Single-agent lenalidomide induces complete remission of acute myeloid leukemia in patients with isolated trisomy 13

Abstract Patients with acute myeloid leukemia (AML) frequently fail chemotherapy due to refractory disease, relapse, or toxicity. Among older AML patients (age > 60 years), there are few long-term survivors. Lenalidomide is a candidate for study in AML based on its clinical activity in a related disorder, myelodysplastic syndrome (MDS), with the 5q− chromosomal abnormality. We report induction of sustained morphologic and cytogenetic complete remission in 2 older AML patients treated with high-dose, single-agent lenalidomide; each patient had trisomy 13 as the sole cytogenetic abnormality. We show for the first time that lenalidomide has clinical activity in this poor-risk cytogenetic subset of AML. The clinical trials described in this paper have been registered with www.clinicaltrials.gov under identifiers NCT00466895 and NCT00546897.

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Granulocyte Colony-Stimulating Factor (Filgrastim) Accelerates Granulocyte Recovery After Intensive Postremission Chemotherapy for Acute Myeloid Leukemia With Aziridinyl Benzoquinone and Mitoxantrone: Cancer and Leukemia Group B Study 9022

Blood ◽

10.1182/blood.v89.3.780 ◽

1997 ◽

Vol 89 (3) ◽

pp. 780-788 ◽

Cited By ~ 76

Author(s):

Joseph O. Moore ◽

Richard K. Dodge ◽

Philip C. Amrein ◽

Jonathan Kolitz ◽

Edward J. Lee ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Complete Remission ◽

Myeloid Leukemia ◽

High Dose ◽

Granulocyte Colony Stimulating Factor ◽

Colony Stimulating Factor ◽

Duration Of Hospitalization ◽

Group B ◽

Stimulating Factor ◽

Acute Myeloid

Abstract This study evaluated the effect of filgrastim (granulocyte colony-stimulating factor [G-CSF]) on the duration of granulocytopenia and thrombocytopenia after intensive consolidation therapy with diaziquone (AZQ) and mitroxantrone for patients less than 60 years of age with acute myeloid leukemia (AML) in complete remission. Patients less than 60 years of age with AML who achieved complete remission (CR) with daunorubicin and cytarabine induction therapy, were scheduled to receive three sequential courses of high-dose cytarabine, cyclophosphamide/etoposide, AZQ, and mitroxantrone in a pilot study to determine their tolerance of these three sequential consolidation regimens. The initial patients treated with AZQ and mitoxantrone experienced prolonged bone marrow suppression and, therefore, subsequent cohorts were treated with G-CSF, 5 μg/kg, beginning the day after completion of the third cycle of chemotherapy. There was a marked decrease in the duration of granulocytopenia less than 500/μL in two groups of patients receiving two different dose levels of AZQ and the same dose of mitoxantrone compared with patients not receiving the G-CSF. There was also a decrease in the need for hospitalization, as well as the duration of hospitalization. There was a trend towards shortening of the duration of thrombocytopenia, as well. The duration of complete remission and overall survival was similar in patients who received or did not receive G-CSF. G-CSF markedly shortened the duration of granulocytopenia in patients with AML receiving intensive postremission consolidation with AZQ and mitoxantrone. There was no adverse effect on CR duration or survival.

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A phase 1 study of azacitidine with high-dose cytarabine and mitoxantrone in high-risk acute myeloid leukemia

Blood Advances ◽

10.1182/bloodadvances.2019000795 ◽

2020 ◽

Vol 4 (4) ◽

pp. 599-606 ◽

Cited By ~ 1

Author(s):

