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Transcript of Early relapse and refractory disease remain risk factors in the anthracycline and autologous...
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: [email protected]
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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