Donor Allogeneic Stem Cell Transplantation Research Articles

Sirolimus, Tacrolimus and Low-Dose Methotrexate Based Graft-Versus-Host Disease (GVHD) Prophylaxis After Non-Ablative or Reduced Intensity Conditioning in Related and Unrelated Donor Allogeneic Stem Cell Transplantation: Decreased Severe Early aGVHD but Persistence of Late Acute Gvhd

AbstractAbstract 4194 Background:The morbidity and mortality associated with acute and chronic graft-versus-host disease (GVHD) remain significant after allogeneic hematopoietic stem cell transplantation (allo-HSCT). Encouraging results have been reported with the combination of sirolimus, tacrolimus, and low-dose methotrexate after non-myeloablative allogeneic peripheral blood stem cell transplantation (PBSCT) (Alyea EP et al, Biol Blood Marrow Transplant 2008). We conducted a retrospective analysis of 74 patients with hematologic malignancies who underwent a non-myeloablative (NMA) or reduced intensity (RIC) allo-HSCT using sirolimus, tacrolimus, and low-dose methotrexate for GVHD prophylaxis. Methods:Between April 2008 and June 2011, 74 patients (M/F: 45/29), median age 51 years (range: 23–69) were transplanted for non-Hodgkin’s lymphoma (63%), chronic lymphocytic leukemia/small lymphocytic lymphoma (20%), Hodgkin lymphoma (12%) and acute lymphoblastic leukemia or myelodysplasia (3%). At transplantation, 36 patients (49%) were in complete remission and 38 patients (51%) had chemotherapy sensitive active disease. Conditioning regimen was NMA in 59 patients and RIC in 15 patients. Donors were HLA-matched related (MRD, n = 30, 41%), matched unrelated (MUD, n = 37, 50%) or 9/10 HLA-mismatched unrelated (MMUD, n = 7). All patients received peripheral blood mobilized grafts. GVHD prophylaxis consisted of sirolimus and tacrolimus that were started on day -3 and doses were adjusted to maintain target serum trough levels of 3–12 ng/mL and 5–10 ng/mL, respectively, followed by methotrexate 5 mg/m2 on days +1, 3, 6. Tapering of sirolimus and tacrolimus began at day 60 in the absence of GVHD or relapse, with the goal of complete discontinuation of immunosuppressants by 6 months or earlier if patients were not in CR at transplant. Recipients of MUD (31 of 37) or MMUD (7 of 7) grafts were given 2 doses of anti-thymocyte globulin (ATG) on days −3, and −2. Forty-eight patients with CD20+ malignancies (65%) received rituximab at day -8 and +21, 28, 35, 42. Acute GVHD (aGVHD) was scored by IBMT Severity Index and chronic GVHD (cGVHD) based on NIH consensus criteria. Results:The cumulative incidence of Grade B-D and C-D classic aGVHD at day +100 were 14.9% and 2.7%, respectively. The cumulative incidence of aGVHD at 1-year was 31.1 % for grade B-D and 5.4 % for grade C-D, due to late-onset Grade B-D and Grade C-D aGVHD rates of 16.2% and 2.7%, respectively. The incidence of cGVHD at 1 and 2 years was 15% and 28%, respectively. The use of peri-transplant rituximab did not affect the incidence of Grade B-D aGVHD (p=0.55) or cGVHD (p=0.94). There was no difference in the incidence of Grade B-D aGVHD at day 100 between ATG (13.9%) and no ATG (15.8%) cohorts. There was a trend towards a modestly higher 2-year incidence of cGVHD in patients who did not receive ATG, despite the fact that these were predominantly recipients of MRD (37% vs. 21% in ATG cohort, p=0.12). Two patients (2.7%) developed thrombotic microangiopathy and 4 patients (5.4%) had renal toxicity, requiring modification of the immunosuppressant treatment. No sinusoidal obstructive sydrome was reported. To date, 15 patients have died; causes of death include disease recurrence (n=9) and GVHD (n=6). The cumulative incidence of non-relapse mortality and relapse at 1 year were 4% and 27%, respectively. The 1-year relapse rate in the ATG and no ATG cohorts was 11% and 28%, respectively (p=0.10). With a median follow up 2.6 (range: 0.8–3.9) years, progression-free and overall survival at 2 years were 64 % and 77 %, respectively. Conclusions:As previously reported this GVHD prophylaxis regimen is safe and effective, providing lower rates of acute GVHD compared to historical data. The incidence of chronic GVHD by NIH criteria was low due to an increase in late-onset acute GVHD. Rituximab therapy did not affect the incidence of acute and chronic GVHD. The addition of ATG in MUD and MMUD recipients resulted in a trend toward lower rates of chronic GVHD with no increase in the rate of relapse. Future strategies will need to focus on decreasing the incidence of late onset acute and chronic GVHD without increasing the risk of relapse. Disclosures:No relevant conflicts of interest to declare.

