Showing papers in "Current Hematologic Malignancy Reports in 2017"
TL;DR: In this paper, the authors discuss barriers to palliative care integration in hematology, highlight several reports of successful integration, and suggest specific indications for involving palliate care in the management of hematologic malignancy patients.
Abstract: Evidence points to many benefits of "early palliative care," the provision of specialist palliative care services upstream from the end of life, to improve patients' quality of life while living with a serious illness. Yet most trials of early palliative care have not included patients with hematologic malignancies. Unfortunately, patients with hematologic malignancies are also known to have substantial illness burden, poor quality of life, and aggressive care at the end of life, including a greater likelihood of dying in the hospital, receiving chemotherapy at the end of life, and low hospice utilization, compared to patients with solid tumors. Given these unmet needs, one must wonder, why is palliative care so underutilized in this population? In this article, we discuss barriers to palliative care integration in hematology, highlight several reports of successful integration, and suggest specific indications for involving palliative care in the management of hematologic malignancy patients.
66 citations
TL;DR: The role of novel agents to improve disease-related parameters remains to be elucidated in frontline induction, disease salvage, and high-dose consolidation or in the maintenance setting.
Abstract: Chemotherapy remains the first-line therapy for aggressive lymphomas. However, 20–30% of patients with non-Hodgkin lymphoma (NHL) and 15% with Hodgkin lymphoma (HL) recur after initial therapy. We want to explore the role of high-dose chemotherapy (HDT) and autologous stem cell transplant (ASCT) for these patients. There is some utility of upfront consolidation for-high risk/high-grade B-cell lymphoma, mantle cell lymphoma, and T-cell lymphoma, but there is no role of similar intervention for HL. New conditioning regimens are being investigated which have demonstrated an improved safety profile without compromising the myeloablative efficiency for relapsed or refractory HL. Salvage chemotherapy followed by HDT and rescue autologous stem cell transplant remains the standard of care for relapsed/refractory lymphoma. The role of novel agents to improve disease-related parameters remains to be elucidated in frontline induction, disease salvage, and high-dose consolidation or in the maintenance setting.
60 citations
TL;DR: Novel gene-editing technologies like CRISPR-Cas9 allow facile editing of specific genes within the genome, generating a powerful platform to further optimize the activity of engineered T cells, leading to impressive responses in patients with B-cell leukemia and lymphoma.
Abstract: In this review, we discuss the most recent developments in gene-editing technology and discuss their application to adoptive T cell immunotherapy. Engineered T cell therapies targeting cancer antigens have demonstrated significant efficacy in specific patient populations. Most impressively, CD19-directed chimeric antigen receptor T cells (CART19) have led to impressive responses in patients with B-cell leukemia and lymphoma. CTL019, or KYMRIAH™ (tisagenlecleucel), a CD19 CAR T cell product developed by Novartis and the University of Pennsylvania, was recently approved for clinical use by the Food and Drug Administration, representing a landmark in the application of adoptive T cell therapies. As CART19 enters routine clinical use, improving the efficacy of this exciting platform is the next step in broader application. Novel gene-editing technologies like CRISPR-Cas9 allow facile editing of specific genes within the genome, generating a powerful platform to further optimize the activity of engineered T cells.
57 citations
TL;DR: Overall and complete response rates to venetoclax monotherapy in relapsed, refractory CLL are approximately 80 and 20%, respectively, even in patients with high-risk 17p deletion, and toxicities have been manageable and include neutropenia, diarrhea, and nausea.
Abstract: The BCL-2 family of proteins integrates pro- and anti-apoptotic signals within the cell and is responsible for initiation of caspase-dependent apoptosis. Chronic lymphocytic leukemia (CLL) cells are particularly dependent on the anti-apoptotic protein BCL-2 for their survival, making this an attractive therapeutic target in CLL. Several early efforts to create inhibitors of the anti-apoptotic family members faced significant challenges, but eventually, the BCL-2 specific inhibitor venetoclax moved forward in CLL. Overall and complete response rates to venetoclax monotherapy in relapsed, refractory CLL are approximately 80 and 20%, respectively, even in patients with high-risk 17p deletion. Toxicities have been manageable and include neutropenia, diarrhea, and nausea. The risk of tumor lysis syndrome (TLS), seen in early experience with the drug, has been mitigated by the use of appropriate TLS risk assessment, prophylaxis, and management. Future studies of venetoclax will focus on combination approaches, predictive biomarker discovery, and mechanisms of resistance.
