Pamela S. Becker, MD, PhD, Department of Hematologic Malignancies, City of Hope, discusses the rationale for investigating uproleselan (GMI-1271) in combination with chemotherapy in relapsed/refractory acute myeloid leukemia (AML).

Preclinical studies of uproleselan done in Australia by a group led by investigator Ingrid Winkler showed that AML cells in mice enhanced proinflammatory mediators, which increased E-selectin expression in the bone marrow microenvironment, Becker says. Additionally, this research demonstrated mediators expressed by AML could not up-regulate the E-selectin, due to prevention from the TNFα blockade , Becker explains.

Moreover, preclinical work with uproleselan generated a decrease to the pro-survival pathways that are active in the AML, Becker continues. This process sensitized the AML cells to chemotherapy, Becker continues. Mouse models elicited an improved survival of mice if they were treated with chemotherapy plus the uproleselan, vs chemotherapy alone, Becker concludes.

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Pamela S. Becker, MD, PhD, discusses the rationale for investigating uproleselan in combination with chemotherapy in relapsed/refractory acute myeloid leukemia.


Dr. Becker on the Rationale for Investigating Uproleselan in Combination with Chemotherapy in AML

	University of Washington School of Medicine

Although many patients with cancer now receive chemotherapy as outpatients, most cancer treatment centers do not extend this practice to patients with acute myeloid leukemia (AML) or advanced myelodysplastic syndromes (MDS) who are receiving initial intensive induction therapy. This reluctance primarily reflects the propensity of such therapy to damage the gastrointestinal tract and aggravate patients’ preexisting low neutrophil counts, thus producing potentially life-threatening infections. AML and its treatment also cause a significant reduction in platelet counts and thus a significant risk of bleeding.

The high-risk nature of AML and its initial treatment has traditionally led physicians to keep patients in the hospital until patients’ neutrophil and platelet counts recover, which doesn’t happen for 4 to 5 weeks after the start of chemotherapy. Based on growing experience with oral prophylactic antibiotics and transfusion support, physicians at Seattle Cancer Care Alliance (SCCA) have begun routinely discharging patients from its inpatient facility at University of Washington Medical Center (UWMC) immediately following the completion of intensive induction chemotherapy for AML and MDS. This allows patients to spend only 5 to 7 days, rather than 4 to 5 weeks, in the hospital. In June 2013, SCCA researchers initiated a pilot clinical trial involving complete outpatient administration of chemotherapy for AML and advanced MDS. The trial’s principal goals are to assess the safety of this practice and its effects on quality of life and cost.

Clinicians at SCCA were pioneers in providing patients with outpatient care following moderately intensive treatments such as high-dose chemotherapy and autologous stem cell transplant or reduced-intensity allogeneic stem cell transplant. The physicians at Fred Hutchinson Cancer Research Center started doing outpatient transplants decades ago, so the idea to be able to give the more standard chemotherapy induction regimens in the outpatient setting seemed feasible.

Before joining the University of Washington and SCCA in 2008, Elihu Estey, MD, professor in the Division of Hematology, had gained experience with early discharge of newly diagnosed patients with AML at The University of Texas MD Anderson Cancer Center in Houston. These patients were typically young and were discharged on an ad hoc basis.

But changing the way things have always been done requires more formal evidence. Doctors, nurses, and patients had come to equate heavyduty chemotherapy with hospitalization.

To build confidence in the potential switch, Roland B. Walter, MD, PhD, assistant professor in the Division of Hematology at the UW School of Medicine, built on Estey’s experience and led an SCCA pilot study exploring the medical and financial effects of early hospital discharge in patients who met medical criteria (ie, good liver, kidney, and heart function; no bleeding; no need for intravenous antibiotics), lived within 30 minutes of SCCA, and had a routinely available caregiver.

The study showed that even though many of the patients who were discharged early required readmission before recovery of their blood counts, no deaths or intensive care admissions resulted.

 Patients spent less time in the hospital and required less IV antibiotic treatment and fewer red blood cell transfusions than they would have without early discharge. The average daily cost of caring for the patient was also reduced (

Overall, the small SCCA study documented the feasibility and safety of outpatient management of selected patients with AML or MDS and signaled a turning point in routine care for leukemia treatment in Seattle.

“We now have regimens that are given partly or almost entirely outpatient,” said Paul Hendrie, MD, PhD, associate professor in the UW Division of Hematology and clinical medical director for the Inpatient Oncology Service. “What we tell new patients has definitely changed. In the past we would tell them to expect to stay in the hospital until their blood counts recovered from chemotherapy. Now it’s changed to, ‘You will come in, receive chemotherapy, and then, if everything is going right, we should be able to discharge you to our outpatient clinics.’”