Kirk E. Cahill ◽

Yasmin H. Karimi ◽

Theodore G. Karrison ◽

Nitin Jain ◽

Margaret Green ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

High Risk ◽

Complete Remission ◽

Myeloid Leukemia ◽

Phase 1 ◽

High Dose ◽

Phase 2 ◽

Phase 1 Study ◽

High Dose Cytarabine ◽

Acute Myeloid

Abstract In this phase 1 study, azacitidine (AZA) was given before high-dose cytarabine (HiDAC) and mitoxantrone (mito) based on the hypothesis that epigenetic priming with a hypomethylating agent before cytotoxic chemotherapy would improve response rates in patients with high-risk acute myeloid leukemia (AML), including relapsed/refractory disease. The primary objective was to establish the recommended phase 2 dose of AZA given before standard HiDAC/mito. In a dose escalation scheme, 46 patients (median age, 66 years) received AZA at 37.5, 50, or 75 mg/m2 subcutaneously or IV once daily on days 1 to 5 followed by HiDAC (3000 mg/m2) and mitoxantrone (30 mg/m2) once each on days 6 and 10 (the HiDAC/mito dose was reduced 33% in elderly subjects). Two dose-limiting toxicities occurred (both in the same patient): acute liver failure and kidney injury at the 50 mg/m2 dose. The 30-day induction death rate was 2.2% (1 of 46). The overall response rate, including complete remission and complete remission with incomplete count recovery, was 61% (28 of 46). Previously untreated patients aged ≥60 years with therapy-related AML and de novo AML were more likely to respond than untreated patients with AML progressing from an antecedent hematologic disorder (myelodysplastic syndrome and chronic myelomonocytic leukemia). Patients with favorable European Leukemia Network risk (P = .008), NPM1 mutations (P = .007), or IDH2 mutations (P = .03) were more likely to respond, and those with TP53 mutations (P = .03) were less likely to respond. The recommended phase 2 dose of AZA is 75 mg/m2 per day on days 1 to 5 followed by HiDAC (3000 mg/m2) and mitoxantrone (30 mg/m2) once each on days 6 and 10. This trial was registered at www.clinicaltrials.gov as #NCT01839240.

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High-dose cytosine arabinoside and mitoxantrone: a highly effective regimen in refractory acute myeloid leukemia

Blood ◽

10.1182/blood.v69.3.744.744 ◽

1987 ◽

Vol 69 (3) ◽

pp. 744-749 ◽

Cited By ~ 141

Author(s):

W Hiddemann ◽

H Kreutzmann ◽

K Straif ◽

WD Ludwig ◽

R Mertelsmann ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Complete Remission ◽

Cytosine Arabinoside ◽

Myeloid Leukemia ◽

High Dose ◽

Antileukemic Activity ◽

First Line ◽

Clinical Phase ◽

Refractory Acute Myeloid Leukemia ◽

Acute Myeloid

Abstract In a clinical phase I/II study, high-dose cytosine arabinoside and mitoxantrone (HAM) were given in combination to 40 patients with refractory acute myeloid leukemia. All patients had received a 9-day combination of thioguanine, Ara-C, and daunorubicin (TAD-9) as standardized first-line treatment. Refractoriness was defined as (a) nonresponse against two TAD-9 induction cycles, (b) early relapse within the first 6 months on monthly maintenance or after TAD-9 consolidation, (c) relapse after 6 months with nonresponse against one additional TAD-9 cycle, and (d) second and subsequent relapses after successful TAD-9 therapy at the preceding relapse. Therapy consisted of HD-Ara-C 3 g/m2 every 12 hours on days 1 through 4; mitoxantrone was started at 12 mg/m2/day on days 3, 4, and 5 and was escalated to 4 and 5 doses of 10 mg/m2/day on days 2 through 5 and 2 through 6. Of the 40 patients, 21 achieved a complete remission (53%), 1 patient had a partial remission, and 5 patients were nonresponders. Thirteen patients died in aplasia due to infections (n = 11), pericardiac effusion, or acute cardiomyopathy. Nonhematologic side effects consisted predominantly of nausea and vomiting, mucositis, and diarrhea. Central nervous system (CNS) symptoms were observed during six treatment courses. Recovery of blood counts occurred at a median of 27 days from the onset of treatment; the median time to complete remission was 36 days. Two of the 21 responders underwent successful bone marrow transplantations. The median remission duration for the remaining 19 patients is 4.5 months, and the median survival time is 9 months. These data emphasize that HAM has high antileukemic activity in refractory AML and strongly suggest starting the combination at earlier stages in AML therapy.

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Randomized Study of Decitabine Versus Observation or Continued Cytotoxic Chemotherapy in Patients with Intermediate and Poor Risk Acute Myeloid Leukemia in First or Subsequent Complete Remission.

