Pre-transplant 18F-fluorodeoxyglucose positron emission ... - Nature

Bone Marrow Transplantation (2013) 48, 551–556 & 2013 Macmillan Publishers Limited All rights reserved 0268-3369/13 www.nature.com/bmt

ORIGINAL ARTICLE

Pre-transplant 18F-fluorodeoxyglucose positron emission tomography-based survival model in patients with aggressive lymphoma undergoing high-dose chemotherapy and autologous SCT S Akhtar1, AS Al-Sugair2, M Abouzied2, Y AlKadhi3, M Dingle1, M Abdelsalam1, H Soudy1, A Darwish1, A Eltigani1, TAM Elhassan1, M Nabil-Ahmed1 and I Maghfoor1 18

F-fluorodeoxyglucose positron emission tomography (FDG-PET) documented response after salvage chemotherapy has been reported to impact survival in patients with aggressive non-Hodgkin’s lymphoma, especially diffuse large B cell lymphoma (DLBCL) undergoing high dose chemotherapy and autologous SCT (HDC auto-SCT). We reviewed the impact of 19 different prognostic/ predictive factors before salvage chemotherapy and post-salvage chemotherapy FDG-PET results in patients with aggressive lymphoma and developed an FDG-PET integrated model for post-HDC auto-SCT outcome. The Fine and Gray method for competing risk analysis and a regression model was used to assess the risk associated with different factors on outcome. Fifty-five patients had FDG-PET after salvage chemotherapy; male 65%, female 45%, relapsed 55%, refractory 45%, DLBCL 82%, T cell lymphoma 18%, median age at auto-SCT 40 years, median follow-up 42.4 months. Multivariate analysis identified only positive FDGPET (P ¼ 0.04) and mediastinal involvement (P ¼ 0.05) with higher hazard rate of disease-specific death (model P ¼ 0.008) but only positive FDG-PET (P ¼ 0.01) for disease-specific events (persistent, progressive or relapsed disease). Cumulative incidence of disease-specific death for patients with 0, 1 and 2 risk factors was 5, 30 and 62%, respectively (P ¼ 0.01). Our model is significant and showed an increasing risk of failure with mediastinal involvement and post-salvage positive FDG-PET. Bone Marrow Transplantation (2013) 48, 551–556; doi:10.1038/bmt.2012.168; published online 10 September 2012 Keywords: autologous SCT; FDG-PET; non-Hodgkin’s lymphoma; diffuse large B cell lymphoma; prognostic factors; prognostic model

INTRODUCTION High dose chemotherapy and autologous SCT (HDC auto-SCT) is well-accepted therapy for patients with aggressive non-Hodgkin’s lymphoma (NHL). HDC auto-SCT has shown superior EFS and OS in patients with relapsed or refractory disease when compared with salvage chemotherapy alone.1,2 Over the past few years, there has been increasing use of 18F-fluorodeoxyglucose positron emission tomography (FDG-PET) scanning in HDC auto-SCT setting. Patients with FDG-PET positive disease after salvage chemotherapy/before HDC auto-SCT are reported to have inferior outcome.3–15 Currently, there is no comprehensive predictive model integrating FDG-PET with other clinical risk factors in this group. We are reporting our experience of pre-transplant FDG-PET results along with other prognostic factors and constructed a predictive model and its impact on outcome.

patients and/or their guardians provided informed consent for all treatments, procedures and HDC auto-SCT as per institutional requirements. This study evaluates the impact of post-salvage chemotherapy/preHDC auto-SCT FDG-PET among other prognostic/predictive factors on post-HDC auto-SCT persistent disease, progression, relapse or death in patients who underwent HDC auto-SCT. We also constructed a predictive model based on pre-transplant FDG-PET results and other prognostic factors for post-HDC auto-SCT residual/progressive disease (PD), relapse and death due to disease in these patients.

Patients All patients with relapsed or primary refractory aggressive lymphoma and diffuse large B cell lymphoma (DLBCL) who underwent HDC auto-SCT in the Section of Adult Medical Oncology were identified from the Oncology Research Unit. Paper and electronic charts were reviewed to collect required data. Before HDC auto-SCT, all patients were required to have adequate hematological, renal, hepatic, pulmonary and cardiac functions.

