A phase II study of dose-dense and dose-intense ABVD(ABVDDD-DI) without consolidation radiotherapy in patientswith advanced Hodgkin lymphoma

Filippo Russo,1* Gaetano Corazzelli,1*Ferdinando Frigeri,1 Gaetana

Capobianco,1 Luigi Aloj,2 Francesco

Volzone,1 Annarosaria De Chiara,3

Annamaria Bonelli,4 Tindaro Gatani,5

Gianpaolo Marcacci,1 Daniela

Donnarumma,1 Cristina Becchimanzi,1

Elisabetta de Lutio,6 Franco Ionna,7

Rosaria De Filippi,8 Secondo Lastoria2

and Antonello Pinto1

1Haematology-Oncology and Stem Cell Trans-

plantation Unit, National Cancer Institute,

Fondazione ‘G. Pascale’, IRCCS, 2Nuclear Medi-

cine, National Cancer Institute, Fondazione ‘G.

Pascale’, IRCCS, 3Pathology, National Cancer

Institute, Fondazione ‘G. Pascale’, IRCCS,4Cardiology, National Cancer Institute, Fondazi-

one ‘G. Pascale’, IRCCS, 5Respiratory Medicine,

National Cancer Institute, Fondazione ‘G.

Pascale’, IRCCS, 6Radiology, National Cancer

Institute, Fondazione ‘G. Pascale’, IRCCS, 7Head

and Neck Surgery Units, National Cancer Insti-

tute, Fondazione ‘G. Pascale’, IRCCS, and8Department of Clinical Medicine and Surgery,

Federico II University, Naples, Italy

Received 2 January 2014; accepted for

publication 24 February 2014

Correspondence: Antonello Pinto, MD,

Haematology-Oncology and Stem Cell

Transplantation Unit, Department of

Haematology, National Cancer Institute,

Fondazione ‘G. Pascale’, IRCCS, Via Mariano

Semmola, I-80131 Napoli, Italy.

E-mail: apinto.int.napoli@tin.it;

a.pinto@istitutotumori.na.it

*Filippo Russo and Gaetano Corazzelli

contributed equally to this work.

Summary

We explored activity and safety of a dose-dense/dose-intense adriamycin,

bleomycin, vinblastine and dacarbazine regimen (ABVDDD-DI) in 82

patients with advanced Hodgkin Lymphoma. Patients entered a two-stage

Bryant-Day Phase II study to receive six cycles of ABVDDD-DI without con-

solidation radiotherapy. Cycles were supported with granulocyte colony-

stimulating factor and delivered every 21 d; drugs were administered on

days 1 and 11 at the same doses of standard ABVD except for doxorubicin

(35 mg/m2; first four cycles only). Co-primary endpoints were complete

response (CR) rate and severe acute cardiopulmonary toxicity; secondary

endpoints were event-free (EFS) and disease-free survival (DFS). All

patients received the four doxorubicin-intensified courses and 96% con-

cluded all six cycles (82�3% within the intended 18 weeks). This translated

into a 66�9% increase of received dose-intensity for doxorubicin and 31�8%for the other agents over standard ABVD. The CR rate was 95�1% (78/82)

and 87�8% (72/82) achieved a metabolic CR after two cycles. Cardiopulmo-

nary toxicity never exceeded grade 2 and affected 14�6% of patients. Most

frequent toxicities were grade 4 neutropenia (10%) and anaemia (9%),

grade 3 infection (17%) and grade 2 mucocutaneous changes (30%). Five-

year EFS and DFS was 88�3% and 93�7%, respectively. ABVDDD-DI regimen

was well-tolerated and ensured substantial CR and EFS rates without radio-

therapy.

Keywords: Hodgkin lymphoma, ABVD, dose intensity, doxorubicin, radio-

therapy.

Despite impressive cure rates obtained with modern chemo-

therapy, the optimal therapeutic strategy in advanced classic

Hodgkin Lymphoma (HL) is still debated due to some

remaining open issues (Longo, 2013). These involve the best

choice of upfront chemotherapy (Bauer et al, 2011; Borch-

mann et al, 2012; Uhm & Kuruvilla, 2012), the duration and

intensity of frontline treatment (Carde et al, 2002; Connors,

2011; Borchmann et al, 2012), the value of consolidation

research paper

ª 2014 John Wiley & Sons Ltd, British Journal of Haematology doi:10.1111/bjh.12862

radiotherapy (Aleman et al, 2003; Johnson et al, 2010; Engert

et al, 2012; Terezakis & Kasamon, 2012), the role of func-

tional imaging in treatment planning and monitoring (Dann

et al, 2007; Avigdor et al, 2010; Gallamini & Kostakoglu,

2012) and the adequacy of risk stratification tools (Moccia

et al, 2012; Scott et al, 2013).

Currently, the combination of doxorubicin, bleomycin,

vinblastine and dacarbazine (ABVD) plus involved field

radiotherapy is recommended as standard of care for most

patients with advanced HL, given its favourable balance

between safety and efficacy (Bauer et al, 2011; Connors,

2011; Lim & Johnson, 2011).

Over the last 20 years, alternative regimens have been

designed in the attempt to outperform ABVD (Diehl et al,

1997; Horning et al, 2002; Sieber et al, 2003; Engert et al,

2009). Randomized studies demonstrated that intensifying

therapy through dose-escalation of most active drugs

and shortening cycle intervals yields a higher response rate

and longer failure-free survival when compared to standard

ABVD, although at the expense of higher levels of acute and

late treatment-related toxicities and without a definite advan-

tage in overall survival (OS; Federico et al, 2009; Bauer et al,

2011; Viviani et al, 2011; Carde et al, 2012).

