Phase 2 study of the JAK kinase inhibitor ruxolitinib in patients with refractory leukemias, including postmyeloproliferative neoplasm acute myeloid leukemia

Abstract We conducted a phase 2 study of ruxolitinib in patients with relapsed/refractory leukemias. Patients with acceptable performance status (0-2), adequate organ function, and no active infection, received ruxolitinib 25 mg orally twice a day for 4 weeks (1 cycle). Response was assessed after every 2 cycles of treatment, and patients who completed 2 cycles were allowed to continue treatment until disease progression. Dose escalation to 50 mg twice daily was permitted in patients demonstrating a benefit. Thirty-eight patients, with a median age of 69 years (range, 45-88), were treated. The median number of prior therapies was 2 (range, 1-6). Twelve patients had JAK2V617F mutation. Patients received a median of 2 cycles of therapy (range, 1-22). Three of 18 patients with postmyeloproliferative neoplasm (MPN) acute myeloid leukemia (AML) showed a significant response; 2 achieved complete remission (CR) and one achieved a CR with insufficient recovery of blood counts (CRi). The responding patients with palpable spleens also had significant reductions in spleen size. Overall, ruxolitinib was very well tolerated with only 4 patients having grade 3 or higher toxicity. Ruxolitinib has modest antileukemic activity as a single agent, particularly in patients with post-MPN AML. The study was registered at www.clinicaltrials.gov as NCT00674479.

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Gemtuzumab ozogamicin (Mylotarg®) as single-agent treatment for frail patients 61 years of age and older with acute myeloid leukemia: final results of AML-15B, a phase 2 study of the European Organisation for Research and Treatment of Cancer and Gruppo Italiano Malattie Ematologiche dell'Adulto Leukemia Groups

Leukemia ◽

10.1038/sj.leu.2403901 ◽

2005 ◽

Vol 19 (10) ◽

pp. 1768-1773 ◽

Cited By ~ 68

Author(s):

S Amadori ◽

S Suciu ◽

R Stasi ◽

R Willemze ◽

F Mandelli ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Single Agent ◽

Gemtuzumab Ozogamicin ◽

Phase 2 ◽

European Organisation ◽

Frail Patients ◽

Phase 2 Study ◽

Agent Treatment ◽

Acute Myeloid

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Pracinostat plus azacitidine in older patients with newly diagnosed acute myeloid leukemia: results of a phase 2 study

Blood Advances ◽

10.1182/bloodadvances.2018027409 ◽

2019 ◽

Vol 3 (4) ◽

pp. 508-518 ◽

Cited By ~ 17

Author(s):

Guillermo Garcia-Manero ◽

Yasmin Abaza ◽

Koichi Takahashi ◽

Bruno C. Medeiros ◽

Martha Arellano ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Older Patients ◽

Myeloid Leukemia ◽

Intensive Therapy ◽

Single Agent ◽

Response To Treatment ◽

Phase 2 ◽

Newly Diagnosed ◽

Phase 2 Study ◽

Acute Myeloid

Abstract Pracinostat, a potent oral pan-histone deacetylase inhibitor with modest single-agent activity in acute myeloid leukemia (AML), has shown synergistic antitumor activity when combined with azacitidine. This single-group, multicenter phase 2 study assessed the safety and efficacy of pracinostat combined with azacitidine in patients who were at least 65 years old with newly diagnosed AML and who were ineligible for standard induction chemotherapy. Patients received pracinostat 60 mg/d, 3 d/wk, for 3 consecutive weeks, plus azacitidine 75 mg/m2 daily for 7 days in a 28-day cycle. Primary endpoints were complete remission (CR), CR with incomplete count recovery (CRi), and morphologic leukemia-free state (MLFS) rates of the combination. Secondary endpoints included safety, progression-free survival (PFS), and overall survival (OS) of the regimen. Fifty patients (33 de novo, 12 secondary, and 5 therapy-related AML) were enrolled. Twenty-six patients (52%) achieved the primary endpoint of CR (42%), CRi (4%), and MLFS (6%). Median OS and PFS were 19.1 months (95% confidence interval [CI], 10-26.5 months) and 12.6 months (95% CI, 10-17.7 months), respectively, with a 1-year OS rate of 62%. Forty-three patients (86%) experienced at least 1 grade 3 or worse treatment-emergent adverse event with the combination, with infections (52%), thrombocytopenia (46%), and febrile neutropenia (44%) reported as the most common toxicities. The 30- and 60-day all-cause mortality rates were 2% and 10%, respectively. DNA sequencing revealed somatic mutations at baseline, and clearance rates correlated with response to treatment. Pracinostat plus azacitidine is a well-tolerated and active regimen in the frontline treatment of older patients with AML unfit for intensive therapy. A larger controlled trial is ongoing. This trial was registered at www.clinicaltrials.gov as #NCT01912274.

