Herpesviridae Viral Infections Following Chemotherapy in Patients with Lymphoma : Incidence, Risk Factors, and Prevention.

Abstract Abstract 3704 Poster Board III-640 Abstract Backgroud Herpesviridae family includes herpes simplex virus, varicella zoster virus, Epstein-Barr virus, and cytomegalovirus, etc. Herpesviridae viral infection(HVI) can lead to serious complications including dissemination, secondary infection, bacterial superinfection in patients with lymphoma undergoing chemotherapy. But there was no consensus on the dose and duration of antiviral agents prophylaxis in lymphoma undergoing chemotherapy. We retrospectively analyzed the incidence, the risk factors and the prevention with low-dose acyclovir for HVI. Method A total of 266 patients who newly diagnosed and received an chemotherapy without prophylaxis of acyclovir at the Kosin University Gospel Hospital, Busan, South Korea between June 1996 and August 2009 were enrolled retrospectively in the current study. HVI was confirmed based on clinical diagnosis, serologic test or pathologic diagnosis. The characteristics of the patients were as follows: the median age was 54years (range 15-83 years) with a female-to-male ratio of 150:116. The enrolled diseases included diffuse large B cell lymphoma (DLBL, n=151, 56.8%), Hodgkin's disease (HD, n=16, 6.0%), T cell lymphoma (TCL, n=43, 16.2%) and other lymphoma (n=56, 21.1%) including mantle cell lymphoma, marzinal zone B cell lymphoma, follicular lymphoma, small lymphocytic lymphoma and burkitt's lymphoma. The results were analyzed using a chi-square test and independent samples T test. For the multivariate analysises, we used logistic regression test. Results Fourty three patients (16.2%) developed HVI at a median of 5.43 months (range 0.43-51.33 months) after initial chemotherapy. In univariate analyses, risk factors for HVI were gender (p=0.002, 10% in male vs 24.1% in female), cumulative dose of prednisone (p < 0.001, 4.0% in less than 4000mg vs 31.6% in more than 4000mg), duration of chemotherapy (p=0.009, 11.8% in less than 6 months vs 24.0% in more than 6 months), presence of relapse (p=0.007, 24.7% in relapse vs 11.9% in non-relapse), receiving salvage chemotherapy (p=0.009, 11.8% in no receiving salvage chemotherapy vs 24.0% in receiving salvage chemotherapy), and presence of neutropenic fever (p=0.019, 26.9% in neutropenic fever vs 13.6% in no neutropenic fever). In multivariate analysis, the results confirmed 2 variables as independent predictive factors for the female (P < 0.001, hazard ratio (HR): 4.915, 95% confidence interval (CI) 2.200-10981) and cumulative dose of prednisone (P < 0.001, HR: 14.269, 95% CI 5.241-38.848). There was no different mortality rate and survival rate between HVI and non-HVI group. Conclusion Female and high dose prednisone was seemed to be high risk for HVI in patients with lymphoma undergoing chemotherapy without acyclovir prophylaxis. Low-dose acyclovir prophylaxis for HVI may be needed in higher risk lymphoma patients undergoing chemotherapy. Disclosures: No relevant conflicts of interest to declare.

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Rituximab Maintenance Therapy After Autologous Stem-Cell Transplantation in Patients With Relapsed CD20+ Diffuse Large B-Cell Lymphoma: Final Analysis of the Collaborative Trial in Relapsed Aggressive Lymphoma

Journal of Clinical Oncology ◽

10.1200/jco.2012.41.9416 ◽

2012 ◽

Vol 30 (36) ◽

pp. 4462-4469 ◽

Cited By ~ 158

Author(s):

Christian Gisselbrecht ◽

Norbert Schmitz ◽

Nicolas Mounier ◽

Devinder Singh Gill ◽

David C. Linch ◽

...

