ORIGINAL ARTICLE
Clinical characteristics of interim-PET negative patients
with a positive end PET from the prospective HD08-01 FIL study
Luigi Rigacci1,2 &Benedetta Puccini1&Alessandro Broccoli3&Manjola Dona4&Manuel Gotti5&Andrea Evangelista6& Armando Santoro7&Maurizio Bonfichi5&Alessandro Re8&Michele Spina9&Barbara Botto10&Alessandro Pulsoni11& Chiara Pagani8&Caterina Stelitano12&Flavia Salvi13&Luca Nassi14&Lara Mannelli1&Sofia Kovalchuk1&Daniela Gioia6& Pier Luigi Zinzani3
Received: 15 April 2019 / Accepted: 6 December 2019
# Springer-Verlag GmbH Germany, part of Springer Nature 2019 Abstract
FDG-positron emission tomography (PET) performed early during therapy in advanced Hodgkin lymphoma patients has been confirmed as being important for progression-free survival. A group of patients with a negative interim-PET (i-PET) showed a positive end induction PET (PET). The aim of this study was to evaluate the clinical characteristics of patients with a positive e-PET as a secondary end point of the HD0801 study. A total of 519 patients with advanced-stage de novo Hodgkin lymphoma received initial treatment and underwent an i-PET. Patients with negative results continued the standard treatment. i-PET negative patients were then evaluated for response with an e-PET and those patients found to have a positive one were also then given a salvage therapy. Among 409 i-PET negative, 16 interrupted the therapy, 393 patients were evaluated with an e-PET, and 39 were positive. Sixteen out of 39 underwent a diagnostic biopsy and 15 were confirmed as HD. Seventeen out of 39 e-PET were reviewed according to the Deauville Score and, in sixteen, it was confirmed positive (10 DS 5, 6 DS 4). With the exception of high LDH value at diagnosis (p = 0.01; HR 95% CI 1.18–4.89), no clinical characteristics were significantly different in comparison with e-PET negative patients. Positive e-PET after a negative PET has a worse outcome when compared with i-PET positive patients salvaged with therapy intensification. It was not possible to identify clinical characteristics associated with a positive e-PET.
Keywords Interim-PET . Prognosis . Advanced Hodgkin lymphoma
Introduction
Pre-treatment prognostic tools for advanced-stage HL disease, notably the International Prognostic Score (IPS), do not accu-rately predict which patients will receive benefit from a more intensive therapy [1].
Recently, several studies have clearly demonstrated the predictive value of a positron emission tomography (PET) scan performed after two cycles of doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) chemotherapy (i-PET) in patients with advanced-stage Hodgkin lymphoma (HL)
[2–7]. It is now clear that the i-PET can be considered a sur-rogate indicator for chemotherapy sensitivity.
A negative i-PET is associated with a better progression-free survival (PFS) and a positive one is associated with a worse PFS.
Approximately 65–70% of patients with advanced-stage Hodgkin lymphoma (HL) can be cured with six to eight cycles of ABVD, with or without consolidation radiotherapy on bulky disease [8,9]. Escalated bleomycin, etoposide, doxoru-bicin, cyclophosphamide, vincristine, procarbazine, and pred-nisone (escBEACOPP) cures around 85% of patients if given as first-line therapy. However, concerns regarding its acute toxicity, the possible onset of loss of fertility, and second can-cers or myeloid neoplasia are limiting factors for its wide-spread use [10,12,13].
Patients with a poor prognosis can be identified according to their early response to induction treatment, as documented by an interim-PET evaluation and a response adapted therapy * Luigi Rigacci
luigi.rigacci@unifi.it; lrigacci@scamilloforlanini.rm.it Extended author information available on the last page of the article https://doi.org/10.1007/s00277-019-03889-3
may be tailored for these patients. Several trials have recently been completed (RAPID, HD0801, H10, SWOG S0816, RATHL, GITIL study) that have confirmed the use of a de-escalate therapy in patients with a favorable early PET re-sponse or of an escalate therapy in those who do not respond well, or to do both [14–22].
