In acute lymphoblastic leukemia (ALL), the standard curative approaches are intensive chemotherapy (IC) and allogeneic stem cell transplantation (allo-SCT). In children, the cure rate of IC alone is an encouraging 80% to 90%. Allo-SCT is mostly applied in adult, high-risk patients and when transplanted in first complete remission (CR1), the cure rate is about 50%.
However, promising cure rates should not be the sole focus as there are toxicities to consider. Intensive chemotherapy is associated with death in CR (complete remission) in up to 3% in children and 10% or higher in adults. Allo-SCT is even more toxic, with a treatment-related mortality of 10% to 20%. In addition, after intensive chemotherapy and particularly after SCT, there are a variety of long-term sequelae that decrease the quality of life. A substantial need exists for new treatments to avoid or reduce this toxicity.
There are several indications for the use of allo-SCT in adults (FIGURE 1). With the implementation of targeted therapies, these are continuously changing. Thus, the dogma that only allo-SCT is curative in patients with relapsed/ refractory disease should be revised to include CAR (chimeric antigen receptor) T cells, which are associated with a cure rate of about 50%.
Substantial progress in the treatment of adult ALL has been made in the last decade by the introduction of new targeted therapies, either with tyrosine kinase inhibitors (TKIs) or by immunotherapeutic approaches only allo-SCT is curative in patients with relapsed/refractory disease should be revised to include CAR (chimeric antigen receptor) T cells, which are associated with a cure rate of about 50% (FIGURE 2).
Patients with Philadelphia (Ph)-positive ALL constitute approximately 25% of adult B-lineage ALL, with an incidence increasing to about 50% among older patients.
In the pre-imatinib (Gleevec) era, CR rates were 60% to 70%, the survival rates associated with chemotherapy about 10%, and after patients underwent allo-SCT, about 30%. With the first-generation TKI imatinib, CR rates increased to 80% to 90%, the rate of BCR-ABL negativity from 5% to 50%, and the 5- to 10-year OS (overall survival) improved to 50% to 70%.1
Patients achieve faster and deeper molecular responses with second-generation TKIs such as dasatinib (Sprycel) and nilotinib (Tasigna), which translates into a survival benefit. The third-generation TKI ponatinib (Iclusig) targets resistant mutations, particularly T315I.2
Treating adult Ph-positive ALL with an allogeneic SCT in CR1 is still a good treatment option for patients with a 5-year OS of 60% to 70%. In older patients, when low-intensity chemotherapy was combined with dasatinib or nilotinib, the CR rate was greater than 90%, but many patients relapsed.3,4 In the next step, combining low-intensity chemotherapy with a TKI and adding an immunotherapy with inotuzumab ozogamicin (Besponsa), demonstrated a CR rate that surpassed 90% and the OS substantially improved.5 Here, the relapse rate was low and only several patients needed an SCT.
The newest approach in frontline Ph-positive ALL is a chemotherapy-free regimen that includes dexamethasone, the TKI dasatinib, and the bispecific antibody blinatumomab (Blincyto). A CR rate of 98% and the OS and disease-free survival (DFS) of 95% and 88%, respectively, for 2 years were observed.6 Interestingly, blinatumomab has been shown to eliminate Ph leukemic cells with resistant mutations.
Treatments with monoclonal antibodies or activated T cells are currently changing the treatment paradigm of ALL. The prerequisite is that B-lineage blast cells express a variety of specific antigens, such as CD19, CD20, and CD22 (TABLE ON PAGE 100), which are targetable with a wide variety of monoclonal antibodies.7 A new treatment principle is the activation of the patients T cells to destroy their CD19-positive leukemic blasts.
Anti-CD20/Rituximab
Rituximab (Rituxan) is a chimeric monoclonal antibody that binds to CD20-positive cells, resulting in cell death. Rituximab is now included in most B-lineage ALL regimens and is administered at the usual dose of 375 mg/m2 at day -1 before chemotherapy, typically for 8 cycles. This leads to a significant increase in the CR rate and MRD negativity rate of about 90% and improved survival of about 70% in standard-risk patients. Previously, rituximab was administered only to patients with more than 20% CD20 expression but is now administered to all patients because corticosteroids upregulate CD20 expression.8
It is difficult to extract the effect of allo-SCT in the context of rituximab-containing regimens with wide variation from 20% to 69%, according to study protocols. It is even more debatable whether the addition of rituximab improves outcomes after SCT.9-11 In one study, investigators examined the newer anti-CD20 antibody ofatumumab (Arzerra) in elderly patients with promising results.12
The anti-CD20 monoclonal body rituximab has substantially increased the cure rate of patients with de novo Burkitt leukemia/lymphoma. With repeated short cycles of intensive chemotherapy, combined with 8 doses of rituximab, the OS has increased to greater than 80%.13
Inotuzumab is an antibody-drug conjugate against CD22 and is linked to a cytotoxic agent from the class of calicheamicins called ozogamicin, which after internalization induces DNA strand breaks. CD22 is expressed in nearly all patients with adult ALL. Clinicians have explored inotuzumab in patients with relapsed/refractory ALL and it is now included in frontline regimens.
