Suzanne Chanel

Leukocytosis and the Retinoic Acid Syndrome in Patients With Acute Promyelocytic Leukemia Treated With Arsenic Trioxide

PURPOSE Arsenic trioxide, like all-trans-retinoic acid (RA), induces differentiation of acute promyelocytic leukemia (APL) cells in vivo. Treatment of APL patients with all-trans RA is commonly associated with leukocytosis, and approximately 50% of patients develop the RA syndrome. We reviewed our clinical experience with arsenic trioxide to determine the incidence of these two phenomena. PATIENTS AND METHODS Twenty-six patients with relapsed or refractory APL were treated with arsenic trioxide for remission induction at daily doses that ranged from 0.06 to 0.17 mg/kg. RESULTS Twenty-three patients (88%) achieved complete remission. Leukocytosis was observed in 15 patients (58%). The median baseline leukocyte count for patients with leukocytosis was 3,900 cells/microL (range, 1,200 to 72,300 cells/microL), which was higher than that for patients who did not develop leukocytosis (2,100 cells/microL; range, 500 to 5,400 cells/microL; P =.01). No other cytotoxic therapy was administered, and the leukocytosis resolved in all cases. The RA syndrome was observed in eight patients (31%). Patients who developed leukocytosis were significantly more likely to develop the RA syndrome (P <.001), and no patient without a peak leukocyte count greater than 10,000 cells/microL developed the syndrome. Among the patients with leukocytosis, there was no observed relation between the leukocyte peak and the probability of developing the syndrome (P =.37). CONCLUSION Induction therapy of APL with all-trans RA and arsenic trioxide is associated with leukocytosis and the RA syndrome. These clinical effects seem to be intrinsically related to the biologic responsiveness and the differentiation process induced by these new agents.

Vaccination with synthetic analog peptides derived from WT1 oncoprotein induces T-cell responses in patients with complete remission from acute myeloid leukemia

A pilot study was undertaken to assess the safety, activity, and immunogenicity of a polyvalent Wilms tumor gene 1 (WT1) peptide vaccine in patients with acute myeloid leukemia in complete remission but with molecular evidence of WT1 transcript. Patients received 6 vaccinations with 4 WT1 peptides (200 microg each) plus immune adjuvants over 12 weeks. Immune responses were evaluated by delayed-type hypersensitivity, CD4+ T-cell proliferation, CD3+ T-cell interferon-gamma release, and WT1 peptide tetramer staining. Of the 9 evaluable patients, 7 completed 6 vaccinations and WT1-specific T-cell responses were noted in 7 of 8 patients. Three patients who were HLA-A0201-positive showed significant increase in interferon-gamma-secreting cells and frequency of WT1 tetramer-positive CD8+ T cells. Three patients developed a delayed hypersensitivity reaction after vaccination. Definite related toxicities were minimal. With a mean follow-up of 30 plus or minus 8 months after diagnosis, median disease-free survival has not been reached. These preliminary data suggest that this polyvalent WT1 peptide vaccine can be administered safely to patients with a resulting immune response. Further studies are needed to establish the role of vaccination as viable postremission therapy for acute myeloid leukemia.

Sequential Cytarabine and α-Particle Immunotherapy with Bismuth-213-Lintuzumab (HuM195) for Acute Myeloid Leukemia

