Management of adverse events in patients with acute myeloid leukemia in remission receiving oral azacitidine: experience from the phase 3 randomized QUAZAR AML-001 trial

Background Most older patients with acute myeloid leukemia (AML) who attain morphologic remission with intensive chemotherapy (IC) will eventually relapse and post-relapse prognosis is dismal. In the pivotal QUAZAR AML-001 trial, oral azacitidine maintenance therapy significantly prolonged overall survival by 9.9 months (P < 0.001) and relapse-free survival by 5.3 months (P < 0.001) compared with placebo in patients with AML in first remission after IC who were not candidates for transplant. Currently, the QUAZAR AML-001 trial provides the most comprehensive safety information associated with oral azacitidine maintenance therapy. Reviewed here are common adverse events (AEs) during oral azacitidine treatment in QUAZAR AML-001, and practical recommendations for AE management based on guidance from international cancer consortiums, regulatory authorities, and the authors’ clinical experience treating patients in the trial. Methods QUAZAR AML-001 is an international, placebo-controlled randomized phase 3 study. Patients aged ≥ 55 years with AML and intermediate- or poor-risk cytogenetics at diagnosis, who had attained first complete remission (CR) or CR with incomplete blood count recovery (CRi) within 4 months before study entry, were randomized 1:1 to receive oral azacitidine 300 mg or placebo once-daily for 14 days in repeated 28-day cycles. Safety was assessed in all patients who received ≥ 1 dose of study drug. Results A total of 469 patients received oral azacitidine (n = 236) or placebo (n = 233). Median age was 68 years. Patients received a median of 12 (range 1–80) oral azacitidine treatment cycles or 6 (1–73) placebo cycles. Gastrointestinal AEs were common and typically low-grade. The most frequent grade 3–4 AEs during oral azacitidine therapy were hematologic events. AEs infrequently required permanent discontinuation of oral azacitidine (13%), suggesting they were effectively managed with use of concomitant medications and oral azacitidine dosing modifications. Conclusion Oral azacitidine maintenance had a generally favorable safety profile. Prophylaxis with antiemetic agents, and blood count monitoring every other week, are recommended for at least the first 2 oral azacitidine treatment cycles, and as needed thereafter. Awareness of the type, onset, and duration of common AEs, and implementation of effective AE management, may maximize treatment adherence and optimize the survival benefits of oral azacitidine AML remission maintenance therapy. Trial registration. This trial is registered on clinicaltrials.gov: NCT01757535 as of December 2012

Differential effect of interleukin 3 on the metabolism of high-dose cytosine arabinoside in normal versus leukemic human bone marrow cells

We have examined the effect of recombinant interleukin 3 (rIL-3) on the metabolism of high-dose cytosine arabinoside (Ara-C), an S-phase-specific agent, in normal human bone marrow mononuclear cells (BMMC) and leukemic blasts from patients with acute myeloid leukemia (AML). Exposure to rIL-3 for 24 h significantly increased the percentage of cycling S-phase cells in normal BMMC as well as leukemic cells. A concomitant expansion of intracellular deoxycytidine triphosphate (dCTP) levels occurred to a significantly greater extent in normal BMMC. Compared to treatment with Ara-C (10 mumol/liter) alone, prior and coadministration of rIL-3 with Ara-C increased Ara-CTP levels in leukemic blasts. However, an identical treatment produced significantly higher dCTP levels in normal BMMC, resulting in a significantly lower mean Ara-CTP to dCTP pool ratio in normal BMMC compared to that observed in each of the samples of AML blasts. Following treatment with Ara-C plus rIL-3 versus Ara-C alone, the alteration in Ara-C DNA incorporation corresponded with the change in Ara-CTP to dCTP ratio observed in normal BMMC and AML blasts. The differential effect of rIL-3 on the metabolism of high-dose Ara-C in normal versus leukemic cells may indicate a role for rIL-3 in enhancing the selectivity of Ara-C toward leukemic myeloblasts

