Durable Remissions with Ivosidenib in IDH1-Mutated Relapsed or Refractory AML.

BACKGROUND: Mutations in the gene encoding isocitrate dehydrogenase 1 ( IDH1) occur in 6 to 10% of patients with acute myeloid leukemia (AML). Ivosidenib (AG-120) is an oral, targeted, small-molecule inhibitor of mutant IDH1. METHODS: We conducted a phase 1 dose-escalation and dose-expansion study of ivosidenib monotherapy in IDH1-mutated AML. Safety and efficacy were assessed in all treated patients. The primary efficacy population included patients with relapsed or refractory AML receiving 500 mg of ivosidenib daily with at least 6 months of follow-up. RESULTS: Overall, 258 patients received ivosidenib and had safety outcomes assessed. Among patients with relapsed or refractory AML (179 patients), treatment-related adverse events of grade 3 or higher that occurred in at least 3 patients were prolongation of the QT interval (in 7.8% of the patients), the IDH differentiation syndrome (in 3.9%), anemia (in 2.2%), thrombocytopenia or a decrease in the platelet count (in 3.4%), and leukocytosis (in 1.7%). In the primary efficacy population (125 patients), the rate of complete remission or complete remission with partial hematologic recovery was 30.4% (95% confidence interval [CI], 22.5 to 39.3), the rate of complete remission was 21.6% (95% CI, 14.7 to 29.8), and the overall response rate was 41.6% (95% CI, 32.9 to 50.8). The median durations of these responses were 8.2 months (95% CI, 5.5 to 12.0), 9.3 months (95% CI, 5.6 to 18.3), and 6.5 months (95% CI, 4.6 to 9.3), respectively. Transfusion independence was attained in 29 of 84 patients (35%), and patients who had a response had fewer infections and febrile neutropenia episodes than those who did not have a response. Among 34 patients who had a complete remission or complete remission with partial hematologic recovery, 7 (21%) had no residual detectable IDH1 mutations on digital polymerase-chain-reaction assay. No preexisting co-occurring single gene mutation predicted clinical response or resistance to treatment. CONCLUSIONS: In patients with advanced IDH1-mutated relapsed or refractory AML, ivosidenib at a dose of 500 mg daily was associated with a low frequency of grade 3 or higher treatment-related adverse events and with transfusion independence, durable remissions, and molecular remissions in some patients with complete remission. (Funded by Agios Pharmaceuticals; ClinicalTrials.gov number, NCT02074839 .).

Comparative Analysis of Calcineurin Inhibitor-Based Methotrexate and Mycophenolate Mofetil-Containing Regimens for Prevention of Graft-versus-Host Disease after Reduced-Intensity Conditioning Allogeneic Transplantation.

The combination of a calcineurin inhibitor (CNI) such as tacrolimus (TAC) or cyclosporine (CYSP) with methotrexate (MTX) or with mycophenolate mofetil (MMF) has been commonly used for graft-versus-host disease (GVHD) prophylaxis after reduced-intensity conditioning (RIC) allogeneic hematopoietic cell transplantation (alloHCT), but there are limited data comparing efficacy of the 2 regimens. We evaluated 1564 adult patients who underwent RIC alloHCT for acute myelogenous leukemia (AML) and acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), and myelodysplastic syndrome (MDS) from 2000 to 2013 using HLA-identical sibling (matched related donor [MRD]) or unrelated donor (URD) peripheral blood graft and received CYSP or TAC with MTX or MMF for GVHD prophylaxis. Primary outcomes of the study were acute and chronic GVHD and overall survival (OS). The study divided the patient population into 4 cohorts based on regimen: MMF-TAC, MMF-CYSP, MTX-TAC, and MTX-CYSP. In the URD group, MMF-CYSP was associated with increased risk of grade II to IV acute GVHD (relative risk [RR], 1.78; P < .001) and grade III to IV acute GVHD (RR, 1.93; P = .006) compared with MTX-TAC. In the URD group, use of MMF-TAC (versus MTX-TAC) lead to higher nonrelapse mortality. (hazard ratio, 1.48; P = .008). In either group, no there was no difference in chronic GVHD, disease-free survival, and OS among the GVHD prophylaxis regimens. For RIC alloHCT using MRD, there are no differences in outcomes based on GVHD prophylaxis. However, with URD RIC alloHCT, MMF-CYSP was inferior to MTX-based regimens for acute GVHD prevention, but all the regimens were equivalent in terms of chronic GVHD and OS. Prospective studies, targeting URD recipients are needed to confirm these results.

