Total Body Irradiation Regimen Research Articles

Successful Engraftment of Cord Blood Transplantation Following Reduced-Intensity Conditioning Regimen Using Fludarabine and Busulfan for Advanced Hematologic Malignancies.

Background: The potential role of reduced-intensity cord blood transplantation (RI-CBT) without total body irradiation (TBI) in adults remains unclear. We investigated the feasibility of RI-CBT using non- TBI regimen for the treatment of patients with advanced hematologic malignancies.Methods: Twenty-three patients (median age, 61, range, 38–74) with advanced hematologic malignancies were enrolled in this study (18 patients in refractory or relapsed phase,5 patients in remission or chronic phase). Conditioning regimen comprised of fludarabine 30 mg/m2 on days −8 to −3, busulfan 4 mg/kg p.o. or 3.2 mg/kg i.v. on days −6 to −5. In one cases. we administered busulfan 3.2mg/kg i.v. on days −6 to −3, because of blastic crisis. Graft-versus-host disease (GVHD) prophylaxis was tacrolimus alone. Engraftment was defined as an absolute neutrophil count > 0.5 x 10E9/l. Primary graft failure was defined as the complete loss of donor-type hematopoiesis without engraftment. Secondary graft failure was defined as the loss of donor-type hematopoiesis after primary engraftment. Median follow-up of surviving patients was 1096 days (range, 53–1207). Primary endpoint was engraftment. All patients provided informed consent in accordance with the requirements of Institutional Review Board.Results: All the patients tolerated the conditioning regimen. Median dose of infused nuclear cells was 2.7x10E7 /kg (range, 1.9–4.6). Twelve patients achieved engraftment at a median of day 20.5 (range, 10–36), but two of them developed secondary graft failure. Complete donor-type chimerism was documented within 30 days of transplant in six patients. Primary graft failure was diagnosed in remaining eleven patients. Six of them, underlying disease progressed despite conditioning regimens. As of August 2007, five patients survived (3 patients in complete remission, one patients relapsed after transplantation, the other one not reached remission). Estimated 1-year overall survival rate was 20.7% (95% confidence interval, 3.0–38.4%).Conclusions: Though the pre-transplant condition of patients were not good, engraftment was obtained with approximately the half patients. This study demonstrated the feasibility of RI-CBT using non-TBI regimen for adult patients with advanced hematological diseases; however, high incidences of disease progression before engraftment was significant problem. RI-CBT may become the choice of treatment for patients with advanced hematologic malignancies that are incurable with conventional treatments.

Clinical Significance and Risk Factors of Delayed-Onset Neutropenia (DON) after Autologous Stem Cell Transplantation (ASCT) for B-Cell Non-Hodgkin Lymphoma: A Single-Institute Analysis.

Background: DON is known as one of the adverse events after ASCT, for which rituximab usage has been reported to be a risk factor. One of the limitations in previous reports is that confounding by indication for rituximab treatment, and thus it is yet unclear if rituximab is an independent risk factor for DON. To examine the impact of rituximab considering such limitation as well as to explore possible other determinants and clinical significance of DON, we conducted a retrospective cohort study.Method: Subjects were consecutive 97 patients with B-cell non-Hodgkin lymphoma receiving ASCT between 1991 and 2007 in Aichi cancer center hospital. We defined DON as absolute neutrophil count < 0.1 x 109/L at any point after 30 days post ASCT without apparent cause of neutropenia. We investigated adverse events and risk factors using propensity score (PS), step-wise method and bootstrap resampling method. PS for preference of rituximab treatment was calculated based upon fourteen clinical factors; rituximab usage, age, sex, performance status, clinical stage, B symptom, bulky lesions, no. of extra nodal sites, lactate dehydrogenase level, no. of prior chemothearpy and local radiation, existence of bone marrow involvement, status at ASCT, and types of conditioning regimens (total-body-irradiation (TBI) containging regimens or not). Unconditional logistic regression models adjusted for PS and other potential risk factors were applied to estimates odds ratios (ORs) and their 95% confidence intervals (CIs) for occurrence of DON. Selection of potential risk factors in validation analysis was done by forward step-wise method (p-value for removal=0.10 and that for inclusion=0.05). Finally, we applied bootstrap resampling method for validation of our analyses (repeating 10,000 times with 97 sampling from original cohort).Results: 56.7% patients were treated with rituximab combined chemotherapy before ASCT, of which 26.3% had prior rituximab exposure. The median number of prior chemotherapy was one (range; one to five), and 47.4% patients received three or more prior regimens before ASCT. 22.7% patients received TBI regimen. With a median follow-up of 3.42 years, DON was observed in 46.7% patients. The lowest neutrophil count was 446 x 106/L (range; 9–992). Of the patients developing DON, 17.2% patients experienced febrile infectious events. Interstitial pneumonia (IP) was observed in 10% of the patients with DON and 5.5% without DON. No patients experienced Grade 4 or 5 events. By step-wise method, selected factors for final validation model were rituximab usage, TBI, female sex, B symptom, and prior radiation therapy. In the validation, usage of rituximab (OR=3.28: 1.07–10.0, p=0.037), and prior radiation before ASCT (1.81: 1.24–2.63, p=0.002) were identified as independent risk factors for DON. Other factors failed to demonstrate significant impact on DON.Conclusion: DON was associated with febrile infectious events in 17% patients and most of the cases achieved rapid clinical improvement. Our retrospective cohort analysis considering confounding by indication for rituximab confirmed significant impact of usage of rituximab on DON among B-cell lymphoma patients receiving autologous HSCT. Further evaluation of the impact of radiation therapy before HSCT on DON is also warranted.