Frequency of BCL-2/J(H) translocations in peripheral blood of follicular lymphoma patients

Polymerase chain reaction (PCR) assays have been developed for follicular lymphoma-associated BCL-2/J(H) translocations. Few data are available on the quantitation by PCR of these translocations in peripheral blood mononuclear cells (PBM) of follicular lymphoma (FL) patients. We report that only one of five studied FL patients had a high level of these translocations in the circulation, namely, about 35,000 translocations per 5 x 10(6) PBM. This patient was stable with an excellent performance status at the time of this assay; however, he died of leukemia 1 month later

Exacerbation of Bleomycin-induced lung injury in mice by amifostine.

Bleomycin (BLM) induces lung injury and fibrosis in the murine lung and enhances tumor necrosis factor (TNF)-alpha and collagen mRNA expression in the murine lung. Amifostine is a cytoprotective agent that protects normal tissues from the cytotoxic effects of chemo- and radiation therapy. We investigated the effect of amifostine in BLM-induced lung injury in mice. Mice received intraperitoneal amifostine (200 mg/kg) 30 min before and/or 1, 3, and 7 days after an intratracheal injection of saline or BLM (4 U/kg). The animals were killed 14 days after BLM exposure, and their lungs were studied for TNF-alpha and collagen mRNA expression, hydroxyproline content, and histopathology. Light microscopy demonstrated that amifostine exacerbated the BLM-induced lung injury in mice. Increased TNF-alpha mRNA expression as a result of BLM exposure was not modulated by amifostine treatment. In contrast, amifostine treatment enhanced the BLM-induced expression of alpha(1)(I) procollagen mRNA in the lung. Similarly, mice treated with amifostine before BLM exposure accumulated significantly higher amounts of hydroxyproline (111 +/- 5 microg/lung) than BLM-treated animals (90 +/- 6 microg/lung). These data suggest that amifostine treatment exacerbates BLM-induced lung injury in mice

CD5-negative mantle cell lymphoma: clinicopathologic features of an indolent variant that confers a survival advantage

Conventionally, mantle cell lymphoma (MCL) is an aggressive CD5-positive B-cell malignancy with poor prognosis and limited survival. However, a small subset of patients presents with indolent disease and can be managed on a ‘watch and wait’ approach. CD5-negative MCL has recently been recognized as a more favorable variant of MCL, but its clinical and biological implications remain ill-defined. We performed the most extensive review to-date of all reported cases of CD5-negative MCL and included unpublished cases diagnosed at our institutions to further characterize this disease subset. Based on our analysis of 356 cases of CD5-negative MCL, we conclude that median overall survival exceeds 14 years and is independent of favorable prognostic markers such as leukemic non-nodal disease, absence of SOX11, and low Ki-67.Fil: Soleimani, Arshia. University of Maryland; Estados UnidosFil: Navarro, Alba. Universidad de Barcelona; EspañaFil: Liu, Delong. National Institutes of Health; Estados UnidosFil: Herman, Sarah E. M.. National Institutes of Health; Estados UnidosFil: Chuang, Shih Sung. Chi-Mei Medical Center; ChinaFil: Slavutsky, Irma Rosa. Consejo Nacional de Investigaciones Científicas y Técnicas. Instituto de Medicina Experimental. Academia Nacional de Medicina de Buenos Aires. Instituto de Medicina Experimental; ArgentinaFil: Narbaitz, Marina. Academia Nacional de Medicina de Buenos Aires. Instituto de Investigaciones Hematológicas "Mariano R. Castex"; ArgentinaFil: Safah, Hana. University of Tulane; Estados UnidosFil: Schmieg, John. University of Tulane; Estados UnidosFil: Lefante, John. University of Tulane; Estados UnidosFil: Roschewski, Mark. National Institutes of Health; Estados UnidosFil: Wilson, Wyndham H.. National Institutes of Health; Estados UnidosFil: Wiestner, Adrian. National Institutes of Health; Estados UnidosFil: Saba, Nakhle S.. University of Tulane; Estados Unido

