Treatment Options for Paediatric Anaplastic Large Cell Lymphoma (ALCL): Current Standard and beyond

Abstract

Anaplastic Lymphoma Kinase (ALK)-positive Anaplastic Large Cell Lymphoma (ALCL), remains one of the most curable cancers in the paediatric setting; multi-agent chemotherapy cures approximately 65–90% of patients. Over the last two decades, major efforts have focused on improving the survival rate by intensification of combination chemotherapy regimens and employing stem cell transplantation for chemotherapy-resistant patients. More recently, several new and ‘renewed’ agents have offered the opportunity for a change in the paradigm for the management of both chemo-sensitive and chemo-resistant forms of ALCL. The development of ALK inhibitors following the identification of the EML4-ALK fusion gene in Non-Small Cell Lung Cancer (NSCLC) has opened new possibilities for ALK-positive ALCL. The uniform expression of CD30 on the cell surface of ALCL has given the opportunity for anti-CD30 antibody therapy. The re-evaluation of vinblastine, which has shown remarkable activity as a single agent even in the face of relapsed disease, has led to the consideration of a revised approach to frontline therapy. The advent of immune therapies such as checkpoint inhibition has provided another option for the treatment of ALCL. In fact, the number of potential new agents now presents a real challenge to the clinical community that must prioritise those thought to offer the most promise for the future. In this review, we will focus on the current status of paediatric ALCL therapy, explore how new and ‘renewed’ agents are re-shaping the therapeutic landscape for ALCL, and identify the strategies being employed in the next generation of clinical trials.

From bench to bedside: the past, present and future of therapy for systemic paediatric ALCL, ALK+

“…As ALCL was not recognised as a distinct entity until the early 1980s, it would have been treated as a NHL. Indeed, retrospective studies have shown that a number of ALCL cases were treated within both B‐ or T‐cell NHL trials (extensively reviewed in Prokoph et al , ). The European Inter‐group for Childhood NHL (EICNHL) led the first international ALCL‐specific clinical trial, initiated in 1999, for patients under the age of 22 years: ALCL99 (NCT00006455) (Attarbaschi et al , ; Mori et al , ).…”

“…Instead, a number of retrospective studies by European and Japanese groups assessed the success with which small cohorts of patients had been treated, using either allogeneic or autologous stem cell transplantation (SCT). There is some evidence to show that allogeneic SCT yields better outcomes for relapse patients, yet there is no consensus on this, nor on the type of conditioning which should be used, although radiotherapy seems to be the most common option (Reviewed in Prokoph et al , ). There is also limited data concerning the best treatment options for refractory patients who do not respond to standard chemotherapy, although some of the more recent trials have shown promise.…”

“…In Europe, this represents fewer than 100 new cases per year (Shiramizu et al , ). In contrast EFS rates are lower, ranging from 59% to 76%, depending on the treatment protocol used (Minard‐Colin et al , ; Prokoph et al , ). Unfortunately, this means that 10–15% of children do not survive a diagnosis of ALCL and many survivors suffer from the late effects of the intensive therapies and/or transplantation required to cure them.…”

“…A number of different chemotherapy regimens have been trialled, but none have been able to breach an OS of 90% and 70% EFS (Lowe & Lim, ; Prokoph et al , ). It is therefore unlikely that modifying current trial protocols further will improve these statistics but modifications could improve the acute side‐effects of therapy.…”

“…Other ALK inhibitors have since been developed, although none have been approved for use in paediatric ALCL to date. However, their use is starting to be trialled in a number of paediatric settings, including ALCL (reviewed in Prokoph et al , ). Results are promising, particularly for refractory adult ALCL patients, for whom the odds of survival have improved significantly, from 30% to 73% (Gambacorti Passerini et al , ).…”