Institution of Standardized Consultation Criteria to Increase Early Palliative Care Utilization in Older Patients With Acute Leukemia.

PURPOSE: Older patients with acute leukemia (AL) have a high symptom burden and poor prognosis. Although integration of palliative care (PC) with oncologic care has been shown to improve quality-of-life and end-of-life care in patients with AL, the malignant hematologists at our tertiary care hospital make limited use of PC services and do so late in the disease course. Using the Plan-Do-Study-Act (PDSA) methodology, we aimed to increase early PC utilization by older patients with newly diagnosed AL. METHODS: We instituted the following standardized criteria to trigger inpatient PC consultation: (1) age 70 years and older and (2) new AL diagnosis within 8 weeks. PC consultations were tracked during sequential PDSA cycles in 2021 and compared with baseline rates in 2019. We also assessed the frequency of subsequent PC encounters in patients who received a triggered inpatient PC consult. RESULTS: The baseline PC consultation rate before our intervention was 55%. This increased to 77% and 80% during PDSA cycles 1 and 2, respectively. The median time from diagnosis to first PC consult decreased from 49 days to 7 days. Among patients who received a triggered PC consult, 43% had no subsequent inpatient or outpatient PC encounter after discharge. CONCLUSION: Although standardized PC consultation criteria led to earlier PC consultation in older patients with AL, it did not result in sustained PC follow-up throughout the disease trajectory. Future PDSA cycles will focus on identifying strategies to maintain the integration of PC with oncologic care over time, particularly in the ambulatory setting.

Efficacy and tolerability of treatment with azacitidine for 5 days in elderly patients with acute myeloid leukemia.

Acute myeloid leukemia (AML) patients aged ≥ 60 years tolerate standard induction chemotherapy poorly. Therapy with azacitidine at a dose of 75 mg/m(2)/day for 7 days appears to be better tolerated, and is approved by the Food and Drug Administration (FDA) for the treatment of elderly AML patients with bone marrow (BM) blast counts of 20-30%. Here, we report the results of a prospective, phase 2, open-label study that evaluated the tolerability and efficacy of a 5-day regimen of single-agent subcutaneous azacitidine 100 mg/m(2)/day administered every 28 days in 15 elderly patients with newly diagnosed AML, 14 of whom had BM blast counts >30%. The overall response rate was 47%. Complete remission, partial remission, and hematologic improvement were achieved by 20, 13, and 13% of patients, respectively. Median overall survival was 355 days for the entire cohort, and 532 days for responders. Median time to best response was 95 days, and median treatment duration was 198 days (range = 13-724 days). Grade 3-4 hematologic toxicities comprised predominantly febrile neutropenia (40%) and thrombocytopenia (20%). Febrile neutropenia was the most common cause of hospitalization. Nonhematologic toxicities, consisting of injection-site skin reactions and fatigue (Grades 1-2), occurred in 73% (n = 11) of patients. No treatment-related deaths occurred during the study. The dose and schedule of therapy remained constant in all but four patients. The findings of this study suggest that administration of subcutaneous azacitidine 100 mg/m(2)/day for 5 days every 28 days is a feasible, well-tolerated, and effective alternative to standard induction chemotherapy in elderly patients with AML.

Azacitidine in the management of patients with myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal hematopoeitic disorders characterized by ineffective hematopoiesis and potential transformation to acute myeloid leukemia (AML). For decades, the mainstay of treatment for MDS was supportive care, including transfusion of blood products and growth factors. Further understanding of disease biology led to the discovery of a high prevalence of hypermethylation of tumor suppressor genes in high-risk MDS and secondary leukemias. Hence, the role of irreversible DNA methlytransferase inhibitors such as azacitidine was investigated with promising outcomes in the treatment of MDS. Azacitidine was initially approved in the USA by the Food and Drug Administration (FDA) in 2004 for the treatment of all subtypes of MDS and was granted expanded approval in 2009 to reflect new overall survival data demonstrated in the AZA-001 study of patients with higher-risk MDS. Azacitidine has demonstrated significant and clinically meaningful prolongation of survival in higher-risk patients with MDS and has changed the natural history of these disorders. The agent maintains a relatively safe toxicity profile, even in older patients. The role of azacitidine has been explored in the treatment of AML and chronic myelomonocytic leukemia and has also been studied in the peritransplant setting. Azacitidine has been combined with other novel agents such as lenalidomide, histone deacetylase inhibitors and growth factors in the hope of achieving improved outcomes. Currently, both intravenous and subcutaneous forms of azacitidine are approved for use in the USA with the oral form being granted fast track status by the FDA.