MATERIALS AND METHODS Study design

Definitions

This is a combined report of Institutional Research Advisory Council approved prospective trial and prospective data collection study. All

All patients were staged according to Ann Arbor/Cotswolds modification staging system. Bulky disease was defined as mediastinal mass greater

1 King Faisal Specialist Hospital and Research Center, Oncology Center, Riyadh, Saudi Arabia; 2Department of Medical Imaging Services, Section of Nuclear Medicine, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia and 3Department of Medical Imaging Services, Section of Abdominal Radiology, King Faisal Specialist Hospital and Research Center, Riyadh, Saudi Arabia. Correspondence: Dr S Akhtar, King Faisal Specialist Hospital and Research Center, Oncology Center, P.O. Box 3354, MBC# 64, Riyadh 11211, Saudi Arabia. E-mail: [email protected] and [email protected] Received 1 August 2011; revised 30 July 2012; accepted 2 August 2012; published online 10 September 2012

Pre-transplant FDG-PET in aggressive lymphoma S Akhtar et al

552 than or equal to one third of the maximum thoracic wall diameter or any mass X10 cm. International Working Group16 response criteria were used for computerized tomography (CT) scan: complete response (CR), disappearance of all lymphoma-related abnormalities; partial response, 450% reduction; no response or stable disease as less than partial response; PD as appearance of any new lesion or 425% increase in the presence of previous lesion or appearance of disease-related symptoms. Refractory disease was defined as partial response, no response/stable disease or PD after planned multiagent chemotherapy with or without radiation therapy (XRT) or relapsing within 3 months of finishing the planned treatment after achieving a CR or CR unconfirmed. For CT scan and FDG-PET, ‘positive study’ was defined as study showing evidence of disease, ‘negative study’ as study showing no evidence of disease.

FDG-PET imaging FDG-PET data of the whole body were obtained on PET-CT Discovery LS system (8 slice CT) by GE (10 patients before October 2005 were scanned on ECAT EXACT scanner, Siemens-CTI, Knoxville, TN, USA). Patients received a dose of 370–444 MBq FDG intravenously and scanned from mid-thigh to the crown upwards starting 90 min after injection. The measured axial field of view extended over 45 cm (3 bed positions). Fortyseven overlapping slices per bed position were acquired. Corrections for attenuation were based on measured transmission scans. Positive FDGPET was defined as any focal or diffuse area of increased activity in a location incompatible with normal anatomy/physiology and suspect for residual disease on visual assessment. Mediastinal blood pool structure activity was used as a reference for normal uptake for residual masses 42 cm. ‘Positive’ results were semi-quantitatively investigated using the standardized uptake value.

Statistical analysis Statistical analysis aims to estimate the hazard rate associated with a group of 19 predictive factors as shown in Table 3. The study included two predictive models; the first, modeled the hazard associated with the predictive risk factor of disease-specific events after HDC auto-SCT (persistent disease, disease progression or recurrence) and the second, modeled the associated risk of disease-specific death (dying of disease) after HDC auto-SCT. Treatment-related mortality and death in remission were considered as competing events. Competing risk analysis was performed. Cumulative incidence function was used in estimating the probability of failure. The hazard associated with the proposed predictive risk factors was modeled using the subdistribution hazard model proposed by Fine and Gray.17 The two proposed models studied the same group of predictive risk factors. The time frame used in modeling the disease-specific event or death was defined as time since transplant up to the occurrence of event or death respectively or last follow-up. Univariate analysis using the competing risk regression model was performed for all the proposed risk factors. Covariates that achieved a significance level of o0.2 were taken to the multivariate model. The multivariate model was built using the backward method. Table 3 illustrates the results obtained by univariate and multivariate analysis using the Fine and Gray Model. Probability of disease-specific event and death for patients with 0, 1, 2 risk was also calculated for the model. Statistical analysis was performed using R 12.2 (free statistical software by http://www.r-project.org, available at http://cran.r-project.org/ 18 mirrors.html).

Salvage chemotherapy, HDC and stem cell mobilization ESHAP (etoposide, solumedrol, cisplatin and Ara-C) was primarily used as salvage chemotherapy and also for mobilization regimen for stem cell collection as we have reported previously.19 BEAM was used as HDC.

