Reduced Intensity Conditioning Therapy Using Campath -1H Is Successful for Stem Cell Transplantation in Non-Malignant Disorders.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1823-1823 ◽  
Author(s):  
Aarati Rao ◽  
Robert Hayashi ◽  
William Grossman ◽  
David Wilson ◽  
Lolie Yu ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Immune Suppression ◽  
Viral Infections ◽  
Normal Pregnancy ◽  
Promising Alternative ◽  
Cd8 Cells ◽  
Post Transplant ◽  
Cell Sources

Abstract Stem cell transplantation (SCT), indicated for many non-malignant disorders, is limited by donor availability, graft rejection (GR), toxicities of conditioning, morbidity and mortality (TRM), and graft versus host disease (GVHD). To overcome these barriers, we tested a novel conditioning for SCT. It was designed to support engraftment by deleting host immune reactive lymphocytes and macrophages. Campath -1H (anti-CD52 mab) was given on days -21, -20, and -19 (total dose 48 mg), fludarabine (day -8 to -4) (total 150 mg/m2) and melphalan on day -3 (140 [n=15] or 70 [n=1] mg/m2). Stem cell sources were related/unrelated bone marrow (BM) (8), peripheral blood (PB) (5) and umbilical cord blood (UCB) (3). GVHD prophylaxis was cyclosporine (tapered after 3 months), methylprednisone (tapered after day +28) and methotrexate on days +1, +3, and +6. Methotrxate was not used in UCBT. End points of the study included engraftment and TRM. Sixteen patients (1.5–40 yrs) diagnosed with aplastic anemia (5), Hurler’s (2), sickle cell anemia, XLAAD, histiocytosis (3), thalassemia, adrenoleukodystrophy, Evan’s syndrome and dyserythropoietic anemia were transplanted. Median follow-up was 219 days (66–845). The regimen was well tolerated. All patients that survived >1 month engrafted. Neutrophils (ANC >500/dL) engrafted at a median of 12.5 (10–36) days and platelets (>50,000/dL) at a median of 21 (12 –63) days. Skin GVHD developed in 3 patients and resolved early. Four are tapering immune suppression; 8 are successfully off immune suppression. All survivors have either stable disease or are cured. One recipient had a normal pregnancy and delivered twins. Two patients died prior to engraftment from previously acquired Pseudomonas infection. A third patient died of CMV disease (day +112) and another recipient died of intracranial hemorrhage/refractory thrombocytopenia (day +43) after engraftment. Other complications were bacterial and viral infections occurring within the first 100 days post-transplant. All but 1 CMV+ recipient reactivated CMV as assessed by PCR. Profound lymphopenia was present in all recipients on day +30. NK cells recovered by day +100, CD8+ cells by day +180, CD4+ and B cells between days 180–270 after transplant. Immunoglobulin (Ig M and A) levels dropped post transplant and normalized by 9 months. Ig A recovered later than IgM. In summary, successful engraftment despite varied stem cell sources, was achieved without significant toxicity or GVHD. Lymphopenia resulted in a significant infection risk within the first 100 days post transplant, requiring close surveillance and early intervention. This transplant regimen is well tolerated and may preserve fertility, making it a promising alternative to conventional SCT.

Reduced-intensity allogeneic stem cell transplantation for diffuse large B-cell lymphoma: Clinical evidence of a graft-versus-lymphoma effect

2006 ◽  
Vol 24 (18_suppl) ◽  
pp. 6546-6546
Author(s):  
M. R. Bishop ◽  
R. M. Dean ◽  
S. Steinberg ◽  
J. Odom ◽  
S. Z. Pavletic ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
B Cell ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Immune Suppression ◽  
B Cell Lymphoma ◽  
Post Transplant ◽  
Large B Cell ◽  
Reduced Intensity

