WO2015085171A1 - Rôle de mcp-1 dans la rechute de leucémie myéloblastique aiguë après transplantation de cellules souches hématopoïétiques - Google Patents

Rôle de mcp-1 dans la rechute de leucémie myéloblastique aiguë après transplantation de cellules souches hématopoïétiques Download PDF

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Publication number
WO2015085171A1
WO2015085171A1 PCT/US2014/068791 US2014068791W WO2015085171A1 WO 2015085171 A1 WO2015085171 A1 WO 2015085171A1 US 2014068791 W US2014068791 W US 2014068791W WO 2015085171 A1 WO2015085171 A1 WO 2015085171A1
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mcp
aml
patient
level
hct
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PCT/US2014/068791
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English (en)
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Khaled YASSER
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Adventist Health Systems/Sunbelt, Inc.
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Publication of WO2015085171A1 publication Critical patent/WO2015085171A1/fr

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    • G—PHYSICS
    • G01—MEASURING; TESTING
    • G01N—INVESTIGATING OR ANALYSING MATERIALS BY DETERMINING THEIR CHEMICAL OR PHYSICAL PROPERTIES
    • G01N33/00—Investigating or analysing materials by specific methods not covered by groups G01N1/00 - G01N31/00
    • G01N33/48—Biological material, e.g. blood, urine; Haemocytometers
    • G01N33/50—Chemical analysis of biological material, e.g. blood, urine; Testing involving biospecific ligand binding methods; Immunological testing
    • G01N33/53—Immunoassay; Biospecific binding assay; Materials therefor
    • G01N33/574—Immunoassay; Biospecific binding assay; Materials therefor for cancer
    • G01N33/57407—Specifically defined cancers
    • G01N33/57426—Specifically defined cancers leukemia

