Bone Marrow Transplantation (2015) 50, 706–714 © 2015 Macmillan Publishers Limited All rights reserved 0268-3369/15 www.nature.com/bmt

ORIGINAL ARTICLE

Secondary malignancies following high dose therapy and autologous hematopoietic cell transplantation-systematic review and meta-analysis I Vaxman1,2,6, R Ram2,3,6, A Gafter-Gvili2,4, L Vidal2,4, M Yeshurun2,4, M Lahav1,2 and O Shpilberg2,5 We performed a systematic review and meta-analysis of randomized controlled trials comparing autologous hematopoietic cell transplantation (HCT) with other treatment modalities to analyze the risk for various secondary malignancies (SMs). Relative risks (RR) with 95% confidence intervals were estimated and pooled. Our search yielded 36 trials. The median follow-up was 55 (range 12–144) months. Overall, the RR for developing SMs was 1.23 ((0.97–1.55), I2 = 4%, 9870 patients). Subgroup analysis of trials assessing TBI-containing preparative regimens and of patients with baseline lymphoproliferative diseases, showed there was a higher risk for SMs in patients given autografts (RR = 1.61 (1.05–2.48), I2 = 14%, 2218 patients and RR = 1.62 (1.12–2.33), I2 = 22%, 3343 patients, respectively). Among all patients, there was a higher rate of myelodysplastic syndrome MDS/AML in patients given HCT compared with other treatments (RR = 1.71 (1.18–2.48), I2 = 0%, 8778 patients). The risk of secondary solid malignancies was comparable in the short term between patients given HCT and patients given other treatments (RR = 0.95 (0.67–1.32), I2 = 0%, 5925 patients). We conclude that overall the risk of secondary MDS/AML is higher in patients given autologous HCT compared with other treatments. In the subgroup of patients given a TBI-based regimen and in those with a baseline lymphoproliferative disease, there was a higher risk of overall SMs. Bone Marrow Transplantation (2015) 50, 706–714; doi:10.1038/bmt.2014.325; published online 9 February 2015

INTRODUCTION High dose chemo/radiotherapy with autologous hematopoietic cell transplantation (HCT) has been shown to be an effective therapy for a variety of hematologic and non-hematologic malignancies. However, it has become apparent as more patients survive both the disease and the early-post HCT period, that other potential long-term complications may hamper patients’ prospects. One complication that raises great concern is the possibility of developing a secondary malignancies (SM) following a successful treatment of the primary disease. The estimated risk for SMs following autolgous HCT is 3.3 times higher compared with the risk in the general population1 with incidences of secondary myelodysplastic syndrome (MDS)/AML and lymphoma of 5–20 and 10%, respectively.2–5 While MDS and AML develop after several years (median 2.5 years), posttransplantation solid tumors have a longer latency time.6 Factors such as age o 35 years, longer interval from diagnosis to HCT,1 graft purging,7 prior alkylator therapy and topoisomerase II inhibitors and higher doses of pre-transplant irradiation have been associated with higher incidence of SMs.5,8 However, it is not clear whether these factors apply explicitly to patients given autografts or to the general population treated with chemotherapy. Thus, we aimed to perform a systematic review assembling all the available data retrieved from randomized controlled trials comparing the addition of autologous HCT with conventional chemotherapy and reporting long term secondary malignancies.

MATERIALS AND METHODS Data sources We conducted a comprehensive search strategy to identify both published and unpublished trials. We searched the Cochrane Central Register of Controlled Trials (CENTRAL) and MEDLINE (January 1966 and until 2013). We searched the following conference proceedings for trials in oncology and hematology (2002–2013): the American Society of Hematology (ASH), the American Society of Clinical Oncology (ASCO), the European Hematology Association (EHA), the American Society for Blood and Marrow Transplantation (ASBMT), the European Group for Blood and Marrow Transplantation (EBMT), and the International Society of Paediatric Oncology (SIOP). We searched the following trial databases for ongoing and unpublished trials: Current Controlled Trials in the metaRegister of controlled clinical trials and the National Institutes of Health Clinical Trials Registry. The references of all identified studies were inspected for more trials. Additionally, the corresponding author of each trial was contacted for information regarding unpublished trials or complementary information on their own trial. We used the following search term: autologous transplantation and ([bone marrow] or 86 hematopoietic or [stem cell]). For MEDLINE, we added the Cochrane highly sensitive 87 search term for identification of clinical trials.9

Study selection We included only randomized controlled trials. We included studies of patients undergoing autologous HCT for the treatment of hematological malignancies, solid tumors and non-malignant diseases (such as autoimmune diseases) that compared between autologous HCT and other treatment modalities. Trials were included irrespective of publication status, language and blinding.

1 Medicine A, Beilinson Hospital, Rabin Medical Center, Petah Tikva, Israel; 2Sackler School of Medicine, Tel Aviv University, Tel Aviv, Israel; 3BMT Unit, Sourasky Medical Center, Tel Aviv, Israel; 4Institute of Hematology, Davidoff Cancer Center, Rabin Medical Center, Tel Aviv, Israel and 5Institute of Hematology, Assuta Medical Center, Tel Aviv, Israel. Correspondence: Dr R Ram, BMT Unit, Sourasky Medical Center, Weizman Street, Tel Aviv 73134, Israel. E-mail: [email protected] 6 These authors contributed equally to this work. Received 13 September 2014; revised 16 December 2014; accepted 19 December 2014; published online 9 February 2015

Secondary cancers post autotransplant I Vaxman et al

707 We excluded trials of patients undergoing allogeneic HCT and trials that compared different preparative regimens prior to autologous HCT.

Potential relevant trials identified and screened for retrieval (2229)

Data extraction and quality assessment Two reviewers (IV and RR) independently inspected each reference identified by the search and applied the inclusion criteria. For possible relevant articles, the full article was obtained and inspected independently by the two reviewers. In the case of any disagreement between the two reviewers, a third reviewer extracted the data (AG-G). Data extraction was discussed, decisions were documented and, where necessary, the authors of the trials were contacted for clarification and complementary information on their trials.

Non-comparative trails (2155)

Full text trials retrieved for more detailed evaluation (n=74)

Publications from conference (n=3)

Trials that did not report SM (n=41)

Quality assessment Trials fulfilling the inclusion criteria were assessed for methodological quality by two reviewers (IV and RR). This was done using the criteria described in the Cochrane Collaboration's tool for assessing risk of bias.9 We separately assessed each domain and graded it as low risk of bias, unclear risk of bias or high risk of bias. In addition, sensitivity analyses were performed to assess the robustness of the findings to different aspects of the trial's methodology.

Definition of outcome The primary outcome was the overall risk for secondary malignancies in patients undergoing autologous HCT compared with other treatment modalities. Secondary outcomes included the risk of two types of specific SM: secondary MDS/AML and secondary solid tumors. We aimed to evaluate these outcomes at the longest reported time point.

Comparisons We defined the intervention as undergoing autologous HCT. The comparison intervention was defined as either no additional chemotherapy or conventional radiotherapy/chemotherapy (any therapy excluded high dose therapy and infusion of hematopoietic cells). Patients who were originally allocated to the non-transplant arm, and relapsed and were given salvaged autologous HCT were analyzed according to the intentionto-treat methodology based on the original allocated arm.

