Response-adapted, time-limited venetoclax, umbralisib, and ublituximab for relapsed/refractory chronic lymphocytic leukemia.

ABSTRACT: Many patients with chronic lymphocytic leukemia (CLL) will develop treatment resistance to Bruton tyrosine kinase (BTK) inhibitors. Phosphatidylinositol-3-kinase (PI3K) inhibitors, including umbralisib, have significant clinical activity in relapsed/refractory CLL, but prolonged exposure is associated with potential toxicities. Owing to the synergistic antitumor effects of combined PI3K and BCL-2 inhibition, we sought to explore the feasibility of response-adapted, time-limited therapy to optimize disease control while mitigating the risks of prolonged treatment. We conducted a phase 1/2 clinical trial to determine the safety and efficacy of venetoclax in combination with umbralisib and the anti-CD20 monoclonal antibody, ublituximab, (U2-VeN) in patients with relapsed/refractory CLL (N = 46) and Richter transformation (N = 5). After 12 cycles, treatment was stopped for patients with CLL who achieved undetectable minimal residual disease (uMRD). Adverse events of special interest included diarrhea in 50% of patients (11% grade 3/4), and aspartate aminotransferase and/or alanine aminotransferase elevation in 15 patients (33%), with 3 (7%) grade 3/4. There were no cases of tumor lysis syndrome related to venetoclax, with outpatient initiation in 96% of patients. The intent-to-treat overall response rate for CLL was 98% with best response of 100% in evaluable patients (42% complete responses). The end-of-treatment rate of uMRD at 10-4 in bone marrow was 77% (30/39), including a 71% uMRD rate among 14 patients refractory to prior BTK inhibitor. Time-limited venetoclax and U2 is safe and highly effective combination therapy for patients with relapsed/refractory CLL including those who have been previously treated with covalent BTK inhibitors. This trial was registered on www.clinicaltrials.gov as #NCT03379051.

Risk of brain metastases in T1-3N0 NSCLC: a population-based analysis.

AIM: Several consensus guidelines recommend against routine brain imaging at diagnosis of T1-3N0 non-small cell lung cancer (NSCLC). METHODS: From the Surveillance, Epidemiology and End Results registry, patients with pathologically confirmed T1-3N0 NSCLC were identified. Risks of brain metastases at time of initial diagnosis were analyzed. RESULTS: Patients selected to not undergo primary NSCLC resection had approximately tenfold greater incidence of brain metastases versus those who did. Younger age, adenocarcinoma histology, higher tumor stage and higher histologic grade were all significantly (p < 0.0001) associated with greater likelihood of presenting with brain metastases. CONCLUSION: Given the morbidity and mortality of brain metastases, routine brain screening after NSCLC diagnosis (particularly adenocarcinoma) may be justifiable, though more refined cost-benefit analyses are warranted.

nab-Paclitaxel-Based Therapy in Underserved Patient Populations: The ABOUND.PS2 Study in Patients With NSCLC and a Performance Status of 2.

INTRODUCTION: The phase II ABOUND.PS2 study (NCT02289456) assessed safety/tolerability of a first-line modified nab-paclitaxel/carboplatin regimen for patients with advanced non-small cell lung cancer (NSCLC) and Eastern Cooperative Oncology Group (ECOG) performance status (PS) 2. METHODS: Chemotherapy-naive patients with stage IIIB/IV NSCLC and ECOG PS 2 received four cycles of nab-paclitaxel 100 mg/m2 days 1 and 8 plus carboplatin area under the curve 5 day 1 q3w (induction). Patients without progression received nab-paclitaxel monotherapy (100 mg/m2 days 1 and 8 q3w) until progression/unacceptable toxicity. Primary endpoint: percentage of patients discontinuing induction due to treatment-emergent adverse events (TEAEs). RESULTS: 11/40 treated patients (27.5%; 95% CI, 14.60-43.89) discontinued chemotherapy induction due to TEAEs; 16/40 (40.0%) continued nab-paclitaxel monotherapy. Median progression-free and overall survival were 4.4 (95% CI, 2.99-7.00) and 7.7 (95% CI, 4.93-13.17) months. Grade 3/4 TEAEs during induction included neutropenia (22.5%), anemia (17.5%), thrombocytopenia (5.0%), and peripheral neuropathy (2.5%). CONCLUSION: This nab-paclitaxel-based regimen was tolerable in patients with advanced NSCLC and ECOG PS 2, with efficacy comparable to historical chemotherapy data.

SWOG0919: a Phase 2 study of idarubicin and cytarabine in combination with pravastatin for relapsed acute myeloid leukaemia.

