Early relapse and refractory disease remain risk factors in theanthracycline and autologous transplant era for patients withrelapsed/refractory classical Hodgkin lymphoma: a single centreintention-to-treat analysis

High-dose therapy with autologous stem cell rescue (HDT/

ASCR) has become the standard of care for younger

(<60 years) patients failing first-line treatment for classical

Hodgkin lymphoma (CHL) (Linch et al, 1993; Schmitz et al,

2002). A course of salvage chemotherapy prior to this is now

the standard and response to it is the major determinant of

eventual outcome, with refractoriness to salvage therapy

conferring dire outcome regardless of subsequent transplant

(Sureda et al, 2001). Positron emission tomography -defined

remission confirms this finding, with patients having evidence

of fludeoxyglucose uptake at the time of HDT/ASCR having a

poorer outcome (Moskowitz et al, 2010). It is usually accepted

that early relapses (ER: within 12 months) and disease that

fails to respond completely to first-line therapy (FTF) confer a

poorer prognosis than later relapses (LR). However some

groups report similar outcomes comparing these groups

(Smith et al, 2011). Of note, most of these analyses are

performed once patients have reached HDT/ASCR (Chopra

et al, 1993; Nademanee et al, 1995; Horning et al, 1997;

Sweetenham et al, 1999; Majhail et al, 2006) rather than by

intention-to-treat (ITT) (Ferme et al, 2002), which limits the

true extent of conclusions that can be drawn on the relative

risk of ER/FTF compared to the LR patients, by selecting the

good-risk group of patients who have responded to salvage

treatment and reached HDT/ASCR.

Optimal salvage therapy has never been determined due to

the absence of large-scale randomized controlled trials. The

intensity, duration and number of lines of non-cross resistant

therapies given prior to transplant varies among centres and

hence, no consensus has been reached. This contrasts with the

relative homogeneity of first-line treatments (ABVD [doxoru-

bicin, bleomycin, vinblastine, dacarbazine] or BEACOPP

[bleomycin, etoposide, adriamycin, cyclophosphamide, vin-

cristine, procarbazine, prednisolone]), the accepted need for

HDT/ASCR in second remission, and the frequent use of

BEAM (BCNU [carmustine], etoposide, cytarabine, melpha-

lan) as the conditioning regimen. Comparison of salvage

regimens is difficult owing to small patient cohorts reported by

individual centres and failure to analyse by ITT but only

reporting outcomes on patients who reach HDT/ASCR.

Since introducing anthracycline-based primary therapy for

younger patients, St Bartholomew’s Hospital, London has used

a relatively non-intense, well tolerated alkylating agent and

steroid-based oral therapy (ChlVPP: chlorambucil, vincristine,

Paul Greaves,1 Andrew Wilson,1 Janet

Matthews,1 Daniel L. P. Brown,2 Rebecca

Auer,1 Silvia Montoto,1 T. Andrew Lister1

and John G Gribben1

1Centre for Haemato-Oncology, Barts Cancer

Institute, Queen Mary University of London,

London, UK and 2School of Electronic Engineering

and Computer Science, Queen Mary University of

London, London, UK

Received 2 November 2011; accepted for

publication 29 November 2011

Correspondence: Paul Greaves, Centre for

Haemato-Oncology, Barts Cancer Institute,

Queen Mary University of London,

Charterhouse Square, London EC1M 6BQ, UK.

E-mail: p.greaves@qmul.ac.uk

Summary

An intention-to-treat (ITT) analysis was performed in 103 unselected

patients with relapsed/refractory classical Hodgkin lymphoma (CHL)

comparing early relapse (<12 months) or failure of first-line therapy (ER/

FTF) with late relapses (LR). Seventy one percentage proceeded to high-dose

therapy/autologous stem cell rescue (HDT/ASCR) following salvage

treatment. By ITT, 5-year overall survival (OS) was 50% for ER/FTF

compared to 73% for LR patients (P = 0Æ012). However OS was equivalent

for both groups if salvage treatment response was adequate to proceed to

HDT/ASCR. ER/FTF patients remain a high-risk group largely due to a

failure of salvage therapy: a point at which novel interventions could impact

survival.

