First-line therapy for patients with newly diagnosed acute promyelocytic leukemia (APL) has been established in a series of randomized clinical trials. Remission induction and consolidation are based ...on the differentiation agent, all-trans retinoic acid (ATRA), and anthracycline-based chemotherapy. Maintenance therapy is also based on ATRA and may involve additional chemotherapy. Established protocols are associated with a high rate of complete responses (CRs) (87% to 97%), and long-term follow-up has indicated a 4-year disease-free survival of greater than 60%. Therapy for patients who relapse or are refractory to ATRA-based regimens is not standardized and there is a need for new approaches. Arsenic trioxide (ATO) has recently been licensed for use in patients with relapsed/refractory APL. Controlled clinical trials have indicated that ATO is associated with a CR rate of 87% in this population. This agent has a manageable toxicity profile and presents a welcome option for patients with relapsed disease for whom other, more debilitating therapies are unsuitable. Several prognostic factors have been defined in patients with APL, and it is possible that novel treatments such as ATO should be differentially applied to specific prognostic groups.
Leukemia cells accumulate DNA damage but altered DNA repair mechanisms protect them from apoptosis. We showed here that formaldehyde generated by serine/one-carbon cycle metabolism contributed to ...accumulation of toxic DNA-protein crosslinks (DPCs) in leukemia cells, especially in driver clones harboring oncogenic tyrosine kinases OTKs: FLT3(ITD), JAK2(V617F), BCR/ABL1. To counteract this effect, OTKs enhanced the expression of DNA polymerase theta (POLq) by ERK1/2 serine/threonine kinase-dependent inhibition of c-CBL E3 ligase-mediated ubiquitination of POLq and its proteasomal degradation. Overexpression of POLq in OTK-positive cells resulted in efficient repair of DPC-containing DNA double-strand breaks (DSBs) by POLq-mediated end-joining (TMEJ). Transforming activity of OTKs and other leukemia-inducing oncogenes, especially of those causing inhibition of BRCA1/2 -mediated homologous recombination (HR) with and without concomitant inhibition of DNA-PK -dependent non-homologous end-joining (D-NHEJ), was abrogated in Polq-/- murine bone marrow cells. Genetic and pharmacological targeting of POLq polymerase and helicase activities revealed that both activities are promising targets in leukemia cells. Moreover, OTK inhibitor or DPC-inducing drug etoposide enhanced anti-leukemia effect of POLq inhibitor (POLqi) in vitro and in vivo. In conclusion, we demonstrated that POLq plays an essential role in protecting leukemia cells from metabolically induced toxic DNA lesions triggered by formaldehyde and that it can be targeted to achieve therapeutic effect.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Pretherapy patients with chronic lymphocytic leukemia (CLL) from US Intergroup trial E2997 were analyzed with single nucleotide polymorphism microarrays to detect acquired chromosomal anomalies. The ...four CLL-typical anomalies (11q-, +12, 13q-, and 17p-) were found at expected frequencies. Acquired anomalies in other regions account for 70% of the total detected anomalies, and their number per participant has a significant effect on progression-free survival after adjusting for the effects of 17p- (and other covariates). These results were compared with those from a previous study of more than 50,000 participants from the GENEVA consortium of genome-wide association studies, which analyzed individuals with a variety of medical conditions and healthy controls. The percentage of individuals with acquired anomalies is vastly different between the two studies (GENEVA 0.8%; E2997 80%). The composition of the anomalies also differs, with GENEVA having a higher percentage of acquired uniparental disomies and a lower percentage of deletions. The four common CLL anomalies are among the most frequent in GENEVA participants, some of whom may have CLL-precursor conditions or early stages of CLL. However, the patients from E2997 (and other studies of symptomatic CLL) have recurrent acquired anomalies that were not found in GENEVA participants, thus identifying genomic changes that may be unique to symptomatic stages of CLL.