Allogeneic stem cell transplantation for acute myeloid leukemia with del(7q) following untreated chronic lymphocytic leukemia

The development of hematologic malignancy in the presence of chronic lymphocytic leukemia (CLL) is rare. We present a case of acute myeloid leukemia (AML) with del(7q) occurring in a patient with a 4-year history of untreated CLL. Application of flow cytometry and immunohistochemistry allowed for characterization of two distinct coexisting malignant cell populations. After undergoing induction and consolidation chemotherapy, the patient achieved complete remission of AML with the persistence of CLL. Allogeneic transplantation was pursued given his unfavorable cytogenetics. Subsequent matched unrelated donor allogeneic stem cell transplantation resulted in full engraftment and complete remission, with no evidence of AML or CLL. Due to a scarcity of reported cases, insight into treatment and prognosis in cases of concurrent AML and CLL is limited. However, prognosis seems dependent on the chemosensitivity of AML. CLL did not have a detrimental effect on treatment or transplant outcome in our case. This is the first reported case of concomitant de novo AML and CLL to undergo allogeneic transplantation. The patient remained in complete hematologic and cytogenetic remission of both malignancies over a year after transplantation.

Impact of ATG on new HLA groups for unrelated donor allogeneic stem cell transplantation.

6536 Background: The outcomes of unrelated donor transplantation have improved with refinements in HLA testing. Recently, grouping of HLA matching for unrelated donor was suggested, defining by well-matched, partially-matched, and mismatched. In the current study, the role of ATG for each group was evaluated. Methods: A total of 92 patients diagnosed as hematologic diseases and received allogeneic stem cell transplantation (SCT) from unrelated donor were retrospectively analyzed. Results: Nineteen patients were classified as well-matched, 42 as partially-matched, and 31 as mismatched. Among them, 57 patients received anti-thymocyte globulin (ATG) as graft-versus-host disease (GVHD) prophylaxis. The overall survival (OS) rate was higher for well-matched group (83%) compared to partially-matched (54%) and mismatched (34%, p=0.076). For partially-matched group, the OS was significantly improved with ATG (83.3% vs. 38.6%, p=0.018). But, the OS was not different between groups with or without ATG for well-matched (87.5% vs. 66.7%, p=0.487) and mismatched (32.4% vs. 41.7%, p=0.215). ATG decreased the cumulative incidence of grade 3-4 acute GVHD (10% vs. 40.2%, p=0.068) and severe chronic GVHD (21.2% vs. 52.2%, p=0.037). The use of ATG (HR=0.248, p=0.029) was related with favorable OS for partially-matched group. However, the favorable effect of ATG was not observed in well-matched and mismatched groups. Conclusions: ATG effectively improved survival rate for partially-matched group in unrelated donor transplantation. However, the positive effect of ATG was not observed in well-matched and mismatched group.

T cell depletion utilizing CD34+ stem cell selection and CD3+ addback from unrelated adult donors in paediatric allogeneic stem cell transplantation recipients

CD34-selected haploidentical and unrelated donor allogeneic stem cell transplantation (AlloSCT) in paediatric recipients is associated with sustained engraftment and low risk of acute graft-versus-host disease (aGVHD), but limited by delayed immune reconstitution and increased risk of viral and fungal infection. The optimal dose of donor T cells to prevent graft failure and minimize risk of early opportunistic infection and post-transplant lymphoproliferative disorder (PTLD), while avoiding severe aGVHD, remains unknown. We prospectively studied CD34-selected 8-10/10 human leucocyte antigen (HLA)-matched unrelated donor (MUD) peripheral blood stem cell transplantation (PBSCT) in a cohort of 19 paediatric AlloSCT recipients with malignant (n=13) or non-malignant (n=6) diseases. T cells were added back to achieve total dose 1·0-2·5×10(5) CD3(+) /kg. GVHD pharmacoprophylaxis consisted only of tacrolimus. All patients engrafted neutrophils. Probabilities of grade II-IV aGVHD, limited chronic GVHD (cGVHD), and extensive cGVHD were 15·8%, 23·3%, and 0%, respectively. One patient developed PTLD. One-year infection-related mortality was 5·6%. T cell immune reconstitution was delayed. One-year overall survival was 82·3%. Five patients with malignant disease ultimately died from progressive disease. CD34-selected MUD PBSCT using a defined dose of T cell add-back resulted in high rates of engraftment and low risk of grade II-IV aGVHD, early transplantation-related mortality, and extensive cGVHD.

Immunomodulatory nonablative conditioning regimen for B-cell lymphoid malignancies

Twenty-six patients with recurrent CD20(+) B-cell lymphoid malignancies received fludarabine, cyclophosphamide, and rituximab-based nonablative conditioning followed by either matched related (n = 18) or unrelated (n = 8) donor allogeneic stem cell transplantation (allo-SCT) between March 2008 and May 2011. Median age of patients at transplantation was 59 years (range, 41-64 years). At diagnosis, 20 (77%) had stage IV disease; 23 (88%) received ≥3 regimens, 14 (54%) received ≥4 regimens, and 4 (15%) had earlier autologous-SCT. All patients had either chemosensitive or stable disease and nine (35%) were in complete remission before transplantation. At the time of analysis, 17 patients were alive with an estimated 2-year overall survival and progression-free survival rate of 63% and nonrelapse mortality of 25%. Grade II to IV acute graft-vs-host-disease occurred in 8 (31%) and chronic graft-vs-host-disease in 6 (23%) patients (extensive, n = 3). Causes of death include progressive disease in four, acute graft-vs-host-disease in two (both after receiving donor lymphocyte infusion for mixed chimerism with residual disease), infection in one, and other (e.g., substance abuse, leukoencephalopathy) in two. Six patients required rehospitalization within 100 days of SCT (mean = 10 days; range, 3-18 days). Our data support fludarabine, cyclophosphamide, and rituximab-based nonablative conditioning allo-SCT in CD20(+) B-cell lymphoid malignancies and it is time to compare this regimen with an alternative reduced-intensity conditioning regimen in B-cell malignancies.

