Hematology/oncology Clinics of North America

As many new systemic therapy options have recently emerged, the standard of care for patients with metastatic renal cell carcinoma (mRCC) is gradually changing. The increasing complexity of treatment options requires more personalized treatment strategies. This evolution in the systemic therapy landscape comes with a need for validated stratification models that facilitate decision making and patient counseling for clinicians through a risk-adapted approach. This article summarizes the available evidence on risk stratification and prognostic models for mRCC, including the International mRCC Database Consortium and Memorial Sloan Kettering Cancer Center models, as well as their association with clinical outcomes...

Despite substantial progress in the clinical management of Waldenström's Macroglobulinemia (WM) and the emergence of chemotherapy-free approaches such as BTK inhibitors, WM is still a disease in which current treatments fail to cure and are in part associated with significant toxicities, compromising treatment outcome and quality of life. Thus, the vision for future front-line therapy should be to develop regimens which combine improved efficacy and excellent applicability with a low toxicity profile. Conventional immunochemotherapy such as bendamustine-rituximab is highly active but limited by hematotoxicity and long-lasting immunosuppression...

The development of brain metastases is a poor prognostic indicator in renal cell carcinoma. Regular imaging and clinical examinations are necessary to monitor the brain before or during systemic therapy. Central nervous system-targeted radiation therapy, including stereotactic radiosurgery, whole-brain radiation therapy, and surgical resection, is a standard treatment option. Clinical trials are currently investigating the role of targeted therapy and immune checkpoint inhibitor combinations in treating brain metastases and decreasing intracranial disease progression...

The most common form of kidney cancer is clear cell renal cell carcinoma (ccRCC). Biallelic VHL tumor suppressor gene inactivation is the usual initiating event in both hereditary (VHL Disease) and sporadic ccRCCs. The VHL protein, pVHL, earmarks the alpha subunits of the HIF transcription factor for destruction in an oxygen-dependent manner. Deregulation of HIF2 drives ccRCC pathogenesis. Drugs inhibiting the HIF2-responsive growth factor VEGF are now mainstays of ccRCC treatment. A first-in-class allosteric HIF2 inhibitor was recently approved for treating VHL Disease-associated neoplasms and appears active against sporadic ccRCC in early clinical trials...

Waldenström macroglobulinemia (WM) is a rare, indolent, and currently incurable B-cell neoplasm characterized by monoclonal immunoglobulin M gammopathy, frequent nodal involvement, and lymphoplasmacytic infiltration of the bone marrow. The clinical pattern at diagnosis is similar to that reported in developed countries but, unfortunately, the tools for a complete diagnosis and access to novel therapies are suboptimal. Older drugs such as bendamustine, cyclophosphamide, and chlorambucil may still play a role in treating WM...

Combination therapies with immune checkpoint blockers have shown improvements in overall response rate, progression free survival, and overall survival over monotherapy with sunitinib in intermediate and poor risk subgroups. Identification of best upfront therapy may be guided by future clinical trials utilizing adaptive strategies, triplet therapy, or novel biomarkers.

Bing-Neel syndrome is a rare manifestation of Waldenström macroglobulinemia (WM), which is caused by infiltration of the malignant lymphoplasmacytic cells in the central nervous system. Patients can present with a diverse range of neurologic symptoms, and differentiation with other comorbidities seen in WM, such as immunoglobulin M-related polyneuropathy, can be challenging. Both the rarity of this disorder and the heterogeneity of the clinical presentation often cause a significant diagnostic delay with the risk of permanent neurologic damage...

Recent advances in our understanding of the molecular alterations underlying different types of renal cell carcinoma (RCC), as well as the implementation of immune checkpoint inhibitors in the treatment of patients with advanced disease, have significantly expanded the role of pathologists in the management of RCC patients and in the identification of predictive biomarkers that can guide patient treatment. In this chapter, we examine pathologists' evolving role in patient care and the development of precision medicine strategies for RCC...

Defining metastatic renal-cell carcinoma as a favorable risk depends on clinical risk-stratification tools such as the International Metastatic Renal Cell Carcinoma Database Consortium or the Memorial Sloan-Kettering Cancer Center scores. The favorable-risk disease tends to have better prognosis and survival compared with disease stratified as either intermediate or poor risk and can be attributed in part to an indolent tumor biology. Several phase 3 clinical trials have demonstrated an improvement in progression-free survival and objective response rate, but not overall survival benefit with combinations of immunotherapy and vascular endothelial growth factor tyrosine kinase inhibitors compared with sunitinib in favorable-risk disease...

Up to 5% of renal cell carcinomas (RCCs) can be associated with a known hereditary RCC syndrome. In addition to the well-characterized RCC syndromes, there are also emerging syndromes associated with increased RCC risk. In the last few years, consensus guidelines have outlined recommendations for who should be referred for genetic evaluation, and what screening should be done for early detection of RCC. Although much progress has been made, work is still needed-guidelines are still mostly based on expert opinion and the role of emerging genetic associations will need to be clarified...