Keyword(s):

Stem Cell ◽

Stem Cell Transplantation ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Salvage Chemotherapy ◽

High Dose ◽

Large B Cell Lymphoma ◽

Relapsed Disease ◽

Large B Cell

Purpose The standard treatment for relapsed diffuse large B-cell lymphoma (DLBCL) is salvage chemotherapy followed by high-dose therapy and autologous stem-cell transplantation (ASCT). The impact of maintenance rituximab after ASCT is not known. Patients and Methods In total, 477 patients with CD20+ DLBCL who were in their first relapse or refractory to initial therapy were randomly assigned to one of two salvage regimens. After three cycles of salvage chemotherapy, the responding patients received high-dose chemotherapy followed by ASCT. Then, 242 patients were randomly assigned to either rituximab every 2 months for 1 year or observation. Results After ASCT, 122 patients received rituximab, and 120 patients were observed only. The median follow-up time was 44 months. The 4-year event-free survival (EFS) rates after ASCT were 52% and 53% for the rituximab and observation groups, respectively (P = .7). Treatment with rituximab was associated with a 15% attributable risk of serious adverse events after day 100, with more deaths (six deaths v three deaths in the observation arm). Several factors affected EFS after ASCT (P < .05), including relapsed disease within 12 months (EFS: 46% v 56% for relapsed disease after 12 months), secondary age-adjusted International Prognostic Index (saaIPI) more than 1 (EFS: 37% v 61% for saaIPI < 1), and prior treatment with rituximab (EFS: 47% v 59% for no prior rituximab). A significant difference in EFS between women (63%) and men (46%) was also observed in the rituximab group. In the Cox model for maintenance, the saaIPI was a significant prognostic factor (P < .001), as was male sex (P = .01). Conclusion In relapsed DLBCL, we observed no difference between the control group and the rituximab maintenance group and do not recommend rituximab after ASCT.

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Dexamethasone (D), High Dose Ara-C (HA) and Carboplatin (DHAC) with or without Rituximab (R) Is an Effective Salvage Regimen for Patients with Relapsed/Refractory B-Cell Lymphoma in Preparation for Autologous Stem Cell Transplantation.

Blood ◽

10.1182/blood.v108.11.4730.4730 ◽

2006 ◽

Vol 108 (11) ◽

pp. 4730-4730

Author(s):

Raymond Cruz ◽

Myron S. Czuczman ◽

Francisco Hernandez ◽

Ajay Kanra ◽

Swaminathan Padmanabhan

Keyword(s):

Stem Cell ◽

B Cell ◽

Median Survival ◽

Overall Response Rate ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Salvage Chemotherapy ◽

High Dose ◽

Cell Transplant ◽

Overall Response

Abstract Introduction: Relapsed/refractory B-cell lymphomas are a constant treatment challenge. High- dose chemotherapy and stem cell transplant (HDC-SCT) continues to be the backbone of treatment for such patients. Adequate cytoreduction with salvage chemotherapy is necessary prior to HDC-SCT and its achievement has been demonstrated to correlate with post-transplant outcomes. Various non-cross resistant salvage regimens have been developed to treat patients with relapsed/refractory B-cell lymphoma. In this report we present our institution’s experience with DHAC±R in patients requiring salvage therapy prior to HDC-SCT. Methods: The DHAC regimen consists of Dexamethasone at 15mg/m2/dose po every 6 hours × 10 doses, High-dose Ara-C at 3gr/m2 (1.5gr/m2 if >50 yrs old) iv over 3 hrs every 12 hrs for 4 doses and Carboplatin at 200mg/m2 iv every 24 hrs for 2 doses. When utilized, patients received rituximab at the standard dose of 375mg/m2, 48 hrs prior to each cycle of DHAC. Growth factor support and anti-microbial prophylaxis was implemented 24 hours after completion of chemotherapy. The regimen was repeated every 21 days for 2-3 cycles prior to HDC-SCT. We treated 37 patients with relapsed/refractory lymphomas, the median age of the entire cohort was 47 years (range 18 – 78); 25 were male and 19 females. While most of the patients treated had diffuse large B-cell lymphoma (DLBCL), various histological subtypes were included (DLBCL (n=16); follicular lymphoma (n=10); marginal zone lymphoma with blastoid features (n=1); small lymphocytic lymphoma (n=1) and Hodgkin’s lymphoma (n=8). The majority of the patients presented with advance stage at the time of DHAC therapy-Stage III (n=43%), Stage IV (n=39%). Seventeen patients were treated with R+DHAC, and 20 were treated with DHAC, either as second line or third line therapy. 19 out of the 37 patients proceeded to Stem cell transplant (SCT). Results: The overall response rate (ORR, CR+PR) for all patients was 61%(CR (n=16); and PR (n=7). The remaining 14 patients had either stable disease (n=10) or progressed (n=4). Complete responders (43%) had a longer mean survival of 107 (range 78 – 136) months compared to 66 months (range 49 – 83) for partial responders (19 percent) and non-responders who had a mean survival of 30.8 months (range 9–54), [P = 0.008]. Patients who proceeded to SCT had an overall response rate of 79% [CR (n=11) and PR (n=4)] compared to only 44% in those who did not [CR (n=5) and PR (n=3)]. The median survival in patients transplanted was longer than non-transplanted patients (92 vs 68 months). Response rates and median survival was similar between patients receiving R-DHAC or DHAC. As expected grade 3&4 hematologic toxicities were seen and effectively managed with appropriate supportive care. Conclusions: DHAC with or without rituximab appears to be an effective salvage treatment for patients with relapsed or refractory advanced-stage B-lymphoma undergoing HDC-SCT. An overall response of 61% which increases to 79% when followed by autologous SCT were demonstrated. Median survival was longer in patients experiencing CRs compared to partial or non-responders suggesting that the quality and quantity of the cytoreduction after salvage chemotherapy is an important predictor factor of post-SCT survival. Data looking at prognostic factors predicting response to DHAC±R treatment are being analyzed and will be reported at the ASH annual meeting.

