scholarly journals Biomodulatory Treatment Regimen, MEPED, Rescues Relapsed and Refractory Classic Hodgkin’s Disease

2021 ◽  
Vol 12 ◽  
Author(s):  
Florian Lüke ◽  
Dennis C. Harrer ◽  
Karin Menhart ◽  
Daniel Wolff ◽  
Ernst Holler ◽  
...  

Introduction: Current combined intensive chemotherapy and radiation regimens yield excellent survival rates in advanced classic Hodgkin’s lymphoma (cHL). However, acute toxicity in elderly, comorbid patients can be challenging and long-term survival in refractory patients remains poor.Patients and Methods: We report on six patients with r/r HL, three patients with long-term follow-up, three newly treated, after biomodulatory therapy. All patients received MEPED (treosulfan 250 mg p.o. daily, everolimus 15 mg p.o. daily to achieve serum trough levels of 15 ng/ml, pioglitazone 45 mg p.o. daily, etoricoxib 60 mg p.o. daily and dexamethasone 0.5 mg p.o. daily). Patients had either received every at that time approved systemic treatment or were ineligible for standard treatment, including immune checkpoint inhibition (ICPi) due to prior demyelinating autoimmune polyneuropathy, myasthenia gravis and previous allogeneic hematopoietic-stem-cell transplant (alloHSCT). Medication was administered continuously from day 1. One patient with relapse after alloHSCT received trofosfamide 50 mg daily instead of treosulfan to avoid risk of increased myelotoxicity. The patients were treated in individual healing attempts outside a clinical trial after institutional review board approval. 18F-fluoro-2-deoxy-d-glucose positron emission tomography combined with computed tomography scan (FDG-PET/CT) was performed to monitor treatment and follow-up.Results: In the three newly treated patients, CT scans showed partial remissions after 2–5 months on MEPED treatment. Two patients had achieved PET Deauville score 2 and 3, while the third remained positive at Deauville score 5. One patient achieving PR became eligible for alloHSCT, while the other two patients continued treatment with MEPED. All patients eventually achieved continuous complete remission (cCR), one after consecutive alloHSCT, one after discontinuing MEPED consolidation for >1 year and one on on-going MEPED consolidation, respectively. Only one patient experienced Grade 3 toxicity (bacterial pneumonia) requiring temporary discontinuation of MEPED for 10 days. All three previously published patients received allo HSCT for consolidation and have achieved cCR.Conclusions: MEPED is well tolerated with low toxicity and highly efficacious in relapsed/refractory cHL, including severely comorbid patients. Due to its immunomodulatory components, MEPED might also have a synergistic potential when combined with ICPi but requires further evaluation within a clinical trial.

Blood ◽  
2012 ◽  
Vol 120 (21) ◽  
pp. 2024-2024
Author(s):  
Ryan D. Gentzler ◽  
Andrew M. Evens ◽  
Alfred W. Rademaker ◽  
Bharat B Mittal ◽  
Adam M. Petrich ◽  
...  

