Long-term follow-up after nonmyeloablative allogeneic hematopoietic stem cell transplantation for systemic sclerosis

Systemic sclerosis (SSc) characteristically consists of fibrotic changes in various organs, and immunological abnormality is the main cause of the disease. Although high-dose immunosuppressive therapies with autologous or allogeneic hematopoietic stem cell support can reverse the disease course, they have a high treatment-related mortality. We report the successful use of nonmyeloablative allogeneic hematopoietic stem cell transplantation (HSCT) for SSc. A 40-year-old woman with diffuse scleroderma and interstitial pneumonia underwent allogeneic peripheral blood stem cell transplantation from an HLA-identical sibling after conditioning with low-dose total-body irradiation and fludarabine. Prophylaxis for graft-versus-host disease (GVHD) consisted of cyclosporine and mycophenolate mofetil. No infection or acute GVHD developed. One year after transplantation, the patient developed membranous glomerulopathy caused by chronic GVHD that was successfully treated with prednisolone. The patient's skin score decreased dramatically, and her pulmonary function is stable 4 years after transplantation. Nonmyeloablative allogeneic HSCT may be more effective than conventional therapies for SSc.     

Risks and outcomes of invasive fungal infections in recipients of allogeneic hematopoietic stem cell transplants after nonmyeloablative conditioning

The incidence of invasive mold infections has increased during the 1990s among patients undergoing allogeneic hematopoietic stem cell transplantation (HCT) after myeloablative conditioning. In this study, we determined risk factors for invasive mold infection and mold infection-related death among 163 patients undergoing allogeneic HCT with nonmyeloablative conditioning. The cumulative incidence rates of proven or probable invasive fungal infections, invasive mold infections, invasive aspergillosis, and invasive candidiasis during the first year after allogeneic HCT with nonmyeloablative conditioning were 19%, 15%, 14%, and 5%, respectively, which were similar to those after conventional myeloablative HCT. Invasive mold infections occurred late after nonmyeloablative conditioning (median, day 107), with primary risk factors including severe acute graft-versus-host disease (GVHD), chronic extensive GVHD, and cytomegalovirus (CMV) disease. The 1-year survival after diagnosis of mold infections was 32%. High-dose corticosteroid therapy at diagnosis of mold infection was associated with an increased risk for mold infection-related death. Overall, nonrelapse mortality was estimated at 22% (36 patients) after nonmyeloablative conditioning, of which 39% (14 patients) were mold infection-related (9% of the overall mortality). More effective strategies are needed to prevent invasive mold infections, which currently account for a notable proportion of nonrelapse mortality after nonmyeloablative allogeneic HCT.     

Influence of the intensity of the conditioning regimen on the characteristics of acute and chronic graft-versus-host disease after allogeneic transplantation

The graft-versus-host disease (GVHD) characteristics of 150 consecutive patients undergoing reduced intensity conditioning allogeneic (allo-RIC) transplants and 88 patients undergoing myeloablative conditioning regimen were analysed. All patients received the same GVHD prophylaxis and peripheral blood stem cells from a human leucocyte antigen identical sibling. The cumulative incidence of acute GVHD (aGVHD) was 67% and 44% in the myeloablative and allo-RIC regimen groups, respectively (P < 0.001), and was 39% vs. 29%, respectively (P = 0.043), for grades 2-4 aGVHD. Only conditioning type (myeloablative versus allo-RIC) significantly influenced the incidence of aGVHD in multivariate analysis: Hazard ratio (HR) = 2.16 [95% confidence interval (CI): 1.52-3.07], P < 0.0001. The cumulative incidence of chronic GVHD (cGVHD) was 63% and 71% among myeloablative and allo-RIC patients respectively (P = 0.084). This trend was because of the higher incidence of limited cGVHD, but not extensive cGVHD among allo-RIC recipients [HR = 3.3 (95% CI: 1.42-8.08), P = 0.0017]. Moreover, among patients who developed cGVHD, the cumulative incidence of limited cGVHD was significantly lower in the myeloablative group than in the allo-RIC group (7% vs. 25%, P = 0.007). Duration of immunosuppression was shorter among allo-RIC patients (35.5% vs. 68.8% required systemic immunosuppression 36 months after transplant, P = 0.028). Although prospective controlled trials are required to further evaluate the effect of the conditioning regimen on GVHD, our results suggest that RIC modifies the incidence and characteristics of both acute and cGVHD after allogeneic transplantation, and decreases the immunosuppression requirements in long-term follow up when compared with myeloablative conditioning.     

