Elliott F. Winton

We sought to evaluate the outcomes of chronic phase (CP) chronic myeloid leukemia (CML) in an era where five tyrosine kinase inhibitors (TKIs) are commercially available for the treatment of CML. Records of patients diagnosed with CP CML, treated with TKIs and referred to our center were reviewed. Between January 2005 and April 2016, 206 patients were followed for a median of 48.8 (1.4–190.1) months. A total of 76 (37%) patients received one TKI, 73 (35%) received two TKIs and 57 (28%) were exposed to >3 TKIs (3 TKIs, n = 33; 4 TKIs, n = 17; 5 TKIs, n = 7). Nineteen (9.2%) patients progressed to advanced phases of CML (accelerated phase, n = 6; myeloid blastic phase, n = 4; lymphoid blastic phase, n = 9). One third (n = 69) achieved complete molecular response (CMR) at first-line treatment. An additional 55 patients achieved CMR after second-line treatment. Twenty-five patients (12.1%) attempted TKI discontinuation and 14 (6.8%) stopped TKIs for a median of 6.3 months (range 1–53.4). The 10-year progression-free survival and overall survival (OS) rates were 81% and 87%, respectively. OS after 10-years, based on TKI exposure, was 100% (1 TKI), 82% (2 TKIs), 87% (3 TKIs), 75% (4 TKIs) and 55% (5 TKIs). The best OS was observed in patients tolerating and responding to first line TKI, but multiple TKIs led patients to gain treatment-free remission.

The randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial evaluated the JAK1/JAK2 inhibitor ruxolitinib in patients with intermediate-2/high-risk myelofibrosis. The primary and planned 3-year analyses of COMFORT-I data demonstrated that ruxolitinib—the first myelofibrosis-approved therapy—reduced splenomegaly and prolonged overall survival versus placebo. Here, we present the final 5-year results. Patients managed in Australia, Canada, and the USA were randomized centrally (interactive voice response system) 1:1 to oral ruxolitinib twice daily (15 or 20 mg per baseline platelet counts) or placebo. Investigators and patients were blinded to treatment. The secondary endpoints evaluated in this analysis were durability of a ≥35% reduction from baseline in spleen volume (spleen response) and overall survival, evaluated in the intent-to-treat population. Safety was evaluated in patients who received study treatment. Patients were randomized (September 2009–April 2010) to ruxolitinib (n = 155) or placebo (n = 154). At termination, 27.7% of ruxolitinib-randomized patients and 25.2% (28/111) who crossed over from placebo were on treatment; no patients remained on placebo. Patients randomized to ruxolitinib had a median spleen response duration of 168.3 weeks and prolonged median overall survival versus placebo (ruxolitinib group, not reached; placebo group, 200 weeks; HR, 0.69; 95% CI, 0.50–0.96; P = 0.025) despite the crossover to ruxolitinib. The ruxolitinib safety profile remained consistent with previous analyses. The most common new-onset all-grade nonhematologic adverse events starting <12 versus ≥48 months after ruxolitinib initiation were fatigue (29.0 vs 33.3%) and diarrhea (27.8 vs 14.6%). New-onset grade 3 or 4 anemia and thrombocytopenia both primarily occurred within the first 6 months, with no cases after 42 months. The most common treatment-emergent adverse event-related deaths in the ruxolitinib-randomized group were sepsis (2.6%), disease progression (1.9%), and pneumonia (1.9%). The final COMFORT-I results continue to support ruxolitinib as an effective treatment for patients with intermediate-2/high-risk MF. ClinicalTrials.gov, NCT00952289

Myelofibrosis (MF) is a chronic malignancy of the blood-forming system caused by hyperactivation of JAK2/STAT signaling pathway. Small-molecule inhibitors of JAK2 can variably ameliorate MF-related symptoms caused by chronic inflammation and hepatosplenomegaly. Anemia is a significant problem and adverse prognostic factor in over a third of MF patients and is often worsened by JAK2 inhibitors. The JAK1/2 inhibitor momelotinib unexpectedly resulted in reduction of anemia in MF patients during Phase I/II trials. Current Phase III trials will be the basis for seeking regulatory approval of momelotinib during 2017. Studies to determine how momelotinib improves anemia are underway, potentially leading to expanded momelotinib use and/or development of other targeted therapies for treating anemia in MF and related diseases.

