Enhanced pretreatment CD25 expression on peripheral blood CD4+ T cell predicts shortened survival in acute myeloid leukemia patients receiving induction chemotherapy

2016 ◽  
Vol 68 (1) ◽  
pp. 12-19 ◽  
Author(s):  
Łukasz Bołkun ◽  
Małgorzata Rusak ◽  
Andrzej Eljaszewicz ◽  
Lothar Pilz ◽  
Urszula Radzikowska ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
T Cell ◽  
Induction Chemotherapy ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Cd4 T Cell ◽  
Cd25 Expression ◽  
Acute Myeloid

scholarly journals Early clearance of peripheral blood blasts predicts response to induction chemotherapy in acute myeloid leukemia

Cancer ◽  
2012 ◽  
Vol 118 (21) ◽  
pp. 5278-5282 ◽  
Author(s):  
Martha Arellano ◽  
Suchita Pakkala ◽  
Amelia Langston ◽  
Mourad Tighiouart ◽  
Lin Pan ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Induction Chemotherapy ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Acute Myeloid

Predicting Duration of Neutropenia After Successful Intensive Induction Chemotherapy for Acute Myeloid Leukemia or High-Grade Myelodysplastic Syndromes

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 4336-4336 ◽  
Author(s):  
Sarah A. Buckley ◽  
Vladimir Vainstein ◽  
Janis L. Abkowitz ◽  
Elihu H. Estey ◽  
Roland B. Walter
Keyword(s):  
Mathematical Modeling ◽  
Acute Myeloid Leukemia ◽  
Induction Chemotherapy ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Intensive Chemotherapy ◽  
Blood Neutrophil ◽  
Neutrophil Recovery ◽  
Peripheral Blood Neutrophil ◽  
Acute Myeloid

Abstract Abstract 4336 Background: Chemotherapy-induced neutropenia (CIN) is a major cause of morbidity and mortality in patients with acute myeloid leukemia (AML) or myelodysplastic syndromes (MDS) due to the risk of overwhelming infection. Although the risk for infections increases with longer duration of neutropenia, no attempts have been undertaken to predict time of neutrophil recovery in AML/MDS patients following intensive chemotherapy. In unpublished work, we have successfully used mathematical modeling of peripheral blood blast kinetics following induction chemotherapy to accurately predict the likelihood of subsequent complete remission (CR). In this retrospective study, we investigated whether data derived from mathematical modeling of early peripheral blood neutrophil or blast dynamics could predict the duration of CIN in AML/MDS patients undergoing intensive induction chemotherapy. Patients and Methods: We retrospectively analyzed a cohort of 59 consecutive patients with newly diagnosed AML or MDS who achieved CR after induction chemotherapy after 1 course of chemotherapy with a 7 + 3-like regimen. Daily peripheral blood neutrophil and blast counts were recorded from the initiation of chemotherapy until the day of neutrophil recovery (defined as an absolute neutrophil count [ANC] ≥ 500 cells/μL). In patients with ≥ 3 measurable neutrophil or blast counts within the first five days of data collection, the rate of peripheral blood neutrophil and blast clearance was calculated by fitting an exponential decay curve to the data points starting on day 1 of chemotherapy. Results: The average age of the study cohort was 54 years (range 25 to 78). Seventy-six percent had primary AML. Cytogenetic risk was favorable in 32%, intermediate in 37%, and adverse in 27% of patients. The 23 patients with initial ANC < 500 cells/μL had a significantly longer duration of neutropenia than the 36 patients with initial ANC ≥ 500 cells/μL (mean: 29 versus 26 days, range: 21 – 39 versus 21 – 34, p=0.045). Neither age nor percentage of blasts in the bone marrow at diagnosis predicted neutropenia duration. In patients for whom decay rates could be modeled, there was no association between duration of neutropenia and decay rate for neutrophils (n = 36) or blasts (n = 20). There was also no association with the day that neutrophils first started to decline (defined as the first drop < 70% of the initial neutrophil count) or the first day of blast clearance from peripheral blood. Seven patients received granulocyte colony-stimulating factor (G-CSF; 1 prior to chemotherapy for antecedent myelodysplastic syndrome and 6 between days 15 and 43 for prolonged neutropenia and/or febrile neutropenia); the duration of neutropenia in this group did not differ significantly from that of the cohort as a whole. Conclusion: While kinetics of normal blood counts following initiation of intensive chemotherapy do not appear helpful to predict the duration of subsequent neutropenia, pre-treatment ANC levels provide limited information, with patients who are severely neutropenic prior to induction chemotherapy for AML having a longer average duration of CIN. This observation may provide some clinical guidance on the risk-adapted use of G-CSF in patients with AML/MDS undergoing induction chemotherapy. Disclosures: Vainstein: Neumedicines Inc: Employment.

