Search

Mantle cell lymphoma is a rare and incurable lymphoproliferative disorder. In the MCL01 trial, patients were treated with the R-HCVAD regimen [rituximab plus HyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin, dexamethasone; R-CVAD) alternating with high-dose methotrexate and cytarabine (AM)] for four cycles followed by autologous stem cell transplantation (ASCT) for those who reached only a partial response. After a median follow-up of 10·5 years, we reported 10-year progression-free and overall survival rates of 35% and 61% respectively, with a 10-years cumulative incidence rate of second malignancies of 10·6%. Mature results of the MCL01 trial confirmed the efficacy of HyperCVAD-AM as a frontline regimen for younger patients (≤65 years)., (© 2020 British Society for Haematology and John Wiley & Sons Ltd.)

For advanced-stage Hodgkin lymphoma (HL), front-line chemotherapy, alone or in combination with radiotherapy, leads to 5-year progression-free survival (PFS) rates and freedom-from-treatment failure (FFTF) rates of 70-85%, regardless of the chemotherapy regimen applied. Patients with HL experiencing disease progression during or within 3 months of front-line therapy (primary refractory) and patients whose disease relapses after a complete response have a second chance of treatment. The standard of care for relapsed or refractory HL is second-line chemotherapy followed by autologous stem cell transplantation (ASCT), which can induce long-term remission in approximately 40-50% of patients. However, HL recurrence occurs in about 50% of patients after ASCT, usually within the first year, and represents a significant therapeutic challenge. Allogeneic transplantation from HLA-matched donors represents the standard of care for patients with HL relapsing after- or refractory to ASCT.

FDG-positron emission tomography (PET) performed early during therapy in advanced Hodgkin lymphoma patients has been confirmed as being important for progression-free survival. A group of patients with a negative interim-PET (i-PET) showed a positive end induction PET (e-PET). The aim of this study was to evaluate the clinical characteristics of patients with a positive e-PET as a secondary end point of the HD0801 study. A total of 519 patients with advanced-stage de novo Hodgkin lymphoma received initial treatment and underwent an i-PET. Patients with negative results continued the standard treatment. i-PET negative patients were then evaluated for response with an e-PET and those patients found to have a positive one were also then given a salvage therapy. Among 409 i-PET negative, 16 interrupted the therapy, 393 patients were evaluated with an e-PET, and 39 were positive. Sixteen out of 39 underwent a diagnostic biopsy and 15 were confirmed as HD. Seventeen out of 39 e-PET were reviewed according to the Deauville Score and, in sixteen, it was confirmed positive (10 DS 5, 6 DS 4). With the exception of high LDH value at diagnosis (p = 0.01; HR 95% CI 1.18-4.89), no clinical characteristics were significantly different in comparison with e-PET negative patients. Positive e-PET after a negative i-PET has a worse outcome when compared with i-PET positive patients salvaged with therapy intensification. It was not possible to identify clinical characteristics associated with a positive e-PET.

