Summary
The prognostic role of TP53 disruption has been established in diffuse large B‐cell lymphoma (DLBCL). Aim of this analysis was to correlate TP53 mutations by Sanger sequencing, cell of origin ...(COO) profile by Lymph2Cx panel on the NanoString platform and MYC, BCL2 and BCL6 overexpression or re‐arrangements by immunohistochemistry (IHC) and fluorescent in‐situ hybridization (FISH), with outcome in DLBCL patients enrolled into the FIL‐DLCL04 trial (NCT00499018). One hundred and twenty‐five DLBCL patients with tumour block available were analyzed. TP53 was mutated in 11/125 (9%) cases; 60/125 patients received high‐dose chemoimmunotherapy up‐front, as for the randomization arm; COO was reported in 88 patients: 48 germinal centre B‐cell like, 25 activated B‐cell like and 17 unclassified; 26 patients were double expressors in IHC and 11 double hit in FISH. After a median follow‐up of 72 months, five‐year failure‐free survival (FFS) for TP53 mutated versus wild‐type was 24% and 72%, and five‐year overall survival (OS) was 34% and 83%, respectively. Adjusted hazard ratio (HR) was 2·28 95% confidence interval (CI) 0·89–5·86, p = 0·086 and 4·05 (95% CI 1·37–11·97, p = 0·011) for FFS and OS, respectively. In this series of young DLBCL patients, TP53 gene mutation identified a poor prognosis subgroup, regardless of treatment and other biological markers.
Primary testicular lymphoma (PTL) has poor prognosis with failures in contralateral testis, CNS, and extranodal sites. To prevent these events, we designed an international phase II trial ...(International Extranodal Lymphoma Study Group 10 IELSG-10) that addressed feasibility and activity of conventional chemoimmunotherapy associated with CNS prophylaxis and contralateral testis irradiation. The trial was conducted by the IELSG and the Italian Lymphoma Foundation.
Fifty-three patients (age 22 to 79 years) with untreated stage I or II PTL were treated with six to eight courses of rituximab added to cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) every 21 days (R-CHOP21); four doses of intrathecal methotrexate (IT-MTX) and radiotherapy (RT) to the contralateral testis (30 Gy) for all patients and to regional lymph nodes (30 to 36 Gy) for stage II disease.
All patients received R-CHOP21, 50 received CNS prophylaxis, and 47 received testicular RT. With a median follow-up of 65 months, 5-year progression-free survival and overall survival rates were 74% (95% CI, 59% to 84%) and 85% (95% CI, 71% to 92%), respectively. Ten patients relapsed or progressed: two in lymph nodes, five in extranodal organs, and three in the CNS. The 5-year cumulative incidence of CNS relapse was 6% (95% CI, 0% to 12%). No contralateral testis relapses occurred. Ten patients died: lymphoma (n = 6), secondary leukemia (n = 2), heart failure (n = 1), and gastric cancer (n = 1). Grade 3 to 4 toxicities were neutropenia, 28%; infections, 4%; and neurologic, 13%. No deaths occurred as a result of toxicity.
This international prospective trial shows that combined treatment with R-CHOP21, IT-MTX, and testicular RT was associated with a good outcome in patients with PTL. RT avoided contralateral testis relapses, but CNS prophylaxis deserves further investigation.