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Outcomes of Relapsed/Refractory B-Cell Lymphoma Is Improved by Salvage Chemotherapy Consisting of Two to Three Cycles of Dexamethasone (D), High Dose Ara-C (HA) and Carboplatin (DHAC) with or without Rituximab (R) Followed by Autologous Stem Cell Transplantation.

Blood ◽

10.1182/blood.v110.11.5130.5130 ◽

2007 ◽

Vol 110 (11) ◽

pp. 5130-5130

Author(s):

Swaminathan Padmanabhan ◽

Anjana Elefante ◽

Prakash Varadarajan ◽

Minoo Battiwalla ◽

Arvinder Bir ◽

...

Keyword(s):

Overall Survival ◽

Stem Cell ◽

B Cell ◽

Median Survival ◽

Salvage Therapy ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Salvage Chemotherapy ◽

High Dose ◽

Overall Response

Abstract Introduction: Relapsed/refractory B-cell lymphomas are challenging to treat but can be salvaged by High- dose chemotherapy and stem cell transplant (HDC-SCT). Various non-cross resistant salvage regimens have been developed to treat patients with relapsed/refractory B-cell lymphoma. In this report we present our institution’s experience with DHAC ± R in patients requiring salvage therapy prior to HDC-SCT. Methods: The DHAC regimen consists of Dexamethasone at 15mg/m2/dose po every 6 hrs x 10 doses, High-dose Ara-C at 3G/m2 (1.5G/m2 if >50 yrs old) iv over 3 hrs every 12 hrs for 4 doses and Carboplatin at 200mg/m2 iv every 24 hrs for 2 doses. When utilized, patients received rituximab at the standard dose of 375mg/m2, 48 hrs prior to each cycle of DHAC. Growth factor support and anti-microbial prophylaxis was implemented 24 hrs after completion of chemotherapy. The regimen was repeated every 21 days for 2-3 cycles prior to HDC-SCT. We treated 37patients with relapsed/refractory lymphomas; median age was 47 yrs (range 18 – 78); 25 male and 19 females. Histological subtypes included (DLBCL (n=16); follicular lymphoma (n=10); marginal zone lymphoma with blastoid features (n=1); small lymphocytic lymphoma (n=1) and Hodgkin’s lymphoma (n=8). The majority of the patients presented with Stage III (n=43%), Stage IV (n=39%) at the time of DHAC therapy. Seventeen patients were treated with R+DHAC, and 20 were treated with DHAC, either as second line or third line salvage therapy. 19 of 37 proceeded to HD-SCT. Results: The overall response rate (ORR, CR+PR) for all patients was 61% (16 CR and 7 PR). The remaining 14 patients had either stable disease (n=10) or progressed (n=4). Complete responders (43%) had a longer median survival of 107 (range 78 – 136) months compared to 66 months (range 49 – 83) for partial responders (19 percent) and non-responders who had a mean survival of 30.8 months (range 9–54),[P = 0.008]. Patients who proceeded to HD-SCT had an ORR of 79% [11CR and 4 PR] compared to only 44% in those who did not [5 CR and 3 PR]. The median survival in patients transplanted was longer than non-transplanted patients (92 vs 68 months). Conclusions: DHAC with or without rituximab appears to be an effective salvage treatment for patients with relapsed or refractory advanced-stage B-lymphoma undergoing HDC-SCT. An overall response of 61% which increases to 79% when followed by autologous SCT were demonstrated. Median survival was longer in patients experiencing CRs compared to partial or non-responders suggesting that the quality and quantity of the cytoreduction after salvage chemotherapy is an important predictor factor of post-SCT survival. Data looking at prognostic factors predicting response to DHAC±R treatment are being analyzed and will be reported at the ASH annual meeting. Figure 1. Overall survival on DHAC±R depends on response to chemotheraphy. Figure 1. Overall survival on DHAC±R depends on response to chemotheraphy.