Total body irradiation followed by bone marrow transplantation: comparison of once-daily and twice-daily fractionation regimens

The purpose of this study was to evaluate the results of two sequential total body irradiation (TBI) regimens, especially focusing on pulmonary complications. Patients with malignant disease who underwent TBI followed by bone marrow transplantation were retrospectively reviewed. There were 86 patients (51 males, 35 females). Altogether, 36 patients were treated on twice-daily fractions of 2 Gy for 3 days to a total 12 Gy (group A). Another 50 patients were treated on once-daily fractions of 2.4 or 3.0 Gy for 4 or 5 days to a total 12 Gy (group B). The 5-year overall survival rate was 49.2%, and relapse-free survival was 44.3%. There were no significant differences between the two groups regarding overall survival (P = 0.1237) or relapse-free survival (P = 0.1548). Two patients in group A had interstitial pneumonitis of grade 3 or higher severity compared with three patients in group B. There was no significant difference between patients in group A (5-year probability rate was 7.6%) and patients in group B (5-year probability rate was 13.9%) (P = 0.9519). We concluded that our once-daily TBI regimen is feasible and had the benefit of reducing the complexity of TBI. We believe that further investigation of the TBI regimen is needed.

A prospective and randomized study of two conditioning regimens in treatment of severe systemic autoimmune diseases with autologous peripheral blood stem cell transplantation

To investigate the differences in immune reconstitution, hematopoietic reconstitution, efficacy, and complication between the two conditioning regimens with or without total body irradiation (TBI) in patients with refractory and severe autoimmune diseases (AID) who receiving autologous peripheral blood stem cell transplantation (APBSCT). Thirty-two AID patients, 5 males and 27 females, aged 29 (15 - 49), underwent APBSCT. The CD34(+) cells were mobilized with cytoxan (CTX) + granulocyte-colony stimulating factor (G-CSF) and selected by clinical magnetic activated cell sorting (CliniMACS). The conditioning regimen included CTX + antithymocyte globulin (ATG) in 11 patients and CTX + TBI in 21 patients. All the patients were followed up for more than 12 months. The median time of granulocyte recovery were 11 and 9 days in the CTX + TBI and CTX + ATG groups respectively (P = 0.003), the median time of platelet recovery were 13 and 8 days respectively (P = 0.001). In both groups, the lymphocyte subsets were recovered with the inverted CD4/CD8 ratio 12 months after transplantation. Relapse was seen in 3 cases of the CTX + TBI group (14.3%), and 2 cases of the CTX + ATG group (18.2%), and the rest of patients remained free of AID. During transplantation incidence of bacteria infection occurred in 5 of the 21 cases in the CTX + TBI group (23.8%) and in 2 of the 11 cases of the CTX + ATG group (18.2%) respectively; viral infection occurred in 1 of the 21 cases of the CTX + TBI group (4.8%) and in 2 of the 11 cases of the CTX + ATG group (18.2%) respectively. The number of radiated parotitis was 4 among the 21 patients of the CTX + TBI group (19%) and was 3 among the 12 patients of the CTX + ATG group (25%). Serum sickness reaction occurred in 3 of the 12 patients of the CTX + ATG group (25%). Bacterial and viral infections were cured soon after antibacterial or antiviral therapy, no fatal bleeding occurred due to thrombocytopenia in both groups. The conditioning regimen of TBI + CTX delays the hematopoietic reconstitution compared with the ATG + CTX regimen in treating AID. The regimen of CTX + TBI can be better tolerated, but there are no significant differences in efficacy and immune reconstitution among these two regimens.

