Showing papers in "Current Hematologic Malignancy Reports in 2012"
TL;DR: A review of minimal criteria for diagnosing myelodysplastic syndromes (MDS) and conditions resembling MDS risks misinforming or harming patients can be found in this article.
Abstract: Just as a pawnshop owner who is unable to distinguish a genuine Rolex™ watch from a cheap knockoff courts financial ruin, the physician who fails to discriminate between authentic myelodysplastic syndromes (MDS) and conditions resembling MDS risks misinforming or harming patients. This review summarizes minimal criteria for diagnosing MDS and discusses common diagnostic challenges. MDS needs to be separated from numerous neoplastic and non-clonal hematologic disorders that can mimic MDS, including other myeloid neoplasms, nutritional deficiencies, toxin exposures, aplastic anemia, and inherited disorders (e.g., congenital sideroblastic anemia). Some distinctions are more critical therapeutically than others; e.g., recognizing B12 deficiency is more important than parsing high-risk MDS from erythroleukemia. Diagnostically ambiguous cases may be assigned holding-pattern terms, “idiopathic cytopenia(s) of undetermined significance” (ICUS) or “idiopathic dysplasia of undetermined significance” (IDUS), while awaiting clarifying information or further clinical developments. In the future, advances in molecular pathology will improve diagnostic accuracy, especially in morphologically non-descript cases.
83 citations
TL;DR: All of these second-generation PIs demonstrate encouraging anti-MM activity and appear to reduce the incidence of PN, with clinical trials ongoing.
Abstract: Proteasome inhibition has a validated role in cancer therapy since the successful introduction of bortezomib for the treatment of multiple myeloma (MM) and mantle cell lymphoma, leading to the development of second-generation proteasome inhibitors (PI) for MM patients in whom currently approved therapies have failed. Five PIs have reached clinical evaluation, with the goals of improving efficacy and limiting toxicity, including peripheral neuropathy (PN). Carfilzomib, an epoxyketone with specific chymothrypsin-like activity, acts as an irreversible inhibitor and was recently FDA approved for the response benefit seen in relapsed and refractory MM patients previously treated with bortezomib, thalidomide and lenalidomide. ONX-0912 is now under evaluation as an oral form with similar activity. The boronate peptides MLN9708 and CEP-18770 are orally bioactive bortezomib analogs with prolonged activity and greater tissue penetration. NPI-0052 (marizomib) is a unique, beta-lactone non-selective PI that has been shown to potently overcome bortezomib resistance in vitro. All of these second-generation PIs demonstrate encouraging anti-MM activity and appear to reduce the incidence of PN, with clinical trials ongoing.
82 citations
TL;DR: Key biologic aspects of BCR-associated kinases in CLL and other B cell neoplasias are reviewed, and perspectives for future development of this exciting new class of kinase inhibitors are developed.
Abstract: B-cell receptor (BCR) signaling is a central pathologic mechanism in B-cell malignancies, including chronic lymphocytic leukemia (CLL), in which it promotes leukemia cell survival and proliferation, and modulates CLL cell migration and tissue homing. BCR signaling now can be targeted with new, small molecule inhibitors of the spleen tyrosine kinase (Syk), Bruton’s tyrosine kinase (Btk), or phosphoinositide 3′-kinase (PI3K) isoform p110δ (PI3Kδ), which have recently entered the clinical stage and show promising results in patients with CLL. During the first weeks of therapy, these agents characteristically induce rapid resolution of lymphadenopathy and organomegaly, accompanied by a transient surge in lymphocyte counts due to “mobilization” of tissue-resident CLL cells into the blood. Then, often after months of continuous therapy, a major proportion of patients achieve remissions. This article reviews key biologic aspects of BCR-associated kinases in CLL and other B cell neoplasias, and develops perspectives for future development of this exciting new class of kinase inhibitors.
69 citations
TL;DR: Improved understanding of the biology of these lymphomas including elucidating the role that EBV plays in their pathogenesis has paved the way for improved therapies targeted at critical signaling pathways as well as the development of novel cellular therapies.
