Non-Hodgkin Lymphoma Treatment & Management
- Author: Sanjay Vinjamaram, MD, MPH; Chief Editor: Emmanuel C Besa, MD more...
The treatment of non-Hodgkin lymphoma (NHL) varies greatly, depending on the following factors:
Phenotype (B-cell, T-cell or natural killer [NK] cell/null-cell)
Histology (ie, low-, intermediate-, or high-grade)
Most of the chemotherapy for NHL, whether combination or single-drug, can be administered in an outpatient setting, at an infusion clinic. In the infusion clinic, specially trained oncology nurses, who are supervised by oncologists, administer the chemotherapy. Growth factor support (eg, granulocyte-colony stimulating factor [GCSF], granulocyte macrophage–colony stimulating factor [GM-CSF], erythropoietin) is also administered in an outpatient treatment setting.
Infusional chemotherapy (eg, infusional cyclophosphamide, doxorubicin, and etoposide [CDE], which should be administered continuously for 4 days) should be administered as inpatient treatment. High-dose chemotherapy and bone marrow and/or stem cell transplantation are administered in an inpatient setting of a tertiary hospital with an approved transplant center.
For the initial treatment of patients with intermediate- or high-grade lymphoma and patients with bulky disease, an inpatient setting is recommended in order to monitor for tumor lysis syndrome and to manage appropriately.
Admit patients with NHL for complications of disease progression (eg, pain control for intractable pain) or adverse effects from chemotherapy (eg, dehydration secondary to diarrhea, vomiting requiring IV hydration, severe mucositis). Patients with fever during neutropenia should be admitted for broad-spectrum antibiotic therapy.
Ensure that patients understand their diagnosis, treatment options, and prognosis and complications of therapy, which, in rare occasions, may result in a fatal event (eg, death secondary to severe infection unresponsive to antimicrobial therapy, in a patient with severe neutropenia). Start the treatment only after the patient has signed an informed consent form.
Management of Indolent NHL
Follicular lymphoma (grade I-IIIa) comprises 70% of this group. Other entities in this group include small lymphocytic lymphoma (SLL), lymphoplasmacytoid lymphoma, and marginal zone lymphomas (MZL, nodal or extranodal).
Indolent stage I and contiguous stage II NHL
Standard management consists of radiotherapy alone. Forty percent of patients with limited-stage disease remained disease-free at 10 years after radiation in a study done by Mac Manus and Hoppe. No randomized study has shown combined chemotherapy and radiation to be better than radiation alone.
A study by Rossier et al found that low-dose involved-field radiotherapy is effective in treating patients with recurrent low-grade lymphoma.
Radiation therapy (2500-4000 cGy) produces a 10-year failure-free survival (FFS) rate of 50-60%, with an overall survival (OS) rate of 60-80%. Offering adjuvant chemotherapy to selected patients with stage I-II NHL who have unfavorable prognostic factors (eg, B symptoms, >2 nodal sites), and to those with follicular mixed histology is not unreasonable. Early treatment in asymptomatic patients has not been shown to improve survival.
Indolent noncontiguous stage II, III, and IV NHL
The treatment of indolent B-cell lymphomas continues to evolve as new therapies with potent antitumor activity and limited toxicity are becoming available. Monoclonal antibodies are changing the treatment paradigm of patients with B-cell lymphomas. However, controversies persist regarding the best treatment strategy and the best time to initiate treatment.
The disease course of indolent lymphomas is characterized by a continuous decrease in the quality and the duration of response with each subsequent treatment or treatments. This effect is primarily due to the acquisition of chemotherapy resistance.
Advanced indolent lymphomas have been accepted to be not curable with currently available therapies. However, sustained complete remissions can be achieved with various treatment modalities.
The use of rituximab, a monoclonal antibody targeting the CD20 antigen, which is present in benign and malignant B-cells, in combination with systemic chemotherapy, has resulted in an improved duration of remission and survival for patients with indolent B-cell lymphomas, compared with chemotherapy alone. Prospective studies and two meta-analyses suggest that rituximab-chemotherapy, also known as chemo-immunotherapy, may be changing the natural progression of indolent lymphomas.
Asymptomatic patients, especially older patients and patients with concomitant medical problems, deferred therapy with careful observation is an option. Early intervention in asymptomatic patients does not appear to prolong survival. The median time to progression is 4-6 years, and OS is 6-10 years.
