Radiotherapy in combination with nivolumab for relapsed/refractory classical Hodgkin lymphoma: About two cases

Hodgkin lymphoma is a highly curable malignancy involving lymph nodes and the lymphatic system. Even at late stage disease, about 70% of patients will be cured with standard first line therapy. For patients who experience relapse or refractory classical Hodgkin lymphoma, the standard treatment option is high-dose chemotherapy followed by autologous stem cell rescue or transplant. However about 50% of patients will have recurrence after high-dose chemotherapy followed by autologous stem cell rescue or transplantation and have worse prognosis with median overall survival of 32% at 5 years. The anti-PD1 checkpoints inhibitors pembrolizumab and nivolumab have remarkably improved outcomes of patients with relapse of refractory classical Hodgkin lymphoma after high-dose chemotherapy followed by autologous stem cell rescue or transplantation. On the other hand, radiotherapy is an entire component of salvage therapy and its efficacy is now well established in term of local disease control in sites of relapsed or refractory Hodkin lymphoma. Defining the optimal modality and timing of radiotherapy as these new agents arrive is a challenge. An interesting approach is the combination of radiotherapy with checkpoint inhibitor and the possibility of stopping the treatment when complete response is achieved. We add to the literature two new cases of combination of radiotherapy with immunotherapy in patients who relapsed after high-dose chemotherapy followed by autologous stem cell rescue or transplantation and consolidation with brentuximab vedotin, resulting in excellent outcomes.     

Treating Hodgkin lymphoma in the new millennium: Relapsed and refractory disease

Although the majority of patients with Hodgkin lymphoma are cured with initial therapy, 10% to 15% of patients with early stage disease and 15% to 30% of patients with advanced disease have primary refractory or relapsed lymphoma. For younger patients whose disease is sensitive to second‐line therapy, more than half of patients will experience long‐term disease control with high‐dose chemotherapy/autologous stem cell rescue (ASCT). For those patients who are chemotherapy refractory, relapse after, or are ineligible for ASCT, brentuximab vedotin, and checkpoint, inhibitors are highly active, although the majority of patients will ultimately experience recurrent lymphoma. Allogeneic transplant is curative in a subset of patients but may be associated with significant toxicity. Novel targeted and immunotherapy approaches, including chimeric antigen receptor T‐cell therapy, are currently being studied in clinical trials with promising early results.     

Stem cell transplantation in Hodgkin lymphoma

Hematopoietic stem cell transplantation is an effective treatment for patients with relapsed or refractory Hodgkin lymphoma. Treatment outcome is better among patients who demonstrate sensitivity to salvage chemotherapy. Approximately half of the patients undergoing autologous stem cell transplantation will be cured and sequential high-dose therapy has been proposed as a means of improving these results further. Lifelong medical surveillance is required following transplantation to monitor for late toxicity, including second malignancy. For young patients who relapse following transplantation, reduced-intensity allogeneic transplantation has shown encouraging response rates, while second autologous stem cell transplantation, radiotherapy and palliative single-agent chemotherapy are other options. For patients with multiple relapses and chemotherapy refractory disease, novel approaches are necessary.     

IIVP salvage regimen induces high response rates in patients with relapsed lymphoma before autologous stem cell transplantation

Patients with relapsed lymphoma can be cured with high-dose chemotherapy and autologous hematopoietic stem cell transplantation (HSCT). New therapeutic approaches with better cytoreductive capacity are needed for relapsed patients to keep their chance for cure with transplantation. We report 30 patients with relapsed lymphoma, median age 43 years, treated with IIVP salvage regimen consisting of ifosfamide, mesna, idarubicin, and etoposide for 2 or 3 cycles. Seventeen patients had non-Hodgkin lymphoma (NHL) and 13 patients had Hodgkin disease (HD). Fourteen (47%) patients were at their first relapse. Overall response rate was 86.6% (n = 26) with 19 patients (63.3%) achieving complete response. Overall response rate was 92% in patients with HD and 82% in NHL. The most frequent side effects observed were grade III-IV neutropenia (87%) and thrombocytopenia (73%). IIVP regimen is a highly effective salvage therapy for patients with relapsed HD or NHL who are candidates for autologous HSCT. Close follow up is necessary because of the high incidence of grade III-IV hematologic toxicity.     