Abstract: We now recognize that the Epstein-Barr virus (EBV), which is a member of the γ- herpesvirus family, plays a pivotal role in the development of several lymphomas and lymphoproliferative disorders that include B-cell, T-cell and NK-cell processes. While over recent years, EBV associated lymphomas that arise in patients with known defects in cellular immunity are relatively well characterized, these diseases are becoming increasingly recognized in patients without overt immunodeficiency. Improved understanding of the biology of these lymphomas including elucidating the role that EBV plays in their pathogenesis has paved the way for improved therapies targeted at critical signaling pathways as well as the development of novel cellular therapies. In this review, we focus on recent progress that has been made in the biology and treatment of the rare EBV-associated disorder lymphomatoid granulomatosis (LYG) and also discuss other EBV-associated processes that occur in both immunocompetent and immunocompromised hosts.
64 citations
TL;DR: This review will be focused on the cytogenetic/molecular advances in pediatric and adult ALL based on recently published articles that identified novel potential targets for therapeutic intervention.
Abstract: During the last decade a tremendous technologic progress based on genome-wide profiling of genetic aberrations, structural DNA alterations, and sequence variations has allowed a better understanding of the molecular basis of pediatric and adult B/T- acute lymphoblastic leukemia (ALL), contributing to a better recognition of the biological heterogeneity of ALL and to a more precise definition of risk factors. Importantly, these advances identified novel potential targets for therapeutic intervention. This review will be focused on the cytogenetic/molecular advances in pediatric and adult ALL based on recently published articles.
52 citations
TL;DR: The activity of these agents confirms that CD33 remains a viable therapeutic target for AML.
Abstract: CD33, a 67-kDa glycoprotein expressed on the majority of myeloid leukemia cells as well as on normal myeloid and monocytic precursors, has been an attractive target for monoclonal antibody (mAb)–based therapy of acute myeloid leukemia (AML). Lintuzumab, an unconjugated, humanized anti-CD33 mAb, has modest single-agent activity against AML but failed to improve patient outcomes in two randomized trials when combined with conventional chemotherapy. Gemtuzumab ozogamicin, an anti-CD33 mAb conjugated to the antitumor antibiotic calicheamicin, improved survival in a subset of AML patients when combined with standard chemotherapy, but safety concerns led to US marketing withdrawal. The activity of these agents confirms that CD33 remains a viable therapeutic target for AML. Strategies to improve the results of mAb-based therapies for AML include antibody engineering to enhance effector function, use of alternative drugs and chemical linkers to develop safer and more effective drug conjugates, and radioimmunotherapeutic approaches.
51 citations
TL;DR: The molecular evolution of CML LSC that promotes CML progression and relapse is reviewed and novel targets that represent important avenues for future therapeutic approaches aimed at selectively eradicating the LSC population while sparing normal hematopoietic progenitors in patients suffering from chronic myeloid malignancies are identified.
Abstract: Leukemia progression and relapse is fueled by leukemia stem cells (LSC) that are resistant to current treatments. In the progression of chronic myeloid leukemia (CML), blast crisis progenitors are capable of adopting more primitive but deregulated stem cell features with acquired resistance to targeted therapies. This in turn promotes LSC behavior characterized by aberrant self-renewal, differentiation, and survival capacity. Multiple reports suggest that cell cycle alterations, activation of critical signaling pathways, aberrant microenvironmental cues from the hematopoietic niche, and aberrant epigenetic events and deregulation of RNA processing may facilitate the enhanced survival and malignant transformation of CML progenitors. Here we review the molecular evolution of CML LSC that promotes CML progression and relapse. Recent advances in these areas have identified novel targets that represent important avenues for future therapeutic approaches aimed at selectively eradicating the LSC population while sparing normal hematopoietic progenitors in patients suffering from chronic myeloid malignancies.