Inhibition of cholesterol synthesis and uptake sensitizes acute myeloid leukaemia (AML) blasts to chemotherapy. A Phase 1 study demonstrated the safety of high dose pravastatin given with idarubicin and cytarabine in patients with AML and also demonstrated an encouraging response rate. The Southwestern Oncology Group (SWOG) trial, SWOG S0919, was a Phase 2 trial evaluating the complete remission (CR) rate in a larger number of patients with relapsed AML treated with idarubicin, cytarabine and pravastatin. This study closed to accrual after meeting the defined criterion for a positive study. Thirty-six patients with a median age of 59 years (range 23-78) were enrolled. The median time from diagnosis to registration was 18 months. Relapse status was first relapse, 17 patients (47%); second relapse, 15 patients (42%); third relapse, two patients (5·5%) and fourth relapse, two patients (5·5%). The response rate was 75% [95% confidence interval: 58-88%; 20 CRs, 7 CR with incomplete count recovery (CRi)], and the median overall survival was 12 months. The P-value comparing 75-30% (the null response rate based on prior SWOG experience) was 3·356 × 10(-4) . Given the encouraging CR/CRi rate, this regimen should be considered for testing in a prospective randomized trial against best conventional therapy.

Sequential cytarabine and alpha-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 ß-emitters, the α-particle-emitting radionuclide bismuth-213 ((213)Bi) was conjugated to lintuzumab. This phase I/II trial was conducted to determine the maximum tolerated dose (MTD) and antileukemic effects of (213)Bi-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/m(2)/d) for 5 days followed by (213)Bi-lintuzumab (18.5-46.25 MBq/kg). RESULTS: The MTD of (213)Bi-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 (213)Bi-lintuzumab was achieved after partial cytoreduction with cytarabine. CONCLUSIONS: Sequential administration of cytarabine and (213)Bi-lintuzumab is tolerable and can produce remissions in patients with AML.

Rapid method for detection of mutations in the nucleophosmin gene in acute myeloid leukemia.

Mutations in exon 12 of the nucleophosmin gene (NPM1) that cause the encoded protein to abnormally relocate to the cytoplasm are found at diagnosis in about 50% of karyotypically normal acute myeloid leukemias and are associated with a more favorable outcome. We have devised a PCR-based assay for NPM1 exon 12 mutations using differential melting of an oligo probe labeled with a fluorescent dye. The nucleobase quenching (NBQ) phenomenon was used to detect probe hybridization, and an oligonucleotide containing locked nucleic acid (LNA) nucleotides was used as a PCR clamp to suppress amplification of the normal sequence and enhance the analytical sensitivity of the assay. After the NBQ assay, the specimens with a mutation were removed from the capillary and sequenced to identify the mutation. The use of the LNA clamp facilitates interpretation of the mutant sequence because of the lower intensity of the overlapping normal sequence. Analysis of a series of 70 patient specimens revealed 17 positive for an NPM1 mutation and 53 negatives. All of the NBQ results (positives and negatives) were confirmed with other methods. The analytical sensitivity of the NBQ assay is variable depending on the concentration of the PCR clamp and other parameters. Using a 100 nmol/L concentration of the LNA clamp, NPM1 mutations were detectable in a 10-fold excess of wild-type DNA. This assay may be valuable for screening disease specimens.

The promise of targeted {alpha}-particle therapy.

The use of monoclonal antibodies to deliver radioisotopes directly to tumor cells has become a promising strategy to enhance the antitumor effects of native antibodies. Since the alpha- and beta-particles emitted during the decay of radioisotopes differ in significant ways, proper selection of isotope and antibody combinations is crucial to making radioimmunotherapy a standard therapeutic modality. Because of the short pathlength (50-80 microm) and high linear energy transfer ( approximately 100 keV/microm) of alpha-emitting radioisotopes, targeted alpha-particle therapy offers the potential for more specific tumor cell killing with less damage to surrounding normal tissues than beta-emitters. These properties make targeted alpha-particle therapy ideal for the elimination of minimal residual or micrometastatic disease. Radioimmunotherapy using alpha-emitters such as (213)Bi, (211)At, and (225)Ac has shown activity in several in vitro and in vivo experimental models. Clinical trials have demonstrated the safety, feasibility, and activity of targeted alpha-particle therapy in the treatment of small-volume and cytoreduced disease. Further advances will require investigation of more potent isotopes, new sources and methods of isotope production, improved chelation techniques, better methods for pharmacokinetic and dosimetric modeling, and new methods of isotope delivery such as pretargeting. Treatment of patients with less-advanced disease and, ultimately, randomized trials comparing targeted alpha-particle therapy with standard approaches will be required to determine the clinical utility of this approach.

Antibody-based treatment of acute myeloid leukaemia.

Monoclonal antibodies have become an important treatment modality in cancer therapy. Genetically engineered chimaeric and humanised antibodies have demonstrated activity against a variety of tumours. Whereas the humanised anti-CD33 monoclonal antibody HuM195 has only modest activity against overt acute myeloid leukaemia (AML), it can eliminate minimal residual disease detectable by reverse transcription-polymerase chain reaction in acute promyelocytic leukaemia. High-dose radioimmunotherapy with beta-particle-emitting isotopes targeting CD33, CD45 and CD66 can potentially allow intensification of antileukaemic therapy before bone marrow transplantation. Conversely, alpha-particle immunotherapy with isotopes such as bismuth-213 or actinium-225 offers the possibility of selective tumour cell kill while sparing surrounding normal cells. Targeted chemotherapy with the anti-CD33-calicheamicin construct gemtuzumab ozogamicin has produced remissions as a single agent in patients with relapsed AML and appears promising when used in combination with standard chemotherapy in the treatment of newly diagnosed AML.