AF

Question 1

What are antibodies? How do they work?

Answer 1

Also known as an immunoglobulins, they are large, Y-shaped protein used by the immune system to identify and neutralize foreign objects such as pathogenic bacteria and viruses. The antibody recognizes a unique molecule of the pathogen, called an antigen. Each tip of the “Y” of an antibody contains a paratope (analogous to a lock) that is specific for one particular epitope (analogous to a key) on an antigen.

On the surface of a B cells there are structures referred to as B-cell receptors (BCR). After an antigen binds to a BCR, the B cell activates to proliferate and differentiate into either plasma cells, which secrete soluble antibodies with the same paratope, or memory B cells, which survive in the body to enable long-lasting immunity to the antigen.

Question 2

How are monoclonal antibodies produced? What are some techniques?

Answer 2

The mAbs bind the same epitope and are produced from a single B-cell. To produce this Ab we induce the growth of a single b-cell and collect the Ab produced by it. The most important production method is the hybridoma technology. It is done by injecting the antigen in a mouse, collecting then the spleen and B cells. Combing the B cells with myeloma cells which produce large amounts of mAbs.
Another technology is CHO, Cinese Hamster Ovary cell. They insert human antibody gene into CHO for manufacture.

Question 3

What is the difference between large molecules such as mAb and small molecules used for therapy?

Answer 3

Large molecules : Very high specificity, administered by IV or subcutaneous route , no drug-drug interaction due to its high specificity, low toxicity risk, longer half life, long lasting effect, often lead to complete remission, hardly cross BBB or other barriers – not indicated for brain tumors, can be interrupted with lower risks, can be immunogenic.

Small molecules : Good specificity, less than mAbs, commonly administered orally, presence of drug-drug interaction that can result in toxicity, shorter half-life therefore more frequent administration - every day, often lead to partial response (especially in solid tumors), can easily cross barriers, when interrupted have higher risks due to their short half-life and frequent administrations, rarely immunogenic.

Ex : If we use ibrutinib (small molecule drug) for example we have an amazing response. We see a reduction in lymphadenopathy and progressive reduction of the leukemic phase in 20 days. If we interrupt the treatment in around 3 days the clinical situation reverses. With monoclonal Abs instead we have remission and a long-term treatment. The problem with mAbs is related to their inability to cross barriers. Brain metastasis for melanoma has excellence response to small molecules since they easily cross the BBB.

Question 4

What is immunogenicity and why is it important when talking about therapies?

Answer 4

Immunogenicity is the ability of a foreign substance, such as an antigen, to provoke an immune response. Immunogenicity can be solved by forming chimeric Abs, humanised Abs and fully human almost non immunogenic Abs.

Question 5

How does mAb nomenclature work?

Answer 5

The suffix is always MAB to indicated it is a mAb. The target and source are also important. For example Trastuzumab, the TU indicated that the target are various neoplasms and the ZU refers to the source which is humanized in this case.

Question 6

How can mAbs trigger T lymphocytes against tumor cells? Why is it important?

Answer 6

Tumor cells are able to induces changes, block T cell receptors or reduce the activity of T cells. Researchers have developed ways to use mAbs to use T cells against the tumor cells.
1st line: Bispecific T-cell Engager : mAbs with 2 different parts; one recognizes the Ab and one the T cell. By doing this it is able to engage the T-cell against the tumor site.
2nd line : Immune Checkpoint Blockade : linking to the PD1 (linked to reactivity in the tumor microenvironment) or CTLA-4 (more important for solid tumors than lymphomas) or linking the ligand, interfering with the negative message and promoting the T-cell activation.
3rd line : Chimeric Antigenic Receptors (CAR-T) : done with a viral transfection we induce the T-cells to produce a T-cell receptor that recognizes the tumor cells. There are called CAR-T cells. We collect the patient’s lymphocytes, they are sent to the Netherlands or USA where they are transfected and they come back and recognize CD19: you will infuse the CAR-T cells and ideally they will constitute the majority of T-cells in the patient, reducing the normal T-cells.

Question 7

What us pseudo progression regarding immune checkpoint blockage therapy?

Answer 7

One of the problems with this therapy is the pseudo-progression. We look at an example of a patient with melanoma and some metastases in the back. When treated with Nivolumab, an anti PD-1:
• After 12 weeks there was a progression in the disease; the lesions and metastasis appear larger
• Week 16 there is a reduction in the disease
• After 72 weeks : Complete Remission Pseudo Progression is due to inflammation: there is accumulation of inflammatory cells (T-cells, macrophages etc.), the density and volume is higher but the vast majority will be constituted by those reactive cells, not by tumoral cells.

Question 8

What is the Abscopal effect? What is an example?

Answer 8

Abscopal effect indicates remission of metastases outside the field of irradiation and has occurred very rarely before the immune-checkpoint inhibitors in combination radiation therapy were introduced. Now anti PD-1 is used frequently in Hodgkin lymphoma with radiation therapy as we think it augments the abscopal effect.

Question 9

What is an example of bispecific monoclonal antibodies? What are some general side effects?

Answer 9

Most bispecific mAbs recognize CD20 and CD3 such as Mosunetzumab and glofitamab. Blinatumomab, it recognizes CD19 and CD3. It was developed to treat lymphomas.
As it may link to normal lymphocytes, lymphocytopenia is a common side effect which is linked to infections. Chemokine release signal and immune complex acute neurotoxicity are other side effects.

Question 10

What are antibody drug conjugates? What are some examples?

