Optimal treatment for relapsing patients with Hodgkin lymphoma

Relapsed or refractory classical Hodgkin lymphoma (HL) remains a therapeutic challenge. Patients with relapsed HL should be identified according to their prognostic factors at relapse (duration of remission and extranodal disease or stage). Patients with refractory disease, defined as progression during induction treatment or within 90 days after the end of treatment, have the worst prognosis. Following non-crossresistant salvage chemotherapy to achieve cytoreduction, high-dose therapy (HDT) and autologous stem cell transplantation has been shown to be better than conventional-dose chemotherapy for first-relapse/refractory HL. For patients with very unfavorable relapse or primary refractory HL, outcome remains poor with HDT. For these patients, the role of tandem HDT or allogeneic stem cell transplantation will be discussed. In this setting, novel investigational treatments will be presented.     

Brentuximab vedotin治疗12例复发性或难治性霍奇金淋巴瘤

目的观察新型靶向治疗药Brentuximab vedotin治疗复发性或难治性霍奇金淋巴瘤（HL）的临床疗效和不良反应。方法选取我院住院治疗的12例复发性或难治性HL患者,经病理及免疫组化证实为CD30抗原阳性的HL。所有病例均接受过二线或三线方案化疗,化疗中位数13个疗程。7例曾接受自体干细胞移植,其中2例行自体干细胞移植后因复发接受异基因干细胞移植。给药方法：Brentuximab vedotin单药剂量1．2～1．8mg／kg,静脉滴注,每21天给药1次。患者共接受2～16个疗程,治疗中位数4个疗程。结果完全缓解2例（17％）,部分缓解7例（58％）,稳定2例（17％）,进展死亡1例（8％o主要不良反应有乏力、白细胞减少、发热、脱发、转氨酶增高、恶心、末梢神经炎、疼痛等,患者均可耐受。结论Brentuximab vedotin治疗复发或难治性HL具有良好的临床疗效,不良反应轻微,患者多能耐受。     

Therapy of relapsed Hodgkin lymphoma

The majority of patients who are diagnosed with Hodgkin lymphoma (HL) will be cured with primary chemotherapy. For those who relapse, autologous stem cell transplantation (ASCT) has become the standard of care. Randomized clinical trials have demonstrated that approximately 50% of patients with chemosensitive relapsed HL can achieve long term disease free survival with ASCT. However, optimal therapy of those who have chemorefractory disease or who relapse after an ASCT has not been established. Reduced intensity allogeneic stem cell transplantation may benefit these patients, although a definite graft versus HL effect has not been demonstrated and treatment-related mortality remains relatively high. New salvage regimens that incorporate gemcitabine, vinorelbine, rituximab, and/or monoclonal antibodies against CD30 are being investigated.     

Relapse of Hodgkin lymphoma after autologous hematopoietic cell transplantation: A current management perspective

Hodgkin lymphoma (HL) is a highly responsive disease with nearly 70% of patients experiencing cure after front-line chemotherapy. Patients who experience disease relapse receive salvage chemotherapy followed by consolidation with autologous hematopoietic cell transplantation (auto-HCT). Nearly 50% of patients relapse after an auto-HCT and constitute a subgroup with poor prognosis. Novel treatments such as immune checkpoint inhibitors and an anti-CD30 monoclonal antibody are currently approved for patients relapsing after auto-HCT; however, the duration of remission with these therapies remains limited. Allogeneic HCT is currently the only potentially curative treatment modality for patients relapsing after a prior auto-HCT. Early clinical trials with chimeric antigen receptor T-cell therapy targeting CD30 are underway for patients with relapsed/refractory HL and are already demonstrating safety and promising efficacy.     

Alternative salvage regimens for relapsed/refractory classical Hodgkin's lymphoma

Objective and importance: Hodgkin's lymphoma (HL) is a well-curable disease. The treatment usually includes combined multiagent conventional chemotherapy and radiotherapy. One-fifth of the patients need repeated treatments because of relapse or primary progressive disease. Those HL patients, who cannot be cured at least with salvage therapy (including autologous haemopoietic stem cell transplantation (auto-HSCT)), have really unfavourable prognosis.