The contest between ABVD and the dose-intensified regi-

men of etoposide, doxorubicin, cyclophosphamide, vincris-

tine, procarbazine and prednisone (escalated BEACOPP) has

been refuelled by a recent meta-analysis, which demonstrated

that treatment with six cycles of escalated BEACOPP confers

a 10% advantage in OS at 5 years over ABVD in patients

with stage III–IV HL (Skoetz et al, 2013). This study also

estimated a comparable risk of developing secondary cancers

between the two regimens, although the relatively short time-

to-event analysis still hampers a definitive conclusion in this

respect (Skoetz et al, 2013). While these evidences further

sustain the value of dose-intensification to improve event-

free survival (EFS), and probably OS, in advanced HL (Eng-

ert et al, 2012; Andre & Bosly, 2013; Skoetz et al, 2013),

many clinicians still feel it inappropriate to expose patients

to the greater risk of treatment-related toxicity and the

demanding clinical management associated with intensive

regimens, such as escalated BEACOPP (Connors, 2011; Fede-

rico et al, 2013; Longo, 2013).

Owing to the unavailability of clinical tools to discrimi-

nate upfront patients who can be cured by ABVD from those

who will benefit from a more intensified programme,

response-oriented approaches based on early metabolic imag-

ing and combination with newer agents, such as brentux-

imab–vedotin, are being pursued to enhance the efficacy of

ABVD with an acceptable safety profile (Gallamini & Kosta-

koglu, 2012; Kostakoglu & Gallamini, 2013; Younes et al,

2013).

We contemplated an alternative way to improve the per-

formance of ABVD while maintaining its favourable trade-off

of activity and toxicity. To this end we designed a dose-den-

sified (DD) three-weekly version of the regimen, which was

also dose-intensified (DI) by escalating the doxorubicin dose

in the first four of six cycles (ABVDDD-DI). This regimen was

intended for administration without consolidation radiother-

apy and also avoided the supra-additive risk of doxorubicin

intensification and mediastinal irradiation.

Here, we report results of a phase II study evaluating the

efficacy and safety of the ABVDDD-DI regimen in newly diag-

nosed patients with advanced HL. The prolonged follow up

allows a definite evaluation of recurrence rate and late time-

to-event analyses.

Patients and methods

Recruitment for this open-label phase II study according to

Bryant-Day design (Bryant & Day, 1995) started in June

2004, the first stage was concluded in December 2006 and

enrolment completed in March 2010. The study was

approved by the institutional review board and conducted in

accordance to the Declaration of Helsinki. All patients gave

written informed consent to treatment.

Eligibility and staging

Patients were eligible if they had untreated, biopsy-proven,

classical HL (Jaffe et al, 2001), aged 16–60 years, Ann Arbor

stage IIB with extranodal involvement and/or bulky mediasti-

nal adenopathy, III and IV (Lister et al, 1989), Eastern

Cooperative Oncology Group performance status 0–3,

human immunodeficiency virus negativity and no active

Hepatitis B virus infection. Neutrophils ≥1�0 9 109/l, plate-

lets ≥75 9 109/l, creatinine clearance >50 ml/min, transam-

inases <39 upper limits of normal (ULN) and/or bilirubin

<34�2 lmol/l, were required. Patients were excluded if preg-

nant or had cardiac arrhythmia, conduction abnormalities,

left ventricular hypertrophy or left ventricular ejection frac-

tion (LVEF) ≤50% at echocardiography, ischaemic cardiopa-

thy, carbon monoxide diffusion capacity (DLCO) tests and/

or forced expiratory volume (FEV1) <50% of predicted.

Pre-treatment assessment included laboratory workup, chest

X-ray, contrast-enhanced computerized tomography (CT) of

neck, chest, abdomen and pelvis, bone marrow biopsy

and 18F-Fluoro-deoxy-glucose (18F-FDG)-positron emission

tomography (PET).

Treatment plan

Patients were planned to receive six cycles of ABVDDD-DI

with primary granulocyte colony-stimulating factor (G-CSF)

support. As compared to standard ABVD, the intercycle per-

iod was shortened from 28 to 21 d. All drugs were adminis-

tered on days 1 and 11 of each cycle, instead of days 1 and

15. Bleomycin, vinblastine and dacarbazine were maintained

at the same dose as in standard ABVD while the doxorubin

dose was increased to 70 mg/m2 (i.e. 35 mg/m2 on day 1

and day 11) in the first four cycles only (Table I). Pegylated

F. Russo et al

2 ª 2014 John Wiley & Sons Ltd, British Journal of Haematology

G-CSF was not allowed in the study and all patients received

lenograstim at the daily flat dose of 263 lg (33�6 Million

International Units), scheduled per protocol at days +6 to +8and +17 to +19, amounting to six G-CSF doses in each cycle.

Consolidation radiotherapy on bulky lesions or residual dis-

ease was not admitted.

The predicted agent-specific dose intensities for doxorubi-

cin, bleomycin, vinblastine and dacarbazine were 21�1 (23�3in the first four cycles), 6�7, 4�0 and 250 mg/m2 per week,

respectively. This represented a 66�9% increase for doxorubi-

cin (86�0%, in the first four courses) over standard ABVD

and of 33% for all other drugs.

