Refractory Hodgkin's Disease Research Articles

High Dose Therapy (HDCT) and Autologous Haematopoietic Stem Cell Transplantation (aSCT) in Paediatric Patients with Recurrent or Refractory Hodgkin's Disease (HD): Results and Outcome.

Objectives To evaluate the outcome of pediatric patients with refractory or relapsed Hodgkin's Disease (HD) who undergo high dose chemotherapy (HDCT) with autologous hemopoietic stem cell rescue (aSCT) and reported to BMT Registry of Italian Pediatric Hematology-Oncology Association Group (AIEOP).Methods From 1986 to 2004, 100 aSCT were performed in 91 pediatric patients, 45 male/35 female, with relapsed or primary refractory HD. At time of transplant the median age was 15 (6–18) years. Ten out 91 patients received a double program transplant. At the time of first transplant, 33 patients were in II CR, 35 in PR and 23 in more advanced phase of disease. First line therapy was a conventional treatment consisting of MOPP/ABVD and involved field radiotherapy for the majority of patients. Most of HDCT consisted of BCNU (38) or Thiotepa (35) based regimens, while TBI was delivered in only 2 cases. The source of stem cell was BM in 44 cases and peripheral blood in 66. A median number of 2.15 x 108/kg MNC (0.48–21.62) and 5.70 x 106/kg CD34+ cells (0.58–45.53) were infused. Pre treatment factors were analyzed by univariate analysis for prognostic significance for 5, 10 and 15-year overall survival (OS) and event free survival (EFS)Results. After a median follow-up of 6,6 (0,1–12) years the 5, 10 and 15-year OS rates were 67.4%, 58.9% and 58.9% respectively, while 5, 10 and 15-year EFS rates were 63.7%, 54.6% and 54.6% respectively. Twenty-nine out 91 patients relapsed after a median time of 9 (2–46) months. Second CR and HDCT regimens containing BCNU can offer a better but not statistically significant 5-year EFS (83.5% and 73.8% respectively). Peripheral blood stem cell sources determined a better significant outcome (5-year EFS 76.2% vs 50.2% p= 0.024). Transplant related toxicity was moderate and 100 days TRM was 3.0%.Discussion. More than half children with relapsed or refractory HD can be successfully treated with HDCT and aSCT, confirming the efficacy of this approach. Patients who undergo aSCT in II CR, conditioned with a BCNU containing HDCT and rescued with peripheral blood hemopoietic stem cell have a better outcome compared with those receiving any other treatment. Alternative treatment such as allogeneic SCT need to develop in patients with early relapse or chemo-resistant relapse after first line chemotherapy associated with a poorer outcome.

Brentuximab Vedotin Plus Bendamustine: As Salvage Regimen for Relapsed or Refractory Hodgkin Lymphoma, King Abdulaziz Medical City - Jeddah - KSA Experience

INTRODUCTION:In advanced stage Hodgkin's Lymphoma (HL), 30% of patients experience recurrence post upfront ABVD 1.Patients with sensitive disease to salvage chemotherapy typically proceed to ASCT with curative intent 2. Achievement of CR is one of the strongest predictor of favorable outcome after ASCT3-4. Recently brentuximab vedotin plus bendamustine (BvB) became an attractive option for relapsed/refractory HL with promising efficacy and non-overlapping toxicity profiles 5-6. CONTEXT: No PubMed searchable articles regarding use of BvB in relapsed/refractory Hodgkin lymphoma in Saudi Arabia could be found. OBJECTIVE:To determine overall response rate( ORR ) , PFS and OS. Secondary objective was to determine if there was a better response rate when BvB was used as a first salvage. DESIGN:Retrospective cohort analysis. PATIENTS:Patients with relapse /refractory hodgkin lymphoma received BvB as salvage between year 2016 and 2018 were included. Chemotherapy software and medical records were reviewed for clinical data. Twenty four patients were identified. One patient was excluded due to incomplete medical information. Patients were divided into two groups based on their indication for salvage therapy either refractory or relapse, and another two groups based on whether they received BvB as a first salvage or subsequent salvage. Brentuximab vedotin dose was 1.8 mg /kg on day 1 and bendamustine dose was 90 mg/m2 on day 1,2 every 21 days. RESULTS: Twenty-three patients (13 primary refractory and 10 relapsed) were included in this analysis. Median age at diagnosis was 28 years. After a median of 3 cycles of combination therapy BvB, the ORR was 82.6%. Ten patients (43%) achieved CR and 9 patients (39%) achieved PR. Patients who received BvB as a first salvage (65%) achieved 86.7% overall response , while ORR was 75% when BvB was given as subsequent salvage with border line P- value. After a median of 11 months follow-up, the estimated 1-year progression-free survival was 83% and 90% OS. Two patients (8.6%) experienced infusion-related reactions during second cycle. CONCLUSIONS:BvB represents a very effective regimen for high risk relapsed or refractory HL patients; in achieving higher CR rates when used as a first salvage, with manageable toxicity profile. REFERENCES Gordon LI, Hong F, Fisher RI, et al. Randomized phase III trial of ABVD versus Stanford V with or without radiation therapy in locally extensive and advanced-stage Hodgkin lymphoma: an intergroup study coordinated by the Eastern Cooperative Oncology Group (E2496). J Clin Oncol. 2013; 31(6):684-691.Hoppe RT, Advani RH, Ai WZ, et al; National comprehensive cancer network. Hodgkin lymphoma, version 2.2015. J Natl Compr Canc Netw. 2015;13(5):554-586.Moskowitz CH, Matasar MJ, Zelenetz AD, et al. Normalization of pre-ASCT, FDG-PET imaging with second-line, non-cross-resistant, chemotherapy programs improves event-free survival in patients with Hodgkin lymphoma. Blood. 2012;119(7):1665-1670.Moskowitz CH, Nimer SD, Zelenetz AD, et al. A 2-step comprehensive high-dose chemo- radiotherapy second-line program for relapsed and refractory Hodgkin disease: analysis by intent to treat and development of a prognostic model. Blood. 2001;97(3):616-623.Ann S. LaCasce, Gregory Bociek,Ahmed Sawas,et al.Brentuximab vedotin plus bendamustine: a highly active first salvage regimen for relapsed or refractory Hodgkin lymphoma. Blood.2018 Jul 5;132(1):40-48.O'Connor OA, Lue JK, Sawas A, et al.Brentuximab vedotin plus bendamustine in relapsed or refractory Hodgkin's lymphoma: an international, multicentre, single-arm, phase 1-2 trial,Lancet Oncol.2018 Feb;19(2):257-26. Disclosures No relevant conflicts of interest to declare.

