Busulfan and cyclophosphamide-based conditioning regimen still holds the promise of being a safe and efficacious regimen for allogeneic transplantation in patients with transfusion-dependent thalassemia, even in high risk.

Busulfan and cyclophosphamide (BuCy)-based regimen has been used as a standard myeloablative chemotherapy for haematopoietic stem cell transplantation in thalassemia. However, treosulfan-based conditioning regimen has emerged due to concerns of toxicities. We retrospectively analysed the safety and efficacy of fludrabine/Bu/Cy/antithymocyte globulin (ATG) versus treosulfan/thiotepa/fludrabine regimens for Hematopoietic Stem Cell Transplant (HSCT) in transfusion-dependent thalassemia (TDT) conducted at our institute (2013-2021). In 75 patients, 36 (48%) received Flu/Bu/Cy/ATG whereas 39 (52%) received Treo/Thio/Flu. Median age was 6 (1-12) and 9 (1-15) years, respectively. Number of patients with Classes I, II, and III were 14, 10, and 12 in Flu/Bu/Cy/ATG versus 2, 19, and 18 in Treo/Thio/Flu group, respectively. Graft was growth factor mobilized bone marrow in Flu/Bu/Cy/ATG versus peripheral blood stem cell in Treo/Thio/Flu group. Mean stem cell dose was 3.82 (2.2-9.1) versus 5 (1.65-8.01) 106 /kg in Flu/Bu/Cy/ATG versus Treo/Thio/Flu group, respectively. Neutrophils and platelets engrafted at a median of 16 (14-21) and 16 (9-47) days in Flu/Bu/Cy/ATG and 15 (10-20) and 13 (9-41) days in Treo/Thio/Flu group. Median duration of follow-up was 28 (23-32.9) months. Five (6.6%) patients had rejection (all secondary). Venoocclusive disease was observed in 2 (5.7%) versus 4 (10.3%) patients (p = .047), respectively. Flu/Bu/Cy/ATG had 4 (11.4%) patients with acute GVHD versus 15 (38.5%) patients which had significant impact on survival (p = .038). We observed chronic GVHD in 4 (11.4%) and 11 (28.2%) patients, respectively, with significant impact on survival (p = .031). Four (5.1%) patients had TRM in Treo/Thio/Flu group, in contrast to none in Flu/Bu/Cy/ATG group. Mixed chimerism was common in Flu/Bu/Cy/ATG {20 (57.1%)} versus Treo/Thio/Flu group {12 (30.1%)}. Five-year Event Free Survival (EFS) and OS of entire cohort were 87% + 4% and 94% + 3%, respectively. Estimated TFS, EFS, OS of Flu/Bu/Cy/ATG versus Treo/Thio/Flu was 97.1% + 2.9% versus 89.2% + 5.1% (p = .251), 97 + 3% versus 80.7 + 6% (p = .041) and 100% versus 90.4 + 5% (p = .067), respectively. In our experience, Flu/Bu/Cy/ATG regimen is safe and effective even in high-risk TDT. However, one needs to be vigilant for mixed chimerism.

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.

Skin toxicity following treosulfan-thiotepa-fludarabine-based conditioning regimen in non-malignant pediatric patients undergoing hematopoietic stem cell transplantation.

TBC regimens are considered as "reduced toxicity" and are increasingly employed in pediatric HSCT. In our center, we commonly use the combination of treosulfan-thiotepa-fludarabine and ATG for pediatric non-malignant diseases. As we often observe acute skin toxicities following this conditioning regimen, we conducted a prospective observational study to describe and characterize these toxicities. Fifteen pediatric patients undergoing HSCT for non-malignant diseases who were treated at Hadassah-Hebrew University Medical Center during 2015 were enrolled. A thorough dermatological assessment was done on days 0, 1, 7, and 14 from treatment initiation and included description of cutaneous reactions, measurement of BSA of affected skin, and response to local treatment. All the fifteen enrolled patients developed some degree of acute skin reaction. Cutaneous manifestations were variable and included erythematous patches in inguinal area and genitalia (80%), in neck and axillae (40%), diffuse hyperpigmentation (73%), erosions in inguinal area and buttock (47%), and xerosis and desquamation (40%). Average affected BSA reached 71.8%. Erosions were more prevalent in children younger than 2 years of age. The eruptions resolved without sequela in all patients and did not necessitate treatment other than topical agents. Observed extracutaneous toxicities included oral mucositis (40%), diarrhea (47%), and elevated liver enzymes (47%). TBC combined with thiotepa is highly toxic to the skin with various cutaneous manifestations. The toxicity resolves with no long-term sequela.

