melphalan and treosulfan

Whole lung irradiation (WLI) represents an important part of multimodal therapy in Ewing sarcoma (EwS) patients diagnosed with pulmonary metastases. This review discusses pulmonary toxicity in EwS patients with pulmonary metastases treated with WLI, who received different modes of high-dose chemotheray (HD-Cth).. Literature was compiled using the Cochrane Library, PubMed database, and the National Institute of Health (NIH) clinical trials register. Relevant patient information, including nature of HD-Cth, acute and late lung toxicities, and pulmonary function disorders, was selected from the above databases.. Nine reports with a total of 227 patients, including 57 patients from a single randomized trial were included in this review. No acute or chronic symptomatic pulmonary toxicities were observed in patients that received WLI after HD busulfan-melphalan (HD-Bu/Mel), but 8% of these patients were diagnosed with asymptomatic restrictive lung disease. Grade 1 or 2 acute or chronic lung adverse effects were observed in up to 30% of patients that received WLI after HD treosulfan/Mel (HD-Treo/Mel) or HD etoposide (E)/Mel. Interstitial pneumonitis was present in 9% of patients treated concurrently with E/Mel and total body irradiation (TBI) with 8 Gy. Radiation doses as well as time between HD-Cth and WLI were both identified as significant risk factors for pulmonary function disorders.. The risk of adverse lung effects after WLI depends on several factors, including cumulative radiation dose and dose per fraction, HD-Cth regimen, and time interval between HD-Cth and WLI. A cumulative radiation dose of up to 15 Gy and a time interval of at least 60 days can potentially lead to a reduced risk of pulmonary toxicities. No evident adverse lung effects were registered in patients that received simultaneous therapy with HD-Cth and TBI. However, pulmonary function testing and lung toxicity reports were lacking for most of these patients.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Child; Combined Modality Therapy; Dose Fractionation, Radiation; Dose-Response Relationship, Radiation; Drug Administration Schedule; Etoposide; Female; Humans; Lung; Lung Diseases, Interstitial; Lung Neoplasms; Male; Melphalan; Procedures and Techniques Utilization; Radiation Pneumonitis; Radiotherapy Dosage; Radiotherapy, Intensity-Modulated; Respiratory Function Tests; Risk; Sarcoma, Ewing; Whole-Body Irradiation; Young Adult

Ewing 2008R3 was conducted in 12 countries and evaluated the effect of treosulfan and melphalan high-dose chemotherapy (TreoMel-HDT) followed by reinfusion of autologous hematopoietic stem cells on event-free survival (EFS) and overall survival in high-risk Ewing sarcoma (EWS).. Phase III, open-label, prospective, multicenter, randomized controlled clinical trial. Eligible patients had disseminated EWS with metastases to bone and/or other sites, excluding patients with only pulmonary metastases. Patients received six cycles of vincristine, ifosfamide, doxorubicin, and etoposide induction and eight cycles of vincristine, actinomycin D, and cyclophosphamide consolidation therapy. Patients were randomly assigned to receive additional TreoMel-HDT or no further treatment (control). The random assignment was stratified by number of bone metastases (1, 2-5, and > 5). The one-sided adaptive-inverse-normal-4-stage-design was changed after the first interim analysis via Müller-Schäfer method.. Between 2009 and 2018, 109 patients were randomly assigned, and 55 received TreoMel-HDT. With a median follow-up of 3.3 years, there was no significant difference in EFS between TreoMel-HDT and control in the adaptive design (hazard ratio [HR] 0.85; 95% CI, 0.55 to 1.32, intention-to-treat). Three-year EFS was 20.9% (95% CI, 11.5 to 37.9) in TreoMel-HDT and 19.2% (95% CI, 10.8 to 34.4) in control patients. The results were similar in the per-protocol collective. Males treated with TreoMel-HDT had better EFS compared with controls: median 1.0 years (95% CI, 0.8 to 2.2) versus 0.6 years (95% CI, 0.5 to 0.9);. In patients with very high-risk EWS, additional TreoMel-HDT was of no benefit for the entire cohort of patients. TreoMel-HDT may be of benefit for children age < 14 years.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Child; Consolidation Chemotherapy; Cyclophosphamide; Disease-Free Survival; Doxorubicin; Etoposide; Humans; Male; Melphalan; Prospective Studies; Sarcoma, Ewing; Vincristine

