Oral decitabine-cedazuridine versus intravenous decitabine for myelodysplastic syndromes and chronic myelomonocytic leukaemia (ASCERTAIN): a registrational, randomised, crossover, pharmacokinetics, phase 3 study.

BACKGROUND: The DNA methyltransferase inhibitors azacitidine and decitabine for individuals with myelodysplastic syndromes or chronic myelomonocytic leukaemia are available in parenteral form. Oral therapy with similar exposure for these diseases would offer potential treatment benefits. We aimed to compare the safety and pharmacokinetics of oral decitabine plus the cytidine deaminase inhibitor cedazuridine versus intravenous decitabine. METHODS: We did a registrational, multicentre, open-label, crossover, phase 3 trial of individuals with myelodysplastic syndromes or chronic myelomonocytic leukaemia and individuals with acute myeloid leukaemia, enrolled as separate cohorts; results for only participants with myelodysplastic syndromes or chronic myelomonocytic leukaemia are reported here. In 37 academic and community-based clinics in Canada and the USA, we enrolled individuals aged 18 years or older who were candidates to receive intravenous decitabine, with Eastern Cooperative Oncology Group performance status 0 or 1 and a life expectancy of at least 3 months. Participants were randomly assigned (1:1) to receive 5 days of oral decitabine-cedazuridine (one tablet once daily containing 35 mg decitabine and 100 mg cedazuridine as a fixed-dose combination) or intravenous decitabine (20 mg/m2 per day by continuous 1-h intravenous infusion) in a 28-day treatment cycle, followed by 5 days of the other formulation in the next treatment cycle. Thereafter, all participants received oral decitabine-cedazuridine from the third cycle on until treatment discontinuation. The primary endpoint was total decitabine exposure over 5 days with oral decitabine-cedazuridine versus intravenous decitabine for cycles 1 and 2, measured as area under the curve in participants who received the full treatment dose in cycles 1 and 2 and had decitabine daily AUC0-24 for both oral decitabine-cedazuridine and intravenous decitabine (ie, paired cycles). On completion of the study, all patients were rolled over to a maintenance study. This study is registered with ClinicalTrials.gov, NCT03306264. FINDINGS: Between Feb 8, 2018, and June 7, 2021, 173 individuals were screened, 138 (80%) participants were randomly assigned to a treatment sequence, and 133 (96%) participants (87 [65%] men and 46 [35%] women; 121 [91%] White, four [3%] Black or African-American, three [2%] Asian, and five [4%] not reported) received treatment. Median follow-up was 966 days (IQR 917-1050). Primary endpoint of total exposure of oral decitabine-cedazuridine versus intravenous decitabine was 98·93% (90% CI 92·66-105·60), indicating equivalent pharmacokinetic exposure on the basis of area under the curve. The safety profiles of oral decitabine-cedazuridine and intravenous decitabine were similar. The most frequent adverse events of grade 3 or worse were thrombocytopenia (81 [61%] of 133 participants), neutropenia (76 [57%] participants), and anaemia (67 [50%] participants). The incidence of serious adverse events in cycles 1-2 was 31% (40 of 130 participants) with oral decitabine-cedazuridine and 18% (24 of 132 participants) with intravenous decitabine. There were five treatment-related deaths; two deemed related to oral therapy (sepsis and pneumonia) and three to intravenous treatment (septic shock [n=2] and pneumonia [n=1]). INTERPRETATION: Oral decitabine-cedazuridine was pharmacologically and pharmacodynamically equivalent to intravenous decitabine. The results support use of oral decitabine-cedazuridine as a safe and effective alternative to intravenous decitabine for treatment of individuals with myelodysplastic syndromes or chronic myelomonocytic leukaemia. FUNDING: Astex Pharmaceuticals.

Use of ifosfamide, carboplatin and etoposide in combination with brentuximab vedotin or romidepsin based on CD30 positivity in relapsed/refractory peripheral T-cell lymphoma.

BACKGROUND: Relapsed/refractory peripheral T-cell lymphoma (R/R PTCL) has a poor prognosis. Romidepsin (Ro) and brentuximab vedotin (Bv), combined with ifosfamide, carboplatin, and etoposide (ICE) has not been significantly studied in PTCL. AIM: We report outcomes of Bv-ICE in CD30 (+) and Ro-ICE in CD30 (-) R/R PTCL treated in "Blinded for peer review" Cancer Center. METHODS AND RESULTS: We retrospectively identified R/R PTCL patients treated with BV-ICE or romidepsin-ICE from May 2016 to September 2019. Out of 13 R/R PTCL patients, 6 were treated with Bv-ICE and 7 with Ro-ICE. Bv-ICE had an overall response rate (ORR) of 66.7%, with all the patients achieving a complete response. ORR was 71.4% for Ro-ICE with 57.1% of patients achieving a complete response. Two patients treated with Bv-ICE and three treated with Ro-ICE received transplantation. CONCLUSION: In our experience, treatment with Bv-ICE and Ro-ICE based on CD30 positivity is feasible and effective to treat patients with R/R PTCL.

Clinical effects of administering leukemia-specific donor T cells to patients with AML/MDS after allogeneic transplant.

