Recurrent Hodgkin Lymphoma

2. Engert A, Plutschow A, Eich HT, et al. Reduced treatment intensity in patients with early-stage Hodgkin's lymphoma. N Engl J Med. 2010;363(7):640-652. ExperimentalTx 1,370 patients To compare 4 treatment groups consisting of a combination chemotherapy regimen of 2 different intensities followed by IFRT at 2 different dose levels. The 2 chemotherapy regimens did not differ significantly with respect to freedom from treatment failure (P=0.39) or OS (P=0.61). At 5 years, the rates of freedom from treatment failure were 93.0% (95% CI, 90.5 to 94.8) with the 4-cycle ABVD regimen and 91.1% (95% CI, 88.3 to 93.2) with the 2-cycle regimen. When the effects of 20-Gy and 30Gy doses of RT were compared, there were also no significant differences in freedom from treatment failure (P=1.00) or OS (P=0.61). Adverse events and acute toxic effects of treatment were most common in the patients who received 4 cycles of ABVD and 30 Gy of RT (group 1). 1


Experimental-Tx 1,370 patients
To compare 4 treatment groups consisting of a combination chemotherapy regimen of 2 different intensities followed by IFRT at 2 different dose levels.
The 2 chemotherapy regimens did not differ significantly with respect to freedom from treatment failure (P=0.39) or OS (P=0.61). At 5 years, the rates of freedom from treatment failure were 93.0% (95% CI, 90.5 to 94.8) with the 4-cycle ABVD regimen and 91.1% (95% CI, 88.3 to 93.2) with the 2-cycle regimen. When the effects of 20-Gy and 30-Gy doses of RT were compared, there were also no significant differences in freedom from treatment failure (P=1.00) or OS (P=0.61). Adverse events and acute toxic effects of treatment were most common in the patients who received 4 cycles of ABVD and 30 Gy of RT (group 1). Observational-Tx 422 patients To evaluate salvage treatment outcome of patients with relapsed HL and to distinguish different risk groups using identified prognostic factors.
Median follow-up time after relapse was 45 months. FF2F and OS were 81% and 89% for relapse after RT, 33% and 46% for early relapse after chemotherapy, and 43% and 71% for late relapse after chemotherapy, respectively. In multivariate analysis, independent risk factors were time to relapse, clinical stage at relapse, and anemia at relapse. 4 subgroups with significantly different FF2F and OS were identified. The prognostic score was predictive for patients who relapsed after RT, chemotherapy with conventional chemotherapy salvage, and chemotherapy with HDCT/ASCT. Experimental-Tx 157 patients To evaluate prospectively the feasibility and efficacy of early intensive therapy, including intensified cytoreductive chemotherapy and HDCT followed by ASCT, in patients with advanced HL who failed to respond completely or relapsed after initial treatment.
With a median follow-up of 50 months, the 5year survival estimates were 30%, 72%, and 76% for the induction failure, partial response, and relapse groups, respectively (P=.0001), 71% for the 101 patients given HDCT, and 32% for the 48 patients treated without HDCT (P=.0001). Multivariate analysis using timedependent Cox model indicated that B symptoms at progression, salvage without HDCT, and chemoresistant disease before HDCT were significantly associated with shorter OS. Observational-Tx 59 patients To further evaluate the prognostic significance of new biological markers in classic HL by comparing the expression of bcl2, Ki67 and CD20 expression in H/RS cells of refractory and early relapse patients to that of responder patients; to compare the expression of TiA1 in surrounding T lymphocytes as a putative marker of an anti-tumoral immune response in both groups of patients; and, to look at the expression of c-kit to evaluate the presence of mastocytes, which might modify the behavior of classic HL.
The results showed that expression of bcl2 and CD20 in Hodgkin and Reed Sternberg cells, and expression of TiA1 in microenvironmental lymphocytes, and c-kit positive mast cells in microenvironment, were independent prognostic markers. Median age at ASCT was 30 years (range, 7-60 years); 21 patients had primary refractory, and 120 had relapsed HL. With a median follow-up of 6.3 years (range, 1-20 years), the probability of PFS at 5 and 10 years was 48% (95% CI, 39%-57%) and 45% (95% CI, 36%-54%) and that of OS was 53% (95% CI, 44%-62%) and 47% (95% CI, 37%-57%), respectively. The median age of the 102 patients included was 34 years (range 21-64 years). 42% of the patients had late relapse, 29% early relapse, 12% multiple relapse and 16% primary progressive/refractory disease. The response rate after 2 cycles of dexamethasone/cisplatin/cytarabine was 89% (21% complete response, 68% partial response). The response rates for patients with late, early, multiple and progressive HL were 91%, 93%, 92% and 65%, respectively. Using the chi-square test for independence, remission status (relapsed HL vs progressive HL) and stage at relapse (stage I/II vs stage III/IV) were significant factors for response to dexamethasone/cisplatin/cytarabine. WHO grade 4 leukocytopenia and thrombocytopenia were the main toxicities occurring in 43% (mean duration 1.1 days, range 0-6) and 48% (mean duration 1.4 days, range 0-11) of all courses, respectively. Neither severe infections nor treatment-related deaths occurred. Peripheral blood stem cells were collected after the first cycle dexamethasone/cisplatin/cytarabine in 8 patients. The hematopoietic progenitors showed a very rapid increase from day 10 with a synchronous and impressive peak on day 12. A mean of 6.1 x 10(6)/kg CD34(+) cells were collected per apheresis. As originally recommended in the protocol, peripheral blood stem cells were routinely collected during sequential HDCT in the remaining patients. Data from 3 centers are reported (n=241) and data from 2 additional centers (n=128) will be available for presentation. Selection for high dose chemotherapy and autotransplantation was center-dependent but primarily represented patient <60 years with stable or responding disease after their last therapy and prior to high dose chemotherapy and autotransplantation. Relapses after high dose chemotherapy and autotransplantation were distributed as follows: 0-3 m(23%), >3-6m(20%), >6-12m (30%) and >12m (27%) for Centers 1-3. Median OS by center (N Patients) and time to relapse after high dose chemotherapy and autotransplantation (0-3, >3-6, >6-12, >12 months) were: Center 1

