Search

Chimeric antigen receptor T cell therapy (CART) has achieved excellent results in the past 10 years for treating of leukemia. Treatment of B cell acute lymphoblastic leukemia by anti-CD19 CART can reach a complete remission rate of 90%. Although CART has greatly improved the treatment of patients with leukemia and lymphoma, as many as one-third of the patients can suffer disease relapse after CART. The tumor surface marker CD19 is negative in most the patients who relapse, and these patients display high expression of CD19 before treatment. In this review, the current causes of CD19-negative relapses after CD19 CART against leukemia, and the mechanisms of target escape are briefly summarized. Also, methods and strategies for treating relapse to provide references for the treatment of leukemia relapse are also discussed.

Mass cytometry of acute B cell lymphoblastic leukemias at diagnosis reveals intrapatient phenotypic heterogeneity and specific signatures that mimic cell developmental stage and predict future relapse.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is a curable strategy for the treatment of hematological malignancies and nonmalignant diseases. However, graft-versus-host disease (GVHD) and relapse are still two major causes of morbidity and mortality after allo-HSCT, and both restrict the improvement of transplant outcomes. Regulatory T cells (Tregs) has been successfully used in allo-SCT settings. In this review, we summarize recent advances in experimental studies that have evaluated the roles played by Tregs in the establishment of novel transplant modalities, the prevention of GVHD and the enhancement of immune reconstitution. We also discuss the application of Tregs in clinical to prevent acute GVHD, treat chronic GVHD, as well as enhance immune reconstitution and decrease leukemia relapse, all of which lead to improving transplant outcomes.

Resistance of extramedullary leukemia growth post-transplant prevents cure. Review of its behavior detailed in 585 published cases should lead to better treatment. Leukemic tumors were found up to 13 years after transplant, most in sites inaccessible to physical exam. In 83%, marrow was not in morphologic relapse; next relapse was most often extramedullary. Induction protocols alone produced few durable responses in acute leukemias and fatal marrow aplasia in 17 %. Overall, 120 patients survived over 2 years, 43 relapse-free up to 18 years, the majority after combined tumor-directed and systemic therapy. Overall median survival was 9 months. This review highlights how results can improve: by defining extent of leukemia involvement with scans before transplant, and emergently when leukemic tumor is found after, ablating tumor directly to abort metastasis, and determining dosing of systemic chemotherapy that protects, without ablating, donor marrow. Monitoring total body remission with body scans should increase transplant cures.

Persons with acute leukemia relapsing after allotransplant and who respond to anti-leukemia interventions are at high risk of a second relapse. We studied the impact of minimal residual disease (MRD)- and graft-vs.-host disease (GvHD)-guided multiple consolidation chemotherapy and donor lymphocyte infusions (DLIs) to prevent second relapse in patients with acute leukemia relapsing post-transplant and who achieved complete remission after induction chemotherapy and DLI. Forty-seven subjects with acute leukemia relapsing after an allotransplant and who achieved complete remission after post-relapse induction chemotherapy and DLI were eligible. The use of consolidation chemotherapy and DLI was guided by the results of MRD testing and whether or not DLI caused acute and/or chronic GvHD. Outcomes were compared with those of 34 similar historical controls who did not receive consolidation chemotherapy and DLIs after induction chemotherapy and DLI. One-year cumulative incidence of relapse (CIR; 22 % 95 % confidence interval (10, 35 %) vs. 56 % (39, 73 %); P

As a malignant hematopoietic stem cell disease, leukemia remains life-threatening due to its increasing incidence rate and mortality rate. Therefore, its early diagnosis and treatment play a very important role. In the present work, we systematically reviewed the current applications and future directions of positron emission tomography (PET) in patients with leukemia, especially 18F-FDG PET/CT. As a useful imaging approach, PET significantly contributes to the diagnosis and treatment of different types of leukemia, especially in the evaluation of extramedullary infiltration, monitoring of leukemia relapse, detection of Richter’s transformation (RT), and assessment of the inflammatory activity associated with acute graft versus host disease. Future investigations should be focused on the potential of PET/CT in the prediction of clinical outcomes in patients with leukemia and the utility of novel radiotracers.

