CD34 Selected Stem Cells Boosts Are Safe and Effective for Patients with Poor Bone Marrow Function After Allogeneic Hematopoietic Cell Transplantation.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 3078-3078
Author(s):  
Sebastian P. Haen ◽  
Michael Schumm ◽  
Christoph Faul ◽  
Lothar Kanz ◽  
Wolfgang A. Bethge ◽  
...  

Abstract Abstract 3078 Introduction: Poor graft function (PGF) can be a life-threatening post-transplantation complication for patients undergoing allogeneic hematopoietic cell transplantation (HCT). While primary graft failure has been quite rare (about 2%) in recent years, about one quarter of patients with full donor chimerism suffer from secondary graft dysfunction defined as leukocytes < 1000/μl or transfusion-dependent platelet counts < 20.000/μl or transfusion-dependent anemia. For these patients, CD34 selected stem cell boosts (SCB) from the same donor can be a treatment option. We here report our experience using SCB in patients with PGF. Patients and Methods: Between 2006 and 2011, 20 patients received CD34 selected SCB at our institution. Indications for allogeneic HCT were ALL (n = 1), AML (n = 11), MDS (n = 1), NHL (n = 4) or PMF (n = 3). The cohort comprised 13 men and 7 women with a median age of 54 years at the time of transplantation (range 21–67 years). Seven patients had thrombocytopenia, another seven both thrombocytopenia and leukopenia, and 6 patients presented with tricytopenia. Poor graft function was confirmed and disease relapse excluded by bone marrow biopsy prior to donor mobilization. CD34+hematopoietic stem cells were isolated from G-CSF mobilized peripheral blood stem cells from leukapheresis products of the initial donor using the CliniMACS system from Miltenyi Biotech (Bergisch-Gladbach, Germany). Clinical and laboratory data of the patients were analyzed retrospectively. Results: An average of 4.32 ×106 CD34+ cells per kilogram bodyweight (1.6–9.1 ×106) with a purity of 97% CD34+ cells (63–99.5%) were transfused at a median of 133 days after HCT (47–1,568 days). An increase of leukocytes (median 3,100/μl, range 150–10,150/μl) was observed in 85% of the patients (n = 17). In 80% (n = 16) an increase of platelets (median 77,000/μl, range 7,000–223,000/μl), and in 55% (n = 11) an increase of hemoglobin (median 2 g/dl, range -1–5 g/dl) was induced through SCB. All patients benefitted from SCB in at least one hematopoietic line. Highest post-SCB values of leucocytes, thrombocytes and erythrocytes were reached on days 38, 59, and 55, respectively. Hence, efficacy of SCB could be best evaluated about eight weeks after transfusion. The mean T cell content of SCB was 0.2 ×104 (0.04–0.5 ×104) cells per kilogram bodyweight. No significant exacerbation or any primary manifestation of graft versus host disease (GvHD) was observed. Median follow-up time was 48 months (7–121 months) until death or last follow-up visit. At the end of follow-up, 11 patients were alive (55%) and 9 patients had died (45%). All patients alive remained disease free and transfusion independent and had stable leukocytes in normal range. Conclusion: In patients with PGF and full donor chimerism after HCT, CD34 selected SCB can durably improve bone marrow function. Patients receiving SCB appear to have a very limited risk of developing or aggravation of GvHD. Of note, effects of SCB can clinically manifest up to eight weeks after transfusion. In conclusion, SCB are safe and effective in patients with PGF. Disclosures: No relevant conflicts of interest to declare.

Blood ◽  
2005 ◽  
Vol 106 (11) ◽  
pp. 2200-2200
Author(s):  
Haegele Matthias ◽  
Christoph Faul ◽  
Peter Lang ◽  
Michael Schumm ◽  
Rupert Handgretinger ◽  
...  

