For relapsed-refractory Hodgkin Lymphoma, standard therapy consists of salvage chemotherapy followed by autologous stem cell transplantation. Adverse risk factors at relapse include response duration less than 12 months, advanced stage, extranodal disease, “B” symptoms and anemia. There is no obvious superior salvage regimen although maintaining dose-intensity is important for optimal responses. Assessment of response to salvage using FDG-PET identifies a distinct poor risk group, especially those with extranodal disease. Either a second salvage regimen or a tandem autologous transplant may benefit some patients with residual disease post-salvage. Reduced-intensity allografting may provide durable responses for some patients relapsing post-autologous transplant.
Key points
- •
For RR-HL, standard therapy consists of salvage chemotherapy followed by HDCT/ASCT + RT.
- •
Key adverse risk factors present at relapse/progression include short response duration <12 months, B symptoms, extranodal disease, as well as advanced stage and anemia.
- •
There is no obvious superior salvage therapy among the commonly used regimens such as DHAP, ICE, IGEV; maintaining dose-intensity is important for optimal responses.
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Functional imaging using FDG-PET scanning after salvage chemotherapy and before ASCT is a critical predictor of outcome; the goal of salvage should be a negative FDG-PET scan.
- •
Either a second line of salvage or a tandem ASCT may benefit some patients with residual FDG avidity post-salvage.
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RIC-alloSCT may provide a GVL effect and durable responses in some patients with HL relapsing or progressing after ASCT.
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New agents, particularly Brentuximab vedotin, are being incorporated earlier into the treatment of RR-HL, such as those with FDG-avid chemoresistant disease, those progressing through second-line salvage, or those relapsing after an ASCT.
Introduction
Most patients with Hodgkin lymphoma (HL) are cured by chemotherapy alone with or without additional external beam radiation; however, up to 10% of patients with early-stage favorable HL and up to 30% of patients with early-stage unfavorable or advanced stage disease will either fail to respond to first-line therapy or relapse after an initial complete remission (CR). For those who relapse or fail to achieve a CR, standard therapy involves salvage chemotherapy followed by high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT). Approximately 40% to 50% of RR-HL patients can be cured with HDCT/ASCT, particularly those with more favorable risk features. In contrast, patients with primary refractory disease and/or adverse risk features at relapse, such as extranodal disease or short response duration, may benefit more from other interventions. These alternative approaches include antibody-drug conjugates and reduced-intensity conditioning allogeneic stem cell transplantation (RIC-alloSCT).
Introduction
Most patients with Hodgkin lymphoma (HL) are cured by chemotherapy alone with or without additional external beam radiation; however, up to 10% of patients with early-stage favorable HL and up to 30% of patients with early-stage unfavorable or advanced stage disease will either fail to respond to first-line therapy or relapse after an initial complete remission (CR). For those who relapse or fail to achieve a CR, standard therapy involves salvage chemotherapy followed by high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT). Approximately 40% to 50% of RR-HL patients can be cured with HDCT/ASCT, particularly those with more favorable risk features. In contrast, patients with primary refractory disease and/or adverse risk features at relapse, such as extranodal disease or short response duration, may benefit more from other interventions. These alternative approaches include antibody-drug conjugates and reduced-intensity conditioning allogeneic stem cell transplantation (RIC-alloSCT).
Salvage therapy and HDCT/ASCT
Which Prognostic Factors at Progression/Relapse Are Important?
Over the last 20 years, there have been several reports identifying key prognostic factors in patients with relapsed/refractory Hodgkin lymphoma (RR-HL) who have undergone salvage chemotherapy and ASCT ( Table 1 ).
- 1.
The Groupe d’Etude des Lymphomes de l’Adulte developed a 2-factor model that included as adverse features short CR1 duration, and extranodal disease at relapse.
- 2.
The Autologous Blood and Marrow Transplant Registry identified 3 adverse risk factors including Karnofsky performance score less than 90%, abnormal lactate dehydrogenase (LDH) at ASCT, and chemoresistant relapse.
