Cyclophosphamide-based Conditioning Regimen Research Articles

442.8: Selective BCL-2 inhibition to promote hematopoietic mixed chimerism and renal allograft tolerance in low-dose cyclophosphamide-based conditioning regimen without myelosuppression.

442.8: Selective BCL-2 inhibition to promote hematopoietic mixed chimerism and renal allograft tolerance in low-dose cyclophosphamide-based conditioning regimen without myelosuppression.

Fludarabine- and Low-Dose Cyclophosphamide-Based Conditioning Regimens for Unmanipulated Hematopoietic Cell Transplantation from Unrelated Donors and Matched Siblings in Patients with Fanconi Anemia: Results from the Cbmtr

Hematopoietic cell transplantation (HCT) is the only option to cure hematopoietic complications in Fanconi anemia (FA). We have analyzed 98 unmanipulated HCT from matched siblings and unrelated donors. Overall, the outcomes were favorable, with 100% primary engraftment, 76.7% (66.3-84.3%) probability of three-year overall survival (OS), and 75.9% (65.5-83.5%) of event-free survival (EFS). The incidence of acute graft-versus-host disease (GvHD) was 38.8% (27.1-50.3%) for grade II-IV and 23.4% (11.2-38.2%) for grade III-IV. The incidence of chronic GvHD was 27.7% (13.2-43.7%) for all grades and 13.0% (1.4-34.1%) for moderate-to-severe disease. Comparing different conditioning regimens, patients conditioned with fludarabine (Flu) and low-dose cyclophosphamide (Cy) achieved 100% probabilities of OS and EFS, which was superior to those with additional busulfan (Bu) or irradiation (P=.024 and .020, respectively). No significant difference was found in the incidences of GvHD across conditioning regimens. We demonstrated that high-dose Bu (> 6.4 mg/kg vs. ≤ 6.4 mg/kg) was associated with an increased risk of death [hazard ratio (HR)=6.705 (2.384-18.855), P<.001] and events [HR=5.434 (2.060-14.334), P=.001]. In conclusion, unmanipulated HCT from matched siblings and unrelated donors achieved favorable engraftment, OS, and EFS in FA patients. Our data suggested that conditioning regimens based on Flu and low-dose Cy provided excellent survival. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

Clinical Characteristics of Patients with Different N-Terminal Probrain Natriuretic Peptide Levels after Hematopoietic Stem Cell Transplantation.

Heart failure (HF) is not uncommon among patients with hematologic malignancies (HM) undergoing hematopoietic stem cell transplantation (HSCT) and is associated with an increased mortality. Among HSCT patients without signs or symptoms of HF, groups with elevated and normal N-terminal probrain natriuretic peptide (NT-proBNP) levels have been poorly characterized in previous literature. Herein, we reviewed consecutive admissions for HM undergoing HSCT (n = 301). Based on NT-proBNP levels and clinical signs or symptoms of HF at follow-up (one month after HSCT), patients were grouped into ENPH (elevated NT‐proBNP > 125 pg/mL, presence of HF symptoms or signs), ENAH (elevated NT‐proBNP > 125 pg/mL, absence of HF symptoms or signs), and NN (normal NT‐proBNP < 125 pg/mL). ENPH, ENAH, and NN were observed in 22.9%, 54.5%, and 22.6% of patients, respectively. ENPH patients had a significantly higher baseline NT-proBNP level, followed by the ENAH and NN groups, respectively (P < 0.001). Frequencies of HLA partially matched related donors, stem cell source (bone marrow+peripheral blood), and utilization of graft-versus-host disease prophylaxis regimens (ciclosporin+methotrexate+antithymocyte globulin±mycophenolate mofetil) were also the highest in the ENPH group, followed by ENAH and NN groups, respectively (all P < 0.05). Uric acid and hemoglobin levels, transplant type, and cyclophosphamide-based conditioning regimens utilized were similar between the ENAH and ENPH groups. We found that ENPH and ENAH are commonly observed in HM hospitalized for HSCT. Serum NT-proBNP levels may allow for earlier identification of HSCT patients at high risk of developing cardiac dysfunction.