	New Patient Benefits—and Responsibilities

While reducing the length of the hospital stay by 2 or 3 weeks can certainly improve the patient’s quality of life—most patients naturally prefer being at home&mdash;the prospect of an early discharge can cause unease in some patients. Certain patients expect to be hospitalized during their cancer treatment. “Some patients are hesitant, but we talk with them,” Hendrie said. “The nurses spend time with them. You have to be reassuring. And for some patients, maybe you wait an extra day. Then once they go home and see that nothing dramatic has happened, they feel more assured.”

		Table 1. Key Results From Early Discharge Pilot Study

					Number of red blood cell transfusions

		IV indicates intravenous. Walter RB et al. 

Estey and Hendrie emphasize the importance of both the patient and the patient’s home caregiver hearing instructions before discharge. In particular, knowing that they must return to the hospital at the first sign of trouble—such as a fever&mdash;is critical. All patients and their caregivers at SCCA receive this mandatory training before discharge. The presence of good family support such as a spouse, parent, or child providing 24/7 care immediately after discharge also makes a difference.

Being ready for rapid readmission is another key to good outcomes, and that’s why patients must remain within 30 minutes of SCCA as they recover. For some, this means staying at a nearby hotel with their caregiver. SCCA House also provides patients and their families access to reasonably priced housing. Longer term, SCCA researchers hope their studies will help convince insurance companies to reimburse patients for the costs of chemotherapy-related lodging.

		Table 2. Selected Eligibility Criteria for Ongoing Early Discharge Study

			High-risk MDS (10%-19% blasts in marrow or blood)

			TRM score <3.91 corresponding to a TRM rate of 1% when chemotherapy of similar intensity is administered to inpatients

			Patient must live within 30 minutes of the Seattle Cancer Care Alliance during outpatient treatment

	AML indicates acute myeloid leukemia; APL, acute promyelocytic leukemia; MDS, myelodysplastic syndrome; TRM, treatment-related mortality.

“I don’t think there is any question that in 10 years this will be the standard of care,” Estey said. “Just look at other trends in medicine. For many years when people gave birth, they stayed in the hospital for a week or several days. Now they go home. Surgery was totally inpatient.

Now it’s routinely outpatient. Treatment of AML is often unpredictable. However, we can always strive to improve the patient’s quality of life as we treat them. That’s why we are moving increasingly toward outpatient chemotherapy.”

	Next Step: Outpatient Chemotherapy for AML and MDS

Their experiences with early discharge have now led SCCA clinicians to explore the feasibility of outpatient-only induction therapy for patients with newly diagnosed AML and high-risk MDS.

The new SCCA pilot clinical trial 7910 started in June 2013 and will enroll 25 patients who are 18 to 59 years of age and in generally good condition.

 As in the early discharge trial, patients must have a caregiver and live within 30 minutes of SCCA during their treatment (

The study’s primary goals are no increase in mortality and to have at least half of the patients complete chemotherapy without the need for hospital admission. Patients will receive all of their induction chemotherapy in the outpatient infusion center at SCCA and will stay in a nearby private residence or hotel. Researchers will also monitor patients’ quality of life and the treatment costs.

Most community hospitals are not yet ready with the resources or staff to offer complete outpatient infusion chemotherapy for acute leukemia.

This protocol requires having the clinical personnel and structure in place. SCCA had to prepare nurses and staff; it was a long process to get everyone on board and set expectations.

The goal is to be able tell patients: “We can give you induction chemotherapy as safely and effectively as any other induction chemotherapy, but at SCCA you have the bonus of not needing to be in the hospital.” Study results, due by early 2015, will determine the feasibility of this next step in chemotherapy’s ongoing evolution from hospital to home.

			Walter RB, Lee SJ, Gardner KM. Outpatient management following intensive induction chemotherapy for myelodysplastic syndromes and acute myeloid leukemia: a pilot study [published online March 10, 2011]. 

			Outpatient induction chemotherapy for newly diagnosed AML or MDS (7910). Seattle Cancer Care Alliance website. http://www.seattlecca.org/clinical-trials/leukemia- NCT01807091.cfm. Updated May 13, 2013. Accessed April 21, 2014.

Articles

Although many patients with cancer now receive chemotherapy as outpatients, most cancer treatment centers do not extend this practice to patients with acute myeloid leukemia (AML) or advanced myelodysplastic syndromes (MDS) who are receiving initial intensive induction therapy. 

Pamela S. Becker, MD, PhD

Articles

Dr. Becker on the Rationale for Investigating Uproleselan in Combination with Chemotherapy in AML

New Model for Outpatient Induction Chemotherapy for AML and MDS Explored