Adverse events (AEs) were graded using the National Can-

cer Institute Common Terminology Criteria for Adverse

Events (CTCAE) criteria version 3.0 (http://ctep.cancer.

gov/protocolDevelopment/electronic_applications/docs/ctcaev3.

pdf). Chemotherapy administration required neutrophils

≥1�0 9 109/l and platelets ≥75 9 109/l. Full blood cell counts

and renal and hepatic function tests were planned every 5 d

for the first two cycles and on days of chemotherapy admin-

istration for subsequent courses. In case of inadequate neu-

trophil recovery (i.e. neutrophil count <1�0 9 109/l on day 1

or 11 of each cycle), two or more G-CSF doses were given

and the patient programmed for restarting cycling at full

chemotherapy doses 3 d after the last additional G-CSF

injection. In such cases, one additional dose of G-CSF was

scheduled on days 5 and 16 of the next cycle. In case of an

inadequate platelet count at recycling, chemotherapy was

delayed until the platelet count had increased to ≥75 9 109/l.

When this platelet threshold was achieved with more than

7 d of delay, doses of doxorubicin and dacarbazine were to

be decreased by 25%. Doses of vinblastine and bleomycin

were not to be modified due to haematological toxicity. Nei-

ther treatment delay nor dose reductions were planned in

case of grades 3–4 anaemia and patients were supported with

blood transfusions as clinically indicated. Due to the short

duration of chemotherapy and the late onset of anaemia, use

of erythropoiesis stimulating agents was not planned, nor

recommended. Rather, patients were carefully evaluated for

subclinical iron deficiency, which was gradually corrected if

present. Dose adjustment guidelines also included: (i) vin-

blastine dosing: reduction by 50% in case of grade 3 consti-

pation or serum bilirubin 26�0–52�0 lmol/l or transaminases

2–3 times ULN; reduction by 75% if serum bilirubin 52�0–86�7 lmol/l; omission if grade 4 constipation or serum bili-

rubin >86�7 lmol/l or aspartate transaminase >180 units/l;

(ii) doxorubicin dosing: reduction by 50% for bilirubin

26�0–52�0 lmol/l and by 75% if bilirubin 52�0–86�7 lmol/l.

Supportive and additional therapies

To minimize the risks for potential pharmacokinetic drug

interactions, supportive and additional therapies were given

only when strictly necessary and a close clinical observation

was preferred to the use of prophylactic agents. In particular,

prescription of QTc interval-prolonging drugs, such as levo-

floxacin and moxifloxacin, for antimicrobial prophylaxis or

empirical treatment was not allowed. Given that doxorubicin

and vinblastine are substrates for CYP3A4 and CYP26D,

attention was paid to avoid concomitant exposure to drugs

inhibitors for such enzymatic systems (Liu & Juurlink, 2004;

Wolbrette, 2004). Hence, the CYP3A4 inhibitors chlarythro-

mycin, azithromycin, fluconazole or itraconazole were not

recommended. Beta-lactams and lincosamides were preferred

if antibiotics were needed; a short course of oral fluconazole

was only allowed as a therapeutic measure in case of mucosi-

tis, while antifungal prophylaxis relied on topical nystatin. As

to prevention and treatment of acute and delayed emesis, the

use of the NK-1R inhibitor aprepitant was not recommended

because it could enhance toxicity of both vinblastine and

doxorubicin by affecting CYP3A (Bjornsson et al, 2003). To

minimize additional cardiotoxicity from HT3-receptor antag-

onists, palonosetron was preferred. Due to the occurrence of

some episodes of moderate (grade 2) gastrointestinal (haem-

orrhoids, proctitis) and cutaneous (onycholysis/onychomade-

sis) toxicities in some of the patients enrolled in the first stage

of the study, the following prescriptions were added to the

protocol: (i) double antibiotic prophylaxis with ciprofloxacin

Table I. Drug doses, schedule and treatment administration details of ABVDDD-DI.

Drug Dose (mg/m2) Route Days

Cycles

1 2 3 4 5 6

Doxorubicin 35 IV 1, 11 ↓ ↓ ↓ ↓

Doxorubicin 25 IV 1, 11 ↓ ↓

Bleomycin 10 IV 1, 11 ↓ ↓ ↓ ↓ ↓ ↓

Vinblastine 6 IV 1, 11 ↓ ↓ ↓ ↓ ↓ ↓

Dacarbazine 375 IV 1, 11 ↓ ↓ ↓ ↓ ↓ ↓

Lenograstim (G-CSF) 263 lg/d* SC 6?8 ↔ ↔ ↔ ↔ ↔ ↔

Lenograstim (G-CSF) 263 lg/d* SC 17?19 ↔ ↔ ↔ ↔ ↔ ↔

IV, intravenous; SC, subcutaneous; G-CSF, granulocyte-colony stimulating factor (lenograstim).

Single course duration: 3 weeks; total treatment length: 18 weeks (4�2 months).

Concomitant and/or supportive care measures, integral to the treatment plan, are detailed in the text.

*Equivalent to 33�6 international million units/d.

Intensified ABVD in Advanced Hodgkin Lymphoma

ª 2014 John Wiley & Sons Ltd, British Journal of Haematology 3

plus clindamycin to prevent abscessualization in patients

developing symptomatic haemorrhoids; (ii) topical and/or

systemic treatment with clindamycin in case of exudative and

frowzy paronychia involving fingernails and/or toenails.