Blood ◽

10.1182/blood.v110.11.2859.2859 ◽

2007 ◽

Vol 110 (11) ◽

pp. 2859-2859 ◽

Cited By ~ 1

Author(s):

Farhad Ravandi ◽

Jean-Pierre Issa ◽

Stefan Faderl ◽

Guillermo Garcia-Manero ◽

Mary Hood ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Complete Remission ◽

Clin Oncol ◽

Myeloid Leukemia ◽

Cytotoxic Chemotherapy ◽

Cytotoxic Agents ◽

High Dose ◽

Poor Risk ◽

Grade 3 ◽

Acute Myeloid

Abstract The role of maintenance therapy in acute myeloid leukemia (AML) remains unclear. Continued therapy with cytotoxic agents similar to those used for induction and consolidation is associated with toxicity but can improve disease free survival (DFS). (Buchner T, J Clin Oncol. 2006;24:2480 and Lowenberg B, J Clin Oncol. 1998;16:872) Immune modulation in this setting may also be effective in prolonging DFS.(Brune M, Blood2006;108:88). Methylation status of tumor suppressor genes in clinical remission predicts the relapse risk in AML with earlier relapse in patients with increased DNA promotor methylation.(Agrawal S, Cancer Res. 2007;67:1370) Therefore, hypomethylating therapy may be effective in maintaining remission and prolonging survival in these patients. We are conducting a clinical trial comparing decitabine to cytotoxic chemotherapy or observation in patients with AML in their first or subsequent complete remission (CR). Patients with non-favorable risk AML (including intermediate and poor risk) receive induction therapy with idarubicin and high dose cytarabine followed by at least 2 cycles of cytarabine based consolidation. They are then stratified by age (≤ 60 vs. > 60) and cytogenetics (intermediate vs. poor risk) and randomized to receive decitabine 20 mg/m2 IV daily × 5 every 4 to 8 weeks for 12 cycles, or to continue chemotherapy/observation. Patients in > first CR are randomized after completion of salvage therapy. Serial samples for methylation studies and determination of minimal residual disease by flow cytometry are collected. To date, 19 (8 M, 11 F) patients with AML (including 14 in first CR and 5 in subsequent CR) have been enrolled onto the study. Median age of the patients is 56 years (range 31 – 74). Fourteen patients are ≤ 60 years. Cytogenetics at diagnosis was intermediate in 10 patients, poor-risk in 8 patients, and favorable [inv(16)] in one relapsed patient. Eight patients were randomized to decitabine and have received a median of 3 cycles (range 1 – 6). Eleven patients were randomized to observation/continued therapy and all, except 2 patients, have received further cytarabine based therapy after consolidation. With a median duration of follow up for the entire group of 5 months (range 1 – 9), 7/8 patients on the decitabine arm and 9/11 patients on the other arm have remained in remission. Toxicity in the decitabine treated patients was limited to 4 episodes of grade 3 neutropenia, 2 episode of grade 3 thrombocytopenia, and 1 episodes of grade 3 anemia. All of these cytopenias were short in duration and reversed without any associated adverse events. We conclude that administration of decitabine in CR at the above schedule/dose is safe and well tolerated.

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Phase II Study of High Dose Lenalidomide as Initial Treatment for Older Acute Myeloid Leukemia Patients: Early Results Show a Significant Reduction of Bone Marrow Blasts after 14 Days of Therapy.

Blood ◽

10.1182/blood.v110.11.916.916 ◽

2007 ◽

Vol 110 (11) ◽

pp. 916-916 ◽

Cited By ~ 3

Author(s):

Todd A. Fehniger ◽

Alissa Nelson ◽

Kathryn Trinkaus ◽

Camille N. Abboud ◽

Amanda F. Cashen ◽

...