Background: The prognosis of young patients with diffuse large B-cell lymphoma at high risk (age-adjusted International Prognostic Index [aa-IPI] score 2 or 3) treated with R-CHOP (rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone) is poor. The aim of this study was to investigate the possible benefit of intensification with high-dose chemotherapy and autologous stem-cell transplantation as part of first-line treatment in these patients., Methods: We did a multicentre, open-label, randomised, controlled, phase 3 trial with a 2 × 2 factorial design to compare, at two different R-CHOP dose levels, a full course of rituximab-dose-dense chemotherapy (no transplantation group) versus an abbreviated course of rituximab-dose-dense chemotherapy followed by consolidation with R-MAD (rituximab plus high-dose cytarabine plus mitoxantrone plus dexamethasone) and high-dose BEAM chemotherapy (carmustine, etoposide, cytarabine, and melphalan) plus autologous stem-cell transplantation (transplantation group) in young patients (18-65 years) with untreated high-risk diffuse large B-cell lymphoma (aa-IPI score 2-3). At enrolment, patients were stratified according to aa-IPI score and randomly assigned (1:1:1:1) to receive R-CHOP (intravenous rituximab 375 mg/m 2 , cyclophosphamide 750 mg/m 2 , doxorubicin 50 mg/m 2 , and vincristine 1·4 mg/m 2 on day 1, plus oral prednisone 100 mg on days 1-5) delivered in a 14-day cycle (R-CHOP-14) for eight cycles; high-dose R-CHOP-14 (R-MegaCHOP-14; R-CHOP-14 except for cyclophosphamide 1200 mg/m 2 and doxorubicin 70 mg/m 2 ) for six cycles; R-CHOP-14 for four cycles followed by R-MAD (intravenous rituximab 375 mg/m 2 on day 1 or 4 plus intravenous cytarabine 2000 mg/m 2 and dexamethasone 4 mg/m 2 every 12 h on days 1-3 plus intravenous mitoxantrone 8 mg/m 2 on days 1-3) plus BEAM (intravenous carmustine 300 mg/m 2 on day -7, intravenous cytarabine 200 mg/m 2 twice a day on days -6 to -3, intravenous etoposide 100 mg/m 2 twice a day on days -6 to -3, plus intravenous melphalan 140 mg/m 2 on day -2) and autologous stem-cell transplantation (day 0); or R-MegaCHOP-14 for four cycles followed by R-MAD plus BEAM and autologous stem-cell transplantation. The primary endpoint was failure-free survival at 2 years in the intention-to-treat population. This study is registered with EudraCT (2005-002181-14; 2007-000275-42) and with ClinicalTrials.gov, number NCT00499018., Findings: Between Jan 10, 2006, and Sept 8, 2010, 399 patients were randomly assigned to receive transplantation (n=199) or no transplantation (n=200); 203 patients were assigned to receive R-CHOP-14 and 196 were assigned to receive R-MegaCHOP-14. With a median follow-up of 72 months (IQR 57-88), 2-year failure-free survival was 71% (95% CI 64-77) in the transplantation group versus 62% (95% CI 55-68) in the no transplantation group (hazard ratio [HR] 0·65 [95% CI 0·47-0·91]; stratified log-rank test p=0·012). No difference in 5-year overall survival was observed between these groups (78% [95% CI 71-83] versus 77% [71-83]; HR 0·98 [0·65-1·48]; stratified log-rank test p=0·91). Grade 3 or worse haematological adverse events were reported in 183 (92%) of 199 patients in the transplantation group versus 135 (68%) of 200 patients in the no transplantation group. Grade 3 or worse non-haematological adverse events were reported in 90 (45%) versus 31 (16%); the most common grade 3 or worse non-haematological adverse event was gastrointestinal (49 [25%] vs 19 [10%]). Treatment-related deaths occurred in 13 (3%) patients; eight in the transplantation group and five in the no transplantation group., Interpretation: Abbreviated rituximab-dose-dense chemotherapy plus R-MAD plus BEAM and autologous stem-cell transplantation reduced the risk of treatment failure compared with full course rituximab-dose-dense chemotherapy in young patients with diffuse large B-cell lymphoma at high risk. However, these results might not be clinically meaningful, since this improvement did not reflect an improvement in overall survival. These results do not support further consideration of the use of intensification of R-CHOP as an upfront strategy in patients with diffuse large B-cell lymphoma with poor prognosis., Funding: Fondazione Italiana Linfomi., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