Long-Term Outcome of Unrelated Donor Transplantation for AML Using Myeloablative Conditioning Incorporating Pretransplant Alemtuzumab

The outcome of 55 patients who underwent matched unrelated donor (MUD) transplantation for acute myelogenous leukemia (AML) following a conditioning regimen of cyclophosphamide and total-body irradiation (TBI) with the addition of Alemtuzumab 10 mg/kg/day on days −5 to −1 is described. All patients received graft-versus-host diesase (GVHD) prophylaxis with cyclosporine as well as 3 doses of posttransplant methotrexate. Forty-one patients were transplanted in complete remission (CR) (20 in CR1, 20 in CR2, and 1 in CR3), and 14 were not in remission at the time of transplantation as they were refractory to chemotherapy either at induction or at relapse. The group consisted of adult patients with a median age of 37 years. Thirty-five patients were fully matched at HLA-A, -B, -C, and -DRB1. All patients engrafted and there were no cases of graft rejection. Grade II-IV acute GVHD occurred in only 2 patients. Chronic GVHD developed in 30% of patients but was extensive in only 3 cases. The predicted TRM was 11% at day 100 and 26% at 1 year. In multivariate analysis the receipt of an HLA mismatched transplant was associated with a higher transplant-related mortality (TRM) (55% versus 15%). Twelve of the 14 transplant-related deaths were due to infection. The 5-year cumulative incidence of relapse was 36% for the whole group and 28% for patients in CR at transplantation. The 5-year cumulative survival for the whole group was 38% and was 49% for those in remission at transplantation. Seven of the 12 patients transplanted in CR1 with adverse risk cytogenetics remain alive and in remission, and the predicted 5-year overall survival (OS) for this group is 50%. These results support the use of Alemtuzumab for unrelated donor hematopoietic stem cell transplant (HSCT) for poor risk AML in CR1 and for relapsed AML in CR2. The addition of Alemtuzumab is highly effective in preventing both rejection and severe acute and extensive chronic GVHD without an increased relapse risk.

Hematopoietic Cell Transplantation as Curative Therapy for Idiopathic Myelofibrosis, Advanced Polycythemia Vera, and Essential Thrombocythemia

A total of 104 patients, aged 18 to 70 years, with a diagnosis of chronic idiopathic myelofibrosis (CIMF), polycythemia vera (PV), or essential thrombocythemia (ET) with marrow fibrosis were transplanted from allogeneic (56 related and 45 unrelated) or syngeneic (n = 3) donors. Busulfan (BU) or total body irradiation (TBI)-based myeloablative conditioning regimens were used in 95 patients, and a nonmyeloablative regimen of fludarabine plus TBI was used in 9 patients. The source of stem cells was bone marrow in 43 patients and peripheral blood in 61 patients. A total of 63 patients were alive at a follow-up of 1.3–15.2 years (median, 5.3 years), for an estimated 7-year actuarial survival rate of 61%. Eleven patients had recurrent/persistent disease, of whom 8 died. Nonrelapse mortality was 34% at 5 years. Patients conditioned with targeted BU (plasma levels 800–900 ng/mL) plus cyclophosphamide (tBUCY) had a higher probability of survival (68%) than other patients. Dupriez score, platelet count, patient age, and comorbidity score were statistically significantly associated with mortality in univariate models. In a multivariable regression model, use of tBUCY ( P = .03), high platelet count at transplantation ( P = .01 for PV/ET; P = .39 for other diagnoses), younger patient age ( P = .04), and decreased comorbidity score ( P = .03) remained statistically significant for improved survival. Our findings show that hematopoietic cell transplantation offers potentially curative treatment for patients with ICMF, PV, or ET.

Umbilical-cord Blood Cell Transplantation Conditioned with a Reduced Intensity-regimen is a Practical Salvage Therapy for Severe Aplastic Anemia Refractory to Immunosuppressive Therapy with Antithymocyte Globulin/Ciclosporin

Immunosuppressive therapy and stem cell transplantation from an HLA-identical donor are the major effective treatments for severe aplastic anemia. However, treatments still need to be developed for patients who do not have a HLA-identical donor and have not shown a clinical response to immunosuppressive therapy. We herein report on 2 patients in whom this problem could be overcome by transplantation of HLA-mismatched umbilical cord blood from unrelated donors. Two Japanese patients with severe aplastic anemia underwent conditioning with fludarabine, cyclophosphamide, and low-dose total-body irradiation and then received transplants of umbilical cord blood. Engraftment of the three lineages occurred without problems. We conclude that umbilical cord blood transplantation with a reduced-intensity conditioning regimen of fludarabine, cyclophosphamide, and total-body irradiation for patients with aplastic anemia is a practical treatment and may be an attractive alternative for patients who does not have an HLA-identical donor and have shown no clinical response to immunosuppressive therapy.