Italian expert panel consensus statement on the optimal use of PD-1 blockade therapy in classical Hodgkin lymphoma

Programmed death 1 (PD-1) blocking antibodies now represent a major advance in the treatment of patients with classical Hodgkin lymphoma (cHL) who relapse after autologous stem cell transplantation (ASCT) and pre- and/or post-ASCT brentuximab vedotin or after at least three lines of therapy. However, uncertainties still remain on the optimal use of these agents in refractory Hodgkin disease. A panel of experts was convened to produce a consensus document aimed at providing practice recommendations for the optimal use of PD-1 blocking antibodies in cHL, especially on pretreatment selection and evaluation of cHL patients’ response and treatment length, management of PD-1 blockade therapy–treated patients, evaluation and management of toxicity. Our hope is that these recommendations might help hematologists to improve optimal management of patients with pretreated cHL.

First Report on Stem Cell Transplant From Iraq.

The Iraqi Bone Marrow Transplantation Center is located in the medical city complex of Bab Almuadham in Baghdad, Iraq. It was established on March 11, 2002, and performed its first mini-allotransplant for acute myeloid leukemia on January 24, 2003. Among 16 patients who received hematopoietic stem cell transplant between January 2003 and January 2010, one patient underwent allogeneic bone marrow transplant for acute myeloid leukemia and 15 patients received autologous bone marrow transplant for the following indications: 5 had multiple myeloma, 9 had lymphoma (8 with Hodgkin disease and 1 with non- Hodgkin lymphoma), and 1 had rhabdomyosarcoma. Median age was 34 years (range, 10-56 y), and our patient group included 8 females and 8 males. Of the 16 patients, 12 are still alive. The mortality rate was 25% as measured during our follow-up from 2 to 96 months. Of the 9 patients with lymphoma, 1 died and 2 relapsed after transplant. Therefore, our survival rate in lymphoma was 88%, with progression-free survival in lymphoma ranging from 2 to 66 months (mean survival of 13 mo, mode of 13 mo). For the 5 patients with multiple myeloma who received transplants, 1 died and 2 relapsed, with effective-free survival of 6 to 13 months. Our results show that high-dose chemotherapy followed by autologous stem cell transplant can induce long-term disease control in this cohort of patients with refractory or advanced Hodgkin disease; progression-free survival for our cohort was 50%, with survival comparable to those reported in the literature.

Comparison of Ifosfamide, Carboplatin and Etoposide versus Etoposide, Steroid, and Cytarabine Cisplatin as Salvage Chemotherapy in Patients with Refractory or Relapsed Hodgkin's lymphoma.

Background:Refractory or relapsed Hodgkin's disease (HD) occurs in 10-50% of patients. The treatment of choice for these patients is high-dose chemotherapy (HDCT) and autologous stem cell transplantation (ASCT). Response to salvage chemotherapy (SCT) partial remission (PR) is necessary before HDCT with ASCT. However, its applicability is restricted mostly to patients responding to salvage chemotherapy. Optimal salvage regimen for these patients is unclear. In this study, our aim was to compare the efficacy profiles of ifosfamide, carboplatin, and etoposide (ICE) and etoposide-steroid-cytarabine-cisplatin (ESHAP) (cytosine arabinoside, cisplatin, and dexamethasone) regimens in the salvage treatment of relapsed or refractory HD.Materials and Methods:In this retrospective analysis, 114 patients with primary refractory or relapsed HD who received ICE or ESHAP salvage regimen were included.Results:Of 114 patients, 47 (41.2%) were females and the median age was 31.5 years. Response could be evaluated in 114 patients. Of 114 patients, 38 (33%) achieved complete remission (CR) and 21 (18.4%) achieved PR, leading to an overall response rate (ORR: CR + PR) of 51.4%. In the evaluable ICE group (n = 41), rates of CR, PR, and ORR were 21.9%, 17.1%, and 39% and in the ESHAP group (n = 73), rates of CR, PR, and ORR were 39.7%, 19.2%, and 58.9% (for ORR, P = 0.04), respectively.Conclusion:In patients with relapsed or refractory HD, treatment with ESHAP seems to have higher rates of response than ICE regimen does.

Alemtuzumab-BEAM as conditioning for allogeneic hematopoietic stem cell transplantation in relapsed/refractory Hodgkin lymphoma: a single-center analysis.