Purpose: Lintuzumab (HuM195), a humanized anti-CD33 antibody, targets myeloid leukemia cells and has modest single-agent activity against acute myeloid leukemia (AML). To increase the potency of the antibody without the nonspecific cytotoxicity associated with β-emitters, the α-particle–emitting radionuclide bismuth-213 (213Bi) was conjugated to lintuzumab. This phase I/II trial was conducted to determine the maximum tolerated dose (MTD) and antileukemic effects of 213Bi-lintuzumab, the first targeted α-emitter, after partially cytoreductive chemotherapy. Experimental Design: Thirty-one patients with newly diagnosed (n = 13) or relapsed/refractory (n = 18) AML (median age, 67 years; range, 37-80) were treated with cytarabine (200 mg/m2/d) for 5 days followed by 213Bi-lintuzumab (18.5-46.25 MBq/kg). Results: The MTD of 213Bi-lintuzumab was 37 MB/kg; myelosuppression lasting >35 days was dose limiting. Extramedullary toxicities were primarily limited to grade ≤2 events, including infusion-related reactions. Transient grade 3/4 liver function abnormalities were seen in five patients (16%). Treatment-related deaths occurred in 2 of 21 (10%) patients who received the MTD. Significant reductions in marrow blasts were seen at all dose levels. The median response duration was 6 months (range, 2-12). Biodistribution and pharmacokinetic studies suggested that saturation of available CD33 sites by 213Bi-lintuzumab was achieved after partial cytoreduction with cytarabine. Conclusions: Sequential administration of cytarabine and 213Bi-lintuzumab is tolerable and can produce remissions in patients with AML. Clin Cancer Res; 16(21); 5303–11. ©2010 AACR.

Pilot study of combination transcriptional modulation therapy with sodium phenylbutyrate and 5-azacytidine in patients with acute myeloid leukemia or myelodysplastic syndrome.

Epigenetic mechanisms underlying tumorigenesis have recently received much attention as potential therapeutic targets of human cancer. We designed a pilot study to target DNA methylation and histone deacetylation through the sequential administration of 5-azacytidine followed by sodium phenylbutyrate (PB) in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Ten evaluable patients (eight AML, two MDS) were treated with seven consecutive daily subcutaneous injections of 5-azacytidine at 75 mg/m2 followed by 5 days of sodium PB given intravenously at a dose of 200 mg/kg. Five patients (50%) were able to achieve a beneficial clinical response (partial remission or stable disease). One patient with MDS proceeded to allogeneic stem cell transplantation and is alive without evidence of disease 39 months later. The combination regimen was well tolerated with common toxicities of injection site skin reaction (90% of the patients) from 5-azacytidine, and somnolence/fatigue from the sodium PB infusion (80% of the patients). Correlative laboratory studies demonstrated the consistent reacetylation of histone H4, although no relationship with the clinical response could be demonstrated. Results from this pilot study demonstrate that a combination approach targeting different mechanisms of transcriptional modulation is clinically feasible with acceptable toxicity and measurable biologic and clinical outcomes.

A pilot vaccination trial of synthetic analog peptides derived from the BCR-ABL breakpoints in CML patients with minimal disease

A pilot vaccination trial of synthetic analog peptides derived from the BCR-ABL breakpoints in CML patients with minimal disease

Pharmacokinetics and safety of ILX23-7553, a non-calcemic-vitamin D3 analogue, in a phase I study of patients with advanced malignancies

Purpose: Differentiation therapy is an alternative to chemotherapy with potentially less toxicity, improved quality of life, and survival. We conducted a phase I trial of ILX23-7553, a formulation of 1,25-dihydroxy-16-ene-23-yne-vitamin D3, a 1,25-dihydroxyvitamin D3 analog with preclinically demonstrated antitumor and differentiating effects and diminished hypercalcemic effects. Patients and methods: The protocol consisted of five daily oral treatments during 14-day cycles at 15 dose levels from 1.3 to 45.0 μg/m2/day. We treated 42 heavily pretreated patients who had a variety of malignancies with 162 treatment cycles, and obtained pharmacokinetics from three patients at the two highest dose levels. Results: There were no grade 3 or 4 toxicities. Grade 1–2 toxicities included diarrhea, nausea, fatigue, constipation, and one grade 1 hypercalcemia. Average day 6 calcium was 9.26 ± 0.55 mg/dl in cycle 1 and 9.30 ± 0.67 mg/dl in cycle 2. Pharmacokinetics at dose levels 14 (40 μg/m2/day) (1 patient) and 15 (45 μg/m2/day) (2 patients) demonstrated an average Cmax of 30.4 ± 7.8 pg/ml (0.07 nM) and 104 ± 38.2 pg/ml (0.25 nM), and AUCs of 222.5 ± 225.2 pg·h/ml and 855 ± 536 pg h/ml, respectively. Eight patients (19%) had stable disease. While in vitro effects have been reported at these concentrations, they were at least 10-fold lower than ED50s, and the study was terminated before an MTD was reached. Conclusion: The drug is safe and has potential benefits at serum concentrations where effects begin to be noted in vitro. Further study is needed with a reformulated higher unit dose compound to determine the safety and efficacy of higher serum concentrations.

