Intensive therapy with peripheral stem cell transplantation in 16 patients with mantle cell lymphoma

Background: Despite improved detection of mantle cell lymphoma (MCL),results of its treatment with conventional therapies remain disappointing andthe survival rate poor. The role of high-dose chemotherapy has recently beeninvestigated but no potential benefit has been clearly established. We reporthere our experience with MCL patients treated with intensive chemotherapy andautologous stem cell transplantation (ASCT).Patients and methods: Of the 16 MCL patients who received high-dosechemotherapy and ASCT beginning in 1989, six were treated in first-line and10 in sensitive relapse. Twelve of 16 patients received regimens whichincluded total body irradiation. All patients received peripheral blood stemcells (PBSC) with the exception of one, who underwent bone marrowtransplantation.Results: Three patients died of toxic effects of treatment. Three monthsafter transplant, seven achieved complete responses (CR) and two partialresponses (PR), two were stable and two had progressed. With a medianfollow-up after transplant of 22 months, five of the six surviving patientswere without progression, and three were in CR. The median times forevent-free survival (EFS) and overall survival (OS) were, respectively, 249and 317 days. The expected three-year EFS and OS were 24%. The mediansurvival after diagnosis was only 29 months. None of the criteria appeared tobe significantly associated with a better outcome, but first-lineintensification and a short delay after initial diagnosis may be favorable.Conclusion: In this study we were not able to confirm the hypotheticalbenefit of high-dose chemotherapy and PBSC transplantation in mantle celllymphoma, even though this approach may be promising in a subgroup of patient.     

Hematopoietic stem cell transplantation in mantle cell lymphoma.

BACKGROUND: Patients with mantle cell lymphoma (MCL) have in general, lower response rates and overall survival (OS) than those with other B-cell non-Hodgkin's lymphomas. The role of hematopoietic stem cell transplantation (HSCT) in MCL is unclear. Hence we decided to study the clinical course of patients who received autologous and allogeneic HSCT for MCL. METHODS: Ninety-seven patients, (80 patients-autologous; 17 patients-allogeneic) who received a HSCT for mantle cell lymphoma were included in the study. RESULTS: The complete response rates at day 100 between the two groups were similar (73% vs. 62%). Day-100 mortality was higher in the allogeneic HSCT group (19% vs. 0%) (P < 0.01). The estimated 5-year relapse rates, 5-year event-free survival (EFS) and 5-year OS among the allogeneic HSCT patients were 21%, 44% and 49%, respectively, similar to 56%, 39% and 47% in the autologous group. Ten patients received HyperCVAD (hyperfractionated cyclophosphamide, vincristine, doxorubicin and dexamethasone + high-dose methotrexate and cytarabine) +/- rituximab prior to transplant. There have been no relapses or deaths amongst these patients at a median follow-up of 16 months. CONCLUSIONS: Patients treated with allogeneic HSCT had a lower relapse rate, but similar EFS and OS to autologous HSCT. Treatment of MCL with HyperCVAD +/- rituximab followed by HSCT seems promising.     

R‐High‐CHOP/CHASER/LEED with autologous stem cell transplantation in newly diagnosed mantle cell lymphoma: JCOG0406 STUDY

Although induction immunochemotherapy including high‐dose cytarabine and rituximab followed by high‐dose chemotherapy (HDC) with autologous stem cell transplantation (ASCT) is recommended for younger patients (≤65 years old) with untreated mantle cell lymphoma (MCL), no standard induction and HDC regimen has been established. We conducted a phase II study of induction immunochemotherapy of R‐High‐CHOP/CHASER followed by HDC of LEED with ASCT in younger patients with untreated advanced MCL. Eligibility criteria included untreated MCL, stage II bulky to IV, and age 20‐65 years. Patients received 1 cycle of R‐High‐CHOP followed by 3 cycles of CHASER every 3 weeks. Peripheral blood stem cells (PBSC) were harvested during CHASER. LEED with ASCT was delivered to patients who responded to R‐High‐CHOP/CHASER. Primary endpoint was 2‐year progression‐free survival (PFS). From June 2008 to June 2012, 45 patients (median age 59 years; range 38‐65 years) were enrolled. PBSC were successfully harvested from 36 of 43 patients. Thirty‐five patients completed ASCT. Two‐year PFS was 77% (80% CI 68‐84), which met the primary endpoint. Five‐year PFS and overall survival were 52% (95% CI 34‐68%) and 71% (95% CI 51‐84%), respectively. Overall response and complete response rates after induction immunochemotherapy were 96% and 82%, respectively. The most common grade 4 toxicities were hematological. In younger patients with untreated MCL, R‐High‐CHOP/CHASER/LEED with ASCT showed high efficacy and acceptable toxicity, and it can now be considered a standard treatment option.     