A 53-Year-Old Stem Cell Transplant Recipient with Meningitis and Bacteremia

A 53-year-old woman with a history of acute lymphocytic leukemia (ALL) was admitted to an outside hospital in Florida. She had received a matched unrelated donor allogeneic peripheral blood stem cell transplant 13 months prior and was on steroid treatment for graft-versus-host disease involving skin

Allogeneic Hematopoietic Stem Cell Transplantation for Blastic Plasmacytoid Dendritic Cell Neoplasm

Abstract 4938 BackgroundBlastic plasmacytoid dendritic cell neoplasm is a rare malignancy that typically follows a highly aggressive clinical course,formerly known as blastic natural killer (NK)-cell lymphoma and CD4+/CD56+ hematodermic neoplasm. Here we report 2 cases of blastic plasmacytoid dendritic cell neoplasm that underwent allogeneic stem cell transplantation. Patients and MethodsCase one was recognized as acute lymphocyte leukemia and then was revised to BPDC at recurrence, and another initially presented with typical cutaneous involvement and was promptly diagnosed by biopsy. After induction/re-induction and subsequent consolidation chemotherapy, 2 cases of BPDC received HLA identical-sibling donor allogeneic stem cell transplantation (Allo-HSCT) after BU/Cy, TBI/Cy+VP-16 conditioning regimen, respectively. Both achieved rapid hematopietic recovery in 2 weeks. Multi-color labeling flow cytometry was performed to monitor minimal residual disease (MRD) and the patient received donor lymphocyte infusion (DLI) to control primary malignancy as MRD-triggered or preventive strategy. ResultsCase 1 survived refractory acyclovir-resistant Epstein-Barr virus viremia after rituximab treatment, but failed in DLI-related grade IV graft versus host disease (GVHD) mixed with thrombotic microangiopathy (TMA) on 1 year post-transplantation. Case 2 died from relapse. Conclusion:Allo-HSCT seems to be a promising treatment for aggressive BPDC aided with MRD monitoring and MRD-triggered DLI. GVHD mixed with TMA deserves more attention for treatment of refractory GVHD. Disclosures:No relevant conflicts of interest to declare.

Impact of ATG on New HLA Groups for Unrelated Donor Allogeneic Stem Cell Transplantation

Abstract 3017 Background:The outcomes of unrelated donor transplantation have improved with refinements in HLA testing. Recently, grouping of HLA matching for unrelated donor was suggested, defining by well-matched, partially-matched, and mismatched. In the current study, the role of ATG for each group was evaluated. Methods:A total of 92 patients diagnosed as hematologic diseases and received allogeneic stem cell transplantation (SCT) from unrelated donor were retrospectively analyzed. Results:Nineteen patients were classified as well-matched, 42 as partially-matched, and 31 as mismatched. Among them, 57 patients received anti-thymocyte globulin (ATG) as graft-versus-host disease (GVHD) prophylaxis. The overall survival (OS) rate was higher for well-matched group (83%) compared to partially-matched (54%) and mismatched (34%, p=0.076). For partially-matched group, the OS was significantly improved with ATG (83.3% vs. 38.6%, p=0.018). But, the OS was not different between groups with or without ATG for well-matched (87.5% vs. 66.7%, p=0.487) and mismatched (32.4% vs. 41.7%, p=0.215). ATG decreased the cumulative incidence of grade 3–4 acute GVHD (10% vs. 40.2%, p=0.068) and severe chronic GVHD (21.2% vs. 52.2%, p=0.037). The use of ATG (HR=0.248, p=0.029) was related with favorable OS for partially-matched group. However, the favorable effect of ATG was not observed in well-matched and mismatched groups. Conclusion:ATG effectively improved survival rate for partially-matched group in unrelated donor transplantation. However, the positive effect of ATG was not observed in well-matched and mismatched group. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

The role of matched sibling donor allogeneic stem cell transplantation in pediatric high-risk acute myeloid leukemia: results from the AML-BFM 98 study