Data synthesis and analysis Dichotomous data were analyzed by calculating the relative risk (RR) for each trial with 95% confidence intervals (CI) (Review Manager Version 5, Copenhagen, the Cochrane Collaboration, 2012). RRo1 favors the interventional arm (autologous HCT), that is. risk for secondary malignancies is lower in patients given autografts. For all outcomes, we performed an intention-to-treat analysis in which we included all known events in both nominator and denominator, even if excluded from the trial’s original analysis. We assessed heterogeneity of trial results by calculating a χ2-test of heterogeneity and the I2 measure of inconsistency. We used the Mantel– Haenszel fixed-effect model for pooling trial results unless statistically significant heterogeneity was found (Po0.10 or I2450%), in which case we used a random-effects model. Heterogeneity was investigated through subgroup and sensitivity analyses as defined above.

RESULTS The search yielded 2229 potentially relevant trials, of which 74 were considered for further investigation. Of these, 41 studies were excluded of various reasons, Figure 1. In addition, three abstract proceedings were identified and also included in the analysis.10–12 Overall 36 trials, enrolling 9870 patients, conducted between the years 1987 and 2011 fulfilled the inclusion criteria.10–44 One trial reported on two cohorts of patients and for the sake of report and analysis was considered as two separate trails. The median follow-up was 55 (range 12–144) months. The median time of follow-up was 45 years in 17 trials, 3–5 years in 15 trials and o3 years in 4 trials. HCT was given for the treatment of lymphoproliferative diseases (16 trials),13–24,29,30,32 solid malignancies (16 trials)25,27,28,31,33–44 © 2015 Macmillan Publishers Limited

Comparative trials included in the meta-analysis (n=36)

Figure 1. Trial flow chart according to QUOROM (quality of reporting meta-analysis) showing flow of trials included in the meta-analysis.

and plasma cell disorders10–12,26 (4 trials). Two trials used purged autografts as the graft source.7,19 In the comparative arm (the non-transplant arm), the regimens were either observation (5 trials) or various standard radio/ chemotherapy (31 trials). Table 1 depicts the characteristics of included trials. Table 2 depicts the risk of bias assessment. Overall, the quality of included trials was moderate. Random sequence generation was adequate in 14 trials and unclear in 22 trials. Allocation concealment was adequate in 23 trials and unclear in 13 trials. All trials reported data according to the intention-to-treat principle and were considered as a low risk of bias. Primary outcome—overall secondary malignancies Overall, there was no difference in the risk of secondary malignancies between patients that received autotransplant and the comparative arm (RR = 1.23 (95% CI 0.97–1.55), I2 = 4%, 36 trials, 9870 patients), Figure 2. Subgroup analysis according to the comparative arm showed similar results when the autologous arm was compared with observation only or to other therapies (RR = 2.73 (95% CI 0.97–7.68), I2 = 0%, 5 trials, 722 patients and RR = 1.2 (95% CI 0.95–1.52), I2 = 12%, 31 trials, 9409 patients, respectively). Among the subgroup of patients with lymphoproliferative diseases there was a higher risk of secondary malignancies in patients given autografts compared with the other group (RR = 1.62 (95% CI 1.12–2.33), I2 = 22%, 16 trials, 3343 patients), Figure 2. When we excluded the two trials in which patients received purged grafts, the overall risk of secondary malignancies was similar between the two groups (RR = 1.16 (95% CI 0.78–1.72), I2 = 0%, 14 trials, 3009 patients). Subgroup analyses of patients with plasma cell disorders and solid malignancies showed similar risks of secondary malignancies between patients who were given or not given autografts ((RR = 2.02 (95% CI 0.62–6.66), I2 = 0%, 4 trials, 706 patients) and (RR = 0.97 (95% CI 0.71–1.32), I2 = 9%, 16 trials, 5821 patients), respectively)), Figure 2. In the subgroup analysis of studies given TBI-containing preparative regimens prior to autografts, there was a higher risk of secondary malignancies in patients given autografts (RR = 1.61 (95% CI 1.05–2.48), I2 = 14%, 9 trials, 2218 patients), Figure 3. When analyzing, among the lymphoproliferative diseases group, only the patients given TBI-containing regimen, there was a higher risk of secondary malignancies in patients given autografts compared with the other group (RR = 1.64 (95% CI 1.05–2.57), I2 = 32%, 7 trials, 1675 patients), while in the subgroup of patients given non-TBI containing regimens the risk for SM was similar between the Bone Marrow Transplantation (2015) 706 – 714

Secondary cancers post autotransplant I Vaxman et al

708 Table 1.

Characteristics of included studies N patients (arm1/ arm2)

N SM (arm1/ arm2)

% SM (arm1/ arm2)

Age (years)

Source of graft

Duration of f/u (median, months)

CLL CLL CLL HL HL NHL

43/39 112/111 71/203 88/73 78/82 48/50

8/7 3/1 4/5 1/0 0/1 1/2

19/18 3/1 6/2 1/0 0/1 2/4

18–60 418 18–65 16–60 18–65 17–60

PBSC PBSC PBSC PBSC or BM PBSC PBSC or BM

77 60 51.2 39 64 55

Haioun, et al.30 Kaiser et al.32 Martelli et al.21 Lenz et al.20 Vitolo et al.24 Deconinck et al.19 Olivieri et al.22 Sebban et al.18 Ladetto et al.17 Gyan et al.7 Dai10 Palumbo12 Blade et al.26

NHL NHL NHL NHL NHL NHL

125/111 158/154 75/75 195/236 60/66 86/82

0/2 2/4 0/0 5/1 2/0 10/0

0/2 1/3 0/0 3/0 3/0 9/0

o55 16–60 15–60 o60 18–60 18–60

BM PBSC or BM PBSC PBSC PBSC PBSC

54 39 24 44 78 60

NHL NHL NHL NHL MM MM MM

117/106 192/209 68/66 86/80 20/20 200/200 81/83

2/2 11/14 6/4 12/1 1/0 3/1 2/2

2/2 8/7 9/6 14/1 5/0 2/1 2/2

15–60 o61 18–60 18–60 18–60 o65 o70

PBSC PBSC PBSC PBSC NR NR PBSC

62 90 51 108 25 26 56

Jaccard11 Crump et al.28

Amyloidosis Breast cancer

50/50 112/111

1/0 1/2

2/0 1/2

NR 416

NR PBSC

36 48

Moore et al.33 Vredenburgh et al.35 Hanrahan et al.31 Nitz et al.34 Basser et al.25 Coombes et al.27 Berthold et al.36 Peters et al.37 Zander et al.38 Crown40 Rodenhui et al.41 Tallman et al.42 Bergh et al.39 Hortobagyi et al.43 Matthay44

Breast cancer Breast cancer

265/271 35/34

3/3 0/0

11/11 0/0

NR 418

PBSC or BM PBSC

70 97

BEAM CY/ etoposide/TBI Mitoxantrone/melphalan CY/TBI High dose melphalan High dose melphalan High dose melphalan or TBI/ melphalan High dose melphalan Cyclophsphamide/mitoxantrone/ carboplatin STAMP I or STAMP V STAMP 1

Breast cancer Breast cancer Breast cancer Breast cancer Neuroblastoma Breast cancer Breast cancer Breast cancer Breast cancer Breast cancer Breast cancer Breast cancer

39/39 201/202 173/171 143/138 149/146 394/391 152/155 48/45 442/443 270/270 274/251 39/39

