Philadelphia‐positive acute lymphoblastic leukaemia (ALL) in Italy during the COVID‐19 pandemic: a Campus ALL study

The recent spread of the coronavirus disease 2019 (COVID‐19) infection has raised important questions within the haematology community on how best to manage and treat patients with haematological malignancies, particularly acute leukaemias. Italy has witnessed a dramatic rise in infections and death rates, which has affected, in particular, certain areas of the most populated northern regions of the country (Lombardia, Veneto, Piemonte, Emilia Romagna). Within the nationwide Campus Acute Lymphoblastic Leukaemia (ALL) programme, in the last week of March, we sent a questionnaire addressing different issues related to the management of adult patients with ALL during the COVID‐19 pandemic to 40 haematology centres located across the country. Twenty‐four centres were based in Northern Italy (i.e. north of Rome), which has been most affected by the COVID‐19 outbreak. So far, in the large majority of centres throughout the country, patients are screened prior to being admitted as inpatients, while this procedure is not routinely carried in most centres for outpatients, unless they present with symptoms potentially ascribable to the COVID‐19 infection. In the present analysis, we focussed on Philadelphia‐positive (Ph+) ALL, for which a second questionnaire was sent at the beginning of April. The interest in Ph+ ALL relates to its incidence, which increases with age accounting for approximately 50% of B‐lineage ALL patients aged >50 years, ¹ to the key role played by tyrosine kinase inhibitors (TKIs) and to the approach taken in Italy to treat adult Ph+ ALL. We obtained information on 267 adult patients with Ph+ ALLs currently managed at these centres. A total of 128 patients came from the four regions most affected by COVID‐19; 62·2% of the patients were aged 18–60 years, and 37·8% were >60 years (20 >70 years, seven >80 years). To date, only one patient has tested COVID‐19 positive. Because of pneumonitis and cellulitis, this patient was transferred to the intensive care unit (ICU) and from there to a department of internal medicine, which developed a COVID‐19 outbreak, where he got infected. He is now well and asymptomatic. Only one patient proved symptomatic but tested negative. This information refers to all Ph+ ALL patients managed at the different centres.

The obvious question is how Ph+ ALL patients should be treated during the COVID‐19 pandemic, which is complicated by the shortage of available ICU beds. In Italy in the last 15 years all adult ALL patients enrolled in the GIMEMA (Gruppo Italiano Malattie EMatologiche dell’Adulto) nationwide trials are evaluated centrally within 1 week from diagnosis during the steroid pre‐phase. Patients with Ph+ ALL are treated in induction with a TKI plus steroids, with no systemic chemotherapy. ² The only chemotherapy is represented by the intrathecal central nervous system prophylaxis. This approach has enabled complete remission rates of 94–100%, with virtually no deaths in induction, including patients aged >70 years. ² , ³ , ⁴ In the last GIMEMA LAL2116 front‐line protocol for adult Ph+ ALL [European Union Drug Regulating Authorities Clinical Trials Database (EudraCT) number 2016‐001083‐11; ClinicalTrials.gov identifier: NTC02744768), with no upper age limit, patients have been treated with an induction based on dasatinib and steroids followed by a consolidation with the bispecific monoclonal antibody, blinatumomab, and further dasatinib. ⁵ To date, despite the current pandemic, patients have continued their treatment as planned. The central molecular monitoring of minimal residual disease has to date been guaranteed for all patients enrolled in the LAL2116 protocol, where the primary endpoint of treatment is the rate of complete molecular responses after the dasatinib/blinatumomab induction‐consolidation. The only problem mentioned by some centres has been the difficulty in allocating patients to an allogeneic stem‐cell transplant when required.

This analysis allows some considerations. The likelihood of a symptomatic COVID‐19 infection in adult Ph+ ALL patients in Italy is close to zero, even in the most affected regions and despite the high rate of elderly individuals in this subgroup of ALL. The strategy of inducing into remission Ph+ ALL patients with a TKI plus steroids and without systemic chemotherapy seems to be of further added value in this dramatic setting. Many patients can reduce their hospitalisation days and can be mainly managed at home with a TKI. In our dasatinib protocols, ⁴ , ⁵ the induction lasts for 3 months. Even at a peak of the COVID‐19 pandemic this ‘soft’ approach allows an effective and mostly home‐based treatment. In addition, a chemotherapy‐free consolidation approach, in our case with blinatumomab, can further reduce the post‐remission hospitalisation.

The possibility that TKIs may play a role in protecting patients from the COVID‐19 infection has been suggested pre‐clinically ⁶ and a randomised study aimed at verifying the effect of imatinib in preventing pulmonary vascular leak in patients with severe COVID‐19 is ongoing (EudraCT 2020‐001236‐10). Finally, an immunosuppressed status may not be a risk factor for COVID‐19 adverse events, ⁷ , ⁸ , ⁹ as documented also in patients with liver transplants. ¹⁰

It becomes increasingly important that patients with Ph+ ALL are rapidly identified at diagnosis and we once again advocate for a chemotherapy‐free induction strategy. It is worth recalling that with dasatinib (and steroids) alone, 20–25% of patients can become molecularly negative ⁴ , ⁵ and that with the addition of blinatumomab this increases to 60%. ⁵ Under such a TKI‐based strategy in Italy, adult Ph+ ALL of all ages could continue to be managed as before even during the outbreak and peak of the COVID‐19 epidemic.