We previously reported results in 71 patients with advanced hematologic malignancies given HLA-matched unrelated granulocyte colony-stimulating factor–mobilized peripheral blood mononuclear cell (G-PBMC) grafts after fludarabine 90 mg/m2, 2 Gy of total body irradiation, and postgrafting mycophenolate mofetil (MMF) 15 mg/kg twice daily and cyclosporine 6.25 mg/kg twice daily orally. Graft rejection was 15%; the cumulative probability of acute graft-versus-host disease (GVHD) was 52%. According to MMF pharmacokinetic studies, which showed a short half-life of its active metabolite, mycophenolic acid, we increased MMF dosing from 15 mg/kg twice daily to 15 mg/kg 3 times daily to increase immunosuppression and reduce the incidence of both graft rejection and acute GVHD. Among 103 patients so treated, graft rejection occurred in 5%, whereas acute GVHD remained at 53%. Outcomes were compared with results of previous G-PBMC recipients given MMF twice daily. Infection rates were slightly higher with MMF 3 times daily than with MMF twice daily. Nevertheless, 2-year nonrelapse mortality and overall and progression-free survivals were similar for MMF 3-times-daily and twice-daily patients (19%, 58%, and 49% versus 20%, 48%, and 37%, respectively). Nonmyeloablative conditioning with postgrafting cyclosporine and MMF given 3 times daily allowed 95% durable engraftment of unrelated donor G-PBMC grafts.

Chronic kidney disease (CKD) following myeloablative allogeneic hematopoietic cell transplantation (HCT) occurs in 20% of survivors at 1 year and is believed to be due to radiation nephritis. Non-myeloablative allogeneic HCT is a recent procedure that employs significantly lower doses of chemoradiotherapy, however, incidence and risk factors for CKD following non-myleoablative HCT have not been defined. We performed a retrospective cohort study of 122 patients from three institutions who were available for analysis at 6 months following non-myeloablative HCT. Patients received two Gy of radiation; 62% received fludarabine as preconditioning. CKD was defined as at least a 25% reduction in glomerular filtration rate (GFR) from baseline using the abbreviated modified diet in renal disease (MDRD) equation. Eighty-one of 122 patients (66%) showed evidence of CKD at follow-up. Multivariate analysis revealed that acute renal failure (ARF) during the first 100 days post-transplant was associated with development of CKD (Adjusted OR 32.8 with 95% CI 4.3-250) after controlling for other variables. Previous autologous HCT, long-term calcineurin inhibitor use and extensive chronic GVHD were independently associated with CKD. CKD following non-myeloablative HCT appears to be a distinct clinical entity and likely not related to radiation nephritis. Future research should focus on possible mechanisms for alleviating chronic injury and decreasing use of calcineurin inhibitors.

The purpose of this study was to define the maximal tolerated dose (MTD), extramedullary toxicities, and pharmacokinetics of docetaxel combined with high-dose melphalan and carboplatin with autologous hematopoietic progenitor cell support. Fifty-nine patients with advanced refractory malignancy (32 breast cancer, 10 non-Hodgkin lymphoma, 6 germ cell tumors, 4 Hodgkin disease, 4 ovarian cancer, 2 sarcoma, and 1 unknown primary adenocarcinoma) with a median of 3 prior chemotherapy regimens and a median of 3 organs involved were enrolled. Treatment included docetaxel (150–550 mg/m2 infused over 2 hours on day −6), melphalan (150–165 mg/m2 infused over 15 minutes from day −5 to −3), and carboplatin (1000-1300 mg/m2 as a 72-hour continuous infusion from day −5). Five patients died from direct regimen-related organ toxicity (2 capillary leak syndrome, 2 enterocolitis, and 1 hepatic toxicity), and 1 additional patient died from pulmonary aspergillosis. The docetaxel MTD was defined as 400 mg/m2, combined with melphalan (150 mg/m2) and carboplatin (1000 mg/m2). The MTD cohort was expanded to enroll a total of 26 patients, 1 of whom died from toxic enterocolitis. The remaining 25 patients presented the following extramedullary toxicity profile, which was manageable and largely reversible: stomatitis, myoarthralgias, peripheral neuropathy, gastrointestinal and cutaneous toxicities, and syndrome of inappropriate antidiuretic hormone secretion. Docetaxel exhibited linear pharmacokinetics in the dose range tested (150–550 mg/m2). Pharmacodynamic correlations were noted between the docetaxel area under the curve and peripheral neuropathy or stomatitis. The response rate among 38 patients with measurable disease was 95%, with 47% complete responses. At a median follow-up of 26 months (range, 7–72 months), the 3-year event-free survival and overall survival were 26% and 36%, respectively. In conclusion, a 4-fold dose escalation of docetaxel, combined with melphalan and carboplatin, is feasible with autologous hematopoietic progenitor cell support. The notable activity of this regimen in treatment-refractory patients warrants its further evaluation.

