Busulfan And Cyclophosphamide Research Articles

Application of Conditioning Regimen with Busulfan and Cyclophosphamide in Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma

To evaluate the safety and efficacy of BUCY (busulfan and cyclophosphamide) conditioning regimen for autologous hematopoietic stem cell transplantation (ASCT) in patients with multiple myeloma (MM). The clinical data of 72 MM patients received transplantation in the Hematology Department of the First Affiliated Hospital of Soochow University from May 2012 to June 2015 were retrospectively analyzed. Among them, 36 patients received BUCY conditioning regimen while the others received high-dose melphalan (HDM) conditioning regimen. The complication, post-transplantation hematopoietic reconstitution and efficacy between the two groups were compared. There were no significant differences in sex, age, isotype, stage, induction therapy, mobilization method and proportion of conditioning regimen with Bortezomib between the two groups. The median time of neutrophil engraftment for the patients in BUCY and HDM groups was 10 (8-17) and 10 (9-13) d (P=0.046), and the median time of platelet engraftment was 10 (8-18) and 11 (9-47) d (P=0.017), respectively. The transplant related mortality of the patients in both groups was 2.7%. The CR rates of the patients after ASCT (38.9% and 50.0%) were higher than those before ASCT (27.8% and 19.4%) in the two groups. For the patients in BUCY group, the median follow-up time was 45 (0-61) months. Fifteen patients (41.7%) achieved disease progression. While for the patients in HDM group, the median follow-up time was 52(0-75) months. Twenty-two patients (61.1%) achieved disease progression. The BUCY conditioning regimen is a safe and effective therapy for ASCT in patients with MM. Besides, in terms of safety and efficacy, BUCY regimen is not inferior to HDM regimen. BUCY regimen may replace HDM regimen as a standard conditioning regimen for ASCT in MM.

Application of the Conditioning Regimen with Busulfan and Cyclophosphamide in Autologous Hematopoietic Stem Cell Transplantation in Multiple Myeloma

Backgroud Busulfan isthe most commonly used drug in conditioning regimens for hematopoietic stem cell transplantation, and high-dose melphalan (HDM)is the standard conditioning regimen in autologous stem cell transplantation(ASCT)for multiple myeloma. Studies have shown that in ASCT for multiple myeloma, conditioning regimens containing busulfan is equally effective as HDM.Aims Evaluate the safety and efficacy of BUCY(busulfan and cyclophosphamide ) conditioning regimen for autologous hematopoietic stem cell transplantation(ASCT)in patients with multiple myeloma(MM).Methods We retrospectively analyzed the clinical data of 72 MM patients who received transplantation in the Hematology Department of the First People's Hospital of Soochow University from May 2012 to June 2015. Among them, 36 patients underwent BUCY regimen, while the others received HDM regimen. Those were compared between the two groups including the complication, the hematopoietic reconstitution and the post-transplantation efficacy.Results There were no significant differences in age, stage, induction therapy, mobilization method between the two groups. The transplantation-related adverse events were similar in both groups but the incidence of pulmonary infection and bloodstream infection were slightly higher in BUCY group .The median time to neutrophil engraftment in the BUCY and HDM groups were 10(8-17)days versus 10(9-13)days, taking the same time on average(P=0.046). On the other hand, the median time to platelet engraftment was 10(8-18)versus 11(9-47)days accordingly (P=0.017). The TRM in both group was 2.7%. The SCR/CR rates after ASCT (47.2% and 50.0%) were higher than those before it (38.9% and 26.6%) in both groups. In the BUCY group, the median follow-up was 12.5(0-26) months. Six patients (16.7%) underwent disease progression. The 2-year progression-free survival(PFS) rate was 68%. Correspondingly, in the HDM group, the median follow-up time was 23 (0-38) months. Fifteen patients (41.7%) developed disease progression and the 2-year PFS rate was 55%.Conclusion The BUCY regimen is a safe and effective therapy for ASCT in patients with multiple myeloma. Besides, BUCY regimen is not inferior to HDM regimen. In conclusion, BUCY regimen may replace HDM regimen as a standard conditioning regimen for ASCT in multiple myeloma. DisclosuresNo relevant conflicts of interest to declare.