The treatment of symptomatic patients with indolent lymphomas should be focused on achieving the best possible quality of response without producing excessive toxicity. Single-agent treatment with chlorambucil or cyclophosphamide (with or without prednisone) is useful in elderly patients with significant comorbidities. However, only a few achieve remission; most achieve palliation.
Combination chemotherapies are used in younger patients with the goal of achieving a complete remission. Frequently used combination regimens are CHOP (cyclophosphamide, hydroxydaunomycin [Adriamycin], vincristine [Oncovin], and prednisone), CVP (cyclophosphamide, vincristine, and prednisone), and fludarabine alone or in combination (eg, with cyclophosphamide or mitoxantrone). Combination agents are useful in bulky and rapidly progressive disease and have higher response rates than single agents, but there is no improvement in overall survival.[23, 24, 25]
Randomized trials have shown that adding rituximab to chemotherapy regimens results in higher response rates, longer time to progression, and longer survival than chemotherapy. For example, Czuczman et al reported a 95% overall response rate and increase in time to progression with addition of rituximab to CHOP chemotherapy (RCHOP). Rituximab as a single agent is also useful in patients who are unable to tolerate chemotherapy or those patients who elect to undergo treatment in the absence of high tumor burden.
Bendamustine plus rituximab has demonstrated efficacy for the first-line treatment of advanced follicular, indolent, and mantle cell lymphomas.[27, 28] Current National Comprehensive Cancer Network guidelines give bendamustine plus rituximab, RCHOP, and RCVP (rituximab, cyclophosphamide, vincristine, prednisone) category 1 recommendations for first-line therapy of follicular lymphoma. Promising outcomes have been seen with the combination of lenalidomide plus rituximab for both rituximab-refractory and non–rituximab-refractory indolent NHL.
A study by Gaulard et al found that rituximab plus low-dose CHOP (R-miniCHOP) offered a good compromise between efficacy and safety in patients older than 80 years. The authors concluded that R-miniCHOP should be considered the new standard of treatment in these patients.
A study by Watanabe et al found that a denser dose R-CHOP strategy was not associated with improved progression-free survival in patients with untreated indolent B-cell lymphoma.
Maintenance therapy with rituximab after induction chemotherapy has been reported to prolong progression-free survival (PFS) in comparison with observation alone in patients with indolent lymphoma. However, long-term follow-up in a randomized phase 3 study found that weekly rituximab every 6 months for 2 years did not influence overall survival, although the PFS benefit was maintained. These researchers concluded that maintenance rituximab should be considered optional for patients with indolent B-cell lymphoma.
In patients with indolent NHL that is refractory to rituximab, obinutuzumab plus bendamustine followed by obinutuzumab maintenance has improved efficacy over bendamustine monotherapy, with manageable toxicity. A phase 3 trial by Sehn et al reported significantly longer PFS with obinutuzumab plus bendamustine (median not reached) than with bendamustine monotherapy (14.9 months; P=0.0001).
Management of Aggressive NHL
Diffuse large B-cell lymphoma is the most common type of NHL. Other distinct entities in this group include immunoblastic, anaplastic, lymphoblastic, large-cell, Burkitt, and Burkitt-like lymphomas (high-grade lymphomas). Mantle cell lymphomas also behave aggressively.
Aggressive stage I and contiguous stage II (nonbulky or < 10 cm) NHL
Based on 2 large randomized trials (ie, Southwest Oncology Group [SWOG], Eastern Cooperative Oncology Group [ECOG]), the preferred treatment option for patients with intermediate-grade NHL is combination chemotherapy (3 cycles of CHOP) plus involved-field radiation therapy.
According to SWOG data, patients who are treated with chemotherapy and involved-field radiation therapy have significantly better progression-free survival rates (ie, 77% versus 66%) and 5-year overall survival (OS) rates (ie, 82% versus 72%) compared with patients surviving 8 cycles of chemotherapy (ie, CHOP) alone. Patients with high-grade disease should be strongly considered for treatment with more aggressive regimens beyond CHOP.