Purpose Treatment of refractory Hodgkin disease deserves specific considerations. Recently, alemtuzumab-BEAM has been introduced in allogeneic hematopoietic stem cell transplantation (HSCT) in these patients.MethodsWe retrospectively analyzed the outcome of 20 patients with relapsed/refractory Hodgkin’s lymphoma (HL) who received allogeneic HSCT following conditioning therapy with alemtuzumab-BEAM.ResultsTreatment-related toxicity was tolerable. Half of the patients (50 %) had infections. Of these, 50 % were found to have pneumonia or catheter-related infections. In 20 %, an oral mucositis was observed. Acute graft-versus-host disease (GvHD) (≥grade 2) was seen in three patients. Complete remission (CR) could be achieved in 17 patients (85 %), 2 patients had persistent Hodgkin disease, and 1 patient died from infection prior to CR evaluation. Median progression-free survival and overall survival were 17.9 and 67.5 months, respectively. From the 17 CR patients, 8 had a relapse after a median of 10 months. Notably, of the eight patients relapsing after HSCT, all patients received another salvage treatment and four patients are still alive, whereas the other four patients died due to further progress. Six out of the remaining nine patients are still in CR, whereas the other three died from chronic GvHD and multi-organ failure. Overall, seven patients experienced chronic GvHD.ConclusionIn summary, alemtuzumab-BEAM is a well-tolerated conditioning therapy for allogeneic HSCT with high response rates in refractory HL.

The Oral Mtor Inhibitor Everolimus in Relapsed and Refractory Hodgkin Lymphoma- Compassionate Use in 8 Centers in Brazil

Purpose- Everolimus is an oral antineoplastic agent that targets the raptor mammalian target of rapamycin (mTORC1). The phosphatidylinositol 3-kinase/mTOR signal transduction pathway has been demonstrated to be activated in tumor samples from patients with Hodgkin Lymphoma (HL). The goal of this study was to evaluate the response, time of response, toxicity and overall survival in patients with refractory disease using everolimus out of clinical trial, in a compassionate use.Patients and Methods- Patients were eligible if they had refractory and active Hodgkin disease. Patients received everolimus 10 mg PO daily. Dose reductions were allowed. Time to response assessement was defined by each center until progression (this was defined by each doctor, some have considered to keep the drug until clinical progression and not radiological progression of the disease). Patients could remain on drug until progression or toxicity.Results- Thirty three patients were enrolled. Median age at the time of everolimus start was 29 years (range, 20-70). Patients had received a median of 5 prior therapies (range, 3-7) , 81% had undergone prior autologous stem cell transplant and 4 patients had undergone alogenic trasnplantation. The ORR was 51% (95% CI: 24-71%) with 14 patients achieving a PR, 3 patient achieving a CR and 10 with stable disease. Thirteen patients used the drug for more than 1 year. Patients received a median of 14 cycles of therapy and 3 remains on therappy at 36 months showing a great tolerability of the drug. The median DR for the responders (CR/PR) was 10 months. The most commons site effects were trombocitopenia and hypercholesterolemia. Three patients had pulmonar toxicity. The adverse events grade III and IV ocurred in 30% of the patients.Conclusions- Everolimus has single-agent activity in relapsed/refractory HL, even in real lyfe and clinical practice and provides proof-of-concept that targeting the mTOR pathway in HL is clinically relevant. DisclosuresOff Label Use: everolimus for refractory hodgkin lymphoma.

Cardiac Toxicity Of High Dose Cyclophosphamide Post T Cell Replete HLA Haploidentical Hematopoietic Stem Cell Transplantation

BackgroundT cell replete (TCR) HLA haploidentical hematopoietic stem cell transplantation (SCT) using high dose cyclophosphamide post-transplant (HDCy) to prevent graft versus host disease (GvHD) and graft's rejection is a promising approach which extends the possibility of grafting patients who lack a conventional donor. Notably, non relapse mortality (NRM) is greatly decreased compared to T-cell depleted haploidentical SCT, giving a low rate of lethal infections or severe GvHD and allowing the possibility to reduce doses of conditioning regiment without impairing the engrafting of the TCR bone marrow. Nevertheless, HDCy post transplant might increase the risk of cardiac toxicity. MethodsFrom March 2012 to July 2013, 11 consecutive adult patients received a TCR haplo-SCT for high risk hematological malignancies: de novo or secondary acute myeloid leukemia (AML) with unfavorable cytogenetics in CR1 (n=5), refractory AML (n=2), chronic myeloid leukemia (n=2), and refractory Hodgkin disease (n=2). Patients with myeloid disease received a myeloablative conditioning (MAC) (Cy 30mg/Kg/d at day -4 and -3 + TBI 12Gy or Busulfan 3.2mg/Kg/d for 4 days + Cy 14.5mg/Kg at day-3 and day-2 + Fludarabine 90mg/m2) or a reduced intensity conditioning (RIC) with Melphalan 140 mg/m2 + Thiotepa 10mg/m2 + Fludarabine 160mg/m2. Two patients with Hodgkin disease and 1 patient who rejected a previous MAC-double cord blood received a RIC with Cy 14.5mg/Kg at day-6 + TBI 2gy + Fludarabine 150mg/m2. Ten patients received HDCy 50 mg/kg/day on days +3 and +4, plus tacrolimus and mycophenolate mophetil for GvHD prophylaxis. In one patient, HDCy was reduced to 50mg/Kg at day+3. All patients but one received a bone marrow graft. Median age was 39.1 (range 22-62). Donors were related for 10, and unrelated for 1 patient with a median of 5.4/10 allele matches (range 5-8). Cardiac evaluation pre-SCT was performed for all patients. Cardiac ultrasound was normal for all (median left ventricular ejection fraction was 62%; range 53-67%). None of the patients had cardiovascular risk factors such as hypertension, diabetes, obesity or history of valvular or ischemic cardiopathy. Median Sorror score was 0.63 (range 0-2). The rate of early deaths (within the 1st month post transplant) related to cardiac toxicity was compared to that of the whole cohort of 875 patients who received an allogeneic HSCT in our center from May 1984 to July 2013 without HDCy post transplantation. ResultsAmong the 11 patients who received HDCy post SCT, 3 patients developed a compressive pericardial effusion at day 4, day 14 and day 41. An extensive microbiological research found no infectious etiology of this cardiac complication and toxicity of HDCy post transplant was the most probable. One patient had received a MAC (TBI 12Gy –Cy) and the 2 other patients had received the RIC Mel-Thio-Flu regimen. Evolution was reversible for 2 patients after the administration of angiotensin-converting enzyme inhibitors and/or pericardial drainage. One patient died at day+16 of a refractory cardiogenic shock.In the control cohort, early death correlated to cardiac toxicity was reported in 6 patients out of 875 (0.69%), as compared to 1/11 (9%) in the haploidentical cohort. In the control cohort, median age of patients who died from cardiac toxicity was 40.1 (range 30-51). All but 1 received a MAC including HDCy pre-transplantation. No HDCy was administered after SCT. The death occurred at a median time of 14.6 days post-transplant. No early death correlated to cardiac toxicity was reported after 1 month post SCT. ConclusionAlthough limited by the small number of patients, the rate of cardiac toxicity seems to be increased after HDCy post TCR haplo-SCT. This toxicity is probably multi-factorial and HLA mismatches syndrom may contribute to the severity of symptoms. Nevertheless, such severe and early cardiac complication is an unusal observation in patients without any particular cardiovascular risk factor or other co-morbidities at the time of transplant. Caution should be taken during the days following the administration of HDCy in collaboration with intensive care specialists. Disclosures:Leblond:Roche : Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Mundipharma: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.