scholarly journals Peripheral blood T cells in acute myeloid leukemia (AML) patients at diagnosis have abnormal phenotype and genotype and form defective immune synapses with AML blasts

Blood ◽  
2009 ◽  
Vol 114 (18) ◽  
pp. 3909-3916 ◽  
Author(s):  
Rifca Le Dieu ◽  
David C. Taussig ◽  
Alan G. Ramsay ◽  
Richard Mitter ◽  
Faridah Miraki-Moud ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
T Cells ◽  
Acute Myeloid Leukemia ◽  
T Cell ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Absolute Number ◽  
Immune Synapses ◽  
Acute Myeloid

Abstract Understanding how the immune system in patients with cancer interacts with malignant cells is critical for the development of successful immunotherapeutic strategies. We studied peripheral blood from newly diagnosed patients with acute myeloid leukemia (AML) to assess the impact of this disease on the patients' T cells. The absolute number of peripheral blood T cells is increased in AML compared with healthy controls. An increase in the absolute number of CD3+56+ cells was also noted. Gene expression profiling on T cells from AML patients compared with healthy donors demonstrated global differences in transcription suggesting aberrant T-cell activation patterns. These gene expression changes differ from those observed in chronic lymphocytic leukemia (CLL), indicating the heterogeneous means by which different tumors evade the host immune response. However, in common with CLL, differentially regulated genes involved in actin cytoskeletal formation were identified, and therefore the ability of T cells from AML patients to form immunologic synapses was assessed. Although AML T cells could form conjugates with autologous blasts, their ability to form immune synapses and recruit phosphotyrosine signaling molecules to the synapse was significantly impaired. These findings identify T-cell dysfunction in AML that may contribute to the failure of a host immune response against leukemic blasts.

scholarly journals Peripheral Blood Blast Clearance As an Independent Predictor of Clinical Response and Outcomes in Acute Myeloid Leukemia

Blood ◽  
2018 ◽  
Vol 132 (Supplement 1) ◽  
pp. 2684-2684
Author(s):  
Noa G. Holtzman ◽  
Firas El Chaer ◽  
Omer Ali ◽  
Ameet Patel ◽  
Maria R. Baer ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Clinical Outcomes ◽  
Induction Chemotherapy ◽  
Induction Therapy ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Total Leukocyte Count ◽  
Risk Category ◽  
The Absolute ◽  
Acute Myeloid