Aggressive noncontiguous stage II, III, and IV NHL
Approximately 40-50% of these patients are cured with standard therapy, approximately 35-40% will respond but ultimately progress or relapse, and the remainder will be have disease that is refractory to primary treatment. Scoring systems such the IPI score have been developed and validated to estimate the response rate or survival rate of a given patient with aggressive lymphomas.
For many years, the treatment of aggressive lymphomas consisted of chemotherapy regimens using multiple drugs. Initial clinical studies were focused on investigating the use of more toxic regimens (higher doses or more drugs).
A prospective randomized trial in patients with diffuse large-cell lymphoma showed no difference in response rate (RR), OS, or time to treatment failure (TTF) at 3 years with any of the following regimens :
Prednisone, methotrexate, leucovorin, doxorubicin, cyclophosphamide, and etoposide—cyclophosphamide, etoposide, Adriamycin, cytarabine, bleomycin, Oncovin, methotrexate, leucovorin, and prednisone (ProMACE-CytaBOM)
Methotrexate, bleomycin, doxorubicin (Adriamycin), cyclophosphamide, Oncovin, and dexamethasone (m-BACOD)
Methotrexate-leucovorin, Adriamycin, cyclophosphamide, Oncovin, prednisone, and bleomycin (MACOP-B)
Hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone, alternating with methotrexate and cytarabine) plus rituximab has been shown to achieve a high rate of durable remission in patients with mantle cell lymphoma. It is a toxic regimen and is typically used in patients with good performance status, who can tolerate it; otherwise, R-CHOP is used. 
Bendamustine and rituximab combination has been successfully used in patients with mantle cell lymphoma in the first and second-line setting.  A study by Weidmann et al found that bendamustine in combination with rituximab may be an alternative treatment for aggressive lymphomas in elderly patients who are not eligible for R-CHOP because of its efficacy and low toxicity. 
Bortezomib has also been used in patients with relapsed or refractory mantle cell lymphoma.
ProMACE-CytaBOM, m-BACOD, and MACOP-B all proved more toxic than CHOP. However, non-CHOP regimens such as MACOP-B are used as first-line therapies in some subtypes of NHL such as primary mediastinal large B-cell NHL.
After more than 2 decades of scientific investigations, the treatment of aggressive lymphomas was changed by the clinical development of rituximab. Currently, 6-8 cycles of CHOP chemotherapy in combination with rituximab is the standard of care in patients with advanced disease.
The GELA (Groupe d'Etude des Lymphomes de l'Adulte) study was the first phase III trial to demonstrate the efficacy of combining rituximab with standard doses of CHOP chemotherapy for elderly (older than 60 y) patients with diffuse large B-cell lymphoma. At 5-year follow-up, OS was 58% with rituximab and CHOP versus 46% with CHOP alone. The results of this study were further validated by other international randomized studies favoring the use of rituximab and chemotherapy in elderly patients with aggressive B-cell lymphomas.
Studies in younger patients also showed the benefit of combining rituximab and CHOP chemotherapy. A large international study, the MabThera International Trial (MInT,) supported the role of rituximab-chemotherapy in young patients with aggressive B-cell lymphomas. The study, which has been presented only in an abstract form, was a phase III trial in which 823 patients (ages 18-60 y) with diffuse large B-cell, CD20+ NHL (DLBCL).
These patients were randomized to receive either rituximab plus a standard anthracycline-containing chemotherapy regimen (standard chemotherapy) or standard chemotherapy alone as induction therapy. The rituximab plus standard chemotherapy regimens increased 2-year overall survival (OS) from 86% to 95% compared with standard chemotherapy alone and resulted in significant improvement in time to treatment failure and projected overall survival.
Ongoing research is being focused on identifying patients at risk for treatment failure and developing tailored treatment for patients with aggressive lymphoma based on clinical scores (IPI score) or gene profiles. Patients at high risk of relapse (IPI intermediate or poor risk groups) might have an improved 5-year event-free survival/overall survival from autologous and allogeneic bone marrow or peripheral stem cell transplantation following chemotherapy.
CNS prophylaxis, usually with 4-6 injections of methotrexate intrathecally, is recommended for patients with paranasal sinus or testicular involvement, diffuse small noncleaved cell or Burkitt lymphoma, or lymphoblastic lymphoma. CNS prophylaxis for bone marrow involvement is controversial.
