HEMONC 160 February 2017 Hematol Oncol Stem Cell Ther (2017) xxx, xxx– xxx No of Pages 10, Model 6+ Available at www.sciencedirect.com ScienceDirect journal homepage: www.elsevier.com/locate/hemonc Relapse of Hodgkin lymphoma after autologous transplantation: Time to rethink treatment? Yogesh Jethava a, Guru Subramanian Guru Murthy b, Mehdi Hamadani b,* 10 11 a b Division of Hematology-Oncology, University of Arkansas for Medical Sciences, Little Rock, AR, USA Division of Hematology and Oncology, Medical College of Wisconsin, Milwaukee, WI, USA Received September 2016; accepted 29 December 2016 12 22 23 14 24 15 25 16 26 17 27 18 28 19 29 20 30 21 31 32 33 34 35 36 37 38 39 40 41 46 43 42 44 45 KEYWORDS Allogeneic; Autologous; Hematopoietic cell transplantation; Immunotherapies; Hodgkin lymphoma; Relapse Abstract Relapse of Hodgkin lymphoma after autologous hematopoietic cell transplantation (autologous HCT) is a major therapeutic challenge Its management, at least in younger patients, traditionally involves salvage chemotherapy aiming to achieve disease remission followed by consolidation with allogeneic hematopoietic cell transplantation (allogeneic HCT) in eligible patients The efficacy of salvage therapy is variable and newer combination chemotherapy regimens have improved the outcomes Factors such as shorter time to relapse after autologous HCT and poor performance status have been identified as predictors of poor outcome Newer agents such as immunoconjugate brentuximab vedotin, checkpoint inhibitors (e.g., pembrolizumab, nivolumab), lenalidomide, and everolimus are available for the treatment of patients relapsing after autologous HCT With the availability of reduced intensity conditioning allogeneic HCT, more patients are eligible for this therapy with lesser toxicity and better efficacy due to graft versus lymphoma effects Alternative donor sources such as haploidentical stem cell transplantation and umbilical cord blood transplantation are expanding this procedure to patients without HLA-matched donors However, strategies aimed at reduction of disease relapse after reduced intensity conditioning allogeneic HCT are needed to improve the outcomes of this treatment This review summarizes the current data on salvage chemotherapy and HCT strategies used to treat patients with relapsed Hodgkin lymphoma after prior autologous HCT Ó 2017 King Faisal Specialist Hospital & Research Centre Published by Elsevier Ltd This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-ncnd/4.0/) * Corresponding author at: Center for International Blood and Marrow Transplant Research, Medical College of Wisconsin, 9200 West Wisconsin Avenue, Suite C5500, Milwaukee, WI 53226, USA E-mail address: mhamadani@mcw.edu (M Hamadani) http://dx.doi.org/10.1016/j.hemonc.2016.12.002 1658-3876/Ó 2017 King Faisal Specialist Hospital & Research Centre Published by Elsevier Ltd This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/by-nc-nd/4.0/) Please cite this article in press as: Jethava Y et al., Relapse of Hodgkin lymphoma after autologous transplantation: Time to rethink treatment?, Hematol Oncol Stem Cell Ther (2017), http://dx.doi.org/10.1016/j.hemonc.2016.12.002 HEMONC 160 February 2017 No of Pages 10, Model 6+ 47 Y Jethava et al Introduction 64 Autologous hematopoietic cell transplantation (HCT) is an established treatment option for relapsed or refractory Hodgkin lymphoma (HL) However, even after autologous HCT, a subset of poor-risk patients, who present with B-symptoms, bulky disease, advanced stage, or extranodal involvement have a high incidence of relapse It is particularly challenging to manage such patients because they are often young, without medical comorbidities, and are able to tolerate additional therapies Hence, the expectations of achieving a cure are high Multiple options such as single agent chemotherapy, combination chemotherapy strategies, radiotherapy, antibody–drug conjugates, immune checkpoint inhibitors, immunomodulatory agents, small molecule inhibitors, or allogeneic HCT are available for HL relapsing after