Successful umbilical cord blood stem cell transplantation for chronic granulomatous disease

Chronic granulomatous disease (CGD) causes growth failure, inflammatory lung damage and often early death. Prophylactic cotrimoxazole improves medium-term survival, but cannot prevent inflammatory sequelae. We report the first patient with CGD who underwent successful HLA identical sibling umbilical cord stem cell transplantation (UCSCT) after myeloablative conditioning. The patient presented with colitis, confirmed as CGD at 2 years of age. Following BU16/CY200 conditioning, he had UCSCT from his unaffected HLA identical sister. A year post-transplant, his colitis had resolved clinically and on radioisotope scan growth has improved. Neutrophil oxidative burst was 92% normal with full donor lymphocyte reconstitution.     

Donor lymphocyte infusion is an effective therapy for relapsed Hodgkin lymphoma after reduced-intensity allogeneic hematopoietic stem cell transplantation

A 3-year-old boy with Hodgkin lymphoma relapsed only 2 months after completion of first-line therapy. He received reduced-intensity conditioning and allogeneic hematopoietic stem cell transplantation (RIC allo-HSCT), but relapsed again. To treat the second relapse, donor lymphocyte infusions were performed four times. He showed no evidence of disease and his quality of life was maintained for 500 days after stem cell transplant. However, his condition worsened and he died 3 years and 3 months after onset. In high-risk patients fully intolerant to myeloablative regimens, RIC allo-HSCT followed by subsequent donor lymphocyte infusions must be considered an effective therapeutic approach.     

非清髓异基因外周血造血干细胞移植治疗慢性粒细胞白血病

目的：探索非清髓异基因外周血干细胞移植(NST)治疗不能耐受清髓性异基因造血干细胞移植的慢性粒细胞白血病(CML)患者的疗效。方法：将5例CML患者中的4例以全身放疗加氟达拉宾，1例以马利兰、氟达拉宾加抗人胸腺细胞免疫球蛋白为预处理方案，联合环孢霉素A、霉酚酸酯和(或)短程氨甲蝶呤预防移植物抗宿主病。结果：5例均造血重建，3例完全供者型植入，2例混合型植入，其中1例植入率持续低于50％，经2次清髓性异基因造血干细胞移植后达到完全供者型植入。2例发生Ⅰ度急性移植物抗宿主病，1例发生Ⅳ度急性移植物抗宿主病，无慢性移植物抗宿主病发生。中位随访时间5(3～37)个月，无病生存3例，死亡2例。结论：对不能耐受清髓性异基因造血干细胞移植的CML患者，NST是可行而有效的。     

Donor lymphocyte infusions for refractory pure red cell aplasia relapsing after both autologous and nonmyeloablative allogeneic peripheral stem cell transplantation

Pure red cell aplasia (PRCA) is characterized by a selective marrow aplasia of the erythroid compartment. Immunosuppressive therapy achieves good results in about 25% of cases, but relapses are frequent. Autologous or allogeneic haematopoietic stem cell transplantation (HSCT) may be valuable in selected patients. Here, we report details of a 29-year-old woman treated successfully by donor lymphocyte infusions (DLIs) following allogeneic HSCT for acquired refractory relapsed PRCA. The nonmyeloablative conditioning regimen consisted of cyclophosphamide 60 mg/kg/day for 2 days and fludarabine 30 mg/m(2) daily for 4 days. Haematopoiesis was still completely 'recipient' 1 month after allo-HSCT, but progressed to full donor engraftment after three doses of 'escalating' DLI. The possible role of a graft-versus-autoimmunity effect induced by allogeneic HSCT followed by DLI infusions in the treatment of the disease is discussed.     

Successful allogeneic hematopoietic stem cell transplantation for chronic granulomatous disease with inflammatory complications and severe infection

We report two patients with chronic granulomatous disease (CGD). The first patient presented with granulomatous colitis and pulmonary aspergillosis, and the second patient with liver abscess and restrictive pulmonary disorder. Both patients underwent allogeneic hematopoietic stem cell transplantation, the first from an HLA-matched sibling donor, and the second from an HLA-matched unrelated donor, after preconditioning with fludarabine, anti-thymocyte globulin, cyclophosphamide, and total-body irradiation of 3 Gy. The engraftment was prompt and the regimen-related toxicity was mild. The patients are able to return to their daily lives with full donor chimerism, although the second patient underwent a living-related-donor orthotopic liver transplantation from his mother for chronic liver graft-versus-host disease. The conditioning regimen we used was feasible and applicable to patients with CGD accompanied by inflammatory disease and severe infection.     

