Autologous hematopoietic cell transplantation following high-dose immunosuppressive therapy for advanced multiple sclerosis: long-term results

The purpose of the study was to determine the long-term safety and effectiveness of high-dose immunosuppressive therapy (HDIT) followed by autologous hematopoietic cell transplantation (AHCT) in advanced multiple sclerosis (MS). TBI, CY and antithymocyte globulin were followed by transplantation of autologous, CD34-selected PBSCs. Neurological examinations, brain magnetic resonance imaging and cerebrospinal fluid (CSF) for oligoclonal bands (OCB) were serially evaluated. Patients (n=26, mean Expanded Disability Status Scale (EDSS)=7.0, 17 secondary progressive, 8 primary progressive, 1 relapsing/remitting) were followed for a median of 48 months after HDIT followed by AHCT. The 72-month probability of worsening 1.0 EDSS point was 0.52 (95% confidence interval, 0.30-0.75). Five patients had an EDSS at baseline of 6.0; four of them had not failed treatment at last study visit. OCB in CSF persisted with minor changes in the banding pattern. Four new or enhancing lesions were seen on MRI, all within 13 months of treatment. In this population with high baseline EDSS, a significant proportion of patients with advanced MS remained stable for as long as 7 years after transplant. Non-inflammatory events may have contributed to neurological worsening after treatment. HDIT/AHCT may be more effective in patients with less advanced relapsing/remitting MS.     

High-dose immunosuppressive therapy and autologous peripheral blood stem cell transplantation for severe multiple sclerosis

There were 26 patients enrolled in a pilot study of high-dose immunosuppressive therapy (HDIT) for severe multiple sclerosis (MS). Median baseline expanded disability status scale (EDSS) was 7.0 (range, 5.0-8.0). HDIT consisted of total body irradiation, cyclophosphamide, and antithymocyte globulin (ATG) and was followed by transplantation of autologous, granulocyte colony-stimulating factor (G-CSF)-mobilized CD34-selected stem cells. Regimen-related toxicities were mild. Because of bladder dysfunction, there were 8 infectious events of the lower urinary tract. One patient died from Epstein-Barr virus (EBV)-related posttransplantation lymphoproliferative disorder (PTLD) associated with a change from horse-derived to rabbit-derived ATG in the HDIT regimen. An engraftment syndrome characterized by noninfectious fever with or without rash developed in 13 of the first 18 patients and was associated in some cases with transient worsening of neurologic symptoms. There were 2 significant adverse neurologic events that occurred, including a flare of MS during mobilization and an episode of irreversible neurologic deterioration after HDIT associated with fever. With a median follow-up of 24 (range, 3-36) months, the Kaplan-Meier estimate of progression (>/= 1.0 point EDSS) at 3 years was 27%. Of 12 patients who had oligoclonal bands in the cerebrospinal fluid at baseline, 9 had persistence after HDIT. After HDIT, 4 patients developed new enhancing lesions on magnetic resonance imaging of the brain. The estimate of survival at 3 years was 91%. Important clinical issues in the use of HDIT and stem cell transplantation for MS were identified; however, modifications of the initial approaches appear to reduce treatment risks. This was a heterogeneous high-risk group, and a phase 3 study is planned to fully assess efficacy.     

Autologous Peripheral Blood Stem Cell Transplantation for Severe Multiple Sclerosis

We describe the results of a clinical trial to evaluate the feasibility and toxicity of autologous hematopoietic stem cell transplantation (auto-HSCT) for patients with progressive multiple sclerosis (MS). Fifteen patients (all patients with secondary progressive MS) were enrolled. The median expanded disability status scale (EDSS) score at baseline was 6.0 (range, 4.5-7.5). Peripheral blood stem cells were obtained by leukapheresis after mobilization with granulocyte colony-stimulating factor. In 9 patients, CD34+ cell selection was performed with a CliniMACS cell selection system, and 6 patients accepted infusion of unmodified peripheral blood stem cells. The modified BEAM (carmustine, teniposide, cytarabine, and melphalan) was the sole conditioning regimen used. The adverse effects included infections, mucositis, transient hepatotoxicity, and diarrhea. Three patients had flares of neurologic deterioration during mobilization, 8 patients had the same manifestation during transplantation, and 2 patients had similar flares within 3 months of transplantation. Six patients experienced continuous neurologic improvement after transplantation, 5 patients experienced neurologic progression, and 4 patients had stabilization of their disease. The confirmed progression-free rate was 63.8% at 49 months. The results of lymphocyte purging were no better than for no purging. Auto-HSCT proved to be safe and beneficial for some MS patients. Further studies are needed to establish the merit of this procedure for MS patients.     