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Phase Ii ◽

Myeloid Leukemia ◽

Phase Ii Study ◽

Active Agent ◽

Trisomy 13 ◽

High Dose ◽

Days Of Therapy ◽

Acute Myeloid

Abstract AML patients over the age of 60 years have a poor prognosis, share disease characteristics with myelodysplastic syndrome (MDS) patients, and warrant novel therapeutic approaches. Lenalidomide has immunomodulatory and anti-neoplastic properties which can induce morphologic and cytogenetic responses in MDS patients, including those with excess blasts. We hypothesized that lenalidomide may be active against AML, and have employed a high dose strategy without dose reductions for hematologic toxicities. Here, we report preliminary results from a phase II study of high dose lenalidomide for front-line treatment of AML ≥ 60 without chromosome 5q deletion or favorable cytogenetics. Treatment included 2 cycles of high dose lenalidomide (50mg/day x 14 days, 30 days of rest, 50mg/day x 21 days), followed by maintenance therapy (10 mg/day) in non-progressing patients. Fifteen patients were enrolled in the first stage between 2/27/07 and 8/3/07. Median age was 71 years (range 60–86 years); ECOG performance status was 0 (4/15, 27%), 1 (10/15, 67%), or 2 (1/15, 7%); 11/15 (73%) patients were male; and 5/15 (33%) patients had prior MDS. Cytogenetics were normal (n=9), loss of chromosome 7 (n=2), loss of chromosome 20 (n=1), trisomy 13 (n=1), or complex (n=2). Overall, the treatment regimen was well tolerated. In the first stage of the study, 12/15 patients are evaluable for day 15 bone marrow and peripheral blood blast changes following the initial high dose lenalidomide cycle (50 mg/day x 14 days). Pre-therapy WBC counts (mean ± SEM) were 13,825 ± 4,447/uL (range 1,100–45,300/uL) and day 15 WBC counts were 4,742 ± 2,136/uL (range 300–24,400/uL). Day 15 bone marrow myeloblast percentages were significantly reduced in 9/12 patients (mean ± SEM decrease of 53 ± 10%, P=0.01, range 18–100%). In addition, the bone marrow blast index (% cellularity x fraction of blasts) decreased significantly after 14 days of high dose lenalidomide (mean ± SEM reduction of 66 ± 11%, P=0.02). Moreover, 5/8 patients with circulating blasts at diagnosis showed clearance of their peripheral blasts at day 15. These findings suggest that lenalidomide is an active agent against acute myeloid leukemia. Results on AML blast changes, response by international working group criteria, and toxicities in this patient cohort with ≥4 months of follow-up will be updated and presented.

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Phase I Study of Lenalidomide in Acute Leukemia: Remissions in Post-Allogeneic Relapse of Acute Myeloid Leukemia.

Blood ◽

10.1182/blood.v114.22.841.841 ◽

2009 ◽

Vol 114 (22) ◽

pp. 841-841 ◽

Cited By ~ 2

Author(s):

Jason C. Chandler ◽

Rebecca B. Klisovic ◽

Mitch A. Phelps ◽

Alison Walker ◽

Ramiro Garzon ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Acute Leukemia ◽