Relapse after allogeneic hematopoietic stem cell transplantation (HCT) is the leading cause of death in patients with acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). Infusion of unselected donor lymphocytes (DLIs) enhances the graft-versus-leukemia (GVL) effect. However, because the infused lymphocytes are not selected for leukemia specificity, the GVL effect is often accompanied by life-threatening graft-versus-host disease (GVHD), related to the concurrent transfer of alloreactive lymphocytes. Thus, to minimize GVHD and maximize GVL, we selectively activated and expanded stem cell donor-derived T cells reactive to multiple antigens expressed by AML/MDS cells (PRAME, WT1, Survivin, and NY-ESO-1). Products that demonstrated leukemia antigen specificity were generated from 29 HCT donors. In contrast to DLIs, leukemia-specific T cells (mLSTs) selectively recognized and killed leukemia antigen-pulsed cells, with no activity against recipient's normal cells in vitro. We administered escalating doses of mLSTs (0.5 to 10 × 107 cells per square meter) to 25 trial enrollees, 17 with high risk of relapse and 8 with relapsed disease. Infusions were well tolerated with no grade >2 acute or extensive chronic GVHD seen. We observed antileukemia effects in vivo that translated into not-yet-reached median leukemia-free and overall survival at 1.9 years of follow-up and objective responses in the active disease cohort (1 complete response and 1 partial response). In summary, mLSTs are safe and promising for the prevention and treatment of AML/MDS after HCT. This trial is registered at www.clinicaltrials.com as #NCT02494167.

The development of T-cell malignancies in patients with pre-existing myeloproliferative neoplasms: a report of three cases.

Secondary acute myeloid leukaemia complicating the natural disease course of pre-existing Philadelphia chromosome-negative myeloproliferative neoplasms (PN-MPN) is well documented and associated with treatment challenges and significant morbidity. The incidence of a T-cell malignancy developing in patients with pre-existing PN-MPN is uncommon, with one case documented in the literature. We present two cases of angioimmunoblastic T-cell lymphoma (AITL) and one case of T-cell acute lymphoblastic leukaemia (T-ALL) that developed in patients with essential thrombocythemia (ET) and primary myelofibrosis (PMF), respectively. All malignancies were advanced at diagnosis and exhibited disease progression, regardless of the mutational status of the underlying ET/PMF, presence of cytogenetic abnormalities, type of T-cell neoplasm or systemic chemotherapy utilised. The median time to diagnosis of AITL or T-ALL from the onset of MPN was 4.5 years (range: 6 months-10 years). This single institutional case series demonstrates the possibility of an association between T-cell neoplasms and PN-MPNs.

Primary CNS Lymphoma Arising from the 4th Ventricle: A Case Report and Review of the Literature.

A 65-year-old male with a history of ischemic strokes, seizures, and subarachnoid hemorrhage presented with a 4-week history of progressive diplopia, vertigo, nausea, and vomiting. Magnetic resonance imaging (MRI) revealed a 2.5 × 1.8 × 1.7 cm posterior fossa mass arising from the roof of the 4th ventricle extending into the cerebellar vermis. Posterior fossa craniotomy with stereotactic biopsy confirmed a locally invasive diffuse large B-cell lymphoma (DLBCL). Primary central nervous system lymphoma (PCNSL) arising from the 4th ventricle is a rare extranodal manifestation of non-Hodgkin lymphoma (NHL), with few cases documented in the literature. Review of available cases lends support that lymphoma arising from the 4th ventricle has a variable clinical presentation, occurs most commonly in immunocompetent males, and should be on the differential of any immunocompetent adult presenting with a posterior fossa mass. Optimal treatment modalities are based largely on phase 2 clinical trials, and recommended guidelines regardless of anatomic location should be adhered to.

Final outcomes of escalated melphalan 280 mg/m2 with amifostine cytoprotection followed autologous hematopoietic stem cell transplantation for multiple myeloma: high CR and VGPR rates do not translate into improved survival.

The most common preparative regimen for autologous transplantation (ASCT) in myeloma (MM) consists of melphalan 200 mg/m2 (MEL 200). Higher doses of melphalan 220-260 mg/m2, although relatively well tolerated, have not shown significant improvement in clinical outcomes. Several approaches have been pursued in the past to improve CR rates, including poly-chemotherapy preparative regimens, tandem ASCT, consolidation, and/or maintenance therapy. Since there is a steep dose-response effect for intravenous melphalan, we evaluated an alternative single ASCT strategy using higher-dose melphalan at 280 mg/m2 (MEL 280) with amifostine as a cytoprotectant as the maximum tolerated dose determined in an earlier phase I dose escalation trial. We report the final long-term outcomes of MM patients who underwent conditioning with MEL 280 with amifostine cytoprotection followed by ASCT. Although the complete response rate was quite high in the era pre-dating the routine use of novel therapies (proteasome inhibitors, immunomodulatory agents) (49%), the progression-free survival was a disappointing 22 months. The implications of this dichotomy between the excellent depth of ASCT response and progression-free survival are discussed.