47 citations
TL;DR: How the treatment of PMBL and CHL-NS has evolved in recent years is outlined, and how MGZL should be approached therapeutically is outlined.
Abstract: Although primary mediastinal large B-cell lymphoma (PMBL) and classic Hodgkin lymphoma of the nodular sclerosis type (CHL-NS) are distinct diseases, they share several clinical characteristics and biologic features. Given that, it is not surprising that there exist mediastinal lymphomas that do not fit well into either category but have clinical and morphologic features overlapping and transitional between PMBL and CHL-NS. The term mediastinal gray zone lymphoma (MGZL) has been used for these tumors, which are included in the World Health Organization classification as “B-cell lymphoma, unclassifiable, with features intermediate between diffuse large B-cell lymphoma and classic Hodgkin lymphoma.” Although several studies have evaluated different therapeutic strategies in PMBL and CHL-NS, there is a paucity of prospective experience treating MGZL, given its rarity and relatively recent recognition. Historically, diseases that today would be categorized as MGZL were probably called “anaplastic large-cell lymphoma Hodgkin-like,” and their outcome with standard approaches was poor, with short overall survivals. In this review—following a discussion of the biology and clinical features of MGZL, and how they compare to PMBL and CHL-NS—we outline how the treatment of PMBL and CHL-NS has evolved in recent years, and how we believe MGZL should be approached therapeutically.
45 citations
TL;DR: The role of genomic instability leading to blastic transformation of CML is discussed and some novel therapeutic approaches are proposed.
Abstract: The BCR-ABL1 oncogenic tyrosine kinase can transform pluripotent hematopoietic stem cells and initiate chronic myeloid leukemia in chronic phase (CML-CP), a myeloproliferative disorder characterized by excessive accumulation of mature myeloid cells. Patients in CML-CP usually respond to treatment with ABL1 tyrosine kinase inhibitors (TKIs) such as imatinib, though some patients who respond initially may become resistant later. CML-CP leukemia stem cells (LSCs) are intrinsically insensitive to TKIs and thus survive in the long term. These LSCs or their progeny may at some stage acquire additional genetic changes that cause the leukemia to transform further, from CML-CP to a more advanced phase, which has been subclassified as either accelerated phase (CML-AP) or blastic phase (CML-BP). CML-BP is characterized by a major clonal expansion of immature progenitors, which have either myeloid or lymphoid features. CML-BP responds poorly to treatment and is usually fatal. This review discusses the role of genomic instability leading to blastic transformation of CML and proposes some novel therapeutic approaches.
42 citations
TL;DR: This overview attempts to summarize pediatric studies on issues such as dose, duration, adverse effects, and steering criteria for TKI treatment, adapting guidelines developed in adult medicine to pediatrics.
Abstract: Childhood chronic myelogenous leukemia (CML) is a rare malignancy, and experience with optimal treatment is very limited. Traditionally, allogeneic hematopoietic stem cell transplantation was considered the only curative treatment. Imatinib, a small-molecule inhibitor of the BCR-ABL tyrosine kinase (TKI), has been proven highly successful in adults with CML, resulting in prolonged molecular response with limited drug toxicity. This drug is now included as front-line therapy for CML in pediatrics as well, though valid concerns about serious late sequelae remain unresolved. Specific pediatric treatment guidelines have not yet been formulated, and most algorithms are derived from experience in adult CML. This overview attempts to summarize pediatric studies on issues such as dose, duration, adverse effects, and steering criteria for TKI treatment, adapting guidelines developed in adult medicine to pediatrics. Most importantly, pediatric patients with CML receiving TKI treatment should be enrolled into formal trials.
39 citations
TL;DR: A phase II study of a defucosylated, humanized anti-CCR4 monoclonal antibody, mogamulizumab, yielded an overall response rate and a median progression-free survival of 5.2 months in relapsed patients with CCR4-positive ATL who had been previously treated with chemotherapy.
