Characteristics and clinical correlation of TIM-3 and PD-1/PD-L1 expressions in leukemic cells and tumor microenvironment in newly diagnosed acute myeloid leukemia

Abstract Abstract 1073 Background: Aberrant receptor tyrosine kinase (RTK) signaling arising from genetic abnormalities, such as FLT3-internal tandem duplications (FLT3-ITD), is an important mechanism in the development and growth of acute myeloid leukemia (AML) and is often associated with a poor outcome. Hence, inhibition of RTK signaling is an attractive novel treatment option, particularly for disease that is resistant to conventional chemotherapy. We evaluated the clinical activity of the multikinase inhibitor sorafenib in children with de novo FLT3-ITD–positive AML or relapsed/refractory AML. Methods: Fourteen patients were treated. Six patients with newly diagnosed FLT3- ITD–positive AML (aged 9–16 years; median, 12 years) received 2 cycles of remission induction therapy and then started sorafenib (200 mg/m2 twice daily for 20 days) the day after completing induction II (low-dose cytarabine, daunorubicin, and etoposide). Nine patients (aged 6–17 years; median, 9 years) with relapsed AML (including one treated on the above regimen) received sorafenib alone (2 dose levels; 200 and 150 mg/m2) twice daily for the first week of therapy, concurrently with clofarabine and cytarabine on days 8–12, and then alone from days 13 to 28. Sorafenib pharmacokinetics were analyzed at steady-state on day 8 of sorafenib in patients with newly diagnosed AML and on day 7 in patients with relapsed AML. In patients with relapsed AML, the effect of sorafenib on signaling pathways in AML cells was assessed by flow cytometry. Results: All 6 newly diagnosed patients, including 2 whose AML was refractory to induction I, achieved a complete remission (CR) after induction II; 5 had negative minimal residual disease (MRD; <0.1% AML cells in bone marrow) after induction II. Both patients in this group who relapsed achieved second remissions, one with sorafenib alone and one on the relapse regimen described above. Of the 9 patients with relapsed AML, 6 (4 with FLT3-ITD) were treated with sorafenib 200 mg/m2. All 6 had a >50% decrease in blast percentage and/or bone marrow cellularity after 1 week of sorafenib. After concurrent sorafenib and chemotherapy, 5 of the 9 patients with relapsed AML achieved CR (2 had negative MRD) and 2 achieved a partial remission (PR; 5%-25% AML cells in bone marrow); all 4 patients with FLT3-ITD had a CR or PR. After sorafenib treatment, 6 patients underwent HSCT while 2 with FLT3-ITD who could not receive HSCT were treated with single-agent sorafenib and have maintained CR for up to 8 months. Hand-foot skin reaction (HFSR) or rash occurred in all patients and improved with cessation of sorafenib. Dose-limiting toxicity (DLT, grade 3 HFSR and/or rash) was observed in 3 of the 6 patients with relapsed AML treated with 200 mg/m2 of sorafenib; no DLT was observed at 150 mg/m2. The effect of sorafenib on downstream RTK signaling was tested in the leukemic cells of 4 patients: in most samples, phosphorylation of S6 ribosomal protein and 4E-BP1 was inhibited. The mean (± SD) steady-state concentration (Css) of sorafenib was 3.3 ± 1.2 mg/L in the newly diagnosed group and 6.5 ± 3.6 mg/L (200 mg/m2) and 7.3 ± 3.6 mg/L (150 mg/m2) in those with relapsed AML. In both groups, the mean conversion of sorafenib to sorafenib N-oxide was 27%-35% (approximately 3 times greater than previously reported), and mean sorafenib N-oxide Css was 1.0–3.2 mg/L (2.1-6.7 μM). In a 442-kinase screen, the inhibitory profiles of sorafenib N-oxide and sorafenib were similar, and FLT3-ITD phosphorylation was potently inhibited by both forms (sorafenib N-oxide Kd = 0.070 μM; sorafenib Kd = 0.094 μM). Sorafenib N-oxide inhibited the growth of an AML cell line with FLT3-ITD (IC50 = 0.026 μM) and 4 AML cell lines with wild-type FLT3 (IC50 = 3.9–13.3 μM) at approximately half the potency of sorafenib. Conclusion: In children with de novo FLT3-ITD and relapsed/refractory AML, sorafenib given alone or with chemotherapy induced dramatic responses and inhibited aberrant RTK signaling in leukemic cells. Sorafenib and its active metabolite (sorafenib N-oxide) likely contribute to both efficacy and toxicity. These results warrant the incorporation of sorafenib into future pediatric AML trials. Disclosures: Inaba: Bayer/Onyx: Research Funding. Off Label Use: Sorafenib and clofarabine: both used for treatment of pediatric acute myeloid leukemia.

