521 lymphoma patients underwent ASCT between 1994 and 2019 (Table 1). Most patients were male (63%) and the median age was 57 years (range, 18–72). At last follow-up (November 2019), the median follow-up time in survivors was 5.3 years (range, 0.1–24.3). The median OS, LSS, and PFS were 13.2, not reached, and 5.7 years (Fig. 1A). OS and PFS at 5 years were 66% and 52% (Table 2). The conditioning regimen was BEAM in 497 patients. Because of occasional melphalan shortages from 2015 onwards, BEAC was used in 20 patients. Three patients with CNS relapse of systemic lymphoma were conditioned with BCNU-thiotepa and the first patient in 1994 received cyclophosphamide-total body irradiation. There was improved outcome over the three calendar periods 1994–2004, 2005–2014, 2015–2019 (2-year OS: 66%, 73%, 83%; P = 0.018; Fig. 1B), partly explained by decreasing NRM (at 100 days, 9.8%, 3.9%, 2.9%, respectively; previously thoroughly described [2]). The OS improvement between 1994–2004 and 2005–2014 was due to lower NRM (P = 0.027), but the 10-percentage point OS advance between 2005–2014 and 2015–2019 (P = 0.029) was not accompanied by a significant reduction in NRM (P = 0.6). Rituximab use increased in B-cell disease (30%, 96%, 100% over the three calendar periods; P < 0.00005), but could not explain the better outcome (Table 1). Neither was it caused by changes in conditioning, because the BEAM regimen never changed, and in the last calendar period, there was a clear tendency for inferior outcome in patients treated with BEAC compared with BEAM (Fig. 1C), with P = 0.059 for OS, P = 0.034 for LSS, and P = 0.062 for PFS. When BEAC patients were excluded, not only OS and NRM, but also LSS was significantly better in the last calendar period (P = 0.040), suggesting the emergence of a new lymphoma-specific survival factor.
The emergence of PET/CT
We compared the prognostic value of pre-transplant CT and PET/CT. Cases were excluded if the last radiology evaluation prior to ASCT was PR but conducted interim (before the last course of chemotherapy prior to conditioning). All assessments showing CR in the last evaluation were included, either when conducted interim or directly before the ASCT. Thus, the last evaluation of response prior to ASCT was CT in 235 patients (62%) and PET/CT in 136 (36%), the remaining 8 (2%) were assessments using MRI, bone marrow biopsy, or palpation. Over time, PET/CT became increasingly common. PET/CT constituted 2% and CT 98% of the final evaluations 1994–2004, the corresponding numbers were 24% and 75% 2005–2014, and 60% and 37% 2015–2019 (P < 0.0005). Of patients evaluated with PET/CT prior to ASCT, 77% were in CR and 23% in PR (Table 3).
Both with CT and PET/CT, PR compared with CR was a poor prognostic marker (OS, P = 0.035, P = 0.0003, respectively). However, PET/CT was markedly more powerful than CT (Table 3; Fig. 1D). For example, at 2 years, the OS rates were in CT-CR 76% and CT-PR 62%, and in PET/CT-CR 93% and PET/CT-PR 55% (Table 3). Because CT had been conducted more in the earlier times with higher NRM, the analysis was repeated with restriction to the last calendar period (2015–2019) with similar results (2-year OS: CT-CR 81%, CT-PR 70%, PET/CT-CR 96%, PET/CT-PR 63%). At the start of conditioning, in patients with PET/CT-CR, 68% had normal C-reactive protein (< 3 mg/L), 25% 3–10 mg/L, and 7% ≥10 mg/L, whereas in PET/CT-PR, the corresponding numbers were 41%, 38%, and 21% (P = 0.005). There were no C-reactive protein differences between CT-CR and CT-PR (P = 0.65).
We further investigated the patients transplanted in PR: 19 were given a planned local therapy after ASCT (18, irradiation; 1, splenectomy). That approach appeared useful in the 10 patients where the local therapy was PET-guided (2-year OS/PFS 80%/60%) but not in those 9 where CT defined PR (2-year OS/PFS 44%/44%; Fig. 1E). The PET/CT-PR patients given local therapy (PET/CT-PR-local) was an intermediate prognostic group between PET/CT-CR and PET/CT-PR-general (several FDG-avid sites; Table 3). With respect to OS and PFS, PET/CT-PR compared with PET/CT-CR showed inferior outcome with hazard ratios (HR) 4.0 (95% confidence interval [CI], 1.8–9.1) and 2.4 (95% CI, 1.3–4.6). For comparison, CT-PR compared with CT-CR had HR 1.5 (95% CI, 1.0-2.2) for OS and HR 1.6 (95% CI, 1.2–2.3) for PFS.