Abstract Abstract 2024 Background: For patients with relapsed or refractory HL, salvage chemotherapy followed by aHSCT is the standard of care. Our group previously reported excellent clinical outcomes with accelerated hyperfractionated TLI followed by high-dose chemotherapy and aHSCT (Ann of Oncol. 16:679, 2007). This strategy has been adopted as the standard at our institution for eligible individuals and we now report long-term outcomes of patients previously reported on the phase I/II clinical trial in addition to those who were subsequently treated as standard of care. Patients and methods: Patients with biopsy confirmed relapsed/refractory classical HL who previously received no more than 20 Gy were eligible. Salvage chemotherapy was chosen by the patient's treating physician. All patients received accelerated hyperfractionated TLI prior to transplantation administered twice daily at 150 cGy, five days/week for 10 days. The morning dose was delivered to all nodal sites including the spleen, and the afternoon dose was delivered to all sites of previous and current disease. The goal was to treat uninvolved nodal sites and spleen to 1500 cGy and sites of current and previous disease to 3000 cGy. Conditioning chemotherapy consisted of high-dose carboplatin, cyclophosphamide, and etoposide. All patients received carboplatin 450 mg/m2 by continuous intravenous infusion (CIV) on days –6 to –4 (total dose = 1350 mg/m2) and cyclophosphamide 60 mg/kg/day over 1 h on days –3 and –2 (total dose = 120 mg/kg). Patients on the phase I portion of the trial received escalating doses of etoposide by CIV from days –6 to –4. Initial dosing levels were 400 mg/m2/day, 450 mg/m2/day, 500 mg/m2/day, 600 mg/m2/day and 700 mg/m2/day. Those treated on the phase II portion of the clinical trial or subsequent to the closing of the trial were treated with etoposide 700 mg/m2/day for a total of 2100 mg/m2. Results: 52 patients with relapsed/refractory HL at Northwestern University were treated with TLI and aHSCT from 1993 to January 2011. One patient was lost to follow-up immediately post-transplant. 51 patients were included in this analysis and had a median follow-up of 47 months (range: 0.07–204 months). Thirty patients were treated on a previously reported prospective phase I/II clinical trial. Most patients had nodular sclerosis histology (n=39, 76%) and more than half had primary induction failure (PIF; n=29). Among patients who achieved a CR with induction, 62% relapsed within one year. The most common salvage regimens were ESHAP and ICE chemotherapy and most had received two lines of chemotherapy prior to aHSCT. Only 21 patients (41%) achieved a complete response (CR) with salvage therapy and in most cases (n=31, 61%), response was determined by functional imaging prior to aHSCT. The 10-year PFS and OS for all patients were 56% and 54%, respectively. Ten-year PFS and OS for patients with PIF was 53%, compared with 63% and 59%, respectively, for those with relapsed disease (p=0.13 and p=0.20, respectively). Patients who had incomplete responses to salvage therapy had a 10-year PFS and OS of 41% and 39%, respectively, compared to 76% and 81%, respectively, for those who achieved a CR (p=0.1 and p=0.056, respectively). Treatment-related mortality within the first 100 days was observed in one patient. Five patients (10%) developed secondary malignancies; three developed MDS (one who had received MOPP induction died with MDS; one had relapsed HL post-aHSCT and died of AML and one is alive with MDS 3+ yrs post-diagnosis). There was one case each of T-cell lymphoma (7 months post-aHSCT) and melanoma. Conclusions: Sequential TLI/chemotherapy conditioning for relapsed/refractory HL for patients with limited or no prior radiotherapy continues to be associated with excellent disease control and long-term survival rates including high-risk populations such as PIF and chemotherapy-resistant disease. Disclosures: No relevant conflicts of interest to declare.


Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 4624-4624
Author(s):  
Sanaz Nicky Soltani ◽  
Ramaprasad Srinivasan ◽  
Theresa Jerussi ◽  
A. John Barrett ◽  
Thomas E Hughes ◽  
...  

Acute SR-GVHD occurs in approximately 15% of patients undergoing allogeneic hematopoietic stem cell transplant (HSCT), and is associated with a 70-90% long-term mortality rate. We previously reported that concomitant blockade of TNF-α and IL-2 pathways with infliximab combined with daclizumab have a synergistic therapeutic effect, with a high probability of complete resolution of SR-GVHD. Although various treatment modalities are effective in the treatment of SR-GVHD, minimal long-term follow up data exists for complete responders to second line treatments. Here we report long-term outcomes in a cohort of 23 subjects developing SR-GVHD treated with infliximab/daclizumab. A consecutive series of 141 patients with a variety of hematological and non-hematological malignancies as well as nonmalignant hematological disorders including severe aplastic anemia (SAA), paroxysmal nocturnal hemoglobinuria and pure red cells aplasia, underwent a reduced intensity allogeneic HSCT from an HLA identical or single antigen mismatched relative at a single institution between 2/2001 and 12/2008. Transplant conditioning consisted of cyclophosphamide (60 mg/kg days -7, -6) and fludarabine (25 mg/m2days -5 to -1) with or without equine ATG or 6-12 Gy of total body irradiation. GVHD prophylaxis was with cyclosporine with or without additional MMF or MTX. Twenty three patients (median age 35 years, range 13-65 years) developed SR-GVHD at a median of 28 days post transplant. SR-GVHD was defined as absence of response to at least 6 days of high dose methylprednisolone therapy. Following a diagnosis of SR-GVHD, patients received a combination of daclizumab (1mg/kg given on days 1, 4, 8, 15, 22), infliximab (10mg/kg given on days 1, 8, 15, 22), broad spectrum bacterial and anti-fungal prophylaxis, and had their methylprednisolone tapered to 1mg/kg/day. Combined cytokine blockade was highly active against SR-GVHD, with 21/23 (87.5%) patients achieving a complete response (CR), defined as total resolution of GVHD in all involved organ systems. All complete responders survived to hospital discharge. With a median follow-up of 9 years (range 5-10 years), 9/23 (39%) survive, including 6 patients without chronic GVHD whose immunosuppressive therapy (IST) has been discontinued and 3 patients with chronic GVHD (2 limited and 1 extensive) who continue to be tapered off IST. Fourteen of 21 patients with resolution of SR-GVHD died a median 173 days post transplant (range 67-1039 days), including 1 from complications related to recurrent SR-GVHD, 6 from progression of malignancy (all solid tumors), 2 from bleeding related to peptic ulcer disease and 5 from infectious complications including invasive fungal infection and CMV disease. A subgroup analysis showed 5/6 patients with SAA developing SR-GVHD had a complete response to combined infliximab/daclizimab. Remarkably, at a median 6 years follow up, 67% (4/6) of these SAA patients were long-term survivors. All these survivors have maintained normal blood counts and remained transfusion independent with 100% donor chimerism in myeloid and T-cell lineages. Conclusion Patients with SR-GVHD treated with infliximab combined with daclizumab had a high probability of achieving a complete response with nearly 40% of patients having long-term survival. This is the first report to show that long-term survival can be achieved in a substantial proportion of patients receiving combined IL-2 and TNF blockade for SR-GVHD. Disclosures: Off Label Use: Infliximab is FDA approved for the treatment of psoriasis, Crohn's disease, ankylosing spondylitis, psoriatic arthritis, rheumatoid arthritis and ulcerative colitis. Daclizumab gained FDA approval for use in transplant rejection.


Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 2448-2448
Author(s):  
Andrew M. Evens ◽  
Jane N. Winter ◽  
Nanjiang Hou ◽  
Fred Rademaker ◽  
Katalin Kelemen ◽  
...  

Abstract MCL is associated with high relapse rates and poor survival when treated with standard chemotherapy (chemoTx). We report long-term outcomes with intent-to-treat (ITT) analysis of a prospective phase II protocol of intensive induction chemoTx, followed by HSCT in first complete or partial remission (CR/PR). MCL diagnosis was based on histology with cyclin D1+ or CCND1/IGH fusion. Induction chemoTx consisted of cyclophosphamide 1.5 gm/m2, teniposide 100 mg/m2, and doxorubicin 50 mg/m2 all given day 1 and prednisone 100 mg/m2 days 1–5 (CTAP); this was followed by vincristine 1.4 mg/m2 and methotrexate 3.0 gm/m2 on day 21 and cytarabine 3.0 gm/m2 × 2 doses 12 hours apart day 22 (VMAC). Patients (pts) who achieved CR/PR after 2 cycles CTAP/VMAC (1 cycle=42 days) received 1 additional cycle. Pts ≤ age 65 then proceeded to aHSCT, while pts < 50 with a matched sibling donor had allogeneic HSCT, both with busulfan/cyclophosphamide200 conditioning. After aHSCT, pts received maintenance αinterferon/interleukin-2 (αIFN/IL-2) given together QD Monday-Friday every other month (mos) × 3 mos (both dosed at 3×106 IU/m2). Responding pts > age 65 proceeded directly to αIFN/IL-2 after 3 cycles chemoTx. 25 newly diagnosed MCL pts were entered onto trial from 2/97 through 11/02. Median age was 57 (range 39–76; 16M/9F); 83% had bone marrow involvement, and 32% had other extranodal disease at diagnosis. On ITT analysis, overall response rate (ORR) was 68% after chemoTx (CR 28%/PR 40%). 17 pts received HSCT (13 autologous and 4 allogeneic); 4 eligible pts did not proceed to transplant due to progressive disease. Following HSCT, ORR was 77%. There were no treatment-related deaths. 5 pts experienced reversible non-hematologic grade 4 toxicities (2 bilirubin, 1 stomatitis, 1 infection, and 1 renal failure). On ITT, 5-year EFS and OS for all pts is 35% and 50%, respectively (Figure 1). With a median follow-up of 61 mos, 5-year EFS and OS for pts who received aHSCT is 54% and 75%, respectively (Figure 2). This includes 7/13 aHSCT pts who are alive and disease free at 49, 51, 61, 63, 61, 77, and 80 mos. Patients who received aHSCT had significantly improved survival compared to pts who received allogeneic or no HSCT (p=0.003 EFS and p=0.001 OS by logrank test). We conclude that CTAP/VMAC induction chemoTx followed by aHSCT in first remission for newly diagnosed MCL results in durable EFS and OS. Incorporation of monoclonal antibody and other novel targeted agents should further improve pt outcomes. Figure 1. 5-year survival rates (confidence interval, CI) for all 25 newly diagnosed MCL pts: EFS 35% (CI, 17%–53%), OS 50% (CI, 29%–68%). Figure 1. 5-year survival rates (confidence interval, CI) for all 25 newly diagnosed MCL pts: EFS 35% (CI, 17%–53%), OS 50% (CI, 29%–68%). Figure 2. 5-year survival rates (confidence interval, CI) for 13 pts who received aHSCT in first CR/PR: EFS 54% (CI, 25%–76%), OS 75% (CI, 41%–91%). Figure 2. 5-year survival rates (confidence interval, CI) for 13 pts who received aHSCT in first CR/PR: EFS 54% (CI, 25%–76%), OS 75% (CI, 41%–91%).


