Reduced-intensity Stem Cell Transplantation Research Articles

Intrabone Marrow Transplantation of Unwashed Cord Blood Using Reduced-Intensity Conditioning Treatment: A Phase I Study

The outcome of cord blood transplantation following reduced-intensity conditioning is suboptimal because of fatal infection triggered by prolonged neutropenia and graft-versus-host disease (GVHD) in addition to graft rejection. Intrabone marrow injection (IBMI) may improve the outcome by providing better hematopoietic engraftment and less GVHD. We therefore evaluated IBMI safety in reduced-intensity stem cell transplantation. Furthermore, we used unwashed cord blood to avoid stem cell loss. Ten patients (median age = 61 years old) were enrolled. Cord blood cells were thawed at the bedside and injected into 4 iliac bone sites (2 at each hemipelvis). The procedure was well tolerated with no injection-related complications. Nine patients achieved donor engraftment. The median time to neutrophil recovery (>0.5 × 10(9)/L) was 17 days, and platelet recovery was achieved in 8 patients. Early full donor chimerism was achieved (median of 15 and 20 days in T cells and myeloid cells, respectively). Three of 9 evaluable patients developed grade II to III GVHD, and 5 of 10 patients died of treatment-related toxicities. The probability of survival at 1 year was 46.7%. IBMI of unwashed cord blood following reduced-intensity conditioning is safe, well tolerated, and may lead to an increased donor engraftment rate.

慢性活動性エプスタイン・バールウイルス感染症に reduced intensity stem cell transplantation (RIST) を施行した1例

慢性活動性エプスタイン・バールウイルス感染症に reduced intensity stem cell transplantation (RIST) を施行した1例

Evolving role of high dose stem cell therapy in multiple myeloma

Conventional chemotherapy has been used in the treatment of multiple myeloma. However the development of autologous stem cell transplant represented a major advance in its therapy. Complete response (CR) rates to the tune of 40-45% were seen and this translated into improvements in progression-free survival and also overall survival in some studies. As a result the autologous stem cell transplants (ASCT) is the standard of care in eligible patients and can be carried out with low treatment-related mortality. Allogenic transplant carries the potential for cure but the high mortality associated with the myeloablative transplant has made it unpopular. Reduced Intensity Stem Cell Transplants (RIST) have been tried with varying success but with a high degree of morbidity as compared to the ASCT. Introduction of newer agents like thalidomide, lenalidomide, bortezomib and liposomal doxorubicin into the induction regimens has resulted in higher CR and very good partial response rates (VGPR) as well as improvement in ease of administration. These drugs have also proved useful in patients with adverse cytogenetics. Recent trials suggest that this has translated into improvements in response rates post-ASCT. There is a suggestion that patients achieving CR/nCR or VGPR after induction therapy should be placed on maintenance and ASCT then could be used as a treatment strategy at relapse. All these trends however await confirmation from further trials. Tandem transplants have been used to augment the results obtained with ASCT and have demonstrated their utility in patients who achieved only a partial response or stable disease in response to the first transplant as well as patients with adverse cytogenetics. Incorporation of bortezomib along with melphalan into the conditioning regimen has also been tried. RIST following ASCT has been tried with varying success but does not offer any major advantage over ASCT and is associated with higher morbidity. It is hoped that recent advances in therapy will contribute greatly to improved survival.

What should we consider in mixed chimerism after hematopoietic stem cell transplantation?

TO THE EDITOR: Mixed chimerism (MC) was initially thought to indicate impending relapse; however, it has become clear that it is an important parameter for estimating immunologic balance after hematopoietic stem cell transplantation (HSCT). Moreover, the emergence of more tailored HSCT procedures, including reduced-intensity stem cell transplantation (RIST), depletion of the donor's T cells from bone marrow graft, and donor lymphocyte infusion (DLI), makes it even more important to estimate the exact chimeric status after HSCT. Recently, Goh et al. reported MC results in 24 myeloablative HSCT patients. MC in nucleated cells (NCs) was significantly correlated with relapse, and MC in NCs, T cells, and NK cells was correlated with mortality. Furthermore, MC in all cell types was uncorrelated with the incidence of acute and chronic graft-versus-host disease (GVHD). These data were analyzed in limited cases, but individual diseases and HSCT strategy were not considered [1]. Myeloablative HSCT without T cell depletion often results in GVHD but is associated with less frequent relapse. T cells in the graft lead to full donor complete chimerism (CC), although early CC indicates GVHD. However, T cell-depleted (TCD) myeloablative HSCT is commonly found to give rise to MC, and is therefore used to avoid GVHD. In the case of RICT, all cases typically experience MC. Therefore, MC has to be precisely evaluated. Low donor T cell and NK cell chimerism levels around the second week after HSCT are associated with high probabilities of graft rejection, whereas early establishment of donor NK cell chimerism is associated with better progression-free survival [2]. In contrast to NK cell chimerism, early establishment of donor T cell chimerism is associated with the development of acute GVHD [3]. In recent interesting reports on lineage-specific chimerism, monitoring of leukemia lineage-specific chimerism has been shown to be important for DLI response in the case of relapse after HSCT [4]. Further, a low donor T cell chimerism of <60% at day 30 may be associated with a poor prognosis in HSCT when using a busulfan-containing reduced-intensity conditioning regimen [5]. Although MC is an important indicator of disease relapse, graft rejection, or GVHD post HSCT, it should be taken into consideration that the recipient cells in MC could be normal hematopoietic cells or leukemic cells. Therefore, it is important to identify those patients who develop an increasing or progressive MC of recipient cells by monitoring serial chimerism levels. Additionally, with respect to accurate analysis of chimerism, it should be recognized that variation in the degree of MC is influenced by a number of factors, including the sensitivity of the method used, the timing of the assay, the disease indication for HSCT, the stage of disease at the time of HSCT, and the choice of conditioning regimen.

