHD and treatment related mortality of all patients were 7.9%, 19.3%, and 11.9%, respectively. Ten year overall survival (OS) and event free survival (EFS) of all patients were 83.7% and 64.1%, respectively. Ten patients died of either disease progression (n=2), or transplant related complications (n=8). Five year OS and EFS according to the conditioning regimen was A: 91.6% and 75.8%, B: 85.7% and 60.9%, C: 100% and 83.3%, D: 77.8% and 48.0%, respectively and they were not significant (P=0.379 in OS and P=0.183 in EFS, respectively). TBI was given to 22 patients with median dose of 4Gy (range 2-10.2) and sustained engraftment was obtained in 19 patients and all of 22 patients are alive. In patients who were not given TBI (n=54), 41 patients obtained engraftment and 44 patients are alive. OS according to presence or absence of TBI was 100% with TBI (n=22) and 86.1% without TBI (n=54) (P=0.091). By multivariate analysis for EFS, BMT and TBI were identified as good prognostic factors compared to CBT or non-TBI (HR 3.303, P=0.005, and HR 3.257, P=0.038, respectively), but OS of CBT was improved after 2005 compared to before 2004 (94.7% vs 68.6%, P=0.090). Conclusion Our results showed that conditioning regimen which includes TBI, even at low dose could provide better transplant outcome and the result of CBT improved after 2005 even though it was proved to be a significantly poor risk factor in the analysis of entire cohort. CBT enables urgent SCT when family donor is not available, and immediate transplant is essential for patients with ALD because of its nature. More precise assessment with brain MRI and neuropsychological examination is mandatory to evaluate the transplant outcomes of patients with ALD. Disclosures: No relevant conflicts of interest to declare.

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The role of B cells in the pathogenesis of graft-versus-host disease

Blood ◽

10.1182/blood-2008-10-161638 ◽

2009 ◽

Vol 114 (24) ◽

pp. 4919-4927 ◽

Cited By ~ 183

Author(s):

Alexander Shimabukuro-Vornhagen ◽

Michael J. Hallek ◽

Rainer F. Storb ◽

Michael S. von Bergwelt-Baildon

Keyword(s):

T Cells ◽

Stem Cell ◽

B Cells ◽

Stem Cell Transplantation ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Chronic Gvhd ◽

Graft Versus Host Reaction ◽

Hematopoietic Stem ◽

Graft Versus Host

Abstract Allogeneic hematopoietic stem cell transplantation is an established treatment modality for malignant and nonmalignant hematologic diseases. Acute and chronic graft-versus-host diseases (GVHDs) are a major cause of morbidity and mortality after allogeneic stem cell transplantation. T cells have been identified as key players in the graft-versus-host reaction and, therefore, most established drugs used against GVHD target T cells. Despite our knowledge on the pathogenesis of the GVH reaction, success of established therapies for prevention and treatment of GHVD is unsatisfactory. Recently, animal and human studies demonstrated that B cells are involved in the immunopathophysiology of acute and chronic GVHD. Early phase clinical trials of B-cell depletion with rituximab have shown beneficial effects on both acute and chronic GVHD. This review summarizes the current experimental and clinical evidence for the involvement of B cells in the pathogenesis of acute and chronic GVHD and discusses the clinical implications for the management of patients undergoing allogeneic stem cell transplantation.

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Reduced intensity allogeneic stem cell transplantation in patients with myelodysplastic syndrome: Does the conditioning matter? A retrospective study of the SFGM-TC on 61 patients

Journal of Clinical Oncology ◽

10.1200/jco.2006.24.18_suppl.6547 ◽

2006 ◽

Vol 24 (18_suppl) ◽

pp. 6547-6547

Author(s):

L. Terriou ◽

Z. Chir ◽

H. Esperou ◽

J. Boiron ◽

N. Gratecos ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

Myelodysplastic Syndrome ◽

Cell Transplantation ◽

Allogeneic Stem Cell Transplantation ◽

Chronic Gvhd ◽

Immunosuppressive Treatment ◽

Conditioning Regimen ◽

The Impact ◽

Reduced Intensity

6547 Background: Reduced-intensity allogeneic stem cell transplantation (RIT) has emerged as an alternative to myeloablative transplantation in pts with myelodysplastic syndrome (MDS). Given the uncertainty regarding the appropriate conditioning, SFGM-TC conducted a retrospective multicenter study with the attempt to evaluate the impact of conditioning on pts’ outcome. Methods: The record of 61 pts (37 males) with MDS who received a RIT between 1998 and 2003, from 22 French transplantation centres, were reviewed. According to the FAB classification, 11 pts had RA at diagnosis, of whom one had progressed to REAB and one to AML before transplantation. Thirty-two pts had REAB, of whom 2 had progressed to REAB-T and 7 to AML. Twelve pts had REAB-T and 6 CMML, of whom 8 progressed to AML. The median time from diagnosis to RIT was 12 months (6–129). Conditioning regimen consisted of fludarabin (Flu) plus busulfan ( n=29), Flu plus 2-Gy TBI ( n=20) and idarubicin plus aracytine and Flu (n=12). Donors were HLA-identical siblings (n=52) and HLA-matched unrelated (n=9). All pts received peripheral blood stem cells. The median of CD34+ infused cell dose was 5 × 106/kg (0.5–17.3). Results: At the reference date of 1 July 2005, median follow-up was 44.7 months (21–85). Estimated 3-year overall survival (OS), progression free survival (PFS), relapse and transplant-relapse mortality (TRM) were 35%, 27%, 66% and 30%, respectively. Neither of the 3 conditioning regimens used had impact on pts’ outcome. In multivariable analyses, while acute III/IV grade GVHD development was the only factor found to adversely influencing OS (HR=3.6; 95% CI: 1.1–12.2), chronic GVHD development was the only favourably influencing PFS and relapse ratios (HR=0.3; 95% CI: 0.1–0.7 and HR=0.2; 95% CI: 0.1–0.6, respectively). TRM was adversely influenced by male sex of pt (HR=9.2; 95% CI: 1.5–66.6). Conclusions: RIT seems to be an effective treatment in MDS pts irrespective of conditioning type. While acute III/IV grade GVHD appeared to be detrimental, the benefit effect of chronic GVHD was to be bound to GVL effect. New approaches with focus on immunosuppressive treatment are needed to enhance the GVL effect with an acceptable risk of GVHD. No significant financial relationships to disclose.

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