autologous HCT This review evaluates the different modalities of treatment for HL patients relapsing after an autologous HCT 65 Risk factors for relapse after autologous HCT 48 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 66 67 68 69 70 71 72 73 74 75 76 77 78 79 80 81 82 83 84 85 86 87 88 89 90 91 92 93 94 95 96 97 98 99 100 It is important to identify HL patients upfront who might be at higher risk of relapse after autologous HCT In a Center for International Blood and Marrow Transplant Research (CIBMTR) analysis of 606 children, adolescents, and young adults with relapsed/refractory HL who underwent autologous HCT between 1995 and 2010, Satwani et al [1] identified four risk factors that predicted poor progression-free survival (PFS) following autologous HCT These include: (1) time from diagnosis to first relapse of 61 year (including primary refractory disease), (2) Karnofsky performance score 12 months from first autologous HCT were associated with improved survival Although this is an alternative option for patients in whom allogeneic HCT is not feasible, it is not the recommended therapy of choice for relapse after prior autologous HCT for HL [31] Allogeneic HCT for HL In patients who relapse after autologous HCT for HL, allogeneic HCT is often considered as the next effective treatment option which could offer long-term cure Prolonged disease control in patients receiving reduced intensity conditioning (RIC) regimens suggest the presence of clinically relevant graft versus lymphoma effect after allogeneic HCT [32] The concept of graft-versus-lymphoma effect is also reinforced by the demonstration of disease control after donor lymphocyte infusions and lesser incidence of disease progression in patients who develop chronic graftversus-host disease (GVHD) Myeloablative conditioning versus RIC in relapsed HL Earlier studies comparing myeloablative conditioning (MAC) versus RIC allogeneic HCT for HL showed superior [33,34] outcomes of RIC strategy as there was a high TRM associated with MAC [33,34] A retrospective analysis of the EBMT database by Sureda et al [35] compared the outcomes of RIC versus MAC in 168 patients with relapsed HL Compared with MAC, recipients of RIC HCT had a lower nonrelapse mortality (NRM; 46% vs 23% at years), better OS (22% vs 28% at years), and a trend towards better PFS, although relapse rate was higher with RIC allogeneic HCT (30.4% vs 57.3%) However, a recent study using EBMT database demonstrated a statistically similar NRM (11% and 12%), PFS (54% and 39%), and OS (75% and 65%) between MAC versus RIC transplants and MAC was found to decrease the relapse risk [36] Hence, in select young fit patients, considering MAC is not unreasonable Studies also demonstrate better outcomes with subsequent allogeneic HCT as compared with conventional salvage therapy in patients with HL who relapse after autologous HCT In a retrospective study, Thompson et al [37] included 72 patients with HL who relapsed after autologous HCT and subsequently underwent RIC allogeneic HCT (n = 38) versus no further HCT (n = 34) They demonstrated a superior OS following RIC HCT compared with conventional therapy (10-year OS 48% vs 15%; p = 0014) In another study, Sarina et al [38] conducted a donor versus no donor analysis to determine the outcomes of patients with relapsed HL They found a significantly better OS and PFS for patients with available donors for allogeneic HCT (4-year OS 43% in the donor group and 15% in the no donor group, 4-year PFS 26% vs 11%, p < 001) It was also demonstrated that chemoresistant disease, shorter time to relapse after autologous HCT, and acute GVHD were predictors of poor survival These studies demonstrate the superiority of RIC allogeneic HCT over conventional chemotherapy for relapse after autologous HCT However, no randomized prospective studies comparing allogeneic HCT against nontransplant modality are available in patients with relapse/ refractory HL 412 Outcomes with RIC allogeneic HCT 424 Outcomes of RIC allogeneic HCT for HL relapse after autologous HCT had been demonstrated