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Understanding the short- and long-term toxicity of therapies for Hodgkin lymphoma ( HL ) is important for guiding treatment decisions , especially for patients in which the benefits of intensified therapy would outweigh the adverse event ( AE ) risks and for patients in which less aggressive treatment would continue to be effective .

In a prospective , randomized , controlled trial published in the New England Journal of Medicine , Peter Johnson , MD , from the Cancer Research UK Centre and the University of Southampton in Southhampton , England , and authors evaluated a response-adapted chemotherapeutic approach in patients with previously untreated advanced classic HL , questioning whether interim positron emission tomography-computed tomography ( PET – CT ) scans could identify patients with good outlook who could de-escalate therapy and those at higher risk for treatment failure who could safely escalate therapy .

Dr . Johnson and colleagues enrolled 1,214 patients into the trial ( median age = 33 years ; range = 18-79 years ). Patients underwent baseline PET – CT scan and received two cycles of doxorubicin , bleomycin , vinblastine , and dacarbazine ( ABVD ); 1,119 patients then underwent an interim PET – CT scan .

Patients were eligible for the study if they had previously untreated advanced classic HL ( defined as an Ann Arbor stage 2B-4 with adverse features , including bulky disease [> 33 % of the transthoracic diameter or > 10 cm elsewhere ] or at least three involved sites ) confirmed by histologic analysis . All patients also had to be eligible to receive a full course of combination chemotherapy .

PET – CT scans were evaluated on a five-point scale measuring uptake of residual F-18 fluorodeoxyglucose at involved sites , with scores 1-3 indicating a negative scan and scores 4-5 indicating a positive scan :

• score 1 ( n = 111 ; 9.9 %)

• score 2 ( n = 483 ; 43.2 %)

• score 3 ( n = 343 ; 30.7 %)

• score 4 ( n = 144 ; 12.9 %)

• score 5 ( n = 38 ; 3.4 %)

Patients with scores 1-3 were randomly assigned to continue ABVD through cycle 6 ( ABVD

TABLE . Therapeutic Outcomes in Each Treatment Cohort Outcome

ABVD ( n = 470 )

AVD ( n = 465 ) group ; n = 470 ) or to omit bleomycin in cycles 3-6 ( AVD group ; n = 465 ). Two patients were excluded from randomization , and 10 patients did not receive the assigned therapy . A total of 458 patients in the ABVD group ( 97.9 %) and 446 in the AVD group ( 97.6 %) completed six full cycles of treatment .

Patients with scores 4-5 received escalated bleomycin , etoposide , doxorubicin , cyclophosphamide , vincristine , procarbazine , and prednisone ( BEACOPP group ; n = 78 ) or BEACOPP-14 ( n = 94 ). Six of these patients withdrew from the study , and four elected to continue with ABVD .

Clinical evaluations were conducted every three months during the first year , every four months during the second year , every six months in the third year , and annually thereafter .

After a median follow-up of 41.2 months ( range = 2-79.7 months ), researchers observed 142 events of disease progression , relapse , or death in the patients who had negative interim PET – CT scans , with similar outcomes in the ABVD and AVD groups ( hazard ratio [ HR ] for AVD = 1.13 [ 95 % CI 0.81-1.57 ]; p = 0.48 ). The three-year progression-free survival ( PFS ) rate ( the

BEACOPP All eligible patients ( n = 172 ) * ( n = 1,203 ) †

3-year PFS 85.7 % ( 95 % CI 82.1-88.6 )

3-year OS 97.2 % ( 95 % CI 95.1-98.4 )

Ann Arbor stage 3 / 4 and age ≤60 years

3-year PFS 82.1 % ( 95 % CI 76.5-86.5 )

3-year OS 95.9 % ( 95 % CI 92.2-97.9 )

84.4 % ( 95 % CI 80.7-87.5 )

97.6 % ( 95 % CI 95.6-98.7 )

82.1 % ( 95 % CI 76.3-86.4 )

97.8 % ( 95 % CI 94.8-99.1 )

67.5 % ( 95 % CI 59.7-74.2 )

87.8 % ( 95 % CI 81.5-92.1 )

63.9 % ( 95 % CI 52.9-72.9 )