Activity of azacitidine in chronic myelomonocytic leukemia.

BACKGROUND: Hypomethylating drugs are useful in the management of myelodysplastic syndrome (MDS). Two of these drugs, azacitidine and decitabine, have received FDA approval for the treatment of MDS and chronic myelomonocytic leukemia (CMML). However, phase 2 and 3 studies that assessed these agents in MDS included only a small number of patients with CMML. The objective of this study was to evaluate the efficacy and safety of azacitidine in the treatment of CMML. METHODS: The records of thirty-eight patients diagnosed with CMML and treated with azacitidine at our institution were reviewed. Azacitidine was administered at 75 mg/m(2) /day for 7 days or 100 mg/m(2) /day for 5 days every 4 weeks. Patients who received at least 1 cycle of the drug were considered evaluable for response. RESULTS: Response was assessed by the modified International Working Group (IWG) criteria. The overall response rate was 39% (14 of 36); complete response (CR) rate was 11% (4 of 36); partial response (PR) rate was 3% (1 of 36); hematologic improvement (HI) was 25% (9 of 36). The median overall survival was 12 months. There was a statistically significant overall survival advantage in responders compared with nonresponders: 15.5 months versus 9 months, respectively (P = .04). Treatment was generally well tolerated. One of 2 patients had complete resolution of a skin rash that was due to monocytic infiltration. CONCLUSIONS: Azacitidine is active in the treatment of CMML. The therapy-associated toxicity is acceptable. Our results support further investigation of azacitidine in CMML, particularly in combination with other agents.

The role of azacitidine in the treatment of myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) are a heterogeneous group of hematopoietic disorders characterized by ineffective hematopoiesis and potential transformation to acute myeloid leukemia. Supportive care including transfusions and growth factors remained the mainstay of treatment for decades; however, further understanding of the biology behind these diseases led to the investigation of novel agents. As hypermethylation of tumor suppressor genes, such as p15, was believed to play a key role in the pathogenesis of these diseases, hypomethylating agents were investigated. Azacitidine is one of two hypomethylating agents used in the treatment of MDS, and the first approved by US FDA. In preclinical studies, azacitidine demonstrated hypomethylating/differentiating activity with low concentration, whereas high concentration was associated with cytotoxic effects. In clinical trials, azacitidine not only improved the cytopenias associated with MDS but also delayed leukemic transformation, improved quality of life and improved overall survival in many patients so treated. Azacitidine was the first agent noted to change the natural history of the disease. Further studies are underway evaluating the role of azacitidine pre- and post-transplantation, in combination with other agents, as well as in treatment of acute myeloid leukemia patients who are not good candidates for intensive chemotherapy. Azacitidine is also likely to be studied in the treatment of other malignant conditions. Although both subcutaneous and intravenous administrations have been approved, oral azacitidine is presently under investigation.

Multiple unit HLA-unmatched sex-mismatched umbilical cord blood transplantation for advanced hematological malignancy.