晚期经典型霍奇金淋巴瘤的治疗进展

晚期经典型霍奇金淋巴瘤的治疗在过去的50年间有了很大的进步,带来了治愈率的提高。不过,患者大都经历了高强度化疗相关的严重并发症。在一线治疗中组合应用“根据疾病危险分层调整治疗策略”和“根据对初始治疗反应调整策略”可能是一个很好的选择。新药如BV和免疫检查点抑制剂使很多复发难治的霍奇金淋巴瘤患者获得了收益。自体造血干细胞移植对于一般状态良好的年轻复发患者来说是挽救治疗的合理选择。为了提高缓解率,双次自体造血干细胞移植和自体造血干细胞移植后BV巩固治疗成为新的研究热点。     

Brentuximab vedotin : nouvelle option thérapeutique dans la prise en charge des lymphomes CD30+

Brentuximab vedotin is a new antibody-drug conjugate composed of the anti-CD30 chimeric monoclonal antibody and the potent antimicrotubule drug monomethylauristatin E. In two phase II clinical trials, treatment with single-agent brentuximab vedotin resulted in response rates of 75% in relapsed/refractory Hodgkin lymphoma and 86% in relapsed/refractory systemic anaplastic large-cell lymphoma. Peripheral sensory neuropathy (40%) and neutropenia (20%) were the most frequent side effects, generally mild and manageable. After a large use in a compassionate program, brentuximab vedotin was approved in France in October 2012 for the treatment of Hodgkin lymphoma after failure of autologous stem cell transplantation or after failure of at least two prior multiagent chemotherapy regimens in patients non eligible for autologous transplantation, and for the treatment of systemic anaplastic large-cell lymphoma after failure of at least one prior multiagent chemotherapy regimen.     

Brentuximab Vedotin in Transplant‐Naïve Relapsed/Refractory Hodgkin Lymphoma: Experience in 30 Patients

Background.

Hodgkin lymphoma (HL) is characterized by the presence of CD30-positive Hodgkin Reed-Sternberg cells. Approximately 30%–40% of patients with advanced disease are refractory to frontline therapy or will relapse after first-line treatment. The standard management of these patients is salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplant (ASCT). The best prognostic factor is the status of disease before ASCT; in particular, the normalization of positron emission tomography (PET) scan. Brentuximab vedotin (BV) has shown a high overall response rate in refractory/relapsed HL after ASCT, whereas few data are available regarding its role before ASCT.

Patients and Methods.

A multicenter, retrospective, observational study was conducted. The primary endpoint of the study was the effectiveness of BV as single agent in patients with relapsed/refractory, ASCT-naïve HL, determined by the conversion of PET status from positive to negative; secondary endpoints were safety, capacity to proceed to ASCT, survival, and progression-free status.

Results.

Thirty patients with relapsed/refractory HL- and PET-positive disease after conventional chemotherapy salvage treatments were treated with a median of 4 cycles of BV. Normalization of PET findings (Deauville score ≤2) occurred in 9 of 30 patients (30%). Those nine patients proceeded to ASCT.

Conclusion.

These data suggest that BV can normalize PET status in a subset of HL patients refractory to conventional chemotherapy salvage treatments, such as ifosfamide-containing regimens, cytarabine- and platinum-containing regimens, prior to ASCT.

Implications for Practice:

Administration of brentuximab vedotin has resulted in a high overall response rate in refractory/relapsed Hodgkin lymphoma after autologous stem cell transplant, whereas few data are available regarding its role before transplant. The data suggest that brentuximab vedotin can normalize positron emission tomography results in a subset of patients refractory to conventional salvage treatments prior to transplant. Experience indicates that patients previously regarded as not ideal candidates for transplantation may be able to undergo further cytoreductive therapy using brentuximab vedotin.     