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.     

自体造血干细胞移植治疗继发进展型多发性硬化36例疗效及预后影响因素分析

目的分析继发进展型多发性硬化(SPMS)患者接受自体造血干细胞移植(auto-HSCT)疗效及预后因素分析。方法收集2001—2009年首都医科大学宣武医院收治的36例SPMS患者。粒细胞集落刺激因子(G-CSF)5μg/kg皮下注射4~6 d动员造血干细胞,采集外周血单个核细胞,其中28例患者分选CD34+细胞。预处理方案为BEAM(卡氮芥、马法兰、替尼泊甙及阿糖胞苷)。结果15例临床缓解,5例疾病稳定,14例移植后复发,2例失访。88个月预期无复发存活率55%。发病时有视神经损伤是移植预后不良的危险因素。结论auto-HSCT是SPMS患者获得长期疾病缓解的有效方法,视神经损伤是移植预后不良因素。     

Hematopoietic stem cell transplantation for progressive multiple sclerosis: failure of a total body irradiation-based conditioning regimen to prevent disease progression in patients with high disability scores

There were 21 patients with rapidly progressive multiple sclerosis (MS) treated on a phase 1/2 study of intense immune suppressive therapy and autologous hematopoietic stem cell (HSC) support with no 1-year mortality. Following transplantation, one patient had a confirmed acute attack of MS. Neurologic progression defined by the expanded disability status scale (EDSS) did not increase in disability by 1.0 or more steps in any of 9 patients with a pretransplantation EDSS of 6.0 or less. In 8 of 12 patients with high pretransplantation disability scores (EDSS > 6.0), progressive neurologic disability as defined by at least a 1-point increase in the EDSS has occurred and was manifested as gradual neurologic deterioration. There were 2 patients with a pretransplantation EDSS of 7.0 and 8.0 who died from complications of progressive disease at 13 and 18 months following treatment. Our experience suggests that intense immune suppression using a total body irradiation (TBI)-based regimen and hematopoietic stem cell transplantation (HSCT) are not effective for patients with progressive disease and high pretransplantation disability scores. Further studies are necessary to determine the role of intense immune suppressive therapy and HSC support in ambulatory patients with less accumulated disability and more inflammatory disease activity. Specifically, more patients and longer follow-up would be required in patients with an EDSS of 6.0 or less before drawing conclusions on this subgroup.     

High-dose immunosuppressive therapy and autologous hematopoietic cell transplantation for severe systemic sclerosis: long-term follow-up of the US multicenter pilot study

More effective therapeutic strategies are required for patients with poor-prognosis systemic sclerosis (SSc). A phase 2 single-arm study of high-dose immunosuppressive therapy (HDIT) and autologous CD34-selected hematopoietic cell transplantation (HCT) was conducted in 34 patients with diffuse cutaneous SSc. HDIT included total body irradiation (800 cGy) with lung shielding, cyclophosphamide (120 mg/kg), and equine antithymocyte globulin (90 mg/kg). Neutrophil and platelet counts were recovered by 9 (range, 7 to 13) and 11 (range, 7 to 25) days after HCT, respectively. Seventeen of 27 (63%) evaluable patients who survived at least 1 year after HDIT had sustained responses at a median follow-up of 4 (range, 1 to 8) years. There was a major improvement in skin (modified Rodnan skin score, -22.08; P < .001) and overall function (modified Health Assessment Questionnaire Disability Index, -1.03; P < .001) at final evaluation. Importantly, for the first time, biopsies confirmed a statistically significant decrease of dermal fibrosis compared with baseline (P < .001). Lung, heart, and kidney function, in general, remained clinically stable. There were 12 deaths during the study (transplantation-related, 8; SSc-related, 4). The estimated progression-free survival was 64% at 5 years. Sustained responses including a decrease in dermal fibrosis were observed exceeding those previously reported with other therapies. HDIT and autologous HCT for SSc should be evaluated in a randomized clinical trial.     

