Evaluating Novel Therapies in Acute Leukemia

By Anjali S. Advani, MD

The treatment of acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML) has not changed significantly during the past decade, and novel therapies are needed.

Several antibody-based strategies are in development. These therapies have demonstrated encouraging preliminary results and will likely alter our current therapeutic paradigm. In this article, I focus on two antibody-drug conjugates that are currently in clinical trials at Cleveland Clinic.

SGN-CD33a as a promising target

The transmembrane receptor protein CD33 is expressed on the surface of myeloblasts in most patients with AML, making it an attractive therapeutic target. SGN-CD33a is an anti-CD33 antibody conjugated to approximately two molecules of a pyrrolobenzodiazepine (PBD) dimer, a highly potent DNA cross-linking agent. Upon binding, SGN-CD33a is internalized and transported to the lysosomes, where the PBD dimer is released through proteolytic cleavage of the linker, cross-linking DNA and leading to cell death.

Cleveland Clinic participated in a phase 1 trial of SGN-CD33a in AML patients with relapsed disease or patients who declined conventional induction therapy.1 The response rate (complete remission [CR], CR with incomplete count recovery [CRi] or morphologic leukemia-free state [MLFS]) was 47 percent in a group of patients categorized as poor risk (median age 75; 45 percent with underlying myelodysplastic syndrome; most patients with intermediate and adverse cytogenetic risk).

The dose escalation for this study has been completed, but enrollment may remain open for the following patient groups:

• Treatment-naïve (SGN-CD33a alone or in combination with hypomethylating agents)
• Acute promyelocytic leukemia
• NPM1-mutated
• Post-allogeneic hematopoietic stem cell transplant

More recently, a trial of SGN-CD33a in combination with induction or post-remission therapy has opened for newly diagnosed AML patients younger than 60 years of age. This phase 1 trial has different arms: SGN-33a in combination with induction, post-remission therapy (with standard chemotherapy), or during maintenance.

This trial will also evaluate minimal residual disease (MRD) at various time points. The maximum tolerated dose has not yet been determined. Our hope is that using such a strategy upfront in newly diagnosed AML patients will decrease the risk of relapse by eliminating MRD. This would be exciting since no change in therapy, other than increasing anthracycline dose during induction in younger AML patients2 has altered outcomes in this patient population.

Encouraging results with inotuzumab

The transmembrane receptor protein CD22 is expressed on the majority of pre-B ALL lymphoblasts. CD22 is internalized upon antibody binding and is not shed into the extracellular environment, which makes it an attractive therapeutic target for antibody drug conjugates. Inotuzumab is an anti-CD22 antibody linked to the cytotoxic agent calicheamicin. In a phase 2 trial of inotuzumab in patients with relapsed/refractory ALL3, the response rate (CR/CRi) was 57 percent.

Because of these encouraging results, Cleveland Clinic and other institutions participated in a phase 3 trial comparing inotuzumab with salvage chemotherapy. The results of this trial were recently reported at the European Hematology Association annual meeting4. The response rates (CR/CRi) as well as rate of MRD negativity were significantly higher in patients receiving inotuzumab than in those receiving standard chemotherapy (response rate: 81 percent vs. 33 percent; MRD negative rate in those patients achieving CR/CRi: 78 percent vs. 28 percent).

Follow-up results evaluating overall survival in the two arms are pending; however, a higher percentage of patients in the inotuzumab arm were able to proceed to allogeneic hematopoietic stem cell transplant, which represents the only chance of cure for a patient with relapsed ALL.

Inotuzumab was generally well-tolerated, with the most common ≥ grade 3 adverse events being hematologic. However, similar to patients’ experience with gemtuzumab ozogamicin, there were cases of hepatic veno-occlusive disease with ≥ grade 3 hepatobiliary events occurring in 9 percent of patients treated with inotuzumab versus 3 percent of patients treated with standard chemotherapy.

Further investigation is needed to determine what can be done to decrease this risk. Prior studies with gemtuzumab ozogamicin demonstrated that allowing a longer time between the last dose of the drug and transplant may decrease veno-occlusive disease risk5. Other data with inotuzumab have suggested that the preparative regimen used for allogeneic hematopoietic stem cell transplant may also be important.

We currently have a phase 1 clinical trial open for patients with relapsed/refractory ALL. This trial combines inotuzumab (in a dose escalation) with chemotherapy (cyclophosphamide, vincristine and prednisone). This trial takes advantage of the potential synergy between chemotherapy and inotuzumab. Enrollment to dose level 3 is ongoing.

Another approach: Chimeric antigen receptors

Many exciting new agents are being evaluated as treatments for acute leukemia. Antibody-based therapies represent one such approach. Another is the development of chimeric antigen receptor (CAR) T cells. We are beginning a trial using CAR T cells to target CD19 in relapsed ALL.

These agents have the potential to significantly change how we treat ALL and AML.

References

1. Stein EM, Stein A, Walter RB, Fathi AT, Lancet JE, Kovacsovic T, Advani AS, DeAngelo DJ, O’Maura M, Zhao B, Kennedy DA, Erba HP. Interim Analysis of a Phase 1 Trial of SGN-CD33A in Patients with CD33-Positive Acute Myeloid Leukemia (AML). Blood. 2014;124(21):623.

2. Fernandez HM, Sun Z, Yao X, et al. Anthracycline dose intensification in acute myeloid leukemia. N Engl J Med. 2009 Dec 24; 361(13):1249-1259.

3. Kantarjian H, Thomas D, Jorgensen J, Jabbour E, Kebriaei P, Rytting M, York S, Ravandi F, Kwari M, Faderl S, Rios MB, Cortes J, Fayad L, Tarnai R, Wang SA, Champlin R, Advani A, O’Brien S. Inotuzumab ozogamicin, an anti-CD22 calechamicin conjugate, for refractory and relapsed acute lymphocytic leukemia: a phase 2 study. Lancet Oncol. 2012 Apr;13(4):403-411.

4. DeAngelo DJ, Stellies M, Martinelli G, Kantarjian M, Stock W, Goekbuget N, Wang K, Pacagnella L, Sleight B, Vandendries E, Advani AS. Efficacy and safety of inotuzumab ozogamicin (INO) vs standard of care (SOC) in salvage 1 or 2 patients with acute lymphoblastic leukemia (ALL): an ongoing global phase 3 study. European Hematology Association 2015; Vienna, Austria. Late-breaking abstract 2.

5. Chevallier P, Prebet T, Turlure P, et al. Prior treatment with gemtuzumab ozogamicin and the risk of veno-occlusive disease after allogeneic haematopoietic stem cell transplantation. Bone Marrow Transplant. 2010 Jan;45(1):165-170.

Dr. Advani is Director of Cleveland Clinic’s Inpatient Leukemia Program and a staff member of the Department of Hematology and Medical Oncology, and of the Department of Translational Hematology and Oncology Research. She also is an Associate Professor of Medicine at Cleveland Clinic Lerner College of Medicine. She can be reached at advania@ccf.org or 216.445.9354.

Photo Credit: ©Russell Lee