Allogeneic hematopoietic stem cell transplantation (HSCT) is highly effective for treating pediatric high-risk or relapsed acute lymphoblastic leukemia (ALL). For young children, total body irradiation (TBI) is associated with severe late sequelae. In the FORUM study (NCT01949129), we assessed safety, event-free survival (EFS), and overall survival (OS) of 2 TBI-free conditioning regimens in children aged <4 years with ALL. Patients received fludarabine (Flu), thiotepa (Thio), and either busulfan (Bu) or treosulfan (Treo) before HSCT. From 2013 to 2021, 191 children received transplantation and were observed for ≥6 months (median follow-up: 3 years). The 3-year OS was 0.63 (95% confidence interval [95% CI], 0.52-0.72) and 0.76 (95% CI, 0.64-0.84) for Flu/Thio/Bu and Flu/Thio/Treo (P = .075), respectively. Three-year EFS was 0.52 (95% CI, 0.41-0.61) and 0.51 (95% CI, 0.39-0.62), respectively (P = .794). Cumulative incidence of nonrelapse mortality (NRM) and relapse at 3 years were 0.06 (95% CI, 0.02-0.12) vs 0.03 (95% CI: <0.01-0.09) (P = .406) and 0.42 (95% CI, 0.31-0.52) vs 0.45 (95% CI, 0.34-0.56) (P = .920), respectively. Grade >1 acute graft-versus-host disease (GVHD) occurred in 29% of patients receiving Flu/Thio/Bu and 17% of those receiving Flu/Thio/Treo (P = .049), whereas grade 3/4 occurred in 10% and 9%, respectively (P = .813). The 3-year incidence of chronic GVHD was 0.07 (95% CI, 0.03-0.13) vs 0.05 (95% CI, 0.02-0.11), respectively (P = .518). In conclusion, both chemotherapeutic conditioning regimens were well tolerated and NRM was low. However, relapse was the major cause of treatment failure. This trial was registered at www.clinicaltrials.gov as #NCT01949129.

• MeSH
• Precursor Cell Lymphoblastic Leukemia-Lymphoma * etiology   MeSH
• Busulfan * analogs & derivatives   MeSH
• Child MeSH
• Humans MeSH
• Graft vs Host Disease * etiology   MeSH
• Child, Preschool MeSH
• Transplantation Conditioning adverse effects   MeSH
• Recurrence MeSH
• Thiotepa therapeutic use   MeSH
• Hematopoietic Stem Cell Transplantation * adverse effects   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Child, Preschool MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Research Support, Non-U.S. Gov't MeSH

Jako standardní přípravný režim se před podáním autologní transplantace krvetvorných buněk (ASCT) u relabujících či refrakterních lymfomů používal BEAM, tedy carmustine (BCNU) v kombinaci s etoposidem, cytarabinem a melfalanem. Recentní nedostatek BCNU však vedl k nutnosti přechodu na alternativní režim, kterým se v našem centru stal od července 2018 režim obsahující thiotepu, tzv. TEAM. Rozhodli jsme se retrospektivně srovnat gastrointestinální (GIT) toxicitu obou přípravných režimů. Zahrnuli jsme 142 konsekutivně autologně transplantovaných pacientů (BEAM = 82, TEAM = 60), z nichž 31 % mělo difuzní velkobuněčný B-lymfom (DLBCL), 20 % Hodgkinův lymfom (HL), 15 % lymfom z plášťových buněk (MCL), 14 % T-buněčné lymfomy (T-NHL) a zbylých 20 % ostatní druhy non-Hodgkinových lymfomů (NHL). Obě kohorty byly srovnatelné stran věku pacientů, zastoupení diagnóz a stavu nemoci v době ASCT. V distribuci jednotlivých stupňů GIT toxicity nebyl mezi dvěma přípravnými režimy nalezen statisticky signifikantní rozdíl, a to ani po seskupení všech stupňů do dvou hlavních skupin pacientů (grade 0 + 1 vs. grade 2–4). Pacienti dostávající režim TEAM však častěji dospěli k potřebě parenterální výživy, a to ve 20 případech (33 %) oproti pouhým 13 případům (16 %) u režimu BEAM (p = 0,04). Nerelapsová mortalita (NRM) byla u obou režimů srovnatelně nízká, během hospitalizace byla 0 %, ve 3 měsících pak 2 % shodně pro oba přípravné režimy (p = 1,0). Nezaznamenali jsme statisticky signifikantní rozdíl v celkovém přežití (overal survival; OS) ani v přežití do známek progrese (progression free survival; PFS) (p = 0,59 pro OS, p = 0,1 pro PFS).