Circulation ◽  
2007 ◽  
Vol 116 (suppl_16) ◽  
Author(s):  
Jeong-Hoon Kim ◽  
Duk-Hyun Kang ◽  
Jong-Young Lee ◽  
Jong-Min Song ◽  
Tae-Jin Yun ◽  
...  

The benefits of surgical closure has been unclear in adult atrial septal defect (ASD) with severe pulmonary hypertension (PHT), and we tried to evaluate improvement of PHT and long-term survival after surgical closure compared to medical follow-up. Methods: From 1996 to 2006, we included a total of 71 adult ASD patients (age; 43±15 years) with severe PHT documented by echocardiography. The inclusion criteria were defined as ASD diameter > 15 mm, enlarged right ventricle, and the baseline peak velocity of tricuspid regurgitation (TR) ≥ 4.0 m/sec. We excluded 5 patients with Eisenmenger syndrome documented by cardiac catheterization. Surgical closure was performed on 55 patients (OP group) and the remaining 16 patients were followed up medically (MED group). The improvement of PHT was defined as TR velocity ≤ 3.5 m/sec on follow-up echo. Results: Baseline characteristics and clinical results were compared between the two groups in table . There were no significant differences in terms of gender, ASD diameter, cardiac rhythm, and TR velocity, but the MED group was significantly older. During follow-up of 46±33 months, there were 5 deaths in the MED group and no operative or late death in the OP group, and the 5-year actuarial survival rate of the OP group was significantly higher than the MED group (58±15%, p<0.05). On subgroup analysis according to age, the OP group showed significantly better survival rates than the MED group (p<0.05) in elderly patients (age > 50). In the OP group, TR velocity was significantly decreased from 4.5±0.4 to 3.0±0.7 m/sec on follow-up echo, and improvement of PHT was observed in 47 (85%) patients. On multivariate analysis, female gender and lower baseline TR velocity were the significant independent predictors of improved PHT after surgery. Conclusions: In adult ASD with severe PHT, surgical closure can be safely performed and improve PHT effectively. Especially in elderly patients, ASD closure is significantly related with the better survival rates.


2019 ◽  
Vol 9 (1) ◽  
Author(s):  
Graziamaria Corbi ◽  
Francesco Cacciatore ◽  
Klara Komici ◽  
Giuseppe Rengo ◽  
Dino Franco Vitale ◽  
...  

AbstractAim of the present study was to assess the impact of gender on the relationship between long-term mortality and clinical frailty. In an observational, longitudinal study on 10-year mortality, we examined 1284 subjects. The Frailty Staging System was used to assess frailty. The Cox model was employed to assess variables independently associated with survival using a backward stepwise algorithm. To investigate the possible interactions between gender and the selected variables, an extension of the multivariable fractional polynomial algorithm was adopted. Women were more likely to be older, have a higher disability, present with more comorbidities, consume more drugs, be frail and have a higher rate of survival at the follow-up than were men. At the Cox multivariate analysis only age (HR 2.26), female gender (HR 0.43), and number of drugs (HR 1.57) were significant and independent factors associated with all-cause mortality. In the survival analyses, only frailty (vs no frailty) showed significant interaction with gender (p < 0.001, HR = 1.92). While the presence of frailty reduced the survival rate in women, no effect was observed in men. Importantly, frail women showed higher survival rates than did both frail and no frail men. The main finding of the present study is that gender shapes up the association between frailty and long-term survival rates.


2020 ◽  
pp. 096914132092303
Author(s):  
Eugenio Paci ◽  
Donella Puliti ◽  
Francesca Maria Carozzi ◽  
Laura Carrozzi ◽  
Fabio Falaschi ◽  
...  