patients
To examine the activity and tolerability of brentuximab vedotin as second-line therapy in patients with HL that was relapsed or refractory after induction therapy.
Of 37 patients, the overall response rate was 68% (13 complete remission, 12 partial remission). The regimen was well tolerated with few grade 3/4 adverse events, including lymphopenia (1), neutropenia (3), rash (2), and hyperuricemia (1). 32 patients (86%) were able to proceed to autologous hematopoietic cell transplantation, with 24 patients (65%) in complete remission at time of autologous hematopoietic cell transplantation. 13 patients in complete remission, 4 in partial remission, and 1 with stable disease (49%) received autologous hematopoietic cell transplantation without salvage combination chemotherapy. CD68 expression did not correlate with response to brentuximab vedotin. The median number of stem cells mobilized was 6.0 x 10(6) (range, 2.6 to 34), and median number of days to obtain minimum collection (2 x 10(6)) was 2 (range, 1 to 6). Of the 23 study patients, 78% were enrolled in the study after a relapse following ASCT and 78% after a relapse following the receipt of brentuximab vedotin. Drug-related adverse events of any grade and of grade 3 occurred in 78% and 22% of patients, respectively. An objective response was reported in 20 patients (87%), including 17% with a complete response and 70% with a partial response; the remaining 3 patients (13%) had stable disease. The rate of PFS at 24 weeks was 86%; 11 patients were continuing to participate in the study. Reasons for discontinuation included stem-cell transplantation (in 6 patients), disease progression (in 4 patients), and drug toxicity (in 2 patients). Analyses of pretreatment tumor specimens from 10 patients revealed copy-number gains in PDL1 and PDL2 and increased expression of these ligands. Reed-Sternberg cells showed nuclear positivity of phosphorylated STAT3, indicative of active JAK-STAT signaling.

patients
To describe a distinct, previously unpublished cohort of 25 heavily pretreated patients with CD30 HL that relapsed after allogeneic stem cell transplantation (median of 9 treatment regimens; range, 5-19) and summarize the safety, efficacy, and potential impact of brentuximab vedotin on the unique postallogeneic stem cell transplantation immunologic milieu.
Overall and complete response rates were 50% and 38%, respectively, among 24 evaluable patients. Median time to response was 8.1 weeks, median PFS was 7.8 months, and the median OS was not reached. Cough, fatigue, and pyrexia (52% each), nausea and peripheral sensory neuropathy (48% each), and dyspnea (40%) were the most frequent adverse events. The most common adverse events ≥grade 3 were neutropenia (24%), anemia (20%), thrombocytopenia (16%), and hyperglycemia (12% Observational-Tx 51 patients To report outcomes for patients with relapsed/refractory HL who received total lymphoid irradiation followed by high-dose chemotherapy and autologous hematopoietic stem cell transplant.
Of 51 patients treated with total lymphoid irradiation and autologous hematopoietic stem cell transplant, 59% had primary refractory disease and 63% had active disease at autologous hematopoietic stem cell transplant.
The 10-year PFS and OS for all patients was 56% and 54%, respectively. Patients with complete response by PET prior to autologous hematopoietic stem cell transplant had a 5year PFS and OS of 85% and 100% compared to 52% and 48% for those without complete response (P=0.09 and P=0.007, respectively).

