Clinical Trial Information
The prognosis of patients with relapsed ALL has substantially improved in recent years, however, at the cost of high and acute long-term toxicity. The current standard of care (SOC) protocol includes an intensive multi-drug chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT).
Patients enrolled in the IntReALL 2020 study are assigned to different treatment plans depending on their risk group. The aim of the standard and high risk protocols is to replace toxic induction chemotherapy with targeted, less toxic immunotherapeutic drugs. Additionally, we hope to minimize the intensity of consolidation and maintenance chemotherapy and to reduce the number of patients that need to undergo HSCT. The aim of the very high risk protocol is to provide individualized treatment recommendations or allocation to appropriate phase I/II clinical trials with promising compounds to improve event-free survival.
The Drugs
Blinatumomab
Blinatumomab (Blina) is a bi-specific immunotherapeutic drug that targets CD3 and CD19 surface proteins. CD3 proteins are activating molecules present on T cells which make up a critical component of the immune system. CD19 proteins are specific to the cancer cell. By linking CD3-positive T cells and CD19-positive target cells, the immune system can more readily identify and eliminate cancer cells which may have otherwise escaped.
Blina has shown a favourable safety profile and superior efficacy to standard chemotherapy in previous childhood relapsed ALL clinical trials.
Inotuzumab Ozogamicin
Inotuzumab ozogamicin (InO) is a immunotherapeutic drug which targets CD22 proteins that are specific to cancer cells. The drug is linked with the toxin calicheamicin which upon binding can readily eliminate the CD22-positive targeted cancer cells.
InO has shown improved treatment outcomes compared to the standard of care therapy in adult clinical trials.
Treatment Protocols
Standard Risk (SR)
Standard risk patients are defined as patients who experienced late bone marrow and without high risk genetic features. SR patients will randomly receive either the SOC induction with the chemotherapeutic drug Mitoxantrone or InO immunotherapy. After induction therapy, all patients will receive an early consolidation chemotherapy element (SCB1) and 1 course of Blina.
Patients exhibiting a positive response after induction will be randomized into either a standard arm with conventional further consolidation and maintenance chemotherapy or an experimental arm with 2 more courses of Blina which replaces the 4th consolidation chemotherapy element (SCB4) and the reinduction pulses during maintenance therapy.
With this randomization, we will be able to clarify the potential advantages offered by Blina in early consolidation and of Blina in late consolidation separately. SR patients exhibiting a poor response will be allocated to allogeneic HSCT after the first consolidation Blina course.
Standard risk treatment protocol as described above. SI: standard risk induction therapy, SC: standard risk consolidation, RI: reinduction pulse, R:randomized
High Risk (HR)
High risk patients are defined as patients who experienced early bone marrow and/or isolated extramedullary relapse and require allogeneic HSCT for consolidation of 2nd remission.
HR patients will be included in the IntReALL 2020 registry and then transferred into an industry-sponsored induction window trial (Pfizer trial). As all patients will receive allogeneic HSCT, these patients will join IntReALL 2020 only for consolidation.
Patients in complete remission after induction will receive one course of consolidation chemotherapy (HC1), one course of Blina, followed by allogeneic HSCT.
High risk treatment protocol as described above. HC: High risk consolidation (SOC chemotherapy), HSCT: hematopoietic stem cell transplantation
Isolated Extramedullary Relapse (IEM Relapse)
Isolated extramedullary relapse patients require a different treatment protocol as they are not suitable for the induction strategy of patients with bone marrow involvement (SR and HR). Patients with IEM relapse will receive the standard induction therapy from the previous IntReALL 2010 trial with Blina replacing the 3rd consolidation chemotherapy element (SC3).
Isolated extramedullary relapse treatment protocol as described above. SI: standard induction SC: standard consolidation, RI: reinduction pulses
Very High Risk (VHR)
Very high risk patients are defined as patients who have high risk genetic features and/or relapse very early (within 18 months after initial diagnosis). These patients often still have an unsatisfactory outcome when treated with chemotherapy followed by allogeneic HSCT. Therefore, we believe that VHR patients deserve individualized treatment with new therapies without the SOC control.
CART cell therapy is another type of immunotherapy in which a patient’s T cells are modified in a laboratory to recognize cancer cells (in this case CD19-positive cancer cells). This makes this treatment highly specific and individualized. Furthermore, T cells can persist in the body long-term and may recognize and eliminate cancer cells if another relapse occurs. So far, CD-19 directed CART cells have induced high remission rates in relapsed ALL patients and is the proposed therapy for this arm.
VHR patients will receive one course of InO as induction therapy and then enter an industry-sponsored CD19 CART cell clinical trial (Miltenyi).
Very high risk patients treatment protocol as described above.
