The Risk of Therapy-Related Myelodysplasia/Acute Myeloid Leukemia in Hodgkin Lymphoma has Substantially Decreased in the ABVD Era Abolishing Mechlorethamine and Procarbazine and Limiting Volumes and Doses of Radiotherapy

Patients with Hodgkin lymphoma treated with DNA-breaking alkylating agents such as mechlorethamine and procarbazine in the MOPP regimen and with topoisomerase II inhibitors, such as etoposide did show a long-term risk of developing therapy-related myelodysplasia and acute myelogenous leukaemia (MDS/AML). With the introduction of the ABVD (adriamycin, bleomycin, vinblastine, dacarbazine) regimen, this risk has substantially been reduced. In this review, different experiences are discussed to determine whether and how modifications of treatment in different cohorts of patients have reduced the overall risk of secondary MDS/AML. These data are drawn from large cohorts of patients treated over time with different therapies with an adequate follow-up

therapy related late adverse events in hodgkin s lymphoma

Hodgkin's lymphoma (HL) is one of the most curable hematologic diseases with an overall response rate over 80%. However, despite this therapeutic efficacy, HL survivors show a higher morbidity and mortality than other people of the same age because of long-term therapy-related events. In the last decades, many efforts have been made to reduce these effects through the reduction of chemotherapy dose, the use of less toxic chemotherapeutic agents, and the introduction of new radiation techniques. In this paper, we will describe the main long-term effects related to chemotherapy and radiotherapy for HL, the efforts to reduce toxicity made in the last years, and the clinical aspects which have to be taken into consideration in the followup of these patients

Development of a CD30-directed CAR-T cell for the treatment of relapsed/refractory classical Hodgkin Lymphoma

Relapsed/refractory classical Hodgkin Lymphoma (cHL) represents an unmet clinical need. CD30 is an ideal target for CAR-T cell therapy in cHL, as its expression is high on tumour cells, but limited on healthy tissues. A proportion of activated T cells upregulates CD30, but the extent, duration and consequences of this on CD30-CAR T cell therapy have not been elucidated. Responses in early phase trials employing CD30-CAR T cells are encouraging, but their duration needs to be improved. To develop an efficacious CD30-CAR T cell, first I studied 11 CD30-binders for binding kinetics, stability and epitope binding. I tested them in vitro as second generation, 41BB co-stimulated CARs for cytotoxicity, cytokine release and proliferation against CD30+ targets. Binder 2 was selected for the best combination of on-target cytotoxicity and IL2 secretion. I studied CD30 expression on T cells at several timepoints after single activation. Expression peaked between day +4 and +5. By day +11, <10% of non-transduced T-cells expressed CD30, compared to up to 50% of CD30-CARs. These cells showed higher expression of activation markers (CD69 and CD62L). To elucidate its impact on CD30-CAR T cells activity, I knocked out CD30 on T cells using CRISPR-Cas9. I tested different timelines to incorporate editing in my in vitro CARs manufacturing and showed that editing non activated T cells was feasible, effective and did not impair subsequent activation or transduction. When tested in vitro, though, CD30 KO CD30-CARs did not show a statistically significant advantage compared to their non-edited counterpart and they achieved inferior tumour control In vivo, in an immunocompromised model. This works generated an efficacious second generation CD30-CAR, which will be used as backbone for further engineering and translation into clinic. While CD30 expression is high and persistent in CD30-CAR T cells, it does not appear to impact significantly on their activity in vitro and in vivo

Decitabine versus best supportive care in older patients with refractory anemia with excess blasts in transformation (RAEBt) - results of a subgroup analysis of the randomized phase III study 06011 of the EORTC Leukemia Cooperative Group and German MDS Study Group (GMDSSG)

In the European Organisation for Research and Treatment of Cancer (EORTC)/GMDSSG phase III trial06011, we compared decitabine (15 mg/m² every 8 h for 3 days) with best supportive care (BSC) in patients >/= 60 years with myelodysplastic syndromes (MDS) by French-Amercian-British (FAB) criteria. Here, we reinvestigate trial 06011 for the activity and efficacy specifically in patients with refractory anemia with excess blasts in transformation (RAEBt). Response rates in the decitabine arm (N=40) were as follow: complete or partial remission, 15 %; hematologic improvement, 15 %; resistant disease, 30 %. RAEBt patients in the decitabine arm had longer progression-free survival (PFS; hazard ratio (HR) 0.30, 95 % confidence interval (CI) 0.18-0.51; median, 6.2 vs 2.8 months) and overall survival (OS; HR 0.68, 95 % CI 0.42-1.11; median, 8.0 vs 6.0 months) than in the BSC arm (N=35). Censoring at allogeneic hematopoietic stem cell transplantation, the OS difference between the treatment groups increased, particularly among patients

Relapse patterns in early-PET negative, limited-stage Hodgkin lymphoma (HL) after ABVD with or without radiotherapy-a joint analysis of EORTC/LYSA/FIL H10 and NCRI RAPID trials.