Response evaluation and post-HDC auto-SCT evaluation Patients on primary chemotherapy (CHOP in 47 (85%) had clinical and radiological response evaluation in the middle and at the end of planned initial treatment. After starting salvage chemotherapy, all patients had response evaluation after 2–3 cycles of ESHAP or rituximab þ ESHAP chemotherapy. Patients had restaging imaging evaluation after HDC autoSCT at B100 days to check the disease status and also when clinically required. Bone Marrow Transplantation (2013) 551 – 556

Prognostic factors evaluation Prognostic factor data were collected both at the time of diagnosis and before the initiation of salvage chemotherapy (after relapse, induction failure or progression) as described in the statistical section and shown in Table 1 and their significance in as shown Table 3.

RESULTS Patients’ characteristics Patients’ characteristics before the initiation of salvage chemotherapy are shown in Table 1. From January 2003 to September 2011, 85 consecutive patients with biopsy-proven aggressive lymphoma underwent HDC autoSCT. Of these, 55 patients had FDG-PET after salvage chemotherapy/before HDC auto-SCT. Forty-five patients (82%) had DLBCL. Eight patients (15%) had anaplastic large cell lymphoma (T cell), one panniculitis-like T cell lymphoma and one peripheral T cell lymphoma not otherwise specified. Median age was 40 years at the time of HDC auto-SCT (14–63 years). Five patients were p21 years old and nineteen were 14–30 years. Only four patients were 460 years (60.35, 60.7, 61 and 62.7 years). In all, 19 out of 45 DLBCL patients had rituximab þ CHOP as first-line therapy. Tissue confirmation at relapse or progression was obtained in 39 (71%) patients. This was 90% for relapsed patient as compared with 48% for refractory patients (P ¼ 0.001). Sixteen patients with no biopsy confirmation had unequivocal clinical/radiological evidence of relapse (three patients) or refractory/PD (thirteen patients). These 16 patients with no biopsy had stages II (4/16), III (5/16) and IV (7/16) before the initiation of salvage chemotherapy. Fourteen out of thirty-three patients who received rituximab þ ESHAP also had rituximab þ CHOP as first-line therapy. Diseasespecific EFS for DLBCL patients who received only CHOP and then rituximab þ ESHAP (20 patients) was 70% as compared with 64% (P ¼ 0.73) for those who had rituximab þ CHOP and then rituximab þ ESHAP (14 patients). Due to the small number of patients, further analysis is not performed. Table 1.

Patients’ characteristics before salvage chemotherapy

Male Female Age 14–30 years DLBCL T cell lymphoma Prior rituximaba Prior radiation therapy Stage I and II Stage III and IV Biopsy before salvage Relapsed Refractory disease Extranonal involvement Spleen involvement Bulky disease Mediastinum involvement Performance status 0-1 Elevated lactic dehydrogenase aa-IPI, 0-1b aa-IPI, 2-3b B symptoms ESHAP as salvage Rituximab þ ESHAPa Bone marrow þ

All patients

Percentage

36 19 18 45 10 19 14 14 41 39 30 25 28 15 10 20 41 22 28 23 15 51 33 7

65 35 33 82 18 35 26 26 75 71 55 45 51 27 18 36 75 40 51 49 27 93 60 13

Abbreviations: DLBCL ¼ diffuse large B cell lymphoma; ESHAP ¼ etoposide, solumedrol, cisplatin and Ara-C; aa-IPI ¼ age adjusted international prognostic index. aFor total of 45 diffuse large B cell lymphoma patients. b Age adjusted international prognostic index at the time of salvage chemotherapy (four patients with missing data).

& 2013 Macmillan Publishers Limited


553 Before February 2005, FDG-PET was not part of routine care and only 5 out of 23 patients who had FDG-PET are included. From February 2005 to September 2011, FDG-PET was part of

Table 2.

Response to treatment and follow-up

Disease status after auto-SCT

cCR CR PR Overall responsea PD

All patients

FDG-PET negative

Total

%

Total

%

Total

%

28 15 1 44 10

51 27 2 80 18

27 3 0 30 2

82 9 0 91 6

1 12 1 14 8

4 54 4 63 36

FDG-PET reading All FDG-PET were reviewed by two experienced nuclear medicine experts (A Al-S and MA) as per uniformed guidelines. CT scan was reported as per institutional guidelines and scans were re-reviewed when needed by one body CT expert (Y Al-K).