In recent years, the human leukocyte antigen-haploidentical stem cell transplantation (haplo-SCT) approach is an attractive option for patients who require transplantation, but relapse is still the main reason that affects the curative effect of transplantation. Some studies have shown that haplo-SCT is superior to sibling or unrelated matching donor transplantation in preventing leukemia relapse after transplantation. In this review, we discussed the known and unknown aspects of relapse post haplo-SCT. Encouragingly, haplo-SCT experienced lower or similar incidence of relapse. But there is currently a lack of multicenter prospective studies evaluating the outcomes of different haplo-SCT strategies. The combination of common prophylactic strategies and pre-emptive interventions might help prevent relapse after transplantation. Novel methods such as target drugs therapy and chimeric antigen receptor T cell therapy may be useful in treatment of relapse.

Dismal outcomes of acute myeloid leukemia (AML), especially in the elderly, are mainly associated with leukemia relapse and primary no response to initial therapy. This review will focus on AML relapse, and how a better understanding of the evolutionary stages that lead to relapse might help us improve disease outcome. The fact that the relapse rate for some AMLs is so high indicates that we do not truly understand the biology of relapse or possibly that we are not implementing our current understanding into, clinical practice. Therefore, this review will also aim to explore some of the current understanding of AML relapse biology in order to identify the gaps in our knowledge and translation. Accumulating evidence suggests that the root of relapse evolves even before the time of diagnosis, meaning that the complex clonal structure of AML is created before patients present to the clinic. Some of the clones that exist at diagnosis can survive chemotherapy and give rise to relapse. Accordingly, in order to better understand the mechanisms of relapse, we must consider both early and late steps in AML evolution.

Allogeneic hematopoietic stem cell transplantation (allo-HSCT) is an effective therapy for patients with relapsed acute myeloid leukemia. In this retrospective, multicenter study, we analyzed the outcome of 63 children (median age, 7 y; range, 0.2 to 17) who received unmanipulated allo-HSCT in second complete remission. Either a matched family donor or an unrelated donor was used in 29 (46%) and 34 (54%) patients, respectively. The stem cell source was bone marrow in 53 children (84%), peripheral blood in 7 (11%), and cord blood in 3 patients (5%). Preparative regimen included total body irradiation in 25 patients (40%). The 5-year estimates of overall survival and leukemia-free survival were 53% [95% confidence interval (CI) 39-66] and 49% (95% CI 35-63), respectively, whereas the cumulative incidence of relapse and transplant-related mortality (TRM) were 26% (95% CI 16-41) and 25% (95% CI 15-40), respectively. In multivariate analysis, the use of a matched family donor predicted a better probability of LFS [relative risk (RR) 2.29, P=0.05]. Both chronic graft-versus-host disease occurrence and age at diagnosis greater than 11 years were associated with an increased TRM (RR 8.08, P=0.04 and RR 4.38, P=0.05, respectively). These results indicate that allo-HSCT is a procedure able to rescue a significant proportion of children with acute myeloid leukemia in second complete remission, especially if an human leukocyte antigen-compatible relative is employed as donor. Both leukemia recurrence and TRM contributed to treatment failure. Optimization of donor selection and of strategies for both prophylaxis and treatment of graft-versus-host disease may improve the results of unrelated donor allo-HSCT.

We have established a novel immunotherapeutic approach involving dendritic cells (DCs) with potent immunoregulatory property (designated as regulatory DCs [rDCs]) for acute graft-versus-host disease (GVHD) and leukemia relapse in allogeneic bone marrow (BM) transplantation (BMT) in mice bearing leukemia. rDCs displayed high levels of MHC molecules and extremely low levels of costimulatory molecules. A single injection of rDCs following allogeneic BMT controlled the ability of the transplanted T cells to induce acute GVHD and graft-versus-leukemia (GVL) effect in the recipients bearing leukemia, and that resulted in protection from the lethality caused by acute GVHD and tumor burden. Thus, the use of rDCs may be therapeutically useful for the treatment of acute GVHD and leukemia relapse in allogeneic BMT.