Allogeneic Stem Cell Transplantation For Primary Refractory Hodgkin's Disease: Ablative Vs Reduced Intensity

Minority of patients with Hodgkin's lymphoma (HL) are primary refractory or relapse very early after first-line chemotherapy or even after high-dose chemotherapy (HDCT) and autologous HSCT. The dismal outcome of these patients was shown by many previous studies. We evaluated the role of allogeneic stem cell transplantation in this setting. We retrospectively analysed 6 consecutive patients (med age 45) with primary refractory advanced stage Hodgkin's lymphoma transplanted between 2011-2013. The median time from initial diagnosis and from autologous HSCT to allogeneic transplantation was 44.1 mo.s and 12.4 mo.s, respectively. The donor sources were sibling in 4, unrelated in one and haploidentical in 1. The conditioning regimen was myeloablative (BU-CY) in 3 and reduced intensity (Flu-Mel±ATG) in 3 adjusted according to their age and comorbid conditions. All of them received peripheral blood stem cells. Engraftment failure was not observed. None of them were complicated with VOD or other early complications of HSCT. Day 100 transplantation related mortality was 16.7% (1 patient). The patient succumbed to carbapenemase+ klebsiella pneumonia sepsis on day +11. Median follow up of the surviving patients was 14.65 months (range, 6-26). At the last follow up 3 of them were in CR, one patient had progression after HSCT and achieved stable disease with brentuximab and DLI. One patient died from acute abdominal infection on +187 while in CR. Only one patient was complicated with both acute and chronic GVHD (unrelated HSCT). The myeloablative regimen was tolerated well and the patients achieved durable remission. The expired patients were both in RIC arm. Although the number of transplanted patients is low we can conclude that allogeneic HSCT using myeloablative regimen is safe and effective in short term. Primary refractory HL patients should be evaluated for allogeneic HSCT, as upfront or following failure of autologous HSCT and HDCT. Ablative regimen is tolerated as well as RIC, and more effective than allo RIC for disease control in the light of our current limited cohort. Disclosures:No relevant conflicts of interest to declare.

Hodgkin's lymphoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up

D. A. Eichenauer1, A. Engert1, M. Andre2, M. Federico3, T. Illidge4, M. Hutchings5, & M. Ladetto6 on behalf of the ESMO Guidelines Working Group* First Department of Internal Medicine, University Hospital Cologne and German Hodgkin Study Group (GHSG), Cologne, Germany; CHU Dinant-Godinne, UCL Namur, Yvoir, Belgium; Department of Oncology, Hematology and Respiratory Diseases, University of Modena and Reggio Emilia, Modena, Italy; Institute of Cancer Sciences, University of Manchester, Manchester, UK; Department of Hematology, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; Divisione di Ematologia, Azienda Ospedaliera Santi Antonio e Biagio e Cesare Arrigo, Alessandria, Italy

Réaction cutanée sévère avec mucite au cours d’une chimiothérapie de type MINE

MINE chemotherapy is used to treat refractory Hodgkin's disease. Cutaneous adverse effects of MINE regimen are uncommon and chiefly consist of erythema and oedema of the extremities. More recently, a number of cases of panniculitis and subcutaneous inflammatory oedema have been described. We report the case of a 17-year-old girl developing acute and painful oedema of the limbs with panniculitis of the trunk. This incident was associated with inflammatory lesions of mucous membrane, in particularly in the genital area and on the tongue. These signs occurred 7 days after initiation of MINE chemotherapy, with no other drugs being introduced. A drug-induced reaction was suspected due to the absence of any other aetiology, particularly infectious disease. The condition gradually improved with symptomatic pain therapy. The patient's chemotherapy was subsequently modified. The chronology of the symptoms, spontaneous improvement after the end of treatment, and the absence of other potential causative factors resulted in a hypothesis of a cutaneous adverse reaction to the MINE regimen. The signs could be due to capillary leak syndrome resulting from the toxicity of vinorelbine on endothelial cells. Dermatologists should be aware of these cutaneous adverse effects and of the inflammatory lesions of mucous membrane newly described herein.