- 3.
Some of the largest studies of prognostic variables have been conducted by the German Hodgkin study group (GHSG).
- a.
In their first analysis of 206 patients with primary progressive disease they identified 3 adverse risk factors including ECOGPS greater than 0, age greater than 50 years, and failure to obtain a temporary remission to initial therapy.
- b.
In a subsequent study among 422 patients with relapsed HL, they defined a GHSG Clinical Risk Score using 3 adverse prognostic factors for overall survival (OS) including advanced disease stage III/IV, initial response duration of less than 12 months, and anemia (Hb <120 g/L and <105 g/L in men and women). Rates of freedom from second failure at 5 years for patients failing first-line therapy were 45%, 32%, and 18%, for patients with prognostic scores of 0 to 1, 2, and 3, respectively. Hence, this score has been used widely in prospective trials and treatment approaches.
- a.
- 4.
From other large studies, consistent adverse prognostic factors have emerged: short initial response duration, usually within 12 months, advanced stage III/IV at relapse, and extranodal disease (see Table 1 ).
- 5.
Finally, in a prospective study of ifosfamide, carboplatin, etoposide (ICE) salvage among 85 patients, Moskowitz and colleagues developed a prognostic model of 3 adverse risk factors at relapse, including B symptoms, extranodal disease, and CR duration less than 12 months. The presence of 0 to 1 risk factors was associated with an event-free survival (EFS) of 83%, decreasing to 10% for 3 risk factors.
| Reference: Author/Year | N | Prognostic Factors |
|---|---|---|
| A. RR-HL to 1st Line | ||
| Lohri et al, 1991 | 80 | Stage IV at diagnosis, B symptoms at relapse, 1st response <12 mo |
| Reece et al, 1994 | 58 | B symptoms, extranodal disease, 1st response <12 mo |
| Brice et al, 1996 | 187 | 1st response <12 mo, stage III/IV at relapse, relapse in prior irradiated field |
| Brice et al, 1997 | 260 | 1st response <12 mo, extranodal relapse |
| Josting et al, 2000 | 206 | ECOGPS >0, age >50 y, no temporary remission to 1st line |
| Lazarus et al, 2001 | 414 | Karnofsky PS <90%, abnormal LDH at SCT, chemoresistance to salvage |
| Moskowitz et al, 2001 | 65 | B symptoms, extranodal disease, response <12 mo |
| Sureda et al, 2001 | 494 | TTF: chemoresistance at ASCT, ≥2 CT lines; OS: ASCT before 1992, ≥2 lines of therapy |
| Ferme et al, 2002 | 157 | “B” symptoms at progression, salvage without ASCT, and chemoresistance to salvage |
| Bierman et al, 2002 | 379 | IPS factors: serum albumin, anemia, age ≥45 y, lymphocytopenia |
| Josting et al, 2002 | 422 | GHSG Clinical Risk Score: 1st response <12 mo, stage III/IV at relapse, anemia (men <120 g/L, women <105 g/L) |
| Czyz et al, 2004 | 341 | <PR at ASCT, ≥3 prior CT lines |
| Popat et al, 2004 | 184 | Chemoresistance to salvage, stage III/IV, >2 prior CT lines |
| Sureda et al, 2005 | 357 | Year of transplant before 1995, CR1 ≤12 mo, chemoresistance, and ≥1 extranodal site at ASCT |
| Josting et al, 2010 | 241 | Stage IV (not III), early or multiple relapse, anemia |
| Balzarotti et al, 2013 | 330 | Refractory to 1st line, age >40 y, bulk, B symptoms |
| B. Relapse After ASCT | ||
| Martinez et al, 2013 | 511 | Relapse <6 mo after ASCT, stage IV, bulky disease, poor PS, and age ≥50 y at relapse |
| von Tresckow et al, 2013 | 149 | Stage III/IV and B symptoms both present at relapse before ASCT |
| Arai et al, 2013 | 756 | TTR after ASCT of 0–3 mo, >3–6 mo, >6–12 mo |
Which Salvage Regimen?
