A Phase I Combination Study of Ribavirin and Low Dose Cytarabine Arabinoside (ara-C) in M4/M5 Acute Myeloid Leukemia (AML) and AML with High eIF4E,

Abstract Abstract 3606 The conventional therapy for acute myeloid leukemia (AML), including cytarabine and an anthracycline with or without transplant, results in a durable remission in only a minority of AML patients. Furthermore, half of all newly diagnosed AML patients are over the age of 65, and many are poor candidates for high dose chemotherapy due to comorbidities and poor performance status. Thus, new effective treatment strategies are needed. Overexpression of the eukaryotic translation initiation factor 4E (eIF4E) occurs in greater than 30% of all cancers including M4 and M5 subtypes of AML. eIF4E is an oncogene that selectively regulates expression post-transcriptionally, both at the levels of mRNA translation and export, for genes that are critical for cell division, growth and angiogenesis. Novel strategies to target eIF4E are entering clinical development and have shown some promising activity in cancer. We have identified ribavirin as an inhibitor of eIF4E with anti-cancer activity in patients with AML. Ribavirin is a well-characterized and well-tolerated anti-viral drug. We have shown that it inhibits oncogenic transformation mediated by overexpression of eIF4E and reduces clonogenic potential of cancer cells with elevated levels of eIF4E. Our phase II proof-of-principle clinical trial examining the efficacy of ribavirin treatment in elderly or relapsed M4 and M5 AML patients was the first clinical study to target eIF4E in human malignancy, and demonstrated that ribavirin effectively targets eIF4E in patients, leading to clinical improvement. Unfortunately, all patients who achieved a response acquired resistance and relapsed shortly thereafter. We have found that ara-C and ribavirin have an additive effect on primary leukemia specimens in vitro. Hence, a Phase I trial was commenced combining low dose ara-C with ribavirin in AML patients. The primary objective of the trial was to determine the maximum tolerated dose and recommended phase II dose of ribavirin and low dose ara-C. Additional objectives were to determine safety and to examine molecular correlates and the pharmacokinetic/pharmacodynamic profile of the combination treatment. A total of 17 patients were enrolled on study and evaluated for safety. No dose limiting toxicities have been observed to date. The current dose being tested is 4400 mg/day of ribavirin and ara-C 20 mg subcutaneous twice a day for 10 days and dose escalation continues. We have observed that ribavirin plasma levels are substantially lower than obtained in the monotherapy trial. In addition, of the 12 patients who completed at least one cycle of therapy, we have seen one complete response (CR), 2 blasts responses, and one stable disease. The patient with CR had treatment-related AML due to breast cancer therapy and had relapsed shortly after an allogeneic stem cell transplantation. She achieved a CR after 5 cycles of low dose ara-C and ribavirin. After 6 cycles, the patient was put on maintenance ribavirin monotherapy and continues to be in remission after 16 cycles. Interestingly, in this patient, toxicities due to ara-C led to its dose reduction that correlated with a near doubling of plasma ribavirin levels prior to achieving remission, suggesting that ara-C may alter absorption of ribavirin. A full molecular response was observed in patients with clinical response and none in patients that did not respond, indicating that ribavirin levels were sufficient to affect eIF4E localization and levels. Further safety, pharmacokinetic, pharmacodynamic, and response data will be presented. Disclosures: Off Label Use: Use of investigational agent Ribavirin for the treatment of AML. Bergeron:Celgene: Research Funding; Merck: Research Funding; Roche: Honoraria.

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Early Results Of a Phase I/II Trial Of Midostaurin (PKC412) and 5-Azacytidine (5-AZA) For Patients (Pts) With Acute Myeloid Leukemia and Myelodysplastic Syndrome

Blood ◽

10.1182/blood.v122.21.3949.3949 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3949-3949

Author(s):

Paolo Strati ◽

Hagop M Kantarjian ◽

Aziz Nazha ◽

Gautam Borthakur ◽

Naval G. Daver ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myelodysplastic Syndrome ◽