The BEAM regimen, i.e., carmustine (BCNU) in combination with etoposide, cytarabine, and melphalan was used as standard conditioning prior to autologous hematopoietic cell transplantation (ASCT) in relapsed or refractory lymphomas. However, the recent unavailability of BCNU necessitated the use of an alternative regimen, which in our centre became from July 2018 the so-called TEAM regimen containing thiotepa. We decided to retrospectively compare the gastrointestinal (GIT) toxicity of both conditioning regimens. We included 142 consecutive autologous transplant patients (BEAM = 82, TEAM = 60), of whom 31% had diffuse large B-cell lymphoma (DLBCL), 20% Hodgkin‘s lymphoma (HL), 15 % mantle cell lymphoma (MCL), 14% T-cell lymphomas (T-NHL) and the remaining 20% other types of non-Hodgkin lymphomas (NHL). Both cohorts were comparable in terms of patient age, prevalence of diagnoses, and disease status at the time of ASCT. There was no statistically significant difference in the distribution of the grades of GIT toxicity between the two cohorts, even after grouping all grades into two main groups of patients (grade 0+1 vs. grade 2–4). Patients receiving the TEAM regimen were more likely to require parenteral nutrition, namely in 20 cases (33%) versus only 13 cases (16%) in the BEAM regimen (P = 0.04). Non-relapse mortality (NRM) was comparably low for both regimens – 0% during hospitalization and 2% at 3 months for both conditioning regimens (P = 1.0). We also compared overall survival (OS) and progression-free survival (PFS): there was no statistically significant difference between the two cohorts (P = 0.59 for OS, P = 0.1 for PFS).

• MeSH
• Transplantation, Autologous MeSH
• Adult MeSH
• Carmustine adverse effects   therapeutic use   MeSH
• Drug Therapy, Combination methods   adverse effects   MeSH
• Middle Aged MeSH
• Humans MeSH
• Lymphoma * drug therapy   MeSH
• Drug-Related Side Effects and Adverse Reactions epidemiology   MeSH
• Transplantation Conditioning * methods   adverse effects   statistics & numerical data   MeSH
• Antineoplastic Agents adverse effects   therapeutic use   MeSH
• Aged MeSH
• Thiotepa adverse effects   therapeutic use   MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Comparative Study MeSH

Optimal conditioning for adults with acute lymphoblastic leukemia (ALL) treated with haploidentical hematopoietic cell transplantation (haplo-HCT) and post-transplant cyclophosphamide has not been established so far. We retrospectively compared outcomes for two myeloablative regimens: fludarabine + total body irradiation (Flu-TBI, n = 117) and thiotepa + iv. busulfan + fludarabine (TBF, n = 119). Patients transplanted either in complete remission (CR) or with active disease were included in the analysis. The characteristics of both groups were comparable except for patients treated with TBF were older. In univariate analysis the incidence of non-relapse mortality (NRM) at 2 years was increased for TBF compared to Flu-TBI (31% vs. 19.5%, p = 0.03). There was a tendency towards reduced incidence of relapse after TBF (p = 0.11). Results of multivariate analysis confirmed a reduced risk of NRM using Flu-TBI (HR = 0.49, p = 0.03). In the analysis restricted to patients treated in CR1 or CR2, the use of Flu-TBI was associated with a decreased risk of NRM (HR = 0.34, p = 0.009) but an increased risk of relapse (HR = 2.59, p = 0.01) without significant effect on survival and graft-versus-host disease. We conclude that for haplo-HCT recipients with ALL, Flu-TBI may be preferable for individuals at high risk of NRM while TBF should be considered in cases at high risk of relapse.

• MeSH
• Precursor Cell Lymphoblastic Leukemia-Lymphoma * complications   therapy   MeSH
• Leukemia, Myeloid, Acute * therapy   MeSH
• Busulfan adverse effects   MeSH
• Whole-Body Irradiation adverse effects   MeSH
• Adult MeSH
• Humans MeSH
• Graft vs Host Disease * etiology   MeSH
• Transplantation Conditioning methods   MeSH
• Recurrence MeSH
• Retrospective Studies MeSH
• Thiotepa adverse effects   MeSH
• Hematopoietic Stem Cell Transplantation * adverse effects   MeSH
• Vidarabine analogs & derivatives   MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Publication type
• Journal Article MeSH

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.