Treatment of acute lymphoblastic lymphoma, a very aggressive form of NHL, is usually patterned after acute lymphoblastic leukemia (ALL) therapy. Other subtypes of high-grade lymphomas are usually treated with more aggressive variations of CHOP chemotherapy, including the addition of high-dose methotrexate or other chemotherapy drugs and higher doses of cyclophosphamide.
Management of Indolent Recurrent NHL
In general, treatment with standard agents rarely produces a cure in patients who have relapsed. Sustained remissions after relapse can often be obtained in patients with indolent lymphomas, but relapse usually ensues. Favorable survival after relapse has been associated with age younger than 60 years, prior complete remission rather than partial remission, and duration of response longer than 1 year. For relapse that remains low grade, the following are possible treatment options:
Single alkylating agents (chlorambucil or bendamustine)
Novel biological agents and small molecule inhibitors showing promising results in patients with indolent lymphomas include ofatumumab, lenalidomide, and temsirolimus 
Combination chemotherapy - CVP, CHOP, and others
Purine analogues - Fludarabine, 2-CDA
Rituximab (results in a 40-50% RR in patients with relapsed/refractory indolent B-cell lymphomas) in standard or extended schedules of administration
131Iodine-rituximab radioimmunotherapy of relapsed or refractory indolent NHL achieves high overall response rates and complete response rates with minimal toxicity. Tositumomab (a murine IgG2a lambda monoclonal antibody directed against CD20 antigen) plus 131I (Bexxar) has been approved by the US Food and Drug Administration (FDA) for relapsed or refractory, low-grade, follicular, or transformed NHL.[44, 45]
Ibritumomab tiuxetan plus 90Yttrium (Zevalin) also has been approved for use in relapsed indolent lymphoma. These radioimmunotherapy agents typically are used only in patients with less than 25% bone marrow involvement with lymphoma and in patients refractory to rituximab.
Idelalisib (Zydelig), a phosphoinositide 3-kinase (PI3K) delta inhibitor, received accelerated approval from the FDA in July 2014 for relapsed follicular B-cell non-Hodgkin lymphoma and small lymphocytic lymphoma in patients who have received at least two prior systemic therapies. The accelerated approval was based on a phase II, open-label study involving 125 patients with indolent NHL that had not responded to treatment with rituximab and an alkylating agent or had relapsed within 6 months afterward.
The response rate was 57% (71 of 125 patients), with 6% meeting the criteria for a complete response. The median time to a response was 1.9 months, the median duration of response was 12.5 months, and the median progression-free survival was 11 months. Similar response rates were observed across all subtypes of indolent non-Hodgkin lymphomas.
The accelerated approval program allows approval of a drug to treat a serious or life-threatening disease based on clinical data showing the drug has an effect on a surrogate end point reasonably likely to predict clinical benefit to patients. This program provides earlier patient access to promising new drugs while confirmatory clinical trials are being conducted.
Local relapse can be treated with radiotherapy. High-dose chemotherapy plus stem cell transplantation is being investigated to determine whether it can produce significantly better survival rates compared with conventional chemotherapy.
Management of Aggressive Recurrent Adult NHL
High-dose chemotherapy plus stem-cell transplantation is the treatment of choice for patients who have recurrent aggressive lymphomas. Preliminary studies indicate that approximately 20-40% of patients have a long-term disease-free status, but the precise percentage depends on patient selection and specific treatment used.
Second-line chemotherapy regimens such as ICE (ifosfamide, carboplatin, etoposide), DHAP (dexamethasone, high-dose cytarabine, cisplatin), or EPOCH (etoposide, vincristine, doxorubicin, cyclophosphamide, prednisone) are usually used with rituximab if the tumor is CD20 positive. A retrospective study by Tixier et al concluded that regimens combining dexamethasone and high-dose cytarabine with oxaliplatin (DHAOX) or carboplatin (DHAC) have more favorable toxicity profiles than DHAP; in particular, they are far less likely to cause renal toxicity.
Gemcitabine and navelbine are also being attempted in these relapsed patients. Chemotherapy is usually followed by stem-cell transplantation.
In the PARMA trial, patients with relapsed NHL who were randomized to autologous bone marrow transplantation followed by involved-field radiation therapy did better than those randomized to conventional chemotherapy and involved-field radiation therapy.[49, 50] After a 5-year median follow-up study, the event-free survival (EFS) rate was significantly better with transplantation (46% versus 12%), and the OS rate was also better (53% versus 32%).