A Phase 1 Trial of CNDO-109-Activated Natural Killer Cells in Patients with High-Risk Acute Myeloid Leukemia.

Natural killer (NK) cells are an emerging immunotherapy approach to acute myeloid leukemia (AML); however, the optimal approach to activate NK cells before adoptive transfer remains unclear. Human NK cells that are primed with the CTV-1 leukemia cell line lysate CNDO-109 exhibit enhanced cytotoxicity against NK cell-resistant cell lines. To translate this finding to the clinic, CNDO-109-activated NK cells (CNDO-109-NK cells) isolated from related HLA-haploidentical donors were evaluated in a phase 1 dose-escalation trial at doses of 3 × 105 (n = 3), 1 × 106 (n = 3), and 3 × 106 (n = 6) cells/kg in patients with AML in first complete remission (CR1) at high risk for recurrence. Before CNDO-109-NK cell administration, patients were treated with lymphodepleting fludarabine/cyclophosphamide. CNDO-109-NK cells were well tolerated, and no dose-limiting toxicities were observed at the highest tested dose. The median relapse-free survival (RFS) by dose level was 105 (3 × 105), 156 (1 × 106), and 337 (3 × 106) days. Two patients remained relapse-free in post-trial follow-up, with RFS durations exceeding 42.5 months. Donor NK cell microchimerism was detected on day 7 in 10 of 12 patients, with 3 patients having evidence of donor cells on day 14 or later. This trial establishes that CNDO-109-NK cells generated from related HLA haploidentical donors, cryopreserved, and then safely administered to AML patients with transient persistence without exogenous cytokine support. Three durable complete remissions of 32.6 to 47.6+ months were observed, suggesting additional clinical investigation of CNDO-109-NK cells for patients with myeloid malignancies, alone or in combination with additional immunotherapy strategies, is warranted.

Acute myeloid leukemia ontogeny is defined by distinct somatic mutations.

Acute myeloid leukemia (AML) can develop after an antecedent myeloid malignancy (secondary AML [s-AML]), after leukemogenic therapy (therapy-related AML [t-AML]), or without an identifiable prodrome or known exposure (de novo AML). The genetic basis of these distinct pathways of AML development has not been determined. We performed targeted mutational analysis of 194 patients with rigorously defined s-AML or t-AML and 105 unselected AML patients. The presence of a mutation in SRSF2, SF3B1, U2AF1, ZRSR2, ASXL1, EZH2, BCOR, or STAG2 was >95% specific for the diagnosis of s-AML. Analysis of serial samples from individual patients revealed that these mutations occur early in leukemogenesis and often persist in clonal remissions. In t-AML and elderly de novo AML populations, these alterations define a distinct genetic subtype that shares clinicopathologic properties with clinically confirmed s-AML and highlights a subset of patients with worse clinical outcomes, including a lower complete remission rate, more frequent reinduction, and decreased event-free survival. This trial was registered at www.clinicaltrials.gov as #NCT00715637.

Elevation of c-MYC disrupts HLA class II-mediated immune recognition of human B cell tumors.

Elevated levels of the transcription factor c-myc are strongly associated with various cancers, and in particular B cell lymphomas. Although many of c-MYC's functions have been elucidated, its effect on the presentation of Ag through the HLA class II pathway has not been reported previously. This is an issue of considerable importance, given the low immunogenicity of many c-MYC-positive tumors. We report in this paper that increased c-MYC expression has a negative effect on the ability of B cell lymphomas to functionally present Ags/peptides to CD4(+) T cells. This defect was associated with alterations in the expression of distinct cofactors as well as interactions of antigenic peptides with class II molecules required for the presentation of class II-peptide complexes and T cell engagement. Using early passage Burkitt's lymphoma (BL) tumors and transformed cells, we show that compared with B lymphoblasts, BL cells express decreased levels of the class II editor HLA-DM, lysosomal thiol-reductase GILT, and a 47-kDa enolase-like protein. Functional Ag presentation was partially restored in BL cells treated with a c-MYC inhibitor, demonstrating the impact of this oncogene on Ag recognition. This restoration of HLA class II-mediated Ag presentation in early passage BL tumors/cells was linked to enhanced HLA-DM expression and a concurrent decrease in HLA-DO in BL cells. Taken together, these results reveal c-MYC exerts suppressive effects at several critical checkpoints in Ag presentation, which contribute to the immunoevasive properties of BL tumors.

