Alemtuzumab-containing Regimen Research Articles

The current standing of autologous haematopoietic stem cell transplantation for the treatment of multiple sclerosis

Autologous haematopoietic stem cell transplantation (aHSCT) is gaining traction as a valuable treatment option for patients affected by severe multiple sclerosis (MS), particularly the relapsing–remitting form. We describe the current literature in terms of clinical trials, observational and retrospective studies, as well as immune reconstitution following transplantation, with a focus on the conditioning regimens used for transplantation. The evidence base predominantly consists of non-randomised, uncontrolled clinical trials or data from retrospective or observational cohorts, i.e. very few randomised or controlled trials. Most often, intermediate-intensity conditioning regimens are used, with promising results from both myeloablative and lymphoablative strategies, as well as from regimens that are low and high intensity. Efficacy of transplantation, which is likely secondary to immune reconstitution and restored immune tolerance, is, therefore, not clearly dependent on the intensity of the conditioning regimen. However, the conditioning regimen may well influence the immune response to transplantation. Heterogeneity of conditioning regimens among studies hinders synthesis of the articles assessing post-aHSCT immune system changes. Factors associated with better outcomes were lower Kurtzke Expanded Disability Status Scale, relapsing–remitting MS, younger age, and shorter disease duration at baseline, which supports the guidance for patient selection proposed by the European Society for Blood and Marrow Transplantation. Interestingly, promising outcomes were described for patients with secondary progressive MS by some studies, which may be worth taking into account when considering treatment options for patients with active, progressive disease. Of note, a significant proportion of patients develop autoimmune disease following transplantation, with alemtuzumab-containing regimens associated with the highest incidence.

Allogeneic Hematopoietic Stem Cell Transplantation in Older Patients Aged 50 Years or Older with Severe Aplastic Anaemia: Results from the European Society for Blood and Marrow Transplant and the Center for International Blood and Marrow Transplant Research

Treatment guidelines for older patients with severe aplastic anaemia (SAA) are incompletely developed. In particular, there is a paucity of data relating to outcomes among older patients with SAA who receive hematopoietic stem cell transplantation (SCT) from HLA-matched sibling (MSD) or unrelated donors (MUD). SCT is usually performed as second line treatment and it has been postulated that with improvements in conditioning protocols and supportive care, results in older patients would have improved over time. We analysed transplant outcomes in 538 patients aged 50 years and older with SAA who were transplanted between 2005 and 2016.275 patients (51%) received grafts from MSD, 224 (42%) from 8/8 HLA-matched MUD and 39 (7%) from 7/8 HLA-matched MUD. Median age at SCT was 58 years (range 50-77yrs,), of whom 347 were aged 50-59 years, 174 were aged 60-69yrs and 17 were aged ≥70yrs. 205 patients (38%) reported a performance score less than 90% and the median time from diagnosis to SCT was 10 months. Cyclophosphamide (Cy) with ATG or Cy with fludarabine and ATG were the predominant conditioning regimens for MSD SCT, whereas for MUD SCT, Cy with TBI 200 cGy and ATG or Cy, TBI 200 cGy, fludarabine with ATG were mostly used. 53% of the patients received bone marrow graft and 75% received calcineurin inhibitor (CNI) containing GVHD prophylaxis; 9% received alemtuzumab as part of GVHD prophylaxis.The day-28 cumulative incidence of neutrophil recovery was 84% (95% CI 81-87) and did not differ by patient age. Overall survival (OS) at 3 years for the entire cohort at 3 years was 56% (95% CI 51-60%) (Figure 1). Multivariate analysis confirmed higher mortality for patients with performance score less than 90% (HR 1.37, 95% CI 1.02-1.82; p=0.04) or who received a MUD SCT (HR 1.48, 95% CI 1.02-2.13, p=0.04). No other patient, disease or transplant characteristic was associated with survival. There were no significant differences in mortality risks for patients aged 65-78 versus those aged 50-64 years (HR1.20, 95% CI 0.08-1.74, p=0.36). However, age was significantly associated with grade II-IV acute GVHD; patients aged 65-78 years were at higher risk (HR 1.80, 95% CI 1.18-2.77, p=0.007). On univariate analysis, stem cell source (bone marrow versus peripheral blood) had no impact on acute (p=0.47) or chronic GVHD (p=0.12). Chronic GVHD risks were lower with CNI plus methotrexate (MTX) (HR 0.52, 95% CI 0.34-0.79, p =0.002) and alemtuzumab containing regimens (HR 0.25, 95% CI 0.13-0.48, p,0.001) than with CNI plus mycophenolate (MMF) GVHD prophylaxis. The group of patients who received alemtuzumab had the lowest rate of acute GVHD: 4% (95% CI: 0-10%) compared with 33% (95% CI: 25-42%) with CNI+MMF, 24% (95% CI: 19-30%) with CNI+MTX and 16% (95% CI:8-25%) with other GVHD prophylaxis (non-CNI containing regimens) (p=0.001). The corresponding 2-year rates of chronic GVHD were 11% (95% CI: 1-21%) with alemtuzumab, 50% (95% CI: 40-60%) with CNI+MMF, 32% (95% CI: 26-39%) with CNI+MTX and 21% (95% CI:10-33%) with other GVHD prophylaxis (p<0.001) (Figure 2). Infection was the predominant cause of death accountiing for 40% of deaths.These data support the feasibility of MSD or MUD SCT in SAA patients aged 50 years and older. However, the data need to be interpreted with caution since the selection of patients very likely has been biased. The importance of the performance status for outcome only underscores that concern. Acute and chronic GVHD adds to the burden of morbidity. Alemtuzumab-containing regimens deserve further study in this patient population. [Display omitted] DisclosuresPetersen:Sanofi: Membership on an entity's Board of Directors or advisory committees. Hallek:Mundipharma: Consultancy, Honoraria, Research Funding; F. Hoffmann-LaRoche: Consultancy, Honoraria, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Gilead: Consultancy, Honoraria, Research Funding; Amgen: Consultancy, Honoraria, Research Funding; AbbVie: Consultancy, Honoraria, Research Funding. Potter:Jazz: Honoraria; Pfizer: Other: Advisory board. Peffault De Latour:Alexion Pharmaceuticals, Inc.: Consultancy, Honoraria, Research Funding; Amgen: Research Funding; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria, Research Funding.