Evaluation and response assessment

Responses were assessed according to Cotswold criteria as

CR, unconfirmed CR (CRu), partial response (PR) or pro-

gression, with gallium scanning replaced by 18F-FDG-PET to

discriminate persistent disease from residual anatomic distor-

tion without active lymphoma (Lister et al, 1989). Patients

underwent interim evaluation after four cycles with CT scans

of initially involved areas. In case of response <CR/CRu after

Cycle 4, patients exited the study and were shifted to alterna-

tive programmes. All patients underwent 18F-FDG-PET imag-

ing after cycle 2 (PET2); in cases of pathological PET2

uptake, a new scan was performed after Cycle 4 (PET4)

together with the pre-planned CT assessment. Details

on18F-FDG-PET studies are given as Supporting Information.

After the final assessment, patients were seen 3-monthly

for the first year, 6-monthly until the fourth year and

yearly thereafter. Cardiopulmonary functions were re-assessed

yearly until the fourth year and thereafter if clinically indicated.

Statistical methods

Co-primary study endpoints were CR/CRu rate and inci-

dence of acute cardio-pulmonary AEs of grade ≥3as detailed

in Supporting Information and assessed throughout treat-

ment until 30 d after the last chemotherapy. Given an antici-

pated CR/CRu rate of 76% with standard ABVD without

radiotherapy (Duggan et al, 2003), a CR/CRu rate >90%for

the experimental treatment was considered relevant. The

incidence of cardio-pulmonary grade ≥3 AEs was considered

acceptable if ≤10% and unacceptable if ≥25%. Hence, 27

patients were to be accrued in stage I, with stopping rules

for inadequate CR/CRu rate (≤21 patients) or severe cardio-

pulmonary toxicity (≥7 patients). In stage II, 50 additional

patients were to be enrolled to assess endpoints with a power

of 90% (efficacy b of 0�10) and a one-sided a level of 0�05(Bryant & Day, 1995). Probabilities of early study termina-

tion were 71% and 90% in case of excessive toxicity with

adequate or inadequate response rates, respectively. Time-to-

event analyses for secondary endpoints were based on the

Kaplan–Meier method with Greenwood point-wise confi-

dence intervals (CIs). EFS was measured from enrolment until

date of last contact, toxicity causing treatment discontinua-

tion, response <CR/CRu, lymphoma progression/relapse,

cardiac and respiratory grade ≥3 events, secondary malig-

nancy, death due to any cause, whichever occurred first; OS

was calculated from study entry to the date of last observa-

tion or death. Disease-free survival (DFS) was defined as

time to relapse, death from any cause or date of last follow-

up. Cut-off date for analysis was June 2012.

Results

Patient characteristics

All of the 82 accrued patients were assessable for toxicity and

response. The median age was 32 years (range, 16–60 years);

25 patients (30%) had stage IIB disease with mediastinal

bulk, 20 stage III (24%) and 37 stage IV (45%) (Table II).

The majority had high-risk features, including B-symptoms

(73%), bulky disease (58%; mediastinal 47%), ≥3 involved

nodal regions (89%), elevated erythrocyte sedimentation rate

(46%) and International Prognostic Score ≥3 (52%).

Treatment delivery and dose intensity

Seventy-nine patients (96%) completed the planned six

courses of ABVDDD-DI. Treatment duration ranged from 17�4to 21�0 weeks, with 82�3% of patients completing the

programme within the intended 18 weeks. Only eight (10�1%),

five (6�3%) and one (1�3%) patients completed treatment with

one, two or three weeks of overall delay, respectively. The 68

Table II. Baseline patient and disease characteristics of the study

population.

Characteristics

Patients (N = 82)

n %

Age, years

Median 32

Range 16–60

>45 years 12 15

Male sex 39 48

Disease stage

IIB (with mediastinal bulk*) 25 30

IIIA 10 12

IIIB 10 12

IVA 12 15

IVB 25 30

Mediastinal bulk* 39 47

Extra-mediastinal bulk (≥10 cm) 9 11

≥3 nodal areas involved 73 89

Splenic involvement 17 21

Extranodal extension (stage II–III) 10 12

Extranodal spread (stage IV only) 37 45

High ESR (>50 mm/h) 38 46

IPS

0–1 27 33

2–3 39 48

4–7 16 19

≥3 43 52

Histological subtype

Nodularsclerosis 69 84

ESR, erythrocyte sedimentation rate; IPS, International Prognostic

Score.

Percentages are rounded up/down to the nearest unit.

*Max width ≥1/3 of thoracic diameter at the level of T5/6 interspace.

F. Russo et al

4 ª 2014 John Wiley & Sons Ltd, British Journal of Haematology

patients who completed treatment within 18 weeks received a

median of 6 d of G-CSF (range, 5–9 d) per cycle. Notably, all

patients completed the first four cycles (doxorubicin-intensi-

fied): 69 (84�1%) within the planned 12 weeks, 12 (14�6%) in

13 weeks and a single patient (1�2%) in 14 weeks. Delays were

due to grade 4 neutropenia (n = 6), grade 3 infection (n = 4)

and grade 3 constipation (n = 3).

Median actual dose intensities (ADI) of 20�94 (23�12 in

the first four courses), 6�69, 3�96 and 245 mg/m2 per week

for doxorubicin, bleomycin, vinblastine and dacarbazine,

were respectively achieved. This represented a median

increase in dose intensity of 66�9% for doxorubicin (85�0%,

in the first four courses) and 31�8% for the other agents,

over standard ABVD (Fig 1).