Significance of additional high-dose cytarabine in combination with cyclophosphamide plus total body irradiation regimen for allogeneic stem cell transplantation

The combination of cyclophosphamide (CY) and total body irradiation (TBI) has been used as a standard conditioning regimen for allogeneic transplantation. Several studies showed an advantage of adding high-dose cytarabine (HDCA) to this regimen. To clarify the significance of additional HDCA, we conducted a retrospective multicenter study and compared the clinical results of these two regimens. From June 1985 to March 2003, 219 patients with hematological malignancies underwent allogeneic transplantation after conditioning with CY+TBI 12Gy (n=73) or CA+CY+TBI 12Gy (n=146). Engraftment, overall survival, transplant-related mortality (TRM), relapse rate and incidence of graft-versus-host disease (GVHD) were compared according to risks and donors. Addition of HDCA had no impact on the relapse rate in all subgroups, and it was associated with lower TRM among standard-risk patients after related transplantation, and with higher TRM and worse survival among standard-risk patients after unrelated transplantation. The incidence of acute GVHD was not significantly different between the two regimens, and HDCA resulted in a higher incidence of chronic GVHD among standard-risk patients after related transplantation. In summary, addition of HDCA is not beneficial for high-risk patients, and is not recommended for standard-risk patients receiving unrelated transplantation.

Clinical Efficacy and Feasibility of an Intensive Preparative Regimen with Busulfan, Cyclophosphamide, and Total Body Irradiation Followed by Allogeneic Stem Cell Transplantation for Patients with Myeloid Malignancies.

Purpose: High-intensity conditioning regimens before allogeneic stem cell transplantation (all-SCT) could reduce relapse but may increase nonrelapse mortality. We have investigated the efficacy and feasibility of an intensive preparative regimen of busulfan (BU), cyclophosphamide (CY), and total body irradiation (TBI) for patients with myeloid malignancies.Patients and methods: From November 1990 to February 2005, 80 patients (acute myeloid leukemia (AML) 33, chronic myeloid leukemia (CML) 29, myelodysplastic syndrome (MDS) 18) treated with BU (8 mg/kg), CY (120 mg/kg), and TBI (10 Gy) followed by related (n=46) or unrelated (n=34) allo-SCT. Thirty-eight consecutive patients with AML in 1st remission, CML in chronic phase, and MDS (refractory anemia) defined as a standard risk group, and 42 patients with advanced AML, CML, and MDS (more than 5% marrow blasts) defined as a poor risk group.RESULTS: With a median follow-up was 6.9 years, the 7-year actuarial overall survival (OS) rate was 58% (standard risk 70% vs poor risk 47%, p=0.0076), and the probability of 7-year relapse rate was 18% (standard risk 17% vs poor risk 18%, p=0.4777). Nonrelapse mortality was 29% (standard risk 26%, poor risk 31%). Multivariate analysis indicated that age older than 40 years (p=0.018) and received allo-SCT before 1998 (p=0.006) had independent predictive value for nonrelapse mortality.CONCLUSION: The BU- CY- TBI regimen resulted in decreased relapse, especially in poor risk patients. The results of this study suggested that the BU- CY- TBI is an effective and feasible preparative regimen for allo-SCT in patients with myeloid malignancies.

The Haploimmunostorm Syndrome: A Distinct Clinical Entity Seen in HLA-Haploidentical Cellular Immunotherapy.

An immune-mediated anti-tumor response is the ultimate goal of allogeneic transplantation for relapsed, refractory malignancies. We developed a transplant protocol with less toxicity compared with standard allogeneic transplantation. We utilize multiple donor lymphocyte infusions after nonmyeloablative HLA-haploidentical stem cell transplantation for refractory disease. We have performed a total of 41 HLA-mismatched transplants with escalation of the CD3+ dose to 2×108 cells/kg using G-CSF primed product, with a conditioning regimen of 100cGy total body irradiation. Our phase I/II study had 26 with hematologic malignancies. This therapy results in loss of detectable macrochimerism. Despite this, 13 responses, six major, occurred outside of macrochimerism. We have observed a new infusion related clinical entity named haploimmunostorm (HIS), observed after infusion. This syndrome occurred in 26 out of 30 (87%) patients with a CD3+ dose more than 1×108 cells/kg. In the syndrome, a constellation of symptoms occurred, some with variable penetrance, in which hyperpyrexia and malaise were a constant feature occurring as early as 4 hrs after cell infusion (median of 14 hrs). A morbilliform rash was seen in 40% of patients. Biopsies revealed no evidence of hyperacute or acute GVHD. Diarrhea was present in a 20% of patients; biopsies taken also failed to show any evidence of GVHD. Transient elevations of liver enzymes occurred in 40% of the patients usually. Steroids were used successfully if the HIS syndrome lasted more than 72 hrs. We used a Bioplex machine and analyzed 17-separate cytokine levels serially in these patients beginning with pre-treatment levels. Cytokine level analysis showed a cluster of cytokines that had up to a 1100 fold level increase compared with baseline pretreatment cytokine levels with significant increases of at least 10 fold in IFN-g, IL-10, IL-13, IL-2, IL-5, IL-6, IL-7, IL-8, MCP-1, and MIP-1b. This syndrome appears to be immunologically based and represents neither hyperacute nor acute GVHD. This syndrome is different than an engraftment syndrome reported in some patients undergoing autologous transplant with a different cluster of cytokine elevation (IL-6, IL-8, IL-10, IFN-g, MCP-1, MIP-1b) compared with (IL-1,IL-2, IL-8, TNFa, IFNg) for engraftment syndrome Engraftment syndrome occurs at time of engraftment, opposed to HIS in which may be a rejection syndrome. HIS deviates from engraftment syndrome with absence of noncardiogenic edema, pulmonary infiltrates, renal insufficiency weight gain and encephalopathy. The skin and intestinal biopsy results are distinctly different than GVHD or engraftment syndrome. The anti-tumor responses may be due to activation of host natural killer and T-cells with increases in MCP-1, MIP-1b and IL-6, essentially breaking host tumor tolerance. In summary, we have observed a new clinical entity that was not previously seen and is a result of the donors having a relatively intact immune system at the time of cell infusion.