Novel Therapy of Relapsed and Refractory Classical Hodgkin’s Lymphoma

Classical Hodgkin’s lymphoma (HL) is generally considered a highly curable disease, with approximately 80 % of patients cured with standard first-line chemotherapy. The standard treatment approach for relapsed/refractory patients is second-line salvage chemotherapy followed by autologous stem cell transplantation (ASCT). About half of all patients undergoing ASCT are rescued and definitely cured by such an approach, but the outcome in patients relapsing or refractory to second-line chemotherapy and ASCT is dismal, with a median survival of less than three years. Therapeutic options for this subset of patients comprise tandem ASCT, reduced-intensity allogeneic stem cell transplantation (allo-SCT) and novel agents. Median overall and progression-free survival rates following allo-SCT have ranged from 27 to 56 % and from 18 to 39 %, respectively, with a treatment-related mortality ranging from 15 to 25 %. Several new compounds have been identified as promising agents for the treatment of patients with relapsed classical HL. These drugs have shown promising activity in a subset of heavily pre-treated relapsed/refractory patients, with response rates and disease control rates exceeding 40 and 70 %. If approved, these compounds will probably change the standard of care, making it possible to develop combination regimens with chemotherapy or other new agents, thus improving efficacy with a decreased toxicity profile.

Engraftment Syndrome (ES) After Reduced-Intensity Stem Cell Transplantation (RIST): ES May Have a Negative Impact on Survival In Standard-Risk Patients

AbstractAbstract 2318 Introduction:ES has been well recognized to increase non-relapse mortality (NRM) in autologous hematopoietic cell transplantation (HCT). However, little information is available on ES in allogeneic HCT, particularly after reduced-intensity conditioning. To determine the incidence, risk factors and outcome of ES after RIST, we retrospectively reviewed the medical records of 285 patients (pts) who underwent RIST at our institution between 1999 and 2007. Patients and Methods:After excluding 37 pts who received cord blood transplantation or a second or subsequent allogeneic HCT, and those who experienced primary graft failure, 248 pts (male 153, female 95) with a median age of 55 y (range, 21–68) fulfilled the criteria of this study. The underlying diagnosis included lymphoma (106 pts; 43%), acute myeloid leukemia (59; 24%), myelodysplastic syndrome (51; 21%), and others (32; 13%). Ninety-two pts (37%) had a standard-risk disease such as acute leukemia or lymphoma in CR1, and 156 (63%) had a high-risk disease. The donor and stem cell source were related PBSC in 170 pts (69%), related BM in 8 (3%), and unrelated BM in 70 (28%). All of the pts received reduced-intensity conditioning with a purine analog and a busulfan-based regimen. With the use of G-CSF after HCT, neutrophil engraftment (ANC ≥500/μ l) was achieved at a median of 12 days (range, 5–28). ES was diagnosed when the patient showed at least 2 of the following symptoms within 96 h of neutrophil engraftment: (1) fever (>38.0°C) without an identifiable source of infection, (2) skin rash (>25% of body surface area) that was not due to a drug reaction, (3) weight gain (>2.5% of baseline body weight), and (4) hypoxia (sPO2 <94%) or pulmonary infiltrates. Results:Among the 248 pts, 45 (18%) developed ES at a median of 14 days (6-23) after allogeneic HCT. Symptoms consisted of fever (100%), skin rash (53%), weight gain (62%) and hypoxia (33%). The incidence of ES in recipients of unrelated donor grafts was significantly higher than that in recipients of related donor grafts (28% vs 14%, p=0.02), and male pts had a significantly higher incidence of ES than female pts (22% vs 12%, p=0.04). No significant difference in the incidence of ES was observed between groups stratified according to age, stem cell source, TNC or CD34+ cell dose, disease risk, GVHD prophylaxis, and the timing of engraftment. By a multivariate analysis, use of an unrelated donor (HR 2.3, 95%CI 1.3–4.1, p=0.007), pts with lymphoid malignancy (HR 2.0, 95%CI 1.1–3.7, p=0.03) and male pts (HR 2.0, 95%CI 1.0–4.0, p=0.04) were associated with a significantly increased risk of ES. Among the 40 pts who required systemic corticosteroid therapy, 31 (78%) achieved a complete response, and the remaining 9 (23%) responded partially. There was a trend toward a higher incidence of grade III-IV acute GVHD (27% vs 18%, p=0.10) in pts with ES, and the incidence of extensive chronic GVHD (69% vs 62%, p=0.04) was significantly higher in pts with ES. Overall survival (OS) and non-relapse mortality (NRM) were not significantly different between the two groups, after a median follow-up of 53 months (range, 2–108) in surviving patents. A multivariate analysis showed that pts with high-risk disease (NRM, HR 1.9, 95%CI 1.1–3.3, p=0.01; OS, HR 2.5, 95%CI 1.6–3.8, p<0.001) and those with myeloid malignancy (NRM, HR 2.0, 95%CI 1.2–3.4, p=0.01; OS, HR 1.5, 95%CI 1.0–2.2, p=0.03) were associated with an increased risk of NRM and worse OS after allogeneic HCT, whereas the development of ES did not affect NRM or OS. In a subgroup analysis of 92 pts with standard-risk disease, pts with ES had a significantly worse OS (50% vs 76% at 3 y, p=0.03, Figure, left panel) and a higher NRM (49% vs 20% at 3 y, p=0.03) compared to those without ES. In a subgroup analysis of 156 pts with high-risk disease, however, OS (42% vs 46% at 3 y, p=0.76, Figure, right panel) and NRM (48% vs 39% at 3 y, p=0.84) of pts with ES were equivalent to those of pts without ES. Conclusions:ES is a rather common complication after RIST, especially in recipients of unrelated donor grafts. Although ES shows an initial good response to corticosteroid therapy, ES may have a negative impact on survival, especially in pts with standard-risk disease, and this effect may be related to the occurrence of GVHD. The development of an optimal treatment for ES may improve the outcome of pts who have received RIST by reducing GVHD-related mortality. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Reduced Intensity Conditioning (RIC) with Double Umbilical Cord Blood Transplantation Has Similar Outcomes Compared to RIC Transplantation From Related or Unrelated Adult Donors