A negative i-PET scan is a strong predictor of favorable outcomes with standard therapy and a long-term progres-sion-free survival (PFS) rate of approximately 95% has been consistently shown in patients with advanced-stage HL treated with ABVD who display an early PET negativity [2–7]. It was surprising and disconcerting that some patients with negative i-PET reveal disease progression with a positive PET at the end of the induction therapy (e-PET).
Concomitantly with the presentation of the final results of the phase II part of an Italian multicenter trial (HD0801 EudraCT 2008-002684-14 and NCT 00784537; Early Salvage With High-Dose Chemotherapy and Stem-Cell Transplantation in Advanced Stage Hodgkin’s Lymphoma), conducted in centers adhering to the Italian Lymphoma Foundation (FIL) [20], we have also analyzed the clinical and biological characteristics and the outcome of those pa-tients with a positive e-PET who underwent a salvage treat-ment, as well as patients with positive i-PET who were offered a chemotherapy salvage treatment followed by high-dose che-motherapy with autologous stem-cell support.
Patients and methods
Study oversight
HD0801 was a multicenter study involving patients with new-ly diagnosed advanced-stage HL [20]. All patients received first-line ABVD treatment and underwent an i-PET evalua-tion. PET scans were interpreted according to Juweid’s criteria [24], which used mediastinal uptake as a reference. Patients with a positive i-PET were treated with salvage treatment consisting of high-dose chemotherapy with a subsequent au-tologous bone marrow transplantation (ABMT) for those pa-tients obtaining a complete remission as per protocol. Papa-tients with negative i-PET continued the planned course of six cy-cles of ABVD as per protocol. The latter set of patients were restaged with an e-PET and patients with a negative e-PET underwent follow-up and the few patients with a positive e-PET underwent salvage therapy. According to the protocol, this group of patients was withdrawn from the study and was evaluated retrospectively.
Patient enrollment and study conduct
Patients aged 18 to 70 years were considered eligible if they had previously untreated and histologically documented HL
(with the exception of nodular lymphocyte–predominant sub-type) in clinical stage IIB to IV according to Ann Arbor stag-ing and at least one bidimensionally measurable target lesion (even if extranodal only). Responses were primarily assessed by centrally reviewed i-PET scans after two cycles of ABVD and at the end of the scheduled treatment plan, provided that all patients had undergone a complete staging workup, includ-ing PET examination, prior to commencinclud-ing treatment. In the protocol was suggested to perform a CT evaluation after 4 cycles of therapy and was mandatory to perform a CT at the end of therapy. The characteristics of patients with negative i-PET and negative or positive e-i-PET are reported in Table1. Patients with a positive e-PET were withdrawn from the study and the authors were asked to summarize the outcome of these patients, in particular regarding the possible biopsy of the e-PET positive nodes and the histological results, and which other methods were used to exclude a false positivity, the treatment they performed, and finally the patient’s condition at the last follow-up. All local ethic committees at each center approved the study protocol and its amendments, in accor-dance with Italian law and in compliance with the Declaration of Helsinki. Patients provided a signed informed consent before being included in the study.
Central PET review
In the HD0801 study, a central PET review played a pivotal role in reducing the variability of visual scan interpretation between various readers, because treatment decisions were made on the basis of the result of i-PET2 scans. A central review of all uncertain results took place within 5 days of the i-PET scan at a central imaging core laboratory at the University of Florence; a panel of 11 nuclear medicine physi-cians served as reviewers for all procedures. PET scans were interpreted according to Juweid’s criteria [24], which used mediastinal uptake as a reference. During the protocol accrual, end of therapy FDG-PET scans were reviewed at the discre-tion of clinicians that was not mandatory during the study.
According to the aim of this study, e-PET scans were reviewed using the Deauville criteria [25], now regarded as the standard criteria for PET interpretation. We decided not to review the i-PET of 39 patients with e-PET positive, because they were considered negative with Juweid’s criteria and thus could be also considered negative with the Deauville criteria.
Statistical analysis
The sample size of the phase II part of the trial has been estimated according to the Fleming-A’Hern design. The pri-mary efficacy end point was calculated as the cumulative pro-portion of patients alive and with 2-year progression-free sur-vival. The PFS for patients with negative e-PET was adequate-ly corrected considering the salvage therapy for patients with
positive e-PET, meaning that we added 4 months to the end of therapy date for negative e-PETs. In practice, PFS was calcu-lated from the end of therapy plus 4 months to last follow-up or death for patients with negative e-PET and from the end of salvage therapy to last follow-up or death for patients with positive e-PET. Overall survival was calculated for all patients from induction therapy start to last follow-up or death.
