Reduced-intensity Hematopoietic Stem Cell Transplantation Research Articles

Hematopoietic Chimerism in Patients with Hematological Malignancies Treated with Donor Lymphocyte Infusions Combined with IL-2 for Relapse after Allogeneic Stem Cell Transplantation.

Donor lymphocyte infusions (DLI) are considered to be the treatment of choice in pts with relapses after allogeneic hematopoietic stem cell transplantation (HSCT). This kind of treatment is based on alloreactivity of donor lymphocytes, mediating a graft-versus-leukemia (GVL) effect. However, the relapses of acute leukemia in many cases are not susceptible to DLI. There were few reports that the concominant administration of cytokines (IL-2, IFN-alfa) and DLI is more efficient for conversion to complete donor chimerism (CC) from mixed chimerism (MC) and leads to remission in pts relapsed after HSCT, but the significance of this therapy is still not estimated. The aim of study was to evaluate the efficacy of DLI treatment combined with IL-2 i.v. administration for CC establishment and remission induction in pts with relapses after HSCT for hematological malignancies. 26 pts were treated with DLI for relapses after ASCT from related siblings in 2001–2007. 12 of them were included in the study. Median age was 25 y (16–44), 9 men/3 woman, 4 pts with AML, 1 - APL, 1 - ALL, 1 -ANL, 3 -CML, 2- MDS. 2 pt received reduced intensity HSCT, 10- conventional one. Median time to relapse was 12,5 months (3,5 – 48 months).10 pts demonstrated hematological relapses, 1 pt with APL and 1 pt with CML - molecular relapses. All pts with AL in overt relapse received chemotherapy first and then DLI was performed in aplasia. CML pts were treated with Hydrea and Glivec and then DLI were administrated. Median dose of infused DL was 6,34 x 108/kg (median 6 transfusions per pt) with median of CD3+ cells. Chimerism status was investigated on BM and PB using VNTR/STR analysis at relapse, before every DLI and monthly after DLI completion. All pts demonstrated MC in bone marrow before chemotherapy (median 74% of host DNA). 9 pts were still MC after chemotherapy and before DLI (median 38% of host DNA), 3 pts became CC before DLI. In all pts DLI were combined with IL-2 (2–6 MU with every DLI). In 6 pts with MC after chemotherapy only 1 (with CML) became CC after 1 course of DLI and developed aGVHD II–III and then cGVHD. 5 pts (with AL and MDS) after DLI were still MC remaining in hematological remission. One of them died of CMV infection. 2 pts recieved the 2nd course of DLI + IL-2, became CC and are still well and alive (1 - with cGVHD, 1 - without GVHD) for 30 months. For 2 pts (AML) with MC 2nd DLI course was not possible (donor was not available) and they received the course of IL-2 (5 days for 6 MU daily) in 2 months after DLI. The both are in complete remission with CC and cGVHD. 4 pts showed no effect and soon relapsed despite the 2nd DLI course in 2 pt and 2nd course of IL-2 in 1 pt. Despite the small and heterogenious group we may conclude, that DLI administration concomitantly with IL-2 leads to more prominent GVL effect and quick conversion from MC to CC. The interesting observation is that the additional infusions of IL-2 were effective for conversion to CC and remission induction in 3 of 4 pts resistant for DLI.

Risk factors and attributable mortality of late aspergillosis after T‐cell depleted hematopoietic stem cell transplantation