Diffuse large B-cell lymphoma (DLBCL) is a heterogeneous disease, including one-third of cases overexpressing MYC and BCL2 proteins (double expressor lymphoma, DEL) and 5-10% of patients with ...chromosomal rearrangements of MYC, BCL2 and/or BCL-6 (double/triple-hit lymphomas, DH/TH). TP53 mutations are detected in 20- 25% of DEL. We report the efficacy of dose-adjusted EPOCH and rituximab (DA-EPOCH-R) in a series of 122 consecutive patients, including DEL (n=81, 66%), DEL-MYC (n=9, 7%), DEL-BCL2 (n=13, 11%), or high-grade lymphomas (DH/TH) (n=19, 16%). Central nervous system (CNS) prophylaxis included intravenous methotrexate (n=66), intrathecal chemotherapy (IT) (n=40) or no prophylaxis (n=16). Sixty-seven patients (55%) had highintermediate or high International Prognostic Index (IPI) and 30 (25%) had high CNS-IPI. The 2-year progression-free survival (PFS) and overall survival (OS) for the entire study population were 74% and 84%, respectively. There was a trend for inferior OS for DH/TH (2-year OS: 66%, P=0.058) as compared to all the others. The outcome was significantly better for the IPI 0-2 versus IPI 3-5 (OS: 98% vs. 72%, P=0.002). DA-EPOCH-R did not overcome the negative prognostic value of TP53 mutations: 2-year OS of 62% versus 88% (P=0.036) were observed for mutated as compared to wild-type cases, respectively. Systemic CNS prophylaxis conferred a better 2-year OS (94%) as compared to IT or no prophylaxis (76% and 65%, respectively; P=0.008). DA-EPOCH-R treatment resulted in a favorable outcome in patients with DEL and DEL with single rearrangement, whereas those with multiple genetic alterations such as DEL-DH/TH and TP53 mutated cases still have an inferior outcome.
Octogenarian patients with diffuse large B-cell lymphoma are managed mainly with palliation, but recent improvement in their overall condition makes potentially curative treatment a possibility. ...Studies have shown that half of selected octogenarians may be cured using reduced-dose anthracycline chemoimmunotherapy. However, patients aged >85 (late octogenarians LO) were underrepresented, and selection criteria were poorly defined. We analyzed the clinical characteristics and outcomes of LO enrolled in the FIL Elderly Project in terms of the treatment received (palliative vs. curative) and of their simplified geriatric assessment (sGA), then compared them with early octogenarians (EO) aged 80- 84 and with those aged 65-79 classified as UNFIT or FRAIL according to sGA enrolled in the same study. Of the 1,163 patients, 370 were >80 and 129 LO. Clinical characteristics were similar between LO and EO, but LO more frequently received palliation (50% vs. 23%; P=0.001) and had worse 2-year overall survival (OS) (48% vs. 63%; P=0.001) and 2-year progression-free survival (PFS) (43% vs. 56%; P=0.01). Patients receiving anthracycline did better than patients receiving palliation (P<0.001), without any difference between full or reduced doses. Rituximab within palliation improved outcome (2-yr OS with or without rituximab 42% vs. 22%; P=0.008). Elderly Prognostic Index (EPI) performed better than sGA in identifying different risk categories, and high-risk EPI retained an independent unfavorable effect on OS and PFS, together with treatment without anthracycline. In conclusion, late octogenarians can benefit from a curative approach with reduced-dose anthracycline and from rituximab within palliation. EPI may help in patient selection more than sGA can.
High-dose chemotherapy followed by autologous stem cell transplantation is the standard treatment for relapsed and/or refractory Hodgkin's lymphoma although half of patients relapse after ...transplantation. Predictive factors, such as relapse within 12 months, Ann-Arbor stage at relapse, and relapse in previously irradiated fields are classically used to identify patients with poor outcome. Recently, 18-fluorodeoxyglucose positron emission tomography has emerged as a new method for providing information to predict outcome. The aim of this study was to confirm the predictive value of positron emission tomography status after salvage therapy and to compare single versus tandem autologous stem cell transplantation in patients with relapsed and/or refractory Hodgkin's lymphoma.
We report a series of 111 consecutive patients with treatment-sensitive relapsed and/or treatment-refractory Hodgkin's lymphoma who achieved complete (positron emission tomography-negative group) or partial remission (positron emission tomography-positive group) at positron emission tomography evaluation after salvage chemotherapy and who underwent single or tandem autologous stem cell transplantation.
