Relapsed or refractory Hodgkin lymphoma (advanced HL) still remains a therapeutic challenge. Recently, unmanipulated haploidentical related donor transplant with reduced conditioning regimen (HAPLO-RIC) and post-transplant cyclophosphamide (PT-Cy) as GvHD prophylaxis has became a promising rescue strategy potentially available to almost every patient. This paper reports our multicenter experience using an IV busulfan-based HAPLO-RIC regimen and PT-Cy in the treatment of 43 patients with advanced HL. Engraftment occurred in 42 patients (97.5%), with a median time to neutrophil and platelet recovery of 18 and 26 days. Cumulative incidences of grades II–IV acute GvHD and chronic GvHD were 39% and 19%, respectively. With a median follow-up of 25.5 months for survivors, 27 patients are alive, with 22 of them disease free. Cumulative incidences of 1-year non-relapse mortality and relapse at 2 years were 21% and 24%, respectively. The estimated 2-year event-free survival (EFS) and overall survival (OS) were 48% and 58%, respectively. CR prior to HAPLO-RIC correlated with better EFS (78.5% vs 33.5%; P=0.015) and OS (86% vs 46%; P=0.044). Our findings further confirm prior reports using HAPLO-RIC in advanced HL in a multicenter approach employing an IV busulfan-based conditioning regimen.
Currently, Hodgkin lymphoma (HL) is a curable disease for >80% of the patients following modern chemotherapy regimens, associated or not with radiotherapy.1 However, relapsed or refractory patients remain a therapeutic challenge. In recent years, salvage strategies, including intensification therapy followed by autologous hematopoietic stem cell transplantation (HSCT), have offered a curative option for 40–50% of these patients, mostly those with chemo-sensitive disease.1 Moreover, allogeneic HSCT with an HLA-identical related or unrelated donor can rescue a further proportion of relapsed/refractory cases, either employing myeloablative conditioning (MAC) or reduced intensity conditioning (RIC) regimens.2, 3, 4, 5, 6, 7 Unfortunately, results are still modest with either approach owing to a high relapse rate in spite of the graft vs HL effect.8, 9
More recently, non-MAC (NMAC)10 and RIC11, 12 transplants using HLA-haploidentical related donors (HAPLO-RIC) with posttransplant high-dose cyclophosphamide (PT-Cy) as prophylaxis for GvHD have shown promising results in the treatment of relapsed/refractory HL patients, comparable to those of RIC transplants from HLA-identical siblings or unrelated donors.10 Furthermore, the last strategy has allowed almost any advanced HL patient to receive an allogeneic HSCT rescue and has been recently reproduced.11, 12 Nevertheless, relapse is still the main issue with this procedure10, 11 as it is with RIC transplant approaches, particularly when employed to treat advanced disease.
In a hypothetical attempt to reduce the relapse rate and in order to facilitate the procedure, we have introduced a modification of the original Baltimore's NMAC regimen that included 200 cGy TBI,13 which has been replaced by an IV busulfan-based RIC regimen. We herein report the Spanish multicenter experience on IV busulfan-based HAPLO-RIC regimen in the treatment of advanced HL patients who lack an HLA-identical related or unrelated donor.
Patients and methods
Patients' and donors' selection
We have retrospectively studied 43 patients (Table 1) with relapsed or refractory HL who received a HAPLO-RIC transplant reported to the Haploidentical Transplantation Subcommittee of the Spanish Group for Hematopoietic Transplantation (GETH). The multicenter accrual involved 11 centers and included patients transplanted between March 2009 and January 2014. The institutional review board of each participating center approved the study. Written informed consent was obtained for all patients in accordance with the Declaration of Helsinki. Patients were eligible for inclusion if they were aged >16 years and <60 years. Our study included refractory HL (primary refractory and multiple relapsed patients without reaching CR) and relapsed HL (multiple relapsed patients, including those relapsing after an autologous HSCT). Disease status at transplant was evaluated and defined by positron emission tomography and categorized as CR if there was a complete metabolic response or non-CR if there was persistence of metabolic activity at any localization.
In addition, patients were stratified according to their disease risk index (DRI) categories following Armand's updated criteria.14 No exclusions were made for disease status or chemotherapy sensitivity.
Donors were selected among patients' first-degree relatives (siblings, parents or children) and they were matched with the recipient at 5/10 to 7/10 HLA antigens. In addition, donors were selected avoiding a positive HLA crossmatch in the host vs graft direction or having donor-specific antibodies as determined by the pretransplantation panel reactive antibody testing. If several donors were available, we favor mothers owing to presumable higher allo-reactivity potential, and moreover, younger and ABO matched donors were preferable.
