Hanna Jean Khoury

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.

Inhibition of the Janus-associated kinases (JAK) with ruxolitinib (RUX) reduces graft-versus-host disease (GVHD) in preclinical and clinical models. In total 19 allograft recipients with moderate/severe steroid-dependent chronic GVHD received RUX as ≥2nd line salvage. RUX was well tolerated, and led to complete/partial resolution of oral (92/7%), cutaneous (82/0%), hepatic (71/28%), gastro-intestinal (75/17%), musculoskeletal (33/67%), pulmonary (0/80%), scleroderma (0/75%), vaginal (0/75%), and ocular (0/100%) chronic GVHD. Overall 18 achieved partial response and 1 complete response according to NIH Consensus Criteria. Responses occurred early and were sustained which enabled discontinuation (68%) or reduction of steroids to physiologic doses (21%). We conclude that RUX is an effective steroid-sparing agent in chronic GVHD.

BACKGROUND: To the authors' knowledge, the optimal frequency of monitoring after tyrosine kinase inhibitor (TKI) discontinuation in patients with chronic myeloid leukemia (CML) has not been established. Data regarding the discontinuation of second‐generation TKIs used in first‐line treatment or after the failure of first‐line treatment with TKIs are limited. Herein, the authors report real‐world experience with “reduced frequency” molecular monitoring in patients with CML in all phases who discontinued treatment with imatinib, dasatinib, or bosutinib.METHODS: The records of patients who discontinued TKIs were reviewed. Patients who discontinued TKIs were monitored prospectively on an intended schedule of monthly blood quantitative reverse transcriptase‐polymerase chain reaction for BCR‐ABL1 for 3 months, quarterly for 12 months, and every 6 months thereafter until loss of major molecular response (MMR). After loss of MMR, the TKI that previously was discontinued was reinitiated.RESULTS: Between January 2010 and September 2015, a total of 24 patients in chronic (21 patients), accelerated (2 patients), and lymphoid blast (1 patient) phase discontinued imatinib (16 patients), dasatinib (5 patients), or bosutinib (3 patients) used in the front‐line treatment or beyond. Blood quantitative reverse transcriptase‐polymerase chain reaction for BCR‐ABL1 was performed 1.3 ± 0.7 times within the first 3 months (24 patients) and 2.7 ± 1.4 times in the following 12 months (18 patients). With a median follow‐up of 36.5 months (range, 3.2‐67.4 months), the probabilities of treatment‐free remission at 1 year and 2 years were 65.7% (95% confidence interval, 55.8%‐75.6%) and 59.7% (95% confidence interval, 49.1%‐70.3%), respectively. Loss of MMR was observed in 9 patients at a median of 2.8 months (range, 1.8‐14.2 months) after discontinuation of TKIs.CONCLUSIONS: With the limitations of a small sample size, the results of the current study demonstrate that less frequent monitoring of BCR‐ABL1 does not appear to affect outcomes, and that discontinuation of TKIs used as first‐line treatment or beyond after resistance or intolerance to first‐line treatment appears feasible. Cancer 2017;123:2482–88. © 2017 American Cancer Society.

7033 Background: Patients with AML failing to achieve complete remission (CR) or in first relapse (Rel1) can have extended leukemia control and survival following allogeneic hematopoietic cell transplantation (HCT). Transplantation in primary induction failure (PIF) or Rel1 versus additional treatment to achieve CR2 and thereafter HCT might yield similar outcomes, but modern data addressing this question is scarce. Methods: We studied patients who proceed to HCT, analyzing comparative survival by disease status: PIF (N = 1440), REL1 (N = 1256) and CR2 (N = 1986) in 2000 – 2013 and median follow up of 5 years. Results: Age, gender, donor, graft type, conditioning intensity and GVHD prophylaxis were similar in the three groups. CR2 patients were more likely to report performance scores of 90 or 100, de novo AML and longer duration CR1. Adverse cytogenetics was more common in PIF patients and duration of CR1 was shorter in REL1 than CR2. Mortality was higher for HCT in Rel1 compared to CR2 regardless of CR1 duration (RR 1.65, p < 0.0001). Similarly, mortality was higher for HCT in PIF compared to CR2 with CR1 duration < 6 (RR 1.26, p < 0.0001), 6-12 (RR 1.60, p < 0.0001) and > 12 months (RR 2.24, p < 0.0001). However, comparing PIF to Rel1, mortality was higher for HCTs in PIF compared to Rel1 with duration of CR1 > 12 months (RR 1.36, p < 0.0001) but not for Rel1 with duration of CR1 6-12 months. Mortality was lower for HCTs in PIF compared to Rel1 with duration of CR1 < 6 months (RR 0.76, p < 0.0001). The probabilities of overall survival by disease status, and adjusted for age, performance score, cytogenetic risk and donor type, the other factors associated with mortality risks are: 6 months: CR2 73 (71-75)%; REL1 53 (50-55)%; PIF 58 (56-61)% and at 2 years, CR2 50 (48-52)%; REL1 27 (24-29)%; PIF 29 (27-32)%. Conclusions: These data demonstrate superior survival for HCT in CR2 than either in REL1 or PIF. Yet HCT for selected patients in PIF or REL1 may still be valuable. These data can guide decision-making about the utility of additional salvage therapy vs. prompt HCT, even for patients not in CR, but should note intrinsically more treatable AML with favorable risk cytogenetics, longer CR1 duration and younger patients with better performance score.

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.

The management of chronic myeloid leukemia (CML) in accelerated or blast phase (advanced phase) remains a significant challenge despite the introduction of very effective tyrosine kinase inhibitors (TKIs). The biology of advanced-phase CML is complex and engages several pathways that are not optimally targeted by TKIs. Allogeneic stem cell transplantation remains the only potentially curative therapy, but the effectiveness of this conventional approach is limited. New strategies are required to improve the outlook for these patients.

BACKGROUND: Flow cytometry (FC) is a commonly requested test in the workup of leukocytosis in community practices. The role of FC in chronic‐phase chronic myeloid leukemia (CP‐CML) is unknown. We hypothesized that finding aberrant cells with FC in CP‐CML may predict early blast‐phase (BP) transformation.METHODS: Results for FC performed at the time of diagnosis for adult and pediatric patients with CP‐CML who were referred to our institution were reviewed, and they were correlated with outcomes.RESULTS: FC was performed at the time of diagnosis for 110 of 233 patients (47%) with CP‐CML. Aberrant populations, representing a median of 2% (range, 0.3%‐15%), were detected with FC in 30% of patients (33 of 110): 2 of these 33 patients expressed lymphoid markers, and 31 expressed aberrant myeloid markers. Patients received imatinib (85%), dasatinib (12%), or nilotinib (3%) as their first‐line treatment. With a median follow‐up of 43 months (range, 2‐113 months), chronic myeloid leukemia transformed to BP in 5 of the 33 patients. The 2 patients with lymphoid markers and the 3 of 31 patients with aberrant myeloid markers experienced a transformation to lymphoid BP at a median of 11 months (range, 4‐72 months) after the initiation of tyrosine kinase inhibitor therapy. Although both cases with detectable lymphoid markers rapidly progressed to lymphoid BP, the positive predictive value of BP transformation by the detection of myeloid aberrant cells with FC was only 10% (3 of 31).CONCLUSIONS: In contrast to aberrant myeloid markers, the detection of lymphoid markers by FC at the time of the diagnosis of CP‐CML appears to be associated with early progression to lymphoid BP. Cancer 2015;121:872–875. © 2014 American Cancer Society.