There are no randomized controlled trials (RCTs) and no consensus as to the most effective salvage regimen for RR-HL. The 2 published RCTs of ASCT (see Table 2 ) used mini-BCNU, etoposide, cytarabine, melphalan (BEAM) or dexa-BEAM as salvage. Although these regimens would still be considered standard, several alternative salvage combinations have been used, reporting overlapping response rates from 60% to 85% ( Table 2 ).
| Regimen | Reference: Author/Year | Number Evaluable | ORR (%) | CR (%) | Toxicity |
|---|---|---|---|---|---|
| Dexa-BEAM | Schmitz et al, 2002 | 144 | 81 | 27 | 5.5% toxic deaths |
| Mini-BEAM | Martin et al, 2001 | 55 | 84 | 51 | IV ANC 86%; 2% deaths |
| MINE | Ferme et al, 2002 | 83 | 75 | NA | 5% toxic deaths (including ASCT) |
| ICE | Moskowitz et al, 2001 | 65 | 88 | 26 | III/IV ANC NR; no toxic deaths |
| ESHAP | Aparicio et al, 1999 | 22 | 73 | 41 | III/IV ANC 59%; 5% toxic deaths |
| MINE-ESHAP | Fernandez de Larrea et al, 2010 | 61 | 79 | 41 | III/IV ANC 46% TCP 40%; 0 toxic deaths |
| ASHAP | Rodriguez et al, 1999 | 56 | 70 | 34 | III/IV ANC 100%; II/III TCP 100%; no toxic deaths |
| DHAP q2 wk | Josting et al, 2002 | 102 | 89 | 21 | IV ANC 43%; IV TCP 48%; no toxic deaths |
| GDP | Baetz et al, 2003 | 23 | 70 | 17 | III/IV ANC/TCP 13%; no toxic deaths |
| GVD | Bartlett et al, 2007 | 91 | 70 | 19 | III/IV ANC 63% TCP 14%; no toxic deaths |
| IGEV | Santoro et al, 2007 | 91 | 81 | 54 | III/IV ANC 28% TCP 20%; no toxic deaths |
| IVE | Proctor et al, 2003 | 51 | 84 | 60 | III/IV ANC 100%; no toxic deaths |
| DICEP | Shafey et al, 2012 | 73 | 86 | 18 | III/IV 1.4% toxic deaths |
| IVOx | Sibon et al, 2011 | 34 | 76 | 32 | III/IV ANC 9%; no toxic deaths |
| O-ESHAP | Martinez et al, 2012 | 45 | 63 | 49 | III/IV ANC 20%; no toxic deaths |
Because most studies incorporate both relapsed and primary refractory HL patients, it is difficult to compare OR and CR rates between regimens. Hematological toxicity is the predominant factor limiting dose intensity, although gastrointestinal (eg, DHAP, Dexa-BEAM) and neurologic (augmented ICE, ifosfamide, gemcitabine, vinorelbine, prednisone) toxicities are also seen. Furthermore, the optimal number of cycles of salvage therapy is not known, although usually 2 to 3 cycles are used, given likely further toxicity and no proven gain in efficacy with additional cycles.
The independent prognostic relevance of dose-density of salvage was also confirmed in the GHSG HDR2 study in relation to progression-free survival (PFS) and OS, thereby supporting the mandatory use of granulocyte colony stimulating factor and in this case the minimal DHAP cycle duration of 14 days.
Why Give HDCT and ASCT?
HDCT/ASCT is considered standard of care for RR-HL patients. The evidence derives from only 2 RCTs comparing HDCT/ASCT conventional chemotherapy. One trial closed prematurely because patients refused randomization and requested ASCT. Although each trial showed no significant improvement in OS, however, PFS was significantly improved with HDCT/ASCT.