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Study of CD25 expression on leukemic cells: a prognostic factor in acute myeloid leukemia

Acta Haematologica Polonica ◽

10.2478/ahp-2018-0004 ◽

2018 ◽

Vol 49 (1) ◽

pp. 20-27

Author(s):

Amina H Hassab ◽

Dalia A Nafea ◽

Rania S Swelem ◽

Basma M Ghazal

Keyword(s):

Acute Myeloid Leukemia ◽

Prognostic Factor ◽

Myeloid Leukemia ◽

University Hospital ◽

Leukemic Cells ◽

Response To Treatment ◽

Molecular Characteristics ◽

Newly Diagnosed ◽

Cd25 Expression ◽

Acute Myeloid

AbstractBackgroundAcute myeloid leukemia (AML) is a heterogeneous hematologic malignancy characterized by a clonal expansion of myeloid blasts. Treatment strategies of patients with AML are based on various prognostic factors, including age and performance status of the patient, as well as cytogenetic and molecular characteristics of the leukemic clone.Our aim was to study the expression of cluster of differentiation (CD)25 in adult Egyptian patients with newly diagnosed AML and to assess its prognostic relevance.MethodsThis study was conducted on 50 newly diagnosed AML patients at the Hematology Unit, Internal Medicine Department, Alexandria Main University Hospital. All patients were subjected to full history taking, thorough clinical examination, and laboratory investigations, including detection of CD25 expression on blast cells by flow cytometry. Conventional karyotyping was done on 11 patients at the time of diagnosis.ResultsIn our study group, 12 patients were positive for CD25 expression, and this positivity was associated with worse overall survival and shorter leukemia-free survival. On evaluating the response to treatment among CD25-positive AML patients with normal karyotype, they had lower complete remission rates and higher relapse and death rates.ConclusionsExpression of CD25 in AML patients at presentation can be considered a poor independent prognostic factor.

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Complete hematologic remissions induced by 2-chlorodeoxyadenosine in children with newly diagnosed acute myeloid leukemia

Blood ◽

10.1182/blood.v84.4.1237.1237 ◽

1994 ◽

Vol 84 (4) ◽

pp. 1237-1242 ◽

Cited By ~ 47

Author(s):

VM Santana ◽

CA Hurwitz ◽

RL Blakley ◽

WR Crom ◽

X Luo ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Plasma Concentrations ◽

Leukemic Cells ◽

Remission Induction ◽

Significant Activity ◽

Newly Diagnosed ◽

Blast Cells ◽

Acute Myeloid

Abstract The majority of children with acute myeloid leukemia (AML) who are treated exclusively with chemotherapy die of progressive disease. Improvement in outcome will likely require new active drugs capable of eradicating resistant blast cells early in the clinical course. We therefore assessed the cytoreductive potential of 2- chlorodeoxyadenosine (2-CdA), a halogenated purine analogue, in 22 consecutive children with newly diagnosed AML. The drug was administered as a single 120-hour continuous infusion (8.9 mg/m2 of body surface area per day) before the introduction of standard remission induction therapy. Six patients (27%) had complete hematologic remissions by a median of 21 days after treatment with the nucleoside (range, 14 to 33 days). Seven others had partial responses, yielding a total response rate of 59%. The drug also eliminated leukemic cells from cerebrospinal fluid in 4 of the 6 patients tested. Concentrations of 2-CdA in cerebrospinal fluid on day 5 after the initiation of treatment ranged from 12.4% to 38.0% (mean, 22.7%) of the steady-state plasma concentrations. Severe but reversible myelosuppression and thrombocytopenia developed in all patients. Analysis of factors that may have influenced the complete remission rate suggested a better outcome in patients with myeloblastic leukemia (M0-M2 subtypes in the revised French-American-British classification system). These results demonstrate clinically significant activity by 2- CdA against previously untreated AML in children, including leukemic blast cells in the central nervous system. Its use in combination chemotherapy may improve the outlook for patients with this often fatal hematologic cancer.

