Biosimilars: Are They Really Safe?

An increasing availability of biosimilars is an important step in the process of delivering optimal care while improving access for patients with cancer. Evolving regulatory mechanisms deal with biosimilars with different approaches within major regulatory agencies. We discuss some of the specific properties of biosimilars that merit attention in terms of optimizing their safety, delivering on appropriate related cost savings, and ensuring that appropriate premiums on innovative research are available to ensure ongoing progress in anticancer therapy.

Posterior reversible encephalopathy syndrome and takotsubo cardiomyopathy associated with lenvatinib therapy for thyroid cancer: a case report and review.

As immunotherapies including tyrosine kinase inhibitors become more widely used for the treatment of a variety of malignancies, it is important for prescribers and patients to understand the potential adverse effects associated with these drugs. It is especially important to understand the potentially fatal side effects associated with these drugs to further determine risk factors for their development. The review presents a case of posterior reversible encephalopathy syndrome with concomitant Takotsubo cardiomyopathy, associated with use of lenvatinib therapy for thyroid cancer. It discusses the interventions performed and outcome. Potential mechanisms for development of these rare adverse effects, as well as cases in which these adverse effects are seen with use of other tyrosine-kinase inhibitors will be presented. It is important to continue to report these side effects, and further studies are needed to elucidate potential risk factors for their development, as well as to determine prognosis after development.

Correction to: An analysis of the kinetics of molecular response during the first trimester of treatment with nilotinib in newly diagnosed chronic myeloid leukemia patients in chronic phase.

Correction to: J Cancer Res Clin Oncol (2017) 143:2059-2066 DOI 10.1007/s00432-017-2445-z.

An analysis of the kinetics of molecular response during the first trimester of treatment with nilotinib in newly diagnosed chronic myeloid leukemia patients in chronic phase.

PURPOSE: This study was aimed to analyze the association of very early molecular response to nilotinib with the achievement of deep molecular response (MR4) at 18 months. We hypothesized that the BCR-ABL1 levels during the first 3 months of therapy, and the kinetics of their descent in this period, could be predictive of deep molecular response thereafter. METHODS: This substudy of the ENEST1st trial included 60 patients with chronic myeloid leukemia in chronic phase treated with front-line nilotinib, and BCR-ABL1IS levels were measured using GUS as the control gene. The analysis included seven time points during the first trimester of treatment (baseline and fortnightly thereafter). RESULTS: The rates of MMR at 12 months, and of MR4 at 18 months (primary variable of the study), were 70 and 41%, respectively, similar to those obtained in the core study. BCR-ABL1IS ≤10% was achieved at 1, 1.5, 2 and 3 months in 50, 70, 83 and 93% of the patients, respectively. The observed shape of the BCR-ABL1IS descent was biphasic, with a faster slope during the first trimester and a median halving time (HT) of 11 days, the shortest reported in the literature. An HT ≤13 days was predictive of MMR at 12 months and MR4 at 18 months. CONCLUSIONS: The association of a shorter HT with response provides a rationale for exploring very early kinetics patterns in all patients treated with potent TKIs such as nilotinib.

Reduced CD62L Expression on T Cells and Increased Soluble CD62L Levels Predict Molecular Response to Tyrosine Kinase Inhibitor Therapy in Early Chronic-Phase Chronic Myelogenous Leukemia.

Purpose Immunologic surveillance of minimal residual disease in chronic myelogenous leukemia (CML) may be relevant for long-term control or cure of CML. Little is known about immune-modulatory effects of nilotinib in vivo, potentially predicting response to therapy. Patients and Methods A prospective and comprehensive flow cytometry-based immunomonitoring program paralleled the ENEST1st clinical study, investigating 52 nilotinib-naïve patients with chronic-phase CML. Data were verified in independent validation cohorts. Results T cells of patients with CML at diagnosis expressed low l-selectin (CD62L) levels, which was not a result of proportional aberrations of T-cell subsets. Low numbers of CD62L-expressing CD4+ and CD8+ T cells correlated with higher Sokal score, increased spleen size, and high leukocyte and peripheral-blood blast counts. At month 6 during nilotinib therapy, CD62L expression returned to levels of healthy individuals. The level of CD62L loss on T cells directly correlated with the extent of soluble CD62L (sCD62L) elevation. In parallel, the proteolytic activity of tumor necrosis factor α-converting enzyme (TACE; ADAM17, CD156b), the metalloproteinase shedding CD62L, was increased at diagnosis and significantly decreased during nilotinib treatment. High CD62L+ expression on both CD4+ and CD8+ T cells and, vice versa, low sCD62L levels at CML diagnosis were linked to superior molecular responses. These findings were corroborated in independent validation cohorts. Conclusion We demonstrate the prognostic impact of CD62L shedding from T cells and increased sCD62L plasma levels at CML diagnosis on molecular response to tyrosine kinase inhibitor therapy in early chronic-phase CML. Functionally, decreased CD62L may be a consequence of increased TACE-mediated CD62L cleavage and potentially impairs immune-cell function. Larger prospective studies are ongoing to confirm the prognostic relevance of this finding.