Nonmyeloablative conditioning regimens for allogeneic HCT were introduced to reduce the non-relapse mortality and as a therapeutic modality to patients (pts) who otherwise would not be considered candidates for HCT. Here, we present data on 727 pts with hematologic malignancies who received either MRD (n=426) or URD (n=301) HCT using a nonmyeloablative regimen consisting of 2 Gy TBI with or without fludarabine (30 mg/m2/day x 3 days) given before HCT. Mycophenolate mofetil and cyclosporine or, more recently, tacrolimus were administered after HCT for both host and donor cell immunosuppression. Ninety-eight percent of pts received unmodified G-CSF-mobilized peripheral blood cells and 2% received marrow (all URD). Transplants were done between 12/97 and 02/05 on multi-institutional studies with a median follow-up of 2.6 (range 0.3–6.9) years amongst survivors. Pts were ineligible for myeloablative conditioning due to advanced age or co-morbidities. Median pt age was 54 (range 5–74) years (MRD 55; URD 54). Diagnoses included ALL (n=26), AML (n=118), CLL (n=70), CML (n=49), HD (n=45), MDS/MPD (n=120), MM (n=155), and NHL (n=144). Forty-nine percent of pts had aggressive advanced stage diseases (MRD 39%, URD 62%) and 22% had failed previous high-dose autologous or allogeneic HCT (MRD 17%; URD 30%). Sustained engraftment occurred in 93% of pts (MRD 96%; URD 90%). Acute GVHD grades II-IV and III-IV occurred in 51% and 13% of pts, respectively (MRD: 44% and 13%; URD: 60% and 13%). Forty-five percent of pts had chronic extensive GVHD (MRD 46%; URD 43%). Overall, the 3-year Kaplan-Meier estimate of relapse-related mortality was 28% (MRD 26%; URD 30%), and non-relapse mortality was 23% (MRD 20%; URD 27%). The rates of 3-year overall and progression-free survivals were 46% and 36%, respectively (MRD 51%, 38%; URD 39%, 31%). Among pts with measurable disease at HCT (65%), the 3-year overall survival was 49% (MRD 50%; URD 45%). The best outcomes were seen in pts with B-cell malignancies, including MM, CLL and NHL, and with early stage myeloid malignancies. In pts who had failed a previous transplant, 3-year overall survival was 39% (MRD 37%; URD 41%). In summary, nonmyeloablative regimens allowed engraftment of allogeneic hematopoietic cells and the development of graft versus tumor effects. Encouraging outcomes were achieved using nonmyeloablative conditioning for both MRD and URD HCT in pts who otherwise were not eligible for myeloablative conditioning regimens, including those who had failed a myeloablative HCT.

The primary objective of this 1.5-day workshop was to critically explore and identify the rationale for clinical trials of allogeneic hematopoietic cell transplantation (HCT) in autoimmune diseases, with particular emphasis on multiple sclerosis (MS) and systemic sclerosis. Meeting participants were HCT physicians and autoimmune disease experts from North America and Europe. The focus of these discussions was to define diseases and patient populations that may benefit from allogeneic HCT, by rethinking disease pathophysiology and natural history in light of today’s allogeneic HCT technology.