Phase I ◽

Phase Ii ◽

Myeloid Leukemia ◽

Research Funding ◽

Flt3 Mutations ◽

Flt3 Inhibitors ◽

Grade 3 ◽

Acute Myeloid

Abstract Background Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS) affect primarily elderly pts. Their treatment with aggressive chemotherapy is frequently challenging. Moreover, pts with FLT3 mutations have very poor prognosis. We hypothesized that the combination of midostaurin, a FLT3 inhibitor, and 5-AZA, a hypomethylating agent, may be an effective and safe regimen. Methods Both untreated (8) and previously treated (36) pts with AML or MDS were eligible for this study, regardless of FLT3 mutation and prior exposure to FLT3 inhibitors. Pts received 5-AZA 75 mg/mq subcutaneously or intravenously on day 1-7 and midostaurin 25 mg bid (in cohort 1 of phase I) or 50 mg bid (in cohort 2 of Phase I and in Phase II) orally on day 8-21 during the first cycle and continuously thereafter, for 12 cycles of 28 days duration. Cytogenetic risk was defined according to MRC criteria. Differences between categorical variables were compared by the chi2 test. CR duration (CRD) was calculated from the time of CR achievement until relapse and estimated by the Kaplan-Meier method and compared by the log-rank test. Results Fourty-four pts were enrolled, 13 included in Phase I and 31 in Phase II. Baseline pts’ characteristics are shown in the Table. Thirty-eight pts (86%) received 50 mg bid of midostaurin, and 6 (14%; Phase I) received 25 mg bid. The median number of administered cycles was 2 (1-9). Grade 3-4 hematological toxicities consisted of 95% neutropenia, 64% anemia and 93% thrombocytopenia. Grade 3-4 non-hematological toxicities consisted of 45% infections, 23% hypokalemia, 16% hyponatremia, 7% reduction in ejection fraction, 7% hyperuricemia, 4% hyperglycemia, 4% nausea/vomiting, 4% QTc prolongation, 4% hyperbilirubinemia, and 4% elevated AST. Eleven pts (25%) achieved a CR, 9 with incomplete platelet recovery (20%), after a median time of 13 (10-16) weeks from treatment start. Five (11%) of these pts relapsed after achieving CR. Two pts (5%) received an allogeneic stem cell transplant while on study, one in CR and one primary refractory (after a blast count drop from 27 to 7%), and they are both still in CR and alive. Among 26 pts with FLT3 ITD and no D835 mutation, 9 (35%) achieved CR/CRp. Six of 18 (33%) pts not previously exposed to FLT3 inhibitors responded. There was no significant correlation of dose with response (24% with 50 mg bid vs 33% with 25 mg bid, p=0.63). After a median follow-up of 15 (3-72) weeks, 20 pts (64%) died, 3 (7%) while on study (2 died of sepsis, 1 of unknown causes with progressive disease). The median CRD was 16 (9-23) months. Factors significantly associated with a longer CRD were male sex (p=0.04), age older than 65 years (0.03) and use of 50 mg bid of midostaurin (p=0.02). Conclusions The combination of midostaurin and 5-AZA is safe and well tolerated. Its efficacy is most noticeable among pts with FLT3 mutations. A longer response duration is observed using midostaurin at 50 mg bid dose and in elderly male pts. Disclosures: Ravandi: CELGENE: Honoraria; NOVARTIS: Honoraria. Cortes:ARIAD: Consultancy, Research Funding; ASTELLAS: Research Funding; AMBIT: Research Funding; AROG: Research Funding; NOVARTIS: Research Funding.

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A Phase I/II Trial of Combination of Midostaurin (PKC412) and 5-Azacytidine (5-AZA) for the Treatment of Patients with Refractory or Relapsed (R/R) Acute Myeloid Leukemia (AML) and Myelodysplastic Syndrome (MDS)

Blood ◽

10.1182/blood.v120.21.3587.3587 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3587-3587 ◽

Cited By ~ 1

Author(s):

Aziz Nazha ◽

Hagop M. Kantarjian ◽

Gautam Borthakur ◽

Guillermo Garcia-Manero ◽

Tapan M. Kadia ◽

...

Keyword(s):