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Anti-CD19 CAR T Cells Administered after Low-Dose Chemotherapy Can Induce Remissions of Chemotherapy-Refractory Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood.v124.21.550.550 ◽

2014 ◽

Vol 124 (21) ◽

pp. 550-550 ◽

Cited By ~ 19

Author(s):

James N Kochenderfer ◽

Robert Somerville ◽

Lily Lu ◽

Alex Iwamoto ◽

James C Yang ◽

...

Keyword(s):

T Cells ◽

T Cell ◽

B Cell ◽

Low Dose ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

High Dose ◽

Car T Cells ◽

Car T ◽

Low Dose Chemotherapy

Abstract We have treated a total of 30 patients with autologous T cells genetically modified to express a chimeric antigen receptor (CAR) targeting the B-cell antigen CD19; 22 of 27 evaluable patients obtained either complete remissions (CR) or partial remissions (PR). Ten patients remain in ongoing CRs of 1 to 37 months duration. The CAR was encoded by a gammaretroviral vector and included the variable regions of an anti-CD19 antibody along with CD28 and CD3-zeta moieties. The first 21 patients treated on this protocol have been reported (Kochenderfer et al. Blood 2010, Blood 2012, and Journal of Clinical Oncology 2014). To enhance the activity of the transferred CAR T cells, T-cell infusions in the previously reported patients were preceded by a chemotherapy regimen of high-dose cyclophosphamide (60-120 mg/kg) plus fludarabine. In an attempt to reduce the overall toxicity of our anti-CD19 CAR treatment protocol, we substantially reduced the doses of chemotherapy administered before CAR T-cell infusions. This abstract communicates results from 9 patients with B-cell lymphoma who received a single infusion of 1x106 anti-CD19-CAR-expressing T cells/kg bodyweight preceded by a low-dose chemotherapy regimen consisting of cyclophosphamide 300 mg/m2 and fludarabine 30 mg/m2 (Table). Each chemotherapy agent was administered daily for 3 days. Eight of the 9 treated patients had DLBCL (diffuse large B-cell lymphoma) that was refractory to chemotherapy (chemo-refractory) or that had relapsed less than 1 year after autologous stem cell transplantation (ASCT). Both of these clinical situations carry a grim prognosis, with median overall survivals of only a few months. Despite the very poor prognoses of our patients, one patient with DLBCL obtained a CR and 4 DLBCL patients obtained PRs. In some patients, PRs included resolution of large lymphoma masses. Compared to our previous experience with anti-CD19 CAR T cells preceded by high-dose chemotherapy, toxicity was reduced when CAR T cells were infused after low-dose chemotherapy. None of the 9 patients treated with low-dose chemotherapy and CAR T cells required vasopressor drugs or mechanical ventilation, although some patients did have short-term neurological toxicity. Cytopenias were mild with a mean of only 1.4 days of blood neutrophils<500/microliter. Blood anti-CD19 CAR T-cell levels were assessed in 6 patients with a quantitative PCR assay; we detected CAR+ cells in the blood of all 6 patients. The mean peak absolute number of blood CAR+ T cells was 73 cells/microliter. Six months after infusion, persisting CAR+ T cells were detected in a lymphoma-involved lymph node by flow cytometry. These results demonstrate that anti-CD19 CAR T cells administered after low-dose chemotherapy have significant activity against chemo-refractory DLBCL and could potentially become a standard treatment for aggressive lymphoma. Table Patient Age/Gender Malignancy Number of Prior Therapies Clinical Situation Response (Duration in Months) 1 66/M DLBCL 3 Post ASCT relapse PR (7) 2* 63/F DLBCL 2 Chemo-refractory PR (7+) 3 63/M FL 7 Not chemo-refractory PR (6+) 4* 22/M DLBCL 6 Chemo-refractory Progression 5 65/M DLBCL 4 Post ASCT relapse PR (5+) 6 47/M DLBCL 2 Chemo-refractory PR (1) 7 28/M DLBCL 7 Chemo-refractory Progression 8 62/M DLBCL 7 Post ASCT relapse CR (1+) 9 54/M DLBCL 3 Chemo-refractory Progression * Compassionate exemption was obtained from regulatory agencies to enroll these patients because their poor performance status precluded standard enrollment; M = male; F = female; FL = follicular lymphoma; + indicates ongoing response Disclosures Rosenberg: Kite Pharma: Membership on an entity's Board of Directors or advisory committees, Research Funding.