Early adverse events

Acute toxicity is detailed in Table III. Grades 3–4 neutrope-

nia occurred in only 17% of patients, reflecting primary

G-CSF prophylaxis. Seven patients (9%) required red blood

cell transfusions while thrombocytopenia never exceeded grade

2. Grade 3 infection occurred in 14 patients and was associated

with neutropenia in five cases (6%). Grade 2 sinus tachycardia

was registered in seven patients (9%); it usually occurred after

four courses, required beta blockers and resolved within

2–4 months. Median LVEF values of 63% (range, 58–73%)

and 60% (range, 48–70%) were recorded after 4 and 6 cycles,

respectively. Grade 1 pneumonitis, as nonspecific infiltrates

at CT imaging, was incidentally encountered at response

assessment in three patients (4%). However, a fatal interstitial

pneumonia, with ‘ground-glass’ opacities/infiltrates and with-

out documented infection, occurred in a 59-year-old male

shortly after achieving CR at Cycle 4.

Notably, while grade 1 ‘hand-foot syndrome’ affected only

9% of patients, grade 2 gastrointestinal (haemorrhoids,

proctitis) and cutaneous (onycholysis/onychomadesis) AEs

occurred in 10% and 30% of patients, respectively. These

toxicities, beyond the scope expected for standard ABVD,

prompted specific prophylactic measures. Nail alterations

usually occurred during the last two cycles and fully resolved

thereafter. Grade 3 sensory neuropathy and grade 2 sensory-

facial and motor-jaw muscles neuropathy occurred in two

patients receiving prophylactic lamivudine (Styrt et al, 1996).

Efficacy outcomes

The CR rate at the completion of ABVDDD-DI was 95�1%(95% CI, 87�7–98�5) (Table IV). At the preplanned interim

evaluation after four cycles, two patients in PR were diverted

‘per protocol’ to alternative treatments; a further patient,

despite the instrumental CR, progressed shortly before final

assessment. Seventy-two patients (87�8%) had a negative

PET2 scan. Eight of the 10 PET2-positive patients achieved a

negative PET status after two further cycles (Table IV).

Three CR patients were irradiated (24 Gy) limited to sites of

initial isolated sacral, chondrosternal and vertebral involve-

ment.

Overall, estimated EFS at 5 and 7 years were 88�3% (95%

CI, 78�5–93�8) and 84�3% (95% CI, 70�4–92�0), respectively(Table IV; Fig 2A). At a median follow up of 57 months

(range, 27–97 months), the following 10 events were regis-

tered: less than CR (n = 2), progression (n = 1), early relapse

(<12 months; n = 2), late relapse (>12 months; n = 2), sec-

ond malignancy (n = 2) and toxic death (n = 1). The proba-

bility of OS at 7 years was 91�4% (95% CI, 75�6–97�2) with

four deaths due to: acute toxicity (n = 1), secondary malig-

nancy (n = 2; after 47 and 75 months), transplant-related

mortality (n = 1; after 17 months); DFS at 5 years was

93�7% (95% CI, 85�5–97�3) (Table IV; Fig 2B,C).

Outcomes of patients with mediastinal bulk

At the final assessment, 37 CRs (94�9%; 95% CI, 82�7–99�4),1 PR and one progression were observed among the 39

Fig 1. Actual dose intensity. Box and whisker

plots showing percentage increases in actual

dose intensity in patients given ABVDDD-DI

over a reference line representing 100% of

planned dose intensity for standard ABVD.

The two ends of the boxes indicate the upper

and lower quartiles, the median value is plotted

as a solid line within each box, and the whis-

kers represent the upper and lower limits of

the data. Data is derived from all administered

courses (n = 487). ADM, doxorubicin; BLM,

bleomycin; VLB, vinblastine; DTIC, dacarb-

azine.

Intensified ABVD in Advanced Hodgkin Lymphoma

ª 2014 John Wiley & Sons Ltd, British Journal of Haematology 5

patients with mediastinal bulk at diagnosis. Notably, 36

patients (92�3%) were PET2-negative, and only one had per-

sisting mediastinal uptakes at PET4. No patient received con-

solidation radiotherapy and all were alive at a median

follow-up of 56 months (range, 28–94 months). In this

patients subset, EFS and DFS at 5 years were 89�7% (95%

CI, 80�2–99�15; Fig 2D) and 94�4% (95% CI, 79�5–98�5)respectively, with only two isolated mediastinal relapses at 10

and 15 months.

Delayed adverse events

Longitudinal assessments of respiratory and cardiac functions

were accomplished in 51 and 72 complete responders,

respectively, throughout a median follow-up of 52 months

(range, 22–92 months) after treatment.

Pulmonary assessment included, beyond FEV1 and DLCO,

the Forced Expiratory Flow (FEF25–75%) to better appreciate

initial impairments of small airway patency. Overall, median

figures of 96�35% (range, 66�0–120�0%), 100�1% (range,

45�2–117�4%) and 82�40% (range, 33–121%) of predicted

were registered for FEV1, DLCO and FEF25–75%, respectively

(Fig 3). Only three patients, two current smokers and one

with a pre-treatment ventilatory disturbance, showed FEF25–

75%, which was below 50% of predicted while FEV1 was nor-

mal. DLCO was >75% in all patients except for a 23-year-old

female with DLCO of 45�2% at 55 months and FEV1 and

FEF25–75 of 68% and 66%, respectively. She had a mediastinal

bulk at presentation and a history of allergic asthma.

At a late assessment, LVEF showed a median value of 64%

(range, 49–77%) and was ≥55% in all patients but a 32-year-

old male with a FEV of 49% at 65 months of follow-up.