Vosaroxin plus cytarabine versus placebo plus cytarabine in patients with first relapsed or refractory acute myeloid leukaemia (VALOR): a randomised, controlled, double-blind, multinational, phase 3 study.

BACKGROUND: Safe and effective treatments are urgently needed for patients with relapsed or refractory acute myeloid leukaemia. We investigated the efficacy and safety of vosaroxin, a first-in-class anticancer quinolone derivative, plus cytarabine in patients with relapsed or refractory acute myeloid leukaemia. METHODS: This phase 3, double-blind, placebo-controlled trial was undertaken at 101 international sites. Eligible patients with acute myeloid leukaemia were aged 18 years of age or older and had refractory disease or were in first relapse after one or two cycles of previous induction chemotherapy, including at least one cycle of anthracycline (or anthracenedione) plus cytarabine. Patients were randomly assigned 1:1 to vosaroxin (90 mg/m(2) intravenously on days 1 and 4 in a first cycle; 70 mg/m(2) in subsequent cycles) plus cytarabine (1 g/m(2) intravenously on days 1-5) or placebo plus cytarabine through a central interactive voice system with a permuted block procedure stratified by disease status, age, and geographical location. All participants were masked to treatment assignment. The primary efficacy endpoint was overall survival and the primary safety endpoint was 30-day and 60-day all-cause mortality. Efficacy analyses were done by intention to treat; safety analyses included all treated patients. This study is registered with ClinicalTrials.gov, number NCT01191801. FINDINGS: Between Dec 17, 2010, and Sept 25, 2013, 711 patients were randomly assigned to vosaroxin plus cytarabine (n=356) or placebo plus cytarabine (n=355). At the final analysis, median overall survival was 7·5 months (95% CI 6·4-8·5) in the vosaroxin plus cytarabine group and 6·1 months (5·2-7·1) in the placebo plus cytarabine group (hazard ratio 0·87, 95% CI 0·73-1·02; unstratified log-rank p=0·061; stratified p=0·024). A higher proportion of patients achieved complete remission in the vosaroxin plus cytarabine group than in the placebo plus cytarabine group (107 [30%] of 356 patients vs 58 [16%] of 355 patients, p<0·0001). Early mortality was similar between treatment groups (30-day: 28 [8%] of 355 patients in the vosaroxin plus cytarabine group vs 23 [7%] of 350 in the placebo plus cytarabine group; 60-day: 70 [20%] vs 68 [19%]). Treatment-related deaths occurred at any time in 20 (6%) of 355 patients given vosaroxin plus cytarabine and in eight (2%) of 350 patients given placebo plus cytarabine. Treatment-related serious adverse events occurred in 116 (33%) and 58 (17%) patients in each group, respectively. Grade 3 or worse adverse events that were more frequent in the vosaroxin plus cytarabine group than in the placebo plus cytarabine group included febrile neutropenia (167 [47%] vs 117 [33%]), neutropenia (66 [19%] vs 49 [14%]), stomatitis (54 [15%] vs 10 [3%]), hypokalaemia (52 [15%] vs 21 [6%]), bacteraemia (43 [12%] vs 16 [5%]), sepsis (42 [12%] vs 18 [5%]), and pneumonia (39 [11%] vs 26 [7%]). INTERPRETATION: Although there was no significant difference in the primary endpoint between groups, the prespecified secondary analysis stratified by randomisation factors suggests that the addition of vosaroxin to cytarabine might be of clinical benefit to some patients with relapsed or refractory acute myeloid leukaemia. FUNDING: Sunesis Pharmaceuticals.

REVEAL-1, a phase 2 dose regimen optimization study of vosaroxin in older poor-risk patients with previously untreated acute myeloid leukaemia.