Allogeneic stem cell transplantation using lymphoablative rather than myeloablative conditioning regimen for relapsed or refractory lymphomas

In relapsed or refractory non‐Hodgkin lymphoma (NHL), allogeneic hematopoietic stem cell transplantation (allo‐HSCT) provides graft‐versus‐lymphoma activity resulting in fewer incidences of relapse. However, therapy‐related mortality (TRM) remains an important challenge. We attempted to introduce our reduced‐intensity conditioning (RIC) regimen. From 2007 to 2013, we treated 28 relapsed or refractory NHLs with allo‐HSCT. All were pre‐conditioned with fludarabine [FLU, 180 mg/body surface area (BSA)/6 days] and melphalan (MEL, 70 mg/BSA/1 day); 25 (all but 3) were additionally treated with total body irradiation (TBI, 800 cGy/4Fx/2 days). Peripheral blood stem cells were collected from matched siblings (n = 10) or suitably matched unrelated (n = 18) donors. There were eight diffuse large B‐cell lymphomas, seven peripheral T‐cell lymphoma not otherwise specified, give lymphoblastic lymphomas, two mantle cell lymphomas, and six various other lymphomas. Of these patients, 10 relapsed after auto‐HSCT, 5 relapsed after chemotherapy, and 13 were refractory lymphomas. After allo‐HSCT, complete remission was achieved in 22 (78.5%) patients. After a median follow‐up of 24.8 months, 3‐year overall survival and disease‐free survival were 62.4 and 59.2% and the 3‐year TRM and relapse incidence were 14.9 and 28.6% respectively. Acute and chronic graft‐versus‐host diseases (GVHDs) were identified in 17 (≥Grade II in 12 patients) and 18 patients respectively, and the group with chronic GVHD showed favourable survival outcomes. In relapsed or refractory NHL, RIC‐allo‐HSCT using FLU + MEL + 800 cGy TBI showed favourable survival outcomes with acceptable TRM and relapse incidence. Copyright © 2015 John Wiley & Sons, Ltd.     

Current status of autologous stem cell transplantation in relapsed and refractory Hodgkin's lymphoma

Despite the relatively high long-term disease-free survival (DFS) rate for patients with Hodgkin lymphoma (HL) with modern combination chemotherapy or combined modality regimens, ～20% of patients die from progressive or relapsed disease. The standard treatment for relapsed and primary refractory HL is salvage chemotherapy followed by high-dose chemotherapy and autologous stem cell transplantation (ASCT), which has shown a 5-year progression-free survival rate of ～50%-60%. Recent developments in a number of diagnostic and therapeutic modalities have begun to improve these results. Functional imaging, refinement of clinical prognostic factors, and development of novel biomarkers have improved the predictive algorithms, allowing better patient selection and timing for ASCT. In addition, these algorithms have begun to identify a group of patients who are candidates for more aggressive treatment beyond standard ASCT. Novel salvage regimens may potentially improve the rate of complete remission prior to ASCT, and the use of maintenance therapy after ASCT has become a subject of current investigation. We present a summary of developments in each of these areas.     

Immunotherapy for the Treatment of Hodgkin Lymphoma: An Evolving Paradigm

Classical Hodgkin lymphoma (cHL) is one of the most common lymphomas in the Western world. Although most patients are cured with standard first-line therapy, up to 20% of patients will have relapsed or refractory disease. Although the conventional approach to treatment has consisted of chemotherapy, radiation, and for those who relapse, autologous or allogeneic transplantation, newer approaches have become available in recent years, including immunoconjugates and checkpoint inhibitors. These approaches have shown significant efficacy in clinical trials and might be associated with fewer long-term toxicities compared with conventional therapies. In this review we discuss the biology of cHL as it pertains to the immunosuppressive tumor microenvironment and then review the existing clinical trial results of several emerging immunotherapies in this context, including immune checkpoint inhibitors and adoptive cellular therapy. Finally, several clinical practice issues pertaining to the use of immunotherapies are discussed.     