Conditioning regimen and GvHD prophylaxis
The conditioning regimen used is a modification of the original described by Luznik et al.13 where IV busulfan substituted 200 cGy of TBI. Our regimen consisted of fludarabine 30 mg/m2/day for 5 consecutive days from −6 to −2, cyclophosphamide 14.5 mg/kg/day on days −6 and −5 and IV busulfan 3.2 mg/kg/day on either day −3 (BUX1) or days −3 and −2 (BUX2), in order to reduce relapses and as a primary physician choice. GvHD prophylaxis consisted of high-dose cyclophosphamide (50 mg/kg/day) administered at days +3 and +4 with hyperhydratation and MESNA support, followed by calcineurin inhibitor (either cyclosporine A or tacrolimus, as per center's choice) and mycophenolate mofetil from day +5. In the absence of acute GvHD, mycophenolate mofetil was discontinued at day +35. Calcineurin inhibitors were maintained until day +90 and tapered thereafter. An earlier taper was allowed for patients transplanted with active disease at the time of transplantation. Graft source used was bone marrow (BM) or unmanipulated PBSC as per physician's or center's choices. Acute and chronic GvHD were assessed and graded according to published criteria.15, 16
Anticonvulsivant prophylaxis was performed according to each institutional practice guidelines, mostly with oral phenytoin. Standard antimicrobial prophylaxis included levofloxacin and acyclovir from day −7; antifungal prophylaxis was performed with micafungin until oral tolerance and then switched to posaconazole. Pneumocystis prophylaxis with cotrimoxazole was given from day −7 until day −1 and resumed after day +30, for 12 months post transplantation. Filgrastim 5 mcg/kg was started on day +5 and continued until neutrophil engraftment. Quantitative CMV PCR monitoring was run twice a week starting on day +1 until day +100 or later if prolonged immunosuppression was needed owing to active GvHD.
Quantitative chimerism analysis was intended to be performed on peripheral blood samples using informative microsatellite DNA polymorphisms as previously described,17 starting on day +15 and every 15 days thereafter until complete donor chimerism was achieved. Complete donor chimerism was defined as the absence of recipient-specific allelic patterns detectable by STR-PCR with a sensitivity of 1%.
Definitions, study end points and statistical methods
Myeloid engraftment was defined when an absolute neutrophil count of ⩾0.5 × 109/L for 3 consecutive days was reached. Platelet engraftment was defined when platelet count of ⩾20 × 109/L were maintained without transfusion support for 3 consecutive days. Patients who survived >30 days after transplantation and who failed to achieve myeloid engraftment were considered as graft failures. Graft rejection was defined as graft failure with documentation of recipient's hematopoiesis return, as determined by chimerism studies.
Non-relapse mortality (NRM), disease relapse or progression, event-free survival (EFS) and overall survival (OS) were defined as primary end points. NRM was defined as death from any cause without previous disease relapse or progression. OS was defined as the time from transplant to death from any cause, and surviving patients were censored at last follow-up. EFS was defined as the time from transplant to relapse, disease progression or death from any cause, whichever occurred first. Follow-up of patients was updated in April 2015.
Quantitative variables were expressed as median and either range or interquartile range (25 and 75 percentiles). Qualitative variables were expressed as frequency and percentage. Estimates of EFS and OS were calculated using Kaplan–Meier method, including 95% confidence interval (95% CI). Cumulative incidence (CI) curves and competing-risk regression were performed as alternative to Cox regression for survival data in the presence of competing risks.18 In our case, competing events were death and any other event that prevents the appearance of the event under study.
For the CI estimates of engraftment, full donor chimerism and acute GvHD, death before the event appearance was considered a competing event. For the CI of chronic GvHD, death and relapse were considered competing events. NRM and relapse were considered competing events for each other.
Except for the CI, all the calculations were made with the SPSS software (IBM SPSS Statistics for Windows, version 21.0., IBM Corp., Armonk, NY, USA). CI calculations were made with the R software (CRAN project).
Patients' and donors' clinical characteristics
Pretransplant patients and donors clinical characteristics are reflected in Table 1. Our study included refractory/relapsed HL patients mostly <40 years, heavily pretreated (median 5 lines), including autologous transplant in 79%, not in CR prior to HAPLO-RIC (67.5%), with high DRI in 21 (49%). Brentuximab-vedotin was employed prior to HAPLO-RIC in 16 patients (37%) trying to obtain the best disease control prior to transplant. No patient received nivolumab prior to transplant. The RIC regimen used included IV busulfan for 1 day (BUX1) in 14 (32.5%) or 2 days (BUX2) in 29 patients (67.5%). Peripheral blood progenitor cells were used as graft source in 32 (72%) and BM progenitors in 11 (28%).