Phase I ◽

Dose Escalation ◽

Myeloid Leukemia ◽

Single Agent ◽

Allogeneic Transplantation ◽

Initial Therapy ◽

Trisomy 13 ◽

Acute Myeloid

Abstract Abstract 841 Lenalidomide is effective in myeloma and low-risk myelodysplastic syndromes (MDS), especially MDS with the 5q- cytogenetic abnormality, and may also have activity in acute leukemia. We designed a phase I dose escalation trial of lenalidomide in adults with relapsed or refractory acute leukemia to determine the maximum tolerable dose (MTD) and dose limiting toxicity (DLT), as well as to provide preliminary efficacy data in this setting. 35 adults with acute leukemia were enrolled: 31 with acute myeloid leukemia (AML) and 4 with acute lymphoblastic leukemia (ALL). Patients had a median age of 63 years (range, 22-79) and had received a median of 2 prior therapies (range, 1-4). 8 patients had relapsed after transplantation (7-allogeneic, 1-autologous). Patients were treated orally with lenalidomide on days 1-21 of 28 day cycles at the following dose levels: 25mg/day (N=4), 35mg/day (N=9), 50mg/day (N=19, including the expansion at the MTD), and 75mg/day (N=3). Patients were eligible to receive additional cycles of treatment beyond cycle 1 in the absence of disease progression defined as 25% increase in blasts relative to pretreatment. The median number of cycles received was 1 (range, 1-7). DLTs were assessed during cycle 1 of therapy. DLTs were sudden death (N=1, autopsy ruled out pulmonary embolism), rash (N=1), line-associated thrombosis (N=1), and fatigue (N=3). Grade 3 fatigue occurred in two patients at 75mg/day; 50mg/day was thus declared the recommended phase 2 dose and 10 additional patients were treated at this dose. The major toxicities associated with treatment were drug and disease associated myelosuppression and infection, as expected; these did not constitute DLT. In spite of concerns that higher dose lenalidomide would be associated with increased risk of thromboembolism, this toxicity was infrequent, even during multiple cycles of therapy. Two events occurred; both were line associated, and neither was life-threatening. Detailed pharmacokinetic results for the dose escalation cohorts in the trial are listed in the table below. Maximum plasma lenalidomide concentrations and area under the concentration-time curve (AUC) increased proportionally with dose. Drug clearance was independent of dose and correlated with calculated creatinine clearance. Of 31 patients with AML there were 5 complete responses (CR) (by IWG criteria for AML; Cheson, JCO 2003). 3/3 with cytogenetically abnormal AML achieved cytogenetic CR (cCR) as well. Achievement of CR was delayed beyond 2 months from initiation of therapy in each case. The duration of CR was 2.4-8.8 months, with two responders still in CR at 2.4+ and 4.7+ months, respectively. At 25mg, a 74 year old with AML in 2nd relapse with widespread leukemia cutis but no blood/marrow involvement had resolution of disease after 2 cycles. At 35mg, a 69 year old with AML and trisomy 13 achieved cCR after 2 cycles. At 50mg, there were three CRs, including two patients who received lenalidomide as initial therapy for relapsed AML following allogeneic stem cell transplant. In both of these cases, lenalidomide therapy was associated with the onset of skin rash requiring temporary discontinuation of drug; CR was achieved after 2 to 3 cycles of therapy and was preceded by cytogenetic remission before count recovery occurred. A third CR at the 50mg level occurred in a 70 year old with AML who had lenalidomide discontinued after 2 cycles due to no apparent response. Subsequently, CR was achieved 1 month later with no intervening therapy. In conclusion, single agent lenalidomide induced CR in 16% (5/31) of relapsed/ refractory AML patients. None of the responders had 5q-. The DLT was fatigue; the MTD was 50mg daily for days 1-21. Achievement of CR without donor leucocyte infusion in 2/4 patients who received lenalidomide as initial therapy for AML relapse following allogeneic transplantation suggests a possible allogeneic immunomodulatory effect. We are now developing a CTEP-sponsored study of lenalidomide as maintenance following allogeneic transplantation for AML. The promising single agent efficacy reported here supports further study of lenalidomide in combination with other agents in high risk AML. Disclosures: Blum: Celgene: Research Funding.

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Practically All Patients with Acute Myeloid Leukemia (AML) in Continuous Complete Remission for 3 Years or More Are Cured of Their Disease: The ECOG Experience

Blood ◽

10.1182/blood.v120.21.132.132 ◽

2012 ◽

Vol 120 (21) ◽

pp. 132-132

Author(s):

Justin M Watts ◽

Lynette Zickl ◽

Mark R Litzow ◽

Selina M Luger ◽

Hillard M Lazarus ◽

...

Keyword(s):