Intervention: For this heavily pretreated subset of HL patients, novel but less toxic treatment strategies should be considered. Brentuximab-vedotin (BV) is a novel targeted treatment option, which was administered after the failure of two different regimens in patients, who were ineligible for auto-HSCT or after the failure of auto-HSCT. Moreover, there are favourable data with chemotherapeutical regimens supplemented with rituximab not only in relapsed but also in newly diagnosed classical HL patients. Bendamustine, an almost forgotten 50-year-old drug, lives its renaissance in the twenty-first century, which can be administered in refractory HL as well. Combination of the ‘new’ and ‘old’ drugs might be also helpful.

Conclusion: Our data suggest that rituximab plus bendamustine (supplemented with or without BV) could be a suitable alternative bridging salvage therapy for heavily pretreated HL patients.     

'GVHD': graft-versus-host disease or graft-versus-Hodgkin's disease? An old acronym with new meaning

The majority of patients with relapsed or refractory Hodgkin's lymphoma (HL) will not be cured with standard therapy. Relapse rates remain high even after autologous stem cell transplantation (SCT), particularly for patients with high-risk disease. Allogeneic SCT offers several potential advantages for patients with HL. It is feasible when autologous stem cells are not available and stem cell grafts will be tumor free. Perhaps a more important advantage is the potential to generate a graft-versus-Hodgkin's lymphoma (GVHL) effect. Unfortunately, although allogeneic SCT may cure some HL patients, treatment-related mortality has been unusually high, and superior survival, when compared to autologous SCT, has not been demonstrated. Nonmyeloablative conditioning and allogeneic SCT may induce a direct GVHL reaction with less conditioning regimen-related toxicity and ultimately may have the potential to improve cure rates and survival for advanced HL patients.     

Combined ifosfamide, etoposide and oxalipatin chemotherapy, a low-toxicity regimen for first-relapsed or refractory Hodgkin lymphoma after ABVD/EBVP: a prospective monocentre study on 34 patients

Around 20% of Hodgkin lymphoma (HL) patients are refractory to first‐line therapy with ABVD (adriamycin–bleomycin–vinblastine–dacarbazine) or relapse after complete remission. Salvage regimens frequently have delayed courses or require dose‐reduction because of haemotoxicity. We evaluated the IVOx (ifosfamide–etoposide–oxaliplatin) salvage regimen in terms of response rate, toxicity and stem‐cell mobilization. Thirty‐four patients with relapsed/refractory HL after anthracycline‐containing chemotherapy prospectively received IVOx, consisting of ifosfamide (1500 mg/m² days 1–3), etoposide (150 mg/m² days 1–3) and oxaliplatin (130 mg/m² day 1). Patients <65 years old received high‐dose therapy followed by autologous stem‐cell transplantation (HDT–ASCT). Response was assessed by computed and positron‐emission tomographies. Overall and complete response rates were 76% and 32%, respectively, after 2 cycles. Three episodes of febrile neutropenia occurred, and three patients required dose‐reductions. Twenty‐six patients underwent HDT–ASCT. With median follow‐up at 5 years, the 5‐year overall and event‐free survival rates were 74% and 63%, respectively. IVOx is a well‐tolerated outpatient regimen for relapsed HL, that does not hamper stem‐cell mobilization, achieves good response rates and compares favourably with previously published salvage regimens.     