CD34+ selected autologous peripheral blood stem cell transplantation for multiple sclerosis: report of toxicity and treatment results at one year of follow-up in 15 patients

BACKGROUND AND OBJECTIVES: Autologous stem cell transplantation (ASCT) is currently being evaluated as a therapy for patients with multiple sclerosis (MS). We report the results of a phase II trial to evaluate feasibility and toxicity of CD34+ selected ASCT (CD34+/ASCT) and treatment results at one year of follow-up. DESIGN AND METHODS: Patients with advanced secondary progressive (SP) or relapsing-remitting (RR) MS and confirmed worsening of the extended disability status scale (EDSS) in the previous year despite interferon or other immunotherapies were included. Peripheral blood stem cells were obtained by leukaphereses after mobilization with cyclophosphamide (Cy) and granulocyte colony-stimulating factor (G-CSF). CD34+ selection was performed by means of an Isolex 300 or CliniMACS device. BCNU, Cy and antithymocyte globulin (ATG) were administered as conditioning regimen. RESULTS: Fifteen patients (9 SPMS and 6 RRMS) with a median EDSS of 6.0 (4.5-6.5) and a median of 3 (1-7) relapses in the previous year were included. Mobilization was unsuccessful in one patient. During mobilization, one patient had a transient neurologic deterioration. The main complication during ASCT were engraftment syndrome, which developed in three patients, CMV reactivation in one, and neurologic deterioration in two patients coinciding with high-fever related to ATG. Hematologic recovery was fast and complete in all cases. At 12 months, the EDSS had improved in three patients, worsened in two and remained stable in nine. Despite withdrawal of all immunosuppressive therapy only two patients had relapses. Magnetic resonance imaging showed disappearance of enhanced T1 lesions but oligoclonal bands persisted in the cerebrospinal fluid of all evaluated cases. INTERPRETATION AND CONCLUSIONS: CD34+/ASCT using BCNU, Cy and ATG as conditioning regimen has an acceptable toxicity and clearly reduces the progression of MS. Further follow-up is necessary to establish the real impact of this procedure on the long-term evolution of the disease.     

High-dose immunosuppressive therapy with PBPC support in the treatment of poor risk multiple sclerosis

High-dose immunoablative chemotherapy with autologous haematopoietic cell support might be beneficial in the treatment of intractable forms of MS. We mobilised PBPC in 11 patients with secondary progressive MS and finally eight patients were grafted after high-dose BEAM chemotherapy with either in vitro or in vivo T cell depletion. Median EDSS and SNRS scores at the time of inclusion were 6.5 (6.5-7.5) and 56 (44-65), respectively. PBPC mobilisation was safe with no serious adverse effects, and without significant aggravation of disability. One patient improved significantly (by 1.0 point on EDSS) after the mobilisation. Two mobilisation failures were observed. No life-threatening events occurred during the transplantation. All grafted patients, except one, at least stabilised their disability status. One patient improved significantly (by 1.5 points on EDSS), two patients improved slightly (by 0.5 points on EDSS), one patient worsened by 1.0 point on the EDSS in 10 months. Improvement occurred with a delay of 2-4 months. Median EDSS and SNRS of grafted patients at the last follow up were 6.5 (5.5-8.5) and 64 (39-73), respectively with median follow-up of 8.5 months. Further follow-up is needed to determine the disease course after complete immune reconstitution. Bone Marrow Transplantation (2000) 25, 525-531.     

Second-line salvage chemotherapy for transplant-eligible patients with Hodgkin's lymphoma resistant to platinum-containing first-line salvage chemotherapy

Background

The management of patients with relapsed or refractory Hodgkin’s lymphoma who achieve less than a partial response to first-line salvage chemotherapy is unclear. The objective of this study was to evaluate response and outcomes to second-line salvage and autologous stem cell transplantation in patients not achieving a complete or partial response to platinum-containing first-line salvage chemotherapy.

Design and Methods

Consecutively referred transplant-eligible patients with relapsed/refractory Hodgkin’s lymphoma after primary chemotherapy received gemcitabine, dexamethasone, and cisplatin as first salvage chemotherapy. Those achieving a complete or partial response, and those with a negative gallium scan and stable disease with bulk <5 cm proceeded to high-dose chemotherapy and autologous stem cell transplantation. Patients with progressive disease or stable disease with a positive gallium scan or bulk ≥5 cm were given second salvage chemotherapy with mini-BEAM (carmustine, etoposide, cytarabine, melphalan). Patients who responded (according to the same definition) proceeded to autologous stem cell transplantation.