This phase 2 study (N = 116) evaluated single-agent vosaroxin, a first-in-class anticancer quinolone derivative, in patients ≥60 years of age with previously untreated unfavourable prognosis acute myeloid leukaemia. Dose regimen optimization was explored in sequential cohorts (A: 72 mg/m(2)  d 1, 8, 15; B: 72 mg/m(2)  d 1, 8; C: 72 mg/m(2) or 90 mg/m(2)  d 1, 4). The primary endpoint was combined complete remission rate (complete remission [CR] plus CR with incomplete platelet recovery [CRp]). Common (>20%) grade ≥3 adverse events were thrombocytopenia, febrile neutropenia, anaemia, neutropenia, sepsis, pneumonia, stomatitis and hypokalaemia. Overall CR and CR/CRp rates were 29% and 32%; median overall survival (OS) was 7·0 months; 1-year OS was 34%. Schedule C (72 mg/m(2) ) had the most favourable safety and efficacy profile, with faster haematological recovery (median 27 d) and lowest incidence of aggregate sepsis (24%) and 30-d (7%) and 60-d (17%) all-cause mortality; at this dose and schedule, CR and CR/CRp rates were 31% and 35%, median OS was 7·7 months and 1-year OS was 38%. Overall, vosaroxin resulted in low early mortality and an encouraging response rate; vosaroxin 72 mg/m(2)  d 1, 4 is recommended for further study in this population. Registered at www.clinicaltrials.gov: #NCT00607997.

A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia.

This randomized phase 3 clinical trial evaluated the potential benefit of the addition of gemtuzumab ozogamicin (GO) to standard induction and postconsolidation therapy in patients with acute myeloid leukemia. Patients were randomly assigned to receive daunorubicin (45 mg/m(2) per day on days 1, 2, and 3), cytarabine (100 mg/m(2) per day by continuous infusion on days 1-7), and GO (6 mg/m(2) on day 4; DA+GO) vs standard induction therapy with daunorubicin (60 mg/m(2) per day on days 1, 2, and 3) and cytarabine alone (DA). Patients who achieved complete remission (CR) received 3 courses of high-dose cytarabine. Those remaining in CR after consolidation were randomly assigned to receive either no additional therapy or 3 doses of GO (5 mg/m(2) every 28 days). From August 2004 until August 2009, 637 patients were registered for induction. The CR rate was 69% for DA+GO and 70% for DA (P = .59). Among those who achieved a CR, the 5-year relapse-free survival rate was 43% in the DA+GO group and 42% in the DA group (P = .40). The 5-year overall survival rate was 46% in the DA+GO group and 50% in the DA group (P = .85). One hundred seventy-four patients in CR after consolidation underwent the postconsolidation randomization. Disease-free survival was not improved with postconsolidation GO (HR, 1.48; P = .97). In this study, the addition of GO to induction or postconsolidation therapy failed to show improvement in CR rate, disease-free survival, or overall survival.

A phase 1b/2 study of vosaroxin in combination with cytarabine in patients with relapsed or refractory acute myeloid leukemia.

Vosaroxin is a first-in-class anticancer quinolone derivative that intercalates DNA and inhibits topoisomerase II. This study assessed the safety and tolerability of vosaroxin plus cytarabine in patients with relapsed/refractory acute myeloid leukemia. Escalating vosaroxin doses (10-minute infusion; 10-90 mg/m(2); days 1, 4) were given in combination with cytarabine on one of two schedules: schedule A (24-hour continuous intravenous infusion, 400 mg/m(2)/day, days 1-5) or schedule B (2-hour intravenous infusion, 1 g/m(2)/day, days 1-5). Following dose escalation, enrollment was expanded at the maximum tolerated dose. Of 110 patients enrolled, 108 received treatment. The maximum tolerated dose of vosaroxin was 80 mg/m(2) for schedule A (dose-limiting toxicities: grade 3 bowel obstruction and stomatitis) and was not reached for schedule B (recommended phase 2 dose: 90 mg/m(2)). In the efficacy population (all patients in first relapse or with primary refractory disease treated with vosaroxin 80-90 mg/m(2); n=69), the complete remission rate was 25% and the complete remission/complete remission with incomplete blood count recovery rate was 28%. The 30-day all-cause mortality rate was 2.5% among all patients treated at a dose of 80-90 mg/m(2). Based upon these results, a phase 3 trial of vosaroxin plus cytarabine was initiated in patients with relapsed/refractory acute myeloid leukemia. (Clinicaltrials.gov identifier: NCT00541866).

Prediction of poor mobilization of autologous CD34+ cells with growth factor in multiple myeloma patients: implications for risk-stratification.

