Concise Reviews of Studies Relevant to Hematology Oncology Pharmacy

JHOP - June 2012, Vol 2, No 2 - From the Literature
Robert J. Ignoffo, PharmD, FASHP, FCSHP

Professor of Pharmacy
College of Pharmacy
Touro University–California, Mare Island
Vallejo, CA
Clinical Professor Emeritus
University of California
San Francisco, CA

Inotuzumab Ozogamicin Shows High Response Rate in Refractory/Relapsed ALL

Background: Patients with refractory or relapsed acute lymphoblastic leukemia (ALL) have a poor prognosis. Inotuzumab ozogamicin is a monoclonal antibody against CD22, which is highly expressed on the surface of leukemic cells in patients with ALL. Studies with other monoclonal antibodies against CD22 or other surface antigens have shown encouraging activity in patients with ALL.

Design: This phase 2 study conducted at M.D. Anderson Cancer Center investigated the use of inotuzumab ozogamicin in patients with relapsed or refractory ALL. The study initially included adults only (aged >18 years) with refractory or relapsed ALL of B-cell origin; after the safe use of ≥1 course of the study medication in ≥10 adults, patients aged <16 years were also eligible to participate. The study enrolled 49 patients, 3 of whom were aged ≤16 years and the remainder were adults. The primary end point was overall response.

Summary: A total of 49 patients were treated. Of these patients, 9 (18%) had a complete response (CR), 19 (39%) had a marrow CR, 19 had resistant disease (39%), and 2 (4%) died within 4 weeks of treatment onset. Median number of courses was 2 (range, 1-5 courses), and median time between courses was 3 weeks (range, 3-6 weeks). The overall response rate was 57%, and the median overall survival (OS) was 5.1 months. The 57% response rate was much higher than the rates reported in previous studies, but the study was of short duration.

The most frequent adverse events (AEs) in the first course of treatment were fever (n = 29), hypotension (n = 13), increased bilirubin (n = 14), and increased aminotransferase concentration (n = 28). These AEs did not increase in frequency with subsequent treatment courses, and no additional events were seen with additional courses.

Takeaway: Although this is only a phase 2 study, single- agent use of this monoclonal antibody produced impressive results, including complete bone marrow responses in more than 50% of the patients receiving this drug, and median survival duration of 5.1 months. This drug warrants further study in refractory or relapsed ALL in a phase 3 clinical trial. Furthermore, because it targets another often-expressed surface marker— CD22—it should also be tested in combination with standard first-line agents.

Kantarjian H, Thomas D, Jorgensen J, et al. Inotuzumab ozogamicin, an anti-CD22-calecheamicin conjugate, for refractory and relapsed acute lymphocytic leukaemia: a phase 2 study. Lancet Oncol. 2012;13:403-411.

 

Allogeneic Transplantation in Young Patients with ALL Who Fail Induction Therapy

Background: Induction therapy failure is rare in children and adolescents with ALL, but it has been associated with a poor outcome in this patient population. Treatment options after induction failure include allogeneic hematopoietic stem-cell transplantation and chemotherapy.

Design: This large, retrospective, international study included data from 14 cooperative groups, totaling 44,017 patients aged 0 to 18 years with newly diagnosed ALL. Induction failure was identified in a subgroup of 1041 (2.4%) of these patients. Data were collected on clinical and biological characteristics, previous treatments used, early responses to treatment, and survival outcomes in this subgroup of patients.

Summary: Conventional risk factors for children and adolescents with ALL, such as high leukocyte count (median, 42 × 109/L), age >6 years at diagnosis (median, 8.1 years), Philadelphia chromosome, and T-cell phenotype, were even more prevalent in this group and were associated with a worse prognosis. The study population was very heterogeneous; characteristics such as age ≥10 years, T-cell leukemia, the presence of an 11q23 rearrangement, and ≥25% blasts in the bone marrow at the end of induction therapy were associated with a particularly poor outcome. In contrast, high hyperdiploidy (a modal chromosome number >50) and age <6 years were associated with more favorable outcomes in patients with precursor B-cell leukemia. Allogeneic stem-cell transplantation was associated with better outcomes than chemotherapy in patients with T-cell leukemia, but it did not show benefit over chemotherapy in patients with precursor B-cell ALL without other adverse genetic features. These patients fared better with chemotherapy.

