MD Anderson Research Highlights: EHA 2022 Special Edition

Featuring clinical advances and novel treatment approaches across hematologic cancers

MD Anderson News Release June 09, 2022

The University of Texas MD Anderson Cancer Center’s Research Highlights provides a glimpse into recent basic, translational and clinical cancer research from MD Anderson experts. This special edition features upcoming oral presentations by MD Anderson researchers at the European Hematology Association (EHA) 2022 Congress focused on novel chemotherapy, targeted therapy and immunotherapy approaches for a variety of hematologic malignancies as well as preclinical findings to better understand mechanisms of treatment resistance.

Ponatinib and blinatumomab combination has high response rates for patients with PH+ ALL (Abstract S114)
The tyrosine kinase inhibitor ponatinib and monoclonal antibody blinatumomab — which targets CD19 on leukemia cells — are highly effective as monotherapies for patients with Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL). The combination may provide an alternative to chemotherapy and stem cell transplant (SCT) without the associated risks and side effects. In a Phase II trial presented by Nicholas Short, M.D., researchers evaluated the safety and efficacy of the chemotherapy-free combination of ponatinib plus blinatumomab in 55 patients with either newly diagnosed (ND) or relapsed/refractory (R/R) Ph+ ALL and patients with chronic myeloid leukemia in lymphoid blast phase (CML-LBP). Complete molecular response was seen in 96% of ND patients, 92% of R/R patients and 83% of CML-LBP patients. For ND patients, the two-year event-free survival (EFS) rate and overall survival (OS) rate each were 93%. No relapses have been observed, and SCT was not needed in first remission. The treatment was well-tolerated, suggesting this combination is safe and effective for patients with Ph+ ALL. The promising outcomes in ND patients with Ph+ ALL suggest that this regimen may be able to eliminate the need for chemotherapy and SCT for these patients. Short will present the results on June 12.

Triplet combination therapy yields high response rates in FLT3-mutated AML (Abstract S127)
FLT3-ITD mutated (FLT3+) acute myeloid leukemia (AML) is an aggressive disease usually resistant to available treatment options, resulting in high frontline response rates but short response durations and low survival rates. Quizartinib (QUIZ) — a potent selective FLT3 inhibitor — can work synergistically with venetoclax (VEN) in AML cell lines and laboratory models. In a Phase I/II trial presented by Musa Yilmaz, M.D., researchers evaluated the safety and efficacy of a triplet combination of VEN, QUIZ and decitabine — a hypomethylating chemotherapy drug — in 23 relapsed/refractory (R/R) AML patients and five newly diagnosed FLT3+ AML patients. The complete response (CR) rate was 78% for R/R patients, with a median overall survival (OS) of 7.6 months, and 100% for newly diagnosed patients with a median OS of 14.5 months. Patients with underlying RAS/MAPK mutations had the lowest response rates (40%) compared to those without (94%), suggesting these mutations may drive resistance. The most common Grade 3/4 side effects included lung infections (42%) and neutropenic fever (30%). The findings suggest this combination warrants further study for patients with FLT3+ AML. Yilmaz will present the results on June 11.

Targeted therapy emavusertib shows encouraging activity in MDS and AML with specific mutations (Abstract S129)
Mutations in SF3B1 and U2AF1 can drive overexpression of activated IRAK4 — which regulates inflammation and promotes cancer cell growth and survival — and are associated with a poor prognosis for patients with high-risk myelodysplastic syndrome (HR-MDS) and acute myeloid leukemia (AML). Emavusertib is a targeted therapy that inhibits IRAK4 and FLT3, which also is frequently mutated in AML. Guillermo Garcia-Manero, M.D., led a Phase I/IIa study to investigate the safety and efficacy of emavusertib alone (Phase I) or in combination with either azacitidine or venetoclax (Phase IIa). In 49 patients treated on the Phase I portion, emavusertib had manageable side effects and no Grade 4-5 treatment-related adverse events. In five AML and seven HR-MDS patients with SF3B1 or U2AF1 mutations, complete response (CR) rates were 40% and 57%, respectively. Of three FLT3-mutant AML patients, one had a CR and two became negative for mutant FLT3. There were limited responses in patients without these mutations. Early data for this ongoing trial suggest emavusertib is well-tolerated with encouraging activity, particularly for patients with select mutations. Garcia-Manero will present the findings on June 11.

Magrolimab and azacitidine show durable responses and encouraging results in TP53-mutant AML (Abstract S132)
High-risk patients with TP53-mutated acute myeloid leukemia (AML) have limited treatment options and very poor prognoses. Magrolimab is a monoclonal antibody designed to block CD47 — an immune macrophage checkpoint molecule that signals “don’t eat me,” thereby allowing leukemia cell destruction. Combining magrolimab with the hypomethylating agent azacitidine (AZA) helped eliminate tumor cells by increasing the number of “eat me” signals in preclinical studies. In a Phase Ib trial presented by Naval Daver, M.D., researchers evaluated the safety, efficacy and tolerability of this combination in 72 patients with newly diagnosed high-risk TP53-mutated AML. The objective response rate (ORR) was 48.6% and the complete response rate was 33.3%. Median time to ORR was 2.2 months. Median CR duration was 7.7 months and median overall survival was 10.8 months. Common side effects included constipation, diarrhea, febrile neutropenia, nausea and fatigue. The findings suggest this combination has a favorable safety profile and encouraging early results. A Phase III trial currently is underway to compare this treatment to the current standard of care therapies in newly diagnosed TP53 AML. Daver will present the results on June 10.