AbstractAbstract 2367Umbilical cord blood is generally regarded as an alternative source of stem cells for patients who lack a well matched related or unrelated donor, but there are little data comparing stem cell sources after reduced intensity conditioning (RIC) SCT. We performed a retrospective study comparing outcomes after RIC SCT using related donors (RD), unrelated donors (URD), and double umbilical cord blood (dUCB) from two partner institutions. Retrospective database review was performed for patients undergoing reduced intensity stem cell transplants from related and unrelated donors occurring at Dana-Farber Cancer Institute (DFCI) and reduced intensity double umbilical cord blood transplants at DFCI and Massachusetts General Hospital (MGH) from 2002–2008. Patient characteristics and outcomes were compared between the three groups based on donor type. Between 2002 and 2008, there were a total of 67 RIC transplants using dUCB, 276 RIC transplants using URD, and 197 RIC transplants using RD. All cord blood units were 4–6/6 HLA matches (allelic typing) with minimum cell dose of 1.5 × 107 TNC/kg recipient weight for each individual unit and the minimum sum of both units being 3.7 × 107 TNC/kg. For the 276 patients undergoing SCT from URD, 247 (90%) were an 8/8 HLA-match by allelic typing while 28 (10%) were a 7/8 match. For the 197 patients undergoing SCT from RD, 195 (99%) were 8/8 HLA-match while 2 (1%) were a 7/8 match. 11 (4%) patients receiving URD transplants and 2 (1%) patients receiving RD transplants received bone marrow while the rest received peripheral blood stem cells. Compared to URD or RD SCT, patients undergoing dUCBT were younger (median age 53 dUCB, 57 URD, 55 RD, p=.009 dUCB vs URD, p=.11 dUCB vs RD) with 54% of patients undergoing dUCBT being 50 years or older vs 73% for URD and 72% for RD (p=.008 dUCB vs URD, p=.02 dUCB vs RD). Conditioning for RIC dUCBT was mainly melphalan/fludarabine/ATG (91%) while it was mainly low-dose busulfan/fludarabine for RIC URD or RD (91% and 96%, respectively). GVHD prophylaxis for dUCBT was cyclosporine/MMF in 31% and tacrolimus/sirolimus in 63% whereas it was tacrolimus/sirolimus based in 73% and 75% for URD and RD, respectively, and tacrolimus/mtx based in 23% for both URD and RD groups. Underlying diseases were similar across all three groups with AML and NHL being the most common indications for SCT. Median follow-up time for survivors was 36.6, 29.4, and 36.1 months, respectively, for UCBT, URD, and RD. Cumulative rates of grades II-IV acute GVHD at day 200 after SCT were 16.2%, 21.4%, and 17.3% (p=0.41 dUCB vs URD, p=0.97 dUCB vs RD). Cumulative rates of transplant-related mortality at 2 years were 28.9% dUCB vs 9.2% URD vs 7.6% RD (p=.0002 dUCB vs URD, p<.0001 dUCB vs RD). Cumulative rates of relapse at 2 years were 37.0% dUCB vs 49.5% URD vs 62.1% RD (p=.02 dUCB vs URD, p<.0001 dUCB vs MRD) with no difference in relapse rates based on disease. 2-year cumulative incidence of extensive chronic GVHD was 7.6% dUCB vs 42.6% URD vs 35.0% MRD (p<.0001 dUCB vs URD, p<.0001 dUCB vs MRD). 2-year progression-free survival (Figure 1) was 34% dUCB vs 41% URD vs 30% MRD (p=0.70 dUCB vs URD, p=0.14 dUCB vs RD) and 2-year overall survival (Figure 2) was 51% dUCB vs 57% URD vs 49% RD (p=0.58 dUCB vs URD, p=0.93 dUCB vs RD). In conclusion, RIC stem cell transplant using dUCB gives similar rates of overall and progression-free survival when compared to RIC SCT using conventional related or unrelated donors in this study from two partner institutions. There was a significantly higher transplant-related mortality with dUCBT, however, there appears to be significantly lower rates of disease relapse and chronic GVHD with dUCBT when compared to URD or RD. Longer follow-up with a larger number of patients are needed to validate these findings, but for patients without an HLA-matched donor indicated for RIC SCT, the use of two partially matched umbilical cord blood units appears to be a suitable alternative. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Successful Reduced-Intensity Stem Cell Transplantation From Unrelated Cord Blood In Three Patients with X-Linked Severe Combined Immunodeficiency.