It is unknown whether clinical characteristics can successfully predict which multiple myeloma (MM) patients would be poor mobilizers with growth factor (GF) alone so they can be assigned to mobilization with chemotherapy + GF or GF + plerixafor. MM patients (N = 477) who underwent autologous mobilization with GF were retrospectively reviewed and assigned into training and validation cohorts. In multiple regression analysis, age, platelet count at time of mobilization, type of GF utilized, and extent of exposure to lenalidomide independently correlated with peripheral blood (PB)-CD34+ and were integrated in a predicting score (PS) for poor mobilizers, defined as PB-CD34+ < 20/mm(3) 4 days after initiation of GF. There was no correlation between institution, gender, time between diagnosis, and mobilization or plasma cells in the bone marrow at time of mobilization and PBCD34+. The PS cut-off found in the training cohort to have 90% sensitivity for prediction of poor mobilizers performed with 89.7% sensitivity but only 34.8% specificity in the validation cohort. Conversely, the PS cut-off developed to have 90% specificity performed with 86.9% specificity but only 37% sensitivity. We conclude that clinical characteristics identifiable before initiation of mobilization should not be used to stratify MM patients for different mobilization strategies.

Similar dynamics of intraapheresis autologous CD34+ recruitment and collection efficiency in patients undergoing mobilization with or without plerixafor.

BACKGROUND: Compared with growth factor (G) alone, the combination of G with plerixafor (G + P) increases peripheral blood CD34+ count (PB-CD34+) and improves CD34+ collection yield (yCD34+) in multiple myeloma and lymphoma patients undergoing autologous hematopoietic progenitor cell (AHPC) mobilization. It is unknown whether the improved yCD34+ with G + P results entirely from expansion of PB-CD34+ or also from increased intraapheresis CD34+ recruitment and collection efficiency. STUDY DESIGN AND METHODS: We retrospectively studied 192 patients who underwent AHPC mobilization and collection with G (n = 73) or G + P (n = 119) to compare the adjusted relative efficiency (aRE), the proportion of the circulating CD34+ pool that is captured for each blood volume processed. Additionally, in a prospective cohort of nine patients mobilizing with G and 11 with G + P, PB-CD34+ after leukapheresis allowed calculation of the recruitment coefficient (RC), proportion of the initial CD34+ pool recruited from the marrow into peripheral blood for each blood volume processed. RESULTS: There was no difference in aRE between G and G + P (0.50 vs. 0.46; p = 0.37) and no substantial decline in aRE with higher blood volumes processed in either group. RC was also not different between G and G + P (median, 0.39 and 0.38, respectively; p = 0.7). Prediction of yCD34+ was determined essentially by PB-CD34+ and not affected independently by plerixafor. CONCLUSION: Kinetics of intraapheresis CD34+ recruitment and collection is proportional to PB-CD34+ but not influenced further by plerixafor.

Results from a randomized trial of salvage chemotherapy followed by lestaurtinib for patients with FLT3 mutant AML in first relapse.

In a randomized trial of therapy for FMS-like tyrosine kinase-3 (FLT3) mutant acute myeloid leukemia in first relapse, 224 patients received chemotherapy alone or followed by 80 mg of the FLT3 inhibitor lestaurtinib twice daily. Endpoints included complete remission or complete remission with incomplete platelet recovery (CR/CRp), overall survival, safety, and tolerability. Correlative studies included pharmacokinetics and analysis of in vivo FLT3 inhibition. There were 29 patients with CR/CRp in the lestaurtinib arm and 23 in the control arm (26% vs 21%; P = .35), and no difference in overall survival between the 2 arms. There was evidence of toxicity in the lestaurtinib-treated patients, particularly those with plasma levels in excess of 20 µM. In the lestaurtinib arm, FLT3 inhibition was highly correlated with remission rate, but target inhibition on day 15 was achieved in only 58% of patients receiving lestaurtinib. Given that such a small proportion of patients on this trial achieved sustained FLT3 inhibition in vivo, any conclusions regarding the efficacy of combining FLT3 inhibition with chemotherapy are limited. Overall, lestaurtinib treatment after chemotherapy did not increase response rates or prolong survival of patients with FLT3 mutant acute myeloid leukemia in first relapse. This study is registered at www.clinicaltrials.gov as #NCT00079482.

Pegfilgrastim- versus filgrastim-based autologous hematopoietic stem cell mobilization in the setting of preemptive use of plerixafor: efficacy and cost analysis.

