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Cancer Nov 2011Because the long-term toxicity of myeloablative radioimmunotherapy remains a matter of concern, the authors evaluated the hematopoietic damage and incidence of secondary... (Clinical Trial)
Clinical Trial
BACKGROUND
Because the long-term toxicity of myeloablative radioimmunotherapy remains a matter of concern, the authors evaluated the hematopoietic damage and incidence of secondary myelodysplastic syndrome and acute myelogenous leukemia (sMDS/AML) in patients who received myeloablative doses of the radiolabeled antibody yttrium-90 (⁹⁰Y)-ibritumomab tiuxetan.
METHODS
The occurrence of sMDS/AML was investigated prospectively in 53 elderly patients with non-Hodgkin lymphoma (NHL) who underwent an autograft after high-dose radioimmunotherapy (HD-RIT) myeloablative conditioning with ⁹⁰Y-ibritumomab tiuxetan. Bone marrow (BM) hematopoietic progenitors and telomere length (TL) also were investigated.
RESULTS
At a median follow-up of 49 months, 4 patients developed sMDS/AML at 6 months, 12 months, 27 months, and 36 months after HD-RIT, and the 5-year cumulative incidence of sMDS/AML was 8.29%. A significant but transient decrease in BM granulocyte-macrophage progenitors was observed; whereas multilineage, erythroid, and fibroblast progenitors were unaffected. A significant and persistent shortening of BM TL also was detected. A matched-pair analysis comparing the study patients with 55 NHL patients who underwent autografts after chemotherapy-based myeloablative conditioning demonstrated a 8.05% 5-year cumulative incidence of sMDS/AML.
CONCLUSIONS
HD-RIT for patients with NHL was associated with 1) limited toxicity on hematopoietic progenitors, 2) accelerated TL shortening, and 3) non-negligible incidence of sMDS/AML, which nevertheless was comparable to the incidence observed in a matched group of patients who received chemotherapy-based conditioning. Thus, in the current series of elderly patients with NHL, the development of sMDS/AML was not influenced substantially by HD-RIT.
Topics: Adult; Aged; Antibodies, Monoclonal; Bone Marrow; Female; Follow-Up Studies; Granulocyte-Macrophage Progenitor Cells; Hematopoietic Stem Cells; Humans; Leukemia, Myeloid, Acute; Lymphoma, Non-Hodgkin; Male; Middle Aged; Myelodysplastic Syndromes; Neoplasms, Second Primary; Radioimmunotherapy; Risk; Telomere; Yttrium Radioisotopes
PubMed: 21567384
DOI: 10.1002/cncr.26182 -
Bioengineering & Translational Medicine May 2019Combination chemotherapy is often employed to improve therapeutic efficacies of drugs. However, traditional combination regimens often utilize drugs at or near-their...
Combination chemotherapy is often employed to improve therapeutic efficacies of drugs. However, traditional combination regimens often utilize drugs at or near-their maximum tolerated doses (MTDs), elevating the risk of dose-related toxicity and impeding their clinical success. Further, high doses of adjuvant or neoadjuvant chemotherapies can cause myeloablation, which compromises the immune response and hinders the efficacy of chemotherapy as well as accompanying treatments such as immunotherapy. Clinical outcomes can be improved if chemotherapy combinations are designed to reduce the overall doses without compromising their therapeutic efficacy. To this end, we investigated a combination of camptothecin (CPT) with doxorubicin (DOX) as a low-dose treatment option for breast cancer. DOX-CPT combinations were synergistic in several breast cancer cell lines in vitro and one particular ratio displayed extremely high synergy on human triple negative breast cancer cells (MDA-MB-231). This combination led to excellent long-term survival of mice bearing MDA-MB-231 tumors at doses roughly five-fold lower than the reported MTD values of its constituent drugs. Impact of low dose DOX-CPT treatment on local tumor immune environment was assessed in immunocompetent mice bearing breast cancer (4T1) tumors. The combination was not only superior in inhibiting the disease progression compared to individual drugs, but it also generated a more favorable antitumor immunogenic response. Engineering DOX and CPT ratios to manifest synergy enables treatment at doses much lower than their MTDs, which could ultimately facilitate their translation into the clinic as a promising combination for breast cancer treatment.