Purpose: The clinical impact of positron emission tomography (PET) evaluation performed early during first-line therapy in patients with advanced-stage Hodgkin lymphoma, in terms of providing a rationale to shift patients who respond poorly onto a more intensive regimen (PET response-adapted therapy), remains to be confirmed., Patients and Methods: The phase II part of the multicenter HD0801 study involved 519 patients with advanced-stage de novo Hodgkin lymphoma who received an initial treatment with doxorubicin, bleomycin, vinblastine, and dacarbazine (ABVD) and who underwent an early ifosfamide-containing salvage treatment followed by stem-cell transplantation if they showed a positive PET evaluation after two cycles of chemotherapy (PET2). The primary end point was 2-year progression-free survival calculated for both PET2-negative patients (who completed a full six cycles of ABVD treatment) and PET2-positive patients. Overall survival was a secondary end point., Results: In all, 103 of the 512 evaluable patients were PET2 positive. Among them, 81 received the scheduled salvage regimen with transplantation, 15 remained on ABVD (physician's decision, mostly because of minimally positive PET2), five received an alternative treatment, and two were excluded because of diagnostic error. On intention-to-treat analysis, the 2-year progression-free survival was 76% for PET2-positive patients (regardless of the salvage treatment they received) and 81% for PET2-negative patients., Conclusion: Patients with advanced-stage Hodgkin lymphoma for whom treatment was at high risk of failing appear to benefit from early treatment intensification with autologous transplantation, as indicated by the possibility of successful salvage treatment in more than 70% of PET2-positive patients through obtaining the same 2-year progression-free survival as the PET2-negative subgroup., (© 2016 by American Society of Clinical Oncology.)

In the frontline high-dose phase 3 FIL-MCL0208 trial (NCT02354313), 8% of enrolled mantle cell lymphoma (MCL) patients could not be randomised to receive lenalidomide (LEN) maintenance vs observation after autologous stem cell transplantation (ASCT) due to inadequate hematological recovery and 52% of those who started LEN, needed a dose reduction due to toxicity. We therefore focused on the role played by CD34 + hematopoietic stem cells (PBSC) harvesting and reinfusion on toxicity and outcome. Overall, 90% (n = 245) of enrolled patients who underwent the first leukapheresis collected ≥ 4 × 106 PBSC/kg, 2.6% (n = 7) mobilized < 4 × 106 PBSC/kg and 7.7% (n = 21) failed the collection. Similar results were obtained for the planned second leukapheresis, with only one patient failing both attempts. Median count of reinfused PBSC was 5 × 106/kg and median time to recovery from neutropenia G4 was 10 days from ASCT. No impact of mobilizing subtype or number of reinfused PBSC on hematological recovery and LEN dose reduction was noted. At a median follow-up of 75 months from ASCT, PFS and OS of transplanted patients were 50% and 73%, respectively. A long lasting G4 neutropenia after ASCT (> 10 days) was associated with a worse outcome, both in terms of PFS and OS. In conclusion, although the harvesting procedures proved feasible for younger MCL patients, long-lasting cytopenia following ASCT remains a significant issue: this can hinder the administration of effective maintenance therapies, potentially increasing the relapse rate and negatively affecting survival outcomes. [ABSTRACT FROM AUTHOR]

We report final results of a phase II trial addressing efficacy and feasibility of lenalidomide maintenance in patients with chemosensitive relapse of diffuse large B-cell lymphoma (DLBCL) not eligible for or failed after autologous stem cell transplantation (ASCT). Patients with relapsed DLBCL who achieved at least a partial response to salvage chemoimmunotherapy were enrolled and treated with lenalidomide 25 mg/day for 21 of 28 days for 2 years or until progression or unacceptable toxicity. Primary endpoint was 1-year PFS. Forty-six of 48 enrolled patients were assessable. Most patients had IPI ≥2, advanced stage and extranodal disease before the salvage treatment that led to trial registration; 28 (61%) patients were older than 70 years. Lenalidomide was well tolerated. With the exception of neutropenia, grade-4 toxicities occurred in <1% of courses. Three patients died of complications during maintenance and three died due to second cancers at 32 to 64 months. There were 13 SAEs recorded in 12 patients; all these patients but two recovered. Lenalidomide was interrupted due to toxicity in other 6 patients, and 25 patients required dose reduction (transient in 21). At 1 year from registration, 31 patients were progression free. After a median follow-up of 65 (range 39-124) months, 22 patients remain progression free, with a 5-year PFS of 48% ± 7%. The duration of response to lenalidomide was longer than response to prior treatment in 30 (65%) patients. Benefit was observed both in de novo and transformed DLBCL, germinal-center-B-cell and nongerminal-center-B-cell subtypes. Twenty-six patients are alive (5-year OS 62% ± 7%). With the limitations of a nonrandomized design, these long-term results suggest that lenalidomide maintenance might bring benefit to patients with chemosensitive relapse of DLBCL not eligible for or failed after ASCT. Lenalidomide was associated with durable disease control and was well tolerated in this elderly population. Further investigations on immunomodulatory drugs as maintenance in these high-risk patients are warranted. [ABSTRACT FROM AUTHOR]

