Acute lymphoblastic leukemia (ALL) is an aggressive hematological disease [1-4]. Combining high-dose chemotherapy and allogeneic hematopoietic cell transplantation (HCT) improved treatment outcomes in ALL patients [5-10]. Historically, Philadelphia chromosome (Ph)-positive cases of ALL, which comprise about 30% of all adult ALL cases, had a very poor prognosis. The incorporation of tyrosine kinase inhibitors (TKIs) in the treatment of ALL significantly improved treatment outcomes . Nevertheless, the treatment of Ph-positive ALL is still challenging, especially in cases of relapsed and refractory disease. In this review, we will focus on the management of newly diagnosed Ph-positive ALL and highlight recent advances in the treatment of relapsed and refractory ALL.
TKI-based treatments improve the rates of complete remission (CR) in Ph-positive ALL patients. After the introduction of TKIs, an allogeneic HCT is performed in up to 80% of patients . Despite the limitations of allogeneic HCT, such as severe graft-versus-host disease (GVHD) and other complications, it remains the standard of care for the treatment of Ph-positive ALL [12, 13]. The UKALLXII/ECOG 2993 study revealed that adult Ph-positive ALL exhibited a significant response to allogeneic HCT [6, 14]. The GRAAPH-2005 trial compared the treatment outcomes after allogeneic HCT with those after autologous stem cell transplantation. The rates of five-year event-free survival and overall survival (OS) were 37% and 46%, respectively. Furthermore, allogeneic HCT showed better survival outcomes in relapse-free survival (hazard ratio of 0.69) and OS (hazard ratio of 0.64) . Other trials suggested a role for allogeneic HCT in the treatment of younger adult patients. [6, 16]. All patients who were eligible for transplantation underwent allogeneic HCT after CR, and they reported high rates of survival.
Using RT-PCR to assess the minimal residual disease (MRD) in cases of BCR-ABL1 provides a useful method to identify high-risk patients. Early and deeper molecular responses before allogeneic HCT are associated with better clinical outcomes. A negative MRD score before allogeneic HCT was associated with a significantly improved survival rate and an incidence rate of 8% for disease relapse over a five-year period. In contrast, 39% of patients who did not undergo allogeneic HCT experienced relapse . Kim
Although the incorporation of TKIs into chemotherapy is considered the standard treatment for cases of Ph-positive ALL, the necessity of chemotherapy remains an important yet controversial issue, especially in older or fragile patients. The results of the early GIMEMA group study suggested that TKI monotherapy yielded a complete hematologic response (CHR) rate of 100% in Ph-positive ALL patients . Foá
Several other studies reported combinations of TKIs with low-intensity chemotherapy. The outcomes of these trials were acceptable with CR rates between 95 and 100% [5, 15, 25]. Chalandon
Although TKI monotherapy and TKIs plus low-intensity chemotherapy have clinical benefits in Ph-positive adult ALL patients, many patients relapsed after treatment. This finding may be due to the high incidence of TKI-resistant T315I mutations among patient populations [9, 23, 25]. TKIs with a higher potency, such as ponatinib, may be effective in treating patients that screen positive for these mutations. Unfortunately, only limited data regarding these findings are available . Combining a TKI with immunotherapy can be a good choice for treatment. Recently, Chiaretti
Allogeneic HCT is a long-established strategy for treating patients with Ph-positive ALL. However, this treatment modality has numerous potential adverse effects such as GVHD, veno-occlusive disease, and infection. Younger patients without comorbidities can expect benefits from allogeneic HCT whereas older patients have an increased risk of treatment-related mortality. Although allogeneic HCT is generally considered to be immune to adverse genetic and cytogenetic mutations, some studies concluded that the results of allogeneic HCT in cases of T315I mutation and deletions of CKND2A/2B, PAX5 genes were poor despite allogeneic HCT [27-29].
