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In November 2013, ibrutinib was approved by the US FDA for treating MCL.
Other targeted agents include the proteasome inhibitor bortezomib, mTOR inhibitors such as temsirolimus, and the P110δ inhibitor GS-1101.
Immune-based therapy is dominated by the use of the rituximab monoclonal antibody, sold under the trade name Rituxan (or as Mabthera in Europe and Australia). Rituximab may have good activity against MCL as a single agent, but it is typically given in combination with chemotherapies, which prolongs response duration. There are newer variations on monoclonal antibodies combined with radioactive molecules known as Radioimmunotherapy (RIT). These include Zevalin and Bexxar. Rituximab has also been used in small numbers of patients in combination with thalidomide with some effect. In contrast to these antibody-based 'passive' immunotherapies, the field of 'active' immunotherapy tries to activate a patient's immune system to specifically eliminate their own tumor cells. Examples of active immunotherapy include cancer vaccines, adoptive cell transfer, and immunotransplant, which combines vaccination and autologous stem cell transplant. Though no active immunotherapies are currently a standard of care, numerous clinical trials are ongoing.
There is no proven or standard first-line chemotherapy that works for the majority of AITL patients. There are several clinical trials that offer treatment options that can fight the disease. Stem cell transplantation is the treatment of choice, with the allogeneic one being the preference because AITL tends to recur after autologous transplants.
Current treatment typically includes R-CHOP, which consists of the traditional CHOP, to which rituximab has been added. This regimen has increased the rate of complete response for DLBCL patients, particularly in elderly patients.R-CHOP is a combination of one monoclonal antibody (rituximab), three chemotherapy agents (cyclophosphamide, doxorubicin, vincristine), and one steroid (prednisone). These drugs are administered intravenously, and the regimen is most effective when it is administered multiple times over a period of months. People often receive this type of chemotherapy through a PICC line (peripherally inserted central catheter) in their arm near the elbow or a surgically implanted venous access port. The number of cycles of chemotherapy given depends on the stage of the disease — patients with limited disease typically receive three cycles of chemotherapy, while patients with extensive disease may need to undergo six to eight cycles. A recent approach involves obtaining a PET scan after the completion of two cycles of chemotherapy, to assist the treatment team in making further decisions about the future course of treatment.Older people often have more difficulty tolerating therapy than younger people. Lower intensity regimens have been attempted in this age group.
Radiation therapy is often part of the treatment for DLBCL. It is commonly used after the completion of chemotherapy. Radiation therapy alone is not an effective treatment for this disease.
Currently Aggressive NK-cell leukemia, being a subtype of PTCL, is treated similarly to B-cell lymphomas. However, in recent years, scientists have developed techniques to better recognize the different types of lymphomas, such as PTCL. It is now understood that PTCL behaves differently from B-cell lymphomas and therapies are being developed that specifically target these types of lymphoma. Currently, however, there are no therapies approved by the U.S. Food and Drug Administration (FDA) specifically for PTCL. Anthracycline-containing chemotherapy regimens are commonly offered as the initial therapy. Some patients may receive a stem cell transplant. Novel approaches to the treatment of PTCL in the relapsed or refractory setting are under investigation.
There is no consensus regarding the best treatment protocol. Several considerations should be taken into account including age, stage, and prognostic scores (see International Prognostic Index). Patients with advanced disease who are asymptomatic might benefit from a watch and wait approach, as early treatment does not provide survival benefit. When patients are symptomatic, specific treatment is required, which might include various combinations of alkylators, nucleoside analogues, anthracycline-containing chemotherapy regimens (e.g., CHOP), monoclonal antibodies (e.g. rituximab),
radioimmunotherapy, autologous (self) and allogeneic (donor) hematopoietic stem cell transplantation. Follicular lymphoma is regarded as incurable, unless the disease is localized, in which case it can be cured by local irradiation. Although allogeneic stem cell transplantation may be curative, the mortality from the procedure is too high to be a first line option.
In 2010 rituximab was approved by the European Commission for first-line maintenance treatment of follicular lymphoma. Pre-clinical evidence suggests that rituximab could be also used in combination with integrin inhibitors to overcome the resistance to rituximab mediated by stromal cells . However, follicular lymphoma which is CD20 negative will not benefit from Rituximab, which targets CD20.