A low thymic function is associated with leukemia relapse in children given T-cell-depleted HLA-haploidentical stem cell transplantation

Chronic graft-versus-host disease is a frequent complication of allogeneic hematopoietic cell transplantation and plays an important role in posttransplant morbidity and mortality, yet is correlated with the graft-versus-tumor effect in some studies. New approaches to separate the graft-versus-tumor from the graft-versus-host effect are urgently needed. Clin Cancer Res; 21(9); 1981–3. ©2015 AACR. See related article by Boyiadzis et al., p. 2020

We describe methclone, a novel method to identify epigenetic loci that harbor large changes in the clonality of their epialleles (epigenetic alleles). Methclone efficiently analyzes genome-wide DNA methylation sequencing data. We quantify the changes using a composition entropy difference calculation and also introduce a new measure of global clonality shift, loci with epiallele shift per million loci covered, which enables comparisons between different samples to gauge overall epiallelic dynamics. Finally, we demonstrate the utility of methclone in capturing functional epiallele shifts in leukemia patients from diagnosis to relapse. Methclone is open-source and freely available at https://code.google.com/p/methclone. Electronic supplementary material The online version of this article (doi:10.1186/s13059-014-0472-5) contains supplementary material, which is available to authorized users.

Acute myelocytic leukemia (AML) is a relapsing and deadly disease. Thus, it is important to early predict leukemia relapse. Recent studies have demonstrated strong correlations of relapse with abnormal localization of immature precursors (ALIP). However, there is no related research on automated detection of ALIP so far. To this end, we have proposed an ALIP detection method to investigate the relevance with AML relapse. Kernelized fuzzy C-means clustering is applied first to separate the foreground (with cells) and background (without cells). Image repairing is then used to wipe out noises to mark region of interest. Then, image partition is introduced to separate the overlapping cells. After that, a set of features are extracted for the classification. Thereafter, support vector machine is applied to classify precursors. At last, filtering operations are applied to obtain the binary-precursor detection results. Thirty-seven patients with AML are examined. The results show that ALIP is efficiently detected in a high sensitivity and positive predictive value by our proposed method. The investigation also demonstrates the strong correlations of AML relapse with ALIP.

Obesity increases the risk of developing all four common subtypes of leukemia. In addition, children and adults who are obese when they are diagnosed with acute lymphoblastic leukemia (ALL), have a higher risk of relapse. While a number of potential mechanisms linking obesity and cancer have been postulated, none can convincingly explain the links between obesity and leukemia incidence or relapse. In the present chapter, we review the evidence that obesity increases leukemia relapse, and explore some mechanisms that might contribute to this observation.

NK cells play an important role in hematopoietic stem cell transplantation (HCT) and in cross talk with dendritic cells (DCs) to induce primary T cell response against infection. Therefore, we hypothesized that blood DCs should augment NK cell function and reduce the risk of leukemia relapse after HCT. To test this hypothesis, we conducted laboratory and clinical studies in parallel. We found that although, phenotypically, NK cells could induce DC maturation and DCs could in turn increase activating marker expression on NK cells, paradoxically, both BDCA1(+) myeloid DCs and BDCA4(+) plasmacytoid DCs suppressed the function of NK cells. Patients who received an HLA-haploidentical graft containing a larger number of BDCA1(+) DCs or BDCA4(+) DCs had a higher risk of leukemia relapse and poorer survival. Further experiments indicated that the potent inhibition on NK cell cytokine production and cytotoxicity was mediated in part through the secretion of IL-10 by BDCA1(+) DCs and IL-6 by BDCA4(+) DCs. These results have significant implications for future HCT strategies.

Leukemia was the first malignant condition in which cancer stem cells were described. Leukemia stem cells (LSCs) have now been described in a number of different types of leukemia and are currently a major focus of research interest. LSCs are an important target for treatment of leukemia, and failure to eradicate these very primitive cancer cells is a common cause of leukemia relapse. Therefore, improved understanding of the biology of LSCs and the differences between normal hematopoietic and leukemic stem cells is likely to lead to the development of novel therapeutic strategies and improvements in leukemia therapy and patient survival.