Bone Marrow ◽

Acute Myeloid Leukemia ◽

Phase I ◽

Phase Ii ◽

Myeloid Leukemia ◽

Research Funding ◽

Response Rate ◽

Allelic Ratio ◽

Bone Marrow Blasts ◽

Acute Myeloid

Abstract Abstract 3587 Background: Midostaurin (PKC412) is a potent orally bioavailable FLT3 inhibitor with activity in acute myeloid leukemia (AML). 5-azacytidine (5-AZA) is a hypomethylating agent that plays an important role in the treatment of AML and MDS. We hypothesized that adding midostaurin to 5-AZA may improve the response rate with limited toxicity profile. Materials and Methods: Patients ≥18 years with MDS, chronic myelomonocytic leukemia (CMML) or AML, who failed prior therapies with performance status ≤ 2, adequate liver (bilirubin ≤ 2 × ULN, ALT ≤ 2.5× ULN) and renal (creatinine ≤2× ULN) functions were eligible. Patients were included in phase I regardless of FLT3 mutation status; only FLT3 mutated patients were included in phase II. Patients received 5-AZA 75 mg/m2 subcutaneously or intravenously for 7 days of each cycle (Days 1–7) and midostaurin at 25 mg (cohort 1) and 50 mg (cohort 2; target dose) orally twice daily for 14 days (Days 8–21) per cycle. Patients were planned to receive up to 12 cycles if benefit from treatment. Supportive care was standard. The study was approved by institutional IRB and conducted in accordance of the declaration of Helsinki. Results: 20 patients have been enrolled: 13 included in phase I (6 in cohort 1 and 7 in cohort 2) and 6 patients in phase II. One patient in cohort 1 was inevaluable for DLT (withdrawal before completing cycle #1). One patient in cohort 2 received midostaurin dose as per cohort 1 dose by patient error. Patients' characteristics and responses are summarized in table 1. Overall response rate (ORR) in phase I was 3/13 (21%) (2 CRi and 1 patient decreased BM blasts from 27% to 7% after 2 cycles and went to transplant). ORR in phase II was 2/6 (33%) (1 patient with AML achieved CRi, 1 patient with CMML {received prior sorafenib} achieved CR). In addition, 1 AML patient had bone marrow blasts improved form 77% to 10% after 1 cycle, completed 3 cycles of therapy and then refused further treatment, and 1 AML patient had bone marrow blasts improve from 34% to 7 % and was continued on treatment). A total of nine patients with FLT3-ITD mutations enrolled in the trial: four patients in phase I with a median allelic ratio of 0.44 (range, 0.219–0.726); 1/4 (25%) achieved CRi, 2 of the non-responders had received prior FLT3 inhibitors (1 had developed FLT3-D835). Five patients in phase II had FLT3-ITD (median allelic ratio 0.06, range 0.014–0.279; one with concomitant D835 mutation) and one patient had FLT3-D835 mutation only (allelic ratio 0.238). 4/6 patients in phase II had failed prior FLT 3 inhibitors. In total, the ORR among patients with FLT3-ITD mutations was 3/9 (33%). All toxicities were grade 1 and 2 with no difference between the 2 dose schedules of midostaurin. No DLT or deaths were identified. Conclusion: The combination of midostaurin/5-AZA is safe and well tolerated at the intended doses (midostaurin 50 mg PO twice daily). Good ORR in high risk patients with relapsed or primary refractory FLT3-ITD positive AML was observed. Schedule is being amended to allow uninterrupted midostaurin administration. Phase II study continues to enroll patients with FLT3 mutations and updated results will be presented at the meeting. Disclosures: Off Label Use: 5-azacytidine in AML. Cortes:Novartis: Consultancy, Research Funding; Celgene: Research Funding; Ambit: Research Funding.

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Clinical benefit of glasdegib plus low-dose cytarabine in patients with de novo and secondary acute myeloid leukemia: long-term analysis of a phase II randomized trial

Annals of Hematology ◽

10.1007/s00277-021-04465-4 ◽

2021 ◽

Author(s):

Michael Heuser ◽

B. Douglas Smith ◽

Walter Fiedler ◽

Mikkael A. Sekeres ◽

Pau Montesinos ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Phase Ii ◽

Clinical Benefit ◽

Myeloid Leukemia ◽

Low Dose ◽

De Novo ◽

Secondary Acute Myeloid Leukemia ◽

Low Dose Cytarabine ◽

Acute Myeloid

AbstractThis analysis from the phase II BRIGHT AML 1003 trial reports the long-term efficacy and safety of glasdegib + low-dose cytarabine (LDAC) in patients with acute myeloid leukemia ineligible for intensive chemotherapy. The multicenter, open-label study randomized (2:1) patients to receive glasdegib + LDAC (de novo, n = 38; secondary acute myeloid leukemia, n = 40) or LDAC alone (de novo, n = 18; secondary acute myeloid leukemia, n = 20). At the time of analysis, 90% of patients had died, with the longest follow-up since randomization 36 months. The combination of glasdegib and LDAC conferred superior overall survival (OS) versus LDAC alone; hazard ratio (HR) 0.495; (95% confidence interval [CI] 0.325–0.752); p = 0.0004; median OS was 8.3 versus 4.3 months. Improvement in OS was consistent across cytogenetic risk groups. In a post-hoc subgroup analysis, a survival trend with glasdegib + LDAC was observed in patients with de novo acute myeloid leukemia (HR 0.720; 95% CI 0.395–1.312; p = 0.14; median OS 6.6 vs 4.3 months) and secondary acute myeloid leukemia (HR 0.287; 95% CI 0.151–0.548; p < 0.0001; median OS 9.1 vs 4.1 months). The incidence of adverse events in the glasdegib + LDAC arm decreased after 90 days’ therapy: 83.7% versus 98.7% during the first 90 days. Glasdegib + LDAC versus LDAC alone continued to demonstrate superior OS in patients with acute myeloid leukemia; the clinical benefit with glasdegib + LDAC was particularly prominent in patients with secondary acute myeloid leukemia. ClinicalTrials.gov identifier: NCT01546038.

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A Phase II of Combination Daunorubicin and Cytarabine (Ara-C) and Nilotinib (TASIGNA) (DATA) in Patients Newly Diagnosed with Acute Myeloid Leukemia and KIT Expression: Final Results

Blood ◽

10.1182/blood-2018-99-118552 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 1443-1443

Author(s):

Aref Al-Kali ◽

Raoul Tibes ◽

Jeanne Palmer ◽

Hassan B. Alkhateeb ◽

Mrinal M. Patnaik ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Stem Cell ◽