Takeaway: This is the largest retrospective analysis of outcomes after treatment failure in childhood ALL. Clinical and biological factors were major determinants in the outcomes observed in these patients. The best outcomes were seen in patients with precursor B-cell ALL who were either aged <6 years or those who had high hyperdiploidy. These patients accounted for approximately 25% of all patients with induction failure, and their outcomes were associated with a 10-year survival rate of >50%. Patients with T-cell ALL who were aged <6 years were best managed with allogeneic bone marrow transplant therapy. In contrast, patients aged <6 years with precursor B-cell ALL did better with chemotherapy than with transplantation. This study had several limitations, most notably the heterogeneity of the patient groups. In addition, the outcomes reported often preceded the use of several new targeted agents, including tyrosine kinase inhibitors. Clinicians should take the results of this study and design trials that will further define the appropriate treatment strategies in this patient population, especially in patient groups with the worst prognosis.

Schrappe M, Hunger SP, Pui C, et al. Outcomes after induction failure in childhood acute lymphoblastic leukemia. N Engl J Med. 2012;366: 1371-1381.

 

Phased Ipilimumab Improves PFS and OS in NSCLC

Background: Ipilimumab, a fully human anticytotoxic Tlymphocyte antigen-4 (anti-CTLA-4) monoclonal antibody, is approved in the United States for unresectable or metastatic melanoma and is being studied alone or as part of a combination regimen in several other cancers.

Design: A double-blind, international, phase 2 study was conducted to evaluate ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in advanced non–small-cell lung cancer (NSCLC). Because the sequence in which chemotherapy and immunotherapy are given can have an impact on outcome, ipilimumab was given with the other agents in a concurrent and in a phased regimen. To supplement each chemotherapy administration, previously untreated adult patients with NSCLC (stage IIIB/IV) were randomly assigned 1:1:1 to a concurrent ipilimumab regimen (4 ipilimumab doses followed by 2 placebo doses), a phased regimen (2 placebo doses followed by 4 ipilimumab doses), or a control regimen (up to 6 doses of placebo). Ipilimumab or placebo, paclitaxel, and carboplatin were administered intravenously once every 3 weeks for up to 18 weeks, followed by ipilim umab or placebo once every 12 weeks until progression, intolerance, or death. The primary end point was immune-related progression-free survival (PFS); PFS and duration of OS were key secondary end points.

Summary: A total of 204 patients were randomized to the concurrent (n = 70), phased (n = 68), and control (n = 66) regimens. Phased ipilimumab improved immunerelated PFS significantly compared with the control group (P = .05), whereas the concurrent regimen did not significantly improve immune-related PFS (P = .13) versus the control group. Phased ipilimumab also improved PFS (P = .02). For both immune-related PFS and PFS, differences in favor of phased ipilimumab over the control group appeared to be greater in patients with squamous histology than those with nonsquamous histology. Median OS durations were 9.7, 12.2, and 8.3 months for the concurrent, phased, and control regimens, respectively. Grade 3 and 4 immune-related AE rates were 20%, 15%, and 6% for the concurrent, phased, and control regimens, respectively.

Takeaway: This randomized phase 2 study of ipilimumab has an interesting study design. It is designed to answer 2 important questions: (1) does the addition of ipilimumab to standard paclitaxel/carboplatin therapy improve PFS, immune-related PFS, or OS. And (2) does the scheduling of ipilimumab matter with regard to outcomes. The results confirm that the phased administration method is preferred and improves immune-related PFS by 4 months (hazard ratio [HR], 0.71). In the accompanying editorial published in the same issue, it is noted that the concurrent administration method also had an HR of 0.81 (P = .15), which the author suggested might have reached significance if the study size were larger. Nevertheless, these results justify the study of combination chemotherapy plus ipilimumab versus a standard platinum doublet.

