Cyclophosphamide and Thiotepa Increases Risk of Transplant-Associated Thrombotic Microangiopathy.

Transplant associated thrombotic microangiopathy (TA-TMA) is a complication of hematopoietic cell transplant (HCT) associated with endothelial injury resulting in severe end organ damage, acute and long-term morbidity, and mortality. Myeloablative conditioning is a known risk factor, though specific causative agents have not been identified. We hypothesized that the combination of cyclophosphamide and thiotepa (CY + TT) is particularly toxic to the endothelium, placing patients at elevated risk for TA-TMA. We conducted a retrospective review of pediatric and young adult patients who received conditioned autologous and allogeneic HCT between 2012 and August 2023 at UCSF Benioff Children's Hospital, San Francisco. We excluded patients undergoing gene therapy or triple tandem transplants for brain tumors. Neuroblastoma tandem transplants were classified a single transplant occurrence. High dose N-acetylcysteine (NAC) prophylaxis was incorporated into the institutional standard of care from December 2016-May 2019 and May 2022-August 2023. Defibrotide was given prophylactically to patients deemed high-risk for sinusoidal obstruction syndrome (SOS) per institutional guidelines or on clinical trial NCT#02851407 for SOS prophylaxis or NCT#03384693 for TA-TMA prophylaxis. Kaplan-Meier analysis was used to estimate the 1-year cumulative incidence of TA-TMA. Univariate analysis was performed for each of the potential risk factors of interest using log-rank tests and bivariate analysis with Cox regression models using backward selection and hazard ratios were built using all covariates with a univariate P-value < .2 for allogeneic HCT. SPSS (v29) was used to estimate all summary statistics, cumulative incidences, and uni- and bi-variate analyses. A total of 558 transplants were performed with 43 patients developing TA-TMA, for a 1-year cumulative incidence of 8.6% (95% CI, 5.9-11.3) and 7.2% (95% CI, 2.9-11.5) in allogeneic and autologous HCTs, respectively (P = .62). In allogeneic recipients (n = 417), the 1-year cumulative incidence of TA-TMA with CY + TT as part of conditioning was 35.7% (95% CI, 15.7-55.7) compared to 11.7% (95% CI, 7.2-16.2) with either CY or TT alone, and 1.2% (95% CI, 0-2.8) if neither agent was included in the conditioning regimen (P < .001). Use of either CY or TT (HR = 10.14; P = .002) or CY + TT (HR = 35.93; P < .001), viral infections (HR = 4.3; P = .017) and fungal infections (HR = 2.98; P = 0.027) were significant factors resulting in increased risk for developing TA-TMA. In subjects undergoing autologous HCT (n = 141), the 1-year cumulative incidence of TA-TMA with CY + TT was 19.6% (95% CI, 8.8-30.6) while TA-TMA did not occur in patients receiving either CY or TT alone or when neither were included (P < .001). TA-TMA occurred only in patients with neuroblastoma receiving CY + TT as part of their conditioning. For autologous patients who received CY + TT, those who were CMV seronegative at the time of HCT had an incidence of TA-TMA of 6.7% (95% CI, 0.1-15.7) compared to 38.1% (95% CI, 35-41.2) for those CMV seropositive (P = .007). These data show that CY or TT alone or in combination as part of pre-transplant conditioning prior to HCT increase the incidence of TA-TMA. Alternative conditioning excluding the combination of CY + TT should be considered whenever possible to limit the development of TA-TMA.

Revisiting intrathecal thiotepa: Efficacy and safety in secondary CNS malignancies.

Treating metastatic malignancies to the central nervous system (CNS) is challenging because many drugs cannot cross the blood-brain-barrier (BBB). Direct intrathecal (IT) drug administration into the cerebrospinal fluid (CSF) is a strategy to overcome this problem. Thiotepa has effective CNS penetration but its popularity has waned over the last two decades due to concerns about its efficacy and potential systemic toxicity. This review evaluates the available evidence for the use of IT thiotepa in hematologic malignancies and non-CNS solid tumors with leptomeningeal disease metastases (LMD). Our search shows that IT thiotepa is a reasonable alternative in hematologic malignancies and LMD due to solid organ malignancies. This suggests a potential role of IT thiotepa in second-or third-line treatment or a substitute role in cases of drug-shortages and adverse effects with other agents. Future research should focus on rigorous comparative trials to establish its definitive role in the evolving landscape of CNS-directed chemotherapy.

