While in childhood ALL the cure rates can be over 80%, in adults the prognosis still remains unsatisfactory. Important advancements have however occurred in the management of adult patients based on the biology of the disease. Ph+ ALL is an illuminating example of how the understanding of a specific genetic abnormality has led over time to the use of targeted therapies. The results obtained with tyrosine kinase inhibitors (TKI) used upfront in adult Ph+ ALL have changed our approach to this condition in patients of all ages. It is thus mandatory that the abnormality is rapidly investigated at presentation. In the GIMEMA network, the presence or absence of the BCR-ABL fusion is tested centrally within one week from diagnosis of ALL, during the steroid pre-phase. TKIs – alone or in combination with chemotherapy – have markedly improved the rates of response and overall survival of Ph+ ALL. The Italian cooperative group GIMEMA over the years has been using an induction strategy based on the use of a TKI (1st, 2nd and 3rd generation) plus steroids and CNS prophylaxis, with no systemic chemotherapy. This has led to a hematologic CR in 94–100% of patients (with no upper age limit) with virtually no deaths in induction. A proportion of patients can obtain a molecular response. Some elderly patients treated only with TKIs are alive and well after many years from diagnosis. Other groups have used a combination between a TKI and de-intensified chemotherapy, in order to reduce the toxicities (and deaths) associated with conventional chemotherapy plus a TKI. With the advent of TKIs, the induction of Ph+ ALL patients – if identified promptly – is a solved issue. Since patients who achieve a molecular response fare significantly better, a molecular response should be the primary endpoint of treatment. Allogeneic stem cell transplant has always been considered the only curative strategy for Ph+ ALL patients. New strategies are however under active investigation. In the last GIMEMA LAL 2116 front-line trial an induction-consolidation strategy based on the use of dasatinib followed by at least two cycles of the bispecific monoclonal antibody blinatumumab were used. This chemo-free induction-consolidation approach is associated with very high rates of molecular response (Chiaretti et al, ASH 2019). In childhood Ph+ ALL, the protocols so far still use an induction based on a combination of chemotherapy plus a TKI.

Great attention has been raised by the so-called Ph-like ALL, a subgroup associated with an unfavorable prognosis. Evidence has been provided that this is contributed by the persistence of minimal residual disease following conventional chemotherapy. Attempts are being carried out by incorporating TKIs or other inhibitors. The GIMEMA LAL 2317 has used blinatumomab in the front-line Ph- ALL protocol (recently closed) and Ph-like cases are being identified using a predictor described by our group (Chiaretti et al, BJH, 2018). In adult B-lineage ALL, Ph+ and Ph-like ALL account for 35–60% of cases, depending on age, making them the most prevalent genetic ALL subgroup.