Answer 10

These recognize an antigen linked usually with a toxin. Brentuximab and Polatuzumab are used as a first line treatment recently.
Brentuximab Vedotin : It is an anti CD30 mAb conjugated to an anti-tubulin agent. It links to CD30, entering the cells by
endocytosis and releasing toxins (MMAE) able to interfere and disrupt the micro tubular network and induce cell cycle arrest and apoptosis. It is used especially in Hodgkin lymphoma.
Polatuzumab : This is used in B-cell diffuse lymphoma, its main target is CD79b, which targets B-cell malignancies. It is functionally related to B-cell receptors. MMAE is the toxin in this mechanism too, leading to microtubule disruption.

Question 11

What is radioimmunotherapy?

Answer 11

It is a mAbs linked to a radioisotope; the only used mAb is Ibritumomab linked to a yttrium atom. This atom is a beta font. It is a large atom that has lower penetrance in the tumor but releases a lot of energy.

Question 12

What are some immune checkpoint blockage mAbs?

Answer 12

Nivolumab (PD-1), Pembrolizumab (PD-1) and Atezolizumab ( PD-1L).

Question 13

What are some nude monoclonal antibodies?

Answer 13

Rituximab (CD20), Obinutuzumab (CD20), Daratumumab (CD38).

Question 14

What are indolent lymphomas? What are some clinical presentations? What are some examples?

Answer 14

They are not exactly prolifera tive disorders but more of accumula ting disorders, because they establish some mechanisms that result in an an tiapoptotic phenomenons.

Patients normally present with painless, swollen lymph nodes, often in the neck, armpit, or groin. Some have swollen lymph nodes inside their body, such as in the chest or abdomen, which can go undetected until they become very large and cause symptoms like cough or abdominal pain. Some examples are follicular lymphoma, CLL, marginal zone lymphoma..

Question 15

What is the incidence of lymphomas? How can the location of the lymphoma indicate severity of the disease?

Answer 15

1/3 of cases are B cell lymphomas, 22% are follicular and other non Hodgkin lymphomas are all under 10%.

The organ with the lymphoma can some times help us to generate a suspicion, for example if the lesion is in the testis or CNS its more probable to be an aggressive lymphoma. On the other hand, a lesion in the salivary glands or stomach is more probable to be indolent. So, indolent lymphomas are more commonly diagnosed in the skin, stomach, lungs and salivary glands, while aggressive ones are more common in testis, bones and CNS.

Question 16

What is follicular lymphoma?

Answer 16

It is the most common indolent lymphoma. Usually diagnosed in adults. The most common presentation is lymph node enlargement. It is disseminated in 60% of cases and most patients are asymptomatic.

They constantly express CD20 and CD79a which are markers of B cells, while they almost constantly express Bcl-2, CD10 and Bcl-6 which are markers of germinal centers.

Cytogene tics : The main mechanism is a transloca tion between chromosome 14 and 18 in which there is a rearrangement of the bcl-2 gene which results in an amplifica tion of this gene which can be detected in 95% of cases. Other mechanisms are p53 and bcl-6 abnormali es.

Prognosis : The prognosis of follicular lymphoma is variable, where a pa tient with follicular lymphoma that doesn’t get treatment has the same survival as the general popula tion. It’s important to not make a mistake in the treatment as you could lower the survival rate of the pa tient.

Staging : Staging is important for the prognosis and treatment choice. The most common staging system in oncology is TNM. However, for lymphomas we use Ann Arbor Staging System.

Question 17

How are follicular lymphomas graded?

Answer 17

Follicular if >75% lymph nodes are follicular. Follicular and diffuse if 25-75% of lymph nodes are follicular. Minimally follicular if <25% of lymph nodes are follicular.

Grade 1: 0-5 centroblasts/HPF
Grade 2: 6-15 centroblasts/HPF
Grade 3: >15 centroblasts/HPF
Grade 3a : presence of centrocytes. Grade 3b : only centroblasts without centrocytes.

Question 18

What is the Ann Arbor Staging system?

Answer 18

Stage 1 is when the lesion is limited to a single area.
Stage 2 is when there is more than 1 site but both are
on the same side with respect to the diaphragm.
Stage 3 is when there are lesions on both sides of the
diaphragm.
Stage 4 is when there’s a mul focal and bilateral
involvement of organs. If the lesion includes either
the liver or bone marrow it is automa cally a stage 4,
they are the 2 organs that define by themselves as
stage 4.

E must be added when there’s the involvement of extra nodal sites (stomach – testis– bowel). X is used to define a bulky large lesion. A indicates no presence of systemic symptoms. B regard the presence of systemic symptoms such as night sweats, fever of unknown origin (higher than 38), and weight loss.

Question 19

How are follicular Lymphomas treated? What are some examples of treatment?

Answer 19

It is the same as the one used for most indolent lymphomas. First off it is important to distinguish between patients that need treatments and patients that need to wait and watch what happens. In patients grade I,A wait and watch is the choice, mild symptoms is treated with rituximab and high tumor burden we use combinations of chemo and immuno.
There are three different combinations used : rituximab with Cyclophosphamide-Vinecristine-Prednisone, R-CVP with hydroxydaunorubicin (R-CHOP), or rituximab with Fludarabine and mitoxantrone (R-FM). In recent years Bendamustine has been used which is hybrid drug, unfortunately the overall survival was the same. Other strategies include BTK inhibitors, PI3K inhibitors and CAR-T cell therapy. The last strategy is allogeneic transplant.

Question 20

What is the toxicity of CAR-T cell therapy?

Answer 20

Chemokine Releasing Syndrome can occur due to immunotherapy and CAR-T cell therapy. An excess of cytokines can lead to cytokine-associated toxicity. There are 4 grades of toxicity. Grade 1 is mostly a fever and is resolved with paracetamol. Grade 2 is a fever that needs Tocilizumab, which is a drug that targets specific cytokines. Grade 3 and 4 usually need high doses of steroids and often admission of the patient to the ICU.