Keywords: Hodgkins lymphoma, transplant, chemosensitivity.

short report

ª 2012 Blackwell Publishing Ltd First published online 9 January 2012British Journal of Haematology, 2012, 157, 201–204 doi:10.1111/j.1365-2141.2011.08993.x

procarbazine, prednisolone) as its mainstay of first-line

salvage, given to almost half of all patients during this period.

We carried out a retrospective survival analysis by ITT with

HDT/ASCR (following salvage therapy) of all patients eligible

for HDT/ASCR measured from the point of commencement of

salvage therapy.

Patients and methods

One hundred and three consecutive human immunodeficiency

virus-negative patients under 60 years of age (38% female)

treated between 1995 and 2008 were eligible for analysis. All

patients had received ABVD or an anthracycline-containing

hybrid chemotherapy as first-line treatment. Patients who had

not received the maximum cardiac-tolerated cumulative dose

of anthracycline (400 mg/m2) as their first-line therapy were

given further anthracycline as initial salvage, whereas the

remainders were treated with ChlVPP, as previously reported

(McElwain et al, 1977), or other regimens. Failure to respond

adequately to 2–4 cycles of ChlVPP lead to a change in therapy;

patients failing to achieve at least a partial response (PR-<50%

response by computerized tomography criteria) following this

were discouraged from pursuing myeloablative treatment due

to the extremely poor outcomes. Stem cells were collected early

in salvage therapy. ER was defined as a complete response (CR)

lasting <12 months and FTF as achieving less than a CR

following first-line therapy. OS was defined as the time from

commencement of first salvage therapy for relapse until death

from any cause. Differences in survival based on Kaplan Meier

analysis were determined by the log-rank method with

significance set at the 0Æ05 level.

Results and discussion

Median age at salvage was 31 years (range: 18–59) and the

median follow-up was 8 years (range: 2–15). Fifty-four (52%)

patients received their initial chemotherapy at another centre

and were then referred to this tertiary centre for salvage. Forty-

one (40%) patients had ER/FTF of whom 16 (39%) were

treated with ChlVPP. The remaining 62 had a LR of whom 32

(52%) received ChlVPP as salvage.

ChlVPP was given as first-line salvage treatment in 48

patients (47%). Thirty-seven patients (36%) had not received

cumulative dose-ceiling anthracycline and were given further

anthracycline as part of the salvage therapy: ABVD in 17

patients (17% of all patients), VAPEC-B (vincristine, doxoru-

bicin, prednisolone, etoposide, cyclophosphamide, bleomycin)

in 13, ChlVPP/EVA (ChlVPP/etoposide, vinblastine, doxoru-

bicin given in alternating cycles) in five, and Stanford-V

(doxorubicin, vinblastine, mechlorethamine, vincristine, bleo-

mycin, etoposide, prednisolone) in two. GeM-P (gemcitabine,

methylprednisolone, cisplatin) was given as first-line salvage in

8 patients during participation in a Phase II clinical trial, while

10 received other regimens. Eight patients who eventually

achieved an adequate response to proceed to BEAM required

more than one line of salvage (11% of all patients receiving

BEAM). Successful second-line salvage treatment was with

Gem-P in three patients, VAPEC-B in three patients, and EVA

in two patients. Thirty of 48 (63%) patients who received

ChlVPP as initial salvage treatment achieved a sufficient

response to proceed to HDT/ASCR. The response rate to this

salvage therapy (CR + PR = 70%) is comparable to other

more intensive regimes (Santoro et al, 2007).

Of the 32 LR patients receiving ChlVPP salvage, 26 (80%)

reached transplant whereas only four (25%) of the 16 ER/FTF

patients proceeded to transplant. Comparison with the group

not receiving ChlVPP is difficult because all patients receiving

ABVD as their primary therapy received ChlVPP salvage,

whereas patients who received an anthracycline-based salvage

had received ChlVPP/EVA or VAPEC-B initial therapy. Hence

the ChlVPP-salvaged group may represent a higher-risk cohort:

being unsuccessfully treated with ABVD in the first instance.