Liver Failure ◽

Phase Ii ◽

Myeloid Leukemia ◽

Research Funding ◽

White Blood Count ◽

Newly Diagnosed ◽

Relapse Rates ◽

Acute Myeloid

Abstract Background: Acute myeloid leukemia (AML) is an aggressive blood cancer with a wide range of response and relapse rates using standard chemotherapy combining anthracycline plus cytarabine (7+3). The stem cell receptor tyrosine kinase KIT is expressed on more than 10% of blasts in 95% of relapsed AML cases and mediates leukemic proliferation and has anti-apoptotic effects (Domen and Weissman 2000). AML with high KIT expression is associated with poorer outcome (Del Poeta, Venditti et al 2003). Goals: To study the efficacy and safety of combination 7+3 and nilotinib in patients (pts) with AML and KIT expression. Primary goal is to determine the complete response (CR) rate; while secondary goals include 2-year overall survival (OS) and disease free survival (DFS) in addition to safety. Methods: A single arm, Phase II study, enrolled pts at Mayo Clinic (MN and AZ). Appropriate IRB was obtained and study was registered (NCT 01806571). Pts were enrolled if they were newly diagnosed with AML with KIT (CD117) expression of ≥ 20% on myeloblasts by flow cytometry. KIT mutations were allowed. Nilotinib 300 mg twice daily was given on days 4-14 of induction and consolidation; and continuous daily maintenance therapy for up to 2 years. Cytarabine 100 mg/m2/day continuous IV x7 days plus daunorubicin 60 mg/m2 IV daily x3 days were used for induction, while consolidation used standard cytarabine 3 gm/m2 twice daily days 1, 3, 5 for a total of 4 cycles. This is a Simon 1-stage design with a safety analysis after enrolling 12 pts, and an interim analysis after enrolling 18 out of 43 pts (Al-Kali, ASH 2015) recommended to continue study accrual. Results: i)- Demographics: Thirty four pts were enrolled from July 2013 to June 2017. Median age was 59 years (range 24-69) with 71% being male. Median laboratory findings include hemoglobin of 8.8 gm/dL, platelets of 56 x109/L, white blood count of 3.3 x109/L (0.4-125), and peripheral blood blasts 17 %(0-94%). Cytogenetics were normal in 43% of the pts and favorable cytogenetics were seen in 6%(inv 16). FLT3 gene testing was done on 26 pts and was positive in 13%. KIT gene sequencing (exon 8, 9, 10, 11, 17) revealed pathogenic mutation in 1/28 cases (4%). ii)- Clinical outcome Out of all 34 pts enrolled on the study, 18 (53%) achieved CR (or CR with incomplete platelet recovery) with a median CR duration of 21.8 months. Of 26 evaluable pts, the overall CR rate was 69%. 4 of the 18 pts (22%) who achieved remission needed a second induction. One pt died due to liver failure (had only one dose of nilotinib and toxicity was attributed to daunorubicin). 13 (38%) pts proceeded to allogeneic stem cell transplant (HSCT), 12 of whom are alive and none were able to initiate nilotinib maintenance. Only 6 (1 had HSCT) out of 34 (18%) pts relapsed after achieving CR. Median DFS was 45.8 months, while median OS was 42.4 months. 2-year DFS and OS were 58% and 72%, respectively. iii)- Safety Thirty four pts were evaluated for adverse events (AE). Fourteen pts had G4 non-hematological AEs, including fourteen G4 AEs related to infection, 2 with electrolyte imbalances, 1 heart failure, 1 elevated bilirubin, 1 elevated lipase, and 1 jejunal hemorrhage. One patient had G5 liver failure. Most common (>20%) G3 non-hematological AEs were febrile neutropenia (56%), hypophosphatemia (21%), elevated ALT (21%) and hypertension (21%). Conclusion: Combination daunorubicin and cytarabine with nilotinib (DATA) appears to be safe and effective. Final results show an acceptable safety profile with most common AE being infection. Thirty day mortality was low (3%). DATA regimen has comparable CR rates of 53% (intent to treat) and 69% in evaluable pts. Relapse rates were very low at 18% with durable responses and encouraging survival rates. Figure. Figure. Disclosures Al-Kali: Novartis: Research Funding. Tibes:Novartis: Research Funding. Palmer:Novartis: Research Funding.

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A Phase 2 Randomized Study of Low Dose Ara-C with or without Glasdegib (PF-04449913) in Untreated Patients with Acute Myeloid Leukemia or High-Risk Myelodysplastic Syndrome

Blood ◽

10.1182/blood.v128.22.99.99 ◽

2016 ◽

Vol 128 (22) ◽

pp. 99-99 ◽

Cited By ~ 26

Author(s):