The prognosis of resistant or relapsing children with neuroblastoma remains very poor, and the search for new therapies is ongoing. In this analysis, we assessed the toxicity of a treosulfan, melphalan, and thiotepa (TMT) regimen in 17 children with recurrent or refractory neuroblastoma who underwent stem cell transplantation (SCT). For allogeneic SCT, fludarabine and antithymocyte globulin were added. The stem cell source was autologous in 8 patients, haploidentical in 8 patients, and a matched unrelated donor in 1 patient. The reported nonhematologic toxicities included grade 3 mucositis, grade 1 to 3 hypertransaminasemia, and in 3 patients, veno-occlusive disease. No neurologic, cardiac, or dermatologic toxicities were observed. The probability of overall survival (OS) in patients with primary resistance was superior to that in patients with relapsed disease (100% versus 22.6%; P = .046). Post-transplantation dinutuximab beta immunotherapy was associated with superior 5-year OS (66.7% versus 11.4%; P = .0007). The use of an allogeneic donor, previous autologous SCT with busulfan and melphalan, and pretreatment with high-dose metaiodobenzylguanidine therapy demonstrated no effect on outcomes. In 4 patients, TMT megatherapy alone was enough to achieve complete remission. The TMT conditioning regimen was well tolerated in heavily pretreated patients with neuroblastoma. The manageable toxicity and addition of new anticancer drugs with optional post-SCT immunotherapy or chemotherapy support further trials with the TMT regimen in patients with neuroblastoma.

Topics: Allografts; Antineoplastic Combined Chemotherapy Protocols; Autografts; Busulfan; Child; Child, Preschool; Disease-Free Survival; Female; Humans; Male; Melphalan; Neuroblastoma; Recurrence; Stem Cell Transplantation; Survival Rate; Thiotepa

This retrospective analysis evaluated 51 children (0.7-17 years; median eight) with high-risk or advanced hematological malignancies, including 18 (35%) patients undergoing second/third hematopoietic SCT (allo-HSCT), not eligible for standard myeloablative regimens and transplanted from matched sibling (MSD) (n=24) or matched unrelated (MUD) (n=27) donors. Preparative regimens were based on treosulfan (TREO) i.v., a structural analog of BU, given at total dose of 30 g/m(2) (n=21) or 36-42 g/m(2) (n=30) in combination with, fludarabine, cyclophosphamide, melphalan and/or VP-16 according to diagnosis, and risk factors. Deaths due to early regimen-related toxicity (RRT) did not occur. Nonrelapse mortality was 8% at 1 year and 16% after 4 years. Myeloid engraftment was achieved in 94%, complete donor chimerism in 90% of patients. A 4-year incidence of relapse was 24%, and was significantly lower after MUD-HSCT (8%) than after MSD-HSCT (39%), but similar in children undergoing first (28%) or second/third HSCT (17%). A 4-year disease-free survival was 61%, but it was significantly better in myeloid (73%), than in lymphoid malignancies (41%). Thus, children with high-risk and advanced hematological malignancies and high-risk of life-threatening RRT can be transplanted effectively and safely using TREO-based regimens. Particularly favorable results were achieved in myeloid malignancies and in children undergoing second HSCT.

Topics: Adolescent; Antineoplastic Agents, Alkylating; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Carmustine; Child; Child, Preschool; Cyclophosphamide; Disease-Free Survival; Etoposide; Female; Hematologic Neoplasms; Humans; Infant; Male; Melphalan; Retrospective Studies; Survival Rate; Transplantation Conditioning; Transplantation, Homologous; Vidarabine