AbstractAbstract 4571Severe combined immunodeficiency (SCID) is the most severe form of the primary immunodeficiencies (PID), the most frequent type of which is X-linked SCID (X-SCID; T-B+NK-SCID). Hematopoietic stem cell transplantation (SCT) is the only curative treatment for these high-risk patients. Recently, some PID cases treated with unrelated cord blood stem cell transplantation (CBT) have been reported. To avoid severe infection during SCT and late complications, such as mental and growth retardation, reduced-intensity conditioning (RIC) regimens have been used for unrelated SCT for PID patients. However, reports of X-SCID patients receiving CBT with reduced-intensity stem cell transplantation (RIST) are quite limited. We report successful allogenic RIST from unrelated cord blood (CB) for treatment of X-SCID in our single centre. Three patients with X-SCID who had no HLA-matched sibling received unrelated CBT. Mutations in the common gamma chain gene were detected in all patients. Pre-transplantation conditioning for all patients consisted of fludarabine (FLU) (30 mg/m2/day) from day -7 to day -2 (total dose 180 mg/m2) and busulfan (BU) 4 mg/kg/day from day -3 to day -2 (total dose 8 mg/kg). All CB units were serologically matched HLA-A, B, and DR loci. Though two of the patients suffered from fungal or bacterial pneumonia before transplantation, there were no additional infectious complications during transplantation. All patients achieved engraftment with an absolute neutrophil count > 500/μ l with a mean of 22 days (range, 19–27 days), and they showed 100% donor chimerism by fluorescence in situ hybridization of their peripheral mononuclear cells using × and Y chromosome probes at one-year post transplantation. Full donor chimerism of both T and B cells was also confirmed. Only one patient (patient 2) developed grade III acute graft versus host disease (GVHD), which resolved with increased oral corticosteroid. None of the patients have developed chronic GVHD, received intravenous immunoglobulin replacements after the transplantations, or showed delayed psychomotor development during 21 to 77 months of follow-up. Only one patient (patient 3) had short stature (-2.4SD) at 21-month follow-up. The most commonly used RIC regimens worldwide have been the FLU/melphalan (LPAM) and the FLU/BU regimens. LPAM has broad stem cell toxicity to both primitive and committed stem cells, while BU may spare committed stem cells, resulting in early onset and a prolonged duration of neutropenia with the FLU/LPAM regimen. Moreover, it has been reported that the LPAM-containing conditioning regimen is a risk factor for hepatic veno-occlusive disease. Although conditioning regimens including standard-dose BU may be associated with a high rate of treatment-related complications due to organ toxicity, reduced-dose BU in combination with FLU is less myelosuppressive and less toxic than the FLU/LPAM regimen. Moreover, CBT has some advantages with regard to incidence and intensity of GVHD and availability compared with other alternative stem cell sources. Patients 1 and 2 had overcome pre-existing fungal and bacterial pneumonias, respectively, and recovered after transplantation. Thus, immediate SCT using an RIC regimen could be indicated for patients with X-SCID to reconstitute the immune system regardless of pre-existing infections. Since pre-existing infections are the principal risk factors for poor SCT outcomes, early diagnosis and transplantation before any infectious episodes is necessary for X-SCID patients. In conclusion, CBT is a suitable alternative to bone marrow transplantation for X-SCID patients requiring urgent SCT with no sibling donors. RIC consisting of FLU and BU is an effective and safe treatment for such cases. Disclosures:No relevant conflicts of interest to declare.

Outcomes of a Prospective Phase II Study of Reduced-Intensity Stem Cell Transplantation for Acute Myeloid Leukemia with t(8;21)- In Comparison with Autologous and Myeloablative Allogeneic Stem Cell Transplantation.