Definitions

  • This application relates to the correspondence between serum Monocyte Chemo-Attractant Protein- 1 (MCP-1) levels and Acute Myeloid Leukemia (AML) or Acute Myeloid Leukemia/Myelodysplastic Syndrome (AML/MDS) or the relapse of AML or AML/MDS.
  • MCP-1 Monocyte Chemo-Attractant Protein- 1
  • AML Acute Myeloid Leukemia
  • AML/MDS Acute Myeloid Leukemia/Myelodysplastic Syndrome
  • MCP-1 serum Monocyte Chemo-Attractant Protein- 1
  • AML Acute Myeloid Leukemia
  • AML/MDS Acute Myeloid Leukemia/Myelodysplastic Syndrome
  • AML treatments may involve, for example, conditioning or induction chemotherapy, for example with DNA-damaging agents. While this initial chemotherapy may kill a majority of leukemia cells, further treatments may be needed to prevent relapse, such as hematopoietic stem cell transplantation (HCT or HSCT). However, relapse after HCT remains a leading cause of treatment failure, and as much as 30-40% of post-HCT patients may suffer a relapse.
  • HCT hematopoietic stem cell transplantation
  • HCT hematopoietic stem cell transplantation
  • relapse after HCT remains a leading cause of treatment failure, and as much as 30-40% of post-HCT patients may suffer a relapse.
  • a means of identifying patients who have received treatment for AML or AML/MDS but who are at high risk for relapse for example, to provide further treatment or supportive care to those patients either to prevent relapse or reduce its intensity. For instance, it may be possible to modify the treatment of those patients at risk for relapse so
  • the present inventor has discovered that a higher than average level of the cytokine protein MCP-1 in an AML/MDS patient after HCT treatment correlates to an increased risk of relapse. (See, e.g., Figure 3.) In contrast, 41 other cytokine markers were tested but found not to correlate with relapse of AML/MDS in post-HCT patients. Accordingly, the present application encompasses methods of treating AML or
  • AML/MDS that incorporate information about the level of MCP-1 protein in a bodily fluid of the patient following previous AML treatment. Further, the present application also encompasses using of MCP-1 levels to detect risk of AML onset in MDS patients.
  • a method of treating relapse of AML in a patient previously treated for AML comprising obtaining a measurement of MCP-1 in a fluid sample from the patient, and providing further AML treatment to the patient if the patient is measured to have an MCP-1 level above that of an average MCP-1 level observed in a population of post-treatment AML patients, such as a population of patients who have received similar AML treatment.
  • an ex vivo method of determining risk of relapse of AML in a patient previously treated for AML comprising measuring MCP-1 level in a fluid sample from the patient or obtaining such a measurement, wherein an MCP-1 level above that of an average MCP-1 level observed in a population of post-treatment AML patients indicates that the patient is at risk for relapse.
  • the patient's MCP-1 level is compared to the average MCP-1 level of post-treatment AML patients who did not show relapse of AML or of AML/MDS within 3 months, 6 months, or 1 year after treatment.
  • the patient suffers from AML/MDS, and in some embodiments, the above average MCP-1 level predicts relapse of MDS.
  • an ex vivo method of determining whether an MDS patient is at risk of developing AML comprising obtaining a measurement of MCP-1 in a fluid sample from the patient, wherein an MCP-1 level above that of an average MCP-1 level observed in a population of MDS patients indicates that the patient is at risk for developing AML.
  • the previous treatment comprises hematopoietic stem cell transplantation (HCT), such as allogenic HCT or autologous HCT, optionally combined with
  • chemotherapy For example, some patients may have received a conditioning regimen of chemotherapy as well as HCT prior to measurement of their MCP-1 level and optional further treatment.
  • the previous chemotherapy treatment may include treatment with one or more of cytarabine, daunorubicin, mitoxantrone, etoposide, idarubicin, fludarabine, busulfan, clofarabine, cyclophosphamide, topetecan, an azanucleoside such as 5- azacytidine or decitabine, sapacitabine, or vosaroxin.
  • cytarabine daunorubicin, mitoxantrone, etoposide, idarubicin, fludarabine, busulfan, clofarabine, cyclophosphamide, topetecan, an azanucleoside such as 5- azacytidine or decitabine, sapacitabine, or vosaroxin.
  • Two or more of these agents may be combined, such as a combination of busulfan and fludarabine (Bu-Flu treatment).
  • a patient may also have been previously treated with a
  • the MCP-1 level is measured post-transplant, such as approximately 20-40 days, approximately 25-35 days, approximately 27-33 days, or approximately 29-31 days post-transplant, or 30 days post-transplant.
  • the average MCP-1 level against which the patient's MCP-1 level is compared is an average MCP-1 level in post-transplant patients, for example, an average MCP-1 level measured the same number of days after transplant that the patient's measurement was taken.
  • the further AML treatment given to patients showing higher than average MCP-1 levels comprises administering one or more of an inhibitor of MCP-1 , an azanucleoside such as 5-azacytidine (Vidaza®) or decitabine, lenalidomide (Revlimid®), a histone deacetylase inhibitor, or an angiotensin converting enzyme (ACE) inhibitor, or a combination of two or more of the above.
  • the further AML treatment comprises HCT, such as an allogenic or autologous HCT. For example, a patient who has already had HCT but who is at risk of relapse due to an above average MCP-1 level may be treated with a further HCT.
  • the further AML treatment comprises chemotherapy.
