Treatment of therapy-related myeloid neoplasms with high-dose cytarabine/mitoxantrone followed by hematopoietic stem cell transplant

Godley, Lucy A.; Njiaju, Uchenna O.; Green, Margaret; Weiner, Howard; Shang, Lin; Odenike, Olatoyosi; Rich, Elizabeth Shima; Artz, Andrew S.; Besien, Koen van; Daugherty, Christopher K.; Zhang, Yanming; Beau, Michelle M. Le; Stock, Wendy; Larson, Richard A.

doi:10.3109/10428191003763468

Cited by 16 publications

(11 citation statements)

References 28 publications

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“…In the same report, the results of 13 different studies including a total of 496 patients with t‐AML were summarized, revealing an overall CR rate of 27% (Kantarjian et al ., 1993). However, the University of Chicago group recently reported an overall remission rate of 82% with high‐dose cytarabine/mitoxantrone in previously untreated patients with t‐MNs (Godley et al ., 2010). For patients who developed t‐MNs with favourable karyotypes – APL with t(15;17) and core‐binding factor leukaemias with either t(8;21) or inv16/t(16;16) – treatment is recommended with high‐dose chemotherapy in accordance with guidelines for their de novo counterparts.…”

Section: Prognosis and Treatmentmentioning

confidence: 99%

Therapy‐related myeloid neoplasms: pathobiology and clinical characteristics

Sill

Olipitz

Zebisch

et al. 2011

British J Pharmacology

109

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Therapy-related myeloid neoplasms (t-MNs) are serious long-term consequences of cytotoxic treatments for an antecedent disorder. t-MNs are observed after ionizing radiation as well as conventional chemotherapy including alkylating agents, topoisomerase-II-inhibitors and antimetabolites. In addition, adjuvant use of recombinant human granulocyte-colony stimulating factor may also increase the risk of t-MNs. There is clinical and biological overlap between t-MNs and high-risk de novo myelodysplastic syndromes and acute myeloid leukaemia suggesting similar mechanisms of leukaemogenesis. Human studies and animal models point to a prominent role of genetic susceptibilty in the pathogenesis of t-MNs. Common genetic variants have been identified that modulate t-MN risk, and t-MNs have been observed in some cancer predisposition syndromes. In either case, establishing a leukaemic phenotype requires acquisition of somatic mutations -most likely induced by the cytotoxic treatment. Knowledge of the specific nature of the initiating exposure has allowed the identification of crucial pathogenetic mechanisms and for these to be modelled in vitro and in vivo. Prognosis of patients with t-MNs is dismal and at present, the only curative approach for the majority of these individuals is haematopoietic stem cell transplantation, which is characterized by high transplant-related mortality rates. Novel transplantation strategies using reduced intensity conditioning regimens as well as novel drugs -demethylating agents and targeted therapies -await clinical testing and may improve outcome. Ultimately, individual assessment of genetic risk factors may translate into tailored therapies and establish a strategy for reducing t-MN incidences without jeopardizing therapeutic success rates for the primary disorders. Abbreviations IntroductionTherapy-related myeloid neoplasms (t-MNs) are serious longterm consequences of chemo-and radiotherapy for an antecedent disorder. According to the World Health Organization (WHO) 'Classification of Tumours of Haematopoietic and Lymphoid Tissues', t-MNs comprise therapy-related myelodysplastic syndrome (t-MDS), acute myeloid leukaemia (t-AML) and myelodysplastic/myeloproliferative neoplasm, and constitute a unique clinical syndrome (Vardiman et al., 2009). They are observed after cytotoxic therapies of haematologic malignancies -mainly Hodgkin's disease (HD) and non-Hodgkin's lymphomas -as well as solid neoplasmsmost commonly breast, ovarian and prostate cancer. In addition, t-MNs have also been reported in patients receiving immunosuppressive treatment for rheumatologic/autoimmune diseases or solid organ transplantation (Offman et al., 2004;Kwong, 2010). The majority of patients with t-MNs present with myelodysplastic syndrome (MDS) or acute myeloid leukaemia (AML) transformed from MDS after a median latency period of 5-10 years following cytotoxic treatments with alkylating agents, immunosuppressive drugs or radiotherapy. Patients frequently exhibit marked peripheral blood cytopenias and dysplastic fe...