Rapid reconstitution of regulatory T-cell subsets is associated with reduced rates of acute graft-versus-host disease and absence of viremia after cord blood transplantation in children with reduced-intensity conditioning using alemtuzumab

Forkhead box P3 (FOXP3)+ regulatory T cell (Treg) reconstitution after unrelated donor umbilical cord blood transplantation in chemotherapy-naïve children is incompletely characterized. We studied 21 children with nonmalignant diseases receiving an identical alemtuzumab-containing regimen. We hypothesized that Treg recovery may be perturbed in patients not only by acute graft-versus-host disease (aGVHD) but also by viremia. Tregs and their memory and naïve subsets were serially monitored for proliferation and apoptosis along with conventional T cells (Tcon). A “reconstitution index” (RI) was calculated relative to pretransplantation values for each parameter. At 3 months post-UCBT, the RI of Tregs was faster compared with other immune components tested and was most rapid in patients free of aGVHD and viremia. There were significantly fewer Tregs in patients experiencing grade I–II aGVHD and/or viremia, leading to an imbalance between Tregs-Tcon ratios. Central and effector memory Tregs were most affected at this time point when they dominated in the circulation. Impaired Treg proliferation without increased apoptosis accounted for the reduced Treg-Tcon ratio. In patients affected with grade II aGVHD and viremia, the overall reduction in circulating Treg pool were associated with a more oligoclonal T-cell receptor β repertoire. Taken together, aGVHD and viremia can lead to defective Treg expansion homeostasis.

Mixed T Cell Chimerism After Allogeneic Hematopoietic Stem Cell Transplantation for Severe Aplastic Anemia Using an Alemtuzumab-Containing Regimen Is Shaped by Persistence of Recipient CD8 T Cells

Prevention of graft-versus-host disease (GVHD) is paramount for allogeneic hematopoietic stem cell transplantation (HSCT) to treat nonmalignant diseases. We previously reported that allogeneic HSCT for severe aplastic anemia (SAA) using the fludarabine, cyclophosphamide, and alemtuzumab (Campath-1H) (FCC) regimen is associated with a very low risk of GVHD and excellent clinical outcomes. We now report a single-center study of 45 patients with longer follow-up and investigation of lymphocyte recovery. Overall survival (OS) was 93%, and event-free survival (EFS) was 90.7%. Acute and chronic GVHD each occurred in 6 patients (13.3%), and only 1 case was severe. Mixed T cell chimerism was frequent and persisted after cessation of immunosuppression. T cells were extensively depleted, representing only 11.3% of lymphocytes at day 30 and rising to 43.8% by 1 year, but still significantly below normal levels (67.2%; P = .018), and deficiency persisted after immunosuppressive therapy (IST) withdrawal. Depletion of CD4 T cells was particularly profound, causing inversion of the normal CD4:CD8 T cell ratio. T cell subset composition was also abnormal, with memory and effector T cells predominating for at least 6 months after FCC HSCT. Analysis of T cell subset chimerism showed that CD4 T cells were predominantly donor-derived at 1 year, whereas recipient-derived CD8 T cells shaped mixed chimerism with a notable contribution of recipient effector CD8 T cells. The prolonged mixed T cell chimerism after IST withdrawal and low incidence of GVHD indicates the establishment of mutual tolerance, but the low incidence of viral disease suggests maintenance of antiviral immunity. Our study shows that despite the abnormal T cell profile after allogeneic HSCT for SAA using the FCC regimen, this regimen is conducive to an excellent clinical outcome.

Patients with chronic lymphocytic leukemia with high-risk genomic features have inferior outcome on successive Cancer and Leukemia Group B trials with alemtuzumab consolidation: subgroup analysis from CALGB 19901 and CALGB 10101

Alemtuzumab consolidation has been investigated to improve remission duration after fludarabine-based induction for chronic lymphocytic leukemia (CLL). The impact on genomic high-risk disease remains unknown. Cancer and Leukemia Group B (CALGB) 19901 and 10101 enrolled previously untreated patients to receive alemtuzumab consolidation after fludarabine-based induction. Immunoglobulin heavy chain gene (IGVH) mutation status and interphase cytogenetics were assessed retrospectively. Treatment response with these alemtuzumab-containing regimens was similar, regardless of genomic risk, except for patients harboring del(17p), where few complete remissions were observed. Progression-free survival (PFS) was similar between IGVH groups, but overall survival (OS) was inferior in IGVH unmutated patients (p = 0.03). Cytogenetic risk group was associated with PFS and OS (p = 0.01 for both), with similarly short PFS in patients with del(17p) and del(11q) and particularly short OS in patients with del(17p). Cytogenetic risk group remained signficantly associated with PFS and OS when controlling for other prognostic factors (PFS: p = 0.009; OS: p = 0.02), as did the negative association of IGVH unmutated disease with OS (p = 0.004). Results were similar when restricting to patients who received at least one dose of alemtuzumab consolidation, demonstrating limited ability to overcome the poor outcome associated with high-risk genetic features (ClinicalTrials.gov identifiers: NCT00004857, NCT00098670).