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Abstract only
e18522
Background: Clinical trials have shown that low-risk APL patients had significantly better outcomes when receiving first-line all-trans retinoic acid (ATRA) + ATO compared with ...standard ATRA + chemotherapy. Few published studies have used real-world data to describe patients using ATO and their current treatment patterns. This study used United States (US) administrative claims data to describe treatment patterns and characteristics of patients receiving first-line ATO. Methods: This retrospective, observational cohort study used claims data from the MarketScan databases. As there is no ICD-9-CM diagnosis code for APL, ATO treatment was used as a surrogate for the diagnosis of APL since ATO is typically used only in APL patients. Patients were selected if they had ≥1 claims for ATO between January 1, 2000, and June 30, 2015. Date of first use was designated the index date. To identify first-line ATO initiation, patients with ATRA or other APL-indicated chemotherapy claims any time before the index date were excluded. Variable baseline and follow-up periods consisting of ≥3 months of pre-index and ≥30 days of post-index continuous enrollment in medical and pharmacy benefit were used. Results: In total, 331 patients were identified with a subset (n = 265) having ≥2 claims for ATO. The analysis focused on these 265 patients, 54% of whom were male. Mean age was 60.6 years; 45% were covered by Medicare. The most common comorbid conditions measured were diabetes (6%), chronic obstructive pulmonary disease (5%), and congestive heart failure (4%). The most commonly selected APL treatments administered during follow-up were ATRA (17%) and daunorubicin (9%) with the use of idarubicin, cytarabine, and mitoxantrone at less than 3%. Maintenance therapy with methotrexate or 6-mercaptopurine was observed in 7% and 6% of patients, respectively. Conclusions: This is one of the first studies to examine patient characteristics and treatment patterns for first-line ATO using real-world data. Further research is needed to evaluate outcomes for patients receiving ATO as first-line therapy and to re-evaluate treatment guidelines in light of these outcomes.
Introduction: Somatic mutations in the metabolic enzymes isocitrate dehydrogenase (IDH) 1 and 2 are found in multiple solid and hematologic tumors and drive tumorigenesis via production of the ...oncometabolite D-2-hydroxyglutarate (2-HG). The mutant IDH1 (mIDH1) inhibitor ivosidenib is approved in the US for the treatment of adults with mIDH1 newly diagnosed acute myeloid leukemia (AML) in patients ≥75 years old or with comorbidities that preclude induction chemotherapy, and mIDH1 relapsed or refractory (R/R) AML. In patients with R/R AML who were enrolled in a phase 1 study (NCT02074839), ivosidenib was associated with an overall response rate of 42%, a complete remission (CR) rate of 24%, and a CR plus CR with partial hematologic response (CR+CRh) rate of 32%, with durable responses and additional clinical benefits observed (Pollyea et al. J Clin Oncol 2018 Abs). Baseline co-occurring mutations in receptor tyrosine kinase (RTK) pathway genes were shown to be associated with primary resistance to ivosidenib (DiNardo et al. N Engl J Med 2018). Case studies of secondary resistance to ivosidenib monotherapy have revealed examples of 2-HG restoring mechanisms at relapse, including IDH2 isoform switching and the emergence of mIDH1-S280F (Harding et al. Cancer Discov 2018; Intlekofer et al. Nature 2018).
Aim: To characterize the mechanisms of response and relapse to ivosidenib monotherapy via a comprehensive genomic analysis of samples from a large cohort of patients with mIDH1 R/R AML enrolled in the pivotal phase 1 study whose starting dose was 500 mg daily (approved dose).
Methods: Baseline and longitudinal co-occurring mutation profiling was performed on whole bone marrow, bone marrow mononuclear cell, and peripheral blood mononuclear cell samples by next generation sequencing (NGS; detection sensitivity 1-5%). 3D modelling of second-site IDH1 mutations was performed with an ivosidenib analog using Molecular Operating Environment 10.0 software. Enzymatic assays were performed with mIDH1 as previously reported. The clinical response data cut-off was Nov 10, 2018.