Two secondary neoplasms, a pancreatic carcinoma and an

acute promyelocytic leukaemia, were diagnosed at 44 and

75 months, respectively. All female patients ≤40 years in

ongoing CR recovered their menses.

Table III. Number of patients with acute adverse events by cycle.

Adverse event*

Cycle 1 Cycle 2 Cycle 3 Cycle 4 Cycle 5 Cycle 6Total

n n n n n n n %

Blood

Neutropenia G3 2 2 1 1 6 7

Neutropenia G4 1 1 1 3 2 8 10

Anaemia G3 1 2 3 4

Anaemia G4 1 3 2 1 7 9

Cardiac

LVS dysfunction G2 1 1 1

Sinus tachycardia G2 1 3 2 1 7 9

Dermatological

HFS reaction G1 1 6 7 9

HFS reaction G2 1 1 1

Nail changes G2 1 2 11 11 25 30

Gastrointestinal

Constipation G3 2 1 3 4

Gastritis/enteritis/proctitis G2 1 3 2 2 1 9 11

Haemorrhoids G2 2 2 2 1 1 8 10

Haemorrhoids G3 1 1 1

Stomatitis G2 1 4 4 6 2 1 18 22

Stomatitis G3 1 1 2 3

Vomiting G3 1 7 2 1 11 13

Infection

Febrile neutropenia G3 1 1 3 5 6

Febrile non-neutropenic G3 1 2 3 3 9 11

Neurology

Cranial neuropathy (V CN) G2 1

Sensory neuropathy G3 1

Pulmonary

Pneumonitis G1 1 2 3 4

Pneumonitis G2 1 1 1

LVS, left ventricular systolic; HFS, hand-foot syndrome; CN, cranial nerve.

The data are listed according to body systems and include any toxicity of grade 3 (G3) to grade 4 (G4). Adverse events of grade <3 are also listed

if they were unequal and/or beyond the expected scope of standard ABVD. Grade 1 (G1) to grade 2 (G2) hair loss/alopecia was universal.

*Counted only once, at the highest grade, in patients experiencing multiple occurrences.

F. Russo et al

6 ª 2014 John Wiley & Sons Ltd, British Journal of Haematology

Discussion

This phase II study demonstrated that time and dose-intensi-

fication of the ABVD regimen was feasible, safe and effective.

Both primary endpoints were met because the incidence of

severe cardio-pulmonary AEs was far below the limits set as

stopping rules for the trial and a final CR rate of 95�1% was

achieved. Moreover, the first two cycles of ABVDDD-DI

induced a substantial rate (87�8%) of early PET-negativity,

one of the strongest predictors of ultimate outcome in

advanced HL patients treated with ABVD (Gallamini &

Kostakoglu, 2012). Treatment with ABVDDD-DI yielded

5-year EFS and DFS rates of 88�3% and 93�7% respectively,

despite the omission of consolidation radiotherapy. Within

the obvious limitations of a phase II design and low power

for secondary endpoints, these efficacy outcomes appear

promising and compare favourably with standard ABVD,

further supporting early therapy intensification as a critical

issue for improving long-term outcomes in advanced HL

(Carde et al, 1983, 2002; Hasenclever et al, 1996).

Adherence to treatment was very high; 96% of patients

received the scheduled six courses and 82% completed the

programme within the planned 18 weeks. These results

uncovered some key findings. First, ABVD can be effectively

administered on a three-weekly basis. Second, a comparable

cumulative dose of doxorubicin (380 mg/m2) can be safely

delivered in about one of half the time (18 weeks) required

for conventional ABVD (400 mg/m2over 32 weeks) (Duggan

et al, 2003). Third, a remarkable increase over standard

ABVD of ADI for doxorubicin (66�9%; 85�0% in the first

four cycles) and the other agents (31�8%) can be achieved

without encumbering toxicity.

Both the CR rate (95�1% vs. 76�4%) and 5-year EFS (88%

vs. 63%) achieved by ABVDDD-DI outnumbered outcomes

from the North American Intergroup study (Duggan et al,

2003). This latter trial, adopted as the reference for antici-

pated proportions of primary endpoints in our statistical

design, still remains a current benchmark for toxicity/efficacy

trade-off of ABVD without consolidation radiotherapy (Dug-

gan et al, 2003; Borchmann et al, 2012).

With regard to treatment-related toxicity, grade 4 anaemia

and grade 3 infections occurred in 9% and 17% of the

patients, respectively. These figures were higher than those

expected with standard ABVD but favourably compared with

more intensified, G-CSF-supported, programmes such as

escalated BEACOPP, notably including the lack of thrombo-

cytopenia grade ≥3 and a much lower rate (17%) of severe

neutropenia (Federico et al, 2009; Bauer et al, 2011; Viviani

et al, 2011; Engert et al, 2012).

Despite the intensification of doxorubicin and co-adminis-

tration of densified bleomycin with G-CSF, no unequal

short- and long-term cardiopulmonary toxicities occurred

(Martin et al, 2005). Transient cardiac AEs affected <10% of

patients during treatment, which never graded >2 or deter-

mined doxorubicin dose reductions/omissions. The overall

profile of acute pulmonary toxicity of ABVDDD-DI (6%,

mostly grade 1) was similar to standard ABVD and com-

pared favourably to intensified regimens, including fatalities

in older patients with HL (Canellos et al, 1992; Duggan et al,

2003; Martin et al, 2005; Engert et al, 2012; Proctor et al,

2012; Boll et al, 2013; Evens et al, 2013). At a median follow

up longer than 4 years, mild declines in LVEF and pulmo-

nary function were observed in only 1�3% and 5�8% of

patients, respectively. We rather documented a profile of

grades 1 to 2 mucocutaneous toxicity reminiscent of bleomy-

cin/vinblastine dose-densified regimens for testicular cancer

(Wozniak et al, 1991; Susser et al, 1999; Gilbar et al, 2009).