PubMed: 31249879
DOI: 10.1002/btm2.10129 -
Stem Cell Research & Therapy Dec 2018A 27-year-old male with HIV-associated naïve and high-risk Burkitt's lymphoma sequentially received short-term, high-dose non-myeloablative chemotherapy and autologous...
A 27-year-old male with HIV-associated naïve and high-risk Burkitt's lymphoma sequentially received short-term, high-dose non-myeloablative chemotherapy and autologous CD34-positive stem cell transfusion in the setting of combined antiretroviral therapy (cART). Prompt hematopoietic recovery was observed after 2 weeks and clinical remission from Burkitt's lymphoma within approximately 30 months after transplantation. The HIV RNA load was inhibited persistently, and drug resistance was not observed. The CD4+ T cell count approached 323 cells/μL in a recent follow-up study. This case suggests that the use of intensive non-myeloablative chemotherapy with transplantation, combined with antiretroviral therapy, in HIV-related naive and high-risk Burkitt's lymphoma was tolerated and safe.
Topics: Adult; Anti-Retroviral Agents; Burkitt Lymphoma; Combined Modality Therapy; HIV Infections; Hematopoietic Stem Cell Transplantation; Humans; Male; Transplantation Conditioning; Transplantation, Autologous
PubMed: 30572947
DOI: 10.1186/s13287-018-1089-5 -
British Journal of Haematology Apr 2008Therapy-associated myelodysplastic syndromes and acute myeloid leukaemia (t-AML/MDS) following high dose chemotherapy are significant problems, with a cumulative... (Clinical Trial)
Clinical Trial
Therapy-associated myelodysplastic syndromes and acute myeloid leukaemia (t-AML/MDS) following high dose chemotherapy are significant problems, with a cumulative incidence of 20% or more in myeloablative treatment regimen. Retrospective findings indicated that t-AML/MDS associated genetic aberrations can be observed directly after exposure to chemotherapy and can precede t-AML by several months. To determine the incidence of post-therapeutic aberrations and their predictive value, we prospectively investigated 316 samples of 95 patients with non-Hodgkin lymphoma (NHL) who were treated with intermediate and high dose chemotherapy (Arm A and B of the megaCHOEP (cyclophosphamide, doxorubicin, etoposide, vincristine, prednisolone) trial of the German High Grade NHL study group). Molecular aberrations (RUNX1/RUNX1T1, PML-RARA, CBFB-MYH11, MLL-MLLT1, BCR-ABL1) were observed in 33.3% (Arm A) and 55.4% (Arm B) of patients and in 14.9% and 28.7% of respective samples. Cytogenetic analysis of 53 NHL patients after high dose therapy showed frequent chromosomal breakage. Clonal aberrations were found in three patients. None of these patients developed a t-AML/MDS during a 3-year clinical follow up period. We concluded that the high incidence of genetic aberrations reflected a dose-dependent, transient therapy-induced genetic damage which is not predictive of a t-AML/MDS.
Topics: Adolescent; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chromosome Aberrations; Cyclophosphamide; Dose-Response Relationship, Drug; Doxorubicin; Etoposide; Follow-Up Studies; Humans; Leukemia, Myeloid, Acute; Lymphoma, Non-Hodgkin; Middle Aged; Prednisolone; Prognosis; Prospective Studies; Reverse Transcriptase Polymerase Chain Reaction; Translocation, Genetic; Vincristine
PubMed: 18324966
DOI: 10.1111/j.1365-2141.2008.07023.x -
Acta Oncologica (Stockholm, Sweden) Jul 2018Data on temozolomide (TEM) and irinotecan (IRI) activity in recurrent Ewing sarcoma (EWS), especially in adult patients, are limited.
BACKGROUND
Data on temozolomide (TEM) and irinotecan (IRI) activity in recurrent Ewing sarcoma (EWS), especially in adult patients, are limited.
METHODS
Patients receiving TEM 100 mg/m/day oral, and IRI 40 mg/m/day intravenous, days 1-5, every 21 days, were included in this multi-institutional retrospective study. Disease control rate (DCR) [overall response rate (ORR) [complete response (CR) + partial response (PR)] + stable disease (SD)], 6-months progression-free survival (6-mos PFS) and 1-year overall survival (OS) were assessed.