High dose chemotherapy and autologous stem cell transplantation in relapsed or refractory Hodgkin lymphoma: Emerging questions,newer agents,and changing paradigm

Primary treatment for adult and pediatric patients with Hodgkin lymphoma (HL) using current multiagent anthracycline-based chemotherapy with or without radiation therapy will cure approximately >70% of the patients; >95% for early stage with a favorable risk profile and 70–75% with advanced stage and high risk features. Managing refractory and relapsed disease, however, remains a challenge. High dose chemotherapy (HDC) and autologous stem cell transplantation (auto-SCT) can salvage 40–70% of patients with relapsed or refractory HL. Two randomized trials in relapsed and refractory patients showed superior progression free survival. This presentation addresses some of the salient differences and changes in the management that have evolved over the last decade and have either already affected, or are likely to affect the outcome of HDC auto-SCT. The following will discussed. 1. Historic trials and other emerging issues impacting the outcome of HDC auto-SCT. 2. Changes in the primary treatment and response adapted therapy. 3. Evaluation and validation of prognostic factors at the time of first failure. 4. Selection of salvage chemotherapy. 5. Conditioning regimens. 6. Consolidation after HDC auto-SCT. 7. Management of failures of HDC auto-SCT. 8. Availability of financial resources in various healthcare systems. Enrolment in clinical trials should be encouraged.     

Treatment of relapsed or refractory acute promyelocytic leukemia

Current treatment for acute promyelocytic leukemia (APL) usually includes an induction phase with all-trans retinoic acid (ATRA) and anthracycline-based chemotherapy, followed by a consolidation phase of anthracycline-based chemotherapy and maintenance therapy with ATRA with or without low-dose chemotherapy for 1-2 years. This treatment strategy results in a high complete remission (CR) rate of about 90% and an overall survival rate of 80%. About 5%-30% of patients relapse, mainly patients with high-risk APL. Relapse at extramedullary sites, which occurs in approximately 3%-5% of patients, is emerging as a new issue. Treatment of relapsed/advanced APL includes the use of arsenic trioxide (ATO), gemtuzumab ozogamicin, and hematopoietic stem cell transplantation. ATO is currently the most effective therapeutic agent in relapsed APL. Hematopoietic stem cell transplantation is becoming a common strategy after achieving remission with ATO. Autologous transplant appears to have a more favorable outcome than allogeneic transplant in this setting, particularly when carried out during second remission, primarily because of significantly higher treatment-related mortality with allogeneic transplants. Allogeneic transplant, however, should be strongly considered for patients who remain molecularly positive. Future directions for APL therapy should include developing agents that can prevent relapse, particularly for high-risk patients. Other future treatment strategies may include use of ATO administered concomitantly or sequentially with chemotherapy, gemtuzumab or FLT-3 inhibitors that may obviate the need for autologous transplantation, and posttransplant maintenance perhaps with FLT-3 inhibitors.     

Hodgkin's lymphoma: current treatment strategies and novel approaches

Approximately 80% of Hodgkin's lymphoma (HL) patients achieve long-term remission after primary chemotherapy or chemo/radiotherapy. Despite these excellent results, further treatment improvement is necessary. HL therapy is associated with severe acute and long-term toxicities. Thus, a major aim of clinical HL research is to evaluate novel schemes that are less toxic than current standard regimens without being less effective. Another focus is the treatment of patients with multiple relapses. Standard treatment for these patients has not yet been defined, and their prognosis is still poor. Reduced-intensity conditioning allogeneic stem cell transplantation was recently shown to be effective in carefully selected young chemosensitive patients. Furthermore, new strategies such as antibody- and small-molecule-based therapy have demonstrated encouraging results in preclinical studies and the first clinical trials.     

Outcome analysis of high-dose chemotherapy and autologous stem cell transplantation in adolescent and young adults with relapsed or refractory Hodgkin lymphoma

Annals of Hematology - High-dose chemotherapy (HDC) and autologous stem cell transplantation (auto-SCT) can salvage many patients with relapsed or refractory Hodgkin’s lymphoma (HL). We are...     

Reduced intensity allogeneic stem cell transplantation for low grade non-Hodgkin's lymphoma

Treatment options for patients with low-grade non-Hodgkin's lymphomas (NHLs) are many and varied. For those with relapsed or refractory disease, outcome following conventional and high dose chemotherapy remains poor. Conventional allogeneic stem cell transplantation has been shown to have curative potential in the management of indolent NHL, but due to the high transplant-related mortality improvement in overall survival has been insignificant. Recent reports have confirmed the feasibility of reduced intensity conditioning allogeneic stem cell transplantation as a treatment option for many older patients with NHL. Here we will discuss the rationale behind reduced intensity transplantation (RIT), the development of the regimens currently adopted in clinical practice and review the published literature on RIT for indolent NHL.     