Engraftment and outcomes following autologous stem cell transplantation in Hodgkin lymphoma patients mobilized with plerixafor

Plerixafor has been used to improve peripheral blood stem cell (PBSC) mobilization in multiple myeloma, non‐Hodgkin lymphoma, and very recently in Hodgkin lymphoma (HL) patients. Because prior studies have suggested that mobilization with plerixafor affects the composition of mobilized cells, there are concerns that this may in turn adversely impact the immune reconstitution and longer term outcomes of transplanted patients. However, data on the engraftment characteristics and long‐term post‐transplant outcomes in patients transplanted with plerixafor‐mobilized PBSCs are lacking. This retrospective study examined the post‐transplant outcomes of 105 consecutive adult HL patients, and compared the post‐transplant outcomes of 21 patients who received plerixafor in addition to G‐CSF ± chemotherapy because of poor mobilization with those of 84 patients who mobilized well without plerixafor. Despite collecting significantly lower CD34+ cell doses (median of 3.41 vs. 6.05 × 10⁶/kg, p < 0.0001) than control patients and requiring more collection days, plerixafor‐mobilized patients showed comparable early engraftment characteristics, except for slightly delayed neutrophil engraftment (median: 11 vs.10 days, p = 0.002) and lower median neutrophil counts (2.1 vs. 2.6 × 10⁹/L, p = 0.04) at one month after transplant. No significant differences were observed in longer term post‐transplant outcomes, including cell counts at 3, 6, and 12 months, RBC and platelet transfusion support during the first 120 days, relapse incidence, overall and progression‐free survival rates up to two years post transplant. The use of plerixafor not only enabled poorly mobilizing HL patients to collect enough PBSCs to proceed to ASCT, but also to have similar post‐transplant outcomes compared to patients who mobilized well with conventional regimens. Copyright © 2016 John Wiley & Sons, Ltd.     

Patterns and outcome of relapse after autologous stem cell transplantation for mantle cell lymphoma

BACKGROUND:

Autologous stem cell transplantation (autoSCT) has improved the outcome of patients with mantle cell lymphoma (MCL) considerably. However, little is known about the patterns and outcome of MCL recurrence after autoSCT.

METHODS:

The authors conducted a retrospective study of 118 patients with MCL who underwent autoSCT from August 1992 to August 2008 at 3 different referral centers in Germany.

RESULTS:

Fifty‐two relapses occurred for a cumulative incidence of 46% after 5 years. Only 3 patients relapsed after 5 years (at 90 months, 91 months, and 171 months) after undergoing autoSCT. A Cox regression analysis of the incidence of relapse identified not receiving rituximab before autoSCT and undergoing salvage autoSCT as predictive factors for relapse, whereas cytosine arabinoside intensification; a total body irradiation‐based, high‐dose regimen; patient age; and year of transplantation had no influence. The median overall survival (OS) after relapse was 23 months. Twenty patients (39%) underwent allogeneic stem cell transplantation (alloSCT) for relapse, and 11 of those patients remained in ongoing complete remission at the time of the current report. It is noteworthy that there were 4 long‐term survivors who lived for >5 years after relapse even without undergoing alloSCT. A Cox regression analysis of OS after relapse revealed that the response duration after autoSCT was an adverse predictor of OS, whereas alloSCT was associated with a significantly longer OS after relapse.