The Role of Autologous Transplantation in Hodgkin Lymphoma

Between 80% and 90% of Hodgkin lymphoma (HL) patients can be cured with up-to-date combined-modality treatments, but patients with disease refractory to first-line therapy and those who relapse after first-line therapy still have a relatively poor prognosis. Dose intensification with stem cell support has been evaluated both to avoid relapses and to cure patients with refractory or relapsed disease. In this review, we focus on the use of high-dose chemotherapy followed by autologous stem cell transplantation (ASCT) in first-line, second-line, and third-line therapy for HL patients. The relevance of salvage therapy before high-dose chemotherapy is discussed, as well as the role of sequential high dose chemotherapy. We also review current evidence for tandem transplantation in high-risk HL patients and ASCT in elderly patients. Finally, we discuss current concepts of ASCT for HL patients and the use of functional imaging and consolidation therapy.     

创新引领未来:从第56届美国血液学会年会展望淋巴瘤的治疗前景

一年一度的美国血液学会(ASH)年会是国际血液学领域最重要的学术会议,2014年ASH会议上有关淋巴瘤诊治进展的报道众多.brentuximab vedotin用于霍奇金淋巴瘤(HL)患者自体干细胞移植后的维持治疗,无进展生存(PFS)率获得显著改善;PD-1抑制剂nivolumab在Ⅰ期临床研究中治疗高度复发难治性HL患者的总有效率为87％,并因此获得FDA批准.BTK抑制剂、PI3K抑制剂、新型抗CD20单抗、bcl-2抑制剂、来那度胺(lenalidomide)均在复发难治性慢性淋巴细胞白血病和非霍奇金淋巴瘤中取得了良好疗效,如何更好地选择和应用这些药物并与化疗方案联合进一步推向一线治疗是临床面临的困惑.针对CD19、CD30、CD20、CD138等表面抗原的各型嵌合型抗原受体基因修饰的T细胞(CAR-T细胞)免疫治疗在淋巴瘤中也展现了一定前景,值得关注.     

Relapsed Hodgkin Lymphoma: Management Strategies

Although Hodgkin lymphoma (HL) is largely curable with first-line therapy, approximately one-third of patients will not have a complete response to frontline treatment or will subsequently relapse. Only 50 % of these patients will be effectively salvaged with conventional therapies. The prognosis is particularly poor for those patients with chemotherapy refractory disease, who are unable to obtain even transient disease control, and for patients who relapse following high dose chemotherapy and autologous stem cell transplant. In this review, we summarize the most recent updates on the management of patients with relapsed HL, the role of novel therapies such as brentuximab vedotin, and an overview of promising new agents currently under investigation. We also discuss the role of consolidation strategies such as high-dose chemotherapy and autologous stem cell transplant, and reduced-intensity allogeneic hematopoietic stem cell transplant, and the need for new strategies in the elderly patient population.     

How to Approach a Hodgkin Lymphoma Patient With Relapse After Autologous SCT: Allogeneic SCT

Hodgkin lymphoma (HL) is a highly curable B-cell lymphoma, and ～90% of patients who present with early-stage (stage I-II) disease and 70% of patients who present with late-stage disease will be cured with standard frontline treatment. For patients with relapsed or refractory (r/r) disease after initial therapy, the standard of care is salvage chemotherapy, followed by autologous transplantation (autoSCT). Although this approach will cure a significant proportion of patients, upto 50% of patients will experience disease progression after autoSCT, and this population has historically had a very poor prognosis. In the past, further salvage chemotherapy, followed by allogeneic transplantation (alloSCT), has been the only option associated with a significant probability of long-term survival, owing to a graft-versus-lymphoma effect. However, this approach has been complicated by high rates of treatment-related morbidity and mortality and a high risk of disease relapse. Furthermore, many patients have been unable to proceed to alloSCT because of disease refractoriness, poor performance status, or the lack of a donor. However, significant therapeutic advances in recent years have greatly expanded the options for patients with post-autoSCT r/r HL. These include the anti-CD30 antibody–drug conjugate brentuximab vedotin and the checkpoint inhibitors nivolumab and pembrolizumab, as well as increasing experience with alternative donor alloSCT, especially from haploidentical donors. In the present review, we discuss the current role of alloSCT in the treatment of HL after autoSCT relapse.     