Thiotepa hyperpigmentation preceding epidermal necrosis: malignant intertrigo misdiagnosed as Stevens-Johnson syndrome-toxic epidermal necrolysis overlap.

Thiotepa is a common alkylating agent known to precipitate cutaneous reactions consistent with toxic erythema of chemotherapy, including erythema and hyperpigmentation. Herein, we describe an atypical case of malignant intertrigo involving preferential erythema and desquamation not only of skin folds but also of occluded areas after thiotepa-based conditioning. The diagnosis was complicated by concurrent stomatitis and oral petechiae in the setting of autologous stem cell transplant 11 days prior for diffuse large B-cell lymphoma. Histopathological examination from two cutaneous sites demonstrated epidermal dysmaturation and eccrine gland necrosis consistent with thiotepa-induced desquamation and not Stevens-Johnson syndrome or graft-versus-host-disease. Malignant intertrigo can present with extensive cutaneous involvement, as evidenced by our patient who had 25% body surface area affected. Mucosal involvement is common with most chemotherapeutic regimens and its presence should not deter the astute clinician from consideration of a diagnosis of toxic erythema of chemotherapy. No further interventions were needed and the patient healed spontaneously.

Feasibility and Safety of Treosulfan, Melphalan, and Thiotepa-Based Megachemotherapy with Autologous or Allogeneic Stem Cell Transplantation in Heavily Pretreated Children with Relapsed or Refractory Neuroblastoma.

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.

Age-adjusted high-dose chemotherapy and autologous stem cell transplant in elderly and fit primary CNS lymphoma patients.

BACKGROUND: Primary central nervous system lymphoma (PCNSL) is a diffuse large B-cell lymphoma (DLBCL) confined to the central nervous system (CNS) with rising incidence among patients > 65 years. Although elderly patients are able to tolerate aggressive systemic chemotherapy, previous studies have demonstrated inferior outcomes for patients who present with a poor performance status (PS) and older age. Usually, intensive treatment approaches including high-dose chemotherapy followed by autologous stem cell transplantation (HDT-ASCT) are only offered to patients younger than 65-70 years of age. METHODS: This is an open-label, multicentric, non-randomized, single arm phase II trial. We will recruit 51 immuno-competent patients with newly diagnosed PCNSL from 12 German centers. The objective is to investigate the efficacy of age-adapted induction treatment followed by HDT-ASCT. All enrolled patients will undergo induction chemotherapy consisting of 2 cycles of rituximab 375 mg/m2/d (days 0 & 4), methotrexate 3.5 g/m2 (d1), and cytarabine 2 × 2 g/m2/d (d2-3) every 21 days. After 2 cycles of induction chemotherapy, patients achieving at least stable disease will undergo HDT-ASCT with busulfan 3.2 mg/kg/d (days - 7-(- 6)) and thiotepa 5 mg/kg/d (days - 5-(- 4)) followed by autologous stem cell transplantation. The primary endpoint of this study is 1-year progression-free survival (PFS). Secondary endpoints include PFS, overall survival, treatment response and treatment-related morbidities. Minimal follow-up after treatment completion is 12 months. DISCUSSION: Current treatment options for PCNSL have improved over the last years, resulting in the potential to achieve durable remission or cure in patients < 70 years. Age alone may not be the only criterion to select patients for this effective treatment approach and probably many elderly patients are undertreated just because of advanced age. There have been no multicentre trials investigating this curative treatment concept in elderly and fit PCNSL patients so far. We aim to answer whether HDT-ASCT is feasible and effective in fit patients > 65 years with newly-diagnosed PCNSL. TRIAL REGISTRATION: German clinical trials registry DRKS00011932 registered 18 August 2017.

