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.

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.

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.

Successful treatment of isolated central nervous system recurrence of primary testicular lymphoma by autologous stem cell transplantation using a conditioning regimen of thiotepa and busulfan.

Primary testicular lymphoma (PTL) frequently relapses in the central nervous system (CNS) despite prophylactic intrathecal chemotherapy, and the outcome for CNS recurrence of PTL is very poor. We report a case of isolated CNS recurrence of bilateral PTL. Our patient achieved complete response (CR) after rituximab-combination chemotherapy for PTL. Approximately five years later, isolated CNS recurrence of PTL occurred. Our patient achieved CR again after high-dose methotrexate therapy and autologous stem cell transplantation (ASCT) with a conditioning regimen of thiotepa and busulfan as a consolidation therapy. The secondary failure of platelet recovery, probably caused by busulfan, occurred after the platelet engraftment. Our patient has remained in CR for over three years. The treatment strategy for CNS recurrence of PTL is mainly whole-brain radiotherapy or high-dose methotrexate-based chemotherapy; however, CNS recurrence of PTL may occur again even after achieving CR. ASCT with a conditioning regimen of thiotepa and busulfan is the optimal consolidation therapy for secondary CNS lymphoma. To the best of our knowledge, this is the second reported case of a patient with isolated CNS recurrence of PTL successfully treated by ASCT with a conditioning regimen of thiotepa and busulfan as a consolidation therapy.

ABT199/venetoclax synergism with thiotepa enhances the cytotoxicity of fludarabine, cladribine and busulfan in AML cells.

ABT199/venetoclax, an inhibitor of the pro-survival BCL-2 protein, has improved AML treatment. Its efficacy in hematopoietic stem cell transplantation (HSCT), when combined with other chemotherapeutic drugs, has not been thoroughly investigated. The present study demonstrates the synergistic cytotoxicity of ABT199/venetoclax with the DNA alkylator thiotepa (Thio) in AML cells. Cleavage of Caspase 3, PARP1 and HSP90, as well as increased Annexin V positivity, suggest potent activation of apoptosis by this two-drug combination; increased levels of γ-H2AX, P-CHK1 (S317), P-CHK2 (S19) and P-SMC1 (S957) indicate an enhanced DNA damage response. Likewise, the increased level of P-SAPK/JNK (T183/Y185) and decreased P-PI3Kp85 (Y458) suggest enhanced activation of stress signaling pathways. These molecular readouts were synergistically enhanced when ABT199/venetoclax and Thio were combined with fludarabine, cladribine and busulfan. The five-drug combination decreased the levels of BCL-2, BCL-xL and MCL-1, suggesting its potential clinical relevance in overcoming ABT199/venetoclax resistance. Moreover, this combination is active against P53-negative and FLT3-ITD-positive cell lines. Enhanced activation of apoptosis was observed in leukemia patient-derived cell samples exposed to the five-drug combination, suggesting a clinical relevance. The results provide a rationale for clinical trials using these two- and five-drug combinations as part of a conditioning regimen for AML patients undergoing HSCT.

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.

Periósteo autógeno no tratamento da necrose de esclera após exérese de pterígio e betaterapia / Autogenous periosteum in scleral necrosis treatment after pterygium graft and betatherapy

Os autores apresentam um estudo no qual se utiliza o periósteo autógeno como alternativa de enxerto para o tratamento cirúrgico de necrose de esclera e exposiçäo uveal em olhos submetidos a betaterapia após exérese de pterígio. A revisäo da literatura demonstrou que o periósteo autógeno ainda näo havia sido utilizada neste tipo de patologia. A técnica foi empregada em cinco pacientes. Houve boa integraçäo em todos os casos. Como complicaçäo relatam um caso de dellen corneano e um caso de reabsorçäo parcial tardia do enxerto. Ressaltam a necessidade de tratar a necrose escleral para evitar a ocorrência de infecçäo que, frequentemente leva esses olhos a dano funcional irreversível.