Question 21

What is splenic marginal zone lymphoma? What are some treatment strategies?

Answer 21

It is most commonly diagnosed in old males. It is a disseminated disease with the involvement of the BM in almost all cases and of course of the spleen. Median survival is 8 years. It is highly associated to HCV infections. In cases of HCV negative SMZL, splenectomy is a valid strategy but recently it’s has been replaced and you must consider anti CD20s. In HCV positive patients anti HCV drugs are used as well such as Simeprevir. In some cases rituximab is not enough and it needs chemo as well, strategies like R-CHOP.

Question 22

What is nodal marginal zone lymphoma? What are some treatment strategies?

Answer 22

It is a primary nodal B cell neoplasms that affects multiple lymph nodes in the body. We must exclude all extra nodal organs to confirm diagnosis. The treatment is similar to follicular lymphoma : radiation or radiotherapy for localized disease, wait and watch for low tumor burden and immu plus chemo for high tumor burden. Usually for high tumor burden bendamustine + rituximab.

Question 23

What is extra nodal marginal zone lymphoma?

Answer 23

Also called MALT type lymphoma and it constitutes 8% of all non Hodgkin’s lymphomas. The most commonly affected organ is the stomach, other organs are the lungs, thyroid, breast and salivary glands. Risk factors include : bacterial infections such as H.Pylori, autoimmune disorders like sjogrens and Hashimoto’s thyroiditis, viral infections like HCV and HBV, and lifestyle factors like smoking.

Question 24

What is the pathogenesis of H.Pylori associated gastric MALT? How is it treated?

Answer 24

There are multiple proposed pathways for how H. pylori leads to dysregulation of apoptosis and, eventually, to gastric cancer. Hyperproliferation of gastric epithelial cells may occur due to the fact that dysplastic gastric proliferating cells may produce increased levels of Bcl-2, an antiapoptotic protein, and thus are more resistant to apoptosis.
For Hp dependent MALT lymphoma antibiotics that eradicate the bacteria should make the lymphoma disappear. In Hp independent MALT lymphoma is usually not responsive to conventional therapies.

Question 25

General guidelines for Extra gastric EMZL?

Answer 25

Complete resection fo tumor —> wait and watch Residual disease + HCV positive —> antivirals Residual disease + infection —> antibiotics Stage IE —> wait and watch, RT or intralesional therapy Stage >1 —> chemo in young patients and rituximab in elderly.

Question 26

What is chronic lymphocytic leukemia? Etiology? Clinical features?

Answer 26

It is the most common type of chronic leukemia. It is strongly related to age and it is the result of colonial B cell malignant proliferations. It is characterized by the accumulation of tumor lymphocytes is different organ such as BM, peripheral blood, spleen, liver and less commonly in the skin. There are two different categories. CLL when it is in the leukemic phase and small lymphocytic lymphoma when the prevalent form is a solid tumor in the lymph nodes. Etiology : Unknown cause, no viral etiology. There is an increased incidence in asbestos workers and rubber manufacturing workers. Familial incidence is at 8.8%. Genetic polymorphism, trisomy 12, structural abnormalities of chromosomes 11, 13, 14, chromosome 17 deletion and proto oncogene c-fgr is over expressed. Clinical features : 30/40% of patients are diagnosed by chance with lymphocytosis and no specific symptoms. They may present lymphadenopathy and splenomegaly, maybe bacterial infections as well. 5/10% of patients present with typical symptoms such as weight loss, fever for 2 weeks or more without infection, night sweats, anemia, bruising. Some other signs are hepatomegaly, cutaneous manifestations like macule and papules, leukemia cutis, in less than 10% of cases membrane proliferative glomerulonephritis can be detected.

Question 27

Pre treatment investigations of patients with CLL should include?

Answer 27

Complete blood count, peripheral blood smear, reticulocyte count, Coombs test: to prevent/predict the autoimmune hemolysis/ thrombocytopenia in other words it checks for antibodies that can attack your red blood cells. Renal and liver function tests, serum protein electrophoresis, immunoglobulin levels, Plasma beta-2 microglobulin levels which are associated with poorer prognosis in CLL as in MM and other indolent lymphomas. Chromosome 17 deletion must be assessed because this deletion or p53 mutations are not responsive to chemotherapy and must be treated differently.

Question 28

What are some laboratory findings in patients diagnosed with CLL?

Answer 28

Lymphocytosis threshold is 5.000 cells per microL. Most patients are diagnosed with moderate lymphocytosis, between 20.000 and 50.000 cells per microL. The number itself is not indicators of severity or treatment but rather the variation of the value in time. For example a patient with stable 150.000 cells per microL for years is in less need of treatment than a patient that varies from 30.000 to 50.000 in a few months. Cytopenias are important to evaluate. The most commonly found is anemia followers by thrombocytopenia and finally neutropenia. Autoimmune disorders may also be found : 10/25% of cases have autoimmune hemolytic anemia, autoimmune thrombocytopenia is also common. Hypogammagloulinemia is present in 80% of affected patients at the time of initial diagnosis and may develop in 2/3 of patients later. Usually all classes are decreased.

Question 29

What are the diagnostic criteria for CLL?

Answer 29

IWCLL (International Workshop on CLL) : 1 criteria is peripheral blood lymphocytes count of >10.000 microL with characteristics of mature lymphocytes, 2 criteria is a bone marrow aspirate with >30% lymphocytes, 3 criteria is peripheral blood lymphocytes identified as monoclonal B cells. To diagnose you must grave 1+2,1+3 or 2+3. NCI (National Cancer Institute) : Peripheral blood lymphocyte count >5.000 microL with >55% of atypical cells, cells should express specific B cel markers like CD19, CD20 and CD24 and should be CD5+, BM lymphocyte infiltration should be >30%.