Abstract: Peripheral T-cell lymphoma (PTCL) is a group of lymphoid malignancy that remains difficult to treat, as most PTCL becomes refractory or relapses, and thus there is an unmet medical need for novel treatment modalities. CC chemokine receptor 4 (CCR4) is expressed in various types of PTCL including adult T-cell leukemia-lymphoma (ATL), which has the worst prognosis among them. A phase II study of a defucosylated, humanized anti-CCR4 monoclonal antibody, mogamulizumab (KW-0761), yielded an overall response rate of 50 % (13/26) and a median progression-free survival of 5.2 months in relapsed patients with CCR4-positive ATL who had been previously treated with chemotherapy. Mogamulizumab also showed potential efficacy for cutaneous T-cell lymphoma in a US phase I/II study. Further preclinical and clinical investigations are needed to examine whether concomitant use of this novel agent with other agents with different mechanisms of action would be more effective for ATL and other PTCLs.
TL;DR: This review focuses on the latest advances in the understanding of the biology of leukemic transformation and current clinical therapies that are available for this patient population.
Abstract: The BCR/ABL-negative myeloproliferative neoplasms (MPNs) of essential thrombocythemia, polycythemia vera, and primary myelofibrosis, over the natural course of their disease, have an increasing predisposition to transform to overt acute myeloid leukemia (AML)-most appropriately referred to as MPN-blast phase (MPN-BP). Although this transformation is a rare event, once AML has occurred, it is associated with a poor response to therapy and short survival. The molecular events leading to transformation are poorly defined. Currently, no therapy other than allogeneic stem cell transplantation (ASCT) has been demonstrated to alter the natural history of this disease. Multiple therapeutic investigations are currently ongoing, including early ASCT, hypomethylating agents, and JAK2 inhibition, to try to alter the course of the disease and improve outcomes. This review focuses on the latest advances in our understanding of the biology of leukemic transformation and current clinical therapies that are available for this patient population.
TL;DR: Understanding this leukemogenic process will provide tools to develop new epigenetic therapies against blood cancers, and appears to be an important regulator of hematopoietic stem cell biology.
Abstract: Recently, 5-hydroxymethylcytosine (5-hmC), the 6th base of DNA, was discovered as the product of the hydroxylation of 5-methylcytosine (5-mC) by the ten-eleven translocation (TET) oncogene family members. One of them, TET oncogene family member 2 (TET2), is mutated in a variety of myeloid malignancies, including in 15% of myeloproliferative neoplasms (MPNs). Recent studies tried to go further into the biological and epigenetic function of TET2 protein and 5-hmC marks in the pathogenesis of myeloid malignancies. Although its precise function remains partially unknown, TET2 appears to be an important regulator of hematopoietic stem cell biology. In both mouse and human cells, its inactivation leads to a dramatic deregulation of hematopoiesis that ultimately triggers blood malignancies. Understanding this leukemogenic process will provide tools to develop new epigenetic therapies against blood cancers.
TL;DR: More intensive chemotherapy regimens with or without autologous stem cell transplantation appear to improve survival and functional imaging such as positron emission tomography and computed tomography may help guide treatment strategy and minimize long-term toxicity.
Abstract: Hodgkin lymphoma (HL) is one of the most common types of non-AIDS-defining tumors in the HIV-infected. Its incidence however seems to have increased under highly active anti-retroviral therapy (HAART). HIV-HL is a different entity from HL in HIV-negative subjects with a poorer prognosis that is associated with tumor-subtype, EBV-infection, and “B” symptoms. Despite the aggressive nature of the disease, clinical outcome has improved with combination therapies including appropriately timed antiretroviral strategies and the quality of supportive care—notably the use of hematopoietic growth factors. More intensive chemotherapy regimens with or without autologous stem cell transplantation appear to improve survival. Functional imaging such as positron emission tomography and computed tomography (FDG-PET) may help guide treatment strategy and minimize long-term toxicity.