All other time-to-event end points included in the study have been estimated using the Kaplan-Meier method.
Baseline patient characteristics were compared according to i-PET negativity using the Mann-WhitneyU test and χ2test (or Fisher’s exact test, if appropriate) for continuous variables and categorical variables, respectively. For the safety analyses, frequency of toxicities was reported by type and grade accord-ing to the National Cancer Institute Common Terminology Criteria for Adverse Events (version 2.0). All analyses were performed by using STATA version 11.1 (STATA, College Station, TX).
Table 1 Patients’ characteristics according to e-PET result (N = 395)
Characteristics Negative e-PET Positive e-PET* Total p value
(N = 356) (N = 39) (N = 395) Median age 33 (26;44) 32 (23;43) 32 (26;44) 0.257 Sex 0.727 Male 193 (54%) 20 (51%) 213 (54%) Female 163 (46%) 19 (49%) 182 (46%) IPS‡ 0.156 0–2 183 (57%) 17 (45%) 200 (56%) ≥ 3 139 (43%) 21 (55%) 160 (44%) Histology 0.356 HL nodular sclerosis 249 (70%) 33 (85%) 282 (71%) HL mixed cellularity 57 (16%) 2 (5%) 59 (15%) HL lymphocyte depletion 8 (2%) 1 (3%) 9 (2%) HL unspecified 27 (8%) 2 (5%) 29 (7%) HL lymphocyte rich 15 (4%) 1 (3%) 16 (4%) Systemic symptoms 0.852 A 124 (35%) 13 (33%) 137 (35%) B 232 (65%) 26 (67%) 258 (65%) Abnormal LDH° 104 (29%) 19 (49%) 123 (31%) 0.013 Performance Status 0.77 0 232 (65%) 27 (69%) 259 (66%) 1 101 (28%) 9 (23%) 110 (28%) 2 23 (6%) 3 (8%) 26 (7%) Stage AA 0.363 II 70 (20%) 7 (18%) 77 (19%) III 126 (35%) 10 (26%) 136 (34%) IV 160 (45%) 22 (56%) 182 (46%) Bulky disease 125 (35%) 17 (44%) 142 (36%) 0.295 Extranodal sites 0.152 0 198 (56%) 17 (44%) 215 (54%) ≥ 1 158 (44%) 22 (56%) 180 (46%)
Bone marrow biopsy§ 0.845
Negative 313 (90%) 34 (89%) 347 (90%)
Positive 33 (10%) 4 (11%) 37 (10%)
Monocyte > 0.75 × 109/l 98 (48%) 10 (43%) 108 (47%) 0.709
*Included the two patients progressed before e-PET ‡35 (9%) missing data
§11 (3%) missing data °
Results
In all, 520 patients who had been enrolled on the study started ABVD treatment between September 2008 and April 2013 in 50 Italian centers. Of those patients, 512 (99%) underwent an i-PET scan, 1 patient withdrew consent before the therapy commenced, and 7 patients interrupted the treatment before the end of the second ABVD cycle. A total of 395 patients performed a final PET, of which 356 were PET negative and 39 (10%) were PET positive. Sixteen patients underwent a biopsy of the PET positive sites, and of these, the site was positive for Hodgkin in 15 patients, and in 1 patient, it was negative. Twenty-three patients did not have a biopsy, either for technical reasons or due to the clinicians’ decision. The patient with the negative biopsy and another patient did not start any salvage therapy. They are alive and free from pro-gression and they were therefore excluded from analysis (false positive e-PET). Moreover, we included the two patients who progressed before e-PET and were considered as progression after i-PET negativity.
A comparison of the clinical characteristics of the 37 e-PET positive patients, the 2 patients who progressed after the i-PET negative result and the 356 e-PET negative patients after a i-PET negative are all reported in Table1. The median age of the patients was 33 years (range 18 to 68 years). With the exclusion of LDH value at diagnosis (p = 0.01; HR 95% CI 1.18–4.89), no other clinical characteristics were significantly different between the two groups. Furthermore, we evaluated a biological index retrospectively (value of monocyte count at diagnosis) and this data did not show a difference between the two groups either. A multivariate logistic regression model was used to identify any clinical characteristics possibly asso-ciated with a prevision of e-PET positivity (Table2) and only abnormal LDH value at diagnosis was significantly associated with a higher probability to have a positive e-PET.