EARLY [18F]FLUORODEOXYGLUCOSE POSITRON EMISSION TOMOGRAPHY–BASED RESPONSE EVALUATION AFTER TREATMENT WITH GEMCITABINE AND VINORELBINE FOR REFRACTORY HODGKIN DISEASE: A CHILDREN’S ONCOLOGY GROUP REPORT

The International Harmonization Project defined complete response (CR) after treatment for Hodgkin disease (HD) by absence of fluorodeoxyglucose avidity, regardless of the size of residual masses. Residual avidity after initial treatment is known to predict inferior survival. In the setting of retrieval therapy, early positron emission tomography (PET) scans may improve assessment of treatment efficacy. Retrospective analysis after 2 cycles of gemcitabine and vinorelbine for refractory HD revealed 6 CR among 13 patients by PET and 1 CR in 13 by computed tomography (CT). No relationship between PET response and event-free or overall survival could be discerned, presumably because of the heterogeneity of subsequent therapies.

Early post transplant (F-18) 2-fluoro-2-deoxyglucose positron emission tomography does not predict outcome for patients undergoing auto-SCT in non-Hodgkin and Hodgkin lymphoma

Positron emission tomography (PET) in conjunction with computed tomography is a frequently used modality for staging patients with lymphoma. Utility of PET-computed tomography before or early following auto-SCT has not been as rigorously evaluated. We retrospectively analyzed patients who received auto-SCT for treatment of relapsed or refractory non-Hodgkins lymphoma or Hodgkins disease between the years of 1996 and 2007. Patients who had either a PET scan following salvage chemotherapy within 14 weeks of transplantation (pre-PET), and/or a PET scan 6-14 weeks following transplantation (post-PET) were included. A total of 90 patients were identified for analysis. The median follow-up time is 3.3 years, with a range of 0.13-12.0 years. The median PFS was 4.6 years, and median OS was 5.1 years. At the time of this analysis, 34 patients (37%) experienced disease relapse, and 25 (27%) of the patients died from disease progression. In multivariate Cox proportional hazards analysis, post-PET did not predict for outcome, pre-PET positivity predicted for decrease in PFS. In conclusion, post-PET scan did not predict for PFS or OS in multivariate analysis. Positive pre-PET scan did predict for PFS as seen in previous studies, and may help identify patients who would benefit from innovative post transplant therapies.

Outpatient reduced-intensity allogeneic stem cell transplantation for patients with refractory or relapsed lymphomas compared with autologous stem cell transplantation using a simplified method

The effectiveness of reduced-intensity conditioning allogeneic stem cell transplantation (allo- RIC) compared with high-dose chemotherapy followed by autologous stem cell transplantation (auto-SCT) in Hodgkin's disease (HD) and in non-Hodgkin's lymphoma (NHL) patients remains poorly defined. The purpose of the study was to demonstrate the usefulness of auto-SCT or allo-SCT, employing a RIC regimen in refractory or relapsed NHL or HD patients. We analyzed the outcome of 71 patients with advanced disease. Twenty-three NHL and 14 HD patients received an allo-RIC using fludarabine, cyclophosphamide, and low-dose busulfan as the conditioning regimen. Sixteen NHL and 18 HD patients received auto-SCT using cyclophosphamide and etoposide as conditioning regimen. All hematopoietic stem cells products were not cryopreserved and the majority of grafts were done on an outpatient basis, including conditioning and post-stem cell infusion care (auto-SCT, 62% and allo-RIC procedure, 91%). The median OS was 45.5 months for the allo-RIC recipients and 53.3 months for auto-SCT recipients. Acute/chronic GVHD incidence in NHL and HL groups was 38%/31% and 14%/7%, respectively. We found no significant difference in overall survival between allo-RIC group and auto-SCT group for NHL patients (P = 0.43) but better OS was observed for auto-SCT group than for allo-SCT group in HL patients (P < 0.001). The relapse rate was higher in autografted patients, both in NHL and HD. Both auto-SCT and allo-RIC appear to be valid treatments for poor-risk patients with relapsed or refractory lymphoma who could not otherwise be cured with conventional salvage regimens.

Metronomic Cyclophosphamide and Vinblastine in Refractory Lymphoma

Full Abstract Introduction A recent phase I report drew attention to the effectiveness of metronomic (daily low-dose oral) CPA and I.V. vinblastine in refractory Hodgkin disease. 1 We used this combination in a patient with Hodgkin lymphoma and extensive prior treatment. The regimen was adapted to include rituximab for another patient who was unfit for R-CHOP (cyclophosphamide/doxorubicin/vincristine/prednisone plus rituximab) therapy due to prior myocardial infarction. Case 1 A 56-year-old patient had first-line chemotherapy for Hodgkin lymphoma stage IVB in 2004, treated with ABVD (doxorubicin/bleomycin/vinblastine/dacarbazine). A year later a recurrence was treated with stem cell transplantation. He presented in February 2008 with extensive bone metastases, for which 45 Gy radiotherapy was given, also with curative intent. In April 2008 we started with metronomic chemotherapy (cyclophosphamide 50 mg + methylprednisolone 32 mg per day orally, vinblastine 3 mg/m 2 intravenously [I.V.] 1 × per week) for retroperitoneal lymph node recurrence. This treatment was well tolerated. After 9 months of treatment, there were no lymph nodes detectable on computed tomography scan. Complete remission now lasts > 3 months. Case 2 An 81-year-old farmer had a myocardial infarction 40 years ago. He presented with cutaneous involvement and axillary lymph node. Biopsy showed a cutaneous involvement by B-cell diffuse large-cell lymphoma. International Prognostic Index score was low. Ejection fraction was 42%. The same chemotherapy was applied (cyclophosphamide 50 mg/d and methylprednisolone 32 mg per day, vinblastine I.V. days 1, 8, 15), but on day 22 of the 28-day cycle, we applied rituximab 375 mg/m 2 . The patient had a complete remission after 4 months of treatment. Conclusion These data confirm the effectiveness of this well-tolerated regimen in refractory lymphoma as well as in a lymphoma patient unfit for anthracyclines. Reference Young S, Whissell M, Noble JC. Phase II clinical results involving treatment with low-dose daily oral cyclophosphamide, weekly vinblastine, and rofecoxib in patients with advanced solid tumors. Clin Cancer Res 2006; 12; 3092-9.