Total body irradiation versus thiotepa/busulfan-based conditioning regimens for myeloablative allogeneic stem cell transplantation in adults with acute lymphoblastic leukemia.

Total body irradiation (TBI)-based conditioning regimens are generally recommended for allogeneic HSCT (allo-HSCT) in patients with acute lymphoblastic leukemia (ALL). Recent evidence suggests that modern chemotherapy-based regimens may be as effective. This multicenter retrospective study compared the clinical outcomes of myeloablative allo-HSCT with thiotepa, busulfan, and cyclophosphamide/fludarabine (TTB) to TBI-based conditioning. Between 2002 to 2018, 63 and 114 patients received TTB- and TBI-based conditioning regimens, respectively. The 5-year cumulative incidence of relapse was lower in the TBI cohort compared to the TTB cohort (30% [95% CI, 22-38] versus 47% [95% CI, 36-59]; P = 0.03). Multivariate analysis identified T-ALL, Ph-negative B-ALL, and measurable residual disease associated with a higher relapse risk. The 5-year cumulative incidence of non-relapsed mortality (NRM) was significantly lower with TTB (12% [95% CI, 5-20]) compared to TBI (25% [95% CI, 18-33]) (P = 0.001). Multivariate analysis found TBI conditioning, older age, and advanced stages of ALL at transplantation associated with a higher NRM. No statistical difference was seen in overall survival (49% [95% CI, 40-58] and 46% [95% CI, 35-60]) in the TBI and TTB groups, respectively; P = 0.9). The study suggests that TTB-based conditioning may be a promising option for ALL patients undergoing allo-HSCT, as it resulted in similar OS and lower NRM than TBI-based conditioning.

Outcomes from hematopoietic stem cell transplantation following treosulfan-based conditioning: A clinical and pharmacokinetic analysis.

BACKGROUND: The aims of this study are to report our experience with treosulfan-based conditioning regimens for patients with non-malignant hematologic conditions, correlating clinical outcomes at different time points post-transplant with treosulfan exposure (AUC). METHODS: This study was a single-center observational study investigating overall survival (OS), disease-free survival (DFS), and event-free survival (EFS) end-points post-transplant. The consequences of treosulfan AUC with respect to toxicity, correction of underlying disease, and long-term chimerism were also explored using pharmacokinetic analysis. RESULTS: Forty-six patients received 49 transplants with treosulfan and fludarabine-based conditioning between 2005 and 2023. Twenty-four patients also received thiotepa. Donor chimerism was assessed on either whole blood or sorted cell lines at different time points post-transplant. Thirty-nine patients received treosulfan pharmacokinetic assessment to evaluate cumulative AUC, with five infants receiving real-time assessment to facilitate daily dose adjustment. OS, DFS, and EFS were 87%, 81%, and 69%, respectively. Median follow-up was 32.1 months (range 0.82-160 months) following transplant. Lower EFS was associated with patient age (<1 year; p = .057) and lower cumulative treosulfan dose (<42 g/m2; p = .003). Stable donor chimerism in B-cell, NK-cell, and granulocyte lineages at 1-year post-transplant were more prevalent in patients receiving thiotepa conditioning. Two infants required daily dose adjustment to treosulfan to avoid high AUC. CONCLUSIONS: Excellent clinical outcomes and stable chimerism were observed in this patient series. The addition of thiotepa conferred no significant toxicity and trended toward sustained ongoing donor engraftment. Correlating treosulfan AUC with long-term patient outcomes is required.

Thiotepa-busulfan-fludarabine-based conditioning as a promising approach prior to allogeneic hematopoietic stem cell transplantation in patients with blastic plasmacytoid dendritic cell neoplasm.

Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a rare and aggressive myeloid malignancy associated with a poor prognosis. Although allogeneic hematopoietic stem cell transplantation (allo-HSCT) has emerged as a potential treatment strategy for BPDCN, standardized conditioning regimens remain lacking. In this manuscript, we present two cases of BPDCN that were treated with a thiotepa-busulfan-fludarabine (TBF)-based conditioning regimen prior to allo-HSCT. Both cases demonstrated complete remission post-transplantation, sustained donor chimerism, and remission maintenance, suggesting the potential efficacy of the TBF conditioning regimen for BPDCN transplantation. Given the small sample size in our study, we emphasize caution and advocate for larger studies to confirm the efficacy of TBF in the treatment of BPDCN.