Invasive aspergillosis occurs in 5-15% of allogeneic hematopoietic stem cell transplant (HSCT) recipients. Through the 1990s there has been an increase in the incidence of late aspergillosis (LA). We report on the incidence, risk factors, and attributable mortality of LA in a cohort of 398 adult and pediatric patients at Memorial Sloan-Kettering Cancer Center from January 1999 through December 2003. LA was defined as occurring > 40 days post HSCT. LA cases were identified by prospective surveillance and examination of a computerized database. Probable or definite aspergillosis was defined by standard EORTC/MSG criteria. Mortality was attributed to LA if it caused or significantly contributed to death. The overall incidence of LA in our cohort was 4.1%. Median time from stem cell infusion to diagnosis of LA was 164 days (range 68-677) after HSCT. The incidence of LA among unmodified, T-cell depleted, or reduced intensity HSCT was 2.2%, 4%, and 6.8%, respectively (P not significant). Risk factors for LA were grade II-IV acute graft-versus-host disease (GVHD) (P=0.002), chronic GVHD (P=0.01), secondary neutropenia (P=0.02), and reduced intensity conditioning containing alemtuzumab (P=0.01). LA was the immediate cause of death in 1 of 10 (10%) T-cell depleted, 2 of 2 (100%) unmodified, and 1 of 4 (25%) of reduced-intensity HSCT. LA developed a median 164 days post HSCT. All-cause 30-day mortality of LA was 56.3%. The majority of LA cases died of concurrent infections and not from invasive aspergillosis.

Host T Cells Affect Donor T Cell Engraftment and Graft-versus-Host Disease after Reduced-Intensity Hematopoietic Stem Cell Transplantation

Mixed chimerism in the T cell compartment (MC T) after reduced-intensity stem cell transplantation (RIST) may influence immune repopulation with alloreactive donor T cells. We examined effects of host T cell numbers on donor T cell engraftment and recovery and on acute graft-versus-host disease (aGVHD) in a relatively homogeneous patient population with respect to residual host T cells through quantified immune depletion prior to RIST and to donor T cells by setting the allograft T cell dose of 1 × 10 5 CD3 + cells/kg. In this setting, 2 patterns of early donor T cell engraftment could be distinguished by day +42: (1) early and complete donor chimerism in the T cell compartment (FDC T) and (2) persistent MC T. FDC T was associated with lower residual host CD8 + T cell counts prior to transplant and aGVHD. With persistent MC T, subsequent development of aGVHD could be predicted by the direction of change in T cell donor chimerism after donor lymphocyte infusion, and no aGVHD occurred until FDC T was established. MC T did not affect recovery of donor T cell counts. These observations suggest that the relative number and alloreactivity of donor and host T cells are more important than the absolute allograft T cell dose in determining donor engraftment and aGVHD after RIST.

Reduced intensity compared with high dose conditioning for allotransplantation in acute myeloid leukemia and myelodysplastic syndrome: A comparative clinical analysis

We evaluated the efficacy of hematopoietic stem cell transplantation (HSCT) using reduced intensity (RI) vs. myeloablative (MA) conditioning for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome. Thirty two patients (median age 54) who underwent a RI HSCT (2000-2003) were compared with 187 patients (median age 39) who received a MA transplant (1990-2003). Neutrophil engraftment was more rapid in the RI group (median 11.5 vs. 21 days). Platelet recovery was similar and graft failure was infrequent. The incidence of graft-versus-host disease (GVHD) and treatment-related mortality was similar though relapse was more frequent after RI conditioning (RR 2.2 [95% CI = 1.1-4.6] P = 0.03). At 2 years, disease-free survival (DFS) (31% vs. 30%, P > 0.1) and overall survival (33% vs. 35%, P > 0.1) were comparable between RI and MA groups, respectively. We suggest that RI allografts can yield satisfactory DFS both for older as well as younger patients with pre-existing comorbidities, who are ineligible for MA allografts. Advances in GVHD management and new approaches for relapsed or refractory disease are necessary to improve these outcomes.