Effects of thioTEPA chemotherapy on cognition and motor coordination.

Cancer survivorship has increased greatly as therapies have become more advanced and effective. Thus, we must now focus on improving the quality of life of patients after treatment. After chemotherapy, many patients experience chemotherapy-induced cognitive decline, indicating a need to investigate pathologies associated with this condition. In this study, we addressed cognitive impairment after thioTEPA treatment by assessing behavior and assaying cytokine production and the structure of dendrites in the hippocampus. Male mice were given three intraperitoneal injections of thioTEPA. Five weeks later, the mice underwent behavior testing, and brains were collected for Golgi staining and cytokine analysis. Behavior tests included y-maze and Morris water maze and licking behavioral task. Cytokines measured include: IL-1α, IL-1ß, IL-2, IL-3, IL-4, IL-5, IL-10, IL-12p70, MCP-1, TNF-α, GMCSF, and RANTES. We observed decreased memory retention in behavioral tasks. Also, dendritic arborization and length were decreased after chemotherapy treatment. Finally, thioTEPA decreased cytokine production in animals treated with chemotherapy, compared to saline-treated controls. Here, we used a mouse model to correlate the decreases in dendritic complexity and inflammatory cytokine production with cognitive impairment after chemotherapy.

Double-conditioning regimen consisting of high-dose thiotepa and melphalan with autologous stem cell rescue for high-risk pediatric solid tumors: A second report.

BACKGROUND: Pediatric patients with high-risk, relapsed, or refractory solid tumors have a poor prognosis. We have previously reported a dose-finding experience of high-dose chemotherapy consisting of thiotepa and melphalan ("double-conditioning regimen"). Using doses derived from that study, we have treated patients since 2005. We now report a retrospective review of patients treated by this fixed dose. PROCEDURE: We reviewed 50 patients (median 4 years; range 0-15 years) with high-risk or relapsed/refractory solid tumors treated by this dose-fixed, double-conditioning regimen from April 2005 to May 2014. Doses were thiotepa 800 mg/m2 and melphalan 280 mg/m2 for children ≥2 years of age, and 32 mg/kg and 6 mg/kg, respectively, for children <2 years of age. Further, doses were reduced according to creatinine clearance with poor renal function. RESULTS: Nonhematological toxicity was mainly gastrointestinal-grade 3 mucositis (n = 41) and grade 3-4 diarrhea (n = 10). Neurological, renal, and endothelial cell toxicity and sinusoidal obstruction syndrome were not observed. There were two toxic deaths (interstitial viral pneumonia). This regimen demonstrated antitumor activity against several types of tumors. Although the frequency of gastrointestinal toxicity was high, other severe toxicity was not observed. CONCLUSIONS: Our double-conditioning regimen was very well tolerated and demonstrated antitumor activity. We are moving forward with multi-institutional trials now.

Thiotepa-induced cutaneous toxicity in pediatric patients: Case report and implementation of preventive care guidelines.

Thiotepa, a highly lipophilic, alkylating agent, and/or its active metabolites may be excreted in part via skin in patients receiving high-dose therapy. We present a case of cutaneous toxicity observed in a 4.5-year-old girl patient with medulloblastoma treated with a high-dose thiotepa conditioning regimen before autologous stem cell transplantation. Skin lesions, as well as their pattern and locations, were evocative of thiotepa toxidermia. After the case herein described, preventive care guidelines were implemented in our unit as from 2014. A retrospective follow-up of 26 pediatric patients receiving thiotepa prior to stem cell transplantation was performed until March 2018. In this series of patients, only one patient experienced cutaneous toxicity as reported herein. Thereafter, only mild cutaneous toxicity was observed, even with double or triple transplantation protocols with high-dose thiotepa. Clear preventive care instructions should be detailed in the Summary of Product Characteristics in order to minimize the cutaneous toxicity of thiotepa.

High-dose thiotepa-related neurotoxicity and the role of tramadol in children.

