ALBERT

Description: We ascertained the prevalence of self-reported late occurrence of diabetes, hypertension, and cardiovascular (CV) disease in 1089 hematopoietic cell transplantation (HCT) survivors who underwent HCT between 1974 and 1998, survived at least 2 years, and were not currently taking immunosuppressant agents and compared them with 383 sibling controls. All subjects completed a 255-item health questionnaire. The mean age at survey completion was 39.3 years for survivors and 38.6 years for siblings; mean follow-up was 8.6 years. Adjusting for age, sex, race, and body mass index (BMI), survivors of allogeneic HCT were 3.65 times (95% confidence interval [CI], 1.82-7.32) more likely to report diabetes than siblings and 2.06 times (95% CI, 1.39-3.04) more likely to report hypertension compared with siblings but did not report other CV outcomes with any greater frequency. Recipients of autologous HCTs were no more likely than siblings to report any of the outcomes studied. Allogeneic HCT survivors were also more likely to develop hypertension (odds ratio [OR] = 2.31; 95% CI, 1.45-3.67) than autologous recipients. Total body irradiation (TBI) exposure was associated with an increased risk of diabetes (OR = 3.42; 95% CI, 1.55-7.52). Thus, HCT survivors have a higher age- and BMI-adjusted risk of diabetes and hypertension, potentially leading to a higher than expected risk of CV events with age.

Description: Abstract 4503 Background&Objective: The management of lymphoma which has relapsed after allogeneic hematopoietic cell transplantation (HCT) is difficult. Therapeutic options may include donor lymphocyte infusion (DLI), withdrawal of immunosuppression, rituximab, chemotherapy, radiation, immunotherapy and experimental treatments, but response and survival are uncertain. Result: We analyzed 72 patients with relapsed or progressive lymphoma after allogeneic HCT (1991-2007); 44 non-Hodgkin's lymphoma (7 mantle cell, 5 indolent, 19 diffuse large B [DLBCL], and 13 T/NK cell) and 28 Hodgkin's lymphoma (HL). At HCT, 62 patients (86%) were in remission (22 CR, 40 PR); nine (13%) had progressive disease and one had stable disease. Conditioning was myeloablative (n=17) or reduced intensity conditioning (RIC) (n=55). Relapse or progression occurred at a median of 99 days (0-1898 days; 25–75% 43–194 days). At relapse, 41 (57%) had extensive nodal disease and 56 (78%) had extranodal organ involvement. Management of relapse included: no therapy (n=5, 7%), reduction of immunosuppression (RIS) (n=58, 81%), chemotherapy alone (n=14, 19%), immunotherapy alone (n=20, 28%), combined chemo-immunotherapy (n=7, 10%) donor lymphocyte infusion (DLI) (n=7, 10%), second allogeneic HCT (n=2, 3%), radiation (n=23, 32%) and other therapy (n=7, 8%). Twenty-four patients achieved a remission (15 CR, 9 PR) to the initial salvage therapy: RIS (n=13), combined chemo-immunotherapy(n=5), chemotherapy alone (n=2), radiation (n=3) or DLI (n=1). Overall, 40 (56%) patients responded (30 CR, 8 PR, 2 stable disease) with a median post-relapse overall survival of 28 months (range 0–147 months). At 3 years following relapse, 44% (95% CI, 32–56%) survive. Favorable prognostic factors for improved 3-year survival after relapse include stage I-III at relapse, single site of relapse and most importantly, later relapse (〉100 days after HCT [3 year survival 53% vs. 36%, p=0.02]). Conclusion: The overall prognosis of relapsed lymphoma after allogeneic HCT differs based upon extent of disease at relapse and time of relapse. Appropriate therapeutic approaches (RIS, combined chemo-immunotherapy, radiation or DLI) in these high risk, post transplant relapsed patients can yield promising outcome. Prospective study of post-relapse therapy to determine the most effective management strategies are warranted. Disclosures: No relevant conflicts of interest to declare.

Description: This Special Report, this month’s CME article, details evidence-based guidelines for the selection of optimal unrelated donors and cord blood units for allogeneic hematopoietic cell transplantation.