Guidelines on the diagnosis, investigation and management of chronic lymphocytic leukaemia

Royal Bournemouth Hospital, Bournemouth, 2 Royal Marsden Hospital, London, 3 Southampton General Hospital, Southampton, Cardiff and Vale NHS Trust, Cardiff Cambridge University Hospitals NHS Foundation Trust, Cambridge UK; St. James's Institute of Oncology, Leeds, Christie Hospital NHS Trust, Manchester Royal Marsden Hospital London; Heart of England NHS Foundataion Trust, Birmingham; 10 Royal Liverpool University Hospital, Liverpool; Churchill Hospital, Headington, Oxford, Norfolk and Norwich University Hospital, Norwich

High Alloreactivity of Low-Dose Prophylactic Donor Lymphocyte Infusion in Patients with Acute Leukemia Undergoing Allogeneic Hematopoietic Cell Transplantation with an Alemtuzumab-Containing Conditioning Regimen

The value of prophylactic donor lymphocyte infusion (pDLI) is unclear and differs among diseases and transplantation protocols. Experience with this approach in patients with acute leukemia undergoing hematopoietic cell transplantation (HCT) with an alemtuzumab-incorporating conditioning protocol is lacking. We conducted a single-center prospective study to investigate the applicability and efficacy of prophylactic donor lymphocyte infusion (pDLI) in patients with leukemia undergoing HCT with a low-dose alemtuzumab-containing conditioning regimen. Inclusion criteria were high-risk acute myelogenous leukemia, acute lymphoblastic leukemia, or increasing mixed chimerism. All patients included were tapered off of immunotherapy. Exclusion criteria were a history of ≥grade II or active graft-versus-host disease (GVHD). Of the 56 consecutive patients who underwent HCT with an alemtuzumab-containing regimen, 15 patients (8 with acute myelogenous leukemia and 7 with acute lymphoblastic leukemia) met the study inclusion criteria and received prophylactic DLI (total of 45 infusions) from 7 sibling donors and 8 unrelated donors. The first infusion was given at a median of 162 days posttransplantation. The median number of DLIs was 3, and the median cumulative CD3+ cell dose was 2 × 106cells/kg. Six of the 8 patients (75%) who received pDLI while in mixed chimerism converted to stable, complete donor chimerism. Some 47% of DLI recipients developed GVHD (4 acute GVHD and 3 with chronic GVHD) after a median cumulative dose of 2 × 106 CD3+ cells/kg. After a median follow-up of 575 days, 11 (73%) pDLI recipients were alive. All 4 deaths were due to GVHD-related causes. None of the patients who received pDLIs relapsed. Patients with leukemia who received low-dose pDLI after conditioning with alemtuzumab are at low risk for relapse; however, this approach is associated with a relatively high incidence of severe GVHD.

L‐index as a novel index to evaluate both the intensity and duration of lymphopenia after allogeneic hematopoietic stem cell transplantation

We retrospectively investigated L-index, which evaluates both the intensity and duration of lymphopenia after allogeneic hematopoietic stem cell transplantation (HSCT) (n = 50). L-index was defined as the area over the lymphocyte curve during lymphopenia (absolute lymphocyte count < 700/μL). We calculated the L-index from the start of conditioning to day 30 - L-index(30) - and to day 100 - L-index(100) - after HSCT. Multivariate analysis revealed that human leukocyte antigen mismatched donor, female gender, and non-lymphoid disease were significantly associated with high L-index(30). Grade III-IV acute graft-versus-host disease, alemtuzumab-containing regimen, and non-lymphoid disease were identified as independent significant factors for high L-index(100). Cytomegalovirus (CMV) antigenemia was detected > 3 cells/2 slides by C10/11 method in 30 patients (CMV-AG ≥ 3 group) and was not detected in 20 patients (CMV-AG < 3 group). Although no significant difference was seen in absolute lymphocyte count on day 30 between the 2 groups, the L-index(30) was significantly higher in the CMV-AG ≥ 3 group than in the CMV-AG < 3 group (P = 0.050). L-index(30) was identified as an independent factor on CMV reactivation in multivariate analysis, when it was treated as a dichotomous variable with a cut-off value of 22,318, determined by receiver operating characteristic curve analysis. In conclusion, both the intensity and duration of lymphopenia in early phase after HSCT evaluated on the basis of L-index(30) showed significant association with CMV reactivation.

Increasing Genetic Complexity Predicts for Inferior Outcomes Following Reduced-Intensity Conditioning Allogeneic Transplant for Chronic Lymphocytic Leukemia