The treatment of advanced renal cell carcinoma (RCC) has changed dramatically with immune checkpoint inhibitors, yet most patients do not have durable responses. There is consequently a tremendous need for novel therapeutic development. RCC, and particularly the most common histology clear cell RCC, is an immunobiologically and metabolically distinct tumor. An improved understanding of RCC-specific biology will be necessary for the successful identification of new treatment targets for this disease. In this review, we discuss the current understanding of RCC immune pathways and metabolic dysregulation, with a focus on topics important for future clinical development...

Waldenström's macroglobulinemia (WM) is an immunoglobulin M monoclonal gammopathy produced by a bone marrow lymphoplasmacytic lymphoma, an indolent non-Hodgkin lymphoma in which the cure is still an unmet challenge. Combinations with alkylating agents, purine analogs, and monoclonal antibodies, Bruton tyrosine kinase, and proteasome inhibitors are used for the treatment of relapsed and refractory patients. Moreover, new additional agents can be seen on the horizon as potential effective therapies. No consensus on a preferred treatment in the relapsed setting is available yet...

The discovery of MYD88 (L265P) mutation led to investigating BTK inhibitors in Waldenström macroglobulinemia (WM). Ibrutinib, the first-in-class agent, was approved based on a phase II trial in relapsed/refractory patients. In the phase III iNNOVATE study, the combination of rituximab and ibrutinib was compared with rituximab and placebo in treatment-naïve and relapsed/refractory patients. Second-generation BTK inhibitor, zanubrutinib, was compared with Ibrutinib in MYD88-mutated WM patients in the phase III ASPEN trial, whereas acalabrutinib was investigated in a phase II trial...

Histologic transformation (HT) to diffuse large B-cell lymphoma occurs rarely in Waldenström macroglobulinemia, with higher incidence in MYD88 wild-type patients. HT is suspected clinically when rapidly enlarging lymph nodes, elevated lactate dehydrogenase levels, or extranodal disease occur. Histologic assessment is required for diagnosis. HT carries a worse prognosis compared with nontransformed Waldenström macroglobulinemia. A validated prognostic score based on three adverse risk factors stratifies three risk groups...

Despite the introduction of effective novel agents, chemoimmunotherapy (CIT), with its widespread use, retains relevance and is one of the 2 vastly disparate strategies to treat Waldenström macroglobulinemia (WM), the alternative being the Bruton tyrosine kinase inhibitor (BTKi)-based approach. Considerable evidence over the past decades supports the integration of the monoclonal anti-CD20 antibody, rituximab, to the CIT backbone in WM, a CD20+ malignancy. Besides substantial efficacy, the finite duration of the treatment, coupled with lower rates of cumulative and long-term, clinically significant adverse effects and greater affordability, make CIT appealing, notwithstanding the lack of quality-of-life data with such an approach in WM...

Initial studies of radiotherapy in renal cell carcinoma (RCC) failed to demonstrate significant clinical impact. With the advent of stereotactic body radiotherapy (SBRT) that allows for delivery of more effective radiation doses in a precise fashion, radiotherapy has become an essential component in the multidisciplinary management of patients with RCC both in the setting of localized and metastatic disease beyond the traditional role of palliative treatment. Recent evidence has demonstrated high rates of long-term local control (∼95%) when SBRT is delivered to kidney tumors with limited toxicity risks and only minor impact on renal function...

The term variant histology renal cell carcinomas (vhRCCs), also known as non-clear cell RCCs, refers to a diverse group of malignancies with distinct biologic and therapeutic considerations. The management of vhRCC subtypes is often based on extrapolating results from the more common clear cell RCC studies or basket trials that are not specific to each histology. The unique management of each vhRCC subtype necessitates accurate pathologic diagnosis and dedicated research efforts. Herein, we discuss tailored recommendations for each vhRCC histology informed by ongoing research and clinical experience...

Proteasome inhibitors (PIs) have long been used in myeloma therapy but also for Waldenström macroglobulinemia. Their use has been successful and has also been investigated for the frontline management of the disease. Bortezomib was effective either as a single agent or in combination with other regimens with high response rates observed in most studies, despite its adverse effects, especially neurotoxicity, which remains a major concern. Clinical trials with second-generation PIs such as carfilzomib and ixazomib have also been conducted, always in combination with immunotherapy in previously untreated patients...

With the increasing availability of sequencing techniques and new polymerase chain reaction-based methods, data regarding the genomic profile of Waldenström macroglobulinemia (WM) are being continuously analyzed and reproduced. MYD88 and CXCR4 mutations are highly prevalent in all the stages of WM, including the early IgM monoclonal gammopathy of undetermined significance or a more advanced stage, such as smoldering WM. Thus, there is a need to define genotypes before starting either standard treatment regimens or clinical trials...

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