RESULTS
The median age of the 51 patients was 21 years (range 3-65 years): 34 patients (66%) were adults (≥18 years of age), 24 (48%) had ECOG 1 and 35 (69%) were presented with multiple site recurrence. TEMIRI was used at first relapse/progression in 13 (25%) patients, while the remainder received TEMIRI for second or greater relapse/progression. Fourteen (27%) patients had received prior myeloablative therapy with busulfan and melphalan. We observed five (10%) CR, 12 (24%) PR and 19 (37%) SD, with a DCR of 71%. 6-mos PFS was 49% (95% CI 35-63) and it was significantly influenced by ECOG (6-mos PFS 64% [95% CI 45-83] for ECOG 0, 34% [95% CI 14-54] for ECOG ≥1; p = .006) and LDH (6-mos PFS 62% [95% CI 44-79] for normal LDH, 22% [95% CI 3-42] for high LDH; p = .02), with no difference according to line of treatment, age and metastatic pattern. One-year OS was 55% (95% CI 39-70), with RECIST response (p = .001) and ECOG (p = .0002) independently associated with outcome. Grade 3 and 4 toxicity included neutropenia in 12% of patients, thrombocytopenia in 4%, diarrhea in 4%.
CONCLUSIONS
This series confirms the activity of TEMIRI in both adults and pediatric patients. This schedule offers a 71% DCR, independently of the line of chemotherapy. Predictive factors of response are ECOG and LDH.
Topics: Adolescent; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Child; Child, Preschool; Dacarbazine; Female; Humans; Irinotecan; Male; Middle Aged; Neoplasm Recurrence, Local; Recurrence; Retrospective Studies; Sarcoma, Ewing; Temozolomide; Young Adult
PubMed: 29533113
DOI: 10.1080/0284186X.2018.1449250 -
Cleveland Clinic Journal of Medicine Nov 2001Chronic myelogenous leukemia (CML) can usually be cured by bone marrow transplantation from matched donors. Donor T-cell activity from the graft is critical to... (Review)
Review
Chronic myelogenous leukemia (CML) can usually be cured by bone marrow transplantation from matched donors. Donor T-cell activity from the graft is critical to maintaining remission. Myeloablation may not be necessary for cure. Non-myeloablative but immunosuppressive preparative regimens allow donor engraftment with less toxicity. Early combination therapy with interferon-alfa and cytarabine was the preferred option for patients who could not undergo bone marrow transplantation. Now, the advent of imatinib mesylate, a specific inhibitor of BCR/ABL tyrosine kinase, promises to change existing treatment paradigms
Topics: Antineoplastic Agents; Benzamides; Bone Marrow Transplantation; Clinical Trials as Topic; Diagnosis, Differential; Enzyme Inhibitors; Graft vs Leukemia Effect; Humans; Imatinib Mesylate; Interferon-alpha; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Piperazines; Practice Guidelines as Topic; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Protein-Tyrosine Kinases; Pyrimidines; Remission Induction
PubMed: 11718431
DOI: 10.3949/ccjm.68.11.913 -
Annals of Oncology : Official Journal... Nov 2000An update of results from the High Risk Protocol of the Meta-EICESS Study, conducted at the Pediatric Stem-Cell Transplant Centers of Düsseldorf and Vienna. In order to... (Comparative Study)
Comparative Study Review
Allogeneic and autologous stem-cell transplantation in advanced Ewing tumors. An update after long-term follow-up from two centers of the European Intergroup study EICESS. Stem-Cell Transplant Programs at Düsseldorf University Medical Center, Germany and St. Anna Kinderspital, Vienna, Austria.
BACKGROUND
An update of results from the High Risk Protocol of the Meta-EICESS Study, conducted at the Pediatric Stem-Cell Transplant Centers of Düsseldorf and Vienna. In order to evaluate a possible therapeutic benefit after allogeneic SCT in patients with advanced Ewing tumors (AET), we compared outcome after autologous and allogeneic stem-cell transplantation (SCT).