Jorge E. Cortes ◽

Florian H. Heidel ◽

Michael Heuser ◽

Walter Fiedler ◽

B. Douglas Smith ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

High Risk ◽

Myeloid Leukemia ◽

Research Funding ◽

Low Dose ◽

P Value ◽

Employment Equity ◽

Equity Ownership ◽

Acute Myeloid

Abstract Background: The Hedgehog signaling pathway (HhP) is aberrantly activated in leukemias and myelodysplastic syndrome (MDS), promoting cancer stem cell maintenance. HhP inhibition reduces leukemic stem cells. Glasdegib is a potent, selective, oral HhP inhibitor, with activity in pre-clinical and clinical studies. The addition of glasdegib to standard chemotherapy (CT) has an acceptable safety profile and appears to have clinical activity in MDS and acute myeloid leukemia (AML). Methods: In this study (NCT01546038), previously untreated AML or high-risk MDS patients (pts) ineligible for intensive CT were randomized 2:1 to receive low-dose cytarabine (LDAC) 20 mg subcutaneously twice a day x 10 days q28 days + oral glasdegib 100 mg daily or LDAC alone for as long as pts received clinical benefit. The primary endpoint was overall survival (OS). The final analysis was conducted after completion of recruitment (Oct 2015) and at least 92 OS events. Results: As of Apr 2016, 132 pts (116 AML, 16 MDS) were randomized to LDAC + glasdegib (n = 88) or LDAC alone (n = 44) (stratified as good/intermediate [int.] vs poor risk) (Table). Demographic and baseline characteristics were similar between arms in median age, baseline cytogenetic risk, and diagnosis. Eighty-four pts received LDAC + glasdegib and 41 pts LDAC alone (7 randomized/not treated pts were followed for survival). Median treatment duration was 83 days for LDAC + glasdegib and 47 days for LDAC alone; median follow up was 14.3 months and 12.4 months, respectively. In the glasdegib arm, 12 pts were continuing treatment and 25 were in follow up; in the LDAC arm, 1 pt was on treatment and 5 in follow up. Cytopenias and gastrointestinal toxicities were the adverse events (AEs) occurring more frequently in the LDAC + glasdegib arm. Hh-associated AEs in the glasdegib arm included dysgeusia (23.8%), muscle spasms (20.2%) and alopecia (10.7%). Serious AEs of febrile neutropenia were more frequent in the glasdegib arm, but sepsis rates were lower and pneumonia rates were similar. The most common cause of death was disease progression in both arms. Grade 2-4 QTcF prolongation was more frequent in the LDAC arm. Investigator-reported complete response (CR) rates were numerically higher for LDAC + glasdegib (n = 17, 15%) vs LDAC alone (n = 1, 2.3%), p-value 0.0142. Based on intent to treat analysis of 96 events, median OS (mOS) for LDAC + glasdegib was 8.3 (80% confidence interval [CI] 6.9, 9.9) vs 4.9 months (80% CI 3.5, 6.0) for LDAC alone (HR 0.511, 80% CI 0.386, 0.675; one-sided log rank p-value 0.0020 stratified by cytogenetic risk). For good/int. risk, mOS for LDAC + glasdegib was 12.2 vs 6.0 months for LDAC alone (HR 0.464, p-value 0.0035). For poor risk, mOS for LDAC + glasdegib was 4.4 vs 2.3 months (HR 0.575, p-value 0.0422). In AML pts, mOS for LDAC + glasdegib was 8.3 vs 4.3 months for LDAC alone (HR 0.462, p-value 0.0004). Conclusions: The addition of glasdegib to LDAC for AML and high-risk MDS pts improved OS compared with LDAC alone. The improvement was consistent among subgroups, particularly in good/int. risk pts. Treatment was associated with an acceptable safety profile. The addition of glasdegib to LDAC may be a treatment option for pts with AML or high-risk MDS. Disclosures Cortes: ARIAD: Consultancy, Research Funding; Bristol-Myers Squib: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Teva: Research Funding. Heuser:Tetralogic: Research Funding; Celgene: Honoraria; Bayer Pharma AG: Research Funding; Novartis: Consultancy, Research Funding; Pfizer: Research Funding; Karyopharm Therapeutics Inc: Research Funding; BerGenBio: Research Funding. Fiedler:Gilead: Other: Travel; Novartis: Consultancy; Ariad/Incyte: Consultancy; Teva: Other: Travel; Pfizer: Research Funding; Kolltan: Research Funding; Amgen: Consultancy, Other: Travel, Patents & Royalties, Research Funding; GSO: Other: Travel. Smith:Actinium Pharmaceuticals, Inc.: Research Funding. Robak:Pfizer: Research Funding. Montesinos Fernandez:Gamida Cell: Consultancy. Ma:Pfizer: Employment, Equity Ownership. Shaik:Pfizer: Employment, Equity Ownership. Zeremski:Pfizer: Employment, Equity Ownership. O'Connell:Pfizer: Employment, Equity Ownership. Chan:Pfizer: Employment, Equity Ownership.

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Decitabine-Induced Differentiation Syndrome in a Patient with Acute Myeloid Leukemia: A Case Report.