  • the patient may receive a combination of two or more of HCT or further HCT, chemotherapy, azanucleoside treatment (e.g. 5-azacytidine and/or decitabine), lenalidomide, histone deacetylase inhibitor treatment, and ACE inhibitor treatment.
  • azanucleoside treatment e.g. 5-azacytidine and/or decitabine
  • lenalidomide e.g. 5-azacytidine and/or decitabine
  • histone deacetylase inhibitor treatment e.g., ACE inhibitor treatment.
  • the MCP-1 level is determined ex vivo in a fluid sample of the patient, such as whole blood, plasma, or serum.
  • the MCP-1 level is measured by an assay comprising binding of an anti-MCP-1 antibody specific for MCP-1 protein in the fluid sample, such as an ELISA assay.
  • the MCP-1 level is measured at the messenger RNA level by reverse transcription and polymerase chain reaction (RT-PCT) amplification of messenger RNA in the sample using primers specific for the MCP-1 coding sequence.
  • RT-PCT reverse transcription and polymerase chain reaction
  • Figure 1 shows the overall survival (OS) at 1 and 2 years and disease free survival at 1 and 2 years.
  • Figure 2 shows cumulative incidence of treatment related mortality at 1 and 2 years and the cumulative incidence of relapse at 1 and 2 years respectively.
  • Figure 3 is shows that of a subset of 30 patients where chemokine analysis was performed, only MCP-1 levels at day 30 post HCT were predictive of relapse out of the 42 biological markers tested.
  • This application encompasses methods of predicting and treating relapse of AML in patients who have previously received AML treatment.
  • "Patients” herein refers to mammalian patients such as human patients, domestic mammals such as dogs and cats, and laboratory animals such as mice or rats.
  • treatment covers any administration or application of a therapeutic or a medical procedure in a mammal, including a human, and includes inhibiting disease progression, partially inhibiting or slowing disease progression, preventing a relapse or partially inhibiting or slowing or reducing the intensity of a relapse, causing the disease to go into remission, and curing the disease.
  • the AML patients are AML/MDS patients.
  • AML/MDS is a form of AML that may arise from an antecedent myelodysplastic syndrome.
  • MDS comprises a group of bone marrow disorders (myelodisplasias).
  • MDS disorders include refractory anemia (low red blood cell count), refractory neutropenia (low white blood cell count), refractory thrombocytopenia (low platelet count), refractory anemia with ring sideroblasts (RARS), refractory anemia with excess blasts (RAEB-l and -2), refractory cytopenia with multilineage dysplasia (RCMD), myelodysplastic syndrome associated with isolated del (5q), as well as unclassified MDS syndromes.
  • An antecedent MDS disorder may predispose a patient to developing AML.
  • AML/MDS often occurs in elderly patients.
  • AML/MDS patients have a particularly poor prognosis and a relatively high rate of relapse.
  • Patients according to the inventive methods may have received previous treatment for AML, and thus the methods may help to predict relapse of AML or AML/MDS.
  • Relapse refers to a diagnosis of the return of AML or AML/MDS in the patient. Diagnosis of AML relapse or initial diagnosis of AML may be based upon detection of leukemia cells in the blood or bone marrow of the patient, for example in a bone marrow aspirate or biopsy, combined with cytogenetics, flow cytometry, and/ or visual inspection of cells.
  • Current AML treatments include chemotherapy regimens, often coupled with further treatment such as HCT.
  • Chemotherapy may involve, for example, an initial conditioning or induction treatment intended to kill as many leukemia cells as possible.
  • the chemotherapy may involve treatment with DNA damaging agents.
  • Exemplary drugs for such treatments include one or more of cytarabine, daunorubicin, mitoxantrone, etoposide, idarubicin, fludarabine, busulfan, clofarabine, cyclophosphamide, topetecan, an azanucleoside such as 5-azacytidine or decitabine, sapacitabine, or vosaroxin, and combinations of two or more of the above agents such as busulfan and fludarabine (Bu- Flu treatment).
  • the intensity of the conditioning chemotherapy may be varied.
  • RIC, FIC reduced and full intensity conditioning
  • Bu- Flu intravenous busulfan plus fludarabine
  • the patient has previously received HCT before the patient's MCP-1 level is determined.
  • the HCT is "allogenic,” meaning that the transplanted stem cells have been derived from a donor, such as a related donor (RD) or an unrelated donor that is otherwise a close match for the patient (a matched unrelated donor or MUD).
  • HCT can also be "autologous,” in which the patient's own stem cells are used.
  • the MCP-1 measurement is obtained at a point in time post-HCT transplant, such as approximately 20-40 days, approximately 25-35 days, approximately 27-33 days, approximately 29-31 days, or approximately 30 days post- transplant.
  • Obtaining the MCP-1 measurement at a particular point in time means that the fluid sample from the patient that is used for the MCP-1 measurement is taken at that point in time, i.e. at approximately 20-40 days, approximately 25-35 days, approximately 27-33 days, approximately 29-31 days, or approximately 30 days post-transplant.
  • the MCP-1 level measured for the individual patient is compared to an average MCP-1 level of a pool of similar patients.
  • the terms "average” and “mean” are used interchangeably herein.
  • the average may be the average MCP-1 level in patients who have undergone prior AML treatments or the average level in patients who have undergone a similar prior treatment.
  • the comparative average MCP-1 level may be that for a pool of AML patients who have also previously received HCT.
  • the comparative average MCP-1 level may be that of a pool of post-HCT patients whose MCP-1 levels were measured within the same number of days post HCT treatment.