Histopathological bone marrow changes after reduced‐intensity hematopoietic stem cell transplantation for follicular lymphoma involving bone marrow

Allogeneic stem cell transplantation (allo-SCT) is used as curative therapy for malignant lymphoma, and reduced-intensity hematopoietic stem cell transplantation (RIST) is sometimes performed to avoid the toxicity and mortality associated with myeloablative allo-SCT. RIST is generally preferred for elderly patients with malignant lymphoma. A 62-year-old woman with follicular lymphoma (FL) involving bone marrow (BM) suffered relapse after autologous SCT. RIST was performed; cells were from an unrelated, fully human leukocyte antigen-matched donor. To study the hematopoietic reconstitution, BM biopsy specimens that were obtained at different times after RIST, were evaluated. Engraftment of donor cells was observed on days 19 and 48 after RIST, and residual FL in BM had completely disappeared by day 73 after RIST. This is the first report to document histological BM regeneration after RIST and disappearance of FL involving the BM.

361: Superior disease-free survival in acute myelogenous leukemia/myelodysplastic syndrome receiving reduced-intensity allogeneic hematopoietic stem cell transplantation from unrelated donors using fludarabine, busulfan, and total lymphoid irradiation

361: Superior disease-free survival in acute myelogenous leukemia/myelodysplastic syndrome receiving reduced-intensity allogeneic hematopoietic stem cell transplantation from unrelated donors using fludarabine, busulfan, and total lymphoid irradiation

Successful Reinduction of Remission by DLI for Relapsing Infant AML after Reduced-Intensity Hematopoietic Stem Cell Transplantation

Successful Reinduction of Remission by DLI for Relapsing Infant AML after Reduced-Intensity Hematopoietic Stem Cell Transplantation

Ex-Vivo Reduction of Allograft T Cell Dose Does Not Prevent Acute Graft-vs-Host Disease after Reduced-Intensity Hematopoietic Stem Cell Transplantation.

Allograft T cell depletion (TCD) reduces acute graft-vs. host disease (aGVHD) after myeloablative hematopoietic stem cell transplantation (HSCT). Lower incidences of aGVHD reported after reduced-intensity stem cell transplantation (RIST) may reflect delayed donor T cell engraftment. We compared the incidence of aGVHD following RIST with TCD (19 patients (pts) vs. T cell replete (TCR) allografts (20 pts)(Table). There was no difference in the incidence aGVHD, occurring in 71% of TCD recipients (median onset Day 47) and 70% of TCR recipients (median onset Day 25). After TCD, 100% of those who engrafted prior to any DLI developed aGVHD compared with 56% of those who engrafted after DLI, including two pts who developed “late-acute” aGVHD after Day 100, upon completion of donor T cell engraftment. T cell engraftment after TCD was uneven: engraftment kinetics were associated with residual host circulating CD8+ T cell counts after immune depletion; and aGVHD did not occur in the setting of mixed T cell chimerism (Figure). These observations demonstrate that aGVHD can occur with very low doses (105/kg) of allograft T cells after RIST. Protection from aGVHD conferred by mixed T cell chimerism may be lost with full donor T cell engraftment. With limited donor T cell numbers, host T cells appear to determine kinetics of engraftment and of aGVHD after RIST. Figure:Post-induction circulating CD8+ T cell counts in TCD recipients with delayed donor T cell engraftment.After TCD, all subjects who developed aGVHD did so at or after the establishment of T cell full donor T cell chimerism, and occasionally prior to any DLI.Shaded triangle represents the theoretical area in which values would fall if subjects developed aGVHD prior to complete donor T cell engraftment. Arrows: DLI.Patient and Transplant Characteristics and OutcomesProtocolTCDTCRMedian (range)Median (range)Recipient Age43 years (32 – 56)44 (19 – 67)CMV Risk14/1916/20Pretransplant Immune DepletionFlu/CyEPOCH-FConditioning RegimenFlu/CyFlu/CyPre-conditioning Host Cell Counts:CD386 (1 – 701)140 (21 – 441)CD4, p=0.01744 (1 – 156)71 (12 – 191)CD834 (0 – 555)55 (2 – 309)NK58 (0 – 376)88 (3 – 467)Day 0 CD3 Cell Count1 (1 – 6)5 (0 – 42)Allograft CD34+ cells/kg7.75 x 106 (5.1 – 12.9)7.68 x 106 (4.6–18.4)Allograft CD3+ cells/kg1.0 x 105 (preset)3.63 x 108 (1.5 – 8.3)Donor T cell engraftmentDay +70 (14 – 180)14 (14 – 100)Flu/Cy: Fludarabine and cyclophosphamide; EPOCH-F: Etoposide, doxorubicin, vincristine, cyclophosphamide, prednisone and fludarabine; FDC: Full donor chimerism. [Display omitted]

The Role of Telomerase Activity and Telomere Length in Cellular Sensitivity to DNA Damaging Agents.