E18503 Background: Induction chemotherapy with cytarabine/anthracycline remains the standard for AML. Regimen-related toxicities and profound myelosuppression lead to a prolonged hospitalization. In a specialized leukemia unit, a team of dedicated providers can deliver cost-effective care using streamlined processes Methods: Analysis of costs of hospitalization for induction in an academic center leukemia unit. Results: Between 1/2006 - 7/2011, 110 consecutive adult AML patients (pts) received induction. Median age was 60 (19-79), median white blood cell count (WBC) was 18.7 x103/mcL (0.3-348), with WBC ≥ 100 x103/mcL in 17. Cytogenetic (CTG) risks were favorable in 21%, intermediate in 47%, unfavorable in 29%, and unknown in 3%; 22 had secondary AML. Length of stay (LOS) was 28 d (9-56), and 12% required ICU care for a median of 3 d (2-17). Overall, 36% required 1, and 24% ≥ 2 consultations from non-hematology specialists. Median follow-up for survivors is 78 months (60-110). 30 d survival was 94%, mortality was 0 vs. 13% for pts < vs. ≥ 60 (p = 0.013), 4 vs. 18% for WBC < vs. ≥ 100 (p = 0.03), and 23% (vs. 4%) for pts requiring ICU care. Age was the only significant predictor of early death by MVA (p = 0.018). OS was 53 vs. 38% for pts < vs. ≥ 60 (p = 0.04), 51 vs. 23% for de novo vs. secondary AML (p = 0.001), and 74, 50, and 22% for favorable, intermediate and high-risk CTG (p = 0.001). Age (p = 0.04), CTG (p = 0.005) and ICU care (p = 0.017) were predictors of OS by MVA. Median hospitalization cost was $58,065 (8,493-442,349), and was affected by LOS (p < 0.001) and the need for ≥ 2 consultants (p = 0.025). Cost for < 20 d LOS was $33,289 (8,493-42,172), $58,370 (10,666-299,991) for 20-39 d, and $80,007 (13,379-124,180) for ≥ 40 d. Costs for pts not requiring consultation from a non-hematologist were $56,395 (8,493-100,766); $56,805 (10,666-299,991) and $72,981 (13,379-$182,311) for those requiring 1 vs. ≥ 2 consultants, respectively. Conclusions: We have reported costs associated with induction for AML in a specialized unit. These costs can serve as benchmark for comparisons. The number of non-hematologists consulted and LOS, both surrogate markers of complexity, were the major drivers of these costs.

Copper is an essential cofactor in many enzymatic reactions vital to the normal function of the hematologic, vascular, skeletal, antioxidant, and neurologic systems. Copper deficiency in the United States is believed to be relatively rare but has been described in the setting of zinc supplementation, myelodysplastic syndrome, use of parenteral nutrition and chronic tube feeding, and in various malabsorptive syndromes, including following gastrectomy and gastric bypass surgery. Features of copper deficiency include hematologic abnormalities (anemia, neutropenia, and leukopenia) and myeloneuropathy; the latter is a rarer and often unrecognized complication of copper deficiency. We here describe two patients who presented with severe gait abnormalities and anemia combined with neutropenia several years after roux‐en‐Y gastric bypass (RYGB) surgery for obesity who were found to be severely copper deficient. Intravenous copper repletion resulted in the rapid correction of hematologic indices; combined intravenous and oral copper supplementation and eventual oral copper supplements alone normalized serum copper levels in each patient, but resulted in only partial resolution of the neurologic deficits. This report serves to alert physicians of the association between RYGB procedures and subsequent copper deficiency in order to avoid diagnostic delays and to improve treatment outcomes.