In a recent systematic review, the Cochrane Collaboration confirmed a nonstatistically significant trend for improved OS for HDCT/ASCT compared with conventional chemotherapy (HR 0.67; 95% CI 0.41–1.07; P = .1, 157 patients). However, again there was a statistically significant increase in PFS for HDCT/ASCT (HR 0.55; 95% CI 0.35 to 0.86; P = .009, 157 patients).
Are There Differences Between Preparative Regimens for ASCT?
There have been no prospective comparative studies of conditioning regimens for ASCT. At present, there are insufficient data to recommend one conditioning regimen over another. Most studies have used either BEAM or cyclophosphamide, BCNU, VP16 (CBV) conditioning, although more intensive preparative regimens have been used successfully.
- 1.
BEAM versus CBV: The Nebraska group recently undertook a retrospective review of 225 RR-HL patients who were alive and disease-free 2 years after ASCT using either BEAM or CBV conditioning. At 5 years, the PFS was 92% for BEAM and 73% for CBV ( P = .002) and the OS was 95% for BEAM and 87% for CBV ( P = .07), whereas at 10 years the differences were maintained. They could not exclude the possibility that the superior outcomes seen in the BEAM group were because of better supportive care, use of peripheral blood stem cells, or improvements in salvage therapies before transplantation.
- 2.
Busulphan plus Melphalan: Conditioning with GemBuMel has been shown by Nieto and colleagues to be feasible and effective in a group of 84 patients with RR-HL. Multivariate analyses showed independent adverse effects of a conditioning regimen different from Gem-Bu-Mel (HR for EFS = 2.3, P = .0008; HR for OS = 2.7, P = .0005). Similarly, Bains and colleagues undertook a retrospective comparison of 60 patients who received novel conditioning with BuMelTt and 40 who received other regimens. At a median follow-up of 4.3 years, the estimated 5-year OS and PFS were superior for patients treated with BuMelTt (73% vs 44%, P = .05) and (66% vs 37%, P = .03). As a cautionary note, these latter regimens incorporating BuMel are associated with more severe mucositis.
Why Evaluate Response to Salvage Using FDG-PET Pre-ASCT?
In addition to the prognostic factors described above, several studies have shown that functional imaging (FI) (usually positron emission tomography, PET) after salvage chemotherapy and before ASCT is a critical predictor of outcome. All these studies report a substantially inferior long-term PFS in patients who are PET-positive (23%–52%) after salvage chemotherapy compared with those who are PET-negative (69%–88%) ( Table 3 ). Moreover, in most of these studies, univariate and multivariate analyses indicate that pre-ASCT PET status was the only prognostic factor for PFS/EFS after transplant. Hence, PET scanning after salvage may be a powerful prognostic tool that could be applied to the selection of patients for either or both ASCT, consolidation therapy (eg, tandem ASCT), maintenance agents, or RIC-alloSCT.
| Reference: Author/Year | Patient No. | PFS PET-ve | PFS PET+ve | P Value | Prognostic Relevance |
|---|---|---|---|---|---|
| Jabbour et al, 2007 | 211 | 3-y 69% (FI) | 3-y 23% (FI) | <.0001 | PFS = B symptoms, CR/CRu pre-ASCT, BEAM, FI-pos |
| 87% (OS) | 58% (OS) | <.0001 | OS = CR/CRu pre-ASCT, IFRT initially, and BEAM | ||
| Moskowitz et al, 2010 | 153 | 5-y 75% (FI) | 5-y 31% (FI) | <.0001 | OS and PFS: FI alone |
| Moskowitz et al, 2010 | 105 | 4-y 77% (FI) | 4-y 33% (FI) | .00004 | FI eliminated difference between 3 prognostic groups |
| Mocikova et al, 2011 | 76 | 2-y 72.7% | 2-y 36.2% | .01 | PET = ns in multivariate |
| 90.3% (OS) | 61.4% (OS) | .009 | |||
| Smeltzer et al, 2011 | 46 | 3-y 82% | 3-y 41% | .02 | PET for EFS (HR 3.2, P = .03) |