Allogeneic Stem Cell Transplantation for Hodgkin's Disease From Sibling and Unrelated Donors: The German Cooperative Transplantation Study Group Experience.

Abstract 2293Poster Board II-270 Introduction:Although modern chemotherapy regimens achieve a high cure rate in primary Hodgkin's disease and relapsed patients can be salvaged by high dose chemotherapy with autologous stem cell transplantation there remains a subgroup of patients with early relapse despite high dose chemotherapy. The prognosis of these patients is dismal with further chemotherapy. Allogeneic transplantation has the potential to exert an alloimmune response against lymphoma cells and has therefor been offered to patients with relapsed or refractory Hodgkin's disease, in particular when a matched sibling donor was available. However only limited information on the feasability of allogeneic transplantion from an unrelated donor is available. Methods:We performed a retrospective analysis of allogeneic transplants for Hodgkins disease within the German Cooperative Transplantation Study Group. 18 centres have provided data on patient and donor characteristics, transplant procedure and outcome. Survival data were analysed by Kaplan-Meier and tested for differences by log rank test. Cumulative incidences for relapse, non-relapse mortality and graft-versus-host-disease were calculated in a competing risk model. Results:79 patients with a median age of 30 years (range 14-59) were included. 65 (82%) patients had failed a previous autologous transplantation 582 days (median) before allotransplantation. Disease status at transplantation was CR in 17.6%, PR in 54.0%, stable disease in 9.5%, PD in 12.2%, and untreated relapse in 6.8%. Donors were matched related in 33%, mismatched related in 5%, matched unrelated in 42% and mismatched unrelated in 20%. With a median follow up of 19 months for surviving patients the median overall survival (OS) after allotransplant was 42 months with a 2 year survival of 51%. Non-relapse mortality was 21.1% after 12 and 24 months. The median progression-free survival was 14.6 months with a 2 year PFS of 42.0%. Patients relapsing after an autologous transplantation had a significantly better OS (median 53.7 vs 8.4 months, p=0.029) and PFS (22.0 vs 7.5 months, p=0.039) than patients without a prior autograft. No significant difference was seen for OS or PFS regarding the use of related or unrelated donors or disease status at transplant. Conclusions:Allogenic transplantation is a feasible option for high-risk patients with relapsed or refractory Hodgkins disease in particular after failing an autograft. Non-relapse mortality appears to be acceptable in view of the intensive prior treatment. Probabilities for overall survival and progression-free survival were similar after transplantation from a related or unrelated donor. Further optimisation strategies have to focus on on efforts to reduce the high relapse-rate after transplantation, thereby potentially increasing overall and progression free survival. Disclosures:No relevant conflicts of interest to declare.

Quality of Life of Long Term Survivors with Hodgkin's Lymphoma After High-Dose Chemotherapy with Autologous Stem Cell Transplantation and Conventional Chemotherapy.

Abstract 2495Poster Board II-472 Introduction:High-dose chemotherapy (HDCT) followed by peripheral blood stem cell transplantation (PBSCT) is frequently applied in eligible patients with relapsed or refractory Hodgkin's disease. The toxicity of HDCT, however, might manifest itself in the respective patients' reduced quality of life (QoL). In this study we investigated the QoL of long term survivors after HDCT in comparison with patients after conventional chemotherapy and the healthy German population. Patients and Methods:QoL was evaluated with two standardized questionnaires: EORTC QLQ-C30 and EQ-5D. The cancer-specific EORTC-QLQ-C30 consists of thirty questions concerning three main categories: global health state, functional and symptomatic state. The single questions belonging to functional and symptomatic state can furthermore be grouped into different subcategories. The EQ-5D visualizes five dimensions of health: mobility, self-care, daily activities, pain, and anxiety. In addition to that, the visual analogue scale (VAS) is included to outline the patients' overall health state. A total of 98 patients were included in the study. 37 patients (13 female, 24 male) with a median age of 46 (range 23-72) received HDCT with PBSCT between 1986 and 2007. This group was compared with 61 patients (36 female, 25 male; median age 41, range 21-72) treated with conventional chemotherapy and supplementary radiation in our institution. In the conventional chemotherapy group BEACOPP was used in most cases (n=31), followed by ABVD (n=20), a combination of both (n=8) and ABV (n=2). All patients were in continuous clinical remission. Median follow-up for the HDCT group is 11 and for the conventional chemotherapy group 3.5 years. In addition, Qol of the patients was compared to QoL of healthy people on the basis of two studies about the general health status of the German population (R. Schwarz and A. Hinz: “Reference data for the quality of life questionnaire EORTC QLQ-C30 in the general German population,” European Journal of Cancer 37 [2001]: 1345-1351; H. H. König et al.: “Health Status of the German Population: Results of a Representative Survey Using the EuroQoL Questionnaire,” Gesundheitswesen 67 [2005]: 173-182). Results:In the HDCT group, the results of the questionnaires show a reduced QoL compared to the healthy population. Regarding the three main categories of the EORTC QLQ-C30, the mean sum score for global health state (ghs) is 68.69, for functional state (fs) 72.49 and for symptomatic state (ss) 21.55 (the ideal score being 100.00 for the first two items and 0.00 for the latter). The mean value for EQ-5D is 0.880 (ideal value: 1.000) and that for VAS is 71.60 (ideal value: 100.00). The one sample t-test evaluation shows that the decrease in QoL is significant with p<0.05 in all of the subcategories of the functional state; four of the nine subcategories of the symptomatic state, namely fatigue, dyspnoea, diarrhoea and financial difficulties. Compared to the group of patients who received conventional chemotherapy (ghs: 73.92; fs: 77.36; ss: 16.27), there is a tendency towards reduced QoL in patients with HDCT in all of the three main categories of the EORTC-QLQ-C30, in particular in the category of symptomatic state. However, these differences were not statistically significant, with the exception of the subcategory of dyspnoea (p<0.001). In the EQ-5D questionnaire, there was a trend for reduced QoL of patients after HDCT compared to conventional chemotherapy patients and healthy people, however these effects were not significant (p = 0.06 and p = 0.089). Conclusions:In this long term follow up study, QoL is reduced in patients after HDCT as well as in patients after conventional treatment compared to the healthy population. There was a trend that QoL might be worse in the HDCT group compared to the conventional therapy group; however this effect was not statistically significant. We conclude that the negative impact of both HDCT and conventional therapy on the QoL of long term survivors with Hodgkin's lymphoma should not be underestimated and should lead to the development of less toxic therapy strategies. Disclosures:No relevant conflicts of interest to declare.