Results

One hundred and thirty-one patients with relapsed/refractory Hodgkin’s lymphoma received first-line salvage gemcitabine, dexamethasone, and cisplatin; of these patients 99 had at least a partial response (overall response rate 76%). One hundred and twelve (85.5%) patients proceeded to autologous stem cell transplantation, while the remaining 19 (14.5%) patients received mini-BEAM. Among these 19 patients, six had at least a partial response (overall response rate 32%), and nine proceeded to autologous stem cell transplantation. The remaining ten patients received palliative care. Seven of the nine patients transplanted after mini-BEAM had a subsequent relapse. Patients receiving second salvage mini-BEAM had poor outcomes, with a 5-year progression-free survival rate of 11% and a 5-year overall survival rate of 20%.

Conclusions

Patients who require a second salvage regimen to achieve disease control prior to autologous stem cell transplantation have a relatively poor outcome and should be considered for alternative treatment strategies.     

Treatment alternatives for hepatitis B cirrhosis: a cost-effectiveness analysis

BACKGROUND: Hepatitis B virus (HBV) patients with cirrhosis are at risk for developing costly, morbid, or mortal events, and therefore need highly effective therapies. Lamivudine is effective but is limited by viral resistance. In contrast, adefovir and entecavir have lower viral resistance, but are more expensive. The most cost-effective approach is uncertain. METHODS: We evaluated the cost-effectiveness of six strategies in HBV cirrhosis: (1) No HBV treatment ("do nothing"), (2) lamivudine monotherapy, (3) adefovir monotherapy, (4) lamivudine with crossover to adefovir on resistance ("adefovir salvage"), (5) entecavir monotherapy, or (6) lamivudine with crossover to entecavir on resistance ("entecavir salvage"). The primary outcome was the incremental cost per quality-adjusted life-year (QALY) gained. RESULTS: The "do nothing" strategy was least effective yet least expensive. Compared with "do nothing," using adefovir cost an incremental US dollars 19,731. Entecavir was more effective yet more expensive than adefovir, and cost an incremental US dollars 25,626 per QALY gained versus adefovir. Selecting between entecavir versus adefovir was highly dependent on the third-party payer's "willingess-to-pay" (e.g., 45% and 60% of patients fall within budget if willing-to-pay US dollars 10K and US dollars 50K per QALY gained for entecavir, respectively). Both lamivudine monotherapy and the "salvage" strategies were not cost-effective. However, between the two salvage strategies, "adefovir salvage" was more effective and less expensive than "entecavir salvage." CONCLUSION: Both entecavir and adefovir are cost-effective in patients with HBV cirrhosis. Choosing between adefovir and entecavir is highly dependent on available budgets. In patients with HBV cirrhosis with previous lamivudine resistance, "adefovir salvage" appears more effective and less expensive than "entecavir salvage."     

High-dose immunosuppressive therapy for severe systemic sclerosis: initial outcomes

Systemic sclerosis (SSc) is a multisystem disease of presumed autoimmune pathogenesis for which no proven effective treatment exists. High-dose immunosuppressive therapy (HDIT) has been proposed as an investigational treatment for severe autoimmune diseases. Nineteen patients with poor-prognosis SSc underwent HDIT. The median age was 40 years (range, 23-61 years), the median modified Rodnan skin score (a measure of dermal sclerosis) was 31, and the median DLCO was 57%. Conditioning therapy involved 800 cGy total body irradiation (TBI) (+/- lung shielding to approximately 200 cGy), 120 mg/kg cyclophosphamide, and 90 mg/kg equine antithymocyte globulin. CD34-selected granulocyte-colony-stimulating factor-mobilized autologous blood stem cells provided hematopoietic rescue. With median follow-up at 14.7 months, the Kaplan-Meier estimated 2-year survival rate was 79%. Three patients died of treatment complications and one of disease progression. Two of the first 8 patients had fatal regimen-related pulmonary injury, a complication not found among 11 subsequent patients who received lung shielding for TBI. Overall, internal organ functions were stable to slightly worse after HDIT, and 4 patients had progressive or nonresponsive disease. As measured by modified Rodnan skin scores and modified health assessment questionnaire disability index (mHAQ-DI) scores, significant disease responses occurred in 12 of 12 patients evaluated at 1 year after HDIT. In conclusion, though important treatment-related toxicities occurred after HDIT for SSc, modifications of initial approaches appear to reduce treatment risks. Responses in skin and mHAQ-DI scores exceed those reported with other therapies, suggesting that HDIT is a promising new therapy for SSc that should be evaluated in prospective randomized studies.     