TL;DR: Despite progress in diagnosis and classification, alongside an evolving understanding of ENKTL pathobiology, EBV’s contribution to lymphomagenesis remains largely unresolved and challenges relate to the rarity of this entity, a lack of clinical and biological correlative data and scarcity of fresh tissue for molecular and functional studies.
Abstract: The potent growth-transforming properties of Epstein-Barr virus (EBV) and its role in pathogenesis of a range of B cell and epithelial malignancies are well established. By contrast, the association of this B lymphotropic virus with malignancies of T and NK cell origin was entirely unexpected. Although a number of mature T and NK lymphoma subtypes have been associated with EBV, evidence for a robust viral/tumour relationship is principally limited to extranodal NK/T lymphoma (ENKTL). Despite progress in diagnosis and classification, alongside an evolving understanding of ENKTL pathobiology, EBV’s contribution to lymphomagenesis remains largely unresolved. Challenges relate to the rarity of this entity, a lack of clinical and biological correlative data and scarcity of fresh tissue for molecular and functional studies. Nonetheless, recent studies on viral and cellular gene expression have permitted new avenues of investigation into ENKTL pathobiology aiming to extend our understanding of disease biology and ultimately improve clinical outcomes.
TL;DR: Semiquantification of fluorodeoxyglucose (FDG) uptake using standardized uptake value (SUV) and assessment of reduction of maximum SUV between baseline and interim PET drastically improves both the interpretation accuracy and the interobserver reproducibility, and better predicts patient outcome than visual analysis.
Abstract: The prognosis value of interim positron emission tomography (PET) remains controversial in diffuse large B-cell lymphoma (DLBCL) patients because of the absence of consensus on criteria able to early identify good and bad responders to treatment. Visual interpretation using the International Harmonization Project (IHP) criteria, primarily established for end of treatment evaluation, was related to a low positive predictive value of treatment failure. The 5-point scale (5PS) that refers the residual uptake to the liver as background tissue was shown to slightly reduce false-positive interim PET interpretations compared to IHP criteria. Semiquantification of fluorodeoxyglucose (FDG) uptake using standardized uptake value (SUV) and assessment of reduction of maximum SUV (SUVmax) between baseline and interim PET drastically improves both the interpretation accuracy and the interobserver reproducibility, and better predicts patient outcome than visual analysis. This latter approach is feasible in a multicenter setting and allows clinicians to design a risk-adapted therapeutic strategy based on early PET response assessment.
TL;DR: Understanding mechanisms underlying LSC behavior in TKI-treated patients may provide important clues to develop an array of strategies that ensure the complete destruction of LSC reservoirs and thereby offer CML patients a definitive cure.
Abstract: The use of tyrosine kinase inhibitors (TKIs) targeted against the BCR-ABL1 oncoprotein has proven remarkably successful in chronic myeloid leukemia (CML) and long-term survival has become a reality. Despite this outstanding progress, detection of minimal residual disease precludes therapy termination in most TKI-receiving patients. CML has thus turned into a chronic illness, raising concerns about long-term safety, medication adherence, and health care costs. Although treatment cessation may be feasible in few selected patients achieving deep molecular responses, a definitive cure remains elusive owing to the discovery that TKIs spare quiescent leukemic stem cells (LSC). Understanding mechanisms underlying LSC behavior in TKI-treated patients may provide important clues to develop an array of strategies that ensure the complete destruction of LSC reservoirs and thereby offer CML patients a definitive cure.
TL;DR: Newer strategies employing allogeneic transplantation earlier in patients with relapsed or refractory AML, as well as the incorporation of novel and effective antileukemic agents into the transplant conditioning regimen, may lead to better outcomes.
