S.K. Sohn

Protective role of interleukin-10 promoter gene polymorphism in the pathogenesis of invasive pulmonary aspergillosis after allogeneic stem cell transplantation

Summary:The current study attempted to evaluate the association between the IL-10 promoter gene single nucleotide polymorphism (SNP) and invasive pulmonary aspergillosis (IPA) after allogeneic stem cell transplantation (SCT) in 105 patients. Three single-nucleotide polymorphisms were investigated in the proximal region of the IL-10 promoter gene (−1082/−819/−592). Two haplotypes (1082*A/819*T/592*A [ATA] and 1082*A/819*C/592*C [ACC]) were found in the current study. The overall incidence of IPA was estimated as 14.1±4.5% with a median onset at 186 days post-transplant (62∼405 days). An increased occurrence of IPA was noted dependent on the IL-10 haplotype (0% vs 11.5±6.4% vs 19.7±7.7% for ACC/ACC vs ATA/ACC vs ATA/ATA haplotype, P=0.0307 when comparing ACC with non-ACC haplotype). In a multivariate survival analysis using Coxs proportional hazard model, the IL-10 promoter gene SNPs were identified as an independent predictive factor for the development of IPA (P=0.012, hazard ratio (HR) 9.3), along with an histocompatibility leukocyte antigen (HLA)-identical donor (P=0.005, HR 16.3), the CD34+ cell dose transplanted (P=0.004, HR 26.5), and time-dependent chronic graft-versus-host disease (GVHD; P=0.049, HR 16.0). The IL-10 ACC haplotype was found to have an apparent protective role in the development of IPA after allogeneic transplantation, regardless of HLA-disparity or chronic GVHD.

Rapid helper T-cell recovery above 200 |[times]| 106|[sol]|l at 3 months correlates to successful transplant outcomes after allogeneic stem cell transplantation

The current study evaluates the role of quantitative measurement of peripheral lymphocyte subsets, especially CD4+ helper T-cell recovery, in predicting transplant outcomes including overall survival (OS) and non-relapse mortality (NRM) after allogeneic stem cell transplantation. A total of 69 allogeneic recipients were included with following diagnoses: acute myeloid leukemia 42, acute lymphoblastic leukemia 5, chronic myeloid leukemia 15, non-Hodgkins lymphoma 5 and high-risk myelodysplastic syndrome 2. The peripheral lymphocyte subset counts (CD3+ T cells, CD3+4+ helper T cells, CD3+8+ cytotoxic T cells, CD19+ B cells, and CD56+ natural killer cells) were measured at 3, 6 and 12 months. The CD4+ helper T-cell reconstitution at 3 months was strongly correlated with OS (P<0.0001), NRM (P=0.0007), and opportunistic infections (P=0.0108) at the cutoff value of 200 × 106/l CD4+ helper T cells. Rapid CD4+ helper T-cell recovery was also associated with a higher CD4+ helper T-cell transplant dose (P=0.006) and donor type (P<0.001). An early CD4+ helper T-cell recovery at 3 months correlated with a subsequent faster helper T-cell recovery until 12 months, yet not with B-cell recovery. In a multivariate analysis, rapid recovery of CD4+ helper T cells at 3 months was a favorable prognostic factor together with higher CD34+ cell transplant dose in terms of OS (P=0.001) and NRM (P=0.005).

New myeloablative conditioning regimen with fludarabine and busulfan for allogeneic stem cell transplantation : comparison with BuCy2

A regimen of busulfan and cyclophosphamide (BuCy2) is regarded as the standard myeloablative regimen for SCT. This study evaluated the hypothesis that fludarabine can replace cyclophosphamide for myeloablative allogeneic SCT. Ninety-five patients underwent allogeneic SCT from HLA-identical donors, following BuCy2 (n=55) or busulfan+fludarabine (BF, n=40). The efficacy of fludarabine compared to cyclophosphamide was retrospectively evaluated. The BF group exhibited a shorter duration until engraftment (P=0.001), lower incidence of acute and chronic GVHD (P<0.001 and P=0.003, respectively), and non-relapse mortality (NRM) (P=0.039). Furthermore, the event-free survival and overall survival were significantly higher for the BF group compared to the BuCy2 group (P=0.004 and 0.002, respectively). After adjusting for age, the risk status of disease, GVHD prophylaxis and donor type, the BF regimen was found to be an independent favorable risk factor for event-free survival (hazard ratio (HR), 0.181; 95% confidence interval, 0.045–0.720; P=0.016) and overall survival (HR, 0.168; 0.035–0.807; P=0.026). The replacement of cyclophosphamide with fludarabine for myeloablative conditioning seems to be more effective in terms of short-term NRM, and GVHD compared to BuCy2 regimen in allogeneic transplantation.