Description: Abstract 661 Objective: To compare 131Iodine-Tositumomab/BEAM to Rituximab/BEAM as the conditioning regimen followed by autologous stem cell transplantation for patients with relapsed chemotherapy sensitive DLBCL. Patients and Methods: The Blood and Marrow Transplant Clinical Trials Network (BMT CTN 0401) study sponsored by the National Heart, Lung, and Blood Institute and the National Cancer Institute enrolled 224 patients between 1/06 and 7/09. Eligible patients were age 18–80 years, had a Karnofsky performance score 〉 70%, persistent or recurrent DLBCL, chemotherapy sensitive disease, and had received 1–3 prior chemotherapy regimens. Patients with transformed DLBCL were excluded. Patients were randomized to receive 131Iodine Tositumomab (dosimetric dose of 5 mCi on day −19 and therapeutic dose of 75 cGy on day −12), carmustine 300 mg/m2 (day −6), etoposide 100 mg/m2 twice daily × 4 (days −5 to −2), cytarabine 100 mg/m2 twice daily × 4 (days −5 to −2), and melphalan 140 mg/m2 (day −1) (Bexxar/BEAM, n=111) vs. rituximab 375 mg/m2 on days −19 and −12 with the BEAM regimen (R/BEAM, n=113). All drugs were given intravenously. The median age at the time of transplant was 56.8 years in the Bexxar/BEAM and 58.8 years in the R/BEAM arm. All 224 patients were included in the intent to treat analysis for the primary endpoint of 2-year PFS. Twelve patients were not transplanted and two patients were ineligible based upon incorrect pathologic subtype and therefore were not included in further analyses Results: The median follow-up of the patients was 25.5 months (mo) (range 13.8– 47.0) in the Bexxar/ BEAM and 24.7 mos (range 4.7 – 58.6) in the R/BEAM arms, respectively. The primary end point of 2-year PFS was 47.9% (95% CI: 38.2%, 57.0%) for Bexxar/BEAM and 48.6% (95% CI: 38.6%, 57.8%) for R/BEAM (p= 0.94). The 2-year OS of all randomized patients was 61.0% (95% CI: 50.9%, 69.6%) for Bexxar/BEAM and 65.6% (95% CI: 55.3%, 74.1%) for R/BEAM (p= 0.38). Patients in complete remission after salvage chemotherapy (CR2) had an improved 2-yr OS compared to patients with primary induction failure (PIF) or chemosensitive relapse (p= 0.005). However, there were no differences in any group by treatment arm. 2-yr OS for CR2 patients with Bexxar/BEAM was 76.9% (95% CI: 62.9%, 86.1%) compared to 79.9% (95% CI: 64.7%, 89.1%) with R/BEAM (p= 0.61). The most common cause of failure was progression/relapse of the lymphoma with a cumulative incidence of relapse/progression at 2 yrs post transplant of 45.0% (95% CI: 35.2%, 54.8%) in the Bexxar/BEAM arm and 48.1% (95% CI: 38.1%, 58.1%) in the R/BEAM arm (p= 0.69). The treatment related mortality was 4.9% (95% CI: 0.8%, 9.0%) in the Bexxar/BEAM and 4.1% (95% CI: 0.2%, 8.0%) in the R/BEAM arms at 2 years post transplant (p= 0.97). Engraftment was similar with neutrophils to 〉 500/ul in 96.1% (95% CI: 92.2%, 100%) of Bexxar/BEAM and 93.5% (95% CI: 88.6%, 98.4%) of R/BEAM patients by day +28 (p= 0.40). Platelet recovery to 〉 20,000/ul with no transfusion by day +100 was present in 84.5% (95% CI: 77.4%, 91.6%) of the Bexxar/BEAM and 81.3% (95% CI: 73.9%, 88.7%) of the R/BEAM patients (p= 0.58). The median maximum mucositis score (by OMAS scale) was higher in the Bexxar/BEAM patients at 0.72 compared to 0.31 in the R/BEAM patients (p 〈 0.0001). One case of myelodysplastic syndrome (MDS) was reported in each arm of the trial and one additional case of acute myelogenous leukemia (AML) was reported in the R/BEAM arm. By exploratory analyses, immune reconstitution as measured by levels of quantitative immunoglobulins and B and T-lymphocyte subsets was not different between the two randomized arms at baseline, day +100, day +365, or day +730. Conclusions: The Bexxar/BEAM and the R/BEAM regimens produced similar 2-yr PFS and OS for patients with chemotherapy sensitive relapsed DLBCL. No differences in engraftment or other toxicities were apparent other than an increase in mucositis with the Bexxar/BEAM regimen. No significant difference in the risk of MDS or AML could be detected with the current follow up. Disclosures: Vose: Genentech: Research Funding; Pharmacyclics: Research Funding; SBio: Research Funding; Exelixis: Research Funding; BMS: Research Funding; Celgene: Research Funding; Millenium: Research Funding; GSK: Research Funding. Off Label Use: 131 Iodine Tositumomab combined with BEAM chemotherapy as a transplant preparative regimen for diffuse large B-cell lymphoma is an off label use. Burns:Novartis: Research Funding. Press:Roche/Genentech: Consultancy, Honoraria; Spectrum: Consultancy, Honoraria. Fenske:Seattle Genetics: Consultancy, Honoraria; Spectrum Pharmaceuticals: Consultancy, Honoraria; Millennium (Takeda) Pharmaceuticals: Research Funding.

