Abstract: Publication date: Available online 28 October 2019Source: Best Practice & Research Clinical HaematologyAuthor(s): Laura M. Calvi, Allison J. Li, Michael W. BeckerAbstractTreating myelodysplastic syndromes (MDS) can be complex. Hematopoiesis occurs within a heterogeneous and complex dynamic microenvironment, and a multiplicity of mutations in hematopoietic stem and progenitor cells (HSPCs) lead to MDS. But is there a role for the microenvironment' Here we review experimental and conceptual arguments that support a role for the microenvironment, provide evidence for the disruption of the microenvironment in MDS, and explore microenvironmental signals that may provide a targetable and conserved vulnerability in MDS that transcend genetic heterogeneity.
Abstract: Publication date: Available online 20 October 2019Source: Best Practice & Research Clinical HaematologyAuthor(s): Richard J. JonesAbstractClose HLA matching of donors and recipients has been the dogma for successful allogeneic blood or marrow transplantation (BMT), to limit the complications of graft rejection and graft-versus-host disease (GVHD). However, many patients in need, especially those in certain racial and ethnic groups such as African-Americans and Hispanics, are unable to find matches despite increased availability of unrelated donors. Unfortunately, despite many early attempts to develop safe, related haploidentical allogenic BMT, mortality rates exceeding 50% from severe GVHD led most centers to steer away from such transplants by the mid-1990s. However, recent advances based largely on the development of high-dose post-transplant cyclophosphamide GVHD prophylaxis, now yield results with haploidentical related donors that approach those with matched donors. With emerging data that younger donor age may be the most important donor selection criterion, HLA-mismatched donors may even have advantages over matched donors in certain situations. Although the exact role that haploidentical donors should play in donor selection strategies is still being defined, the lack of an HLA-matched donor should no longer ever be an exclusion for allogeneic BMT. Unfortunately, this progress in donor availability has not yet been fully recognized by the medical community. Such a discordance between new advances and their clinical translation highlights that changing standard practice is difficult and takes longer than it should, at least in part because it requires “unlearning” long-standing behaviors.
Abstract: Publication date: Available online 19 October 2019Source: Best Practice & Research Clinical HaematologyAuthor(s): Selina LugerAbstractSurvival rates for patients with acute myeloid leukemia (AML) older than 75 years are still quite dismal. Recent approvals, therefore, of two agents specifically to treat older patients—glasdegib and venetoclax—have created excitement among the medical community. Clinical data, particularly complete response (CR) rates and CR with incomplete hematologic recovery (CRi), look quite promising and are reviewed here. Yet the question remains whether fit elderly patients should receive combination therapy containing the newer agents, particularly since intensive chemotherapy remains the only treatment that has demonstrated the ability to achieve long-term disease-free survival.
Abstract: Publication date: Available online 18 October 2019Source: Best Practice & Research Clinical HaematologyAuthor(s): Eunice S. WangAbstractMutations of FLT3 occur in around a third of acute myeloid leukemia (AML) patients and are associated with poor outcomes. Multiple targeted tyrosine kinase inhibitors (TKI) have been developed with different selectivity and potency for FLT3 mutant clones. Indications for which FLT3-inhibitor to use depend on the clinical setting and disease status. Patients with relapsed or refractory AML benefit from a different TKI than those with de novo AML or following stem cell transplant. Moreover, each FLT3 TKI displays a different toxicity and inhibitory profile and may be most useful in patients with varying comorbidities and types of FLT3 mutations.
Abstract: Publication date: Available online 18 October 2019Source: Best Practice & Research Clinical HaematologyAuthor(s): Luke Maese, Elizabeth A. RaetzAbstractPhiladelphia chromosome-like acute lymphoblastic leukemia (Ph-like ALL) is a high-risk subset of B-cell ALL with a spectrum of underlying genetic alterations that activate kinase or cytokine receptor signaling. Ph-like ALL occurs at all ages but is most common in adolescents and young adults and is postulated to be a factor in the inferior outcomes in this age group. Ph-like ALL confers a poor prognosis with conventional chemotherapy and the pediatric and adult oncology communities are conducting trials utilizing molecularly targeted approaches. In parallel, the role of immunotherapy is being assessed for this unique and biologically diverse ALL subgroup.
Abstract: Publication date: Available online 18 October 2019Source: Best Practice & Research Clinical HaematologyAuthor(s): Frederick R. AppelbaumAbstractWith improvements in the safety of allogeneic hematopoietic cell transplantation, disease recurrence following the procedure is now the most frequent reason for treatment failure. Administration of maintenance therapy after transplantation is one way to try and prevent recurrence. This paper provides a brief review of the topic.