Pembrolizumab plus pomalidomide and dexamethasone for patients with relapsed or refractory multiple myeloma (KEYNOTE-183): a randomised, open-label, phase 3 trial

BACKGROUND: Pomalidomide and dexamethasone is a standard of care for patients with multiple myeloma in whom bortezomib and lenalidomide treatment has failed. KEYNOTE-183 assessed efficacy and safety of pomalidomide and dexamethasone with or without pembrolizumab in patients with relapsed or refractory multiple myeloma. Here, we present the findings of an unplanned, ad-hoc interim analysis at the request of the US Food and Drug Administration (FDA). METHODS: KEYNOTE-183 was a randomised, open-label, phase 3 trial done at 97 medical centres across 11 countries (Australia, Canada, France, Germany, Israel, Italy, Japan, New Zealand, Norway, Spain, and USA). Patients aged at least 18 years with multiple myeloma, an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, previously treated with at least two lines of therapy (excluding pomalidomide) and refractory to the last line were randomly assigned 1:1 to the pembrolizumab plus pomalidomide and dexamethasone group or the pomalidomide and dexamethasone group via an interactive voice response or integrated web response system. Patients received oral pomalidomide 4 mg daily on days 1-21 and oral low-dose dexamethasone 40 mg on days 1, 8, 15, and 22 in 28-day cycles, with or without intravenous pembrolizumab 200 mg every 3 weeks. The dual primary endpoints were progression-free survival and overall survival. Efficacy was assessed in all randomly assigned patients and safety was assessed in patients who received at least one dose of study treatment. The trial is registered at ClinicalTrials.gov, number NCT02576977, and it is closed for accrual. FINDINGS: Between Jan 18, 2016, and June 7, 2017, 249 patients were randomly assigned to either the pembrolizumab plus pomalidomide and dexamethasone group (n=125) or the pomalidomide and dexamethasone group (n=124). On July 3, 2017, the FDA established that risks associated with the triple combination outweighed benefits and halted the study. Median follow-up was 8\ub71 months (IQR 4\ub75-10\ub79). Median progression-free survival was 5\ub76 months (95% CI 3\ub77-7\ub75) in the pembrolizumab plus pomalidomide and dexamethasone group versus 8\ub74 months (5\ub79-not reached) in the pomalidomide and dexamethasone group; progression-free survival estimates at 6 months were 48% (95% CI 37-58) versus 60% (49-69) at 6 months (hazard ratio [HR] 1\ub753; 95% CI 1\ub705-2\ub722; p=0\ub798). Median overall survival was not reached (95% CI 12\ub79-not reached) versus 15\ub72 months (12\ub77-not reached; HR 1\ub761; 95% CI 0\ub791-2\ub785; p=0\ub795); overall survival estimates at 6 months were 82% (95% CI 74-88) versus 90% (82-95). Serious adverse events occurred in 75 (63%) of 120 patients in the pembrolizumab plus pomalidomide and dexamethasone group versus 56 (46%) of 121 patients in the pomalidomide and dexamethasone group. Four (3%) treatment-related deaths occurred in the pembrolizumab plus pomalidomide and dexamethasone group (one each of unknown cause, neutropenic sepsis, myocarditis, and Stevens-Johnson syndrome); myocarditis and Stevens-Johnson syndrome were considered related to pembrolizumab. No treatment-related deaths were reported in the pomalidomide and dexamethasone group. INTERPRETATION: The results from this unplanned, FDA-requested, interim analysis showed that the benefit-risk profile of pembrolizumab plus pomalidomide and dexamethasone is unfavourable for patients with relapsed or refractory multiple myeloma. FUNDING: Merck Sharp &amp; Dohme, a subsidiary of Merck &amp; Co (Kenilworth, NJ, USA)