Central FDG-PET revision
Seventeen out of 39 e-PET positive patients (44%) were ret-rospectively reviewed according to the Deauville criteria. Sixteen patients were confirmed as positive (10 DS of 5 and 6 DS of 4) by the reviewers; one patient could not be agreed upon and the case was considered inconclusive.
Response to treatment
All positive e-PET patients but one (who had a rapid progres-sive disease) performed a CT: in 3 patients was not reported an enlargement of lymph nodes (all these patients were treated with radiotherapy), in the other 35 patients was observed an increment of lymph nodes dimension in comparison with a CT usually performed after 4 cycles or, in the rare cases who
did not have a CT after 4 cycles, the comparison was made with the co-registered CT of the PET/CT.
Among the 39 patients, 38 were treated with salvage treat-ment and 1 patient had a very rapid progression and died. Among the 38 patients treated with salvage therapy, 23 were treated with two or three cycles of salvage schemes (IGEVand BEACOPP) and consolidation with an autologous transplant, 6 were treated with an allogenic transplant after several sal-vage therapies, 6 were treated either with polychemotherapy and brentuximab vedotin (BV), and 4 were treated with radio-therapy alone (Table3).
Twenty-seven patients obtained a complete remission: 4 were treated with radiotherapy alone, 2 were treated with che-motherapy and BV, 17 patients were consolidated with an autologous transplant, and 4 with an allogeneic transplant. Nine patients had progressive disease (2 allotransplanted) and died and 3 further patients were lost at follow-up but all three had active disease.
After a median period of 27 months from enrollment, in-dependently from the salvage type of therapy, on the basis of intention-to-treat analysis, the 3-year progression-free survival and overall survival of these group of patients was 54% (95% CI, 33 to 71%; Fig. 1a) and 77% (95% CI, 55 to 89%) respectively.
Table 2 Multivariate logistic regression model to identify e-PET positive predictors
Odds ratio (95% CI) p Age (unit increase) 0.98 (0.95 to 1.01) 0.176
Female 1.03 (0.49 to 2.16) 0.944 IPS≥ 3 1.45 (0.64 to 3.3) 0.37 Histology HL nodular sclerosis 1 -HL mixed cellularity 0.36 (0.1 to 1.34) 0.128 HL lymphocyte depletion 0.55 (0.05 to 6.61) 0.637 HL unspecified 0.61 (0.13 to 2.85) 0.528 HL lymphocyte rich 0.54 (0.06 to 4.55) 0.573 B symptoms 0.88 (0.39 to 1.95) 0.744 Abnormal LDH 2.4 (1.18 to 4.89) 0.016 Performance status 0 1 -1 0.72 (0.31 to 1.68) 0.445 ≥ 2 1.08 (0.27 to 4.39) 0.916 Stage AA II 1 -III 0.91 (0.3 to 2.78) 0.866 IV 1.51 (0.32 to 7.09) 0.602 Bulky disease 1.23 (0.59 to 2.58) 0.579 Extranodal sites≥ 1 0.88 (0.24 to 3.27) 0.849 Bone marrow biopsy 0.53 (0.13 to 2.17) 0.377 Monocyte > 0.75 × 109/l 0.71 (0.28 to 1.82) 0.481
For the entire population calculated from the trial outset, after a median follow-up of 27 months from enrollment, the Kaplan-Meier estimates were 97% (95% CI, 94 to 98%) for 3-year OS and 80% (95% CI, 76 to 83%) for 3-3-year PFS.