67 69 31 22 2 9

27 24 9 4 — 3

82 73 27 12 — 9

12 14 8 8 1 2

55 64 36 36 4 9

29

5

15

11

50

Post-HDC auto-SCT evaluation and follow-up Post-HDC auto-SCT evaluation results are shown in Table 2. Median follow-up of all alive patients from auto-SCT is 42.5 months (5–133 months). After HDC auto-SCT, 43 (78%) patients were in CR. Twenty-eight (50%) of these patients were already in CR as a result of ESHAP chemotherapy. PD was observed in 10 (18%) patients. At the time of current evaluation in June 2012 (Table 2), 36 patients (66%) are still in CR. For the entire group, median disease-specific EFS and OS have not reached yet.

Last evaluation, 01 June 2012 CR/cCR 37 Total alive 38 17 Deadb Dead of disease 12 Alive with disease 1 Relapsed after auto5 SCT Total disease specific 16 events

FDG-PET positive

Abbreviations: auto-SCT ¼ autologous stem cell transplant; CR ¼ complete remission; cCR ¼ continued complete remission; FDG-PET ¼ 18F-fluorodeoxyglucose positron emission tomography; PD ¼ progressive disease; PR ¼ partial response. aOne patient died before any evaluation. bThree patients died of treatment-related mortality and two patients died in remission due to unrelated causes.

Table 3.

routine care and 50 out of 62 patients are included. The main reason for not having FDG-PET after 2005 was closure of the cyclotron facility for repair/installation of a new cyclotron. Some patients were unable to get FDG-PET as they were referred from outside after completing all salvage treatment and radiological work-up excluding FDG-PET. From July 2005 to June 2007, 34 patients included in this analysis were enrolled in a prospective study evaluating FDG-PET before HDC auto-SCT. All these patients followed the same treatment guidelines and treatment was approved in the stem cell meeting.

FDG-PET negative after salvage chemotherapy and outcome after HDC auto-SCT Thirty-three patients were FDG-PET negative after salvage chemotherapy. Of these 33 patients, 15 (45%) had negative CT

Univariate and multivariate analysis of factors at the time of relapse/before the initiation of salvage chemotherapy

Covariates

Estimates Disease-specific event HR (95% CI)

Univariate analysis Gender Age up to 30 years vs 430 R-CHOP vs CHOPa DLBCL vs T cell Prior radiation therapy vs no Stage I-II vs III-IV Tissue confirmation vs no Refractory vs relapsed CT positive vs negative Extranodal involvement vs no Spleen involvement vs no Bulky disease vs no Mediastinal involvement vs no PS 0,1 vs higher Elevated lactic dehydrogenase vs no Age adjusted IPI 0-1 vs 2-3 B symptoms vs no R-ESHAP vs ESHAPb PET positive vs negative Multivariate analysis PET positive vs negative Mediastinal involvement vs no

1.19 0.6 1.1 1.17 0.95 0.6 0.6 1.6 1.8 1.2 1.1 1.2 2.1 0.99 0.74 0.99 2.2 1.4 3.9

Disease-specific death P-value

(0.4, 3.2) (0.2, 1.8) (0.3, 3.2) (0.34, 4) (0.3, 2.7) (0.2, 1.8) (0.2, 2.4) (0.5, 4.2) (0.5, 6) (0.4, 3.1) (0.3, 3.4) (0.3, 4.6) (0.7, 5.5) (0.2, 3.7) (0.2, 2.2) (0.5, 1.6) (0.8, 6.3) (0.4, 4.5) (1.3, 11.1)

0.7 0.4 0.8 0.8 0.9 0.4 0.5 0.3 0.3 0.7 0.8 0.8 0.1 0.9 0.6 0.9 0.1 0.5 0.01

3.9 (1.3, 11.1) —

0.01 —

HR (95% CI) 0.5 0.9 1.04 1.11 1.1 0.65 0.9 1.9 2.1 1 1.6 1.5 3.6 1.v2 1.3 1.3 1.9 1.8 3.4