Abstract 3090Several biologic markers have been identified which predict an unfavorable course in CLL. Reduced-intensity conditioning (RIC) allogeneic transplant may be able to overcome some of these. This retrospective analysis evaluates the effect of cytogenetics, including metaphase cytogenetics, on outcomes with RIC-allogeneic SCT.From 2005–2011, 51 RIC-allogeneic SCTs were performed at The Ohio State University for CLL. There were 38 males (74.5%) and 13 females (25.5%) with a median age of 58 (range 37–73). The median interval between diagnosis and SCT was 48 months (range 9–270). Before SCT, a median 4 lines of chemotherapy were given (range 1–11). One patient was in CR at the time of SCT, 39 were in PR, and 11 had stable or progressive disease; the median CMI was 3 (range 0–7). Fifty-nine percent of patients had del17; 53% had 3 or more abnormalities on metaphase cytogenetics, and 37% had 5 or more abnormalities. The source was PBSC in 48 (94%), BM in 1 (2%) and CB in 2 (4%). Of the PB or BM SCTs, 19 donors (39.6%) were related and 29 (60.4%) were volunteer; 45 (92%) were matched and 4 (8%) had a 1 allele mismatch. There were 21 (41%) pairs with an ABO mismatch and 16 (31.4%) pairs with a gender mismatch. Conditioning was Flu/Bu +/− ATG in 42 patients (82.2%), FluCamTBI in 6 (11.8%), FluCy in 1 (2%), and FluCyTBI-based in 2 receiving CB (4%). Following transplant, 34 (66.6%) developed AGVHD (gr 1–2: 28, gr 3–4: 6) and 27 of 48 evaluable patients (56.3%) developed CGVHD (limited: 7, extensive: 20). With a median follow-up of 17.3 months (range 1–60), the estimated 3-year OS and PFS following transplant were 56.5% and 42.9% respectively. Table 1 lists variables which had a p-value of ≤0.1 on univariate analysis. The presence of del13 and ≥5 karyotype abnormalities remained significant on multivariate analysis for OS while ≥5 karyotype abnormalities and conditioning with an alemtuzumab-containing regimen were significant for PFS (Table 2). The estimated 3 year OS for patients with del13 was 32.2% and 23% for patients with ≥5 karyotype abnormalities, compared with 72.7% and 73.5% for those without, respectively. The estimated 3-year PFS was 21.5% for patients with ≥5 karyotype abnormalities and 0% for patients with an alemtuzumab-containing regimen and 53.9% and 49.3% for those without, respectively.TableVariables included in multivariate analysis model.Variablelogrank p-valuePFSOSAge ≥550.0072*…Del13 ≥4.7%0.0039*Del17p ≥5.7%0.0019*0.0878Karyotype abnormalities ≥50.0002*0.0138*Karyotype abnormalities ≥30.0186*0.0623Largest node ≥4 cm0.0277*…Marrow involvement ≥50%0.0752…Alemtuzumab conditioning…0.0001*GVHD prophylaxis0.0001*0.0374*HLA mismatch<0.0001*…*statistically significant at p<0.05Table 2Multivariate analysis of OS, PFS.OSVariableHR95% CIp-valueDel13q<4.7%1≥4.7%3.581.36 to 9.420.01Karyotype<41≥55.161.97 to 13.560.001PFSVariableHR95% CIp-valueConditioningno alemtuzumab1alemtuzumab9.83.28 to 29.290Karyotype<41≥54.351.67 to 11.280.002Due to small numbers, the alemtuzumab data should be interpreted with caution, but are consistent with previous reports. Increasing genomic complexity is known to predict for diminished chemosensitivity. Accordingly, the presence of 5 or more abnormalities on metaphase cytogenetics was demonstrated to be a poor prognostic indicator for both PFS and OS following SCT. There was substantial, but not universal, overlap among patients with del17, del13, and highly complex karyotype; this interplay merits further consideration. Better understanding of the evolution of genetic complexity will better define how to time transplant to allow for maximum benefit to those patients likely to evolve. [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Chronic lymphocytic leukemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Chronic lymphocytic leukemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Chronic lymphocytic leukaemia: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

Outcome following Reduced-Intensity Allogeneic Stem Cell Transplantation (RIC AlloSCT) for Relapsed and Refractory Mantle Cell Lymphoma (MCL): A Study of the British Society for Blood and Marrow Transplantation

Reduced-intensity allogeneic stem cell transplantation (RIC-AlloSCT) is being increasingly considered for patients with aggressive lymphoma, but limited evidence exists in mantle cell lymphoma (MCL). We report a retrospective study of transplant outcomes of RIC-AlloSCT for MCL in 70 patients (median age, 48 years, range: 30-67 years), with 57 patients receiving an Alemtuzumab-containing regimen. Thirty-four percent of patients had received a prior autologous stem cell transplant. The 1- and 5-year nonrelapse mortality (NRM) was 18% (95% confidence interval [CI] 10-27) and 21% (95% CI 12-31), respectively. The incidence of severe (grade III and IV) acute graft-versus-host disease (aGVHD) was 10%, and the 5-year incidence of chronic GVHD (cGVHD) was 61%. The cumulative relapse risk was 65% (95% CI 48-77) at 5 years, significantly affected by disease status at transplant (P = .0495), specifically the presence of chemosensitive disease (P = .0364). Fifteen of 18 relapsed patients received donor lymphocyte infustion (DLI) (n = 14) or a second RIC-AlloSCT (n = 1), with 11 of 15 currently in CR. The 5-year overall survival (OS) and progression-free survival (PFS) were 37% (95% CI 25%-56%) and 14% (95% CI 6%-34%), respectively. Age at transplantation and having <2 prior lines of therapy influenced the OS, whereas having <2 prior lines of therapy was the only factor to influence PFS. The use of Alemtuzumab in the conditioning was associated with an improved OS at 3 years (P = .0271). RIC-AlloSCT is a potential treatment modality for aggressive MCL. For patients relapsing post-AlloSCT, the disease is salvageable with DLI. The timing of RIC-AlloSCT should be explored in prospective studies to establish the optimal role in the management of this aggressive lymphoma.

Excessive Rate of Late Infections and Treatment Related Mortality Associated with the Use of Alemtuzumab in Reduced Intensity Conditioning for Allogeneic Hematopoietic Stem Cell Transplantation: Results of a Prospective Trial.