Outcome after autologous stem cell transplantation in primary refractory or relapsed Hodgkin lymphoma—a long-term follow-up single center experience

Autologous stem cell transplantation (autoSCT) can achieve long-term remission in primary refractory or relapsed Hodgkin lymphoma (r/r HL); however, still up to 50% of patients relapse after autoSCT. In this retrospective analysis, we investigated the impact of autologous stem cell transplantation in a consecutive, unselected cohort of primary refractory and relapsed Hodgkin lymphoma patients (n = 66) with the majority of patients treated in the pre-brentuximab vedotin and immune checkpoint inhibitor era. In our cohort, a 5-year overall survival (OS) from autoSCT of 59.5% and a 5-year progression-free survival (PFS) after autoSCT of 46.1% was achieved. Multivariate analysis revealed primary refractory disease and early relapse (< 12 months) after initial therapy as well as the presence of B symptoms at relapse as independent risk factors associated with a higher risk for relapse and an inferior PFS and OS. Several other clinical factors, including the presence of extranodal disease at relapse and failure to achieve a complete response to salvage chemotherapy, were associated with a trend towards an inferior survival. Patients relapsing after autoSCT had a particularly poor outcome, regardless of eligibility to undergo allogeneic stem cell transplantation (alloSCT). We further evaluated recently published prognostic models for r/r HL patients undergoing autoSCT and could validate several risk scores in our independent “real world” cohort.     

Tandem haematopoietic stem cell transplantation for High Risk relapsed/refractory Hodgkin Lymphoma: a LYSA study

Tandem stem cell transplantation (SCT) is an option for high‐risk relapsed/refractory Hodgkin Lymphoma (HL) patients. We evaluated the tolerance/efficacy of double autologous or autologous SCT (ASCT) followed by allogenic SCT (alloSCT) in 120 HL patients prospectively registered on a French nationwide database. Median age was 26 (14–56) years. Complete remission rate was 60%, including 33% after a single line, and another 27% after two or more salvage regimens. Partial response rate was 32%, and 8% suffered treatment failure. Overall, 115 (96%) patients underwent a first ASCT, and 73 (61%) had a tandem SCT, including alloSCT in 44 (60%) and ASCT in 29 (40%). The median follow‐up was 43 months (4.8–73.7 months). The two‐year progression‐free survival rate for the whole population and for patients receiving tandem transplant was 56% (95% confidence interval [CI]: 46–65%) and 71% (95% CI: 49–84%), respectively. Among tandem transplants, we observed 20 deaths (17%), 10 of which were transplant‐related (6 alloSCT and 4 ASCT). We suggest that tandem SCT is efficient in high‐risk relapsed/refractory HL patients, although transplant‐related mortality remains high. The benefit of tandem SCT should be balanced with the efficacy of Brentuximab vedotin‐based post‐transplant consolidative strategies in high‐risk relapsed/refractory HL patients.     

Autologous stem cell transplantation with selected CD34+ cells and unmanipulated peripheral blood stem cells in patients with relapsed and refractory Hodgkin's lymphoma: a single centre experience

