Prognostic implications of cytogenetics in adults with acute lymphoblastic leukemia treated with inotuzumab ozogamicin

Karyotype is frequently used to predict response and outcome in leukemia. This post hoc exploratory analysis evaluated the relationship between baseline cytogenetics and outcome in patients with relapsed/refractory acute lymphoblastic leukemia (R/R ALL) treated with inotuzumab ozogamicin (InO), a humanized CD22 antibody conjugated to calicheamicin, in the phase 3, open-label, randomized INO-VATE trial. Data as of March 8, 2016, are presented in this analysis. Of the 326 patients randomized, 284 had screening karyotyping data (144 in the InO arm and 140 in the standard care [SC] arm). With InO, complete remission or complete remission with incomplete hematologic recovery (CR/CRi), minimal residual disease negativity rates, and overall survival (OS) were not significantly different between cytogenetic subgroups. CR/CRi rates favored InO over SC in the diploid with ≥20 metaphases, complex, and “other” cytogenetic subgroups. The OS hazard ratio favored InO over SC in the diploid with ≥20 metaphases, complex, and other cytogenetic subgroups. Generally, InO is effective and provides substantial clinical benefit in patients with R/R ALL who have specific baseline karyotypes.     

Outcome of relapsed or refractory acute B-lymphoblastic leukemia patients and BCR-ABL-positive blast cell crisis of B-lymphoid lineage with extramedullary disease receiving inotuzumab ozogamicin

Acute lymphoblastic leukemia (ALL) can relapse in the extramedullary compartment, with or without medullary involvement. Response to treatment may be individual. We evaluated response to inotuzumab ozogamicin in 31 patients with relapsed/refractory B-ALL with extramedullary disease. Median age was 31 years (range, 19-81). All patients were heavily pretreated, including allogeneic hematopoietic stem cell transplantation (HSCT; n=18). Overall response rate after two cycles of inotuzumab ozogamicin was 84% (complete remission, 55%; partial remission, 29%; resistant disease, 13%; early death, 3%). The median follow-up was 29 months and median overall survival was 12.8 months. One-year and 2-year overall survival rates were 53% (95% CI: 37-76%) and 18% (95% CI: 8-43%), respectively. Age had no impact on overall survival when assessed as a continuous variable or dichotomized at 60 years. Twelve patients proceeded to allogeneic HSCT (complete remission, n=6; partial remission, n=3; resistant disease, n=3). Prior to allogeneic HSCT, eight patients received two or fewer cycles and four patients received three or four cycles of inotuzumab ozogamicin. Sinusoidal obstruction syndrome was reported in three patients, including one after transplantation. Allogeneic HSCT, evaluated as a time-dependent variable, had no impact on overall survival. Inotuzumab ozogamicin seems to be effective as a debulking strategy in relapsed/refractory ALL with extramedullary disease. However, inotuzumab ozogamicin followed by allogeneic HSCT seems not to be effective in maintaining long-term disease control.     

Gemtuzumab ozogamicin: first clinical experiences in children with relapsed/refractory acute myeloid leukemia treated on compassionate-use basis

Gemtuzumab ozogamicin (GO; Mylotarg) was developed to treat CD33(+) acute myeloid leukemia (AML). To date, only studies in adults and preliminary data from a phase 1 study in children have been reported. We report data on 15 children with relapsed/refractory CD33(+) AML who were treated with GO monotherapy on compassionate use basis (4-9 mg/m(2) up to 3 courses). Eight children showed a reduction in bone marrow blasts to 5% or less, including 5 in complete remission without full platelet recovery (CRp). Three of the 5 children with CRp received transplants almost directly following the last GO course, without awaiting further platelet regeneration. Hence in these children no clear discrimination between complete remission (CR) and CRp could be made. In 6 of 8 responding patients further treatment was given consisting of stem cell transplantation (SCT). Two patients are still alive, currently 6 and 9 months after SCT. Hematologic toxicity was difficult to assess due to subsequent SCT or leukemia. Side effects, in one patient each included veno-occlusive disease, transient grade 3 hyperbilirubinemia, transient grade 3 transaminase elevation, and grade 3 hypotension during GO administration. No infections or mucositis occurred. This report demonstrates clinical efficacy of GO in a subset of relapsed/refractory pediatric CD33(+) AML patients and suggests that intensive postremission therapy after remission induction by GO may result in durable responses in some patients, although follow-up is still short. Further studies are needed to determine the efficacy and safety of GO in children with AML.     