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A Phase 2 Trial of AZD1152 in Relapsed/Refractory Diffuse Large B-Cell Lymphoma

Blood ◽

10.1182/blood.v124.21.4481.4481 ◽

2014 ◽

Vol 124 (21) ◽

pp. 4481-4481

Author(s):

Graham P Collins ◽

Eyre A Toby ◽

Chris S. Hatton ◽

John Radford ◽

Kim M Linton

Keyword(s):

B Cell ◽

Confidence Intervals ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Neutropenic Fever ◽

Aurora B ◽

High Dose ◽

Aurora B Kinase ◽

Large B Cell Lymphoma ◽

Large B Cell

Abstract Introduction Diffuse large B-cell lymphoma (DLBCL) is the most common non-Hodgkin lymphoma (NHL) and has an aggressive natural history. R-CHOP has improved patient (pt) survival and established a standard of first line care. In the rituximab era the prognosis for relapsed DLBCL is poor, with salvage chemotherapy and autologous stem cell transplantation (ASCT) only curing a small proportion (<25% of all relapses) of those with adequate performance status. Relapsed DLBCL in those unfit for ASCT or post-ASCT is rarely curable, and remains an unmet clinical need. AZD1152 (barasertib) is a highly selective and potent Aurora B kinase inhibitor. Aurora B kinase has an important function at the spindle assembly check-point in mitosis. The kinase is overexpressed in 48% of DLBCL. Exposure of high grade lymphoma B cells to AZD1152-HQPA in vitropotently induced growth arrest and apoptosis via caspase-dependent and independent mechanisms. AZD1152 was well tolerated in a phase I study in relapsed/refractory acute myeloid leukaemia. We performed a phase II single arm open-label trial to determine the efficacy and tolerability of AZD1152 in relapsed/refractory DLBCL pts who had failed or were ineligible for salvage/high dose chemotherapy and had received at least one line of potentially curative immunochemotherapy. Methods Pts with relapsed/refractory (de novoor transformed indolent NHL) DLBCL with measurable disease (at least a non-irradiated single lesion (>1.5cm)) were treated with up to six cycles of 96-hour continuous intravenous (iv) infusions of AZD1152 as an inpt every 3 weeks. Due to concerns over possible precipitation of drug in the line, regular 4 hourly saline flushes were required via each lumen to maintain patency. Prophylactic G-CSF was permissible per ASCO guidelines. Ongoing cycles were commenced when neutrophils recovered to ≥1.0x109/L and platelets to ≥50x109/L. The primary endpoint was overall response rate (ORR). Secondary end-points were progression-free survival (PFS) at one year, % change in tumour size, and safety measured by the incidence and severity of adverse events (AEs). Response assessment using FDG-PET was completed at day 15 of cycle 2. Pts with stable disease (SD), minimal, partial (PR) or complete response (CR) according to Cheson criteria remained on protocol, but those with progressive disease (PD) were taken off study. As data that suggests MYC overexpression may enhance responses to aurora B kinase inhibition, MYC by IHC and FISH for c-MYC translocation was performed. All diagnostic specimens were reviewed by specialist haemato-pathologists. Results Fifteen pts were enrolled in 20 months, and received 1-6 cycles. Overall, 42 cycles were administered (41 at full dose). One pt completed all six planned cycles. The cohort included 8 males and 7 females, with a median age of 65 (35-74 years). 13% had a low International Prognostic Index (IPI) (0-1), 53% an intermediate IPI (2-3) and 33% a high IPI (4-5). The best ORR was 20% (see Fig 1 for tumour percentage reduction) with no cases of CR and 3 PR. 33% obtained SD for between 2-6 cycles. The median PFS was 60 days (95% CI 36-84 days) (see Fig 2). IPI (p=0.584) (See Fig 3), gender (p=0.113), disease bulk at diagnosis (p= 0.654) or c-MYC dysregulation (p=0.331) did not predict PFS. Early discontinuation occurred in 14 pts from PD. Safety Most AEs were grade 1-2. 18 episodes of neutropenic fever occurred, including one grade 4 bacteraemia. There were no fatal SAEs and each episode resolved with iv antibiotics and G-CSF. All other toxicities were transient, manageable and expected. 13% of pts developed a total of 2 episodes of mucositis following 42 total doses. Neutropenia (grade 3-4), diarrhoea and nausea were common but manageable and expected. No Suspected Unexpected Serious Adverse Reactions occurred. Conclusions Three-weekly AZD1152 was safely administered to pts with relapsed DLBCL. Responses were seen, providing a proof of concept that Aurora B kinase is a valid target in DLBCL. However, efficacy was modest. The infusate delivery was cumbersome. Dose intensity was maintained during treatment. Important but manageable AEs included neutropenic fever and mucositis. Aurora B kinase is a rational target for further investigation. NCT01354392. Fig 1: Best % change in SPD from baseline Fig 1:. Best % change in SPD from baseline Fig 2: PFS with 95% confidence intervals Fig 2:. PFS with 95% confidence intervals Fig 3: PFS by IPI Fig 3:. PFS by IPI Disclosures No relevant conflicts of interest to declare.