PATIENTS AND METHODS
We analyzed 36 patients treated with the myeloablative Hyper-ME protocol (hyperfractionated total body irradiation, melphalan, etoposide +/- carboplatin) between November 1986 and December 1994. Minimal follow-up for all patients was five years. All patients underwent remission induction chemotherapy and local treatment before myeloablative therapy. Seventeen of thirty-six patients had multifocal primary Ewing's tumor, eighteen of thirty-six had early, multiple or multifocal relapse, one of thirty-six patients had unifocal late relapse. Twenty-six of thirty-six were treated with autologous and ten of thirty-six with allogeneic hematopoietic stem cells. We analyzed the following risk factors, that could possibly influence the event-free survival (EFS): number of involved bones, degree of remission at time of SCT, type of graft, indication for SCT, bone marrow infiltration, bone with concomitant lung disease, age at time of diagnosis, pelvic involvement, involved compartment radiation, histopathological diagnosis.
RESULTS
EFS for the 36 patients was 0.24 (0.21) +/- 0.07. Eighteen of thirty-six patients suffered relapse or died of disease, nine of thirty-six died of treatment related toxicity (DOC). Nine of thirty-six patients are alive in CR. Age > or = 17 years at initial diagnosis (P < 0.005) significantly deteriorated outcome. According to the type of graft, EFS was 0.25 +/- 0.08 after autologous and 0.20 +/- 0.13 after allogeneic SCT. Incidence of DOC was more than twice as high after allogeneic (40%) compared to autologous (19%) SCT, even though the difference did not reach significance (P = 0.08, Fisher's exact test).
CONCLUSIONS
Because of the rather short observation period. secondary malignant neoplasms (SMN) may complicate the future clinical course of some of our patients who are currently viewed as event-free survivors. EFS in AET is not improved by allogeneic SCT due to a higher complication rate. The patient group was to small to analyze for a possible graft-versus-tumor effect.
Topics: Adolescent; Adult; Age Factors; Antineoplastic Combined Chemotherapy Protocols; Bone Neoplasms; Case Management; Cause of Death; Child; Combined Modality Therapy; Disease-Free Survival; Dose Fractionation, Radiation; Female; Follow-Up Studies; Hematopoietic Stem Cell Transplantation; Humans; Immunologic Factors; Interleukin-2; Male; Myelodysplastic Syndromes; Neoplasm Metastasis; Neoplasms, Second Primary; Prognosis; Radiotherapy, Adjuvant; Remission Induction; Risk Factors; Sarcoma, Ewing; Survival Analysis; Transplantation Conditioning; Transplantation, Autologous; Transplantation, Homologous; Treatment Outcome
PubMed: 11142486
DOI: 10.1023/a:1026539908115 -
Targeted Oncology Mar 2024Multimodal treatment of newly diagnosed high-risk neuroblastoma (HRNB) includes induction chemotherapy, consolidation with myeloablative therapy (MAT) and autologous... (Meta-Analysis)
Meta-Analysis
BACKGROUND
Multimodal treatment of newly diagnosed high-risk neuroblastoma (HRNB) includes induction chemotherapy, consolidation with myeloablative therapy (MAT) and autologous stem cell transplantation (ASCT), followed by anti-disialoganglioside 2 (GD2) immunotherapy, as recommended by the Children's Oncology Group (COG) and the Society of Paediatric Oncology European Neuroblastoma (SIOPEN). Some centres proposed an alternative approach with induction chemotherapy followed by anti-GD2 immunotherapy, without MAT+ASCT.
OBJECTIVE
The aim of this systematic literature review was to compare survival outcomes in patients with HRNB treated with or without MAT+ASCT and with or without subsequent anti-GD2 immunotherapy.
PATIENTS AND METHODS
The review followed the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. MEDLINE via PubMed and EMBASE databases were systematically searched for randomised controlled trials (RCT) and observational comparative studies in patients with HRNB using search terms for 'neuroblastoma' and ('myeloablative therapy' OR 'stem cell transplantation'). Reporting of at least one survival outcome [event-free survival (EFS), progression-free survival, relapse-free survival and/or overall survival (OS)] was required for inclusion. Outcomes from RCTs were synthesized in meta-analysis, while meta-analysis of non-RCTs was not planned owing to expected heterogeneity.