Short Report: Engraftment of T-cell-depleted allogeneic haematopoietic stem cells using a reduced intensity conditioning regimen

Graft-versus-host disease (GVHD) remains a significant complication in patients undergoing allogeneic stem cell transplantation (SCT) using a reduced intensity conditioning regimen. Although T-cell depletion (TCD) reduces the risk of GVHD after a myeloablative conditioning regimen, it is associated with an increased risk of graft failure. We have therefore examined whether TCD compromises engraftment using a fludarabine-based conditioning regimen. Fifteen patients have been transplanted using such a regimen of whom 13 underwent ex vivo TCD. All but one patient demonstrated durable engraftment and no patient receiving a TCD product developed severe GVHD. Thus, TCD may play a role in GvHD prophylaxis using such regimens.     

Hepatic injury after nonmyeloablative conditioning followed by allogeneic hematopoietic cell transplantation: a study of 193 patients

Liver injury is a frequent, serious complication of allogeneic hematopoietic cell transplantation (HCT) following myeloablative preparative regimens. We sought to determine the frequency and severity of hepatic injury after nonmyeloablative conditioning and its relationship to outcomes. One hundred ninety-three consecutive patients who received 2 Gy total body irradiation with or without fludarabine were evaluated for end points related to liver injury. Patients with diseases treatable by HCT who were ineligible for conventional myeloablative allogeneic HCT because of advanced age and/or comorbid conditions were included. Fifty-one patients (26%) developed hyperbilirubinemia of 68.4 microM (4 mg/dL) or greater, most commonly resulting from cholestasis due to graft-versus-host disease (GVHD) or sepsis. Pretransplantation factors associated with liver dysfunction were a diagnosis of aggressive malignancy (hazard ratio [HR] 1.9; P =.04) and the inclusion of fludarabine in the conditioning regimen (HR 1.8; P =.07). Overall survival at 1 year was superior for patients who had maximal serum bilirubin levels in the normal (78%) or minimally elevated (22.23-66.69 microM [1.3-3.9 mg/dL]) ranges (69%) compared with those in the 68.4 to 117.99 microM (4-6.9 mg/dL; 20%), 119.7 to 169.29 microM (7.0-9.9 mg/dL; 17%), and 171.0 microM (10 mg/dL; 19%) or greater groups. In summary, significant jaundice occurred in 26% of patients and was predominantly due to cholestasis resulting from GVHD and/or sepsis. Aggressive malignancies (mainly advanced disease) and later development of jaundice after transplantation predicted inferior survival.     

Allogeneic hematopoietic stem cell transplantation in ovarian carcinoma: results of five patients