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Risk factors of venous thrombosis in elderly patients with diffuse large B-cell lymphoma

Academic Journal of Second Military Medical University ◽

10.3724/sp.j.1008.2015.00342 ◽

2015 ◽

Vol 36 (3) ◽

pp. 342

Author(s):

Jin LIU ◽

Jian-min YANG

Keyword(s):

Risk Factors ◽

Elderly Patients ◽

Venous Thrombosis ◽

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

Large B Cell Lymphoma ◽

Large B Cell

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Impact of High-Dose Methotrexate on the Outcome of Patients with Diffuse Large B-Cell Lymphoma and Skeletal Involvement

Cancers ◽

10.3390/cancers13122945 ◽

2021 ◽

Vol 13 (12) ◽

pp. 2945

Author(s):

Mélanie Mercier ◽

Corentin Orvain ◽

Laurianne Drieu La Rochelle ◽

Tony Marchand ◽

Christopher Nunes Gomes ◽

...

Keyword(s):

B Cell ◽

Cell Lymphoma ◽

B Cell Lymphoma ◽

High Dose ◽

High Dose Methotrexate ◽

Skeletal Involvement ◽

Large B Cell Lymphoma ◽

Dose Methotrexate ◽

The Impact ◽

Large B Cell

Diffuse large B-cell lymphoma (DLBCL) with extra nodal skeletal involvement is rare. It is currently unclear whether these lymphomas should be treated in the same manner as those without skeletal involvement. We retrospectively analyzed the impact of combining high-dose methotrexate (HD-MTX) with an anthracycline-based regimen and rituximab as first-line treatment in a cohort of 93 patients with DLBCL and skeletal involvement with long follow-up. Fifty patients (54%) received upfront HD-MTX for prophylaxis of CNS recurrence (high IPI score and/or epidural involvement) or because of skeletal involvement. After adjusting for age, ECOG, high LDH levels, and type of skeletal involvement, HD-MTX was associated with an improved PFS and OS (HR: 0.2, 95% CI: 0.1–0.3, p < 0.001 and HR: 0.1, 95% CI: 0.04–0.3, p < 0.001, respectively). Patients who received HD-MTX had significantly better 5-year PFS and OS (77% vs. 39%, p <0.001 and 83 vs. 58%, p < 0.001). Radiotherapy was associated with an improved 5-year PFS (74 vs. 48%, p = 0.02), whereas 5-year OS was not significantly different (79% vs. 66%, p = 0.09). A landmark analysis showed that autologous stem cell transplantation was not associated with improved PFS or OS. The combination of high-dose methotrexate and an anthracycline-based immunochemotherapy is associated with an improved outcome in patients with DLBCL and skeletal involvement and should be confirmed in prospective trials.

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