Donor cell leukemia after allogeneic peripheral blood stem cell transplantation: a case report and literature review

A 49-year-old male developed recurrent acute myeloid leukemia 27 months after allogeneic peripheral blood stem cell transplantation (PBSCT) from an HLA-identical brother. The immunophenotype of the blastic cell population was incompatible with that of the pre-transplant blast cells; a mutation in C/EBPA gene was found in the pre-transplant blast cells that was not present in the post-transplant blast cells, and short tandem repeat analysis of marrow cells, which included 71% blasts, showed complete donor chimera. Thus, this recipient developed donor cell leukemia (DCL). The donor was healthy when DCL developed in the recipient as well as before donation of the peripheral blood stem cells. Only five cases of DCL after PBSCT have been reported in the literature. As a mechanism for the development of DCL, a vigorous proliferative demand on the donor cells, which often correlates with a higher likelihood of replication error or mutation, has been proposed. Peripheral blood stem cells might have an advantage in that they are associated with a low incidence of DCL development because PBSCT recipients receive a higher total cell dose than recipients of bone marrow or cord blood cells.     

Donor cell myelodysplastic syndrome after allogeneic stem cell transplantation responding to donor lymphocyte infusion: case report and literature review

Allogeneic hematopoietic stem cell transplantation (SCT) is a potentially curative treatment for patients with myelodysplastic syndrome (MDS). Relapses after transplantation however, are not uncommon and are usually due to re-emergence of a recipient derived, neoplastic, stem cell clone. We report a unique case of MDS recurring 5 months after non-myeloablative, sibling, allogeneic SCT. Interestingly, chimerism analysis at relapse showed hematopoiesis to be entirely of donor origin confirming donor cell MDS. Donor lymphocyte infusion (DLI) produced a hematological response lasting several months. Our review of the literature shows donor-derived MDS to be very rare, with only four such cases described previously. In this report, we describe the details of our case and discuss putative mechanisms underlying the genesis of donor cell MDS and the observed response to DLI.     

Individually adjusted prophylactic donor lymphocyte infusions after CD34-selected allogeneic peripheral blood stem cell transplantation.

T cell depletion of the graft increases graft failure and relapse rate in allogeneic PBSC transplantation. Delayed lymphocyte add-back after T cell-depleted transplants might prevent these complications. We present 22 consecutive allogeneic PBSC transplants from related histocompatible donors with positive selection of CD34+ cells. Recipients received prophylactic donor lymphocyte infusions (DLI) depending on their risk of relapse and of developing GVHD. Patients were considered at high risk of relapse with AML > first CR, ALL > second CR, and CML in accelerated or blastic phase. Patients were considered at high risk of developing GVHD if older than 35 years, or with a donor sensitized through previous pregnancy or blood transfusion. Patients at high risk of relapse and low risk of GVHD were scheduled to receive three DLI. Patients at low risk of relapse and high risk of GVHD did not receive DLI. The remaining patients were scheduled to receive two DLI. The DLI were administered on days +28 (2 x 10(5)/kg), +60 (2 x 10(5)/kg) and +90 (2 x 10(6)/kg) after transplant. G-CSF mobilized peripheral stem cells from healthy donors were positively selected by an immunomagnetic method. The mean CD34+ cells and CD3+ cells infused were 4.4 x 10(6)(range 1.9-10.6) and 0.085 x 10(5) (range 0.01-0.67). Cyclosporin A was given to prevent GVHD. All the patients engrafted. Twenty-two prophylactic DLI were performed in 12 patients: seven developed acute GVHD (one case grade III-IV) and none presented pancytopenia. At a mean follow-up of 585 days (range 89-1103), 14 patients were alive in CR, one patient was alive in relapse, four patients had died of relapse and three had died of transplant-related complication. Individually adjusted prophylactic DLI at the doses we used with an escalating schedule allowed an acceptable GVHD rate and a good engraftment of donor hematopoiesis.     