儿童难治性自身免疫性疾病自体外周血干细胞动员采集和分选的临床研究

目的 探讨儿童难治性自身免疫性疾病进行自体外周血干细胞动员采集的安全性和CD34+细胞分选纯化的可行性及其临床意义.方法 8例儿童难治性自身免疫性疾病,包括4例系统性红斑狼疮、2例皮肌炎,1例幼年型类风湿关节炎和1例多发性硬化,予行CD34+细胞纯化的自体外周血干细胞移植.首先采用环磷酰胺(CTX)联合粒细胞集落刺激因子(G-CSF)方案动员外周血干细胞,然后采用CS-3000血细胞分离机采集外周血,通过CliniMACS细胞分选仪分选自体外周血CD34+细胞,将其用保养液配置冻存于-80℃冰箱.采用非清髓内去除T的预处理方案,即卡氮芥+足叶乙苷+阿糖胞苷+马法兰+抗胸腺球蛋白(ATG)或CTX+ATG或CTX+马法兰+ATG,于第0天回输自体外周血CD34+细胞.结果 儿童能够耐受自体外周血干细胞动员采集过程,无动员相关死亡,动员后获得的单个核细胞数和CD34+细胞数的平均值分别为8.35×108/kg和7.92×106/kg,纯化后的白体外周血CD34+和CD3+细胞数的平均值分别为6.28×106/kg和0.71×105/kg.回输后中性粒细胞和血小板的植入中位时间分别为+11d和+15 d.结论 经CTX联合G-CSF方案可动员出足量的外周血干细胞,经CS-3000血细胞分离机采集可获得足够的单个核细胞,在动员过程中原发病无明显进展恶化,患儿能耐受动员方案,采集过程顺利安全;经CliniMACS细胞分选仪分选的自体外周血CD34+细胞纯度高,移植后造血恢复;采用CD34+细胞纯化的自体外周血移植治疗是常规治疗无效的儿童难治性自身免疫性疾病的可选择治疗措施之一.     

Tandem autologous hematopoietic stem cell transplantation for treatment of adult T-cell lymphoblastic lymphoma: a multiple center prospective study in China

T-cell lymphoblastic lymphoma (T-LBL) is a highly aggressive form of lymphoma with poor clinical outcomes and no standard treatment regimen. In this study, we assessed the safety and efficacy of tandem autologous hematopoietic stem cell transplantation (auto-HSCT) for adult T-LBL and evaluated prognostic factors affecting survival. A total of 181 newly-diagnosed adult T-LBL patients were enrolled: 89 patients were treated with chemotherapy alone, 46 were allocated to the single auto-HSCT group, 46 were treated with tandem auto-HSCT. Median follow-up time was 37 months; the 3-year progression/relapse rate of the tandem auto- HSCT group was significantly lower than that of the single auto-HSCT and chemotherapy groups (26.5% vs. 53.1% and 54.8%). The 3-year progression- free survival (PFS) and overall survival (OS) rates of the tandem auto- HSCT group (73.5% and 76.3%) were significantly higher than those of the single auto-HSCT group (46.9% and 58.3%) and the chemotherapy group (45.1% and 57.1%). In the tandem auto-HSCT group, age and disease status after the first transplant impacted OS and PFS. Multivariate analysis identified that disease status after the first transplant was the only independent prognostic factor for patients treated with tandem-HSCT. In addition, diagnostic models of the initial CD8⁺CD28⁺/CD8⁺CD28^– T-cell ratio in predicting the disease status were found to be significant. Taken together, tandem auto- HSCT can be considered an optimal strategy for adult T-LBL patients. (Study registered at: ChiCTR-ONN-16008480).     