An international learning collaborative phase 2 trial for haploidentical bone marrow transplant in sickle cell disease.

ABSTRACT: In the setting of a learning collaborative, we conducted an international multicenter phase 2 clinical trial testing the hypothesis that nonmyeloablative-related haploidentical bone marrow transplant (BMT) with thiotepa and posttransplant cyclophosphamide (PTCy) will result in 2-year event-free survival (no graft failure or death) of at least 80%. A total of 70 participants were evaluable based on the conditioning protocol. Graft failure occurred in 8 of 70 (11.4%) and only in participants aged <18 years; all had autologous reconstitution. After a median follow-up of 2.4 years, the 2-year Kaplan-Meier-based probability of event-free survival was 82.6%. The 2-year overall survival was 94.1%, with no difference between children and adult participants. After excluding participants with graft failure (n = 8), participants with engraftment had median whole blood donor chimerism values at days +180 and +365 after transplant of 100% (n = 58), respectively, and 96.6% (57/59) were off immunosuppression 1 year after transplant. The 1-year grade 3 to 4 acute graft-versus-host disease (GVHD) rate was 10%, and the 2-year moderate-severe chronic GVHD rate was 10%. Five participants (7.1%) died from infectious complications. We demonstrate that nonmyeloablative haploidentical BMT with thiotepa and PTCy is a readily available curative therapy for most adults, even those with organ damage, compared to the more expensive myeloablative gene therapy and gene editing. Additional strategies are required for children to decrease graft failure rates. The trial was registered at www.clinicaltrials.gov as #NCT01850108.

An expanded-access clinical study of thiotepa (DSP-1958) high-dose chemotherapy before autologous hematopoietic stem cell transplantation in patients with malignant lymphoma.

Thiotepa, an antineoplastic ethylenimine alkylating agent that can penetrate the central nervous system, was recently approved in Japan as high-dose chemotherapy prior to autologous hematopoietic stem cell transplantation (HSCT) for patients with malignant lymphoma. To further evaluate the safety and efficacy of thiotepa, a multicenter, open-label, non-comparative, expanded access program was undertaken in Japan, including a larger population of Asian patients with malignant lymphoma. Intravenous thiotepa (200 mg/m2/day) was administered over 2 h on days -4 and -3 before scheduled HSCT, plus intravenous busulfan (0.8 mg/kg) over 2 h every 6 h on days -8, -7, -6 and -5. In the safety analysis population (N = 51), 25 patients (49.0%) had primary central nervous system lymphomas. The most common treatment-emergent adverse event was febrile neutropenia (49/51 [96.1%]). No unexpected safety events were observed, and no event resulted in death or treatment modification. Forty-seven patients (92.2%) had engraftment (neutrophil count ≥ 500/mm3 for three consecutive days after bone-marrow suppression and HSCT). The survival rate at day 100 post-transplantation was 100%. These data confirm the safety of thiotepa prior to autologous HSCT for patients with malignant lymphoma.Trial registration: JapicCTI-173654.

Myeloablative Carboplatin and Thiotepa With Autologous Stem Cell Rescue for Nonmedulloblastoma High-risk CNS Tumors in Young Children.

Malignant central nervous system (CNS) tumors in young children have a poor prognosis and pose a therapeutic challenge. We describe 11 patients with high-risk CNS tumors (6 atypical teratoid/rhabdoid tumor, 4 nonmedulloblastoma CNS embryonal tumors, and 1 glioblastoma multiforme) who received 32 consolidation cycles of myeloablative carboplatin/thiotepa followed by autologous peripheral blood stem cell rescue. All patients underwent successful stem cell harvest without significant complications. Mean time to absolute neutrophil count ≥0.5×103/µL was 10.2±1.3 days and the mean length of hospital stay was 15.7±3.0 days. There were no regimen-related deaths. Five-year event-free survival and overall survival were 45.5±15.0% and 58.4±16.3%, respectively. Tandem carboplatin/thiotepa consolidation with autologous stem cell rescue is well-tolerated in young children with nonmedulloblastoma CNS tumors.