Increased risk of extensive chronic graft-versus-host disease after allogeneic peripheral blood stem cell transplantation using unrelated donors

The long-term follow-up of a study including 214 patients receiving either peripheral blood stem cells (PBSCs) or bone marrow (BM) from an HLA-A, -B, and -DR-compatible unrelated donor is presented. Median follow-up was 4.4 (2.3-7.3) and 5.0 (0.7-8.4) years in the 2 groups, respectively. Cumulative incidence of overall chronic graft-versus-host disease (GVHD) was similar in the 2 groups (78% vs 71%), while extensive chronic GVHD was significantly more common in the PBSC group compared with the BM group (39% vs 24%, P = .03). The 5-year transplant-related mortality (TRM) was 37% in the PBSC group and 35% in the BM controls (P = .7), and overall survival was 42% in both groups. The relapse incidences were 26% and 27% in the 2 groups, respectively, resulting in a disease-free survival of 41% in both groups. In conclusion, PBSCs from HLA-compatible unrelated donors results in similar outcome compared to BM but implies an increased risk for extensive chronic GVHD.     

Mycobacterium genavense duodenitis following allogeneic peripheral blood stem cell transplantation

Abstract: A 56‐year‐old man was diagnosed with Mycobacterium genavense duodenitis 21 months after an allogeneic peripheral stem cell transplant complicated by graft‐versus‐host disease requiring intense immunosuppression. This duodenitis responded to prolonged therapy with clarithromycin, ciprofloxacin, and rifabutin and reduction of immunosuppression.     

Successful peripheral blood stem cell mobilization using pegfilgrastim in allogeneic stem cell transplantation

Pegfilgrastim is produced by binding a 20,000-dalton polyethylene glycol molecule to granulocyte colony-stimulating factor (G-CSF), increasing the mass of the compound, and resulting in a longer-lasting form of G-CSF. This makes it more convenient to use pegfilgrastim as a single-day injection. This study was a prospective phase II single-center trial. Fifteen normal related donors received pegfilgrastim 12 mg subcutaneously to mobilize peripheral blood stem cells (PBSC) for allogeneic stem cell transplantation. Leukapheresis was planned to start 3 days after injection. All harvests were successful. Median number of leukapheresis was 2 days (range 1–3 days). There were 7/15 donors who only required single leukapheresis. The maximum concentration of white blood cells (WBC) and circulating CD34 cells occurred 3 days after pegfilgrastim injection (WBC: median 62,200/μl; CD34: median 69.76/μl). The median yield of CD34 cells was 6.78 × 10⁶/kg recipient weight. The median CD3 cells was 1.89 × 10⁸/kg recipient weight. The main adverse events were bone pain and headache. Median neutrophil and platelet engraftments in the recipients occurred on day 12 and day 13, respectively, after transplantation. PBSC mobilization with single-day injection of pegfilgrastim in normal donor is feasible. Further comparisons of this protocol to standard G-CSF for allogeneic stem cell mobilization should be conducted in future.     

Liver graft-versus-host disease after donor lymphocyte infusion for relapses of hematologic malignancies post allogeneic hematopoietic stem cell transplantation

Graft-versus-host disease (GVHD) is the commonest complication after donor lymphocyte infusion (DLI). In 19 patients undergoing DLI for relapses of hematologic malignancies post hematopoietic stem cell transplantation (HSCT), 11 developed GVHD, of whom nine had isolated liver involvement, and two had liver and skin involvement. The clinical diagnosis of liver GVHD was hepatitic in six patients (55%) and classical in five patients (45%). Patients with GVHD post-DLI showed a different clinical pattern when compared to a cohort of 106 cases of GVHD post-HSCT, in having significantly more isolated liver involvement (9/11 vs 17/106, P<0.001), and less skin (2/11 vs 80/106, P<0.001) and gut (0/11 vs 28/106, P<0.001) involvement. However, liver GVHD post-DLI and post-HSCT had comparable patient characteristics, underlying diseases, clinical subtypes (classical and hepatitic) and response to treatment.     

Hepatic graft-versus-host disease presenting as an acute hepatitis after allogeneic peripheral blood stem cell transplantation.