Manejo del carcinoma superficial de vejiga; BCG intravesical: la nueva alternativa / BCG in the management or superficial blader neoplasms: the new alternative

La BCG intravesical representa una nueva forma de terapia intravesical para el tratamiento del cáncer superficial de vejiga reportado en un rango que va de 10 (por ciento) a 20 (por ciento). La rata de recurrencia es comparable al 40 (por ciento) de la thiotepa y 60 (por ciento) de fulguración sólo. Presenta un 59 (por ciento) a 83 (por ciento) de incidencia de regresión del tumor residual, lo cual es comparable con el 30 a 50 (por ciento) de la thiotepa y una incidencia de un 60 a 80 (por ciento) de regresión del carcinoma in situ, el cual es comparable con el 55 (por ciento) de la thiotepa y el 8 (por ciento) de la fulguración. Hay muchos protocolos en la aplicación de la terapia, uno de los más aceptados es Pasteur BCG 120 MG. en 50 cc de Salina administrado semanalmente por seis semanas, empezando 1 ó 2 semanas después de la resección, una dósis de BCG equivale en costo a 30 MG de thiotepa el agente quimioterapéutico más barato. La terapia es seguida de cistoscopía, biopsias y citología, cada 3 meses por 2 años. El estado de la prueba cutánea con PPD, la radiografía de torax y la química sanguínea, deben ser monitorizados antes y después de la terapia. La conversión de la prueba cutánea es positiva en el transcurso de la terapia y la aparición de granulomas en la vejiga se considera un efecto terapéutico beneficioso. Los efectos secundarios de la BCG son síntomas irritativos leves que no tienen trascendencia. Todavía no hay nada conclusivo en la relación sobre la cepa óptima y la ruta de administración. No se conoce a largo plazo el efecto antitumoral y efecto secundario de la BCG en la vejiga. Para finalizar, la terapia con BCG es sin duda alguna la mejor opción para el paciente con cáncer superficial de vejiga, pero todavía hay mucho que aprender para mejorar la eficacia óptima de este tratamiento

Revisión de 21 casos de carcinoma vesical y de 3 caso de carcinoma de la pelvis renal / Review of 21 cases of carcinoma of the bladder and of 3 cases of the renal pelvis

Se presentan los casos de 21 pacientes de carcinoma vesical y tres de carcinoma de pelvis renal bajo control de la Consulta Externa del Servicio de Urología, Hospital de Especialidades, Centro Médico de Puebla, IMSS. Se encontró carcinoma vesical superficial en 15 (71.4%) de los pacientes; de éstos siete (46.6%) se trataron mediante resección transuretral a la que se añadió quimioterapia intravesical, y uno (6.6%) mediante radioterapia radical. La enfermedad resultó invasora en seis (28.5%). De los 21 pacientes, 16 (76.2%) se encontraban vivos sin datos de actividad tumoral en el momento de terminar la redacción de este informe; otros más (4.7%) lo estaba pero con actividad tumoral, tres habían fallecido a causa del padecimiento, y el deceso del último se debió a una causa ajena al mismo. Dos de los pacientes que padecían carcinoma de la pelvis renal se sometieron a nefroureterectomía con resección de un segmento vesical, y el otro a operación conservadora de la pelvis renal. Los tres se encontraban libres de actividad tumoral en el momento de terminarse de redactar este informe. La finalidad de este artículo es valorar los aspectos aplicados e informar las experiencias obtenidas con el tratamiento de los carcinomas de estos tipos.

Thiotepa y recidiva del cáncer vesical / Thiotepa and relapse of vesical cancer

Se realiza un análisis de los resultados del tratamiento local con thiotepa en un grupo de pacientes que previamente fueron operados de cáncer vesical (cistectomía parcial) con el fin de evitar o retardar las recidivas del tumor y compararlo con otro grupo al que sólo se le realizó cistectomía parcial. Se obtuvieron buenos resultados sin recidiva tumoral en el primer grupo con el 65,3 , mientras que en el segundo grupo sólo el 4 no tuvo recidiva