87.8 % ( 95 % CI 78.9-93 )

82.6 % ( 95 % CI 80.2-84.7 )

95.8 % ( 95 % CI 94.4-96.8 )

79.8 % ( 95 % CI 76.3-82.9 )

94.6 % ( 95 % CI 92.5-96.2 )

* This includes all patients who received BEACOPP and BEACOPP-14 ( the escalated dose ). † This includes patients who dropped out before randomization , declined BEACOPP , or were ineligible for the randomized comparison owing to a non-protocol PET – CT scan after two cycles of ABVD . ABVD = doxorubicin , bleomycin , vinblastine , and dacarbazine ; AVD = doxorubicin , vinblastine , and dacarbazine ; BEACOPP = bleomycin , etoposide , doxorubicin , cyclophosphamide , vincristine procarbazine , and prednisone ; HL = Hodgkin lymphoma ; PFS = progression-free survival ; OS = overall survival study ’ s primary outcome ) was 85.7 percent in the ABVD group ( 95 % CI 82.1-88.6 ) and 84.4 percent in the AVD group ( 95 % CI 80.7-87.5 ).

No baseline characteristics were associated with observable differences in PFS ; however , the HR favored ABVD for patients with systemic B symptoms ( including weight loss , night sweats , and fever ; HR = 1.76 ; 95 % CI 1.04-2.97 ).

OS rates were also similar in the ABVD and AVD groups : 97.2 percent ( 95 % CI 95.1-98.4 ) versus 97.6 percent ( 95 % CI 95.6-98.7 ).

Among the positive interim PET – CT cohort , therapy escalation was effective in “ roughly two-thirds of cases ,” the authors noted , with a three-year PFS rate of 67.5 percent ( 95 % CI 59.7-74.2 ). The OS rate was 87.8 percent ( 95 % CI 81.5-92.1 ).

“ We have shown that de-escalating therapy by stopping the administration of bleomycin after negative interim PET – CT scan is safe and effective ,” Dr . Johnson told ASH Clinical News . Though its inclusion in the earlier cycles might have a positive effect on disease control , its omission was associated with reduced toxic effects , including fatigue and respiratory events . Any-grade AEs occurred in :

• 16 % of those receiving ABVD in cycles 1-2 ( n = 188 )

• 31 % of those receiving ABVD in cycles 3-6 ( n = 143 )

• 21 % of those receiving AVD in cycles 3-6 ( n = 96 )

• 55 % of those receiving BEACOPP-14 ( n = 96 )

• 60 % of those receiving BEACOPP ( n = 47 )

The incidence of any pulmonary or upper respiratory event was slightly lower among patients receiving ABVD and AVD :

• 1 % of those receiving ABVD in cycles 1-2 ( n = 8 )

• 3 % of those receiving ABVD in cycles 3-6 ( n = 15 )

• 1 % of those receiving AVD in cycles 3-6 ( n = 3 )

• 4 % of those receiving BEACOPP-14 ( n = 4 )

• 5 % of those receiving BEACOPP ( n = 4 )

“ Although the results fall just short of the specified noninferiority margin , the omission of bleomycin from the ABVD regimen after negative findings on interim PET resulted in a lower incidence of pulmonary toxic effects but not significantly lower efficacy than with continued ABVD ,” Dr . Johnson and colleagues wrote .

The researchers analyzed potential predictors of treatment failure after a negative PET – CT scan and found that advanced disease ( defined as higher Ann Arbor stage at baseline ) was associated with the risk of disease progression ( TABLE ).

The study is limited by its short follow-up , which was not long enough to draw any definite conclusions . In addition , future research should examine optimizing chemotherapy prior to the PET scan , as more effective treatment seems likely to result in less recurrences in the PET-negative group . In addition , incorporating newer agents such as brentuximab vedotin into the initial therapy might be a way to achieve this without producing too much toxicity . Better treatments for the PET-positive group are also needed . ●

REFERENCE

Johnson P , Federico M , Kirkwood A , et al . Adapted treatment guided by interim PET – CT scan in advanced Hodgkin ’ s lymphoma . N Engl J Med . 2016 ; 374:2419-29 .

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