Allogeneic hematopoietic stem cell transplantation is often used to treat hematologic malignancies. The efficacy of this procedure is due to both myeloablative conditioning and graft-versus-leukemia (GVL). However, the disadvantages of allogeneic transplantation include graft-versus-host disease (GVHD), relapse from the original tumor, and patient susceptibility to opportunistic infections. Lately, allogeneic transplantation has been developed to treat solid tumors, with the expectation that graft-versus-tumor (GVT), like GVL, will have a significant anti-tumor effect. This effect has been demonstrated in renal carcinomas, and with less evidence in breast cancers. Five patients with malignant ovarian tumors resistant to chemotherapy underwent allogeneic transplantation, four from bone marrow, and one from peripheral blood stem cells. All donors were HLA-identical siblings. One patient received a myeloablative conditioning regimen, while the other four received a non-myeloablative regimen. Two patients received donor lymphocyte infusions (DLI). Four of the patients presented with acute or chronic GVHD associated with tumor regression of at least 50%. These tumor regressions were measured by CA-125 levels and CT scans. The fifth patient died of rapid progression just after transplantation. Of the four transplantation survivors, three received a non-myeloablative regimen which did not seem to reduce treatment effectiveness. While it did reduce toxicity, one of these patients died of GVHD after 127 days. DLI was administered to two patients. These infusions seemed to promote GVHD which was able to control disease progression for one patient and had no apparent effect on the other. Allograft of hematopoietic stem cells might be of interest in ovarian cancer. The results in one patient also suggest that DLI may be an effective immunotherapy, although doses and timing need to be determined. The number of cases presented is small, however, and clinical experience on a larger scale will be required to determine the real clinical efficacy of graft versus cancerous ovarian cells.     

Autologous stem cell transplantation in a patient with diffuse systemic sclerosis

Systemic Sclerosis (SSc) is a systemic disease of unknown etiology presenting with disseminated skin thickening and fibrotic impairment of various organs including lung and kidney. According to the rate and degree of skin involvement, SSc can be classified in a limited and a diffuse form, the latter showing a severe and progressive lung involvement, which is responsible for its high related morbidity and mortality along with resistance to standard therapeutic protocols. High dose chemotherapy, followed by autologous stem cell transplantation, is a standard therapeutic regimen for haematological diseases: re-infusion of mobilised peripheral blood progenitor cells overcomes the myeloablative effect of super-maximal eradicative doses of chemotherapeutic agents. Recently, this therapeutic approach has been applied in some cases of resistant SSc and, albeit the low number of cases, it has been proven effective in early diagnosed and rapidly progressive forms of the disease showing a clinical improvement and an instrumentally detectable decrease of fibrosis extent. We report the case of a young woman affected by diffuse SSc with a rapid progression of clinical signs and instrumentally detectable lesions who underwent a conditioning regimen with fludarabine, cyclophosphamide and anti-thymoglobulines followed by re-infusion of autologous peripheral blood stem cells. Two years after transplantation a clinical and instrumental evidence of treatment was observed, with good control of disease evolution. The only sign of disease resumption was a slow worsening of skin involvement.     

Curative therapies: Allogeneic hematopoietic cell transplantation from matched related donors using myeloablative,reduced intensity,and nonmyeloablative conditioning in sickle cell disease

Sickle cell disease (SCD) chronically damages multiple organs over the lifetime of affected individuals. Allogeneic hematopoietic cell transplantation (allo-HCT) is the most studied curative intervention. Fully matched related marrow, peripheral blood derived, or cord blood HCT have the best transplant outcome for symptomatic patients with SCD. For patients with asymptomatic or milder disease who have this donor option available, risks and benefits of HCT should be discussed among the patient, family, treating hematologist, and transplant physician, and decision to proceed to HCT should be individualized. Myeloablative conditioning with busulfan, cyclophosphamide, and ATG has been a commonly employed regimen for children and young adults. Recently, low intensity conditioning with low dose total body irradiation and alemtuzumab is emerging as an efficacious and safe regimen for adults, young adults, and possibly children. Mixed donor chimerism (minimum ≥20% myeloid cells), from myeloablative or nonmyeloablative conditioning regimen, produces robust normal donor erythropoiesis and is sufficient to provide a clinical cure. The proportion of patients remaining on immunosuppression beyond 2 years post-HCT is likely <10% with either myeloablative or low intensity regimens. Late effects from myeloablative or reduced intensity conditioning, or from several more months of immunosuppression in low intensity conditioning may be less common than those observed in HCT for malignant indications. Nonmyeloablative approaches with low toxicities should be the focus of future research efforts. Prevention of GVHD is a shared goal in all approaches of allo-HCT in SCD.     