Question 30

How is CLL staged?

Answer 30

Rai Staging System (USA) : - Stage 0 lymphocytosis only. - Stage 1 lymphocytosis and lymphadenopathy. - Stage 2 lymphocytosis and splenomegaly with or without lymphoadenopathy. - Stage 3 lymphocytosis and anemia (Hb < 11 g/ dL) with or without lymphadenopathy or hepatosplenomegaly. Stage 4 lymphocytosis and thrombocytopenia (Plt < 100.000/UL) with or without anemia, lymphoadenopathy/hepatosplenomegaly. Binet classification (Europe) : A - no anemia, no thrombocytopenia, <3 lymphadenopathy zones. B - normal blood count and >3 areas involved. C - Anemia and thrombocytopenia with any number of areas involved.

Question 31

What is the Charlson score?

Answer 31

It evaluates comorbidities according to the presence or absence of different degrees of organ dysfunction. A score of 2 ore more is usually associated with a worse prognosis.

Question 32

What is Richter syndrome regarding CLL? What are some other transformations?

Answer 32

It is an important event in which there is a transformation fro CLL to a high grade, more aggressive disease. Richter syndrome is characterized by transformation from CLL to DLBCL. It is a devastating conditions as it is not responsive to conventional treatment and prognosis is very poor. CLL could also transform into : Hodgkin’s lymphoma, multiple myeloma, prolymphocytic leukemia and acute leukemia.

Question 33

How is CLL treated?

Answer 33

In the ESMO guidelines one of the most important factors to define the 1st line treatment is the p53 mutation or deletion of 17p : in these cases, patients do not receive chemotherapy and are treated with BTK inhibitors (ibrutinib, acalabrutinibd) or Bcl- 2 antagonists (venetoclax) or PI3K inhibitors (idelalisib). For the other subgroups without p53 mutation or 17p deletion, we can distinguish fit patients from unfit patients : - Fit patients : we try to use chemoimmunotherapy while in unfit patients Bcl-2 antagonists with BTK inhibitors. The chemoimmunotherapy is typically Fludarabine+Cyclophosphamide+Rituximab. Rituximab increases results with respect to chemo alone.

Question 34

What are Ibrutinib, Idelalisib and Venetoclax?

Answer 34

Ibrutinib : It is a drug able to irreversibly link with BTK and block the activity of the kinase for 24h. The response rate of this drug alone is 68%. TKI in general have a good response rate but a lower complete remission rate. Acalabrutinib is an alternative which is less cardiotoxic. Idelalisib : It is the best PI3K inhibitor, associated with improved survival. Venetoclax : It is a Bcl-2 antagonist. Often combined with Obinutuzumab.

Question 35

What is the treatment for CLL relapse?

Answer 35

Disease relapse is not a criterion to re-start therapy unless the disease is progressive and symptomatic. Second-line treatment decisions should follow the same indications as those used for the first-line treatment. A recent study demonstrated the superiority of targeted therapy in respect to chemoimmunotherapy in relapsed CLL patients. Using Venetoclax+Rituximab instead of Bendamustine+Rituximab.

Question 36

How did Covid 19 affect CLL patients?

Answer 36

CLL patients affected by COVID-19 are those with the highest mortality in oncology and oncohematology. CLL patients Are prevalently > 65 yo, have several and severe comorbidities and have constitutional immunodeficiencies. CLL treatments include anti-CD20 mAbs, BCR targeting drugs, chemo agents associated with severe immunodepression. All this associated to other respiratory complications. When COVID occurs: - It is severe in 80-90% of patients. - Mortality is 30%.

Question 37

What are some palliative treatment? What are some supportive therapies for CLL patients?

Answer 37

Palliative treatments : Radiotherapy, specifically irradiation of the spleen, which was used for decades as primary treatment. Splenectomy. Supportive therapy : IV immunoglobulins for hypogammaglobulinemia, prednisone for autoimmune manifestations of the disease, Leukapheresis which is the removal fo leukemic cells, and long term antibiotics against bacterial infections.

Question 38

What is Waldenstrom’s Macroglobulinemia?

Answer 38

Waldenstrom macroglobulinemia is a type of non-Hodgkin lymphoma. The cancer cells make large amounts of an abnormal protein (called a macroglobulin). Another name for WM is lymphoplasmacytic lymphoma. The accumulation of the M protein is what causes most of the symptoms in WM patients. The WM cells grow mainly in the bone marrow, where they can crowd out the normal cells that make the different types of blood cells.

Question 39

What are some important markers for WM?

Answer 39

The IgM+ B cells present CD19, CD20, CD79a and PAX5; are negative fro CD5, CD10 and CD23. These markers are important to distinguish WM from CLL and other lymphomas.

Question 40

What are some predisposing factors to WM? What is the most important mutation in WM?

Answer 40

Chronic antigen stimulation, Ashkenazi ethnicity, familiarity and Common Variable Immunodeficiency Disorder. Patients with IgM MGUS (Monoclonal Gammopathy of Unknown Significance) have 2% chance of developing WM in the first 10 years and then 1% more every year. MYD88 mutation is a molecule strongly related to TLRs, close to BCR. This gene is mutated in 100% of WM cases. MYD88 is a universal adapter protein as it is used by almost all TLRs to activate the transcription factor NF-κB.

Question 41

What are the clinicopathological manifestations of WM?