Blood ◽

10.1182/blood.v104.11.4528.4528 ◽

2004 ◽

Vol 104 (11) ◽

pp. 4528-4528

Author(s):

William Blum ◽

Kristie A. Blum ◽

Cheryl Kefauver ◽

Mollie Moran ◽

Kenneth Chan ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Retinoic Acid ◽

Phase I ◽

Myeloid Leukemia ◽

Phase I Trial ◽

Low Dose ◽

Myeloid Differentiation ◽

Induced Differentiation ◽

Retinoic Acid Syndrome ◽

Acute Myeloid

Abstract We report here for the first time a case of “decitabine-induced differentiation syndrome” in a patient (pt) with acute myeloid leukemia (AML). The cytosine analog decitabine, after incorporating into DNA, irreversibly binds DNA methyltransferase (DNMT) enzymes where cytosine residues are targeted for methylation. This allows replication of unmethylated DNA with subsequent re-expression of genes previously silenced by promoter methylation. It has been suggested that decitabine at low doses may have differentiating effects, as compared to cytotoxic effects at higher doses. A previous phase I trial demonstrated clinical activity of low dose decitabine in patients with myeloid malignancies (Issa, et al., Blood 2004). Given the close relationship of DNA methylation and histone deacetylation in modulating gene expression, we are currently conducting a phase I trial (OSU 0336) of low dose decitabine (15mg/m2 IV over 1 hour on days 1–10) alone (step 1) or in combination with escalating doses of the histone deacetylase inhibitor valproic acid (step 2) in AML. An 82 year old male pt with untreated, secondary AML (65% bone marrow blasts, 95% marrow cellularity) was enrolled on step 1 of the study and given 15mg/m2/day of decitabine for 10 consecutive days. At the time of initiation of therapy, the pt had a white blood cell (WBC) count of 8,700/uL with absolute neutrophil count (ANC) of 1,500/uL and absolute blast count (ABC) of 3,200/uL. At day 11, the pt had WBC 1,000/uL with ANC of 450/uL and ABC of 150/uL and was clinically well. However, at day 17, he presented with cough and shortness of breath, without fever. WBC had risen to 18,700/uL with ANC of 11,000/uL and ABC of 750/uL. The patient developed worsening hypoxia and required mechanical ventilation. Chest radiograph demonstrated diffuse interstitial infiltrates, but bronchoscopy and lavage (on day 18 and repeated on day 24) did not identify an infectious etiology. Due to clinical concern for a differentiation syndrome similar to the “retinoic acid syndrome” occurring in acute promyelocytic leukemia patients treated with all-trans-retinoic-acid (ATRA), the pt was started on dexamethasone 10mg IV q12 hours beginning on day 18, in addition to broad spectrum antimicrobial coverage. Peripheral blood smears during the following week showed evidence of myeloid differentiation, and by day 25 no circulating blasts were found (WBC 4,300/uL, ANC 3,000/uL) while the overall clinical condition improved. The pt was finally extubated on day 38 but within 24 hours required emergent re-intubation due to nasogastric feeding aspiration and died at day 53. In summary, these preliminary data support the biological activity of low dose decitabine in AML and suggest that clinical precautions similar to those implemented for the “retinoic acid syndrome” in ATRA-treated APL should be considered in decitabine-treated AML when myeloid differentiation and rising neutrophil counts are observed.

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Low-Dose Lenalidomide Plus Low Dose Cytarabine Induce Complete Remission That Can Be Predicted By Genetic Profiling In Very Elderly Acute Myeloid Leukemia Patients

Blood ◽

10.1182/blood.v122.21.496.496 ◽

2013 ◽

Vol 122 (21) ◽

pp. 496-496

Author(s):

Giuseppe Visani ◽

Francesco Di Raimondo ◽

Felicetto Ferrara ◽

Federica Loscocco ◽

Pier Paolo Piccaluga ◽

...

Keyword(s):

Gene Expression ◽

Acute Myeloid Leukemia ◽

Treatment Response ◽

Phase Ii ◽

Myeloid Leukemia ◽

Low Dose ◽

Phase Ii Study ◽

Expression Profiles ◽

Low Dose Cytarabine ◽

Acute Myeloid

Abstract Outcome for older patients with acute myeloid leukemia (AML) is extremely poor. Intensive induction chemotherapy is often unsuitable. In this phase II study we tested, for the first time, the efficacy of a novel combination therapy with low-dose lenalidomide plus low-dose cytarabine. Further, based on the hypothesis that genetic features might influence treatment response, we aimed at identifying a possible biomarker by studying the global gene expression profiles (GEP). We designed a prospective phase II study to assess the efficacy of the concomitant administration of low-dose lenalidomide and low-dose cytarabine in patients with acute myeloid leukemia (AML) aged more than 70 years. Forty-five patients (median age 76 years, range: 70-85) ineligible for standard therapy, were consecutively treated with low-dose lenalidomide (10 mg/day orally, days 1-21) plus low-dose cytarabine (10mg/m2 twice daily, subcutaneously, days 1-15) every six weeks, up to 6 cycles. Median white blood cell count at diagnosis was 3.2x109/l (range: 0,4-46,8x109/l), whereas median hemoglobin was 8,9 g/dl and median platelet count was 31x109/l. Twenty-three out of 45 patients had an intermediate karyotype (18/23 normal), 18/45 an unfavorable karyotype and 4/45 were not evaluable. Nineteen patients had a de novo AML, whereas 26 patients had a secondary AML (18 after MDS, 3 after a CMPD, 2 after myelofibrosis, 3 after chemo-radiotherapy for a breast cancer). To identify possible biomarkers associated to sensitivity/resistance, global gene and miRNA expression profiling (Affymetrix Transciptome 2.0) was performed on purified AML cells. Induction-period mortality was 17%, with 8 deaths occurring during cycle 1. Thirty-seven patients completed at least one cycle of therapy and are evaluable for response. Overall CR rate was 43% among evaluable patients. Nine out of 16 responding patients are still in CR after a median follow-up of 12 months (range: 2-39). Statistical analysis showed that responding patients had a longer median overall survival than non-responders (428 vs. 74 days, P = .000). Conversely, by studying the global miRNA and gene expression profile we identified a molecular signature, including 114 genes and 18 miRNA associated with the clinical response (CR vs. no CR). Of note, the involved genes belonged to relevant functional categories such as angiogenesis, cell cycle regulation and immune response. Of note, based on the expression of 5 genes, we developed an algorithm to predict treatment response that was successfully validated by showing an 87% overall accuracy. In conclusion, low-dose lenalidomide plus low-dose cytarabine has high clinical activity, predictable by GEP, in elderly AML patients with poor prognosis. The study was registered at EMA (EUDRA-CT 2008-006790-33). Acknowledgments Celgene is acknowledged for providing Lenalidomide for the patients. The study was supported in part by AIL Pesaro Onlus. Disclosures: No relevant conflicts of interest to declare.