• MeSH
• Precursor Cell Lymphoblastic Leukemia-Lymphoma pathology   therapy   MeSH
• Busulfan administration & dosage   analogs & derivatives   MeSH
• Whole-Body Irradiation mortality   MeSH
• Chemoradiotherapy mortality   MeSH
• Child MeSH
• Etoposide administration & dosage   MeSH
• Equivalence Trials as Topic MeSH
• Humans MeSH
• International Agencies MeSH
• Survival Rate MeSH
• Adolescent MeSH
• Follow-Up Studies MeSH
• Child, Preschool MeSH
• Prognosis MeSH
• Antineoplastic Combined Chemotherapy Protocols therapeutic use   MeSH
• Thiotepa administration & dosage   MeSH
• Vidarabine administration & dosage   analogs & derivatives   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Child, Preschool MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Clinical Trial, Phase III MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH
• Randomized Controlled Trial MeSH

Treosulfan-based conditioning prior to allogeneic transplantation has been shown to have myeloablative, immunosuppressive, and antineoplastic effects associated with reduced non-relapse mortality (NRM) in adults. Therefore, we prospectively evaluated the safety and efficacy of treosulfan-based conditioning in children with hematological malignancies in this phase II trial. Overall, 65 children with acute lymphoblastic leukemia (35.4%), acute myeloid leukemia (44.6%), myelodysplastic syndrome (15.4%), or juvenile myelomonocytic leukemia (4.6%) received treosulfan intravenously at a dose of 10 mg/m2/day (7.7%), 12 g/m2/day (35.4%), or 14 g/m2/day (56.9%) according to their individual body surface area in combination with fludarabine and thiotepa. The incidence of complete donor chimerism at day +28 was 98.4% with no primary and only one secondary graft failure. At 36 months, NRM was only 3.1%, while relapse incidence was 21.7%, and overall survival was 83.0%. The cumulative incidence of acute graft-vs.-host disease was 45.3% for grades I-IV and 26.6% for grades II-IV. At 36 months, 25.8% overall and 19.4% moderate/severe chronic graft-vs.-host disease were reported. These data confirm the safe and effective use of treosulfan-based conditioning in pediatric patients with hematological malignancies. Therefore, treosulfan/fludarabine/thiotepa can be recommended for myeloablative conditioning in children with hematological malignancies.

• MeSH
• Busulfan analogs & derivatives   MeSH
• Child MeSH
• Hematologic Neoplasms * therapy   MeSH
• Humans MeSH
• Graft vs Host Disease * MeSH
• Transplantation Conditioning * MeSH
• Thiotepa MeSH
• Hematopoietic Stem Cell Transplantation * MeSH
• Vidarabine analogs & derivatives   MeSH
• Check Tag
• Child MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

Východiská: Leptomeningeálne metastázy (LM) karcinómu prsníka sú asociované s nepriaznivou prognózou. Hoci žiadna randomizovaná štúdia nepotvrdila, že intratekálna liečba predlžuje prežívanie, táto liečba je považovaná za štandard. Prognóza pacientov s LM je nepriaznivá, s mediánom celkového prežívania menej ako 6 mesiacov. Metódy: V tejto kazuistike uvádzame prípad mladej ženy s karcinómom prsníka s LM v čase recidívy, liečenej dvoma líniami intratekálnej chemoterapie s predĺženým prežívaním. Výsledky: Dvadsaťosemročnej žene bez pozoruhodnej anamnézy bol diagnostikovaný triple-negatívny invazívny duktálny karcinóm. Osem mesiacov po adjuvantnej terapii sa rozvinuli mnohopočetné mozgové metastázy a následne 1 mesiac po ukončení rádioterapie na centrálny nervový systém sa vyvinuli nové LM. Iniciálne bola liečená kombináciou metotrexát, cytarabín a dexametazón intratekálne, ale po 3 mesiacoch u pacientky došlo k zhoršeniu klinického stavu a vzostupu nádorových buniek v likvore. Následne dostala kombináciu tiotepy a metotrexátu intratekálne s predĺžením odpovede v trvaní 10 mesiacov. Pacientka zomrela 32 mesiacov od stanovenia diagnózy a 18 mesiacov od infiltrácie leptomenigov v dôsledku progresie ochorenia v pečeni a pľúcach ako aj v leptomeningoch. Záver: Prognóza pacientov s LM zostáva nepriaznivá v dôsledku limitovanej účinnosti súčasne dostupných látok používaných v intratekálnej liečbe, avšak intratekálna chemoterapia by mohla podstatne predĺžiť prežívanie u vybraných pacientov.