1/0 1/0 4/1 1/2 1/1 16/20 4/8 1/0 21/15 15/9 1/13 1/0

3/0 5/0 2/1 1/2 1/1 4/5 3/5 2/0 5/3 6/3 0/5 3/0

o65 18–60 o66 o60 0–20 18–55 o60 18–60 o56 15–60 o60 o65

PBSC PBSC PBSC PBSC PBSC BM PBSC PBSC PBSC PBSC or BM PBSC PBSC or BM

144 48.6 70 68 42 90 44 52 57 73 34.4 78

CEP Epirubicin/thiotepa/CY Epirubicin/cyclophsphamide CY/carboplatin/thiotepa Melphalan/etoposid/carboplatin CY/cisplatinum/BCNU CY/thiotepa/mitoxantrone Mitoxantrone/etoposide/CY CY/thiotepa/carboplatin CY/thiotepa CY/thiotepa/carboplatin CY/ciplatin/etoposide

2/1

1/1

418

BM

Study

Baseline disease

Brion et al.13 Michallet et al.14 Sutton et al.15 Schmitz et al.23 Arkelyan et al.16 Gianni et al.29

Neuroblastoma 189/190

96

Preparative regimen

CY/TBI CY/TBI or BEAM CY/TBI BEAM BEAM TBI/Melphalan or mitoxantrone/ melphalan CBV BEAM BEAC CY/TBI Mitoxantrone/melphalan CY/TBI

Carboplatin/etoposide/melphalan/ TBI

Abbreviations: BEAC = BCNU, etoposide, cytarabine; CBV = CY, BCNU, etoposide, CY; CEP = CY, etoposide, cisplastin; f/u = follow-up; MM = multiple myeloma; NR = not reported; NHL = Non-Hodgkin's lymphoma; SM = secondary malignancy; STAMP I = CY, cisplastin, carmustine; STAMP V = CY, carboplatin; thiotepa.

2 groups (RR = 1.58 (95% CI 0.85-2.94), I2 = 21%, 9 trials, 1668 patients). Sensitivity analysis according to quality of studies including studies with a lower risk of bias according to allocation concealment, random sequence generation and studies reporting complete outcome data showed similar risks of overall SM between patients who were given autoglous HCT and those not given (RR = 1.12 (95% CI 0.85–1.48), I2 = 21%, 23 trials, 5680 patients; RR = 1.24 (95% CI 0.85–1.82), I2 = 0%, 14 trials, 3292 patients; RR = 1.17 (95% CI 0.93–1.48), I2 = 11%, 32 trials, 9180 patients, respectively). Secondary outcomes—specific secondary malignancies Secondary MDS/AML. Overall there was a higher risk for MDS/ AML in patients receiving autografts compared with patients given other therapies (RR = 1.71 (95% CI 1.18–2.48), I2 = 0%, 33 Bone Marrow Transplantation (2015) 706 – 714

trials, 8778 patients), Figure 4. Among the subgroup of patients with lymphoproliferative diseases there was a higher risk of MDS/ AML in patients given autografts compared with the other group (RR = 2.35 (95% CI 1.36–4.05), I2 = 0%, 16 trials, 3090 patients). This was also true after excluding the two studies in which patients were given purged grafts (RR = 1.83 (95% CI 1.01–3.29), I2 = 0%, 14 trials, 2756 patients). Among both plasma cell disorders and solid malignancies, there was no difference between the groups (RR = 1.41 (95% CI 0.28–7.08), I2 = 0%, 3 trials, 304 patients and RR = 1.24 (95% CI 0.72–2.15), I2 = 8%, 14 trials, 5384 patients, respectively). Subgroup analysis according to TBI-containing regimens prior to autologous HCT showed that both in patients given TBIcontaining regimens and in non-TBI containing regimens there was a higher risk of secondary MDS/AML in patients given autografts compared with patients not given autografts, albeit risk was higher in patients given a TBI-containing regimen (RR = 1.98 © 2015 Macmillan Publishers Limited

Secondary cancers post autotransplant I Vaxman et al

Table 2.

Quality assessment of included randomized controlled trials according to the Cochrane Handbook for Systematic Reviews of Interventions (Version 5.0.0, updated February 2008, http://handbook. cochrane.org/v5.0.0/)

Brion et al.13 15

Sutton et al. Gyan et al.7 Ladetto et al.17 Arkelyan et al. 16 Sebban et al.18 Olivieri et al.22 Deconinck et al.19 Vitolo et al.24 Lenz et al.20 Martielli et al.21 Schmitz et al.23 Kaiser et al.32 Haioun et al.30 Gianni et al.29 Dai10 Jaccard11 Palumbo12 Blade et al.26 Crump et al.28 Moore et al. 33 Vredenburgh et al.35 Hanrahan et al.31 Nitz et al.34 Basser et al.25 Coombes et al.27 Berthold et al. 36 Peters et al.37 Zander et al.38 Crown40 Rodenhuis et al.41 Tallman et al.42 Bergh et al.39 Hortobagyi et al.43 Matthay et al.44

Random sequence generation

Allocation concealment

Incomplete outcome data

UR LR UR LR LR UR UR LR UR LR UR LR LR LR UR UR UR UR UR LR UR UR UR LR UR LR LR LR LR LR UR UR UR UR LR UR

LR LR LR LR LR UR LR LR LR LR UR LR LR LR UR UR UR UR UR LR UR UR UR LR LR LR LR LR LR LR UR UR UR LR LR UR

LR LR LR LR LR LR LR LR LR LR LR LR LR LR LR LR LR UR LR LR LR LR LR LR LR LR LR LR LR LR LR LR LR LR LR LR

Abbreviations: LR = low risk of bias; UR = undetermined risk of bias.

(95% CI 1.02–3.83), I2 = 0%, 9 trials, 2188 patients and RR = 1.60 (95% CI 1.02–2.50), I2 = 0%, 9 trials, 6590 patients, respectively). Subgroup analysis of patients given autografts vs observationonly showed a higher risk of MDS/AML in patients allocated to autologous HCT (RR = 3.76 (95% CI 1.10–12.87), I2 = 0%, 5 trials, 692 patients). When we analyzed the subgroup of patients given autografts compared with chemotherapy/radiotherapy therapies there was also a higher risk of MDS/AML in patients given autografts (RR = 1.56 (95% CI 1.06–2.31), I2 = 0%, 26 trials, 8086 patients). Subgroup analysis according to the median period of follow-up (o 3 years, 3–5 years and 45 years) showed that in the patients with lymphoproliferative diseases in both 3–5 years and 45 years there was higher incidence of secondary MDS/AML (RR = 2.31 (95% CI 1.03–5.14), I2 = 0%, 7 trials, 1455 patients and RR = 2.38 (95% CI 1.14–5), I2 = 0%, 8 trials, 1405 patients, respectively). In patients with plasma cell disorders with a median follow-up period of o 3 years and 3–5 years there were similar risks of secondary MDS/AML between the 2 groups (RR = 3 (95% CI 0.13–69), 1 trial, 40 patients and RR = 1.01 (95% CI 0.14–7.14), I2 = 0%, 2 trials, 264 patients, respectively). Of note, none of the © 2015 Macmillan Publishers Limited

