Secondary malignancies after allogeneic stem-cell transplantation in the era of reduced-intensity conditioning; the incidence is not reduced

Subsequent neoplasms (SN) following hematopoietic cell transplantation (HCT) cause significant patient morbidity and mortality. Risks for specific SN types vary substantially, with particularly elevated risks for post-transplant lymphoproliferative disorders, myelodysplastic syndrome/acute myeloid leukemia, and squamous cell malignancies. This consensus document provides an overview of the current state of knowledge regarding SN after HCT and recommends priorities and approaches to overcome challenges and gaps in understanding. Numerous factors have been suggested to impact risk, including patient-related (e.g., age), primary disease-related (e.g., disease type, pre-HCT therapies), and HCT-related characteristics (e.g., type and intensity of conditioning regimen, stem cell source, development of graft-versus-host disease). However, gaps in understanding remain for each of these risk factors, particularly for patients receiving HCT in the current era due to substantial advances in clinical transplantation practices. Additionally, the influence of non-transplant-related risk factors (e.g., germline genetic susceptibility, oncogenic viruses, lifestyle factors) is poorly understood. Clarification of the magnitude of SN risks and identification of etiologic factors will require large-scale, long-term, systematic follow-up of HCT survivors with detailed clinical data. Most investigations of the mechanisms of SN pathogenesis after HCT have focused on immune drivers. Expansion of our understanding in this area will require interdisciplinary laboratory collaborations utilizing measures of immune function and availability of archival tissue from SN diagnoses. Consensus-based recommendations for optimal preventative, screening, and therapeutic approaches have been developed for certain SN after HCT, whereas for other SN, general population guidelines are recommended. Further evidence is needed to specifically tailor preventative, screening, and therapeutic guidelines for SN after HCT, particularly for unique patient populations. Accomplishment of this broad research agenda will require increased investment in systematic data collection with engagement from patients, clinicians, and interdisciplinary scientists in order to reduce the burden of SN in the rapidly growing population of HCT survivors.

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“…11,19,33,46,69,137–142 Risks associated with cGVHD vary by malignancy type (Supplementary Table 3). SCC is the most commonly reported SN.…”

Section: Disease- and Transplant-related Risk Factorsmentioning

confidence: 99%

National Institutes of Health Hematopoietic Cell Transplantation Late Effects Initiative: The Subsequent Neoplasms Working Group Report

Morton

Saber

Baker

et al. 2017

Biology of Blood and Marrow Transplantation

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“…18,81,86,[88][89][90][91][92][93][94][95] Interestingly, the risk for secondary malignancies does not appear to be lower for RIC vs myeloablative transplants despite the lower doses of chemotherapy and radiation. 96 The differences in the toxicity profile impact the timing of complications. In one study of RIC vs myeloablative conditioning, NRM was lower for RIC in the first year after transplant, primarily in patients over age 40, but there were no significant differences after longer follow-up (13% vs 18% at 3 years).…”