Purpose: To evaluate the safety of concurrent treatment with trastuzumab and high-dose chemotherapy (HDC), using cyclophosphamide, cisplatin, and 1,3-bis(2-chloroethyl)-1-nitrosourea (BCNU), with autologous hematopoietic progenitor cells support, in patients with HER2+ advanced breast cancer. Experimental Design: Patients with HER2-overexpressing high-risk primary breast cancer (HRPBC; defined as ≥4 involved nodes or inflammatory disease), or metastatic breast cancer (MBC) were eligible. Treatment consisted of a loading dose of trastuzumab at 4 mg/kg (day −5), HDC (days −5 to −2), autologous hematopoietic progenitor cells infusion on day 0, and weekly maintenance trastuzumab (2 mg/kg) from day +1 (minimum of 9 doses). Cardiac monitoring included serial left ventricular ejection fraction measurements before treatment and on days +20 and +65. Results: Thirty-three patients were prospectively enrolled (13 HRPBC, 20 MBC). Toxicity seemed similar to that expected with this HDC regimen alone. Neutrophils and platelets engrafted promptly. There were no cases of grade 4 or 5 toxicity. One patient experienced symptomatic grade 3 acute cardiac failure on day −4, responsive to treatment. Trastuzumab did not alter the pharmacokinetics of HDC. Eleven of twelve MBC patients with measurable disease (nine of them refractory to previous chemotherapy) experienced an objective response (9 complete and 2 partial responses). At median follow-up of 34 (13–58) months, all HRPBC patients remain alive and free of disease; the MBC group has event-free survival and overall survival rates of 45 and 70%, respectively. Conclusions: Incorporation of trastuzumab into HDC (cyclophosphamide, cisplatin, and BCNU) is feasible, with no apparent increased toxicity or pharmacokinetic interactions.

Patients (pts) with progressive HD following autologous HCT have limited treatment options and poor prognosis. We evaluated the utility of nonmyeloablative conditioning and allogeneic HCT for pts ineligible for high dose conventional allogeneic HCT due to age and/or comorbidities. Between December 1998 and October 2002, 27 pts (18 MRD, 9 URD) received 2 Gy total body irradiation alone (n = 7 MRD) or with 90 mg/m2 fludarabine (n = 11 MRD, n = 9 URD), G-CSF mobilized peripheral blood HCT and postgrafting immunosuppression with mycophenolate mofetil and cyclosporine. Median age was 37 (range 21–65) years. Pts were heavily pretreated and had advanced disease with a median number of prior regimens of 5 (range 2–9). Most pts had prior radiation therapy (25/27) and prior high dose autologous HCT (24/27). Median time between autologous HCT and salvage therapy was 8 (range 2–73) months. Median time between autologous HCT and allogeneic HCT was 16 (range 2–78) months. At allogeneic HCT, 5 pts were in complete remission (CR), 11 in partial remission (PR), 4 had relapsed disease and 7 had refractory disease. All pts engrafted and there were no graft rejections. The overall incidence of acute Grade II, III, and IV GVHD was 33%, 15%, and 4% respectively. Incidence of chronic extensive GVHD was 55% at 1 year. The overall response rate, defined as those pts with measurable disease prior to transplant who achieved a CR or PR after allogeneic HCT was 55%. Currently, 9 of 27 pts are alive; 6 are in CR and 3 have relapsed or have progressive disease (PD), with a median follow up of 18 (6–54) months. Eighteen pts have died; 9 from non-relapse causes (8/9 died of infections ± GVHD) and 9 from relapse/PD a median of 7 (range 1–38) months post transplant. Day 100 and 1 year NRM was 7% and 35% respectively. One year overall survival, progression free survival and relapse/PD incidence were 51%, 18% and 47% respectively. A detailed description of the MRD and URD pts is shown in Table 1. In summary, salvage nonmyeloablative conditioning and allogeneic HCT provides anti-tumor activity in pts with relapsed or refractory HD who are ineligible for conventional allogeneic transplant. Future efforts incorporating tumor-specific antibody therapy after nonmyeloablative conditioning HCT are being developed in an effort to improve disease free survival, anti-tumor activity and overall survival in pts with relapsed or refractory HD. TableResults of Nonmyeloablative Conditioning Followed by Allogeneic HCT for HD Using MRD or URDMRD (n = 18)URD (n = 9)Median follow up of living patients (range)36 (12–54) months11 (6–24) monthsDisease status at HCT4 CR, 7 PR, 4 Rel, 3 Ref1 CR, 4 PR, 4 RefOverall response rate57% (7 CR, 1 PR)50% (3 CR, 1 PR)Living patients/status3 CR, 2 PD3 CR, 1 RelAcute GVHD grade II, III, IV33%, 11%, 6%33%, 22%, 0%1 year chronic extensive GVHD50%60%Day 100 NRM11%0%One year NRM39%26%One year overall survival39%75%One year progression free survival11%35%One year Rel/PD incidence50%40%Rel, relapse; Ref, refractory. Open table in a new tab Rel, relapse; Ref, refractory.