Daily Dosing of Busulfan in Allogeneic Hematopoietic Cell Transplantation Reduces Costs with Equivalent or Superior Outcomes

Introduction Higher costs of healthcare in the United States have not consistently been associated with improved health outcomes or quality of care, necessitating interventions to improve value-based care. We identified busulfan dosing frequency during preparation for allogeneic hematopoietic cell transplantation (HCT) as a potential target for optimization. To improve patient convenience and decrease the cost of the busulfan preparative regimen, our institution changed busulfan dose frequency from every 6 hours (q6h) to once-daily dosing (q24h). We examined differences in costs and patient outcomes between these two protocols. Methods In June 2017, our institution transitioned from q6h to q24h busulfan dosing. We compared patients who received inpatient busulfan and cyclophosphamide (BU/CY) preparative regimens for allogeneic HCT from one year prior to one year after implementation of the dosing change. The primary outcomes were difference in cost, day +90 mortality, and day +90 relapse. Secondary outcomes included hospital length of stay and peak serum total bilirubin level. Two-sided T-test and Chi-squared analyses were conducted to compare these outcomes between the two treatment groups. Results There were a total of 104 patients (age 49 ± 11 years, 55% male) who received the preparatory BU/CY regimen before allogeneic HCT from June 1, 2016 to June 1, 2018 (Table 1). Of these, 43% (N=45) received q24h busulfan. There were fewer men in the q24h busulfan cohort (42%) compared to the q6h busulfan cohort (64%, p=0.024), but there were no other significant differences between the treatment groups (Table 1). There was an average cost savings of $12,554.34 per patient who received q24h busulfan compared to q6h busulfan. There was a significantly lower day +90 mortality in the q24h busulfan cohort compared to the q6h busulfan cohort (0% vs 10%, p=0.028, Table 2). There were no differences in relapse at day +90 or hospital length of stay. Conclusions Busulfan dosing during preparation for allogeneic HCT represents a target for improving value-based care in the inpatient setting. At our institution, patients who received a q24h busulfan dosing regimen had similar or superior outcomes with those receiving q6h dosing, with a reduction in annual hospital drug charges of approximately $500,000. This retrospective study serves as a proof of concept for the adoption of q24h busulfan dosing as a standard of care to improve value-based care in allogeneic HCT.

Optimizing the pretransplant regimen for autologous stem cell transplantation in acute myelogenous leukemia: Better outcomes with busulfan and melphalan compared with busulfan and cyclophosphamide in high risk patients autografted in first complete remission: A study from the acute leukemia working party of the EBMT.

Autologous stem cell transplantation remains a clinical option to consolidate some adult patients with acute myelogenous leukemia (AML) in first complete remission (CR1). In a small cohort of patients, we have previously shown better outcomes following Busulfan and Melphalan (BUMEL) over Busulfan and Cyclophosphamide (BUCY). To identify the subpopulations that might get the highest benefit with BUMEL, we designed a larger study. All adult patients with primary AML and available cytogenetics, autografted from January 2000 to December 2016 in CR1, were included: 1137 patients received BUCY and 512 BUMEL. All factors differing in distribution between the 2 conditioning groups were introduced in multivariate analyzes. In a primary analysis, we found an interaction between conditioning and the poor risk group defined as poor cytogenetics and/or presence of the FLT3-ITD mutation. During analysis of the poor risk group, 176 patients received BUCY and 62 BUMEL. BUMEL was associated with a lower RI at 5 years (53% versus 69%, HR: 0.52, P = .002), a better Leukaemia-free survival (LFS) (42% versus 25%, HR: 0.54, P = .002) and a better OS (54% versus 36%, HR: 0.61, P = .02). During analysis of the non poor risk group, 961 patients received BUCY and 450 BUMEL. At 5 years, the RI was 50% and 47%, the LFS 45% and 48% and the OS 56% and 60% respectively, with no significant difference. We conclude that BUMEL is the preferable conditioning regimen for the poor risk leukemic patients, while in AML patients without poor risk cytogenetics or FLT3 both conditioning regimens are valid.