BACKGROUND: Serious neurological adverse events (NAE) have occurred during treatment with high-dose thiotepa regimens of children with high-risk solid tumours. The objective was to assess the incidence of NAE related to high-dose thiotepa and to identify potential contributing factors that could exacerbate the occurrence of this neurotoxicity. METHODS: From May 1987 to March 2011, children with solid tumours treated with high-dose thiotepa were retrospectively identified. Each NAE detected led to an independent case analysis. Potential contributing factors were pre-specified and univariate/multivariable analyses were performed. RESULTS: Three hundred seven courses of thiotepa (251 patients) were identified. The total dose per treatment ranged from 600 to 900 mg/m2. 81 NAE (26%) were identified. 46 NAE were related to high-dose thiotepa during the first course (18.3%) and 11 during the second course (19.6%). The symptoms appeared in a median time of 2 days after the introduction of thiotepa. Central and peripheral symptoms were headaches, tremors, confusion, seizures, cerebellar syndrome, and coma. High-dose thiotepa was reintroduced in 18 cases and symptoms reappeared in 5 children. For 3 patients who had seizures during the first course, premedication with clonazepam for the second course has prevented recurrence of NAE. As contributing factors, brain tumour and tramadol treatment increased the risk of thiotepa-related neurotoxicity by 2 to 6 times respectively. CONCLUSIONS: The incidence of neurotoxicity was 18.3%. Brain tumours and tramadol treatment are risk factors to consider when using high-dose thiotepa. The outcome of patients was favourable without sequelae in all cases and rechallenge with thiotepa was possible.

Thiotepa, busulfan and fludarabine compared to busulfan and cyclophosphamide as conditioning regimen for allogeneic stem cell transplant from matched siblings and unrelated donors for acute myeloid leukemia.

Busulfan plus cyclophosphamide (BuCy) is the traditional conditioning regimen for allogeneic stem cell transplant (allo-SCT) for young, fit patients with acute myeloid leukemia (AML). The thiotepa-busulfan-fludarabine (TBF) protocol has recently demonstrated promising outcome in cord blood and haploidentical SCT; however, there is limited evidence about this regimen in transplant from matched siblings (MSD) and unrelated donors (UD). We retrospectively compared outcomes of 2523 patients aged 18-50 with AML in remission, undergoing transplant from MSD or UD prepared with either TBF or BuCy conditioning. A 1:3 pair-matched analysis was performed: 146 patients receiving TBF were compared with 438 patients receiving BuCy. Relapse risk was significantly lower in the TBF when compared with BuCy group (HR 0.6, P = .02), while NRM did not differ. No significant difference was observed in LFS and OS between the two regimens. TBF was associated with a trend towards higher risk of grades III-IV aGVHD (HR 1.8, P = .06) and inferior cGVHD (HR 0.7, P = .04) when compared with BuCy. In patients undergoing transplant in first remission, the advantage for TBF in terms of relapse was more evident (HR 0.4, P = .02), leading to a trend for better LFS in favor of TBF (HR 0.7, P = .10), while OS did not differ between the two cohorts. In conclusion, TBF represents a valid myeloablative conditioning regimen providing significantly lower relapse and similar survival when compared with BuCy. Patients in first remission appear to gain the most from this protocol, as in this subgroup a tendency for better LFS was observed when compared with BuCy.

Tandem thiotepa with autologous hematopoietic cell rescue in patients with recurrent, refractory, or poor prognosis solid tumor malignancies.

BACKGROUND: The purpose of this study was to determine the feasibility and tolerability of tandem courses of high-dose thiotepa with autologous hematopoietic cell rescue (AHCR) in patients with recurrent, refractory solid tumors who were ineligible for a single course of high-dose therapy due to greater than minimal residual disease. Patients with decreased hearing or poor renal function were eligible. PROCEDURE: Thiotepa was administered intravenously at a dose of 200 mg/m2 /day (6.67 mg/kg/day) daily for 3 days followed by AHCR. A second course of thiotepa was given 4 weeks later provided blood counts recovered sufficiently without evidence of tumor progression. RESULTS: Fifty-eight patients received 96 courses. Thirty-eight (65%) patients received two courses of therapy. Twenty-seven courses (28%) were administered completely in the outpatient setting. A toxic mortality rate of 3.4% was observed. Five of 26 patients with medulloblastoma were alive at a median of 35 months, whereas 21 patients died at a median of 11.7 months. Four of five patients with central nervous system germ cell tumors (CNS GCT) were alive 68-103 months following AHCR. CONCLUSIONS: Two cycles of high-dose thiotepa with AHCR were well tolerated even in these heavily pretreated patients. This therapy may provide prolonged survival in patients with recurrent malignant brain tumors, particularly medulloblastoma and CNS GCT.

