A multicentre CUTALLO study provides prospective and controlled data supporting the use of allogeneic haematopoietic stem cell transplantation (HSCT) in patients with advanced-stage, high-risk cutaneous T-cell lymphomas (CTCLs). Allogeneic HSCT was associated with a higher probability of progression-free survival (PFS) and increased mean improvement in quality-of-life (QoL) measurements over time compared with non-HSCT treatment in patients with high-risk advanced CTCLs.
This study represents the first prospective randomised clinical study evaluating the efficacy of allogeneic HSCT versus non-HSCT in a matched control population in patients with CTCL, laying the foundation for future prospective studies evaluating novel conditioning regimens and incorporating maintenance and consolidative strategies to mitigate relapse risk. The findings are published by Prof. Adèle de Masson of the Department of Dermatology, Saint-Louis Hospital, Assistance Publique–Hôpitaux de Paris in Paris, France, and colleagues on 24 April 2023 in The Lancet.
CTCLs, including mycosis fungoides and Sézary syndrome, are rare malignancies of skin-homing T-cells. Advanced-stage CTCLs are associated with a median overall survival (OS) of less than 5 years. Independent prognostic markers of worse survival include advanced age, the presence of large-cell transformation, and stage IV disease. CTCLs substantially affects QoL, inducing visible skin changes such as erythroderma, and tumours, pruritus, infections, pain, and asthenia.
Few treatments have been shown to improve PFS in advanced CTCLs in prospective controlled studies. No treatments have proven to increase OS. Case series suggest that allogeneic HSCT potentially induces a graft-versus-lymphoma effect leading to long-lasting CTCLs remission in some patients and the guidelines are based on case series without available controlled data. In the 1990s, a method for obtaining unbiased estimates of the effects of allogeneic HSCT was proposed, in which the presence or absence of an available donor could be used, equivalent to a mendelian randomisation.
In this prospective, multicentre, matched controlled study, conducted at 30 hospitals, patients with advanced CTCLs were allocated treatment: if they had an available compatible related donor, they were assigned to allogeneic HSCT, or if not, they were allocated to non-HSCT treatment. Key inclusion criteria were age 18–70 years, advanced stage mycosis fungoides or Sézary syndrome, and at least one poor prognostic criterion. Participants were excluded if they were not in complete or partial remission of the disease.
Propensity score 1:1 matching with replacement was used to handle confounding factors, with the balance of covariate distribution between HSCT and non-HSCT groups assessed using standardised mean differences. The primary endpoint was PFS in the matched intention-to-treat (ITT) population. This study is currently active, but not recruiting.
From 1 June 2016 to 3 March 2022, total of 99 participants were enroled at 17 centres in France. Patients with a sibling or matched unrelated donor were assigned to allogeneic HSCT group (n=55) and patients without a donor were assigned to non-HSCT group (n=44). The median follow-up among survivors was 12.6 months. In the allogeneic HSCT group, 51 patients (93%) were 1:1 matched to those from the non-HSCT group.
In the ITT analysis, median PFS was significantly longer in the allogeneic HSCT group, 9.0 months (95% confidence interval [CI] 6.6–30.5) than in the non-HSCT group, 3.0 months (2.0–6.3), with a hazard ratio of 0.38 (95% CI 0.21–0.69; p < 0.0001).
In the per-protocol population, 40 patients (78%) in the allogeneic HSCT group had 101 serious events and 29 (67%) in the non-HSCT group had 70 serious adverse events. The most common serious adverse event other than graft-versus-host disease in both groups was infections, occurring in 30 patients (59%) in the allogeneic HSCT group and in 19 (44%) in the non-allogeneic HSCT group.
The authors commented that their study has some limitations. The number of participants was low, with heterogeneity of the study groups. This limitation decreases the reliability of subgroup and especially post-hoc analyses, which should be considered as exploratory and interpreted with caution. Although multicentric, this study was performed in a single country. Given the study follow-up, the long-term effects of allogeneic HSCT should be further evaluated.
The study investigators did not check the modelling assumptions for the logistic propensity score model because their purpose was to balance the characteristics of the treatment groups instead of making any statistical inference. The standardised mean differences after matching showed that the two groups were well matched; therefore, they did not reassess the model specifications.
The investigators could not exclude unmeasured confounding and measurement bias in ITT estimates, although the prospective, matched, mendelian randomised, controlled design reduced the risk of bias compared with the use of propensity score matching in retrospectively collected data.
In an accompanied editorial article, Drs. Madiha Iqbal and Mohamed A Kharfan-Dabaja of the Department of Hematology and Oncology, Mayo Clinic Cancer Center in Jacksonville, FL, US wrote that until now, the optimal timing for allogeneic HSCT in CTCL was unclear. Published clinical practice recommendations suggest that allogeneic HSCT should not be relegated to the last resort and ought to be considered early in the disease course. This study showed improved outcomes for patients allografted earlier in the disease course. Only 20% of the patients were in complete remission at the time of transplantation and this also probably contributed to the still-high observed relapse rates. A longer follow-up would shed further light on the durability of responses.
The study was not powered to detect a difference in outcomes between mycosis fungoides and Sézary syndrome, but in the ITT population a higher PFS was observed with allogeneic HSCT, both in patients with mycosis fungoides and Sézary syndrome. Despite the small number of patients, the significantly better PFS is noteworthy and will probably encourage a practice change to offer allogeneic HSCT to patients with CTCL earlier in the disease course. Biological assignment clinical studies can overcome the feasibility of patient accrual in a rare study population.
Prognostic factor imbalances are an important limitation in this design and are notable in diseases such as CTCL, where it is difficult to define a control group and patients receive treatments based on physician choice. Yet, propensity score matching, as used in this study, helps to diminish the imbalances according to the editorialists.
The study was funded by the French Ministry of Health, French National Cancer Institute, Programme Hospitalier de Recherche Clinique en Cancérologie.