Comparison of Total Body Irradiation-based Versus Chemotherapy-based Conditionings for Early Complications of Allogeneic Hematopoietic Stem Cell Transplantation in Children With ALL.

BACKGROUND: Total body irradiation (TBI) is the cornerstone of conditioning regimens in pediatric hematopoietic stem cell transplantation for acute lymphoblastic leukemia. As the late effects and survival comparison between TBI and chemotherapy were well analyzed before, in this study, we aim to focus on the first 100 days and early complications of transplantation. METHODS: This retrospective study involves 72 pediatric patients (0 to 18 y) underwent first hematopoietic stem cell transplantation for acute lymphoblastic leukemia between October 2015 and May 2019. Patients are divided into 2 groups regarding conditioning regimens. Conditionings includes either TBI 1200 cGy/6 fractions/3 days and etoposide phosphate or busulfan, fludarabine, and thiotepa. Busulfan was administered IV and according to body weight. RESULTS: The incidences of acute graft versus host disease grade 2 to 4, veno-occlusive disease, capillary leakage syndrome, thrombotic microangiopathy, blood stream infection, hemorrhagic cystitis and posterior reversible encephalopathy syndrome before day 100 were similar for both conditioning regimens; however, patients received TBI-based conditioning had significantly longer neutrophil engraftment time (17.5 vs. 13 d, P=0.001) and tended to have more engraftment syndrome (ES) (45.5% for TBI vs. 24.0% for chemotherapy, P=0.069). Multivariate analysis showed that TBI-based conditioning was associated with a longer neutrophil engraftment time (hazard ratio [HR]=1.20, P=0.006), more cytomegalovirus (CMV) reactivation (HR=3.65, P=0.038) and more ES (HR=3.18, P=0.078). CONCLUSIONS: Our findings support chemotherapy-based regimens with early neutrophil engraftment, less ES and CMV reactivation compared with TBI. Although there is no impact on survival rates, increased incidence of ES and CMV reactivation should be considered in TBI-based regimens.

Full donor chimerism after allogeneic hematopoietic stem cells transplant for myelofibrosis: The role of the conditioning regimen.

The aim of this retrospective study was to assess the rate of full donor chimerism (F-DC) in patients with myelofibrosis, prepared for an allogeneic stem cell transplant, with one or two alkylating agents. We analyzed 120 patients with myelofibrosis, for whom chimerism data were available on day +30. There were two groups: 42 patients were conditioned with one alkylating agent (ONE-ALK), either thiotepa or busulfan or melphalan, in combination with fludarabine, whereas 78 patients were prepared with two alkylating agents, thiotepa busulfan and fludarabine (TBF). Patients receiving TBF were older (57 vs 52 years), were less frequently splenectomized pre-HSCT (31% vs 59%), had more frequently intermediate-2/high DIPSS scores (90% vs 74%), were grafted more frequently from alternative donors (83% vs 33%) and received more frequently ruxolitinib pre-HSCT (26% vs 7%). The proportion of patients with F-DC on day +30, in the TBF vs the ONE-ALK group, was respectively 87% vs 45% (P < .001). The 5-year cumulative incidence of relapse was 9% in the TBF group, vs 43% for the ONE-ALK group (P < .001). The 5-year actuarial disease-free survival was 63% for TBF and 38% for the ONE-ALK group (P = .004). In conclusion, early full donor chimerism is a prerequisite for long term control of disease in patients with myelofibrosis, undergoing an allogeneic HSCT. The combination of two alkylating agents in the conditioning regimen, provides a higher chance of achieving full donor chimerism on day+30, and thus a higher chance of long term disease free survival.

Graft-versus-host Disease Prophylaxis With Abatacept Reduces Severe Acute Graft-versus-host Disease in Allogeneic Hematopoietic Stem Cell Transplant for Beta-thalassemia Major With Busulfan, Fludarabine, and Thiotepa.