46 citations
TL;DR: Using as single agents, hypomethylating agents (HMAs) induce only 15 to 25% complete remissions, but current data suggest that median OS observed after HMAs is comparable to that observed after more intensive therapies, suggesting long-term cure may be obtained in some patients treated with HMAs.
Abstract: Acute myeloid leukemia (AML) is predominantly a disease of older adults associated with poor long-term outcomes with available therapies. Used as single agents, hypomethylating agents (HMAs) induce only 15 to 25% complete remissions, but current data suggest that median OS observed after HMAs is comparable to that observed after more intensive therapies. Whether long-term cure may be obtained in some patients treated with HMAs is unknown. Combinations of HMAs to novel agents are now extensively investigated and attractive response rates have been reported when combining HMAs to different drug classes. The absence of reliable predictive biomarkers of efficacy of HMAs in AML and the uncertainties regarding their most relevant mechanisms of action hinder the rational design of the combinations to be tested in priority, usually in untreated older AML patients.
43 citations
TL;DR: The purpose of this review is to describe the risk factors associated with bleeding and thrombosis in MPN, as well as to review prevention strategies and management of these complications.
Abstract: The Philadelphia chromosome-negative myeloproliferative neoplasms (MPN) are characterized by both thrombotic and bleeding complications. The purpose of this review is to describe the risk factors associated with bleeding and thrombosis in MPN, as well as to review prevention strategies and management of these complications. Well-described risk factors for thrombotic complications include older age and history of prior thrombosis, along with traditional cardiovascular and venous thromboembolic risk factors. More recently, JAK2 V617F mutation has been found to carry an increased risk of thrombotic complications, whereas CALR has a lower risk than JAK2 mutation. Factors associated with an increased risk of bleeding in MPN include a prior history of bleeding, acquired von Willebrand syndrome, and primary myelofibrosis. Recent findings suggest that thrombocytosis carries a higher risk of bleeding than thrombosis in MPN, and aspirin may exacerbate this risk of bleeding, particularly in CALR-mutated ET. Much of the management of MPN focuses on predicting risk of bleeding and thrombosis and initiating prophylaxis to prevent complications in those at high risk of thrombosis. Emerging evidence suggests that sub-populations may have bleeding risk that outweighs thrombotic risk, particularly in setting of antiplatelet therapy. Future work is needed to better characterize this balance. At present, a thorough assessment of the risks of bleeding and thrombosis should be undertaken for each patient, and herein, we review risk factors for and management of these complications.
40 citations
TL;DR: The distinct clinical phenotype of FLT3-mutated AML, historically and currently available therapeutics, mechanisms of resistance, ongoing trials, and future outlook at treatment strategies are discussed.
Abstract: Internal tandem duplications (ITD) and tyrosine-kinase domain (TKD) mutations of the FMS-like tyrosine-kinase 3 (FLT3) can be found in up to one third of patients with acute myeloid leukemia (AML) and confer a poor prognosis. First discovered 20 years ago, these mutations were identified as viable therapeutic targets, and FLT3 tyrosine-kinase inhibitors (TKIs) have been in development for the last decade with steadily increasing potency. However, FLT3-mutated AML often acquires resistance to the growing armamentarium of FLT3 inhibitors through a variety of mechanisms. In this review, we discuss the distinct clinical phenotype of FLT3-mutated AML, historically and currently available therapeutics, mechanisms of resistance, ongoing trials, and future outlook at treatment strategies.
40 citations
TL;DR: In this review, the recently reported results of clinical trials conducted utilizing CAR T cell therapy in multiple myeloma (MM) are summarized.