Abstract 2230Poster Board II-207 Background:Reduced intensity conditioning (RIC) for allogeneic hematopoietic stem cell (HSC) transplantation is a well established therapy for patients with advanced hematological malignancies who are not suitable candidates for fully myeloablative conditioning. The use of alemtuzumab as part of RIC has been associated with decrease in incidence and severity of graft versus host disease (GVHD), particularly in unrelated donor transplants. Methods:This is a single center, prospective study. Patients with relapsed or refractory hematological malignancies who were not candidates for fully myeloablative conditioning regimens received an non-alemtuzumab (nA) containing RIC regimen or an alemtuzumab-containing regimen (A) based on the use of a matched sibling or an allele-matched unrelated donor, respectively. Patients in the nA group were conditioned with either Fludarabine 30mg/m2/day for 5 days and total body irradiation 200cG or Fludarabine 25mg/m2/day for 5 days and Melphalan 70mg/m2/day for 2 days. Patients in the A group received alemtuzumab 20 mg/m2/day for 2 days, Fludarabine 30mg/m2/day for 5 days and Melphalan 70mg/m2/day for 2 days. All patients received peripheral blood HSC grafts. Prophylaxis against graft versus host disease with cyclosporine and mycophenolate mofetil as well as infectious disease prophylaxis and supportive care guidelines were standard across both groups. Results:From January 2003 to March 2009, 56 patients were enrolled in the study and 50 patients who actually received a HSCT are the subject of this analysis. Twenty nine patients were in group nA and 21 in group A. Median age of the patients in the entire cohort was 55 years (range 14-65). Eighteen patients had AML, 12 NHL, 8 MDS, 6 CML, 3 CLL and 3 MM. Twenty-three patients were considered to be at high-risk for post transplant relapse (45% of group nA vs. 47% of group A, P= 0.84). All patients in group nA had hematological engraftment while 2 patients in A (9.5%) failed to engraft. Despite the fact that all patients in group A received a transplant from an unrelated donor, the incidence of severe (grades C or D) acute GVHD was significantly higher in group nA (20.7% vs. 0%, P=0.03). Day 100 mortality was similar between the 2 groups (20.7% for nA vs 33.1% for A, P=0.31). Cumulative incidence of progression did not differ between the two groups (P=0.7) while the cumulative incidence of treatment related mortality was higher in group A (P=0.02, Figure 1). Both median overall survival (OS) (44.1 vs. 5.3 months; P=0.01, figure 2) and progression-free survival (PFS) (8.7 vs 5.3 months, P= 0.02) were superior in group nA. Cox regression analysis including conditioning regimen, age and risk of post-transplant relapse showed that conditioning with alemtuzumab was the only variable significantly associated with inferior OS (RR 2.8, P=0.009) and PFS (RR 2.42, P= 0.01). Group A had a higher incidence of late (after Day 100) infectious complications resulting in death (43% vs.10%, p=0.01). [Display omitted] [Display omitted] Conclusion:Even though alemtuzumab-based RIC in unrelated HSCT has a protective effect against acute GVHD and risk of D+100 TRM comparable with non-alemtuzumab containing RIC regimens in related donor transplant, its beneficial effect is overcome by excessive late infectious complications. Disclosures:Fouts:Genzime: Consultancy.

Treatment of fludarabine-refractory chronic lymphocytic leukemia.

The development of resistance to purine analogs defines a poor-risk subset of patients with chronic lymphocytic leukemia (CLL). Although in recent years chemoimmunotherapeutic combinations such as fludarabine, cyclophosphamide, and rituximab have induced response rates of 95% in previously untreated patients and increased the rates of failure-free survival, CLL remains incurable for many patients because of a lack of disease response or the development of refractoriness to fludarabine. Fludarabine-refractory disease is defined as CLL that does not respond to fludarabine or that recurs within 6 months of treatment with a fludarabine-containing regimen. The natural course of the disease is associated with poor survival. Salvage therapeutic strategies include alemtuzumab-containing regimens, targeted agents, and allogeneic stem cell transplantation. Single-agent alemtuzumab induces response in up to 40% of patients with fludarabine-refractory CLL, but responses are not durable, and the median survival is approximately 1 to 2 years. Alemtuzumab is also combined with fludarabine, cyclophosphamide, and/or rituximab, and other agents such as lenalidomide and flavopiridol, as well as targeted agents, and used in fludarabine-refractory CLL. Cumulative evidence suggests that allogeneic stem cell transplantation is an efficacious therapeutic strategy for patients who do not respond to fludarabine or who develop disease recurrence within 12 months after purine analog treatment. In conclusion, chemoimmunotherapy regimens that include alemtuzumab and/or rituximab and allogeneic stem cell transplantation improve the prognosis of this disease, but there is a continued need for novel, more effective therapies.

BK Virus Infection is Associated with Hematuria and Renal Impairment in Recipients of Allogeneic Hematopoetic Stem Cell Transplants