AbstractAbstract 4559Patients with acute myeloid leukemia (AML) and t(8;21) generally have a favorable prognosis with a higher rate of first complete remission (CR1) and higher rate of cure with high-dose cytarabine (HDARA-C). However, some studies comparing stem cell transplantation (SCT) and conventional consolidation chemotherapy raised questions regarding improved survival with autologous SCT (ASCT) in these patients. Moreover, there has been some concern that the rate of relapse after HDARA-C is higher than previously reported and resultingly, only 50 – 60% of these patients are cured with contemporary treatment. Role of reduced intensity conditioning (RIC)-SCT has not been determined in this population. To date, few studies have analyzed the outcome of RIC-SCT for this population specifically. From this point of view, we performed a prospective phase II study to evaluate the efficacy of RIC-SCT for AML with t(8;21) and also compared the results with those of the historical cohort who treated with ASCT or myeloablative conditioning (MC)-SCT in our institution.We included adult patients aged between 16 and 65 with AML who had t(8;21) with or without additional aberration at the time of diagnosis. Since Mar 2007, we transplanted 19 consecutive adult patients with AML and t(8;21) after RIC from matched sibling (n = 12) or unrelated (n = 7) donor. Patients in RIC-SCT group were given a RIC regimen consisting of fludarabine (30 mg/m2/d, days –6, –5, –4, –3, and –2), busulfan (3.2 mg/kg/d, days –6 and –5) and low dose total body irradiation (400 cGy). Their clinical features were compared with historical patients who were transplanted with autografting (n = 47) or MC (n = 38) in our institution from 2001. The pretransplant characteristics among the three groups were well balanced except for patient age and time to SCT. For recipients of RIC, probability of overall survival (OS) and disease free survival (DFS) was 77.5 ± 9.9% and 78.2 ± 9.7%, respectively, with a median follow-up of 30 months (range: 9.5+ – 41.2+ months) for surviving patients (Fig 1a and b). 2-year cumulative incidence of relapse (CIR) and nonrelapse mortality (NRM) was 11.9 ± 7.9%, respectively (Fig. 1c and d). OS and DFS in this group were not different from those of ASCT and MC-SCT group. CIR appears to be lower than that of ASCT, but failing to demonstrate statistical difference. Patients in ASCT group showed clearly lower NRM (P = .049). By univariate analysis, age (£ 50 vs > 50 years) seems to be a dominant factor affecting DFS and OS in RIC-SCT and ASCT group (P = 0.25 and 0.29, respectively, for RIC-SCT group, and P = 0.36 and 0.13, respectively, for ASCT group). In ASCT group, presence of –Y was associated with inferior DFS (p = 0.049, Fig. 2a), whereas this difference disappeared when RIC or MC was applied for these patients (Fig. 2b and c). CIR was significantly lower in patients without –Y than with –Y (P = 0.012, Fig. 2d), while there was no difference in NRM between the two subgroups. Of 41 male patients with –Y, probability of DFS of allogeneic SCT recipients was slightly better than that of ASCT, although failing to demonstrate a statistical difference (Fig. 2e).RIC-SCT is effective treatment modality in terms of relapse and survival, judging from no difference in CIR and survival in comparison with those of MC-SCT, but greater effort should be put to reduce NRM further. Because ASCT was associated with extremely low NRM and demonstrated comparable efficacy to those of allo-SCT, this modality might be a preferable treatment option for this disease except for the subgroup of patients with –Y. Several previous studies reported that –Y was associated with shorter survival. In our study, patients with –Y demonstrated inferior survival only in the setting of ASCT, and these differences disappeared in allo-SCT groups, justifying that allo-SCT should be considered in this subgroup of patients. Superior survival in patients without –Y seems to be result of lowered CIR rather than improved NRM. Finally, MC-SCT is not recommended in patients with t(8;21) in CR1 because it has no advantages in terms of relapse and NRM. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

18F-deoxyglucose PET: useful in the management of patients with stem cell transplantation for lymphoma?

Evaluation of: Lambert JR, Bomanji JB, Peggs KS et al. Prognostic role of PET scanning before and after reduced-intensity allogeneic stem cell transplantation for lymphoma. Blood 115(14), 2763–2768 (2010).18F-deoxyglucose (FDG) positron emission tomography (PET) and more recently FDG PET/computed tomography (CT) has become an important tool in the management of patients with Hodgkin and non-Hodgkin lymphoma. It adds metabolic and functional information to conventional anatomical imaging, mainly assessed by CT. Especially for the detection of early response to treatment and prognostic considerations, this type of information seems better suited than anatomical information. Consequently, the ability of FDG PET to predict the outcome in patients with stem cell transplantation (SCT) for lymphoma has been tested in several studies. Results in patients with autologous SCT have been promising, and pretransplant FDG PET is likely to become routine in this group of patients. The evaluated study investigates, for the first time, the predictive value of pretransplant FDG PET in allogeneic SCT, as well as the utility of FDG PET for the follow-up of these patients. All 80 patients included in the prospective study had reduced-intensity conditioning. In contrast to FDG PET before autologous SCT, there was no correlation at all between pretransplant FDG PET results and the outcome after allogeneic SCT. This reflects the fact that other or additional reasons, especially the graft-versus-leukemia effect, are substantial for the outcome of allogeneic SCT in comparison with autologous SCT. Follow-up with FDG PET after reduced-intensity allogeneic SCT was significantly more sensitive than CT to detect disease progression or relapse, and was useful in guiding treatment in the situation of disease relapse.