Clinical outcome of autologous peripheral blood stem cell transplantation in opticospinal and conventional forms of secondary progressive multiple sclerosis in a Chinese population

To evaluate clinical outcomes of autologous peripheral blood stem cell transplantation (APBCST) between opticospinal multiple sclerosis (OSMS) and conventional multiple sclerosis (CMS) during disease progressive stage in a Chinese population. Thirty-six secondary progressive MS patients, among whom 21 were with OSMS and 15 with CMS, underwent APBSCT and were followed up for an average of 48.92 months (range, 10–91 months). Peripheral blood stem cells were obtained by leukapheresis after mobilization with granulocyte colony-stimulating factor. Modified BEAM conditioning regimen (Tiniposide, melphalan, carmustin, and cytosine arabinoside) were administered. Outcomes were evaluated using the expanded disability status scale (EDSS). No maintenance treatment was administered if there was no disease progression. No treatment-related mortality occurred. Among the 36 patients, one OSMS patient dropped during the follow-up. Among the 22 relapse-free patients, 20 were with continuous neurological improvement without any relapse events, and two remained in neurologically stable states. Among the 13 relapse patients, seven had experienced of neurological relapse, but with no progression during the follow-up period; and six experienced neurological deterioration after transplantation and needed further immunosuppressant treatment. The confirmed relapse-free survival rate was 62.9% and progression-free survival rate was 83.3% after 91 months according to Kaplan and Meier survival curves. Eleven of the 20 OSMS patients (55%) and two of the 15 CMS patients (13.3%) stayed in disease active group (P = 0.014). For the 20 OSMS patients, the overall EDSS score decreased significantly after transplantation (P = 0.016), while visual functions had no significant improvement (P = 0.716). Progressive OSMS has a higher relapse rate than CMS following APBSCT.     

Comparison of the clinical courses of the opticospinal and conventional forms of multiple sclerosis in Japan

We evaluated the clinical courses of 216 patients with multiple sclerosis (MS) diagnosed according to the recommended diagnostic criteria of McDonald et al (10). Sixty-five patients clinically displaying selective involvement of the optic nerves and spinal cord were classified as opticospinal MS (OS-MS), while the other 151 showing disseminated involvement of the central nervous system were classified as conventional MS (C-MS). The disease duration did not differ significantly between the two subtypes (11.2 years vs. 11.5 years). In addition to a higher age of onset, female preponderance and higher Kurtzke's expanded disability status scale (EDSS) scores, the OS-MS patients showed a markedly lower frequency of secondary progressive MS than the C-MS patients (4.6% vs. 29.1%, p=0.0001). The EDSS scores of the C-MS patients were significantly correlated with the disease duration, while those of the OS-MS patients were not. Among the C-MS patients, the frequency of secondary progressive MS was significantly more common in patients with a disease duration of more than 10 years than in those with a shorter duration. These results suggest that the irreversible disability in OS-MS is determined by relapses, rather than by chronic progression, whereas C-MS has a similar clinical course to MS in Westerners.     

Treatment of classical Hodgkin lymphoma in the era of brentuximab vedotin and immune checkpoint inhibitors

The majority of Hodgkin lymphoma patients are now cured with conventional first-line therapy; however, 10–15% of early-stage disease and less than 30% of advanced-stage patients are refractory(rare) or relapsed. Salvage second-line therapy combined with high-dose therapy and autologous stem-cell transplantation can cure 40–50% of patients. Recently novel agents (Brentuximab Vedotin and Immune Checkpoint inhibitors) have demonstrated evidence of therapeutic activity and are potential bridge to an allogeneic stem-cell transplantation. The review is aimed to present not only salvage strategies; indeed, the paper contains paragraphs about therapy and new treatment options at diagnosis.     

Development of a secondary autoimmune disorder after hematopoietic stem cell transplantation for autoimmune diseases: role of conditioning regimen used