Dyskeratosis congenita (DC) is a premature aging syndrome characterized by progressive bone marrow failure, abnormal skin pigmentation and nail dystrophy. We have described an autosomal dominant form of DC (AD DC) in a large three-generation kindred that is due to a mutation in the gene encoding human telomerase RNA (hTR). While telomere shortening is a normal consequence of the aging process, DC patients display extremely short telomeres in many somatic cell types, including hematopoietic cells, and they often suffer from bone marrow failure. Allogeneic hematopoietic stem cell transplant (HSCT) remains the only curative therapy for marrow failure in DC. However, HSCT in DC is generally poorly tolerated and associated with significant morbidity, perhaps as a consequence of increased sensitivity of dividing cells to cytotoxic agents during myeloablative therapy. To test this hypothesis, we characterized lymphocytes from various AD DC patients and age matched controls that had been placed in long term culture following in vitro exposure to irradiation (137Cs) and varying doses of Taxol, Adriamycin, and Etoposide. Cell proliferation and viability were quantified by direct visual counting on a hemocytometer, and flow cytometry was employed to assess apoptosis and cell surface expression of senescent markers. In addition to DC lymphocytes having a decreased proliferative capacity and higher basal apoptotic levels, an increased sensitivity to irradiation, Taxol, Adriamycin, and Etoposide was noted. These results suggest that telomere shortening may be an important factor in determining cellular tolerance to cytotoxic therapy and support the concept of reduced intensity HSCT regimens in both aged individuals and DC patients. Further studies have been initiated to determine whether reconstitution of telomere length in DC cells alters response to cytotoxic agents.

Age-Related Risk of Non-Relapse Mortality Associated with Acute Graft-Versus-Host Disease.

Background: Although acute GVHD (aGVHD) is a significant cause of non-relapse mortality (NRM) after allogeneic hematopoietic stem cell transplantation (HSCT), its impact on outcomes has not been fully evaluated in older patients who receive reduced-intensity HSCT (RIST).Patients and Methods: We retrospectively surveyed the data of 334 patients (median age, 46 years: range, 1–68) with hematological malignancies who underwent allogeneic HSCT between January, 2000, and June, 2005. The diagnoses included AML/MDS (n=164), CML (n=31), ALL (n=39), lymphoma (n=95), and other malignancies (n=5). Sixty-nine patients (21%) had low- and 265 (79%) had high-risk disease. Patients were conditioned with a fludarabine-based reduced-intensity (n=169) or conventional myeloablative regimen (n=165). Patients received bone marrow (n=131), G-CSF-mobilized PBSC (n=173) or cord blood (n=30) from either an HLA-matched relative (n=138), a mismatched relative (n=41) or an unrelated volunteer (n=155). The median follow-up of surviving patients was 1,210 days (range, 346–2,317).Results: Grade II-IV aGVHD occurred in 146 patients (44%; grade II, n=82; grade III, n=43; grade IV, n=21), 73 patients each in the myeloablative and RIST groups, and the timing was before disease progression or relapse in 144 patients. The incidence of NRM in these 144 patients with aGVHD was 41% (59/144), while this was 29% in the overall 334 patients. The causes of NRM included GVHD (n=22), infections with (n=19) or without (n=9) GVHD, and others (n=9). Hence, aGVHD was the primary cause of NRM. Among these 144 patients with grade II-IV aGVHD, 121 (84%) received ≥1 mg/kg/day of methylprednisone as a primary treatment for GVHD, and 19 of the 121 patients (16%) required additional treatment including switching to tacrolimus (n=11), MMF (n=9), or ATG (n=4). Subsequently, 93 patients (65%) developed chronic extensive GVHD (46 progressive and 47 quiescent). The 2-year probability of NRM after the development of aGVHD was higher as the patient age increased; i.e. 29% for <40 years, 41% for 40–49 years, 55% for 50–59 years, and 67% for ≥60 years (Figure). The 2-year NRM in patients who developed stage 2–4 gut and liver GVHD was significantly higher than that in those who did not (59% vs 30%, and 73% vs 29%, respectively). In a multivariate analysis, the maximum grade of aGVHD (HR 3.4 [95% CI, 2.3–5.1], p<0.0001), transplant from a donor other than an HLA-matched relative (HR 1.9 [95% CI, 1.1–3.4], p=0.03) and older patient age (HR 1.9 [95% CI, 1.4–2.5], p<0.0001) were associated with an increased risk for NRM after the development of aGVHD. In this analysis, disease risk and the intensity of conditioning regimens, i.e. myeloablative or reduced-intensity, were not significant risk factors for NRM.Conclusions: Our data suggest that older patient age is a significant risk factor for NRM after the development of aGVHD, regardless of the type of conditioning regimen. The development of a careful management of aGVHD, focusing on older patients should be the subject of intense clinical research. [Display omitted]