Hepatic graft-versus-host disease (GVHD) generally presents as cholestatic jaundice, and increased serum alkaline phosphatase (ALP) is followed by hyperbilirubinemia and clinical jaundice. Currently accepted standards for evaluating the clinical severity of GVHD are based not on serum aminotransferase levels but on the serum bilirubin level. We describe a 17-year-old Japanese female who had increased aminotransferases without cholestasis on day 23 after allogeneic peripheral blood stem cell transplantation (allo-PBSCT). Liver biopsy revealed lymphocytic infiltration of the portal tracts and pericentral necrosis of the lobuli. The limiting plates were not clearly defined due to cellular infiltrates. There was periductal lymphocytic infiltration and vacuolization of the biliary epithelial cells with exocytosis, compatible with GVHD of cholangiohepatitic type. These findings indicate that acute hepatic GVHD may present as acute hepatitis and this should be included in the differential diagnosis for patients with increased aminotransferases after allogeneic stem cell transplantation.     

Remission induction of refractory diffuse large B-cell lymphoma with allogeneic peripheral blood stem cell transplantation followed by interferon-alpha and donor lymphocyte infusion

Graft-versus-lymphoma (GVL) effect has been described in patients with malignant lymphoma after allogeneic stem cell transplantation (alloSCT). The effect of interferon-alpha (IFN-alpha) on the GVL effect still remains unclear. Here we report on a 29-year-old woman with refractory diffuse large B-cell lymphoma (DLBL). Her clinical findings included multiple masses in the liver, stomach, bilateral kidneys, thyroid, vertebral bones and a bulky mediastinal mass. Since the patient did not respond to various combination chemotherapies and further developed superior vena cava syndrome, allogeneic peripheral blood stem cell transplantation (PBSCT) from a HLA-identical brother was carried out after a myeloablative TBI/CY-based conditioning regimen. DLIs have been also performed every 4 weeks since day +14. As a result, the lymphoma masses showed a partial response. In order to enhance the GVL effect, IFN-alpha was further given at a maximum of 3 MU four times per week. Although the patient only experienced graft-versus-host disease of the skin (grade II) even after both DLIs and IFN, complete clinical remission was observed. 200 days after transplantation, the patient is still disease-free and in good condition. This report suggests the curative potential of IFN-alpha combined with DLI after allogeneic SCT in refractory DLBL.     

Primary transplantation of allogeneic peripheral blood stem cell for severe aplastic anemia

 Primary allogeneic peripheral blood stem cell transplantation (allo-PBSCT) has not been previously described in the treatment of severe aplastic anemia (SAA). We report a patient with SAA who underwent primary allo-PBSCT with cells from her HLA-identical sibling and achieved rapid bone marrow reconstitution. The patient has been in complete remission with normal blood counts for 9 months following allo-PBSCT. This suggests that primary allo-PBSCT is a safe and effective alternative in the treatment of SAA. Received: 13 November 1996 / Accepted: 29 January 1997     

Chronic graft-versus-host disease after allogeneic blood stem cell transplantation

The incidence, characteristics, risk factors for, and impact of chronic graft-vs-host disease (GVHD) were evaluated in a consecutive series of 116 evaluable HLA-identical blood stem cell transplant recipients. Minimum follow-up was 18 months. Limited chronic GVHD occurred in 6% (95% confidence interval [CI], 0%-13%), and clinical extensive chronic GVHD in 71% (95% CI, 61%-80%). The cumulative incidence was 57% (95% CI, 48%-66%). In univariate analyses, GVHD prophylaxis other than tacrolimus and methotrexate, prior grades 2 to 4 acute GVHD, use of corticosteroids on day 100, and total nucleated cell dose were significant risk factors for clinical extensive chronic GVHD. On multivariate analysis, GVHD prophylaxis with tacrolimus and methotrexate was associated with a reduced risk of chronic GVHD (hazard ratio [HR], 0.35; P =.001), whereas the risk was increased with prior acute GVHD (HR, 1.67; P =.046). When adjusted for disease status at the time of transplantation, high-risk chronic GVHD had an adverse impact on overall mortality (HR, 6.6; P <.001) and treatment failure (HR, 5.2; P <.001) at 18 months. It was concluded that there is a substantial rate of chronic GVHD after HLA-identical allogeneic blood stem cell transplantation, that clinical factors may alter the risk of chronic GVHD, and that high-risk chronic GVHD adversely affects outcome.