This randomized, multicenter study evaluates the addition of bortezomib (13 mg/m2) to IGEV (B-IGEV) in patients with relapsed/refractory Hodgkin Lymphoma (HL). Patients received either four courses of IGEV alone (n = 40) or B-IGEV (n = 40). The primary endpoint was the complete response (CR) proportion, evaluated by FDG-PET, after induction chemotherapy. CR proportion was 39% with B-IGEV and 53% with IGEV. PFS and OS were similar between the two groups (two-year PFS: 58% vs 56%; two-year OS: 93% vs 81%). The PET-negative status after treatment was the only variable favorably influencing both PFS (two-year PFS: 77% vs 40%;p = 0.002) and OS (two-year OS: 100% vs 76%;p < 0.001). Toxicity was overall similar with the two regimens. The addition of bortezomib to IGEV does not improve response in relapsed/refractory HL patients. However, its favorable therapeutic and safety profile, and the prognostic role of pre-transplant PET negativity in patients receiving IGEV-based regimens are confirmed. [ABSTRACT FROM AUTHOR]

The management of patients with Hodgkin lymphoma ( HL) recurring after stem cell transplantation ( SCT) and multiply relapsed disease remains challenging. We report on 41 such patients who received bendamustine hydrochloride, a bifunctional mechlorethamine derivative mechanistically unrelated to traditional alkylators, after a median of four prior chemotherapy lines, including SCT in 85% of cases. Bendamustine was given at doses of 90-120 mg/m2 every 21 or 28 d. At first assessment (2-4 cycles), the overall response rate ( ORR) was 78% with 12 (29%) complete ( CR) and 20 (49%) partial responses ( PR). Upon treatment prolongation to 6-8 courses, 40% of PRs progressed, yielding a final ORR of 58% with 31% of CRs. Eight patients (two CRs, six PRs) were subsequently allotransplanted. Median progression-free and overall survival exceeded 11 and 21 months respectively; complete responders displayed a median disease-free survival above 9 months with a relapse rate of only 30%. Outcomes were independent of disease chemosensitivity, previous transplant and bendamustine dose-intensity. No life-threatening or unexpected adverse events occurred. Within the limits of a retrospective analysis and schedule heterogeneity, these results appear very encouraging and prompt prospective trials to confirm bendamustine as a valuable option in the palliative setting and in cytoreductive strategies before allotransplantation. [ABSTRACT FROM AUTHOR]

Summary This study investigated the clinical activity and toxicity of R-HCVAD-AM [rituximab plus HyperCVAD (R-HCVAD) alternating with high-dose cytarabine and methotrexate (AM)] in patients with newly diagnosed Mantle Cell Lymphoma (MCL). Patients aged ≤70 years with confirmed MCL received four alternating cycles each of R-HCVAD and AM. Patients who obtained a partial response proceeded to autologous stem cell transplant. Sixty-three patients were enrolled and 60 were fully eligible. Median age was 57 years (22-66); 60%, 33% and 7% were classified at low (L)-, intermediate (I)- or high (H)-risk, respectively, according to the MCL International Prognostic Index (MIPI). Only 22 patients (37%) completed the four cycles and three patients died during therapy. Overall response and complete response rates were 83% and 72% respectively. After a median follow-up of 46 months (range 1-72) the estimated 5-year overall survival (OS) and progression-free survival rates were 73% [95% confidence interval (CI) 59-83%], and 61% (95%CI 45-73%) respectively. MIPI maintained the prognostic value with an estimated 5-year OS of 89%, 80% and 24% for L, I, and H groups respectively ( P < 0·001). This multicentre study confirms that R-HCVAD-AM is an active regimen for the initial treatment of patients with MCL, but is associated with significant toxicity. [ABSTRACT FROM AUTHOR]