On the basis of intention-to-treat analysis, after a median follow-up of 25 months from i-PET scanning, the 3-year PFS
for the negative i-PET patients planned to receive six courses of ABVD was 81% (95% CI, 76 to 84%), whereas the 3-year PFS for the positive i-PET patients (n = 101, independently from the salvage treatment they received) was 76% (95% CI, 66 to 84%). Conversely, the PFS of e-PET positive patients at 36 months was 54% (95% CI, 33 to 71%; see Fig.1b). Table 3 Salvage therapy of
patients with i-PET negative and e-PET positive
Patient Therapy Outcome
1 IGEV, ABMT Death
2 BeGEV, BEACOPP, BV*, allotransplant Death
3 BeGEV, ABMT Alive CR°
4 IGEV, ABMT Alive CR
5 IGEV, ABMT Alive CR
6 IGEV, ABMT Death
7 IGEV, BEACOPP, ABMT, bendamustine BV Death
8 IGEV, ABMT, allotransplant Alive with disease
9 BeGEV Alive CR
10 IGEV, ABMT Alive CR
11 IGEV, BEACOPP, ABMT Death
12 BeGEV, ABMT, BV, allotransplant Alive CR
13 RT^ Alive CR
14 IEV, ABMT, BV Alive CR
15 IEV, ABMT Alive CR
16 IGEV, ABMT Alive CR
17 IGEV Lost to follow-up with active disease
18 IGEV Death
19 IGEV, ABMT Alive CR
20 IGEV, ABMT Alive CR
21 RT Alive CR
22 Unknown Death
23 IGEV, ABMT Lost to follow-up with active disease
24 BV, BEACOPP, bendamustine Alive CR
25 IGEV, ABMT Alive CR
26 IGEV, ABMT Alive CR
27 IGEV, ABMT Alive CR
28 IGEV, BEACOPP, ABMT Alive CR
29 BeGEV, ABMT Alive CR
30 RT Alive CR
31 IGEV, DHAP, ABMT, RT, BV Alive CR
32 IGEV, BV, BEACOPP, ABMT, allotransplant Alive CR
33 RT Alive CR
34 BEACOPP Lost to follow-up with active disease
35 IGEV, ABMT, BV, BEACOPP, bendamustine, allotransplant Death
36 IGEV, BEACOPP, ABMT Alive CR
37 IGEV, ABMT Alive CR
38 IGEV, ABMT Alive CR
39 IGEV, ABMT Death
*BV brentuximab vedotin ^RT radiotherapy °CR complete remission
The OS at 36 months for patients was 99% (95% CI, 98 to 100%), 78% (95% CI, 57 to 89%), and 89% (95% CI, 80 to
94%) respectively for i-PET negative/e-PET negative, i-PET negative/e-PET positive, and i-PET positive (Fig.2).
Comparing i-PET positive patients who underwent a sal-vage autologous transplantation (43 patients) and e-PET pos-itive patients (37), the 3-year OS was respectively 95% (95% CI, 82 to 98%) and 78% (95% CI, 58 to 90%), and this per-centage is significantly different (p = 0.02) (Fig.3).
Discussion
Survival rates for patients with HL, even in advanced stages, have substantially increased over the last few decades. The standard first-line is ABVD regimen but with this approach about 20–25% of patients relapse or show refractoriness [12,
13]. A second-line treatment with high-dose chemotherapy followed by ABMT is generally reserved for these patients. An alternative approach consists of trying to cure as many patients as possible with a more aggressive regimen (i.e., esca-lated BEACOPP), which should be used from the beginning. Systematic review and network meta-analysis have shown bet-ter PFS and OS rates, although this more intense approach exposes patients to considerable acute and late chemotherapy-related toxicity [15,26]. A randomized comparison of ABVD and BEACOPP in patients with advanced-stage HL has recent-ly been reported [8,9] and its results have led some authors to conclude that initial therapy may not necessarily be highly ag-gressive in all patients because those who relapse could receive subsequent intensive salvage therapy. The predictive value of FDG-PET has been reported in several retrospective studies [3,
4], in particular regarding chemosensitivity when applied after two or three cycles of ABVD as initial treatment. Recently, prospective studies have been published in which an i-PET scan was used to identify those patients not responding to ABVD; the i-PET positive patients were moved on to a more intensive Fig. 1 a PFS of 27 patients with positive e-PET treated with salvage
therapy.b PFS of e-PET negative patients (upper line), i-PET positive patients (median line), and i-PET negative/e-PET positive patients (lower line)
Fig. 3 Overall Survival for patients with i-PET negative but e-PET positive (lower line) and patients with i-PET positive salvaged with early intensified treatment (upper line).p value = 0.02
Fig. 2 Overall survival for patients with i-PET negative/e-PET negative (upper line), i-PET negative/e-PET positive (lower line), and i-PET positive (median line)