BEAM Vs Cyclophosphamide-Based Conditioning Regimen in Aggressive Multiple Sclerosis: A Retrospective Analysis of European Blood and Marrow Transplantation Society

Background Multiple Sclerosis (MS) is a chronic, immuno-mediated disease of Central Nervous System (CNS), mostly affecting young adults and frequently resulting in a progressive, irreversible disability despite the administration of approved Disease Modifying Treatments (DMTs). Autologous HSCT was shown to induce a high rate of sustained, treatment-free remissions in cases of aggressive MS, seldom associated to a partial reversal of disability. Toxicity of Conditioning Regimen is still a major concern. We retrospectively analyzed the outcome of 926 MS patients reported to the EBMT Registry who underwent autologous HSCT following the two most frequent CRs for this indication in the last 20 years. Patients and Methods Patient data were extracted from both the EBMT database and a disease-specific database developed by the EBMT Autoimmune Diseases Working Party (ADWP). Patients were selected for having received either BEAM + ATG (BEAM) or HD-Cyclophosphamide + ATG (CYC) as conditioning regimen. Hematological toxicity was assessed through Neutrophil (PMN) engraftment and 100-days (early) mortality (eTRM). MS forms at HSCT were reported as Relapsing-Remitting (RR), Secondary Progressive (SP), Primary Progressive (PP) and Progressive-Relapsing (PR). The impact of variables related to both patients (age, gender, year of HSCT, EDSS at HSCT) and disease characteristics (MS form, interval diagnosis-HSCT) at HSCT in the two groups were also evaluated. Results The utilization of conditioning regimens along the observed time period (1998-2018) was variable, with an increase of the HSCT activity in general after 2010 (230 vs 697 procedures) and a prevalence of BEAM before 2010 (205 BEAM vs 25 CYC) and of CYC thereafter (205 BEAM vs 492 CYC, p=0.001). Also, RR forms of MS prevailed over Progressive forms after 2010 (p=0.001) which is reflected in the different distribution across the two regimens, with RR significantly more frequently treated with CYC-based regimen (p&lt;0.001). Gender distribution and age at HSCT was similar in the two groups (p=ns), whilst the interval between diagnosis and HSCT was longer in BEAM group than CYC (8.47 years ± 5.9 vs 7.57 ±5.5, mean ± SD, p=0.012). PMN engraftment in BEAM/ATG- and CYC/ATG-treated patients occurred at +11.0 (8-42) and +10.9 (8-95) days, respectively (median and range, p=ns). Overall eTRM was low (1.4%), but slightly higher in BEAM over CYC (8/402, 2% vs 5/517, 1%, p=ns). Discussion Although autologous HSCT is increasingly used as a treatment in highly active MS, toxicity remains a principal concern in the neurological community despite a marked decrease of TRM over time. The intensity of conditioning regimens has varied in the literature, but the best toxicity/efficacy ratio remains unclear. The non-myeloablative regimen CYC-ATG has become the most common conditioning regimen despite a lack of comparative data with more intense regimens. In our large retrospective analysis of the two most frequent conditioning regimens in the EBMT Registry, there was no significant difference in major toxicity indicators despite differences in chronological period and patients characteristics in the two groups. Comparative analysis of neurological efficacy is currently ongoing and will inform the toxicity/efficacy ratio and clinical choice of conditioning regimen in autologous HSCT in MS. Disclosures Mielke: Bellicum: Consultancy, Honoraria, Other: Travel (via institution); Jazz Pharma: Honoraria, Other: Travel support, Speakers Bureau; IACH: Other: Travel support; Kiadis Pharma: Consultancy, Honoraria, Other: Travel support (via institution), Speakers Bureau; Miltenyi: Consultancy, Honoraria, Other: Travel and speakers fee (via institution), Speakers Bureau; DGHO: Other: Travel support; GILEAD: Consultancy, Honoraria, Other: travel (via institution), Speakers Bureau; Celgene: Honoraria, Other: Travel support (via institution), Speakers Bureau; ISCT: Other: Travel support; EBMT/EHA: Other: Travel support.