The AALL0031 study reported the long-term outcomes of Ph-positive pediatric ALL patients after allogeneic HCT. Survival outcomes were similar in patients with and without allogeneic HCT (five-year rates of disease-free survival were 70±12% in the without transplant group, 65±11% in the allogeneic HCT from related donor group, and 59±15% in the allogeneic HCT from unrelated donor group;
Despite promising results in pediatric studies, the application of this strategy to Ph-positive adult ALL patients is still being debated. In the UKALLXII/ECOG 2993 study, some patients who did not undergo transplantation sustained a long-term disease-free status after treatment. However, the majority of patients who underwent allogeneic HCT after CR achieved better outcomes (four-year OS rates of 50% in myeloablative conditioning transplant group compared with 39% in the reduced-intensity conditioning transplant group and 19% in the chemotherapy-only group) . Ravandi
Although limited data exists regarding the efficacy of the third-generation multi-TKI, ponatinib, Jabbour
Adding TKIs to chemotherapy regimens and following this with allogeneic HCT improved patient outcomes; unfortunately, the prognosis of relapsed and refractory cases of Ph-positive ALL is still very poor. Kadia
The use of immunotherapy to treat relapsed and refractory cases of Ph-positive ALL has been less explored compared to the use of immunotherapy to treat cases of Ph-negative ALL. In the Phase II ALCANTARA study, blinatumomab showed promising results in patients with Ph-positive ALL and yielded a median OS of 7.1 months and RFS of 6.7 months. Sixteen out of the 45 (36%) patients achieved CR (with 14 patients achieving CMR) regardless of prior TKI therapy. Meanwhile, 4 out of 10 patients (40%) with a T315I mutation experienced CR. The authors concluded that blinatumomab showed effective antileukemic effects in relapsed and refractory Ph-positive cases of ALL . Assi
Inotuzumab ozogamicin, a humanized anti-CD22 monoclonal antibody conjugated to calicheamicin, is another promising agent for treating ALL. In the Phase III randomized INO-VATE study, remission rates did not differ significantly between the inotuzumab ozogamicin group and the standard chemotherapy group among patients with Ph-positive ALL . Although this study failed to prove the clinical superiority of inotuzumab ozogamicin over standard chemotherapy regimens in patients with relapsed and refractory Ph-positive ALL, inotuzumab ozogamicin showed favorable rates of CR (78.6% vs. 44.4%,
The incorporation of TKIs in the treatment of Ph-positive ALL significantly improved clinical outcomes. However, the clinical outcomes in patients with relapsed and refractory Ph-positive cases of ALL are still grave. The rapid development of monoclonal antibodies led to a breakthrough in the treatment of relapsed and refractory cases of ALL. Future studies should reveal the optimal combinations of monoclonal antibodies with or without standard chemotherapy. Currently, studies using monoclonal antibodies to treat newly diagnosed cases of Ph-positive ALL are ongoing. If these potent monoclonal antibodies can reduce the intensity of standard chemotherapy regimens, treatment-related mortality rates may reduce during treatment. Moreover, if these approaches can achieve deeper and durable molecular responses, it may decrease the demand for allogeneic HCT.
There are several issues regarding chimeric antigen receptor (CAR) T-cell therapies for Ph-positive ALL. Currently, the anti-CD19 CAR T-cell is approved for the treatment of relapsed and refractory ALL cases in children and young adults. Long-term follow-up data on CD19 CAR T-cell therapy for treating relapsed ALL cases showed impressive outcomes, especially in 16 Ph-positive adult ALL patients . The positive effects of CAR T-cell treatments are undeniable, but there is debate over whether CAR T-cell therapy can replace allogeneic HCT . Whether CAR T-cell therapy is to be applied before or after immunotherapy is another question because there are concerns about target-antigen modulation after immunotherapy .
Treatment strategies for Ph-positive ALL patients are rapidly changing. Fortunately, the introduction of effective agents, such as potent TKIs and monoclonal antibodies, may improve the possibility of remission in Ph-positive ALL patients and hopefully cure this disease.
No potential conflicts of interest relevant to this article were reported.