With the aim to evaluate the long term outcome after high-dose chemotherapy and autologous stem cell transplantation (HDCT+ASCT) in patients with relapsed or refractory Hodgkin's lymphoma (HL) we performed a retrospective analysis of patients transplanted at our centre. Between January 1993 and December 2005, 126 consecutive patients with relapsed or refractory HL in the age of 16 to 65 years underwent HDCT+ASCT at our centre and were enrolled in this retrospective analysis. Patients were autografted with either CD34+ positively selected or unmanipulated periferal blood stem cells (PBSC). With a median follow up of 69 months (3-162 months), the actuarial 5-y PFS and OS for all patients after HDCT+ASCT were 59% and 72%, respectively. In patients transplanted from 1996 the actuarial 5-y PFS and OS for CD34+ selected group were 64% and 79% and for unmanipulated PBSC group 63% and 66%, respectively. A total of 42/126 (33%) patients died. Treatment related mortality (TRM) was 3% (4 patients). In univariate analysis, chemosensitive disease and increased LDH were the strongest prognostic factors for PFS and OS. Our results confirm the efficacy of HDCT+ASCT in relapsed or refractory HL with acceptable toxicity. The use of CD34+ positively selected stem cells for autografting is feasible, safe and effective procedure. Key words: Hodgkin's lymphoma, high-dose chemotherapy, autologus transplantation, CD34+ selected stem cells.     

Allogeneic bone marrow transplantation for juvenile myelomonocytic leukaemia: a single centre experience and review of the literature

Juvenile myelomonocytic leukaemia (JMML) is a rare paediatric disease and allogeneic stem cell transplantation is the only curative approach. The roles of pretransplant treatment, conditioning regimen and graft-versus-host disease (GVHD) are still unclear. Eleven children with JMML underwent allogeneic BMT in our institution. Donors were matched unrelated (n = 6) matched siblings (n = 4) and one mismatch family donor. Transplant-related mortality (TRM) was 36%. Three patients relapsed after transplantation. Two of three patients with relapse are in continuous remission after donor lymphocyte infusion or second BMT, respectively. To evaluate the role of pretransplant treatment, conditioning regimen and GVHD, we have summarised our series with other published single centre reports and give an overview on a total of 65 patients with JMML who underwent allogeneic BMT. No significant correlation between pretransplant treatment, conditioning regimen and TRM could be observed. Overall relapse rate is high (47%). TBI is associated with a significantly higher relapse rate (P = 0.012). Other conditioning modalities, intensive chemotherapy and splenectomy prior to stem cell transplantation do not seem to have a significant impact on relapse rate. Patients with or without GVHD showed no significant difference in relapse rate (58% vs 45%). In the event of relapse after transplantation withdrawal of immunosuppression, donor lymphocyte infusion or second transplant was successful in 6/11 patients. Graft-versus-leukaemia effect seems to play an essential role in bone marrow transplantation for JMML.     

Autologous transplantation in patients with relapsed or high-grade follicular lymphoma provides long term disease-free survival and best median duration of response

The best treatment option for patients with relapsed or high-grade follicular lymphoma (FL) is unknown. In spite of major advances in the therapy for FL, disease-free survival remains short, and median time to progression is just over a year. Autologous stem cell transplantation in patients with relapsed FL is safe and appears to improve disease-free survival. In an attempt to examine whether autologous stem cell transplantation provides long-term disease control in patients with relapsed or high-grade FL, we retrospectively evaluated our experience and analyzed the outcomes of autologous stem cell transplantation in patients with FL from 1991 to 2003. Seventeen men and seven women (n=24) of median age 47.5 years (range 28–64 years) were treated. Three patients with high-risk FL were in first remission. Twenty-one patients were salvaged after relapse with second-line chemotherapy. Of these, 14 were in CR at the time of transplantation, and seven patients were transplanted with active disease. Bone marrow was used in six patients as the source of stem cells prior to 1995 and peripheral blood stem cells were used in 18 patients. Twenty-three of 24 patients engrafted (96%). Median time for neutrophil recovery was 11.5 days (range 9–35 days) and 15 days (range 10–40 days) for platelets. Median duration of follow-up was 6 years (range 7 months–8 years). Of the 24 patients, six have died—with one patient death due to transplant-related pulmonary complications. Overall survival (OS) and disease-free survival (DFS) of all evaluable patients were 71.6 and 40%, respectively. Median duration of response was 4.3 years. OS and DFS in patients transplanted in CR were 80 and 57%, respectively. For those transplanted with disease, a complete response was achieved in 43% of patients, with the OS and DFS of 57 and 19%, respectively. Disease status at transplantation was not a significant variable for survival (p>0.3). Three patients developed moderate to severe treatment-related toxicity, two with grade III mucositis and one with life-threatening infection. When these results are compared with historical controls or patients treated with other modalities, autologous stem cell transplantation appears to be providing the longest disease-free survival and best duration of response.     