The role of allogeneic stem cell transplantation in post-remission management of children with high-risk acute myeloid leukemia remains controversial. In the multi-center AML-BFM 98 study we prospectively evaluated the impact of allogeneic stem cell transplantation in children with high-risk acute myeloid leukemia in first complete remission. HLA-typed patients with high-risk acute myeloid leukemia, who achieved first complete remission (n = 247), were included in this analysis. All patients received double induction and consolidation. Based on the availability of a matched-sibling donor, patients were allocated by genetic chance to allogeneic stem cell transplantation (n = 61) or chemotherapy-only (i.e. intensification and maintenance therapy; n = 186). The main analysis was done on an intention-to-treat basis according to this allocation. Intention-to-treat analysis did not show a significantly different 5-year disease-free survival (49 ± 6% versus 45 ± 4%, P(log rank) = 0.44) or overall survival (68 ± 6% versus 57 ± 4%, P(log rank) = 0.17) between the matched-sibling donor and no-matched-sibling donor groups, whereas late adverse effects occurred more frequently after allogeneic stem cell transplantation (72.5% versus 31.8%, P(Fischer)<0.01). These results were confirmed by as-treated analysis corrected for the time until transplantation (5-year overall survival: 72 ± 8% versus 60 ± 4%, P(Mantel-Byar) 0.21). Subgroup analysis demonstrated improved survival rates for patients with 11q23 aberrations allocated to allogeneic stem cell transplantation (5-year overall survival: 94 ± 6% versus 52 ± 7%, P(log-rank) = 0.01; n = 18 versus 49) in contrast to patients without 11q23 aberrations (5-year overall survival: 58 ± 8% versus 55 ± 5%, P(log-rank) = 0.66). Our analyses defined a genetic subgroup of children with high-risk acute myeloid leukemia who benefited from allogeneic stem cell transplantation in the prospective multi-center AML-BFM 98 study. For the remainder of the pediatric high-risk acute myeloid leukemia patients the prognosis was not improved by allogeneic stem cell transplantation, which was, however, associated with a higher rate of late sequelae.

Favorable preliminary results using TLI/ATG‐based immunomodulatory conditioning for matched unrelated donor allogeneic hematopoietic stem cell transplantation in pediatric severe aplastic anemia

To assess whether a tolerance-induction regimen could be applied for unrelated (MUD) HCT in SAA, we retrospectively reviewed our HCT experience using unmanipulated 10/10 HLA-matched bone marrow grafts from MSD vs. MUD donors. Conditioning was CTX 200 mg/kg (CTX) + rabbit ATG 10 mg/kg (ATG) for MSD (n = 9) and TLI (800 cGy) + CTX/ATG for MUD HCT ( n = 5). Immunoprophylaxis was CSA and short-course MTX. Median patient age was 14.7 yr, median time to HCT 1.5 yr, and median follow-up 3 yr. Outcome measures included EFS, time to engraftment, and cumulative incidence of GVHD (CIN of GVHD) for MSD and MUD cohorts. EFS and stable engraftment rate were 100%. CIN of acute GVHD was: MSD, Grade I-II: 1 (11%), Grade III-IV: 0%; MUD, Grade I-II: 1 (20%), Grade III-IV: 1 (20%). CIN of chronic GVHD was: MSD, limited: 1 (11%), extensive: 0%; MUD, limited: 0%, extensive: 0%. All immunosuppressive-compliant patients successfully weaned immunosuppression. Although in limited patients, our results suggest that immunomodulatory TLI added to backbone CTX/ATG conditioning is a promising option for MUD HCT in SAA patients, which we will examine in a prospective clinical trial.

Haploidentical Allogeneic Haematopoietic Stem Cell Transplantation as Salvage Therapy for Engraftment Failure after Unrelated and Autologous Stem Cell Transplantation: A Case Report and Review of the Literature

Engraftment failure is a rare but life-threatening complication of haematopoietic stem cell transplantation (HSCT) and treatment of this condition is often challenging. This case report describes a patient with acute myeloid leukaemia and engraftment failure after unrelated donor allogeneic stem cell transplantation. Rescue treatment with granulocyte-colony stimulating factor and reinfusion of autologous 'back-up' stem cells failed, but transplantation of haploidentical donor stem cells following a fludarabine and antithymocyte globulin (ATG)-based conditioning regimen resulted in haematological reconstitution and long-term disease-free survival. The use of haploidentical donor stem cell transplantation as salvage therapy after engraftment failure in adult patients has not, to the authors' knowledge, been previously reported. Additionally, a review of the relevant literature is presented. This case report and literature review suggest that reinfusion of cryopreserved 'back-up' haematopoietic stem cells is a safe and effective salvage therapy for engraftment failure after allogeneic HSCT. Haploidentical donor stem cell transplantation after a fludarabine and ATG-based conditioning regimen could provide effective second-line therapy in adult patients.

Predictive impact of allele-matching and EBMT risk score for outcome after T-cell depleted unrelated donor transplantation in poor-risk acute leukemia and myelodysplasia

Many parameters predict for outcome after unrelated donor (URD) allogeneic hematopoietic stem cell transplantation (alloSCT). High-resolution HLA-matching significantly impacts outcome and also the European Group of Blood and Marrow Transplantation (EBMT) risk score, based on patient age, disease stage, donor type, time from diagnosis to SCT and gender combination, may predict for non-relapse mortality and overall survival (OS). We evaluated the individual and combined effects of allele-matching and the EBMT risk score in 327 patients with poor-risk acute leukemia or myelodysplasia, who received a T-cell depleted URD alloSCT. Matching for HLA-A, -B, -C and -DRB1 alleles (8/8 match) was associated with a 5-year OS of 40% compared with 30% for mismatched (≤7/8) pairs (P=0.02). Patients with EBMT risk scores of 1-2, 3, 4 and 5-7 had 5-year OS estimates of 53, 43, 30 and 20%, respectively (P<0.001). The favorable prognostic impact of an 8/8 donor was most pronounced if the EBMT risk score was low (1-2). Five-year OS was 74±8% vs 39±11% for fully matched patients with a low-risk EBMT score as compared with EBMT low-risk patients with ≤7/8 donors. These data underscore the importance of incorporating both the EBMT risk score and the degree of high-resolution HLA-matching in the risk assessment prior to URD alloSCT.