Impact of prior invasive aspergillosis on outcome in patients receiving reduced-intensity conditioning allogeneic hematopoietic stem cell transplant

Invasive aspergillosis (IA) is a major cause of morbidity in patients with hematological malignancies, and a major impediment to the success of allogeneic stem cell transplant (allo-SCT). The aim of this single-center retrospective study was to determine the impact of pre-transplant IA on the outcome of allo-SCT after reduced-intensity conditioning (RIC). Twenty-eight cases of proven or probable IA were diagnosed prior to RIC allo-SCT at the Paoli-Calmettes Institute Cancer Center between January 2000 and January 2008. These cases were identified among 360 patients undergoing allo-SCT. IA was defined according to EORTC criteria. Patients had predominantly (82%) acute myeloid leukemia, were diagnosed with IA at a median of 8 months (range, 1–16) pre-transplant, and received antifungal therapy for a median of 5 months (range, 1–13). IA therapy included: voriconazole (71%); single-agent itraconazole (14%); and a combination of agents (14%). Secondary prophylaxis against aspergillosis was maintained during conditioning and post-transplant in 89% of patients. After transplant, only three patients (11%) had reactivation of their IA and one patient developed disseminated fusariosis. The latter four patients experienced severe acute GVHD treated with high-dose corticosteroids. None of these patients died of IA. Eighteen patients (64%) are still alive, with a median follow-up of 23.5 months (range, 12.6–48.5). Overall survival at 2 years was 59% (95% CI, 43–83%). These data suggest that patients with adequately controlled IA can tolerate RIC allo-SCT without significant post-transplant complications.

Reduced-intensity conditioning allogeneic stem cell transplant for relapsed or transformed aggressive B-cell non-Hodgkin lymphoma

The role of reduced-intensity conditioning allogeneic stem cell transplant (RIC allo-SCT) in aggressive B-cell non-Hodgkin lymphoma (NHL) remains a matter of debate. This single-center analysis aimed to assess the potential benefit of RIC allo-SCT in 19 consecutive patients with relapsed or transformed aggressive B-cell NHL. Aggressive transformation (primary or secondary) was documented for these patients by pathological examination. In this series, all patients but two (n = 17; 89.5%) could actually receive autologous stem cell transplant (auto-SCT) prior to RIC allo-SCT. At the time of allo-SCT, eight patients (42%) were in first complete remission (CR), six (31.5%) were beyond first CR, and five (26.5%) were in partial remission. With a median follow-up of 32 (range, 3–86) months, nine patients experienced grade 2–4 acute GVHD (47.5%) and 10 patients had extensive chronic GVHD (52.5%). Overall, the incidence of non-relapse mortality was 26% (95% CI, 8–44%). At last follow-up, 12 patients (63%) were in sustained CR. The Kaplan–Meier estimates of progression-free and overall survival rates were 68% and 68%, respectively, at 4 years. We conclude that RIC allo-SCT after auto-SCT is feasible and a potentially efficient therapy for relapsed or transformed aggressive B-cell NHL, warranting further prospective evaluation.

Extramedullary relapses after allogeneic stem cell transplantation for acute myeloid leukemia and myelodysplastic syndrome

Allogeneic stem cell transplant is a potentially curative treatment for patients with acute myeloblastic leukemia and myelodysplastic syndrome. In this issue of the journal, Craddock et al. [1][1] report the largest reported series of T-cell depleted reduced intensity stem cell transplant for acute

Reduced Intensity Stem Cell Transplantation (RIT) In An Ambulatory Setting For Children With Severe Primary Immunodeficiency (PID): A Nursing Perspective On Infection

RIT is routinely performed in an outpatient infusion center at Children's Memorial Hospital (CMH), Chicago, IL. We reviewed infection patterns in children with PID who received RIT. Since 2000, 25 patients with the following diagnoses underwent RIT at CMH: SCID (13), hyper-IgM syndrome (3), IPEX (2), WAS (2), XLPD (2), reticular dysgenesis (1), Chediak-Higashi Syndrome (1), and MHC class II deficiency (1). Sixty-four percent (16/25) of patients received RIT on an outpatient basis. The remaining 9 patients were hospitalized for RIT due to pre-existing infection, complication or parental preference.

Peripheral Blood Is The Stem Cell Source Of Choice For Reduced Intensity Stem Cell Transplant In Children

Peripheral Blood Is The Stem Cell Source Of Choice For Reduced Intensity Stem Cell Transplant In Children

Cladribine (2CdA) Is Comparable To Fludarabine In A Busulfan-Based Reduced- Intensity Regimen

