Conditioning Regimen For Patients Research Articles

Post-transplantation cyclophosphamide for GVHD prophylaxis in severe aplastic anemia

Post-transplantation cyclophosphamide for GVHD prophylaxis in severe aplastic anemia

Retrospective analysis of treosulfan-based conditioning in comparison with standard conditioning in patients with myelodysplastic syndrome

Myelodysplastic syndromes (MDSs) often occur in older adults with significant comorbidities. Therefore, a reduced-toxicity conditioning regimen may be more suitable than standard conditioning regimens before allogeneic blood stem cell transplantation. Here, we retrospectively compare the outcome of a treosulfan-based conditioning regimen with standard myeloablative TBI-based conditioning regimens in patients (pts) with MDS. A total of 48 pts with MDS were included in the study, of which 29 (60%) pts received TBI-based and 19 (40%) pts received a treosulfan-based conditioning regimen. A significantly lower relapse incidence (5% vs 34% at 3 years, P=0.019) resulting in a better, but not statistically significant relapse-free survival (RFS) (57% vs 31%, P=0.086) was observed after treosulfan-based conditioning. In pts with increased risk for significant side effects due to comorbidities (haematopoietic stem cell transplantation specific comorbidity index), the estimated 3-year RFS was significantly better in the treosulfan group: 54% (95% confidence interval (CI), 17-90%) compared with pts in the TBI group: 11% (95% CI, 0-44%; log-rank test P=0.0455). Treosulfan-based conditioning therapy is a feasible and effective regimen for pts with MDS, especially in pts with preexisting comorbidities.

Conditioning with Treosulfan and Fludarabine followed by Allogeneic Hematopoietic Cell Transplantation for High-Risk Hematologic Malignancies

In this prospective study 60 patients of median age 46 (range: 5-60 years), with acute myelogenous leukemia (AML; n= 44), acute lymphoblastic leukemia (ALL; n = 3), or myelodysplastic syndrome (MDS; n = 13) were conditioned for allogeneic hematopoietic cell transplantation with a treosulfan/fludarabine (Flu) combination. Most patients were considered at high risk for relapse or nonrelapse mortality (NRM). Patients received intravenous treosulfan, 12 g/m(2)/day (n = 5) or 14 g/m(2)/day (n = 55) on days -6 to -4, and Flu (30 mg/m(2)/day) on days -6 to -2, followed by infusion of marrow (n = 7) or peripheral blood stem cells (n = 53) from HLA-identical siblings (n = 30) or unrelated donors (n = 30). All patients engrafted. NRM was 5% at day 100, and 8% at 2 years. With a median follow-up of 22 months, the 2-year relapse-free survival (RFS) for all patients was 58% and 88% for patients without high-risk cytogenetics. The 2-year cumulative incidence of relapse was 33% (15% for patients with MDS, 34% for AML in first remission, 50% for AML or ALL beyond first remission and 63% for AML in refractory relapse). Thus, a treosulfan/Flu regimen was well tolerated and yielded encouraging survival and disease control with minimal NRM. Further trials are warranted to compare treosulfan/Flu to other widely used regimens, and to study the impact of using this regimen in more narrowly defined groups of patients.

A Phase II study of 153Sm‐EDTMP and high‐dose melphalan as a peripheral blood stem cell conditioning regimen in patients with multiple myeloma