Abstract: The recent clinical success of CD19-directed chimeric antigen receptor (CAR) T cell therapy in chronic and acute leukemia has led to increased interest in broadening this technology to other hematological malignancies and solid tumors. Now, advances are being made using CAR T cell technology to target myeloma antigens such as B cell maturation antigen (BCMA), CD138, and kappa-light chain as well as CD19 on putative myeloma stem cells. To date, only a limited number of multiple myeloma patients have received CAR T cell therapy but preliminary results have been encouraging. In this review, we summarize the recently reported results of clinical trials conducted utilizing CAR T cell therapy in multiple myeloma (MM).
35 citations
TL;DR: Clinical approaches to harness the immune system to overcome this defect with a focus on antibody based and adoptive cellular therapies hold enormous potential in the field of multiple myeloma and in the near future can be combined with or even replace the current standard of care.
Abstract: The treatment landscape of multiple myeloma is rapidly changing; however, despite improvement in patients’ survival, it still remains a largely incurable disease. One hallmark of myeloma is substantial immune dysfunction leading to an increased infection rate and the inability of immune surveillance to detect neoplastic cells. Here, we critically analyze clinical approaches to harness the immune system to overcome this defect with a focus on antibody based and adoptive cellular therapies. Clinical trials exploring these immunotherapies to treat myeloma are now well underway and show promising results. In relapsed myeloma, monoclonal antibodies directed against plasma cell antigens and immune checkpoints have already shown substantial efficacy. In parallel, trials of adoptive cellular therapy have exciting promise in myeloma, having induced dramatic responses in a handful of early study participants. Taken together, immunotherapeutic approaches hold enormous potential in the field of multiple myeloma and in the near future can be combined with or even replace the current standard of care.
35 citations
TL;DR: Although novel oral therapies such as ibrutinib, idelalisib, and venetoclax have been shown to be extremely effective in the management of CLL, prospective data from larger numbers of patients with longer follow-up are needed prior to recommending their routine use in the Management of autoimmune cytopenias in CLL.
Abstract: Chronic lymphocytic leukemia (CLL) is frequently associated with autoimmune complications such as autoimmune hemolytic anemia, immune thrombocytopenia, pure red cell aplasia, and autoimmune granulocytopenia. It is critical to diagnose cytopenias from these secondary complications of CLL accurately, since prognosis and therapy are substantially different from patients who have cytopenias due to extensive bone marrow infiltration by CLL. The pathogenesis of autoimmune cytopenias in CLL is complex; and it involves antigen presentation by CLL cells to polyclonal B cells resulting in production of autoantibody, and alteration of the T cell milieu tilting the balance in favor of an autoimmune response. Traditional therapy of autoimmune complications in CLL consists of immunosuppression with corticosteroids and/or anti-CD20 monoclonal antibodies. In patients who have a suboptimal response, treating the underlying CLL is generally effective in ameliorating secondary cytopenias. Although novel oral therapies such as ibrutinib, idelalisib, and venetoclax have been shown to be extremely effective in the management of CLL, prospective data from larger numbers of patients with longer follow-up are needed prior to recommending their routine use in the management of autoimmune cytopenias in CLL.
35 citations
TL;DR: Targeting IDH mutations in AML is a biologically informed and rational strategy to promote clinical responses, primarily through differentiation and maturation of the malignant clone.
Abstract: Over the past decade, the pathogenic role of mutations in isocitrate dehydrogenases (IDH) 1 and 2, affecting approximately 20% of patients with AML, has been defined, allowing for the development of specific therapeutic strategies for IDH-mutant AML. In this review, the landscape and progress of targeted therapeutics aimed at IDH mutations in AML and related myeloid malignancies will be described. Since 2013, several mutant IDH-targeted inhibitors have been developed, and nearly a dozen clinical trials have opened specifically for IDH-mutant hematologic malignancies. Preliminary results for several of these investigations have shown evidence of safety, tolerability, and encouraging evidence of efficacy. Targeting IDH mutations in AML is a biologically informed and rational strategy to promote clinical responses, primarily through differentiation and maturation of the malignant clone. The use of IDH targeted therapy is expected to soon become part of a genomically defined and individualized AML treatment strategy.
TL;DR: New treatment strategies are discussed, including purine nucleoside analogs, monoclonal antibodies, antibody drug conjugates, mammalian target of rapamycin (mTOR) inhibitors, proteasome inhibitors, histone deacetylase (HDAC) inhibitor, hypomethylating agents, spleen tyrosine kinase inhibitors, and the impact of diagnostic approaches on management of ALL.