Daunorubicin in patients with relapsed and refractory acute nonlymphoblastic leukemia previously treated with anthracycline

While the efficacy of daunorubicin (DNR) in first induction of patients with acute nonlymphoblastic leukemia (ANLL) has been well documented, little data are available concerning the activity of DNR in patients with relapsed and refractory ANLL previously treated with anthracycline. We administered DNR (60 mg/m²/day for 3-5 days) in 21 patients with relapsed (n=12) or refractory (n=9) ANLL previously treated with anthracycline. The general response rate was 48%, with a complete response (CR) rate of 38%. Five of 12 patients with relapsed ANLL and 3 of 9 patients with refractory ANLL achieved CR. Among these cases with CR in refractory ANLL, the evolution of one patient is particularly illustrative since he had received previously a large cumulative dose of anthracycline (540 mg/m²) and has been shown to be refractory to high-dose cytosine arabinoside. This study suggests that previous administration of DNR or adriamycin does not Induce significant resistance to anthracycline: DNR appears to be almost as efficient in patients with relapsed and refractory ANLL previously treated with anthracycline as in first induction.     

Phase I trial of a novel human monoclonal antibody mAb216 in patients with relapsed or refractory B-cell acute lymphoblastic leukemia

Background

This phase I trial was conducted to determine the safety and pharmacokinetics of monoclonal antibody 216, a human monoclonal Immunoglobulin M antibody targeting a linear B-cell lactosamine antigen, administered alone and in combination with vincristine in patients with relapsed or refractory B-cell acute lymphoblastic leukemia, and to preliminarily assess tumor targeting and efficacy.

Design and Methods

Three cohorts of patients received escalating doses of monoclonal antibody 216 administered as an intravenous infusion. In the case of poor response to the first dose of monoclonal antibody 216 alone, defined as less than 75% reduction in peripheral blood blast count, a second dose of the antibody with vincristine was given between days 4 and 7. Responses were assessed weekly until day 35. Serum concentration of monoclonal antibody 216 was measured before and after infusion. Monoclonal antibody 216 targeting was determined with an anti-idiotypic antibody to monoclonal antibody 216 and preliminary efficacy was analyzed by changes in peripheral blood blasts.

Results

Thirteen patients were enrolled. One episode of grade 3 epistaxis was the only dose-limiting toxicity observed. All patients showed a poor response to the first monoclonal antibody 216 infusion with a decrease in peripheral blasts from 6–65% in 9 patients. In 8 patients, addition of vincristine to monoclonal antibody 216 resulted in an average reduction of the peripheral blasts of 81%. One patient without peripheral blasts achieved a hypoplastic marrow without evidence of leukemia after one infusion of monoclonal antibody 216 and monoclonal antibody 216/vincristine each. Monoclonal antibody 216 was detected on peripheral blasts in all patients.

Conclusions

Treatment with monoclonal antibody 216 in combination with vincristine is feasible and well tolerated in patients with relapsed or refractory B-cell acute lymphoblastic leukemia. Binding of monoclonal antibody 216 to leukemic blasts was efficient, and favorable early responses were observed.     

