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R-CHOP or R-HyperCVAD With or Without Autologous Stem Cell Transplantation for Older Patients With Mantle Cell Lymphoma
Clinical Lymphoma Myeloma and Leukemia
Although intensive induction and autologous stem cell transplantation (ASCT) prolong survival in younger patients with mantle cell lymphoma (MCL), benefit in older patients remains uncertain because data supporting these approaches come almost exclusively from younger cohorts.
Patients and Methods
We reviewed outcomes for 38 patients with MCL aged ≥ 60 years who received R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) (n = 19) or R-HyperCVAD (rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine) (n = 19) with or without ASCT.
Median progression-free survival (PFS) of R-CHOP + ASCT (3.2 years) and R-HyperCVAD alone (4.0 years) was longer than that for R-CHOP alone (1.6 years; P = .013 and P = .009, respectively). R-CHOP + ASCT and R-HyperCVAD resulted in similar PFS (P = .66). R-HyperCVAD induction led to a higher incidence of toxicity, including therapy discontinuation and need for transfusions, compared with R-CHOP, although rates of adverse events were similar for R-HyperCVAD alone and R-CHOP + ASCT.
R-CHOP alone is less effective therapy for fit older patients with MCL. Intensifying therapy with R-HyperCVAD induction or ASCT consolidation after R-CHOP is associated with prolonged PFS and similar rates of toxicity. Consideration should be given to individual preferences regarding the differing method of administration and relative timing of toxicity with each regimen.
Keywords: Chemotherapy, Non-Hodgkin lymphoma, Survival, Toxicity, Treatment outcomes.
Mantle cell lymphoma (MCL) represents 5% to 7% of all non-Hodgkin lymphomas1 and 2 and predominantly affects older adults with a median age at diagnosis of 68 years. 3 Despite recent improvements in overall survival (OS),1 and 4 progression-free survival (PFS) remains short: only 2 to 4 years after initial therapy.2, 5, and 6 Commonly used first-line therapies in MCL include R-CHOP (rituximab plus cyclophosphamide, doxorubicin, vincristine, and prednisone) and R-HyperCVAD (rituximab plus hyperfractionated cyclophosphamide, vincristine, doxorubicin, and dexamethasone alternating with high-dose methotrexate and cytarabine). R-CHOP has a response rate of > 90% in MCL7 and 8 but a median PFS of only 16 months without consolidation. 8 R-HyperCVAD, a more intense induction regimen, prolongs PFS compared with R-CHOP 6 but can cause significant toxicity.3, 9, 10, and 11 Consolidation with high-dose chemotherapy and autologous stem cell transplantation (ASCT) is also frequently incorporated into the management of fit patients with MCL. ASCT can prolong PFS after R-CHOP5 and 6 but may not provide additional benefit after R-HyperCVAD. 6
Despite the high incidence of MCL in older adults, data supporting standard treatment approaches come almost exclusively from analyses of younger patients. In studies including older patients, subgroup analyses indicate that therapy-related toxicity might be a more prominent concern in the elderly. Studies of R-HyperCVAD including older patients have suggested both excess toxicity 11 and poorer outcomes in this group.9, 11, and 12 Reported outcomes in older adults undergoing ASCT are discrepant: 1 study of ASCT suggested poorer outcomes for the elderly, 13 although recent evidence shows similar survival regardless of age. 14 ASCT remains a cornerstone of therapy for MCL 15 and, given recent evidence supporting the use of R-CHOP and R-DHAP (rituximab plus dexamethasone, cytarabine, and cisplatin) followed by ASCT in younger patients, 16 this regimen may also become more commonly used in fit older adults.
Although current recommendations support the use of intensive treatment regimens in fit older patients, 15 agreement on the best first-line therapy does not exist.17 and 18Accordingly, we examined a cohort of exclusively older patients who underwent R-CHOP or R-HyperCVAD with and without ASCT consolidation, comparing both survival and toxicity. This study was approved by the Institutional Review Board of the University of Pennsylvania.