A randomized, placebo-controlled pilot trial of aprepitant combined with standard antiemetic therapy for the prevention of chemotherapy-induced nausea and vomiting in patients undergoing cyclophosphamide-based conditioning regimens prior to hematopoietic stem cell transplant (HSCT).

The aim of this study was to evaluate the safety and efficacy of aprepitant when used prophylactically to prevent nausea and vomiting during cyclophosphamide-based conditioning regimens. The primary objective of this study was to determine if there was a difference in the number of emesis-free days in patients who received aprepitant as compared to those who received placebo. This prospective, randomized, double blind, placebo-controlled study was performed in 40 adult patients who received a cyclophosphamide-containing HSCT conditioning regimen. Twenty patients were randomized to receive aprepitant, ondansetron, and dexamethasone, and 20 were randomized to receive placebo, ondansetron, and dexamethasone. Complete response (CR) was defined as the absence of emesis and the absence of mild to moderate nausea. The average number of emesis-free days was 14.25 (standard deviation 1.48 days) in the aprepitant group compared to 12.45 days (standard deviation 2.16 days) for patients in the placebo group. Eight patients (40%) in the aprepitant group achieved CR as compared to four patients (20%) in the placebo group. In the setting of cyclophosphamide-containing conditioning regimens, the addition of aprepitant to a standard antiemetic regimen decreased the incidence of emesis as compared to placebo. Aprepitant was well tolerated.

Pilot trial of risk‐adapted cyclophosphamide intensity based conditioning and HLA matched sibling and unrelated cord blood stem cell transplantation in newly diagnosed pediatric and adolescent recipients with acquired severe aplastic anemia

Cyclophosphamide-based conditioning regimens and allogeneic hematopoietic stem cell transplantation (AlloHSCT) from matched related donors (MRD) has resulted in the highest survival rates in children and adolescents with acquired severe aplastic anemia (SAA). Time to transplant has consistently been associated with decreased overall survival. Reduced toxicity conditioning and AlloHSCT has been used successfully in other pediatric non-malignant diseases. We piloted a risk-adapted AlloHSCT approach, using fludarabine and anti-thymocyte globulin based conditioning with high (200 mg/kg) and low (60 mg/kg) dose cyclophosphamide as upfront treatment in newly diagnosed pediatric patients with acquired SAA incorporating alternative donor sources, including cord blood. Average risk for non-engraftment patients with <10 transfusions received low dose cyclophosphamide (60 mg/kg); High Risk, those with ≥10 transfusions received conditioning regimen with higher intensity cyclophosphamide (200 mg/kg). Seventeen patients were enrolled and underwent AlloHSCT including 12 males and 5 females with mean age of 8 years (range 3-16), and median follow-up time of 39 months (range 1-135). Donor sources included MRD BM (6/6 [n = 9], 5/6 [n = 2]) and unrelated CB (5/6 [n = 4], 4/6 [n = 2]). Five year OS was 67.6% (37.9-85.4). Three secondary graft failures (17.6%) occurred in the low dose cyclophosphamide arm. Upfront treatment with risk-adapted cyclophosphamide conditioning AlloSCT is well tolerated for the management of newly diagnosed pediatric and adolescent patients with acquired SAA. However, the increased risk of graft rejection in the lower dose arm warrants additional research regarding the optimal intensity of cyclophosphamide-based conditioning regimen to reduce toxicity without increasing graft failure.

More Intensity Immuno-Suppression In Conditioning Regimen may Favor Donor Stem Cell Sustained Engraftment In Allogeneic Stem Cell Transplantation For Acquired Severe Aplastic Anemia Patients