The rate of secondary tumours observed in our study (2�4%)

appeared to be in line with standard ABVD; however, the

danger of additional events, albeit mitigated by the absence

of radiotherapy, needs to be reassessed at a longer follow-up

(Franklin et al, 2005).

Taking into proper account the power of a single-arm

phase II design, limits of cross-trial comparison and

heterogeneity in event/failure definition across studies, the

5-year EFS of ABVDDD-DI (88�3%) compared favourably with

outcomes of standard ABVD arms from modern phase III

studies. In these trials, EFS or failure-free survival, ranged

from 61% to 64% for studies without pre-planned

Table IV. Treatment response, events and survival outcomes.

Outcome n % 95% CI

Final treatment response 82

Complete remission 78 95�1 87�7–98�5Partial remission 2 2�4Progression 1 1�2Unknown* 1 1�2

Cycle 2 PET 82

Negative 72 87�8 78�8–93�4Positive 10 12�2

Cycle 4 PET 10

Negative 8

Positive 2

Cycle 6 PET 79

Negative 78

Positive 1

Events 10 12�2 6�6–21�2<Complete remission 2

Progression 1

Early relapse (3–12 months) 2

Late relapse (>12 months) 2

Secondary tumour 2

Death from acute toxicity 1

5-year

Event-free survival 88�3 78�5–93�8Disease-free survival 93�7 85�5–97�3Overall survival 95�5 86�2–98�6

CI, confidence intervals; PET, Positron Emission Tomography.

*Unknown indicates no final restaging result was documented

because of death during treatment not due to lymphoma.

Intensified ABVD in Advanced Hodgkin Lymphoma

ª 2014 John Wiley & Sons Ltd, British Journal of Haematology 7

irradiation (Canellos et al, 1992; Carde et al, 2012) and from

65% to 78% for those in which 36–62% of the patients were

also given radiotherapy (Gobbi et al, 2005; Johnson et al,

2005; Federico et al, 2009; Hoskin et al, 2009; Viviani et al,

2011; Gordon et al, 2013).

Interestingly, the 5-year EFS curve for ABVDDD-DI is close

to the freedom from treatment failure (FFTF) achieved with

regimens that exploit the principles of dose escalation and

time intensification as developed by the German Hodgkin

Study Group (GHSG) (Diehl et al, 2003; Borchmann et al,

2011; Engert et al, 2012). Comparable survival proportions

at 3 years can be also appreciated for ABVDDD-DI (EFS

90�2%) and the seminal GHSG study that tested ‘pure’

time-intensification through BEACOPP14 (FFTF 90%), even

though two thirds of patients in this latter trial were also

irradiated (Sieber et al, 2003).

Given the low overall relapse rate (5�1%) and the excellent

outcome of cases with mediastinal bulk (CR: 94%, 5-year

EFS: 89�7%), ABVDDD-DI corresponds with the HD15 trial in

supporting the redundancy of consolidation radiotherapy in

patients who are PET-negative following upfront intensified

regimens (Eich et al, 2011; Engert et al, 2012). Indeed, while

the proportion of patients receiving radiotherapy progres-

sively reduced through the GHSG studies, from 71% (HD9)

to 38% (HD12) down to 11% (HD15) (Engert et al, 2009,

2012; Eich et al, 2011), at least one half (46–67%) of patients

(A) (B)

(D)(C)

Fig 2. Kaplan–Meier estimates with asymmetric confidence limits according to the Greenwood formula. (A) Event-free survival, (B) overall sur-

vival and (C) disease-free survival for the entire study population (n = 82), and (D) event-free survival for the subset of patients with mediastinal

bulky adenopathy at presentation (n = 39). Median observation time for event-free survival was 57 months (range, 27–97 months). Severe toxic-

ity causing definite treatment discontinuation, cardiac and respiratory grade ≥3 adverse events, less than CR, relapse/progression, secondary malig-

nancy and death were counted as events for event-free survival. Death from any cause was counted as an event in overall survival. Relapse and

death from any cause was counted as event in disease-free survival. OS, overall survival; EFS, event-free survival; DFS, disease-free survival; 95%

CI, 95% confidence interval.

Fig 3. Late assessment of pulmonary function according to Common Terminology Criteria for Adverse Events v3.0. Carbon monoxide diffusion

capacity (DLCO), forced expiratory volume (FEV1) and Forced Expiratory Flow (FEF25–75%) values are shown before treatment administration

and at the last follow-up evaluation. Median observation time was 52 months (range, 26–92 months) after treatment completion. Paired data

(pre-treatment and late follow up) were available for 51 of the 82 accrued patients. CTCAE, Common Terminology Criteria for Adverse Events.

F. Russo et al

8 ª 2014 John Wiley & Sons Ltd, British Journal of Haematology

accrued in most recent trials of standard ABVD was still

irradiated (Gobbi et al, 2005; Federico et al, 2009; Viviani

et al, 2011).