Impact of ABO incompatibility on outcome after allogeneic peripheral blood stem cell transplantation

Summary:Few studies have addressed the incidence of graft-versus-host disease (GVHD) or survival after ABO-incompatible allogeneic peripheral blood stem cell transplantation (PBSCT). We analyzed the clinical outcome of ABO incompatibility after allogeneic PBSCT. A total of 89 consecutive adult patients with hematological diseases including 49 ABO-identical, 20 major, 15 minor, and five bidirectional ABO-incompatible transplants were enrolled from four medical centers in Korea. No significant difference in engraftment times, graft failure, or transfusion requirements between groups was noted. A clinical diagnosis of severe immune hemolysis or pure red cell aplasia was not made for any patient after transplantation. The incidence of acute or chronic GVHD did not statistically differ between groups. With a median follow-up duration of 13 months (range, 0.5–61 months), the 3-year overall survival estimates for the ABO-identical, major/bidirectional, and minor group were 44.6.0±9.0, 43.1±11.6, and 43.8±13.5%, respectively (P=0.8652), while the 3-year disease-free survival estimates were 33.8±7.6, 39.9±11.4, and 45.7±13.1%, respectively (P=0.8546). We observed that time to neutrophil, platelet, and red blood cell engraftment, transfusion requirements, incidence of acute or chronic GVHD, relapse, and survival were not influenced by ABO incompatibility after allogeneic PBSCT from HLA-matched sibling donors.

Successful allogeneic stem-cell transplantation with prophylactic stepwise G-CSF primed-DLIs for relapse after autologous transplantation in mantle cell lymphoma: a case report and literature review on the evidence of GVL effects in MCL.

Mantle cell lymphoma (MCL) is a distinctive clinicopathologic entity and represents 2–8% of all non‐Hodgkins lymphomas. The median survival of patients with MCL is only 3 years, and none of the available conventional chemotherapy regimens appears curative. Encouraging results have been reported with high‐dose chemotherapy with autologous stem‐cell transplantation (autoSCT). However, a plateau in disease‐free survival was not observed in relapsed MCL on the autoSCT trials. Promisingly, alloSCT appears to induce durable remissions via a graft‐versus‐lymphoma (GVL) effect. Donor lymphocyte infusions (DLIs), by virtue of a GVL effect, have been shown to induce durable remissions in a few cases with refractory MCL that recur after alloSCT. In this article, we review the literature on the evidence of the GVL effects in MCL and describe a patient with relapsed MCL shortly after high‐dose chemotherapy with autoSCT. The patient was then successfully treated with Bu/Cy/VP‐16 for an alloSCT followed by DLIs in a stepwise fashion. MNCs > 10 × 108/kg were collected by two large‐volume leukaphereses from the donor. Harvested stem cells from the 2nd day were cryopreserved for the future use as prophylactic DLIs to be given in a stepwise fashion. Cyclosporin and methotrexate were used for GVHD prophylaxis. He had achieved only a partial response by D+64 post transplant. G‐CSF‐primed cryopreserved DLIs were then infused on D+64 and D+92 to enhance the GVL effect. Grade 3 intestinal GVHD developed 20 days after the 2nd DLI and was partially controlled with the combination of cyclosporin, prednisone, and mycophenolate mofetil. Clinical complete remission was observed at D+112, and maintained until the last follow‐up day (D+615). Our findings suggest that alloSCT followed by prophylactic DLIs may offer a curative approach to refractory MCL. Am. J. Hematol. 65:75–80, 2000.

Prophylactic growth factor-primed donor lymphocyte infusion using cells reserved at the time of transplantation after allogeneic peripheral blood stem cell transplantation in patients with high-risk hematologic malignancies.

Standard allogeneic bone marrow transplantation (BMT) offers only a small chance of cure for most adult patients with advanced hematologic malignancies. The authors postulated that allogeneic peripheral blood stem cell transplantation (PBSCT) followed by prophylactic growth factor‐primed donor lymphocyte infusion (DLI) with cells reserved at harvest would maximize the graft‐versus‐tumor effects in patients with hematologic malignancies who had a high risk of recurrence.

Impact of transplanted CD34+ cell dose in allogeneic unmanipulated peripheral blood stem cell transplantation.

