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BV-DHAP in relapsed or refractory Hodgkin lymphoma
Patients' characteristics for the phase II patients are summarized in Table 1. Median age was 29 years, and 27 patients were female (49%). Twenty-three patients (43%) had primary refractory disease and 16 patients (29%) had relapsed within one year of first-line treatment. Among the first 20 patients of phase II (stage 1), enough responses were observed (16 mCR) with acceptable toxicity (7 patients experienced significant toxicity) for the DSMB to approve proceeding to stage 2.
Of the 55 enrolled patients, 49 (89%) completed all three cycles of BV-DHAP, and 47 (85%) underwent BEAM and auto-PBSCT (Figure 1). Two patients withdrew con- sent after cycle 1 due to psychological issues, and two patients had PD after cycle 2. In cycle 3, two patients did not receive BV due to toxicity. One of these patients received VIM (ifosfamide, mitoxantrone and etoposide) in cycle 3 because of hepatotoxicity and was not evaluable for response. However, this patient still proceeded suc- cessfully to BEAM and auto-PBSCT. The other patient received DHAP without BV because of an anaphylactic shock following BV infusion in cycle 2. This patient went off study thereafter because of toxicity and a mixed response by local PET-CT assessment (which was eventu- ally considered mCR by central PET-CT review) and pro- ceeded to auto-PBSCT after additional treatment with miniBEAM.
Besides the two patients who did not receive BV in cycle 3, dose reductions or delays included three delays of cycle 2 due to infection (n=1), venous thrombosis (n=1), or neutropenia (n=1), and three delays of BV infusion due to IRR (grade 1/2). Cycle 3 was delayed in two patients (malaise and neutropenia), and there were two delays of BV infusion (IRR: one grade 2 and one grade 3). Furthermore, eight patients switched from cisplatin to car- boplatin due to ototoxicity (n=7; grade 1/2) or nephrotox- icity (n=1; grade 3, recovered completely), and one patient received no cisplatin and cytarabine in cycle 3 due to elec- trolyte disorder and sepsis.
Efficacy and stem cell harvest
Three patients were not evaluable for response after three cycles of BV-DHAP: two patients withdrew consent after cycle 1, and one patient did not have a PET-CT scan after cycle 3. By independent central PET-CT review, 42 of 52 evaluable patients achieved an mCR (81% [95%CI: 67- 90]) and five patients an mPR (10%), resulting in an overall response rate of 90% (95%CI: 79-97). A total of five patients had PD (10%) and did not proceed to BEAM. Two of those patients showed PD on a CT scan after cycle 2 and three had PD on the PET-CT scan after cycle 3 (Figure 1). After auto-PBSCT, four out of five patients with mPR converted to mCR. One patient had a persisting mPR and received additional radiotherapy according to the local physician’s decision, and is still in mCR thereafter.
There were no significant differences in baseline charac- teristics (i.e., age, time to relapse and first-line treatment) between patients with mCR or mPR. The mCR rate was lower for patients with primary refractory disease com- pared to patients with a later relapse, but this was not sta- tistically significant (mCR rate 73% [95%CI: 69-96] vs. 86% [95%CI: 50-89]; P=0.29, respectively).
Stem cell harvest after cycle 2 was successful using G- CSF in all patients, with one apheresis session in 43 patients and two apheresis sessions in nine patients, of whom two patients received plerixafor (3 patients went
Table 1. Patients' characteristics.
Age, years Median [range]
Female
Ann Arbor stage at baseline
I
II
III
IV Unknown
ECOG PS at baseline
0
1 Unknown
Baseline B symptoms Bone marrow involvement First-line treatment
ABVD
BEACOPP baseline Escalated BEACOPP Other
Prior radiotherapy
Response to first-line treatment
CR
PR
SD 2(4)
Phase II patients (n=55) N of patients (%)
29 [19-71]
27 (49)
8 (15) 16 (29) 10 (18) 20 (36) 1 (2)
35 (64) 17 (31) 3 (5) 20 (36) 2 (4)
40 (73) 2 (4) 8 (15) 5 (9) 9 (16)
PD
Time from response to first-line treatment to relapse
Primary refractory disease* Relapse within 1 year
Relapse after 1 year
Median time, months [range])
11 (20)
23 (42) 16 (29) 16 (29) 5 [0-160]
32 (58) 10 (18)
*Primary refractory disease is defined as failure to obtain a complete response with front-line therapy. N: number; ECOG PS: Eastern Cooperative Oncology Group Performance Score;ABVD:adriamycin,bleomycin,vinblastine,and dacarbazine;BEA- COPP: bleomycin, etoposide, adriamycin, cyclophosphamide, vincristine, procar- bazine, and prednisone; CR: complete response; PR: partial response; SD: stable dis- ease; PD: progressive disease.
off study before apheresis). The median yield was 5.3x106 CD34+/kg (range: 1.8-22.7).
Safety
During BV-DHAP treatment, 20 patients (36%) experi- enced one or more AE that met the dose-limiting toxicity criteria (considered significant toxicity).
Grade 3/4 neutropenia and thrombocytopenia were common (Online Supplementary Table S3). After BEAM/auto-PBSCT, the median recovery time to an absolute neutrophil count (ANC) ≥0.5x109/L was 12 days (range: 8-29), and the median recovery time to platelets ≥20x109/L was 15 days (range: 6-46) (Online Supplementary Table S3).
During BV-DHAP, febrile neutropenia (n=14) was the most common non-hematologic grade 3/4 toxicity, fol- lowed by elevated liver enzymes (n=10) and electrolyte disorders (n=6) (Table 2). After BEAM/auto-PBSCT, one
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