Psychosexual development and satisfaction in long-term survivors of childhood cancer: Neurotoxic treatment intensity as a risk indicator.

BACKGROUND: Risk factors for impairment in psychosexual development and satisfaction among adult survivors of childhood cancer are poorly understood. The authors compared psychosexual outcomes between survivors and healthy controls, and tested whether at-risk survivors can be identified by 1) treatment neurotoxicity or 2) diagnosis. METHODS: A total of 144 young adult survivors of childhood cancer and 144 matched controls completed questionnaires regarding psychosexual development, sexual satisfaction, and satisfaction with relationship status. Survivors were aged 20 to 40 years and were 5 to 34 years after diagnosis. Using medical chart data, survivors were divided into non-neurotoxic (48 survivors), low-dose (36 survivors), and high-dose (58 survivors) neurotoxic treatment groups. RESULTS: Apart from having fewer lifetime sex partners, survivors did not appear to differ from controls. However, survivors of brain tumors and any survivor who received high-dose neurotoxic treatment reported the lowest rates of achieving milestones of psychosexual development, whereas sexual and relationship status satisfaction were found to be related to relationship status. Neurotoxic treatment intensity further distinguished between survivors of brain tumors with and without psychosexual impairment. CONCLUSIONS: The intensity of neurotoxic treatment may be a valuable indicator of risk for psychosexual impairment relative to diagnosis alone. Health care providers should assess romantic/sexual problems among survivors at risk and make referrals if needed. Cancer 2017;123:1869-1876. © 2017 American Cancer Society.

Treosulfan-fludarabine-thiotepa conditioning before allogeneic haemopoietic stem cell transplantation for patients with advanced lympho-proliferative disease. A single centre study.

In recent years, with the aim of reducing transplant-related mortality, new conditioning regimens have been explored in patients not eligible for conventional haemopoietic stem cell transplantation. In this setting, we investigated safety and feasibility of the treosulfan-fludarabine-thiotepa combination prior to allogeneic haemopoietic stem cell transplantation in patients with advanced lympho-proliferative diseases and at high transplant risk. Twenty-seven consecutive patients, median age 43 years (range 19-60), entered this study. All of them were affected by lympho-proliferative disease in advanced phase and have been heavily pre-treated. The median haemopoietic stem cell transplant co-morbidity index was 1 (range 0-3). Twenty-five patients had regular engraftment, while the remaining two patients were not evaluable for early deaths. Non-haematological toxicity was limited. No patient developed veno-occlusive disease. The estimated probability of overall survival and progression-free survival with a median follow-up of 40 months was 52% (95% confidence interval 33-73) and 50% (95% confidence interval 30-70) respectively. Six patients have relapsed; all of them were not in remission before transplantation. The treosulfan-fludarabine-thiotepa combination is a reduced toxicity but myeloablative regimen that can be proposed to patients not fitting criteria for conventional myeloablative transplant regimens. Longer follow-up and prospective randomized studies are necessary to evaluate this regimen.

High-Dose Melphalan Plus Thiotepa as Conditioning Regimen before Second Autologous Stem Cell Transplantation for "De Novo" Multiple Myeloma Patients: A Phase II Study.