Description: We have reported on the safety and efficacy of RIC UCB transplantation for patients with advanced hematologic diseases. Here we report on 65 patients, median age of 46 yrs (range, 6–68), who underwent RIC UCB transplantation for the treatment of advanced lymphoid malignancies between October 2001 and December 2006. Patients received either one (n=9) or two (n=56) UCB unit grafts matched at 4–6/6 HLA loci. Forty were male and 27 CMV seropositive. Diagnoses were follicular lymphoma (FL, n=11), small lymphocytic lymphoma/chronic lymphocytic leukemia (SLL/CLL, n=9), mantle cell lymphoma (MCL, n=8), large cell lymphoma (LCL, n=14), and Hodgkin’s lymphoma (HL, n=23). Conditioning regimen was cyclophosphamide 50 mg/kg (Day-6), fludarabine 40mg/m2 for 5 days (Day-6 to -2), and single fraction total body irradiation of 200cGy (Day -1), plus cyclosporine A and mycophenolate mofetil (to day +30). At transplantation 53 patients (81%) had chemotherapy sensitive disease, 5 (8%) had bulky adenopathy (≥ 5 cm), 27 (42%) had prior radiation therapy, 26 (40%) had prior autologous transplant, 22 (34%) had an elevated LDH, and 10 (15%) had marrow involvement. The median number of prior treatment courses was 4 (range, 1–9). The median follow-up for survivors is 23 mos. (range, 4–62). Patients were analyzed as indolent (IND=FL+ SLL/CLL), aggressive (AGR=LCL+MCL), and HL. Incidence of acute GVHD grades II–IV was 57% (95%CI, 43–70); grades III–IV 25% (95%CI, 14–35); chronic GVHD 23% (95%CI, 11–35), with similar incidence of acute and chronic GVHD between lymphoma subgroups. The 3-year nonrelapse mortality (NRM) was 15% (95%CI, 5–26) with no significant difference among lymphoma subgroups (IND 5% vs. AGR 24% vs. HL 13%, p=.41). Thirty-five patients (53%) had relapsed or progressive disease with a 3-year progression-free survival (PFS) of 31% (95%CI, 19–44); IND 44% (95%CI, 22–66); AGR 20% (95%CI, 2–39); HL 35% (95%CI, 15–54) (p=.30). Fourteen of these 35 patients were treated with tapering of immunosuppression and rituximab and/or chemotherapy or radiation therapy, and 8 achieved a complete remission. Three-year OS was 55% (95%CI, 42–68); IND 69% (95%CI, 48–90); AGR 54% (95%CI, 33–75); HL 43% (95%CI, 18–69) (p=.37). We conclude that RIC UCB is effective alternative for the treatment of patients with advanced lymphoid malignancy resulting in acceptable NRM and encouraging OS and PFS. Patients with advanced lymphoid malignancies should be considered for a RIC UCBT as a promising alternative for those with no available sibling donor.