trials had a median follow-up period 45 years. In patients with solid malignancies with a median follow-up period 3–5 years there were similar risks for secondary MDS/AML between the 2 groups (RR = 1.29 (95% CI 0.32–5.18), I2 = 0%, 2746 patients, 6 trials); however at a median follow-up 45 years there was a higher incidence of secondary MDS/AML in patients given autografts compared with other treatment options (RR = 2.48 (95% CI 1.17–5.25), I2 = 0%, 9 trials, 2113 patients). Sensitivity analysis according to quality of studies including studies with a lower risk of allocation concealment, lower risk of random sequence generation and studies reporting complete outcome data showed a higher risk of MDS/AML in patients given autoglous HCT compared with those not given (RR = 1.62 (95% CI 1.04–2.52), I2 = 0%, 21 trials, 5083 patients; RR = 2.34 (95% CI 1.28–4.29), I2 = 0%, 15 trials, 3399 patients and RR = 1.69 (95% CI 1.17–2.46), I2 = 0%, 32 trials, 8678 patients, respectively). Secondary solid malignancies. Overall, the risk of secondary solid malignancies was not increased in patients that received autografts (RR = 0.95 (95% CI 0.67–1.32) I2 = 0%, 18 trials, 5925 patients). In subgroup analysis, the risk was not increased in the 3 subgroups of baseline diseases (lymphoproliferative diseases (RR = 1.06 (95% CI 0.63–1.78) I2 = 9%, 9 trials, 1871 patients), plasma cell disorders (RR = 2.05 (95% CI 0.19–22.16), 1 trial, 164 patients) and solid tumors (RR = 0.85 (95% CI 0.54–1.33) I2 = 0%, 8 trials, 3890 patients)). Subgroup analysis according to TBIcontaining preparative regimens showed similar results (RR = 1.20 (95% CI 0.64–2.16), I2 = 0%, 6 trials, 1185 patients). Subgroup analyses according to the median period of follow-up showed comparable risks between the two groups. DISCUSSION Our systematic review compiled all published randomized controlled trials assessing the risk of secondary malignancies in patients given autologous HCT, and showed that overall there was no higher risk of secondary malignancies in patients given autografts compared with patients allocating to other treatments. However, in the subgroup of patients given a TBI-based regimen and in those with a baseline lymphoproliferative disease, there was a higher risk of secondary malignancies. When we focused only on secondary MDS/AML, the risk was increased for the whole cohort, in the subgroup of patients with lymphoproliferative diseases who were given autologous HCT and in patients with solid malignancies (only in trials with 45 years of follow-up). There was no increase in secondary solid malignancies in patients given autologous HCT compared with other treatment modalities; however, for this outcome the follow-up period was relatively short. Autologous HCT has been shown to be associated with prolongation of both PFS and OS in patients with lymphoproliferative diseases and plasma cell disorders. However, the utilization of a more intensive therapy may be associated with subsequent secondary malignancies. We showed that when comparing patients given autologous HCT to patients allocating to other treatments, the overall risks of secondary malignancies were comparable. We hypothesize that the fact that both arms (transplant and non-transplant) contained high doses of anthracyclines and topoisomerase II inhibitors, contributed to the relatively even risks of developing secondary malignancies in both arms.5 Interestingly although this did not reach statistical significance, the RR for secondary malignancies was higher in the comparison of transplant arm vs observation only and was lower in the comparison of transplant arm vs non-observational treatments. We found that baseline disease may interact with the risk of secondary malignancies after autologous HCT. Patients with lymphoproliferative diseases that received autologous HCT had Bone Marrow Transplantation (2015) 706 – 714

709

Secondary cancers post autotransplant I Vaxman et al

710 Study or subgroup

HCT Events Total

Control Events Total

Weight

Risk ratio M-H, Fixed, 95% Cl

Year

Risk ratio M-H, Fixed, 95% Cl

2.1.1 Lymphoproliferative diseases Gianni, NEJM 1997 Haioun, JCO 2000 Kaiser, JCO 2002 Schmitz, Lancet 2002 Martielli, JCO 2003 Lenz, JCO 2004 Olivieri, AOO 2005 Vitolo, Hematologica 2005 Deconinck, Blood 2005 Sebban, Blood 2006 Ladetto, Blood 2008 Arkelyan, Cancer 2008 Gyan, Blood 2009 Sutton, Blood 2011 (2) Sutton, Blood 2011 Michallet, Blood 2012 Brion, BMT 2012 Subtotal (95% CI)

1 0 2 1 0 5 2 2 10 11 6 0 12 2 2 3 8

48 125 158 88 75 195 117 60 86 192 68 76 86 34 37 112 43 1600

2 2 4 0 0 1 2 0 0 14 4 1 1 4 1 1 7

50 111 154 73 75 236 106 66 82 209 66 82 80 135 68 111 39 1743

1.6% 2.1% 3.2% 0.4% 0.7% 1.7% 0.4% 0.4% 10.7% 3.2% 1.2% 0.8% 1.3% 0.6% 0.8% 5.9% 34.9%

129 83 50 20 202 355

1.6% 0.4% 0.4% 0.8% 3.2%

0.52 [0.05, 5.56] 1997 0.18 [0.01, 3.66] 2000 0.49 [0.09, 2.62] 2002 2.49 [0.10, 60.33] 2002 Not estimable 2003 6.05 [0.71, 51.36] 2004 0.91 [0.13, 6.32] 2005 5.49 [0.27, 112.14] 2005 20.03 [1.19, 336.47] 2005 0.86 [0.40, 1.84] 2006 1.46 [0.43, 4.93] 2008 0.36 [0.01, 8.69] 2008 11.16 [1.49, 83.91] 2009 1.99 [0.38, 10.39] 2011 3.68 [0.34, 39.20] 2011 2.97 [0.31, 28.15] 2012 1.04 [0.41, 2.59] 2012 1.62[1.12, 2.33]

67 44 Total events z z Heterogeneity: Chi = 19.23, df = 15 (P = 0.20); | = 22% Test for overall effect: Z = 2.59 (P = 0.010) 2.1.2 Plasma cell dyscrasia Segeren, Blood 2003 Blade, Blood 2005 Jaccard, ASH 2010 Dai, ASH 2011 Palumbo, ASH 2011 Subtotal (95% CI)

3 2 1 1 3

132 81 50 20 200 351

Total events 7 Heterogeneity: Chiz = 0.72, df = 3 (P = 0.87); |z = 0% Test for overall effect: Z = 1.16 (P = 0.25)

0 2 0 0 1

Not estimable 1.02 [0.15, 7.10] 3.00 [0.13, 71.92] 3.00 [0.13, 69.52] 3.03 [0.32, 28.88] 2.02 [0.62, 6.66]

2003 2005 2010 2011 2011

3

2.1.3 Solid tumors Matthay, NEJM 1999 Hortobagyi, JNCI 2000 Bergh, Lancet 2002 Tallman NEJM 2003 Rodenhuis, NEJM 2003 Zander, JCO 2004 Crown, AOO 2004 Peters, JCO 2005 Coombes, AOO 2005 Berthold, Lancet 2005 Vredenburgh, BMT 2006 IBCSG, JCO 2006 Nitz, Lancet 2006 Emer, Cancer 2006 Moore, JCO 2007 Crump, JCO 2008 Subtotal (95% CI)

2 1 1 15 21 4 1 16 1 1 0 4 1 1 3 1

189 39 274 270 442 152 48 394 143 149 35 173 201 39 265 112 2925

1 0 13 9 15 8 0 20 2 1 0 1 0 0 3 2

190 39 251 270 443 155 45 391 138 146 34 171 202 39 271 111 2896

0.8% 0.4% 10.8% 7.2% 12.0% 6.3% 0.4% 16.0% 1.6% 0.8% 0.8% 0.4% 0.4% 2.4% 1.6% 61.9%