Total Body Irradiation, Etoposide, Cyclophosphamide and Autologous Peripheral Blood Stem Cell Transplantation Followed by Randomization to Therapy with Interleukin-2 Versus Observation for Patients with Non-Hodgkin's Lymphoma: Results of a Phase III Randomized Trial by the Southwest Oncology Group (SWOG 9438).

Purpose: To determine the effect of post-transplant immunotherapy with Interleukin-2 (IL-2) on the progression-free and overall survival of patients with non-Hodgkin's lymphoma (NHL) after autologous stem cell transplantation and to assess the toxicity of post-transplant IL-2 therapy.Patients and Methods: Patients with previously treated low, intermediate, or high grade NHL (except Working Formulation Groups A and I) were treated with high-dose cyclophosphamide, etoposide, and total body irradiation (TBI) and an autologous peripheral blood stem cell transplant (PBSCT). Twenty-eight to 80 days after PBSCT, patients were randomized to treatment with IL-2 versus observation.Results: Between January 1995 and July 2004, three hundred ninety-four patients with low-grade (n=61) or intermediate-high grade NHL (n=315) were registered at one of 39 SWOG transplant centers. One hundred ninety patients did not proceed to randomization, because of patient refusal (44), grade V toxicity (30), disease progression (28), toxicity (28), or other reasons. Two hundred four patients were randomized to treatment with continuous infusion intravenous IL-2 (9 ×106 units/m2/day for four days followed five days later by 1.6 ×106 units/m2/day for 10 days) versus observation. The 4-year progression-free survival estimate for all eligible patients is 34%, and the 4-year overall survival estimate is 52%. There was no difference in progression-free survival (hazard ratio (HR) of IL-2 to observation = 0.90; p = 0.56) nor in overall survival (HR of IL-2 to observation = 0.88; p = 0.55). There were no deaths related to IL-2 treatment. Grade IV IL-2-related toxicities included hematologic (n=10), cardiovascular (4), renal/bladder (2), flu-like symptoms (1), lung (1), metabolic (1), and neurologic (1) and were reversible in all cases.Conclusions: These results confirm earlier SWOG findings that a regimen of cylophosphamide, etoposide and TBI followed by PBSCT can be administered to patients with relapsed or refractory NHL with acceptable toxicity and with encouraging progression-free and overall survival. Post-transplant therapy with IL-2 given at this dose and schedule of administration had no significant effect on post-transplant relapse, progression-free survival or overall survival.

Biologically Effective Dose in Total-Body Irradiation and Hematopoietic Stem Cell Transplantation

Total-body irradiation (TBI) is an important part of the conditioning regimen for hematopoietic stem cell transplantation (HSCT) in patients with hematologic malignancies. The results after treatment with various TBI regimens were compared, and dose-effect relationships for the endpoints relapse incidence, disease-free survival, treatment-related mortality, and overall survival were derived. The aim was to define requirements for an optimal treatment schedule with respect to leukemic cell kill and late normal-tissue morbidity. A literature search was performed. Three randomized studies, four studies comparing results of two or three TBI regimens, and nine reports with results of one specific TBI regimen were identified. Biologically effective doses (BEDs) were calculated. The results of the randomized studies and the studies comparing results of two or three TBI regimens were pooled, and the pooled relative risk (RR) was calculated for the treatments with high BED values versus treatments with a low BED. BED-effect relationships were obtained. RRs for the high BED treatments were significantly lower for relapse incidence, not significantly different for disease- free survival and treatment-related mortality, and significantly higher for overall survival. BED-effect relationships indicate a decrease in relapse incidence and treatment-related mortality and an increase in disease-free and overall survival with higher BED values. "More dose is better", provided that a TBI setting is used limiting the BEDs of lungs, kidneys, and eye lenses.

