Utility of Established Prognostic Scoring Systems for Patients with Advanced Pancreatic Adenocarcinoma Enrolled in Immunotherapy-Based Early-Phase Clinical Trials.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy for which multiagent chemotherapy is the mainstay of treatment resulting in limited survival and symptomatic benefit. Treatment with immune checkpoint inhibitors (ICI) has proven effective in a growing number of solid tumors but has yet to show clinical benefit in patients with PDAC. Given the growing number of ICI-based clinical trials in development for patients with PDAC and lack of clinical benefit thus far with ICI-based therapies in these patients, we sought to (1) determine the outcomes of patients with PDAC treated with ICI-based therapies as part of an early phase clinical trial, (2) validate the utility of established prognostic scoring systems, and (3) identify novel prognostic factors in an attempt to better identify patients that would benefit from enrollment onto an ICI-based early phase clinical trial. METHODS: We conducted a single-center retrospective analysis of patients with advanced PDAC who were treated with ICI-based therapy as part of an early-phase clinical trial. RESULTS: Patients were only able to stay on study for a limited time due to disease progression and/or a change in performance status and had a poor overall survival. Established prognostic scoring systems were not effective in predicting outcomes in this patient population, but factors such as pre-treatment albumin neutrophil to lymphocyte ratio (NLC) may be helpful in patient selection. CONCLUSIONS: This study underscores the need for larger studies to help identify patient and tumor intrinsic factors that predict response to ICI-based therapies in patients with PDAC.

Association of hematologic response and assay sensitivity on the prognostic impact of measurable residual disease in acute myeloid leukemia: a systematic review and meta-analysis.

Measurable residual disease (MRD) is associated with relapse and survival in acute myeloid leukemia (AML). We aimed to quantify the impact of MRD on outcomes across clinical contexts, including its association with hematologic response and MRD assay sensitivity. We performed systematic literature review and meta-analysis of 48 studies that reported the association between MRD and overall survival (OS) or disease-free survival (DFS) in AML and provided information on the MRD threshold used and the hematologic response of the study population. Among studies limited to patients in complete remission (CR), the estimated 5-year OS for the MRD-negative and MRD-positive groups was 67% (95% Bayesian credible interval [CrI], 53-77%) and 31% (95% CrI, 18-44%), respectively. Achievement of an MRD-negative response was associated with superior DFS and OS, regardless of MRD threshold or analytic sensitivity. Among patients in CR, the benefit of MRD negativity was highest in studies using an MRD cutoff less than 0.1%. The beneficial impact of MRD negativity was observed across MRD assays and timing of MRD assessment. In patients with AML in morphological remission, achievement of MRD negativity is associated with superior DFS and OS, irrespective of hematologic response or the MRD threshold used.

Genomic profiles and clinical outcomes of de novo blastoid/pleomorphic MCL are distinct from those of transformed MCL.

Blastoid and pleomorphic mantle cell lymphomas (MCLs) are variants of aggressive histology MCL (AH-MCL). AH-MCL can arise de novo (AH-DN) or transform from prior classic variant MCL (AH-t). This study is the first integrated analysis of clinical and genomic characteristics of AH-MCL. Patient characteristics were collected from diagnosis (AH-DN) and at transformation (AH-t). Survival after initial diagnosis (AH-DN) and after transformation (AH-t) was calculated. Regression tree analysis was performed to evaluate prognostic variables and in univariate and multivariate analyses for survival. Whole-exome sequencing was performed in evaluable biopsy specimens. We identified 183 patients with AH-MCL (108 were AH-DN, and 75 were AH-t; 152 were blastoid, and 31 were pleomorphic). Median survival was 33 months (48 and 14 months for AH-DN and AH-t, respectively; P = .001). Factors associated with inferior survival were age (≥72 years), AH-t category, Ki-67 ≥50% and poor performance status. AH-t had a significantly higher degree of aneuploidy compared with AH-DN. Transformed MCL patients exhibited KMT2B mutations. AH-MCL patients with Ki-67 ≥50% had exclusive mutations in CCND1, NOTCH1, TP53, SPEN, SMARCA4, RANBP2, KMT2C, NOTCH2, NOTCH3, and NSD2 compared with low Ki-67 (<50%). AH-t patients have poor outcomes and distinct genomic profile. This is the first study to report that AH-MCL patients with high Ki-67 (≥50%) exhibit a distinct mutation profile and very poor survival.

Tyrosine kinase inhibitor discontinuation in patients with chronic myeloid leukemia: a single-institution experience.