We evaluated tacrolimus/mycophenolate mofetil (MMF) for graft-versus-host disease (GVHD) prophylaxis after a nonmyeloablative stem cell transplantation (NST) from a matched sibling donor (MSD). Thirty-two patients (median age, 57 years) with advanced hematologic malignancies, who were poor candidates for a conventional myeloablative transplantation, received fludarabine (30 mg/m(2), day -4 to day -2), total-body irradiation (TBI) (200 cGy, day 0), infusion of donor peripheral blood progenitor cells (day 0), oral tacrolimus 0.06 mg/kg twice daily (from day 3), and oral MMF at 15 mg/kg twice daily (days 0-+27). Tacrolimus was tapered from day +100 to day +180 in those patients with indolent malignancies (n = 25), and from day +35 to day +56 in those with aggressive tumors (n = 7). Regimen toxicities and myelosuppression were mild, allowing 75% of patients to have entirely outpatient transplantations. One patient (3%) experienced a nonfatal graft rejection. Rates of grades II-IV and III-IV acute GVHD were 15.6% and 3%, respectively. Acute GVHD was diagnosed at median day +78 (range, days +31-+84). Extensive chronic GVHD was observed in 10 of 24 evaluable patients (41.6%) at a median onset of day +198 (range, days +128-+277), either spontaneously (n = 5) or elicited after tumor progression (n = 5). Five patients experienced transplantation-related mortality (TRM) (15.6%) from either acute GVHD-related multiorgan failure (MOF) (n = 3) or infectious complications (n = 2). At median follow-up of 19 months (range, 2-41 months), the overall survival, progression-free survival, and disease-free survival rates are 62.5%, 50%, and 40%, respectively. In conclusion, the use of tacrolimus/MMF after MSD NST is associated with encouraging rates of GVHD control.

Purpose: The purpose of this study was to evaluate the prognostic effect of early posttransplant lymphocyte recovery in patients with advanced breast cancer receiving high-dose chemotherapy with autologous hematopoietic progenitor cell transplantation.Experimental Design: We analyzed the effect of the absolute lymphocyte count on day +15 posttransplant on freedom from relapse and overall survival in patients with high-risk primary breast cancer or metastatic breast cancer, enrolled between 1990 and 2001 in prospective high-dose chemotherapy trials, using a uniform regimen of cyclophosphamide, cisplatin, and 1,3-bis(2-chloroethyl)-1-nitrosourea.Results: Four hundred and seventy-six patients (264 high-risk primary breast cancer and 212 metastatic breast cancer patients) were evaluated at median follow-up of 8 years (range, 1.5-11 years). The disease-free survival and overall survival rates in the high-risk primary breast cancer group were 67% and 70%, respectively. Patients with metastatic breast cancer patients had 21.8% disease-free survival and 31.5% overall survival rates. Day +15 absolute lymphocyte count correlated with freedom from relapse (P = 0.007) and overall survival (P = 0.04) in the metastatic breast cancer group, but not in the high-risk primary breast cancer group (P = 0.5 and 0.8, respectively). The prognostic effect of absolute lymphocyte count in metastatic breast cancer was restricted to those patients receiving unmanipulated peripheral blood progenitor cells (P = 0.04). In contrast, absolute lymphocyte count had no significant effect in those metastatic breast cancer patients receiving bone marrow or a CD34-selected product. In multivariate analyses, the prognostic effect of day +15 absolute lymphocyte count in metastatic breast cancer was independent of other predictors, such as disease status, pre-high-dose chemotherapy treatment, number of tumor sites, or HER2.Conclusions: Early lymphocyte recovery is an independent outcome predictor in metastatic breast cancer patients receiving high-dose chemotherapy and an autologous peripheral blood progenitor cell transplant. These observations suggest that immune strategies targeting minimal posttransplant residual disease may prove worthwhile.