BACKGROUND: Plerixafor enhances the ability of filgrastim (FIL) to mobilize CD34+ cells but adds cost to the mobilization. We hypothesized that replacing weight-based FIL with flat-dose pegfilgrastim (PEG) in a validated cost-based mobilization algorithm for patient-adapted use of plerixafor would add convenience without increased cost. STUDY DESIGN AND METHODS: A single-center retrospective analysis compared two consecutive cohorts undergoing FIL or PEG mobilization before autologous hematopoietic stem cell transplantation for multiple myeloma or lymphoma. FIL dose was 10 µg/kg/day continuing until completion of collection and a 12-mg flat dose of PEG. Peripheral blood CD34+ cells (PB-CD34+) enumeration was performed on the fourth day after initiation of growth factor. Subjects surpassing a certain target-specific threshold of PB-CD34+ started apheresis immediately while subjects with lower PB-CD34+ received plerixafor with apheresis starting on the fifth day. RESULTS: Overall 68 of 74 in the FIL group and 52 of 57 patients in the PEG group met the mobilization target. Only one patient in each cohort required remobilization. Median PB-CD34+ on Day 4 was significantly higher in patients in the PEG group (18.1×10(6) vs. 28.7×10(6)cells/L, p=0.01). Consequently, patients in the PEG group were less likely to require administration of plerixafor (67.5% vs. 45.6%, p=0.01). Cohorts had near identical mean number of apheresis sessions and comparable CD34+ yield. The estimated cost associated with growth factor was higher in patients in the PEG group, but it was counterbalanced by lower cost associated with use of plerixafor. CONCLUSION: Single administration of 12 mg of PEG is associated with better CD34+ mobilization than FIL allowing for effective, convenient mobilization with less frequent use of plerixafor.

Efficacy and safety of ciprofloxacin for prophylaxis of polyomavirus BK virus-associated hemorrhagic cystitis in allogeneic hematopoietic stem cell transplantation recipients.

Polyoma virus BK-induced hemorrhagic cystitis is an important cause of morbidity after hematopoietic stem cell transplantation (HSCT). Fluoroquinolones have been shown in vitro to inhibit BK viral replication by direct inhibition of the BK-encoded DNA gyrase. We hypothesized that extended prophylaxis with ciprofloxacin may decrease the incidence of severe (grades 3 and 4) BK virus-associated hemorrhagic cystitis (sBKHC) after HSCT. We retrospectively collected patient and transplant data, as well as incidence of sBKHC, for all consecutive patients undergoing allogeneic HSCT between June 2006 and August 2010 at our institution. Prophylaxis for sBKHC with ciprofloxacin 500 mg orally twice daily from day 0 until day 60 had been instituted in March 2009, delimiting a group receiving ciprofloxacin prophylaxis (CP) or no prophylaxis (NP). We compared the cumulative incidence of sBKHC in CP and NP, including death in absence of sBKHC as a competing risk. Ninety-two consecutive patients were included in the analysis, 44 in CP and 48 in NP. Median age of patients was 50 years (range: 19-70), and 47% received a myeloablative conditioning regimen. The cumulative incidence of sBKHC was significantly reduced in CP (2.6% versus 20.9%, P = .01). Multivariate Cox regression analysis revealed that assignment to CP and concomitant acute graft-versus-host disease (GVHD) were the only factors independently associated with the occurrence of sBKHC. Patients in CP did not experience a higher risk of Clostridium difficile diarrhea and were less likely to develop episodes of bacteremia. Ciprofloxacin prophylaxis appears safe and effective in reducing the incidence of severe BKHC after allogeneic HSCT.

Beyond CD34+ cell dose: impact of method of peripheral blood hematopoietic stem cell mobilization (granulocyte-colony-stimulating factor [G-CSF], G-CSF plus plerixafor, or cyclophosphamide G-CSF/granulocyte-macrophage [GM]-CSF) on number of colony-forming unit-GM, engraftment, and Day +100 hematopoietic graft function.