Influence of immunosuppressive treatment on risk of recurrent malignancy after allogeneic hematopoietic cell transplantation

This study was conducted to elucidate the influence of immunosuppressive treatment (IST) and GVHD on risk of recurrent malignancy after allogeneic hematopoietic cell transplantation (HCT). The study cohort included 2656 patients who received allogeneic HCT after high-intensity conditioning regimens for treatment of hematologic malignancies. Rates and hazard ratios of relapse and mortality were analyzed according to GVHD and IST as time-varying covariates. Adjusted Cox analyses showed that acute and chronic GVHD were both associated with statistically similar reductions in risk of relapse beyond 18 months after HCT but not during the first 18 months. In patients with GVHD, resolution of GVHD followed by withdrawal of IST was not associated with a subsequent increase in risk of relapse. In patients without GVHD, withdrawal of IST was associated with a reduced risk of relapse during the first 18 months, but the risk of subsequent relapse remained considerably higher than in patients with GVHD. In summary, the association of GVHD with risk of relapse changes over time after HCT. In patients without GVHD, early withdrawal of IST might help to prevent relapse during the first 18 months, but other interventions would be needed to prevent relapse at later time points.     

Acute leukemia in adults: novel allogeneic transplant strategies

Acute myeloid leukemia (AML) is the most common indication for hematopoietic cell transplantation (HCT). Significant improvements in histocompatibility testing have resulted in identifying better alternative donors to provide grafts; coupled with expanding use of reduced-intensity conditioning (RIC) regimens, patient outcomes have improved. Most AML patients in complete remission now can undergo allogeneic HCT procedures with an anticipated result that approaches that obtained with sibling donors and myeloablative conditioning (MAC). Treatment-related mortality (TRM), relapse, GVHD and, for umbilical cord blood (UCB) grafts, slow engraftment/engraftment failures, however, continue to plague HCT. Newer strategies include the use of double unit UCB HCT and ex vivo expansion of UCB units using: multipotent mesenchymal stromal cells (MSCs); polyamine copper chelator tetraethylenepentamine (TEPA); and Notch ligand. Haploidentical bone marrow and blood HCT are increasing in numbers given the improved outcome with post-HCT cyclophosphamide therapy. Novel chemotherapeutic preparative regimens incorporating agents such as clofarabine and treosulfan, and novel radiation preparative regimens utilizing selective radiation approaches (helical tomotherapy) and targeted myeloablative radioimmunotherapy appear to enhance the anti-AML effect. Immunological approaches with chimeric antigen receptor-redirected T lymphocytes have been added to the armamentarium. Other novel maneuvers include more sophisticated T-cell depletion of the donor graft and post-transplant immunotherapy with regulatory T cell (Treg) therapy and MSCs for GVHD prevention. These and other strategies are improving the outlook of AML HCT recipients.     

Allogeneic hematopoietic cell transplantation for metastatic breast cancer

We reviewed 66 women with poor-risk metastatic breast cancer from 15 centers to describe the efficacy of allogeneic hematopoietic cell transplantation (HCT). Median follow-up for survivors was 40 months (range, 3-64). A total of 39 patients (59%) received myeloablative and 27 (41%) reduced-intensity conditioning (RIC) regimens. More patients in the RIC group had poor pretransplant performance status (63 vs 26%, P=0.002). RIC group developed less chronic GVHD (8 vs 36% at 1 year, P=0.003). Treatment-related mortality rates were lower with RIC (7 vs 29% at 100 days, P=0.03). A total of 9 of 33 patients (27%) who underwent immune manipulation for persistent or progressive disease had disease control, suggesting a graft-vs-tumor (GVT) effect. Progression-free survival (PFS) at 1 year was 23% with myeloablative conditioning and 8% with RIC (P=0.09). Women who developed acute GVHD after an RIC regimen had lower risks of relapse or progression than those who did not (relative risk, 3.05: P=0.03), consistent with a GVT effect, but this did not affect PFS. These findings support the need for preclinical and clinical studies that facilitate targeted adoptive immunotherapy for breast cancer to explore the benefit of a GVT effect in breast cancer.     