Allogeneic transplants have lower relapse rates but higher transplant-related mortality than autologous transplants.
In general, patients who respond to initial therapy and who respond to conventional salvage therapy prior to bone marrow transplantation have better survival outcomes. Patients who relapse late (>12 mo after diagnosis) have better OS than patients who relapse earlier. Patients who are not candidates for transplantation can be treated with chemotherapy with or without monoclonal antibodies. If possible, these patients should be enrolled into clinical trials.
Tumor vaccines are still being investigated for use in patients with lymphoma. Novel biological and small agents showing promising results in ongoing clinical trials include CMC-544, lenalidomide, bortezomib, and temsirolimus.
A study by Witzig et al concluded that lenalidomide is well tolerated and produces durable responses in patients with relapsed or refractory aggressive NHL.
Management of T-cell Lymphomas
The treatment of T-cell lymphomas continues to be challenging. T-cell lymphomas are divided into 2 subgroups: cutaneous or systemic T-cell disorders. Typically, cutaneous T-cell lymphomas (CTCL) are managed with topical agents and oral disease modifiers during the early stage of the disease. See Cutaneous T-Cell Lymphoma for more information on this topic. Systemic chemotherapy is usually incorporated late in the course of the disease with modest activity. Systemic T-cell lymphomas represent a challenge to the practicing oncologist.
The complexity of each subtype of T-cell lymphomas, the low incidence, and poor response to standard therapies are important factors that contribute to the poor clinical outcomes of this group of neoplasms. Most patients with T-cell lymphomas are better served by participating in clinical trials exploring dose-intense regimens, early bone marrow transplantation, and/or novel chemotherapeutic agents. Treatment options for T-cell lymphoma can be categorized as follows:
Combination chemotherapy regimens - CHOP, CHOP plus etoposide, gemcitabine based-regimens
Single chemotherapy agents - Pralatrexate
Monoclonal antibodies - Alemtuzumab (effective in prolymphocytic T-cell leukemia and hepatosplenic gamma-delta T-cell lymphoma)
Immunotoxin - Denileukin diftitox (discontinued January 2014)
Novel biological agents and small molecule inhibitors - Histone deacetylase inhibitors (vorinostat, panobinostat, romidepsin, belinostat), lenalidomide, and bortezomib
The US Food and Drug Administration (FDA) granted accelerated approval for pralatrexate injection (Folotyn) as a single agent for the treatment of patients with relapsed or refractory peripheral T-cell lymphoma (PTCL).
In June 2011, the FDA granted accelerated approval for romidepsin (Istodax) for treatment of PTCL in patients who have received at least one prior therapy.
In July 2014 the FDA approved the histone deacetylase inhibitor belinostat (Beleodaq) for treatment of relapsed or refractory PTCL. Approval was based on the results of a multicenter, single-arm, nonrandomized trial of 120 patients with refractory or relapsed PTCL and included patients with baseline platelet levels below 100,000/μL. The overall complete and partial response rates were 10.8% and 15.0%, respectively. The median response duration (first date of response to disease progression or death) was 8.4 months.[55, 56]
Jacobsen et al concluded that hematopoietic stem cell transplantation (HSCT) can result in long-term remissions in patients with relapsed or refractory T-cell lymphoma, especially those with nodal histologies.
The role of surgery in the treatment of patients with NHL is limited. Surgery is useful in selected situations (eg, GI lymphoma), particularly if the disease is localized or if risk of perforation, obstruction, and massive bleeding is present. Orchiectomy is part of the initial management of testicular lymphoma.
Complications of Therapy
Potential chemotherapy and other treatment-related complications include the following:
Cytopenias (ie, neutropenia, anemia, thrombocytopenia)
Nausea or vomiting
Dehydration after diarrhea or vomiting
Cardiac toxicity from doxorubicin
Tumor lysis syndrome
Tumor lysis syndrome
This syndrome commonly occurs after treatment of high-grade bulky NHLs because of their exquisite sensitivity to therapy, which is caused by their high proliferative capacity. Tumor lysis syndrome is characterized by hyperuricemia, hyperkalemia, hyperphosphatemia, hypocalcemia, and renal failure. Death from cardiac asystole can occur from hyperkalemia.