CONCLUSIONS:

The current results indicated that autoSCT was capable of inducing long‐term remission up to 16 years after treatment, but the outcome of patients with MCL who relapsed after autoSCT was poor, especially if their response duration after autoSCT was short. However, for a subset of patients with relapsed MCL, alloSCT may offer the possibility of durable survival, and individual patients can enjoy long‐term survival after relapse even without undergoing alloSCT. Cancer 2011. © 2010 American Cancer Society.     

Rituximab consolidation after high-dose chemotherapy and autologous blood stem cell transplantation in follicular and mantle cell lymphoma: a prospective, multicenter phase II study.

BACKGROUND: Patients with follicular (FL) or mantle cell lymphoma (MCL) are incurable with conventional therapy. We investigated the safety and efficacy of rituximab consolidation after autologous stem cell transplantation (ASCT) in order to prevent relapse by clearance of minimal residual disease (MRD). METHODS: Rituximab was given approximately 8 weeks after CD34+ cell enriched ASCT at 375 mg/m2, weekly for 4 weeks. Monitoring of MRD was performed by repetitive PCR analyses. RESULTS: Thirty-one patients were included; one died early after ASCT before rituximab administration. Thirty patients (20 FL, 10 MCL) were evaluable after rituximab consolidation, and 27 of these were assessable for MRD detection. Rituximab consolidation post-ASCT was safe, the most common toxicity being infection. At a median follow-up of 42 months (range 13-96) after ASCT, 25 patients were censored with an actuarial event-free survival (EFS) of 81% at 4 and 5 years. Four patients (two FL, two MCL) relapsed, and one additional MCL patient died unexpectedly in complete remission. PCR-negativity was observed in 22% of the patients before ASCT, 53% post-ASCT (P=0.0547), 72% after rituximab (P=0.0018) and 100% at 6 months post-transplant (P < 0.001). CONCLUSIONS: One single course of rituximab consolidation given after ASCT is safe, may help to eliminate MRD and may translate into improved EFS in both FL and MCL patients.     

Serum beta‐2 microglobulin as a prognostic biomarker in patients with mantle cell lymphoma

Although serum beta‐2 microglobulin (B2M) has been suggested as a prognostic factor for mantle cell lymphoma (MCL), additional data are necessary to confirm its role. Between November 2005 and July 2014, a total of 52 patients with MCL were identified from the database of Asan Medical Center, Seoul, Korea. Pretreatment serum B2M information was available in 50 patients (96%). Overall survival (OS) was compared according to the serum B2M level with a cut‐off value of 2.5 mg/L. The median MCL international prognostic index (MIPI) score was 5.84 (range 4.72–7.80), and the median biologic MIPI (MIPI‐b) score was 6.27 (4.93–8.47). Pretreatment serum B2M was elevated in 30 patients (60%) and was significantly related to advanced stage (p = 0.02) and high MIPI (p = 0.03) and MIPI‐b (p = 0.03) scores. With median follow‐up duration of 29.8 months (range 0.8–87.0 months), the median OS was 56.2 months [95% confidence interval (CI) 36.6‐75.9 months] in all patients, and serum B2M was significantly associated with OS (p = 0.001). In multivariate analyses adjusted for MIPI or MIPI‐b scores and rituximab, elevated serum B2M was significantly associated with poor OS (when adjusting MIPI, hazard ratio = 26.4, 95% CI 2.9–241.3, p = 0.004; when adjusting MIPI‐b, hazard ratio = 20.1, 95% CI 2.4–170.1, p = 0.006). Thus, pretreatment serum B2M may be an independent and significant prognostic factor in patients with MCL. Copyright © 2015 John Wiley & Sons, Ltd.     