Five-year overall and progression-free survival rates were 81% and 64%, respectively. There were significant differences in 5-year progression-free survival (79% versus 23%; P<0.001) and 5-year overall survival (90% versus 55%, P=0.001) between the positron emission tomography-negative and -positive groups, respectively. A complete response, as determined by positron emission tomography evaluation, after salvage therapy predicted significantly better 5-year overall survival rates in both intermediate (91% versus 50%; P=0.029) and unfavorable (89% versus 58%; P=0.026) risk subgroup analyses. In the positron emission tomography-positive subgroup, tandem transplantation improved 5-year progression-free survival from 0% (in the single transplantation group) to 43% (P=0.034). Multivariate analysis showed that positron emission tomography status (hazard ratio: 5.26 2.57-10.73) and tandem transplantation (hazard ratio: 0.39 0.19-0.78) but not risk factors at relapse (hazard ratio: 1.77 0.80-3.92) significantly influenced progression-free survival, while only tomography status significantly influenced overall survival (hazard ratio: 4.03 1.38-11.75).
In patients with relapsed/refractory Hodgkin's lymphoma responding to prior salvage therapy, positron emission tomography response at time of autologous stem cell transplantation favorably influences outcome and enables identification of patients requiring single or tandem transplantation.
From the Department of Medical Oncology and Hematology, Istituto Clinico Humanitas, Rozzano, Italy (AS, MM, LS, AN, BS, EM, LC, MB), Department of Medical Oncology, Centro di Riferimento Oncologico, ...Aviano, Italy (MS, MM, UT), Division of Medical Oncology, Ospedale di Circolo, Varese, Italy (GP)
Correspondence: Armando Santoro, M.D., Department of Medical Oncology and Hematology, Istituto Clinico Humanitas, via Manzoni 56, 20089 Rozzano, Milan, Italy. E-mail: armando.santoro{at}humanitas.it
Background and Objectives: Response to pre-transplant salvage chemotherapy remains the most important prognostic factor for outcome in refractory or relapsed Hodgkins lymphoma. Results of a new induction regimen are reported in terms of response rates, toxicity, and stem cell mobilization.
Design and Methods: Ninety-one patients with refractory or relapsed Hodgkins lymphoma were treated prospectively with a salvage regimen consisting of ifosfamide 2000 mg/m 2 on days 1 to 4, gemcitabine 800 mg/m 2 on days 1 and 4, vinorelbine 20 mg/m 2 on day 1, and prednisolone 100 mg on days 1 to 4 (IGEV).
Results: Forty-nine patients (53.8%) achieved a complete remission and 25 (27.5%) a partial response for an overall response rate of 81.3%. In the multivariate analysis response to the last chemotherapy (p<0.0001) and involvement of 3 sites (p<0.049) were the most important prognostic factors for response. Adequate CD34 + cell collection was achieved in 78 out of 79 (98.7%) mobilized patients. So far, no treatment-related death has been documented. Thirteen (4.2%) and 27 (8.6%) out of 313 evaluated cycles had to be delayed or reduced, respectively, mainly because of neutropenia and thrombocytopenia. No grade 4 non-hematologic toxicity was observed, except for one episode of mucositis.
Interpretation and Conclusions: The high response rate, in particular the complete remission rate, the low toxicity profile, and the very high mobilizing potential of the IGEV regimen strongly suggest that patients with relapsed/refractory Hodgkins lymphoma may benefit from the use of this salvage induction regimen.
Key words: Hodgkins lymphoma, salvage chemotherapy, complete remission, CD34 + cell mobilization.
Related Article
Treatment of refractory and relapsed Hodgkin's lymphoma: facts and perspectives
Ercole Brusamolino, Angelo Michele Carella
Haematologica 2007 92: 6-10.
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Compared to other patients suffering from hematological malignancies, classical Hodgkin lymphoma (cHL) and diffuse large B-cell lymphoma (DLBCL) patients have a long life expectancy when in complete ...remission at the end of first, or sometimes second, line treatments ....
To assess the predictive value of
F-fluorodeoxyglucose positron emission tomography/computed tomography (PET/CT) for disease recurrence after immunochemotherapy (R-CHT) and mediastinal irradiation ...(RT), using the recently published criteria of the Lugano classification to predict outcomes for patients with primary mediastinal large B-cell lymphoma.