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Phase II Pilot Clinical Trial of Pazopanib in Patients with Relapsed or Refractory Acute Myeloid Leukemia (AML) or at Initial Diagnosis When No Intensive Treatment Is Possible

Blood ◽

10.1182/blood-2018-99-118095 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 5176-5176

Author(s):

Torsten Kessler ◽

Steffen Koschmieder ◽

Christoph Schliemann ◽

Martina Crysandt ◽

Jan-Henrik Mikesch ◽

...

Keyword(s):

Clinical Trial ◽

Acute Myeloid Leukemia ◽

Phase Ii ◽

Myeloid Leukemia ◽

Research Funding ◽

Intensive Therapy ◽

Initial Diagnosis ◽

Intensive Treatment ◽

Response Criteria ◽

Acute Myeloid

Abstract Background: Patients with AML who are not eligible for intensive therapy or stem cell transplantation have a dismal prognosis. Autocrine and paracrine secretion of angiogenic and hematopoietic growth factors such as vascular endothelial growth factor in the bone marrow (BM) microenvironment may promote proliferation and survival of leukemic blasts. The oral multikinase inhibitor pazopanib was reported to exert growth inhibitory and proapoptotic effects in myeloid cells. Methods: This phase II study evaluated pazopanib (800 mg orally once daily) in patients with relapsed or refractory AML or at initial diagnosis when no intensive treatment is possible. All patients who received pazopanib for 14 days or longer were included into the analysis of safety, tolerability and efficacy. Response criteria are defined according to the Revised Recommendations of the International Working Group for Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting Standards for Therapeutic Trials in Acute Myeloid Leukemia. Co-primary endpoints were cumulative response rate (CR, CRp, CRi, PR) within up to one year and reduction of BM microvessel density (MVD) on day 28. Overall survival (OS) and progression free survival (PFS, time from first dose until progression or death from any cause) were measured from the first day of treatment until death of any cause or progression of disease. Results: Between February 2012 and September 2015, 20 AML patients with a median (range) age of 76 (52 - 86) years were treated with pazopanib. The majority of patients (n = 15, 75%) had relapsed (n = 7) or refractory (n = 8) AML, five patients (25%) were enrolled with newly diagnosed AML. Median (range) ECOG performance status was 1 (1 - 3). According to ELN 2010 criteria, four patients (20%) had adverse risk, 15 (75%) had intermediate risk, and one patient (5%) had favorable cytogenetic/molecular risk. Overall, the safety profile of pazopanib was similar to that reported in previous studies. The most common AEs of any grade, related to pazopanib as assessed by the investigator, were gastrointestinal AEs, including nausea (n = 8), diarrhea (n = 6), inappetence (n = 5) and vomiting (n = 3). Two out of 20 treated patients (10%) had a partial remission (reduction of blast count > 50%) and 14 (70%) a stable disease (SD) while on pazopanib. Four patients (20%) experienced initial PD. Median PFS was 65 days (95% CI 29 - 105). After the end of study period three remarkable responses occurred on subsequent therapies such as demethylating agents resulting in one CRi and one CRp and one CR after secondary BM transplantation. All these patients had SD while on pazopanib and improved general condition allowing escalation of therapy. However, at the time of OS evaluation all patients had died due to PD and/or infections. Median OS of the treated study cohort was 191 days (95% CI 87 - 435), and 1-year survival altogether was 35%. There was no significant change in BM MVD between day 1 and day 28. Conclusion: Pazopanib was found to be safe in patients with AML not eligible for intensive therapy. The survival data are encouraging but clearly necessitate a controlled randomized clinical trial for confirmation. Clinical trial information: NCT01361334. Disclosures Stelljes: Amgen: Honoraria; JAZZ: Honoraria; MSD: Consultancy; Pfizer: Consultancy, Honoraria, Research Funding; Novartis: Honoraria. Lenz:Roche: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding; Bayer: Consultancy, Honoraria, Research Funding, Speakers Bureau; Novartis: Research Funding; Gilead: Consultancy, Honoraria; Janssen: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding, Speakers Bureau; Celgene Corp.: Consultancy, Honoraria, Other: Travel, Accomodations, Expenses, Research Funding, Speakers Bureau. Brümmendorf:Takeda: Consultancy; Novartis: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Janssen: Consultancy; Merck: Consultancy.