Oral Busulfan and Cyclophosphamide (BU/CY) versus Cyclophosphamide, Melphalan and Vepsid (Etoposide) (CMV) with Autologous Stem Cell Transplant in Patients with Relapsed Non-Hodgkin Lymphomas (NHL)

Oral Busulfan and Cyclophosphamide (BU/CY) versus Cyclophosphamide, Melphalan and Vepsid (Etoposide) (CMV) with Autologous Stem Cell Transplant in Patients with Relapsed Non-Hodgkin Lymphomas (NHL)

Autologous stem cell transplantation for adult acute myelocytic leukemia in first remission-Better outcomes after busulfan and melphalan compared with busulfan and cyclophosphamide: A retrospective study from the Acute Leukemia Working Party of the European Society for Blood and Marrow Transplantation (EBMT).

Autologous stem cell transplantation (ASCT) for adult acute myelogenous leukemia (AML) is a valid therapeutic option for patients with good-risk and intermediate-risk disease. The authors used the registry of the European Society for Blood and Marrow Transplantation to compare combined busulfan and melphalan (BUMEL) with combined busulfan and cyclophosphamide (BUCY) before transplantation. From 2005 to 2013, 853 patients with available cytogenetics underwent ASCT in first remission, including 257 after receiving BUMEL and 596 after receiving BUCY. The proportion of patients with good-risk AML was lower in those who received BUMEL (14% vs 20%; P = .02). More patients who received BUMEL underwent autograft in molecular remission (89% vs 78%; P = .02). Three years after transplantation, the relapse incidence (RI) was 48.7%, the leukemia-free survival (LFS) rate was 47.7%, the overall survival (OS) rate was 66.2%, and the nonrelapse mortality (NRM) rate was 3.6%. Patients who underwent an autograft after receiving BUMEL fared better than those who underwent an autograft after receiving BUCY with a lower RI (39.5% vs 52.2%; hazard ratio [HR], 0.65; 95% confidence interval [CI], 0.49-0.87; P = .003) a better LFS (55.4% vs 44.6%; HR, 0.69; 95% CI, 0.53-0.89; P = .005), and a better OS (73.8% vs 63%; HR, 0.62; 95% CI, 0.47-0.82; P = .0007). There was no difference in the NRM rate (BUMEL vs BUCY, 4.5% vs 3.2%, respectively). Among 74 patients in the BUMEL group and 187 in the BUCY group who underwent autograft in molecular remission, the RI was 30% versus 51%, respectively (univariate analysis; P = .01), and the LFS rate was 66% versus 47%, respectively (univariate analysis; P = .03). In patients with AML in first complete remission who undergo ASCT, the BUMEL combination is a better preparative regimen. Cancer 2017;123:824-31. © 2016 American Cancer Society.

Autologous Stem Cell Transplantation for Adult Acute Myelocytic Leukemia in First Remission: Better Outcome Following Busulfan and Melphalan Compared to Busulfan and Cyclophosphamide : A Retrospective Study from the Acute Leukemia Working Party of the EBMT