Trial results released in June 2012 show that bendamustine, a drug first developed in East Germany in the 1960s, more than doubled disease progression-free survival when given along with rituximab. This combination therapy also left patients with fewer side effects than the older treatment (a combination of five drugs—rituximab, cyclophosphamide (Cytoxan), doxorubicin (Adriamycin), vincristine and prednisone, collectively called R-CHOP).
There are many recent and current clinical trials for follicular lymphoma. For example, personalised idiotype vaccines have shown promise, particularly as upfront therapy, but have still to prove their efficacy in randomized clinical trials.
Treatment is dependent if the lymphoma is causing issues in regards to the overall health of the individual. Since this a slow moving cancer, many patients start treatment when the symptoms appear. If the individual tests positive for hepatitis C, then anti-viral treatment is suggested since it will often get rid of the lymphoma as well. If further treatment is required the options include chemotherapy, monoclonal antibodies, and/or radiation. Radiation therapy is used for stage I and II nodal marginal zone NHL. Clinical trials show success in treatment when using drugs such as bendamustine and lenalidomida in combination with rituximab.
The original route of treatment for MALT is antibiotics to treat an underlying infection such as H.pylori. H.pylori is directly related to the development of this lymphoma. Since most patients respond well to this treatment, then no further treatment is needed. If the lymphoma is not linked to an infection, then radiotherapy and chemotherapy are needed. If the disease is more advanced, then immunoradiotherapy with chemotherapy will be needed. Among the common first-line treatments are bendamustine plus rituximab and R-CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, prednisone). Recently, antibiotic therapy such as doxycycline has been shown to be effective in marginal zone lymphoma that affects the area around the eye ("ocular adnexal marginal zone lymphoma").
If a patient is resistant to either cladribine or pentostatin, then second-line therapy is pursued.
Monoclonal antibodies The most common treatment for cladribine-resistant disease is infusing monoclonal antibodies that destroy cancerous B cells. Rituximab is by far the most commonly used. Most patients receive one IV infusion over several hours each week for four to eight weeks. A 2003 publication found two partial and ten complete responses out of 15 patients with relapsed disease, for a total of 80% responding. The median patient (including non-responders) did not require further treatment for more than three years. This eight-dose study had a higher response rate than a four-dose study at Scripps, which achieved only 25% response rate. Rituximab has successfully induced a complete response in Hairy Cell-Variant.
Rituximab's major side effect is serum sickness, commonly described as an "allergic reaction", which can be severe, especially on the first infusion. Serum sickness is primarily caused by the antibodies clumping during infusion and triggering the complement cascade. Although most patients find that side effects are adequately controlled by anti-allergy drugs, some severe, and even fatal, reactions have occurred. Consequently, the first dose is always given in a hospital setting, although subsequent infusions may be given in a physician's office. Remissions are usually shorter than with the preferred first-line drugs, but hematologic remissions of several years' duration are not uncommon.
Other B cell-destroying monoclonal antibodies such as Alemtuzumab, Ibritumomab tiuxetan and I-131 Tositumomab may be considered for refractory cases.
Interferon-alpha Interferon-alpha is an immune system hormone that is very helpful to a relatively small number of patients, and somewhat helpful to most patients. In about 65% of patients, the drug helps stabilize the disease or produce a slow, minor improvement for a partial response.
The typical dosing schedule injects at least 3 million units of Interferon-alpha (not pegylated versions) three times a week, although the original protocol began with six months of daily injections.
Some patients tolerate IFN-alpha very well after the first couple of weeks, while others find that its characteristic flu-like symptoms persist. About 10% of patients develop a level of depression. It is possible that, by maintaining a steadier level of the hormone in the body, that daily injections might cause fewer side effects in selected patients. Drinking at least two liters of water each day, while avoiding caffeine and alcohol, can reduce many of the side effects.
A drop in blood counts is usually seen during the first one to two months of treatment. Most patients find that their blood counts get worse for a few weeks immediately after starting treatment, although some patients find their blood counts begin to improve within just two weeks.
It typically takes six months to figure out whether this therapy is useful. Common criteria for treatment success include:
- normalization of hemoglobin levels (above 12.0 g/dL),
- a normal or somewhat low platelet count (above 100 K/µL), and
- a normal or somewhat low absolute neutrophil count (above 1.5 K/µL).
If it is well tolerated, patients usually take the hormone for 12 to 18 months. An attempt may be made then to end the treatment, but most patients discover that they need to continue taking the drug for it to be successful. These patients often continue taking this drug indefinitely, until either the disease becomes resistant to this hormone, or the body produces an immune system response that limits the drug's ability to function. A few patients are able to achieve a sustained clinical remission after taking this drug for six months to one year. This may be more likely when IFN-alpha has been initiated shortly after another therapy. Interferon-alpha is considered the drug of choice for pregnant women with active HCL, although it carries some risks, such as the potential for decreased blood flow to the placenta.