Effect of long term imatinib on bone in adults with chronic myelogenous leukemia and gastrointestinal stromal tumors

Patients with chronic myelogenous leukemia (CML) or gastrointestinal stromal tumors (GIST) who take imatinib have abnormalities of bone metabolism. However, it is unclear what impact these changes have on bone mineral density (BMD). We prospectively analayzed levels of osteocalcin, a marker of bone formation secreted by osteoblasts, and serum N-telopeptide of type I collagen (NTX), a marker of bone resorption, as well as other minerals involved in bone metabolism in 19 patients with either CML or GIST We correlated these results with changes in bone mineral density as measured by serial dual energy X-ray absorptiometry (DEXA) scans over a two year period. Osteocalcin levels were low in 95% of patients and 37% had no measurable amount. Levels of NTX were less consistent. Nine patients (47%) had a decrease in BMD, four patients (2%) had an increase in BMD, and six patients (32%) had no change. There was no correlation between metabolic markers and change in BMD. We suggest that ongoing management of patients who take imatinib should include monitoring of bone health on a long term basis.

Phase 2 trial of a multivalent WT1 peptide vaccine (galinpepimut-S) in acute myeloid leukemia

A National Cancer Institute consensus study on prioritization of cancer antigens ranked the Wilms tumor 1 (WT1) protein as the top immunotherapy target in cancer. We previously reported a pilot study of a multivalent WT1 peptide vaccine (galinpepimut-S) in acute myeloid leukemia (AML) patients. We have now conducted a phase 2 study investigating this vaccine in adults with AML in first complete remission (CR1). Patients received 6 vaccinations administered over 10 weeks with the potential to receive 6 additional monthly doses if they remained in CR1. Immune responses (IRs) were evaluated after the 6th and 12th vaccinations by CD4+ T-cell proliferation, CD8+ T-cell interferon-γ secretion (enzyme-linked immunospot), or the CD8-relevant WT1 peptide major histocompatibility complex tetramer assay (HLA-A*02 patients only). Twenty-two patients (7 males; median age, 64 years) were treated. Fourteen patients (64%) completed ≥6 vaccinations, and 9 (41%) received all 12 vaccine doses. Fifteen patients (68%) relapsed, and 10 (46%) died. The vaccine was well tolerated, with the most common toxicities being grade 1/2 injection site reactions (46%), fatigue (32%), and skin induration (32%). Median disease-free survival from CR1 was 16.9 months, whereas the overall survival from diagnosis has not yet been reached but is estimated to be ≥67.6 months. Nine of 14 tested patients (64%) had an IR in ≥1 assay (CD4 or CD8). These results indicated that the WT1 vaccine was well tolerated, stimulated a specific IR, and was associated with survival in excess of 5 years in this cohort of patients. This trial was registered at www.clinicaltrials.gov as #NCT01266083.

Hsp90 inhibition disrupts JAK-STAT signaling and leads to reductions in splenomegaly in patients with MPNs.

The introduction of JAK inhibitors into clinical practice has improved outcomes for patients with myeloproliferative neoplasms (MPNs). Ruxolitinib, the only approved JAK inhibitor for MPN patients, has demonstrated an ability to decrease splenomegaly and relieve constitutional symptoms.[1][1]–[3][