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Myelodysplastic syndrome is not merely “preleukemia”

Blood ◽

10.1182/blood.v100.3.791 ◽

2002 ◽

Vol 100 (3) ◽

pp. 791-798 ◽

Cited By ~ 90

Author(s):

Maher Albitar ◽

Taghi Manshouri ◽

Yu Shen ◽

Diane Liu ◽

Miloslav Beran ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Growth Factors ◽

Myelodysplastic Syndrome ◽

Cell Sorting ◽

Early Phase ◽

Myeloid Leukemia ◽

Leukemic Cells ◽

Newly Diagnosed ◽

Therapeutic Approaches ◽

Acute Myeloid

Abstract Myelodysplastic syndrome (MDS) is a disease characterized by ineffective hematopoiesis. There are significant biologic and clinical differences between MDS and acute myeloid leukemia (AML). We studied a cohort of 802 patients, 279 (35%) with newly diagnosed MDS and 523 (65%) with newly diagnosed AML, and compared clinical and biologic characteristics of the 2 groups. Complete clinical and cytogenetic data were available on all patients, and a subgroup of patients was studied for apoptosis, angiogenesis, proliferation, and growth factors. Our results demonstrate that MDS is a discrete entity that is different from AML and is characterized primarily by increased apoptosis in early and mature hematopoietic cells. Using cell sorting and loss of heterozygosity, we demonstrate that the leukemic cells from MDS patients are capable of differentiation into mature myeloid cells and monocytes. We also demonstrate that there is a significant overlap between AML and MDS when MDS is defined on the basis of an arbitrary percentage of blasts of 20% or 30%. These data suggest that despite similarities between AML and MDS in their responses to treatment and outcomes, MDS is biologically and clinically different from AML and should not be considered an early phase of AML. The data indicate that MDS must be better defined on the basis of its biology rather than the percentage of blasts; further, the data suggest that there is a need to develop therapeutic approaches that specifically address the biologic abnormalities of MDS.

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After Treatment Decrease of Bone Marrow Tregs and Outcome in Younger Patients with Newly Diagnosed Acute Myeloid Leukemia

Journal of Immunology Research ◽

10.1155/2020/2134647 ◽

2020 ◽

Vol 2020 ◽

pp. 1-11

Author(s):

Mario Delia ◽

Paola Carluccio ◽

Anna Mestice ◽

Roberta Frappampina ◽

Francesco Albano ◽

...

Keyword(s):

Bone Marrow ◽

Immune Response ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Leukemic Cells ◽

Newly Diagnosed ◽

Partial Responder ◽

Younger Patients ◽

Number Of Patients ◽

Acute Myeloid

An emerging body of evidence demonstrates that defects in antileukemic effector cells in patients with acute myeloid leukemia (AML) can contribute to the development and/or persistence of the disease. In particular, immune suppressive regulatory T cells (Tregs) may contribute to this defective antileukemic immune response, being recruited by bone marrow leukemic cells to evade immune surveillance. We evaluated Tregs (CD4+/CD45RA-/CD25high/CD127low), performing multiparametric flow cytometry on freshly collected bone marrow aspirate (BMA), in addition to the usual molecular and cytogenetic work-up in newly diagnosed AML patients to look for any correlation between Tregs and the overall response rate (ORR). We studied 39 AML younger patients (<65 years), all treated with standard induction chemotherapy. ORR (complete remission (CR)+CR with incomplete hematologic recovery (CRi)) was documented in 21 out of 39 patients (54%); two partial responder patients were also recorded. Apart from the expected impact of the molecular-cytogenetic group ( p = 0.03 ) and the NPM mutation ( p = 0.05 ), diagnostic BMA Tregs did not show any correlation with ORR. However, although BMA Tregs did not differ in the study population after treatment, their counts significantly decreased in responder patients ( p = 0.039 ), while no difference was documented in nonresponder ones. This suggested that the removal of Treg cells is able to evoke and enhance anti-AML immune response. However, the role of BMA Tregs in mediating immune system-AML interactions in the diagnostic and posttreatment phase should be confirmed in a greater number of patients.