Brentuximab vedotin administered to platinum‐refractory,transplant‐naïve Hodgkin lymphoma patients can increase the proportion achieving FDG PET negative status

Normalization of fluorodeoxyglucose positron emission tomography (FDG PET) imaging prior to high‐dose therapy and autologous stem cell transplantation (ASCT) improves outcomes in relapsed and refractory (RR) Hodgkin lymphoma (HL), but many patients refractory to platinum‐based salvage regimens are unable to achieve this goal. We therefore investigated whether brentuximab vedotin (BV) could normalize FDG PET in platinum‐refractory HL prior to ASCT. Fifteen consecutive patients with RR HL and FDG PET positive disease after platinum‐based salvage therapy were treated with a median of 4 cycles of BV. Normalization of FDG PET (Deauville ≤2) occurred in 8/15 (53%) patients but was only observed in patients that had achieved partial remission or stable disease after platinum‐based salvage therapy. All patients eventually proceeded to ASCT, regardless of FDG PET status. Our data suggest that BV can normalize FDG PET in a subset of patients with platinum‐refractory HL prior to ASCT. Copyright © 2014 John Wiley & Sons, Ltd.     

Radiotherapy in mantle cell lymphoma: A literature review

Mantle cell lymphoma (MCL) is a B-cell malignancy, comprising between 3% and 10% of all adult-onset non-Hodgkin lymphomas. MCL is considered incurable with current treatment modalities and most patients require multiple lines of treatment during their lifetime. MCL is very sensitive to radiotherapy (RT), even when delivered in low doses. In limited-stage MCL, RT can enable the de-escalation of systemic therapy. RT monotherapy is a valid option for frail patients. In advanced-stage disease, RT is very potent mode of palliation, even in heavily pretreated and chemo-resistant patients. Furthermore, it can provide a respite during which systemic treatment is unnecessary. In general, RT has a favorable toxicity profile and can be repeated as necessary for local relapse or distant disease. This effective, safe, and relatively inexpensive modality of therapy has been underutilized for patients with MCL. In this review, we will outline the use of RT for limited and advanced-stage disease and its potential application in combination with novel drugs.     

Alternating R‐CHOP and R‐cytarabine is a safe and effective regimen for transplant‐ineligible patients with a newly diagnosed mantle cell lymphoma

Implementation of cytarabine into induction therapy became standard of care for younger patients with mantle cell lymphoma (MCL). On the basis of its beneficial impact, many centers incorporated cytarabine at lower doses also into first‐line treatments of elderly patients. We conducted a multicenter observational study that prospectively analyzed safety and efficacy of alternating 3 + 3 cycles of R‐CHOP and R‐cytarabine for newly diagnosed transplant‐ineligible MCL patients. A total of 73 patients were enrolled with median age 70 years. Most patients had intermediate (39.7%) and high‐risk (50.7%) disease according to MCL international prognostic index. Rituximab maintenance was initiated in 58 patients. Overall response rate reached 89% by positron emission tomography–computed tomography, including 75.3% complete remissions. Two patients (2.7%) did not complete the induction therapy because of toxicity. Three patients (4.1%) were considered nonresponders, which led to therapy change before completion of induction. Estimated progression‐free survival and overall survival were 51.3% and 68.6% at 4 years, respectively. Mantle cell lymphoma international prognostic index, bulky disease (≥ 5 cm), and achievement of positron emission tomography–negativity independently correlated with progression‐free survival. Grade 3 to 4 hematologic and nonhematologic toxicity was documented in 48% and 20.5% patients, respectively. Alternation of R‐CHOP and R‐cytarabine represents feasible and very effective regimen for elderly/comorbid MCL patients. This study was registered at GovTrial ( clinicaltrials.gov ) NCT03054883.     