Pretransplantation Liver Function Impacts on the Outcome of Allogeneic Hematopoietic Stem Cell Transplantation: A Study of 455 Patients

Liver dysfunction is frequent before allogeneic stem cell transplantation (allo-SCT). However, its characteristics and impact on transplantation outcomes are uncertain, especially in the reduced-intensity conditioning (RIC) setting. We analyzed 455 patients receiving an allo-SCT in 3 Spanish centers. Pretransplantation aspartate aminotransferase (AST), alanine aminotransaminase (ALT), gamma-glutamyl transpeptidase (GGT), alkaline phosphatase (AP), total bilirubin, and international normalized ratio were analyzed. Pretransplantation liver function test abnormalities were found in 94 (22%) patients. The most frequent cause of pretransplantation liver dysfunction was isolated elevation of GGT/AP (n = 49, 53%). Patients with high bilirubin levels before allo-SCT showed higher 4-year nonrelapse mortality (4y-NRM) (hazard ratio [HR] 2 [95% confidence interval [CI] 1.1-3.8] P = .02) and patients with high GGT levels showed higher 100-day NRM and lower 4-year overall survival (OS) (HR 3.4 [95% CI 1.8-6.7] P < .001, and HR 2 [95% CI 1.4-3], P = .001), respectively. High levels of transaminases did not influence on survival or mortality. In conclusion, hepatic dysfunction before allo-SCT is frequent and has an impact on transplantation outcomes. The best indicator of liver dysfunction still has to be determined.

Donor-derived adult T-cell leukaemia

In July, 2008, a 55-year-old woman was referred to us with a 2-month history of progressive aphasia after a febrile episode. She had been diagnosed with chronic adult T-cell leukaemia in June, 1999, and had had a nonmyeloablative peripheral-blood stem-cell transplant with conditioning of pentostatin and 2 Gy total body irradiation in March, 2002. The stem cells had been harvested from her brother, an asymptomatic carrier of human T-cell lymphotropic virus type 1 (HTLV-1). After treatment, she had complete remission. Ciclosporin was discontinued 6 months after the transplant ation because of graft-versus-host disease. Our patient had had no bacterial or viral infections. She had no skin lesions, lymphadenopathy, or splenomegaly. Her leucocyte count was 8·74×109/L with 2·5% adult T-cell leukaemia-like cells. The leukaemia was therefore con sidered to be in remission. CD3-positive cells in the peripheral blood were confi rmed as donor derived by XY-fl uorescence insitu hybridisation (XY-FISH). Serum IgG was 13·7 g/L, IgA was 2·82 g/L, and IgM was 1·16 g/L. Our patient was immunocompetent; absolute number of circulating cells positive for CD4 was 1·74×109/L, CD8 0·475×109/L, CD19 0·522×109/L, and CD56 0·326×109/L. Brain MRI showed hyperintense, non-enhancing lesions in the left temporoparietal lobe and right frontal lobe (fi gure A), which suggested encephalitis, progressive multiple leukoencephalopathy, demyelinating disorder, or lymphoma. Serum concentrations of calcium, lactate dehydro genase, soluble interleukin-2 receptor, and β-2 microglobulin were not raised. CSF examination, culture, and PCR, abdominal ultrasonography, endoscopy, and 18F-fl urodeoxyglucose (18F-FDG) PET were normal. Craniotomy and biopsy of the left temporal lobe was done in July, 2008. Histopathology showed perivascular accumulation and cerebral infi ltration by mononuclear tumour cells with large, indented nuclei (fi gure B). Tumour cells were positive for CD3, CD4, CD8, and CD45RO, but negative for B-cell markers (CD20 and CD79a), suggesting cerebral invasion by adult T-cell leukaemia cells (webappendix). XY-FISH showed an XY genotype of the tumour cells (fi gure C), suggesting that they had originated from the donated leucocytes. After whole brain irradiation and localised irradiation of the left temporoparietal lobe, our patient’s aphasia improved remarkably, and repeat MRI showed shrinkage of the brain lesions. In October, 2010, our patient was fully recovered. For patients with adult T-cell leukaemia, asymptomatic carriers of HTLV-1 have been widely considered acceptable as donors in allogeneic stem-cell transplantation. The immune system is thought to have an important role in leukaemia occurrence in HTLV-1-seropositive carriers. The only reported case of donor-derived adult T-cell leukaemia was in 2006, in an immunosuppressed recipient of a peripheral-blood stem-cell transplant. No cases of donorderived adult T-cell leukaemia have been reported in immunocompetent patients. The prognosis tends to be better for these patients than for those with CNS involvement subsequent to systemic adult T-cell leukaemia. Only two cases of isolated CNS involvement have been reported so far. The function of CD4-positive cells was not fully analysed, so there is a possibility of some functional defi cit in immune reconstitution. Our patient’s case suggests that the consent practices in patients who receive HTLV-1-positive cells should be re-evaluated.