| Sucak et al, 2011 | 43 | 3-y 70.6% | 3-y 37.6% | .008 | PFS: PET-pos pre- and post-ASCT. OS: PET-pos post-ASCT only |
| Devillier et al, 2012 | 111 | 5-y 79% | 5-y 23% | <.001 | PFS: PET (HR: 5.26) and tandem ASCT (HR: 0.39) but not the SFGM 3 risk factors |
| 90% (OS) | 55% (OS) | .001 | OS: PET only (HR, 4.03) | ||
| Moskowitz et al, 2012 | 97 | 4-y 80% | 4-y 28.6% | <.001 | After 1 or 2 salvage regimens (ICE, GVD) |
| Akhtar et al, 2013 | 141 | NR | NR | .011 (OS) | Disease-related death: postsalvage PET ( P = .011); HR: 3.4 (1.3–8.9). Disease-specific event: postsalvage PET ( P = .001); HR: 3.3 (1.7–6.7) |
| Nassi et al, 2013 | 54 | 5-y 88% | 5-y 42% | .0001 | PPV = 58% and NPV = 88% |
| Bramanti et al, 2013 | 67 | 3-y 84% | 3-y 52% | .008 | PET2 and PET4 for PFS ( P = .01) |
| 94% (OS) | 60% (OS) | .002 |
Prospectively, FDG-PET scanning has already been used as part of a response-adapted approach in which patients with 0 to 2 risk factors (B symptoms, extranodal disease, and CR <12 months) who achieve less than a complete metabolic CR (mCR) to initial salvage chemotherapy go on to receive second-line salvage. Moskowitz and colleagues used 2 cycles of ICE in a standard or augmented dose, followed by restaging PET scan. PET-negative patients received an ASCT; PET-positive patients received 4 biweekly doses of a second salvage regimen gemcitabine, vinorelbine, liposomal doxorubicin (see Table 3 ). Patients without evidence of disease progression proceeded to ASCT; those with progressive disease were study failures. At a median follow-up of 51 months, EFS analyzed by both intent to treat and for transplanted patients was 70% and 79%, respectively. Patients transplanted with negative pre-ASCT PET (after 1 or 2 salvage regimens) had an EFS of greater than 80% versus 28.6% for PET-positive patients ( P <.001). Notably, there was no difference in EFS and OS between relapsed and refractory patients. These data argue that the goal of salvage in patients with RR-HL should be a negative FDG-PET scan before ASCT.
Can Results of ASCT Be Improved by Sequential HDCT or Tandem ASCT?
Other attempts to intensify the salvage therapy have included additional sequential HDCT (SHDCT), or tandem ASCT.
SHDCT
There has been one RCT, the HDR2 study, evaluating the effect of SHDCT before ASCT in 284 relapsed HL patients. All patients received 2 cycles of DHAP, followed either directly by ASCT with BEAM, or first by sequential cyclophosphamide, methotrexate, and etoposide before BEAM. Both the final trial analysis and the analysis undertaken by the Cochrane Collaboration found no difference between treatment arms for OS (HR 0.93; P = .86, 3-year OS: 80% SHDCT vs 87% HDCT) or PFS (HR 0.87; P = .505). There was also no benefit for SHDCT for those patients in early relapse (3–12 months) following initial induction therapy.
Tandem ASCT
Five phase II studies addressed the role of tandem ASCT in RR-HL ( Table 4 ). The largest of these trials, the H96 study, evaluated a risk-adapted salvage treatment with either single or tandem ASCT for 245 patients. Poor-risk patients (n = 150) had primary refractory HL (n = 77) or unfavorable relapse (≥2 risk factors: time to relapse <12 months, stage III/IV, and relapse within previously irradiated sites, n = 73) and were eligible for tandem ASCT. Intermediate-risk patients (n = 95) had one risk factor at first relapse and were eligible for a single ASCT. The 45% 5-year OS in patients with first-line chemotherapy-resistant disease who completed tandem transplant compares favorably with previously reported 5-year OS rates of 30%. At a recent 10-year follow-up, freedom from treatment failure and OS were 64% and 70%, respectively, for the intermediate-risk group (single ASCT), and 40% and 47%, respectively, for the poor-risk group (tandem ASCT).