  • the MCP-1 level in the patient's fluid sample is compared to that of an average of post-HCT patients whose fluid samples for MCP-1 measurement were taken within the same approximate date ranges as that of the patient.
  • the average may be the average of a pool of MDS patients.
  • an MCP-1 level above that of the average MCP-1 level of a pool of similar patients may indicate risk of relapse or of developing AML.
  • the MCP-1 level indicating risk of relapse or of developing AML may be at least about 20%, 25%, 30%, 40%, 45%, 50%, 55%, 60%, or 65% higher than of the average MCP-1 level of a pool of similar patients.
  • the MCP-1 level indicating risk of relapse or of developing AML may be higher than about 0.5 standard deviation, 1.0 standard deviation, 1.5 standard deviations, or 2 standard deviations above the average MCP-1 level of a pool of similar patients.
  • the pool or population of patients used for the comparative average MCP-1 level may be a historical pool, such that the average MCP-1 level against which the patient's MCP-1 level is compared is one that was determined in earlier AML clinical studies, for example.
  • the patient's MCP-1 level can be compared to the MCP-1 level in a pool of AML patients, such as patients who had received similar prior treatments, who did not show relapse after AML treatment, such as patients who did not show relapse after 3 months, 6 months ,or 1 year post-HCT transplant.
  • the MCP-1 level indicating risk of relapse may be at least about 20%, 25%, 30%, 40%, 45%, 50%, 55%, 60%, or 65% higher than of the average MCP-1 level of a pool of similar patients who did not relapse after a period of time such as 3 months, 6 months, or 1 year.
  • the MCP-1 level indicating risk of relapse may be higher than about 0.5 standard deviation, 1.0 standard deviation, 1.5 standard deviations, or 2 standard deviations above the average MCP-1 level of a pool of similar patients who did not relapse after a period of time such as 3 months, 6 months, or 1 year.
  • prediction of relapse due to a high MCP-1 level may allow for the better tailoring of treatments seeking to prevent that relapse from occurring. For example, in some embodiments where a patient is receiving
  • the patient may be given a further chemotherapy treatment, such as with one or more of cytarabine, daunorubicin, mitoxantrone, etoposide, idarubicin, fludarabine, busulfan, clofarabine, cyclophosphamide, topetecan, an azanucleoside such as 5-azacytidine or decitabine, sapacitabine, or vosaroxin, such as a combination of busulfan and fludarabine (Bu-Flu treatment).
  • a further chemotherapy treatment such as with one or more of cytarabine, daunorubicin, mitoxantrone, etoposide, idarubicin, fludarabine, busulfan, clofarabine, cyclophosphamide, topetecan, an azanucleoside such as 5-azacytidine or decitabine, sapacitabine, or vosaroxin, such as a combination of busulfan and
  • the patient may be given one or more further HCT treatments, such as a further allogenic HCT or an autologous HCT treatment, optionally in addition to further chemotherapy.
  • the patient may also be treated with an MCP-1 inhibitor.
  • the patient may be treated with lenalidomide and/ or a histone deacetylase inhibitor and/ or an antiotensin converting enzyme (ACE) inhibitor.
  • ACE antiotensin converting enzyme
  • the patient may be further treated with a combination of any of the above treatments.
  • treatment regimes may also be modified, for example, by providing an MCP-1 inhibitor such as azacytidine, or by testing for the presence of leukemia cells, such as in a bone marrow biopsy or aspirate at least once following the MCP-1 analysis.
  • an MCP-1 inhibitor such as azacytidine
  • MCP-1 (also known as chemokine (C-C motif) ligand 2 or CCL2) binds to the CCR2 receptor protein in vivo. MCP-1 recruits monophages and mactocytes to sites of inflammation and may be overexpressed in sites of inflammation in diseases such as atherosclerosis, rheumatoid arthritis, and multiple sclerosis. A variety of chemokines including MCP-1 may have altered expression levels in certain tumor cell lines. The present inventor has found, in a study of 42 different chemokines or cytokines, however, that MCP-1 was the only one whose expression levels correlated with risk of relapse in post-HCT AML/MDS patients.
  • the MCP-1 level may be tested in a variety of ways.
  • a patient's bodily fluid such as whole blood, plasma, or serum, may be used for the test.
  • the test may be conducted ex vivo.
  • MCP-1 may be detected in the sample at the protein level, for instance, by using an assay involving an MCP-1 -specific monoclonal antibody and detecting binding of the antibody to MCP-1 in the sample via a label.
  • An exemplary specific antibody assay is an enzyme-linked immunoabsorbent assay (e.g. an ELISA assay).
  • the sample may be immobilized on a plate or substrate and a solution containing a labeled MCP-1 -specific antibody may be added to it, and the sample may then be washed, leaving behind bound MCP-1 /antibody complexes.
  • the label for example a fluorescent or luminescent label, may be attached to the MCP-1 -specific antibody, or to a secondary or tertiary antibody that binds to the MCP-1 specific antibody, or the label may be activated through a chemical reaction that occurs upon binding of a secondary or tertiary antibody.
  • the MCP-1 -specific antibody may be immobilized on a substrate to which the fluid sample is applied. MCP-1 may then be detected by means of a label attached to the bound antibody, such as a luminescent or fluorescent label attached to a second MCP-1 -specific antibody.
  • MCP-1 level can be detected at the messenger RNA level using reverse transcription and polymerase chain reaction amplification using MCP-1 -specific primers.
  • GVHD grade II-IV acute graft versus host disease