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Phase 2 study of azacytidine plus sorafenib in patients with acute myeloid leukemia and FLT-3 internal tandem duplication mutation

Blood ◽

10.1182/blood-2013-01-480228 ◽

2013 ◽

Vol 121 (23) ◽

pp. 4655-4662 ◽

Cited By ~ 248

Author(s):

Farhad Ravandi ◽

Mona Lisa Alattar ◽

Michael R. Grunwald ◽

Michelle A. Rudek ◽

Trivikram Rajkhowa ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Tandem Duplication ◽

Phase 2 ◽

Internal Tandem Duplication ◽

Phase 2 Study ◽

Key Points ◽

Acute Myeloid

Key Points Azacytidine and sorafenib are effective in patients with relapsed and refractory FLT3-mutated AML.

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A phase 2 study of vorinostat in acute myeloid leukemia

Haematologica ◽

10.3324/haematol.2009.009217 ◽

2009 ◽

Vol 94 (10) ◽

pp. 1375-1382 ◽

Cited By ~ 75

Author(s):

E. W. Schaefer ◽

A. Loaiza-Bonilla ◽

M. Juckett ◽

J. F. DiPersio ◽

V. Roy ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Myeloid Leukemia ◽

Phase 2 ◽

Phase 2 Study ◽

Acute Myeloid

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Safety and Efficacy of Bendamustine and Idarubicin in Combination Therapy for Patients Age ≥50 with Untreated Acute Myeloid Leukemia and High-Risk Myelodysplastic Syndrome – Results From a Phase I/II Adaptive Design Study.

Blood ◽

10.1182/blood.v120.21.2622.2622 ◽

2012 ◽

Vol 120 (21) ◽

pp. 2622-2622

Author(s):