Results: In 167 patients with baseline NGS data from whole bone marrow, the genes with most frequent co-occurring mutations were DNMT3A (35%), NPM1 (26%), SRSF2 (24%), ASXL1 (18%), RUNX1 (18%), NRAS (14%), and TP53 (13%). RTK pathway mutations, and mutations in the individual genes NRAS and PTPN11, were significantly associated with a lack of CR or CRh response to ivosidenib (p<0.001 RTK, p=0.004 NRAS, and p=0.016 PTPN11, Fisher's exact test). Investigation of clonal hierarchy at baseline showed that neither subclonal nor clonal status of mIDH1 was associated with clinical response (p=0.4, Fisher's exact test). To characterize mechanisms of secondary resistance to ivosidenib, longitudinal NGS profiling was performed for 129 patients, 74 of whom had data at both baseline and relapse or disease progression. Mutations not detected at baseline but identified at the time of relapse/progression were categorized into canonical biological pathways. Mutations in RTK pathway genes were identified at relapse/progression in 20 of 74 (27%) patients, with IDH1/2 mutations detected at a comparable rate (17 23%; Table). IDH2-R140Q mutations were newly detected during treatment in 9 of 74 patients (12%). IDH1 second-site mutations emerged in 10 of 74 patients (14%), including previously unreported mutations at 5 amino acid positions. Detection of these IDH1 second-site mutations was concurrent with an increase in plasma 2-HG. Five patients acquired both RTK pathway mutations and 2-HG restoring mutations (IDH1 and/or IDH2) at relapse/progression. All identified second-site IDH1 mutations were clustered into two sub-regions and were predicted by 3D modeling to impact ivosidenib and/or co-factor (NADPH) binding either directly or indirectly. Biochemical characterization of two of these mutations confirmed loss of ivosidenib inhibitory potency.
Conclusions: Relapse to ivosidenib monotherapy is mediated by diverse mechanisms that include emergent mutations, most frequently in RTK pathway genes and IDH1/IDH2. The observation of frequent 2-HG restoration at relapse underscores the key role of 2-HG production in mIDH AML disease. These results are important for the rational design of combination treatment strategies in mIDH1 AML, and to understand whether these patterns are replicated in ongoing combination trials.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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Optimal post-remission therapy for adolescents and young adults (AYAs, 16-39 years) with Ph-negative (Ph-) acute lymphoblastic leukemia (ALL) in first complete remission (CR1) is not well ...established. We hypothesized that post-remission therapy with a pediatric-inspired regimen would yield superior outcomes to myeloablative allogeneic HCT for AYA patients with Ph- ALL in CR1. We compared overall survival (OS), disease-free survival (DFS), relapse, and non-relapse mortality (NRM) for patients receiving post-remission therapy on CALGB 10403 to a contemporary matched AYA cohort undergoing myeloablative allogeneic HCT in CR1 reported to the CIBMTR (Table). The allogeneic HCT cohort consisted of patients 16-39 years of age with Ph- ALL in CR1 undergoing myeloablative transplant from a matched sibling/relative or unrelated donor using peripheral blood or bone marrow stem cells between 11/2002 and 8/2012 in the United States. Patients receiving post-remission therapy with pediatric-inspired chemotherapy had superior OS (P<0.0001), DFS (P=0.0011), and NRM (P<0.001) compared to allogeneic HCT. Patterns of relapse were time-dependent and examined in the Cox model. In multivariate analysis of Cox model, receiving allogeneic HCT was associated with inferior OS (HR 1.99, 95% CI 1.5-2.65, P <0.001), inferior DFS (HR 1.51, 95% CI 1.17-1.94, P 0.002), and increased NRM (HR 3.93, 95% CI 2.53-6.10, P <0.001; Figure). In the early post-remission period (≤15 months after CR1), relapse was more likely with allogeneic HCT (HR 1.63, 95% CI 1.03-2.59, p=0.04) whereas beyond 15 months after CR1 relapse was more likely in the chemotherapy arm (HR 0.35, 95% CI 0.19-0.62, P <0.001; Figure). Obesity (BMI ≥30) was independently associated with inferior OS (HR 2.22, 95% CI 1.69-2.91, P<0.001), inferior DFS (HR 1.96, 95% CI 1.52-2.53, P <0.001), increased relapse (1.90, 95% CI 1.37-2.64, P <0.001), and increased NRM (HR 1.99, 95% CI 1.33-2.97, P <0.001). Extramedullary disease at diagnosis was independently associated with inferior OS (HR 1.34, 95% CI 1.00-1.79, P=0.05). We conclude from this large retrospective study that post-remission therapy with pediatric-inspired chemotherapy as given on CALGB 10403 was superior to allogeneic HCT in CR1 for OS, DFS, and NRM in AYAs with newly-diagnosed Ph-negative B- and T-cell ALL. Late relapse was more likely with chemotherapy whereas early relapse was more likely with allogeneic HCT. Future study should aim to elucidate the impact of measurable residual disease at CR1 and high-risk genetics, including Ph-like ALL, on the superiority of post-remission pediatric-inspired chemotherapy over allogeneic HCT.
