Day Of Stem Cell Infusion Research Articles

Allogeneic Transplantation after an Alemtuzumab-Containing Myeloablative Conditioning Regimen for CD52 Positive Acute Lymphoblastic Leukemia (ALL).

Alemtuzumab is an effective agent in the treatment of various B- and T-cell malignancies that express CD52. Patients with advanced or refractory ALL have poor outcome after allogeneic stem cell transplantation (SCT). We investigated whether the addition of alemtuzumab to a standard myeloablative conditioning regimen would have any additional therapeutic effect and improve outcome after SCT in CD52+ ALL.Patients and Methods: Patients were eligible if their disease expressed CD52 in >20% blasts by flow cytometry. The conditioning regimen consisted of cyclophosphamide (Cy, 60 mg/kg daily x 2 doses) and total body irradiation (TBI, 12 Gy in four daily fractions). Alemtuzumab at 10 mg was intravenously administered daily on days -6 to -2 prior to day of stem cell infusion. Patients received additional graft versus host disease (GVHD) prophylaxis with tacrolimus and methotrexate.Results: Fifteen patients (9 M/6 F) with median age 33 years (range 22–57) were studied. Twelve patients had B-lineage and 3 had T-lineage disease. Cytogenetic data were available for 12 patients; all had high-risk cytogenetics, including 5 with Ph+ disease. The median number of prior chemotherapy regimens was 3 (range 1–6). At time of study entry, 3 patients were in CR1, 3 were in ≥ CR1, and 9 were in primary or refractory relapse. Five patients received a matched related donor transplant and 10 received an unrelated donor graft. The source of stem cells was bone marrow (n=7) or peripheral blood (n=8). The median CD34+ cell dose infused was 4.67 x 106/kg (range 1.85–6.43). Median time to ANC ≥ 0.5 x 109/L was 15 days (range 11–20). Median time to platelet count ≥ 20 x 109/L was 19 days (range 13–34). The cumulative incidence of non-relapse mortality at 2 years was 13% (95% CI, 4%–43%). The incidence of grade II-IV acute GVHD was 7% (95% CI, 1%–38%); no grade III/IV acute GVHD was observed. The incidence of chronic extensive GVHD was 20%. Overall survival at 2 years was 16% (95% CI, 3%–40%). Failure was related mainly to progression; thirteen of 15 patients had disease progression at a median time of 4 months (range 1–22).Conclusion: These data suggest that alemtuzumab can be safely added to the standard transplant conditioning regimen for ALL without delayed engraftment or increased regimen-related toxicity. However, any potential direct antileukemia effect in CD52+ ALL patients with advanced disease appears to be negated by in-vivo T-cell depletion of the donor graft. Strategies to restore the graft-versus-leukemia effect in this setting are needed.

A Prospective Study of Gastric Emptying and Its Relationship to the Development of Nausea, Vomiting, and Anorexia after Autologous Stem Cell Transplantation

Gastric motor dysfunction may be responsible, in some patients, for the nausea and emesis that occur following high-dose chemotherapy (HDT) and autologous stem cell transplantation (SCT). We sought to define the prevalence of gastric emptying abnormalities and their relationship to the development of nausea, vomiting, and anorexia in patients undergoing HDT and autologous SCT. We prospectively studied patients with a variety of malignancies who received standard transplantation doses of chemotherapeutic agents and antiemetics. Gastric emptying was assessed prior to HDT and on Days 0 (day of stem cell infusion), +7, and +14 from SCT. Symptom assessment was obtained daily from initiation of HDT to 28 days after SCT. Twenty-four patients were studied. Prior to HDT, gastric emptying was rapid in two patients. Nausea, emesis, and anorexia occurred in all patients, peaked in severity at Day +7 after SCT and, with the exception of anorexia, had returned toward baseline levels by Day +28. As a group, gastric emptying was significantly slower on Days 0 and +7 and returned to baseline level by Day +14. Twenty-six percent and 44% of patients demonstrated delayed gastric emptying (T(1/2) >90 min) on Days 0 and +7, respectively, while 13% and 31% of patients had rapid gastric emptying (T(1/2) <30 min) on Days 0 and +7, respectively. Thirty-nine percent and 75% of patients had either rapid or delayed gastric emptying on Days 0 and +7, respectively. There was an association between delayed gastric emptying and moderate-severe anorexia on Day +7 and between delayed gastric emptying and at least mild vomiting on Day 0. Additionally, there was an association between rapid gastric emptying and at least mild vomiting on Day +7. Finally, an association was found between either rapid or delayed gastric emptying and at least mild nausea on Day +7. Both delayed and rapid gastric emptying occur commonly during the 2-wk period following HDT and autologous SCT and may be responsible, at least in part, for upper gastrointestinal symptoms that occur in these patients.