Clinical Trials ◽

Acute Myeloid Leukemia ◽

Complete Remission ◽

Myeloid Leukemia ◽

Late Relapse ◽

Published Data ◽

High Dose ◽

Acute Myeloid

Abstract Abstract 132 Late relapse in acute myeloid leukemia (AML) has been infrequently studied and variably defined in the literature. Two series have shown that late relapse of AML ≥5 years after first complete remission (CR1) is uncommon, with rates of 1.19–3% (Medeiros et al, Leuk Lymphoma 2007; Verma et al, Leuk Lymphoma 2010). We searched the long-term data available on 784 adults (<60 years-old) who were treated on 1 of 4 ECOG clinical trials (E3483, PC486, E3489, or E1900) and achieved CR1 for reports of late relapse (defined as recurrence of AML ≥3 years after CR1). Median follow-up for the 553 patients last known alive was 11.1 years. The longest median follow-up was 17.2 years on trial PC486. Outcomes We found that 11 patients (1.4%) relapsed late; of these, 2 were treated on E3483, 1 on PC486, 5 on E3489, and 3 on E1900. Seven patients with late relapse died from their disease and 4 were living at last known follow-up. Only 1 patient (0.13%) had recurrence of AML ≥5 years after achieving CR1. It is possible that more late relapses will occur on E1900 (a more recent study with ongoing follow-up). All of these trials except E3483 treated some patients with autologous hematopoietic cell transplantation (autoHCT) as part of post remission therapy. On PC486, no post remission consolidation chemotherapy was administered before autoHCT. Ninety-eight total patients on E3489 and PC486 received autoHCT, and there were no late relapses; on E1900, 2 of the 141 patients treated with autoHCT developed late relapse. No patients who underwent allogeneic (allo) HCT in CR1 experienced late relapse on any of the 4 clinical trials. Nine of the 11 patients with late relapse did not undergo HCT; of these, 5 were consolidated with high-dose cytarabine, 2 received maintenance with low-dose cytarabine and 6-thioguanine, and 2 received unknown post remission therapy. Of the 3 patients with late relapse on E1900, 2 received standard-dose and 1 high-dose daunorubicin with induction. Conclusions Across all 4 trials, only 2 of the 239 patients (0.8%) treated with post remission autoHCT experienced late relapse of AML (≥3 years after CR1), which reinforces previously published data that late relapse after autoHCT is uncommon (Cassileth et al, J Clin Oncol 1993). Furthermore, of the 35 patients treated with autoHCT on PC486, 11 relapsed early and no patients relapsed late, suggesting that post remission chemotherapy may not be necessary before autoHCT. Based on this large AML cohort of nearly 800 patients with long-term follow-up, patients who remain in CCR for at least 3 years have a very low risk of relapse and can be considered cured of their disease. Moreover, given that recurrent AML was extremely rare after 5 years or more of CCR (<0.2%), the risk of therapy-related AML from contemporary induction and post remission strategies including HCT appears to be minimal. Disclosures: No relevant conflicts of interest to declare.

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Randomized study of induction therapy comparing standard-dose idarubicin with high-dose daunorubicin in adult patients with previously untreated acute myeloid leukemia: the JALSG AML201 Study

Blood ◽

10.1182/blood-2010-03-273243 ◽

2011 ◽

Vol 117 (8) ◽

pp. 2358-2365 ◽

Cited By ~ 147

Author(s):

Shigeki Ohtake ◽

Shuichi Miyawaki ◽

Hiroyuki Fujita ◽

Hitoshi Kiyoi ◽

Katsuji Shinagawa ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Complete Remission ◽

Induction Therapy ◽

Myeloid Leukemia ◽

Standard Dose ◽

Randomized Study ◽

Survival Rates ◽

Adult Patients ◽

High Dose ◽

Acute Myeloid

Abstract We conducted a multi-institutional randomized study to determine whether high-dose daunorubicin would be as effective as standard-dose idarubicin in remission-induction therapy for newly diagnosed adult patients younger than 65 years of age with acute myeloid leukemia. Of 1064 patients registered, 1057 were evaluable. They were randomly assigned to receive either daunorubicin (50 mg/m2 daily for 5 days) or idarubicin (12 mg/m2 daily for 3 days) in combination with 100 mg/m2 of cytarabine by continuous infusion daily for 7 days as induction therapy. Complete remission was achieved in 407 (77.5%) of 525 patients in the daunorubicin group and 416 (78.2%) of 532 in the idarubicin group (P = .79). Patients achieving complete remission received intensive postremission therapy that consisted of either 3 courses of high-dose cytarabine or 4 courses of standard-dose therapy. Overall survival rates at 5 years were 48% for the daunorubicin group and 48% for the idarubicin group (P = .54), and relapse-free survival rates at 5 years were 41% and 41% (P = .97), respectively. Thus, high-dose daunorubicin and standard-dose idarubicin were equally effective for the treatment of adult acute myeloid leukemia, achieving a high rate of complete remission and good long-term efficacy. This study is registered at http://www.umin.ac.jp/ctrj/ as C000000157.

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New Allosteric Inhibitors of Mutant IDH1 in Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v126.23.787.787 ◽

2015 ◽

Vol 126 (23) ◽

pp. 787-787

Author(s):

Ujunwa Cynthia Okoye-Okafor ◽

Boris Bartholdy ◽

Jessy Cartier ◽

Enoch Gao ◽

Beth Pietrak ◽

...