Figure. Allogeneic HCT (HCT) vs. CALGB 10403 pediatric-inspired chemotherapy (chemo) after CR1: Adjusted (left-truncated) overall survival, disease-free survival, cumulative incidence of relapse, and cumulative incidence of non-relapse mortality.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Background
Hairy cell leukemia (HCL) is a rare and indolent lymphoproliferative disorder. Frontline treatment with a single course of the purine nucleoside analog (PNA) cladribine (or pentostatin) ...produces a high rate of complete remission (CR) with prolonged durations. At the time of relapse, treatment guidelines recommend re-treatment with a PNA alone or in combination with rituximab (R) but practice patterns vary and data supporting each approach are limited.
Methods
We conducted a multi-site outcomes analysis of patients treated for HCL between 1995-2018 at 5 US medical centers. All patients were treated with frontline PNA and subsequently required treatment for relapsed/refractory (r/r) disease with a PNA alone (PNA) or a PNA with R (PNA+R). Decision to use R was made by the treating physician. Baseline characteristics were compared between treatment cohorts using Fisher's exact and Wilcoxon rank sum tests. Overall survival (OS) and progression free survival (PFS) used log rank test.
Results
Of the 78 patients analyzed, 49 (62.8%) received a PNA (44 with cladribine and 5 with pentostatin) and 29 (37.2%) received a PNA+R (25 with cladribine and 4 with pentostatin) as second line treatment for r/r HCL. Among the PNA+R cohort, the median number of R doses was 8 (range 1-8). R was administered concurrently in 35% and sequentially in 65% of PNA+R treated patients (N=20 with available data). Baseline characteristics were similar between the PNA and PNA+R cohorts. The median age at diagnosis in the PNA cohort was 52 yo (range 49-87) and 49 yo (range 30-79) in the PNA+R cohort (P=0.62). In the PNA cohort, 36% of patients were female and 64% male vs. 40% and 60%, respectively in the PNA+R cohort (P=0.79). There was no difference in the median time from initial treatment to relapse between the PNA vs. PNA+R cohort 59 months (4-273) vs 61 months (1-99), P=0.29. At the time of relapse, age, hemoglobin, WBC, ANC, platelet count, and LDH showed no statistical difference between cohorts. Median follow-up for living patients was 57 months (1-197). Median time to best response after second line therapy was 2.4 months (1.0-30.0) in the PNA cohort and 1.2 months (1.0-11) in the PNA+R cohort (P=0.12). Among cases with known responses after second line treatment (N = 50), there was no difference in CR or PR for the PNA vs PNA+R cohorts (93% and 3.4% vs. 95% and 0%, respectively, P = 0.99). Six patients died, 3 from each cohort. Cause of death was due to septic shock in 1 patient and unknown in 5. As shown in the accompanying Figure, there was no difference in median PFS 62 months (95% CI 43.8-not reached) vs. 65 months (95% CI 60-not reached) or 5-year OS 98% (95% CI 0.93-1) vs. 93% (95% CI 0.8-1), P=0.118 in the PNA vs. PNA+R cohorts, respectively.
Conclusion
Patients with r/r HCL after PNA frontline treatment who receive second line PNA or PNA+R have similar PFS and excellent OS. To our knowledge, this is the largest study evaluating the role of R in treatment of r/r HCL and suggests that there is no clinically discernable advantage to the addition of R to PNA therapy at the time of first re-treatment. The results of this study should be interpreted within the context of a recently reported prospective trial demonstrating improved minimal residual disease-free state with concurrent vs. sequential R with PNA in treatment naïve HCL patients (Chihara, et al. JCO, 37, 2019 (suppl; abstr 7003)).
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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