in retrospective studies (Table 3) In a large retrospective study by Robinson et al [39] 285 patients with HL underwent RIC allogeneic HCT, 80% of whom had failed prior autologous HCT The majority of patients (43%) had chemosensitive disease and received stem cells from matched related donor (MRD; 60%) and 48.1% received T-cell depleted graft A 3-year OS of 29% and PFS of 25% were demonstrated The cumulative incidence of disease progression at years was shown to be 59% In a retrospective analysis of the CIBMTR database by Devetten et al [40], 143 patients with relapsed HL who underwent allogeneic HCT from matched unrelated donors (MUD) were included and showed a 2-year PFS of 20%, 2year OS of 37%, TRM of 33% (at years), and 47% relapse rate Notably, 47% of these patients were chemoresistant at the time of allogeneic HCT Prospective studies have also demonstrated the effectiveness of RIC allogeneic HCT in relapsed HL In a study by Alvarez et al [41], 40 patients who underwent RIC allogeneic HCT for relapsed HL were demonstrated to have a 2-year OS of 52% and PFS of 34% with 1-year TRM of 25% Another prospective trial by Peggs et al [32] included 49 patients with relapsed HL, 90% of patients with disease progression after autologous HCT Subsequent RIC allogeneic HCT in this population resulted in a 4-year OS and PFS of 55.7% and 39.0%, respectively The optimal donor for allogeneic HCT in HL had been an 425 Fig Management of Hodgkin lymphoma relapsing after autologous hematopoietic cell transplantation (auto-HCT) Note Allo = allogeneic; cHL = classical Hodgkin lymphoma; pts = patients Please cite this article in press as: Jethava Y et al., Relapse of Hodgkin lymphoma after autologous transplantation: Time to rethink treatment?, Hematol Oncol Stem Cell Ther (2017), http://dx.doi.org/10.1016/j.hemonc.2016.12.002 413 414 415 416 417 418 419 420 421 422 423 426 427 428 429 430 431 432 433 434 435 436 437 438 439 440 441 442 443 444 445 446 447 448 449 450 451 HEMONC 160 February 2017 No of Pages 10, Model 6+ Y Jethava et al 463 area of active research While MRD is often considered the preferred donor, a study by Majhail et al [42] showed comparable rates of GVHD, TRM, and survival with cord blood HCT Anderlini et al [43] also reported a single center experience with fludarabine–melphalan-based conditioning for RIC allogeneic HCT and demonstrated that the TRM, OS, and PFS were comparable between MRD and MUD transplants However, the incidence of acute GVHD (12% vs 39% at Day 100, p = 04) and chronic GVHD (57% vs 85%, p = 006) was higher in MUD allogeneic HCT More research is needed to find the optimal donor strategies and to reduce the incidence of relapse after RIC allogeneic HCT for HL 464 Prognostic factors for RIC allogeneic HCT 452 453 454 455 456 457 458 459 460 461 462 486 Numerous studies have tried to address the pretransplant and transplant characteristics which could influence the outcomes Chemosensitive disease status at transplant was found to be a predictor of better response in many retrospective and prospective studies [28,41–43] However, a CIBMTR data analysis by Devetten et al [40] did not show chemosensitivity as a predictor of transplant outcomes Late relapse after allogeneic HCT (>12 months) has also been shown to be associated with better outcomes [41] Although early relapse (45 years were associated with poor NRM, although older patient age and use of an unrelated donor did not negatively impact on the PFS or OS or NRM 487 Haploidentical and cord blood HCT for HL 488 Although most cases of HL are curable in the current era, about 10–20% of patients with refractory disease or relapse after prior autologous HCT may be candidates for haploidentical HCT A study by Raiola et al [44] included 26 patients with advanced HL who had progressed after prior autologous HCT This study demonstrated a 3-year actuarial survival and disease-free survival of 77% and 63%, respectively, and a relapse rate of 31% In a different retrospective analysis by Burroughs et al [45], haploidentical HCT in patients with heavily