Oligoclonality and new agent evaluation in acute lymphoblastic leukaemia

Abstract

New agent development rests on the fundamental assumption that candidate agents or drug combinations that induce objective responses after relapse will prevent relapse, if applied prior to relapse. However, cumulative experience now includes at least 5 examples of interventions with post-relapse objective response rates greater than 50% that failed to improve outcomes when applied prior to relapse. Emerging insights into oligoclonality provide some explanation. In acute lymphoblastic leukaemia, the predominant clones at relapse differ from the predominant clones at presentation. Arguably, the more highly proliferative clones that predominate at relapse differ in drug sensitivity from the less proliferative clones that escape primary therapy. Interventions effective against the predominant clones at relapse may have no effect on the antecedent escapee clones. Response is not sufficient in new agent development. Duration of response has attracted less attention because of variability in post-remission therapy but some patient subsets have such a uniformly dismal outcome that details of post-remission therapy may be irrelevant. Benchmarks are needed. Are recovering blasts members of the same clone or do they represent a new clone? When you eradicate the predominant clones you get a response. When you eradicate all clones, you get a cure.

Genomic characterization of paediatric acute lymphoblastic leukaemia: an opportunity for precision medicine therapeutics

“…Relapsed ALL is frequently associated with treatment resistance, possibly arising from enrichment of pre‐existing resistant subclone(s) and/or from mutation acquisition during chemotherapy exposure (Hunger & Mullighan, ). The roles of leukaemia oligoclonality in initial chemotherapy responses and at time of leukaemia recurrence remain incompletely understood, but are probably critical determinants of relapse risk and of durable remission (Gaynon & Sun, ).…”

Bortezomib reinduction chemotherapy in high‐risk ALL in first relapse: a report from the Children's Oncology Group

“…Patients with relapsed T‐ALL have a particularly poor event free survival (EFS) of <15% (Teachey & Hunger, ). The treatment of relapsed disease is made more difficult by the development of drug‐resistant subclones following initial therapy (Gaynon & Sun, ). Patients with relapsed ALL are often highly resistant to corticosteroids, one of the principal components of ALL therapy (Bhadri et al , ).…”

Bortezomib Comes to the Rescue: Comment on the Article by Nachmias et al. Entitled “A Bortezomib-Based Protocol Induces a High Rate of CR with Minor Toxicity in Adult Patients with Relapsed/Refractory ALL”

“…This was followed by our own observation that bortezomib and a standard 4-drug combination had remarkable activity in relapsed/refractory childhood B-cell ALL [4]. This has since been confirmed by other studies on childhood ALL, with activity even being seen in childhood T-cell ALL (Table 1).…”

“…Although both vincristine and bortezomib are known to cause peripheral neuropathy, this was not a significant problem in any studies to date. Interestingly, though, among these heavily treated adults, only 2 bacterial infections were reported and no significant sepsis, in contrast to the high concern for bacterial and fungal infections raised by the TACL group (3 infectious deaths) [4] and the European group (3 infectious deaths) [7]. …”