2.01 [0.18, 21.99] 1999 3.00 [0.13, 71.46] 2000 0.07 [0.01, 0.53] 2002 1.67 [0.74, 3.74] 2003 1.40 [0.73, 2.69] 2003 0.51 [0.16, 1.66] 2004 2.82 [0.12, 67.40] 2004 0.79 [0.42, 1.51] 2005 0.48 [0.04, 5.26] 2005 0.98 [0.06, 15.52] 2005 Not estimable 2006 3.95 [0.45, 35.01] 2006 3.01 [0.12, 73.57] 2006 3.00 [0.13, 71.46] 2006 1.02 [0.21, 5.02] 2007 0.50 [0.05, 5.39] 2008 0.97 [0.71, 1.32]

73 75 Total events z z Heterogeneity: Chi = 15.42, df = 14 (P = 0.35); | = 9% Test for overall effect: Z = 0.22 (P = 0.82) Total (95% CI)

4876

4994 100.0%

147 122 Total events z z Heterogeneity: Chi = 35.52, df = 34 (P = 0.40); | = 4% Test for overall effect: Z = 1.74 (P = 0.08) z z Test for subgroup differences: Chi = 5.18, df = 2 (P = 0.08), | = 61.4%

1.23 [0.97, 1.55]

0.01

0.1

1

Favours [experimental]

10

100

Favours [control]

Figure 2. Forest plot—the overall risk of secondary malignancies. Black squares represent the point estimate, their size represents their wt in the pooled analysis and the horizontal bars represent the 95% CI. The black diamond at the bottom represents the pooled point estimate.

a higher risk of both overall malignancies and MDS/AML. However, they did not have a higher risk of secondary solid tumors. Conversely, patients treated due to solid malignancies or plasma cell disorders that were given autografts were not at a higher risk of overall or specific secondary malignancies. However, when we performed a subgroup analysis according to the median period of follow-up, we did find that after at least 5 years, patients with solid malignancies given autografts may be at a higher risk of secondary MDS/AML. Bone Marrow Transplantation (2015) 706 – 714

As stated above, we did not find a higher risk of secondary solid tumors among all the analyzed subgroups. However, as the latency period for solid malignancies may be prolonged and the median follow-up period of all studies was only 55 months, one may presume that after a sufficient follow-up time, 45 years, an increase in the risk of secondary tumors may be seen among patients given autografts. The higher risk of secondary malignancies in patients with lymphoproliferative diseases was shown in a large survey of the © 2015 Macmillan Publishers Limited

Secondary cancers post autotransplant I Vaxman et al

711 HCT Study or subgroup Events Total 4.1.1 Lymphoproliferative diseases

Control Events Total

Gianni, NEJM 1997 1 48 2 1 Lenz, JCO 2004 5 195 14 Sebban, Blood 2006 11 192 1 Gyan, Blood 2009 12 86 Sutton, Blood 2011 2 37 1 34 Sutton, Blood 2011 (2) 2 4 Michallet, Blood 2012 3 112 1 Brion, BMT 2012 8 43 7 Subtotal (95% CI) 747 Total events 44 31 Heterogeneity: Chi2 = 10.32, df = 7 (P = 0.17); |2 = 32% Test for overall effect: Z = 2.16 (P = 0.03)

Weight

Risk ratio M-H, Fixed, 95% Cl

50 236 209 80 68 135 111 39 928

6.3% 2.9% 43.3% 3.3% 2.3% 5.2% 3.2% 23.7% 90.4%

0.52 [0.05, 5.56] 6.05 [0.71, 51.36] 0.86 [0.40, 1.84] 11.16 [1.49, 83.91] 3.68 [0.34, 39.20] 1.99 [0.38, 10.39] 2.97 [0.31, 28.15] 1.04 [0.41, 2.59] 1.64 [1.05, 2.57]

1997 2004 2006 2009 2011 2011 2012 2012

83 83

6.4% 6.4%

1.02 [0.15, 7.10] 1.02 [0.15, 7.10]

2005

190 190

3.2% 3.2%

2.01 [0.18, 21.99] 2.01 [0.18, 21.99]

1999

1201

100.0%

1.61 [1.05, 2.48]

Risk ratio M-H, Fixed, 95% Cl

Year

4.1.2 Plasma cell dyscrasia Blade, Blood 2005 Subtotal (95% CI)

2

81 81

Total events 2 Heterogeneity: Not applicable Test for overall effect; Z = 0.02 (P = 0.98)

2 2

4.1.3 Solid tumors Matthay, NEJM 1999 Subtotal (95% CI)

2

189 189

2 Total events Heterogeneity: Not applicable Test for overall effect; Z = 0.57 (P = 0.57) Total (95% CI)

1017

1 1

34 Total events 48 2 2 Heterogeneity: Chi = 10.47, df = 9 (P = 0.31); | = 14% Test for overall effect: Z = 2.18 (P = 0.03) Test for subgroup differences: Chi2 = 0.25, df = 2 (P = 0.88), |2 = 0%

0.01

0.1 Favours [HCT]

1

10

100

Favours [control]

Figure 3. Forest plot—overall secondary malignancies—subgroup analysis in patients given TBI containing preparations. Black squares represent the point estimate, their size represents their wt in the pooled analysis and the horizontal bars represent the 95% CI. The black diamond at the bottom represents the pooled point estimate. CI = confidence interval, RR = relative risk.

EBMT, calculating the rate of secondary MDS/AML in patients with lymphoproliferative diseases to be 5% at 5 years after HCT,45 which was higher than the rate reported in non-transplant patients.46 In addition, a recent a retrospective study suggested that the rate of secondary MDS/AML is correlated with the intensity of the regimen.46 There are two main types of secondary MDS/AML—one is associated with topoisomerase II inhibitors, and usually occurs at a lag of 2–3 years from exposure, and the second is associated with previous exposure to radiation and alkylating agents, and usually occurs later, 5–7 years after therapy.47 Thus, as we showed in the subgroup of patients with baseline solid malignancies, only in studies reporting outcomes after 45 years (in which patients were given mostly alkylator-based regimens) there was association between autologous HCT and subsequent secondary MDS/AML. We identified TBI (given in all studies at a cumulative dose 410 Gy) among the whole cohort as a risk factor for both overall secondary malignancies and for secondary MDS/AML. In patients with lymphoma, radiation therapy has been considered as the most significant risk factor for developing secondary solid tumors, with the majority of secondary cancers arising either within or at the edges of radiation fields.48,49 In addition, TBI-containing regimens have been previously associated with a major impact on the incidences of secondary MDS/AML in patients given autografts.45,47 Several limitations of our study merit consideration. The included studies were heterogeneous regarding the type of patients, type of baseline diseases, the chemotherapy regimens and the conditioning protocols. To address this limitation, we performed subgroup analyses according to various domains to identify specific groups that are at a higher risk for secondary © 2015 Macmillan Publishers Limited

malignancies. In most of the studies the question of secondary malignancies was not specifically addressed as primary or secondary endpoints, thus potentially introducing incomplete data collection bias. To address this limitation, we performed sensitivity analyses in which we included only studies of high quality (low risk of bias) that reported complete data. Last, the follow-up period in the majority of the trials was not sufficient to address the question of secondary malignancies, specifically when considering secondary solid malignancies. Thus, with a prolonged follow-up, results may change. To conclude, we showed that the risk of secondary MDS/AML is increased after autologous HCT for treating lymphoproliferative malignancies and possibly also for treating solid malignancies. Lacking sufficient follow-up period, studies with a long-term follow-up are necessary to adequately evaluate the association between autologous HCT and secondary solid malignancies. When deciding to perform an autologous HCT in a patient, clinicians should balance the risks and the benefits. While taking into account the potential efficacy and long-term survival benefit of autologous HCT, considering the long-term risks such as secondary malignancies influenced by individual and therapy-related risk factors, a tailoring approach can be optimized.