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Phase I Study of Ixazomib in Addition to Chemotherapy for the Treatment of Acute Myeloid Leukemia in Older Adults

Blood ◽

10.1182/blood-2018-99-117566 ◽

2018 ◽

Vol 132 (Supplement 1) ◽

pp. 4059-4059

Author(s):

Philip C. Amrein ◽

Eyal C. Attar ◽

Traci M. Blonquist ◽

Andrew M. Brunner ◽

Gabriela S. Hobbs ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Phase I ◽

Dose Escalation ◽

Proteasome Inhibitor ◽

Myeloid Leukemia ◽

Research Funding ◽

Remission Rate ◽

Secondary Aml ◽

Grade 3 ◽

Acute Myeloid

Abstract Introduction: Treatment of acute myeloid leukemia (AML) has remained largely unchanged for several decades despite the emergence of new agents. Long-term survival for patients aged >60 years is less than 10% (median survival 10.5 months). Targeting the proteasome in treating AML is attractive, since leukemia stem cells have demonstrated sensitivity to proteasome inhibition, perhaps through down regulation of nuclear NF-KB (Guzman, Blood 2001). Preclinical studies in leukemia cell lines revealed synergistic cytotoxicity when bortezomib, a proteasome inhibitor, was combined with the standard agents daunorubicin and cytarabine. We have shown that adding bortezomib to standard treatment in AML results in a high remission rate, although neurotoxicity was noted among treated patients, 12% grade 3 sensory (Attar, …, Amrein, et al. Clin Cancer Res 2008, Attar, … Amrein, J Clin Oncol 2012). The next generation proteasome inhibitor, ixazomib, which is less frequently associated with neurotoxicity, was therefore selected for combination with conventional chemotherapy in this phase I trial. The primary objective was to determine the maximum tolerated dose (MTD) in the combination, initially in induction, and then in combination with consolidation in a subsequent portion of the overall study. We report here the results of the induction portion of the study, which has been completed. Methods: Adults >60 years of age with newly diagnosed AML were screened for eligibility. Patients with secondary AML were eligible, including those with prior hypomethylating agent therapy for myelodysplastic syndromes (MDS). We excluded those with promyelocytic leukemia. The induction treatment consisted of the following: cytarabine 100 mg/m2/day by continuous IV infusion, Days 1-7; daunorubicin 60 mg/m2/day IV, Days 1, 2, 3; ixazomib orally at the cohort dose, Days 2, 5, 9, and 12 A standard 3 + 3 patient cohort dose escalation design was used to determine whether the dose of ixazomib could be safely escalated in 3 cohorts (1.5 mg/day, 2.3 mg/day, 3.0 mg/day), initially in induction and subsequently in consolidation. The dose of 3.0 mg/day was the maximum planned for this study. The determined MTD of ixazomib in the first portion of the trial would be used during induction in the second portion, which seeks to test dose escalation of ixazomib during consolidation. Secondary objectives included rate of complete remission and disease-free survival. Results: Fourteen patients have been analyzed for toxicity and activity during the induction portion of the study. There were 4 (28%) patients with either secondary AML or treatment related AML, 9 (64%) were male, and the median age was 67 years (range 62-80 years). There have been no grade 5 toxicities due to study drug. Three patients died early due to leukemia, 2 of which were replaced for assessment of the MTD. Nearly all the grade 3 and 4 toxicities were hematologic (Table). There was 1 DLT (grade 3 thrombocytopenia) indicated at the highest dose level. There has been no neurotoxicity with ixazomib to date. Among the 14 patients, there have been 10 complete remissions (CR's) and 1 CRi for a remission rate of 79%. Conclusions: The highest dose level planned for this portion of the trial, 3.0 mg of ixazomib, was reached with 1 DLT and is the recommended dose for induction in the next portion of this study, which will seek to determine a safe ixazomib dose in combination with conventional consolidation therapy. That no neurotoxicity was encountered was reassuring, and the remission rate in this older adult population is favorable. Table. Table. Disclosures Amrein: Takeda: Research Funding. Attar:Agios: Employment, Equity Ownership. Brunner:Takeda: Research Funding; Novartis: Research Funding; Celgene: Consultancy, Research Funding. Fathi:Celgene: Consultancy, Honoraria, Research Funding; Boston Biomedical: Consultancy, Honoraria; Astellas: Honoraria; Agios: Honoraria, Research Funding; Jazz: Honoraria; Seattle Genetics: Consultancy, Honoraria; Takeda: Consultancy, Honoraria.

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