6546 Background: Despite being the most common non-Hodgkin’s lymphoma, there have been no specific reports on the use of reduced-intensity (RI) allogeneic stem cell transplantation (alloSCT) to treat patients (pts) with diffuse large B-cell lymphomas (DBCL). This may be due to a lack of definitive evidence for a therapeutic graft-versus-lymphoma (GVL) effect against DLBC. We undertook a retrospective analysis to assess clinical outcomes and evidence of a GVL effect in DLBC pts undergoing RI alloSCT. Methods: The analysis was limited to 18 pts with primary refractory (n = 6) or relapsed (n = 12) DLBC. The median age was 43 years (range: 31–61); median number of previous treatments was 3 (range: 2–9). Nine (50%) pts had undergone autologous transplantation. Three (16%) pts were determined to have chemo-sensitive disease to last treatment prior to RI alloSCT. All pts received a RI conditioning regimen consisting of fludarabine (30 mg/m2/d × 4d) and cyclophosphamide (1200 mg/m2/d × 4d) followed by a T-cell replete allograft from HLA-matched siblings. Results: Median potential follow-up from transplant is 43 months. Seven (39%) pts developed grade II-IV acute GVHD. Response at day +100 post-transplant was as follows: complete response (CR/CRu) = 5; partial response = 5; progressive disease = 8. Nine of 17 (53%) evaluable pts developed chronic GVHD. Median progression-free survival (PFS) was 4.8 months; however, PFS after 9 months post-transplant was 31% with 5 pts in continuous CR/CRu > 12 months post-transplant. Among 14 pts who were not in CR/CRu (n = 12) or progressed after achieving a CR/CRu (n = 2) at day +100 post-transplant, 8 (57%) subsequently achieved a CR/CRu after removal of immune suppression and/or donor lymphocyte infusion (DLI) ± chemotherapy. Seven of these 8 pts remain in continuous (median = 34 months; range: 6–55+) CR/CRu without further treatment. Median survival for all 18 pts was 19 months with survival probability of 40% plateauing at 25 months post-transplant. Conclusions: The clinical observations of sustained CR/CRu after withdrawal of immune suppression and DLI suggest that a GVL effect exists against DLBC. RI alloSCT should be considered as a treatment option for pts with primary refractory and relapsed DLBC. No significant financial relationships to disclose.

Reconstitution of Lymphocyte Subsets and Outcomes After Matched and Mismatched Hematopoietic Stem-Cell Transplantation

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4485-4485
Author(s):  
Antonio Di Stasi ◽  
Michelle Poon ◽  
Amir Hamdi ◽  
Hila Shaim ◽  
Susan Xie ◽  
...  
Keyword(s):  
Stem Cell ◽  
T Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Lymphocyte Subsets ◽  
T Cell Subsets ◽  
Cell Recovery ◽  
Cd8 Cells ◽  
Post Transplant

Abstract Abstract 4485 Allogeneic stem-cell transplantation (ASCT) is curative for many malignant and nonmalignant hematological disorders. Limitations of expanding this form of treatment are related primarily to non-relapse mortality (NRM) associated with reconstituting the recipient's immune system. We aimed to study reconstitution of lymphocyte subsets after matched and mismatched transplantation. Lymphocyte subsets (absolute numbers of CD3, CD4, CD8, CD19, CD56, CD25, CD45RA, CD45RO) were evaluated by flow cytometry at 1,3,6 and 12 months (mo) post-ASCT. Lymphocyte recovery was determined using means at each time point and group differences were assessed using analysis of variance. Kaplan-Meier survival curves were used to estimate time-to-event outcome measures and the log-rank test was used to evaluate differences between groups. 100 patients (pts) were included in the study. 25 pts received a matched sibling donor transplant (MSD), 20 pts a 10/10 MUD, 18 pts a 9/10 MUD, 9 pts a T cell depleted haploidentical (TCD haplo), and 28 a T cell replete haploidentical donor (TCR haplo). 53 pts received bone marrow and 47 had peripheral blood stem cells. Most patients were treated for acute leukemia (AML 41, ALL 23), 16 MDS, 6 CML, 4 CLL, 5 lymphoma. Median age was 43 years (range: 20–71). The median follow-up was 13.6 mo. 60 pts were alive and disease-free at last follow-up and 28 pts died 75% due to relapse. Non-relapse mortality (NRM) was 6% for the entire cohort. Overall, alive pts (vs who died) had higher mean CD3 (615 vs 349, p=0.03 on day 90), CD8 (427 vs 187, p=0.03 on day 90), CD4 (391 vs 54, p=0.01, on day 365) cells, and lower mean CD56 cells (178 vs 300, p=0.01, on day 30) post ASCT. Pts who progressed (vs did not), had lower 1 year mean CD4 cells (123 vs 394, p=0.02), lower mean CD3 cells (359 vs 1147, p=0.06), with no differences in CD8, NK, and CD45RA. NRM was associated with higher mean NK numbers at 6 months (499 vs 188, p=0.01) and with lower mean CD3 at day 90 (184 vs 557, p=0.07). T-cell recovery occurred most rapidly in MSD transplants (Figure1C), and compared with 10/10 MUD had higher mean CD3 cells in the first mo (1085 vs 510, p=0.01), CD4 in the first 6 mo (310 vs 147, p<0.01 day 180) and CD4CD45RA in the first 6 mo (105 vs 31, p=0.02 on day 180). Interestingly, we have found that higher CD4CD25 cell numbers recovered early and most rapidly in the MSD transplants, which may partly explain a lower incidence of GVHD in this group. Overall, TCR haplos had a similar pattern of T-cell recovery and outcomes as 10/10 MUDs (Figure1C-E). There was a significant delay in CD3 recovery between MSD and TCR haplos in the first 3 mo (mean 779 vs 483, p=0.04 on day 90), CD4 (mean 270 vs 170, p=0.03 day 90) and in the first 6 months for CD45RA (mean 105 vs 28, p=0.01 on day 180), while these differences were significant only at day 30 for CD8 cells (mean 703 vs 88, p<0.01). No significant differences in T cell subsets were found between 10/10 MUD and TCR HaploSCT for CD3, CD4, CD8, CD45RA and CD4CD25 for any time points. Of all types of transplant, TCD haplos had most impaired T-cell reconstitution and worst outcomes (Figure 1A and 1B). As previously reported it was characterized by rapid early NK cell recovery and delayed CD3, CD4, CD8 reconstitution. Interestingly, pts surviving 6–9 months post-transplant recovered CD3, C4, CD8 cells; however, naïve T-cell recovery remained impaired for more than 1 year post-transplant, suggesting that T cell recovery comes predominantly from the memory T cell compartment. In conclusion, these results suggest that recovery of lymphocyte subsets may vary widely with the type of transplant, may correlate with outcomes, and it is important to be further explored in this setting. Disclosures: No relevant conflicts of interest to declare.