Abstract Introduction Acute myeloid leukemia (AML) is a heterogeneous disease that depends on precise risk-stratification for predicting outcomes and optimizing therapy plans. Despite the current clinical landscape of incorporating karyotype and mutations into prognostic models, chemosensitivity (or lack thereof) is usually not evaluated or appreciated until a patient undergoes a day 14 bone marrow (D14BM) evaluation during induction treatment. While the D14BM aspirate and biopsy are regularly used to predict achievement of CR versus need for further reinduction therapy, some have questioned its utility. Further, the invasive nature of the procedure leads to significant patient discomfort, anxiety, increased risk of complications (infections, bleeding, damage to surrounding tissues) and, at times, is not feasible due to a patient's critical state. Therefore, alternative criteria are needed to help risk-stratify these patients and predict treatment responses. We report here a single center analysis of the relationship between the rate of peripheral blood blast (PBB) clearance with cytotoxic induction therapy and clinical outcomes. Methods Patients diagnosed with AML (non-M3) with detectable PBB via manual differential or flow cytometry at University of Maryland Greenebaum Comprehensive Cancer Center (UMGCCC) during 2007-2018 were identified. Only patients who underwent induction with a "7+3" regimen with cytarabine and an anthracycline (idarubicin or daunorubicin), or "7+3" plus a third agent, were included. Patient and disease characteristics, treatment courses, and clinical outcomes were collected. The absolute PBB count was calculated by percent PBB multiplied by total leukocyte count (103/mcL). PBB rate of clearance (PBB-RC) was defined as the percentage of the absolute PBB count at diagnosis that was cleared each day, on average, until clearance or D14 of induction chemotherapy. Patients were divided into three groups based on PBB-RC: high, if PBB-RC >30% (n=15); low, if PBB-RC <10% (n=16); and intermediate, if PBB-RC fell between 10-30% (n=133). Primary outcomes included D14BM status, achievement of complete remission (CR) with or without full count recovery, and overall survival (OS). Multivariate logistic regression and Cox proportional hazards models were conducted and adjusted for the disease risk category, age, sex, ethnicity, and use of leukapheresis or hydroxyurea. Cox models were also adjusted for allogeneic stem cell transplantation (SCT) status. Results Treatment-naive AML patients with PBB at diagnosis and who underwent cytotoxic induction therapy were identified (n=164). Patient characteristics are shown in Table 1. Sixty-eight percent of patients underwent induction with "7+3", and 28% with "7+3" with a third agent. Pre-induction leukoreduction included hydroxyurea (29%) and/or leukapheresis (12%). Most (68%) patients received only one course of induction; 18% received 2 courses, and 8% received ≥3. Chemoablation on D14BM was achieved in 70% of patients (n=113); 27% (n=45) had residual disease, and 4% (n=6) were indeterminate. CR was achieved in 74% of patients (n=121), 19 of which required ≥ 2 induction courses. Forty-one patients proceeded to SCT. Median OS was 18.5 months (range 0.5-122). Each 5% increase in PBB-RC approximately doubled the likelihood of D14BM clearance (OR=1.97; 95% CI: 1.39-2.80, p<0.001). The adjusted area under the ROC curve of PBB-RC for predicting D14BM clearance was 0.72, with a positive predictive value (PPV) of high PBB-RC of 93% and negative PV (NPV) of low PBB-RC of 81%. PBB-RC was also significantly associated with CR (OR per 5% =2.08; 95% CI: 1.38-3.14, p<0.001). CR was achieved in all patients in the high PBB-RC group, while only 44% in the low PBB-RC group. PBB-RC was significantly associated with improved OS (HR per 5%=0.67; 95% CI: 0.52-0.85, Figure 1). Other factors associated with longer OS included favorable risk category (HR=0.03; 95% CI: 0.01-0.23) and SCT (HR=0.50; 95% CI: 0.26-0.95). African American patients had poorer OS adjusted for PBB-RC (HR=2.22; 95% CI: 1.16-4.25), while race was not associated with D14BM or CR rate. Conclusion PBB-RC during induction chemotherapy is predictive of achievement of CR and improved OS in AML. PBB-RC is also significantly associated with D14BM clearance and can therefore serve as a surrogate predictive marker for treatment response in AML patients with PBB at diagnosis. . Disclosures Emadi: NewLink Genetics: Research Funding.