Abstract: Most drugs used in standard regimens for acute lymphoblastic leukemia (ALL) were developed more than 30 years ago. Since that time, several new drugs have been developed and incorporated into ALL treatment. In spite of this, novel therapeutic approaches are still needed to improve outcomes for high-risk or relapsed ALL. This manuscript discusses newer treatment strategies, including purine nucleoside analogs, monoclonal antibodies, antibody drug conjugates, mammalian target of rapamycin (mTOR) inhibitors, proteasome inhibitors, histone deacetylase (HDAC) inhibitors, hypomethylating agents, spleen tyrosine kinase inhibitors, Bruton’s tyrosine kinase (BTK) inhibitors, Janus kinase-signal transducer and activator of transcription (JAK-STAT) inhibitors, anti-programmed cell death protein (anti-PD-1) antibodies, mitogen-activated protein kinase (MEK) inhibitors, CXCR4 antagonists, poly (ADP-ribose) polymerase (PARP) inhibitors, and FMS-like tyrosine kinase 3 (FLT3) inhibitors. Additionally, this manuscript discusses the impact of diagnostic approaches on management of ALL. Specifically, minimal residual disease is increasingly felt to be important and will likely dramatically impact the care of ALL patients in the near future.
TL;DR: Future MRD evaluations in AML likely will require an integrated approach combining multi-parameter flow cytometry and high-sensitivity molecular techniques applied to time points during and after completion of therapy in order to provide the most accurate and comprehensive assessment of treatment response.
Abstract: The presence of measurable (“minimal”) residual disease (MRD) after induction and/or consolidation chemotherapy is a significant risk factor for relapse in patients with acute myeloid leukemia (AML). In recognition of the clinical significance of AML MRD, the European LeukemiaNet (ELN) recently recommended the establishment of CR-MRDNegative as a separate category of treatment response. This recommendation represents a major milestone in the integration of AML MRD testing in standard clinical practice. This review article summarizes the methodologies employed in AML MRD detection and their application in clinical studies that provide evidence supporting the clinical utility of AML MRD testing. Future MRD evaluations in AML likely will require an integrated approach combining multi-parameter flow cytometry and high-sensitivity molecular techniques applied to time points during and after completion of therapy in order to provide the most accurate and comprehensive assessment of treatment response.
TL;DR: Recent data suggest that deferral of therapy until after the first trimester is desirable if it is perceived that postponement of therapy will not compromise maternal outcome.
Abstract: The diagnosis of lymphoma in pregnant patients poses a therapeutic challenge necessitating consideration of the developing fetus without compromise of therapy with curative potential for the mother. The decision to initiate therapy during pregnancy is heavily influenced by fetal, maternal, and disease-related factors, of which the most influential are the trimester at diagnosis, the stage, and aggressiveness of the disease and the presence of life-threatening symptoms. Recent data suggest that deferral of therapy until after the first trimester is desirable if it is perceived that postponement of therapy will not compromise maternal outcome. For some patients, delay of therapy to the postpartum period is feasible.
TL;DR: This review will provide an overview of some of the molecular pathways and possible novel therapeutic strategies that may be of relevance for the field of BPDCN.
Abstract: Blastic plasmacytoid dendritic cell neoplasm (BPDCN) is a historically rare hematologic malignancy with poor overall outcomes, a challenging pathologic and clinical presentation, and no consensus therapeutic approach [1]. After decades of changing nomenclature (e.g., CD4+CD56+ hematodermic tumor, blastic NK cell lymphoma), the WHO ultimately solidified the name “BPDCN” and placed it under “Acute myeloid leukemia (AML) and related family of neoplasms” in 2008 [2]. With increasing understanding of BPDCN, further recognition of its distinct clinical presentation and course, and evolving molecular insights, the disease has now been designated as its own separate category under myeloid malignancies in the latest WHO re-classification schema [3]. Because there are no approved therapies for the treatment of either frontline or relapsed/refractory BPDCN, there have been a variety of therapeutic strategies utilized around the world [4].Most groups have implementedmulti-agent chemotherapy regimens inspired by AML, acute lymphoblastic leukemia (ALL), or lymphoma treatment regimens [5, 6]. However, despite these intensive therapies, median overall survival for adults with BPDCN, as reported by many groups, remains approximately 8–14 months [6, 7]. Although several reports indicate that younger/fit performance status patients with BPDCN may have long-term benefit from stem cell transplant (SCT), most patients with BPDCN are older, or have multiple co-morbidities, or are unfit for SCT [8, 9]. It is therefore, in this clinical setting, that novel therapies are urgently needed for patients with BPDCN. This review will provide an overview of some of the molecular pathways and possible novel therapeutic strategies that may be of relevance for the field of BPDCN.