RESULTS
Literature searches produced 2587 results with 41 publications reporting 34 comparative studies included in the review. Of these, 7 publications reported 4 RCTs, and 34 publications reported 30 non-RCT studies. Studies differed with respect to included populations, induction regimen, response to induction, additional treatments and transplantation procedures. Subsequent treatments of relapse were rarely reported and could not be compared. In the meta-analysis, EFS was in favour of MAT+ASCT over conventional chemotherapy or no further treatment [hazard ratio (HR) = 0.78, 95% confidence interval (CI) 0.67-0.91, p = 0.001] with a trend favouring MAT+ASCT for OS (HR = 0.86, 95% CI 0.73-1.00, p = 0.05). Tandem MAT+ASCT was found to improve EFS compared with the single procedure, with improvement in both EFS and OS in patients treated with anti-GD2 therapy. Non-RCT comparative studies were broadly consistent with evidence from the RCTs; however, not all reported survival benefits of MAT+ASCT (single or tandem). Limited comparative evidence on treatment without MAT+ASCT in patients treated with anti-GD2 immunotherapy suggests an increased risk of relapse. In relapsed patients, MAT+ASCT appears to improve OS, but evidence remains scarce.
CONCLUSIONS
Survival benefits in patients treated with MAT+ASCT confirm that the procedure should remain an integral part of multimodal therapy. In patients treated with anti-GD2 immunotherapy, limited evidence suggests that omitting MAT+ASCT is associated with an increased risk of relapse, and therefore, a change in clinical practice can currently not be recommended. Evidence suggests the use of tandem MAT+ASCT compared with the single procedure, with greater benefits observed in patients treated with anti-GD2 immunotherapy. Limited evidence also suggests improved survival following MAT+ASCT in relapsed patients, which needs to be viewed in light of emerging chemoimmunotherapy in this setting.
Topics: Child; Humans; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Hematopoietic Stem Cell Transplantation; Neoplasm Recurrence, Local; Neuroblastoma; Recurrence; Stem Cell Transplantation
PubMed: 38401028
DOI: 10.1007/s11523-024-01033-4 -
Biology of Blood and Marrow... May 2014Hematopoietic stem cell transplantation (HSCT) is a potentially life-saving therapy for patients with malignant and nonmalignant disease states. Transplant has been... (Review)
Review
Hematopoietic stem cell transplantation (HSCT) is a potentially life-saving therapy for patients with malignant and nonmalignant disease states. Transplant has been associated with high treatment-related morbidity and mortality, therefore limiting its usefulness in patients with baseline liver dysfunction. In the event that a patient with hepatic insufficiency is selected for HSCT, dosage adjustments may be considered; however, no reliable endogenous biomarkers can serve as a guide for adjustments. There is no clear standard or guideline for how to approach these patients, and most adjustments are made empirically on the basis of expert opinion. This article offers practical advice and outlines our personal approaches to provide dosing recommendations for commonly-used preparative agents in the setting of hepatic impairment with the aim to optimize dosing for this patient population.
Topics: Drug Administration Schedule; Drug Dosage Calculations; Drug Monitoring; Guidelines as Topic; Hematologic Diseases; Hematopoietic Stem Cell Transplantation; Humans; Liver Diseases; Myeloablative Agonists; Transplantation Conditioning
PubMed: 24492142
DOI: 10.1016/j.bbmt.2014.01.029 -
Proceedings of the American Thoracic... May 2010Serious infections due to non-Aspergillus molds are being encountered with increasing frequency. Factors likely responsible for the rise of these infections include... (Review)
Review
Serious infections due to non-Aspergillus molds are being encountered with increasing frequency. Factors likely responsible for the rise of these infections include aging populations in countries with advanced medical technologies, the resultant increase in incidence of many cancers, increasingly intensive myeloablative therapies for these cancers, increasingly intensive care for critically ill patients, and increases in the frequency of solid organ and hematopoietic stem cell transplantation. Although diagnostic and therapeutic modalities have improved, mortality rates for invasive mold infections remain high. In this review, we summarize current knowledge about non-Aspergillus mold infections of the chest, with a focus on risk factors, clinical features, diagnosis, and treatment.
Topics: Drug Therapy, Combination; Fusarium; Humans; Immunocompromised Host; Lung Diseases, Fungal; Mucormycosis; Mycetoma; Mycoses; Pneumonia; Pseudallescheria
PubMed: 20463250
DOI: 10.1513/pats.200906-033AL