Patients and Methods
We identified a cohort of transplant-eligible patients ≥ 60 years who achieved at least a partial response (PR) to R-CHOP or R-HyperCVAD induction chemotherapy. All patients with MCL ≥ 60 years treated at the Abramson Cancer Center of the Hospital of the University of Pennsylvania from January 2003 to June 2012 were identified from a database maintained by our institution since 2003. The inpatient and outpatient electronic medical records for each patient (including inpatient and outpatient provider notes, medication administration records, microbiology data, and pathology, laboratory, and radiology reports) were systematically reviewed to identify patients who received R-CHOP or R-HyperCVAD as initial therapy and subsequently achieved a PR or complete response (CR). 19 Patients were excluded if they were ineligible to receive ASCT based on satisfaction of objective criteria (ejection fraction ≥ 50%, bilirubin level ≤ 2 mg/dL, creatinine level ≤ 2 mg/dL, diffusing capacity for carbon monoxide ≥ 50%) or clinical assessment by the treating physician.
For patients meeting inclusion criteria, data on baseline patient and disease characteristics, treatment, toxicity of treatment, disease response, and survival were systematically abstracted from the electronic medical record.
The induction regimen was chosen based on treating physician or patient preference, or both. R-CHOP 20 and R-HyperCVAD 11 have been described previously. In addition to standard dose reduction of cytarabine from 3 to 1 g/m2 during “B” cycles, institutional modifications of HyperCVAD included omission of mesna during “A” cycles and administration of cytarabine before checking a serum methotrexate level during “B” cycles. All patients with responding disease on interim imaging assessment were intended to receive 8 cycles of treatment. Adverse events during induction (including intensification/mobilization cycles) were defined as those resulting in hospitalization, a reduction in chemotherapy dose, or a delay in therapy of ≥ 7 days. Adverse events that did not require hospitalization or alteration in treatment were not included. For patients who deescalated from R-HyperCVAD to R-CHOP because of toxicity, adverse events were attributed to the regimen being administered when they occurred. Significant adverse events during ASCT were defined as documented infection, mucositis requiring patient-controlled analgesia (PCA) or nutritional support, clinically significant organ dysfunction (as detailed in provider notes, microbiology data, and laboratory/radiology reports), and events requiring either transfer to the intensive care unit or readmission within 100 days for management of an ASCT-associated complication. Patients who received both R-CHOP and R-HyperCVAD cycles were excluded from the survival analysis. Follow-up data were obtained through May 31, 2013.
PFS was defined as time from initiation of therapy to radiographic or biopsy proven progression or death in remission. OS was defined as time from diagnosis to death from any cause. Date of death from the medical record was confirmed using the Social Security Death Index. PFS and OS curves were estimated by the Kaplan-Meier method, with comparisons between groups made using the log-rank (Mantle-Cox) test. The Fisher exact test was used to compare categorical variables and the Mann-Whitney U test was used to compare continuous variables. For all tests, statistical significance was determined by a 2-sided test with an alpha of .05. Statistical analysis was conducted using SPSS v. 21 (SPSS Inc, Chicago IL).
Thirty-eight eligible patients were identified and included in this analysis. The median age at treatment was 65 years. Baseline patient- and disease-related characteristics were similar between induction groups ( Table 1 ). All patients had an Eastern Cooperative Oncology Group performance status of 0 or 1, and there were no cases of a blastoid variant of MCL. The median time from diagnosis to therapy initiation was 1 month.