Description: Chronic graft versus host disease (CGVHD) is classically defined as occurring more than 100 days after hematopoietic cell transplant (HCT). But, with newer donor types and transplant strategies being used [eg. non myeloablative (NMA) and reduced intensity conditioning (RIC)] the presentation of the syndrome is changing. Clinical syndromes resembling acute GVHD (aGVHD) are often recognized beyond 100 days after HCT; possibly misdiagnosed as CGVHD. Additionally, the old grading system of limited versus extensive GVHD was designed to identify patients likely to benefit from systemic immune suppression and does not capture the severity of organ involvement. The Diagnosis and Staging Working Group of the NIH Consensus Development Project on Criteria for Clinical Trials in chronic graft-versus-host-disease proposed criteria for diagnosis and assessment of overall CGVHD severity. We retrospectively reviewed 197 patients who underwent sibling donor transplant between January 2002 to December 2005 to assess the applicability of the new criteria in predicting survival and transplant related mortality (TRM). Fifty four patients were diagnosed with CGVHD [cumulative incidence 28% (95% CI 22–34%)]. Of these, 8 [cumulative incidence 4% (95% CI 2–6%)] were reclassified as Late aGVHD; 31 [cumulative incidence 16% (95% CI 11–21%) had classic CGVHD and 15 [cumulative incidence 8% (95% CI 5–11%] had Overlap syndrome. Forty six patients with Overlap syndrome and classic CGVHD were graded. Six patients (13%) had Mild, 29 (63%) Moderate and 11 (24%) Severe CGVHD. After a median follow up of 35 months (range 4.3–59.2mo), 3 year probability of overall survival was significantly worse in Late aGVHD [25%(95% confidence interval 4–56%)] as compared to Overlap [87%(56–96%)] or CGVHD [75%(54–87%), p=0.001].). Amongst patients with Overlap and CGVHD (n = 46), similar survival was seen between mild or moderate disease. However, patients with severe disease had a trend to worse survival. [Mild-moderate 3 year probability of survival 85% (68–94%) versus Severe 57%(21–82%)]. Additonally, 3 year cumulative incidence of TRM was higher in patients with Late aGVHD [38% (9–67%)] versus Overlap syndrome [13%(0–27%)] or CGVHD [7%(0–13%)], p= 0.003. A trend towards greater TRM was seen in patients with severe GVHD [18%(0–36] versus mild+ moderate GVHD [6%(0–14%)]. This analysis indicates that the consensus guidelines are applicable to related donor HCT recipients and more reliably predicts survival and TRM than older classification of CGVHD. Prospective validation and testing in alternative donor cohorts is still needed before widespread acceptance is justified.

Description: White blood cell (WBC) count and specific cytogenetic abnormalities at diagnosis, patient age and disease status at HSCT have previously been identified as risk factors associated with LFS in patients with ALL. As the use of umbilical cord blood (UCB) is relatively new, particularly for adults, we sought to evaluate the relative impact of donor source. In this single center study, 126 adults aged 18–61 (median 31) years (yrs) underwent myeloablative conditioning (cyclophosphamide 120 mg/kg and total body irradiation 1320–1375 cGy based regimen in 92%) followed by allogeneic HSCT. Stem cell source was an HLA matched related donor (MRD) in 85, HLA matched unrelated donor (URD:M) in 15, HLA mismatched unrelated donor (URD:MM) in 14 and HLA 0–2 (A, B, DRB1) mismatched UCB in 12. At the time of HSCT, 64 patients were in CR1, 51 in CR2, and 11 patients in ≥ CR3; 20 pts had T-lineage disease; 38 pts (30%) had either t(9;22)(n=28), t(4;11) or t(1,19) (n=10) with the remainder (70%) having normal cytogenetics. WBC ≥ 30 x 109/l at diagnosis was documented in 50%. Demographics, disease characteristics at initial diagnosis and transplant variables were similar in all 4 groups except: year of transplant after 1996 and use of growth factor for all UCB recipients. Outcomes by donor source: MRD URD:M URD:MM UCB P N 85 15 14 12 Median follow up in yrs 9.3 3.5 7.2 1.2 OS 1 yr % (95% CI) 41 (31–52) 33 (9–57) 14 (0–33) 75 (51–100) 0.02 LFS 1 yr % (95% CI) 35 (25–45) 27 (4–49) 14 (0–33) 67 (40–93) 0.03 Relapse 1 yr % (95% CI) 21 (12–30) 20 (0–40) 0 8 (0–23) 0.22 TRM 1 yr % (95% CI) 44 (33–55) 53 (27–79) 86 (57–100) 25 (1–49) 30 x 109/l (RR 2.4, 95% CI, 1.4–4.1, p