CONFLICT OF INTEREST The authors declare no conflict of interest.

Bone Marrow Transplantation (2015) 706 – 714

Secondary cancers post autotransplant I Vaxman et al

712 Study or subgroup

Autologous HCT Events Total

Control Events Total

Weight

Risk ratio M-H, Fixed, 95% Cl

Risk ratio M-H, Fixed, 95% Cl

1.4.1 Lymphoproliferative diseases Arkelyan, Cancer 2008 Brion, BMT 2012

0 2

76 43

1 1

82 39

3.3% 2.4%

0.36 [0.01, 8.69] 1.81 [0.17, 19.23]

Deconinck, Blood 2005 Gianni, NEJM 1997 Gyan, Blood 2009 Haioun, JCO 2000 Kaiser, JCO 2002 Ladetto, Blood 2008 Lenz, JCO 2004 Martielli, JCO 2003 Michallet, Blood 2012 Schmitz, Lancet 2002 Sebban, Blood 2006 Sutton, Blood 2011 Sutton, Blood 2011 (2) Vitolo, Hematologica 2005 Subtotal (95% CI)

6 0 6 0 2 5 5 0 3 1 2 2 1 2

86 48 86 125 158 68 195 75 112 88 192 37 34 60 1483

0 1 1 1 2 1 1 0 1 0 4 0 1 0

82 50 80 111 154 66 236 75 111 73 209 68 105 66 1607

1.2% 3.4% 2.4% 3.7% 4.7% 2.4% 2.1% 2.3% 1.3% 8.9% 0.8% 1.1% 1.1% 41.2%

12.40 [0.71, 216.71] 0.35 [0.01, 8.31] 5.58 [0.69, 45.35] 0.30 [0.01, 7.20] 0.97 [0.14, 6.83] 4.85 [0.58, 40.44] 6.05 [0.71, 51.36] Not estimable 2.97 [0.31, 28.15] 2.49 [0.10, 60.33] 0.54 [0.10, 2.94] 9.08 [0.45, 184.27] 3.09 [0.20, 48.05] 5.49 [0.27, 112.14] 2.35 [1.36, 4.05]

83 20 50 153

3.4% 1.2% 1.2% 5.8%

0.34 [0.01, 8.26] 3.00 [0.13, 69.52] 3.00 [0.13, 71.92] 1.41 [0.28, 7.08]

23.0% 2.3%

0.05 [0.00, 0.82] 0.98 [0.06, 15.52] Not estimable

Total events 37 Heterogeneity: Chiz = 12.38, df = 14 (P = 0.58); |z = 0% Test for overall effect: Z = 3.07 (P = 0.002)

15

1.4.2 Plasma cell dyscrasia 81 20 50 151

1 0 0

2 Total events z z Heterogeneity: Chi = 1.20, df = 2 (P = 0.55); | = 0% Test for overall effect: Z = 0.42 (P = 0.67)

1

Blade, Blood 2005 Dai, ASH 2011 Jaccard, ASH 2010 Subtotal (95% CI)

0 1 1

1.4.3 Solid tumors Bergh, Lancet 2002 Berthold, Lancet 2005 Coombes, AOO 2005

0 1 0

274 149 143

9 1 0

251 146 138

Crump, JCO 2008 Emer, Cancer 2006 Hortobagyi, JNCI 2000 Matthay, NEJM 1999 Moore, JCO 2007 Nitz, Lancet 2006 Peters, JCO 2005 Rodenhuis, NEJM 2003 Tallman NEJM 2003 Vredenburgh, BMT 2006 Zander, JCO 2004 Subtotal (95% CI)

0 1 1 1 3 1 7 0 9 0 1

112 39 39 189 265 201 394 442 270 35 152 2704

0 0 0 1 3 0 4 1 0 0 0

111 39 39 190 271 202 391 443 270 34 155 2680

1.1% 53.1%

Not estimable 3.00 [0.13, 71.46] 3.00 [0.13, 71.46] 1.01 [0.06, 15.95] 1.02 [0.21, 5.02] 3.01 [0.12, 73.57] 1.74 [0.51, 5.89] 0.33 [0.01, 8.18] 19.00 [1.11, 324.82] Not estimable 3.06 [0.13, 74.50] 1.24 [0.72, 2.15]

4440

100.0%

1.71 [1.18, 2.48]

25 Total events z z Heterogeneity: Chi = 10.82, df = 10 (P = 0.37) ; | = 8% Test for overall effect: Z = 0.79 (P = 0.43) Total (95% CI)

4338

1.2% 1.2% 2.3% 6.9% 1.2% 9.3% 3.5% 1.2%

19

64 35 Total events z z Heterogeneity: Chi = 24.95, df = 28 (P = 0.63) ; | = 0% Test for overall effect: Z = 2.83 (P = 0.005) z z Test for subgroup differences: Chi = 2.66, df = 2 (P = 0.26), | = 24.8%

0.01

0.1

1

10

100

Favours [experimental] Favours [control]

Figure 4. Forest plot—the risk of secondary MDS/AML. Black squares represent the point estimate, their size represents their wt in the pooled analysis and the horizontal bars represent the 95% CI. The black diamond at the bottom represents the pooled point estimate.

REFERENCES 1 Forrest DL, Nevill TJ, Naiman SC, Le A, Brockington DA, Barnett MJ et al. Second malignancy following high-dose therapy and autologous stem cell transplantation: incidence and risk factor analysis. Bone Marrow Transplant 2003; 32: 915–923. 2 Brown JR, Yeckes H, Friedberg JW, Neuberg D, Kim H, Nadler LM et al. Increasing incidence of late second malignancies after conditioning with cyclophosphamide and total-body irradiation and autologous bone marrow transplantation for non-Hodgkin's lymphoma. J Clin Oncol 2005; 23: 2208–2214. 3 Darrington DL, Vose JM, Anderson JR, Bierman PJ, Bishop MR, Chan WC et al. Incidence and characterization of secondary myelodysplastic syndrome and acute myelogenous leukemia following high-dose chemoradiotherapy and autologous stem-cell transplantation for lymphoid malignancies. J Clin Oncol 1994; 12: 2527–2534.