TL;DR: More work is needed to understand functioning during survivorship and impacts on patient medical outcomes, and to truly leverage the dyad to optimize individual- and relationship-level adjustment.
Abstract: The aims of this study were to identify and systematically evaluate studies published from 2005–2017 that took a dyadic approach to assessing or intervening upon hematopoietic cell transplant (HCT) recipients and their informal caregivers. Our search yielded 20 studies. Regarding sample demographic characteristics, most participants were Caucasian and most caregivers were related to the patient by marriage. Regarding design characteristics, 18 studies were quantitative and two were qualitative; five were cross-sectional, ten were longitudinal, one was experimental, and four were interventional. Most outcomes were psychosocial and the interventions were largely psycho-educational in nature. Large variation in quality of the studies emerged (six were rated as low quality, seven as adequate, and seven as high quality). Understudied populations include racial/ethnic minorities and same-sex couples. More work is needed to understand functioning during survivorship and impacts on patient medical outcomes, and to truly leverage the dyad to optimize individual- and relationship-level adjustment.
TL;DR: Somatic mutations can refine risk stratification and improve the accuracy of existing prognostic models, often upstaging or downstaging patients across the boundary of higher- and lower-risk MDS.
Abstract: The purpose of this study is to review established prognostic models in myelodysplastic syndromes (MDS) and describe how molecular data can be used to improve patient risk stratification. Somatic mutations are common in MDS and are associated with disease features including outcomes. Several recurrently mutated genes have prognostic significance independent of risk stratification tools used in practice. However, this prognostic impact can depend on the clinicogenetic context in which mutations occur. Qualitatively, SF3B1 mutations appear favorable only in patients with < 5% bone marrow blasts while mutations of several genes, including ASXL1, SRSF2, U2AF1, NRAS, and IDH2, appear adverse in this context. Mutations of TP53, RUNX1, and EZH2 appear adverse regardless of blast percentage. Consensus on how to best incorporate mutations into risk assessment is still being developed. Somatic mutations can refine risk stratification and improve the accuracy of existing prognostic models, often upstaging or downstaging patients across the boundary of higher- and lower-risk MDS.
TL;DR: Recent data suggest that both T cell depleted and T cell-replete haplo-HSCT are suitable options to treat children with several types of non-malignant disorders lacking an HLA-identical donor.
Abstract: Purpose of Review
Hematopoietic stem cell transplantation (HSCT) is a treatment option for children with malignant and non-malignant disorders as well as an expanding number of inherited disorders. However, only a limited portion of patients in the need of an allograft have an HLA-compatible, either related or unrelated, donor. Haploidentical HSCT is now considered a valid treatment option, especially in view of the recent insights in terms of graft manipulation. This review will offer an overview of clinical results obtained through the use of haploidentical HSCT in non-malignant diseases. We will analyze major advantages and drawbacks of both T cell depleted and unmanipulated HSCT, discussing future challenges for further improving patients’ outcome.
TL;DR: This dynamic evolution of MRD testing has complicated comparisons between individual studies and an ever-growing body of data demonstrates that a positive MRD test at various time points throughout chemotherapy and hematopoietic cell transplantation identifies patients at particularly high risks of disease recurrence and short survival even after adjustment for other risk factors.