Multiple myeloma (MM) remains an incurable illness affecting nearly 20,000 individuals in the United States per year. High-dose melphalan (HDM) with autologous hematopoietic stem cell support (ASCT) is one of the mainstays of therapy for younger patients, but little advancement has been made with regards to conditioning regimens. We opted to combine (153)Samarium ethylenediaminetetramethylenephosphonate ((153)Sm-EDTMP), a radiopharmaceutical approved for the palliation of pain caused by metastatic bone lesions, with HDM and ASCT in a Phase II study. Individualized doses of (153)Sm were based on dosimetry and were calculated to deliver 40 Gy to the bone marrow. The therapeutic dose of (153)Sm-EDTMP was followed by HDM and ASCT. Forty-six patients with newly diagnosed or relapsed disease were treated. Study patients were compared to 102 patients contemporaneously treated with HDM and ASCT. Fifty-nine percent of study patients achieved a very good partial response (VGPR) or better. With a median follow-up of 7.1 years, the median overall survival and progression free survival (PFS) from study registration was 6.2 years (95% CI 4.6-7.5 years) and 1.5 years (1.1-2.2 years), respectively, which compared favorably to contemporaneously treated non-study patients. Addition of high-dose (153)Sm-EDTMP to melphalan conditioning appears to be safe, well tolerated, and worthy of further study in the context of novel agents and in the Phase III setting.

Second Allogeneic Hematopoietic Stem-Cell Transplantation Using Fludarabine Treosulfan Conditioning Regimen in Patients Previously Treated with Busulfan-Based Regimens; Myeloablation with Acceptable Toxicity.

Abstract 2255Poster Board II-232The prognosis of patients (pts) with leukemia who relapse after a prior autologous and or allogeneic hematopoietic stem cell transplantation (SCT) is dismal. A second allogeneic SCT can salvage some of these pts but myeloablative conditioning is associated with high rates of non-relapse mortality (NRM) in this setting and a relatively poor outcome. Reduced intensity conditioning allows reduction of NRM following a second SCT, but may be associated with a high relapse rate, mostly when leukemia is not in remission at the time of SCT. Similarly, allogeneic SCT for pts who develop secondary leukemia after a prior autologous SCT for a primary malignancy is associated with similar risks. The combination of fludarabine and treosulfan (FT) has been previously reported as a dose intensive myeloablative regimen with reduced toxicity and effective anti-leukemia capability, but its merit in second SCT is not defined. We explored a regimen consisting of fludarabine (total 150 mg/m2) and treosulfan (total 30-36 gr/m2) with the addition of ATG to recipients of unrelated or mismatched donor SCT, as a conditioning regimen for a second SCT. The study included 17 pts, 10 male, 7 female, median age 58 years (range, 20-70). Patient diagnosis at second SCT was AML (n=11), MDS (n=3), myelofibrosis (n=2) and CML in accelerated phase (n=1). The first transplant was autologous (n=6) or allogeneic (n=11). Autologous SCT was given for AML (n=3, 1 of them APL) or for a primary malignancy (lymphoma - 2, multiple myeloma -1). Second allogeneic SCT was given for relapse after a prior SCT or for secondary AML/MDS in the 3 pts having autologous SCT for lymphoma and myeloma. The Donor for the second SCT was an HLA-match sibling (n=6) or matched unrelated (n=11). In the 11 pts having a second allogeneic SCT after failure of a first allogeneic SCT the donor was the same donor in 3 transplants and a different donor in 8 transplants. The conditioning regimen for the first SCT contained high-dose intravenous busulfan (12.8 mg/kg) in 9 pts and reduced dose busulfan (6.4-9.6 mg/kg) in 5 pts. The three pts with primary lymphoma and myeloma were given BEAM and high-dose melphalan, respectively. The median time between the first and second SCT was 28 months (range, 3-48 months). Only 4 pts were in remission at the time of second SCT. Six pts were chemo-refractory and 7 pts were transplanted in untreated malignancy. Results:12 pts engrafted with a median time to ANC > 0.5 × 109/L of 12 days (range, 9-38) and for PLT > 20 × 109 of 15 days (range, 11-44). Five pts died prior to engraftment, 3 of infections, 1 of cerebral hemorrhage and 1 of graft failure. There were no deaths related to organ toxicity (e.g. VOD or pneumonitis) and no late deaths due to NRM. Acute GVHD grade II-IV occurred in 2 pts, cumulative incidence 28%. Chronic GVHD occurred in 4 of 8 evaluable pts, cumulative incidence 57%. There were no deaths attributed to acute or chronic GVHD. The cumulative incidence of NRM was 30% (95%CI, 14-62). Three pts relapsed with a cumulative incidence of 25% (95%CI, 9-69). In all, with a median follow-up of 12 months (range, 1-59 months) the estimated 2-year overall and disease-free survival were both 45% (95CI, 17-73). Best results were achieved in the group of 8 pts having a second SCT form a second allogeneic donor; 5 pts are currently disease-free for a median of 18 months (range, 3-38), despite transplantation in advanced phase; 3 refractory to salvage chemotherapy and one in untreated relapse after the first SCT. The estimated 2 year survival in this group was 60%, a promising outcome in this setting. In conclusion, the fludarabine-treosulfan regimen is feasible for a second allogeneic SCT. NRM especially in the early post-transplant period is substantial, but can be expected in a group of heavily pretreated pts, many with active and refractory leukemia. The regimen has a promising anti-leukemia effect in this setting with a low recurrence rate, especially when using a different donor than in the prior transplant. The FT regimen can be considered a reduced toxicity myeloablative regimen that is feasible in pts given a prior transplant including pts previously given myeloablative doses of busulfan. Disclosures:No relevant conflicts of interest to declare.