Engraftment and chimerism
The cumulative incidence of neutrophil and platelet engraftment was 97.5% and 84%. Median time to neutrophil and platelet recovery was 18 days (range: 13–44) and 26 days (range: 13–150), respectively.
Primary graft failure was observed in 1 patient (2.3%), followed by autologous recovery at day +90. Full donor chimerism on peripheral blood and T cells was observed in 39 patients analyzed by day +30 (range: 14–100), with a CI of complete chimerism of 95% by day +120.
Toxicities and infections
Main toxicities observed were neutropenic fever (74.5%), World Health Organization grades 1–2 mucositis (51%) and CMV reactivations (54%). No EBV-related disease was observed. Severe veno-occlusive disease and interstitial pneumonia were diagnosed in 1 patient each.
Severe procedure-related events resulted in death episodes in 11 patients (pneumonia—2 cases, acute respiratory distress syndrome, BK virus encephalitis, CMV pneumonia, pneumococcal sepsis, multiorgan failure—2 cases, grade IV acute GvHD, overlapping GvHD complicated by sepsis of unknown origin and pulmonary chronic GvHD complicated by respiratory infection).
Eighteen patients developed acute grades II–IV GvHD at a median of 43 days (range, 21–124 days). The cumulative incidence of grades II–IV acute GvHD at day +100 was 39% (95% CI, 26–58%) and 14% (95% CI, 7–30%) for acute GvHD grades III–IV (Figure 1).
Chronic GvHD was seen in 9 of the 34 evaluable patients. It was limited in 6 cases (18%) and extensive in 3 cases (9%). The cumulative incidence of chronic GvHD at 2 years was 19% (95% CI, 10–36%) and 7% (95% CI, 2–21%) for extensive chronic GvHD (Figure 2).
NRM, relapse, EFS and OS
Four patients (9%) died before day +100 after HAPLO-RIC as a result of acute respiratory distress syndrome, multiorgan failure, pneumonia and BK virus encephalitis on days +11, +50, +66 and +75, respectively. With a median follow-up for surviving patients of 25.5 months (range, 8–72 months), the CI of NRM at 1 year was 21% (95% CI, 12–38%) (Figure 3). The causes of death within the first year post-HAPLO-RIC were acute GvHD complicated by sepsis, pneumonia and grade IV acute GvHD. Additionally, two more patients died 14.5 and 25 months after transplant owing to CMV pneumonia and pulmonary GvHD with respiratory infection.
Of the 29 patients not in CR at HAPLO-RIC, 13 were in CR at day +100 and continued in CR at 6 months post transplant. Relapse or progression was diagnosed in 10 patients, 4 of them who never achieved CR progressed and died 11, 17, 19 and 24 months posttransplant. This yields a cumulative incidence of relapse or progression at 2 years of 24% (95% CI, 14–41%), with a median time to relapse or progression of 7 months (range, 3.5–14 months) (Figure 3). In the univariate analysis, only CR status prior to the HAPLO-RIC showed a statistical trend as protective factor for relapse when comparing with patients not in CR (7% vs 33%, P=0.077). Brentuximab-vedotin was used to treat seven patients at relapse, combined with DLI in five of them. Only two patients were rescued with the combination of brentuximab-vedotin and DLI achieving CR lasting >2 years at last follow-up. Nivolumab was not employed at relapse after HAPLO-RIC.
The projected 2-year OS and EFS were 58% (95% CI, 42–74%) and 48% (95% CI, 32–64%), respectively (Figure 4). In the univariate analysis, EFS was different when patients were stratified by their disease status prior to transplant (CR vs non-CR: 78.5% vs 33.5%; P=0.015; Figure 5) and the disease response prior to the HAPLO-RIC also predicted OS (CR vs non-CR: 86% vs 46%; P=0.044; Figure 6). In our present analysis, EFS did not reach statistically significant differences between patients treated with <4 treatment lines vs those treated with ⩾4 lines (<4 vs ⩾4 lines: EFS 64% vs 44%, P=0.311), as observed in a preliminary analysis with shorter follow-up.19
No significant differences were observed in terms of NRM, relapse, EFS and OS when comparing BUX1 against BUX2 conditioning regimens (data not shown). Relapse incidence between patients who developed either acute or chronic GVHD showed no statistical differences (data not shown). No significant differences were found in any end point when comparing the mothers as donors against any other donors or the use of BM against PBSC as graft source (data not shown).
Allogeneic transplantation has become the preferred rescue treatment in recent years for relapsed/refractory HL patients since the introduction of HAPLO-RIC by American and European investigators.10, 11, 12 In this regard, our multicentric study confirms the favorable results in terms of disease control even in advanced phases of HL, outside strictly controlled phase II clinical trials.