Abstract: Publication date: Available online 18 October 2019Source: Best Practice & Research Clinical HaematologyAuthor(s): Charles G. MullighanAbstractDespite high cure rates in children, acute lymphoblastic leukemia (ALL) remains a leading cause of cancer death in the young, and the likelihood of treatment failure increases with age. With the exception of tyrosine kinase inhibitors, there have been few advances in repurposing or developing new therapeutic approaches tailored to vulnerabilities of ALL subtypes or individual cases. Large-scale genome profiling studies conducted over the last decade promise to improve ALL outcomes by refining risk stratification and modulation of therapeutic intensity, and by identifying new targets and pathways for immunotherapy. Many of these approaches have been validated in preclinical models and now merit testing in clinical trials. This review discusses the advances in our understanding of the genomic taxonomy and ontogeny of B-progenitor ALL, with an emphasis on those discoveries of clinical importance.
Abstract: Publication date: Available online 18 October 2019Source: Best Practice & Research Clinical HaematologyAuthor(s): David P. SteensmaAbstractPatients diagnosed with myelodysplastic syndromes (MDS) often ask their physicians whether earlier detection of disease or more prompt initiation of treatment might have resulted in a better outcome. The concept of starting therapy at an early point in the disease process when the clonal burden of abnormal hematopoietic stem cells may be lower and somatic mutational complexity less, and therefore treatment more likely to be effective, is attractive. However, at present there is no evidence that therapy with any of the available drugs for MDS (ie, erythropoiesis stimulating agents, lenalidomide, azacitidine or decitabine) early after diagnosis is associated with better outcomes than later initiation of drug therapy. For those patients who are eligible for allogeneic hematopoietic cell transplant and have a suitable donor, early transplant of lower-risk MDS is associated with worse outcomes compared to nontransplant approach, whereas early transplant therapy of higher-risk disease improves outcomes compared to delaying transplant. Here I review available data about MDS diagnostic patterns and early versus later diagnosis and therapy initiation.
Abstract: Publication date: Available online 18 October 2019Source: Best Practice & Research Clinical HaematologyAuthor(s): Indumathy Varadarajan, Karen K. BallenAbstractAggressive curative therapies have now been extended to patients older than 65 years, a fast-growing segment of the population. As the number of allogeneic transplants in patients older than age 65 is increasing, attention is now focused on improving outcomes in this group. This paper discusses important aspects of allogeneic transplant in the older patient, focusing on donor and patient selection, choice of conditioning regimen and graft source, and the importance of timely access to a transplant center.
Abstract: Publication date: Available online 18 October 2019Source: Best Practice & Research Clinical HaematologyAuthor(s): Saar I. GillAbstractChimeric antigen receptor (CAR) T-cell therapy for acute myeloid leukemia (AML) has thus far been elusive, in part owing to the absence of truly AML-specific surface antigens, making AML difficult to target. However, progress has been made toward the use of CAR T-cell therapy in this disease, prompting the topic of this paper. Discussion and clinical examples of potential solutions to creating a safe and effective CAR T cell for AML include: (1) Decreasing the potency or activity of CAR T cells; (2) Using transient or depleted CAR T cells as part of pre-transplant conditioning; and (3) Using a gene-edited allogeneic donor hematopoietic stem cell transplant in order to allow safe and protracted anti-AML CAR T-cell function.
Abstract: Publication date: Available online 18 October 2019Source: Best Practice & Research Clinical HaematologyAuthor(s): Mathew L. Cooper, John F. DiPersioAbstractAt present, the only curative therapy for patients with T-cell malignancies is allogeneic stem cell transplant, which has associated risks and toxicities. Novel agents have been tried in relapsed T-cell acute lymphoblastic leukemia (T-ALL), but only one, with 20%-30% complete remission rates, has been approved by the US Food and Drug Administration. T-ALL is a heterogeneous disease, but it has universal overexpression of CD7 as well as several other T-cell markers, such as CD2 and CD5. T cells engineered to express a chimeric antigen receptor (CAR) are a promising cancer immunotherapy. Such targeted therapies have shown great potential for inducing both remissions and even long-term relapse-free survival in patients with B-cell leukemia and lymphoma. UCART7 for CD7+ T-cell malignancies is in development for treatment of relapsed T-ALL in children and adults. It may also have potential in other CD7+ hematologic malignancies that lack both effective therapies and targeted therapies. The challenges encountered and progress made in developing a novel fratricide-resistant “off-the-shelf” CAR-T (or UCART7) that targets CD7+ T-cell malignancies are discussed here.