Autologous hematopoietic stem cell transplants that utilize total body irradiation can safely be carried out entirely on an outpatient basis

Outpatient hematopoietic stem cell transplants (HSCT) are usually performed in patients receiving minimally mucotoxic preparative regimens; total body irradiation (TBI)-based regimens typically are excluded. To improve resource utilization and patient satisfaction, we developed a totally outpatient HSCT program for TBI regimens and compared outcomes for our first 100 such transplants to 32 performed as in-patients during the same interval, for caregiver or financial reasons. Symptoms were managed predominately with oral agents; pain management consisted of transdermal fentanyl and oral morphine solution. Except for more unmarried in-patients, the two groups were matched. Time to engraftment, severity of mucositis and transplant duration were identical for the two groups. Twenty-seven of the outpatients were admitted (median-6 days), primarily for progressing infection. Thus 92% of all transplant days were outpatient. There were no septic episodes or hospital admissions for pain management. There were no deaths to day 30 in either group and 100-day survival was identical. There was a mean cost savings of Dollars 16,000 per outpatient transplant and outpatient patient/caregiver quality of life was similar to that reported for in-patients. Patients undergoing severely mucotoxic regimens can be safely transplanted in an outpatient setting with a significant cost saving, with no increase in morbidity or mortality.

Autologous hematopoietic stem cell transplantation for progressive multiple sclerosis: report of efficacy and safety at three yr of follow up in 21 patients

To observe the efficacy and toxicity of autologous hematopoietic stem cell transplantation (HSCT) in progressive multiple sclerosis (PMS). Twenty-one patients with PMS were treated with autologous HSCT. Stem cells were mobilized with cyclophosphamide (CY) and granulocyte colony-stimulating factor. After conditioning regimen of CY and total body irradiation or BEAM, stem cells were reinfused. CD34+ cell selection of the graft was performed and anti-thymocyte globulin was given for T-cell depletion. The probabilities of confirmed progression-free survival and disease activity-free survival were used to assess the efficacy and the adverse experiences were recorded to detect the toxicities. The median follow-up time was 42 (6-65) months. The probabilities of confirmed progression-free survival and the disease activity-free survival were 75% and 33.3%, respectively. The principal adverse events included allergy, infection, elevation of liver enzymes, transient neurologic deterioration and depression. Two patients died of severe pneumonia and varicella-zoster virus hepatitis, at 4.5 and 15 months post-transplant, respectively. Autologous HSCT seems beneficial to PMS. However, more patients and longer follow up would be required to assess the risk/benefit ratio.

Long-Term Remissions in Patients with Myelodysplastic Syndrome and Secondary Acute Myelogenous Leukemia Undergoing Allogeneic Transplantation Following a Reduced Intensity Conditioning Regimen of 550 cGy Total Body Irradiation and Cyclophosphamide

We analyzed outcomes of patients with myelodysplastic syndrome (MDS) or secondary acute myelogenous leukemia (sAML) that were treated at our institution with a reduced intensity conditioning (RIC) regimen of 550-cGy total body irradiation and cyclophosphamide followed by related donor (RD) or unrelated donor (URD) transplantation. Fifty-one consecutive patients with MDS or sAML received this RIC regimen and URD (n = 30) or RD (n = 21) stem cells. Graft-versus-host disease prophylaxis consisted of cyclosporine alone (RD) or with corticosteroids and methotrexate (URD). Median patient age was 44 years. With a median follow-up of 3.7 years after transplantation in the 19 surviving patients (37%), Kaplan-Meier estimates of overall survival were 88%, 46%, 33%, and 11% for patients transplanted with sAML in remission, refractory anemia, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, or sAML refractory/untreated, respectively. Kaplan-Meier estimates of relapse-free survival were 75%, 46%, 33%, and 11%, respectively. Overall, the cumulative incidences of relapse and transplant-related mortality were 27% and 37%, respectively. In patients with MDS, this is an effective RIC regimen for allogeneic transplantation that can be used as an alternative to other RIC or conventional conditioning regimens.

Total body irradiation, fludarabine, melphalan, and allogeneic hematopoietic stem cell transplantation for advanced pediatric hematologic malignancies

We evaluated the efficacy and toxicity of adding 9 Gy of total body irradiation (TBI), in three single daily fractions of 3 Gy, to the reduced intensity regimen of fludarabine 30 mg/m2 i.v. x 4 days and melphalan 140 mg/m2 i.v. x 1 day in advanced pediatric hematologic malignancies. Twenty-two acute lymphoblastic leukemia (ALL), six acute myeloid leukemia (AML), and one non-Hodgkin lymphoma patients were transplanted. Of these, 13 were beyond second remission, and five had prior hematopoietic stem cell transplant (HSCT). Twenty-one donors were unrelated, of which 19 were from cord blood (CB) units. Three of the eight related donors were genotypically disparate. Oral mucositis and diarrhea were the most common toxicities. Twenty-seven patients achieved neutrophil engraftment (median 16 days), and 23 had platelet engraftment (median 42 days). One patient had primary graft failure. Seven patients died of non-relapse causes in the first 100 days. With a median follow-up of 52 months, seven of 22 ALL, five of six AML, and one of one lymphoma patients are alive and in remission. The regimen of TBI, fludarabine, and melphalan allows the engraftment of allogeneic hematopoietic stem cells (including mismatched CB). It was fairly well tolerated in pediatric patients, even for second transplants. Its efficacy requires further evaluation.

