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Allografting is becoming a more frequent therapeutic consideration for symptomatic CLL. The most frequently used preparative regimen historically has been Cy/TBI but flu-based conditioning is a recently reported alternative. Two cases in which Cy/TBI failed to impact on high pre-transplant peripheral blood (PB) lymphocyte counts prompted us to compare the outcome of stem cell allografts after TBI and non-TBI-based conditioning in 11 patients (pts) from two institutions. All pts had flu-refractory CLL. Five pts received flu 25mg/m2 with either melphalan 120mg/m2 (n=4) or Cy 120mg/kg; the other six received Cy 120mg/kg with fractionated TBI 12Gy. The two groups were comparable for age (median 50 yr overall; range 42–57), number of prior therapies (4; 2–6), extent of marrow involvement pre-transplant (90%; 65–99%) and incidence of cytogenetic abnormalities (abnormal in 8/9 evaluable). PB stem cells were used in 10 pts and marrow in one, with cyclosporine/methotrexate as GVHD prophylaxis in 8 and Campath/tacrolimus in 3. All patients receiving flu-alkylator conditioning had substantial initial cytoreduction with disappearance of PB lymphocytosis (including 2 with >30x109/L pre-transplant), reduction in marrow infiltration to 25%, 15% and 300 and 30x109/L during the first month. Median marrow CLL involvement was 93%, 80% and 77% at days 30, 60 and 100 post transplant in this group. Two pts subsequently experienced late onset cytoreduction in the context of chronic GVHD but have yet to achieve CR; three died of progressive disease and one of GVHD. In vitro studies in one patient demonstrated resistance of CLL cells to irradiation. These preliminary data demonstrate that advanced CLL may be resistant to TBI and despite prior resistance to single agent flu, a combination of melphalan and flu may be the optimal cytoreductive regimen in this context.

Acute graft-versus-host disease (aGVHD) is partly mediated by host antigen presenting cells (APCs) that activate donor T-cells. Extracorporeal photoimmune therapy with UVADEX® (ECP) has shown benefit in some patients (pts) with GVHD, which was associated with decreased host APCs. We report preliminary results of the first multi-institutional phase II study examining ECP with a standard myeloablative preparative regimen prior to allogeneic hematopoietic stem cell transplantation (ASCT). ECP was given on two consecutive days between D-10 and D-6, followed by cyclophosphamide 60 mg/kg/day for 2 days and TBI 1200 cGy over 3 days. GVHD prophylaxis was Cyclosporine 3–5 mg/kg IV daily beginning D-1, and latter switched to PO, adjusted to keep levels 200–600 ng/ml, and methotrexate 10 mg/m2 on D1, 3, 6, and 11 for pts who had matched unrelated donors (MUD) or HLA class 1 one-antigen mismatched related donors (MMRD), or 10 mg/m2 on D1 and 5 mg/m2 on D3, 6, and 11 for pts who had matched related donors (MRD). Enrollment has been completed and data are available on 61 of 65 pts. The median age was 39 (20–60) years and 40 (66%) pts were male. Diagnoses included AML/MDS (n=20), ALL (n=14), CML (n=16), lymphoma (n=5), CLL (n=3), and other (n=3). Pts who received bone marrow (n=28) engrafted at a median of 20 (9–30) days, and pts who received peripheral blood (n=33) engrafted at a median of 15 (10–32) days. Grade II–IV and III/IV aGVHD occurred in 11 (38%) and 2 (7%) pts, respectively, who received MRD transplants (n=29), and in 16 (52%) and 10 (32%) pts, respectively, who received MUD transplants (n=31). No aGVHD occurred in 1 pt who received a MMRD transplant. Mild reversible hypotension related to ECP occurred in 1 pt who was able to continue on study. Chronic GVHD occured in 23 (42%) of 54 evaluable pts; limited in 15, extensive in 6, and unknown in 2 pts. There are 49 (80%) pts alive at a median follow up of 272 (23–560) days. Actuarial estimates of survival at one year are 93% for pts who received MRD transplants and 69% for pts who received MUD or MMRD transplants. Causes of death include relapse (n=4), aGVHD (n=3), multi-organ-system-failure (n=2), and 1 each of infection, interstitial pneumonitis, and neurologic toxicity. Preliminary results of this study reveal no adverse affects of ECP in combination with conventional preparative regimens or on engraftment after a standard myeloablative ASCT. Data correlating measurement of APCs with the incidence and severity of acute and chronic GVHD is pending. The overall survival of pts in this trial is encouraging and warrants further study.