BK virus (BKV) is an important pathogen and cause of nephropathy in recipients of renal transplants, but its clinical significance in patients (pts) following hematopoetic stem cell transplantation (HSCT) is less well described. Over a 16 month period we prospectively measured BKV in the blood and urine of 124 pts who had undergone allogeneic HSCT [HLA-identical donor (n = 70), alternative-donor (HLA-mismatched-related, matched-unrelated, or cord) (n = 54)] between 1998–2007 and who were receiving in- or outpatient post-transplant care. Most pts (73%) received alemtuzumab-containing regimens. BK viruria was manifest at some time in 64.8% of pts; 16.9% developed BK viremia. All pts with BK viremia also had viruria. BK viruria developed at a median time post-HSCT of 24 d (range 3–138 d), while viremia was detected at a significantly longer median time of 128 d (range 62–307 d) (P<0.0001). Among clinical factors (disease, transplant type, alemtuzumab use, CMV viremia, GVHD, HLA C locus status), only CMV viremia was significantly more common in pts with BK viruria and viremia. Given the association of BKV with hemorrhagic cystitis, urinalyses from all pts were analyzed for the presence and number of red blood cells. There was a direct relationship between higher median and maximum levels of urinary BKV with both an increased occurrence, and greater degree, of microscopic hematuria (P<0.03). BK viremia was also associated with the development of hematuria (P = 0.03). Finally, BKV infection was analyzed along with other clinical factors in relation to the development of post-HSCT renal impairment. On multivariate analysis, only BK viremia (P = 0.000001) and undergoing an alternative-donor transplant (P = 0.002) were independent predictors of development of post-HSCT renal impairment, with BK viremia associated with a median 1.62 mg/dL rise in creatinine from the pre-transplant baseline. Two pts with BK viremia developed biopsy-proven BKV nephropathy, with both requiring hemodialysis. In summary, BK viruria is a common early finding in pts undergoing allogeneic HSCT, and higher urinary BKV levels are directly related to increased hematuria. BK viremia occurs later and less commonly, is associated with hematuria, and is an independent predictor of worsening renal function post-HSCT. Investigation of whether prophylaxis against, or treatment of, BKV in the post-HSCT setting mitigates the associated morbidities, especially kidney injury, warrants prospective evaluation. BK virus (BKV) is an important pathogen and cause of nephropathy in recipients of renal transplants, but its clinical significance in patients (pts) following hematopoetic stem cell transplantation (HSCT) is less well described. Over a 16 month period we prospectively measured BKV in the blood and urine of 124 pts who had undergone allogeneic HSCT [HLA-identical donor (n = 70), alternative-donor (HLA-mismatched-related, matched-unrelated, or cord) (n = 54)] between 1998–2007 and who were receiving in- or outpatient post-transplant care. Most pts (73%) received alemtuzumab-containing regimens. BK viruria was manifest at some time in 64.8% of pts; 16.9% developed BK viremia. All pts with BK viremia also had viruria. BK viruria developed at a median time post-HSCT of 24 d (range 3–138 d), while viremia was detected at a significantly longer median time of 128 d (range 62–307 d) (P<0.0001). Among clinical factors (disease, transplant type, alemtuzumab use, CMV viremia, GVHD, HLA C locus status), only CMV viremia was significantly more common in pts with BK viruria and viremia. Given the association of BKV with hemorrhagic cystitis, urinalyses from all pts were analyzed for the presence and number of red blood cells. There was a direct relationship between higher median and maximum levels of urinary BKV with both an increased occurrence, and greater degree, of microscopic hematuria (P<0.03). BK viremia was also associated with the development of hematuria (P = 0.03). Finally, BKV infection was analyzed along with other clinical factors in relation to the development of post-HSCT renal impairment. On multivariate analysis, only BK viremia (P = 0.000001) and undergoing an alternative-donor transplant (P = 0.002) were independent predictors of development of post-HSCT renal impairment, with BK viremia associated with a median 1.62 mg/dL rise in creatinine from the pre-transplant baseline. Two pts with BK viremia developed biopsy-proven BKV nephropathy, with both requiring hemodialysis. In summary, BK viruria is a common early finding in pts undergoing allogeneic HSCT, and higher urinary BKV levels are directly related to increased hematuria. BK viremia occurs later and less commonly, is associated with hematuria, and is an independent predictor of worsening renal function post-HSCT. Investigation of whether prophylaxis against, or treatment of, BKV in the post-HSCT setting mitigates the associated morbidities, especially kidney injury, warrants prospective evaluation.

Favorable Long-Term Survival After Reduced-Intensity Allogeneic Transplantation for Multiple-Relapse Aggressive Non-Hodgkin's Lymphoma

The role of allogeneic transplantation with reduced-intensity conditioning in diffuse large B-cell lymphoma (DLBCL) is currently unclear, with relatively little published data. We report the outcome of reduced-intensity transplantation (RIT) in a cohort of 48 consecutive patients with relapsed/refractory DLBCL (30 patients with de novo disease and 18 patients with transformed follicular lymphoma) who underwent transplantation with an alemtuzumab-containing regimen, with a median follow-up of 52 months. Patients had experienced treatment failure with a median of five lines of prior therapy, including autologous transplantation in 69%, and 17% of patients were chemotherapy refractory at transplantation. Median age was 46 years, and 38% of patients had matched/mismatched unrelated donors. Conditioning was with alemtuzumab, fludarabine, and melphalan, and additional graft-versus-host disease (GVHD) prophylaxis was with cyclosporine. All patients were successfully engrafted. Only 17% of patients developed grade 2 to 4 acute GVHD, with 13% experiencing extensive chronic GVHD. Four-year estimated nonrelapse mortality was 32%, and relapse risk was 33%. Twelve patients received donor lymphocyte infusions +/- chemoimmunotherapy for relapse, and five patients obtained durable remissions, giving current progression-free survival (PFS) and overall survival (OS) rates at 4 years of 48% and 47%, respectively. Patients who had chemotherapy-sensitive disease before RIT had current PFS and OS rates at 4 years of 55% and 54%, respectively. Chemotherapy-refractory patients had a poor outcome. The encouraging survival rates with extended follow-up suggest a role for RIT in chemotherapy-sensitive relapsed DLBCL, even in patients who have previously experienced treatment failure with autologous transplantation. Future studies will be required to determine whether any subset of patients with relapsed DLBCL should be considered for RIT versus autologous transplantation.