Abstract: Patients with primary resistant and relapsed acute myeloid leukemia (AML) are rarely cured without undergoing allogeneic stem cell transplantation. What is currently debated is whether a trial of re-induction chemotherapy prior to transplantation is beneficial. Data from multiple retrospective analyses have shown that pretreatment variables are useful in predicting response to salvage chemotherapy. For patients unlikely to respond, re-induction attempts may be detrimental, leading to added organ toxicity and possible increased tumor resistance. Allogeneic transplantation in the setting of active disease is the alternative strategy. Multiple studies have demonstrated the feasibility of this approach, but cure rates have been low with the use of traditional transplant approaches. Newer strategies employing allogeneic transplantation earlier in patients with relapsed or refractory AML, as well as the incorporation of novel and effective antileukemic agents into the transplant conditioning regimen, may lead to better outcomes.
TL;DR: Recent developments in the areas of CD40 ligand (CD40L/CD154) gene therapy, immunomodulatory agents such as lenalidomide, and adoptive transfer of T cells bearing chimeric antigen receptors are focused on.
Abstract: Chronic lymphocytic leukemia (CLL) is associated with a profound immune defect, which results in increased susceptibility to recurrent infections as well as a failure to mount effective antitumor immune responses. Current chemotherapy-based regimens are not curative and often worsen this immune suppression, so their usefulness is limited, particularly in the frail and elderly. This article reviews the immune defect in CLL and discusses strategies aimed at repairing or circumventing this defect. In particular, it focuses on recent developments in the areas of CD40 ligand (CD40L/CD154) gene therapy, immunomodulatory agents such as lenalidomide, and adoptive transfer of T cells bearing chimeric antigen receptors.
TL;DR: The molecular pathways that may lead to genomic instability in CML and the potential of these pathway constituents to be therapeutic targets are examined.
Abstract: Philadelphia positive (Ph+) chronic myeloid leukemia (CML) is characterized by the occurrence of nonrandom genetic and cytogenetic abnormalities during disease progression. Many of these abnormalities are markers for genes which, when altered, can drive the blastic transformation process. Thus, such genetic alterations may be manifestations of an underlying genomic instability resulting from a compromised DNA damage and repair response, leading to advanced stages of CML and resistance to therapy. This article examines the molecular pathways that may lead to genomic instability in CML and the potential of these pathway constituents to be therapeutic targets.
TL;DR: JAK2 ATP-competitive inhibitors or drugs that indirectly inhibit the JAK-STAT pathway, like RAD001, are the new candidates for splenomegaly in MPN-MF, but in spite of their strong rationale, they have shown only a palliative benefit.
Abstract: Myeloproliferative neoplasms (MPNs) are clonal disorders characterized by excessive production of mature cells. In most of the classic Philadelphia-negative MPNs—polycythemia vera (PV), essential thrombocythemia (ET), and MPN-associated myelofibrosis (MPN-MF)—oncogenic mutations affecting JAK2 or MPL lead to constitutive activation of cytokine-regulated intracellular signalling pathways. The traditional therapy for PV and ET is the prevention of thrombotic events with antiproliferative agents in association with aspirin. New drugs such as pegylated interferon and anti-JAK agents are candidates for slowing the evolution to myelofibrosis or leukemia. Conventional therapy for MPN-MF is driven by clinical needs, primarily anemia and splenomegaly. Lenalidomide and pomalidomide are new candidates for treating anemia. JAK2 ATP-competitive inhibitors or drugs that indirectly inhibit the JAK-STAT pathway, like RAD001, are the new candidates for splenomegaly in MPN-MF, but in spite of their strong rationale, they have shown only a palliative benefit. Allogeneic stem cell transplantation remains the only potentially curative approach.
TL;DR: The rationale for targeting tyrosine kinase pathways is discussed and the current clinical trial data for agents targeting Syk, BTK, and PI3K is summarized.
Abstract: It is becoming increasingly apparent that tonic signaling through the B cell receptor provides a growth and survival signal in many types of B cell lymphomas, and that disruption of B cell receptor signaling can be lethal to malignant B cells. Several small molecule tyrosine kinase inhibitors, which block signaling pathways downstream from the B cell receptor, are in active clinical development. Preliminary data suggests impressive activity in relapsed and refractory B cell lymphomas. Among the kinases which have been targeted are Spleen tyrosine kinase (Syk), the Bruton’s tyrosine kinase (BTK), and phosphoinositide 3-kinase (PI3K). This article discusses the rationale for targeting these pathways and summarizes the current clinical trial data for agents targeting Syk, BTK, and PI3K.