Mazyar Shadman ◽

Jack M. Lionberger ◽

Raya Mawad ◽

Ravinder K Sandhu ◽

Carol Dean ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

High Risk ◽

Myelodysplastic Syndrome ◽

Myeloid Leukemia ◽

Posterior Probability ◽

Performance Status ◽

Outpatient Setting ◽

Ecog Performance Status ◽

Grade 3 ◽

Acute Myeloid

Abstract Abstract 2622 Background: Acute myeloid leukemia (AML) and high-risk myelodysplastic syndrome (MDS with 10–19% blasts) are associated with higher mortality in the elderly population. This poor outcome is in part attributed to therapy resistance and therefore, using combinations of agents with different mechanisms of action may improve outcomes. The nitrogen mustard Bendamustine combines unique alkylating characteristics with putative anti-metabolite activity while Idarubicin inhibits DNA and RNA synthesis by intercalation between DNA base pairs. In this single-arm adaptive phase I/II dose-escalation trial, we assessed increasing doses of Bendamustine in combination with a uniform dose of Idarubicin. We used a Bayesian approach to determine whether there was a dose of Bendamustine which, together with Idarubicin can provide a complete response (CR) rate of at least 40%, with minimal (<30%) grade 3–4 extramedullary toxicity in untreated AML or high-risk MDS patients age > 50. Methods: Eligible patients were age 350 with untreated AML or high-risk MDS, had an ECOG performance status <3 and creatinine and bilirubin each less <2.0. Patients received 1 of 3 doses of Bendamustine (45, 60 or 75 mg/m2 daily days 1–5) together with Idarubicin (12 mg/m2 days 1–2). Response was assessed according to the International Working Group (IWG) criteria (Cheson et. al., JCO, 2003) and non-hematologic toxicities according to the NCI CTCAE v.3. After each cohort of 3 patients at a given dose had been evaluated for toxicity and response, Bayesian posterior probabilities based on the data and non-informative prior probabilities were computed. If no Bendamustine dose was associated with a >95% posterior probability of both grade 3–4 extramedullary toxicity <30% (between the 1/6 and 2/6 of the conventional 3+3) and CR rate >40%, the study stopped. Otherwise, the study would continue at the highest dose that met the above criteria until 45 patients had been treated. Treatments were administered in the outpatient setting and patients were admitted to the hospital only if medically indicated. Results: Between October 2010 and May 2012, 39 patients were treated per protocol. The median age was 73 (range, 56–82). Patients had ECOG performance status of 1 (92%), or 2 (7%). AML patients comprised majority of the cases (34/39; 87%). Among AML patients, 35% (12/34) had primary AML, 47% (16/34) had AHD (antecedent hematologic disorders) and 18% (6/34) had secondary AML with a prior history of chemotherapy or radiation. None of the patients had favorable-risk cytogenetic (CG) and 19 (49%) had poor-risk CG including 9 patients (23%) with monosomal karyotype. None of the patients with normal CG had favorable molecular markers. Treatment was given in 1, 2, and 3 cycles in 25 (64%), 7 (18%) and 7(18%) patients, respectively. The number of patients in each cohort and the treatment efficacy and toxicity is reported in the table below. The MTD (maximum tolerated dose) was established at 60 mg/m2 of Bendamustine as two grade 3 toxicities were seen at the dose of 75 mg/m2 (congestive heart failure and mucositis in one patient each). Patients were treated as outpatients but hospitalization was required in 90% of the patients (35/39; 90%). The leading cause of admission was febrile neutropenia (26/35; 74%) followed by fungal infections (4/35; 11%). Conclusion: The combination of Bendamustine (60 mg/m2 (for 5 days) with Idarubicin (12 mg/m2 for 2 days) can be delivered in the outpatient setting and had a <95% posterior probability of >30% toxicity. However, the posterior probability of a CR rate >40% was also <95%, suggesting that continued exploration of new therapeutic combinations is warranted in elderly patients with AML or high-grade MDS. Disclosures: Off Label Use: Bendamustine is indicated for the treatment of CLL and indolent non-Hodgkin's lymphoma. In our study we are using Bendamustine to treat AML.

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A Phase 2 Study of Bortezomib Combined with Reinduction Chemotherapy in Children and Young Adults with Recurrent, Refractory or Secondary Acute Myeloid Leukemia: A Children's Oncology Group (COG) Study

Blood ◽

10.1182/blood.v120.21.3580.3580 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3580-3580 ◽

Cited By ~ 3

Author(s):

Terzah M. Horton ◽

John Perentesis ◽

Alan S. Gamis ◽

Todd A. Alonzo ◽

Robert B. Gerbing ◽

...

Keyword(s):

