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Novel Agents Lead Charge Against Adult ALL

Angelica Welch
Published: Thursday, Sep 13, 2018

Julio C. Chavez, MD

Julio C. Chavez, MD

Although acute lymphoblastic leukemia (ALL) occurs in both children and adults, the disease differs both in terms of presentation and outcomes. This is due to genetic abnormalities and fitness of the patient, as the median age of adult patients with ALL is 64 years old, making therapeutic advances a challenge.

In a presentation during the 2018 OncLive® State of the Science Summit™ on Hematologic Malignancies, Julio C. Chavez, MD, assistant member, Lymphoma Section, Department of Malignant Hematology, Moffitt Cancer Center, discussed prognostic indicators and systemic treatment updates for patients with ALL.

Minimal residual disease (MRD) is a strong prognostic factor in ALL, Chavez said. Patients who have MRD-positive disease do poorly in comparison to patients who have MRD-negative disease.

"We traditionally divide patients, genetically speaking, into having very high-risk, high-risk, or standard-risk disease. However, MRD status actually overcomes the prognostic impact of these genetic mutations," said Chavez. "That is how important MRD is in patients with ALL."

Chavez explained that the biggest unmet needs in ALL were the treatment of patients with relapsed B-ALL, those with primary refractory disease, elderly patients, those with Philadelphia chromosome (Ph)-like ALL, and patients with MRD-positive disease. However, ALL has a unique advantage of having multiple novel agents approved by the FDA. These include monoclonal antibodies, bispecific antibodies, and chimeric antigen receptor (CAR) T-cell therapy.

The CD20 antibody rituximab (Rituxan) was one of the first monoclonal antibodies to show benefit in adult patients with ALL.

In 2010, investigators evaluated the combination of a modified hyper-CVAD and rituximab regimen in patients with de novo Ph-negative precursor B-lineage ALL. Results showed that the addition of rituximab to hyper-CVAD appears to add benefit for younger patients with CD20-positive Ph-negative precursor B-lineage ALL.1 This was not true for patients over 60 years of age though, noted Chavez.

These findings led to the GRAALL-R 2005 study of rituximab plus pediatric-inspired chemotherapy for adult patients with ALL.2 This was a randomized phase III, multicenter study that took place from 2005 to 2014 in patients with CD20-positive Ph-negative, taxane-naive, B-cell precursor (BCP) ALL who were between the ages of 18 and 59 (n = 220). These patients had ≥20% blasts and no other current or recent malignancies.

Patients were randomized to either pediatric-inspired chemotherapy plus rituximab (n = 105) or pediatric-inspired chemotherapy (n = 104). The primary endpoint was event-free survival (EFS), with a follow-up of 30 months.

Results of GRAALL-R 2005 demonstrated that the addition of rituximab to pediatric-inspired chemotherapy improved EFS in patients with BCP ALL. The 2-year EFS for patients in the rituximab arm was 65% (95% CI, 56%-75%) compared with 52% (95% CI, 43%-63%) in the control arm (HR, 0.66; 0.45-0.98; P = .038).

Blinatumomab (Blincyto) is a bispecific antibody designed to direct cytotoxic T cells to CD19-expressing cancer cells. It is currently approved for patients with Ph-negative relapsed/refractory BCP ALL. However, Chavez noted that there is a boxed warning on blinatumomab’s label for cytokine release syndrome and neurological toxicities.

The phase III TOWER study evaluated blinatumomab in patients with relapsed/refractory BCP Ph-negative ALL. The median overall survival (OS) for patients treated with blinatumomab was 7.7 months versus 4.0 months for those treated with standard chemotherapy.3 Six-month EFS estimates were 30.7% with blinatumomab versus 12.5% with chemotherapy, respectively (HR, 0.55; 95% CI, 0.43-0.71).

"For patients who relapse early, our standard treatment is blinatumomab, especially for those who go to allogeneic hematopoietic stem cell transplant," said Chavez. "There is a signal that allogeneic transplant may further improve survival in patients who respond to blinatumomab."

Additionally, it is possible that blinatumomab may provide benefit for patients with MRD-positive BCL ALL, which Chavez reiterated was an area of unmet need in this disease.

Inotuzumab ozogamicin (Besponsa) is an antibody-drug conjugate linked to CD22 on the cell surface. "Once it is linked to the CD22, it releases this molecule calicheamicin, which binds to the DNA and that is the mechanism of cell killing," Chavez explained.

The FDA approved inotuzumab ozogamicin in August 2017 for the treatment of adult patients with relapsed/refractory BCP ALL. This approval was based on the analysis of the first 218 selected patients of the primary analysis from the phase III INO-VATE trial.4

Of these 218 patients, the complete remission (CR) rate for inotuzumab ozogamicin was 35.8% compared with 17.4% with chemotherapy. Of those treated with inotuzumab ozogamicin who achieved a CR, 89.7% were MRD-negative compared with 31.6% for those treated with chemotherapy.

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