ALBERT

Description: Relapse of acute myeloid leukemia (AML) following myeloablative allogeneic stem cell transplantation portends a dismal prognosis. Therapy aimed at enhancing graft-versus-leukemia (GVL) effect, e.g., by donor leukocyte infusion, has limited success in AML, and a second ablative transplant is associated with prohibitive mortality in adults. From April 2001 to March 2006, nine patients, ranging in age from 21 to 57, with high risk myeloid malignancy (7 AML and 2 advanced myelodysplasia) and overt bone marrow relapse less than one year after ablative busulfan/cyclophosphamide conditioning have been treated with a cytoreductive regimen of fludarabine (30 mg/m2/day) and cytarabine (2g/m2/day) for 5 days (-7 through -3) and G-CSF administration (5 ug/kg daily starting day -8) with or without idarubicin (8 mg/m2 days -7, -5, and -3) (8 cases) or fludarabine 30 mg/m2 for 3 days and 200 cGy total body irradiation (1 case). G-CSF mobilized peripheral blood stem cells from their original HLA-matched donor (8 siblings, 1 unrelated) were infused. Graft versus host disease (GVHD) prophylaxis was mycophenolate mofetil for 30 days and cyclosporine with a rapid taper. The mean onset of relapse after the initial ablative transplant was day 172 (range 106–271). Fludarabine-based therapy was well tolerated with no treatment related mortality. Full donor chimerism was established by day 72 (range 26–113) in 6 patients (67%). Five patients died: 2 from relapse without GVHD at day +30 and +301 after RIST (one patient with complex and one with Ph+ cytogenetic abnormalities), 3 from relapse with evidence of GVHD. Four patients survive: one has relapsed at 91 days after RIST and is receiving alternate therapy, while three patients (30%) survive in complete remission at 100+, 635+ and 1795+ days after salvage RIST. In 5 cases (56%), the duration of complete remission after RIST was longer than after the initial ablative transplant. We conclude that fludarabine-based RIST is a safe and effective salvage therapy offering a chance for increased survival with low morbidity in patients relapsing after ablative transplant. In addition, RIST therapy has resulted in long-term disease free survival in over 20% of cases in this study.

Description: Introduction: There are limited options for acute myeloid leukemia (AML) patients who are too frail to receive intensive induction chemotherapy or who have relapsed /refractory disease. Early phase II trials published in 2016 demonstrated promising outcomes in AML with the BCL-2 inhibitor venetoclax, which was FDA approved in November 2018. We conducted a retrospective review of AML patients who received venetoclax at Kaiser Permanente Northern California (KPNC) specifically examining patients' characteristics and outcomes. Methods: This is a retrospective review of all KPNC patients who had a diagnosis of AML and received at least 1 prescription of venetoclax from January 1, 2016 through March 31, 2019. Data was abstracted from our electronic medical record. Variables included age, complete blood count, AML type, lines of therapy, prior use of hypomethylating agent, cytogenetics, somatic mutation, duration of treatment and chemotherapy regimen. Because none of the patients were treated under clinical trial protocol, most did not have a scheduled bone marrow biopsy to formally document disease status. Hematologic response (HR), defined here as neutrophil ≥ 0.5 x 109/L, platelet ≥ 50 x 109/L and RBC transfusion independence was used to access treatment effectiveness. Results were analyzed via descriptive statistics. Results: A total of 68 patients received venetoclax-based chemotherapy for treatment of AML. The median age was 68 (range 12-87). Among those 68 patients, 35% had venetoclax-based treatment as first line therapy, 35% as second line, and the remaining as third or later line (Table 1). Among those who received venetoclax as first line treatment, 58% had a HR. Among those who received venetoclax as second line treatment, 29% had a HR and 43% of those went on to allogeneic bone marrow transportation (BMT). 20% of those that received venetoclax in the third line setting had a HR and all went on to BMT. Patients who received venetoclax in fourth line or above did not have any significant response. Only 2 out of the 16 patients who received prior hypomethylating agent responded to venetoclax combination therapy. Four patients did not even complete cycle 1. 12 out of 68 patients were prescribed venetoclax based on FDA approved guidelines in November 2018. Of those 75% demonstrated HR. Conclusion While most of our patients used off-label venetoclax in a non-clinical trial setting, we confirm that venetoclax-based regimen is an effective treatment for AML, similar to published data. Our cohort represents a more heterogeneous population, which is more generalizable to the community. There is a higher response rate among those who used it in the first- and second-line setting (58% and 29% respectively). Venetoclax also showed efficacy in the second- or third-line setting, bridging patients to allogeneic BMT. Patients with prior hypomethylating agent are less likely to benefit from this drug. Venetoclax in combination with a hypomethylating agent is an effective AML regimen. Its efficacy deserves further studies, perhaps as a front-line treatment, sparing patients from intensive toxic inpatient induction chemotherapy. Disclosures No relevant conflicts of interest to declare. OffLabel Disclosure: This retrospective study evaluates the use of venenoclax-based regimen for treatment of AML. Clinicians have been using it since 2016, but the drug was not formally FDA approved for AML until November 2018.

Description: Introduction: Patients with acute myeloid leukemia (AML) may receive more appropriate care when treated regionally instead of locally, but studies have not adequately accounted for baseline differences between regional and local cohorts. In 2015, Kaiser Permanente Northern California, an integrated healthcare delivery system, started to shift AML induction from local (N=21) to regional (N=3) centers. We assessed the association of regionalization with the frequency of use of induction therapy and bone marrow transplantation, and with 60-day mortality. Methods: Information for all adult health plan members with ≥1 year of enrollment before receiving a diagnosis of AML during 2013-17 was obtained from the electronic health record. Multivariable methods were used to compare risk of induction, bone marrow transplantation, and death before and after 2015 (i.e., 2013-14 and 2016-17) after adjustment for baseline characteristics. Results: Of 662 patients, 38% were ≥75 years, 30% had an Elixhauser comorbidity index ≥5, and 10% died within the week following diagnosis. Among non-APL patients, we observed increased use of induction therapy (65% vs 49%, p=0.0003) and bone marrow transplantation (23% vs 13%, p=0.007) after 2015, while the 60-day mortality rate did not change (before 2015, 94 of 278 [32.7%]; after 2015, 82 of 249 [32.9%]; p=0.83). Conclusion: In this community-based population that includes advanced elderly patients with substantial comorbidity, regionalization was associated with increased use of induction therapy and bone marrow transplantation but no increase in the risk of 60-day mortality. Older patients can benefit from AML induction therapy at specialized centers. Figure Disclosures No relevant conflicts of interest to declare.