Impact of TBI on late effects in children treated by megatherapy for Stage IV neuroblastoma. A study of the French Society of Pediatric oncology

To determine the contribution of total body irradiation (TBI) to late sequelae in children treated with high-dose chemotherapy and autologous bone marrow transplantation for Stage IV neuroblastoma. We compared two populations that were similar with regard to age, stage, pre-autologous bone marrow transplantation chemotherapy (CT) regimen, period of treatment, and follow-up (12 years). The TBI group (n = 32) received TBI as part of the megatherapy procedure (1982-1993), whereas the CT group (n = 30) received conditioning without TBI (1985-1992). Analysis 12 years later focused on growth, weight and corpulence (body mass index) delay; hormonal deficiencies; liver, kidney, heart, ear, eye, and dental sequelae; school performance; and the incidence of secondary tumors. Impact of TBI was most marked in relation to growth and weight delay, although the mean delay was not severe, probably because of treatment with growth hormones. Other consequences of TBI were thyroid insufficiency, cataracts, and a high incidence of secondary tumors. Hearing loss and dental agenesis were more prominent in the group treated with CT alone. No differences were observed in school performance. The most frequent side effects of TBI were cataracts, thyroid insufficiency, and growth delay, but more worrying is the risk of secondary tumors. Because of the young mean age of patients and the toxicity of TBI regimens without any survival advantage, regimens without TBI are preferable in the management of Stage IV neuroblastoma.

Reduced-Intensity Conditioning Followed by Unrelated Umbilical Cord Blood Transplantation for Advanced Hematologic Malignancies: Rapid Engraftment in Bone Marrow

Reduced-intensity (RI) conditioning followed by cord blood transplantation (CBT) is a new treatment modality, but failure to engraft is a major concern. We describe 12 patients with advanced hematologic malignancies who underwent RI conditioning and CBT with a conditioning regimen consisting of 200 mg/m(2) fludarabine (Flu), 50 mg/kg cyclophosphamide (CY), and 3 Gy total body irradiation (TBI). Cyclosporin A and/or methotrexate were used for graft-versus-host disease prophylaxis. Cord blood grafts were not mismatched for more than 2 serologically defined HLA alleles but were later found by high-resolution DNA typing to be mismatched for 2 to 4 alleles in most cases. Short tandem repeat analysis of bone marrow cells at day 14 showed complete donor chimerism in 6 of the patients and mixed chimerism in 5, indicating rapid engraftment in the bone marrow, whereas the remaining patient experienced graft rejection. Neutrophil recovery was achieved at a median of day 17 (range, days 11-24) in 10 of the 11 patients with marrow chimerism at day 14. Of these 10 patients, however, transplantation-related mortality within 100 days occurred in 4 patients who showed failed platelet recovery and a lack of durable engraftment. Overall survival and disease-free survival rates were 41.7% and 33.3%, respectively. These results show that CB mismatched at 2 to 4 HLA alleles and transplanted with the Flu/CY/3 Gy TBI regimen is able to engraft in the bone marrow as early as day 14.

The Impact of Rituximab in the Development of Acute Graft Versus Host Disease (GVHD) Following Allogeneic Stem Cell Transplantation (SCT) for Acute Lymphoblastic Leukemia (ALL).