BACKGROUND: The dose of CD34+ cells/kg in the mobilized peripheral blood product is the main determinant of neutrophil and platelet (PLT) engraftment after autologous hematopoietic stem cell transplantation (AHSCT). Whether the method of mobilization, namely, granulocyte-colony-stimulating factor (G-CSF) alone (G), G-CSF plus plerixafor (G+P), or cyclophosphamide + G/granulocyte-macrophage (GM)-CSF (Cy+G/GM), independently affects number of colony-forming unit (CFU)-GM, engraftment, and hematopoietic graft function is unknown. STUDY DESIGN AND METHODS: We used a database of AHSCT patients with multiple myeloma or lymphoma to identify three groups with different mobilization strategies receiving transplantation with similar CD34+ cell doses. Groups were compared in terms of CFU-GM, ratio of CFU-GM/CD34+, engraftment of neutrophils and PLTs, and hematopoietic graft function on Day +100. RESULTS: Ninety-six patients were included in the analysis, 26 G, 32 G+P, and 38 Cy+G/GM, with median cell doses of 4.21 × 10(6) , 4.11 × 10(6) , and 4.67 × 10(6) CD34+/kg, respectively (p = 0.433). There was no significant difference in number of CFU-GM between the three groups; however, the ratio of CFU-GM/CD34+ was significantly lower for G+P (p = 0.008). Median time for neutrophil engraftment was 13 days in G+P and 12 days in G and Cy+G/GM (p = 0.028), while PLT engraftment happened at a median of 14.5 days in G+P versus 12 days in G and 11 days in Cy+G/GM (p = 0.012). There was no difference in hematopoietic graft function at Day +100. CONCLUSION: Plerixafor-based mobilization is associated with slightly reduced number of CFU-GM and minimal delay in engraftment that is independent of CD34+ cell dose. Hematopoietic graft function on Day 100 is not affected by mobilization strategy.

CPX-351 versus 7+3 cytarabine and daunorubicin chemotherapy in older adults with newly diagnosed high-risk or secondary acute myeloid leukaemia: 5-year results of a randomised, open-label, multicentre, phase 3 trial.

BACKGROUND: Daunorubicin and cytarabine are used as standard induction chemotherapy for patients with acute myeloid leukaemia. CPX-351 is a dual-drug liposomal encapsulation of daunorubicin and cytarabine in a synergistic 1:5 molar ratio. Primary analysis of the phase 3 trial in adults aged 60-75 years with newly diagnosed high-risk or secondary acute myeloid leukaemia provided support for approval of CPX-351 by the US Food and Drug Administration and European Medicines Agency. We describe the prospectively planned final 5-year follow-up results. METHODS: This randomised, open-label, multicentre, phase 3 trial was done across 39 academic and regional cancer centres in the USA and Canada. Eligible patients were aged 60-75 years and had a pathological diagnosis of acute myeloid leukaemia according to WHO 2008 criteria, no previous induction therapy for acute myeloid leukaemia, and an Eastern Cooperative Oncology Group performance status of 0-2. Patients were randomly assigned 1:1 (stratified by age and acute myeloid leukaemia subtype) to receive up to two induction cycles of CPX-351 (100 units/m2 administered as a 90-min intravenous infusion on days 1, 3, and 5; on days 1 and 3 for the second induction) or standard chemotherapy (cytarabine 100 mg/m2 per day continuous intravenous infusion for 7 days plus intravenous daunorubicin 60 mg/m2 on days 1, 2, and 3 [7+3]; cytarabine for 5 days and daunorubicin on days 1 and 2 for the second induction [5+2]). Patients with complete remission or complete remission with incomplete neutrophil or platelet recovery could receive up to tw cycles of consolidation therapy with CPX-351 (65 units/m2 90-min infusion on days 1 and 3) or chemotherapy (5+2, same dosage as in the second induction cycle). The primary outcome was overall survival analysed in all randomly assigned patients. No additional adverse events were collected with long-term follow-up, except data for deaths. This trial is registered with ClinicalTrials.gov, NCT01696084, and is complete. FINDINGS: Between Dec 20, 2012, and Nov 11, 2014, 309 patients with newly diagnosed high-risk or secondary acute myeloid leukaemia were enrolled and randomly assigned to receive CPX-351 (153 patients) or 7+3 (156 patients). At a median follow-up of 60·91 months (IQR 60·06-62·98) in the CPX-351 group and 59·93 months (59·73-60·50) in the 7+3 group, median overall survival was 9·33 months (95% CI 6·37-11·86) with CPX-351 and 5·95 months (4·99-7·75) with 7+3 (HR 0·70, 95% CI 0·55-0·91). 5-year overall survival was 18% (95% CI 12-25%) in the CPX-351 group and 8% (4-13%) in the 7+3 group. The most common cause of death in both groups was progressive leukaemia (70 [56%] of 124 deaths in the CPX-351 group and 74 [53%] of 140 deaths in the 7+3 group). Six (5%) of 124 deaths in the CPX-351 group and seven (5%) of 140 deaths in the 7+3 group were considered related to study treatment. INTERPRETATION: After 5 years of follow-up, the improved overall survival with CPX-351 versus 7+3 was maintained, which supports the previous evidence that CPX-351 can contribute to long-term remission and improved overall survival in patients aged 60-75 years with newly diagnosed high-risk or secondary acute myeloid leukaemia. FUNDING: Jazz Pharmaceuticals.