Autotransplants in leukemia are controversial; their rationale and results have been questioned. Here we consider several issues central to this debate: (1) Are there convincing data to suggest that more intensive therapy increases cures? (2) Are results post-autotransplant a consequence of the transplant, or do they reflect subject-selection and time-to-treatment (time censoring) biases? (3) Does leukemia relapse after an autotransplant develop from persisting leukemia cells in the subject or the graft? (4) Do autotransplants using hematopoietic stem cells from different sources have distinct outcomes? (5) Are immune-mediated anti-leukemia mechanisms likely to prevent relapse after autotransplants? and (6) Can comparably intensive therapy be given without an autotransplant?

PURPOSE: To report a case of granulocytic sarcoma involving the eyelids and caruncles after bone marrow transplantation. METHODS: Case report. A 30-year-old man with acute myeloid leukemia in remission developed multiple friable eyelid and caruncular lesions in addition to two cutaneous lesions on the chest wall and right axilla approximately 3 months after a successful autologous bone marrow transplant. RESULT: Pathologic examination was consistent with granulocytic sarcoma. CONCLUSION: This condition should be considered in the differential diagnosis of cutaneous or eyelid masses in patients with a history of leukemia.

In this issue of Blood , Hassane and colleagues describe the discovery of new therapeutic agents effective against leukemic initiating cells through an in silico approach, demonstrating the power of collective knowledge deposited in publicly available gene-expression databases. Putative leukemic

Recurrent or residual leukemia found in extramedullary sites after intensive treatments adversely affects prognosis. To summarize the sites and outcomes when extramedullary relapses have been reported after stem cell transplants, and to elucidate when long survival has been achieved, 207 cases were analysed. Authors were contacted for follow-up information. The most commonly reported sites are soft tissue in acute leukemias and bone in CML. Extramedullary relapse occurred typically within 2 years in ALL, but later in one-third of myeloid leukemias. Most testicular relapses reported in AML followed non-TBI conditioning. Marrow relapse was not inevitable if aggressive treatment was begun early. Local therapy alone was generally inadequate. Intensive therapy has produced lengthy remissions in cases of acute leukemias involving various sites, whereas CML cases, particularly involving bone, were most resistant to treatment. Heightened awareness and aggressive treatment should improve the prospect for cure after extramedullary relapse.

In this issue of Blood , Green et al provide additional information supporting that cytomegalovirus (CMV) reduces leukemia relapse after allogeneic stem cell transplantation.[1][1] CMV has been called the troll of transplantation mainly due to the high mortality in CMV pneumonia early in the

Recent studies suggest that components of the prosurvival signal transduction pathways involving the Ras-mitogen-activated protein kinase (MAPK) can confer an aggressive, apoptosis-resistant phenotype to leukemia cells. In this study, we report that acute promyelocytic leukemia (APL) cells exploit the Ras-MAPK activation pathway to phosphorylate at Ser112 and to inactivate the proapoptotic protein Bad, delaying arsenic trioxide (ATO)-induced apoptosis. Both in APL cell line NB4 and in APL primary blasts, the inhibition of extracellular signal-regulated kinases 1/2 (ERK1/2) and Bad phosphorylation by MEK1 inhibitors enhanced apoptosis in ATO-treated cells. We isolated an arsenic-resistant NB4 subline (NB4-As(R)), which showed stronger ERK1/2 activity (2.7-fold increase) and Bad phosphorylation (2.4-fold increase) compared to parental NB4 cells in response to ATO treatment. Upon ATO exposure, both NB4 and NB4-As(R) cell lines doubled protein levels of the death antagonist Bcl-xL, but the amount of free Bcl-xL that did not heterodimerize with Bad was 1.8-fold greater in NB4-As(R) than in the parental line. MEK1 inhibitors dephosphorylated Bad and inhibited the ATO-induced increase of Bcl-xL, overcoming ATO resistance in NB4-As(R). These results may provide a rationale to develop combined or sequential MEK1 inhibitors plus ATO therapy in this clinical setting.