High-dose carmustine, etoposide, and cisplatin for autologous stem cell transplantation with or without involved-field radiation for relapsed/refractory lymphoma: An effective regimen with low morbidity and mortality

Over a 10-year period (January 1993 to October 2002), 101 relapsed or refractory non-Hodgkin lymphoma patients were treated at our center with high-dose chemotherapy and autologous transplantation. The median patient age was 54 years (range, 25-70 years). Thirty-two patients had indolent (low-grade), 42 had aggressive (intermediate-grade), and 27 had very aggressive (high-grade) non-Hodgkin lymphoma. Thirty-six patients had primary refractory disease, 20 had a chemoresistant relapse, 35 patients had a chemosensitive relapse, and 10 patients were "initial high risk" patients. The median number of prior chemotherapy regimens was 2 (range, 1-5). The preparative regimen (BEP) was bischloroethylnitrosourea (BCNU) 600 mg/m 2 , etoposide 2400 mg/m 2 , and Platinol (cisplatin) 200 mg/m 2 given intravenously over 5 days. Within 3 weeks before transplantation, 70 patients received involved-field radiotherapy (IFR) 20 Gy to sites of currently active (>2 cm) or prior bulky (>5 cm) disease. Most patients (n = 93) received mobilized peripheral blood stem cells (median CD34 + cell dose, 6.7 x 10 6 /kg). Median neutrophil (>500/microL) and platelet (>20 000/microL, untransfused) recoveries were 11 days (range, 7-19 days) and 14 days (range, 7-36 days), respectively. At a median follow-up of 41 months (range, 4 to 118 months) for survivors, Kaplan-Meier 5-year probabilities of overall survival (OS) and disease-free survival (DFS) were 58.6% and 51.1%, respectively. Four patients (4%) died within 30 days of stem cell infusion (1 pulmonary embolism, 2 septicemias with multiorgan failure, and 1 progressive lymphoma). Two patients (2%) developed interstitial pneumonitis most likely secondary to high-dose BCNU. Three cases (3%) of secondary acute myelogenous leukemia occurred. On multivariate analysis, age (<60 or > or =60 years), histologic grade (low versus intermediate or high), the use of IFR, and chemotherapy response at baseline did not affect OS or DFS. Of 70 patients given IFR, 27 relapsed: 10 (37%) within and 17 (63%) outside the radiation field. The use of IFR did not affect either OS or DFS, probably because IFR was offered to patients with bulky or chemoresistant disease. BEP with or without IFR is a highly effective and well-tolerated regimen in the relapsed/refractory lymphoma setting. It has low morbidity and transplant-related mortality and a low incidence (3%) of posttransplantation malignancy.

Direct Adoptive Transfer of Cytomegalovirus-Specific CTL from Unrelated Donors to Stem Cell Transplant Patients Following Selection by HLA-Peptide Tetramers.

Cytomegalovirus (CMV) infection remains an important cause of morbidity and mortality in patients undergoing allogeneic stem cell transplantation (SCT). This is particularly true in patients transplanted using volunteer unrelated donors (VUDs) where despite improvements in antiviral therapy CMV positive serostatus remains an adverse prognostic indicator. Adoptive transfer of donor-derived CMV-specific CD8+ T cell clones reduces the rate of viral reactivation but the complexity of this approach severely limits its clinical application.We have previously reported the purification of CMV-specific CD8+ cytotoxic T lymphocytes (CMV-CTL) from the blood of stem cell transplant donors using HLA-peptide tetramers and their subsequent transfer. Six patients undergoing stem cell transplantation from HLA identical sibling donors were studied. CMV-CTL were infused on a pre-emptive basis in patients who developed evidence of CMV viremia. All patients showed prompt and durable CMV-specific immune reconstitution demonstrating durable CMV-specific immune reconstitution. CMV-CTL constituted up to 21% of the patient lymphocyte CD8+ T cell compartment and were detectable up to 24 months in all patients. There was a reduced requirement for anti-viral agents in treated patients (33%) compared with a control group (82%) p=0.11. No secondary reactivation was seen in any patient in the treatment group. No infusion-related toxicity was seen in any treated patients. We have now extended these studies to recipients of VUD transplants in whom no CMV-CTL are detectable within the first 100 days of stem cell infusion. Tetramer-selected CMV-CTL have been adoptively transferred into six patients undergoing transplantation from an unrelated donor. CMV-CTL were given either for treatment of refractory CMV infection (n=5) or prophylactically 21 days post SCT (n=1). A cell dose of between 6x102/kg and 1.25x105/kg was administered with median purity of 95% of the infused T cell dose. No infusional toxicity or acute graft-versus-host disease was noted. CMV-CTL were not present in any patient prior to therapy. Within 7 days of adoptive transfer CMV-CTL were detectable in all patients comprising 0.6% – 20% of CD8+ T cell compartment. All patients demonstrated a reduction in the viral load and 5/6 cleared their viremia. In the patient who received prophylactic therapy durable expansion of CMV-CTL were observed up to 20% of CD8+ T cell pool. Taken together these data are consistent with the hypothesis that antigen-specific CMV specific CTL can be safely infused to recipients of VUD SCT and expand directly in vivo. Such an approach has considerable potential in the treatment or prophylaxis of CMV infection in patients undergoing VUD SCT.

Bleeding risk and platelet transfusion refractoriness in patients with acute myelogenous leukemia who undergo autologous stem cell transplantation.