Abstract: Publication date: Available online 18 October 2019Source: Best Practice & Research Clinical HaematologyAuthor(s): Hrishikesh K. Srinagesh, James L.M. FerraraAbstractAcute graft-versus-host disease (GVHD) is the major complication of allogeneic hematopoietic cell transplantation and is the primary cause of early non-relapse mortality (NRM) after transplant. GVHD of the gastrointestinal (GI) tract fuels the systemic inflammatory reaction and consequently is the principal driver of mortality. Recently, the MAGIC algorithm probability (MAP) that is computed from two biomarkers of GI GVHD has been validated to accurately predict risk of NRM throughout the course of early acute GVHD. This review focuses on the biology, clinical evidence, and practical application of the biomarkers in the measurement of acute GVHD.
Abstract: Publication date: Available online 18 October 2019Source: Best Practice & Research Clinical HaematologyAuthor(s): Craig T. JordanAbstractDe novo acute myeloid leukemia (AML) leukemia stem cell (LSC) populations are uniquely dependent on amino acid metabolism to drive the TCA cycle and oxidative phosphorylation. Oxidative phosphorylation can be selectively downregulated in de novo AML LSC populations by perturbing amino acid metabolism via BCL2 inhibition with venetoclax. While venetoclax-based therapies have shown high response rates, not all patients achieve remission. It may be possible to prospectively identify the patients who will most likely respond to venetoclax-based treatment by analyzing the metabolic properties of individual patients. Specifically, it appears that patients who are likely to be resistant to venetoclax-based therapy are able to employ alternate metabolic pathways to drive oxidative phosphorylation.
Abstract: Publication date: Available online 18 October 2019Source: Best Practice & Research Clinical HaematologyAuthor(s): Courtney DiNardoAbstractThe therapeutic landscape for acute myeloid leukemia (AML) has changed dramatically with the approval of targeted agents, including venetoclax, midostaurin, gilteritinib, ivosidenib, and enasidenib, among others. However, older patients with AML continue to experience poorer outcomes and are in ongoing need of more effective and less toxic regimens. This review examines the efficacy of novel therapeutics and promising combination approaches to further improve outcomes in the treatment of patients with AML.
Abstract: Publication date: Available online 18 October 2019Source: Best Practice & Research Clinical HaematologyAuthor(s): Jacob M. RoweAbstractIn recent years, several drugs—including midostaurin, gilteritinib, and gemtuzumab ozogamicin, to name a few—have been approved or reapproved in the United States to treat patients with acute myeloid leukemia (AML). Yet survival rates for younger patients had improved with chemotherapy alone even before the approvals of these new agents. This begs the question whether the new therapies will actually have a positive impact on survival. The 5-year survival rate for older patients has also risen, again without the addition of these new agents. The challenge will be to incorporate new therapies and use them where they will have the greatest impact—major work for clinicians and researchers alike.
Abstract: Publication date: Available online 18 October 2019Source: Best Practice & Research Clinical HaematologyAuthor(s): Jeffrey W. Tyner, Daniel Bottomly, Beth Wilmot, Shannon McWeeneyAbstractWhile molecular genetic abnormalities can tell us much about the pathogenesis of acute myeloid leukemia (AML), these molecular genetics do not always explain drug resistance or sensitivity, leaving room for other mechanisms of tumor pathogenesis outside of genetic events. The Beat AML 1.0 project was a multicenter project to sequence and functionally query AML samples against over 120 drugs. The results have helped form disease models on how mutations affect disease phenotype and drug sensitivity and have assisted in identifying gene signature profiles that may facilitate selecting the most effective treatment options. However, there are factors outside of genetic abnormalities that affect disease pathogenesis. For example, tumor-associated macrophages in the tumor microenvironment play a role in pathogenesis and represent therapeutic targets.
Abstract: Publication date: Available online 18 October 2019Source: Best Practice & Research Clinical HaematologyAuthor(s): Nelson J. ChaoAbstractAllogeneic hematopoietic stem cell transplantation (HSCT) has the potential for providing a cure for several hematologic malignancies. Although in most circumstances, allogeneic HSCT is preceded by disease-directed or cytoreductive therapy, it is unclear if these toxic conditioning regimens can be circumvented. This review summarizes evidence that will provide insights into factors that influence outcomes in allogeneic HSCT and whether this curative therapy could be used right at diagnosis.