Intensive multimodality therapy including paclitaxel and reduced-intensity allogeneic hematopoietic stem cell transplantation in the treatment of adrenal cancer with multiple metastases

Adrenocortical carcinoma is a rare malignancy in adolescents and young adults. The prognosis of unresectable/metastatic adrenocortical carcinoma remains very poor because the rarity of the tumor has made it difficult to establish treatment guidelines, and diagnosis and the resultant treatment can be greatly delayed. We treated a 24-year-old woman who was diagnosed with adrenocortical carcinoma of the right adrenal gland which extended to the inferior vena cava. Although she underwent surgical resection of the extensive tumor as the primary treatment, the disease recurred in the lung and liver as multiple metastases shortly after surgery. She received intensive multimodality therapy, including chemotherapy with paclitaxel, ifosfamide, and cisplatin (TIP regimen), embolization of the feeding arteries, and proton irradiation for the liver mass. Finally, she underwent reduced-intensity allogeneic hematopoietic stem cell transplantation from an HLA 1-locus-mismatched sibling donor. A prolonged survival of 39 months after the onset of the disease was achieved. Although this experience is limited, we suggest that TIP chemotherapy was effective for adrenocortical carcinoma, and a graft-versus-tumor effect after reduced-intensity stem cell transplantation may have contributed to the prolonged survival.

Successful Reduced-Intensity Hematopoietic Stem Cell Transplantation in Myelodysplastic Syndrome with Severe Coronary Artery Disease

A 60-year-old Japanese man with myelodysplastic syndrome (MDS) and effort angina was referred to our clinic for treatment of MDS. The patient was transfusion-dependent and displayed coronary artery disease (CAD) with 99% obstruction of the left anterior descending coronary artery. Treatment comprised reduced-intensity hematopoietic stem cell transplantation with administration of fludarabine phosphate (180 mg/m(2)) and busulfan (8 mg/kg), followed by allogeneic peripheral blood stem cell transplantation from an HLA-matched sister. The regimen was well tolerated, and engraftment occurred rapidly without any therapy-related complications, including cardiovascular attack. Sex chromosome analysis by fluorescence in situ hybridization revealed complete donor chimerism on day 29 for bone marrow cells and on day 59 for peripheral blood leukocytes. The patient became transfusion-independent on posttransplantation day 8. As of 22 months postoperatively, he remains well, with 100% Karnofsky performance status, a limited type of chronic graft-versus-host disease, and no recurrence of disease. The clinical course of the patient suggests that this preparative regimen allows safe allogeneic stem cell transplantation for MDS patients with severe CAD.