TL;DR: This review will evaluate four antigens in ALL and therapeutic strategies to target them and review the clinical and preclinical data surrounding rituximab, epratuzumab, inotuzumAB ozogamicin, alemtuzumabs, blinatumomab, and chimeric antigen receptor-modified T-cell therapy.
Abstract: Advances in chemotherapy administration have made acute lymphoblastic leukemia (ALL) a curable disease; however, most patients will relapse, despite readily attaining a complete remission. Treatment of relapse has shown dismal results with little advances made in the recent decades. Antigenic-directed therapy of ALL can complement cytotoxic chemotherapy and has shown encouraging results. This review will evaluate four antigens in ALL (CD20, CD22, CD52, and CD19) and therapeutic strategies to target them. We will review the clinical and preclinical data surrounding rituximab, epratuzumab, inotuzumab ozogamicin, alemtuzumab, blinatumomab, and chimeric antigen receptor-modified T-cell therapy.
TL;DR: This article reviews MRD methodologies and clinical applications with emphasis on recently reported technical advances and prognostic associations, and the practical issues related to the implementation of MRD monitoring in the clinic.
Abstract: In acute lymphoblastic leukemia (ALL), the advent of methods to measure disease not detectable by morphology, ie, minimal residual disease (MRD), has set a new standard to define remission. The clinical importance of MRD has been demonstrated by numerous studies using either flow cytometry or polymerase chain reaction and involving thousands of patients. Results are in remarkable agreement on the association between MRD persistence and risk of subsequent relapse, regardless of the MRD detection method used. More recent data indicate that MRD can also be informative in specific subgroups of ALL patients, such as infants or those with T-lineage ALL. Hence, MRD is now being used in clinical trials to inform treatment decisions and guide patients’ clinical management. This article reviews MRD methodologies and clinical applications with emphasis on recently reported technical advances and prognostic associations, and the practical issues related to the implementation of MRD monitoring in the clinic.
TL;DR: Data support the use of low dose ZDV/IFN with chemotherapy as first line treatment for patients with newly diagnosed aggressive ATLL, and the mechanisms of action are incompletely understood.
Abstract: Adult T cell leukaemia / lymphoma (ATLL) is a mature (post thymic) T cell lymphoma caused by the human T-lymphotropic virus type 1 (HTLV-1) infection. Overall survival in the aggressive subtypes (Acute Leukaemia and Lymphomatous) remains poor in part due to chemotherapy resistance. To improve treatment outcome for de novo disease, better induction therapies are required and since the pathogenic agent is known it would seem sensible to target the virus. In a recent meta-analysis the use of zidovudine and interferon alpha (ZDV/IFN) has been associated with improved response rates and prolonged overall survival in leukemic subtypes of ATLL (both acute and Chronic) confirmed in a multivariate analysis. In a more recent UK study the overall response rate for patients with aggressive ATLL treated with chemotherapy alone was 49 % compared to 81 % with combined first line therapy (chemotherapy with concurrent or sequential ZDV/IFN). Combined first line therapy prolonged median OS in acute (p = 0.0081) and lymphomatous ATLL (p = 0.001).These data support the use of low dose ZDV/IFN with chemotherapy as first line treatment for patients with newly diagnosed aggressive ATLL. Although the mechanisms of action are incompletely understood, some possible explanations for their efficacy will be discussed.
TL;DR: The most important prognostic factors are anemia, age over 65 years, constitutional symptoms, leukocytosis, blood blasts, and some cytogenetic abnormalities, which have recently been systematized into an International Prognostic Scoring System (IPSS) and further refined in a dynamic IPSS (DIPSS), useful at any time over the disease course.