Answer 41

In 27% of cases it is asymptomatic. In symptomatic patients in order of frequency we can observe anemia, hyper viscosity, B symptoms, bleeding, neurological symptoms, lymphadenopathy, hepatosplenomegaly, weight loss etc. Hyperviscosity syndrome can cause generalized neurological dysfunction, impaired platelet function, congestive heart failure and retinal changes. IgM deposition can cause secondary amyloidosis and usually manifests in the skin of the patient. Autoimmune hemolysis secondary to WM can also develop due to links between IgM and RBC. IgM can also react with specific neural antigens causing specific clinical syndromes. Cyroglobulinemia can occur where cryoglobulins, which are abnormal proteins in the blood, precipitate and clump together below 37 C. This can impede blood circulation and damage several organs including the skin, kidney, liver etc.

Question 42

How is WM treated? What are the results?

Answer 42

Treatement of WM patients is based on what symptoms and related syndromes is the patient showing. If the patient has hyperviscosity, cryoglobulinemia and related syndromes, chemotherapy will not work. In this case patients should be managed with plasmapheresis which is a therapeutic intervention that involves extracorporeal removal, return, or exchange of blood plasma or components. When plasmapheresis is not needed, chemotherapy will be used, very similar to those proposed for CLL : pure analogue based such as FCR, alkylating agent based such as R-CHOP, DRC and R-Bendamustine, Bortezomib based which is a proteasome inhibit and lastly rituximab alone. DRC response rate is good, 83% but unsatisfactory remission rate of only 7%. Bortezomib combination therapy achieved 96% response rate and 22% complete remission.

Question 43

What is Diffuse Large B Cell Lymphoma? Morphology? Immunophenotypes? Cytogenetics?

Answer 43

It is the most common lymphoma and the most common aggressive lymphoma. It’s incidence is increasing and most commonly diagnosed in elderly patients. The median age prevalse is 60/70 yo. It is slightly more common in males. It can be de novo or secondary in which immunodeficiencies play an important role. Histopathological variants can be outlined and are related to the morphological appearance of the cell : centroblastic, immunoblastic, T cell/histiocyte rich and anaplastic. The tumor cells express B cell markers such as CD20, CD19 and CD79a. Expression of markers of follicular cells like CD10, bcl2 and bcl6 is variable. CD5 and CD138 in a few rare cases. There is no specific chromosomal abnormality. More than 60 abnormalities can be found in a single cell. Commonly identified ones are t(14;18) in 20/30% of cases and bcl6 abnormalities.

Question 44

What are the different subgroups of DLBCL? What are the differences?

Answer 44

Three subgroups have been identified : actives B cell like, germinal center B cell like and primary mediastinal B cell lymphoma. Exploring the gene expression differences of the three subgroups and the 5 year survival of patients it is possible to notice that PMBL has the best 5 year survival (64%), GCB in second place but very close (59%) and last is ABC type (30%). A gene expression profile is useful to distinguish different categories which helps for treatment. Unfortunately gene expression is time consuming so some researchers tried to replace it with IHC by using three markers ; CD10, bcl6 and MUM1. This Hans algorithm is no longer used as it is not reliable for prognostic values.

Question 45

What are the different types of aggressive B cell lymphomas and how are they categorized?

Answer 45

DLBCL : classified based on cell of origin (GC, activated or unclassified) and presents 2 main categories : double expressed positive for MYC and Bcl2 and double hit lymphoma which is very aggressive, presents rearranged MYC, Bcl2 and Bcl6. High grade B cell lymphoma : no MYC involvement, Burkitts lymphoma : arises in GC, starry sky appearance, very high proliferation index, CD10+, Bcl6+ and Bcl2-. Involvement of MYC.

Question 46

How is DLBCL treated?

Answer 46

Elderly patients : R-CHOP is the first choice treatment. Doxorubicin is quite toxic and presents common side effects like cardio toxicity, tumor lysis syndrome, photo sensitivity an others. It is usually administered every 21 days as a study which administered it every 14 showed no increased overall survival only increased toxicity. Young patients : R-CHOP with or without radiation. With radiation studies show a significant overall survival improvement. Autologous stem cell translator as a first line treatment has been tested in high risk cases but it showed a poorer survival than conventional treatement. The strategy is R-CHOP and then maybe consider ASCT.

Question 47

What new approaches and drugs have been tested to increase R-CHOP efficacy against DLBCL?

Answer 47

Several trials aimed at improving R-CHOP with the addition of several drugs. They tried : R-CHOP + X a novel agent such as lenalidomide, Bortezomib, ibrutinib and bevacizumab ; R-CHOP + intensified chemo ; R-CHOP + maintenance therapy. None of these increased the overall survival of patients. The only drug that workers was Polatuzumab which is an anti CD69, it was accompanied by a cytotoxic agent. Pola-R-CHP is used in Italy.

Question 48

How are DLBCL relapsed patients treated?

Answer 48

If they are ASCT ineligible (elderly, unfit) they will undergo R-Chemo, Pola-BR, Tara-Len or clincical trials. If they are eligible for ASCT, the patients who do not respond will be divided in CAR-T eligible and CAR-T ineligible.

Question 49

What is bridging therapy?

Answer 49

It is the therapy given to the patient to control the tumor growth in between the collection of cells and the reintroduction of the cell in CAR-T therapy. The time in between is around 30/40 days.

Question 50

What are some bispecific antibodies used in DLBCL treatement?

Answer 50

Anti CD3/CD20 such as Glofitamab and Epcortitamab are used in combination with other therapies.

Question 51

What are extra nodal DLBCL? What are some examples?

Answer 51

There are other forms of DLBCL that arise in other organs and they show intrinsic differences in natural behavior, clinical presentation, staging, treatment response, and prognosis. Primary CNS lymphoma : It mostly affects elderly patients and is a very aggressive disease which must be managed with drugs that are able to cross the BBB. In europe MATRIX is used, Methotrexate-Arabinoside-Thiotepa-Rituximab. Gastric DLBCL : There are some forms that can be treated with antibiotics alone, like the tumors associated with H.Pylori.