Reduced-intensity stem cell transplantation (RIST) with a purine analog most often involves fludarabine (Flu). The alternative drug, 2CdA, is rarely used partly because of a potential risk of renal toxicity. We retrospectively reviewed the medical records of 282 patients (median age, 54 y; range, 21-68) with various hematological malignancies who underwent RIST between 1999 and 2007 with a conditioning regimen that consisted of busulfan (po 8 mg/kg or iv 6.4 mg/kg) in combination with either 2CdA (0.66 mg/kg, n=71, C-group) or Flu (180 mg/m2, n=211, F-group). Seventy-four patients also received 2-4 Gy of TBI. The donor was related (BM 8, PB 177) in 185 patients, and unrelated in 97 (BM 79, PB 1, CB 17). GVHD prophylaxis consisted of cyclosporine (CSP, starting dose 3 mg/kg/day civ, target whole blood conc. 250-350 ng/ml, n=232) or tacrolimus (starting dose 0.03 mg/kg/day civ, target whole blood conc. 10-20 ng/ml, n=50), with (n=131) or without (n=151) MTX. Sixty-nine patients also received anti-human T- lymphocyte immunoglobulin (ATG, 5-10 mg/kg). Except for the stem cell sources, there were no significant differences between the C- and F-groups. Acute renal failure (ARF) within 100 days was defined as there was a greater than two-fold rise in the serum creatinine concentration compared to the baseline. The median follow-up in surviving patients was 1589 days (50-3291). The 275 patients who survived more than 30 days (except for one patient who died of relapse) all achieved neutrophil engraftment in a median 13 days (range, 5-42 days). No significant difference was observed between C- and F-group with regard to OS (59% vs 48% at 3 y, p=0.20), relapse rate (42% vs 35% at 3 y, p=0.42), NRM (7% vs 6% on d100, 22% vs 32% at 3 y, p=0.15), or the cumulative incidences of ARF (34% vs 27% on d 100, p=0.26), grade II-IV acute GVHD (46% vs 47%, p=0.40), and extensive chronic GVHD (62% vs 54% at 3 y, p=0.21). Multivariate analyses showed that TBI [HR 2.96 (1.86-4.72), p<0.001] for NRM, TBI [HR 1.75 (1.23-2.49), p=0.002] and high-risk disease [HR 2.39 (1.62-3.55), p<0.001] for OS, and TBI [HR 1.98 (1.25-3.14), p=0.004] and CSP [HR 2.10 (1.06-4.17), p=0.03] for ARF were significant factors for poor outcomes. However, 2CdA was not significantly associated with NRM, OS or ARF. Our study suggested that a relatively low dose of 2CdA was tolerable and feasible as part of a reduced-intensity regimen, and was not associated with any significant nephrotoxicities.

Successful treatment of acute myelogenous leukemia with favorable cytogenetics by reduced-intensity stem cell transplantation

Acute myelogenous leukemia (AML) with favorable cytogenetics responds well to chemotherapy. If the leukemia relapses, allogenic hematopoietic stem transplantation (allo-HSCT) is considered as a treatment option. Since the efficacy of reduced-intensity stem cell transplantation (RIST) for AML with favorable cytogenetics has not been established, we retrospectively analyzed the outcomes of allo-HSCT in AML patients according to cytogenetic risks. The outcome of allo-HSCT for AML patients with favorable cytogenetics seemed to be superior to that for AML patients with intermediate cytogenetics. In AML patients with favorable cytogenetics, the 3-year overall survival (OS) and relapse-free survival (RFS) rates were 88 and 76%, respectively, in the RIST group. Both the 3-year OS and RFS rates were 81% in the conventional stem cell transplantation (CST) group. The outcome of RIST for AML patients with favorable cytogenetics was comparable to that for patients who received CST despite the more advanced age and greater organ dysfunction in RIST group than in CST group. None of the patients died within 90 days after RIST. Moreover, there was no relapse in patients with favorable cytogenetics who were in hematological remission prior to RIST. Thus, RIST for AML patients with favorable cytogenetics in remission is safe and effective.

Long-Term Outcome of ATL Patients Who Underwent Reduced-Intensity Stem Cell Transplantation (RIST): Suggested Potent Graft-Versus-ATL and HTLV-1 Effects.

Long-Term Outcome of ATL Patients Who Underwent Reduced-Intensity Stem Cell Transplantation (RIST): Suggested Potent Graft-Versus-ATL and HTLV-1 Effects.

Renal Complications after Busulfan-Based Reduced-Intensity Stem Cell Transplantation in 286 Patients with Hematological Disorders.