We would like to emphasize that our study used mainly PBSCs as graft source, IV busulfan in the conditioning regimen and reduced duration of the posttransplant immunosuppressive therapy in an attempt to reduce the high relapse rate observed in this high-risk HL patients. Of note, IV busulfan allowed easier conditioning programming than TBI and, owing to its radiomymetic properties,20, 21 could even enhance antitumoral activity in a well-known radiosensitive neoplasm such as HL. Moreover, it could be useful to reduce the graft failure incidence previously reported with the HAPLO-RIC strategy.13
In the present series, 72% of patients received PBSCs as graft source. The comparison of BM vs PBSCs did not show significant influences in any of the major end points analyzed (EFS, OS, NRM and acute/chronic GvHD cumulative incidences). In our experience, PBSCs can be safely employed as graft source in the HAPLO-RIC setting to treat HL as recently reported by other authors.22, 23
Instead of 200 cGy TBI usually employed in the Baltimore's protocol,13 our conditioning regimen included IV busulfan × 1 or × 2 days attempting to reduce the high relapse rate of these advanced HL patients. After a median follow-up of 25.5 months for surviving patients, the CI of relapse in our series was 24% at 2 years, the estimated 2-year EFS was 48% and the estimated 2-year OS was 58%. These results compare similarly with those reported by other groups using TBI conditioning.10, 11 Moreover, taking into account the DRI of our patients, their EFS and OS are similar to those reported by McCurdy et al.24 for patients with the same DRI. Additionally, the subanalysis comparing patients receiving IV BUX1 against BUX2 did not show any significant advantage in all the analyzed end points. Nevertheless, the 1-year NRM observed in our patients was 21%, which appears slightly higher than that previously reported10, 11, 12 probably owing to the advanced disease of our patients, the multicenter nature of our experience and the higher GvHD incidence in our series.
The tolerance of our HAPLO-RIC procedure is acceptable in a population of heavily treated patients and with persistent disease in most of them, which are well-known influencing factors for this end point, reflecting the cumulative toxicity that these patients suffer. No major influence of the remission status prior to HAPLO-RIC on NRM has been observed, without significant differences in toxicity between those patients in CR vs those not in remission. Conversely, in our hands, the remission status was the main determinant of the relapse incidence and justifies the differences observed in terms of EFS (CR vs non-CR: 78.5% vs 33.5%; P=0.015) and OS (CR vs non-CR: 86% vs 46%; P=0.044). Interestingly, one-third of patients transplanted with persistent disease remain in CR with a median follow-up of 2 years. Treatment at relapse was brentuximab-vedotin in seven patients, combined with DLIs in five of them, what could have prolonged survival in some of them, as recent reports suggest,25, 26 but our numbers are insufficient to draw any relevant conclusion on that.
Cumulative incidence of grades II–IV acute GvHD in our study was 39%, being 14% more than grade II and 19% for chronic GvHD. These are higher than those reported by Burroghs et al.10 and Raiola et al.,11 probably owing to the use of PBSC grafts and early tapering of immunosuppressive therapy in our strategy. However, mortality attributable to acute or chronic GvHD in our patients was <10% (4 out of 41 at risk).
Finally, the results of our study nearly reproduce those previously reported, confirming the feasibility and security of the PT-Cy HAPLO-RIC strategy to treat advanced HL, in this case in a multicentric and daily practice setting, which emphasizes its value, being closer to the real-life management of these patients.
In conclusion, our experience shows comparable survival to previously reported HAPLO-RIC strategies in advanced HL but employing an IV busulfan-based conditioning regimen and PBSC grafts.
Relapse is still the main problem for these patients, particularly in those with persistent disease prior to HAPLO-RIC. Innovative ways to improve these results are eagerly needed. Improvements could be attempted using more appropriate donor selection, treating patients in earlier phases of their disease, optimally in CR, after the use of new drugs such as brentuximab-vedotin or nivolumab or using post-transplant strategies such as adoptive immunotherapy with donor lymphocyte infusions to prevent or treat relapses.25, 26
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This work was partially supported by the Ministry of Economy and Competitiveness ISCIII-FIS grants PI11/00708, PI14/01731 and RD12/0036/0061, co-financed by ERDF (FEDER) Funds from the European Commission, ‘A way of making Europe’, as well as grants from Asociación Española Contra el Cáncer (AECC) and Fundación Mutua Madrileña (FMM).
The authors declare no conflict of interest.
About this article
Peripheral Blood Stem Cells versus Bone Marrow for T Cell–Replete Haploidentical Transplantation with Post-Transplant Cyclophosphamide in Hodgkin Lymphoma
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