Treatment Sequencing, MRD Status in Hematologic Malignancies Fuel Medical Crossfire

Elias Jabbour, MD

The defining feature of the 5th Annual Live Medical Crossfire®: Hematologic Malignancies program is the extensive interactivity between faculty and audience. The 1-day program on July 17 will be hosted by Physicians’ Education Resource®, LLC (PER®), with discussions centered around acute and chronic myeloid leukemia (AML and CML), acute and chronic lymphocytic leukemia (ALL and CLL), myeloproliferative neoplasms (MPNs), and myelodysplastic syndromes (MDS) (AGENDA see page 99). The event will conclude with a plenary panel discussion covering immune effectors, chimeric antigen receptor (CAR) T cells, and bispecific therapies across hematologic malignancies.¹

In an interview with Targeted Therapies in Oncology, program cochair Elias Jabbour, MD, a professor in the Department of Leukemia at The University of Texas MD Anderson Cancer Center in Houston, provided his perspective on the unique program and an overview of the quickly evolving treatment landscape for leukemias.

“This is not a meeting in which attendees just come and listen all day long. It’s more practical and geared toward providing attendees with information today that can be used in the clinic with patients tomorrow,” Jabbour said. “The second feature is that the program encourages learning from each other. It’s peer-to-peer education.”

SequencingAccording to Jabbour, an overarching theme for treating patients with CLL or ALL is choosing the sequence of therapies that will provide the patient with optimal benefit.

Traditional frontline management for CLL includes chemotherapy (fludarabine, cyclophosphamide, bendamustine, or chlorambucil) used in combination with anti-CD20 monoclonal antibodies (rituximab [Rituxan], ofatumumab [Arzerra], or obinutuzumab [Gazyva]). Recently approved targeted therapies in frontline, relapsed/refractory, and high-risk disease, although welcome additions to the armamentarium, add another layer of complexity, especially for patients who progress following therapy in the first-line setting.²

In ALL, 3 FDA-approved agents are currently avail-able: blinatumomab (Blincyto), inotuzumab ozogamicin (Besponsa), and the CAR T-cell therapy tisagenlecleucel (Kymriah). These agents have demonstrated improved response rates and survival compared with historical treatments. Thus, with several agents avail-able, choosing which agent to use and how to sequence these treatments is a challenge for clinicians.³

“In ALL, I expect the discussion to focus on how to tailor therapy—how do we sequence these therapies and how do I choose blinatumomab over CAR T-cell therapy,” said Jabbour. “As a follow up, can we tailor our therapy today, based on response? What is the role of MRD assessment by next-generation sequencing [NGS] in deciding how to treat our patients?” he asked.

MRD Status

In acute leukemias, measurable residual disease (MRD) is defined as the presence of residual leukemic cells in bone marrow or in peripheral blood in patients who achieved morphologic complete remission.

Jabbour noted a meta-analysis conducted by Donald A. Berry, PhD, and colleagues, which quantified the relationship of MRD status and event-free survival (EFS) and overall survival (OS) in adult and pediatric patients with ALL, based on clinical trials and other databases.4 In that study, the investigators determined that MRD status was a useful indicator of therapeutic benefit in clinical practice and had the potential for making drug development more efficient by providing early evidence of treatment benefit.

To further elucidate the role of MRD, Jabbour highlighted a presentation at the 2020 American Society of Hematology (ASH) Annual Meeting. Results from the trial in discussion focused on the assessment of MRD using ultrasensitive NGS. Nicholas J. Short, MD, and colleagues, performed a retrospective study of 67 patients with previously untreated Philadelphia chromosome-negative ALL who received frontline therapy consisting of a hyper-CVAD (cyclophosphamide, vincristine, doxorubicin [Adriamycin], and dexamethasone)-based regimen (n = 44) or a lower-intensity hyper-CVD–based regimen (n = 23), which was usually combined with inotuzumab ozogamicin, and who achieved complete remission (CR).⁵

In the study, 20 patients (30%) underwent allogeneic stem cell transplant in the first remission. In the entire cohort, 14 patients relapsed (21%), including 2 with central nervous system–only relapses. The median duration of follow-up for the entire cohort was 51 months.