High Incidence of Hyperacute GVHD (HaGVHD) in Patients (pts) Undergoing Unrelated Donor Allogeneic Hematopoeitic Stem Cell Transplantation (URalloHSCT) Receiving a Non-Methotrexate (Non-MTX) Containing Regimen

HaGVHD is a syndrome characterized by unexplained fevers, diarrhea, skin rash and hepatic toxicity that occurs before engraftment (less than 14 days) in alloHSCT pts and is associated with significant morbidity and mortality. We describe the incidence and clinical characteristics of URalloHSCT recipients in our institution that developed this complication after we adopted a new policy in GVHD prophylaxis that aborted the use of MTX.

Early lymphocyte reconstitution is associated with improved transplant outcome after cord blood transplantation

Previous studies have shown that rapid recovery of the absolute lymphocyte count (ALC) is associated with improved transplant outcomes after related and unrelated donor allogeneic stem cell transplantation (allo-SCT). No consistent association has been reported between lymphocyte recovery and transplant outcome after cord blood transplantation (CBT). We reviewed the records of 40 consecutive CBT patients at our institution to determine the impact of lymphocyte recovery on transplant outcome. The majority of patients (83%) received CBT for hematologic malignancies. Patients with ALC ≥150/μL at 30 days post-CBT had decreased non-relapse mortality (NRM) (P = 0.011) and improved survival (P = 0.013) compared with ALC <150/μL. Patients with ALC <100/μL at 30 days post-CBT had a significantly higher rate of graft failure than those with ALC ≥100/μL (four of 10 versus one of 29; P = 0.011). ALC was positively correlated with the nucleated cell dose and inversely correlated with the patient's age. There was no relationship between disease risk, type of conditioning regimen, anti-thymocyte globulin and number of cord units on ALC recovery. Our results indicate that ALC 30 days post-CBT is a surrogate for engraftment, and that low ALC (<150/μL) identifies an 'at-risk' population of patients after CBT. Studies are needed to determine ways to increase ALC cell numbers post-CBT, including ex vivo-expanded natural killer cells using adoptive immunotherapy, which might improve outcome after CBT.

Combination of Mycophenolate Mofetil with Cyclosporine A and Methotrexate as Gvhd Prophylaxis In Unrelated Donor Allogeneic Hematopoietic Stem Cell Transplantation.

AbstractAbstract 1280Graft-versus-host disease (GVHD) is the dominant complication limiting the efficacy and safety of hematopoietic stem cell transplantation (HSCT), especially from unrelated donors. The most widely used regimen of prophylaxis is the combination of cyclosporine A (CSA)and a short-course of methotrexate (MTX). But the patients receiving grafts from matched unrelated donors still have a 50–80% risk of clinical significant GVHD. Thus, more effective prophylaxis is needed. In this study, we try to evaluate the efficacy and safety of the new GVHD prophylaxis regimen combining mycophenolate mofetil (MMF) with CSA and MTX in unrelated donor allogeneic stem cell transplantation. Between November 1998 and June 2008, 153 patients with a variety of hematologic malignancies were enrolled. There were 102 males and 51 females, median age 26 (range, 8–52) years. Diagnoses were acute myeloid leukemia (n=54), acute lymphoblastic leukemia (n=47),myelodysplastic syndrome (n=8), multiple myeloma (n=1) and chronic myeloid leukemia (n=53). One hundred and eight patients had HLA compatible unrelated donors, 37 patients had single locus-mismatched unrelated donors and 8 patients had 2 loci-mismatched unrelated donors. GVHD prophylaxis consisted of CSA,MTX and MMF. CSA was started on day -7 with the initial dosage of 2.5mg/kg daily, and the dose was adjusted to maintain a whole blood steady-state level of 200–400ng/ml. The dose was tapered during the second to third month post-transplant depending on GVHD status. MTX was given at a dosage of 10mg on days+1, +3 and +6. MMF was administered at an oral dose of 500mg daily from day 0 to day +100. The cumulative incidence of grades II-IV aGVHD and grades III-IV aGVHD for all patients were 43.9% and 17.9% respectively for entire group. The cumulative incidence of grades II-IV aGVHD for patients who had HLA-matched donors and mismatched donors were 40.2% and 51.9% respectively (P=0.079). The cumulative incidence of grades III-IV aGVHD for patients who had HLA-matched donors and mismatched donors were 14.0% and 26.9% respectively (P=0.026). The cumulative incidence of cGVHD was 41.4%, with 19.3% extensive cGVHD. At 3 years, the incidence of relapse for entire group was 24.0%. The cumulative incidence of transplant-related mortality at 100 days and 3 years were 12.5% and 34.9%, respectively. The probabilities of overall survival at 2 years and 5 years were 59.2% and 50.2%, respectively. The probabilities of disease-free survival at 2 years and 5 years were 56.3% and 46.7%, respectively. From these results, we conclude that the combination of MMF with CSA and MTX is an effective prophylaxis regimen for acute and chronic GVHD in unrelated donor allogeneic stem cell transplantation without increasing the risk of relapse. Disclosures:No relevant conflicts of interest to declare.