treatment regimen. All studies concluded that intensification of PET2-positive patients increased the 2-year PFS from 12% of the historical control to more than 65%. Moreover, more than 90% of patients with a negative i-PET, who continued treatment with ABVD, obtained a complete remission. The main problem which confounded clinicians was the observation of a number of patients who presented a positive e-PET after a negative i-PET. For this reason, in reconsidering the HD0801 study, we analyzed those patients who in a prospective study presented a positive e-PET after a negative i-PET. These patients were con-sidered as failures after a complete induction therapy and were treated with salvage therapy. The aim of this retrospective study in a prospective cohort of consecutively enrolled patients was to evaluate the clinical or pathological characteristics of these pa-tients at diagnosis and to compare them with the same charac-teristics of patients with a negative i-PET and e-PET. Currently, even if this phenomenon is well known, no significant data are reported in literature. In the paper by Mesguich et al. [27], among 23 patients with negative i-PET, 3 had a positive e-PET and 2 of these patients had treatment failure. The authors pointed out that the sensitivity of end of treatment FDG-PET is rather high (80%) although it remains in the range of values reported in literature [27–30]. Furthermore, the authors con-firmed the very bad prognosis for patients with a negative i-PET but a positive e-i-PET.
We observed 39 patients out 395 patients with negative i-PET who then presented a positive e-i-PET at the end of thera-py. About half of these patients had a histological biopsy to confirm the persistence of disease, and in 15 of 16 patients, the histology results were positive. We succeeded in performing a retrospective centralized revision of e-PET in 17 patients; in the remaining patients, it was not possible for technical rea-sons. The revision according to new Deauville criteria showed that 16 were positive (Deauville score 4 and 5) and 1 could not be decided upon by the reviewers. Unfortunately, we did not find any association of clinical and/or pathological character-istics and the positive outcome of the PET at the end of therapy after a promising negative i-PET. The only parameter that showed a statistical significance in univariate and multivariate analysis was the elevated value of LDH at diagnosis. This data could lead one to believe that there was a histological modifi-cation or an initial diagnostic mistake in particular the possi-bility to have a composite lymphoma. The revision of diag-nostic samples and the new biopsies of positive PET nodes, even if only in half the patients, does not allow us to confirm this hypothesis. Nevertheless, a biopsy in patients with posi-tive e-pET should be considered mandatory to guide the future program having in mind false positives.
Following recent data that reported a significant asso-ciation of monocytes count at diagnosis and prognosis, we analyzed this data in 108 patients, but we did not find any differences between i-PET negative and e-PET negative or positive.
The revision of e-PET with Deauville criteria, even if not performed in all e-PET positive cases, confirms that e-PET positivity was really a progression of the disease.
Interestingly, patients with negative i-PET but with a pos-itivity at the end of therapy had a very bad prognosis; these patients had a worse prognosis in comparison with i-PET pos-itive patients, intensified with a PFS at 36 months of 76% vs. 54% and an OS at 36 months of 95% vs. 78%. Although cross-study comparisons cannot be made, at first glance, it would be notable that this difference, in term of PFS, is con-firmed in RATHL and SWOG studies [21,31]. These patients are those who we had observed in the past before the use of the interim-PET and who demonstrated chemo-refractoriness at the end of the induction therapy (after six or eight ABVD) and were very difficult to salvage. How novel agents now in use for HL (i.e., PD-1 blockade) [32] may be able to alter the natural history of these patients when incorporated into front-line therapy or used as salvage therapy following i-PET negative/e-PET positive results will be evaluated in the next future.
Conclusions
Our study, unfortunately, has not been able to identify clinical or pathological characteristics at diagnosis that could be useful to select patients who showed an apparent chemosensitivity, but who, in reality, were refractory to ABVD. LDH value at diagnosis was the only parameter associated with a significant probability to have a positive e-PET. The low number of pa-tients could account for the lack of identification of more consistent parameters and for this reason, the collection of clinical and pathological data of these patients from other prospective studies could be evaluable in the future. Moreover, a more accurate histopathological, biological anal-ysis and more accurate PET evaluation at diagnosis or at in-terim evaluation (MTV or TLG) could be useful to increase i-PET specificity to identify those patients who could then have a positive e-PET. For sure, these data confirm that we cannot omit FDG-PET at the end of therapy.