Cord blood transplantation with a reduced-intensity conditioning regimen for patients with relapsed aggressive multiple myeloma after cytoreduction with bortezomib

Two multiple myeloma patients relapsed after autologous stem cell transplantation (ASCT). Conventional chemotherapy, including thalidomide, showed very little effect, but both patients responded well to a standard dose of bortezomib. One patient was treated with two additional cycles of bortezomib, but his clinical course suddenly deteriorated. Unrelated cord blood transplantation (CBT) with reduced-intensity conditioning regimen (RIC) was performed in refractory disease. After CBT, the clinical course was aggravated by tumor lysis syndrome and other conditions, thus resulting in patient death on day 34. Thereafter, we administered CBT with RIC on the second patient after just one course of bortezomib therapy since she was in partial remission. The second patient developed acute and chronic GVHD, and both responded to the steroid therapy. She has been in complete remission for more than 48 months after CBT. These results suggested that the timing of CBT with RIC may be very important, and cytoreduction with not only ASCT but also bortezomib could give a promising chance for a successful CBT.

Radioimmunotherapy: Strategies for the future in indolent and aggressive lymphoma

The conjugation of radioisotopes to monoclonal antibodies, or radioimmunotherapy (RIT), is a highly active treatment in non-Hodgkin's lymphoma. RIT has demonstrated high response rates and durable remissions in extensively pretreated patients and has proved highly effective as consolidation after induction chemotherapy in the first-line therapy of follicular lymphoma. Early-phase clinical trials have shown highly promising results using RIT as part of conditioning regimens in patients who are to undergo transplantation and as consolidation after chemotherapy in patients with aggressive lymphomas. Recent data suggest that integrating RIT with immunochemotherapy and transplant conditioning regimens may further improve outcomes for patients.

Brazilian experience with two conditioning regimens in patients with multiple sclerosis: BEAM/horse ATG and CY/rabbit ATG

Studies have shown that autologous hematopoietic SCT (HSCT) can be used as an intensive immunosuppressive therapy to treat refractory patients and to prevent the progression of multiple sclerosis (MS). This is a prospective multicentric Brazilian MS trial comparing two conditioning regimens: BEAM/horse ATG and CY/rabbit ATG. Most (80.4%) of the 41 subjects in the study had the secondary progressive MS subtype and the mean age was 42 years. The baseline EDSS score in 58.5% of the subjects was 6.5 and 78% had a score of 6.0 or higher, respectively. The complication rate during the intra-transplantation period was 56% for all patients: 71.4% of the patients in the BEAM/hATG group and 40% in the CY/rATG group (P=0.04). Three subjects (7.5%) died of cardiac toxicity, sepsis and alveolar hemorrhage, all of them in the BEAM/ATG group. EFS was 58.54% for all patients: 47% in the BEAM/hATG group and 70% in the CY/rATG group (P=0.288). In conclusion, the CY/rATG regimen seems to be associated with similar outcome results, but presented less toxicity when compared with the BEAM/hATG regimen. Long-term follow-up would be required to fully assess the differences in therapeutic effectiveness between the two regimens.