Clinical Trial ◽

Acute Myeloid Leukemia ◽

Study Design ◽

Proteasome Inhibitor ◽

Myeloid Leukemia ◽

Response Rate ◽

Dose Finding ◽

Phase 2 ◽

Phase 2 Study ◽

Acute Myeloid

Abstract Abstract 3580 Purpose: Bortezomib is a 26S proteasome inhibitor that is effective for the treatment of multiple myeloma and indolent lymphomas in adults. Bortezomib at a dose of 1.3 mg/m2 is well tolerated in pediatric patients as a single agent and in combination with cytotoxic chemotherapy. In vitro studies indicate that the proteasome inhibitor bortezomib sensitizes bulk myeloid leukemia and leukemia initiating cells (LIC) to chemotherapy. This Phase 2 study examined the tolerability and efficacy of bortezomib combined with reinduction chemotherapy for relapsed pediatric acute myeloid leukemia (AML). Patients and Methods: This study was a two-arm, non-randomized, open label clinical trial in which patients received bortezomib twice weekly (1.3 mg/m2 on days 1, 4, and 8) in a 28-day cycle. Arm A (for patients with prior anthracycline exposure <400mg/m2) combined bortezomib with idarubicin (12 mg/m2 on days 1–3) and cytarabine (100mg/m2 on days 1–7). Arm B (for patients with prior anthracycline exposure >400 mg/m2) combined bortezomib with cytarabine (1000mg/m2 q12h on days 1–5) and etoposide (150 mg/m2on days 1–5). Arm B included an initial dose finding phase (n=12) which determined that bortezomib at 1.3 mg/m2/dose was safe to combine with cytarabine/etoposide. Bortezomib was then tested in a 2-stage efficacy phase for both arms. A second cycle of protocol therapy was allowed for patients with a response of at least stable disease. Results: The clinical trial enrolled a total of 52 patients for a total number of 61 cycles of therapy. Arm A enrolled 18 patients (16 eligible, 14 evaluable) and Arm B enrolled 34 patients (n=12 dose finding phase, n=22 efficacy phase (21 evaluable)) for a total of 24 patients evaluable for efficacy in Arm B. The addition of bortezomib to chemotherapy was tolerable in both arms. Severe toxicities included febrile neutropenia (29%) and transient hypokalemia (29%). Although tolerable, both Arm A and Arm B were closed after stage 1 of a two stage study design for failure to meet the efficacy threshold. Arm A response rate was 28% (3 CR and 1 CRp) and Arm B response rate was 42% (8 CR and 2 CRp). Although bortezomib was tolerated in both arms, response rates were adversely affected by a delay in neutrophil count recovery (ANC). Four patients in Arm A and 1 patient in Arm B had a complete response with delayed neutrophil recovery (CRi) which was considered a treatment failure in the study design. If a response of CRi had been included as a treatment success, both Arms A and B would have continued into the second stage of efficacy assessment. The 2-year overall survival (OS) for all evaluable patients was 35 ± 21%, and there was no difference in OS between the two treatment arms (Figure 1). Conclusion: Bortezomib is tolerable when added to chemotherapy regimens for children with relapsed/refractory or treatment-related AML. The overall response to the bortezomib containing chemotherapy regimens in the patients enrolled on the efficacy phase (CR + CRp + CRi) (50%) was similar to other salvage regimens for childhood acute myeloid leukemia. Bortezomib, however, did not improve either the CR rate or the OS of this patient cohort. Disclosures: Off Label Use: Testing of bortezomib for pediatric AML in the context of a phase 2 clinical trial.

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Autophagy Promotes the Survival and Therapy Resistance of Human Acute Myeloid Leukemia Cells Under Hypoxia

Blood ◽

10.1182/blood.v124.21.2236.2236 ◽

2014 ◽

Vol 124 (21) ◽

pp. 2236-2236 ◽

Cited By ~ 1

Author(s):

Dirkje W Hanekamp ◽

Megan K Johnson ◽

Scott Portwood ◽

Joshua Acklin ◽

Eunice S. Wang

Keyword(s):