Objectives Overdiagnosis in low-dose computed tomography randomized screening trials varies from 0 to 67%. The National Lung Screening Trial (extended follow-up) and ITALUNG (Italian Lung Cancer Screening Trial) have reported cumulative incidence estimates at long-term follow-up showing low or no overdiagnosis. The Danish Lung Cancer Screening Trial attributed the high overdiagnosis estimate to a likely selection for risk of the active arm. Here, we applied a method already used in benefit and overdiagnosis assessments to compute the long-term survival rates in the ITALUNG arms in order to confirm incidence-excess method assessment. Methods Subjects in the active arm were invited for four screening rounds, while controls were in usual care. Follow-up was extended to 11.3 years. Kaplan-Meyer 5- and 10-year survivals of “resected and early” (stage I or II and resected) and “unresected or late” (stage III or IV or not resected or unclassified) lung cancer cases were compared between arms. Results The updated ITALUNG control arm cumulative incidence rate was lower than in the active arm, but this was not statistically significant (RR: 0.89; 95% CI: 0.67–1.18). A compensatory drop of late cases was observed after baseline screening. The proportion of “resected and early” cases was 38% and 19%, in the active and control arms, respectively. The 10-year survival rates were 64% and 60% in the active and control arms, respectively ( p = 0.689). The five-year survival rates for “unresected or late” cases were 10% and 7% in the active and control arms, respectively ( p = 0.679). Conclusions This long-term survival analysis, by prognostic categories, concluded against the long-term risk of overdiagnosis and contributed to revealing how screening works.


2015 ◽  
Vol 2 (4) ◽  
pp. 199-204 ◽  
Author(s):  
Paul D. Brown ◽  
S. Keith Anderson ◽  
Xiomara W. Carrero ◽  
Brian P. O'Neill ◽  
Caterina Giannini ◽  
...  

Abstract Background Pilocytic astrocytoma is a rare tumor in adults. This report is of a prospective clinical trial with long-term follow-up. Methods Between 1986 and 1994, 20 eligible adults with supratentorial pilocytic astrocytomas were enrolled in a prospective intergroup trial of radiotherapy (RT) after biopsy (3 patients) or observation after gross (11 patients) or subtotal (6 patients) resection. Results At the time of analysis (median follow-up, 20.8 years), 2 patients (10%) have died and 18 patients (90%) are alive. Neurologic and cognitive function were stable or improved over time for the majority of patients. No toxic effects of treatment or malignant transformations have been recorded at last follow-up. For the entire cohort the 20-year time to progression and overall survival rates are 95% and 90% respectively. The cause of death (2.2 and 16.1 years after enrollment) in both patients was unrelated to tumor although both were biopsy-only patients. One subtotally resected tumor progressed 1 month after enrollment requiring P32 injection into an enlarging cyst. Because of further progression this patient required RT 18 months later. This patient is alive without evidence of progression 18 years after RT. Conclusion The long-term follow-up results of this prospective trial confirm that adults with pilocytic astrocytomas have a favorable prognosis with regard to survival and neurologic function. Close observation is recommended for adults with pilocytic astrocytomas, reserving RT for salvage, as the majority remain stable after gross or subtotal resection and no adjuvant therapy.


2019 ◽  
Vol 45 (2) ◽  
pp. 160-166 ◽  
Author(s):  
Farhad Farzaliyev ◽  
Hans-Ulrich Steinau ◽  
Halil-Ibrahim Karadag ◽  
Alexander Touma ◽  
Lars Erik Podleska

In this retrospective study, we analysed the long-term oncological and functional results after extended ray resection for sarcoma of the hand. Recurrence-free and overall survivals were calculated using the Kaplan–Meier method. The function of the operated hand was assessed with the Michigan Hand Questionnaire and compared with the contralateral side. Extended ray resection was performed in 25 out of 168 consecutive patients with soft-tissue and bony sarcomas of the hand. The overall 5- and 10-year, disease-specific survival rates were 86% and 81%, respectively. Local recurrences were observed in two patients. The Michigan Hand Questionnaire score for the affected hand at follow-up in nine patients was 82 points versus 95 for the healthy contralateral hands. We conclude that extended ray resection of osseous sarcomas breaking through the bone into the soft tissue or for soft tissue sarcomas invading bone is a preferable alternative to hand ablation when excision can be achieved with tumour-free margins. Level of evidence: III


Sign in / Sign up

Export Citation Format

Share Document