|Ahead of print
Challenging role of new agents on the treatment of ALCL
Carolina V Mahuad
Hematology Service, Hospital Alemán, Buenos Aires, Argentina
|Date of Submission||28-Mar-2020|
|Date of Decision||25-Apr-2020|
|Date of Acceptance||28-Apr-2020|
|Date of Web Publication||17-Oct-2020|
Carolina V Mahuad,
Hematology Service, Hospital Alemán, Buenos Aires
Source of Support: None, Conflict of Interest: None
The article entitled “Successful combination of crizotinib and hematopoietic stem cell transplantation in relapsed ALK-positive ALCL” represents a valuable contribution to a developing field mainly because the treatment of relapsed/refractory ALCL patients hasn't been standardized.
While the majority of ALK-positive ALCL patients are expected to be cured with frontline chemotherapy, relapses occur in up to 30%–40% of patients. Interestingly, relapsed disease maintains chemotherapy sensitivity in a significant proportion of patients and intensive salvage regimens might transit patients to consolidative hematopoietic stem cell transplantation procedures with curative intent.
The relapsed/refractory ALCL has an ominous prognosis and there are numerous successful cases to date to achieve complete remission with crizotinib, sustained even without allotransplantation., In this last reported case, the patient is still alive after 8 years of continuous treatment.
Crizotinib and anti-CD30 (brentuximab vedotin) are therapeutic options for relapsed/refractory ALCL that should be considered as bridging treatments before allogenic bone marrow transplantation.,,, Anaplastic lymphoma kinase perpetual activation and downstream events play a cardinal role in pathogenesis and progression of ALK-positive ALCL. It is therefore, highly relevant to study the use of specific ALK inhibitors in both frontline and relapsed/refractory patients. Crizotinib demonstrated significant activity in pediatric population with ALK-positive malignancies.
The use of allogeneic stem cell transplantation in patients with relapsed/refractory ALK-positive ALCL is mostly supported by a few small retrospective studies in patients with various peripheral T-cell lymphomas (PTCL) subtype categories, including rare cases of ALK-positive ALCL. Conclusions are sometimes limited by the fact that authors describe results in ALCL patients whose ALK status is not reported. A French study retrospectively evaluated the role of allogeneic transplant typically in relapsed or refractory patients, which included 27 patients (median age 12–55 years) with ALCL. Information on ALK status was available in 13 patients and 8 were ALK-positive. The 5 year event-free survival (EFS) and overall survival (OS) for ALCL patients were 58% and 55%, respectively, which was comparable to the other PTCL subtypes. On chemotherapy-resistant patients, the 5-year OS was 29% for the whole group. Chemoresistant disease at the time of transplant and the occurrence of severe grade 3–4 acute graft-versus-host disease were the strongest adverse prognostic factors for OS, while an human leukocyte antigen (HLA)-mismatched donor increased treatment-related mortality. Similar results were reported by Lu et al. in another Chinese retrospective analysis of a cohort of 33 ALCL cases.
To date, the decision to transplant or not is likely to depend upon the patient's age, comorbidities, drug tolerance, and donor availability/acces to allotransplant.
New targeted therapies might represent more effective strategies than the conventional polychemotherapy protocols, since the former might have a significantly less toxic profile. Even heavily treated patients respond and sustain prolonged remissions with these drugs used as monotherapy. Despite high curability of ALK-positive ALCL with cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP)-like combinations, novel treatment platforms that would maintain at least current cure rates but significantly reduce early and late sequalae of aggressive regimens are highly desirable. One such trial is currently evaluating the feasibility of ALK-inhibitor (ceritinib) and brentuximab vedotin combination in patients with newly diagnosed ALK-positive ALCL. If successful, these “chemotherapy-free” platforms might become a new or altenative standard employing biology-driven approach.
In my opinion, the questions that a clinician should now raise when evaluating a newly diagnosed or relapsed/refractory patient with ALK-positive ALCL are those related to best frontline or salvage therapy, need for consolidative strategies, incorporation of novel immunoconjugates and ALK inhibitors into treatment paradigms, and timing and the best use of hematopoietic stem cell or chimeric antigen receptor (CAR) T-cell therapies. Hopefully, new trials are going to answer relevant questions like what the potential utility of this agent as first-line treatment is, what the optimal treatment duration is, and, consequently, what the optimal moment for allotransplantation/CART would be, considering the morbidity and mortality associated to these procedures.
| » References|| |
Sun X, Fang X, Jiang Y. Successful combination of crizotinib and hematopoietic stem cell transplantation in relapsed ALK-positive ALCL. Indian J Cancer [Ahead of Print].
Gambacorti Passerini C, Farina F, Stasia A, Redaelli S, Ceccon M, Mologni L,et al
. Crizotinib in advanced, chemoresistant anaplastic lymphoma kinase-positive lymphoma patients. J Natl Cancer Inst 2014;106:djt378.
Mahuad CV, Repáraz Mde L, Zerga ME, Aizpurua MF, Casali C, Garate G. Three years sustained complete remission achieved in a primary refractory ALK-positive anaplastic T large cell lymphoma treated with crizotinib. Rare Tumors 2016;8:6266.
Murga-Zamalloa C, Lim MS. ALK-driven tumors and targeted therapy: Focus on crizotinib. Pharmgenomics Pers Med 2014;7:87-4.
Mosse YP, Lim MS, Voss SD, Wilner K, Ruffner K, Laliberte J,et al
. Safetyand activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: Achildren's oncology group phase 1 consortium study. Lancet Oncol 2013;14:472-80.
Ordemann R, Stohlmacher J, Beuthien- Baumann B, Platzek I, van den Hoff J, Kroschinsky F,et al
. Use of targeted therapy for refractory ALK-positive anaplastic large cell lymphoma as a bridging strategy prior to allogeneic transplantation. Ann Hematol 2013;92:125-7.
Gambacorti-Passerini C, Messa C, Pogliani EM. Crizotinib in anaplastic large-cell lymphoma. N
Engl J Med 2011;364:775-6.
Le Gouill S, MilpiedN, Buzyn A, Buzyn A, De Latour RP, Vernant JP, et al
.; Société Française de Greffe de Moëlle et de Thérapie Cellulaire. Graft-versus-lymphoma effect for aggressive T-cell lymphomas in adults: A study by the Societe Francaise de Greffe de Moelle et de Therapie Cellulaire. J Clin Oncol 2008;26:2264-71.
Lu N, Li XF, Dong YJ, Wang YN, Fu XR, Wu YM,et al
.[Outcomes of 33 patients with anaplastic large cell lymphoma treated after hematopoietic stem cell transplantation]. Zhonghua Xue Ye Xue Za Zhi 2020;41:117-22.