RationaleAutologous stem cell transplantation for adult acutemyelogenousleukemia (AML) is a therapeutic option for good and intermediate risk patients. New compounds and new formulations in conjunction with pre andpost transplant targeted therapy may improve outcome.A recent EBMT retrospective survey investigating on Busulfan administered IV (Nagler A et al:Haematologica. 2014 ) pre autologous stem cell transplantation (ASCT) suggested that the combination of Busulfan and High dose Melphalan (BUMEL) was associated with the best overall survival. To address this question, we compared this regimen with the historical Busulfanand Cyclophosphamide (BUCY) association.MethodsEligibilitycriteria consistedof all adult patients (age >18 years) with AMLautograftedin CR1, following a preparative regimen consisting of either BUCY or BUMEL, reported to the EBMT registry in the period from January 2005 to December 2013. The doses of Busulfan were either oral at 16 mg/kg over 4 days or IV at 12.8 mg/kg over 4 days. High dose Melphalan was 140mg/m². The data came from 231 centers 23 ofwhich usedboth regimens. The relationships between outcomes and patient, disease and transplant characteristics was evaluated in multivariate analyses using the Cox model.Results1120 patients received BUCY and 436 BUMEL prior to autografting in first remission. Patients receiving BUMEL were older (median 52 years versus 50 years, p=0.01) with less good risk diseases by cytogenetics (16% versus 28%, p=0.001). They were autografted with a longer interval from CR1 to autografting (120 days versus 104 days, p=0.001) and they were more frequently in a negative minimal residual disease (MRD) status by molecular biology (89% versus 82%, p= 0.03).The nature of the pretransplant regimen interacted with the interval from diagnosis to autografting on both relapse incidence (p=0.005) and leukemia free survival (p= 0.02): the outcome post BUMEL was superior to BUCY only in patients transplanted within less than six months post diagnosis. In these patients, following BUMEL and BUCY respectively, the RI was 35%versus 50.6% (p< 10-3), the LFS 61.1% versus 46.2% (p< 10-3) and the OS 79.4% versus 64.8% (p= 0.003). There was no difference for NRM.When considering only patients autografted at the time when MRD detection was negative, the LFS at two years was 75.8% for 134 patients receiving BUMEL and 58.6% in the 371 patients receiving BUCY, with no significant difference (p= 0.1). The major cause of death in the two groups was leukemia recurrence.ConclusionWe conclude that the BUMEL combination pre ASCT in AML CR1 is superior to BUCY when the transplant is performed less than 6 months after diagnosis. These registry data should be confirmed in a well designed two arm study assessing the role of ASCT in good risk and possibly intermediate -1 risk adult patients with AML.TablepHR95% CINRMBUMEL vs BUCY0.4501.3760.5993.16Age atTx/ 10years0.0011.0641.0251.10Time from diagnosis to Transplant.0.9000.9990.9841.01Cytogenetics :Intermediatevs good0.6100.7090.1912.63Poor versus good0.7100.7080.1124.46Missing0.4200.5910.1642.11centre (frailty)0.360RIBUMEL vs BUCY0.0010.6020.4450.816Age at Transplant / 10years0.0051.0121.0031.020Time from diagnosis to Transplant:0.7201.0000.9961.004Cytogenetics : Intermediatevs good0.5101.1450.7641.714Poor versus good0.0311.7991.0553.067Missingversus good0.4801.1500.7791.699centre (frailty)0.110OSBUMEL vs BUCY0.0020.6140.4490.841Age at Transplant / 10years<10-41.0251.0141.036Time from diagnosis toransplant0.940.9990.9951.004Intermediatevs good0.881.0360.6491.653Poor versus good0.111.6320.9012.956Missingversus good0.811.0580.6721.665centre (frailty)0.29LFSBUMEL vs BUCY0.0020.6490.4900.858Age at Transplant / 10years<10-41.0151.0061.023Time from diagnosis to Transplant0.7401.0000.9961.004Cytogenetics : Intermediatevs good0.5901.1100.7551.630Poor vs good0.0461.6791.0082.796Missingversus good0.5901.1060.7631.604centre (frailty)0.170Multivariate analyses of prognostic factors in patients autografted within 6 months [Display omitted] DisclosuresNemet:Celgene: Honoraria; Pliva: Honoraria; Amgen: Honoraria; Sanofi: Honoraria; Pfizer: Honoraria; Janssen: Honoraria. Mohty:Janssen: Honoraria; Celgene: Honoraria. Nagler:Biokine LTD: Consultancy.

Modified Busulfan and Cyclophosphamide Conditioning Regimen for Allogeneic Hematopoietic Stem Cell Transplantation in the Treatment of Patients With Hematologic Malignancies