Single daily dose of intravenous busulfan and melphalan as a conditioning regimen for patients with multiple myeloma undergoing autologous stem cell transplantation: a phase II trial

We evaluated the toxicity and outcome of a conditioning regimen comprising intravenous (iv) busulfan (BU) and melphalan (MEL) in 55 patients (median age, 61 years; range, 34–71) with multiple myeloma (MM) undergoing autologous stem-cell transplantation (ASCT). In 49 patients, this was the first ASCT. At transplant, 3 patients were in complete response (CR), 8 in near CR (nCR) and 30 in partial response (PR). The conditioning regimen comprised ivBU (3.2 mg/kg in a single daily dose, days −5 to −3) and MEL (140 mg/m2, day −2). Mucositis was the most frequent non-hematopoietic toxicity (47 patients). No patient developed sinusoidal occlusive syndrome. Febrile events were observed in 46 patients and were the cause of death in two (3.6%) transplant-related deaths. With a median follow-up of 15 months, 27 patients achieved CR/nCR (11 CR) and 21 a PR. The one-year actuarial overall and progression-free survival rates are 96% and 87%, respectively. This ivBU-containing regimen is associated with an acceptable toxicity and a high-response rate.

Cord blood transplantation using minimum conditioning regimens for patients with hematologic malignancies complicated by severe infections

Patients with severe infections are thought to be ineligible for cord blood stem cell transplantation (CBT) because the conventional 5-6 day-conditioning regimens potentially makes them susceptible to fatal infections by the time neutrophil engraftment occurs. Two patients were treated with minimum conditioning regimens consisting of 30 mg/m(2) fludarabin (Flu) and 2 g/m(2) cyclophosphamide (CY) on day-1 and total body irradiation (TBI) of 2 or 4 Gy on day -1 or 0 followed by single unit CBT. The reasons for adopting such weak regimen were febrile neutropenia due to the rejection of the first cord blood (CB) graft given to a patient with follicular lymphoma resistant to chemotherapy and pulmonary aspergillosis in another patient with AML who relapsed after CBT. The AML patient received 40 mg/m(2) of melphalan on day-2 to reduce the leukemia burden. Both patients achieved 100% donor chimerism by day 19 and day 20 after CBT without an apparent exacerbation of the infections and remained in remission at 23 and 18 months after the CBT. These findings suggest that the 1-2 day regimens excluding antihuman thymocyte globulin may be sufficiently potent to ensure engraftment of CB in immunocompromised patients and safely administered even when patients are complicated by active infections.

Reduced Intensity Conditioning with Thiotepa and Fludarabine for Allogeneic Transplantation: Evidence for Low Toxicity and Long-Lasting Disease Control in MDS with Low/Intermediate-1 IPSS Score and in AML from MDS in Complete Remission.