Myelofibrosis is a rare disease characterized by progressive obliteration of the marrow space by fibrosis, extramedullary hematopoiesis, splenomegaly, and presence of immature hematopoietic cells in the blood. It is a clonal disorder of pluripotent hematopoietic stem cells that release fibrogenic

Reduced-intensity conditioning (RIC) regimens have been increasingly used for allogeneic hematopoietic stem cell transplantation (HSCT) in follicular lymphoma (FL). We compared traditional myeloablative conditioning regimens to RIC in FL. Outcomes of HLA-identical sibling HSCT for FL in 208 recipients reported to the Center for International Blood and Marrow Transplant Research (CIBMTR) between 1997 and 2002 were studied. Conditioning regimens were categorized as myeloablative (N = 120) or RIC (N = 88). Use of RIC regimens increased from 80% in 2002 signaling a major shift in practice. Patients receiving RIC were older and had a longer interval from diagnosis to transplant. These differences did not correlate with outcomes. Median follow-up of survivors was 50 months (4-96 months) after myeloablative conditioning versus 35 months (4-82 months) after RIC (P < .001). At 3 years, overall survival (OS) for the myeloablative and RIC cohorts were 71 (63%-79%) and 62 (51%-72%; P = .15) and progression free survival (PFS), 67 (58%-75%) and 55 (44%-65%; P = .07), respectively. Lower Karnofsky performance score (KPS) and resistance to chemotherapy were associated with higher treatment-related mortality (TRM) and lower OS and PFS. On multivariate analysis, an increased risk of lymphoma progression after RIC was observed (relative risk = 2.97, P = .04). RIC has become the de facto standard in allogeneic HSCT for FL, and appears to result in similar long-term outcomes. Although disease-free survival (DPS) is similar compared to myeloablative conditioning, an increased risk of late disease progression after RIC is concerning.

Low incidence of graft-versus-host disease provides the major rational for pursuing umbilical cord blood (UCB) stem cell transplantation (SCT). Considerable evidence also suggests a lower rate of recurrence after UCB SCT than after transplantation from adult donors. Recent advances in understanding of the human fetal immune development provide a rational underpinning for these clinical outcomes. The fetal immune system is geared toward maintaining tolerance to foreign antigens, particularly to the maternal antigens to which it is exposed throughout gestation. To this purpose it is dominated by a unique population of peripheral T regulatory cells that actively maintain tolerance. This and other features of the UCB lymphoid system explains the low incidence of graft-versus-host disease and superior outcomes of UCB SCT with noninherited maternal antigen–matched grafts. At the same time, highly sensitized maternal microchimeric cells are frequently detected in UCB and likely contribute to superior graft-versus-leukemia effects and low rates of disease recurrence in inherited paternal antigen–matched UCB recipients. However, historically erratic and slow hematopoietic recovery after UCB SCT leads to increased early morbidity and mortality, excessive hospitalization, and increased costs. This has held up the widespread utilization of UCB SCT in adults. Here we summarize recent data on UCB SCT with an emphasis on studies of co-infusion of adult CD34 selected hematopoietic stem cells with UCB SCT. This procedure, through transient engraftment of adult hematopoietic stem cells, largely overcomes the problem of delayed engraftment. It also results in predictable engraftment of a UCB with the desired characteristics. We also briefly discuss unresolved issues and possible future applications of this technology.

We tested the independent prognostic impact of 2 commonly used biomarkers, C-reactive protein (CRP) and interleukin (IL)-6, on the outcomes of allogeneic hematopoietic cell transplantation (HCT). Consecutive patients who underwent a uniform reduced-intensity conditioning (RIC) regimen of fludarabine (Flu), melphalan (Mel), and alemtuzumab were evaluated retrospectively. Cryopreserved serum samples drawn before the RIC were available to measure CRP levels in 81 patients and IL-6 levels in 79 patients. Patients with CRP levels above the median of 18.5 mg/L had significantly more grade 3-4 hepatic toxicity (P = .01), longer HCT hospital stay (P = .005), more acute graft-versus-host disease (aGVHD) (P = .003), greater nonrelapse mortality (NRM) (P = .01), and inferior overall survival (OS; P = .02). Higher baseline CRP showed no significant correlation with grade 3-4 infectious toxicity (P = .09). In contrast to CRP, pre-HCT IL-6 levels above the median of 78.3 pg/mL did not confer a statistically significant increased risk of toxicity or mortality. An elevated HCT comorbidity index (HCT-CI) did not predict for any measure of HCT morbidity. After adjustment for disease status, comorbidity, performance status, and age, elevated CRP concentration remained predictive of NRM. These data require confirmation in non–T cell–depleted conditioning regimens. If validated, they suggest that preconditioning CRP holds promise for enhancing estimates of transplantation tolerance.