BackgroundHematopoietic stem cell transplantation (HSCT) is the first-line therapy for patients younger less than 40 years old with severe aplastic anemia (SAA). And the long-term survival for patients with SAA who received HSCT reaches to 70%-90%. Cyclophosphamide-based conditioning regimen with or without antithymocyte globulin (ATG) has been adopted in majority of HSCT for SAA patients with HLA matched related donor. However the graft rejection and graft failure in HSCT for SAA with cyclophosphamide-based conditioning regimen is still as high as 5%-16%. The aim of this study is to explore whether more immue suppression in conditioning regimen could favor the donor stem cells sustained engraftment for severe aplastic anemia patients receiving allogeneic hematopoietic stem cell transplantation. Fludarabine and busulfan were added in cyclophosphamide-based conditioning regimen to intensity immune suppression in conditioning. MethodsTo analyze the outcomes and chimeras of 40 patients with SAA who received HLA matched allo-HSCT from 2000 to 2012 with either fludarabine-based conditioning regimen or cyclophosphamide-based conditioning regimen retrospectively and to explore the relationship between the chimeras and conditioning regimen. ResultsForty patients with SAA who received HLA matched allo-HSCT From May, 2000 to Dec. 2012. Twelve patients ( median age 25 year old range 13-52, male 7, femal 5) received fludarabine-based conditioning regimen which composed of fludarabine (30 mg/m2/d ×5d), busulfan ( 3 mg/kg ×2d ), cyclophosphamide ( 60mg/kg/d×2d) and ATG (2.5mg/kg/d ×5d). Twenty patients( median age 23 year old range 12-42, male 19, femal 9) received cyclophosphamide-based conditioning regimen which composed of cyclophosphamide (50mg/kg/d ×4d )and ATG (2.5mg/kg/d ×2d ). The median dose of MNC were 4.5×108/kg (range 3.8-7.0×108/kg )and 3.58×108/kg (range 3.2-6.8×108/kg ) and CD34+ cells were 4.5×108/kg and 3.58×108/kg respectively. GVHD prophylaxis were cyclosporine and short-term course methotrexate. Donor chimera was detected on day+30, +90, +180, and 360 after HSCT by short tandem repeat polymerase chain reaction, or fluorescein in situ hybridization for X and Y chromosomes in cases when patients and donors were sex mismatched. ResultsAll patients with fludarabine-based conditioning regimen were successful Hematopoietic reconstitution and no graft failure occurred in this group patients. But two patients could not get recovery in cyclophosphamid-based conditioning regimen group. And complete donor chimeras always present when chimeras were detected by STR-PCR or FISH at day 30,day 60, day 90 and d 180 post transplantation in fludarabine-based conditioning regimen group, while seven patients with cyclophosphamide-based conditioning regimen were mixed chimeras at day 30 post transplant. The graft was rejected in six of the seven patients at day 90 post transplant in cyclophosphamide-based conditioning regimen group. The complete donor chimera in fludarabine-based conditioning regimen group was obvious higher than that in cyclophosphamide-based conditioning regimen group ( p=0.037). The incidence of aGVHD in the fludarabine group was 16.7% and 10.7% in the cyclophosphamide-based group. There is no significant difference of aGVHD between two group (P = 0.627). The incidence of cGVHD was 8.3% and 10.7% respectively. The bacterial infections developed in 16.7% and 28.6% of patients respectively (P=0.693), The overall survival were 83.33% and 82.14% in fludarabine-based conditioning regimen group and cyclophosphamide-based group respectively (p=0.870). ConclusionsMore intensity immuno-suppression in conditioning regimen may favor donor stem cell sustained engraftment in allogeneic stem cell transplantation for acquired severe aplastic anemia patients. Disclosures:No relevant conflicts of interest to declare.

French Multicenter 22-Year Experience in Stem Cell Transplantation for Beta-Thalassemia Major: Lessons and Future Directions

Although hematopoietic stem cell transplantation (HSCT) offers curative potential for beta-thalassemia major (beta-TM), it is associated with a variable but significant incidence of graft rejection. We studied the French national experience for improvement over time and the potential benefit of antithymocyte globulin (ATG). Between December 1985 and December 2007, 108 patients with beta-TM underwent HSCT in 21 different French transplantation centers. The majority of patients received a matched sibling transplant (n = 96) and a busulfan- and cyclophosphamide-based conditioning regimen (n = 95), also with ATG in 57 cases. Ninety-five of the 108 patients survived, with a median follow-up of 12 years. Probabilities of 15-year survival and thalassemia-free survival after first HSCT were 86.8% and 69.4%, respectively. Graft failure occurred in 24 patients, 11 of whom underwent a second HSCT. The use of ATG was associated with a decrease in rejection rate from 35% to 10%. Thalassemia-free survival improved significantly with time, reaching 83% in the 54 patients undergoing HSCT after 1994 (median time of HSCT). In view of the increased risk of graft rejection after matched sibling HSCT, current French national guidelines recommend, for all children at risk for beta-TM, the systematic addition of ATG to the myeloablative conditioning regimen and special attention to optimize transfusion and chelation therapy in the pretransplantation period.