Early peripheral blood blast clearance during induction chemotherapy for acute myeloid leukemia predicts superior relapse-free survival

Blood ◽  
2007 ◽  
Vol 110 (13) ◽  
pp. 4172-4174 ◽  
Author(s):  
Michelle A. Elliott ◽  
Mark R. Litzow ◽  
Louis L. Letendre ◽  
Robert C. Wolf ◽  
Curtis A. Hanson ◽  
...  
Keyword(s):  
Acute Myeloid Leukemia ◽  
Induction Chemotherapy ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Lymphoblastic Leukemia ◽  
Rapid Decline ◽  
Relapse Free Survival ◽  
Free Survival ◽  
Acute Myeloid

In childhood acute lymphoblastic leukemia (ALL), a rapid decline of circulating leukemic blasts in response to induction chemotherapy or prednisone is one of the most important prognostic factors, not only for achieving remission but also for relapse-free survival (RFS). However, in acute myeloid leukemia (AML) parameters of chemosensitivity have been restricted mainly to the rapidity of achievement of complete remission (CR) or the assessment of residual leukemic bone marrow blasts during aplasia. We hypothesized that the time to circulating peripheral blood blast clearance, as a potential surrogate for in vivo chemosensitivity, would have prognostic relevance in AML also. In a retrospective analysis of a cohort of 86 adult patients with AML receiving uniform induction and consolidation chemotherapy, we demonstrate that the time to clearance of circulating blasts during induction chemotherapy is an independent prognostic marker of RFS, superseding other known or established risk factors, including karyotype and number of inductions to achieve CR.

T-Cell Large Granular Lymphocyte Leukemia of Donor Origin Following Myeloablative Allogeneic Peripheral Blood Stem Cell Transplantation for Acute Myeloid Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 5021-5021
Author(s):  
Guilherme Rabinowits ◽  
Roger H. Herzig ◽  
Geoffrey P. Herzig
Keyword(s):  
Acute Myeloid Leukemia ◽  
T Cell ◽  
Cell Transplantation ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Clonal Expansion ◽  
Large Granular Lymphocyte ◽  
Post Transplant ◽  
Acute Myeloid ◽  
Lgl Leukemia

Abstract Lymphoproliferative disorders are a recognized complication of allogeneic hematopoietic cell transplantation (HCT). Most are B-cell disorders, often associated with Epstein-Barr virus infection. We report the fourth case of T-cell, large granular lymphocyte leukemia. In May 2005, a 63-year-old woman with acute myeloid leukemia in first relapse underwent reduced intensity, myeloablative, allogeneic peripheral blood HCT from her HLA-genotypically matched brother. Three months later, she received a donor-lymphocyte infusion (DLI) for recurrent leukemia. She developed acute graft-versus-host disease (GvHD) and remission of leukemia. GvHD was controlled with high-dose steroids. Multiple episodes of asymptomatic cytomegalovirus viremia were treated with pre-emptive valganciclovir. In June 2006, 10 months post-DLI, PCR-based chimerism studies revealed 100% donor peripheral blood cells. One month later, immunophenotyping of peripheral blood to evaluate neutropenia and lymphocytosis, revealed expansion of CD3+, CD8+, CD2+, CD11c+ and HLA-DR+ lymphocytes with clonally rearranged T-cell receptor genes, consistent with the diagnosis of large granular lymphocyte (LGL) leukemia. Evaluation of her donor, including bone marrow aspiration and biopsy, showed normal hematopoiesis with no evidence of LGL expansion. PCR of donor peripheral blood mononuclear cells was negative for TCRγ rearrangements. During the year since diagnosis of T-cell LGL leukemia the CBC has been stable, without specific treatment, and AML remains in remission. Discussion: lymphocytosis due to expansion of T-cell large granular lymphocytes is a rare occurrence after allogeneic HCT. Non-clonal expansion is more common, with 6 cases described in a series of 201 patients (Mohty et al. Leukemia2002; 16:2129–33). To our knowledge, this is the fourth documented case of donor-derived T-cell LGL leukemia (clonal expansion) after allogeneic HCT. The course of post-transplant LGL leukemia appears to resemble de novo disease. Of the previously reported cases, 2 patients were alive 6 and 18 months (Chang et al. Am J Clin Pathol2005; 123:196–9), and 1 died 7 months post-LGL leukemia diagnosis (Au et al. Am J Clin Pathol 2003; 120:626–30). Our patient is 12 months since diagnosis without therapy. Etiologic factors responsible for post-transplant LGL leukemia have not been identified. In all cases tested, the leukemia arose in donor cells, but was not transmitted from the donor. An association between long-term antigenic stimulation due to GvHD or viral infection has been proposed. Our patient had both GvHD and recurrent CMV viremia before developing T-cell LGL leukemia. Of interest, our patient experienced long-lasting complete remission of AML after DLI. Whether the T-cell LGL leukemia, which developed almost one year after DLI, has any impact on maintaining remission (graft-versus-leukemia effect) is unknown, but has been suggested by other authors.