High-dose chemotherapy followed by autologous stem cell transplantation for relapsed or refractory Hodgkin lymphoma: prognostic features and outcomes

Between January 1990 and April 2001, 115 patients received high-dose chemotherapy (HDT) followed by autologous stem cell transplantation (ASCT) for relapsed or refractory Hodgkin lymphoma (HL). With a median follow-up of 58 months (range, 1 - 175 months), 5-year progression-free survival (PFS) and overall survival (OS) were 46% and 58%, respectively. Twelve patients with primary refractory disease had a 5-year PFS of 41% and OS of 58%, not significantly different from those of the remaining cohort. Early and overall regimen related mortality were 7% and 16%, respectively. Male gender (P = 0.04) and a time to relapse (TTR) < 12 months (P = 0.03) were associated with decreased OS by univariate analysis. In multivariate analysis, TTR < 12 months remained statistically significant (P = 0.04). We have confirmed that HDT and ASCT result in long-term survival for a proportion of patients with relapsed or refractory HL. All patients, including those with primary refractory disease, benefited from HDT and ASCT.     

Hodgkin lymphoma: A review and update on recent progress

Hodgkin lymphoma (HL) is a unique hematopoietic neoplasm characterized by cancerous Reed‐Sternberg cells in an inflammatory background. Patients are commonly diagnosed with HL in their 20s and 30s, and they present with supradiaphragmatic lymphadenopathy, often with systemic B symptoms. Even in advanced‐stage disease, HL is highly curable with combination chemotherapy, radiation, or combined‐modality treatment. Although the same doxorubicin, bleomycin, vinblastine, and dacarbazine chemotherapeutic regimen has been the mainstay of therapy over the last 30 years, risk‐adapted approaches have helped de‐escalate therapy in low‐risk patients while intensifying treatment for higher risk patients. Even patients who are not cured with initial therapy can often be salvaged with alternate chemotherapy combinations, the novel antibody‐drug conjugate brentuximab, or high‐dose autologous or allogeneic hematopoietic stem cell transplantation. The programmed death‐1 inhibitors nivolumab and pembrolizumab have both demonstrated high response rates and durable remissions in patients with relapsed/refractory HL. Alternate donor sources and reduced‐intensity conditioning have made allogeneic hematopoietic stem cell transplantation a viable option for more patients. Future research will look to integrate novel strategies into earlier lines of therapy to improve the HL cure rate and minimize long‐term treatment toxicities. CA Cancer J Clin 2018;68:116‐132 . © 2017 American Cancer Society .     

Role of Hematopoietic Stem Cell Transplant in the Management of Follicular Lymphoma

Despite decades of published data regarding the application of autologous and allogeneic stem cell transplant in patients with follicular lymphoma, there remain no uniform indications for its use in this disease. Autologous transplant has been shown to lead to longer progression‐free survival times in randomized trials when compared with postremission interferon‐based chemoimmunotherapy. However, the development of rituximab and its use in frontline, salvage, and maintenance therapy complicates the decision to pursue autologous transplant, a modality developed prior to the advent of anti‐CD20 monoclonal antibodies. Allogeneic transplant offers the advantages of lymphoma‐free grafts and the immunologic graft‐versus‐lymphoma effect. These factors may confer the possibility of long‐term remission, though historically they have been accompanied by high rates of upfront morbidity and mortality, especially in heavily pretreated patients with a poor performance status or chemotherapy‐refractory disease. Advances in patient selection, human leukocyte antigen (HLA) matching, conditioning regimens, and supportive care have reduced transplant‐related mortality and the incidence of graft‐versus‐host disease. Recently published data focus on the incorporation of rituximab and radioimmunoconjugates prior to, during, and following autologous transplant. Furthermore, reduced‐intensity allogeneic stem cell transplantation has increasingly been used for relapsed follicular lymphoma patients with comorbidities or advanced age. Several recent reports suggest that reduced‐intensity regimens may provide a high likelihood of long‐term disease‐free survival for patients up to 70 years of age with a good performance status, chemotherapy‐sensitive disease, and HLA‐matched sibling donors. Such patients with relapsed disease should be referred to a transplant center that can enroll them in one of the forthcoming clinical trials that aim to confirm these outcomes.     

