Modern Management Options for Ph+ ALL

Abstract

Impressive advances have been achieved in the management of patients with Philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+ ALL) since the initial concurrent use of imatinib and standard chemotherapy. The attenuation of chemotherapy has proven to be equally effective and less toxic, the use of third generation TKI upfront has improved the frequency of complete molecular response and the survival rate, and the combination of tyrosine kinase inhibitors with immunotherapy has further increased the rate of molecular response to 70–80% after consolidation, which has been translated into a survival rate of 75–90% in recent trials. As a result of these improvements, the role of allogeneic hematopoietic stem cell transplantation is being redefined. The methodology of measurable residual disease assessment and the detection of ABL1 mutations are also improving and will contribute to a more precise selection of the treatment for newly diagnosed and relapsed or refractory (R/R) patients. Finally, new compounds combined with immunotherapeutic approaches, including cellular therapy, are being used as rescue therapy and will hopefully be included in first line therapy in the near future. This article will review and update the modern management of patients with Ph+ ALL.

Blinatumomab and Inotuzumab Ozogamicin Sequential Use for the Treatment of Relapsed/Refractory Acute Lymphoblastic Leukemia: A Real-Life Campus All Study

“…Immunotherapy with Blina and InO has profoundly changed the outcomes of both R/R Ph-negative and Ph+ B-ALL, improving significantly the prognosis of adult patients [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ], and new strategies for their use in maintenance, MRD eradication, and debulking prior to Blina and the association of different combinations/sequencing of Blina and InO with a reduced intensity chemotherapy are being explored.…”

“…Historically, for relapsed/refractory (R/R) ALL occurring in adult patients, survival is unsatisfactory, with long-term survival in <10% [ 1 , 2 , 3 ]. Novel immunotherapy agents, in particular CAR-T cells and the monoclonal antibodies blinatumomab (Blina) and inotuzumab ozogamicin (InO), have profoundly improved outcomes in R/R B-ALL (B-ALL) patients [ 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 , 13 , 14 , 15 , 16 , 17 , 18 ], compared to traditional chemotherapy, increasing the possibility of performing allogeneic hematopoietic stem cell transplantation (allo-HSCT) with long-term disease control [ 9 , 10 , 11 , 12 , 13 ].…”

Ponalfil trial for adults with Philadelphia chromosome‐positive acute lymphoblastic leukemia: Long‐term results

“…Although our results are comparable with those of phase 2 trials using second‐ or third‐generation TKI and blinatumomab as first‐line therapy, 4,8 our trial is only applicable to young adults fit for alloHSCT. The need for transplant in all patients with Ph+ ALL is being re‐evaluated and could potentially be limited to patients not achieving CMR after consolidation or having poor molecular features (e.g., IKZF1 plus signature) 8,10–12 . On the other hand, the pre‐emptive strategy for ponatinib after transplantation was feasible and allowed a reduction of ponatinib exposure in 17 out of 26 transplanted patients.…”

“…The need for transplant in all patients with Ph+ ALL is being re‐evaluated and could potentially be limited to patients not achieving CMR after consolidation or having poor molecular features (e.g., IKZF1 plus signature). 8 , 10 , 11 , 12 On the other hand, the pre‐emptive strategy for ponatinib after transplantation was feasible and allowed a reduction of ponatinib exposure in 17 out of 26 transplanted patients. Re‐treatment with ponatinib after molecular relapse is a possibility that can allow the control of the disease in most patients without additional cytotoxic chemotherapy.…”

Oral Manifestations: A Warning-Sign in Children with Hematological Disease Acute Lymphocytic Leukemia

“…Over the last decade, the prognosis for children with ALL has improved due to the use of precision medicine, identification of distinct subgroups and development of targeted therapies [ 50 ]. Immunotherapy, alone or combined with chemotherapy, is used for pediatric refractory/relapsing ALL (R/R ALL) and for Philadelphia-positive (Ph+) children, a rare and poor prognosis subgroup with a defective chromosome—22—resulting from a genetic translocation [ 51 , 52 ]. Tyrosine kinase inhibitors (TKI), monoclonal antibodies and chimeric antigen receptor T (CAR-T) cells are already used, with limited oral manifestations.…”