Allogeneic Hematopoietic Stem Cell Transplantation in Advanced Stage Mycosis Fungoides and Sézary Syndrome

A Concise Review

William T. Johnson; Reetu Mukherji; Saritha Kartan; Neda Nikbakht; Pierluigi Porcu; Onder Alpdogan

Disclosures

Chin Clin Oncol. 2019;8(1) 

In This Article

The Utility of Stem Cell Transplantation in Patients With CTCL

Autologous HSCT in CTCL

Retrospective data showed autologous stem cell transplant had excellent ORR with the majority of cases achieving a complete response (CR).[37–39] However, 75% of these cases relapsed with the median time to disease progression of a mere 2.3 months.[40] Graft T-cell depletion prior to autologous transplant unfortunately also showed high relapse rates attributed to compromised cytotoxic response post-transplant.[41] In a meta-analysis by Wu et al., superior OS rates and event free survival rates were observed with allogeneic transplant over autologous.[42] Given this data, autologous transplant is no longer sought as a treatment modality for these patients.

Allogeneic HSCT in CTCL

Allogeneic HSCT for advanced stage CTCL dates back as early as the 1980s[42] and several publications have since indicated that HSCT could provide a cure in patients with a previously incurable disease (Table 1). We will now review in detail 6 of the largest and most recently published case series followed by a brief summary of what we have learned about HSCT for CTCL to date.

In 2010, two of the largest reports to date were published in the Journal of Clinical Oncology just four months apart. The first by Duvic et al.at the MD Anderson Cancer Center details the outcomes of 19 patients over a 7-year span with CTCL prospectively treated with HSCT using a reduced intensity-conditioning (RIC) regimen.[53] Subsequently in 2015, Hosing et al. published the updated results and the results of 28 additionally treated patients (47 total).[49] Forty-two of these patients received tumor debulking in the form of total body skin electron beam radiation (TBSEB) with 36 Gy over an 8-week course just prior to transplant. All patients had advanced CTCL (stage IIB or higher) with a median age of 51.5 years. Only patients who received unrelated[24] or mismatched[2] grafts received in vivo T-cell depletion using anti-thymocyte globulin (ATG) as a part of their conditioning. Most of the patients were in either CR (15%) or partial response (PR) (60%) prior to transplant.

The Kaplan-Meier estimated OS at 4 years was 51% and the estimated 4-year progression-free survival (PFS) was 26%. PFS was superior in patients who had SS vs. those with MF (72.7% vs. 11.5%; P=0.04), but there were no OS differences. The 4-year PFS in patients with MF with large cell transformation (LCT) was dismal at 8.6%. The cumulative non-relapse mortality (NRM) rate was 10.4% and 16.7% at 1 and 2 years, respectively. Contrary to other studies, the authors were not able to show an increased risk of relapse/progression (REL) with the use of ATG. The cumulative incidence grade III–IV acute GVHD was 10%. The cumulative incidence of chronic GVHD was 28%. The most common organ involved was the skin. At the time of their 2015 updated results with a median follow-up after HSCT of 2 years, 27/47 patients were alive; of these patients, 20 had CR, 1 had a PR, 3 had stable disease, and 3 had progressive disease. A total of 22 patients received additional therapy of which 8 achieved a second CR.

The second major publication in 2010 came from Duarte et al. from the European Society for Blood and Marrow Transplantation (EBMT) when they published one of the largest multi-center retrospective analyses of 60 patients with advanced stage CTCL with a median age of 46.5 years.[54] Only ten patients had <10% residual disease at time of HSCT, and 16 patients (27%) received myeloablative condition regimens (MAC). The initial publication was of limited follow-up of 36 months reporting an estimated OS of 66% at 1-year and 54% at 3 years, but in 2014 they published their extended analysis reporting on OS rates of 46% and 44% at 5 and 7 years, respectively.[47] PFS was reported at 32% and 30% at 5 and 7 years, respectively. A total of 27 patients (45%) experienced REL at a median of 3.8 months after HSCT and the 7-year NRM was 22%. Only 2 of these 27 patients had relapsed after 2 years suggesting that HSCT provides long-term disease control. MAC was associated with poorer NRM [hazard ratio (HR), 4.5; 95% CI, 1.43–14.15; P=0.0101] and OS (HR, 2.99; 95% CI, 1.40–6.36; P=0.0046) while RIC was not associated with higher incidence of REL. Forty (67%) of these patients were classified as having an "advanced phase" of disease course (defined as third or later CR, PR or REL, and those whom were primary refractory to systemic therapy). Patients with this defined "advanced phase" or a higher disease burden prior to HSCT and patients receiving T-cell depletion carried a higher risk of REL. Out of 17 patients whom received donor lymphocyte infusion (DLI) for REL, 10 responded with 8 CR. Twenty-seven patients were alive (45%) and 26 of 27 patients were in CR at the last follow-up visit.