Lynch TJ, Bondarenko I, Luft A, et al. Ipilimumab in combination with paclitaxel and carboplatin as first-line treatment in stage IIIB/IV non–smallcell lung cancer: results from a randomized, double-blind, multicenter phase II study. J Clin Oncol. 2012;30:2046-2054. Epub 2012 Apr 30.

 

Immunotherapy with Ipilimumab and GVAX Combination Safe for Metastatic Castration-Resistant Prostate Cancer

Background: In 2011, prostate cancer represented 11% of all cancer-related deaths in men. The granulocyte-macrophage colony-stimulating factor (GMCSF)-transduced allogeneic prostate cancer cells vaccine (GVAX) has been studied in hormone-refractory prostate cancer. When GM-CSF–secreting tumor-cell vaccines have been combined with the anti-CTLA-4 monoclonal antibody ipilimumab in preclinical studies, these agents have acted synergistically. An open-label, phase 1 study in men with metastatic castration-resistant prostate cancer was undertaken to determine whether immunotherapy with these 2 agents can be combined safely in the clinical setting.

Design: The dose-escalation study included 12 treatment- naïve patients with metastatic castration-resistant prostate cancer. A subsequent extension phase enrolled 16 patients, for a total of 28 patients overall. All patients received a priming GVAX intradermal dose. The patients then received additional doses every 2 weeks for 24 weeks, for a total of 13 injections. The patients received an escalating dose of ipilimumab 0.3, 1.0, 3.0, or 5.0 mg/kg every 4 weeks, for a total of 6 infusions, each administered on the same day as the GVAX vaccination. The primary end point was the safety of GVAX.

Summary: No severe immune-related AEs were reported with the lowest 2 doses. Other AEs included hypophysitis in 3 patients with the 3.0-mg/kg dose and in 2 patients with the 5.0-mg/kg dose. In addition, 1 patient had grade 4 sarcoid alveolitis with the 5.0-mg/kg dose, a dose-limiting effect. This led to the decision to expand the patient enrollment for the 3.0-mg/kg dose rather than the 5.0-mg/kg dose. In addition, the findings included durable prostate-specific antigen (PSA) responses, bone scan improvements, and tumor regression, indicating that this immunotherapy has clinical activity in this type of advanced prostate cancer. The most common AEs were injection-site reactions, fatigue, and pyrexia.

Takeaway: The goal of this phase 1 trial was to establish the safety of the anti-CTLA-4 antibody, ipilimumab, in combination with GM-CSF–secreting tumor-cell vaccine (ie, GVAX) in patients with metastatic hormonerefractory prostate cancer. At the highest dose levels attained, 3 and 5 mg/kg, immune-related reactions occurred, including hypophysitis and alveolitis (lifethreatening). The additional study of the 3-mg/kg dose demonstrated a manageable toxicity level. A total of 5 of the 28 patients had PSA responses. In addition, tumorspecific immune reactivity to GVAX (antibody responses to filamin B and prostate-specific membrane antigen [PSMA]) were tested. Patients who developed a PSMAspecific antibody response had a median OS of 46.5 months compared with 20.6 months in those without a PSMA-specific antibody response (P = .028). In addition, 15 patients showed stabilization of disease on bone scan. These results indicate that this immune-based combination therapy is worthy of further study.

van den Eertwegh AJM, Versluis J, van den Berg HP, et al. Combined immunotherapy with granulocyte-macrophage colony-stimulating factor- transduced allogeneic prostate cancer cells and ipilimumab in patients with metastatic castration-resistant prostate cancer: a phase 1 dose-escalation trial. Lancet Oncol. 2012;13:509-517.

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Last modified: May 21, 2015