To ascertain the consequences of severe leukopenia and the tempo of recovery, we studied the immunity of 56 adult patients treated for multiple sclerosis or systemic sclerosis with autologous CD34 cell transplantation using extremely lymphoablative conditioning. NK cell, monocyte, and neutrophil counts recovered to normal by 1 month; dendritic cell and B cell counts by 6 months; and T cell counts by 2 years posttransplant, although CD4 T cell counts remained borderline low. Initial peripheral expansion was robust for CD8 T cells but only moderate for CD4 T cells. Subsequent thymopoiesis was slow, especially in older patients. Importantly, levels of antibodies, including autoantibodies, did not drop substantially. Infections were frequent during the first 6 months, when all immune cells were deficient, and surprisingly rare (0.21 per patient year) at 7–24 months posttransplant, when only T cells (particularly CD4 T cells) were deficient. In conclusion, peripheral expansion of CD8 but not CD4 T cells is highly efficient. Prolonged CD4 lymphopenia is associated with relatively few infections, possibly due to antibodies produced by persisting pretransplant plasma cells.

We investigated the feasibility of HLA-matched unrelated donor (URD) HCT in pts with advanced stage, poor-risk multiple myeloma after nonmyeloablative conditioning. Nineteen pts, median age 52 years (range, 28–65), were treated between 5/2000 and 2/2004. Eight pts had known complex cytogenetic abnormalities including Δ13. At study entry, 12 pts had relapsed or refractory disease after a previous autologous HCT, 5 pts had refractory disease following multiple standard chemotherapy regimens, and 2 pts achieved a partial remission (PR) after standard chemotherapy. Before URD HCT, 10 pts underwent a planned high dose autologous HCT (Melphalan 200 mg/m2) to provide cytoreduction a median of 85 days prior to URD HCT, including 4 pts with relapsed/refractory disease after a prior autologous HCT. Three pts were in complete remission (CR) immediately prior to URD HCT. Nonmyeloablative conditioning consisted of fludarabine (30 mg/m2 x 3 days) and 2 Gy total body irradiation followed by PBSC grafts from URDs matched for HLA-A, −B, −C antigens and -DRB1 and -DQB1 alleles. Postgrafting immunosuppression included mycophenolate mofetil and cyclosporine. Durable engraftment was achieved in 18 of 19 pts. One pt had graft rejection at day +56 and received a second successful nonmyeloablative HCT from another URD. Acute GVHD occurred in 13 (68%) pts and was exclusively grades II and III in 11 and 2 pts, respectively. Chronic extensive GVHD occurred in 12/17 (70%) of evaluable pts. After allografting, 9 pts (47%) were in CR and 3 (16%) in PR, for an overall response rate of 63%. Four pts (21%) died of progressive disease and 4 pts (21%) died of non-relapse causes at a median of 5.3 months. The 2-year overall survival, progression-free survival and non-relapse mortality was 62%, 51% and 24%, respectively. The median follow-up was 25 months. Eleven of 19 pts (58%) were alive, 6 (32%) in CR, 1 (5%) in PR, 2 (10%) with stable disease (SD) and 2 (10%) with relapse after initially achieving CR. Of the 10 pts who underwent a planned high dose autologous HCT for cytoreduction followed by nonmyeloablative URD HCT, 8 were alive: 6 CR, 1 SD, 1 relapse. Of the 9 pts who underwent nonmyeloablative URD HCT without planned autologous HCT, 3 were alive: 1 PR, 1 SD and 1 relapse. Of the 12 pts who entered the study with relapsed/refractory disease after a previous autologous HCT, 5 were alive: 2 CR, 1 PR, 1 SD, 1 relapse. In summary, URD HCT after nonmyeloablative conditioning is feasible with relatively low non-relapse mortality and provides a high response rate for pts with relapsed or refractory multiple myeloma, including pts with disease relapse following an autologous HCT. The data suggest that a treatment strategy consisting of two sequential transplants (1) intensive cytoreductive therapy with autologous HCT followed by (2) nonmyeloablative URD HCT, may be highly effective for treating pts with poor risk, chemotherapy-refractory multiple myeloma or after relapse following autologous HCT.