|Characteristic||All Patients n (%)||R-CHOP n (%)||R-HyperCVAD n (%)|
|Male||27 (71)||14 (74)||13 (68)|
|Female||11 (29)||5 (26)||6 (32)|
|Median Age at Treatment, years (range)||65 (61-74)||65 (61-74)||65 (61-70)|
|1/2||1/38 (3)||1/19 (5)||0/19 (0)|
|3/4||37/38 (97)||18/19 (95)||18/19 (100)|
|Median (range)||5.9 (5.4-7.1)||5.9 (5.4-6.7)||5.9 (5.6-7.1)|
|Elevated LDH Levels||6 of 27 (22)||3 of 15 (20)||3 of 12 (25)|
|Bone Marrow Disease||26 of 33 (79)||12 of 15 (80)||14 of 18 (79)|
|Extranodal Disease||33 of 38 (87)||17 of 19 (90)||16 of 19 (84)|
|Bulky Lymphadenopathy (>5 cm)||10 of 34 (29)||4 of 18 (22)||6 of 16 (38)|
Abbreviations: LDH = lactate dehydrogenase; MIPI = Mantle cell lymphoma international prognostic index.
Nineteen patients (50%) received R-CHOP induction and 19 (50%) patients received R-HyperCVAD. Patients who underwent R-CHOP received a median of 4 cycles of R-CHOP (range, 3-8 cycles) and a median of 6 total cycles of chemotherapy including mobilization/intensification (range, 6-8 cycles). Patients treated with R-HyperCVAD received a median of 8 total A and B cycles (range, 2-8 cycles) and a median of 8 total cycles of chemotherapy including mobilization (range, 5-8 cycles). Mobilization/intensification regimens included RICE (rituximab plus ifosfamide, carboplatin, and etoposide; 6 patients), R-ESHAP (rituximab plus etoposide, methylprednisolone, cytarabine, and cisplatin; 5 patients), R-ESHAP/RICE (2 patients), R-DHAP (2 patients), and high-dose cyclophosphamide (2 patients). A complete response (CR) after induction was documented in 31 patients (82%): 13 (68%) with R-CHOP and 18 (95%) with R-HyperCVAD (P = .09). A PR was achieved in all remaining patients.
During induction, there was more toxicity associated with R-HyperCVAD than with R-CHOP. Toxicity by induction regimen (including any mobilization/intensification) is summarized in Table 2 . Most adverse events resulted in hospitalization (26 of 38 events; 68%), 7 (18%) in a dose reduction without admission and 4 (11%) in therapy delay only. Of adverse events in patients who received R-CHOP, 6 of 15 (40%) occurred during non–R-CHOP cycles of mobilization/intensification. Recipients of R-HyperCVAD required significantly more transfusion support compared with patients who received R-CHOP (100% vs. 62%; P = .008) and more frequently did not complete all cycles of therapy (33% vs. 0%; P = .011). Three of these patients underwent deescalation to R-CHOP. Five additional patients (33%) required a dose reduction during R-HyperCVAD treatment compared with only 1 (6%) during R-CHOP administration (P = .076). The difference in number of adverse events experienced by patients receiving R-HyperCVAD and R-CHOP was not statistically significant (median of 2.0 for R-HyperCVAD vs. 1.0 for R-CHOP; P = .126). The number of induction adverse events in the cohort was consistent across the 10-year study period. There was a median of 1 adverse event both in those undergoing induction in the first half of the study period and those treated with induction in the second half (P = .726).