Umbilical cord blood (UCB) transplantation is potentially curative for acute leukemia. This analysis was performed to identify risk factors associated with leukemia relapse following myeloablative UCB transplantation. Acute leukemia patients (n = 177; 88 with acute lymphoblastic leukemia and 89 with acute myeloid leukemia) were treated at a single center. Patients received a UCB graft composed of either 1 (47%) or 2 (53%) partially human leukocyte antigen (HLA)–matched unit(s). Conditioning was with cyclophosphamide and total body irradiation with or without fludarabine. The incidence of relapse was 26% (95% confidence interval [CI], 19%-33%). In multivariate analysis, relapse was higher in advanced disease patients (≥ third complete remission [CR3]; relative risk [RR], 3.6; P < .01), with a trend toward less relapse in recipients of 2 UCB units (RR = 0.6; P = .07). However, relapse was lower for CR1-2 patients who received 2 UCB units (RR 0.5; P < .03). Leukemia-free survival was 40% (95% CI, 30%-51%) and 51% (95% CI, 41%-62%) for single- and double-unit recipients, respectively (P = .35). Although it is known that transplantation in CR1 and CR2 is associated with less relapse risk, this analysis reveals an enhanced graft-versus-leukemia effect in acute leukemia patients after transplantation with 2 partially HLA-matched UCB units. This trial was registered at http://clinicaltrials.gov as NCT00309842.

We report here a preliminary experience with gemtuzumab ozogamicin (GO) used at low dosage (3 mg/m2) in 3 elderly patients with acute promyelocytic leukaemia (APL) who presented molecular relapse and were unfit for intensive chemotherapy.

Tumor relapse remains a major obstacle to the success of allogeneic bone marrow transplantation (BMT) as a treatment for leukemia. Due to limited treatment options, the outlook for most patients that relapse following allogeneic BMT has been poor. The infusion of normal immunocompetent leukocytes from the original marrow donor has become a promising new option for treating/preventing leukemia relapse in allogeneic BMT recipients. This form of treatment has often been referred to as donor leukocyte infusion (DLI) therapy. Our laboratory is using murine models of allogeneic BMT to address important unresolved issues regarding DLI therapy in an effort to make the treatment more effective. These include identification of the antileukemic effector cells, augmentation of the antileukemic effect, and understanding why graft-versus-host-disease (GVHD) is less severe than anticipated. This article reviews our work in murine models of DLI and introduces our current working hypotheses concerning DLI therapy.

ABLATIVE chemotherapy with allogeneic bone-marrow transplantation has become an accepted means of therapy for acute leukemia.1 It is the only treatment capable of producing long-term unmaintained remissions in patients with acute lymphoblastic leukemia who have had relapses during the course of conventional chemotherapy, and it has been advocated for acute myeloblastic leukemia in first remission.1 An initially unforeseen and rare form of failure of such therapy has been the relapse of leukemia in donor cells.2 3 4 5 We report here our experience with a patient with acute lymphoblastic leukemia who had a relapse after therapy with high-dose cyclophosphamide, total-body irradiation, and bone-marrow . . .

Modern intensive induction chemotherapy produces remissions in > 90% of individuals with acute lymphoblastic leukemia (ALL) and > 60–80% of those with acute myelogenous leukemia (AML). If these individuals receive no further therapy two distinct outcomes will occur. A small proportion, probably substantially < 10%, will remain in remission, for a prolonged period; probably most of these individuals are cured. A more frequent outcome is for leukemia to recur. Leukemia relapse also occurs in a substantial proportion of adults with ALL and children and adults with AML despite intensive post-remission chemotherapy.

One of the major problems in todays leukemia treatment employing either allogeneic or autologous bone marrow transplantation (BMT) is leukemia relapse. Apparently, leukemic cells have survived high dose conditioning treatment prior to BMT. In case of autologous BMT, leukemic cells reinfused with the graft might in addition contribute to leukemia relapse after BMT.

Summary Human immune systems are variable, and immune responses are often unpredictable. Systems-level analyses offer increased power to sort patients on the basis of coordinated changes across immune cells and proteins. Allogeneic stem cell transplantation is a well-established form of immunotherapy whereby a donor immune system induces a graft-versus-leukemia response. This fails when the donor immune system regenerates improperly, leaving the patient susceptible to infections and leukemia relapse. We present a systems-level analysis by mass cytometry and serum profiling in 26 patients sampled 1, 2, 3, 6, and 12 months after transplantation. Using a combination of machine learning and topological data analyses, we show that global immune signatures associated with clinical outcome can be revealed, even when patients are few and heterogeneous. This high-resolution systems immune monitoring approach holds the potential for improving the development and evaluation of immunotherapies in the future.