| Reference: Author/Year | N | Preparative Regimen | FFP | OS |
|---|---|---|---|---|
| Brice et al, 1999 | 42 | IVA75 salvage: | ||
| 39 (asct-1) | 1. CBV + Mitox | 2-y 65% (itt) | 2-y 65% (itt) | |
| 32 (asct-2) | 2. AraC + Mel + TBI or Bu | 2-y 74% (asct-2) | 2-y 74% (asct-2) | |
| Castagna et al, 2007 | 32 | IGEV salvage: | ||
| 29 (asct-1) | 1. Mel 200 | 3-y 63% (itt) | 3-y 79% (itt) | |
| 27 (asct-2) | 2. BEAM | |||
| Fung et al, 2007 | 46 | Cy/Et or other salvage: | 5-y 49% (itt) | 5-y 54% (itt) |
| 44 (asct-1) | 1. Mel 150 | |||
| 41 (asct-2) | 2. Cy + Et + BCNU or TBI | 5-y 49% (asct-2) | 5-y 57% (asct-2) | |
| Morschhauser et al, 2008 | 150 (bad risk) | IVA75 or MINE salvage: | 5-y 41%–52% (itt) | 5-y 53%–61% (itt) |
| 137 (asct-1) | 1. CBV-Mx or BEAM | |||
| 118 (asct-2) | 2. TAM or BAM | 5-y 36%–64% (asct-2) | 5-y 45%–75% (asct-2) | |
| Dean et al, 2012 | 42 | Mixed salvage: | ||
| 37 (asct-1) | 1. Mel 150 | Med = 15.5 mo (asct-2) | Med = 54.9 mo (asct-2) | |
| 37 (asct-2) | 2. CBV or BuCyEt | vs = 26.3 mo in controls | vs = 73.1 mo in controls |
In a recent retrospective analysis, Devillier and colleagues described 111 patients who were assigned to either a single or tandem ASCT depending on a combination of the 3 SFGM adverse prognostic factors at relapse and PET responsiveness to salvage. They showed that PET status before ASCT was a much stronger predictor of outcomes than classical risk factors at relapse, and that tandem ASCT could be superior to single ASCT (5-year PFS of 74% vs 48%, respectively, P = .002). Furthermore, in the PET-positive group, tandem ASCT improved the 5-year PFS from 0% in the single ASCT to 43% ( P = .034).
Taken together, these studies suggest that a tandem ASCT may represent an effective option for a substantial subset of poor risk RR-HL patients.
Can Results of ASCT Be Improved by Incorporating Novel Agents?
Recent strategies designed to improve the results of HDCT/ASCT have added novel agents such as Brentuximab vedotin (BV) either to the salvage regimen (ESHAP, DHAP) or as post-ASCT maintenance, particularly in those patients considered at high risk of relapse.
- 1.
In a current phase III trial (AETHERA) those deemed at high risk of relapse (primary refractory, relapsed/progressive HL <12 months from frontline therapy, or extranodal involvement at relapse) are randomized to placebo or maintenance BV ( www.ClinicalTrials.gov No. NCT01100502 ).
- 2.
An important question is whether BV could replace ICE or DHAP salvage. With that in mind, investigators at MSKCC are evaluating single-agent BV as initial pre-ASCT salvage ( www.ClinicalTrials.gov No. NCT01508312 ). PET-negative patients after 2 BV cycles proceed to ASCT; FDG-avid patients receive 2 cycles of augmented dose ICE followed by ASCT.
- 3.
In addition, a phase II study in patients with primary refractory or progressive HL after standard frontline therapy is evaluating salvage with single-agent BV (maximum 4 cycles) before ASCT ( www.ClinicalTrials.gov No. NCT01393717 ).
What is the Prognosis for Patients Who Relapse Post-ASCT?