Description: RIC regimens permit older and less fit patients to receive allogeneic stem cell transplantation (SCT). We designed a novel RIC regimen (cyclophosphamide, fludarabine, TBI [CY/FLU/TBI]) to achieve sufficient anti-neoplastic potency for cytoreduction and adequate immunosuppression for engraftment yet have limited treatment related mortality (TRM). We report the results of 72 patients (58% male) receiving sibling donor HLA-identical (n=66; 92%) or single antigen mismatched (n=6; 8%) G-CSF mobilized peripheral blood SCT from 2002–2005. Eligible patients were 〉55 years or had prior SCT, ongoing but controlled infections, ventricular ejection fraction 35–45% or corrected DLCO 30–50%. All patients had chemotherapy sensitive disease or remission. Most patients had lymphoma (n=29; 40%) or acute leukemia/MDS (n=23; 32%); others (28%) had multiple myeloma, CML, CLL, aplastic anemia, or renal cell carcinoma. All acute leukemia patients were in CR (CR1=14, ≥CR2=4). All lymphoma patients were chemosensitive; 4 were in CR. All patients received conditioning with FLU 40 mg/m2/day × 5 days, CY 50 mg/kg and 200 cGy TBI. Equine ATG 90 mg/kg plus methylprednisolone were given to those without recent combination chemotherapy (29%). GVHD prophylaxis included mycophenolate mofetil 1 gm BID and cyclosporine. The median age was 55 years (range, 11–65). The median graft cell dose infused was 5.4 × 106 CD34+ cells/kg (range, 0.6–15.5). Seventeen (24%) had previous SCT (14 autologous, 3 allogeneic). Neutrophil engraftment occurred at a median of 7 days (range, 0–13) and median time to platelet recovery 〉20K and 〉50K was 9 days (range, 0–51) and 14 days (range, 0–68), respectively. Median bone marrow chimerism by day 28 was 100% (range, 50–100); only 11 patients were

Description: Treatment options for refractory AML are usually ineffective. Previously, we tested adoptive transfer of haploidentical peripheral blood (PB) derived NK cells without transplantation and demonstrated correlation between in vivo NK cell expansion and those who achieved a complete remission. This therapy is limited by: the inability to expand NK cells in most patients, prolonged neutropenia in some patients and inconsistent efficacy. UCB, in contrast to adult PB, is rich in NK precursors with CD34+/CD7−, CD34+/CD7+ and CD34−/CD7+ phenotypes. We hypothesized that UCB-derived NK cells may show better in vivo expansion than adult derived NK cells after cytoreduction. Therefore, we tested our triple UCBT strategy in patients with refractory relapsed AML who were

Description: The nature of aGVHD after umbilical cord blood transplant (UCBT) has not been well characterized. We analyzed acute graft-versus-host disease (aGVHD) incidence and response to therapy in 136 recipients of unrelated UCBT. aGVHD developed in 72 receiving myeloablative (MA) (n=39) and non ablative stem cell transplant conditioning (NST) (n=33) (indicated if age 〉45 years, prior transplant and major co-morbidity). MA transplant recipients were significantly younger (median age 14 years, range 0.8–50) than NST transplant recipients (median 48 years, range 0.7–59), p 〈 0.0001 and had fewer advanced malignant disease at transplant (8% versus 24%), p = 0.09. At diagnosis of aGVHD, the clinical grades and organ involvement were similar in the 2 groups. Grade II–IV aGVHD developed in 34% of MA transplant recipients and 45% (p = 0.1) of NST transplant recipients at a median of 35 days (12–137) and 30 days (15–96) post transplant whereas grade III–IV aGVHD developed in 9% and 13% (p=0.6), respectively. 87% of MA vs. 85% of NST recipients (p=0.8) had skin involvement; 39% vs. 49% had GI disease (p=0.4); and 10% vs.9% (p=0.9) had liver GVHD, respectively. Response to therapy was assessed at 28 and 56 days after diagnosis of aGVHD. A high frequency of complete response (CR) was seen across all grades at day 28 (47%, 48% and 43% CR in grades I, II and III–IV, respectively). At day 56, CR was more frequent in grade I aGVHD (68% vs 64% and 50% in patients with grade II and III–IV disease, respectively, p 0.08). Response rates were similar in MA and NST transplant recipients (CR in 49% vs 46% by day 28, p=0.1, and 64% vs 61% by day 56, p=0.5. Age 〈 20 years (CR or PR 82% vs 64%, p = 0.09) and single organ GVHD (81% vs 52%, p=0.01) were associated with a higher response. A higher response rate was seen in patients with skin GVHD (85%) vs GI disease (63%) vs skin + GI (56%) vs liver involvement with skin/GI (43%), p=0.04. After a median follow up of 1.0 year (0.8–7 years) in both groups, 67% (95% CI 52%–81%) of MA versus 45% (95% CI 28%–62%) of NST patients survive (p=0.05). Higher 1 year survival of 70% (95% CI 58%–83%) was seen in patients with day 28 CR or PR to treatment versus non responders (24%, 95% CI 6%–42%), p20, multiorgan disease, GI or liver GVHD) should facilitate timely assignment of intensified therapy.