B lymphoma with large cells
Large-cell Diffuse B lymphoma (LDGCB) is the most common of non-Hodgkin lymphomas. It is also the one for which the cure rates are highest thanks to the polychemotherapy associated with the monoclonal anti-CD20 antibody rituximab. When I meet in consultation with a patient with diffuse large cell lymphoma, I first look carefully at the histological report to check the description of the large lymphocyte cells distributed in diffuse beaches, the Different markers in immunohistochemistry that confirms the B phenotype of the proliferation CD20 +, CD79 + and if other markers were made to classify this lymphoma in the international Classification [1] of lymphomas with a quarantine of sub-groups (table 1).
Diagnosis
The diagnosis can only be done by histological analysis of a ganglion or organ. Extraganglionnaires locations are very common, sometimes isolated. The sampling must be of sufficient size to allow the various immunohistochemical studies. The freezing of a fragment is recommended because it alone allows the carrying out of molecular biology tests. Due to the frequency of deep or mediastinal organ damage, it was developed more than ten years ago by multiple biopsy sampling techniques with large needles, which allow to bring back tissue for the majority of tests Necessary. This procedure requires good cooperation between laboratories and radiologists and avoids surgical procedures, which are painful for the patient and which delay treatment [2]. The technique has thus become one of the indispensable tools to guide the therapy; I use it even for peripheral ganglia. Many histopathological prognostic factors have been individualized, including the expression of BCL-2, C-MYC, or p53 mutations. In addition, the study of the expression of genomic profiles distinguishes two molecular types of LDGCB, of prognostic interests. Thus, lymphomas with a molecular signature resembling that of B cells of the germ centre (GCB, CD10 +) and those resembling activated B cells (ABC, CD10-, Bcl6-, MUM1 +) are isolated. All of these tests provide information on the characteristics and scalability of these lymphomas – when they are difficult to classify – but do not always have therapeutic implications. On the other hand, it is necessary to eliminate, because the treatment is different, a lymphoma of Burkitt, especially when there is a hyperexpression of the Ki67, marking at 100% the cells in cycle.
I always ask that reading or proofreading come from a centre specialized in lymphoid hemic that can complement, depending on the clinic or the evolution, the characterizations of this lymphoma by other monoclonal antibodies or Molecular biology analysis.
EXTENSION Balance
The extension balance is started without delay, because these are evolutionary diseases that can get complicated quickly. The inventory of the affected sites will serve as a target for judging the response to treatment, and only their disappearance makes it possible to hope for complete remission and healing. The clinical examination, medical history, age and general condition very quickly provide decision-making factors that will guide the choice of treatments. Imaging is the most important step; It includes a CT (CT) thorax/abdomen and a pet-TDM (positron emission tomography) that will allow comparative evaluation at the end of the treatment. Pet-TDM has become indispensable; The LDGCB fixes the 18FDG and allows to confirm or increase the number of sites affected, in particular ostéomédullaires lesions. Medullary biopsy is still recommended in all severe forms, as well as lumbar puncture, to eliminate meningeal impairment in high-risk forms of neurological relapse. The biological and haematological balance is standard, but a rapid determination of the enzyme lactate dehydrogenase (LDH) is required. A viral checkup is necessary because of the risks of reactivation of the viruses under treatment, and necessarily includes HBV and HCV hepatitis, as well as HIV, supplemented by HTLV1 according to geographical origin. Finally: Evaluate the comorbidities.
It is easy to classify patients in one of the prognostic groups (table 2):
First according to the stage of Ann SLA, which is summed up in localized forms ganglion or extraganglionnaires and disseminated forms,
Then, by the International Prognostic Index (IPI), comprising: Age > 60 years, performance status (PS) who index > 1, abnormal LDH, localized or disseminated stage and the existence of several extraganglionnaires attacks.
Depending on the presence of one or more factors, prognostic groups are defined and allow for easy and reproducible discrimination of long-term healing probabilities [3, 4]. This index remained largely valid after the arrival of the rituximab associated with chemotherapy. As a general rule, extraganglionnaires attacks, which are very common, should be treated as ganglion afflictions with the same prognostic score.
Assessment of the response
Very quickly after the onset of chemotherapy, there is a regression of peripheral tumor masses and general signs. The number of chemotherapy cycles is between six and eight. I recommend at least one intermediate balance, most of the time carried out in the fourth cycle, to evaluate the rate of regression of the tumor masses which can be complete at this stage, but must be confirmed on the final balance, after the end of the treatment. It is a question of redoing radiological tests and measuring the biological parameters initially disturbed. It is done four weeks after the last chemotherapy cycle. The pet-TDM must be carried out to confirm the complete remission with disappearance of any significant abnormal fixation [5]. In severe forms, in young subjects, this assessment is carried out after two or four cycles, to determine whether a therapeutic change is necessary or not.