This study investigated Thiotepa (TT) and Fludarabine (Fluda) as a preparative regimen for allogeneic peripheral stem cell transplantation in patients with myelodysplastic syndrome (MDS) or acute leukemia from MDS (MDS-AML) older than 50 or with comorbidities contraindicating standard conditioning. Patients were prepared with TT, given over 3 hours as an i.v. infusion at a dose of 10 mg/kg over two days (day -8 and day -7) and Fluda at the dose of 125 mg/m2 i.v. over five days ( from day -7 to day -3). Fresh or cryopreserved allogeneic peripheral stem cells were infused on day 0 or +1. Graft-versus-Host Disease (GvHD) prophylaxis consisted of cyclosporine A (CyA) at the dose of 1.5 mg/kg day as a continuous iv infusion from day -5 until engraftment. The CyA was then administered orally at the dose of 3 mg/kg twice a day. Doses were adjusted to maintain plasma level concentrations between 150–350 mg/dL. From day +60, in the absence of acute GvHD, the CyA was tapered down by 20% every 2 weeks until withdrawal. In addition, patients received methotrexate 10 mg/m2 on day +1, and 8 mg/m2 on days + 3, +6 and +11 after transplantation. At the time of transplantation, patients were classified in two risk groups (low vs high risk) according to IPSS score (low/intermediate-1 vs. intermediate-2/high) for MDS patients, and disease status (CR vs. not CR) for MDS-AML. Kaplan-Meier survival analysis was carried out to compare Overall Survival (OS), Transplant-Related Mortality (TRM) and probability of relapse. Fifty patients (29 males, 21 females) entered the study; the median age was 54 years (range 38–71). Sixteen MDS patients had a low/intermediate 1 score according to the International Prognostic Score System (IPSS), 16 had an intermediate 2/high IPSS score, 18 had MDS-AML. Thirty patients underwent transplantation as front-line therapy, 20 received one or more cycles of chemotherapy before transplant. Among the latter, nine with MDS-AML were in complete remission at the time of their transplant, while four were in a partial remission. The interval from diagnosis to transplantation ranged from 1 to 52 months (median value 11 months). Contraindications to a standard conditioning regimen were liver disease, hypertrophic cardiomyopathy secondary to hypertension or valvular stenosis, cardiac arrhythmia, diabetes mellitus, hypothyroidism, previous CNS bleeding, and a history of sepsis. All but one patient achieved engraftment, with full donor chimerism by day +30. Patients were followed up for a median time of 21 months (range 0.2–87). TRM at 1 and 2 years after transplantation was 25% and 33%; the 5-year probability of relapse was 27%. Twenty-six patients are alive in complete remission, and the 5-year OS is 50%. The 5-year OS was 73% and 28% in low- and high-risk patients respectively (p=0.002). TRM at 1 and 2 years after transplantation was 13% and 21% in the low-risk group and 39% and 45% in the high-risk group (p=0.046); the 5-year probability of relapse was 10% and 50% in the low- and high-risk group respectively (p=0.015). In a multivariate Cox regression, risk group retained a borderline significance (HR=2.6, p=0.07) when adjusted by age at transplantation (p=0.03) and interval from diagnosis to transplant (n.s.). The combination of Thiotepa and Fludarabine is an effective and well-tolerated conditioning regimen in patients with MDS or MDS-AML who are poor candidates for standard myeloablative transplantation, particularly in MDS patients with low/intermediate-1 IPSS score and MDS-AML patients in CR.

Incorporating targeted therapy into conditioning regimen for patients undergoing autologous stem cell transplant (ASCT) for aggressive CD20 positive B-cell lymphoma has altered the natural history of the disease: A multivariate analysis of the prognostic factors

19510 Background: ASCT has been typically used for patients with relapsed aggressive non-hodgkin lymphoma(NHL) with most treatment failures occuring within 1 to 2 years of transplant. We hypothesiz...

Reduced Cyclophosphamide Combined with Etoposide and Total Body Irradiation as a Conditioning Regimen for Patients with Impaired Cardiac Function Undergoing Allogeneic Stem Cell Transplantation.