Abstract: Primary myelofibrosis (PMF) is a Philadelphia chromosome-negative chronic myeloproliferative neoplasm usually affecting elderly people Median survival currently approaches 6 years, with a few patients surviving more than 20 years but others dying soon after diagnosis In 10% to 20% of patients, PMF evolves into acute leukemia Conventional treatment is merely palliative and does not prolong survival The only chance for cure is allogeneic hemopoietic stem-cell transplantation (allo-HSCT), which is associated with high morbidity and mortality Introduction of less aggressive forms of allo-HSCT and the prospect of molecular-targeted therapies has renewed interest in prognostication in PMF The most important prognostic factors are anemia, age over 65 years, constitutional symptoms, leukocytosis, blood blasts, and some cytogenetic abnormalities These factors have recently been systematized into an International Prognostic Scoring System (IPSS) and further refined in a dynamic IPSS (DIPSS), useful at any time over the disease course, as well as a DIPSS-plus model including karyotypic information
TL;DR: The indications for allogeneic transplantation within the risk-oriented paradigm are summarized, and the latest literature on reduced intensity transplant regimens, as well as alternative donor transplantation for patients with ALL are explored.
Abstract: Allogeneic hematopoietic stem cell transplantation (alloHSCT) is an effective post-remission therapy in patients with acute lymphoblastic leukemia (ALL), but is associated with significant toxicity, so the optimal timing and use of this modality remains an issue of debate. Increased advances in reduced-intensity transplant preparative regimens and alternative donors has increased the accessibility of allogeneic transplantation. A risk adapted paradigm, using minimal residual disease analysis, may help in the selection of patients at highest risk for relapse, who may benefit most from alloHSCT. In this review, we summarize the indications for allogeneic transplantation within the risk-oriented paradigm, and also explore the latest literature on reduced intensity transplant regimens, as well as alternative donor transplantation for patients with ALL.
TL;DR: The most interesting and relevant developments are in the understanding of the genetics of T-ALL/LBL and how the genetics relate to clinical outcome.
Abstract: T-cell acute lymphoblastic leukemia and T-cell lymphoblastic lymphoma are uncommon disorders classified together by the World Health Organization classification as “T-lymphoblastic leukemia/lymphoma.” This review gives an overview on the treatment of these aggressive but curable T cell malignancies in adult patients, in order to highlight current developments. The most interesting and relevant developments are in our understanding of the genetics of T-ALL/LBL and how the genetics relate to clinical outcome. These studies will inform clinicians as to which targeted novel agents may be of value and how patients may be best risk-stratified to receive them.
TL;DR: This review summarizes the most important prognostic and predictive factors in CLL, with particular emphasis on factors affecting treatment decisions in clinical trials and routine practice.
Abstract: Chronic lymphocytic leukemia (CLL) shows a heterogeneous clinical course, which can be explained in part by prognostic factors. Most patients do not need treatment at the time of first diagnosis. The identification of prognostic factors is of major interest if strategies can be devised to treat patients according to their individual risk profile or biological subgroup. Currently, in spite of a wealth of prognostic factors, individualized treatment approaches in different genetic or risk groups are the exemption in CLL. This review summarizes the most important prognostic and predictive factors in CLL, with particular emphasis on factors affecting treatment decisions in clinical trials and routine practice.
TL;DR: Some of the results of treatment in older patients with CLL are discussed, and a discussion of factors that often affect outcome, such as comorbidities, renal function, bone marrow reserve, and infection, are reviewed.
Abstract: Chronic lymphocytic leukemia (CLL) is typically a disease of older individuals. Yet most of the literature on various chemotherapeutic regimens includes patients who are 10 to 15 years younger than the median age at diagnosis of this disease. The older patient population is grossly underrepresented in clinical trials. Currently available therapies are often too toxic for this older patient population, so their efficacy is reduced. This review discusses some of the results of treatment in older patients with CLL. A discussion of factors that often affect outcome, such as comorbidities, renal function, bone marrow reserve, and infection, are also reviewed, along with quality of life.