Interferon-alpha works by sensitizing the hairy cells to the killing effect of the immune system hormone TNF-alpha, whose production it promotes. IFN-alpha works best on classic hairy cells that are not protectively adhered to vitronectin or fibronectin, which suggests that patients who encounter less fibrous tissue in their bone marrow biopsies may be more likely to respond to Interferon-alpha therapy. It also explains why non-adhered hairy cells, such as those in the bloodstream, disappear during IFN-alpha treatment well before reductions are seen in adhered hairy cells, such as those in the bone marrow and spleen.
Breast implant-associated ALCL is a recently recognized lymphoma and definitive management and therapy is under evaluation. However, it appears that removal of the implant, and resection of the capsule around the implant as well as evaluation by medical and surgical oncologists are cornerstones. Still under evaluation is the extent of capsulectomy: partial versus complete capsulectomy; similarly it is not defined the significance of replacement of the implant in the affected breast, or the removal of contralateral implant. Similarly, the value of radiation therapy and chemotherapy are under evaluation.
Currently, there is a drug, LDK378, undergoing Phase III clinical trials at Vanderbilt University that targets ALK positive small cell lung cancer, and has showed clinical promise in its previous clinical trials. Because approximately 70% of ALCL neoplasms are also ALK positive, there is hope that similar highly selective and potent ALK inhibitors may be used in the future to treat ALK positive cases of ALCL.
Splenectomy can produce long-term remissions in patients whose spleens seem to be heavily involved, but its success rate is noticeably lower than cladribine or pentostatin. Splenectomies are also performed for patients whose persistently enlarged spleens cause significant discomfort or in patients whose persistently low platelet counts suggest Idiopathic thrombocytopenic purpura.
Bone marrow transplants are usually shunned in this highly treatable disease because of the inherent risks in the procedure. They may be considered for refractory cases in younger, otherwise healthy individuals. "Mini-transplants" are possible.
People with anemia or thrombocytopenia may also receive red blood cells and platelets through blood transfusions. Blood transfusions are always irradiated to remove white blood cells and thereby reduce the risk of graft-versus-host disease. Patients may also receive a hormone to stimulate production of red blood cells. These treatments may be medically necessary, but do not kill the hairy cells.
People with low neutrophil counts may be given filgrastim or a similar hormone to stimulate production of white blood cells. However, a 1999 study indicates that routine administration of this expensive injected drug has no practical value for HCL patients after cladribine administration. In this study, patients who received filgrastim were just as likely to experience a high fever and to be admitted to the hospital as those who did not, even though the drug artificially inflated their white blood cell counts. This study leaves open the possibility that filgrastim may still be appropriate for patients who have symptoms of infection, or at times other than shortly after cladribine treatment.
Although hairy cells are technically long-lived, instead of rapidly dividing, some late-stage patients are treated with broad-spectrum chemotherapy agents such as methotrexate that are effective at killing rapidly dividing cells. This is not typically attempted unless all other options have been exhausted and it is typically unsuccessful.
CHOP frequently induces remission initially, but most patients relapse and die within two years. Autologous bone marrow transplantation is currently being investigated in the treatment of hepatosplenic lymphoma. Allogeneic bone marrow transplant has been proven to attain remission for over five years and possibly cure hepatosplenic lymphoma.
Currently PTCL is treated similarly to B-cell lymphomas. However, in recent years, scientists have developed techniques to better recognize the different types of lymphomas, such as PTCL. It is now understood that PTCL behaves differently from B-cell lymphomas and therapies are being developed that specifically target these types of lymphoma. Currently, however, there are no therapies approved by the US Food and Drug Administration (FDA) specifically for PTCL. Anthracycline-containing chemotherapy regimens are commonly offered as the initial therapy. Some patients may receive a stem cell transplant. Novel approaches to the treatment of PTCL in the relapsed or refractory setting are under investigation.
Pralatrexate is one compound currently under investigations for the treatment of PTCL. For information please consult the US clinical trials database (http://www.clinicaltrials.gov).
When primary or secondary resistance invariably develops, salvage therapy is considered. Allogeneic stem cell transplantation can induce durable remissions for heavily pre-treated patients.