Immunotoxin – a new treatment option in patients with relapsed and refractory Hodgkin lymphoma

Background

Even though Hodgkin lymphoma is a highly curable disease, some of the patients have either a refractory disease or experience a relapse following a successful primary therapy. Durable responses and remissions in patients with relapsed or refractory disease may be achieved in approximately one-half with salvage chemotherapy followed by high dose chemotherapy (HDT) and autologous hematopoietic cell rescue (SCT). On the other hand, patients who relapse after HDT and autologous SCT or those who have failed at least two prior multi-agent chemotherapy regimens and are not candidates for HDT have limited treatment options.

Conclusions

A new treatment option in this population is an immunotoxin Brentuximab vedotin composed of a CD30 directed antibody linked to the antitubulin agent monomethyl auristatin E. It has demonstrated a substantial effectiveness and an acceptable toxicity. In the pivotal study, the overall response rate was 75% with 34% of complete remissions. The median durations of response were 20.5 and 6.7 months for those with complete remission and all responding patients, respectively. The median overall survival was 40.5 months (3-years overall survival 54%) and the median progression-free survival 9.3 months. The most common non-hematologic toxicities were peripheral sensory neuropathy, nausea, and fatigue while the most common severe side effects were neutropenia, thrombocytopenia, anemia, and peripheral sensory neuropathy.     

A Review of Autologous Stem Cell Transplantation in Lymphoma

Purpose of Review

Chemotherapy remains the first-line therapy for aggressive lymphomas. However, 20–30% of patients with non-Hodgkin lymphoma (NHL) and 15% with Hodgkin lymphoma (HL) recur after initial therapy. We want to explore the role of high-dose chemotherapy (HDT) and autologous stem cell transplant (ASCT) for these patients.

Recent Findings

There is some utility of upfront consolidation for-high risk/high-grade B-cell lymphoma, mantle cell lymphoma, and T-cell lymphoma, but there is no role of similar intervention for HL. New conditioning regimens are being investigated which have demonstrated an improved safety profile without compromising the myeloablative efficiency for relapsed or refractory HL.

Summary

Salvage chemotherapy followed by HDT and rescue autologous stem cell transplant remains the standard of care for relapsed/refractory lymphoma. The role of novel agents to improve disease-related parameters remains to be elucidated in frontline induction, disease salvage, and high-dose consolidation or in the maintenance setting.

     

Treatment of adult patients with Philadelphia chromosome-positive acute lymphoblastic leukemia

In the pre-imatinib era, treatment outcomes of adult patients with Philadelphia chromosome (Ph)-positive acute lymphoblastic leukemia (ALL) were dismal. Despite the use of intensive chemotherapy and allogeneic hematopoietic stem cell transplantation (HSCT), complete remission and overall survival rates were less than 70% and 20%, respectively. However, imatinib, in combination with conventional chemotherapy, has dramatically changed outcomes, producing approximately 95% complete remission and 50% overall survival with or without allogeneic HSCT. Current research is now focusing on how to prevent relapse. Improvement of postremission therapy is indispensable. Although allogeneic HSCT during first complete remission is still the first choice for feasible patients, post-HSCT imatinib therapy and imatinib plus chemotherapy combinations should also be studied. New BCR-ABL tyrosine kinase inhibitors are expected to improve outcomes in imatinib-resistant leukemia. Our hope is that, in the near future, Ph-positive ALL will become a leukemia in which allogeneic HSCT is offered only for relapsed or refractory cases.