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Allogeneic hematopoietic cell transplantation for renal cell carcinoma: ten years after.

ABSTRACT: The first series of patients with metastatic renal cell carcinoma (RCC) treated by non-myeloablative allogeneic hematopoietic cell transplantation (HCT) was reported in 2000 and demonstrated an allogeneic graft-versus-tumor (GVT) effect that encouraged further investigation of this approach. However, the past 10 years have also witnessed profound changes in the medical management of metastatic RCC with the introduction of targeted therapies directed against VEGF or mammalian target of rapamycin (mTOR) signaling pathways creating uncertainty about a continued role for allogeneic HCT in the treatment of RCC.A total of 21 published reports describing clinical outcomes for 398 patients with metastatic RCC treated by allogeneic HCT compiled herein provide a composite overview of the world wide experience for key efficacy and toxicity outcomes. Review of correlative studies that identify donor-derived T cells as mediators of RCC-specific GVT effects offers insight into both the potential as well as the technical barriers to the delivery of antigen-specific post-transplant cellular therapy or vaccination designed to augment the allogeneic GVT effect.The future development of non-myeloablative allogeneic HCT for metastatic RCC will require novel treatment protocols designed to augment and sustain post-transplant GVT effects against RCC to generate renewed enthusiasm for this approach.

SUBMITTER: Tykodi SS

PROVIDER: S-EPMC3201801 | biostudies-literature | 2011 Jun

REPOSITORIES: biostudies-literature

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Allogeneic hematopoietic cell transplantation for renal cell carcinoma: ten years after.

Tykodi Scott S SS Sandmaier Brenda M BM Warren Edus H EH Thompson John A JA

Expert opinion on biological therapy 20110321 6

<h4>Introduction</h4>The first series of patients with metastatic renal cell carcinoma (RCC) treated by non-myeloablative allogeneic hematopoietic cell transplantation (HCT) was reported in 2000 and demonstrated an allogeneic graft-versus-tumor (GVT) effect that encouraged further investigation of this approach. However, the past 10 years have also witnessed profound changes in the medical management of metastatic RCC with the introduction of targeted therapies directed against VEGF or mammalian ...[more]

PMID: 21417772

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Project description:Noninfectious pulmonary toxicity (NPT), a significant complication of allogeneic hematopoietic cell transplantation (alloHCT), includes idiopathic pneumonia syndrome (IPS), diffuse alveolar hemorrhage (DAH), and cryptogenic organizing pneumonia (COP), with an overall incidence ranging from 1% to 15% in different case series and a variable mortality rate. A registry study of the epidemiology and outcomes of NPT after alloHCT has not been conducted to date. The primary objective of the present study was to assess the incidence of and risk factors for IPS, DAH, and COP; the secondary objective was to assess overall survival (OS) in patients developing NPT. This retrospective study included adult patients who underwent alloHCT between 2008 and 2017 and reported to the Center for International Blood and Marrow Transplant Research. Multivariable Cox proportional hazards regression models were developed to identify the risk factors for development of NPT and for OS, by including pretransplantation clinical variables and time-dependent variables of neutrophil and platelet recovery, and acute graft-versus-host disease (GVHD) post-transplantation. This study included 21,574 adult patients, with a median age of 55 years. According to the HCT Comorbidity Index (HCT-CI), 24% of the patients had moderate pulmonary comorbidity and 15% had severe pulmonary comorbidity. The cumulative incidence of NPT at 1 year was 8.1% (95% confidence interval [CI], 7.7% to 8.5%). Individually, the 1-year cumulative incidences of IPS, DAH, and COP were 4.9% (95% CI, 4.7% to 5.2%), 2.1% (95% CI, 1.9% to 2.3%), and .7% (95% CI, .6% to .8%), respectively. Multivariable analysis showed that severe pulmonary comorbidity, grade II-IV acute GVHD, mismatched unrelated donor and cord blood transplantation, and HCT-CI score ≥1 significantly increased the risk of NPT. In contrast, alloHCT performed in 2014 or later, non-total body irradiation (TBI)- and TBI-based nonmyeloablative conditioning and platelet recovery were associated with a decreased risk. In a landmark analysis at day+100 post-transplantation, the risk of DAH was significantly lower in patients who had platelet recovery by day +100. Multivariable analysis for OS demonstrated that NPT significantly increased the mortality risk (hazard ratio, 4.2; P < .0001).

Project description:The oral multikinase inhibitor sunitinib malate was approved by the U.S. Food and Drug Administration in January 2006 for use in patients with advanced renal cell carcinoma (RCC). Since then, it has been approved globally for this indication and for patients with imatinib-resistant or -intolerant gastrointestinal stromal tumors and advanced pancreatic neuroendocrine tumors. As we mark the 10-year anniversary of the beginning of the era of targeted therapy, and specifically the approval of sunitinib, it is worthwhile to highlight the progress that has been made in advanced RCC as it relates to the study of sunitinib. We present the key trials and data for sunitinib that established it as a reference standard of care for first-line advanced RCC therapy and, along with other targeted agents, significantly altered the treatment landscape in RCC. Moreover, we discuss the research with sunitinib that has sought to refine its role via patient selection and prognostic markers, improve dosing and adverse event management, and identify predictive efficacy biomarkers, plus the extent to which this research has contributed to the overall understanding and management of RCC. We also explore the key learnings regarding study design and data interpretation from the sunitinib studies and how these findings and the sunitinib development program, in general, can be a model for successful development of other agents. Finally, ongoing research into the continued and future role of sunitinib in RCC management is discussed.The oncologist2017;22:41-52 IMPLICATIONS FOR PRACTICE: Approved globally, sunitinib is established as a standard of care for first-line advanced renal cell carcinoma (RCC) therapy and, along with other targeted agents, has significantly altered the treatment landscape in RCC. Research with sunitinib that has sought to refine its role via patient selection and prognostic markers, improve dosing and adverse event management, and identify predictive efficacy biomarkers has contributed to the overall understanding and management of RCC. Key learnings regarding study design and data interpretation from the sunitinib studies and the sunitinib development program, in general, can be a model for the successful development of other agents.

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Allogeneic hematopoietic cell transplantation for renal cell carcinoma: ten years after.

Publications

Allogeneic hematopoietic cell transplantation for renal cell carcinoma: ten years after.

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