Treatment of Acute Leukemias

After a long period of time, we are witnessing progress in the upfront treatment of acute myeloid leukemia (AML). Previous improvements in survival have largely been ascribed to advances in the understanding and outcomes of stem cell transplant for consolidation of high-risk and relapsed leukemia. 2017 has proven to be a banner year for meaningful advancements in AML treatment. The FDA approved three new medications for upfront and relapsed acute leukemia, which has changed the standard of care for induction chemotherapy of elderly AML and AML with mutations in FLT3. Midostaurin in addition to 7+3 is now the standard of care for younger patients with FLT3 mutant AML.1 Liposomal cytarabine/daunorubicin was approved as a new standard of care over 7+3 in the elderly AML population and improves overall survival and remission rates.2  Finally, enasidenib, another targeted therapy with a novel mechanism of action, was approved for relapsed and refractory AML with mutant IDH2.3  The hope is that these successes will be the start of more therapeutic advances for this difficult to cure disease. We are working to provide novel approaches for patients with small molecular targeted therapies such as next generation FLT3 inhibitors, antibody drug conjugates, and innovative techniques for transplantation as we seek to improve outcomes for this difficult to treat population.

Meanwhile, the treatment landscape for lymphoblastic leukemia has been changing with a rapid pace in the last decade. The FDA approval of the immunotherapeutic blinatumomab, a bispecific T-cell engager against CD22 provided a new standard of care for relapsed B-cell ALL. Liposomal vincristine provided yet another option for acute lymphoblastic leukemia. This year, the FDA announced the approval inotuzumab ozogamicin, an antibody drug conjugate with high rates of complete remission in B-cell ALL with CD22 expression.4  All of these treatments are available to our patients.

Our clinical trial portfolio for relapsed and refractory ALL include antibody drug conjugates against CD19 – a universal surface marker on B-cells –for treatment of relapsed disease. We are exploring the feasibility of inotuzumab ozogamicin as a maintenance therapy after allogeneic stem cell transplant for patients with high risk of relapsed disease.

Studies for acute leukemia at UH Seidman Cancer Center include multicenter trials for upfront therapy, maintenance therapy, novel options for transplantation and early phase trials for patients without standard of care options, including investigator-initiated studies.

Our frontline studies for acute myelogenous leukemia aim at bringing targeted therapies to current standards of care. Second generation FLT3 inhibitors (DCSK1916), HDAC inhibitors with pacrinostat (HLSN1917) and SYK inhibitors (GSI1916) are being explored both in combination with intensive therapy and in low-intensity therapy for older or frail patients. For patients who do not proceed to allogeneic stem cell transplant in 1st complete remission, immunotherapy is being explored as maintenance therapy is available as a maintenance therapy (UCCC1915)

Salvage options for relapsed and refractory AML include a variety of different options. Hypomethylating agents are being explored in combination with immunotherapy, and will be explored in patient relapsed with or without prior allogeneic stem transplant (DFCI1917). For patients without standard-of-care therapies available, we are exploring novel mechanisms, including arginine deprivation (AGLA1916) and inducers of KLF4 (APTOS1916). For B-cell acute lymphoblastic leukemia, we offer a novel antibody-drug conjugate against CD-19 (ADCT1916).

Transplantation for active leukemia include methods trying to bring potentially curative therapy to patients where it usually would not be an option. We are exploring total marrow irradiation in a phase I setting in combination with reduced intensity conditioning (CASE9Z13). For B-cell ALL patients with substantial risk of relapse, the CD-22 antibody-drug conjugate inotuzumab ozogamicin is being explored as maintenance therapy after allogeneic stem cell transplant (CASE1916). Finally, for patients 55 and older, we are also participating in a registration trial for a novel therapy with a radioactively labeled anti-CD45 antibody known as Iomab-B, originally developed at the Fred Hutchinson Cancer center (ACTN1916). Patients randomized to the Iomab-B arm receive the agent and 6-12 days after receive allogeneic HCT. Patients randomized to a conventional therapy arm receive salvage therapy and those achieving complete remission can proceed to allogeneic HCT. Those failing to achieve remission may cross over to the Iomab-B arm and still proceed to transplant.

The broad variety of current and upcoming studies reflects our goal of having a diverse portfolio of clinical studies, in the hope that we can offer novel therapy options for acute leukemia patients at any stage of their disease.

Our next edition will discuss chimeric antigen receptor cells for acute lymphocytic leukemia and lymphomas.

If you would like to refer a patient for one of these trials or discuss a consult, please contact Dr. Marcos de Lima or Dr. Benjamin Tomlinson.

Marcos de Lima, MD
Director, Hematologic Malignancies and Stem Cell Transplant Program
University Hospitals Cleveland Medical Center
UH Seidman Cancer Center
Professor of Medicine
Case Western Reserve University School of Medicine

Benjamin Tomlinson, MD
Hematologic Malignancies and Stem Cell Transplant Program
University Hospitals Cleveland Medical Center
Instructor of Medicine
Case Western Reserve University School of Medicine

References:

1. Stone RM, Mandrekar S, Sanford BL, et al. The Multi-Kinase Inhibitor Midostaurin (M) Prolongs Survival Compared with Placebo (P) in Combination with Daunorubicin (D)/Cytarabine (C) Induction (ind), High-Dose C Consolidation (consol), and As Maintenance (maint) Therapy in Newly Diagnosed Acute My…. Blood. 2015-12-03 00:00:00 2015;126(23):6-6.
2. Lancet JE, Uy GL, Cortes JE, et al. Final results of a phase III randomized trial of CPX-351 versus 7+3 in older patients with newly diagnosed high risk (secondary) AML. Journal of Clinical Oncology. 2016/05/20 2016;34(15_suppl):7000-7000.
3. Stein EM, DiNardo CD, Pollyea DA, et al. Enasidenib in mutant-IDH2 relapsed or refractory acute myeloid leukemia. Blood. 2017.
4. Kantarjian HM, DeAngelo DJ, Stelljes M, et al. Inotuzumab Ozogamicin versus Standard Therapy for Acute Lymphoblastic Leukemia. New England Journal of Medicine. 2016;375(8):740-753.