Influence of Lower Dose Antithymocyteglobulin As Conditioning Regimen on Viral Infection after Haploidentical Allogeneic Stem Cell Transplantation

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 825-825 ◽  
Author(s):  
Ren Lin ◽  
Yu Wang ◽  
Fen Huang ◽  
Zhiping Fan ◽  
Shen Zhang ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Viral Infection ◽  
Cell Transplantation ◽  
Natural Science ◽  
Research Funding ◽  
Viral Infections ◽  
Conditioning Regimen ◽  
Hematopoietic Stem ◽  
Post Transplant

Abstract Background: Antithymocyteglobulin (ATG), used as conditioning regimen, can reduce graft-versus-host disease (GVHD) in haploidentical hematopoietic stem cell transplantation (haplo-HSCT). Notwithstanding, immunosuppressive effect of ATG may increase the risk of viral infections after HSCT. To evaluate the effect of different doses of ATG on post-transplant viral infection, we conducted a multicenter prospective study to compare EBV and CMV infection in haplo-HSCT recipients receiving 7.5 mg/kg or 10 mg/kg ATG. Methods Between May 2013 and November 2015, 350 consecutive patients with hematological malignancies undergoing haplo-HSCT were randomized in 5 hospitals. One hundred and seventy-two patients received ATG with a total dosage of 7.5 mg/kg and 175 received 10 mg/kg ATG. Three patients did not received allocated intervention and transplantation due to leukemia relapse before transplant or toxicity of conditioning regimens. Results The cumulative incidence of EBV viremia on day 180 was 23.3±3.2% in 7.5 mg/kg ATG arm which was lower than that in 10 mg/kg arm (34.6±3.7%, P=0.037). CMV viremia were comparable in the two arms (7.5 mg/kg arm: 79.0±3.1% vs. 10 mg/kg arm: 76.9±3.2%, P=0.950). The incidences of CMV diseases were 0.6±0.6% and 2.4±1.2% in 7.5 mg/kg and 10 mg/kg arms, respectively (P=0.093). No difference in the incidence of post-transplant lymphoproliferative disorder (PTLD) was found between the two arms (2.4±1.2% in 7.5 mg/kg arm vs. 5.4±1.8% in 10 mg/kg arm, P=0.150). Besides, acute GVHD grade II to IV within 100 days occurred in 55 recipients with the incidence of 31.4% in 7.5mg/kg ATG arms and 45 recipients in 10 mg/kg arms with the incidence of 26.2% (P=0.279). The incidences of aGVHD grade III to IV were similar in the two arms (8.0% in 7.5 mg/kg arm: vs. 4.7% in 10 mg/kg arm, P=0.196). The 2-years overall survival were 69.5±4.7% and 69.4±3.9% for 7.5 mg/kg and 10 mg/kg group (P=0.540). Conclusion Compared with 10 mg/kg of ATG, the application of 7.5 mg/kg might reduce the risk of EBV infection after haplo-HSCT and not increase aGVHD. Disclosures Lin: National Natural Science Foundation of China 81270647: Research Funding; Science and technology planning project of Guangdong Province 2014B020226004: Research Funding; The project of health collaborative innovation of Guangzhou City 201400000003-4: Research Funding; National Natural Science Foundation of China 81400141: Research Funding.

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