Question 52

DLBCL and CNS recurrences?

Answer 52

The dissemination probability of the disease in the CNS is about 5% but it is associated to an 80% mortality. In patients with high IPI, involvement of adrenal glands, testis or kidney are associated to a higher risk of dissemination in the CNS. Therefore a CNS prophylaxis has to be achieved through molecules that are able to pass the BBB. An example is Methotrexate which is delivered at the end of R-CHOP course. In patients who received high dose methotrexate after complete remission had a 20% improvement in overall survival.

Question 53

What is Burkitt’s lymphoma? Morphology? Molecular features?

Answer 53

It was described for the first time more than 60 years ago in central africa and the most important detail was its associated to EBV. It affects young people, children and young adults, as a highly aggressive lymphoma, with frequent extra-nodal involvement (particularly CNS, bone marrow, and kidney). There are three main variants : African endemic, sporadic form and immunodeficiency related. Morphologically it can present as : classic burkitt’s, burkitt’s with lymphoplasmocytoid differentiation or as atypical burkitt’s. The tumor shows a constant immunophenotype : CD20+, CD10+, Bcl-6+, Bcl2-, CD5-. The Ki67 is almost 100%, which means that is a very fast-growing lymphoma. Most common molecular feature involve : t(8;14) involving IgG heavy chain in 80% of cases, t(2;8) MYC gene placed near kappa light chain on chromosome 2, t(8;22) MYC gene placed near lambda light chain on chromosome 22. The last two occur in 20% of cases. It is staged using Ann Arbor or st. Judes.

Question 54

How is Burkitt’s lymphoma treated?

Answer 54

The treatment involves short term intensified chemotherapy. CSN prophylaxis has to be carried out as well because brain involvement occurs in 70% of cases. In SR hospital the CAREMEN regimen is used. The most effective drug in the regimen is Methotrexate. Relapses occur very early during the 1 year of follow- up so that the patients that achieved complete remission for 2 years are considered cured.

Question 55

What is mantle cell lymphoma? Clinical feature? Molecular features? Subtypes?

Answer 55

Most lymphomas cause death because of side effects and complications, but this disease causes death because of the progression of the disease itself. Classification is different based on the country : indolent lymphoma USA, aggressive lymphoma Europe. The median age of presentation is 60 with a strong prevalence in males. Localized manifestation of mantle cell lymphoma is highly rare. In 90% of cases, it constitutes a disseminated disease with extra-nodal involvement of the bone marrow, blood, liver, and GI. Generalized adenopathy is present in 70% to 90% of cases. CNS involvement can occur after the 5th relapse and can be asymptomatic. The main chromosomal abnormality is t(11;14) between the BCL1 gene and the heavy chain of IgG on ch14. The fusion protein is called cyclin D1 and interrupts phosphorylation of RB1 causing uncontrolled cell cycles. The three subtypes are : nodular form, classical form (pleomorphic) and blastoid form, the most aggressive.

Question 56

How is mantle cell lymphoma treated?

Answer 56

The treatment for mantle cell lymphoma should include 4 components: • Cytarabine (delivered at high dose), the most effective drug. • Rituximab, because the mantle lymphocytes are among the cells that express the highest amount of CD20 on the surface. • Anthracycline (or bendamustine). • High-dose-chemotherapy supported by autologous stem cell transplantation (ASCT). Maintenance with rituximab was associated to a better progression free survival after ASCT or chemotherapy in the elderly. In some cases Rituximab and bendamustine are used with or without cytarabine, and in combination with other drugs such as ibrutinib.

Question 57

What are Hodgkin’s lymphoma? Epidemiology? Clinical presentation?

Answer 57

It is a rare type of lymphoma first described by hodgkins, a British surgeon. The hallmark of diagnosis of HL are Reed Sternberg cells. In the next century the mortality has been progressively reduced thanks to the use of new therapies. HL is associated to the EBV in about 1/3 of cases. There is increased risk in siblings, even more so of the same sex. There is a predisposition in Jewish people. Clinical presentation : Lymphadenopathy and splenomegaly are relatively common. Most cases are asymptomatic, 15% of cases have constitutional symptoms. Rare extra-nodal disease. Behavior is similar to a solid tumor. Blood work is not used to diagnose HL but it may be useful to asses the stage and help with a better overview. LDH and copper levels can be useful. It is mostly important to check for HIV and EBV.

Question 58

What is the WHO classification of HL?

Answer 58

The WHO classification separates two different disease entities, one of which is subdivided : • Nodular Lymphocyte Predominant Hodgkin Lymphoma (NLPHL, 5% of cases) : CD20+ disease. The behaviour is similar to indolent B lymphomas, it is related to multiple relapses and sometimes high grade of transformation and less responsive to chemo. • Classic Hodgkin Lymphoma (CHL, 95% of cases) : CD20- disease in the tumor cells. Subtypes are: 1. Nodular sclerosis classic Hodgkin lymphoma, the most common one 2. Mixed cellularity classic Hodgkin lymphoma, the most common one in HIV positive patients. 3. Lymphocyte-rich classic Hodgkin lymphoma, extremely rare, the prof has never seen any case in his carrier. 4. Lymphocyte-depleted classic Hodgkin lymphoma, associated with poor prognosis.

Question 59

What are some DDX of HL?