High-dose melphalan (MEL) is the standard therapy for autologous stem cell transplantation (ASCT) in multiple myeloma (MM), although the optimal conditioning regimen remains yet to be identified. Thiotepa (THIO) appears to be a potentially effective option, with broad-spectrum antitumor efficacy that can be added to myeloablative multiagent regimens for ASCT in hematopoietic tumors. We conducted a phase II trial, adding THIO (275 mg/m(2)) to high-dose MEL (140 mg/m(2)) before a second ASCT, in a tandem ASCT strategy, in 64 patients with "de novo" MM. Overall, there was no transplant-related mortality. The incidence of neutropenic fever and mucositis (grades 3 to 4) was 39% and 9%, respectively. Median number of days to neutrophil and platelet engraftment were 11 and 12, respectively. After the second transplantation, the complete response improved to 43.8%. Overall response rate was 86%. After a median follow-up of 18.1 months, 13 patients had progressed and 3 died from MM. Median progression-free survival was not reached, and actuarial 2-year rates of progression-free and overall survival were 71% and 88.9%, respectively. Our results suggest that THIO/MEL is a feasible and safe conditioning regimen for ASCT in MM and should be explored for efficacy in a phase III study.

Transformation of alkylating regimen of thiotepa into tepa determines the disease progression through GSTP1 gene polymorphism for metastatic breast cancer patients receiving thiotepa containing salvage chemotherapy.

BACKGROUND: The shifts to second-line chemotherapy for metastatic breast cancer (MBC) were widely required based on pharmaceutical molecular profiles to reach out precision medicine. The emerging precise treatment of cancer requires the implementation of clarified pharmacogenetic profiles which are capable of elucidating the predictive responses to cancer chemotherapy. Therefore we were interested in the analysis of the roles of single nucleotide polymorphism (SNP) of GSTP1 (glutathione S-transferase pi 1 gene) alleles to identify pharmacological links with predictors of clinical responses and toxicities. METHODS: 93 MBC patients receiving thiotepa plus docetaxel chemotherapy were enrolled in this study. Optimized CYP3A5, CYP2B6, and GSTP1 were predominantly selected as candidate genes and their three SNPs (CYP2B6 G516T, CYP3A5 A6986G, and GSTP1 A313G) were genotyped by matrix-assisted laser desorption ionization/time of flight (MALDI-TOF) mass spectrometry. Progression-free survival (PFS), disease control rate, and chemo-related toxicities were recorded. RESULTS: GSTP1 A313G (rs1695) was identified to be related with disease progression. In particular, patients harboring AG/GG genotype demonstrated a statistically longer PFS than those with AA. Multivariate analysis confirmed that AG/GG genotype was associated with both clinical responses and liver-localized metastatic lesions. No correlation was found between these three SNPs and chemotherapy-induced toxicity. CONCLUSIONS: These results suggest that the GSTP1 polymorphism is a novel prognostic marker for clinical response to thiotepa-containing chemotherapy regimens. Such evidence could provide insight into the role of pharmacogenetics to deprive of biases in shifting regimens solely by empirical choices.

A phase II trial of high-dose chemotherapy (HDCT) supported by hematopoietic stem-cell transplantation (HSCT) in germ-cell tumors (GCTs) patients failing cisplatin-based chemotherapy: the Multicentric TAXIF II study.

BACKGROUND: High-dose chemotherapy (HDCT) is an effective salvage treatment of germ-cell tumors (GCTs) patients. In the first salvage setting, 30%-70% of patients may achieve durable remissions. Even when HDCT is administered as subsequent salvage treatment, up to 20% of patients may still be definitively cured. However, patients with refractory/relapsed disease still have a very poor long-term prognosis, requiring earlier intervention of HDCT. PATIENTS AND METHODS: This phase II trial was addressed to nonrefractory patients failing Cisplatin-based chemotherapy. Inclusion criteria included seminomatous GCT in relapse after two lines of chemotherapy, nonseminomatous GCT in relapse after first or second lines, partial remission after first line, primary mediastinal GCT in first relapse. Patients received two cycles combining Epirubicin and Paclitaxel (Epi-Tax), followed by three consecutive HDCT, one using a Paclitaxel/Thiotepa (Thio-Tax) association and two using the 5-day Ifosfamide-Carboplatin-Etoposide regimen. The main objective was to determine the complete response rate. RESULTS: Forty-five patients were included between September 2004 and December 2007: 44 received the first HDCT cycle, 39 two HDCT cycles, 29 could receive the whole protocol. Sixteen patients did not receive the entire protocol, including eight (17.7%) for toxic side-effects. Two patients (4.4%) died of toxicities, and 17 (37.7%) of disease progression. With a median follow-up time of 26 months (range, 4-51), the final overall response rate was 48.8% (including a complete response rate of 15.5% and a partial response/negative serum markers rate of 26.6%) in an intent-to-treat analysis. The median progression-free survival (PFS) and overall survival (OS) times were 22 months [95% confidence interval (CI) 2-not reached] and 32 months (95% CI 4-49), respectively. The 2-year PFS was a plateau setup at 50% (95% CI 32-67) and the 2-year OS was 66% (95% CI 44-81). CONCLUSION: The TAXIF II protocol was effective in nonrefractory GCT patients failing Cisplatin-based chemotherapy. The toxic death rate remained acceptable in the field of HDCT regimens. TRIAL REGISTRATION NUMBER: NCT00231582.