Abstract: The purpose of this review was to evaluate recent literature on detection methodologies for, and prognostic significance of, measurable (“minimal”) residual disease (MRD) in acute myeloid leukemia (AML). There is no “one-fits-all” approach to MRD testing in AML. Most exploited to date are methods relying on immunophenotypic aberrancies (identified via multiparameter flow cytometry) or genetic abnormalities (identified via PCR-based assays). Current methods have important shortcomings, including the lack of assay platform standardization/harmonization across laboratories. In parallel to refinements of existing technologies and data analysis/interpretation, new methodologies (e.g., next-generation sequencing-based assays) are emerging that eventually may complement or replace existing ones. This dynamic evolution of MRD testing has complicated comparisons between individual studies. Nonetheless, an ever-growing body of data demonstrates that a positive MRD test at various time points throughout chemotherapy and hematopoietic cell transplantation identifies patients at particularly high risks of disease recurrence and short survival even after adjustment for other risk factors.
TL;DR: A sustained increase in the number of Twitter users, number of tweets, numbers of impressions, and number of retweets over time is observed, demonstrating the feasibility of creating and maintaining a disease-specific hashtag for a rare cancer over time.
Abstract: The use of social media has now become a standard means of communication for many individuals worldwide. The use of one specific form of social media, Twitter, has increased among healthcare providers, both as a means of information gathering and as a conduit for original content creation. Recently, major efforts by users have been put forward to help streamline the unprecedented amount of information that can be found on Twitter. These efforts have led to the creation of diseasespecific hashtag (#) medical communities and have greatly enhanced the ability to understand and better categorize the available data on Twitter. Specifically, for those involved in rare cancer fields, adhering to organically designed and consistently used hashtags has led to the rapid, reliable dissemination of information and the ability to efficiently discuss and debate topics of interest in the field. For the field of myeloproliferative neoplasms (MPNs), the creation of #MPNSM (myeloproliferative neoplasms on social media) in 2015 has facilitated interactions among healthcare stakeholders from all over the world in the MPN field. In order to better understand the trends and topics of interest to Twitter users of this novel medical community, we conducted the present analysis which focuses on Twitter analytics from the first two years of #MPNSM. In this analysis, we observed a sustained increase in the number of Twitter users, number of tweets, number of impressions, and number of retweets over time, demonstrating the feasibility of creating and maintaining a disease-specific hashtag for a rare cancer over time.
TL;DR: Exploring and understanding patient subgroups based on socioeconomic status, age, race/ethnicity, insurance carrier, and geographic location that may affect healthcare utilization and patient outcomes would certainly help address disparities and lead to further equity in healthcare access and, hopefully, patient outcomes.
Abstract: Multiple myeloma treatment has changed tremendously over recent years leading to overall improvement in patient outcomes. With therapeutic advancements, patient care has become increasingly complex and variability is seen in healthcare delivery as well as outcomes when various patient subgroups are analyzed based on sociodemographic factors. It is imperative to understand this variability so that while overall the outcomes get better, specific focus is placed on subgroups that may remain disadvantaged and may not be able to fully access the advancements in therapeutics. Research in multiple myeloma has specifically looked at several such patient subgroups based on socioeconomic status, age, race/ethnicity, insurance carrier, and geographic location that may affect healthcare utilization and patient outcomes. Exploring and understanding these would certainly help address disparities and lead to further equity in healthcare access and, hopefully, patient outcomes.
TL;DR: The latest evidence regarding the prognostication and management of POEMS syndrome is outlined, using a case vignette, with a focus on its relapsing-remitting course.
Abstract: POEMS syndrome is a paraneoplastic disorder secondary to an underlying plasma cell dyscrasia. By definition, all patients with POEMS syndrome must display polyneuropathy and monoclonal plasma cell disorder. In addition, at least one major criterion (Castleman's disease, sclerotic bone lesions, or vascular endothelial growth factor elevation) and one minor criterion (organomegaly, extravascular volume overload, endocrinopathy, skin changes, papilledema, thrombocytosis, or polycythemia) are required for diagnosis. Treatment is based on extent of the disease. Radiotherapy is used for localized disease. Systemic therapy is required for disseminated disease, with bone marrow involvement by clonal plasma cells, or in patients who progress shortly after radiation. Upfront autologous stem cell transplantation is the treatment of choice for transplant-eligible patients. Outcomes are typically superior to that of standard myeloma. Herein, using a case vignette, we outline the latest evidence regarding the prognostication and management of POEMS syndrome, with a focus on its relapsing-remitting course.