BACKGROUND: Patients with CML treated with TKI can have a life expectancy comparable to that of the general population. Due to the extended duration of TKI administration, treatment discontinuation has been increasingly sought. METHODS: Medical records of 100 patients with CML who were in MR4.5 and discontinued their TKI outside clinical trials were reviewed. RESULTS: After a median follow-up of 30 months (range, 5-112 months) after discontinuation, 35% and 17% lost MR4.5 and major molecular response (MMR), respectively. Only six patients lost MMR 12 months or more after discontinuation. Loss of MR4.5 was observed in 29% and 7% of patients with sustained MR4.5 duration of more than 2 and 6 years before discontinuation, respectively. By univariate analysis, there was a higher risk of loss of MR4.5 for patients who were treated for less than 87 months, received second or subsequent line TKI, never received interferon, or those with sustained MR4.5 for less than 6 years. By multivariate analysis, sustained MR4.5 for 6 years or more was the only significant predictor for durable response. Overall, 30% of patients who discontinued while in MR4.5 were retreated with 93% regaining MR4.5 at a median of 5 months. CONCLUSION: These results demonstrate that under proper conditions, treatment discontinuation is feasible outside of clinical trial setting. MR4.5 duration of 6 years or more before discontinuation is associated with very low risk of loss of MR4.5.

Clonal chromosomal abnormalities appearing in Philadelphia chromosome-negative metaphases during CML treatment.

Clonal chromosomal abnormalities in Philadelphia chromosome-negative (CCA/Ph-) metaphases emerge as patients with chronic phase chronic myeloid leukemia (CP-CML) are treated with tyrosine kinase inhibitors (TKIs). We assessed the characteristics and prognostic impact of 598 patients with CP-CML treated on clinical trials with various TKIs. CCA/Ph- occurred in 58 patients (10%); the most common were -Y in 25 (43%) and trisomy 8 in 7 patients (12%). Response to TKI therapy was similar for patients with CCA/Ph- and those without additional chromosomal abnormalities (ACAs). We further categorized CCA/Ph- into those in which -Y was the only clonal abnormality, and all others. We found that patients with non -Y CCA/Ph- had worse failure-free survival (FFS), event-free survival (EFS), transformation-free survival (TFS), and overall survival (OS) compared with those without ACAs with the following 5-year rates: FFS (52% vs 70%, P = .02), EFS (68% vs 86%, P = .02), TFS (76% vs 94%, P < .01), and OS (79% vs 94%, P = .03). In a multivariate analysis, non -Y CCA/Ph- increased the risk of transformation or death when baseline characteristics were considered with a hazard ratio of 2.81 (95% confidence interval, 1.15-6.89; P = .02). However, this prognostic impact was not statistically significant when achieving BCR-ABL <10% at 3 months was included in the analysis. In conclusion, non -Y CCA/Ph- are associated with decreased survival when emerging in patients with chronic-phase CML across various TKIs. This trial was registered at www.clinicaltrials.gov as #NCT00048672, #NCT00038649, and #NCT00050531 (imatinib); #NCT00254423 (dasatinib); #NCT00129740 (nilotinib); and NCT01570868 (ponatinib).

Ruxolitinib for symptom control in patients with chronic lymphocytic leukaemia: a single-group, phase 2 trial.

BACKGROUND: Disease-related symptoms impair the quality of life of patients with chronic lymphocytic leukaemia (CLL) who do not require systemic therapy. Available therapies are not specifically aimed at symptom control. Because stimulation of the B-cell receptor activates JAK2 in CLL cells and the JAK2 inhibitor ruxolitinib improves symptoms in patients with myelofibrosis, we postulated that ruxolitinib would improve disease-related symptoms in patients with CLL. We did a phase 2 trial of ruxolitinib to test this hypothesis. METHODS: Symptomatic patients with CLL who did not require systemic therapy were enrolled at MD Anderson Cancer Center (Houston, TX, USA) between Sept 15, 2014, and Sept 20, 2015. Participants were given 10 mg ruxolitinib orally twice a day. Scores on the Brief Fatigue Inventory (BFI), CLL module of the MD Anderson Symptom Inventory (MDASI) and symptom-associated interference in daily activities, were assessed before treatment and after 3 months. This trial is ongoing and is registered at ClinicalTrials.gov (NCT02131584). FINDINGS: 41 patients (25 previously untreated for CLL and 16 previously treated) were enrolled. At 3 months, the mean percentage change from baseline in BFI score was 44·3% (SD 35·0, p<0·0001), in symptom interference score was 43·4% (51·5, p<0·0001), and in MDASI score was 42·1% (37·4, p<0·0001). 32 (78%) of the patients experienced 20% or greater reduction in the mean BFI, and 24 (59%) had a reduction of two units or more in worst fatigue score in past 24 hours as assessed by the BFI. The most comment grade 3-4 adverse events were neutropenia (n=2 [5%]), hypertension (n=2 [5%]), insomnia (n=1 [2%]), tinnitus and dizziness (n=1 [2%]), and thrombocytopenia (n=1 [2%]). INTERPRETATION: In patients with CLL, ruxolitinib was associated with significant improvements in disease-related symptoms as measured by BFI, MDASI, and symptom interference scores. Further studies to test the therapeutic efficacy of ruxolitinib in CLL are warranted. FUNDING: Incyte, National Cancer Institute.