We investigated the safety and efficacy of administering rituximab in combination with a standard myeloablative conditioning regimen of cyclophosphamide (Cy, 60 mg/kg daily x 2 doses) and total body irradiation (TBI, 12 Gy in four daily fractions) with allogeneic SCT in adult patients (pts) with ALL. Pts were eligible if their disease expressed CD20 in >20% blasts by flow cytometry. Rituximab was administered at 375 mg/m2 on days 6, −1, +7 and +14 following stem cell infusion. 24 pts were entered on study. The results were retrospectively compared with those of a historical control group of 31 pts receiving the same preparative regimen without rituximab. The two treatment groups had similar numbers of matched sibling and unrelated donor grafts. Pt and donor characteristics are detailed in Table 1. GVHD prophylaxis consisted of tacrolimus and methotrexate for nearly all pts in both study and control groups; 4 pts in the control group and 1 pt in the study group received pentostatin in addition to tacrolimus and methotrexate. Preliminary data suggests that pentostatin reduces the incidence of acute GVHD (de Lima et al. Blood 2004; 104:727a). The cumulative incidence of non-relapse mortality (NRM) at 2 years was 18% for the study group and 33% for the controls. There was no delay in engraftment or increased incidence of infection in pts treated with rituximab. Despite the greater use of pentostatin in the control group, the incidence of grade II–IV acute GVHD tended to be lower in pts treated with rituximab as compared to controls: 17% vs. 39%, p=0.07. The incidence of chronic extensive GVHD was not significantly different between the two groups: 37% vs. 34%, p=0.7. OS at 2 years was 45% for the study group and 38% for the controls, p=0.5. PFS at 2 years was 31% for the study group and 38% for the control group, p=0.8. Treatment outcomes are summarized in Table 1. In conclusion, our results demonstrate that the addition of rituximab to standard Cy/TBI conditioning for allogeneic SCT in ALL is associated with a relatively low rate of acute GVHD and NRM. Differences in pt characteristics preclude direct comparison. However, there is no apparent benefit for the addition of rituximab on disease relapse.Table 1Patient, Donor Characteristics, and OutcomesCy/TBI/rituximab No. ptsCy/TBI No. ptsP-valueTotal Pts2431Median Recipient Age, yrs (range30 (18–54)35 (18–53)Median Pt Age, yrs (range)138 (15–53)36 (14–54)Donor Type (%)Matched related15 (62)21 (68)Matched unrelated9 (38)10 (32)0.7Stem Cell Source (%)BM9 (38)17 (55)PB15 (62)14 (45)0.2Sex donor/pt mismatch (%)8 (33)12 (40)0.7CMV donor/pt mismatch (%)10 (43)12 (40)0.8ABO donor/pt mismatch (%)14 (58)10 (33)0.05Graft Composition, median (range)Total nucleated cells (x108/kg)4 (1–14)4 (1–9)0.6CD34+(x106/kg)5 (1–9)5 (2–8)0.9CD3+ (x106/kg)110 (8–370)37 (5–286)0.2Disease Status at SCT (%)CR16 (25)17 (54)Remission, beyond CR113 (54)7 (23)Not in Remission5 (21)7 (23)0.03Acute GVHD II–IV17%39%0.07Chronic Extensive GVHD37%34%0.7OS, 2 yrs45%37%0.5PFS, 2 yrs31%38%0.81. Donor age missing for 1 pt in each treatment group.

Very High Hospital Admission Rate after Outpatient Non-Myeloablative Allogeneic Stem Cell Transplant Using Fludarabine and Low Dose TBI.

One of the theoretic advantages of non-myeloablative (“mini”) preparative regimens such as fludarabine and low dose total body irradiation (TBI) is that the transplant can be performed as an outpatient. Data is surprisingly sparse concerning the later hospital admission rate of such transplanted patients. We transplanted 71 patients from 1/1/00 to 6/15/05 using a “mini” preparative regimen of fludarabine and TBI (200cGy, n=53, 400cGy, n=18) and examined the rates of admission after transplant. All transplants and preparative regimens were delivered as an outpatient. The admission rate was similar between those receiving 200cGy and 400cGy, and the two groups were combined for this analysis. Median patient age was 52 (range, 15–65). Diagnoses included NHL (n=16 [23%]), AML (n=13, [18%]), myeloma (n=7, [10%)]), CML (n=7, [10%]), MDS (n=7, [10%], myelofibrosis (n=6, [8%]), CLL (n=4, [6%]), other (n=11, [15%]). Approximately 40% had resistant or untreated disease at transplant. 63 of 71 patients (89%) were admitted within 1 year of their original transplant. Rates of admissions were similar for related donor transplants (41/47, 33%) and unrelated donor transplants (22/24, 92%). Of 63 patients admitted to the hospital after their outpatient transplant, 52 (83%) were admitted within 3 months of the transplant. The most common reason for admission was fever (n=30, [58%]). Four patients were admitted for cardiac events (chest pain, tachycardia, possible MI and atrial fibrillation) and 7 patients were admitted for acute graft vs host disease. Of the 30 patients with fever at the time of transplant, the absolute neutrophil count was 0.94 k/μL (range, 0–16.49), and 9 had an absolute neutrophil count <500 k/μL. 11 patients were admitted to the hospital between 3 and 12 months after their initial transplant, most commonly because of either acute graft vs host disease or infection. The median number of all post-transplant hospitalizations for matched related transplants was 2 (range, 0–8) and for matched unrelated transplants was 3 (range, 0–11). The median time from transplant to the first admission to the hospital was Day +22 for matched related transplants, and Day +6 for matched unrelated transplants. Median length of stay for the admissions was 6 days for the entire group. 32/71 (45%) of patients were admitted to the hospital at least 3 or more times within 18 months of their original transplant. Patients admitted to the hospital 0 or 1 time had a superior survival than those admitted 2 or more times, (overall survival 54% vs 24%, p value = 0.022) In conclusion, while the delivery of a “mini” transplant preparative regimen and the infusion of hematopoietic stem cells may safely be given as an outpatient, our experience suggests that the vast majority of patients have at least one hospital admission for various complications within 3 months of the transplant. This data does not support the concept that non-myeloablative allogeneic transplants can be performed as an outpatient in their entirety.