Phase 3 randomized trial of chemotherapy with or without oblimersen in older AML patients: CALGB 10201 (Alliance).

Overexpression of B-cell leukemia/lymphoma 2 (BCL2) renders acute myeloid leukemia (AML) cells resistant to chemotherapy and has been associated with unfavorable outcomes. Oblimersen (G3139) is a phosphorothioate 18-mer antisense oligonucleotide directed against the first 6 BCL2 codons. In a phase 1 study of AML patients treated with G3139, cytarabine, and daunorubicin induction with cytarabine consolidation, no antisense-related toxicity was reported, and BCL2 downregulation occurred in patients achieving complete remission. In this phase 3 trial, untreated older AML patients were randomized to cytarabine (100 mg/m2 per day on days 4-10) and daunorubicin (60 mg/m2 per day on days 4-6) followed by cytarabine consolidation (2000 mg/m2 per day on days 4-8) with (arm A) or without (arm B) G3139 (7 mg/m2 per day on days 1-10 [induction] or days 1-8 [consolidation]). A total of 506 patients were enrolled. No differences in toxicity were observed between arms. Estimated overall survival (OS) at 1 year was 43% for arm A and 40% for arm B (1-sided log rank P = .13), with no differences in disease-free (DFS; P = .26) or event-free survival (P = .80). Subgroup analyses showed patients age <70 years in arm A had improved OS by 1 month vs those in arm B (P = .04), and patients with secondary AML in arm A had better DFS vs those in arm B (P = .04). We conclude that addition of G3139 to chemotherapy failed to improve outcomes of older AML patients. However, more effective means of inhibiting BCL2 are showing promising results in combination with chemotherapy in AML. This trial was registered at www.clinicaltrials.gov as #NCT00085124.

Comanagement Strategy Between Academic Institutions and Community Practices to Reduce Induction Mortality in Acute Promyelocytic Leukemia.

PURPOSE: Acute promyelocytic leukemia (APL) is a curable leukemia with > 90% survival in clinical trials. Population-based studies from Sweden and US SEER data have shown long-term survival rates of 62% and 65.7%, with the lower rate being from a higher percentage of early deaths. METHODS: In this prospective, multicenter trial, we developed a simplified algorithm that focused on prevention and early treatment of the three main causes of death: bleeding, differentiation syndrome, and infection. All patients with a diagnosis of APL were included. The initial 6 months were spent educating oncologists about early deaths in APL. At the time of suspicion of an APL, an expert was contacted. The algorithm was made available followed by discussion of the treatment plan. Communication between expert and treating physician was frequent in the first 2 weeks, during which time most deaths take place. RESULTS: Between September 2013 and April 2016, 120 patients enrolled in the study from 32 hospitals. The median age was 52.5 years, with 39% > 60 years and 25% with an age-adjusted Charlson comorbidity index > 4. Sixty-three percent of patients were managed at community centers. Two patients did not meet the criteria for analysis, and of 118 evaluable patients, 10 died, with an early mortality rate of 8.5%. With a median follow-up of 27.3 months, the overall survival was 84.5%. CONCLUSION: Induction mortality can be decreased and population-wide survival improved in APL with the use of standardized treatment guidelines. Support from experts who have more experience with induction therapy is crucial and helps to improve the outcomes.

Southwest Oncology Group Study S0530: a phase 2 trial of clofarabine and cytarabine for relapsed or refractory acute lymphocytic leukaemia.

Clofarabine and cytarabine target different steps in DNA synthesis and replication, are synergistic in vivo, and have non-overlapping toxicities, making this combination a potentially promising treatment for acute lymphocytic leukaemia. Thirty-seven patients were treated. The median age was 41 years, 44% of patients were either in ≥2nd relapse or had refractory disease and 59% of patients had poor risk cytogenetics. Six out of 36 patients (17%) achieved a complete remission with or without complete count recovery; median overall survival was 3 months. Nucleoside transporter expression did not predict outcome. This regimen lacked sufficient activity to warrant further testing.