Therapy for acute myelogenous leukemia can be complicated by alloimmunization to histocompatibility antigens (HLA), with resultant refractoriness to platelet transfusions. Autologous peripheral blood or bone marrow stem cell transplantation (referred here collectively as 'autoBMT') is emerging as a standard consolidative strategy in acute myelogenous leukemia (AML). We had noted life-threatening bleeding associated with platelet transfusion refractoriness following autoBMT; we therefore retrospectively analyzed 39 AML patients for this complication following BMT. All patients received high-dose chemoradiotherapy, followed by infusion of allogeneic sibling donor (n = 12, alloBMT) or autologous (n = 27, autoBMT) stem cells. HLA alloimmunization was assessed if patients were suspected of immune refractoriness to random donor platelet transfusions. Within 100 days of stem cell infusion, one of three alloBMT and six of 12 autoBMT recipients tested were HLA alloimmunized (not statistically significant, NS). Five of six HLA alloimmunized autoBMT patients experienced delayed bleeding, which contributed to their demise while still in remission (P < 0.001). Increased platelet requirements in HLA alloimmunized autoBMT recipients were observed between days 61 and 100 post-BMT, at a median of 211 platelet transfusions vs 0 in non-alloimmunized autoBMT patients (P < 0.01) and 17 in alloBMT patients. Our data suggest that platelet transfusion refractoriness, when associated with HLA alloimmunization, is a risk factor for increased platelet transfusion requirements, delayed bleeding, and poor outcome following autoBMT for AML.

Adenovirus infections in hematopoietic stem cell transplant recipients.

We report a 12% incidence of adenovirus infections among 532 recipients of hematopoietic stem cell transplant (HSCT) from January 1986 through March 1997. The median time from day of stem cell infusion to first positive culture was 41 days. Recipients of allogeneic stem cells, as opposed to autologous stem cell recipients, were more likely to have a culture positive for adenovirus (16% vs. 3%; P<.0001). Pediatric patients were also more likely than adults to have a positive culture (23% vs. 9%; P<.0001). Among stem cell recipients with partially matched related donors, pediatric recipients appear to be at significantly greater risk for infection than adult recipients (P<.001). Positive cultures were associated with evidence of invasion in 64% of cases (41 of 64). A multiple logistic regression analysis showed that isolating adenovirus from more than 1 site correlated with greater risk for invasive infections (P=.002). Invasive infections were associated with poorer chance of survival.

Optimizing recovery from aplasia after high-dose therapy and hematopoietic stem cell transplantation

Objective. Discussion of the roles of hematopoietic growth factors and the role of stem cells in shortening aplasia after transplant. In addition, the role of the treatment regimen in determining the length of aplasia. Data Sources. A series of original research stud ies from H. Lee Moffitt Cancer center which was published from 1993 to the present. In addition, selected references were reviewed and quoted to support selective arguments. Study Selection. Since 1989 data from four allo cated, parallel, high-dose phase I/II trials conducted at H. Lee Moffitt Cancer Center, Tampa, Fla and include the following treatment regimens: (1) ifosfamide, carbo platin, and etoposide (ICE); (2) mitoxantrone and thio tepa (MITT); (3) busulfan and cyclophosphamide (BUCY2); and (4) Taxol, Novantrone, thiotepa (TNT). The results of hematopoietic recovery from consecutive patients allocated on these trials will be discussed. Data Extraction. Granulocyte engraftment was defined as having occurred when an absolute granu locyte count of 500/μL has been surpassed on 3 or more consecutive days. The period of aplasia was defined as the number of days from the day of stem cell infusion to the day of engraftment. The period of granulocyte engraftment and aplasia was examined comparatively as a function of the source of stem cells given to the patient at their initial reinfusion. Time to engraftment was evaluated by Kaplan-Meier Product Limit Method and probability curves were compared by logrank analysis. Data Synthesis. The duration of aplasia after high-dose therapy and stem cell transplantation deter mines the risk of opportunistic infection and the cost of the transplant. Prospective, randomized, controlled trials for both sargramostim and filgrastim have clearly demonstrated a significantly shorter period of aplasia produced by high-dose therapy by several days. From sequential comparison trials, it appears that filgrastim may be superior to sargramostim in shortening aplasia after bone marrow stem cell transplantation following high-dose therapy. Erythropoietin, while not shorten ing the period of aplasia, has been demonstrated to reduce erythrocyte transfusion requirements; whereas the question about cost-effectiveness remains to be unanswered. In comparing granulocyte recovery of bone marrow stem cell transplants with peripheral blood stem cell transplants, both perform similarly, especially, if collected under identical stimulatory conditions. Both the mobilizing regimen and the treatment regimen, but not the anatomic compart ment, are significant factors which determine the speed of engraftment after high-dose therapy and hematopoietic stem cells are transplanted. Conclusions. The purpose of high-dose therapy is to improve the cure rate for selected malignancies. Shortening aplasia can reduce the death rate from infections but only has a marginal impact on the cure rate as the death rate is relatively low. It behooves us, then, to develop the best treatment and with that regimen determine how best to shorten the period of aplasia.