SAFETY OF HEMATOPOIETIC STEM CELL TRANSPLANTATION IN CHILDREN LESS THAN THREE YEARS OF AGE

Allogeneic hematopoietic stem cell transplantation (HSCT) is a standard treatment for a variety of hematologic conditions. However, very young children may experience different complications of HSCT compared to older patients. The authors retrospectively analyzed the results of 51 transplants performed on children less than 3 years of age between June 1987 and October 2005. Donors were matched-related (n = 21), partially mismatched related (n = 3), and unrelated (n = 27). The majority of patients had one or more grade III organ toxicities, but all nonrelapse deaths were attributable to infection. Perineal dermatitis was found in a large number (73%) of recipients of cyclophosphamide-based conditioning regimens. The 1-year transplant-related mortality (TRM) was 14%, but significantly declined in the more modern period. Grades II–IV acute graft-versus-host-disease (GvHD) was seen in 22% of patients, while chronic extensive GvHD developed in only 7% of patients. Relapse was seen in 40% of transplants performed for a malignant condition, most commonly in those patients not in remission at time of HSCT. The 5-year event-free survival (EFS) and overall survival (OS) were 53 and 64%, respectively. Recipients of fractionated total body irradiation (fTBI) were more likely to have at least one long-term sequelae than patients who received chemotherapy-based regimens (p =. 014). These data demonstrate that HSCT can be performed safely in very young children, especially as supportive-care techniques improve. Cyclophosphamide-related perineal dermatitis is a unique complication in very young children. Finally, the incidence of acute and chronic GvHD in this population is low.

Allogeneic stem-cell transplantation of renal cell cancer after nonmyeloablative chemotherapy: feasibility, engraftment, and clinical results. Rini BI, Zimmerman T, Stadler WM, Gajewski TF, Vogelzang NJ, University of California San Francisco, Comprehensive Cancer Center, San Francisco, CA: J Clin Oncol 2002;20:2017–2024

Purpose To evaluate the feasibility and safety of nonmyeloablative allogeneic stem-cell transplantation in patients with metastatic renal cell cancer (RCC) and to evaluate efficacy with respect to engraftment and tumor regression. Patients and methods Between February 1999 and June 2001, patients with refractory, metastatic RCC were screened for enrollment. A fludarabine and cyclophosphamide-based conditioning regimen was used. Patients received granulocyte-macrophage colony-stimulating factor-mobilized, unmanipulated stem cells from a 6/6 HLA-matched sibling donor. Prophylaxis against graft rejection and graft-versus-host disease (GVHD) included tacrolimus and mycophenolate mofetil. Results A total of 284 patients with metastatic RCC were seen during this time period. Eighty-four patients who had siblings available for HLA typing were actively screened for enrollment, and 15 patients have undergone treatment. Durable donor engraftment was achieved in one of the first four patients treated. Patients 5 through 15 received a more immunosuppressive conditioning regimen, and all have achieved sustained donor engraftment. In the 12 patients with at least 180 days of follow-up, acute GVHD has occurred in 2 patients and chronic GVHD in 6 patients, with 4 transplant-related mortalities. Four partial responses have been observed (response rate, 33% in all patients; 44% in the 9 patients with sustained donor engraftment). Conclusion Nonmyeloablative allogeneic stem-cell transplantation is feasible for a minority of patients with metastatic RCC. Adequately immunosuppressive conditioning is required for sustained donor engraftment, which is required for an antitumor response. Acute and chronic GVHD are the major causes of substantial morbidity and mortality. Metastatic RCC is susceptible to a graft-versus-tumor effect promoted by allogeneic stem-cell transplantation.