TL;DR: Past work of primary treatment resistance, new resistance mechanisms in de novo AML, functional mechanism of resistance inherent to the leukemic blasts, and resistance mechanisms attributed to host factors are reviewed and acquired mechanisms of resistance are reviewed.
Abstract: Acute myeloid leukemia (AML) is the most common type of acute leukemia and is characterized by a wide variety of distinct cytogenetic and molecular subgroups that impact upon response and survival. Despite decades of trials trying to improve short- and long-term responses, outcomes have been stubbornly stable. Thus, the problem of chemotherapy resistance remains unsolved. Indeed, the use of novel targeted agents has uncovered new mechanisms of chemotherapy resistance. In this review, we will cover past work of primary treatment resistance, new resistance mechanisms in de novo AML, functional mechanism of resistance inherent to the leukemic blasts, and resistance mechanisms attributed to host factors and also review acquired mechanisms of resistance.
TL;DR: Standardization of halving time or velocity of ratio reduction will likely help establish more stringent recommendation and modify current clinical practices and help identify poor-risk patients.
Abstract: Purpose of Review
Although tyrosine kinase inhibitors (TKIs) spectacularly improve the disease burden and the overall survival of chronic myeloid leukemia patients, early identification of a subset of poor TKI responders has been recognized as a critical goal to prevent disease progression in these patients. We herein review the past and recent evidence on the impact of early response.
TL;DR: Recent advance has improved the understanding of high-risk multiple myeloma, and new therapeutic agents are now coming through the pipeline for this patient group with once dismal outcome.
Abstract: New risk stratification systems and treatment strategies have been introduced in recent years. We aim to provide an overview of these recent changes and summarise these data in a concise article that would be useful for clinicians. Apart from clinical stage, disease genetics are now recognised as important prognostic risk factors, and various new cytogenetic changes with negative prognostic impact have been identified. New technologies such as minimal residual disease detection are also playing an important role in prognostic assessment. Recent introduction of combination therapy with proteasome inhibitors and immunomodulatory drugs is showing promising results in high-risk patients and may partially abrogate the negative impact associated with some of the adverse risk factors. Recent advance has improved our understanding of high-risk multiple myeloma, and new therapeutic agents are now coming through the pipeline for this patient group with once dismal outcome.
TL;DR: Understanding of CNL and aCML has greatly advanced over the last few years, which will improve clarity for the diagnosis of these diseases, provide a strategy for risk stratification, and guide risk-adapted therapy.
Abstract: We reviewed recent diagnostic and therapeutic progress in chronic neutrophilic leukemia (CNL) and atypical chronic myeloid leukemia (aCML). We summarized recent genetic data that may guide future efforts towards implementing risk-adapted therapy based on mutational profile and improving disease control and survival of affected patients. Recent genetic data in CNL and aCML prompted modifications to the World Health Organization (WHO) diagnostic criteria, which have improved our understanding of how CNL and aCML are different diseases despite sharing common findings of peripheral granulocytosis and marrow myeloid hyperplasia. The overlap of recurrently mutated genes between aCML and CMML support considering CSF3R-T618I mutated cases as a distinct entity, either as CNL or CNL with dysplasia. Ongoing preclinical and clinical studies will help to further inform the therapeutic approach to these diseases. Our understanding of CNL and aCML has greatly advanced over the last few years. This will improve clarity for the diagnosis of these diseases, provide a strategy for risk stratification, and guide risk-adapted therapy.
TL;DR: This review highlights genetic variants that have been consistently associated with TRT across treatment groups, as well as those that best illustrate the underlying pathophysiology of TRT.