In 2012, Paralkar et al. published their experience on 12 patients with advanced stage CTCL whom were HSCT recipients between 2004 and 2010 at The University of Pennsylvania.[45] Seven of the patients had HLA-identical sibling donors and 10 received RIC. The median age at transplant was 53 years. Two patients (1 RIC) died within the first 100 days of transplant and of the other 10 patients who survived to 100 days, 8 reached CR. Four out of these 8 CR patients relapsed between 8–13 months after transplant of which 2 achieved a second CR by tapering immunosuppression and DLI. At the time of publication with a median follow-up of 24 months, five patients remained in CR. The Kaplan-Maier estimated 2-year OS was 58%, and the estimated median OS was 37 months. Acute GVHD developed in 9 of 12 patients with four patients developing grade III–IV GVHD. Six patents developed GVHD of the skin half of which were grade III. GVHD was the cause of death in one patient.

Recently, Lechowicz et al. analyzed the CIBMTR data, which included outcomes of 129 patients, reported between 2000–2009.[48] Most of the patients had relapsed/refractory disease. Sixty-four percent received non-myeloablative/RIC conditioning regimens. NRM at 1 and 5 years was 19%. Risk of disease progression was 50% (95% CI, 41–60%) at 1-year and 61% (95% CI, 50–71%) at 5 years. OS at 1 and 5 years was 54% (95% CI, 45–63%) and 32% (95% CI, 22–44%), respectively.

de Masson and colleagues from the French Society of Bone Marrow Transplantation (FSBMT) and French Study Group on Cutaneous Lymphomas published their experience on 37 cases of HSCT for advanced stage CTCL. One caveat was the fact that many patients (54%) had LCT-MF.[46] The median age was 44 years and 24 patients (66%) had stage IV disease. Seventeen patients (46%) had sibling donors, and 20 (54%) received their transplant from unrelated donors (2 cord blood). The use of ATG in 16 (43%) patients was driven by local protocol. No regimens constituted depletion of T cells in vitro. RIC was used in 25 (68%) of patients.

After a median follow-up of 29 months, 23 patients were alive (62%) and 14 had died (38%); 8 (22%) from disease REL and 6 (16%) from NRM. The type of conditioning regimen had no significant impact on NRM in univariate analysis. The estimated 1 and 2-year OS rates were 65% and 57%, respectively. The estimated PFS was 39% at 1 year and 31% at 2 years. For LCT-MF (n=20), 1 and 2-year PFS were 39% and 26%, respectively. In total, 19 (51%) patients experienced REL after transplantation with a median time to progression of 10 weeks. Ninety percent of all relapses occurred within the first year after HSCT. While 8 of these 19 patients died from REL, 6 patients went on to achieve a second CR and 5 patients experienced at least PR with additional therapy after their REL. Pre-transplant CR or very good PRs was associated with a decreased risk of REL in univariate analysis. The absence of ATG was the only factor significantly associated with NRM in univariate analysis. Interestingly, also in multivariate analysis the use of ATG was the only factor significantly associated with decreased PFS suggesting that intact immune system is required for the graft-versus-lymphoma activity.

The most recently published study provided by Cudillo et al. details a retrospective cohort of 16 patients treated with HSCT with a 76-month median follow-up.[52] With a median age of 54 years, 10/16 patients received RIC conditioning regimens, and ATG was used in mismatched or matched unrelated donors. Only 11 patients were evaluable for efficacy as 5 patients had died early in their treatment course including 3 patients treated with RIC and 4 patients dying from complications of GVHD. However, for those alive the REL rate was just 20% at 1-year and 27% at 10 years. Remarkably, 9/16 patients were alive while 8 remained in CR at the 76-month median follow-up. For all patients the probability of OS was 61% (95% CI, 40–91%) and 54% (95% CI, 33–86%), at 1- and 10-year post-transplant, respectively. At relapse, DLI was incorporated in four patients treated with RIC. Two of these 4 patients responded with minimal and no GVHD, respectively. Of the 2 patients whom did not respond to DLI, 1 died from GVHD complications.

One very interesting finding described by the authors was the clinical outcomes measured at "an interval time from diagnosis to transplant less than or greater than 46 months", which was their median time observed in their 16-patient cohort. The OS at both 1 and 10 years was 88% (95% CI, 67–100%) for patients transplanted less than 46-months from diagnosis. The OS was 37% (95% CI, 15–92%) and 25% (95% CI, 8–83%) at 1 and 10 years, respectively, for patients transplanted greater than 46 months from diagnosis (log-rank P<0.04) [HR 7.26; 95% CI, 0.86–60.95; P<0.068]. Similarly, they found the probability of disease-free survival (DFS) at 1 year to be 73% (95% CI, 47–100%) and at 10 years to be 58% (95% CI, 32–100%), for patients undergoing transplant less than 46 months from diagnosis which was significantly worse than the DFS of 13% at both 1 and 10 years (95% CI, 2–78%) for patients transplanted at greater than 46 months (log-rank P<0.05), [HR 3.68; 95% CI, 0.91–14.87; P<0.067].

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