Hematopoietic cell transplantation after reduced-intensity conditioning for older adults with acute myeloid leukemia in complete remission

PURPOSE OF REVIEW: Allogeneic hematopoietic cell transplantation with myeloablative conditioning is a well established therapy for patients with acute myeloid leukemia. Its efficacy depends, in part, on the destruction of recipient acute myeloid leukemia cells by the conditioning regimen and, in part on their removal by donor immune cells contained in the graft (graft-versus-tumor effect). Due to regimen-related toxicities, the use of myeloablative allogeneic hematopoietic cell transplantation has been restricted to younger patients in good condition. More recently, the introduction of allogeneic hematopoietic cell transplantation following reduced-intensity or nonmyeloablative conditioning regimens, which rely mainly on graft-versus-tumor effects for tumor cell eradication, has permitted extending hematopoietic cell transplantation to include older patients and those with medical comorbidities. RECENT FINDINGS: Early results with allogeneic hematopoietic cell transplantation after nonmyeloablative and reduced-intensity conditioning for patients with acute myeloid leukemia in first complete remission are encouraging, with 2-year survivals after hematopoietic cell transplantation ranging from 48 to 79% among studies. Further, retrospective studies have demonstrated similar outcomes in adult patients with acute myeloid leukemia in complete remission given either myeloablative or nonmyeloablative conditioning. SUMMARY: Prospective studies are needed to define the place of allogeneic hematopoietic cell transplantation after nonmyeloablative or reduced-intensity conditioning in patients with acute myeloid leukemia in complete remission, and to determine a role for consolidation chemotherapy before hematopoietic cell transplantation, if any.     

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.     

Pathogenesis of graft-versus-host disease: innate immunity amplifying acute alloimmune responses

In addition to reduced-intensity conditioning, which has expanded the eligibility for hematopoietic cell transplantation (HCT) to older patients, increased availability of alternative donors, including HLA-mismatched unrelated donors, has increased access to allogeneic HCT for more patients. However, acute graft-versus-host disease (GVHD) remains a lethal complication, even in HLA-matched donor–recipient pairs. The pathophysiology of GVHD depends on aspects of adaptive immunity and interactions between donor T-cells and host dendritic cells (DCs). Recent work has revealed that the role of other immune cells and endothelial cells and components of the innate immune response are also important. Tissue damage caused by the conditioning regimen leads to the release of exogenous and endogenous “danger signals”. Exogenous danger signals called pathogen-associated molecular patterns and endogenous noninfectious molecules known as damage-associated molecular patterns (DAMPs) are responsible for initiating or amplifying acute GVHD by enhancing DC maturation and alloreactive T-cell responses. A significant association of innate immune receptor polymorphisms with outcomes, including GVHD severity, was observed in patients receiving allogeneic HCT. Understanding of the role of innate immunity in acute GVHD might offer new therapeutic approaches.     

Low incidence and severity of graft-versus-host disease after outpatient allogeneic peripheral blood stem cell transplantation employing a reduced-intensity conditioning

Background: The prevalence and features of graft‐versus‐host disease (GVHD) in patients receiving allografts using peripheral blood stem cells (PBSCs) after a reduced‐intensity conditioning (RIC) regimen are not well known. Several features of GVHD in patients at two institutions using RIC were assessed. Methods: We analysed the overall survival (OS) and prevalence of GVHD in patients who underwent outpatient allogeneic PBSC transplantation after RIC between October 1998 and July 2008. Results: We included 301 patients with a median age of 30 yrs (range, 1–71 yrs). In 37 cases, allogeneic peripheral blood stem cell transplantation was indicated for non‐malignant disease, and in 264 for malignant disease. The median OS was 35 months. The estimated 3‐yr OS was 48%. A total of 154 patients developed GVHD: there were 64 acute, 50 chronic and 40 cases that progressed from acute to chronic. Of the 104 patients with acute GVHD (aGVHD), 40% had grade I and 60% had grades II–IV. Of the 90 patients with chronic GVHD (cGVHD), 67% had limited and 33% had extensive forms. A total of 160 patients died, 40 as a result of GVHD (24 from aGVHD and 16 from cGVHD), 50 as a result of progressive disease and 70 from diverse causes. Conclusions: The incidence of GVHD was lower than in other series using conventional myeloablative preparative regimens. Most importantly, the severity of GVHD did not significantly affect the long‐term survival.     

