Secondary malignancies following high dose therapy and autologous hematopoietic cell transplantation-systematic review and meta-analysis

Vaxman, Iuliana; Ram, Ron; Gafter‐Gvili, Anat; Vidal, Liat; Yeshurun, Moshe; Lahav, Meir; Shpilberg, Ofer

doi:10.1038/bmt.2014.325

Cited by 31 publications

(16 citation statements)

References 48 publications

(39 reference statements)

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“…31,32 Although scleroderma is associated with an increased risk of cancer, chemotherapy and irradiation are also associated with increased cancer risk. 33,34 Patients who are exposed to total-body irradiation are at increased risk for secondary cancers over a lifetime. Additional follow-up will be needed to quantify the risk of late cancer in patients with scleroderma who are treated with total-body irradiation as well as long-term outcomes of the trial.…”

Section: Discussionmentioning

confidence: 99%

Myeloablative Autologous Stem-Cell Transplantation for Severe Scleroderma

et al. 2018

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BACKGROUND Despite current therapies, diffuse cutaneous systemic sclerosis (scleroderma) often has a devastating outcome. We compared myeloablative CD34+ selected autologous hematopoietic stem-cell transplantation with immunosuppression by means of 12 monthly infusions of cyclophosphamide in patients with scleroderma. METHODS We randomly assigned adults (18 to 69 years of age) with severe scleroderma to undergo myeloablative autologous stem-cell transplantation (36 participants) or to receive cyclophosphamide (39 participants). The primary end point was a global rank composite score comparing participants with each other on the basis of a hierarchy of disease features assessed at 54 months: death, event-free survival (survival without respiratory, renal, or cardiac failure), forced vital capacity, the score on the Disability Index of the Health Assessment Questionnaire, and the modified Rodnan skin score. RESULTS In the intention-to-treat population, global rank composite scores at 54 months showed the superiority of transplantation (67% of 1404 pairwise comparisons favored transplantation and 33% favored cyclophosphamide, P = 0.01). In the per-protocol population (participants who received a transplant or completed ≥9 doses of cyclophosphamide), the rate of event-free survival at 54 months was 79% in the transplantation group and 50% in the cyclophosphamide group (P = 0.02). At 72 months, Kaplan–Meier estimates of event-free survival (74% vs. 47%) and overall survival (86% vs. 51%) also favored transplantation (P = 0.03 and 0.02, respectively). A total of 9% of the participants in the transplantation group had initiated disease-modifying antirheumatic drugs (DMARDs) by 54 months, as compared with 44% of those in the cyclophosphamide group (P = 0.001). Treatment-related mortality in the transplantation group was 3% at 54 months and 6% at 72 months, as compared with 0% in the cyclophosphamide group. CONCLUSIONS Myeloablative autologous hematopoietic stem-cell transplantation achieved long-term benefits in patients with scleroderma, including improved event-free and overall survival, at a cost of increased expected toxicity. Rates of treatment-related death and post-transplantation use of DMARDs were lower than those in previous reports of nonmyeloablative transplantation. (Funded by the National Institute of Allergy and Infectious Diseases and the National Institutes of Health; ClinicalTrials.gov number, NCT00114530.)

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Section: Discussionmentioning

confidence: 99%

Myeloablative Autologous Stem-Cell Transplantation for Severe Scleroderma

et al. 2018

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“…activity in these heavily pretreated patients 62,67,85,90 ; therefore, the use of these therapies earlier in the treatment course of lymphoma might increase the likelihood of success, if for no other reason than patients are more likely to be healthy enough to undergo such treatment, and because the disease is likely to still be sensitive to chemotherapy, thus enabling lower lymphoma burdens to be obtained before cell infusion. Application of CAR-T-cell therapy earlier in the course of treatment might also avoid some of the negative consequences of prolonged exposure to cytotoxic agents, such as the development of myelodysplastic syndrome and other secondary malignancies, which are a substantial risk, especially following auto-HSCT 157,158 . Another potential advantage is that patients who have never been exposed to chemotherapy might have higher blood T-cell counts and perhaps T cells that are more appropriate for CAR-T-cell therapy -both of these factors would facilitate production of CAR T cells.…”