Concurrent use of proton pump inhibitors or H2 blockers did not adversely affect nilotinib efficacy in patients with chronic myeloid leukemia.

PURPOSE: The impact of proton pump inhibitors (PPIs) and histamine H2 receptor antagonists (H2 blockers) on the efficacy of nilotinib was evaluated. METHODS: Retrospective analyses were performed in patients with newly diagnosed Philadelphia chromosome-positive (Ph+) chronic myeloid leukemia in chronic phase (CML-CP; N = 492) and in patients with imatinib-resistant or imatinib-intolerant Ph+ CML-CP (N = 256) treated with nilotinib. RESULTS: In the newly diagnosed population, 87 (17.7 %) and 49 (10.0 %) patients received PPIs and H2 blockers, respectively. Major molecular response at 12 months was achieved by 59 (49.6 %) patients who received at least one PPI or H2 blocker (n = 119) and 153 (41.0 %) patients who did not receive any comedication (n = 373; P = 0.13). PPIs and H2 blockers were used by 77 (30.1 %) and 17 (6.6 %) patients with imatinib-resistant or imatinib-intolerant CML-CP, respectively. Major cytogenetic response by 12 months was achieved by 55 (64.0 %) patients who received at least one PPI or H2 blocker (n = 86) versus 98 (57.6 %) patients who did not receive any comedication (n = 170; P = 0.40); 39 (45.3 %) versus 65 (38.2 %), respectively, achieved complete cytogenetic response by 12 months (P = 0.34). Similar findings were observed in patients who received comedication for >50 % of the time on nilotinib therapy. Nilotinib steady-state trough concentration was not affected by the presence of PPIs or H2 blockers. CONCLUSIONS: Concurrent use of PPIs or H2 blockers did not affect the pharmacokinetics and efficacy of nilotinib in patients with Ph+ CML-CP.

Elacytarabine--lipid vector technology overcoming drug resistance in acute myeloid leukemia.

INTRODUCTION: Ara-C (cytarabine arabinoside) is a deoxycytidine analog that has an established role in the treatment of hematologic malignancies, especially acute myeloid leukemia. Resistance to ara-C occurs and impacts negatively on survival. To combat this, an elaidic acid ester of ara-C, called elacytarabine, has been developed. This novel agent is highly efficacious in cells with demonstrable resistance to the parent agent, including in solid tumor xenografts. AREAS COVERED: The mechanisms that account for the increased clinical activity of elacytarabine are discussed, including its ability to bypass the specialized transmembrane nucleoside transport system on which ara-C depends, its prolonged retention within the cell and its alternative effect on the cell cycle. The development and synthesis and pharmacokinetics are outlined, with emphasis on lipid vector technology. Ten clinical trials involving elacytarabine, either as monotherapy or part of a combination regimen, have been carried out in both solid tumor and hematologic malignancies. The efficacy and side effect profile results are summarized. EXPERT OPINION: Clinical trials in patients with hematological malignancies are reporting very encouraging efficacy results with an acceptable side effect profile. Elacytarabine has the potential to play an important role in the treatment of multiple malignancies in the future and results from an ongoing Phase III clinical trial are eagerly awaited.

Laromustine (cloretazine).

IMPORTANCE OF THE FIELD: In spite of the recent progress, the prognosis of acute myelogenous leukemia (AML) remains poor, particularly in patients with relapsed disease and in the elderly. In these situations, there is at present no standard of care, and new drugs are urgently needed. AREAS COVERED IN THIS REVIEW: Preclinical and clinical studies of Laromustine (formerly cloretazine, VNP-40101M), a new sulfonylhydrazine alkylator, in AML published between 2000 and September 2009 are presented and discussed. WHAT THE READER WILL GAIN: Mechanisms of action of Laromustine and preclincal data that support the rationale for its use in patients with AML are summarized. Laromustine has limited extramedullary toxicity. In Phase II studies, it produced 32% complete responses in elderly patients with previously untreated AML. In a Phase III comparative study of its combination with cytarabine in relapsed AML, increased response rate was offset by excessive toxicity. TAKE HOME MESSAGE: Laromustine has significant activity in AML. As a single agent, laromustine may represent an alternative to conventional treatments for elderly patients. Although significant activity was seen, safety and optimal dosing in combination regimen remain to be established and are now being investigated.