Among chemosensitive patients with relapsed HL, 40% to 50% will fail to respond to salvage chemotherapy and HDCT/ASCT; among patients refractory to first-line therapy, up to 60% to 75% will fail to respond.
- 1.
From a large retrospective analysis of the EBMT-GITMO databases 511 patients were identified who relapsed after ASCT (see Table 1 ). Treatment included conventional chemotherapy and/or radiation in 294 (64%), a second ASCT in 35 (8%), and an alloSCT in 133 (29%). Independent risk factors for OS were early relapse less than 6 months after ASCT, stage IV, bulk, poor ECOGPS, and age ≥50 years. At 5 years, OS ranged from 62% for those with no risk factors to 12% for those with ≥2 risk factors.
- 2.
The GHSG identified 149 patients who relapsed or progressed after ASCT. For the entire group, the median survival was less than 2 years with 20% survival at 5 years. For those with the 0, 1, and 2 risk factors (stage III/IV and B symptoms before ASCT), 5-year OS was 41%, 27%, and 8%, respectively (see Table 1 ).
- 3.
OS strongly correlates with the time to relapse after ASCT; for patients who relapse within 6 months of ASCT, median survival is 1.5 years. These adverse outcomes were again highlighted in a recent international collaborative analysis of 756 patients, which showed the median OS and PFS after ASCT failure was 2.4 years and 1.3 years. The data confirmed time to relapse after ASCT as a prognostic factor, with median PPS of 0.98 versus 2.26 years for relapses less than 12 months or greater than 12 months, respectively.
These correlates of prognostic factors and survival outcomes help to identify post-ASCT relapsing patients as a reference group for whom novel strategies can be assessed.
Do we need RIC-alloSCT for RR-HL?
The standard of care for patients whose disease progresses or relapses following an autoSCT has not been fully established and has led to exploration of allogeneic SCT, which combines the antitumor effect of chemotherapy with the potential advantage of a graft-versus-lymphoma (GVL) effect mediated by donor T cells and natural killer cells.
There have been no randomized comparisons between a second ASCT and an alloSCT. Numerous retrospective comparisons have been performed. Notwithstanding the caveats of such analyses including the patient heterogeneity, and the use of both myeloablative conditioning (MAC) and RIC, these studies do suggest the presence of a long-term survival benefit for allo-SCT in a subset of patients with high-risk RR-HL.
What About Myeloablative Allogeneic SCT?
MAC derives its benefit from a combination of the intensive preparative regimen and the putative GVL effect. However, MAC is associated with high rates of nonrelapse mortality (NRM) ranging from 39% to 61%. The high NRM is likely a result of the cumulative toxicity of previous combined modality treatments, intensive salvage chemotherapy, selection of high-risk patients with advanced disease, and the immunodeficiency seen commonly in HL that predisposes patients to infectious complications.
What Is the Advantage of RIC-alloSCT Compared to MAC?
Direct comparisons of MAC and RIC regimens are difficult because patients are often selected for the latter because of prior extensive therapy or comorbidities. Nevertheless, in the largest series comparing MAC with RIC, Sureda and colleagues showed that RIC significantly decreases NRM even in patients with poor prognostic features at the time of allograft with a 3-year NRM of 24% for RIC versus 48% for MAC. In that study, the improved NRM associated with RIC-alloSCT was offset substantially by the increase in disease progression/relapse of 58% versus 32% for RIC and MAC, respectively. In other studies, reduced NRM rates of 8% to 24% have translated into a better OS and a trend toward better PFS for patients treated with the RIC regimens ( Table 5 ).
Related posts:
Brentuximab Vedotin for the Treatment of Patients with Hodgkin Lymphoma
Early Intensification Treatment Approach in Advanced-stage Hodgkin Lymphoma
FDG-PET Response–adapted Therapy
First Hodgkin Cell Line L428 and the CD30 Antigen
Induction Therapy for Advanced-stage Hodgkin Lymphoma
FDG-PET Response–adapted Therapy
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