Bone Marrow Transplantation (2015) 706 – 714

4 Friedberg JW, Neuberg D, Stone RM, Alyea E, Jallow H, LaCasce A et al. Outcome in patients with myelodysplastic syndrome after autologous bone marrow transplantation for non-Hodgkin's lymphoma. J Clin Oncol 1999; 17: 3128–3135. 5 Metayer C, Curtis RE, Vose J, Sobocinski KA, Horowitz MM, Bhatia S et al. Myelodysplastic syndrome and acute myeloid leukemia after autotransplantation for lymphoma: a multicenter case-control study. Blood 2003; 101: 2015–2023. 6 Ortega JJ, Olive T, de Heredia CD, Llort A. Secondary malignancies and quality of life after stem cell transplantation. Bone Marrow Transplant 2005; 35: S83–S87. 7 Gyan E, Foussard C, Bertrand P, Michenet P, Le Gouill S, Berthou C et al. High-dose therapy followed by autologous purged stem cell transplantation and doxorubicin-based chemotherapy in patients with advanced follicular lymphoma: a randomized multicenter study by the GOELAMS with final results after a median follow-up of 9 years. Blood 2009; 113: 995–1001.

© 2015 Macmillan Publishers Limited

Secondary cancers post autotransplant I Vaxman et al

713 8 Appelbaum FR, Forman SJ, Blume KG. Thomas Hematopoietic Cell Transplantation, 4th edn, Wiley-Blackwell, Hoboken, NJ, 2009. 9 Higgins JPT, Green S (eds). Cochrane handbook for systematic reviews of interventions: version 5.1.0 [updated March 2011]. The Cochrane Collaboration 2011. www.cochrane-handbook.org 2013. 10 Dai L, O'Sullivan A, Kennedy R, Abbas M, Shuai Y, Passero VA et al. A randomized clinical trial of lenalidomide and dexamethazone with and without autologous stem cell transplantation in patients with newly diagnosed multiple myeloma: interim study results. ASH Conference; 12 December 2011; San Diego, CA, USA. Abstract No. 4142. 11 Jaccard A, Moreau P, Leblond V. Autologous Stem cell transplantation versus oral melphalan and high dose dexamethasone in patients with AL (primary) amyloidosis: long term follow-up of the french multicenter randomized trial. Blood 2005; 106: 421a. 12 Palumbo P, Cavallo F, Hardan I, Lupo B, Redoglia V, Levin M et al. Melphalan \prednisone\lenalidomide versus high-dose melphalane and autologous transplantation (MEL 200) in newly diagnosed MM patients o65 years: results of randomized phase III study. ASH Conference; 11 December 2011; San Diego, CA, USA. Abstract No. 3069. 13 Brion A, Mahe B, Kolb B, Audhuy B, Colombat P, Maisonneuve H et al. Autologous transplantation in CLL patients with B and C Binet stages: final results of the prospective randomized GOELAMS LLC 98 trial. Bone Marrow Transplant 2012; 47: 542–548. 14 Michallet M, Dreger P, Sutton L, Brand R, Richards S, van Os M et al. Autologous hematopoietic stem cell transplantation in chronic lymphocytic leukemia: results of European intergroup randomized trial comparing autografting versus observation. Blood 2011; 117: 1516–1521. 15 Sutton L, Chevret S, Tournilhac O, Divine M, Leblond V, Corront B et al. Autologous stem cell transplantation as a first-line treatment strategy for chronic lymphocytic leukemia: a multicenter, randomized, controlled trial from the SFGM-TC and GFLLC. Blood 2011; 117: 6109–6119. 16 Arakelyan N, Berthou C, Desablens B, de Guibert S, Delwail V, Moles MP et al. Early versus late intensification for patients with high-risk Hodgkin lymphoma-3 cycles of intensive chemotherapy plus low-dose lymph node radiation therapy versus 4 cycles of combined doxorubicin, bleomycin, vinblastine, and dacarbazine plus myeloablative chemotherapy with autologous stem cell transplantation: five-year results of a randomized trial on behalf of the GOELAMS Group. Cancer 2008; 113: 3323–3330. 17 Ladetto M, De Marco F, Benedetti F, Vitolo U, Patti C, Rambaldi A et al. Prospective, multicenter randomized GITMO/IIL trial comparing intensive (R-HDS) versus conventional (CHOP-R) chemoimmunotherapy in high-risk follicular lymphoma at diagnosis: the superior disease control of R-HDS does not translate into an overall survival advantage. Blood 2008; 111: 4004–4013. 18 Sebban C, Mounier N, Brousse N, Belanger C, Brice P, Haioun C et al. Standard chemotherapy with interferon compared with CHOP followed by high-dose therapy with autologous stem cell transplantation in untreated patients with advanced follicular lymphoma: the GELF-94 randomized study from the Groupe d'Etude des Lymphomes de l'Adulte (GELA). Blood 2006; 108: 2540–2544. 19 Deconinck E, Foussard C, Milpied N, Bertrand P, Michenet P, Cornillet-LeFebvre P et al. High-dose therapy followed by autologous purged stem-cell transplantation and doxorubicin-based chemotherapy in patients with advanced follicular lymphoma: a randomized multicenter study by GOELAMS. Blood 2005; 105: 3817–3823. 20 Lenz G, Dreyling M, Schiegnitz E, Haferlach T, Hasford J, Unterhalt M et al. Moderate increase of secondary hematologic malignancies after myeloablative radiochemotherapy and autologous stem-cell transplantation in patients with indolent lymphoma: results of a prospective randomized trial of the German Low Grade Lymphoma Study Group. J Clin Oncol 2004; 22: 4926–4933. 21 Martelli M, Gherlinzoni F, De Renzo A, Zinzani PL, De Vivo A, Cantonetti M et al. Early autologous stem-cell transplantation versus conventional chemotherapy as front-line therapy in high-risk, aggressive non-Hodgkin's lymphoma: an Italian multicenter randomized trial. J Clin Oncol 2003; 21: 1255–1262. 22 Olivieri A, Santini G, Patti C, Chisesi T, De Souza C, Rubagotti A et al. Upfront highdose sequential therapy (HDS) versus VACOP-B with or without HDS in aggressive non-Hodgkin's lymphoma: long-term results by the NHLCSG. Ann Oncol 2005; 16: 1941–1948. 23 Schmitz N, Pfistner B, Sextro M, Sieber M, Carella AM, Haenel M et al. Aggressive conventional chemotherapy compared with high-dose chemotherapy with autologous haemopoietic stem-cell transplantation for relapsed chemosensitive Hodgkin's disease: a randomised trial. Lancet 2002; 359: 2065–2071. 24 Vitolo U, Liberati AM, Cabras MG, Federico M, Angelucci E, Baldini L et al. High dose sequential chemotherapy with autologous transplantation versus dose-dense chemotherapy MegaCEOP as first line treatment in poor-prognosis