ObjectiveWe aim to evaluate the clinical efficacy of a modified busulfan and cyclophosphamide (BU/CY) conditioning regimen for allogeneic hematopoietic stem cell transplantation (allo-HSCT) in the treatment of hematologic malignancies. MethodsA total of 45 patients with hematologic malignancies were treated using stem cell transplantation between March 2007 and June 2012. All the patients received a modified BU/CY conditioning regimen before transplantation. The outcomes of the patients were followed up including mortality, survival, relapse, and complications. ResultsThe median of follow-up duration was 527 days. All the patients who received modified BU/CY conditioning regimen achieved hematopoietic recovery successfully. Among the patients, 24 were survived without complications, 5 had relapsed hematologic malignancies, and 16 died. The median time to leucocyte engraftment was 14 days and to platelet engraftment was 12 days. Acute graft-versus-host disease (aGVHD; grades I-IV) occurred in 15 patients (30%). The cumulative incidence of grades I aGVHD was 22.2% (10 patients), grades II was 6.7% (3 patients), and grades III-IV was 4.4% (2 patients). Among 40 appreciable patients, 8 (20%) developed chronic GVHD. The incidence rate of hemorrhagic cystitis and veno-occlusive disease were 15.5% and 2.2%, respectively. ConclusionsThe modified BU/CY conditioning regimen for allo-HSCT is effective and safe for the treatment of hematologic malignancies.

Unrelated Cord Blood Transplantation in India: Breaking the Cost Barrier

Abstract 4768 Background –India, with more than a billion population, has a huge burden of blood and cancer disorders many of which can be cured only by hematopoietic stem cell transplantation (HSCT). More than 1500 transplants have been done till 2005 over a 20 year period in about 10 centers out of which 880 have been allogeneic HSCT and all have been from matched related donors (MRD).Unrelated HSCT is the only option for the patients without a MRD. It is almost impossible to find an unrelated matched donor in India due to ethnic diversity and lack of unrelated donor registries. Some public cord blood banks have been set up in India. So finding a suitable cord blood unit within India is possible. Unrelated Cord Blood Transplant (UCBT) is the only feasible option for patients who need to undergo unrelated HSCT in India but lack of experience and huge costs are perceived barriers. Data from USA showed mean cost of graft for pediatric UCBT was $58,910 and mean cost per day survived in first 100 days (excluding graft cost) was $4522 ((Majhail NS et al. Pediatr Blood Cancer 2010;54:138–143). The costs of UCBT among children in India have not been described previously. Method -We calculated the costs of UCBT within the first 100-days among four children who received UCBT at Sir Ganga Ram hospital from April 2008 to Dec 2010. We also analyzed costs of transplantation in relation to patient age, weight, single vs. double cord, conditioning, Graft vs. Host Disease (GVHD) and mean duration of stay before day 100. Results -The 100-day probability of overall survival was 100%. The mean cost per day survived (excluding costs of graft acquisition) was $402 (range $360-460)) for UCBT recipients. Average total cost of each UCBT was $43500 (Range $32000-52000). Average duration of stay in hospital in first 100 days was 89 days (range 75–100). All grafts were procured from a public cord bank in India. Average cost of graft per cord unit was $5000. Diagnosis was thalassemia major-2, Familial Hemophagocytic Lympho Histiocytosis (HLH)-1 and AML-1. Lowest cost was for AML ($32000) and highest was for Pesaro class III thalassemia major ($52000). Mean age was 2.75 years (range 1–5 year). Mean weight was 12.25 kg (range 10–16 kg). Mean cell dose infused was 7 × 107 nucleated cells/kg weight of recipient (range 3–10 × 107nucleated cells/kg). Conditioning was Busulfan and Cyclophosphamide (BuCY) and Rabbit Anti-Thymoglobulin (ATG) for two patients (1 Thalassemia, 1 AML) costing $1500 per patient, Fludarabine & Melphalan and Campath for HLH costing $2500 and Treosulfan, Thiotepa, Fludarabine and ATG for class III thalassemia costing $7500. Mean cost per day for single cord was $385 and for double cord UCBT was $420. One patient rejected the graft. Three engrafted at median of 32 days (range 28 –39 days). GVHD was seen in two patients (both with double cord). CMV reactivation was seen in all cases. Invasive aspergillosis was seen in one patient who had thalassemia and it lead to highest expenditure. Campath based conditioning was associated with maximum hospital stay in child with HLH. All had Lansky score >90 pre-transplant No one needed dialysis, mechanical ventilation or hepatic veno-occlusive disease. Conclusions -Total cost of UCBT in India is less than the cost of the UCBT graft in USA and mean cost per day in India is almost one tenth of cost per day in USA. Low cost of UCBT in India would make this treatment feasible for many more patients who need to undergo unrelated HSCT. Disclosures:No relevant conflicts of interest to declare.