Among 125 patients prospectively enrolled in the IELSG-26 study, 88 were eligible for central review of PET/CT scans after completion of RT. Responses were evaluated using the 5-point Deauville scale at the end of induction R-CHT and after consolidation RT. According to the Lugano classification, a complete metabolic response (CMR) was defined by a Deauville score (DS) ≤3.
The CMR (DS1, -2, or -3) rate increased from 74% (65 patients) after R-CHT to 89% (78 patients) after consolidation RT. Among the 10 patients (11%) with persistently positive scans, the residual uptake after RT was slightly higher than the liver uptake in 6 patients (DS4; 7%) and markedly higher in 4 patients (DS5; 4%): these patients had a significantly poorer 5-year progression-free survival and overall survival. At a median follow-up of 60 months (range, 35-107 months), no patients with a CMR after RT have relapsed. Among the 10 patients who did not reach a CMR, 3 of the 4 patients (positive predictive value, 75%) with DS5 after RT had subsequent disease progression (within the RT volume in all cases) and died. All patients with DS4 had good outcomes without recurrence.
All the patients obtaining a CMR defined as DS ≤3 remained progression-free at 5 years, confirming the excellent negative predictive value of the Lugano classification criteria in primary mediastinal large B-cell lymphoma patients. The few patients with DS4 also had an excellent outcome, suggesting that they do not necessarily require additional therapy, because the residual
F-fluorodeoxyglucose uptake may not reflect persistent lymphoma.
The finding of hematological malignancies within bone marrow in heterotopic ossification has been reported only a handful of times previously in the literature. We described a case of true trilineage ...hematopoiesis in an excised area of heterotopic ossification from an enucleated blind painful eye.
A 70-year-old Caucasian man, positive for asymptomatic lymphoplasmacytic lymphoma, presented with a blind painful right eye in our ophthalmology department to evaluate enucleation bulbi. After enucleation, a histopathologic examination revealed the presence of intertrabecular infiltration in the metaplastic bone marrow of non-Hodgkin B lymphoma, with small lymphocytes, with similar characteristics to the already known disease.
This uncommon case reveals the possibility of the localization of malignant cells within bone metaplasia of intraocular ossification in an enucleated blind painful eye. From a practical point of view, a careful systematic histopathological examination of all resected tissues in patients with a history of malignant neoplastic pathology is necessary to confirm the diagnosis and exclude occult malignancies.
Preclinical studies have highlighted the activity of lenalidomide in mantle cell lymphoma and its anti-proliferative synergy with dexamethasone.
In this prospective, multicenter, phase II study, ...patients with relapsed/refractory mantle cell lymphoma who were not eligible for, or had relapsed after, intensive treatments received lenalidomide 25 mg/day (days 1-21 of each 28-day cycle) and dexamethasone (40 mg/day on days 1, 8, 15, and 22) for up to 12 months.
The primary end-points, overall and complete response rates, were achieved by 17 of 33 (52%; 95% confidence interval CI, 35-68%) and 8 of 33 patients (24%; 95% CI, 13-41%), respectively, by the end of treatment. Fifteen patients (45%) discontinued treatment prematurely, 13 due to lack of response. The median progression-free and overall survival were 12 months (95% CI, 5-19 months) and 20 months (95% CI, 12 months to not estimable), respectively. Treatment resulted in a significant increase in microvessel density (P=0.033) and non-significant increases in macrophage and natural killer cell counts, while serum levels of neoangiogenic factors did not change significantly. Grade 3/4 adverse events were neutropenia (53%), leukopenia (25%), thrombocytopenia (22%), infections (12%), and febrile neutropenia (12%).
These results confirm a favorable safety and activity profile of lenalidomide in relapsed/refractory mantle cell lymphoma. The contribution of dexamethasone in achieving these results is unclear because of its possible detrimental effect on the immune activation generated by lenalidomide and a higher risk of developing infectious complications. (clinicaltrials.gov identifier: NCT00786851).
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