(0.2, 2) (0.2, 3.1) (0.3, 3.6) (0.26, 4.8) (0.2, 3.8) (0.2, 2.1) (0.2, 3.1) (0.6, 5.9) (0.4, 9.6) (0.3, 3) (0.4, 5.3) (0.38, 6.1) (1.1, 12.2) (0.3, 4.5) (0.4, 4.5) (0.7, 2.3) (0.6, 5.9) (0.5, 6.4) (1.01, 11.5)

3.4 (1.1, 10.5) 3.4 (0.96, 12)

P-value 0.3 0.9 0.9 0.9 0.9 0.4 0.8 0.25 0.3 0.99 0.4 0.5 0.04 0.7 0.6 0.4 0.25 0.3 0.04 0.04 0.05

Abbreviations: CI ¼ confidence interval; CT ¼ computerized tomography; DLBCL ¼ diffuse large B cell lymphoma; ESHAP ¼ etoposide, solumedrol, cisplatin and Ara-C; HR ¼ hazard ratio; IPI ¼ age adjusted international prognostic index; PET ¼ positron emission tomography; PS ¼ performance status. aOnly for 45 patients with DLBCL and with first-line chemotherapy. bFor 45 patients with DLBCL.


Bone Marrow Transplantation (2013) 551 – 556


554 scan and 18 (55%) had positive CT scan. After HDC auto-SCT, 7 FDG-PET negative patients (21%) had a disease-specific event. FDG-PET positive after salvage chemotherapy and outcome after HDC auto-SCT Twenty-two patients were FDG-PET positive after salvage chemotherapy. Of these, 21 (95%) also had positive CT scan. After HDC auto-SCT, 10 FDG-PET positive patients (45.5%) had a disease-specific event. The impacts of mediastinal involvement and FDG-PET positivity on disease-specific events and diseasespecific death with their P-values are provided in Figure 1. No patient received XRT between salvage chemotherapy and HDC auto-SCT. In all, 6 (27%) out of 22 FDG-PET positive patients as compared with 8 (24%) out of 33 FDG-PET negative (P ¼ 0.8) received XRT post-HDC auto-SCT. Prognostic model development and outcome Statistical section provides the details of prognostic model development. Univariate analysis for disease-specific event

included 19 factors, only 3 factors (B symptoms, mediastinal involvement and FDG-PET positive vs negative) showed a P-value of o0.2 and hence included into the multivariate model (Table 3). FDG-PET was the only significant predictive factor for disease-specific event, HR ¼ 3.9(1.3–11.1), P-value ¼ 0.01. Univariate analysis included the same group of risk factors for disease-specific death. FDG-PET positive vs negative and mediastinal involvement were the only significant factors, P-value was o0.2 and hence included into the multivariate analysis (Table 3). Both remained significant (Figure 1). Multivariate model revealed a significant P-value of 0.008. Models were developed using a 95% confidence level. Each patient was then given a score of 0, 1 or 2 depending upon the number of these significant risk factors. Probability of disease-specific death at 5 year for patients with 0, 1, 2 risk factors was 5, 30 and 62%, respectively (P ¼ 0.01 and confidence interval 3–3.9%, 25.7–34.3% and 49.4–74.6%, respectively). This scorebased analysis indicates increasing risk of treatment failure for higher scores.