Keyword(s):

Cell Death ◽

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Cellular Growth ◽

Driver Mutations ◽

Clinical Activity ◽

High Dose ◽

Allosteric Inhibitors ◽

Mutant Idh1 ◽

Acute Myeloid

Abstract Mutations in the isocitrate dehydrogenase 1 (IDH1) gene are known driver mutations in acute myeloid leukemia (AML) and other cancer types. Patient outcomes in AML have remained poor, especially for patients above 60 years of age who typically do not tolerate high dose chemotherapy and stem cell transplantation, leading to cure rates below 20%. The development of novel targeted therapies for defined AML subtypes is urgently desired. Inhibitors of mutants of the closely related IDH2 gene as well as IDH1 have recently been described and show promising pre-clinical and early phase clinical activity. However, the specific molecular and functional effects of IDH1 inhibitors in AML, including in primary patients' cells, have not been reported yet. Here, we report the development of novel allosteric inhibitors of mutant IDH1 for differentiation therapy of acute myeloid leukemia. A high-throughput biochemical screen targeting an IDH1 heterodimer composed of R132H and WT IDH1 led to the identification of a tetrahydropyrazolopyridine series of inhibitors. Structural and biochemical analyses revealed that these novel compounds bind to an allosteric site that does not contact any of the mutant residues in the enzymes active site and inhibit enzymatic turnover. The enzyme complex locked in the catalytically inactive conformation inhibits the production of the oncometabolite 2-hydroxyglutarate (2-HG). In biochemical studies, we observed potent inhibition of several different clinically relevant R132 mutants in the presence or absence of the cofactor NADPH, accompanied by significant decrease in H3K9me2 levels. Allosteric inhibitor treatment of primary AML patients' cells with different clinically relevant R132 mutants of IDH1 ex vivo uniformly led to a decrease in intracellular 2-HG, abrogation of the myeloid differentiation block, increased cell death and induction of differentiation both at the level of leukemic blasts and immature stem-like cells. Allosteric inhibition of IDH1 also led to a decrease in blasts in an in vivo xenotransplantation model. At the molecular level, enhanced reduced representation bisulfite sequencing showed that treatment with allosteric IDH1 inhibitors led to a significant reversal of the DNA cytosine hypermethylation pattern induced by mutant IDH1, accompanied by gene expression changes of key sets of genes and pathways, including "Cell Cycle", "G1/S transition", "Cellular growth and proliferation", and "Cell death and survival". Taken together, our findings provide novel insight into the cellular and molecular effects of inhibition of mutant IDH1 in primary AML patients' cells. Furthermore, our study provides proof-of-concept for the molecular and biological activity of novel allosteric inhibitors for targeting of different mutant forms of IDH1 in leukemia, and opens new avenues for future investigations with these and other allosteric inhibitors for targeting mutant IDH1 in leukemia and other cancers. Disclosures Gao: GlaxoSmithKline: Employment. Pietrak:GlaxoSmithKline: Employment. Rendina:GlaxoSmithKline: Employment. Rominger:GlaxoSmithKline: Employment. Quinn:GlaxoSmithKline: Employment. Smallwood:GlaxoSmithKline: Employment. Wiggall:GlaxoSmithKline: Employment. Reif:GlaxoSmithKline: Employment. Schmidt:GlaxoSmithKline: Employment. Qi:GlaxoSmithKline: Employment. Zhao:GlaxoSmithKline: Employment. Joberty:GlaxoSmithKline: Employment. Faelth-Savitski:GlaxoSmithKline: Employment. Bantscheff:GlaxoSmithKline: Employment. Drewes:GlaxoSmithKline: Employment. Duraiswami:GlaxoSmithKline: Employment. Brady:GlaxoSmithKline: Employment. Concha:GlaxoSmithKline: Employment. Adams:GlaxoSmithKline: Employment. Schwartz:GlaxoSmithKline: Employment. McCabe:GlaxoSmithKline: Employment.

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Treatment with JNJ-26483327 (Pan Her/Src/VEGFR-3 kinase inhibitor) Prolongs Survival of Mice Engrafted with Systemic Human Acute Myeloid Leukemia

Blood ◽

10.1182/blood.v112.11.4026.4026 ◽

2008 ◽

Vol 112 (11) ◽

pp. 4026-4026

Author(s):