Allogeneic nonmyeloablative hematopoietic cell transplantation in metastatic colon cancer: tumor-specific T cells directed to a tumor-associated antigen are generated in vivo during GVHD

A pilot study was conducted to evaluate safety and activity of nonmyeloablative allogeneic hematopoietic cell transplantation (HCT) in colorectal carcinoma (CRC) and to determine whether a T-cell response to a tumor-associated antigen (TAA) was induced. Fifteen patients with metastatic CRC underwent HCT from human leukocyte antigen (HLA)-matched siblings after a nonmyeloablative conditioning regimen. All patients engrafted with a median donor T-cell chimerism of 72% at day +56. Eight patients experienced grades II to IV acute graft-versus-host disease (GVHD). Despite progressive disease before HCT, partial remission and disease stabilization longer than 90 days were observed in 1 and 3 patients, respectively. Induction of TAA-specific T cells was evaluated with a carcinoembryonic antigen (CEA)-specific HLA-A(*)0201 pentamer in 6 patients with CRC. CEA-specific CD8(+) T cells were detected in 3 of 3 patients concomitant with GHVD onset, but not in 3 of 3 patients without GVHD. They were also not detected in 9 of 9 control patients with GVHD who received transplants for diagnoses other than CRC. Antitumor activity of CEA-specific T cells was also validated in vitro. In one patient, the induction of CEA-specific T cells was associated with a decrease of serum CEA levels and a partial response. Thus, graft-versus-host reactions associated with allogeneic HCT can trigger the generation of T cells specific for CEA, and this may be associated with a clinical response.     

Autologous non-myeloablative hematopoietic stem cell transplantation in patients with systemic sclerosis

Autologous hematopoietic stem cell transplantation (HSCT) utilizing a myeloablative regimen containing total body irradiation has been performed in patients with systemic sclerosis (SSc), but with substantial toxicity. We, therefore, conducted a phase I non-myeloablative autologous HSCT study in 10 patients with SSc and poor prognostic features. PBSC were mobilized with CY and G-CSF. The PBSC graft was cryopreserved without manipulation and re-infused after the patient was treated with a non-myeloablative conditioning regimen of 200 mg/kg CY and 7.5 mg/kg rabbit antithymocyte globulin. There was a statistically significant improvement of modified Rodnan skin score whereas cardiac (ejection fraction, pulmonary arterial pressure), pulmonary function (DLCO) and renal function (creatinine) remained stable without significant change. One patient with advanced disease died 2 years after the transplant from progressive disease. After median follow-up of 25.5 months, the overall and progression-free survival rates are 90 and 70% respectively. Autologous HSCT utilizing a non-myeloablative conditioning regimen appears to result in improved skin flexibility similar to a myeloablative TBI containing regimen, but without the toxicity and risks associated with TBI.     