Importantly, ABVDDD-DI achieved a high rate of PET-

negative scans after two cycles, i.e. only six weeks of treat-

ment: 87�8% overall and 92�3% in patients with bulky

mediastinum. These proportions favourably match with data

from ongoing trials reporting PET-negativity rates of 76–

80% and 53–87% after two courses of standard ABVD and

escalated BEACOPP, respectively (Gallamini & Kostakoglu,

2012).

The present results may be set in the context of the

continuing controversy of whether the optimal approach in

advanced HL should rely on a demanding strategy such as

the escalated BEACOPP, to exploit the ‘first hit princi-

ple’(Borchmann et al, 2012; Skoetz et al, 2013) possibly fol-

lowed by de-escalation in early responders (Dann et al, 2007;

Avigdor et al, 2010; von Tresckow et al, 2012), rather than

on the less aggressive ABVD with subsequent intensification

for poor responders (Gallamini et al, 2011; Viviani et al,

2011; Andr�e et al, 2012; Kostakoglu & Gallamini, 2013; Lon-

go, 2013). Such debate should not overshadow the fact that

dose intensity of upfront chemotherapy remains a key factor

for antitumor efficacy and long-term survival in HL as sug-

gested by early seminal studies (Carde et al, 1983, 2002; Ha-

senclever et al,1996) and confirmed by modern trials

(Landgren et al, 2003; Borchmann et al, 2012; Engert et al,

2012; Boll et al, 2013).

Improved outcomes of patients with advanced HL in the

modern era have been partly explained by greater attention

to the preservation of dose-intensity while delivering ABVD

(Moccia et al, 2012). In this regard, previous studies have

shown that a dose intensity approaching 100% can be

achieved for standard ABVD without growth factor support

(Boleti & Mead, 2007; Evens et al, 2007). Furthermore, the

present study provided evidence that the dose intensity of

standard ABVD can be substantially overstepped, through a

limited amount of G-CSF doses per cycle, while maintaining

an advantageous risk-to-benefit ratio.

In light of this, ABVDDD-DI embodies an accelerated and

dose-powered ABVD variant unburdened by the toxicity of

escalated BEACOPP and the supra-additive risks of consoli-

dation radiotherapy. In addition, ABVD intensification may

possibly reduce the recourse to ‘second shot’ salvage high-

dose chemotherapy (Viviani et al, 2011), which, beyond the

additional toxic load, may not always cure patients with pri-

mary refractory disease (Lavoie et al, 2005; Sureda et al,

2005; Majhail et al, 2006; Corazzelli et al, 2011; Greaves et al,

2012). Interestingly, a brief dose-dense ABVD-like regimen

also proved to be safe and effective in paediatric HL and a

very recent phase I study in 24 adult patients with HL con-

firmed the feasibility of an 80% increase in doxorubicin

dose-intensity within the ABVD regimen (Schwartz et al,

2009; Gibb et al, 2013).

The concept underlying the ABVDDD-DI design may retain

validity also into context of current strategies aimed at

improving efficacy of ABVD through combination with

newer agents, such as brentuximab-vedotin (Younes et al,

2013), rituximab (Kasamon et al, 2012; Younes et al, 2012),

or lenalidomide (NCT01056679). Given the very high rates

of early PET-negativity, a few cycles of ABVDDD-DI could be

optimally and safely implemented by earlier consolidation

with brentuximab-vedotin or other targeted-agents. Beyond

this, availability of an improved ABVD platform allowing

omission of consolidation radiotherapy may be advantageous

in health-care settings where the availability of updated radi-

ation delivery modalities is problematic (Terezakis & Kas-

amon, 2012). Given that access to novel agents to implement

standard ABVD and the highly specialized supportive mea-

sures advocated by GHSG investigators to fully exploit sur-

vival benefit from escalated BEACOPP may not apply to all

health-care systems worldwide (Skoetz et al, 2013), ABVDDD-

DI may represent a sound and affordable option for high-risk

patients with HL.

Based on the present data and early evidences from an

independent phase II study of dose-dense ABVD in early

HL from the Fondazione Italiana Linfomi, the inclusion of

ABVDDD-DI in a randomized phase III trial for advanced

HL is under evaluation by this cooperative lymphoma

network.

Dedication

The Authors dedicate this work to the memory of

Dr Tindaro Gatani (1957–2013).

Acknowledgements

The authors thank Mrs. Rosaria Nota, administrative assis-

tant to the Department of Haematology IRCCS Fondazione

Pascale, Italy, for logistic support and contribution. This

study was supported in part by the Ministero della Salute,

RicercaCorrente IRCCS, Rome, Italy.

Author contributions

FR, GC and AP conceived and designed the research; FR,

GC, FF, GC, LA, FV, ADC, AB, TG, GM, DD, CB, EDL, FI,

RDF, SLS, and AP provided study materials or patients;

FR, GC, FF, GC, LA, FV, ADC, AB, TG, GM, DD, CB, EDL,

FI, RDF, SLS, and AP collected and assembled data; FR, GC,

SLS, and AP analysed and interpreted data; and all authors

contributed to the manuscript writing and approved the final

version of the manuscript.

Conflict of interest

All authors declare no competing financial interests.

Intensified ABVD in Advanced Hodgkin Lymphoma

ª 2014 John Wiley & Sons Ltd, British Journal of Haematology 9

Supporting Information

Additional Supporting Information may be found in the

online version of this article:

Data S1. Listing of cardiac and pulmonary Adverse Events

of grade ≥3 leading to definitive treatment withdrawal and

considered for the primarysafety endpoint.

Data S2. Methodology details on 18F-FDG-PET assess-

ment.

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