Historically, the dog has been a valuable model for bone marrow transplantation studies, with many of the advances achieved in the dog being directly transferable to human clinical bone marrow transplantation protocols. In addition, dogs are also a source of many well-characterized homologues of human genetic diseases, making them an ideal large animal model in which to evaluate gene therapy protocols. It is generally accepted that progenitor cells for many human hematopoietic cell lineages reside in the CD34+ fraction of cells from bone marrow, cord blood, or peripheral blood. In addition, CD34+ cells are the current targets for human gene therapy of diseases involving the hematopoietic system. In this study, we have isolated and characterized highly enriched populations of canine CD34+ cells isolated from dogs 1 week to 3 months of age. Bone marrow isolated from 2- to 3-week-old dogs contained up to 18% CD34+ cells and this high percentage dropped sharply with age. In in vitro 6-day liquid suspension cultures, CD34+ cells harvested from 3-week-old dogs expanded almost two times more than those from 3-month-old dogs and the cells from younger dogs were also more responsive to human Flt-3 ligand (Flt3L). In culture, the percent and number of CD34+ cells from both ages of dogs dropped sharply between 2 and 4 days, although the number of CD34+ cells at day 6 of culture was higher for cells harvested from the younger dogs. CD34+ cells harvested from both ages of dogs had similar enrichment and depletion values in CFU-GM methylcellulose assays. Canine CD34+/Rho123lo cells expressed c-kit mRNA while the CD34+/Rhohi cells did not. When transplanted to a sub-lethally irradiated recipient, CD34+ cells from 1- to 3-week-old dogs gave rise to both myeloid and lymphoid lineages in the periphery. This study demonstrates that canine CD34+ bone marrow cells have similar in vitro and in vivo characteristics as human CD34+ cells. In addition, ontogeny-related functional differences reported for human CD34+ cells appear to exist in the dog as well, suggesting pediatric CD34+ cells may be better targets for gene transfer than adult bone marrow. The demonstration of similarities between canine and human CD34+ cells enhances the dog as a large, preclinical model to evaluate strategies for improving bone marrow transplantation protocols, for gene therapy protocols that target CD34+ cells, and to study the engraftment potential of various cell populations that may contain hematopoietic progenitor cell activity.

Little is known about the impact of cytomegalovirus (CMV) infections that occur after human leucocyte antigen (HLA)-matched unrelated donor (MUD) non-myleoablative haematopoietic stem cell transplantation (HCT). We analysed the incidence, onset and outcomes of CMV infections in 59 recipients of MUD and in 109 recipients of HLA-matched related donor (MRD) allogeneic HCT following non-myeloablative conditioning containing 2 Gy total body irradiation and fludarabine. In CMV seropositive recipients, antigenaemia occurred in 68% (MUD) and in 49% (MRD, P = 0.08); there were no differences in the maximum levels of CMV antigenaemia and the time to cessation with antiviral therapy. CMV viraemia by culture was more common in MUD compared with MRD HCT recipients in univariate analysis (26% vs. 6%, P = 0.01), however, this difference was not detectable after controlling for other factors. The rates of CMV disease in the first 100 d were similar in MUD (9%) and MRD (5%) HCT recipients. CMV disease tended to occur earlier in the MUD compared with the MRD recipients (median day 41 vs. day 80). Beyond day 100, rates of CMV disease remained similar in both cohorts (cumulative incidence: MUD 21% and MRD 14%). The 30-d and 1-year survivals after CMV disease diagnosis were not significantly different in both groups. Thus, there appeared to be a trend toward increased CMV reactivation in MUD compared with MRD non-myeloablative allogeneic HCT recipients; however, these differences did not reach statistical significance in this cohort and preemptive therapy was similarly effective in preventing CMV diseases.