Answer 59

• Infective lymphadenopathies : viruses, bacteria, fungi (EBV, CMV, Toxoplasmosis, HIV) 7 years ago, it was very common to perform lymphadenectomy due to the bartonella infection (causative agent of cat scratch disease), which generates lympadenopathies especially in the axillary regions and inguinal regions. Since the differential diagnosis between bartonella infection and hodgkin lymphomas were not able to be done before. • Infective mononucleosis: The professor encountered 5/6 young patients started with the diagnosis of an infective mononucleosis and 6 months later they develop hodgkin lymphoma. Both confirmed histologically. In fact the role of the EBV very early for the development of the disease. • Autoimmune disorders. • Other tumors especially head and neck carcinomas. Head and neck carcinomas are usually found in elderlies which are smokers, drinkers affected by some form of psychopathy. In contrast Hodgkin lymphoma is usually encountered in students, people with high socioeconomic level.

Question 60

What are RS cells? Immunophenotypes?

Answer 60

They are distinctive, giant cells found with light microscopy in biopsies from individuals with Hodgkin lymphoma. They are usually derived from B lymphocytes, classically considered crippled germinal center B cells. Despite having the genetic signature of a B cell, the Reed–Sternberg cells of classical Hodgkin lymphoma fail to express most B cell specific genes, including the immunoglobulin genes. They are usually CD15 and CD30 positive and CD45, CD20 and BCR negative. An exceptional cases is in the nodular lymphocyte predominant HL, which are negative for CD15 and CD30 and positive for CD20 and CD45. Other markers expressed by RS cells include PAX5, MHC class II and CD40.

Question 61

What is the relationship between EBV and HL?

Answer 61

In particular it depends when EBV is linked to CD40 receptor and generate signalling of acti- vation of nuclear factor kappa B, NFkB (post-transcriptional molecule, induce the cell prolif- eration so anti-apoptotic agent.). Conversely, in the patients without the EBV, in this case the activation of R-S cells is mediated by Fas receptor, in truncated form, the receptor induces signalling directly of “no apoptosis.”

Question 62

How is HL staged?

Answer 62

Based on physical examination considering the peripheral lymphadenopathies, enhanced CT scan thorax-abdomen-pelvis and in some cases when PET is not clear with the results, bone marrow biopsy or suspicion related specific examinations. Bone marrow biopsy is currently performed only to confirm the PET positivity at the BM level. If the PET is negative, at the bone marrow we do not perform biopsy. Staging is based on the Ann Arbor staging system.

Question 63

What is the general approach to treatment in regards to HL? What are the different treatment groups?

Answer 63

The goal is of course to cure the lymphoma, but also to minimize the toxicity of the therapy. When patients surpass the 3 years mark, which is the period in which most relapses occur, the relapse curve stabilizes. The risk of secondary malignancies and cardiovascular events increases with time due to the toxicity of the treatments. Todays treatment try to reduce the amount of drugs used to combat this issue. The most common secondary cancer is AML due to radiation therapy and the use of alkylating agents. To better tailor the therapies used for HL patients there are three groups with different regimens : early favorable stage, early unfavorable stage and advanced stage.

Question 64

Treatment of early stage favorable HL?

Answer 64

This stage consist of patients in 1,2a or 2b without risk factors. The standard care is the short course of ABVD (Adriamycin, Bleomycin, Vinblastine and Dacarbazine) chemotherapy and 20-30 Gy of radiation therapy. With this strategy, a patient with an early favourable stage has a survival of 10 years of 95%. Bleomycin is an alkylating agent that is used only for Hodgkin lymphoma. Bleomycin is metabolised by a hydrolase, which is present in all tissues apart from the skin and the lungs. The toxicity is most commonly pruritus and pulmonary fibrosis. In HL, if you look at the lymph node, there are lots of eosinophils and patients complain pruritus. Sometimes patients need to use neuroleptics to interrupt this. The problem is if the patient receives bleomycin without the steroids. It causes patient to have some darkness in the skin which remains irreversible. Bleomycin must be used with steroids, because steroids potentiate the expression of hydrolase in all organs. If we forget steroids, the patient can develop pulmonary fibrosis or some forms of cutaneous toxicity. Decarbazine : Is an alkylating agent and the most hematogenous drug in oncology which is associated with nausea and vomiting and with some anticipatory affects.It is important to give the patient an antiemetic to reduce this side effect. The most important side effect of dacarbazine is cardiotoxicity.

Question 65

Treatment of early stage unfavorable HL?

Answer 65

In this stage patients are in stage 1, 2a or 2b with risk factors. In this case the gold standard is the HD11 trial : 4 courses of ABVD and 30 Gy radiation therapy or 4 courses of BEACOPP and 20 Gy radiation therapy. The final results of the trial suggest that the treatment used for favorable HL is not enough in unfavorable HL. BEACOPP : Bleomycin, Etoposide, Doxorubicin, Cyclophosphamide, Vinicristine, Procarbazine and Prednisone.

Question 66

Treatment of advanced stage HL?

Answer 66

Advanced stage is considered : III, IVA,B OR IIB or Bulk>10 cm. Italian trials compared 8 courses of ABVD vs BEACOPP or a hybrid between the two. ABVD showed lower progression free survival compared to BEACOPP but overall survival was similar. Patients often relapsed with BEACOPP and experienced other complications. Therefore ABVD 6 courses is the treatment choice. Randomized trials suggested that RT did not improve free survival and the overall survival. RT is also associated to secondary malignancies therefore consolidation RT is not used in patients with complete remission. It may be used in patients that have a single lesion left, PET positive. Brentuximab vedotin + Adriamycin, Viniblastine and Decarbazine : BV+ADV is used in stage four patients. BV is an anti CD30 antibody complex, it releases toxic agent in the CD30+ tumor cells. Used in anaplastic large cell lymphoma and HL.

Question 67

How are relapsing HL patients treated?

Answer 67

Autologous Stem Cell Transplant, is able to cure 30% of patients with relapsing HL. In these patients brentuximab is used as a sort of maintenance. Other drugs used are anti PD1, Nivolumab and pembrolizumab.