Among the 109 remission samples, 84 were MRD negative, 24 were MRD positive, and 1 was indeterminate by multiparameter flow cytometry (MFC; FIGURE5). All 24 MRD-positive samples by MFC were also determined to be MRD positive by NGS. Among the 84 MRD-negative samples by MFC, 32 (38%) were MRD-positive by NGS. For those discordant cases, the median level of MRD by NGS was below the expected level of detection by MFC (median, 0.002% [range, 0.00002%-1.15%]).

The investigators noted that among patients treated with the intensive hyper-CVAD regimen, achieving MRD-negative status as determined by NGS at CR provided additional prognostic information compared with MRD status by MFC at the same time point. In addition, it identified patients with an excellent long-term outcome. The 5-year OS rate for patients who achieved MRD-negative status by NGS at CR was 100% vs 55% for those who were MRD positive by NGS.

By using this ultrasensitive NGS, investigators were able to obtain an early assessment of MRD that helped to identify patients with ALL who might have a very low risk of relapse and excellent long-term survival. The investigators noted in their poster that further assessment about de-intensification of therapy is feasible for this subpopulation of patients who are able to rapidly achieve MRD-negative remission.⁵

Additionally, defining MRD below the morphological level of 5% blast cells is changing the landscape of response to initial treatment. In the multicenter AML-02 study (NCT02440568), investigators demonstrated that morphological assessment of treatment response had limited value compared with MFC.⁶ Further, MRD positivity after induction was predictive of lower EFS and a higher relapse rate (P < .001), providing strong prognostic information regardless of the morphologic results.

De-Intensification of Therapy

The debate surrounding moderate vs intensive-based chemotherapy in ALL is ongoing. The German Multicenter Study Group for Adult ALL reported the results from a trial evaluating this question. The trial used a modified induction backbone divided into 2 courses, with 6 consolidation courses.⁷

In the trial, a key prognostic factor was age of the patient. For patients aged 55 to 65 years, the CR rate was 84% and the early mortality rate was 7%. In patients aged 66 to 75 years, the CR rate was 74% with a 14% early mortality rate; and for those over 75 years, the rates were 52% and 37%, respectively.⁷

One of the most exciting developments in AML, Jabbour noted, was defining short-term therapy based on response, because it may be possible to stop therapy. “If we can assess for MRD with a very deep technique, then patients will be spared the need for intensive chemo-therapy or prolonged therapy,” he said.

Ongoing studies will continue to elucidate the role of maintenance therapy to improve clinical outcomes with a focus on immunotherapies, hypomethylating agents, and targeted therapies.

_References:

_{1. 5th Annual Medical Crossfire®: Hematologic Malignancies. Physicians’ Education Resource®, LLC (PER®). Accessed May 20, 2021. https://bit.ly/2T9Vep7}

_{2. Barrientos JC. Sequencing of chronic lymphocytic leukemia therapies. Hematology Am Soc Hematol Educ Program. 2016;2016(1):128-136. doi:10.1182/asheducation-2016.1.128}

_{3. Curran E, O’Brien M. Role of blinatumomab, inotuzumab, and CAR T-cells: which to choose and how to sequence for patients with relapsed disease. Semin Hematol. 2020;57(3):157-163. doi:10.1053/j.seminhema-tol.2020.11.001}

_{4. Berry DA, Zhou S, Higley H, et al. Association of minimal residual dis-ease with clinical outcome in pediatric and adult acute lymphoblastic leu-kemia: a meta-analysis. JAMA Oncol. 2017;3(7):e170580. doi:10.1001/jamaoncol.2017.0580}

_{5. Short NJ, Kantarjian HM, Patel K, et al. Ultrasensitive next-generation sequencing-based measurable residual disease assessment in Philadelphia chromosome-negative acute lymphoblastic leukemia after frontline therapy: correlation with flow cytometry and impact on clinical outcomes. Blood. 2020;136(suppl 1):26-28. doi:10.1182/blood-2020-141971}

_{6. Inaba H, Coustan-Smith E, Cao X, et al. Comparative analysis of differ-ent approaches to measure treatment response in acute myeloid leukemia. J Clin Oncol. 2012;30(29):3625-3632. doi:10.1200/JCO.2011.41.5323}

_{7. Goekbuget N, Beck J, Brueggemann M, et al. Moderate intensive che-motherapy including CNS-prophylaxis with liposomal cytarabine is feasible and effective in older patients with Ph-negative acute lymphoblastic leukemia (ALL): results of a prospective trial from the German Multicenter Study Group for Adult ALL (GMALL). Blood. 2012;120(21):1493. doi:10.1182/blood.V120.21.1493.1493}