Section: Toxicitymentioning

confidence: 99%

Reduced-intensity conditioned allogeneic SCT in adults with AML

Reshef

Porter

2015

Bone Marrow Transplant

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AML is currently the most common indication for reduced-intensity conditioned (RIC) allo-SCT. Reduced-intensity regimens allow a potent GVL response to occur with minimized treatment-related toxicity in patients of older age or with comorbidities that preclude the use of myeloablative conditioning. Whether RIC SCT is appropriate for younger and more standard risk patients is not well defined and the field is changing rapidly; a prospective randomized trial of myeloablative vs RIC (BMT-CTN 0901) was recently closed when early results indicated better outcomes for myeloablative regimens. However, detailed results are not available, and all patients in that study were eligible for myeloablative conditioning. RIC transplants will likely remain the standard of care as many patients with AML are not eligible for myeloablative conditioning. Recent publication of mature results from retrospective and prospective cohorts provide contemporary efficacy and toxicity data for these attenuated regimens. In addition, recent studies explore the use of alternative donors, introduce regimens that attempt to reduce toxicity without reducing intensity, and identify predictive factors that pave the way to personalized approaches. These studies paint a picture of the future of RIC transplants. Here we review the current status of RIC allogeneic SCT in AML. ( Bone Marrow Transplantation THE RATIONALE FOR RIC IN AMLTraditional myeloablative transplants are effective in part due to a potent immunologic GVL effect independent of the conditioning regimen. The GVL response has been repeatedly demonstrated in allo-SCT 1,2 and through the use of DLI. 3,4 The ability to harness GVL yet minimize toxicity is highly relevant in AML, which is common in older patients and often incurable with chemotherapy alone. In 2013, AML was the most common indication for allo-SCT, 35% of AML transplants were in patients over age 60 and over 40% were performed with reduced-intensity conditioning (RIC) regimens (data from CIBMTR-Center for International Blood and Marrow Transplant Research).Data from animal models 5,6 and clinical observations regarding GVL activity [1][2][3][4]7 facilitated the development of RIC regimens. The success of initial attempts to use low-dose (2 Gy) TBI alone as conditioning was hindered by frequent graft rejections. The addition of fludarabine to low-dose TBI promoted engraftment with encouraging outcomes. [8][9][10][11][12] This supported a conceptual shift in allo-SCT away from dose intensity toward less myelotoxic regimens that rely on a potent GVL response. EFFICACY-IS THERE AN IDEAL CONDITIONING REGIMEN?The definition of RIC has been a moving target. The term 'reduced intensity' describes regimens characterized by lower rates of toxicities compared with myeloablative transplants. RIC regimens can be further classified as non-myeloablative when they result in minimal cytopenias. These regimens presumably have minimal or no direct effect on leukemic cells, relying solely on the GVL response. 13 The CIBMTR defines a RIC regimen ...

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“…Unfortunately, these drugs have many side effects and lead to broad and unspecific immunosuppression. Long-term immunosuppression increases the patient's risk of secondary cancers and severe lifethreatening infections (37,38). Moreover, despite the profound immunosuppression induced by these agents, many patients still suffer from active disease.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Protein Geranylgeranylation Specifically Interferes with CD40-Dependent B Cell Activation, Resulting in a Reduced Capacity To Induce T Cell Immunity

Shimabukuro‐Vornhagen

Zoghi

Liebig

et al. 2014

The Journal of Immunology

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Ab-independent effector functions of B cells, such as Ag presentation and cytokine production, have been shown to play an important role in a variety of immune-mediated conditions such as autoimmune diseases, transplant rejection, and graft-versus-host disease. Most current immunosuppressive treatments target T cells, are relatively unspecific, and result in profound immunosuppression that places patients at an increased risk of developing severe infections and cancer. Therapeutic strategies, which interfere with B cell activation, could therefore be a useful addition to the current immunosuppressive armamentarium. Using a transcriptomic approach, we identified upregulation of genes that belong to the mevalonate pathway as a key molecular event following CD40-mediated activation of B cells. Inhibition of 3-hydroxy-3-methylglutaryl CoA reductase, the rate-limiting enzyme of the mevalonate pathway, by lipophilic statins such as simvastatin and atorvastatin resulted in a specific inhibition of B cell activation via CD40 and impaired their ability to act as stimulatory APCs for allospecific T cells. Mechanistically, the inhibitory effect resulted from the inhibition of protein geranylgeranylation subsequent to the depletion of mevalonate, the metabolic precursor for geranylgeranyl. Thus, inhibition of geranylgeranylation either directly through geranylgeranyl transferase inhibitors or indirectly through statins represents a promising therapeutic approach for the treatment of diseases in which Ag presentation by B cells plays a role.

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Secondary malignancies after allogeneic stem-cell transplantation in the era of reduced-intensity conditioning; the incidence is not reduced

Cited by 56 publications

References 28 publications

National Institutes of Health Hematopoietic Cell Transplantation Late Effects Initiative: The Subsequent Neoplasms Working Group Report

National Institutes of Health Hematopoietic Cell Transplantation Late Effects Initiative: The Subsequent Neoplasms Working Group Report

Reduced-intensity conditioned allogeneic SCT in adults with AML

Inhibition of Protein Geranylgeranylation Specifically Interferes with CD40-Dependent B Cell Activation, Resulting in a Reduced Capacity To Induce T Cell Immunity

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