CAG-GO therapy for patients with relapsed or primary refractory CD33-positive acute myelogenous leukemia

We previously tested a less toxic CAG regimen consisting of low-dose cytarabine, aclarubicin and granulocyte-colony stimulating factor for the treatment of patients with relapsed or refractory myeloid malignancies or elderly patients with untreated ones, obtaining a satisfactory complete remission rate of 62%. Gemtuzumab ozogamicin, an anti-CD33 monoclonal antibody conjugated to calicheamicin, has recently been approved as a single agent in Japan for the treatment of relapsed/refractory CD33-positive acute myelogenous leukemia (9 mg/m(2) on days1 and 15). Complete remission rate was reported as 30% in a phase 2 trial in Japan. In this study, effectiveness and safety of combining dose-attenuated gemtuzumab ozogamicin (3 mg/m(2) on day5) and original CAG regimen were assessed in nine patients with relapsed/refractory CD33-positive acute myelogenous leukemia and a median age of 70 years. Rate of complete remission with or without platelet recovery was 44% (4/9). The median duration of complete remission and overall survival were 5.5 and 16 months, respectively. Reversible myelosuppression and liver toxicity were the main adverse events, but no regimen-related death was recorded. Although only a small number of cases were included in this preliminary study, this CAG-GO regimen was found to be feasible and useful even in high-risk relapsed or refractory patients.     

Molecular response in two children with relapsed acute myeloid leukemia treated with a combination of gemtuzumab ozogamicin and cytarabine

Phase I/II studies of gemtuzumab ozogamicin (GO) in pediatric refractory/relapsed acute myeloid leukemia (AML) have been reported. We present the cases of two children with relapsed AML who were treated with GO plus cytarabine, leading to a decrease of minimal residual disease down to levels not previously obtained. The toxicity profile of this treatment was relatively mild, except for severe but manageable myelosuppression.     

Progress and strategies for patients with relapsed and refractory acute myeloid leukemia

PURPOSE OF REVIEW: The treatment of patients with refractory or relapsed acute myeloid leukemia remains challenging. Management of these patients must take into account patient and leukemia-related factors in order to organize a comprehensive approach to treatment. Many new therapies are under study. RECENT FINDINGS: New molecular markers that represent mutations or gene overexpression have been identified including FMS-like tyrosine kinase-3 and nucleophosmin, which will enhance our ability to more accurately prognosticate for patients with acute myeloid leukemia. Monoclonal antibodies and peptide vaccination with leukemia-associated antigens bring the hope of increasing the remission and cure rates for patients with acute myeloid leukemia. The use of reduced-intensity conditioning blood or marrow transplantation is finding a broader role in the treatment of acute myeloid leukemia. SUMMARY: Patients with relapsed or refractory acute myeloid leukemia should be entered on clinical trials whenever feasible given the lack of consensus on the most effective treatment in this setting. Blood and marrow transplantation remains the only known curative therapy for these patients and the use of reduced-intensity conditioning blood or marrow transplantation offers the option of this approach to older and more infirm patients. Greater understanding of the biology of acute myeloid leukemia will provide new molecular targets of use in diagnosis, monitoring, and for the development of new, targeted therapies.     

CD33 expression and P-glycoprotein-mediated drug efflux inversely correlate and predict clinical outcome in patients with acute myeloid leukemia treated with gemtuzumab ozogamicin monotherapy

Gemtuzumab ozogamicin (GO) contains an anti-CD33 antibody to facilitate uptake of a toxic calicheamicin-gamma(1) derivative. While recent in vitro data demonstrated a quantitative relationship between CD33 expression and GO cytotoxicity, previous correlative studies failed to identify a significant association between CD33 expression and clinical outcome. Studying patients undergoing GO monotherapy for relapsed acute myeloid leukemia (AML), we now find that AML blasts of responders have a significantly higher mean CD33 level and lower P-glycoprotein (Pgp) activity compared with nonresponders. CD33 expression and Pgp activity are inversely correlated. While both variables are associated with outcome, Pgp remains significantly associated with outcome even after adjusting for CD33, whereas CD33 does not show such an association after adjusting for Pgp. The inverse relationship between CD33 and Pgp suggests a maturation-stage-dependent expression of both proteins, and offers the rationale for using cell differentiation-promoting agents to enhance GO-induced cytotoxicity.     