BACKGROUND: We hypothesized that the addition of 4 doses of abatacept to our standard acute graft-versus-host disease (GVHD) prophylaxis would reduce the incidence of day +100 severe acute GVHD in children with transfusion-dependent beta-thalassemia major undergoing a myeloablative allogeneic hematopoietic stem cell transplant (HSCT), without impacting engraftment. METHODS: Twenty-four children with beta-thalassemia major received abatacept at a dose of 10 mg/kg intravenously on days -1, +5, +14, and +28 after HSCT in addition to calcineurin inhibitors and methylprednisolone. Outcomes were compared to 8 beta-thalassemia patients who received standard acute GVHD prophylaxis. RESULTS: There was no difference in engraftment between the 2 groups. No patient had grades III-IV acute GVHD by day +100 in the abatacept cohort compared with 50% in the standard acute GVHD prophylaxis group (P = 0.001). Viral reactivation occurred in 5 children in the standard acute GVHD cohort and in 20 children in the abatacept cohort (P = 0.2). Thalassemia-free survival after HSCT was 100% in the abatacept cohort compared to 62.5% in the standard cohort at last follow-up (P = 0.007). CONCLUSIONS: Adding abatacept to our routine GVHD prophylaxis reduced the incidence of day +100 severe acute GVHD without impacting engraftment or survival.

Total Body Irradiation or Chemotherapy Conditioning in Childhood ALL: A Multinational, Randomized, Noninferiority Phase III Study.

PURPOSE: Total body irradiation (TBI) before allogeneic hematopoietic stem cell transplantation (HSCT) in pediatric patients with acute lymphoblastic leukemia (ALL) is efficacious, but long-term side effects are concerning. We investigated whether preparative combination chemotherapy could replace TBI in such patients. PATIENTS AND METHODS: FORUM is a randomized, controlled, open-label, international, multicenter, phase III, noninferiority study. Patients ≤ 18 years at diagnosis, 4-21 years at HSCT, in complete remission pre-HSCT, and with an HLA-compatible related or unrelated donor were randomly assigned to myeloablative conditioning with fractionated 12 Gy TBI and etoposide versus fludarabine, thiotepa, and either busulfan or treosulfan. The noninferiority margin was 8%. With 1,000 patients randomly assigned in 5 years, 2-year minimum follow-up, and one-sided alpha of 5%, 80% power was calculated. A futility stopping rule would halt random assignment if chemoconditioning was significantly inferior to TBI (EudraCT: 2012-003032-22; ClinicalTrials.gov: NCT01949129). RESULTS: Between April 2013 and December 2018, 543 patients were screened, 417 were randomly assigned, 212 received TBI, and 201 received chemoconditioning. The stopping rule was applied on March 31, 2019. The median follow-up was 2.1 years. In the intention-to-treat population, 2-year overall survival (OS) was significantly higher following TBI (0.91; 95% CI, 0.86 to 0.95; P < .0001) versus chemoconditioning (0.75; 95% CI, 0.67 to 0.81). Two-year cumulative incidence of relapse and treatment-related mortality were 0.12 (95% CI, 0.08 to 0.17; P < .0001) and 0.02 (95% CI, < 0.01 to 0.05; P = .0269) following TBI and 0.33 (95% CI, 0.25 to 0.40) and 0.09 (95% CI, 0.05 to 0.14) following chemoconditioning, respectively. CONCLUSION: Improved OS and lower relapse risk were observed following TBI plus etoposide compared with chemoconditioning. We therefore recommend TBI plus etoposide for patients > 4 years old with high-risk ALL undergoing allogeneic HSCT.

Tandem High-dose Chemotherapy without Craniospinal Irradiation in Treatment of Non-metastatic Malignant Brain Tumors in Very Young Children.