Allogeneic hematopoietic stem cell transplantation (HSCT) is the only definitive treatment for severe bone marrow dysfunction and clonal disorders in patients diagnosed with Shwachman-Diamond syndrome (SDS). In an attempt to minimize regimen-related toxicity (RRT), we have initiated a fludarabine/treosulfan/melphalan-based pilot protocol avoiding the combination of busulfan and cyclophosphamide. Median age at transplantation was 9.6 years (range 1.5-17 years). All three patients received conditioning with fludarabine (30 mg/m2/day x 6), treosulfan (12 g/m2/day x 3) and melphalan (140 mg/m2/day x 1). CAMPATH-1H (0.1 mg/kg x 2) was added in two cases, while rabbit ATG (Genzyme; 3 x 2.5 mg/kg) was given to the cord blood recipient. One patient was transplanted with a non-manipulated marrow graft from an HLA-identical sibling, one with a marrow graft from a 10/10 matched unrelated donor, and one with a 9/10 matched unrelated umbilical cord blood (UCB) unit. Mean cell doses given were 3.6 x 10(8) nucleated cells/kg BW for the bone marrow recipients and 4.2 x 10(7) nucleated cells/kg BW for UCB recipient. Overall, two of three patients are alive and display 100% donor chimerism. Acute graft-versus-host disease grade II was seen in one patient, while no GVHD exceeding grade I occurred in the remaining two.

Topics: Abnormalities, Multiple; Adolescent; Bone Marrow Diseases; Busulfan; Child; Child, Preschool; Cyclophosphamide; Drug Therapy, Combination; Female; Hematopoietic Stem Cell Transplantation; Humans; Infant; Male; Melphalan; Pilot Projects; Syndrome; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Vidarabine

An international collaborative group of cancer registries and hospitals identified 114 cases of leukemia following ovarian cancer. We investigated the possible etiologic role of chemotherapy, radiotherapy, and other factors, using a case-control study design, with three controls matched to each case of leukemia. Chemotherapy alone was associated with a relative risk of 12 (95 percent confidence interval, 4.4 to 32), as compared with surgery alone, and patients treated with both chemotherapy and radiotherapy had a relative risk of 10 (95 percent confidence interval, 3.4 to 28). Radiotherapy alone did not produce a significant increase in risk as compared with surgery alone. The risk of leukemia was greatest four or five years after chemotherapy began, and the risk was elevated for at least eight years after the cessation of chemotherapy. The drugs cyclophosphamide, chlorambucil, melphalan, thiotepa, and treosulfan were independently associated with significantly increased risks of leukemia, as was the combination of doxorubicin hydrochloride and cisplatin. Chlorambucil and melphalan were the most leukemogenic drugs, followed by thiotepa; cyclophosphamide and treosulfan were the weakest leukemogens, and the effect per gram was substantially lower at high doses than at lower doses. The extent to which the relative risks of leukemia are offset by differences in chemotherapeutic effectiveness is not known.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Case-Control Studies; Chlorambucil; Combined Modality Therapy; Cyclophosphamide; Female; Humans; Leukemia; Melphalan; Multicenter Studies as Topic; Neoplasms, Multiple Primary; Ovarian Neoplasms; Registries; Risk Factors; Thiotepa

Chediak-Higashi syndrome is a rare immunodeficiency disorder for which hematopoietic stem cell transplant (HSCT) is the only curative treatment option. HSCT only corrects the hematologic and immunologic manifestations of the disease but neurologic complications may still progress after transplant. Haploidentical HSCT (haplo-HSCT) has evolved as a feasible alternative for patients with primary immunodeficiency. More recently, there has been use of haplo-HSCT with post-transplant cyclophosphamide. However, only 4 cases of Chediak-Higashi syndrome have been reported using this approach. Here, the authors describe a case of a 17-month-old boy who was successfully treated by haplo-HSCT with reduced-toxicity conditioning (fludarabine/treosulfan/melphalan) and post-transplant cyclophosphamide.