Measures to prevent this complication include aggressive hydration, allopurinol administration, and urine alkalinization. Frequent monitoring of input and output, electrolytes, uric acid, and creatinine is necessary. Dialysis is sometimes required.
In a 3-year study, Bilora et al found evidence that patients receiving radiotherapy and chemotherapy for lymphoma (either NHL or Hodgkin lymphoma) are predisposed to early development of atherosclerosis. In 96 patients, the investigators found increased intima-media thickness at 1-year follow-up; thickness had decreased at 3-year follow-up, but reduction in flow-mediated dilatation measured in the patients at 1 year had not improved by the 3-year examination.
Usually, a regular diet is adequate, except when the patient is neutropenic. Patients with neutropenia should not eat raw fruits or vegetables.
Transplant patients who have severe mucositis, decreasing albumin levels, or both may be administered total parenteral nutrition (TPN) until they can tolerate oral feedings.
The following restrictions apply to patients who are neutropenic, thrombocytopenic, or both:
Avoid exposure to or contact with other patients with communicable or infectious diseases
Use a soft toothbrush during episodes of neutropenia and thrombocytopenia
Do not shave with a razor
Ideally, patients with neutropenia should be admitted directly to a private room and should not stay long in the emergency department for evaluation. All medical personnel should wash hands before and after examining these patients
Management of NHL in Special Populations
Pediatric patients with NHL are best treated by pediatric oncologists.
NHL during pregnancy is uncommon, but it presents an ethical dilemma. Remission may be obtained with chemotherapy, but chemotherapy has potentially harmful effects to the fetus. Consider fetal exposure to transplacental chemotherapy when evaluating therapy options and carefully evaluate the timing of delivery.
For patients diagnosed with NHL during the second or third trimester of pregnancy, few literature reports suggest that they can be treated with chemotherapy without significant toxicity to the fetus. If possible, alkylating agents should be avoided. If the fetus can be delivered safely prior to administration of chemotherapy and a short wait will not affect the treatment outcome and prognosis of the patient, starting the treatment after the birth of the baby is better.
If the patient has high-grade NHL (eg, Burkitt or lymphoblastic lymphoma) diagnosed during the first trimester of pregnancy, immediate institution of therapy is necessary; otherwise, the condition could be fatal. Discuss at length with the patient and family that chemotherapy treatment at this period of pregnancy is very risky for the fetus, and whether therapeutic termination of pregnancy should be performed before the patient is treated should be decided. Consultation with the ethical committee of the hospital should be obtained in these very difficult situations.
A hematologist-oncologist should treat patients with NHL.
Consult a radiation oncologist for treatment of patients with localized or limited-stage low-grade lymphoma and for palliative radiation therapy (eg, for treatment of SVC syndrome, treatment of painful metastases [especially to bone] as an adjunctive treatment for CNS lymphomas).
Consult an infectious disease specialist for the management of patients with neutropenic fever who are not responding to the usual broad-spectrum antibiotics.
Surgical consultation is needed for lymph node biopsy, palliative procedures, or placement of a venous access device (eg, Port-a-Cath, Hickman catheter) for blood drawing and chemotherapy access.
Treatment and follow-up care of patients with NHL are usually performed on an outpatient basis. Monitoring patients’ blood cell counts while they are receiving chemotherapy (eg, prior to each treatment cycle and 10-14 d after each treatment cycle) is important.
Monitor adverse effects of chemotherapy with a detailed patient history, an examination, a CBC, and serum chemistries (especially liver function tests, electrolytes, lactate dehydrogenase, and blood urea nitrogen [BUN]/creatinine).
Treat symptomatic adverse effects such as nausea, vomiting, diarrhea, mucositis, anorexia, pain, and fatigue. Administer packed red blood cell (PRBC) transfusions for patients with symptomatic anemia and provide platelet transfusions for patients with a platelet count less than 10,000- 20,000/mm3. Provide growth factor (eg, granulocyte colony-stimulating factor [GCSF], granulocyte-macrophage colony-stimulating factor [GM-CSF], erythropoietin) support as necessary.
Perform a disease and response to treatment evaluation by obtaining patient history, physical examination (at intervals q2-3mo), and imaging studies (eg, CT scans at intervals q4-12mo).
Provide psychosocial support for the patient and family.
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