Primary and transformed aggressive B-cell lymphomas
In total, 228 (121 primary and 107 transformed) patients were transplanted for aggressive B-cell lymphoma. Outcome did not differ between diffuse large B-cell or other types of primary aggressive lymphoma; likewise, there were no differences between transformed follicular or other transformed indolent lymphomas, nor, overall, between primary or transformed aggressive lymphomas (Table 2), and the curves were roughly similar (Fig. 2A-B). There were no outcome differences between primary or transformed aggressive lymphoma in the upfront or relapsed/refractory setting (Fig. 2C), why the 228 aggressive B-cell patients were subsequently grouped for statistical power. Patients transplanted upfront in first remission had better outcome than those who had had relapsed or refractory disease (OS, P = 0.003; LSS, P = 0.010; PFS, P = 0.031; Fig. 2D), similarly, the number of prior lines of chemotherapy was highly predictive for outcome (OS, P = 0.001; LSS, P = 0.0002; PFS, P = 0.0002; Fig. 2E). PET/CT was a valuable predictive tool for OS (P = 0.004), LSS (P = 0.006), and PFS (P = 0.032), while remission status by CT had no value (Fig. 2F; Table 3).
Indolent B-cell lymphomas
Short- and long-term outcome of the 49 patients with indolent lymphoma are shown in Table 2; late relapses were seen. In follicular lymphoma, 31% were alive and in remission after 10 years. Outcome was almost identical (Fig. 3A; Table 2) in transformed and not-transformed indolent lymphoma, apart from an expected initial higher mortality in transformed disease. There were too few events for investigating the PET/CT method in not-transformed indolent lymphoma. When combining transformed and not-transformed disease, PET/CT was highly predictive for OS (P = 0.0003) and PFS (P = 0.013), while CT was not predictive (P > 0.5 for both comparisons).
Mantle cell lymphoma
85 out of 99 mantle cell lymphoma patients were transplanted upfront in or according to the Nordic MCL2 trial [19]. These patients showed excellent outcome with median PFS 9.4 years (Fig. 3B). Patients with more aggressive variants of MCL (blastic, pleomorphic, TP53+, or Ki67 > 60%) showed poor outcome (Table 2), also after upfront ASCT according to the MCL2 protocol (Fig. 3C). CR compared with PR, regardless whether obtained from PET/CT or CT, was highly predictive of outcome (OS, P = 0.039; LSS, P = 0.044; PFS = 0.025; Fig. 3D). Late relapses were seen.
T-cell lymphomas
78 out of 85 patients had peripheral T-cell lymphoma, and 56/78 were transplanted upfront in or according to the Nordic NLG-T-01 trial [20]; these patients showed good outcome (Fig. 3E) with 5-year OS at 75% (Table 2). The two-year OS/PFS in patients with peripheral T-cell lymphoma were 91%/78% if PET/CT-CR, 33%/33% if PET/CT-PR (P = 0.024; Table 3). In contrast, CT could not predict outcome.
Classical Hodgkin lymphoma
These 60 patients, all relapsed/refractory, showed excellent outcome (OS at 5 years, 83%; Table 2). However, refractory disease portended poorer survival than relapsed disease (Fig. 3F; OS, P = 0.002; LSS, P = 0.022; PFS, P = 0.021). In PET/CT-CR, 2-year OS/PFS were 100%/89% and in PET/CT-PR 75%/50%, but there were too few events to achieve statistical significance (Table 3).
Relapse after ASCT
The estimated fraction of relapses at 2 years were with PET/CT-CR 18%, PET/CT-PR 41%, CT-CR 29%, CT-PR 43%. 205 out of 521 patients relapsed after ASCT, at a median time of 308 days. Of these 205 patients 118 died from lymphoma, 3 from treatment toxicity, 18 from other causes, while 66 stayed alive. Relapse was most common in indolent (53%), transformed (42%), and primary aggressive (44%) B-cell lymphoma. It was seen in 36%, 35%, and 25% of mantle cell, T-cell, and Hodgkin lymphoma. Five-year OS after relapse was 30%, and particularly poor in aggressive B-cell lymphoma (16%), but 51% in Hodgkin lymphoma. The 44 patients who underwent allogeneic transplantation for relapsed disease showed better survival than those who did not (5-year OS 63% vs 21%; P < 0.00005), particularly in aggressive or transformed B-cell lymphoma (5-year OS 70% vs 11%; P < 0.00005). No patient had undergone CAR-T cell therapy at last follow-up. Long-term adverse events in our patients, including myeloid disease, have been described previously [2].