Background: Leptomeningeal metastasis (LM) in breast cancer is associated with a poor prognosis. Although no randomised trial has demonstrated that intrathecal chemotherapy actually prolongs survival, this treatment is considered standard of care in this setting. The prognosis of patients with LM is poor, with a median overall survival time of less than 6 months. Methods: Herein, we report a case of a young woman with breast cancer who presented with LM at the time of relapse and was subsequently treated with two lines of intrathecal chemotherapy that prolonged survival. Results: A 28-year old woman without a significant past medical history was diagnosed with triple-negative invasive ductal carcinoma. Eight months after adjuvant treatment she developed multiple brain metastases and LM developed subsequently 1 month after finishing whole brain irradiation. Initially, she was treated with a combination of methotrexate, cytarabine and dexamethasone intrathecally but after 3 months she presented with a worsening clinical status and increased numbers of cancer cells in cerebrospinal fluid. Subsequently, she received a combination of thiotepa and methotrexate intrathecally, which resulted in a prolonged response lasting 10 months. The patient died 32 months after initial diagnosis and 18 months from LM infiltration due to disease progression in the liver and lungs as well as LM. Conclusion: The prognosis of patients with LM remains poor because of the limited effectiveness of currently available therapies; however, intrathecal chemotherapy could substantially prolong survival in selected patients.

• MeSH
• Adult MeSH
• Humans MeSH
• Meningeal Neoplasms * drug therapy   secondary   MeSH
• Neoplasm Metastasis MeSH
• Breast Neoplasms * drug therapy   MeSH
• Antineoplastic Protocols MeSH
• Death MeSH
• Thiotepa therapeutic use   MeSH
• Treatment Outcome MeSH
• Check Tag
• Adult MeSH
• Humans MeSH
• Female MeSH
• Publication type
• Case Reports MeSH

Clinical information about thiotepa-based autologous stem cell transplantation (auto-SCT) outside the primary central nervous system lymphoma (PCNSL) field is sparse. In this registry-based retrospective study, we evaluated potential risks and benefits of thiotepa-based preparative regimens compared with BEAM (carmustine, etoposide, cytarabine, melphalan) in auto-SCT for diffuse large B-cell lymphoma (DLBCL, excluding PCNSL), follicular lymphoma (FL) or Hodgkin lymphoma (HL). A total of 14 544 patients (589 thiotepa and 13 955 BEAM) met the eligibility criteria, and 535 thiotepa- and 1031 BEAM-treated patients were matched in a 1:2 ratio for final comparison. No significant differences between thiotepa and BEAM groups for any survival end point were identified in the whole sample or disease entity subsets. For a more detailed analysis, 47 TEAM (thiotepa, etoposide, cytarabine, melphalan)-treated patients were compared with 75 matched BEAM patients with additional collection of toxicity data. Again, there were no significant differences between the two groups for any survival end point. In addition, the frequency of common infectious and non-infectious complications including secondary malignancies was comparable between TEAM and BEAM. These results indicate that thiotepa-based high-dose therapy might be a valuable alternative to BEAM in DLBCL, HL and FL. Further evaluation by prospective clinical trials is warranted.

• MeSH
• Autografts MeSH
• Cytarabine administration & dosage   MeSH
• Adult MeSH
• Carmustine administration & dosage   MeSH
• Middle Aged MeSH
• Humans MeSH
• Lymphoma mortality   therapy   MeSH
• Melphalan administration & dosage   MeSH
• Survival Rate MeSH
• Adolescent MeSH
• Podophyllotoxin administration & dosage   MeSH
• Disease-Free Survival MeSH
• Antineoplastic Combined Chemotherapy Protocols administration & dosage   MeSH
• Registries * MeSH
• Retrospective Studies MeSH
• Aged MeSH
• Thiotepa administration & dosage   MeSH
• Stem Cell Transplantation * MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Adolescent MeSH
• Male MeSH
• Aged MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Multicenter Study MeSH
• Research Support, Non-U.S. Gov't MeSH

