These data suggest that a number of FDA-approved chemotherapeutic agents have considerable activity against MLL-rearranged ALL and AML cell lines and some patient samples. This paper forms part of key pre-clinical groundwork for analysis of these agents as therapy for MLL- rearranged leukemia. We suggest that the data found herein form a basis for considering new treatment options for patients with MLL-rearranged leukemia following therapy with standard regimens.
We have identified a number of categories of drugs, as well as specific drugs, that are cytotoxic to MLL-rearranged cell lines. These include microtubule-interfering drugs, DNA intercalating agents, topoisomerase poisons, mTOR inhibitors, and proteasome inhibitors. In addition to these categories of drugs, some specific agents, such as mitomycin C, gemcitabine, clofarabine, and dasatinib, showed better efficacy than MTX and AraC. Overall, 42 out of the 89 agents tested were potent in at least one leukemia cell line. A total of 12 and 15 of these were potent in five or four cell lines, respectively, with an IC50 less than 1 μM. The twelve agents that were potent in all five cell lines include cladribine, docetaxel, vinblastine, mitomycin C, triethylenemelamine, mitoxantrone, daunorubicin, dactinomycin, gemcitabine, topotecan, etoposide, and teniposide. Some of the drugs, such as cladribine, ixabepilone, valrubicin, plicamycin, and vinorelbine, also performed well in the MLL-rearranged patient sample. Overall, this suggests there are a number of agents within the Approved Oncology Drug Set II that could be further evaluated for future clinical trials for MLL-rearranged pediatric leukemia.
The most active drugs against the patient sample in this study were cladribine, ixabepilone, valrubicin, plicamycin, and vinorelbine. Cladribine has historically been used for treatment of hairy cell leukemia.25
However, it has also been used to treat several refractory hematological malignancies, including AML.26
Complete and partial remission (CR and PR) rates were 27% and 32%, respectively, in pediatric AML patients pretreated with cladribine prior to induction therapy.27
Combination therapy of cladribine with AraC in adult AML patients who had relapsed or failed to respond to initial therapy enhanced the effective dose of AraC in the blood by 40% in seven out of nine patients.28
However, cladribine should be used cautiously in patients with renal dysfunction, as demonstrated by a case study of a pediatric AML patient treated with cladribine for 5 days.29
These previous studies, along with the data in this paper, suggest some potential for cladribine during treatment of MLL
-rearranged pediatric leukemia, as has been used anecdotally for a number of years, often when combined with etoposide.
The microtubule-interfering drugs produced promising results in this study. Vinorelbine, in combination with topotecan, thiotepa, dexamethasone, and gemcitabine, has been used to treat patients with relapsed or refractory acute leukemia.30
In one study, 36% of pediatric patients achieved CR and 11% achieved PR on this regimen.30
In another study, 37% of adult patients with refractory ALL achieved CR with a similar regimen.31
Ixabepilone is a new generation microtubule stabilizer that has mainly been used for metastatic breast cancer therapy in patients with few treatment options.32
It has also been used in a Phase II trial of patients with a variety of treatment- refractory sarcomas, malignant peripheral nerve sheath tumors, neuroblastoma, and Wilms tumors.33
Considering the potency of the microtubule-interfering agents in this study and others,34
and the prominent use of vincristine in current leukemia treatment protocols, vinorelbine and ixabepilone are reasonable candidates for further consideration in MLL-
Valrubicin is a derivative of doxorubicin, an anthracyline antibiotic with DNA intercalation abilities. Valrubicin has only been used for treatment of bladder cancer35
and topical application of developing skin tumors.36
Although, not previously used in leukemia patients, the effectiveness of valrubicin in cell lines and the patient sample suggest it for further analysis as a new therapeutic for MLL
Some of the agents tested in these experiments have been used for leukemia or lymphoma treatment already, although they are not part of typical frontline treatment regimens. For example, decitabine has gained increasing attention in leukemia and myelodysplastic syndrome settings.37
In Phase II studies of decitabine in combination with clofarabine and low-dose AraC, 59% of elderly patients with AML achieved CR with manageable toxicity profiles.39
In adult patients with refractory AML, CR was achieved in 34% of patients who received decitabine therapy.40
POETIC is currently conducting a Phase I study of decitabine in combination with AraC, daunorubicin, and etoposide chemotherapy for newly diagnosed patients with AML. Plicamycin has also been used, in combination with interferon-α or hydroxyurea, to treat patients with chronic myeloid leukemia (CML) and myeloid blast crisis.41
This treatment regimen has had limited success in CML or AML therapy. Three of thirteen patients with CML had PR or CR, while two became stabilized on treatment.41
The median survival of these patients increased to 24 months from previously reported 6-month median survival.41
A Phase II study of plicamycin and hydroxurea in patients with high-risk, relapsed, or refractory AML resulted in no patients with CR or PR, and considerable toxicity.42
These data suggest some caution against selecting plicamycin for clinical trial evaluation in pediatric patients with MLL-
In this report, we have attempted to identify agents that show effective in-vitro cytotoxicty against malignant cells and cell lines derived from patients with refractory leukemia. However, the spectrum of effective agents includes drugs that have acceptable toxicities, as well as those that carry the potential to induce molecular abnormalities with increased risk of secondary malignancies in the future. In deciding future clinical application of any selected agent, the benefit of inducing remission in a highly refractory malignancy should be carefully considered against the risk of such possibilities. Similarly, we have based their activity profiles largely on IC50 values. Although lower IC50 values are generally considered to suggest effectiveness against neoplastic cells, it does not necessarily mean it would be the most applicable clinically because of untested toxicity in the patient. Utilization of the information presented in this paper should take into consideration, particularly in heavily pretreated children, the potential adverse effects such as neurotoxicity, hepatotoxicity, and nephrotoxicity. Taken together, the results from this study highlight potential alternative therapeutic options for MLL-rearranged leukemias. The data presented herein demonstrate the need for further characterization of these drugs, either as single agents or in effective combination with novel targeted agents, for possible future clinical trials.