Disease specific events, all patients

1.0

Disease specific event by PET results

1.0

0.8

0.8

0.6

0.6

P-value=0.009

0.4

PET +ve

46%

PET -ve

18%

0.4

Event of interest

29%

0.2

0.2

Competing event

9%

0.0

0.0

Months

0

Pts. at risk

55

10

20

30

50

40 18

28

60

Months

0

8

PET +ve pts at risk

22

11

8

4

PET -ve pts at risk

33

17

10

4

Disease specific death, all patients

1.0

0.8

0.6

0.6

20

40

30

50

60

Disease specific death by PET results

1.0

0.8

10

P-value= 0.03

0.4 0.2

0.2

Competing event

10

20

30

40

50

60 9

19

31

55

Disease specific death by mediastinum result

1.0 0.8

Months PET +ve pts at risk

0 22

PET -ve pts at risk

33

10

0.6

50

0.8

P -value=0.01

60 5 4

10

Disease specific death by 0,1,2 risk factors

2 risk factors

62%

1 risk factor

30%

0 risk factor

5%

48%

0.4

0.4

0.2

0.2

Mediastinum -ve

40 9

30

1.0

0.6 Mediastinum +ve

20 12 19

P -value=0.02

12%

0.0 Months

17%

PET -ve

9% 0.0

0

Pts. at risk

39%

25%

0.0 Months

PET +ve

0.4 Event of interest

0.0 0

10

20

30

40

50

60

Med+ve pts at risk 20

10

5

3

Med+ve pts at risk 33

20

14

6

Months 0 2 factors, pts at risk 9

10

20 3

30

40 2

50

60 1

1 factor, pts at risk

23

15

10

6

0 factor, pts at risk

21

11

7

3

Figure 1. Probability of cumulative incidence of disease-specific event (persistent disease, progression or relapse after HDC auto-SCT) and disease-specific death. (a) Disease-specific event for all patients. (b) Disease-specific event for FDG-PET negative vs positive patients. (c) Diseasespecific death for all patients. (d) Disease-specific death for FDG-PET negative vs positive patients. (e) Disease-specific death for no mediastinal involvement vs. mediastinal involvement. (f) Disease-specific death for patients with 0, 1 and 2 factors. All percentages are rounded. Bone Marrow Transplantation (2013) 551 – 556



555 DISCUSSION King Faisal Specialist Hospital and Research Center is a major transplant center, performing 4250 transplants every year. All aggressive lymphoma patients 14 years or older are seen and managed by adult oncologists. Patients with relapsed or refractory disease at other institutions are referred here for HDC auto-SCT. Due to this referral bias, almost 50% of our patients had HDC autoSCT for refractory disease. There is emerging data indicating that patients with positive FDG-PET after salvage chemotherapy/before HDC auto-SCT have poor outcome as compared with patients with negative FDG-PET. Main limitation is relatively small numbers of patients and diverse histology and management. Many reports combined Hodgkin’s and NHL together. In addition, only this, large number of reports combined patients with DLBCL, follicular NHL, mantle cell lymphoma and other aggressive NHL. Studies reporting 30 or more ‘aggressive NHL’ in this setting are limited.3–5,7–9,12,13,15 Most commonly reported adverse factors are short duration of CR, elevated lactic dehydrogenase, extranodal disease, mediastinal mass, poor response to salvage chemotherapy, presence of B symptoms, poor performance status, bulky disease and primary induction failure. Almost all studies have reported significantly inferior PFS in patients who have positive FDG-PET pre-transplant patients as compared with a negative FDG-PET. Schot et al.12 reported 101 patients, 77 of whom underwent HDC auto-SCT and integrated FDG-PET with other prognostic factors. This study reported the impact of prognostic factors; second age adjusted international prognostic score and relapsed Hodgkin’s prognostic score (rHPS) along with FDG-PET response. The patients were scored for three risk factors and outcome tabulated against FDG-PET CR, PR and no response. Although non-transplant patients were included in the analysis, the results revealed that patients with 2–3 risk factors and a positive pre-transplant FDG-PET had dismal prognoses. Hoppe et al.8 (83 DLBCL patients only) reported PFS of 48% for FDG-PET positive vs 77% for FDG-PET-negative patients (estimated from Kaplan–Meier graph as percentages are not reported). Multivariate analysis showed better PFS with negative FDG-PET, no extranodal disease and having involved field XRT as significant factors. Factors predicting a better OS were negative FDG-PET, no extranodal disease and TBI as conditioning, gender (P ¼ 0.051) and involved field XRT (P ¼ 0.059) in this study. We came across only two negative studies in auto-SCT setting, Stefani et al.20 reported 60 patients and failed to show any significance of pre-transplant negative FDG-PET. This is still in the abstract form and details are not available. This study also included 17 Hodgkin’s lymphoma in addition to 13 NHL patients transplanted in first complete remission. The reported OS was 78.1 vs 60.2% and PFS of 62.9 vs 60.4% for FDG-PET negative vs positive group, respectively. Roland et al.5 used BEAM with and without Zevalin and failed to show any significance of negative FDG-PET (81 vs 88% P ¼ 11 for PFS and OS 88 vs 92% P ¼ 0.68). In most of the studies, a negative FDG-PET after salvage chemotherapy has been reported as a predictor for better PFS (66–96%) as compared with a positive FDG-PET scan (23–35% PFS) and in some studies, even for OS (77– 100 vs 39–61%, respectively).3,4,7,9,13,15 Recently, there have been some reports of FDG-PET in reduced intensity or full allogeneic transplant. Four of these studies failed to show any impact of FDG-PET results21–24 while only one showed a negative effect of FDG-PET positivity in this setting.25 As the treatment setting is completely different, we will not discuss this. Our report supports previous studies reporting a negative impact of FDG-PET positivity before HDC auto-SCT both on disease-specific event and on mortality. Our data are from a large single institution PDG-PET pre-HDC auto-SCT data reporting the outcome of relapsed or refractory aggressive lymphoma. Our report includes a uniform data set including patients with aggressive lymphoma treated uniformly with ESHAP/R-ESHAP & 2013 Macmillan Publishers Limited