B-CHOP与CHOP方案对老年复发性套细胞淋巴瘤患者的疗效比较

目的 对比硼替佐米联合CHOP（B-CHOP）方案和CHOP方案对老年复发性套细胞淋巴瘤患者的疗效。方法 收集2009年1月至2015年1月老年复发性套细胞淋巴瘤患者38例,随机分为试验组（B-CHOP方案）和对照组（CHOP方案）,每组各19例。试验组采用B-CHOP方案治疗：硼替佐米1.6 mg／m2静推,第1、8天;环磷酰胺750 mg／m2静滴,第2天;阿霉素50 mg／m2静滴,第2天;长春新碱 1.4 mg／m2（最大剂量为2 mg）静滴,第2天;强的松100 mg／天口服,第2～6天。对照组采用CHOP方案：环磷酰胺750 mg／m2静滴,第1天;阿霉素50 mg／m2静滴,第1天;长春新碱 1.4 mg／m2（最大剂量为2 mg）静滴,第1天;强的松100 mg／天口服,第1～5天。两组均以28天为1周期,共化疗8个周期。分别于第4、8个周期化疗完成后采用非霍奇金淋巴瘤国际疗效判断标准进行评价,根据随访资料分析远期生存情况。结果 试验组化疗4个周期后获完全缓解（CR）10例、部分缓解（PR）4例、无反应（NR）3例、进展（PD）2例,8个周期后获CR 12例、PR 4例、NR 1例、PD 2例;对照组化疗4个周期后获CR 3例、PR 2例、NR 10例、PD 4例,8个周期后获CR 5例、PR 3例、NR 7例、PD 4例。试验组第4、8个周期化疗完成后的有效率（RR）为73.7％和84.2％,均高于对照组的26.3％和42.1％,差异有统计学有意义（P＜0.05）。试验组的中位总生存时间为56.0个月,高于对照组的29.0个月（P＜0.05）。两组主要不良反应为发热、白细胞减少、血小板减少和周围神经炎等,且两组不良反应发生率的差异无统计学意义（P＞0.05）。结论 在改善老年复发性套细胞淋巴瘤患者的RR和OS方面,B-CHOP方案明显优于CHOP方案。     

Treatment patterns and clinical outcomes of mantle cell lymphoma: A retrospective cohort study by CHOICE

Regimens based on Bruton's tyrosine kinase inhibitors (BTKi) have been increasingly used to treat mantle cell lymphoma (MCL). A real-world multicenter study was conducted to characterize treatment patterns and outcomes in patients with newly diagnosed MCL by Chinese Hematologist and Oncologist Innovation Cooperation of the Excellent (CHOICE). The final analysis included 1261 patients. Immunochemotherapy was the most common first-line treatment, including R-CHOP in 34%, cytarabine-containing regimens in 21% and BR in 3% of the patients. Eleven percent (n = 145) of the patients received BTKi-based frontline therapy. Seventeen percent of the patients received maintenance rituximab. Autologous hematopoietic stem cell transplantation (AHCT) was conducted in 12% of the younger (<65 years) patients. In younger patients, propensity score matching analysis did not show significant difference in 2-year progression-free survival and 5-year overall survival rate in patients receiving standard high-dose immunochemotherapy followed by AHCT than induction therapy with BTKi-based regimens without subsequent AHCT (72% vs 70%, P = .476 and 91% vs 84%, P = .255). In older patients, BTKi combined with bendamustine plus rituximab (BR) was associated with the lowest POD24 rate (17%) compared with BR and other BTKi-containing regimens. In patients with resolved hepatitis B at the baseline, HBV reactivation rate was 2.3% vs 5.3% in those receiving anti-HBV prophylaxis vs not; BTKi treatment was not associated with higher risk of HBV reactivation. In conclusion, non-HD-AraC chemotherapy combined with BTKi may be a viable therapeutic strategy for younger patients. Anti-HBV prophylaxis should be implemented in patients with resolved hepatitis B.     

Salvage chemoimmunotherapy with rituximab,ifosfamide and etoposide (R‐IE regimen) in patients with primary CNS lymphoma relapsed or refractory to high‐dose methotrexate‐based chemotherapy