Anti proliferative activity of ELACY (CP-4055) in combination with cloretazine (VNP40101M), idarubicin, gemcitabine, irinotecan and topotecan in human leukemia and lymphoma cells.

This study evaluated combination drug partners for CP-4055, the C18:1(Delta9,trans) unsaturated fatty acid ester of cytarabine in HL-60 and U937 cells. Growth inhibition was assessed by ATP assay and drug interaction by the combination index and three dimensional methods. Synergy was observed in HL-60 cells for simultaneous combinations of CP-4055 with gemcitabine, irinotecan and topotecan, while combinations with cloretazine (VNP40101M) and idarubicin were additive. In U937 cells, synergy was observed with gemcitabine and additivity for the other drugs. In HL-60, the IC50 concentration of CP-4055 could be reduced 10-fold and that of gemcitabine 3-fold in combination versus the agents alone, an interaction that was independent of drug sequence, ratio and exposure time. In contrast, interactions of CP-4055 with the topoisomerase inhibitors became antagonistic when the drugs were administered 24 h prior to CP-4055 and at certain drug ratios, particularly in U937 cells. In summary, CP-4055 produced additive to synergistic anti proliferative activity when combined simultaneously with drugs from four mechanistic classes in cell culture models of human leukemia and lymphoma. The impact of drug sequence and ratio on the interactions argues for incorporation of these parameters into the design of combination chemotherapy regimens.

Plasma inhibitory activity (PIA): a pharmacodynamic assay reveals insights into the basis for cytotoxic response to FLT3 inhibitors.

We have developed a useful surrogate assay for monitoring the efficacy of FLT3 inhibition in patients treated with oral FLT3 inhibitors. The plasma inhibitory activity (PIA) for FLT3 correlates with clinical activity in patients treated with CEP-701 and PKC412. Using the PIA assay, along with in vitro phosphorylation and cytotoxicity assays in leukemia cells, we compared PKC412 and its metabolite, CGP52421, with CEP-701. While both drugs could effectively inhibit FLT3 in vitro, CEP-701 was more cytotoxic to primary samples at comparable levels of FLT3 inhibition. PKC412 appears to be more selective than CEP-701 and therefore less effective at inducing cytotoxicity in primary acute myeloid leukemia (AML) samples in vitro. However, the PKC412 metabolite CGP52421 is less selective than its parent compound, PKC412, and is more cytotoxic against primary blast samples at comparable levels of FLT3 inhibition. The plasma inhibitory activity assay represents a useful correlative tool in the development of small-molecule inhibitors. Our application of this assay has revealed that the metabolite CGP52421 may contribute a significant portion of the antileukemia activity observed in patients receiving oral PKC412. Additionally, our results suggest that nonselectivity may constitute an important component of the cytotoxic effect of FLT3 inhibitors in FLT3-mutant AML.

Novel agents in acute myeloid leukemia.

In the past 40 years, advances in supportive care and development of chemotherapeutic agents have led to improved outcomes in patients with acute myeloid leukemia. High relapse rates following remission have led to extensive efforts to develop techniques and regimens for detecting and eliminating minimal residual disease. However, the best postremission therapy has not been identified. Better understanding of the biology and the molecular pathogenesis of AML has led to the development of new, more specific agents and strategies for AML treatment. Targeted therapy has improved outcomes in some patients. Most of the new agents are less toxic then their predecessors, and they can be used in combination with the more intensive traditional regimens.

Cloretazine for the treatment of acute myeloid leukemia.

Cloretazine is a new sulfonylhydrazine alkylating agent with antileukemic activity. Phase I studies have shown myelosuppression to be the dose limiting toxicity in both solid tumors and leukemias. A large Phase II study of single agent cloretazine (600 mg/m2) confirmed its activity in patients with relapsed acute myeloid leukemia, and in elderly patients with previously untreated acute myeloid leukemia or myelodysplastic syndrome. It also confirmed the limited nonhematological toxicity, even in elderly patients. Cloretazine can be safely combined with cytarabine, and this combination regimen is currently being tested in a large Phase III study in patients with relapsed acute myeloid leukemia. Cloretazine is a promising new antileukemic agent that may be incorporated into an intensive combination regimen.