Cardiac toxicity due to conditioning regimens is a critical problem in the hematopoietic stem cell transplantation (HSCT). High-dose cyclophosphamide, which is a major component of conventional myeloablative regimens, is considered to be a main cause of cardiac toxicity. Although reduced intensity conditioning regimens have been developed in order to diminish regimen related toxicities for patients with pre-transplant co-morbidity, their anti-neoplastic effects have been revealed to be insufficient especially for patients with acute lymphoblastic leukemia. Therefore, it is imperative to establish an alternative preparative regimen with myeloablative intensity for patients with impaired pre-transplant cardiac function. From June 1995 at the University of Tokyo, we have adopted a heart protective regimen (VP/rCY/TBI) which is composed of continuous infusion of VP-16 20 mg/kg for 2 days, CY 40 mg/kg for 1 day, and 12 Gy of fractionated total body irradiation (TBI) for 17 patients because they had impaired cardiac function defined by ejection fraction (EF) less than 0.55 (n=15) or a history of congestive heart failure (n=1) or pulmonary hypertension (n=1). The clinical relevance of VP/rCY/TBI regimen was evaluated by retrospectively comparing the outcome of VP/rCY/TBI recipients with that of conventional CY/TBI (CY 60 mg/kg for 2 days + fractionated TBI 12 Gy, which was administered to 140 patients during the same period) recipients. The characteristics analysis revealed that VP/rCY/TBI recipients had higher cumulative doses of anthracyclines (354 mg/m2 vs 150 mg/m2 calculated as the equivalence of native doxorubicin, p<0.0001), lower EF (0.51 vs 0.66, p=0.005), larger left ventricular end-systolic dimension (LVDs) (35 mm vs 30 mm, p<0.0001), and worse Karnofsky performance scales (KPS) (90 vs 100, p=0.0037) than CY/TBI recipients. There was no difference in the other characteristics between the two groups, including age, disease status, ferritin level, and the other UCG findings. The median follow up period for surviving patients was 43.9 months after transplantation (range: 4–146 months). Survival analysis was conducted considering non-relapse mortality (NRM) and relapse rates as competing risk factors of each other. The relapse rate was not significantly different between the two groups (p=0.24), which indicates that VP/rCY/TBI regimen has a comparable anti-tumor effect to standard CY/TBI regimen. In addition, despite poorer KPS and more cardiac co-morbidity in the VP/rCY/TBI arm, no difference in the NRM rates was observed between the two groups. Especially, it is noteworthy that Bearman grade III-IV cardiac toxicity within 28 days after HSCT was not significantly increased in VP/rCY/TBI group (one in VP/rCY/TBI recipients (5.9%) and five in CY/TBI recipients (3.6%), p=0.64). There was no significant difference in the incidence of grade II-IV (p=0.35) or grade III-IV (p=0.10) acute GVHD. From these results, we conclude that VP/rCY/TBI regimen can be safely administered for patients with pre-transplant cardiac co-morbidity while preserving anti-neoplastic effects.

Nonmyeloablative stem cell transplantation in follicular B-cell lymphoma

Myeloablative allogeneic stem cell transplantation carries the promise of long-term disease control by graft-versus-lymphoma (GVL) immunity but is associated with a 30% to 40% risk of transplant-related mortality. Nonmyeloablative stem cell transplantation (NST) aims to exploit the GVL effect without the attendant toxicity of myeloablative conditioning. At the M.D. Anderson Cancer Center, the standard NST conditioning regimen for patients with follicular lymphoma is fludarabine, cyclophosphamide, and rituximab (FCR). Using this regimen, transplant-related mortality is currently 10%, and 85% of patients remain alive without disease at 3 to 4 years. This review discusses the current issues in NST for follicular lymphomas, including the optimization of conditioning intensity, the use of rituximab in immunomodulation, and the role of donor lymphocyte infusion.

Alkylator‐free conditioning regimen for patients with acquired aplastic anemia, transplanted from genetically identical twins

Allogeneic stem cell transplantation remains the best option for young patients with SAA. With genetically identical twin as an ideal donor, the majority of SAA patients require appropriate immunosuppression before and after stem cell transplantation to obtain long-term hematopoietic reconstitution. Alkylating agents, used during conditioning, are associated with short- and long-term toxic effects that lead to poor compliance of treatment and could compromise the quality of future life. Three SAA patients, transplanted from genetically identical twins without using alkylating agents during conditioning, showed rapid and sustained hematological reconstitution without any evidence of conditioning-related toxicity.