BACKGROUND: Infants and very young children with malignant brain tumors have a poorer survival and a higher risk for neurologic deficits. The present study evaluated the feasibility and effectiveness of multimodal treatment including tandem high-dose chemotherapy and autologous stem cell transplantation (HDCT/auto-SCT) in minimizing use of radiotherapy (RT) in very young children with non-metastatic malignant brain tumors. METHODS: Twenty consecutive patients younger than 3 years were enrolled between 2004 and 2017. Tandem HDCT/auto-SCT was performed after six cycles of induction chemotherapy. Local RT was administered only to patients with post-operative gross residual tumor at older than 3 years. Since September 2015, early post-operative local RT for patients with atypical teratoid/rhabdoid tumor or primitive neuroectodermal tumor was administered. RESULTS: All 20 enrolled patients underwent the first HDCT/auto-SCT, and 18 proceeded to the second. Two patients died from toxicity during the second HDCT/auto-SCT, and four patients experienced relapse/progression (one localized and three metastatic), three of whom remained alive after salvage treatment including RT. A total of 17 patients remained alive at a median 7.8 (range, 2.5-5.7) years from diagnosis. Nine survivors received no RT, six survivors received local RT alone, and two survivors who experienced metastatic relapse after tandem HDCT/auto-SCT received both local and craniospinal RT. The 5-year overall, event-free, and craniospinal RT-free survival rates were 85.0% ± 8.0%, 70.0% ± 10.2%, and 75.0% ± 9.7%, respectively. Neuroendocrine and neurocognitive functions evaluated 5 years after tandem HDCT/auto-SCT were acceptable. CONCLUSION: Our results suggest that non-metastatic malignant brain tumors in very young children could be treated with multimodal therapy including tandem HDCT/auto-SCT while minimizing RT, particularly craniospinal RT.

Secondary failure of platelet recovery in patients treated with high-dose thiotepa and busulfan followed by autologous stem cell transplantation.

Autologous stem cell transplantation (ASCT) with high-dose thiotepa and busulfan is a treatment option for patients with central nervous system (CNS) lymphoma. We report here the occurrence of secondary failure of platelet recovery (SFPR) in three out of 24 patients who received high-dose thiotepa and busulfan followed by ASCT. Although there was no obvious abnormality in the primary platelet engraftment as well as the recovery of other blood cells, they developed SFPR with a median time to onset of day 38, and the platelets gradually recovered over several months with steroid therapy. During the same period, there was no development of SFPR among 50 patients who received ASCT with a conditioning regimen of MEAM (ranimustine, etoposide, cytarabine, and melphalan) or high-dose melphalan. However, one of the two patients who received a conditioning regimen of busulfan and melphalan developed SFPR, suggesting that the use of a busulfan-based conditioning regimen may be one of the risk factors for SFPR. It is important to be aware of this possible adverse effect of ASCT with high-dose thiotepa and busulfan to ensure timely diagnosis and prevention of subsequent serious complications.

Changes in glomerular filtration rate and clinical course after sequential doses of carboplatin in children with embryonal brain tumors undergoing autologous stem cell transplantation.

BACKGROUND: Treatment for malignant embryonal brain tumors in young children usually employs cycles of standardly dosed cisplatinum followed by high-dose carboplatinum-containing conditioning with single or tandem autologous stem cell rescue (HDC-ASCR). High-dose carboplatin is potentially nephrotoxic, and additive platinum exposure may acutely impact renal function. Aiming to determine if decrease in renal function during conditioning assessed prior to each carboplatin dose was associated with acute increases in creatinine, requirement for dialysis or transplant-related mortality (TRM). This was a retrospective study of consecutive patients with medulloblastoma (n = 15) / atypical teratoid/rhabdoid tumor (AT/RT, n = 5) receiving HDC-ASCR. Fifteen patients underwent 1 HDC-ASCR (carboplatin × 3 doses/ etoposide/ thiotepa) and 5 patients underwent at least 1 of 3 planned tandem HDC-ASCR (carboplatin × 2 doses/ thiotepa). Renal function was assessed by daily creatinine and nuclear medicine glomerular filtration rate (GFR)/ creatinine clearance before each carboplatin dose. RESULTS: In this cohort of 20 patients, 3 had doses of carboplatin omitted due to decreases in GFR: 1 did not develop nephrotoxicity, 1 experienced nephrotoxicity without need for dialysis, and 1 required dialysis temporarily but recovered renal function. Two patients did not have GFR changes but developed post-ASCR renal failure requiring dialysis and TRM. CONCLUSION: Daily assessment of renal function by GFR, prior each dose of carboplatin during HDC-ASCR, will help in protecting the kidney in heavily treated population of oncology/HSCT patients. Although the study had a small number of patients which is a major limitation of the study, but it points to a serious transplant-related morbidity and mortality. So, larger scale studies are needed to clarify the best approach to carboplatin dosing to insure the optimal balance between efficacy and toxicity.

Retrospective analysis of high-dose chemotherapy followed by autologous stem cell transplantation for high-risk pediatric osteosarcoma.