Abstract: Publication date: Available online 18 October 2019Source: Best Practice & Research Clinical HaematologyAuthor(s): Aziz NazhaAbstractMyelodysplastic syndromes (MDS) are clonal bone marrow disorders characterized by complex genomic abnormalities that define disease phenotype, prognosis, and progression. The overall outcomes of MDS patients are very heterogeneous and can be measured in months in some patients and years in others. Several scoring systems have been developed in MDS, with the International Prognostic Scoring System (IPSS) and its revised version (IPSS-R) the most widely accepted risk stratification tools in clinical practice and trial eligibility. Recently, somatic mutations have been shown to impact overall survival and the risk of progression to acute myeloid leukemia. Attempts to add this information to current models or develop newer models are underway, but the optimal approach remains controversial. Newer methods to develop a personalized prediction model that provides outcomes specific for a patient were developed and could change the prognostic paradigm for MDS patients in the near future.
Abstract: Publication date: Available online 18 October 2019Source: Best Practice & Research Clinical HaematologyAuthor(s): Benjamin A. Derman, Richard A. LarsonAbstractRecent advances in remission induction treatment strategies for acute myeloid leukemia (AML) have improved the rates of complete remission (CR) and overall survival (OS), owing to a concerted effort to tailor therapies toward specific AML subtypes. However, without effective post-remission therapy, most patients will relapse. The extent to which post-remission therapies is individualized in the current paradigm is quite varied. Core binding factor (CBF) AML is typically treated with post-remission high-dose cytarabine (HiDAC) without allogeneic hematopoietic stem cell transplantation (HSCT), whereas those with intermediate or adverse-risk cytogenetics are treated with post-remission cytarabine followed by allogeneic HSCT in CR1 when feasible. A lack of clarity regarding the proper dosing of post-remission cytarabine has made consensus building on dosing and schedule a challenge. CBF AML benefits most from high-dose cytarabine (HiDAC), and dasatinib appears promising as an adjunct for those for KIT-mutated CBF AML. Other than series using CPX-351 or lomustine in older adults, multiagent chemotherapy approaches have resulted in excess toxicity without a survival benefit. Neither hypomethylating agents nor gemtuzumab ozogamicin have shown a material OS benefit. Targeted agents such as FLT3 inhibitors and IDH1/IDH2 inhibitors show potential for the patients who harbor these druggable targets, but few data are available. Many studies evaluating post-remission strategies to target AML in the MRD-positive state are already underway, and these remain a promising area of investigation.
Abstract: Publication date: Available online 4 September 2019Source: Best Practice & Research Clinical HaematologyAuthor(s): Thomas P. Loughran, Thierry Lamy
Abstract: Publication date: Available online 12 June 2019Source: Best Practice & Research Clinical HaematologyAuthor(s): Eric Tse, Yok-Lam KwongAbstractNK/T-cell lymphomas are extranodal EBV-related malignancies, mostly of NK-cell and occasionally of T-cell lineage. They are divided into nasal, non-nasal, and disseminated subtypes. Nasal NK/T-cell lymphomas involve the nose, nasopharynx and the upper aerodigestive tract. Non-nasal NK/T-cell lymphomas involve the skin, gastrointestinal tract, testis and other sites. Disseminated NK/T-cell lymphoma involves multiple organs, and may present with a leukemic phase. Initial evaluation requires positron emission tomography computed tomography (PET/CT) and quantification of circulating EBV DNA. Radiotherapy alone is inadequate with frequent relapses. Anthracycline-containing regimens are ineffective. Regimens incorporating asparaginase are currently the standard. For stage I/II disease, combined chemotherapy and radiotherapy is recommended. For stage III/IV disease, asparaginase-containing regimens are needed. Autologous hematopoietic stem cell transplantation (HSCT) is of limited efficacy, whereas allogeneic HSCT may be useful in patients with stage III/IV and relapsed diseases. Immunotherapy with antibodies against CD30, programmed cell death protein 1 and CD38 is promising.