Valganciclovir prevents cytomegalovirus reactivation in patients receiving alemtuzumab-based therapy

Alemtuzumab is an immunosuppressive antibody that depletes normal T cells and B cells. Prophylaxis for herpes virus and Pneumocystis carinii is standard with this agent. Approximately 20% to 25% of patients will experience cytomegalovirus (CMV) reactivation. We conducted a randomized trial wherein patients being treated with an alemtuzumab-containing regimen received prophylaxis with either valaciclovir 500 mg orally daily or valganciclovir 450 mg orally twice daily. The study design planned to enroll 128 patients, but stopping rules for early termination were met. Forty patients were evaluable. Median age was 58 years (range, 25-83 years); median number of prior therapies was 2 (range, 0-10). Diagnoses included chronic lymphocytic leukemia (29), T-cell prolymphocytic leukemia (3), hairy cell leukemia (1), adult T-cell leukemia/lymphoma (ATLL) (1), marginal zone leukemia (1), large granular lymphocyte leukemia (2), acute lymphoblastic leukemia (1), and T-cell lymphoma (2). Patients received various alemtuzumab-containing regimens, including single agent (5) or combined with: rituximab (2), pentostatin (6), fludarabine, cyclophosphamide, and rituximab (23), or fractionated cyclophosphamide, vincristine, adriamycin, and dexamethasone (hyper-CVAD) (4). Seven of 20 patients enrolled on the valaciclovir arm experienced CMV reactivation. None of the 20 patients randomized to valganciclovir experienced CMV reactivation (P = .004). In conclusion, this agent was highly effective for prophylaxis of CMV reactivation in patients receiving alemtuzumab. This trial was registered at www.ClinicalTrials.gov as #NCT00562770.

Extended Follow-Up of Reduced Intensity Transplantation with an Alemtuzumab-Containing Regimen for Follicular Lymphoma.

Allogeneic transplant with reduced intensity conditioning (RIC) is currently being investigated as potential curative therapy for patients with lymphoma. We report 64 consecutive patients with follicular lymphoma (FL) transplanted at 9 centres with a RIC regimen containing fludarabine 150mg/m2, melphalan 140mg/m2 and alemtuzumab (20–100mg). Cyclosporin A was given at 3mg/kg. Donors were HLA-matched siblings in 34 (53%), and unrelated in 30 (47%), of whom 9 (14%) were HLA-mismatched at up to 2/10 loci. Median age was 44 yrs (26–65), median lines of previous therapy was 3 (1–8) and 17 (27%) had failed a prior autograft. Fifty-five patients (86%) had chemosensitive disease pre-RIC (complete remission 11, partial remission 44), 8 (12%) were chemorefractory and 1 had untreated relapse. Median follow-up was 39 months (1–98). Non-relapse mortality (NRM) at 5 yrs was 12%, with 9% at 5 yrs for sibling donors and 15% for unrelated (p=0.41). There was no significant impact of prior autograft on NRM. Acute graft-versus-host disease (GVHD) grade II occurred in 11 (17%) with no grade III-IV, and extensive chronic GVHD occurred in 9 (16%). Relapse rate (RR) was 18% at 1 year and 32% at 5 years. Those who had failed a prior autograft had an increased RR (53% at 5 yrs) compared to those with no prior autograft (22% at 5 yrs; p=0.01). Median time to relapse from RIC was 8 months (1–43) with 15/17 events occurring within the 1st 2 years. Donor lymphocyte infusions (DLI) were given to 13 patients, at a starting dose of 1–10×106 CD3+/kg. Nine patients remitted, of whom 6 had no GVHD and 7 had received prior rituximab. Median follow-up from last DLI dose was 34 months (3–72). Overall survival (OS) for the whole cohort was 80% at 1 yr and 76% at 5 yrs. On univariate analysis, those with sibling donors had significantly improved OS (88% at 5 yrs), compared to unrelated donors (61% at 5 yrs; p=0.016), as did those with chemosensitive disease pre-RIC (80% at 5 yrs) compared to chemorefractory disease (50% at 5 yrs; p=0.028), and those who had not undergone a prior autograft (86% at 5 yrs) compared to those who had (47% at 5 yrs; p=0.001). Similarly, current progression-free survival (cPFS) for the whole cohort was 79% at 1 yr and 77% at 5 yrs, with significantly superior outcome in those with sibling donors (88% at 5 yrs) compared to unrelated donors (63% at 5 yrs; p=0.018), those with chemosensitive disease (81% at 5 yrs) compared to those with chemorefractory disease (50% at 5 yrs; p=0.0198), and those who had not failed a prior autograft (86% at 5 yrs) compared to those who had (50% at 5 yrs; p=0.001). No factor remained significant for OS or cPFS on multivariate analysis. In conclusion, RIC for FL using an alemtuzumab-containing regimen can be undertaken with relatively low rates of significant acute and chronic GVHD, and low NRM for both HLA-matched and mismatched related and unrelated donors. Responses to DLI occur, often in the absence of clinical GVHD, and appear durable so far, although further follow-up is required.

Long-Term Follow-Up of Reduced Intensity Transplantation with an Alemtuzumab-Containing Regimen for Aggressive Non-Hodgkins Lymphoma.