Patients undergoing autologous hematopoietic stem cell transplantation (auto-HSCT) for autoimmune disease may have an added propensity to develop a second autoimmune disorder, given the genetic predisposition to autoimmunity. Therefore, we undertook a retrospective analysis of all patients who have undergone auto-HSCT for an autoimmune disease in our institution to determine the occurrence of a second autoimmune disorder and possible risk factors. In all, 155 patients underwent auto-HSCT for various autoimmune diseases; of those patients, 6 manifested a distinct secondary autoimmune disease at a median of 8.5 months (range, 2-30 months) after auto-HSCT. There were 2 patients with systemic lupus erythematosus, conditioned with a regimen containing antithymocyte globulin (ATG), who developed factor VIII inhibitors with severe bleeding. There were 4 patients (2 with multiple sclerosis, one each with lupus and systemic sclerosis) who received an alemtuzumab-containing conditioning regimen who developed autoimmune cytopenias. Among the 155 patients, the frequency of secondary autoimmune complications was 16.0% with alemtuzumab (4/25), 1.9% for ATG (2/102), and 0% for conditioning regimens without lympho-depleting antibodies (0/28)-a difference that was found to be significantly higher with alemtuzumab exposure (P = .011). In contrast, sex, type of ATG used, and CD34-selection of peripheral blood stem cells were not found to be significantly associated with development of a secondary autoimmune disorder.     

Therapeutic options for resistant lupus nephritis

OBJECTIVES: To summarize the therapeutic options for proliferative and membranous lupus nephritis that is resistant to conventional treatment. METHODS: Treatment trials in human lupus nephritis from years 1985 to 2005 that have been published in the English literature were searched by Medline using the keywords "lupus," "nephritis," "glomerulonephritis," "renal," "refractory," "resistant," "recalcitrant," "cyclophosphamide," "mycophenolate," "cyclosporin," "tacrolimus," "leflunomide," "intravenous immunoglobulin," "apheresis," "plasmapheresis," "immunoadsorption," "marrow transplantation," "stem cell transplantation," "immunoablative," "rituximab," and "biologics." Laboratory, histological, and nonrenal lupus studies were excluded. RESULTS: There is no universal definition of treatment resistance in lupus nephritis. Controlled trials in refractory lupus nephritis are largely unavailable. Open-labeled studies have reported success of newer immunosuppressive drugs, immunomodulatory therapies, and the biological agents such as mycophenolate mofetil (MMF), calcineurin inhibitors, leflunomide, intravenous immunoglobulin, immunoadsorption, and rituximab in the treatment of cyclophosphamide (CYC) resistant proliferative lupus nephritis. More aggressive CYC regimens have been used in lupus nephritis, but at the expense of more toxicities. For membranous lupus nephritis (MLN), a combination of corticosteroids with either azathioprine, chlorambucil, cyclosporin A, MMF, or CYC is initially effective in two-thirds of patients. More aggressive and costly regimens should be reserved for truly refractory disease with persistent nephrotic syndrome or declining renal function. Evidence regarding the efficacy of MMF in refractory MLN is conflicting and controlled trials are necessary to resolve the controversy. CONCLUSIONS: The treatment of refractory lupus nephritis remains anecdotal. An international consensus in the renal response criteria should be developed and validated so that controlled trials can be performed to compare the efficacy of various treatment modalities.     

Extended routine polymerase chain reaction surveillance and pre-emptive antiviral therapy for cytomegalovirus after allogeneic transplantation

Pre-emptive treatment strategies based on sensitive screening for cytomegalovirus (CMV) infection up to day +100 after allogeneic transplantation have been shown to reduce the incidence of CMV disease during the period of surveillance. However, the use of ganciclovir has been associated with delays in immune reconstitution and an increased incidence of late CMV disease after day +100. In the present study, 81 patients undergoing allogeneic transplantation received polymerase chain reaction (PCR)-guided pre-emptive therapy based on detection of CMV DNA by PCR on 2 consecutive weeks up to day +180. Thirty-three of the 52 high-risk patients (CMV-seropositive donor or recipient) received a total of 45 treatment episodes up to day +100. Three of these patients (5.7%) developed CMV disease, with one fatality. Twelve of the surviving 44 high-risk patients (27%) required pre-emptive treatment between days +101 and +192, but none of these patients developed late CMV disease with a median follow-up of 402 d (range 117-952 d). Antiviral therapy was stopped after a single negative PCR result with no subsequent episodes of CMV disease while patients remained off antiviral treatment. As all initial episodes of CMV DNA detection occurred within 60 d of transplantation, it may be possible to discontinue monitoring beyond day +100 in patients who have remained CMV PCR negative before this. Thus, we have confirmed that PCR-guided pre-emptive therapy results in a low incidence of CMV disease before day +100 and that discontinuing treatment on the basis of viral clearance as determined by CMV PCR appears to be safe practice. In addition, we have observed no episodes of late CMV disease with an extension of surveillance to 26 weeks.