Impact of BCR-ABL transcript type on outcome in patients with chronic-phase CML treated with tyrosine kinase inhibitors.

The most common breakpoint cluster region gene-Abelson murine leukemia viral oncogene homolog 1 (BCR-ABL) transcripts in chronic myeloid leukemia (CML) are e13a2 (b2a2) and e14a2 (b3a2). The impact of the type of transcript on response and survival after initial treatment with different tyrosine kinase inhibitors is unknown. This study involved 481 patients with chronic phase CML expressing various BCR-ABL transcripts. Two hundred patients expressed e13a2 (42%), 196 (41%) expressed e14a2, and 85 (18%) expressed both transcripts. The proportion of patients with e13a2, e14a2, and both achieving complete cytogenetic response at 3 and 6 months was 59%, 67%, and 63% and 73%, 81%, and 82%, respectively, whereas major molecular response rates were 27%, 49%, and 50% at 3 months, 42%, 67%, and 70% at 6 months, and 55%, 83%, and 76% at 12 months, respectively. Median (international scale) levels of transcripts e13a2, e14a2, and both at 3 months were 0.2004, 0.056, and 0.0612 and at 6 months were 0.091, 0.0109, and 0.0130, respectively. In multivariate analysis, e14a2 and both predicted for optimal responses at 3, 6, and 12 months. The type of transcript also predicted for improved probability of event-free (P = .043; e14a2) and transformation-free survival (P = .04 for both). Compared to e13a2 transcripts, patients with e14a2 (alone or with coexpressed e13a2) achieved earlier and deeper responses, predicted for optimal European Leukemia Net (ELN) responses (at 3, 6, and 12 months) and predicted for longer event-free and transformation-free survival.

Ponatinib as first-line treatment for patients with chronic myeloid leukaemia in chronic phase: a phase 2 study.

BACKGROUND: Ponatinib has shown efficacy in patients with refractory chronic myeloid leukaemia (CML) and in those with CML with a Thr315Ile mutation. We aimed to investigate the activity and safety of ponatinib as first-line treatment for patients with chronic-phase CML. METHODS: We did a single-arm, phase 2 trial at MD Anderson Cancer Center in Houston, TX, USA. Between May 3, 2012, and Sept 24, 2013, we enrolled patients with early (<6 months) chronic-phase CML and treated them with oral ponatinib once a day. Patients enrolled before July 25, 2013, were given a starting dose of 45 mg per day; we lowered this due to tolerability issues and patients enrolled after this date were given a starting dose of 30 mg per day. After a warning by the US Food and Drug Administration (FDA) in Oct 6, 2013, for vascular complications with ponatinib, we started all patients on aspirin 81 mg daily and reduced the dose of ponatinib to 30 mg or 15 mg per day for all patients. The primary endpoint was the proportion of patients who achieved complete cytogenetic response by 6 months in the per-protocol population. This trial is registered with ClinicalTrials.gov, number NCT01570868. FINDINGS: We enrolled 51 patients. Median follow-up was 20·9 months (IQR 14·9­25·2). 43 patients were started on 45 mg ponatinib every day; eight patients were started on 30 mg per day. 43 (94%) of 46 evaluable patients achieved complete cytogenetic response at 6 months. Most frequent toxicities included skin-related effects (n=35; 69%) and elevated lipase (n=32; 63%). Cardiovascular events (mainly hypertension) occurred in 25 (49%) patients. Grade 3­4 myelosuppression occurred in 15 (29%) patients. Five (10%) patients developed cerebrovascular or vaso-occlusive disease. 43 (85%) patients needed treatment interruptions at some time and 45 (88%) needed dose reductions. The study was terminated June 18, 2014, at the recommendation of the FDA due to concern about the increased risk of thromboembolism with ponatinib. INTERPRETATION: Patients with newly diagnosed CML in chronic phase respond well to treatment with ponatinib, with most achieving a complete cytogenetic response. Dose adjustment, extensive monitoring, and counselling of the patients for thromboembolic events is needed for patients on ponatinib therapy. However, due to the risk of vascular thrombotic events and the availability of alternative options for these patients, other drugs should be considered first in the frontline setting. FUNDING: MD Anderson Cancer Center, National Cancer Institute, ARIAD Pharmaceutical.