The outlook for patients with relapsed or refractory high-grade NHL failing autologous transplant is poor. Allogeneic transplant with myeloablative conditioning carries a high non-relapse mortality (NRM) in this setting, and reduced intensity conditioning is being investigated. We report 54 consecutive patients with a diagnosis of diffuse large B cell lymphoma (n=48;89%: presenting de novo [n=31] or following transformation from follicular lymphoma [FL, n=17]) or anaplastic large cell lymphoma (n=6;11%) who underwent reduced intensity allogeneic transplantation (RIC) at 8 centres. Conditioning was with fludarabine 150mg/m2, melphalan 140mg/m2 and alemtuzumab (20–100mg), and cyclosporin A was given at 3mg/kg. Donors were HLA-matched siblings in 34 (63%), and unrelated in 20 (37%), of whom 11 were HLA-mismatched at up to 3/10 loci. Median age was 44 yrs (18–64), median lines of prior therapy was 4 (1–7), 37 (69%) patients had previously undergone autologous transplantation, and 11 (20%) had chemorefractory disease at the time of RIC. Median follow-up from RIC was 49 months (8–87). NRM was 30% at 1 yr and 34% at 5 yrs, with 18/19 events occurring within the 1st 16 months. There was no significant association between NRM and donor type or prior autograft. Estimated relapse rate was 32% at 5 years for all patients: 25% in de novo high-grade NHL and 46% in those with transformed FL. Fifteen of the 16 relapses occurred within the 1st yr post-transplant, at a median of 3 months (1–42). Twelve patients received donor lymphocyte infusions (DLI) at a starting dose of 1–10 × 106 CD3+ cells/kg. Of the 12, 5 had primary DLBCL- 4 died within 5 months of DLI having had no response, and 1 had additional anti-tumor therapy pre-DLI and remitted. Of the 7 with transformed FL, 4 remitted, 2 with therapy prior to DLI and 1 with GVHD. Overall survival (OS) for the whole cohort was 45% at 5 yrs, with current progression-free survival (cPFS) of 46% at 5 yrs. There was no significant difference in OS or cPFS when analysed by donor type (5 yr OS 46% for sibling donors, 44% for unrelated donors;p=0.612), presence of prior autologous transplant (5 yr OS 43% for those having failed autograft, 51% for those who had not undergone autograft;p=0.614), or presence of de novo high-grade NHL (OS 39% at 5 yrs for those with de novo high-grade NHL, 58% for those with transformed FL;p=0.208). Both OS (p=0.003) and cPFS (p=0.002) were significantly impacted by the presence of chemorefractory disease pre-RIC, with both OS and cPFS 55% at 5 yrs for chemosensitive disease, and 9% at 5 yrs for chemorefractory. In conclusion, given the median follow-up of over 4 yrs and the aggressive nature of the disease in these patients, with extensive pre-treatment including a failed autologous transplant in the majority, these are encouraging results raising the prospect of long-term survival in a significant cohort. We propose that all patients with DLBCL relapsing following an autograft whose disease is sensitive to salvage chemotherapy should be strongly considered for RIT, using related or unrelated donors.

Impact of Myeloablative Versus Reduced Intensity Conditioning Regimens on Early Lymphocyte Recovery and Its Impact on Transplant Outcomes after Allogeneic Peripheral Blood Stem Cell Transplantation in Adult Patients with Hematologic Malignancies.

Background: The association between early lymphocyte recovery and improved outcomes after allogeneic (Kim et al BJH 2004) and autologous stem cell transplantation (SCT) has been established. However, the impact of conditioning regimen intensity on early recovery of absolute lymphocyte count (ALC) has not been described. The current study attempted to determine different effect of early lymphocyte recovery on transplant outcomes after allogeneic peripheral blood SCT (PBSCT) followed by myeloablative (MAC) or reduced intensity conditioning (RIC). Methods: This study retrospectively assessed 225 consecutive allogeneic peripheral blood stem cell recipients at Princess Margaret Hospital, Toronto, Canada between 2000 and 2007. All patients received related donor transplants. Myeloablative conditioning (MAC) was employed in 157 patients (TBI based regimens, n=117; Busulfan based regimens, n=40), while 68 patients received RIC excluding alemtuzumab-containing regimens. The endpoints were overall survival, non-relapse mortality (NRM) and relapse incidence after PBSCT according to the day +30 absolute lymphocyte count (ALC). Results: No difference in ALC was noted between MAC and RIC groups except at 2 (p=0.036) and 3 months (p=0.036). Eighty patients (36%) had an ALC of 0.5 x 109/L or less at 30 days after SCT. No correlation was noted between the ALC prior to SCT and post-transplant ALC. The 2-year OS was significantly better in patients with an ALC ≥0.5x109/L at 30 days compared to those with an ALC &lt; 0.5x109/L in overall group (75% vs. 48%, p=0.00008; Figure 1A) or in the MAC group (p=0.00005; Figure 1B), but not in RIC group (p=0.3; Figure 1C). The NRM at 1-year was significantly lower in the group with an ALC ≥0.5x109/L at 30 days compared to those with an ALC &lt; 0.5x109/L (14% vs. 32%, p=0.00008), especially in the MAC group (p=0.00002), but not in the RIC group (p=0.5). However, no difference in relapse incidence was noted according to the ALC count either in the overall (p=0.07), MAC (p=0.3), or RIC groups (p=0.4). The incidences of acute or chronic GVHD were not significantly different between MAC and RIC groups. Delayed lymphocyte reconstitution was noted up to 6 months for the group with ALC of 0.5x109/L or less. Conclusion: Conditioning regimen intensity did not affect day +30 lymphocyte counts. However, we demonstrated that early lymphocyte recovery may be a prognostic marker for improved OS and better NRM after myeloablative allogeneic PBSCT. Figure 1. comparison of overall survival between groups with high and low ALC counts at day 30 in overall group (A), myeloablative conditioning group (B) and reduced intenmsity conditioning group (C). Figure 1. comparison of overall survival between groups with high and low ALC counts at day 30 in overall group (A), myeloablative conditioning group (B) and reduced intenmsity conditioning group (C).