High-Dose Therapy with Peripheral Blood Stem Cell Transplantation for Patients with Relapsed or Refractory Hodgkin's Disease: A Single-Institution 20-Year Follow-up Experience.

Most patients with Hodgkin disease achieve durable remission with radiation therapy, combination chemotherapy, or both. However, patients who relapse after attaining complete remission with chemotherapy and those who have primary refractory disease have a poor outcome with conventional dose salvage chemoradiotherapy regimens. In the past 20 years, several clinical trials using high-dose chemotherapy (HDCT) or chemoradiotherapy with autologous stem cell transplantation have been reported, but only few of them focused on long term outcome, late toxicity and different treatment options after relapse.From March 1986 to August 2007, 107 patients with relapsed or refractory Hodgkin's disease underwent HDCT with peripheral blood stem cell transplantation in our center. There were 64 males and 43 females with a median age of 31 years (range 17 – 63 years). For HDCT, 82 patients were treated with CBV (cyclophosphamide, etoposide, carmustine), while 20 patients received BEAM (carmustine, etoposide, cytarabine, melphalan) or other regimens (n=5).For the entire group, the probabilities of freedom from progression (FFP), overall survival (OS) and event-free survival (EFS) after HDCT were 65%, 61%, and 53% at 10 years, respectively, after a median follow-up of 12.4 years (range, 0.15 – 20.3 years). Notably, no relapse occurred later than 48 months post transplant. Cox analyses identified duration of remission (≤12 versus >12 months) as well as disease status prior to transplantation (complete remission versus partial remission versus stable / refractory disease) as significant prognostic factors for FFP, EFS, and OS.Early mortality rate (≤100 days) declined from 17.1% to 8.3% after 1992 subsequent to introduction of hematopoietic growth factors for stem cell mobilization. Late mortality rate (>100 days) was 30.8% (n=33), causes of death were Hodgkin's disease (n=21), secondary malignancies (n=6), fibrosis of the lung (n=3), myocardial fibrosis (n=1), perforated sigmoid diverticulitis (n=1) and septicemia (n=1). The probability of secondary malignancies was 6.4% and 12.1% after 5 and 10 years, respectively.For the patients relapsing after HDCT (n=33), the median OS was 17.3% at 5 years. We found that patients with a remission time of >6 months after transplantation had a prolonged 5-year OS of 50.3% versus 0% (p=0.03) in patients with remission times of ≤6 months. To date, three of 33 patients live disease-free more than 5 years after relapse. These patients were treated with allogeneic transplantation (n=1), secondary HDCT (n=1) or conventional chemotherapy (n=1), suggesting that different treatment approaches have the potential to rescue individual patients although the overall outcome after HDCT failure is poor.In conclusion, HDCT can provide long-term disease control in patients who have failed primary therapy for Hodgkin's disease. Although the results as a whole are encouraging for chemosensitive patients and have improved over time, new therapeutic strategies are needed to reduce toxicity of HDCT and improve the clinical outcome of those patients who relapse after HDCT.

Using Noval Experimental PM 701 in Refractory Hodgkin's Disease Combined with conventional Therapy