A Pilot Phase II Study of Erlotinib for the Treatment of Patients with Relapsed/Refractory Acute Myeloid Leukemia.

Erlotinib, an epidermal growth factor receptor (EGFR) inhibitor, may have off-target activity inducing acute myeloid leukemia (AML) differentiation, possibly through SYK inhibition. We investigated erlotinib in a pilot phase II study for efficacy in relapsed/refractory AML patients at a dose of 150 mg once daily in 28-day cycles. Twenty-nine patients were treated for a median of 29 days (range 12-142 days). Seven patients (24%) received > 1 cycle of therapy and 12 (41%) discontinued treatment before day 28 due to disease progression. One patient (3%) achieved complete remission and 2 (7%) a > 50% reduction in blasts. The most common toxicities associated with erlotinib were fatigue in 10 patients (34%), diarrhea in 10 (34%), nausea in 8 (28%), and rash in 7 (24%). Only 2 patients (7%) had study drug-related adverse events requiring dose reductions and eventual discontinuation. The main reason for treatment discontinuation was disease progression in 26 patients (90%). All patients had died by the time of the last follow-up. Progression of disease was the primary cause of death in all patients. Median overall survival was 14 weeks (range 2.3-96.9 weeks) and median event-free survival was 5 weeks (range 1.7-21.0 weeks). Erlotinib as a single agent has limited clinical efficacy in patients with relapsed/refractory AML.

An exploratory clinical trial of bortezomib in patients with lower risk myelodysplastic syndromes.

Myelodysplastic syndromes (MDSs) are characterized by ineffective hematopoiesis and an increased risk of transformation. Few effective therapies are available for lower risk MDS patients, especially after the failure of hypomethylating agents. MDS progenitor cells are dependent on the nuclear factor-κB (NF-κB) for survival, which makes it an attractive therapeutic target. As a proteosomal inhibitor, bortezomib is thought to have inhibitory activity against NF-κB. We designed a proof-of-principle study of subcutaneous (SC) bortezomib in lower risk MDS patients with evidence of NF-κB activation in their bone marrow. Fifteen patients were treated, their median age was 71 (range 56-87), 33% were low and 67% int-1 by IPSS, median number of prior therapies was 2, all patients were transfusion dependent. Baseline median pp65 percentage was 31% and 11 patients had evidence of ring sideroblasts (RS). SC bortezomib was safe, well tolerated with no excess toxicity. Three patients out of the 15 (20%) had evidence of response with hematologic improvement (HI-E). Bortezomib caused a decrease in pp65 levels in 7 out of 13 evaluable patients (54%, P = .025). Of interest, unexpectedly, we observed a significant decrease in RS in 7 out of 10 (70%) evaluable patients during treatment. In conclusion, this study suggests that NF-κB activation, measured by pp65 levels, may be a useful biomarker in MDS. Bortezomib is safe in this patient population but has modest clinical activity. The role of the proteasome in the genesis of RS needs further study.

A review of supportive care and recommended preventive approaches for patients with chronic lymphocytic leukemia.

Chronic lymphocytic leukemia (CLL) is the most prevalent type of adult leukemia encountered in the western world. Patients with CLL are typically older, with a median age in the 70s, and are at risk for certain complications due to the disease itself and due to the therapies imparted for this. Patients with CLL are at a higher risk of infections, partly due to disease and partly due to the immune dysfunction induced by treatment, such as purine analogous-based chemoimmunotherapy, which leads to lymphocyte depletion. Infections are a leading cause of complications and death in CLL patients. Also, CLL patients have been shown to have a higher incidence of other malignancies. Despite this knowledge, there are no definite guidelines as to what is the best approach to manage or prevent these associated complications of CLL. In this review, the authors discuss the data available and outline recommendations as to the best way to approach this issue in daily practice.

Splenomegaly in myelofibrosis--new options for therapy and the therapeutic potential of Janus kinase 2 inhibitors.

Splenomegaly is a common sign of primary myelofibrosis (PMF), post-polycythemia vera myelofibrosis (post-PV MF), and post-essential thrombocythemia myelofibrosis (post-ET MF) that is associated with bothersome symptoms, which have a significant negative impact on patients' quality of life. It may also be present in patients with advanced polycythemia vera (PV) or essential thrombocythemia (ET). Until recently, none of the therapies used to treat MF were particularly effective in reducing splenomegaly. The discovery of an activating Janus kinase 2 (JAK2) activating mutation (JAK2V617F) that is present in almost all patients with PV and in about 50-60 % of patients with ET and PMF led to the initiation of several trials investigating the clinical effectiveness of various JAK2 (or JAK1/JAK2) inhibitors for the treatment of patients with ET, PV, and MF. Some of these trials have documented significant clinical benefit of JAK inhibitors, particularly in terms of regression of splenomegaly. In November 2011, the US Food and Drug Administration approved the use of the JAK1- and JAK2-selective inhibitor ruxolitinib for the treatment of patients with intermediate or high-risk myelofibrosis, including PMF, post-PV MF, and post-ET MF. This review discusses current therapeutic options for splenomegaly associated with primary or secondary MF and the treatment potential of the JAK inhibitors in this setting.