Safety and efficacy of ofatumumab, a fully human monoclonal anti-CD20 antibody, in patients with relapsed or refractory B-cell chronic lymphocytic leukemia: a phase 1-2 study

Safety and efficacy of the fully human anti-CD20 monoclonal antibody, ofatumumab, was analyzed in a multicenter dose-escalating study including 33 patients with relapsed or refractory chronic lymphocytic leukemia. Three cohorts of 3 (A), 3 (B), and 27 (C) patients received 4, once weekly, infusions of ofatumumab at the following doses: (A) one 100 mg and three 500 mg; (B) one 300 mg and three 1000 mg; (C) one 500 mg and three 2000 mg. Sixty-seven percent of the patients were Binet stage B, and the median number of previous treatments was 3. The maximum tolerated dose was not reached. The majority of related adverse events occurred at first infusion, and the number of adverse events decreased at each subsequent infusion. Seventeen (51%) of 33 patients experienced infections, 88% of them of grade 1-2. One event of interstitial pneumonia was fatal; all other cases resolved within one month. The response rate of cohort C was 50% (13/26), one patient having a nodular partial remission and 12 patients partial remission. In conclusion, ofatumumab was found to be well tolerated in patients with chronic lymphocytic leukemia (CLL) in doses up to 2000 mg. Preliminary data on safety and objective response are encouraging and support further studies on the role of ofatumumab in CLL patients. This trial was registered at www.clinicaltrials.gov as no. NCT00093314.     

Murine monoclonal antibody therapy in two patients with chronic lymphocytic leukemia

We infused the murine monoclonal antibody T101 into two patients with advanced refractory chronic lymphocytic leukemia (CLL) after confirming its reactivity with their CLL cells. One patient received doses of 1, 3, and 12 mg; the second patient received 10 mg. Antibody was delivered over 10--15 min. The major observations were: (1) T101 murine monoclonal antibody did bind to cells with T65 surface antigen and saturated these cells in vivo; (2) cells that bound T101 disappeared from the circulation by 2 hr after treatment, as evidenced by a marked drop in lymphocyte counts; (3) T101 serotherapy resulted in some intravascular cell injury associated with sequestration and probably destruction in the liver and lung; (4) free serum T101 was demonstrable, but disappeared by 2--4 hr after infusion; (5) rapid infusion of T101 did not induce significant modulation of T65; (6) rapid infusion of greater than 10 mg of T101 was associated with significant systemic reactions. Monoclonal antibodies may someday have an application in leukemia therapy, but additional experimental trials are clearly indicated.     

Gemtuzumab ozogamicin in combination with vorinostat and azacitidine in older patients with relapsed or refractory acute myeloid leukemia: a phase I/II study

Epigenetic therapeutics such as the histone deacetylase inhibitor, vorinostat, and the DNA methyltransferase I inhibitor, azacitidine, enhance gemtuzumab ozogamicin efficacy in vitro. We therefore investigated vorinostat/azacitidine/gemtuzumab ozogamicin in 52 adults aged 50 years or over with acute myeloid leukemia requiring therapy for first relapse (remission duration ≤12 months) or primary refractory disease in a phase I/II trial. Vorinostat and gemtuzumab ozogamicin were escalated step-wise during the phase I portion of the trial. Vorinostat (400 mg/day orally from Days 1–9), azacitidine (75 mg/m²/day intravenously or subcutaneously from Days 1–7), and gemtuzumab ozogamicin (3 mg/m²/day intravenously on Days 4 and 8) were identified as the maximum tolerated dose. Among the 43 patients treated at this dose, 10 achieved a complete remission and 8 achieved a complete remission with incomplete blood count recovery, for an overall response rate of 41.9% (exact 95% confidence interval (CI): 27.0–57.9%). Four of these 18 patients (2 with complete remission and 2 with complete remission with incomplete blood count recovery) had persistence of minimal residual disease by flow cytometry at the time of best response. Four patients died within 28 days of treatment initiation. Median overall survival for the 18 patients achieving complete remission/complete remission with incomplete blood count recovery was significantly longer than for those 21 patients who failed therapy but lived at least 29 days after treatment initiation (224.5 days (range 70–798) vs. 95 days (range 36–900); P=0.0023). These data indicate that vorinostat/azacitidine/gemtuzumab ozogamicin has activity in this difficult-to-treat acute myeloid leukemia patient subset. (ClinicalTrials.gov: identifier 00895934).     