Positive impact of chronic graft‐versus‐host disease on the outcome of patients with de novo myelodysplastic syndrome after allogeneic hematopoietic cell transplantation: a single‐center analysis of 115 patients

To evaluate the impact of graft‐versus‐host disease (GVHD) and prognostic factors for patients with myelodysplastic syndrome (MDS) after allogeneic hematopoietic cell transplantation (allo‐HCT), we retrospectively reviewed 115 patients with MDS or acute myeloid leukemia with multilineage dysplasia (AML‐MLD) after allo‐HCT at our center. Eighty one patients received reduced‐intensity conditioning (RIC) regimens, whereas 34 received myeloablative conditioning regimens. Although the RIC group was significantly older and included more patients with poor cytogenetic risk, no difference in 4‐yr overall survival (OS) was seen between the two groups. In a multivariate analysis, covariates associated with a worse OS were the French‐American‐British stage of refractory anemia excess blasts in transformation/AML‐MLD at peak, poor cytogenetic risk, bone marrow blasts of 20% or higher at HCT and the absence of chronic GVHD (cGVHD). By using semi‐landmark analyses, we found that the presence of cGVHD significantly improved OS in high‐risk patients or the RIC group. However, there was no difference in OS between those with and without cGVHD among low‐risk MDS patients. These findings suggest that the graft‐versus‐leukemia effect may be more beneficial in high‐risk patients who do not receive intensive preparative regimens.     

Allogeneic hematopoietic cell transplantation for paroxysmal nocturnal hemoglobinuria

BACKGROUND: Although allogeneic hematopoietic cell transplantation (HCT) has a potential to cure patients with paroxysmal nocturnal hemoglobinuria (PNH), appropriate indication and conditioning regimen for HCT have not been established. PATIENTS AND METHODS: Between July 1999 and December 2001, five patients with PNH underwent allogeneic HCT: three for refractory hemolysis and two for aggravating cytopenia. Four patients with hypercellular marrow received Bu-Fludara-ATG (busulfan 4 mg/kg/d for 2 d, fludarabine 30 mg/m2/d for 6 d, and ATG 20 mg/kg/d for 4 d) for conditioning therapy and one patient with hypocellular marrow was conditioned with Cy-ATG (cyclophosphamide 50 mg/kg/d for 4 d and ATG 30 mg/kg/d for 3 d). Three patients received stem cell graft from matched sibling donor and two patients from 1-antigen mismatched unrelated donor. RESULTS: One patient who was conditioned with Bu-Fludara-ATG failed to engraft and died at post-transplant day 62. The other four patients showed three lineage engraftment and normal expression of CD55 and CD59 antigens by flow cytometric analysis. They are alive with stable engraftment and full donor chimerism between post-transplant day 510 and 1116. Acute graft vs. host disease (GVHD) of grade II or more occurred in two patients and extensive chronic GVHD in four. CONCLUSION: HCT using related or unrelated donor could eradicate PNH clones and may cure patients with the disease. Further studies are needed to establish the role of allogeneic HCT, especially with reduced intensity conditioning therapy, in the treatment of PNH.     

The graft-versus-leukemia effect of nonmyeloablative stem cell allografts may not be sufficient to cure chronic myelogenous leukemia

We treated 12 patients with chronic myelogenous leukemia (CML) with a low-intensity preparative regimen followed by allogeneic stem cell transplantation in an attempt to confer a curative graft-versus-leukemia (GVL) effect with minimum morbidity. Seven patients in first chronic phase (CP1) and five in second chronic phase (CP2) (age 15-68 years) received a nonmyeloablative conditioning regimen of fludarabine and cyclophosphamide, followed by a G-CSF-mobilized peripheral blood stem cell (PBSC) transplant from an HLA-identical sibling. Cyclosporine (CsA) was used for graft-versus-host disease (GVHD) prophylaxis. Median follow-up was 384 days. Neutrophil recovery occurred at a median of 12 days. There was no transplant-related mortality. Of the seven CP1 patients transplanted, seven achieved a stable molecular remission; two with no post-transplant intervention, three after donor lymphocytes, imatinib and interferon, and two after a myeloablative stem cell transplant. Four of five CP2 patients died in blast crisis and one survived in molecular remission. Of the 12 patients with durable engraftment, six had Grades II-IV acute GVHD; six had limited chronic GVHD. These results suggest that cytoreduction is required to optimize the curative effect of allogeneic stem cell transplantation for CML.