Flow Cytometry ◽

Cell Death ◽

Acute Myeloid Leukemia ◽

Tyrosine Kinase Inhibitor ◽

Myeloid Leukemia ◽

Kinase Inhibitor ◽

Single Agent ◽

Xenograft Models ◽

Acute Myeloid

Abstract Background: Acute myeloid leukemia (AML) is an aggressive hematological malignancy occurring primarily in older adults. Despite high remission rates following upfront therapy, the disease eventually recurs in most patients, and overall cure rates remain only 20-30%. Preclinical studies have recently demonstrated that the marrow microenvironment in acute leukemic hosts to be intrinsically hypoxic, with AML progression associated with further hypoxia. Moreover, human AML cells and primary AML colonies cultured under hypoxia are markedly less sensitive to cytarabine chemotherapy than normoxic cells. We hypothesized that AML cells may respond to hypoxic stress and mediate chemoresistance in part by invoking autophagy, a highly regulated catabolic process by which cells evade apoptosis by degrading damaged cellular components. To test our hypothesis, we investigated the effects of two known autophagy inhibitors (bafilomycin A1 (Baf) and chloroquine (CQ)) on the sensitivity of human AML cells to various therapeutic agents under differing oxygen levels. Methods: We treated HEL (FLT-3 wildtype) and MV4-11 (FLT-3 ITD mutant) AML cells with autophagy inhibitors (Baf and CQ) alone and in combination with a chemotherapeutic drug (cytarabine (AraC), doxorubicin (Dox), decitabine (Dac)) or a tyrosine kinase inhibitor (sorafenib, SFN) under normoxic (21% O2) or hypoxic (1% O2) conditions. Apoptosis /cell death and proliferation were measured by flow cytometry for Annexin-PI and MTT assays, respectively. Autophagy was assessed by flow cytometry using Cyto-ID Green Dye (Enzo Life Sciences), fluorescent microscropy for acridine orange dye accumulation, and western blot analysis. Results: Autophagy in human ALL and AML cell lines was significantly increased following 24-72 hours of hypoxia (1% O2) as compared with normoxia and was a relatively late response to prolonged low oxygen levels (> 24 hours). Treatment with cytotoxic agents (AraC or Dox) or hypomethylating agent (Dac) resulted in a dose-dependent increases in the number of autophagic vesicles in AML cells consistent with autophagy induction. Low-doses of Baf which selectively inhibits the vacuolar H+ ATPase to prevent lysosomal acidification, and CQ, which blocks lysosome-autophagosome fusion by raising the pH of lysosomes and endosomes, both resulted in buildup of autophagic vesicles by flow cytometry consistent with inhibition of autophagic flux in human AML cells. Combination treatment with an autophagy inhibitor (Baf, CQ) and cytotoxic chemotherapy (AraC, Dox) significantly enhanced apoptosis and cell death over single agent therapy. Treatment with Baf combined with hypomethylating therapy (Dac) synergistically improved the anti-leukemic effects as compared with monotherapy (CI 0.09-0.31)(see Figure). The addition of Baf also improved cell death induced by sorafenib (SFN) on FLT-3 ITD mutant human AML cells (MV4;11) (CI 0.36-0.9) (see Figure). Single agent Baf or CQ treatment resulted in significantly higher levels of apoptosis and cell death in AML cells under hypoxia. The anti-tumor activity of almost all combination regimens was consistently improved under hypoxic versus normoxic culture conditions. In vivo CQ treatment (25-50 mg/kg i.p. daily) in preclinical human AML xenograft models significantly inhibited systemic leukemia progression as a single agent. Further experiments investigating the in vivo effects of CQ combined with other chemotherapeutic agents in preclinical AML xenograft models are ongoing. Conclusions: Our data suggest that human AML cells preferentially induce autophagy to promote survival under chronic hypoxia and following cytotoxic, hypomethylating, and FLT-3 tyrosine kinase inhibitor therapy. Strategies targeting autophagy therefore may have the potential to improve therapeutic responses and overcome chemoresistance of AML cells within the hypoxic bone marrow microenvironment. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

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A phase 1 clinical trial of single-agent selinexor in acute myeloid leukemia

Blood ◽

10.1182/blood-2016-11-750158 ◽

2017 ◽

Vol 129 (24) ◽

pp. 3165-3174 ◽

Cited By ~ 56

Author(s):

Ramiro Garzon ◽

Michael Savona ◽

Rachid Baz ◽

Michael Andreeff ◽

Nashat Gabrail ◽

...

Keyword(s):

Acute Myeloid Leukemia ◽

Nuclear Export ◽

Myeloid Leukemia ◽

Phase 1 ◽

Single Agent ◽

Objective Response ◽

Nuclear Accumulation ◽

Phase 2 ◽

Safety And Efficacy ◽

Acute Myeloid

Abstract Selinexor is a novel, first-in-class, selective inhibitor of nuclear export compound, which blocks exportin 1 (XPO1) function, leads to nuclear accumulation of tumor suppressor proteins, and induces cancer cell death. A phase 1 dose-escalation study was initiated to examine the safety and efficacy of selinexor in patients with advanced hematological malignancies. Ninety-five patients with relapsed or refractory acute myeloid leukemia (AML) were enrolled between January 2013 and June 2014 to receive 4, 8, or 10 doses of selinexor in a 21- or 28-day cycle. The most frequently reported adverse events (AEs) in patients with AML were grade 1 or 2 constitutional and gastrointestinal toxicities, which were generally manageable with supportive care. The only nonhematological grade 3/4 AE, occurring in >5% of the patient population, was fatigue (14%). There were no reported dose-limiting toxicities or evidence of cumulative toxicity. The recommended phase 2 dose was established at 60 mg (∼35 mg/m2) given twice weekly in a 4-week cycle based on the totality of safety and efficacy data. Overall, 14% of the 81 evaluable patients achieved an objective response (OR) and 31% percent showed ≥50% decrease in bone marrow blasts from baseline. Patients achieving an OR had a significant improvement in median progression-free survival (PFS) (5.1 vs 1.3 months; P = .008; hazard ratio [HR], 3.1) and overall survival (9.7 vs 2.7 months; P = .01; HR, 3.1) compared with nonresponders. These findings suggest that selinexor is safe as a monotherapy in patients with relapsed or refractory AML and have informed subsequent phase 2 clinical development. This trial was registered at www.clinicaltrials.gov as #NCT01607892.

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