salvage and BEAM as HDC. Our study has some limitations like other studies: a large number of high risk/refractory patients due to referral bias and changing salvage from ESHAP to R-ESHAP. We analyzed a large number of prognostic factors in the setting of FDG-PET use including R-ESHAP vs ESHAP and age adjusted international prognostic index. Our results show the significance of this model (P ¼ 0.008). Prospective studies with an appropriate sample size to validating this model should be the next step. Our model, or any other, after validation, can be used for selecting potential high risk patients for clinical studies. With time, use of R-CHOP, R-Salvage, R-maintenance and other newer strategies will create multiple diversely treated groups of patients for similar conditions and this will make it difficult to find a uniform group in retrospective setting. CONFLICT OF INTEREST The authors declare no conflict of interest.

ACKNOWLEDGEMENTS We appreciate Ms Ruqaya Belkhedim, Mr Fayez Abu Zeid and Ms Fadia Mansour from BMT clinic, Mr Edgardo Colcol and Riad Youniss from Oncology Research Unit for their valuable contribution. Author contributions: SA was the principal investigator, designed research, collected data, analyzed and interpreted data, wrote the manuscript. A Al-S and M Abu collected data, read PET scans and critically reviewed/provided input for manuscript; YA collected data, read CT scans and critically reviewed/T Elhassan performed statistical analysis and wrote statistical portion of the manuscript. M Abd, MD, HS, M Nabil-A, AD and AE collected data and critically reviewed/provided input for manuscript; IM designed research, collected data, interpreted data, helped in manuscript writing.

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APPENDIX 1. Akhtar S, Al-Sugair A, Al Kadhi Y, Al-Zahrani A, Abdelsalam M, Bazarbashi S, Ajarim D, Maghfoor I. Prospective evaluation of 18 F-fluorodeoxyglucose (FDG) positron emission tomography as a predictor of residual disease and subsequent relapse in patients with diffuse large cell lymphoma and Hodgkin’s lymphoma undergoing HDC and ASCT. Transplantation 2008; 4 (supplemental 1): S213, Abstract O 262. 34th Annual Meeting of the European Group for Blood and Marrow Transplantation. 30 March–02 April 2008, Florence, Italy. 2. Akhtar S, Al-Sugair A, Abuzaid M, Al Kadhi Y, Dingle M, Abdelsalam M, Soudy H, Darwish A, Altijani A, Nabil M, Maghfoor I. 18 F-fluorodeoxyglucose (FDG) positron emission tomography (PET) prior to high dose chemotherapy and autologous stem cell transplant predicts outcome after ASCT in patients with diffuse large cell lymphoma and Hodgkin’s lymphoma. Results of 110 patients. European Group for Blood and Marrow Transplantation 36th Annual Congress (EBMT) 2010, Vienna, Austria, 21–24 March 2010. Bone Marrow Transplantation 2010; (45)S2: S247, Abstract P819. 3. Akhtar S, Al-Sugair A, Abuzaid M, Al Kadhi Y, Dingle M, Abdelsalam M, Soudy H, Darwish A, Eltigani A, Nabil M, Maghfoor I. A new pre-transplant predictive model for event-free survival incorporating functional imaging using FDG-PET in lymphoma patients undergoing HDC and ASCT. European Hematology Association 15th Congress, 10–13 June 2010. Barcelona, Spain. Hematologica 2010; 95: S2; 208–209, Abstract 0510.