Reduced-intensity allogenic hematopoietic stem cell transplantation for myelodysplastic syndrome

Reduced-intensity allogenic hematopoietic stem cell transplantation for myelodysplastic syndrome

Graft-versus-Tumor Effect Against Advanced Pancreatic Cancer after Allogeneic Reduced-Intensity Stem Cell Transplantation

The prognosis of advanced pancreatic cancer is extremely poor and therefore a novel treatment strategy is desired. The authors thus started a prospective study of allogeneic reduced-intensity hematopoietic stem cell transplantation (RIST) for patients with advanced pancreatic cancer to evaluate the feasibility and efficacy of this approach for such patients. Only patients with pathologically proven pancreatic cancer that was locally advanced or metastatic and not amenable to curative resection were included. The conditioning regimen consisted of gemcitabine, fludarabine, and busulfan. In the first stage of this study, the authors treated seven patients. Treatment-related mortality before day 100 was observed in one patient. The median survival after RIST was 229 days. An objective response on computed tomographic scan was observed in two patients and another had a tumor marker response. Marked tumor shrinkage was observed in one of the remaining patients after donor lymphocyte infusion. These antitumor effects appeared after the effect of the conditioning regimen had disappeared. In addition, some of these responses were associated with an increase in the serum anticarcinoembryonic antigen antibody level. Pancreatic cancer appeared to be sensitive to a graft-versus-tumor effect; therefore, a larger clinical study with a refined strategy is warranted.

Chronic graft-versus-host disease after reduced-intensity stem cell transplantation versus conventional hematopoietic stem cell transplantation

The aim of this study was to retrospectively analyse clinical characteristics of chronic GVHD (cGVHD) and requirements for immunosuppressive treatment (IST) in patients receiving reduced-intensity stem cell transplantation (RIST). About 29 patients who underwent RIST between September 1999 and April 2003 were evaluable for cGVHD; they were compared to an age-matched cohort of 29 patients who received conventional stem cell transplantation (CST). A total of 26 patients in the RIST group and 24 in the CST group developed cGVHD, which was graded as limited disease in 15 (52%) and 12 (41%) cases, respectively, and as extensive disease in 11 (38%) and 12 (41%) cases, respectively. Kaplan–Meier estimates of the risk of cGVHD at 1 year after transplant were 96 and 82%, respectively (p=0.4). The median day of onset of cGVHD was 117 (range 93–220) in RIST group and 112 (range 77–225) in CST group. The skin was the most common target organ, involving 22 (84%) patients in the RIST group and 17 (71%) in the CST group. The probability of withdrawal from systemic IST at 3 years was 63 and 52% in the two groups, respectively, (p=0.7). By multivariate analysis, RIST was the only, independent, prognostic factor for the development of refractory cGVHD (?p=0.01). In conclusion, we did not find major differences between patients receiving RIST and CST respect to timing, clinical characteristics and incidence of cGVHD. Refractory disease was more frequently observed in patients receiving RIST, although the probability of withdrawal from systemic IST was not significantly different between the two groups.

Reduced intensity hematopoietic stem-cell transplantation across human leukocyte antigen barriers in a patient with congenital amegakaryocytic thrombocytopenia and monosomy 7

Congenital amegakaryocytic thrombocytopenia (CAMT) is a rare inherited bone marrow failure syndrome that has the potential to progress to pancytopenia and acute myeloid leukemia. Hematopoietic stem-cell transplantation (HSCT) is presently the only curative treatment approach. We used a reduced intensity transplantation regimen in a CAMT patient with aplastic anemia and monosomy 7 who had no matched related donor. The patient had rapid and durable engraftment with minimal complications and is well 24 months post-transplantation. Thus, reduced intensity conditioning might be a feasible approach to stem-cell transplantation in patients with CAMT who do not have a related donor and who are at increased risk of toxicity from standard conditioning regimens.