Abstract: The aim of this review is to summarize the most recent and most robust pharmacogenetic predictors of treatment-related toxicity (TRT) in childhood acute lymphoblastic leukemia (ALL). Multiple studies have examined the toxicities of the primary chemotherapeutic agents used to treat childhood ALL in relation to host genetic factors. However, few results have been replicated independently, largely due to cohort differences in ancestry, chemotherapy treatment protocols, and definitions of toxicities. To date, there is only one widely accepted clinical guideline for dose modification based on gene status: thiopurine dosing based on TPMT genotype. Based on recent data, it is likely that this guideline will be modified to incorporate other gene variants, such as NUDT15. We highlight genetic variants that have been consistently associated with TRT across treatment groups, as well as those that best illustrate the underlying pathophysiology of TRT. In the coming decade, we expect that survivorship care will routinely specify screening recommendations based on genetics. Furthermore, clinical trials testing protective interventions may modify inclusion criteria based on genetically determined risk of specific TRTs.
TL;DR: Genome-wide association studies in family clusters of MPN have identified a number of genetic variants that are associated with increased germline risk for developing clonal MPN, and the strongest association discovered so far is the presence of JAK2 46/1 haplotype.
Abstract: Chronic myeloproliferative neoplasms (MPN) characteristically arise from a somatic mutation in the pluripotent hematopoietic stem cell, and most common recurring mutations are in the JAK2, CALR, and cMPL genes. However, these mutations are not founder mutations, but mainly drive the disease phenotype and a pre-existing germline predisposition has been long speculated, but has not been clearly defined to date. Genome-wide association studies in family clusters of MPN have identified a number of genetic variants that are associated with increased germline risk for developing clonal MPN. The strongest association discovered so far is the presence of JAK2 46/1 haplotype, and subsequently, many studies have found additional variants in other genes, most notably in TERT gene. However, these still account for a small fraction of familial MPN, and more in-depth studies including whole genome sequencing are needed to gain better insight into familial genetic predisposition of clonal MPNs.
TL;DR: Promising targets under investigation in myelofibrosis in the Janus kinase (JAK) inhibitor era include JAK1 and JAK2 and downstream intermediates in related signaling pathways, epigenetic modifiers, pro-inflammatory cytokines, and immune regulators.
Abstract: The purpose of the review was to provide a contemporary update of novel agents and targets under investigation in myelofibrosis in the Janus kinase (JAK) inhibitor era. Myelofibrosis (MF) is a clonal stem cell disease characterized by marrow fibrosis and a heterogeneous disease phenotype with a variable degree of splenomegaly, cytopenias, and constitutional symptoms that significantly impact quality of life and survival. Overactive JAK/STAT signaling is a hallmark of MF. The only approved therapy for MF, JAK1/2 inhibitor ruxolitinib, can ameliorate splenomegaly, improve symptoms, and prolong survival in some patients. Therapeutic challenges remain, however. Myelosuppression limits the use of ruxolitinib in some patients, eventual drug resistance is common, and the underlying malignant clone persists despite therapy. A deeper understanding of the pathogenesis of MF has informed the development of additional agents. Promising targets under investigation include JAK1 and JAK2 and downstream intermediates in related signaling pathways, epigenetic modifiers, pro-inflammatory cytokines, and immune regulators.
TL;DR: Clinical experience in this setting is limited to several small clinical trials and case series, but together they suggest that treatment with CBT can effectively amplify anti-tumor immune responses, however, intrinsic to its mechanism is the risk that CBT in the HSCT setting may also cause significant immune toxicity.
Abstract: Allogeneic hematopoietic stem cell transplant (HSCT) relies primarily upon graft-versus-tumor activity for cancer eradication. Relapse remains the principal cause of treatment failure after HSCT, implying frequent immune escape, which in at least some cases, appears to be mediated by increased expression of inhibitory immune checkpoints. In an attempt to restore anti-tumor immunity, checkpoint blockade therapy (CBT) targeting PD-1 and CLTA-4 has been used in conjunction with both allogeneic and autologous HSCT. Clinical experience in this setting is limited to several small clinical trials and case series, but together they suggest that treatment with CBT can effectively amplify anti-tumor immune responses. However, intrinsic to its mechanism is also the risk that CBT in the HSCT setting may also cause significant immune toxicity. Fatal immune-related adverse events and graft-versus-host disease have been observed, but in most cases, immune side effects appear to be reversible with steroids and CBT discontinuation. As clinical investigation continues, improved understanding of immune checkpoint biology will be critical to optimize safe and efficacious treatment strategies.