We conducted a phase I-II study of transplantation conditioning with clofarabine-melphalan-alemtuzumab for patients with advanced hematologic malignancies. Ten patients were accrued to the phase I portion, which utilized an accelerated titration design. No dose-limiting toxicity was observed, and clofarabine 40 mg/m(2) × 5, melphalan 140 mg/m(2) × 1, and alemtuzumab 20 mg × 5 was adopted for the phase II study, which accrued 72 patients. Median age was 54 years. There were 44 patients with acute myelogenous leukemia or myelodysplastic syndromes, 27 with non-Hodgkin lymphoma, and nine patients with other hematologic malignancies. The largest subgroup of 35 patients had American Society for Blood and Marrow Transplantation high-risk, active disease. All evaluable patients engrafted with a median time to neutrophil and platelet recovery of 10 and 18 days, respectively. The cumulative incidence of treatment-related mortality was 26% at 1 year. Cumulative incidence of relapse was 29% at 1 year. Overall survival was 80% (95% confidence interval [CI], 71-89) at 100 days and 59% (95% CI, 47-71) at 1 year. Progression-free-survival was 45% (95% CI, 33-67) at 1 year. Rapid-onset renal failure was the main toxicity in the phase II study and more frequent in older patients and those with baseline decrease in glomerular filtration rate. Grade 3-5 renal toxicity was observed in 16 of 74 patients (21%) treated at the phase II doses. Clofarabine-melphalan-alemtuzumab conditioning yields promising response and duration of response, but renal toxicity poses a considerable risk particularly in older patients.

Relapse is a major cause of treatment failure after allogeneic hematopoietic stern cell transplantation (alloHSCT). Treatment options for relapse have been inadequate, and the majority of patients ultimately die of their disease. There is no standard approach to treating relapse after alloHSCT. Withdrawal of immune suppression and donor lymphocyte infusions are commonly used for all diseases; although these interventions are remarkably effective for relapsed chronic myelogenous leukemia, they have limited efficacy in other hematologic malignancies. Conventional and novel chemotherapy, monoclonal antibody therapy, targeted therapies, and second transplants have been utilized in a variety of relapsed diseases, but reports on these therapies are generally anecdotal and retrospective. As such, there is an immediate need for well-designed, disease-specific trials for treatment of relapse after alloHSCT. This report summarizes current treatment options under investigation for relapse after alloHSCT in a disease-specific manner. In addition, recommendations are provided for specific areas of research necessary in the treatment of relapse after alloHSCT.

Comprehensive geriatric assessment (CGA) is frequently used in oncology to measure the health status of older adults with cancer, but it has not been studied in allogeneic hematopoietic cell transplantation (HCT). We conducted a prospective pilot study of CGA in allogeneic HCT recipients aged ≥50 years to examine the prevalence of vulnerabilities in this population. Patients aged ≥50 years eligible for HCT were enrolled. CGA consisted mainly of self-reported, performance-based, and chart-extracted measures evaluating domains of comorbidity, physical and mental function, frailty, disability, and nutrition. Of 238 eligible patients, 166 completed CGA and underwent HCT. Only 1% had a Zubrod Performance Status score >1; 44% had high comorbidity defined by the Hematopoietic Cell Transplantation Comorbidity Index, and 66% had high comorbidity defined by the Cumulative Illness Rating Scale–Geriatrics. The presence of additional vulnerability was frequent. Disability was present in 40% by Instrumental Activities of Daily Living. Self-reported physical and mental function were significantly lower than population age group norms, 58% were pre-frail, and 25% were frail. Among those with Zubrod Performance Status score of 0, 28% demonstrated disability, 58% were pre-frail, 15% were frail, 35% reported low physical function, and 55% reported low mental function. CGA uncovers a substantial prevalence of undocumented impairments in functional status, frailty, disability, and mental health in older allogeneic HCT recipients.

Background Data are lacking on whether lenalidomide maintenance therapy prolongs the time to disease progression after autologous hematopoietic stem-cell transplantation in patients with multiple myeloma. Methods Between April 2005 and July 2009, we randomly assigned 460 patients who were younger than 71 years of age and had stable disease or a marginal, partial, or complete response 100 days after undergoing stem-cell transplantation to lenalidomide or placebo, which was administered until disease progression. The starting dose of lenalidomide was 10 mg per day (range, 5 to 15). Results The study-drug assignments were unblinded in 2009, when a planned interim analysis showed a significantly longer time to disease progression in the lenalidomide group. At unblinding, 20% of patients who received lenalidomide and 44% of patients who received placebo had progressive disease or had died (P