Topics: Antineoplastic Combined Chemotherapy Protocols; Busulfan; Chediak-Higashi Syndrome; Combined Modality Therapy; Cyclophosphamide; Hematopoietic Stem Cell Transplantation; Humans; Infant; Male; Melphalan; Prognosis; Transplantation Conditioning; Vidarabine

This retrospective single-center analysis studied the impact of the conditioning and the graft-versus-host disease (GVHD) prophylaxis on outcome in unselected patients allografted for chronic myelomonocytic leukemia (CMML) and acute myeloid leukemia (AML) secondary to documented prior CMML. A total of 44 patients (median age 61 years) allografted between 2002 and 2019 in our institution were analyzed. Fifteen patients had secondary AML. The conditioning regimen was fractionated 6-8 Gy total body irradiation (TBI) in combination with fludarabine in 33 (75%) patients. Eleven patients (25%) received alkylator-based conditioning therapy without TBI. For GVHD prophylaxis, a calcineurin inhibitor (CNI) backbone in combination with methotrexate (MTX) or mycophenolate mofetil (MMF) was applied in 21 and 23 patients, respectively. All patients allografted from an unrelated donor (UD) received antithymocyte globuline. In univariate analysis of the entire cohort, TBI-based conditioning and MMF-containing immunosuppression were associated with improved leukemia-free survival (LFS, HR 0.16, P < 0.001 and HR 0.41, P = 0.030, respectively). After stratification according to conditioning and GVHD prophylaxis into four groups (TBI-MMF [n = 17], TBI-MTX [n = 16], alkylator-MMF [n = 6], alkylator-MTX [n = 5]), TBI-MMF was associated with improved overall survival (OS) and LFS (P = 0.001 and P < 0.001, respectively). Patient and disease characteristics did not differ between the groups. The associations of TBI-based conditioning and MMF with prolonged LFS were observed across the CMML (n = 29), secondary AML (n = 15), and UD allograft (n = 34) subgroups. In summary, our study suggests that allografting based on intermediate-dose TBI conditioning and MMF-containing GVHD prophylaxis is associated with increased disease control in CMML. Larger (registry-based) studies are warranted to confirm our findings.

Topics: Adult; Aged; Antilymphocyte Serum; Busulfan; Calcineurin Inhibitors; Disease-Free Survival; Female; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Leukemia, Myeloid, Acute; Leukemia, Myelomonocytic, Chronic; Male; Melphalan; Methotrexate; Middle Aged; Mycophenolic Acid; Myeloablative Agonists; Neoplasms, Second Primary; Proportional Hazards Models; Retrospective Studies; T-Lymphocytes; Transplantation Conditioning; Transplantation, Homologous; Vidarabine; Whole-Body Irradiation

Reduced toxicity conditioning for hematopoietic stem cell transplantation of patients with hemophagocyticlymphohistiocytosis (HLH) results in favorable survival, however at the expense of relevant rates of mixed chimerism. Factors predisposing to mixed chimerism remain to be determined.. Patients with primary HLH transplanted 2009-2016 after treosulfan- or melphalan-based conditioning regimens were analyzed in a retrospective multicenter study for survival, engraftment, chimerism, and adverse events. Mixed chimerism was considered substantial if < 25% donor chimerism occurred and/or if secondary cell therapy was administered. Donor type, graft source, type of alkylating agent, type of serotherapy, and remission status were analyzed as potential risk factors in a multivariable logistic regression model.. Among 60 patients, engraftment was achieved in 95%, and the five-year estimated overall survival rate was 75%. Prevalence of any recipient chimerism was 48%. Substantial recipient chimerism was recorded in 32% of patients. Secondary post-HSCT cell therapy was administered in 30% of patients. A human leukocyte antigen (HLA)-mismatched donor (< 10/10) was the only significant risk factor for the occurrence of substantial recipient chimerism (P = 0.01; odds ratio, 5.8; CI 95%, 1.5-26.3).. The use of an HLA-matched donor is the most important factor to avoid substantial recipient chimerism following treosulfan -or melphalan-based conditioning in primary HLH.