Massive Pleural Effusions and Anasarca After Allogeneic Hematopoietic Cell Transplantation.

AbstractAbstract 4556A 37 year old male with T cell acute lymphoblastic leukemia with normal cytogenetics 46XY in second complete remission (CR2) after 8 cycles of HyperCVAD and 4 cycles of salvage nelarabine underwent myeloablative conditioning with cyclophosphamide TBI for a matched related donor allogeneic stem cell transplant from his brother. His day+100 bone marrow biopsy showed CR2 and was 100% donor. His post transplant course was unremarkable until he relapsed d+162. The immunosuppression was tapered off rapidly and 2 cycles of nelarabine and a donor lymphocyte infusion (1×107 CD3 cells/kg) were completed by d+254 and CR3 was achieved. He did well until d+608 when he presented with a month long history of dyspnea and recurrent bilateral large pleural effusions (despite multiple large volume thoracenteses) and anasarca including facial edema. He had gained 15 kilograms in 2 weeks. He had no fever, skin rash, sicca syndrome or lichen planus. Chest and abdomen CT showed massive bilateral pleural effusions, but no lung infiltrate, pericardial effusion or ascites or lymphadenopathy. The complete blood count, renal function and liver function tests were normal and there was normal hepatopedal flow in the main portal vein and its branches. The echocardiogram showed a left ventricular ejection fraction of 60% (normal) and there were no vegetations. The serum ANA, anti-Ro and anti-La were negative. The bone marrow biopsy showed no evidence of relapse of T cell ALL. The peripheral blood STR was 100% donor. The pleural fluid was transudative and cytology showed no malignancy. Pleural fluid flow cytometry showed no CD20+ B cells but did show polyclonal T cells with a CD4:CD8 ratio of 0.22. The pleural biopsy showed reactive mesothelial cells with mixed acute and chronic inflammation and no malignancy. Ebstein Barr virus in-situ hybridization and HHV-8 immunohistochemistry was negative on the pleural biopsy. All bacterial, fungal and viral (including CMV, EBV, HSV, adenovirus, VZV, HIV, BK) of the blood, urine and pleural fluid were unremarkable. A random skin biopsy of the forearm showed scleroderma. Methylprednisolone 2 mg/kg iv daily and therapeutic tacrolimus with extracorporeal photoporesis was begun with resolution of the pleural effusions and anasarca two months later. On d+903 he remains in CR3 and is on tapering courses of prednisone and tacrolimus without recurrence of the pleural effusions or anasarca. Conclusion: Isolated sterile pleural effusions with anasarca should be recognized as a rare feature of late onset chronic graft versus host disease so as to allow prompt initiation of immunosuppression. The patient shared the HLA antigens HLA DR15 and HLA DQW6 which are associated with autoimmune disease such as systemic lupus erythematosus suggesting that patients with this HLA combination may be more prone to this presentation. Disclosures:No relevant conflicts of interest to declare.

Haploidentical Allogeneic Hematopoietic Cell Transplantation as Salvage Therapy for Engraftment Failure After Unrelated and Autologous Cell Transplantation.

AbstractAbstract 4529Engraftment failure is a rare but life-threatening complication of hematopoietic stem cell transplantation. The treatment of this condition is often challenging. We firstly reported haploidentical donor stem cells transplantation resulted in hematological reconstitution and long-time disease-free survival in a patient who developed engraftment failure after unrelated donor allogeneic stem cell transplantation and failure rescue treatment by re-infusion of autologous “back-up” stem cells. The 39-years-old male patient with acute myeloid leukemia(AML)-M2a achieved complete remission (CR) after one course of induction chemotherapy. He entered a lasting CR with 7 courses post-remission consolidation therapy and decided to receive unrelated donor allogeniec stem cell transplantation. In case of engraftment failure after allo-HSCT, autologous “back-up” cells were harvested after the last course chemotherapy (IDA 15 mg on days 1–2, 10 mg on day 3, Ara-c 300 mg on days 1–3, 200 mg on day 4), and mobilized with G-CSF 5 mg/kg/day for 5 days. The “back-up” cells consisting of 9.94×106/kg CD34+ cells were cryopreservated in liquid nitrogen. Fifteen months after de novo AML, the patient received a myeloablative conditioning regimen of busulfan and cyclophosphamide (busulfan 3.2 mg/kg/day on days -7 to -4, and cyclophosphamide 60 mg/kg/day on days -3 to -2), and an infusion of unrelated allogeneic peripheral stem cells from the Chinese Marrow Donor Program with a HLA-Cw allele mismatch on day 0. The graft contained 11.07×108/kg nucleated cells and 6.35×106/kg CD34+ cells. Pancytopenia was continuously observed during 28 days after transplantation and short tandem repeat-polymerase chain reaction (STR-PCR) analysis showed no donor chimera. As a rescue attempt for graft failure, cryopreservated autologous cells were re-infused on day +28. Unfortunately, pancytopenia was still continuously observed during 23 days after re-infused of “back-up” cells(51 days after unrelated transplantation), and bone marrow examination revealed severe bone marrow hypoplasia. On day +57 and +58 after unrelated transplantation, bone marrow cells containing 2.1×106/kg CD34+ stem cells and peripheral blood cells containing 2.81×106/kg CD34+ stem cells from a haploidentical donor sister (HLA matched in 5/10 alleles by high-resolution genotyping) were infused respectively after reduced-intensity conditioning with fludarabine and ATG (fludarabine 30mg/m2/d on day -5 to -1, ATG 100mg/d on day -4 to -1). Absolute neutrophil count >0.5×109/L was documented on day 12 after haploidentical transplantation. He achieved platelets count >20×109/L on day 28 after haploidentical transplantation. Twenty-nine days after haploidentical transplantation, bone marrow examination showed reconstitution and STR-PCR analysis indicated complete donor chimera. No grades III -IV aGVHD, extensive chronic GVHD, and severe infection after transplantation were observed. Recurrent bone marrow aspiration examinations showed the patient had been in CR. The patient remained alive during a 18-month follow-up after haploidentical transplantation. Our experience suggests that combined haploidentical donor BM and PBSC transplantation after Flu- and ATG-based conditioning could provide an effective therapeutic strategy for engraftment failure after unrelated allo-HSCT in adult patients. Considering the accessibility of haploidentical donors, haploidentical transplantation has the potential to act as a first-line choice for salvage therapy. Disclosures:No relevant conflicts of interest to declare.