Conditioning regimen using busulfan plus melphalan in hematopoietic stem cell transplantation

Conditioning regimen using busulfan plus melphalan in hematopoietic stem cell transplantation

Establishment of an animal model of oral mucositis induced by conditioning regimen of haematopoietic stem cell transplantation

To establish a rat model of oral mucositis (OM) induced by busulfan and cyclophosphamide (BUCY) conditioning regimen of hematopoietic stem cell transplantation (HSCT). In the model group, busulfan (6.0 mg.kg(-1).d(-1) x 4 d) and cyclophosphamide (120 mg.kg(-1).d(-1) x 2 d) were administered by intra-stomach perfusion and intraperitoneal injection, respectively. The left cheek mucosa were irritated by superficial scratching on day 6. The oral mucosal score (OMS) was assessed daily. Animals were sacrificed on day 7, 10, 13, 16 and 18. The samples of blood, bone marrow, and the oral mucosa were harvest to evaluate the clinical and histological changes. The incidence of oral mucositis in model group was as high as 80.00% with a survival rate of 73.33%. The initial lesion on the oral mucosa was noted on day 7 with red spot and edema, and then progressive mucositis was characterized by large areas of ulcer formation. The duration of oral mucositis was 8 to 10 days. A continuous weight loss, white blood cell count decrease and bone marrow suppression occurred in the process of oral mucositis. An animal model of conditioning regimen-induced oral mucositis was successfully established.

Autologous transplantation for relapsed non-Hodgkin lymphoma using intravenous busulfan and cyclophosphamide as conditioning regimen: A single center experience

18508 Background: High-dose chemotherapy followed by autologous stem cell transplanatation has become standard of care for patients with relapsed, chemosensitive non-Hodgkin’s lymphoma (NHL). In an effort to improve safety and efficacy of this therapeutic approach, new conditioning regimens are being developed. Methods: We retrospectively reviewed the clinical data of 44 consecutive patients with relapsed NHL who had been treated with intravenous Busulfan and Cyclophosphamide (BU/CY) as conditioning regimen for autologous stem cell transplantation between January 2000 and April 2005. Busulfan was administered at a total dose of 3.2 mg/kg on days -7 to -4 (given in two or four divided doses), followed by Cyclophosphamide at a dose of 120 mg/kg intravenously on days -3 and -2. We determined treatment-related morbidity and mortality, event-free survival (EFS, defined as time period between transplantation and occurrence of serious morbidity, disease relapse, disease progression, or death), disease-free survival (DFS), and overall survival (OS). Results: The distribution by histologic type of the 44 patients was as follows: 29 diffuse large B-cell lymphoma, 8 follicular lymphoma, 4 mantle cell lymphoma, and 3 peripheral T-cell lymphoma. Median age was 50 (range 20 to 68 years). At the time of transplantation, 27 patients had attained a complete response (CR or CRu) to salvage chemotherapy, 13 had achieved a partial response, and 4 had stable disease. Median time to neutrophil recovery post transplantation was 11 days. Treatment-related toxicities included nausea/vomiting (77%), diarrhea (43%), and mucositis (66%), which were mild in the majority of cases. Neutropenic fever occurred in 82% of patients. The 100-day mortality rate was 4 (9%) of patients: sepsis (n=1), pneumonia (n=1), and hepatic veno-occlusive disease (n=2). After a median follow-up of 52 months, 3-year Kaplan-Meier estimates of EFS, DFS, and OS were 35%, 41% and 44% respectively. Conclusions: Intravenous BU/CY is a safe and effective conditioning regimen as part of autologous transplantation for relapsed NHL. Our outcomes are comparable to those of other published regimens. Further investigation of this treatment approach is warranted. No significant financial relationships to disclose.