Adding targeted therapy to chemoimmunotherapy offers long-term benefits for patients with IGHV-mutated CLL (Abstract S149)
Chemoimmunotherapy with fludarabine, cyclophosphamide and rituximab (FCR) is effective in treating patients with chronic lymphocytic leukemia (CLL), and patients with mutated IGHV have favorable long-term outcomes. In a Phase II study led by MD Anderson, researchers evaluated the efficacy of ibrutinib, fludarabine, cyclophosphamide and obinutuzumab (iFCG) ­— a chemoimmunotherapy and targeted therapy combination — in 45 previously untreated patients with IGHV-mutated CLL. Nitin Jain, M.D., reported on long-term outcomes of the study after a median follow-up of 56.8 months. After just three cycles, 87% of patients had undetectable measurable residual disease (U-MRD), with improved responses after continued therapy. The five-year progression-free survival (PFS) and overall survival (OS) were 97.7% and 97.8%, respectively. One patient had CLL progression. No patient had Richter’s transformation. The findings reveal that iFCG offers high rates of U-MRD remission and long-term survival with only three cycles of chemotherapy, as opposed to previous treatments with six cycles of chemotherapy. Jain will present the findings on June 12.

Researchers identify potential target signal to develop therapies for CMML and avoid treatment failure (Abstract S160)
Chronic myelomonocytic leukemia (CMML) is an aggressive disease that arises from hematopoietic stem and progenitor cells (HSPCs), and most patients do not respond well to standard hypomethylating agent therapy. Those with mutations in ASXL1 or in RAS pathway genes have a higher risk of disease progression to acute myeloid leukemia (AML) and a poorer prognosis. In a preclinical study presented by Guillermo Montalbán Bravo, M.D., researchers performed single-cell analysis on HSPCs and BM mononuclear cells (MNSCs) to determine factors involved in CMML maintenance and progression to AML. They found that CMML relies on a large number of active HSPCs that trigger NF-κB signaling to reprogram monocytes and to survive an immune response. NF-κB signaling also expands immature myeloid progenitors and reduces T cells, contributing to therapy resistance and disease progression. Future therapies could target downstream effectors of the NF-κB pathway. Montalbán Bravo will present the results on June 11.

Momelotinib improves complications often seen in previously treated anemic myelofibrosis patients (Abstract S195)
Patients with myelofibrosis (MF) frequently develop enlarged spleens, inflammatory symptoms and anemia due to bone marrow scarring. Patients typically are treated with JAK inhibitors, which can worsen therapy-related anemia, and chronic anemia in MF is associated with poor prognosis. Previous trials showed momelotinib (MMB) — a potent ACVR1/ALK2 and JAK 1/2 inhibitor — improved issues with anemia and transfusion dependency in MF patients previously treated with a JAK inhibitor. In a Phase III trial presented by Srdan Verstovsek, M.D., Ph.D., researchers tested MMB versus danazol (DAN), a synthetic androgen currently used for treating anemia in MF patients. Overall, MMB showed greater improvements in Total Symptom Score (24% in MMB versus 9.2% in DAN) and an upward trend toward improved overall survival (OS). MMB met all primary and secondary endpoints, including transfusion requirements and spleen responses, with comparable safety profiles between the two drugs. The findings suggest MMB was superior to DAN in alleviating MF complications, particularly for patients with anemia. Verstovsek will present the results on June 11.

Blocking CD47-SIRPα interaction may be efficient alternative to traditional CD47 therapies (Abstract S219)
CD47 is an immune checkpoint molecule overexpressed in various malignancies, allowing cancer cells to avoid elimination by binding to SIRPα on macrophages. Previous studies have shown promising results from blocking CD47 in combination with rituximab, which inhibits CD20. However, the broad expression of CD47 on normal cells lowers therapeutic efficacy and causes undesirable side effects. Instead, targeting SIRPα to inhibit the CD47-SIRPα interaction could be a viable option. In a multicenter Phase I trial led by Paolo Strati, M.D., researchers evaluated the safety and tolerability of a novel anti-SIRPα antibody (CC-95251) along with rituximab for CD20+ relapsed/refractory patients with non-Hodgkin lymphoma. Seventeen patients received a median of four weekly cycles of CC-95251, with full receptor occupancy at weekly doses over 3 mg/kg. Among evaluable patients, the overall response rate was 56% and four patients (25%) achieved a complete response. The treatment had manageable side effects, with neutropenia and infection being the most common treatment-related adverse events. The study is ongoing and currently in the dose-expansion phase. Strati will present the results on June 11.

Allogeneic CAR T cell therapy shows promising early results for patients with TCL (Abstract S262)
Patients with relapsed/refractory (R/R) T-cell lymphoma (TCL) have limited treatment options. Chimeric antigen receptor (CAR) T cell therapy has been challenging in these patients because of the state of their T cells. CTX130 is an allogeneic (from a healthy donor) CAR T cell therapy targeting CD70 on cancerous T cells, offering a potential cell therapy option for these patients. In a Phase I study led by Swaminathan P. Iyer, M.D., researchers evaluated the safety and efficacy of CTX130 in 17 patients with relapsed/refractory (R/R) TCL. At the two highest dose levels, the overall response rate was 71% in seven patients, including two complete responses (29%). Responses were seen both in patients with peripheral TCL (PTCL) and transformed cutaneous TCL (CTCL). The therapy had an acceptable safety profile, with no instances of graft versus host disease and no Grade 3 or higher cytokine release syndrome or immune effector cell-associated neurotoxicity syndrome. The early results suggest CTX130 is safe and, as a first-in-class allogeneic CAR T cell therapy, offers clinically meaningful benefits for patients with advanced TCL. Iyer will present updated findings on June 11.

In case you missed it
Read below to catch up on recent MD Anderson press releases.