Targeted therapy attacks cancer cells at a specific target, with the aim of not harming normal cells.
- Alemtuzumab is a mAb directed against CD52 used in CLL.
- Rituximab, ofatumumab, and obinutuzumab are antibodies against CD20 used to treat CLL.
- Ibrutinib, a Bruton's tyrosine kinase (BTK) inhibitor, is used to treat CLL.
- Idelalisib is a PI3K inhibitor. and is taken orally.
- Venetoclax is a Bcl-2 inhibitor used to treat people with CLL who have 17p deletion (deletion located on the chromosome 17 short arm) and who have been treated with at least one prior therapy.
Should treatment be started it should address both the paraprotein level and the lymphocytic B-cells.
In 2002, a panel at the International Workshop on Waldenström's Macroglobulinemia agreed on criteria for the initiation of therapy. They recommended starting therapy in patients with constitutional symptoms such as recurrent fever, night sweats, fatigue due to anemia, weight loss, progressive symptomatic lymphadenopathy or spleen enlargement, and anemia due to bone marrow infiltration. Complications such as hyperviscosity syndrome, symptomatic sensorimotor peripheral neuropathy, systemic amyloidosis, kidney failure, or symptomatic cryoglobulinemia were also suggested as indications for therapy.
Treatment includes the monoclonal antibody rituximab, sometimes in combination with chemotherapeutic drugs such as chlorambucil, cyclophosphamide, or vincristine or with thalidomide. Corticosteroids, such as prednisone, may also be used in combination. Plasmapheresis can be used to treat the hyperviscosity syndrome by removing the paraprotein from the blood, although it does not address the underlying disease. Ibrutinib is another agent that has been approved for use in this condition.
Recently, autologous bone marrow transplantation has been added to the available treatment options.
Radiotherapy is a valid first option for "MALT lymphoma". It provides local control and potential cure in localized gastric stage IE and II 1E disease with 5-year EFS of 85-100% reported in retrospective studies. However, the irradiation field is potentially large as it must include the whole stomach, which can vary greatly in size and shape. Irradiation techniques have improved considerably in the last 20 years, including treating the patient in a fasting state, decreasing the irradiated field and required dose. The moderate dose of 30 Gray (Gy) of involved-field radiotherapy administered in 15 fractions (doses) can be associated with tolerable toxicity and excellent outcomes. Hence, radiotherapy is the preferred approach for local disease where antibiotic therapy has failed, or is not indicated. Evidence also suggests that radiotherapy can be utilized to control localized relapses outside the original radiation field.
Combination chemotherapy regimens are effective in both newly diagnosed and relapsed CLL. Combinations of fludarabine with alkylating agents (cyclophosphamide) produce higher response rates and a longer progression-free survival than single agents:
- FC (fludarabine with cyclophosphamide)
- FR (fludarabine with rituximab)
- FCR (fludarabine, cyclophosphamide, and rituximab)
- CHOP (cyclophosphamide, doxorubicin, vincristine, and prednisolone)
Although the purine analogue fludarabine was shown to give superior response rates to chlorambucil as primary therapy, no evidence shows early use of fludarabine improves overall survival, and some clinicians prefer to reserve fludarabine for relapsed disease.
Chemoimmunotherapy with FCR has shown to improve response rates, progression-free survival, and overall survival in a large randomized trial in CLL patients selected for good physical fitness. This has been the first clinical trial demonstrating that the choice of a first-line therapy can improve the overall survival of patients with CLL.
Alkylating agents approved for CLL include bendamustine and cyclophosphamide.
In general, the first line of treatment for Burkitt’s lymphoma is intensive chemotherapy. A few of these regimens are: the GMALL-B-ALL/NHL2002 protocol, the modified Magrath regimen (R-CODOX-M/IVAC). COPADM, hyper-CVAD, and the Cancer and Leukemia Group B (CALGB) 8811 regimen; these can be associated with rituximab. In older patients treatment may be dose-adjusted EPOCH with rituximab.
The effects of the chemotherapy, as with all cancers, depend on the time of diagnosis. With faster-growing cancers, such as Burkitt's, the cancer actually responds faster than with slower-growing cancers. This rapid response to chemotherapy can be hazardous to the patient, as a phenomenon called "tumor lysis syndrome" could occur. Close monitoring of the patient and adequate hydration is essential during the process. Since Burkitts lymphoma has high propensity to spread to the central nervous system (lymphomatous meningitis), intrathecal chemotherapy with methotrexate and/or ARA-C and/or prednisolone is given alongside with systemic chemotherapy.