© 2015 Macmillan Publishers Limited

25

26

27

28

29

30

31

32

33

34

35

36

37

38

39

40

diffuse large cell lymphoma: an "Intergruppo Italiano Linfomi" randomized trial. Haematologica 2005; 90: 793–801. Basser RL, O'Neill A, Martinelli G, Green MD, Peccatori F, Cinieri S et al. Multicycle dose-intensive chemotherapy for women with high-risk primary breast cancer: results of International Breast Cancer Study Group Trial 15-95. J Clin Oncol 2006; 24: 370–378. Blade J, Rosinol L, Sureda A, Ribera JM, Diaz-Mediavilla J, Garcia-Larana J et al. High-dose therapy intensification compared with continued standard chemotherapy in multiple myeloma patients responding to the initial chemotherapy: long-term results from a prospective randomized trial from the Spanish cooperative group PETHEMA. Blood 2005; 106: 3755–3759. Coombes RC, Howell A, Emson M, Peckitt C, Gallagher C, Bengala C et al. High dose chemotherapy and autologous stem cell transplantation as adjuvant therapy for primary breast cancer patients with four or more lymph nodes involved: long-term results of an international randomised trial. Ann Oncol 2005; 16: 726–734. Crump M, Gluck S, Tu D, Stewart D, Levine M, Kirkbride P et al. Randomized trial of high-dose chemotherapy with autologous peripheral-blood stem-cell support compared with standard-dose chemotherapy in women with metastatic breast cancer: NCIC MA.16. J Clin Oncol 2008; 26: 37–43. Gianni AM, Bregni M, Siena S, Brambilla C, Di Nicola M, Lombardi F et al. High-dose chemotherapy and autologous bone marrow transplantation compared with MACOP-B in aggressive B-cell lymphoma. N Engl J Med 1997; 336: 1290–1297. Haioun C, Lepage E, Gisselbrecht C, Salles G, Coiffier B, Brice P et al. Survival benefit of high-dose therapy in poor-risk aggressive non-Hodgkin's lymphoma: final analysis of the prospective LNH87-2 protocol--a groupe d'Etude des lymphomes de l'Adulte study. J Clin Oncol 2000; 18: 3025–3030. Hanrahan EO, Broglio K, Frye D, Buzdar AU, Theriault RL, Valero V et al. Randomized trial of high-dose chemotherapy and autologous hematopoietic stem cell support for high-risk primary breast carcinoma: follow-up at 12 years. Cancer 2006; 106: 2327–2336. Kaiser U, Uebelacker I, Abel U, Birkmann J, Trumper L, Schmalenberg H et al. Randomized study to evaluate the use of high-dose therapy as part of primary treatment for "aggressive" lymphoma. J Clin Oncol 2002; 20: 4413–4419. Moore HC, Green SJ, Gralow JR, Bearman SI, Lew D, Barlow WE et al. Intensive dose-dense compared with high-dose adjuvant chemotherapy for high-risk operable breast cancer: Southwest Oncology Group/Intergroup study 9623. J Clin Oncol 2007; 25: 1677–1682. Nitz UA, Mohrmann S, Fischer J, Lindemann W, Berdel WE, Jackisch C et al. Comparison of rapidly cycled tandem high-dose chemotherapy plus peripheralblood stem-cell support versus dose-dense conventional chemotherapy for adjuvant treatment of high-risk breast cancer: results of a multicentre phase III trial. Lancet 2005; 366: 1935–1944. Vredenburgh JJ, Madan B, Coniglio D, Ross M, Broadwater G, Niedzwiecki D et al. A randomized phase III comparative trial of immediate consolidation with highdose chemotherapy and autologous peripheral blood progenitor cell support compared to observation with delayed consolidation in women with metastatic breast cancer and only bone metastases following intensive induction chemotherapy. Bone Marrow Transplant 2006; 37: 1009–1015. Berthold F, Boos J, Burdach S, Erttmann R, Henze G, Hermann J et al. Myeloablative megatherapy with autologous stem-cell rescue versus oral maintenance chemotherapy as consolidation treatment in patients with high-risk neuroblastoma: a randomised controlled trial. Lancet Oncol 2005; 6: 649–658. Peters WP, Rosner GL, Vredenburgh JJ, Shpall EJ, Crump M, Richardson PG et al. Prospective, randomized comparison of high-dose chemotherapy with stem-cell support versus intermediate-dose chemotherapy after surgery and adjuvant chemotherapy in women with high-risk primary breast cancer: a report of CALGB 9082, SWOG 9114, and NCIC MA-13. J Clin Oncol 2005; 23: 2191–2200. Zander AR, Kroger N, Schmoor C, Kruger W, Mobus V, Frickhofen N et al. High-dose chemotherapy with autologous hematopoietic stem-cell support compared with standard-dose chemotherapy in breast cancer patients with 10 or more positive lymph nodes: first results of a randomized trial. J Clin Oncol 2004; 22: 2273–2283. Bergh J, Wiklund T, Erikstein B, Lidbrink E, Lindman H, Malmstrom P et al. Tailored fluorouracil, epirubicin, and cyclophosphamide compared with marrowsupported high-dose chemotherapy as adjuvant treatment for high-risk breast cancer: a randomised trial. Scandinavian Breast Group 9401 study. Lancet 2000; 356: 1384–1391. Crown JP, Leyvraz S, Verrill M. Effect of tandem highdose chemotherapy (HDC) on long-term complete remissions (LTCR) in metastatic breast cancer (MBC), compared to conventional dose (CDC) in patients (pts) who were not selected on the basis of response to prior C: Mature results of IBDIS-I. J Clin Oncol 2004; 22: 14s (abstract 631).

Bone Marrow Transplantation (2015) 706 – 714

Secondary cancers post autotransplant I Vaxman et al

714 41 Rodenhuis S, Bontenbal M, Beex LV, Wagstaff J, Richel DJ, Nooij MA et al. High-dose chemotherapy with hematopoietic stem-cell rescue for high-risk breast cancer. N Engl J Med 2003; 349: 7–16. 42 Tallman MS, Gray R, Robert NJ, LeMaistre CF, Osborne CK, Vaughan WP et al. Conventional adjuvant chemotherapy with or without high-dose chemotherapy and autologous stem-cell transplantation in high-risk breast cancer. N Engl J Med 2003; 349: 17–26. 43 Hortobagyi GN, Buzdar AU, Theriault RL, Valero V, Frye D, Booser DJ et al. Randomized trial of high-dose chemotherapy and blood cell autografts for highrisk primary breast carcinoma. J Natl Cancer Inst 2000; 92: 225–233. 44 Matthay KK, Reynolds CP, Seeger RC, Shimada H, Adkins ES, Haas-Kogan D et al. Long-term results for children with high-risk neuroblastoma treated on a randomized trial of myeloablative therapy followed by 13-cis-retinoic acid: a children's oncology group study. J Clin Oncol 2009; 27: 1007–1013. 45 Milligan DW, Ruiz De Elvira MC, Kolb HJ, Goldstone AH, Meloni G, Rohatiner AZ et al. Secondary leukaemia and myelodysplasia after autografting for lymphoma: results from the EBMT. EBMT Lymphoma and Late Effects Working Parties.

Bone Marrow Transplantation (2015) 706 – 714

46

47

48

49

European Group for Blood and Marrow Transplantation. Br J Haematol 1999; 106: 1020–1026. Eichenauer DA, Thielen I, Haverkamp H, Franklin J, Behringer K, Halbsguth T et al. Therapy-related acute myeloid leukemia and myelodysplastic syndromes in patients with Hodgkin lymphoma: a report from the German Hodgkin Study Group. Blood 2014; 123: 1658–1664. Döhner H, Estey EH, Amadori S, Appelbaum FR. Diagnosis and management of acute myeloid leukemia in adults: recommendations from an international expert panel, on behalf of the European LeukemiaNet. Blood 2010; 115: 453–474. Travis LB, Hill DA, Dores GM, Gospodarowicz M, van Leeuwen FE, Holowaty E et al. Breast cancer following radiotherapy and chemotherapy among young women with Hodgkin disease. JAMA 2003; 290: 465–475. van Leeuwen FE, Klokman WJ, Stovall M, Dahler EC, van't Veer MB, Noordijk EM et al. Roles of radiation dose, chemotherapy, and hormonal factors in breast cancer following Hodgkin's disease. J Natl Cancer Inst 2003; 95: 971–980.

© 2015 Macmillan Publishers Limited