Reduced-intensity Hematopoietic Stem Cell Transplantation (RIST) for Solid Malignancies

Reduced intensity stem cell transplantation (RIST) is a new approach of stem cell transplantation, which has shown promising features as reported in multiple phase I and II studies. Elderly patients, who are not eligible for conventional myeloablative hematopoietic stem cell transplantation (HSCT), are now treatable with RIST. It has also reduced regimen-related toxicity and provided better prognosis in short-term follow-up than conventional HSCT. Among solid tumors, metastatic renal cell carcinoma was found to respond well to RIST. Clinical studies are currently being conducted to evaluate the efficacy of RIST in other types of solid tumors. However, the mechanism of graft-versus-host disease (GVHD) and graft-versus-tumor (GVT) effects remains unclear. More knowledge on the mechanism is crucial to enhance the antitumor effect and to improve the prognosis further.

Reduced-Intensity Hematopoietic Stem Cell Transplantation for a Patient with Myelodysplastic Syndrome and Chronic Obstructive Pulmonary Disease

Allogeneic hematopoietic stem cell transplantation (SCT) following high-dose chemotherapy and total body irradiation (TBI) has improved the prognosis of advanced hematological diseases. In order to assess a patient’s suitability for SCT, a thorough pretransplantation survey is performed. However, patient eligibility has expanded because of the progress of supportive care, so it is difficult to define SCT eligibility limitations due to organ dysfunction. Moreover, recent progress in reduced-intensity stem cell transplantation (RIST) has facilitated the use of SCT in older patients and patients with various underlying diseases [1,2]. This article describes the case of a 65-year-old man with myelodysplastic syndrome (MDS), refractory anemia, and chronic obstructive pulmonary disease (COPD) (emphysema) who underwent SCT. The patient had a history of smoking for more than 40 years and had suffered from Burger’s disease since the age of 40 years. He occasionally complained of lower limb pain and was treated with prostaglandin. In 1998, he presented with anemia, and MDS (refractory anemia) was diagnosed. Two years prior to this report he required frequent red cell transfusions, the frequency of which gradually increased. In June 2004, he was admitted to our hospital for allogeneic hematopoietic SCT. Laboratory examinations confirmed bicytopenia: hemoglobin concentration, 5.7 g/dL; red blood cell count, 2010 109/L; white blood cell count, 3.3 109/L; platelet count, 183 109/L. The bone marrow survey demonstrated normocellular bone marrow with mild dysplasia and a small amount of blasts (<5%). The karyotype analysis showed 3 populations; 4 of 20 analyzed cells were 46XY, del(7)(q20); 3 of 20 analyzed cells were 46XY, +13; the remaining cells were 46XY. Prior to SCT the patient had received a total of 46 transfusions of 2 units of red cells. The pretransplantation Reduced-Intensity Hematopoietic Stem Cell Transplantation for a Patient with Myelodysplastic Syndrome and Chronic Obstructive Pulmonary Disease

Association of Telomere Length in Dyskeratosis Congenita Lymphocytes with Increased Sensitivity to Radiation and Anti-Mitotic Agents.