The outcomes of osteosarcoma with poor prognostic factors, such as poor responders, metastatic disease at diagnosis, and relapsed or refractory disease, are poor. We reviewed the clinical records of the patients diagnosed with osteosarcoma at our institute between 2004 and 2018 who received high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) in our institute. Ten patients of osteosarcoma with poor responder, refractory status, and metastatic disease at diagnosis received high-dose chemotherapy followed by ASCT. Four patients underwent high-dose chemotherapy followed by ASCT with the conditioning regimen consisted of thiotepa and melphalan (MEL). Five patients underwent high-dose chemotherapy followed by ASCT with the conditioning regimen consisted of intravenous busulfan (BU) and MEL. One patient underwent tandem high-dose chemotherapy followed by ASCT with BU and MEL followed by carboplatin and etoposide. None of the ten patients died of regimen related toxicities. None of the five patients with poor responders who underwent high-dose chemotherapy followed by ASCT as part of consolidation therapy died of disease after ASCT. High-dose chemotherapy followed by ASCT might be effective for poor responders in osteosarcoma.

Effect of the Thiotepa Dose in the TBF Conditioning Regimen in Patients Undergoing Allogeneic Stem Cell Transplantation for Acute Myeloid Leukemia in Complete Remission: A Report From the EBMT Acute Leukemia Working Party.

BACKGROUND: Allogeneic stem cell transplantation is a potentially curative therapy for patients with acute myeloid leukemia (AML) after achieving complete remission (CR). The aim of this study is to evaluate the optimal dose of thiotepa, administered as part of the thiotepa-busulfan-fludarabine (TBF) conditioning regimen for allogeneic stem cell transplantation in adults with AML in CR. PATIENTS AND METHODS: In a retrospective multicenter analysis, we identified 240 patients allotransplanted from matched related or unrelated donors or T replete haplo-identical donors. We compared the transplantation outcomes of patients who received 5 mg/kg thiotepa and 2 days of intravenous busulfan at 6.4 mg/kg (T1B2F) versus those who received 10 mg/kg thiotepa with 2 days of intravenous busulfan at 6.4 mg/kg (T2B2F). The median follow-up was 20 months. RESULTS: On univariate analysis, the incidence of acute graft versus host disease (GVHD) grade II to IV was significantly lower in the T1B2F group (19%) versus 32% in the T2B2F group (P = .029). This result was confirmed on multivariate analysis; acute GVHD was higher for patients receiving T2B2F (hazard ratio, 2.22; P = .024). No significant change in non-relapse mortality, progression-free survival, or overall survival was observed between the 2 groups. CONCLUSION: T2B2F is associated with a higher incidence of acute GVHD compared with T1B2F. These results suggest that a lower dose-intensity of thiotepa and busulfan in the TBF regimen may yield better results in patients with AML in CR.

Induction therapy with the MATRix regimen in patients with newly diagnosed primary diffuse large B-cell lymphoma of the central nervous system - an international study of feasibility and efficacy in routine clinical practice.

The MATRix chemoimmunotherapy regimen is highly effective in patients with newly diagnosed primary diffuse large B-cell lymphoma of the central nervous system (PCNSL). However, nothing is known about its feasibility and efficacy in everyday practice, where patients are more often older/frailer than those enrolled in clinical trials. We conducted a retrospective study addressing tolerability/efficacy of MATRix in 156 consecutive patients with newly diagnosed PCNSL treated outside a clinical trial. Median age and ECOG Performance Status of considered patients were 62 years (range 28-78) and 2 (range 0-4). The overall response rate after MATRix was 79%. Nine (6%) treatment-related deaths were recorded. After a median follow-up of 27.4 months (95% confidence interval [CI] 24.4-31.9%), the two-year progression-free and overall survival were 56% (95% CI 48.4-64.9%) and 64.1% (95% CI 56.7-72.5%) respectively. Patients not eligible for the IELSG32 trial were treated with lower dose intensity and had substantially worse outcomes than those fulfilling inclusion criteria. This is the largest series of PCNSL patients treated with MATRix outside a trial and recapitulates the IELSG32 trial outcomes in the non-trial setting for patients who fit the trial criteria. These data underscore the feasibility and efficacy of MATRix as induction treatment for fit patients in routine practice.