Characterization of Immune Reconstitution Following High Dose Chemotherapy in Acute Myeloid Leukemia.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 3888-3888
Author(s):  
Christian F. Meyer ◽  
Christopher Thoburn ◽  
Ferdynand Kos ◽  
Christopher Gocke ◽  
Hyam I. Levitsky ◽  
...  
Keyword(s):  
Bone Marrow ◽  
T Cells ◽  
Acute Myeloid Leukemia ◽  
T Cell ◽  
Peripheral Blood ◽  
Myeloid Leukemia ◽  
Immune Reconstitution ◽  
Consolidation Therapy ◽  
Time Points ◽  
Acute Myeloid

Abstract Recovery of immune function after initial treatment of acute myeloid leukemia (AML) is critical, not only for protection against infections but also for surveillance against recurrent disease. A better understanding of the nature of lymphocyte recovery following induction and consolidation therapy for AML could guide the design of immunotherapy strategies aimed at boosting the anti-leukemia activity of a reconstituted immune system. Prior studies examining thymic T cell production following bone marrow transplantation (BMT) have found varying levels of thymic output post-transplant, as measured by T cell Receptor Excision Circle (TREC) levels in the peripheral blood of adult patients. Of note, relapse of chronic myeloid leukemia (CML) following BMT is correlated with decreased levels of TREC positive T cells. In order to characterize immune reconstitution in AML, we studied 26 patients after induction or consolidation time sequential chemotherapy. Their median age was 52 (range 23–69). Thirteen patients received cytarabine, daunorubicin, and etoposide (AcDVP-16) induction therapy, 3 patients received cytarabine, daunorubicin, and cytarabine (AcDAc) consolidation therapy and 10 patients received flavopiridol, cytarabine, and mitoxantrone (FLAM) either as induction or consolidation therapy. Peripheral blood samples were collected approximately every other day for 3–5 time points after each patient’s white blood cell count exceeded 200 cells/cubic mm on three consecutive days. Among the four patients evaluated to date, flow cytometry results show that a majority of cells seen early in immune reconstitution are CD3+ lymphocytes (range 69–97%). Subset analyses on 3 of these 4 patients have shown CD4:CD8 ratios ranging from 3:1 to 4:1, while the fourth patient exhibited an inverse of this ratio at 1:5. In addition, CD25+FOXP3+ T cells represented a median of 5.1% (range 2.5–12.3%) of the CD3+ T cells. Since T cells represented the abundance of cells in the peripheral blood during early bone marrow recovery, we then assessed whether these cells represented recent thymic emigrants or naïve T cells by examining TRECs using real time PCR (RT-PCR). TRECs were present in 24 of the 26 patients with levels ranging between 100 and 100,000 copies per 100,000 cells. Furthermore, 4 control samples from normal volunteers (ages 37–43) revealed the absence of TREC positive cells. Further analyses of these time points and correlations between TREC levels and clinical responses are ongoing.

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