Acute renal failure (ARF) is a common life-threatening complication after myeloablative allogeneic hematopoietic cell transplantation (HCT). Nonmyeloablative HCT aims to eradicate the malignancy with graft-versus-tumor effect, rather than with high doses of chemoradiotherapy. It may be anticipated that a lower risk of ARF exists in nonmyeloablative HCT as a result of the milder preconditioning regimen. However, the patients who receive the nonmyeloablative HCT are older individuals who are not eligible for the more toxic allogeneic myeloablative procedure. The goal of this study was to evaluate ARF in a large group of patients who received nonmyeloablative HCT. This cohort study enrolled patients who were undergoing nonmyeloablative HCT at four major centers from 1998 to 2001. Conditioning therapy involved total body irradiation 2 Gy +/- fludarabine 30 mg/m2. Posttransplantation immunosuppression consisted of cyclosporine or tacrolimus and mycophenolate mofetil. ARF was classified into four grades, similar to previous studies in the literature. Collectively, 253 patients were recruited into this study. ARF (>50% decrease in GFR) occurred in 40.4% of patients over a 3-mo period, with 4.4% of patients requiring dialysis. The overall mortality in the study population was 34% at 1 yr. The mortality increased with worsening grade of ARF. The combined need for dialysis and artificial ventilation was associated with a mortality exceeding 80%. Although the number of patients who develop ARF is significant, the risk of developing ARF that requires dialysis after nonmyeloablative HCT is infrequent despite the older age of the patients. The data are also suggestive that ARF may contribute to mortality after nonmyeloablative HCT.

Aim To study immune reconstitution in patients recovering from extreme lymphopenia. Methods Fifty-six patients with autoimmune diseases (systemic sclerosis or multiple sclerosis) were conditioned with total body irradiation, cyclophosphamide and anti-thymocyte globulin and received autologous CD34 cells. Results On day 7, circulating T and B cells were undetectable, and NK cell, monocyte and granulocyte counts were low. NK cell, monocyte and granulocyte counts recovered to normal by day 30, B cell counts by 6 months and CD8 T cell counts by 2 years. CD4 T cell counts were still low at 2 years (median 388/microliter). In the first 3 months T cells recovered primarily through peripheral expansion, whereas de novo generation predominated thereafter (Ki67 and TREC analysis). Serum levels of total IgM, IgA, IgG and IgG2 remained normal throughout the 2 years of follow up. Also, levels of antibodies for tetanus, H.influenzae, S.pneumoniae and Scl-70 (in Scl-70-seropositive patients pretransplant) did not change substantially. A total of 23 infections, excluding presumed respiratory tract infection or gastroenteritis, occurred between day 0 and 15, 25 infections between day 16 and 180, 9 infections between day 181 and 365, and 9 infections between day 366 and 730. Conclusions After severe lymphopenia in adults, CD4 T lymphopenia persists for more than 2 years, and appears to be mildly clinically significant. The minimal change of levels of antibodies, including autoantibodies, suggests that autoimmune diseases caused by autoantibodies may not be improved by autologous transplantation.

Many patients with acute myeloid leukaemia (AML) in first complete remission (CR1) are ineligible for allogeneic transplantation as a result of age or medical problems other than leukaemia. Eighteen patients (median age 59 years, range 36-73 years) with de novo (n = 13) and secondary (n = 5) AML in morphological CR1, who were not candidates for conventional allografting, received non-myeloablative peripheral blood stem cell transplants from human leucocyte antigen identical sibling donors after conditioning with 2 Gy total body irradiation (TBI; n = 10) or 2 Gy TBI and 90 mg/m2 of fludarabine (n = 8). Postgrafting immunosuppression was with cyclosporine and mycophenolate mofetil. Two rejections were observed in patients not given fludarabine and one died with relapse. Overall, 10 patients died between 77 and 841 d, seven from relapse and three from non-relapse mortality (NRM). Day +100 NRM was 0% with a 1-year estimated NRM of 17%[95% confidence interval (CI) 0-35%]. The median follow-up among the eight survivors was 766 d (range, 188-1141 d). Seven of these eight survivors remain in complete remission (CR). One-year estimates of overall and progression-free survivals were 54% (95% CI 31-78%) and 42% (95% CI 19-66%) respectively. While follow-up is short, this analysis demonstrates that the procedure is sufficiently safe to be studied in a wider group of patients.