CONTEXT: The European Association of Urology non-muscle-invasive bladder cancer (NMIBC) guidelines recommend that all low- and intermediate-risk patients receive a single immediate instillation of chemotherapy after transurethral resection of the bladder (TURB), but its use remains controversial. OBJECTIVE: To identify which NMIBC patients benefit from a single immediate instillation. EVIDENCE ACQUISITION: A systematic review and individual patient data (IPD) meta-analysis of randomized trials comparing the efficacy of a single instillation after TURB with TURB alone in NMIBC patients was carried out. EVIDENCE SYNTHESIS: A total of 13 eligible studies were identified. IPD were obtained for 11 studies randomizing 2278 eligible patients, 1161 to TURB and 1117 to a single instillation of epirubicin, mitomycin C, pirarubicin, or thiotepa. A total of 1128 recurrences, 108 progressions, and 460 deaths (59 due to bladder cancer [BCa]) occurred. A single instillation reduced the risk of recurrence by 35% (hazard ratio [HR]: 0.65; 95% confidence interval [CI], 0.58-0.74; p<0.001) and the 5-yr recurrence rate from 58.8% to 44.8%. The instillation did not reduce recurrences in patients with a prior recurrence rate of more than one recurrence per year or in patients with an European Organization for Research and Treatment of Cancer (EORTC) recurrence score ≥5. The instillation did not prolong either the time to progression or death from BCa, but it resulted in an increase in the overall risk of death (HR: 1.26; 95% CI, 1.05-1.51; p=0.015; 5-yr death rates 12.0% vs 11.2%), with the difference appearing in patients with an EORTC recurrence score ≥5. CONCLUSIONS: A single immediate instillation reduced the risk of recurrence, except in patients with a prior recurrence rate of more than one recurrence per year or an EORTC recurrence score ≥5. It does not prolong either time to progression or death from BCa. The instillation may be associated with an increase in the risk of death in patients at high risk of recurrence in whom the instillation is not effective or recommended. PATIENT SUMMARY: A single instillation of chemotherapy immediately after resection reduces the risk of recurrence in non-muscle-invasive bladder cancer; however, it should not be given to patients at high risk of recurrence due to its lack of efficacy in this subgroup.

• MeSH
• Administration, Intravesical MeSH
• Time Factors MeSH
• Doxorubicin administration & dosage   analogs & derivatives   MeSH
• Epirubicin administration & dosage   MeSH
• Carcinoma, Transitional Cell mortality   pathology   therapy   MeSH
• Humans MeSH
• Neoplasm Recurrence, Local prevention & control   MeSH
• Survival Rate MeSH
• Mitomycin administration & dosage   MeSH
• Urinary Bladder Neoplasms mortality   pathology   therapy   MeSH
• Disease Progression MeSH
• Antineoplastic Combined Chemotherapy Protocols administration & dosage   MeSH
• Randomized Controlled Trials as Topic MeSH
• Risk Factors MeSH
• Neoplasm Staging MeSH
• Thiotepa administration & dosage   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Meta-Analysis MeSH
• Review MeSH

• Keywords
• Bendamustin, Ibritumomab, Imatinib, Oftatumumab, Nilotinib, Tepadina thiotepa, Pomalidomid,
• MeSH
• Alemtuzumab MeSH
• Bortezomib MeSH
• Cytostatic Agents * administration & dosage   pharmacology   classification   adverse effects   therapeutic use   MeSH
• Dasatinib MeSH
• Child MeSH
• Adult MeSH
• Hematologic Neoplasms * drug therapy   therapy   MeSH
• Hematology * methods   trends   MeSH
• Immunomodulation drug effects   MeSH
• Lenalidomide MeSH
• Humans MeSH
• Molecular Biology methods   trends   MeSH
• Antibodies, Monoclonal pharmacology   classification   therapeutic use   MeSH
• Nitrogen Mustard Compounds pharmacology   therapeutic use   MeSH
• Thalidomide MeSH
• Thiotepa pharmacology   therapeutic use   MeSH
• Protein-Tyrosine Kinases antagonists & inhibitors   pharmacology   classification   therapeutic use   MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH

• Keywords
• hematologické malignity, nádory CNS, autologní a allogenní transplantace krvetvorných progenitorových buněk,
• MeSH
• Transplantation, Autologous MeSH
• Child MeSH
• Adult MeSH
• Financing, Organized MeSH
• Hematologic Neoplasms drug therapy   MeSH
• Drug Evaluation statistics & numerical data   MeSH
• Transplantation, Homologous MeSH
• Humans MeSH
• Central Nervous System Neoplasms drug therapy   MeSH
• Thiotepa pharmacology   therapeutic use   MeSH
• Hematopoietic Stem Cell Transplantation MeSH
• Check Tag
• Child MeSH
• Adult MeSH
• Humans MeSH