The small numbers in each subgroup, heterogeneity of salvage

therapy in the non-ChlVPP group and probable difference in

disease relapse characteristics between the ChlVPP and non-

ChlVPP groups as described above, means that any formal

comparison of outcome between these two groups is statisti-

cally underpowered. With this caveat acknowledged, we report

that of the LR patients who received non-ChlVPP salvage, 24/

30 (80%) were able to proceed to transplant, compared to 16/

23 (70%) of the ER/FTF patients receiving non-ChlVPP

salvage. Data is missing on the remaining patients.

Stem cell harvest was performed with granulocyte colony-

stimulating factor priming alone in 58 patients (56%), primed

with first cycle of salvage chemotherapy in 21 (20%), with

cytarabine in 16 (16%) and with cyclophosphamide in three

(3%), with a median yield of 3Æ4 · 106/kg CD34+ cells

(1Æ1–68Æ0 · 106/kg).

Overall, 72 (71%) patients proceeded to HDT/ASCR: 71%

of these (n = 51) were in CR or unconfirmed CR at the time of

HDT/ASCR, 19 (26%) were in PR and two (3%) patients had

Overall survival following HDT/ASCR

0 5 10 150

20

40

60

80

100

LRER/FTF

10-year OSRefractory: 64%Relapsed: 66%

5-year OSRefractory: 70%Relapsed: 78%

Time

Per

cent

sur

viva

l

Fig 1. Overall survival of all patients proceeding to high-dose therapy

with autologous stem cell rescue (HDT/ASCR). OS, overall survival;

LR, late relapse; ER, early relapse; FTF, failure of first-line therapy.

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202 ª 2012 Blackwell Publishing LtdBritish Journal of Haematology, 2012, 157, 201–204

less than PR. The 100-d transplant-related mortality was 4%

(n = 3). OS for the entire cohort based on ITT was 66% at

5 years and 57% at 10 years whereas the OS for patients who

received HDT/ASCR was 72% at 5 years and 65% at 10 years.

Of note, outcomes following BEAM were not significantly

inferior (Fig 1) for ER/FTF patients compared to LR patients

(P = 0Æ38, hazard ratio [HR] 0Æ68; 95% confidence interval

[CI] 0Æ23–1Æ8). However, by ITT (Fig 2) there was a clear

survival difference between these groups (5-year OS was 73%

and 50% for ER/FTF and LR respectively, and 10-year OS: 65%

and 46%; P = 0Æ012, HR 0Æ42; 95% CI 0Æ21–0Æ84). This was

accounted for by failure of more ER/FTF patients to reach

HDT/ASCR, usually due to refractoriness to salvage therapy:

36% of ER/FTF patients (n = 15) were unsuccessfully salvaged

compared to 8% of LR patients (n = 5).

This single centre analysis demonstrates the effectiveness of a

low toxicity oral regimen as first-line salvage of CHL in

patients relapsing after 1 year, with survival both by ITT and

following HDT/ASCR comparable to the literature. However,

it also demonstrates the unacceptable failure rate in ER/FTF

patients not accounted for by outcome following HDT/ASCR,

but rather by failure to demonstrate adequate chemo-respon-

siveness at salvage: an effect not demonstrable in studies

analysing only outcome following HDT/ASCR.

The treatment of patients having ER/FTF using the tradi-

tional approach of non-cross-resistant chemotherapy as

salvage prior to HDT/ASCR has unacceptable response rates.

However if an adequate response to this salvage is achieved, the

outcomes following HDT/ASCR are equivalent. This may

account for the failure to find survival differences between the

ER/FTF and LR groups in many analyses of HDT/ASCR

outcomes, which are not performed by ITT. This analysis of

unselected patients by ITT has demonstrated that the high risk

ER/FTF group needs to be targeted with more intensive or

novel agents at the point of salvage therapy. Agents such as

anti-CD30-MMAE are showing great promise (Younes et al,

2010) and may be candidates for use at this stage. This

approach will help to ensure that these patients achieve the

best possible remission, proceed to HDT/ASCR and are hence

offered the best opportunity for cure.

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