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Abstract

La présente invention concerne, inter alia, un procédé de prédiction de rechute de leucémie myéloblastique aiguë (AML) chez un patient précédemment traité pour AML, comprenant l'obtention d'une mesure de protéine chimioattractive monocytaire 1 (MCP-1) dans un échantillon de fluide provenant du patient par comparaison avec le niveau de MCP-1 moyen observé chez une population de patients AMT post-traitement. La présente invention concerne également un procédé de traitement d'AML par la fourniture en outre d'un traitement d'AML au patient si on mesure chez le patient un niveau de MCP-1 au-dessus de celui d'un niveau de MCP-1 moyen observé chez une population de patients AML post-traitement. Selon certains modes de réalisation, le patient souffre d'AML/syndrome myélodysplasique (AML/MDS). La présente invention concerne également un procédé de détermination d'un risque qu'un patient MDS développe l'AML, comprenant la mesure de niveaux de MCP-1 dans un échantillon de fluide du patient ou l'obtention d'une telle mesure, un niveau de MCP-1 au-dessus de celui d'une moyenne de patients MDS indiquant un risque accru de développement d'AML.
PCT/US2014/068791 2013-12-06 2014-12-05 Rôle de mcp-1 dans la rechute de leucémie myéloblastique aiguë après transplantation de cellules souches hématopoïétiques WO2015085171A1 (fr)

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Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9845499B2 (en) 2016-04-04 2017-12-19 Combinati Incorporated Microfluidic siphoning array for nucleic acid quantification
US11951478B2 (en) 2016-04-04 2024-04-09 Combinati Incorporated Microfluidic siphoning array for nucleic acid quantification

Citations (3)

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Publication number Priority date Publication date Assignee Title
US20100119478A1 (en) * 2008-08-20 2010-05-13 Probiodrug Ag ANTIBODIES DIRECTED AGAINST PYROGLUTAMATE MONOCYTE CHEMOATTRACTANT PROTEIN-1 (MCP-1 N1pE)
US20110038856A1 (en) * 2006-11-02 2011-02-17 Seattle Genetics, Inc. Methods of treating neoplastic, autoimmune and inflammatory diseases
US20130230528A1 (en) * 2005-05-18 2013-09-05 Xoma Technology Ltd. Methods for diagnosis and treatment of proliferative disorders mediated by cd40 signaling

Patent Citations (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US20130230528A1 (en) * 2005-05-18 2013-09-05 Xoma Technology Ltd. Methods for diagnosis and treatment of proliferative disorders mediated by cd40 signaling
US20110038856A1 (en) * 2006-11-02 2011-02-17 Seattle Genetics, Inc. Methods of treating neoplastic, autoimmune and inflammatory diseases
US20100119478A1 (en) * 2008-08-20 2010-05-13 Probiodrug Ag ANTIBODIES DIRECTED AGAINST PYROGLUTAMATE MONOCYTE CHEMOATTRACTANT PROTEIN-1 (MCP-1 N1pE)

Cited By (2)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US9845499B2 (en) 2016-04-04 2017-12-19 Combinati Incorporated Microfluidic siphoning array for nucleic acid quantification
US11951478B2 (en) 2016-04-04 2024-04-09 Combinati Incorporated Microfluidic siphoning array for nucleic acid quantification

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