Abstract: Publication date: Available online 7 June 2019Source: Best Practice & Research Clinical HaematologyAuthor(s): Elsa Maitre, Xavier TroussardAbstractFlow cytometry diagnostic practices can detect very low levels of clonal B cells in the peripheral blood. In the absence of clinical symptoms, cytopenia or organomegaly, the small clones may correspond to monoclonal B-cell leukemia (MBL) diagnosis. Most MBLs harbor a chronic lymphocytic leukemia (CLL) phenotype (e.g., CD5+, CD23+) and are referred to as CLL-type MBL. The two other types are atypical CLL-type MBL and non-CLL-type MBL. In addition to the phenotypical classification, the clonal B count is a major issue because of the impact on the prognosis and the risk of progression in CLL. It allows for the discrimination of two distinct types: high-count (HC) MBL and low-count (LC)-MBL based on a cutoff value of 0.5 × 109/L clonal B cells. LC MBL appears to be very stable over time and is probably related to immunosenescence. Conversely, HC MBL could be a premalignant state before the occurrence of CLL.
Abstract: Publication date: Available online 6 June 2019Source: Best Practice & Research Clinical HaematologyAuthor(s): Xochiquetzal U. Martinez, Cosimo Di Raimondo, Farah R. Abdulla, Jasmine Zain, Steven T. Rosen, Christiane QuerfeldAbstractMycosis fungoides (MF) and Sézary syndrome (SS) are the most common types of cutaneous lymphoma, accounting for approximately 60% of cutaneous T-cell lymphomas. Diagnosis requires correlation of clinical, histologic, and molecular features. A multitude of factors have been linked to the aetiopathogenesis, however, none have been definitively proven. Erythrodermic MF (E-MF) and SS share overlapping clinical features, such as erythroderma, but are differentiated on the degree of malignant blood involvement. While related, they are considered to be two distinct entities originating from different memory T cell subsets. Differential expression of PD-1 and KIR3DL2 may represent a tool for distinguishing MF and SS, as well as a means of monitoring treatment response. Treatment of E-MF/SS is guided by disease burden, patients’ ages and comorbidities, and effect on quality of life. Current treatment options include biologic, targeted, immunologic, and investigational therapies that can provide long term response with minimal side effects. Currently, allogeneic stem cell transplantation is the only potential curative treatment.
Abstract: Publication date: Available online 6 June 2019Source: Best Practice & Research Clinical HaematologyAuthor(s): Katharine B. Moosic, Uma Devi Paila, Kristine C. Olson, Karolina Dziewulska, T. Tiffany Wang, Jeffrey C. Xing, Aakrosh Ratan, David J. Feith, Thomas P. Loughran, Thomas L. OlsonAbstractGenomic analysis of cancer offers the hope of identifying new treatments or aiding in the selection of existing treatments. Rare leukemias pose additional challenges in this regard as samples may be hard to acquire and when found the underlying pathway may not be attractive to drug development since so few individuals are affected. In this case, it can be useful to identify common mutational overlap among subsets of rare leukemias to increase the number of individuals that may benefit from a targeted therapy. This chapter examines the current mutational landscape of LGL leukemia with a focus on STAT3 mutations, the most common mutation in LGL leukemia to date. We examined the linkage between these mutations and autoimmune symptoms and disorders, in cases of obvious and suspected LGL leukemia. We then summarized and compared mutations in a set of other rare leukemias that also have JAK/STAT signaling pathway activation brought about by genomic changes. These include T-cell acute lymphoblastic leukemia (T-ALL), T-cell prolymphocytic leukemia (T-PLL), cutaneous T-cell lymphoma (CTCL), select peripheral T-cell lymphoma (PTCL), and adult T-cell leukemia/lymphoma (ATLL). Though STAT3 activation is common in these leukemias, the way in which it is achieved, such as the activating cytokine pathway and/or the co-mutational background, is quite diverse.
Abstract: Publication date: Available online 6 June 2019Source: Best Practice & Research Clinical HaematologyAuthor(s): M. Cross, C. DeardenAbstractProlymphocytic leukaemias B-PLL and T-PLL are rare disorders, typically with an aggressive clinical course and poor prognosis. Combining morphology, immunophenotyping, cytogenetic and molecular diagnostics reliably separates B-PLL and T-PLL from one another and other disorders. In T-PLL discovery of frequent mutations in the JAK-STAT pathway have increased understanding of disease pathogenesis. Alemtuzumab (anti-CD52) produces excellent response rates but long-term remissions are only achieved in a minority following consolidation with allogeneic stem cell transplant. Molecular abnormalities in B-PLL are less understood. Disruption of TP53 is a key finding, conveying chemotherapy resistance requiring novel therapies such as B-cell receptor inhibitors (BCRi). Both conditions require improved pathobiological knowledge to identify new treatment targets and guide therapy with novel pathway inhibitors.
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