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Complete hematologic remissions induced by 2-chlorodeoxyadenosine in children with newly diagnosed acute myeloid leukemia

Blood ◽

10.1182/blood.v84.4.1237.bloodjournal8441237 ◽

1994 ◽

Vol 84 (4) ◽

pp. 1237-1242 ◽

Cited By ~ 1

Author(s):

VM Santana ◽

CA Hurwitz ◽

RL Blakley ◽

WR Crom ◽

X Luo ◽

...

Keyword(s):

Cerebrospinal Fluid ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Plasma Concentrations ◽

Leukemic Cells ◽

Remission Induction ◽

Significant Activity ◽

Newly Diagnosed ◽

Blast Cells ◽

Acute Myeloid

The majority of children with acute myeloid leukemia (AML) who are treated exclusively with chemotherapy die of progressive disease. Improvement in outcome will likely require new active drugs capable of eradicating resistant blast cells early in the clinical course. We therefore assessed the cytoreductive potential of 2- chlorodeoxyadenosine (2-CdA), a halogenated purine analogue, in 22 consecutive children with newly diagnosed AML. The drug was administered as a single 120-hour continuous infusion (8.9 mg/m2 of body surface area per day) before the introduction of standard remission induction therapy. Six patients (27%) had complete hematologic remissions by a median of 21 days after treatment with the nucleoside (range, 14 to 33 days). Seven others had partial responses, yielding a total response rate of 59%. The drug also eliminated leukemic cells from cerebrospinal fluid in 4 of the 6 patients tested. Concentrations of 2-CdA in cerebrospinal fluid on day 5 after the initiation of treatment ranged from 12.4% to 38.0% (mean, 22.7%) of the steady-state plasma concentrations. Severe but reversible myelosuppression and thrombocytopenia developed in all patients. Analysis of factors that may have influenced the complete remission rate suggested a better outcome in patients with myeloblastic leukemia (M0-M2 subtypes in the revised French-American-British classification system). These results demonstrate clinically significant activity by 2- CdA against previously untreated AML in children, including leukemic blast cells in the central nervous system. Its use in combination chemotherapy may improve the outlook for patients with this often fatal hematologic cancer.

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Current challenges in clinical development of “targeted therapies”: the case of acute myeloid leukemia

Blood ◽

10.1182/blood-2015-01-561373 ◽

2015 ◽

Vol 125 (16) ◽

pp. 2461-2466 ◽

Cited By ~ 53

Author(s):

Elihu Estey ◽

Ross L. Levine ◽

Bob Löwenberg

Keyword(s):

Clinical Trials ◽

Acute Myeloid Leukemia ◽

Targeted Therapies ◽

Myeloid Leukemia ◽

Residual Disease ◽

Leukemic Cells ◽

Newly Diagnosed ◽

Preclinical Models ◽

First Choice ◽

Acute Myeloid

Abstract A fundamental difficulty in testing “targeted therapies” in acute myeloid leukemia (AML) is the limitations of preclinical models in capturing inter- and intrapatient genomic heterogeneity. Clinical trials typically focus on single agents despite the routine emergence of resistant subclones and experience in blast-phase chronic myeloid leukemia and acute promyelocytic leukemia arguing against this strategy. Inclusion of only relapsed-refractory, or unfit newly diagnosed, patients risks falsely negative results. There is uncertainty as to whether eligibility should require demonstration of the putative target and regarding therapeutic end points. Although use of in vivo preclinical models employing primary leukemic cells is first choice, newer preclinical models including “organoids” and combinations of pharmacologic and genetic approaches may better align models with human AML. We advocate earlier inclusion of combinations ± chemotherapy and of newly diagnosed patients into clinical trials. When a drug plausibly targets a pathway uniquely related to a specific genetic aberration, eligibility should begin with this subset, including patients with other malignancies, with subsequent extension to other patients. In other cases, a more open-minded approach to initial eligibility would facilitate quicker identification of responsive subsets. Complete remission without minimal residual disease seems a particularly useful short-term end point. Genotypic and phenotypic studies should be prespecified and performed routinely to distinguish responders from nonresponders.

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