Impact of the intensity of the pretransplantation conditioning regimen in patients with prior invasive aspergillosis undergoing allogeneic hematopoietic stem cell transplantation: a retrospective survey of the Infectious Diseases Working Party of the European Group for Blood and Marrow Transplantation

AbstractIn this retrospective study, we analyzed the outcomes of 129 patients who underwent an allogeneic hematopoietic stem cell transplantation (allo-HSCT) and had a history of probable or proven invasive aspergillosis (IA), of whom 57 (44%) received a reduced-intensity conditioning (RIC). Overall, 27 patients with IA progressed after the allo-HSCT (cumulative incidence [CumInc] at 2 years, 22%). The variables that increased the 2-year CumInc of IA progression were (1) longer duration of neutropenia after transplantation; (2) advanced status of the underlying disease; and (3) less than 6 weeks from start of systemic anti-Aspergillus therapy and the allo-HSCT. In addition, (4) conventional myeloablative conditioning increased the risk of progression early after transplantation (before day 30) only, while 3 variables increased the risk beyond day 30 were (5) cytomegalovirus disease; (6) bone marrow or cord blood as source of stem cells; and (7) grades II to IV acute graft-versus-host disease (GVHD). A risk model for progression was generated, defined as low (0-1 risk factors, 6% incidence), intermediate (2-3 risk factors, 27% incidence), or high risk (≥ 3 risk factors, 72% incidence [P < .001]). These findings may help in the interpretation and design of future studies on secondary prophylaxis of IA after an allo-HSCT.

Multicenter study of intravenous busulfan, cyclophosphamide, and etoposide (IV Bu/Cy/VP-16) as conditioning regimen for autologous stem cell transplantation in patients with non-Hodgkin’s lymphoma

17544 Background: The current study aimed to evaluate the efficacy and toxicity of the combination of intravenous busulfan, cyclophosphamide, and etoposide (IV Bu/Cy/VP-16) as a preparative regimen prior to autologous hematopoietic stem cell transplantation (ASCT) in patients with non-Hodgkin’s lymphoma (NHL). Methods: Forty patients with relapsed (n = 24) or high-risk (n = 16) lymphoma were enrolled into the study. High-dose chemotherapy consisted of intravenous busulfan (0.8 mg/kg i.v. q 6 hr from day-7 to day-5), cyclophosphamide (50 mg/kg i.v. on day-3 and day-2), and etoposide (400 mg/m2 i.v. on day-5 and day-4). Results: The median age of patients was 34 years (range, 17–63 years), and 21 (52.5%) patients were male. Pathologic subtypes were as follows: diffuse large B cell (n = 20), peripheral T cell, unspecified (n = 8), extranodal NK/T cell (n = 4), angioimmunoblastic T cell (n = 3), anaplastic large cell (n = 4), nodal marginal zone B cell (n = 2), and lymphoblastic (n = 3). The median dose of infused CD34+ cells and MNC was 3.95 (range, 0.7–20.6) × 106 and 8.12 (range, 3.0–13.6) × 108, respectively. WBC and platelet were successfully engrafted after ASCT in all patients, and the median days of engraftment of WBC and platelet was 12 (range, 9–48) and 27 (range, 8–263) days, respectively. After the ASCT, 34 complete responses (CR; 85.0%) and 4 partial responses (PR; 10.0%) were confirmed. Thirty-three (82.5%) patients experienced a fever without documented infection, while 2 patient developed fungal infection. However, there was no treatment-related death. After median follow-up duration of 360 (range, 83–639) days, 33 patients are in continuous complete remission, 4 patients are alive in relapse, and 3 patients died of disease. The estimated event-free and overall survival rate at 1.5-year was 80.9 ± 10.0 % and 92.5 ± 5.7 %, respectively. Conclusions: IV Bu/Cy/VP-16 was found to be well-tolerated and effective as a conditioning regimen in patients with NHL. Accordingly, this regimen can be regarded as an alternative high-dose treatment option in the ASCT for NHL. No significant financial relationships to disclose.