Long-term results of brentuximab vedotin in relapsed and refractory Hodgkin lymphoma: multi-center real-life experience

Classical Hodgkin lymphoma (cHL) is considered a curable disease; however, approximately one-third of responders experience disease relapse following first-line therapy. Several studies have shown the efficacy of brentuximab vedotin (BV) in patients with relapsed/refractory HL. We present a retrospective analysis of 58 patients with relapsed/refractory HL treated with BV in a named patient program from 11 centers. The median follow-up duration was 20 (range, 4–84) months. The best overall response rate was 64% (complete response [CR], 31%; partial response [PR], 33%). The 5-year progression-free survival (PFS) and overall survival (OS) rates were 12% (95% confidence interval [CI], 0.05–0.22) and 26% (95% CI, 0.16–0.38), respectively. Among patients who achieved CR, the estimated 5-year PFS and OS rates were 32% (95% CI, 0.13–0.54) and 60% (95% CI, 0.33–0.78), respectively. A total of 26 patients underwent subsequent stem cell transplantation. The 5-year PFS and OS rates for 10 patients who had consolidative stem cell transplantation were 28% and 30%, respectively. Twenty-seven patients required further therapy following BV. At the time of the analysis, 12 patients (21%) were alive. Five patients (9%) had long-term remission after achieving CR with BV monotherapy, with a median PFS of 76 months. Three of them (5%) did not receive any other treatment following BV and their median PFS was 75 months. Our long-term results showed that a small subset of patients with relapsed/refractory cHL may benefit from and even be cured with BV monotherapy.     

Mini-BEAM is effective as a bridge to transplantation in patients with refractory or relapsed Hodgkin lymphoma who have failed to respond to previous lines of salvage chemotherapy but not in patients with salvage-refractory DLBCL

Patients with relapsed or refractory lymphoma can be cured with stem cell transplantation if they are shown to have disease that is responsive to salvage chemotherapy. Patients who fail to respond to first-line salvage chemotherapy tend to do very poorly. Here we report on 39 such patients who received mini-BEAM (carmustine, etoposide, cytarabine, melphalan) chemotherapy as second or subsequent-line salvage chemotherapy. Fifty-six percent of these patients had primary refractory disease and a further 28% had responses to first-line therapy that lasted <12 months. Seventy-two percent had progressive disease following the salvage chemotherapy administered immediately prior to mini-BEAM and the remaining 28% had stable disease. Overall there was a 38% response to mini-BEAM (complete response = 28%, partial response = 10%). Patients with Hodgkin lymphoma (HL) had a higher response rate compared to those with diffuse large B cell lymphoma (DLBCL) (63% vs. 20%). Seventy-four percent of HL patients were able to proceed to transplantation compared with 30% of patients with DLBCL. Mini-BEAM is a very effective bridge to transplantation in very poor risk patients with HL who have failed to respond to first-line salvage chemotherapy. Its efficacy in non-Hodgkin lymphoma is more modest.     

The combination of thalidomide,cyclophosphamide and dexamethasone is potentially useful in highly resistant Hodgkin’s lymphoma

Few diseases have a prognosis worse than Hodgkin’s lymphoma (HL), patients relapsing after autologous or allogeneic stem cell transplantation. Here, we report two highly refractory patients with HL who successfully responded to a combination of thalidomide, cyclophosphamide and dexamethasone (ThaCyDex). Despite the use of a very large number of different drugs (>5 different schemes) including high‐dose therapy and autologous and allogeneic stem cell transplantation, both patients proved to be suffering from a highly resistant disease. Fortunately, they finally responded to the ThaCyDex combination, achieving sustained complete remission that would support the running of a trial within this setting.