Outcome in patients with Wiskott–Aldrich syndrome following stem cell transplantation: an analysis of 57 patients in Japan

A total of 57 patients with Wiskott-Aldrich syndrome (WAS) were studied after undergoing stem cell transplantation (SCT) in Japan between January 1985 and December 2004. Eleven patients received transplants from human leucocyte antigen (HLA)-matched related donors, 10 from HLA-mismatched related donors, 21 from unrelated bone marrow donors, and 15 from unrelated cord blood donors. Nine of the 57 patients rejected the initial graft. The overall 5-year survival rate was 73.7% and the 5-year failure-free survival rate was 65.7% (failure was defined as rejection or death). The overall 5-year survival rates for patients receiving bone marrow and cord blood from unrelated donors were both 80.0%. Based on univariate analysis, the factors associated with poor survival were: transplantation from an HLA-mismatched related donor, patient age of more than 5 years at the time of transplantation, and a conditioning regimen other than busulfan and cyclophosphamide (BU-CY) or busulfan, cyclophosphamide and antithymocyte globulin (BU-CY-ATG). In a multivariate analysis, a conditioning regimen other than BU-CY and BU-CY-ATG was the only independent factor associated with transplantation failure. Given the improved outcome for WAS patients following transplantation from an unrelated donor, we conclude that patients with WAS should receive SCT as soon as possible after diagnosis.

Transplantation in Patients With Multiple Myeloma

We performed a multicenter comparative analysis of autologous peripheral blood stem cell transplantation (PBSCT) and allogeneic bone marrow transplantation (alloBMT) in multiple myeloma. Forty-eight consecutive patients received either PBSCT (24 patients) or alloBMT (24 patients) at one of three institutions in the study group. Preparatory regimens consisted of melphalan and total body irradiation (TBI) or melphalan alone in the PBSCT group. The alloBMT group received one of four regimens: cyclophosphamide and TBI; cyclophosphamide, VP-16 and 1,3-bis(2-chloroethyl)-1-nitrosourea (CVB); busulfan and cyclophosphamide (BU/CY) and total marrow irradiation (TMI); or melphalan and TBI. Procedure-related mortality was 12.5% for the PBSCT group and 25% for the alloBMT group. With a median follow-up for survivors in the PBSCT and alloBMT groups of 11 months (range, 4-46) and 15 months (range, 2-84 months), respectively, there was no significant difference in median overall survival (33.5 versus 38.6 months, p = 0.7637) or event-free survival (16.7 versus 31 months, p = 0.8450). There was, however, a plateau in survival at 40% in the alloBMT group. No plateau in survival was seen in the PBSCT group. Clinical relapses occurred as late as 39 months posttransplant. Patients have survived up to 28 months postrelapse.

Growth in children undergoing bone marrow transplantation after busulfan and cyclophosphamide conditioning.

The purpose of this study was to evaluate the effect of busulfan and cyclophosphamide (BUCY) as conditioning regimen for bone marrow transplantation (BMT) on growth of children following BMT. Growth assessment was prospectively done in all 25 children who underwent BMT following BUCY conditioning from 1989 to 1994 at Children's Hospital of Philadelphia. The height and growth rates were expressed as standard deviation scores (SDS). The height SDS prior to BMT were compared with 1, 2, and 3 years post-BMT. The growth rate SDS 1 year and 2 years post-BMT were also compared. Pubertal children were excluded from the analysis of growth rate. Median age of patients was 7 years (range, 1.3-15 years). A total of 22/25 patients were transplanted for AML, and three patients had myelodysplastic syndrome. Equal numbers of patients had autologous and allogeneic transplants. Seven patients received corticosteroids for varying lengths of time. The pre-BMT height SDS (mean +/- SD) for the group was -0.4 +/- 1.3. The mean height SDS for 19 children at 1 year post-BMT was +/- 0.1 +/- 1.2 and for 10 children, 2 years post-BMT was -0.3 +/- 1.6. Seven children who were 3 years post-BMT had the mean height SDS of -0.2 +/- 1.5. There was no statistically significant difference between pre-BMT height SDS and 1 year post-BMT (p = 0.49) and 2 years post-BMT (p = 0.42). The mean growth rate at 1 year post-BMT was -0.1 +/- 2.7 and at 2 years post-BMT was -0.9 +/- 2.3. The difference was not statistically different (p = 0.15). Somatomedin-C (insulin growth factor 1, IGF-1) levels were normal in all 13 children tested at 1 year post-BMT. IGF binding protein (BP)-3 levels were done in 10 children at 1 year and were found to be normal in all. Thyroid function studies were done in all patients pre-BMT and 1 year post-BMT and were normal for all. Bone age assessment was appropriate for age in all 14 patients tested at 1 year post-BMT. There was no evidence of growth failure following BMT with BUCY conditioning in this group of patients.