Section: Improving Car-t-cell Therapymentioning

confidence: 99%

Chimeric antigen receptor T-cell therapies for lymphoma

2017

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New therapies are needed for patients with Hodgkin or non-Hodgkin lymphomas that are resistant to standard therapies. Indeed, unresponsiveness to standard chemotherapy and relapse after autologous stem-cell transplantation are indicators of an especially poor prognosis. Chimeric antigen receptor (CAR) T cells are emerging as a novel treatment modality for these patients. Clinical trial data have demonstrated the potent activity of anti-CD19 CAR T cells against multiple subtypes of B-cell lymphoma, including diffuse large-B-cell lymphoma (DLBCL), follicular lymphoma, mantle-cell lymphoma, and marginal-zone lymphoma. Importantly, anti-CD19 CAR T cells have impressive activity against chemotherapy-refractory lymphoma, inducing durable complete remissions lasting >2 years in some patients with refractory DLBCL. CAR-T-cell therapies are, however, associated with potentially fatal toxicities, including cytokine-release syndrome and neurological toxicities. CAR T cells with novel target antigens, including CD20, CD22, and κ-light chain for B-cell lymphomas, and CD30 for Hodgkin and T-cell lymphomas, are currently being investigated in clinical trials. Centrally manufactured CAR T cells are also being tested in industry-sponsored multicentre clinical trials, and will probably soon become a standard therapy. Herein, we review the clinical efficacy and toxicity of CAR-T-cell therapies for lymphoma, and discuss their limitations and future directions with regard to toxicity management, CAR designs and CAR-T-cell phenotypes, conditioning regimens, and combination therapies.

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“…In childhood cancer studies, there are multiple reports on effect of radiation and/or chemotherapy on risk of subsequent secondary malignant solid tumors. [34][35][36][37] Irradiation containing conditioning regimens have been identified as a risk factor for posttransplant malignancy in patients with severe aplastic anemia and FA 20,38 ; and similar efforts of removing radiation from the conditioning regimen have been successful in patients with severe 39 aplastic anemia. A study by Rosenberg et al showed a trend toward increasing malignancy in patients with FA receiving a TBI-based regimen.…”

Section: Discussionmentioning

confidence: 99%

Radiation-free, alternative-donor HCT for Fanconi anemia patients: results from a prospective multi-institutional study

Mehta

Davies

Leemhuis

et al. 2017

Blood

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• Alternative donor HCT can be performed in patients with FA without using radiation.• All 26 patients younger than 10 years of age undergoing HCT for marrow failure using lower-dose busulfancontaining regimen survived.Fanconi anemia (FA) is an inherited bone marrow failure syndrome characterized by chromosomal fragility, progressive marrow failure, and cancer predisposition. Hematopoietic cell transplantation (HCT) is curative for FA-related marrow failure or leukemia, but both radiation exposure during transplant and graft-versus-host disease (GVHD) may increase risk of later malignancies of the head and neck and anogenital area. In this study, we tested a radiation-free conditioning regimen with a T-cell-depleted graft to eliminate radiation exposure and minimize early and late toxicities of transplant. Forty-five patients (median age, 8.2 years; range 4.3-44) with FA underwent HCT between June 2009 and May 2014. The preparative regimen included busulfan, cyclophosphamide, fludarabine, and rabbit anti-thymocyte globulin. Busulfan levels were monitored to avoid excess toxicity. All grafts were CD34-selected/T-cell-depleted using the CliniMacs CD34 columns (Miltenyi). Thirty-four patients (75.6%) with marrow failure and 11 (24.4%) with myelodysplastic syndrome underwent HCT using matched unrelated (n 5 25, 55.5%), mismatched unrelated (n 5 14, 31.1%), or mismatched related donors (n 5 6, 13.4%). One year probabilities of overall and disease-free survival for the entire cohort, including patients with myeloid malignancy and those receiving mismatched related/haploidentical grafts, were 80% (66%) and 77.7% (66.2%), respectively (median follow-up 41 months). All young children (<10 years of age) undergoing HCT for marrow failure using low-dose busulfancontaining regimen survived. No patients developed acute grade 3-4 GVHD. Sequential reduction of busulfan dose was successfully achieved per study design. Our results show excellent outcomes in patients with FA undergoing alternative donor HCT without radiation exposure. The study is registered to www.clinicaltrials.gov as #NCT01082133. (Blood. 2017;129(16):2308-2315

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Secondary malignancies following high dose therapy and autologous hematopoietic cell transplantation-systematic review and meta-analysis

Cited by 31 publications

References 48 publications

Myeloablative Autologous Stem-Cell Transplantation for Severe Scleroderma

Myeloablative Autologous Stem-Cell Transplantation for Severe Scleroderma

Chimeric antigen receptor T-cell therapies for lymphoma

Radiation-free, alternative-donor HCT for Fanconi anemia patients: results from a prospective multi-institutional study

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