Associated co-morbidity
Large-cell diffuse lymphoma can occur at any age, but especially after 60 years; A review of comorbidities is required to adjust and monitor the toxicity of chemotherapy agents. The main risk is the cumulative cardiotoxicity associated with anthracyclines, including doxorubicin, a major drug of the combination called CHOP: cyclophosphamide, doxorubicin, Oncovin, prednisone. The electrocardiogram is necessary, but also a study of the fraction of systolic ejection which must be equal to at least 50%. In borderline situations, doxorubicin analogues may be used with caution. They are excluded in case of heart failure. The older the patient, the higher the risk of having comorbidities or triggering complications is important. The established geriatric scales make it possible to adjust the criteria [6], but often only the general state PS is to be taken into account. Studies have shown that patients can be treated with standard chops in the majority of cases up to the age of 80 years, if there is no significant comorbidity. After 80 years, prospective studies have shown that reduced doses of 50% are perfectly tolerable and allow for prolonged full remissions beyond five years. Monitoring of comorbidities is associated with the monitoring of all chemotherapy.
The treatment
The treatment strategy should be stratified according to the age-adjusted IPI (AaIPI) and the feasibility of intensive treatment or not. In all cases, inclusion in a forward-looking protocol should be considered. There is a network of care and research in France, with the LYSA (Lymphoma study Association), which offers studies to improve the treatments and biological knowledge of lymphomas. In the absence, I recommend to refer to the standard arm of the protocols in progress, since they have been established on a generally international consensus and follow technological progress. The various recommendations are also useful but often lag in relation to therapeutic innovations.
In the majority of cases, the treatments are carried out in ambulatory, and in the first cycle, prophylactic measures must be instituted which will limit readmissions. It is at the beginning that there is a maximum of complications. These measures are simple, they have demonstrated, for the most part in randomized studies, especially in the elderly. This is:
The administration of GCSF growth factors to limit the duration of febrile neutropenia,
The prevention of viral reactivations herpes type with Aciclovir,
Prevention of opportunistic infections, including Pneumocystis, with Cotrimoxazole twice/week and possibly broad-spectrum antibiotic therapy in the case of documented Grade 4 neutropenia (aminoxicilline).
In cases of high tumour mass and mainly in older subjects, many teams recommend a brief prephase of a few days including prednisone (100 mg/d), with or without vincristine (1 mg). A systematic prevention of the risks of tumor lysis syndrome should be considered with allopurinol and good hydration.
In front of a young subject, without a bad prognosis factor
In such a subject, without large tumor mass, the standard recommendation is six CHOP cycles associated with the rituximab every twenty-one days; A consolidation by radiotherapy in the initial site does not bring clear benefits and exposes to long-term toxicity. In young intermediate-risk patients with 1-aaIPI, and those with a aaIPI and a tumor mass > 7.5 cm, the choice is a type R-CHOP treatment: six cycles associated with or without radiation therapy on large tumor sites. However, treatment without radiotherapy is possible when using more intensive chemotherapy: R-ACVBP (rituximab, doxorubicin, Vindesine, cyclophosphamide, bleomycin, prednisone) every fourteen days followed by consolidation Sequential. This treatment is higher than the R-CHOP without radiotherapy, but it is more hematological toxic and reserved for under 60 years [7]. In the future, it is likely that it will be possible to adjust the duration of treatments based on the metabolic response to toe-CT after two to four cycles of chemotherapy.
Subjects at high or intermediate risk < 60, AAIPI ≥ 2
Since the establishment of the CHOP in the 1970s, various improvements have been attempted by intensifying the chemotherapy [8].
The use of the chop every fourteen days is not greater than the chop every twenty-one days, based on two randomized studies. The use of the more intensive R-ACVBP treatment is greater than R-CHOP, especially for ABC forms [9], but is more toxic especially after 60 years. Consolidation after initial treatment with an autograft produces results that are difficult to interpret in the absence of demonstrated benefit on survival. Nevertheless, two studies have shown an improvement in survival without progression compared to R-CHOP with curves at four years > 75% [10].
Currently, I advise this approach in the young subject with bad prognostic factors, because the results were very reproducible [11] and appear, in all cases, higher or equal to the R-CHOP. The ambiguity arises from the heterogeneity of the prognostic factors of still incompletely decrypted lymphomas and the definition of the population that can benefit from them. A pragmatic attitude is often proposed which is to look at evolution after four cycles of chemotherapy. If the patients are in complete remission-TEP-negatives-We continue with a consolidation by chemotherapy alone. If the patients remain toe-positive, a biopsy is verified that there is residual disease. In the face of a confirmed partial response, a rescue treatment with different chemotherapy is recommended, followed by consolidation and autografting of stem cells. Given the difficulties of treating relapse, it is a conservative attitude, without loss of chances for the patient, pending the supply of new molecules in this disease.
Subjects aged over 80 years
When I see a patient over 80 years old and I have all the elements of the extension balance and its prognostic factors, I have to appreciate the geriatric component. There are many tests, some are simple and come in addition to a global appreciation. Most of the time, patients and their families require treatment when the general condition is maintained and a treatment involving rituximab and attenuated dose of chemotherapy is proposed. It is necessary to explain that these treatments are moderately toxic, allow to obtain remissions in one case in two and to prolong the survival over several years. Of course, the treatment will be adjusted to tolerance, and an assessment of toxicity and efficacy after a few cycles will guide the subsequent decision to be made in common agreement with the patient and his family. The main change that is usually made is to stop doxorubicin if cardiac functions are altered, or to replace it with other liposomal forms. Palliative treatment by monochemotherapy is possible, especially in the case of poor response to conventional treatments. Pixantrone proved to be one of the most effective molecules with a median survival of ten months.