Despite a high proportion of patients with primary CNS lymphoma (PCNSL) experiences failure after/during first‐line treatment, a few studies focused on salvage therapy are available, often with disappointing results. Herein, we report feasibility and activity of a combination of rituximab, ifosfamide and etoposide (R‐IE regimen) in a multicentre series of patients with PCNSL relapsed or refractory to high‐dose methotrexate‐based chemotherapy. We considered consecutive HIV‐negative patients ≤75 years old with failed PCNSL treated with R‐IE regimen (rituximab 375 mg/m², day 0; ifosfamide 2 g/m²/day, days1–3; etoposide 250 mg/m², day 1; four courses). Twenty‐two patients (median age 60 years; range 39–72; male/female ratio: 1:4) received R‐IE as second‐line (n = 18) or third‐line (n = 4) treatment. Eleven patients had refractory PCNSL, and 11 had relapsing disease. Twelve patients had been previously irradiated. Sixty (68%) of the 88 planned courses were actually delivered; only one patient interrupted R‐IE because of toxicity. Grade 4 hematological toxicity was manageable; a single case of grade 4 non‐hematological toxicity (transient hepatotoxicity) was recorded. Response was complete in six patients and partial in three (overall response rate = 41%; 95%CI: 21–61%). Seven patients were successfully referred to autologous peripheral blood stem cell collection; four responders were consolidated with high‐dose chemotherapy supported by autologous stem cell transplant. At a median follow‐up of 24 months, eight responders did not experience relapse, two of them died of neurological impairment while in remission. Six patients are alive, with a 2‐year survival after relapse of 25 ± 9%. We concluded that R‐IE is a feasible and active combination for patients with relapsed/refractory PCNSL. This regimen allows stem cell collection and successful consolidation with high‐dose chemotherapy and autologous transplant. Copyright © 2012 John Wiley & Sons, Ltd.     

112 例套细胞淋巴瘤临床病理分析*

目的：探讨套细胞淋巴瘤（mantle cell lymphoma,MCL ）的临床病理特点。方法：收集112 例MCL 的临床及病理资料,采用免疫组织化学（Envision二步法）行相关抗体标记,荧光原位杂交技术（fluorescence in situ hybridization,FISH）对其中24例作IgH/CCND1 基因断裂检测。结果：112 例（包括2 例多形性和母细胞变亚型）均表达B 细胞相关抗原,94.6%（106/112）表达cyclinD1,92.9%（104/112）表达CD5。不同免疫表型的经典型MCL 的Ki-67及平均生存期无统计学差异（P>0.05）。 3 例CD5-的MCL未检测出IgH/CCND1 基因断裂,2 例经典型MCL 检测出IgH/CCND1 多倍体。结论：MCL 是一种具有特殊免疫表型的B 细胞淋巴瘤,多形性及母细胞变异型的预后较差,对特殊亚型的MCL 诊断有必要细分。     

Subclonal evolution of a classical Hodgkin lymphoma from a germinal center B‐cell‐derived mantle cell lymphoma

Composite lymphomas (CL) represent the occurrence of two distinct lymphomas in the same patient. Often, CL share a common cellular origin, thus representing a unique model to investigate the multistep genetic path leading to lymphomagenesis in general and to the specific development of each distinct lymphoma component in particular. Here, we present the molecular analysis of a case consisting of an unusual Hodgkin lymphoma (HL) and a mantle cell lymphoma (MCL), intimately admixed within one another in lymph nodes and bone marrow yet phenotypically distinct, in a patient who first presented with splenic/leukemic MCL two years earlier. MCL and Hodgkin and Reed/Sternberg (HRS) cells harbored identical immunoglobulin (Ig) V_H gene rearrangements with shared somatic mutations, proving their common clonal origin from a (post‐)germinal center (GC) B cell. This also demonstrates the (post‐)GC origin of MCL with mutated IgV genes. Both lymphomas carried the same CCND1/IGH translocation and, unexpectedly for HL, expressed cyclin D1 and OCT2. Thus, HRS cells are able to preserve IGH locus activity (otherwise usually silenced in HL) to promote expression of an oncogene translocated into this locus. Both lymphoma populations further showed an identical TP53 function‐impairing mutation, and later acquired a TP53 heterozygous deletion independently from one another (convergent evolution). The surprisingly close genetic relationship of the lymphomas, together with their histological intermingling and the clinical history of the patient, suggests subclonal evolution of HL from MCL as a plausible pathway in alternative to that so far described in CL, i.e. separate development from a common precursor.