Overcoming graft rejection in heavily transfused and allo‐immunised patients with bone marrow failure syndromes using fludarabine‐based haematopoietic cell transplantation

Allogeneic haematopoietic cell transplantation (HCT) can cure a variety of non-malignant haematological disorders. Although transplant outcomes for selected patients with severe aplastic anaemia (SAA) and paroxysmal nocturnal haemoglobinuria (PNH) have improved, older age, allo-immunisation from transfusions, prior immunosuppressive therapy and a prolonged time from diagnosis to transplantation are associated with worse outcome. Because of its potent immunosuppressive effects, we investigated a fludarabine-based non-myeloablative conditioning regimen in patients with transfusion-dependent non-malignant haematological disorders at increased risk for graft rejection with conventional transplant conditioning. Twenty-six patients with transfusion dependent/anti-thymocyte globulin (ATG)-refractory SAA, PNH or pure red cell aplasia underwent HCT from a human leucocyte antigen (HLA)-compatible relative. Transplant conditioning consisted of cyclophosphamide (120 mg/kg) and fludarabine (125 mg/m2) with or without ATG. Ciclosporine, alone or combined with mycophenolate mofetil or methotrexate, was used as graft-versus-host disease (GVHD) prophylaxis. All patients achieved durable engraftment and transfusion-independence. Twenty-four of 26 patients are alive at a median of 21 months following transplantation. Although a high cumulative incidence of acute (65% grades II-IV, 54% grades III-IV) and chronic GVHD (56%) was observed, only one patient died from transplant-related causes (cumulative incidence 7%). These data show that HCT following fludarabine-based non-myeloablative conditioning results in durable engraftment and excellent survival in SAA and PNH patients at high risk for graft rejection.

Pharmacokinetics of alemtuzumab after haploidentical HLA-mismatched hematopoietic stem cell transplantation using in vivo alemtuzumab with or without CD52-positive malignancies

We recently reported that the addition of in vivo alemtuzumab to the conditioning regimen enables 2- or 3-locus-mismatched hematopoietic stem cell transplantation without an excessive risk of graft rejection or graft-versus-host disease. In a later series of patients, however, one patient with refractory chronic lymphocytic leukemia with large residual tumors at transplantation developed graft rejection. While the peak alemtuzumab concentration in the previous patients without graft rejection was higher than 5 micro g/ml, the peak alemtuzumab concentration in this patient was only 1.44 micro g/ml. We considered that alemtuzumab was bound to the large residual tumors, which resulted in a low blood concentration of alemtuzumab. Therefore, it is important to debulk tumors before the conditioning regimen for patients with refractory CD52-positive hematological malignancies, or the dose of alemtuzumab should be adjusted by monitoring the blood concentration, when alemtuzumab is used for in vivo T-cell depletion in 2- or 3-locus-mismatched transplantation.

188Re or 90Y‐labelled anti‐CD66 antibody as part of a dose‐reduced conditioning regimen for patients with acute leukaemia or myelodysplastic syndrome over the age of 55: results of a phase I–II study

In a phase I-II study for patients aged 55-65 years, we employed radioimmunotherapy using an anti-CD-66 antibody as part of a dose-reduced conditioning regimen, which was followed by a T-cell-depleted graft. 20 patients with a median age of 63 years suffering from acute leukaemia (n=17) or myelodysplastic syndrome (n=3) received the antibody labelled either with 188Rhenium (n=8) or with 90Yttrium (n=12) during conditioning. Radioimmunotherapy provided a mean dose of 21.9 (+/-8.4) Gy to the bone marrow with a significantly higher dose when 90Yttrium was used. Additional conditioning was fludarabine-based plus anti-thymocyte globulin in matched related donor transplants (n=11), or plus melphalan in matched unrelated donor transplants (n=9). Regimen-related toxicity was low, with two patients developing three episodes of grade III organ toxicity. All patients engrafted, grade II-IV acute graft-versus-host disease (GvHD) was observed in one patient (5%) and chronic GvHD in three patients (15%). The cumulative incidence of non-relapse mortality was 25%, the cumulative incidence of relapse 55%. The probability of survival was estimated to be 70% at 1 year and 52% at 2 years post-transplant, although no plateau was reached afterwards. In conclusion, radioimmunotherapy using the anti-CD66 antibody was feasible and safe in our elderly patient group and provided a high marrow dose.