Abstract 3353Poster Board III-241 [Background]Renal dysfunction is a life-threatening complication after hematopoietic stem cell transplantation, and the incidence of acute and chronic renal dysfunction after non-myeloablative transplantation is reportedly, 40 to 50% and 16 to 35%, respectively. In this study, we evaluated this complication after reduced-intensity stem cell transplantation (RIST) at a single institute. [Patients and Methods]We retrospectively reviewed the medical records of 286 patients (median age, 54 years; range, 21-68) with various hematological disorders who underwent RIST between 1999 and 2007, using a conditioning regimen that consisted of busulfan (oral 8 mg/kg or iv 6.4 mg/kg) and fludarabine (180 mg/m2, n=214) or cladribine (0.66 mg/kg, n=72). Sixty-seven patients also received 2-4 Gy of total body irradiation (TBI). The diagnosis included AML (n=77), ALL (n=9), MDS (n=56), malignant lymphoma (n=116), CML (n=14), and other (n=14). Whereas 188 patients were transplanted from a related donor (BM n=8, PB n=180), 98 were transplanted from an unrelated donor (BM n=80, PB n=1, CB n=17). GVHD prophylaxis consisted of cyclosporine (CSP, starting dose 3 mg/kg/day civ, target whole blood conc. 250-350 ng/ml, n=235) or tacrolimus (starting dose 0.03mg/kg/day civ, target whole blood conc. 10-20 ng/ml, n=51), with (n=131) or without (n=155) methotrexate, and 71 patients also received anti-human T-lymphocyte immunoglobulin (ATG, Fresenius, 5-10 mg/kg). Renal function was assessed in terms of the serum creatinine concentration and the estimated glomerular filtration rate (eGFR) as calculated by the Modification of Diet in Renal Disease equation (MDRD) for our population (eGFR=0.741*175*Age-0.203*Cr-1.154, *0.742, if female). Acute renal failure (ARF) within 100 days was categorized as grade 0 (decrease in eGFR of <25% of the baseline value), grade 1 (less than two-fold rise in the serum creatinine concentration with a decrease in eGFR of >25% but <50% of the baseline value), grade 2 (greater than two-fold rise in the serum creatinine concentration compared to the baseline value but not requiring dialysis), and grade 3 (same as grade 2 but requiring dialysis). Chronic kidney disease (CKD) was defined as two or more estimates of eGFR <60 ml/min/1.73 m2 within a minimum 30-day interval after day 100. Patients with eGFR <60 at baseline and/or less than 131 days of follow-up (n=121) were excluded from the CKD study cohort, which left 165 patients eligible for analysis. [Results]The median follow-up in surviving patients was 746 days (87-3291). The numbers of patients who developed grade 1, 2 and 3 ARF were 139, 72 and 9, respectively. The cumulative incidence of grade 2-3 ARF was 29 % at 100 days after RIST. The overall survival was significantly better in patients with grade 0-1 ARF than in those with grade 2-3 ARF (62% vs 42% at 2 years, p<0.0001, Figure 1). There was no significant difference in the occurrence of ARF between the cladribine and fludarabine groups (p=0.28). Multivariate analyses for ARF showed that TBI and CSP were significantly associated with a higher incidence of grade 2-3 ARF. CKD developed in 15 of the 165 evaluable patients (9.1%), and all had received PBSCT and CSP for GVHD prophylaxis. The cumulative incidence of CKD was 3.8% at 1 year, 9.0% at 2 years and 11.7% at 3 years after RIST. Grade 2-3 ARF (p=0.014) and the development of chronic GVHD (p=0.048) were significantly associated with a higher incidence of CKD. There was no significant difference in survival between patients with and without CKD (p=0.16). [Conslusion]We found that ARF was significantly associated with a higher mortality after busulfan-based RIST, and that preceding grade 2-3 ARF led to the occurrence of CKD in surviving patients, which highlights the importance of preventing ARF. This study also indicated that the incidence of acute and chronic renal complications was lower in our population compared to previously reported data from Western countries. Therefore, ethnicity should be taken into account when designing future international clinical trials. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Busulfan Dosing May Affect Survival Following Reduced Intensity Stem Cell Transplantation in Patients with Acute Myelogeneous Leukemia.

Abstract 4328The prognosis for patients with acute myelogeneous leukemia over age 60 is poor, with a 5 year survival of less than 10%. Reduced intensity allogeneic transplantation has been employed in an attempt to improve survival. We report 23 patients who received reduced intensity allogeneic transplantation after a conditioning regimen of busulfan and fludarabine. Fifteen patients received a transplant from a matched sibling donor,1 patient from a 5/6 matched child and 7 patients from a fully matched (10/10) unrelated donor. We treated 10 patients with the reduced intensity conditioning regimen of busulfan IV 0.8 mg/kg daily Days -6, -5, -4, -3 (total dose 3.2 mg/kg) and fludarabine IV 30 mg/m2 Days -6,-5, -4, -3 (total dose 120mg/kg). After November, 2007, 10 patients were treated with twice daily busulfan IV 0.8mg/kg (total dose 6.4 mg/kg) with the same dose of fludarabine. Three patients were treated on a national protocol in which the same dose of busulfan (6. 4 mg/kg) was administered but given at 0.8 mg/kg four times daily for 2 days on Days -4 and -3 with fludarabine. GVHD prophylaxis was cyclosporine or tacrolimus with either cellcept or (after July, 2008) methotrexate. Seven recipients of unrelated donor or mismatched transplants also received rabbit antithymocyte globulin 1.5 mg/kg Days -3, -2, -1 (total dose 4.5 mg/kg) as part of their GVHD prophylaxis. Median age was 65 years (range 46-70 years). Fourteen patients were in 1st complete remission, 8 were in 2nd complete remission, and one patient had active disease at the time of transplant. Two patients had received a prior autologous stem cell transplant and 2 patients had received a prior allogeneic transplant. The median days to neutrophil (ANC >500) and platelet engraftment (plt >20K) were 15 and 14 respectively. The median length of stay was 25 days (range 13-40 days). Median follow-up was 12 months among the 10 patients still alive. The incidence of acute GVHD Grades II-IV and chronic GVHD were 44% and 35% respectively. Transplant related (non relapse) mortality at 100 days and at 6 months was 0. The overall non-relapse mortality was 4%. Relapse rate was 67% in the daily busulfan group and 46% in the higher dose busulfan group. The one-year overall and disease-free survivals for all patients were 44% and 25% respectively. Causes of death were relapse in 12 patients and in one patient sepsis six years after transplant. In multivariate analysis, disease status, age, and GVHD did not predict for survival, perhaps due to the small sample size. There was a trend to improved survival in the higher dose busulfan group but the follow up was shorter for these patients. In summary, 1) Reduced intensity transplantation is tolerated well in an older population with acute myelogeneous leukemia, with no transplant related mortality at Day 100 or at 6 months post transplant; 2) Relapse rermains the most common cause of death; 3) There was a trend to improved survival with a twice daily busulfan dosing. Future studies will address the outcomes of twice daily busulfan dosing in a larger cohort of older patients with AML in complete remission. Disclosures:Spitzer:Genzyme: Consultancy.