Background: To the many profound changes we now face in health care, Complementary and Alternative Medicine (CAM) must be added as a major factor. There is evidence of the increasing use of CAM by patients diagnosed with cancer. Interest in CAM continues to grow at an exponential rate despite the advances made by conventional medicine. Given the increasing desire of cancer patients to use CAM, it is important that clinicians have a good understanding of the evidence available in this field and build a trust with their patients. Many oncologists are not familiar with CAM used by many of their patients.Aims: To report the effectiveness and safety of a natural experimental agent used with conventional therapy in a patient with Stage IV Hodgkin's lymphoma refractory to treatment.Methods: An eight-years-old Saudi girl was diagnosed as Stage IV Hodgkin's lymphoma with lung infiltration. The patient was started on chemotherapy (ABVD), and needed prolonged hospitalization due to weakness, loss of appetite, cachexia, dyspnea, cough, fever, and marked hepatosplenomegaly. She had six cycles of chemotherapy with a slight improvement in her general condition. However, she as considered refractory to conventional therapy. We were planning to refer her for bone marrow transplant. The patient was sent home to be readmitted for the seventh cycle of ABVD. Unfortunately, the patient's general condition deteriorated and she was admitted to the Intensive Care Unit (ICU), with acute Respiratory Distress Syndrome (RDS). She was markedly unstable and required respiratory ventilation support. After discussions involving the parents, it was suggested to use an experimental natural remedy of proven efficacy in inducing apoptosis in tissue cultures and animals in our laboratories. On the fifth day in ICU, the patient was initiated with full dose ABVD combined with the natural remedy, classified as PM 701. Within 2 days, the patient became fully conscious, showed improved general condition and returned to the pediatric ward to continue her treatment.Results: After the seventh cycle of chemotherapy and the use of natural remedy, her general condition improved markedly with significant reduction of the hepatosplenomegaly and pleural effusions. Repeated CT scans of chest and abdomen showed marked regression of her disease. She had one more cycle of chemotherapy combined with PM 701 and assessment after the eighth cycle showed complete remission of her disease including in the lungs. This natural agent has been fully studied with animal models at the King Fahed Medical Research Center's laboratory and showed potent selective apoptosis of cancer cells, effective and safe in animal models.Summary: Most childhood malignancy is curable with combined intensive conventional chemotherapy, however up to 30% may have relapse or be resistant to chemotherapy. We report in this case successful management with the combination of conventional therapy with experimental medicine (PM 701) in the treatment of refractory Hodgkin's lymphoma, which needs further control studies in the future to prove the efficacy and safety to be used on oncology patients. Integration between chemotherapy and natural CAM should be under close supervision to ensure safety and effectiveness. Scientific research needs more effort to support this line of medicine.

A Phase II Study of Oral Panobinostat (LBH589) for Chronic Phase Chronic Myeloid Leukemia (CML) with Resistance to ≥2 BCR-ABL Tyrosine Kinase Inhibitors

Background: Panobinostat (LBH589) is a novel, high potent pan-deacetylase inhibitor, which acetylates HSP90 and promotes degradation of its client proteins, such as BCR-ABL. It induces degradation of wild-type, as well as BCR-ABL with the T315i and E255K mutations in BaF3 cells. Based on this encouraging data, we initiated a Phase II trial to investigate the efficacy and safety of oral panobinostat in patients (pts) with chronic phase (CP) CML who had received at least 2 prior BCR-ABL tyrosine kinase inhibitors (TKI).Methods: This was a single arm, 3-stage, open-label, multicenter, Phase II study. The primary objective was to estimate the proportion of pts attaining major cytogenetic response (MCyR). Complete hematologic response (CHR) was one secondary objective. All patients received panobinostat orally 20 mg/day on a thrice weekly, consecutive weekly schedule. If ≥3 confirmed MCyRs were observed among 25 pts in Stage 1, Stage 2 was planned to be opened with a total of 32 pts. Dose reduction to 10 and 5 mg/day for toxicity and re-escalation to 20 mg/day was allowed. Dose escalation beyond 20 mg/day for poor response was not foreseen.Results: 29 pts were enrolled in Stage 1 between February and November 2007. Median age was 56 years (yrs) (range 31–75). Time since diagnosis of CML was ≥5 yrs in 69% and <2 yrs in 3%. All pts met the study criteria for TKI resistance. Best cytogenetic response to any prior TKIs was evaluable in 26 pts: MCyR in 7 pts, minor in 6 pts, and no response in 13 pts. Median time since last treatment of any kind, including hydroxyurea, was 20 days (range 0–224). Median duration of panobinostat treatment was 26 days (1–334). No MCyR was observed, and therefore, Stage 2 of the study was not opened. However, one CHR, accompanied by the eradication of the BCR-ABL T315i mutated clone, occurred in Cycle 2 (Week 6). This pt remained on panobinostat without progression until Cycle 12 (Week 48). Overall, non-hematological AEs were similar to the safety profile of 20 mg/day panobinostat reported before.1 Gastrointestinal AEs were reported by 10 pts (nausea; all Gr 1–2, but 1 Gr 3), diarrhea in 7 pts, and vomiting in 5 pts. Fatigue was reported in 8 pts and asthenia in 3 pts. An atrial fibrillation (Gr 2) in 1 pt and a QTcF prolongation >500 ms (Gr 3) in another pt required study drug discontinuation. 5 serious AEs were reported as possibly related to study drug: pulmonary embolism and the QTcF prolongation (see above) in 1 pt, and sepsis, followed by multiple organ failure with fatal outcome in a second pt. SAEs considered as non-related to study drug included: 1 case each of DVT, lung infection, pericardial effusion, pleural effusion, and cardiac failure. To date, 452 post baseline ECGs were assessed: minimal QTcF prolongations (30–60 ms) were seen in 4 and >60 ms in 1 pt. Gr 3/4 hematologic lab abnormalities were: anemia and neutropenia in 4 pts each and thrombocytopenia in 3 pts. Nonhematologic lab abnormalities were: Gr 4 hypokalemia (1), Gr 3 hyponatremia (1), hyperkalemia (1), and hypermagnesemia (2).Conclusions: No MCyR but 1 CHR with eradication of the T315i mutation were observed in 29 TKI-resistant CP CML pts, treated orally with 20 mg/day panobinostat, thrice weekly. Since the number of MCyRs required by the protocol was not seen, Stage 2 of the study was not opened. Safety/tolerability were comparable to what was reported for the same dose/schedule in other panobinostat studies, and no new safety findings were identified. The explanation that no more CRs were seen might be 2-fold:a dosing issue considering encouraging responses reported with oral, thrice weekly ≥40 mg/day single-agent panobinostat in pts with refractory Hodgkin's disease and AML1 andquite early hematologic progression in many pts, not allowing for longer exposure to panobinostat in this more resistant population.