|Toxicity||Total n (%)||R-CHOP n (%)||R-HyperCVAD n (%)||P Value|
|Infection||15 of 32 (47)||7 of 17 (41)||8 of 15 (53)||.72|
|Venous thrombosis||5 of 32 (16)||3 of 17 (18)||2 of 15 (13)||1.0|
|Acute kidney injury||2 of 32 (6)||2 of 17 (12)||0 of 15 (0)||.49|
|No. of adverse events|
|Median (range)||1.0 (0-3)||1.0 (0-2)||2 (0-3)||.13|
|No. of Admissions for Adverse Events|
|Median (range)||1.0 (0-3)||1.0 (0-2)||1.0 (0-3)||.17|
|Transfusions Required||26 of 31 (84)||8 of 13 (62)||18 of 18 (100)||.008|
|Dose Reduction||6 of 32 (19)||1 of 17 (6)||5 of 15 (33)||.08|
|Completed All Cycles||28 of 34 (82)||19 of 19 (100)||10 of 15 (67)||.01|
Twenty-one patients (55%) underwent ASCT consolidation: 14 (74%) after R-CHOP and 7 (37%) after R-HyperCVAD. The most common reason for not undergoing ASCT was physician preference (6 patients [35%]) followed by patient preference (5 patients [29%]). Stem cells were collected peripherally by apheresis, with a minimum of 2 million/kg reinfused. It was not possible to collect adequate stem cells (after R-HyperCVAD) in only 1 patient. The conditioning regimen was BEAM (BCNU [bis-chloroethylnitrosourea], etoposide, cytarabine, and melphalan) for 17 patients (81%), Cy/TBI (cyclophosphamide/total body irradiation) for 3 patients (14%), and BCV (BCNU, cyclophosphamide, and etoposide) for 1 patient (5%). All patients who underwent ASCT achieved CR after transplantation, including all 5 patients with PR after induction.
There was no ASCT-related mortality. Adverse events included infection (15 patients [71%]) and mucositis requiring patient-controlled analgesia or nutritional support (8 patients [38%]). Five patients (24%) required a stay in the intensive care unit, and 4 patients (19%) required readmission after discharge within 100 days for ASCT-related complications. There was no statistically significant difference in the median number of adverse events during ASCT after R-HyperCVAD or R-CHOP induction (2.5 vs. 1.0, respectively; P = .392).
Adverse events over the total treatment course were similar between R-CHOP + ASCT and R-HyperCVAD alone. Patients treated with R-CHOP + ASCT experienced a median of 2.0 total adverse events from induction and consolidation combined, whereas patients treated with R-HyperCVAD alone had a median of 1.0 adverse event (P = .297). The most adverse events occurred in patients treated with both R-HyperCVAD induction and ASCT (median of 4.0), significantly more than with R-CHOP + ASCT (median of 2.0; P = .007), R-HyperCVAD alone (median of 1.0; P = .008), and R-CHOP alone (median of 1.5; P = .016). The total number of adverse events during the total treatment course was consistent in the cohort across the 10-year study period. There was a median of 1.5 adverse events in the first half of the study and a median of 2.0 in those treated in the second half (P = .606).
With a median length of follow-up of 2.7 years (range, 0.5-9.0 years), there were 20 progression events (57%) during observation. Median PFS for the cohort was 3.2 years and median OS was 6 years ( Figure 1 ). PFS was significantly longer after R-CHOP + ASCT (3.2 years) or R-HyperCVAD alone (4.0 years) compared with R-CHOP alone (1.6 years) (P = .013 and P = .009, respectively) ( Figure 2A ). PFS after R-HyperCVAD + ASCT was 0.9 years, but this was not statistically different from R-CHOP + ASCT or R-HyperCVAD alone (P = .181 and P = .125, respectively). After R-CHOP + ASCT, PFS was similar to that seen with R-HyperCVAD alone (P = .656). No significant differences in OS were found ( Figure 2B ).
Six recipients of R-HyperCVAD alone (50%) received rituximab maintenance. One patient received maintenance after R-CHOP + ASCT, and no patients received maintenance after R-CHOP alone or R-HyperCVAD + ASCT. There was no difference in PFS between those who received rituximab maintenance after R-HyperCVAD and those who received R-HyperCVAD alone (P = .410).