Summary:The impact of the CD34+ cell dose on chronic graft-versus-host disease (cGVHD) and the clinical outcome was analyzed in 41 consecutive adult patients submitted to allogeneic peripheral blood stem cell transplantation from HLA-identical siblings. The patients were classified into ‘low’ or ‘high’ CD34+ cell dose groups based on whether they received less or more than a median CD34+ cell dose of 10.5 × 106/kg, respectively. There was a significant difference in the incidence of extensive cGVHD (low vs high group, 25.0 vs 66.7%, P=0.021) and relapse (47.6 vs 20.0%, P=0.049) between the two groups. With a median follow-up of 335 days, the 3-year survival estimate for the whole population was 47.9%, while that for the low and high groups was 29.9 and 67.8%, respectively (P=0.0434). An inverse relation was noted between the relapse rate and the incidence of extensive cGVHD (P=0.043). It would appear reasonable that the optimal dose of CD34+ cells should be determined based on the disease status or aggressiveness of the malignant cells in each patient. Yet, in the case of patients with a high risk of relapse, transplantation with a CD34+ cell dose of >10.5 × 106/kg would seem to be acceptable to minimize the risk of relapse.

Prognostic significance of platelet recovery pattern after allogeneic HLA-identical sibling transplantation and its association with severe acute GVHD.

Thrombocytopenia (TP) is a frequent complication after allogeneic stem cell transplantation (SCT) and regarded as a poor prognostic factor when assessed beyond day 100. However, little is known about the clinical significance of the platelet recovery pattern before chronic graft-versus-host disease (GVHD) develops. Eighty-five patients undergoing HLA-identical sibling SCT were stratified according to their platelet recovery pattern between day +30 and +90 and the transplant outcomes analyzed, along with the association of each component of the acute GVHD grading system. Fifteen patients (18%) were classified with persistent TP, 33 patients (39%) with unstable TP, and 37 patients (43%) as non-TP. Persistent TP, which was strongly associated with severe acute GVHD (P<0.001), exhibited the worst 2-year OS (P<0.0001) and highest NRM (P<0.0001) and opportunistic infection rates (P<0.0001). In multivariate analyses, the platelet recovery pattern was identified as an independent prognostic factor (P=0.02) together with the disease risk (P=0.02) in terms of OS, and the only independent prognostic factor in terms of NRM (P=0.005) and the incidence of infectious events (P<0.001). Persistent TP was strongly associated with the development of extensive chronic GVHD (P=0.03). The platelet recovery pattern between day +30 and +90 can be used to predict the prognosis of SCT recipients.

Pilot study on the use of zoledronic acid to prevent bone loss in allo-SCT recipients

Bone loss is recognized as worsening the quality of life in long-term survivors of Allo-SCT. This study evaluated the risk factors associated with bone loss and the role of zoledronic acid in preventing bone loss in allogeneic recipients. Fifty-three patients who underwent HLA-matched Allo-SCT were evaluated for their bone mineral density (BMD) in the lumbar spine and femoral neck at regular intervals. Zoledronic acid (4u2009mg) was given i.v. to 18 patients (ZA patients) at 2 months after SCT and then every 3 months until 2 years. Grade 2–4 acute GVHD was associated with bone loss (odds ratio (OR)=4.90, 95% confidence interval (CI)=1.41–16.99; P=0.012) at 1 year after SCT, whereas extensive chronic GVHD and steroid use were both unfavorable prognostic factors (OR=9.00 and 7.22, 95% CI=1.52–53.40 and 1.44–36.22; P=0.016, respectively) in terms of osteopenia/osteoporosis at 2 years after transplantation. The use of zoledronic acid significantly prevented bone loss in the femoral neck as well as the spine (OR=0.18, 95% CI=0.05–0.69, P=0.012). Therefore, BMD measurements and the use of zoledronic acid are recommended in cases of GVHD or long-term steroid use after Allo-SCT to prevent bone loss and threatening skeletal events.

Clinical impact of hyperacute graft-versus-host disease on results of allogeneic stem cell transplantation.

Summary:The current study defines the incidence and clinical manifestations of hyperacute graft-versus-host disease (haGVHD; fever, skin rash, diarrhea, and hepatic dysfunction) and analyzes the risk factor and the impact of haGVHD on the results of allogeneic stem cell transplantation (SCT). In all, 90 patients underwent allogeneic SCT from 71 matched siblings or 19 alternative donors. Immediate high-dose steroids were administered to 22 patients who met the criteria. The overall incidence of haGVHD was 36.7% (n=34) and haGVHD was also strongly correlated with acute (aGVHD) (P<0.001) and extensive chronic GVHD (cGVHD) (P=0.007), and found to be associated with decreased probability of relapse (P=0.0017). Early intervention with steroids within 7 days after the diagnosis of haGVHD might be associated with better survival. A survival analysis of the overall survival and disease-free survival did not reveal any difference between haGVHD+ and haGVHD− groups. In multivariate analysis, the use of an alternative donor (P=0.020) was identified as the only risk factor. Immediate high-dose steroids were effective in treating haGVHD. We conclude that in an allogeneic setting, haGVHD is not an uncommon manifestation, associated with the development of aGVHD or cGVHD. The only risk factor for haGVHD was the use of an alternative donor.