patients
To evaluate a tandem ASCT in terms of toxicity and efficacy in unfavorable patients.
Hematologic recovery was normal after ASCT1 but delayed platelet recovery was observed after ASCT2 with busulfan in the conditioning regimen. Two grade 4 venoocclusive disease with 1 fatal occurred with busulfan at 16 mg/kg and 1 hemorrhagic cystic, no further grade 4 toxicity was observed with the reduced doses of busulfan (12 mg/kg). After ASCT2, 83% of these unfavorable patients were in remission and 20% relapsed within the first year. On an intent-to-treat analysis, 22/43 patients are in continuous complete response (including 8 patients with induction failure). For the whole population (n = 43) and for patients receiving the 2 ASCT (n = 32), the 2-year survival from the date of progression were respectively at 65% and at 74%. Meta-analysis 1,245 patients; 5 randomized controlled trials studies To perform a systematic review with metaanalysis of randomized controlled trials comparing chemotherapy alone with combined-modality therapy in patients with early stage HL with respect to response rate, PFS (alternatively tumor control) and OS. 5 randomized controlled trials involving 1,245 patients were included. The hazard ratio was 0.41 (95% CI, 0.25 to 0.66) for tumor control and 0.40 (95% CI, 0.27 to 0.61) for OS for patients receiving combined-modality therapy compared to chemotherapy alone. Complete response rates were similar between treatment groups. In sensitivity analyses another 6 trials were included that did not fulfill the inclusion criteria of our protocol but were considered relevant to the topic. These trials underlined the results of the main analysis. Observational-Tx

patients
To report the failure-free outcomes of patients with and without postchemotherapy PET positivity treated with consolidative RT, and we also discuss the implications of midtreatment PET positivity in the context of routine postchemotherapy radiation treatment. To show noninferiority of tumor control for the experimental groups and to assess if RT given only to patients with a persistent mass measuring 2.5 cm or more, and positive on PET scan after chemotherapy, was adequate.
A total of 1,364 patients with clinical stage I or II HL were treated with initial RT, of whom 473 relapsed. The probability of survival 10 years after relapse was 63%. For cause-specific survival, both multivariate and univariate analysis identified the importance of age at presentation and histological subtypes. When all causes of death were considered, the multivariate analysis identified age as the only significant factor. The length of initial disease-free interval had no influence on prognosis after relapse, but the 169 patients with nodal relapse had a higher cause-specific survival than those with an extranodal component of relapse (74% vs 51% at 10 years, P<0.005). At a 4-year follow-up, no difference in survival was evidenced. In patients with unfavorable prognostic indicators, 3 MOPP-RT-3 MOPP were compared with 3 ABVD-RT-3 ABVD. From H1 to H5 trials, the proportion of patients having received chemotherapy during the course of the disease gradually decreased; the data suggest that a further reduction in the proportion of patients aggressively treated is conceptually possible. On the basis of the prognostic factors identified, one can delineate 3 subsets of patients and modulate toxic cost of the initial treatment according to the characteristics of these subsets. In the most favorable subgroup, RT alone produces high survival and chemotherapy is not justified. Patients with relapsed HL should be identified according to their prognostic factors at relapse (duration of remission and extranodal disease or stage). This enables relapsing patients to be separated in to 3 different prognostic groups; primary refractory patients should be included in the unfavorable group because of their poor prognosis. All relapsed HL should receive second-line chemotherapy and the response to this chemotherapy is crucial for the outcome. Benefit of ASCT has been shown in a large randomized study and, although is often proposed in relapsed HL, it may be not necessary in the rare group of patients with stage I/II and late relapse who can receive additional RT after response to chemotherapy. Patients with intermediate and unfavorable relapse should receive HDCT and ASCT when chemosensitive; the first goal is to achieve this chemosensitivity. For patients in the unfavorable group, including refractory patients, the role of tandem HDCT or ASCT will be discussed and should be proposed for patients not in complete remission at the time of HDCT.

Evidence Table Key
Study Quality Category Definitions  Category 1 The study is well-designed and accounts for common biases.
 Category 2 The study is moderately well-designed and accounts for most common biases.  Category 3 There are important study design limitations.
 Category 4 The study is not useful as primary evidence. The article may not be a clinical study or the study design is invalid, or conclusions are based on expert consensus. For example: a) the study does not meet the criteria for or is not a hypothesis-based clinical study (e.g., a book chapter or case report or case series description); b) the study may synthesize and draw conclusions about several studies such as a literature review article or book chapter but is not primary evidence; c) the study is an expert opinion or consensus document.