We investigated the effect of multiple-unit umbilical cord blood (UCB) transplantation on engraftment in the setting of severe human leukocyte antigen (HLA) mismatch. Ten poor-risk adult patients with hematological malignancy received multiple unit, HLA-unmatched, sex-mismatched, unrelated UCB transplantation after a reduced intensity-conditioning regimen (RICR) with engraftment as the primary endpoint. The median age of the patients was 55 years with a range of 28-67. Patients received one unit of UCB per 10 kg of recipient body weight (5-7 units). The median number of nucleated cells and CD34(+) cells per kilogram of recipient body weight infused was 6.3 x 10(7) (range 3.8-10.0) (NC/kg) and 5.7 x 10(5) (range 1.1-11.9) (CD34/kg), respectively. Three patients expired before day 28 and were not evaluable for engraftment. Five of the remaining 7 patients showed increasing neutrophil counts. Fluorescent in situ hybridization (FISH) for the Y chromosome or HLA-typing showed only donor cells in the peripheral blood. After engraftment, HLA typing was done on 3 patients and their infused UCB units. All revealed the presence of a single HLA type concordant with one of the infused units. Moreover, the order of infusion did not influence which UCB unit engrafted. The engrafting UCB units were infused first or second in one case and fourth in the other two. One patient transplanted for refractory acute lymphoblastic leukemia (ALL) survives in continuous complete remission 4 years after transplant. He engrafted with one UCB unit, is fully hematologically reconstituted, has no evidence of graft-versus-host disease (GVHD), and takes no immunosuppressive medication. HLA typing reveals that the recipient and the engrafted cord blood match at only one HLA-B locus using conventional 6 antigen typing (A, B, and DR). Although engraftment was not accelerated, it did occur in the majority of evaluable patients. Long-term disease-free survivorship without debilitating GVHD is possible in patients with refractory hematological malignancy who receive unmatched multiple unit UCB.

Recent advances in myelodysplastic syndromes.

Myelodysplastic syndromes (MDS) are a heterogeneous group of clonal bone marrow disorders characterized by both bone marrow failure and a propensity for development of acute myeloid leukemia. The incidence of these conditions has risen sharply over the past several years, making them the most common malignant bone marrow disorders. While the majority of patients are diagnosed with low-grade disease, approximately two-thirds will succumb to complications of peripheral blood cytopenias or progression to acute leukemia. In recent years, there has been striking progress in our understanding of the pathogenesis of these disorders. For example, the recognition of the roles of angiogenesis and cytokine abnormalities in the development of these diseases led to clinical trials with agents such as thalidomide, which yielded encouraging erythroid responses. Subsequent work with the thalidomide derivative lenalidomide resulted in marked erythroid and cytogenetic responses in individuals with the 5q- abnormality. Additionally, the identification of hypermethylation as an important aspect in the pathogenesis of these and other hematological diseases led to clinical trials utilizing the demethylating agents azacitidine and decitibine. These agents are now known to result in trilineage responses in 30% to 50% of patients with MDS with as many as 20% achieving partial or complete remissions. These results have altered the natural history of these diseases in a significant number of patients. Investigators anticipate that further studies with tyrosine kinase, histone deacetylase, and farnesyl transferase inhibitors will contribute to already promising attempts to reverse or block the pathogenesis of these diseases. Other novel agents are being evaluated as investigators continue to make progress for patients affected by these disorders.

Treatment of acute myelogenous leukemia with outpatient azacitidine.

BACKGROUND: Patients older than 55 years of age with acute myelogenous leukemia (AML) are less likely to achieve complete remission and more likely to experience toxicity with conventional induction chemotherapy than younger patients. Azacitidine administered in the outpatient setting is well tolerated and can induce complete hematological remission in patients with myelodysplastic syndromes (MDS). At higher doses, azacitidine has activity in AML. METHODS: Twenty patients were retrospectively identified who had been treated with azacitidine with bone marrow blast counts between 21 and 38%. Patients with blast counts up to 29% were initially treated as MDS, but by WHO now meet criteria for AML. Patients with blast counts over 29% were treated with azacitidine after being deemed poor candidates for induction chemotherapy. Azacitidine 75 mg/m2/day was administered subcutaneously for 7 days every 4 weeks, which was defined as 1 cycle. RESULTS: The overall response rate was 60% (12/20): complete response (CR; n = 4; 20%); partial response (PR; n = 5; 25%); hematologic improvement (HI; n = 3; 15%). The median survival of responders was 15+ months compared with 2.5 months for nonresponders (P = .009). During therapy, responders had an Eastern Cooperative Oncology Group (ECOG) performance status of 1 or 0. The most common toxic event was infection (n = 8). Four patients were hospitalized during the first cycle of treatment. CONCLUSIONS: Azacitidine administered in the outpatient setting can induce remission in AML. The therapy is well tolerated and might be an alternative for patients unlikely to tolerate standard induction chemotherapy.