Use of Adjuvant Immunotherapy in Children and Adolescents with Relapsed Acute Lymphoblastic Leukemia

Acute lymphoblastic leukemia (ALL) is a cancer of the hematopoietic system. If the disease returns after initial treatment (recurrence), the prognosis has improved in recent years, but the standard therapy required to treat it is very intensive. It usually consists of a combination of multiple chemotherapy drugs and often an allogeneic hematopoietic stem cell transplant (HSCT), in which blood stem cells from a donor are transplanted. To reduce the burden on young patients, the IntReALL 2020 study is investigating the use of modern immunotherapies. These include, among others, the investigational drugs inotuzumab ozogamicin and blinatumomab, as well as personalized CAR-T cell therapy. CAR-T cells are the body’s own immune cells that are harvested from the affected patients and genetically modified in the lab so that they can specifically recognize and destroy cancer cells when they are reinfused into the patients. Inotuzumab-ozogamicin is an antibody conjugated to a chemotherapeutic agent (calicheamicin) (antibody-drug conjugate) that targets a surface receptor (CD22) on leukemia cells. This allows it to act specifically on affected cells. The drug is approved in Germany as monotherapy for adult patients with relapsed or refractory CD22-positive B-cell progenitor ALL. Blinatumomab is a so-called bispecific antibody. It directly links certain immune cells (T cells) to the leukemia cells, enabling the body’s own immune system to specifically attack and destroy the cancer cells. The drug is approved for patients aged 1 year and older with Philadelphia chromosome-negative, CD19-positive B-cell progenitor ALL, provided the disease is refractory or recurrent.

The aim of this study is to investigate the efficacy and safety of inotuzumab ozogamicin and blinatumomab as components of the treatment strategy in patients with relapsed ALL. The treatments administered as part of the study depend on the patients’ individual risk profiles.

Patients without a genetic risk profile and with late relapse (standard risk) are randomly assigned to two treatment groups. The study arm receives induction therapy with inotuzumab ozogamicin, and the control arm receives induction therapy with standard chemotherapy. Subsequently, all patients receive standard early consolidation therapy with chemotherapy in combination with one cycle of blinatumomab. Afterward, patients who respond to this therapy are again randomly assigned to two groups. One group receives standard consolidation and maintenance chemotherapy. The other group receives another course of blinatumomab before and after consolidation therapy, followed by maintenance therapy. Patients who do not initially respond to blinatumomab therapy receive treatment with donor stem cells (allogeneic stem cell transplant).

Patients with early relapse and/or isolated involvement of organs outside the bone marrow who require an allogeneic stem cell transplant (high-risk) are enrolled in a separate study conducted by Pfizer for induction therapy and subsequently receive consolidation chemotherapy and blinatumomab, followed by a stem cell transplant.

Patients with relapse and isolated involvement of organs outside the bone marrow receive the induction therapy from the previous IntReALL 2010 study. In consolidation therapy, part of the treatment is replaced by blinatumomab, and patients receive standard maintenance therapy.

Patients with a genetically very high-risk profile and a very early recurrence (within 18 months of the initial diagnosis) will receive standard induction therapy, followed by individualized CAR-T cell therapy, which will be conducted as part of a separate study by Miltenyi.

Children and adolescents with relapsed ALL are eligible to participate in this study. In accordance with the standard of care for relapsed ALL, patients will have weekly follow-up visits at the treatment centers. Participation in the study does not necessarily require patients to be hospitalized or to have more frequent medical visits.