Our analysis suggests that fit older patients with MCL may benefit from treatment with either R-CHOP + ASCT or R-HyperCVAD without consolidation therapy. Patients treated with these 2 approaches had similar PFS and number of adverse events, although toxicity tended to occur during induction in the R-HyperCVAD group and during ASCT consolidation in the R-CHOP + ASCT group. As with previous trials of R-HyperCVAD, toxicity prevented a significant number of patients in the present cohort from completing the regimen. However, the 33% receiving fewer than 8 cycles is similar to the 29% who stopped therapy early in the MD Anderson Cancer Center trial, despite that cohort’s younger age. 11
Poorer outcomes were seen with the other 2 therapy groups. As with younger patients, older adults in our cohort who received R-CHOP without ASCT showed inferior survival compared with those whose R-CHOP induction was consolidated with ASCT. On the other end of the spectrum, patients treated with R-HyperCVAD + ASCT also did poorly, with significantly more toxicity and a trend toward poorer PFS. This last finding contrasts with results from a previous study of younger patients demonstrating similar PFS in patients after R-HyperCVAD + ASCT compared with patients receiving R-CHOP + ASCT or R-HyperCVAD alone. 6 Although it is not possible to determine the reason for this result given the small size of this group, this may not be an appropriate regimen in older adults outside of a clinical trial.
The present study has some limitations. Given the retrospective design, we could not control for possible differences between ASCT conditioning regimens or administration of rituximab maintenance, which may improve PFS after R-CHOP, 21 R-HyperCVAD, 22 or ASCT. 23 Half of the patients receiving R-HyperCVAD not consolidated with ASCT in our study received maintenance therapy, although none did after R-CHOP treatment alone, and it is possible that PFS may have been improved with the administration of rituximab maintenance after R-CHOP induction. Previous studies of older patients ineligible for high-dose therapy concluded that R-CHOP alone followed by rituximab maintenance therapy prolongs PFS. 21 However, it is not clear that this is an appropriate strategy for older patients felt to be eligible to receive ASCT. Our results suggest that in patients fit enough for intensive therapy, high-dose therapy prolongs PFS over less intense regimens. This supports the continued use of such intensive chemotherapy in eligible older patients. Additionally, although all patients in this study were eligible for ASCT, and therefore met minimum criteria for fitness, treatment decisions and clinical transplantation evaluation were made at the discretion of the treating physician. Therefore, it is possible that physicians chose more aggressive therapies in patients they believed had worse disease. Finally, the sample size of 38 patients is small and may be underpowered to detect additional differences between groups; however, our sample size is similar to11 and 13 or larger than9 and 10 cohorts of older patients with MCL described in other published studies. Despite these limitations, the present analysis is of importance in describing outcomes regarding survival and toxicity from an exclusively older cohort, information that is not well represented in the current literature.
First-line treatment with either R-CHOP + ASCT or R-HyperCVAD without ASCT may be associated with similar PFS and number of adverse events in older patients with MCL, and both of these treatment strategies may lead to prolonged PFS compared with R-CHOP alone. Consideration should be given to individual preferences regarding the differing methods of administration and relative timing of toxicity associated with both treatment plans before initiating therapy. These findings should be confirmed in larger or prospective studies, or both, and formal quality of life measures could be assessed to further guide therapy decisions.
Clinical Practice Points
- It is known that younger patients with MCL benefit from intensive chemotherapy, but benefit in older patients is uncertain.
- This analysis demonstrates prolonged survival in fit older patients with MCL after treatment with either R-CHOP + ASCT or R-HyperCVAD without ASCT compared with R-CHOP alone.
- This suggests that intensive chemotherapy regimens can produce benefit in the fit older patient with MCL.
- R-CHOP + ASCT and R-HyperCVAD are both appropriate regimens, exhibiting similar overall rates of toxicity, although with differential timing.
- Based on these results, clinicians can recommend either avoidance of intensive induction or of ASCT consolidation to older patients with MCL and still anticipate prolonged PFS.
The authors have stated that they have no conflicts of interest.
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1 Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
2 Division of Hematology and Oncology, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA
∗ Address for correspondence: Sunita D. Nasta, MD, Perelman School of Medicine, Perelman Center for Advanced Medicine, 2 West Pavilion, 3400 Civic Center Blvd, Philadelphia, PA 19104 Fax: 215-615-5887
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