Abstract Haploidentical allogeneic hematopoietic cell transplantation (HHCT) using megadoses of CD34-selected hematopoietic stem cells (HSC) is complicated by slow engraftment and delayed immune reconstitution leading to intensive transfusional support, high risk of rejection and high incidence of life threatening infections. Graft CD3/CD19 depletion on a CliniMACS device results in grafts not only containing CD34+ stem cells but also CD34 negative progenitors, natural killer-, dendritic- and facilitating-cells, potentially leading to improved engraftment and immune reconstitution. We report a retrospective comparative study of eleven HHCTs with CD34 selected HSC (CD34) and seven HHCTs with CD3/CD19 depleted grafts (CD3/CD19) performed sequentially at a single institution with a median follow-up > 1 year. Conditioning was 12 Gy TBI, cyclosphosphamide (120 mg/kg) and ATG with or without either etoposide (40 mg/kg) or thiotepa (10mg/kg) in the CD34 group. All patients in the CD3/CD19 group received fludarabine (200 mg/m2), thiotepa (10 mg/kg), melphalan (120 mg/m2) and OKT-3 (5 mg/day, day −5 to +14). No postgrafting immunosuppression was used. Only the CD34 group received G-CSF posttransplant. Median age was 30 (range, 19–47) years in the CD34 group compared to 37 (range, 31–58) years in the CD3/CD19 group. Diagnoses in the CD34 group included acute myeloid leukaemia (AML, n=3), acute lymphoblastic leukaemia (ALL, n=3), chronic myeloid leukaemia (CML, n=2), and one patient each with Non-Hodgkin’s lymphoma, myelodysplastic syndrome and paroxysmal nocturnal hemoglobinuria. Diagnoses in the CD3/CD19 group were AML (n=3), ALL(n=3), and multiple myleoma (n=1). Graft composition was comparable with a median of 9,6x10E6 CD34+ cells/kg and 2,2x10E4 CD3+ cells/kg in the CD34 group versus 7,6x10E6 CD34+ cells/kg and 1,3 x10E4 CD3+ cells/kg in the CD3/CD19 group. The grafts in the CD3/CD19 group, however, contained significantly more CD34 negative cells (99 versus 3 %, p=<0.0001) such as NK-cells, monocytes and granulocytes. Engraftment in the CD3/19 group was significantly faster than in the CD34 group, with a median time to >500 neutrophils/μL of 13 versus 19 days (p=<0.0265) and a median time to >20000 platelets/μL of 13 versus 35 days (p=<0.0001). There was also a significant faster recovery of NK-cells with a median day 100 CD56+ count of 1808 versus 209 cells/μL (p=0.0413). The number of CD3+ cells on day 100 showed no significant difference. No cases of graft rejection have been observed in both groups. Transfusional requirements in the CD3/19 group were lower with a median of 11 versus 35 days with platelet support (p=0.039). There was no significant difference in the incidence of GVHD which was ≤ II in both groups. We observed a lower incidence of bacterial infections in the CD3/C19 group. In conclusion, CD3/19 depleted grafts allow haploidentical hematopoietic cell transplantation with faster engraftment and NK-cell reconstitution leading to a lower rate of bacterial infections and less transfusional requirements.


Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3072-3072
Author(s):  
Wolfgang A. Bethge ◽  
Martin Bornhaeuser ◽  
Dietrich W. Beelen ◽  
Gernot Stuhler ◽  
Matthias Stelljes ◽  
...  

Abstract Introduction: Haploidentical hematopoietic cell transplantation (HHCT) after high dose conditioning with a megadose of CD34-selected stem cells has been complicated by regimen related toxicities, slow engraftment and delayed immune reconstitution leading to a high treatment related mortality (TRM). A new regimen using graft CD3/CD19 depletion and reduced intensity conditioning (RIC) may allow HHCT with lower toxicity and faster engraftment. CD3/CD19 depleted grafts not only contain CD34+ stem cells but also CD34 negative progenitors, dendritic-, natural killer- and other graft-facilitating cells which may allow stable engraftment even without the use of a megadose of CD34+ cells. Methods: A multicenter phase I/II study of HHCT using RIC with fludarabine (150–200 mg/m2), thiotepa (10 mg/kg), melphalan (120 mg/m2), OKT-3 (5 mg/day, day −5 to +14) and graft CD3/CD19 depletion with anti-CD3 and anti-CD19 coated microbeads on a CliniMACS device has been initiated. No post grafting immunosuppression was applied if the graft contained <5×104 CD3+ cells/kg. Results: To date, 36 patients (median age=46 [range, 21–65] years) have been enrolled in this study. Diagnosis were AML (n=20), ALL (n=7), NHL (n=3), MM (n=2), CML (n=2) and MCL (n=2). Patients were high risk with refractory disease or relapse after preceding HCT (auto=6, allo=12). The CD3/CD19 depleted haploidentical grafts contained a median of 7.5 × 106 (range, 3.4–17×106) CD34+cells/kg, 2.8×104(range, 0.4–44×104) CD3+T-cells/kg and 3.8×107 (range, 0.02–37.3 x107) CD56+cells/kg. Donor-recipient KIR-ligand-mismatch was found in 20 of 36 patients. The regimen was well tolerated with maximum acute toxicity being grade 2–3 mucositis. Five cases of reversible peripheral neuropathy and 3 cases of progressive multifocal leukencephalopathy (PML) occurred posttransplant in heavily pretreated patients. Engraftment was rapid with median time to >500 granulocytes/μL of 12 (range, 9–21) days, >20000 platelets/μL of 11 (range, 7–30) days and full donor chimerism after 2–4 weeks in all but one patient. Incidence of grade II-IV GVHD was 36% with grade II=9, III=2 and IV=2. TRM in the first 100 days was 10/36 (27%). Overall survival is 16/36 patients (44%) with deaths due to relapse (n=9), infection (n=9), GVHD (n=1) and PML (n=1) with a median follow-up of 194 days (range, 14–1271), resulting in a Kaplan-Meier 1 year survival estimate of 41%. We did not observe a statistical significant survival advantage for patient transplanted from a KIR-mismatched donor. Conclusion: This regimen is promising in high risk patients lacking a suitable donor, and a prospective phase I/II study is ongoing.


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