Effects of monoclonal antibody therapy in patients with chronic lymphocytic leukemia

A phase I clinical trial was initiated to treat patients with stage IV B-derived chronic lymphocytic leukemia (CLL) with the IgG2a murine monoclonal antibody T101. This antibody binds to a 65,000-mol wt (T65) antigen found on normal T lymphocytes, malignant T lymphocytes, and B- derived CLL cells. All of the patients had a histologically confirmed diagnosis of advanced B-derived CLL and were refractory to standard therapy, and more than 50% of their leukemia cells reacted with the T101 antibody in vitro. The patients received T101 antibody two times per week, over two to 50 hours by intravenous administration in 100 mL of normal saline containing 5% human albumin. Twelve patients were treated with a fixed dosage of 1, 10, 50, or 100 mg, and one patient was treated with 140 mg of antibody. It was demonstrated that patients given two-hour infusions of 50 mg developed pulmonary toxicity, with shortness of breath and chest tightness. This toxicity was eliminated when infusions of 50 or 100 mg of T101 were prolonged to 50 hours. All dose levels caused a rapid but transient decrease in circulating leukemia cell counts. In vivo binding to circulating and bone marrow leukemia cells was demonstrated at all dose levels with increased binding at higher dosages. Antimurine antibody responses were not demonstrated in any patients at any time during treatment. Circulating free murine antibody was demonstrated in the serum of only the two patients treated with 100 mg of antibody as a 50-hour infusion and the patient treated with 140 mg of antibody over 30 hours. Antigenic modulation was demonstrated in patients treated at all dose levels but was particularly apparent in patients treated with prolonged infusions of 50 and 100 mg of antibody. We were also able to demonstrate antigenic modulation in lymph node cells, which strongly suggests in vivo labeling of these cells. Overall, T101 antibody alone appears to have a very limited therapeutic value for patients with CLL. The observations of in vivo labeling of tumor cells, antigenic modulation, antibody pharmacokinetics, toxicity, and antimurine antibody formation may be used in the future for more effective therapy when drugs or toxins are conjugated to the antibody.     

Risk factors for candidemia in patients with acute lymphocytic leukemia

Between 1983 and 1987 the overall incidence of candidemia at the Institut Gustave Roussy, a tertiary care referral hospital for patients with cancer, increased from 0.1% (7 of 6,801) to 0.32% (24 of 7,515) (P = .009). Because acute lymphocytic leukemia (ALL) was the most common underlying disease in patients with candidemia, risk factors for candidemia were analyzed in this subset of patients. A case-control study comparing the eight ALL patients who had candidemia with 18 ALL control patients revealed that previous bacteremia, prolonged neutropenia, prolonged fever, prolonged administration of antimicrobial agents, treatment with multiple antimicrobial agents, and a relatively high concentration of Candida organisms in stool were significant risk factors for candidemia. In a logistic regression analysis, however, only receipt of vancomycin and/or imipenem was identified as an independent risk factor for candidemia. Further analysis showed that administration of vancomycin promoted proliferation of Candida organisms in the gastrointestinal tract and that this proliferation was associated with an increased risk of candidemia.