Acknowledgments The authors want to thank Mrs Lara Cox for the language revision of the manuscript.
Author’s contributions Conception and design: R.L., Z.PL.
Provision of study materials or patients: R.L., P.B., B.A., D.M., G.M., E.A., S.A., B.M., R.A., S.M., B.B., P.A., P.C., S.C., S.F., N.L., M.L., K.S., G.D., Z.P.
Collection and assembly of data: R.L., P.B., B.A., D.M., G.M., E.A., S.A., B.M., R.A., S.M., B.B., P.A., P.C., S.C., S.F., N.L., M.L., K.S., G.D., Z.PL.
Data analysis and interpretation: R.L., P.B., B.A., E.A., M.L., K.S.,Z.PL.
Manuscript writing: all authors Final approval of manuscript: all authors
Data Availability Materials are available upon request.
Compliance with ethical standards
Competing interests The authors declare that they have no competing interests
Ethics approval and consent to participate Patients signed informed consent, after internal institutional review board approval, to participate at the clinical study.
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Affiliations
Luigi Rigacci1,2 &Benedetta Puccini1&Alessandro Broccoli3&Manjola Dona4&Manuel Gotti5&Andrea Evangelista6& Armando Santoro7&Maurizio Bonfichi5&Alessandro Re8&Michele Spina9&Barbara Botto10&Alessandro Pulsoni11& Chiara Pagani8&Caterina Stelitano12&Flavia Salvi13&Luca Nassi14&Lara Mannelli1&Sofia Kovalchuk1&Daniela Gioia6& Pier Luigi Zinzani3
Benedetta Puccini bpuccini@aou-careggi.toscana.it Alessandro Broccoli alessandro.broccoli@unibo.it Manjola Dona manjiola.dona@uslcentro.toscana.it Manuel Gotti manuel.gotti@hotmail.it Andrea Evangelista andrea.evangelista@cpo.it Armando Santoro armando.santoro@cancercenter.humanitas.it Maurizio Bonfichi bonfichi@smatteo.pv.it Alessandro Re alessandro.re@asst-spedalicivili.it Michele Spina mspina@cro.it Barbara Botto bbotto@cittadellasalute.to.it Alessandro Pulsoni bce@uniroma1.it Chiara Pagani pagani@asst-spedalicivili.it Caterina Stelitano caterinastelitano27@gmail.com Flavia Salvi flaviasalvi@hotmail.com Luca Nassi luca.nassi@uniupo.it Lara Mannelli la.mannelli25@gmail.com Sofia Kovalchuk to.sofia@mail.ru Daniela Gioia dgioia@filinf.it Pier Luigi Zinzani pl.zinzani@unibo.it
1
Department of Hematology, AOU Careggi, Florence, Italy 2 Hematology Unit and Bone Marrow Transplant Unit, AO San
Camillo Forlanini, Rome, Italy 3
Institute of Hematology“L. e A. Seràgnoli”, University of Bologna, Bologna, Italy
4
Department of Nuclear Medicine, Ospedale Santo Stefano, Prato, Italy
5 Policlinico San Matteo Pavia Fondazione, IRCCS, Pavia, Italy 6
Unit of Cancer Epidemiology, AO Città della Salute e della Scienza di Torino and FIL Secretary, Turin, Italy
7
Humanitas Cancer Center, IRCCS, Rozzano, Italy
8
Department of Hematology, Spedali Civili, Brescia, Italy 9 Oncology Centre of Reference, Aviano, Italy
10
Hematology, Azienda Ospedaliero Universitaria Città della Salute e della Scienza di Torino, Turin, Italy
11
Institute of Haematology, Catholic University, Rome, Italy 12 Hematology Ospedale Bianchi Melacrino Morelli, Reggio
Calabria, Italy 13
Division of Hematology, A.O. SS Antonio e Biagio e Cesare Arrigo, Alessandria, Italy
14
Division of Hematology, Department of Translational Medicine, University of Eastern Piedmont, Novara, Italy