Chemotherapy
- cyclophosphamide
- doxorubicin
- vincristine
- methotrexate
- cytarabine
- ifosfamide
- etoposide
- rituximab
Other treatments for Burkitt's lymphoma include immunotherapy, bone marrow transplants, stem cell transplant, surgery to remove the tumor, and radiotherapy.
There is no standard therapy for multicentric Castleman disease. Treatment modalities change based on HHV-8 status, so it is essential to determine HHV-8 status before beginning treatment. For HHV-8-associated MCD the following treatments have been used: rituximab, antiviral medications such as ganciclovir, and chemotherapy.
Treatment with the antiherpesvirus medication ganciclovir or the anti-CD20 B cell monoclonal antibody, rituximab, may markedly improve outcomes. These medications target and kill B cells via the B cell specific CD20 marker. Since B cells are required for the production of antibodies, the body's immune response is weakened whilst on treatment and the risk of further viral or bacterial infection is increased. Due to the uncommon nature of the condition there are not many large scale research studies from which standardized approaches to therapy may be drawn, and the extant case studies of individuals or small cohorts should be read with caution. As with many diseases, the patient's age, physical state and previous medical history with respect to infections may impact the disease progression and outcome.
"MALT lymphoma" is exquisitely immunotherapy sensitive. Chemotherapy is reserved for those uncommon patients with disseminated disease at presentation or lack of response to local treatment. Rituximab, the anti-CD20 chimeric antibody, is a key component of therapy. Responses vary from 55% to 77% with monotherapy and 100% in combination with chemotherapy. Oral alkylating agents such as cyclophosphamide or chlorambucil have been administered for a median duration of 12 months with high rates of disease control (CR up to 75%) but appear not to be active in t(11;18) disease. The purine nucleoside analogs fludarabine and cladribine also demonstrate activity, the latter conferring a CR rate of 84% (100% in those with gastric primaries) in a small study. A pivotal study of rituximab plus chlorambucil compared with chlorambucil alone (IELSG-19 study, n = 227) demonstrated a significantly higher CR rate (78% vs. 65%; p = 0.017) and 5-year EFS (68% vs. 50%; p = 0.024) over chlorambucil alone. However, 5-year OS was not improved (88% in both arms). First-line treatment of choice is generally rituximab in combination with single alkylating agents or fludarabine, or a combination of all three drugs. The final results of this study, including the later addition of a rituximab-alone arm, are pending.
Two other genetic alterations are known:
- t(1;14)(p22;q32), which deregulates BCL10, at the locus 1p22.
- t(14;18)(q32;q21), which deregulates MALT1, at the locus 18q21.
These seem to turn on the same pathway as API2-MLT (i.e., that of NF-κB). They both act upon IGH, which is at the locus 14q32.
For HHV-8-negative MCD (idiopathic MCD), the following treatments have been used: corticosteroids, rituximab, monoclonal antibodies against IL-6 such as tocilizumab and siltuximab, and the immunomodulator thalidomide.
Prior to 1996 MCD carried a poor prognosis of about 2 years, due to autoimmune hemolytic anemia and non-Hodgkin's lymphoma which may arise as a result of proliferation of infected cells. The timing of diagnosis, with particular attention to the difficulty of determining the cause of B symptoms without a CT scan and lymph node biopsy, may have a significant impact on the prognosis and risk of death. Left untreated, MCD usually gets worse and becomes increasingly difficult and unresponsive to current treatment regimens.
Siltuximab prevents it from binding to the IL-6 receptor, was approved by the U.S. Food and Drug Administration for the treatment of multicentric Castleman disease on April 23, 2014. Preliminary data suggest that treatment siltuximab may achieve tumour and symptomatic response in 34% of patients with MCD.
Other treatments for multicentric Castleman disease include the following:
- Corticosteroids
- Chemotherapy
- Thalidomide
Combined modality therapy is the most common approach for the initial treatment of thyroid lymphomas. The CHOP regimen (cyclophosphamide, doxorubicin, vincristine and prednisone) has been shown high effectiveness for many types of thyroid lymphoma. However, it is suggested to perform radiation therapy only for MALT resulting a 96% complete response, with only a 30% relapse rate. Surgical treatment might be performed for patients with thyroid lymphoma in addition to chemotherapy and radiation, particularly for MALT lymphomas.
Pralatrexate is one compound currently under investigations for the treatment of PTCL.