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Section: Prognosis and Treatmentmentioning

confidence: 99%

Therapy‐related myeloid neoplasms: pathobiology and clinical characteristics

Sill

Olipitz

Zebisch

et al. 2011

British J Pharmacology

109

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“…In vivo and in vitro evidence suggest synergistic activity against leukemic cells by combining selinexor with anthracyclines or DNA-damaging agents [ 13 ]. The combination of high-dose cytarabine (HiDAC) with the anthracycline mitoxantrone (Mito) is an effective induction regimen for patients with AML [ 14 – 17 ] and is frequently utilized at the University of Chicago as frontline therapy for patients with high-risk AML, either de novo or relapsed/refractory. The HiDAC/Mito regimen demonstrated an overall response rate (ORR) of 55% in the high-risk AML population at this institution [ 16 ] and an ORR of 82% in another study of previously untreated patients with therapy-related myeloid neoplasms [ 17 ].…”

Section: Introductionmentioning

confidence: 99%

A phase I study of selinexor in combination with high-dose cytarabine and mitoxantrone for remission induction in patients with acute myeloid leukemia

et al. 2018

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BackgroundNovel therapies for patients with acute myeloid leukemia (AML) are imperative, particularly for those with high-risk features. Selinexor, an exportin 1 (XPO1/CRM1) inhibitor, has demonstrated anti-leukemia activity as a single agent, as well as in combination with anthracyclines and/or DNA-damaging agents.MethodsWe report the findings of a phase I dose escalation trial with cohort expansion in 20 patients with newly diagnosed or relapsed/refractory AML that combined selinexor with age-adjusted high-dose cytarabine and mitoxantrone (HiDAC/Mito).ResultsThree (15%) patients received the initial dose of 60 mg of selinexor (~ 35 mg/m2), and 17 (85%) received the target level of 80 mg (~ 50 mg/m2). No dose-limiting toxicities were observed. Common adverse events included febrile neutropenia (70%), diarrhea (40%), anorexia (30%), electrolyte abnormalities (30%), bacteremia (25%), cardiac toxicities (25%), fatigue (25%), and nausea/vomiting (25%). None were unexpected given the HiDAC/Mito regimen. Serious adverse events occurred in 6 (30%) patients; one was fatal. Ten (50%) patients achieved a complete remission (CR), 3 (15%) achieved CR with incomplete recovery (CRi), 1 (5%) achieved partial remission (PR), and 6 (30%) had progressive disease for an overall response rate (ORR) of 70%. Eight of 14 (57%) responders proceeded to allogeneic stem cell transplantation. Correlative studies of WT1 levels showed persistently detectable levels in patients who either did not respond or relapsed quickly after induction.ConclusionThe selinexor/HiDAC/Mito regimen is feasible and tolerable at selinexor doses of 80 mg/day (~ 50 mg/m2/day) twice weekly. The recommended phase II dose is 80 mg and warrants further study in this combination.Trial registrationClinicalTrials.gov, NCT02573363. Registered October 5, 2015

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“…The fatal course of t-MDS/AML is due to profound and persistent cytopenias due to ineffective hematopoiesis regardless of the fraction of immature blasts accumulating in the bone marrow [61] . In contrast, a subsequent study reported a surprisingly high CR rate of 82% for t-MDS/AML treated with high-dose cytarabine + mitoxantrone [62] . For therapy-related acute promyelocytic leukemia (t-APL) and t-AML with good-risk cytogenetics, specifically inv(16) and t(8;21), induction chemotherapy is recommended, similar to the treatment guidelines for their de novo counterparts [28] .…”

Section: Conventional Chemotherapymentioning

confidence: 89%

Therapy-related myeloid neoplasms - what have we learned so far?

Zahid¹,

Parnes²,

Savani³

et al. 2016

WJSC

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Therapy-related myeloid neoplasms are neoplastic processes arising as a result of chemotherapy, radiation therapy, or a combination of these modalities given for a primary condition. The disease biology varies based on the etiology and treatment modalities patients receive for their primary condition. Topoisomerase Ⅱ inhibitor therapy results in balanced translocations. Alkylating agents, characteristically, give rise to more complex karyotypes and mutations in p53. Other etiologies include radiation therapy, high-dose chemotherapy with autologous stem cell transplantation and telomere dysfunction. Poor-risk cytogenetic abnormalities are more prevalent than they are in de novo leukemias and the prognosis of these patients is uniformly dismal. Outcome varies according to cytogenetic risk group. Treatment recommendations should be based on performance status and karyotype. An in-depth understanding of risk factors that lead to the development of therapyrelated myeloid neoplasms would help developing riskadapted treatment protocols and monitoring patients after treatment for the primary condition, translating into reduced incidence, early detection and timely treatment.

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Treatment of therapy-related myeloid neoplasms with high-dose cytarabine/mitoxantrone followed by hematopoietic stem cell transplant

Cited by 16 publications

References 28 publications

Therapy‐related myeloid neoplasms: pathobiology and clinical characteristics

Therapy‐related myeloid neoplasms: pathobiology and clinical characteristics

A phase I study of selinexor in combination with high-dose cytarabine and mitoxantrone for remission induction in patients with acute myeloid leukemia

Therapy-related myeloid neoplasms - what have we learned so far?

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