Dyskeratosis congenita (DC) is a premature aging syndrome characterized by progressive bone marrow failure, abnormal skin pigmentation and nail dystrophy. We have recently described an autosomal dominant form of DC (AD DC) in a large three-generation kindred that is due to a mutation in the gene encoding human telomerase RNA (hTR). Importantly, we have noted progressive shortening of telomeres in lymphocytes from the most recent generation, correlating with earlier onset of severe cytopenias in some of these patients. While telomere shortening is a normal consequence of the aging process, DC patients display accelerated telomere shortening in many somatic cell types. Allogeneic hematopoietic stem cell transplant (HSCT) remains the only curative therapy for marrow failure in DC. However, HSCT in DC is generally poorly tolerated and associated with significant morbidity, perhaps as a consequence of increased sensitivity of dividing cells to cytotoxic agents. To test this hypothesis, we characterized lymphocytes from nine AD DC patients and age matched controls that had been placed in long term culture following in vitro exposure to irradiation (137Cs) and varying doses of Taxol. Cell proliferation and viability were quantitated by direct visual counting on a hemocytometer, and flow cytometry was employed to assess apoptosis and cell surface expression of senescent markers. CD57 and CD95, markers of cellular senescence and apoptosis, were significantly upregulated on DC T lymphocytes after two weeks in culture relative to controls. In addition to DC lymphocytes having a decreased proliferative capacity, an increased sensitivity to Taxol was noted, with an average decrease of 21% in cell growth relative to similarly treated control cells. This effect was also noted in irradiated DC cells. Finally, DC lymphocytes displayed an increased apoptotic index in the presence of varying doses of Taxol. These results suggest that telomere shortening may be an important factor in determining cellular tolerance to cytotoxic therapy and support the concept of reduced intensity HSCT regimens in both aged individuals and DC patients.

Reduced Intensity Compared to High Dose Conditioning for Allotransplantation in Acute Myeloid Leukemia and Myelodysplastic Syndrome: A Comparative Clinical Analysis.

We evaluated the comparative safety and efficacy of stem cell transplantation using reduced intensity (RI) vs myeloablative (MA) conditioning for patients with acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS) who underwent allogeneic hematopoietic stem cell transplantation (HSCT). Thirty two patients [18 males, median age 54 (range 19–69)] underwent a RI HSCT from January 2000- September 2003, and these were compared to 187 patients [93 males, median age 39 (range 18.4–60.3)] who received MA transplants between January 1990 – September 2003. Disease status in the 2 groups was similar, (AML in CR1: RI 38% vs MA 38%; CR2: 22% vs 15%; AML relapse: 13% vs 20% and MDS 28% vs 27%). Patients were eligible for RI if age &gt;55 with HLA matched sibling donor (Sib) or &gt;45 with unrelated bone marrow (BM) or umbilical cord blood (UCB) donor; extensive previous therapy including previous transplant or major co-morbidity. RI donors were Sib (n=17, 53%), unrelated UCB (n=14, 44%), or unrelated BM (n=1). MA donors were Sib (n=176, 94%) and UCB (n=11, 6 %), p&lt;0.01. RI conditioning included an alkylator (busulfan (Bu) or cyclophosphamide (Cy), a nucleoside analogue (fludarabine or cladribine) and 200 cGy total body irradiation (TBI), while MA conditioning was Cy/TBI (1320 cGy) (n=177) or Bu/Cy (n=10). Median follow up is 1.7 years in RI recipients and 4.2 years in MA. Neutrophil engraftment was more rapid in the RI group (median =11.5 days vs 21 days) with 3% and 6% graft failure respectively in the RI and MA groups. The cumulative incidence of Grade III–IV acute graft versus host disease (GVHD) was 22%±14% in RI vs 12±4% after MA HSCT. The cumulative incidence of relapse or disease progression at 1 year was 31% after RI vs 22% after MA HSCT (p=0.06). Disease free survival (DFS) at 1 year was 31± 16% in RI and 37%± 7% in the MA group (p=0.14). Multivariate regression analysis showed that neither conditioning intensity (NST RR=1.4, p=0.14) nor donor choice (UCB RR 0.9, p=0.63) significantly altered DFS. More failures (relapse or death) followed transplant for AML in relapse (RR=1.5, p=0.05), recipient seropositive for CMV (RR1.4, p=0.03) and development of Grade III/IV GVHD (RR 1.9, p&lt;0.01), with MDS having an outcome similar to AML in remission (RR 1.2,p=0.28). These data suggest that allografts for AML or MDS using RI conditioning, even for older patients or using unrelated UCB can yield satisfactory outcomes and extended DFS. Advances in GVHD management and new approaches for patients in relapse are needed to improve these outcomes.