In an international, randomized multicenter trial (INO-VATE; NCT01564784), inotuzumab was compared with standard of care (SOC). Investigators reported that the CR rate was significantly higher in the inotuzumab group, 81% compared with 29% in SOC.14 Similarly, the inotuzumab group achieved a higher MRD- negativity rate of 78% versus 28% in the SoC group. This resulted in a transplant rate of 41% with the inotuzumab group compared with 11% in the SOC. Interestingly, this indicates that the achievement of a much higher MRD negativity by inotuzumab resulted in a higher rate for allo-SCT in CR1.
Inotuzumab has now moved to frontline therapy based on the results from a study involving older patients (60-97 years old) when combined with a reduced chemotherapy regimen of hyper-CVAD (cyclophosphamide, vincristine, doxorubicin [Adriamycin], and dexamethasone). Investigators reported a CR rate of 81% in this patient population, an MRD negativity of 100%, a DFS of 87%, and an OS of 70%.15 Taking the age of this patient group into consideration, the allo-SCT rate was only 6%, but the OS may also indicate that a substantial proportion of patients no longer need SCT.
Inotuzumab is a highly effective drug for achieving a fast tumor reduction in frontline therapy. If this combination of immunotherapies is considered, inotuzumab may be the first to reduce the tumor load and could be followed by blinatumomab to reduce remaining MRD.
Targeting CD19 is of great interest, as this antigen is highly expressed in all B-lineage cells, most likely including early lymphoid precursor cells. In contrast to the other antibodies, CD19-directed therapies act via T-cell activation to kill leukemic cells.
Blinatumomab
A new, promising approach is the bispecific antibody blinatumomab, which combines single chain antibodies to CD19 and CD3. Blinatumomab has been extensively explored in the MRD setting, which means that patients remained MRD positive after induction or with a molecular relapse.
In a pilot study evaluating 21 patients, the conversion rate to MRD negativity was 80%; 40% of these MRD-negative patients received an SCT.16 Interestingly, a fraction of patients also survived without undergoing an allo-SCT.
In an international, confirmatory, single-arm study (BLAST; NCT01207388) evaluating 116 patients in hematological remission, the rate of conversion to MRD negativity was high, with 78% achieving a complete MRD response with blinatumomab. In this setting, 40% of patients received an allo-SCT.17 Further, there was a fraction of patients who did not receive an allo-SCT.
Chimeric Antigen Receptor (CAR) T cells
The adoptive transfer of CAR-modified T cells directed against CD19 is another new promising approach for the treatment of CD19-positive disease in pediatric or adult ALL.18 In the first of 3 larger studies in adults with relapsed/refractory ALL, the CR rate ranged from 67% to 91%, with MRD negativity in 60% to 81% of patients who experienced a CR. OS was reported as 50% or greater at 2 years or more, which is remarkable for those heavily pretreated patients. It is noteworthy that CAR T cells are also effective in CNS leukemia and other extramedullary manifestations. Furthermore, CAR T-cell therapies are moving to frontline therapies.
CAR T-cell therapy in relapsed/refractory ALL was first considered as a bridge to allo- SCT and was applied in 10% to 50% of patients. Currently, however, the role of allo-SCT after CAR T-cell therapy remains unclear. Whereas in some institutions the therapy is always considered as a bridge to SCT, others have explored this treatment in different populations, such as in patients with high tumor burden, insufficient expansion of CAR T cells, or loss of MRD negativity.19
CD19-negative relapses after CAR T-cell therapy or blinatumomab because of CD19 escape are a relevant obstacle. To overcome this, bispecific antibodies targeting CD19/CD22 and other antigens are under development.
ALL immunotherapies are associated with toxicities, such as hepatotoxicity observed after the administration of inotuzumab, or cytokine release syndrome (CRS) and neurotoxicity after the administration of blinatumomab or CAR T cells. But despite these hurdles, death in CR is nearly zero, and this is the promise for further immunotherapies.
References:
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What Is the Role of Allogeneic-SCT in Adult Acute Lymphoblastic Leukemia in the Era of Targeted Therapies? - Targeted Oncology