In the H10 and RAPID randomised trials, chemotherapy+radiotherapy (combined modalities treatment, CMT) was compared with chemotherapy (C) in limited-stage Hodgkin lymphoma (HL), with negative early positron emission tomography (ePETneg). We analysed patterns of relapses in the H10 trial, validated findings in the RAPID trial and performed a combined analysis stratified by trial. The impact of radiotherapy (RT) on risk of relapse was studied using adjusted Cox models, with time-varying effects. In H10, 1,059 ePETneg patients were included (465 European Organisation for Research and Treatment of Cancer (EORTC) favourable [F], 594 unfavourable [U]). Among the F patients, 2/227 (1%) relapsed after CMT, 30/238 (13%) after C: of these relapses, 21/30 (70%) occurred in less than 2 years and 25/30 (83%) affected originally involved areas. Among the U group, 16/292 (5%) relapsed after CMT: 8/16 (50%) in less than 2 years, 11/16 (69%) in originally involved areas. After C 30/302 (10%) relapsed: 27/30 (90%) in less than 2 years, and 26/30 (87%) in originally involved areas. Similar results were observed in 419 ePETneg RAPID patients (241 F, 128 U, 50 unclassified): among F patients, 6/118 (5%) relapsed after CMT; 13/123 (11%) after C: 11/13 (85%) in less than 2 years and 11/13 (85%) affecting originally involved areas. In U patients, 3/65 (5%) relapsed after CMT and 5/63 (8%) after C. In both trials, omitting RT in ePETneg HL resulted in more early relapses, mainly affecting originally involved areas. RT significantly reduced risk of early relapses in the combined stratified analysis

Autologous stem cell transplantation with in vivo purged progenitor cells shows long-term efficacy in relapsed/refractory follicular lymphoma

High dose chemotherapy with autologous stem cell transplantation (ASCT) has been shown effective in the control of relapsed/refractory follicular lymphoma. We evaluate the long-term outcome of patients with relapsed or refractory follicular lymphoma treated with ASCT with in vivo purged progenitors cells. We report the long-term results of a prospective multicenter phase 2 trial on 124 relapsed/refractory follicular lymphoma patients with a program of anthracycline-based debulking chemotherapy, immunochemotherapy, mobilization of in vivo purged PBSC followed by ASCT. Median age was 52 years; 14% of patients had grade 3A histology. Debulking chemotherapy produced CR in 16% and PR in 71%, while 13% of patients progressed. After rituximab, cyclophosphamide, vincristine, prednisone (R-COP), CR was obtained in 60% and PR in 35%; 118 patients successfully mobilized PBSC and 117 proceeded to ASCT. The harvest in all the 32 molecularly informative patients was bcl-2 negative. TRM was 0%. The 5-yr PFS was 54% and the 5-yr OS was 83%. After a median f-up of 6.7 years (range 1.5-13.6), 53% are still in CR. These data show that prolonged PFS is achievable in relapsed/refractory patients with high dose autologous transplantation of in vivo purged progenitor cells

Independent prognostic impact of tumour-infiltrating macrophages in early-stage Hodgkin's lymphoma

Although patients with early-stage Hodgkin's lymphoma have a high rate of cure, a portion of these are resistant to or relapse after standard treatment. Current prognostic criteria based on clinical and laboratory parameters at diagnosis do not allow to accurately identify the subset of patients with less favourable clinical outcome. An increased number of tumour-infiltrating macrophages was found to be associated with shortened survival in patients with classic Hodgkin's Lymphoma. The aim of this study was to assess the clinical significance of the proportion of CD68-positive infiltrating macrophages in patients with early-stage classic Hodgkin's lymphoma. By using immunohistochemistry technique, we evaluated for CD68 expression diagnostic biopsies of 106 patients affected by supradiaphragmatic early-stage classic Hodgkin's lymphoma treated at our institution since 2000 to 2010. All patients were treated with adriamycin, bleomycin, vinblastine, and dacarbazine chemotherapy followed by radiotherapy in the majority. The 2-year overall survival and progression-free survival (PFS) in the entire cohort were 97% and 83% respectively. The 2-year PFS was statistically different between patients with favourable and those with unfavourable prognosis according to the European Organisation for Research and Treatment of Cancer (EORTC) risk criteria (96% vs 79%, p = 0.039) and between patients having less than 25% of CD68-positive infiltrating macrophages and those with more than 25% (85% vs 67%, p = 0.012). All patients with favourable EORTC criteria had CD68 expression lower than 25%. Within those with unfavourable EORTC criteria, patients with a CD68+ count greater than 25% had a worse 2-year PFS than patients having values lower than 25% (64% vs 82%, p = 0.03). Moreover, in multivariate analysis, after adjusting for CD68+ macrophages count and EORTC score, only CD68+ macrophages count higher than 25% retained a prognostic effect on PFS (hazard ratio = 2.8, 95%CI: 1.1-7.6, p = 0.038). Our data show that a proportion of tumour-infiltrating macrophages greater than 25% is associated with unfavourable clinical outcome in patients with early-stage Hodgkin's lymphom