Busulfan/cyclophosphamide as conditioning regimen for allogeneic bone marrow transplantation for myelodysplasia.

A non-radiation-containing regimen of busulfan and cyclophosphamide (BU/CY) was evaluated for toxicity, relapse, and long-term survival in patients who received allogeneic bone marrow transplantation (BMT) for myelodysplasia (MDS). Thirty-eight patients with MDS, including eight with therapy-related MDS, were prepared for BMT using BU/CY. Fourteen patients remain in first remission 18 to 60 months posttransplant. Five patients relapsed after BMT, and four of these patients died. Eight additional patients died of acute or chronic graft-versus-host disease (GVHD), and 11 died of regimen-related toxicity, primarily systemic mycoses. Overall survival rate at 2 years was 45% (95% confidence interval [CI], 0.30 to 0.61), with a 24% probability of relapse (95% CI, 0.10 to 0.49). Regimen-related toxicity was manifested primarily as hepatic dysfunction in 72% of patients, with 16% developing overt venoocclusive disease (VOD). Non-radiation-containing preparative regimens offer long-term survival in allogeneic BMT for MDS that is comparable to that of radiation-containing regimens, and are useful in patients with therapy-related MDS. Monitoring BU levels may reduce regimen-related mortality and improve survival.

Ex Vivo Chemopurging of Autologous Bone Marrow with 4-Hydroperoxycyclophosphamide to Eliminate Occult Leukemic Cells

The application of autologous bone marrow transplantation (ABMT) in treating acute leukemias in children has been limited by the presence of residual occult viable leukemic cells in the marrow cell suspension. One approach to this problem is the ex vivo treatment ("purging") of the autograft to eradicate these tumor cells yet spare the normal lymphohematopoietic stem cells. Initial studies of acute myeloid leukemia (AML) in a rodent model demonstrated that incubation with 4-hydroperoxycyclophosphamide (4HC), a congener of cyclophosphamide and an active alkylating agent in aqueous solution, could effectively eliminate viable AML cells from marrow cell suspensions without apparent toxicity to normal stem cells. We have conducted clinical trials of ABMT with 4HC-treated marrow in children with acute leukemia in remission; marrow was collected, treated ex vivo with 4HC (100 micrograms/ml), and cryopreserved in liquid nitrogen until reinfusion. Children received pre-ABMT conditioning with either high-dose cyclophosphamide and total body irradiation (CY-TBI) for acute lymphocytic leukemia (ALL) or high-dose busulfan and cyclophosphamide (BU-CY) for AML. Of nine children who underwent ABMT with 4HC-treated marrow for ALL in second complete remission (CR2), all relapsed (eight in the marrow, one in the central nervous system) at a median of 5 months (range, 2-17) after ABMT and all have died with relapsed ALL or as a consequence of its treatment. Twenty-nine children with AML (five in CR1, 24 in CR2) received autografts with chemopurged marrow at a median remission duration of 3 months (range, 2-15). Three patients died from sepsis during aplasia; 10 children (one in CR1 and nine in CR2) relapsed with AML at a median of 7 months (range, 2-23) after ABMT, for an actuarial relapse rate of 47%. Sixteen patients with AML (four in CR1, 12 in CR2) are in unmaintained remission at a median of 16 months (range, 6-102) after ABMT, for an actuarial disease-free survival of 49%. Although ABMT with 4HC-treated marrow appears to have a limited role in the treatment of children with ALL who lack a suitable related donor, the results in AML are encouraging and compare favorably with both syngeneic and allogeneic BMT in similar groups of patients.