pretreated HL showed a 2-year OS of 58%, PFS of 51%, and 40% incidence of relapse/progressive disease Also, the NRM and risk of relapse were found to be significantly lower with haploidentical HCT as compared with MRD and MUD HCT in this study More recently, analysis of the EBMT registry data by Martinez et al [46] showed that haploidentical HCT for HL produced similar OS, PFS, NRM, and relapse compared with MRD HCT A large retrospective analysis of the CIBMTR database in a study by Kanate et al [47] demonstrated a 3-year PFS of 45% and 3-year OS of 68% with haploidentical HCT In another study by Ghosh et al [48] haploidentical HCT produced a 3-year PFS of 34% and 465 466 467 468 469 470 471 472 473 474 475 476 477 478 479 480 481 482 483 484 485 489 490 491 492 493 494 495 496 497 498 499 500 501 502 503 504 505 506 507 508 3-year OS 60% Hence, haploidentical HCT remains as a valuable alternate option for patients with HL who relapse after prior autologous HCT To demonstrate the outcomes of cord blood HCT, Majhail et al [42] examined 21 patients with HL who were conditioned with total body irradiation and either fludarabine plus busulfan or cyclophosphamide followed by MRD (n = 12; median age, 42 years) or umbilical cord blood grafts (n = 9; median age 28 years) With a median follow-up of 17 months (umbilical cord blood recipients) and 24 months (MRD recipients), the 2-year OS and PFS were comparable between the groups: 51% and 25% for umbilical cord blood recipients, and 48% and 20% for MRD donor recipients, respectively There was also no difference in 180-day NRM (umbilical cord = 22%, MRD = 25%) Alternative donor sources are viable options for HL in need of allogeneic HCT Conclusion Relapse of HL after autologous HCT is a therapeutic challenge with variable response to subsequent therapy Currently, several new drugs and RIC allogeneic HCT are available as valuable treatment options However, more research is needed to improve their efficacy and minimize the toxicities Achieving disease response prior to HCT is important in improving the outcomes Newer modalities such as PET-computed tomography is helpful in assessing disease response prior to autologous HCT, although its value prior to allogeneic HCT has been questioned in recent studies [49] Strategies to minimize relapse after the first autologous HCT and subsequent RIC, allogeneic HCT would be a cornerstone to improve the disease outcomes For cases of relapsed HL after an autologous HCT, integrating novel therapies whether as a part of preparative regimen or as a maintenance strategy postallografting or as cytoreductive therapy prior to donor lymphocyte infusion, are important research questions that need to be addressed in future clinical trials A potential treatment algorithm summarizing these options is described in Fig 509 510 511 512 513 514 515 516 517 518 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survival outcomes after t cell-depleted allogeneic transplantation for Hodgkin lymphoma Biol Blood Marrow Transplant 2016;22:1234–41 785 Please cite this article in press as: Jethava Y et al., Relapse of Hodgkin lymphoma after autologous transplantation: Time to rethink treatment?, Hematol Oncol Stem Cell Ther (2017), http://dx.doi.org/10.1016/j.hemonc.2016.12.002 741 742 743 744 745 746 747 748 749 750 751 752 753 754 755 756 757 758 759 760 761 762 763 764 765 766 767 768 769 770 771 772 773 774 775 776 777 778 779 780 781 782 783 784 ... hematopoietic cell transplantation in relapsed hodgkin lymphoma Relapse of Hodgkin lymphoma after autologous transplant Please cite this article in press as: Jethava Y et al., Relapse of Hodgkin. .. al., Relapse of Hodgkin lymphoma after autologous transplantation: Time to rethink treatment? , Hematol Oncol Stem Cell Ther (2017), http://dx.doi.org/10.1016/j.hemonc.2016.12.002 Table No of patients... cite this article in press as: Jethava Y et al., Relapse of Hodgkin lymphoma after autologous transplantation: Time to rethink treatment? , Hematol Oncol Stem Cell Ther (2017), http://dx.doi.org/10.1016/j.hemonc.2016.12.002