CENTRAL Nervous system prophylaxis
Patients with an IPI score of > 2, and mainly those with extraganglionnaires and elevation of LDH, are at risk of relapse at the level of the central nervous system. The arrival of rituximab, by improving the effectiveness of treatments, has reduced its incidence, so that only sufficiently young patients at high risk are subjected to this prophylaxis. There are a few sites where this prophylaxis is necessary, such as testicular injury. Intrathecal injections of methotrexate or cytarabine are questionable and often insufficient efficacy, so it is recommended to incorporate into chemotherapy, methotrexate or cytarabine at high doses, in the midst of R-CHOP or later.
POST-Remission Monitoring
The follow-up is mainly clinical. If the complete remission is obtained, the radiological examinations are unnecessary in the absence of symptoms. The risk of relapse is major in the first two years. A CT examination is often performed 6 months or a year after the end of the treatment to reassure the patient and his doctor about the quality of the remission. There is no indication to prescribe, apart from suggestive signs, a pet-TDM. The risk of false positivity associated with a banal infection usually triggers inappropriate and anxiety examinations.
Refractory relapses and Lymphomas
The risk of relapse is based on prognostic factors; It ranges between 10 and 40%. With the results obtained by modern treatments, its incidence is estimated at 1/100 000 per year. When a clinical or radiological anomaly appears, a new biopsy is required to confirm relapse that may be of another histological type, especially in late relapse, where it is not uncommon to have lymphoma Follicles after diffuse lymphoma with large cells. Again, needle-guided biopsies avoid unnecessary surgeries and allow immuno-histo-chemistry. The distinction between GCB and ABC phenotypes is important for the choice of medications.
Once the relapse is documented, a new extension balance is required to determine the IPI prognostic factors that are of great importance on the likelihood of obtaining a response to the second-line therapy. In such circumstances, I explain to the patient that there are effective chemotherapy treatments, different from those used on the front line, that allow a complete or partial remission to be obtained and that it can be maintained if it is associated with a therapeutic intensification with autografting of hematopoietic stem cells. Nevertheless, the first step is to test the sensitivity to catch-up chemotherapy [12]. Various associations exist, but none seem to be much superior to others, so that in Europe the majority of patients are treated by a combination ptwi: dexamethasone, high dose of cytarabine and a derivative of platinum. This one was initially cisplatin, and I recommend, in the majority of cases, to use a non-toxic derivative for the kidney, such as oxaliplatin or carboplatin. Most treatments are hematotoxic and require the use of growth factors and a dose adjustment as a function of age. The use of rituximab is recommended if relapses are more than six months old. The new monoclonal antibodies, for rituximab-resistant forms, as well as new molecules, will be used quickly in the future. The R-Ptwi Association is also more effective in GCB forms than the other Classical association, R-ICE, used primarily in the United States [13].
Only half of the patients will actually go to the autograft of consolidation if they are under 65 years of age – or slightly more, if they are in good general condition. Most centres use BEAM-type conditioning (BCNU, etoposide, Aracytine ®, Melphalan) and add complementary irradiation in localized or large tumour mass relapses without any evidence that it is important. There is, for the time being, no effective post-transplant maintenance treatment – the rituximab, in particular, is unnecessary in this situation.
The evaluation of the pre-transplant response is subject to the same rules as in the initial treatment. In fact, only the patients in response to the second line treatment will be able to benefit in the long term from this consolidation. When there is no answer or the patient progresses, the autograft does not solve any situation. Postautogreffe monitoring, in young people, is important, since in the case of a new relapse, it is possible to resume therapy and propose a consolidation with a allograft with attenuated conditioning if there is a donor Compatible [14].
For refractory forms in the first line, i.e. those that are not in complete remission after the first treatment, whether this is defined by CT or pet-TDM, the attitude is to resume alternative chemotherapy, as in relapses. In case of an answer, it is possible in almost one case in two, to propose a consolidation with autograft or Allograft. The indication of allograft in diffuse large cell lymphomas is difficult, due to the generally poor control of the disease, but when conditions are met, it has allowed to consolidate long-term remissions in the subjects of Less than 60 years.
For patients who, because of their age, will not benefit from an autograft, relapse associations are substantially the same with a dose adjustment. However, a combination of R-gemcitabine and Oxaliplatin (GemOx) is increasingly used because it is very handy in ambulatory [15]. This is where the new targeted molecules will make significant progress.
Conclusion
Overall, the treatment of diffuse large-cell lymphoma B is well codified: diagnosis, extension, appropriate treatment by risk factors, evaluation of treatment, if remission: monitoring, if relapse: new treatment after Evaluation, consolidation with Autograft in the youngest population, surveillance. Currently, no new molecules are expected to be used alone to hope for a huge upheaval in the therapeutic strategy of large-cell diffuse lymphomas. So you have to play everything to win straight away.
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