Topics: Adolescent; Antineoplastic Combined Chemotherapy Protocols; Busulfan; Child; Child, Preschool; Chimerism; Female; Follow-Up Studies; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; HLA Antigens; Humans; Infant; Lymphohistiocytosis, Hemophagocytic; Male; Melphalan; Prognosis; Retrospective Studies; Risk Factors; Survival Rate; Tissue Donors; Transplantation Conditioning; Transplantation, Homologous

Infantile malignant osteopetrosis (IMO) is an autosomal recessive condition characterized by defective osteoclast activity, with hematopoietic bone marrow transplant being the only available cure. Over the past several years, new conditioning regimes and donor options have emerged, thus extending the possibility of cure to a greater number of patients and improving the outcomes of bone marrow transplant. Here we detail the outcomes of bone marrow transplant in a cohort of 31 patients treated with a combination of fludarabine, treosulphan, thiotepa, and antithymocyte globulin.. Thirty-one patients with IMO who underwent hematopoietic stem cell transplantation with fludarabine, treosulphan, thiotepa, and antithymocyte globulin at our center from 2012 to 2017 are retrospectively reviewed in this study. Twenty-six patients were transplanted from 10/10 matched donors (13 from siblings, 11 from unrelated, and two from extended family donors), four from 9/10 matched unrelated donors, and one from a 9/10 matched family donor.. Overall survival was 100% with a median follow-up of 363 days (range 74-1891). There were 12 cases of acute graft versus host disease (GvHD) (38.7%), no cases of veno-occlusive disease, and eight cases of hypercalcemia (25.8%). Almost 80% of patients suffered viral reactivations with two cases of Epstein-Barr-virus-driven post-transplant lymphoproliferative disease. All cases of GvHD and viral reactivation were successfully treated.. We conclude that transplantation in children with IMO using fludarabine, treosulphan, thiotepa, and antithymocyte globulin is safe and effective and should be performed as early as possible following diagnosis, prior to the development of severe disease sequelae.

Topics: Adolescent; Adult; Antilymphocyte Serum; Busulfan; Child; Child, Preschool; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Infant; Infant, Newborn; Male; Melphalan; Myeloablative Agonists; Osteopetrosis; Prognosis; Retrospective Studies; Transplantation Conditioning; Vidarabine; Young Adult

Multiple myeloma is a non-curable haematological disease involving transformed plasma cells. High rates of complete remission can be achieved with autologous peripheral blood stem cell transplantation. Treosulfan is an alkylating substance that has been used in the treatment of ovarian carcinomas for many years. It has a favourable side-effect profile even at high-dose protocols. Thus, the objective of this study was to evaluate the effect of treosulfan on myeloma cells. The treatment of the myeloma cell lines, NCI-H929 and U266, with treosulfan led to apoptosis in both cell lines in a dose- and time-dependent manner. The induction of apoptosis was accompanied by cleavage of caspases -3 and -9 as well as downregulation of the antiapoptotic protein Mcl-1 and upregulation of the inhibitor of cyclin-dependent kinases, p21WAF1/CIP1. Furthermore, 100 micro mol/l treosulfan was capable of inducing cell death in 63.6 +/- 23.9% of primary myeloma cells, whereas treatment with the same concentration of melphalan showed 59.7 +/- 26% cell death. These in vitro concentrations were at least 10-fold lower than achievable plasma levels, even at conventional doses of treosulfan. Our results suggest that treosulfan might be an appropriate candidate for novel treatment protocols for patients with multiple myeloma.

Topics: Aged; Aged, 80 and over; Antineoplastic Agents, Alkylating; Apoptosis; Busulfan; Caspases; Cell Death; Dose-Response Relationship, Drug; Down-Regulation; Female; Humans; Male; Melphalan; Middle Aged; Multiple Myeloma; Myeloid Cell Leukemia Sequence 1 Protein; Neoplasm Proteins; Proto-Oncogene Proteins c-bcl-2; Tumor Cells, Cultured

Three human carcinogens, 4-aminobiphenyl, treosulphan, and melphalan, were tested for the induction of micronuclei or chromosomal aberrations in the bone marrow cells of male B6C3F1 mice. These studies were conducted to provide further information on the in vivo genetic toxicity of compounds known to cause cancer in humans. All three compounds gave positive results in the mouse bone marrow micronucleus test, and melphalan, the only compound tested for aberration induction, was positive in this assay. These results extend the evidence that nearly all known human carcinogens are detected in relatively simple and widely employed short-term in vivo tests.

Topics: Aminobiphenyl Compounds; Animals; Bone Marrow; Busulfan; Carcinogens; Chemical Phenomena; Chemistry; Chromosome Aberrations; Male; Melphalan; Mice; Micronucleus Tests