Autologous stem cell transplantation with thiotepa-based conditioning in patients with systemic sclerosis and cardiac manifestations.

OBJECTIVE: The aim of this study was to find a new and less cardiotoxic conditioning regimen for high-dose chemotherapy and autologous stem cell transplantation (aSCT) in patients with severe SSc and pre-existing cardiac involvement. METHODS: Six patients with cardiac involvement were treated for SSc with a conditioning regimen including reduced-dose CYC plus the non-cardiotoxic alkylant thiotepa. All patients received an implantable cardioverter defibrillator (ICD) before aSCT. The response at months 6 and 12 was measured according to reduction of the modified Rodnan skin score (mRSS). CT histography was used to monitor pulmonary manifestations, as were echocardiography, N-terminal pro-brain natriuretic peptide (NT-proBNP) and troponin for the cardiac involvement. Cardiac events were defined as death or hospitalisation due to heart failure or appropriate discharge of the ICD. RESULTS: Between December 2008 and May 2012, four male and two female patients with a median age of 41 years received aSCT. The median mRSS significantly decreased from 26.5 to 18 and 17.5 at month 6 and 12, respectively. The total lung volume also significantly improved. Within the median follow-up of 1.6 years (range 1-3.8) two patients experienced a relapse of SSc, which results in a progression-free survival rate of 66.6%. Three patients experienced ICD discharge. CONCLUSION: For patients with SSc and cardiac involvement, the use of thiotepa and reduced-dose CYC is feasible and effective. The rate of ICD discharge underlines the need for protection in these endangered patients. This preliminary experience allowed us to use this regimen for our currently recruiting prospective trial (NCT01895244).

Phase II trial of clofarabine with topotecan, vinorelbine, and thiotepa in pediatric patients with relapsed or refractory acute leukemia.

BACKGROUND: Outcomes for children with relapsed/refractory (R/R) acute lymphoblastic leukemia (ALL) and acute myelogenous leukemia (AML) are dismal. In an effort to improve outcomes, we performed a phase I/II study of a novel clofarabine based combination regimen called TVTC. Herein, we report the response rates of patients in the phase II portion of the study. PROCEDURE: Seventeen patients with R/R ALL, AML, or biphenotypic leukemia were enrolled. Sixteen patients were evaluable for response. Patients were treated at the maximum tolerated dose (MTD) from the phase I portion of the study (clofarabine 40 mg/m(2) /day IV × 5 days, topotecan 1 mg/m(2) /day IV continuous infusion × 5 days, vinorelbine 20 mg/m(2) /week IV × 3 weeks, thiotepa 15 mg/m(2)/day IV × 1 day). The primary endpoint was overall response rate (ORR), defined as CR or CR without platelet recovery (CRp). RESULTS: The ORR was 69% (10 CR, 1 CRp). Among the 11 responders, 9 (82%) proceeded to hematopoietic stem cell transplantation. The most common grade 3+ non-hematologic toxicities were febrile neutropenia (82%) and transient transaminase elevation (47%). CONCLUSIONS: TVTC demonstrates significant activity in patients with R/R acute leukemia. The activity in R/R AML patients was very encouraging, with 8 of 12 (67%) patients achieving a CR/CRp. Patients with high risk de novo AML may benefit from incorporation of TVTC therapy into frontline treatment regimens. This regimen warrants further exploration in a larger cohort of patients with R/R leukemia.

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.