Nathaniel C. Doro ◽

Deepika Lal ◽

Peter King ◽

Eddy Freyne ◽

Tim Perera ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Low Dose ◽

Single Agent ◽

Antibody Therapy ◽

Tumor Burden ◽

High Dose ◽

Human Acute Myeloid Leukemia ◽

Acute Myeloid ◽

Daily Total

Abstract JNJ-26483327 is a novel oral Pan Her/Src/VEGFR-3 inhibitor which has previously been shown in preclinical models to cross the blood-brain barrier and to reach high levels in brain, solid tumor, and bone marrow sites. JNJ-26483327 is not an active substrate for P-glycoprotein pumps and has been well tolerated to date in an ongoing phase I trial. VEGF-C signaling through the VEGFR-3 (FLT-4) receptor has been shown to promote growth of acute myeloid leukemia (AML) cells and to mediate resistance to multiple chemotherapy drugs in vitro. Anti-VEGFR-3 antibody therapy decreased angiogenesis, increased hypoxia and necrosis, and reduced lymph node metastases in solid tumor xenografts. To date, however, VEGF-C/VEGFR-3 inhibition has not been actively been investigated for treatment of hematological malignancies. We hypothesized that JNJ- 26483327 treatment of VEGFR-3 expressing systemic AML would limit tumor growth and lymphatic spread via VEGF-C/VEGFR-3 mechanisms. An initial dose-finding pilot experiment was performed using SCID mice engrafted via tail vein with ten million HELluc cells, human acute myeloid leukemia cells with known expression of VEGF-A/C and VEGFR-2/3 and stably transfected with luciferase constructs to facilitate small animal imaging. Mice were treated with PBS, vehicle (200 mL by mouth twice daily), low dose JNJ-26483327 (75 mg/kg by mouth twice daily, total 150 mg/kg/day) and high dose JNJ- 26483327 (125 mg/kg by mouth daily, total 250 mg/kg/day) for 10 consecutive days. We found that low dose JNJ-26483327 therapy significantly improved the median survival of HELluc systemic xenografts by 46% (26 days longer than vehicle-treated controls) (p<0.05). Although high dose JNJ-26483327 prolonged median survival over vehicletreated controls, the difference was not statistically significant. Moreover, although JNJ- 26483327 improved survival, HELluc leukemia burden (as measured by bioluminescent imaging) was not significantly reduced or eradicated as compared to control, consistent with cytostatic but not cytotoxic anti-tumor effects. VEGFR-3 signaling has also been shown to mediate leukemia cell proliferation, survival, and resistance to chemotherapy. Based on preclinical and clinical data demonstrating improved anti-tumor activity of VEGF inhibitors when combined with chemotherapy, we hypothesized that combining JNJ-26483327 with chemotherapy used in conventional AML therapy may result in additive synergistic anti-tumor effects. To determine if JNJ-26483327 inhibition enhanced the effects of cytotoxic chemotherapy, systemic HELluc tumor bearing mice were treated with low dose JNJ-26483327 (150 mg/kg/day for 10 days) and a single maximally tolerated dose of doxorubicin (1.5mg/kg). Both single agent doxorubicin and single agent JNJ-26483327 treatment resulted in significant reduction of HELluc tumor burden. However, no significant decrease in leukemia burden was observed after combination JNJ-26483327+doxorubicin treatment when compared to single agent groups. Lastly we postulated that combination therapies of JNJ-26483327 with other anti-VEGF therapies directed at inhibition of VEGF-A, VEGFR-1, or VEGFR-2 would result in inhibition of all known VEGFR signaling pathways and result in improved anti-leukemic effects of JNJ-26483327 therapy. Systemic HELluc bearing mice were treated with PBS, vehicle, low dose JNJ-26483327, an anti-hVEGF-A antibody BV (bevacizumab, Genentech) or combination JNJ-26483327+ BV. Results showed that single agent low dose JNJ- 26483327 or single agent BV significantly reduced HELluc tumor burden up until day 20. Combination JNJ-26483327+BV treatment, however, did not result in additive/synergistic anti-leukemic effects as compared to single agent therapy and may in fact have resulted in possible antagonistic effects. Conclusions: Single agent JNJ-26483327 therapy prolongs survival of mice engrafted with VEGFR-3+ HEL AML cells. Limitations of the above studies include the short duration of JNJ-26483327 administration (10 days only) and lack of synergistic effects of JNJ-26483327 when combined with doxorubicin and anti-hVEGF-A antibody therapy. Future studies will address the effects of long-term JNJ-26483327 administration on AML stem cell growth using NOD/SCID mouse models engrafted with patient samples and combination JNJ-26483327+ cytarabine/anthracycline chemotherapy.

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