Total Outpatient Care for Myeloablative Unrelated Donor Hematopoietic Cell Transplantation: A Safe and Effective Alternative to Standard In-Patient Care

AbstractAbstract 3525Total Outpatient Care for Myeloablative Unrelated Donor Hematopoietic Cell Transplantation: A Safe and Effective Alternative to Standard In-Patient CareMyeloablative unrelated donor allogeneic stem cell transplantation (UD-SCT) is associated with a high risk of transplant related toxicity, traditionally requiring patients to remain hospitalized from administration of the high-dose preparative regimen until recovery from the cytopenic phase. We previously published a comprehensive outpatient approach for the management of patients undergoing matched sibling donors myeloablative allogeneic stem cell transplant, showing comparable clinical outcomes to those reported for an inpatient approach (Solomon et al, Bone Marrow Transplantation 2010). Given the higher morbidity and mortality associated with UD-SCT, we analyzed the feasibility of outpatient management with this group of patients. For the current study, we reviewed the clinical outcomes of 59 consecutive myeloablative UD-SCT recipients, performed as outpatient procedures, at our institution between March 2005 and March 2010. Patients received their stem cell infusion on the inpatient unit but were not scheduled to stay overnight. Expectant admissions occurred for complications more safely managed in the hospital (febrile neutropenia, mucositis, uncontrolled nausea/vomiting). Fifty-nine consecutive patients who underwent outpatient myeloablative UD-SCT (10/10 locus matched n=46, 9/10 locus matched n=11, and 8/10 locus matched n= 2). Patient characteristics were: median age 50 years (range 19–75); diagnoses AML= 30, ALL=14, CML= 5, MDS=6, MPS=3 and CLL=1; CIBMTR disease risk- high risk (54%), intermediate risk (15%) or low risk (31%); preparative regimen- busulfan (16mg/kg or equivalent) (66%) or TBI ≥ 12 Gy (44%) based. Peripheral blood was the stem cell source for 56 patients and bone marrow for 3. Excluding the 8 patients admitted to receive Thymoglobulin®, only four patients (7%) required hospital admission during their preparative regimen for reasons of GI toxicity (1), drug rash (1), DVT (1) or cerebral aneurysm (1). Forty-eight patients (81%) were discharged from the hospital either the day of or day after stem cell infusion. The median time from stem cell infusion to the first readmission was Day +6 (range 3–23). Mucositis was the primary cause of readmission, occurring in 19 patients. Significant post transplant infections requiring admission prior to day +30 included neutropenic fever (8), staphylococcus epidermidis bacteria (6), RSV (1), CMV (1), clostridium difficile (1) or serratia marcescens (1). The median hospital length of stay (LOS) from the start of the preparative regimen through Day +30 was 12 days (range 1–31 days). Median times to neutrophil and platelet engraftment were 14 and 19 days, respectively. Acute (grade II-IV) and chronic graft versus host disease occurred in 57% and 68% of patients, respectively. Cumulative rates of 100 day and 1 year non-relapse mortality were 5% and 9%, respectively. With a median follow-up of 2.4 years (range 0.5–5.3), the estimated 1, 2, and 3 year overall survival were 76%, 60%, and 54%, respectively. In summary, we show that outpatient myeloablative UD-SCT with expectant inpatient management for treatment related toxicities can be done safely in an unselected group of patients. In spite of the high risk features of the transplant population (advanced age, high risk disease), outpatient UD-SCT was associated with low transplant related morbiditiy and mortality, and favorable transplant outcomes. This approach significantly decreases the length of inpatient hospitalization for UD-SCT, with the potential to free-up inpatient resources, improve quality of life, and decrease costs. Disclosures:No relevant conflicts of interest to declare.