Question 68

What are peripheral T cell lymphomas? Different categories? Diagnosis? Immunohistochemistry?

Answer 68

They are fast growing, aggressive lymphomas with poor prognosis. Quite rare. They are dived in four categories : leukemic, extra nodal, nodal and cutaneous forms. It is diagnosed using immunophenotypic analysis in conjunction with cellular morphology and molecular genetic assays. Excisional biopsy is usually required. CD3 and CD2 are pretty common. CD4 and CD8 vary according to the type of cell. CD5 only in certain types.

Question 69

What is the leukemic phase of PTCL?

Answer 69

Leukemic : T cell large granular lymphocytic leukemia is the only one which has indolent behavior, the others such as adult T cell leukemia are much more aggressive and have a high rate of mortality. Most of them are associated to HTLV-1.

Question 70

What are PTCL of extra nodal involvement?

Answer 70

NK/T cell lymphoma of nasal or non nasal type which are mid face tumors that grow destroying the nasal cavity and infiltrating the brain. Enteropathy associated T cell lymphoma. Hepatosplenic T cell Lymphoma are very aggressive, high mortality. They are diagnosed in young people with chrons or ulcerative colitis.

Question 71

What are some nodal forms of PTCL?

Answer 71

The most common forms of T cell lymphomas. Peripheral T-cell lymphoma,if not otherwise specified (the most common one among them), angioimmunoblastic T-cell lymphoma and anaplastic large-cell lymphoma (ALCL, further subdivided into ALK+ and ALK-, anaplastic lymphoma kinase). ALK is mutated in 4% of the lung cancers. It can be treated with ALK inhibitors such as crizotinib, which produce very good results. In this type of lymphomas the positivity of ALK distinguish the only form of a curable T cell lymphoma which is the Anaplastic large-cell lymphoma ALK+, from the other (ALK-) which is associated with poor prognosis. The only form of T cell lymphoma that can be cured with conventional treatment (CHOP) is the ALK+ anaplastic large-cell lymphoma.

Question 72

How are PTCL treated? What are the guidelines for extranodal NK/T cell lymphoma nasal type? How is enteropathy associated T cell lymphoma treated?

Answer 72

There is some heterogeneity in the treatment mostly based on the different clinical forms. Usually they are treated with CHOP-21 or CHOEP-21, which adds etoposide, with the addition of ASCT. RT is also used in some cases like for the extra nodal T cell lymphomas , usually double the dose of B cell lymphomas, 50 Gy. Combination chemotherapy (L-asparaginase based) : Dexamethasone, methotrexate, ifosfamide, L-asparaginase, etoposide (SMILE) L-asparaginase, methotrexate, dexamethasone (AspaMetDex). Concurrent chemoradiotherapu (CCRT) : 50 Gy RT + 3 courses dexamethasone, etoposide, ifosfamide, carboplatin (DeVIC) 40 to 52.8 Gy RT + cisplatin followed by 3 cycles etoposide, ifosfamide, cisplatin, dexamethasone (VIPD). Newcastle regimen : Includes 1 course of CHOP followed by IVE (ifosfamide, etoposide, epirubicin, methotrexate), so at the end of the chemotherapy followed by ASCT.

Question 73

What is multiple myeloma? Etiology?

Answer 73

It’s a neoplastic proliferation of a single clone of plasma-producing monoclonal immunoglobulins. Less than 1% of cases of multiple myeloma are not able to produce and secrete immunoglobulins, while the vast majority of these tumors produce IgA, IgM, and IgG. The median age of diagnosis is close to 65 years of age and its incidence rate is close to 10% of all hematological diseases. 60% of multiple myelomas release IgG, 20% of multiple myelomas release IgA, 20% of multiple myelomas are micromolecular myelomas (tumor cells that are only able to produce free chains),1% of multiple myelomas release IgM or IgD or IgE or biclonal. In rare cases, pathologic plasma cells do not secrete Ig nor light chains. The etiopathogenesis is mostly unknown.

Question 74

Why is multiple myeloma considered a multi step disease?

Answer 74

Multiple myeloma is a multistep disease that starts in the germinal center of B cell and then follows a process: 1. Germinal Center of B cell 2. MGUS 3. Smoldering Myeloma 4. Intramedullary Myeloma Stroma 5. Extra-Medullary Myeloma Dependance 6. Myeloma Cell Line There are some conditions in which the first two steps can be skipped and the cells develop from intra medullary myeloma. he proliferating index is progressively higher from the left to the right with a higher proportion of wound destruction and angiogenesis. Moreover, you can appreciate a progressively lower stroma dependence and progressively higher drug resistance.

Question 75

Why is the progression of MM characterized by lower stroma dependence and higher drug resistance?

Answer 75

This progressive reduction in stroma dependence and increased drug resistance is mostly due to the gain of karyotypic abnormalities (ex. hyperdiploid and some chain mutations generating proliferating signaling). The activation (as a result of mutations) of genes like KRAS, Myc, and p53, may drive the dysregulated growth of these tumors. Chr14 is close to many oncogenes, there could be an amplification of anti-apoptotic signaling that results in accumulation of tumor cells.

Question 76

What is the importance of the interaction between myeloma cells and the stroma?

Answer 76

The interaction between the myeloma cells and stromal cells can cause the activation of several pathways such as : MEK, JAK/STAT, PI3K/AKT and Nf-kb all of which promote the survival of the tumoral cells. Also the interaction between adhesion molecules such as ICAM and VCAM-1 on the stromal cells interact with the myeloma cells. Finally myeloma cells can interact with osteoblasts stimulating the release of RANKL. This then binds to RANK generating positive signaling. This causes the growth of the tumor, destruction of the bone.

Question 77

Pathogenesis of MM? Clinical presentation of MM?

Answer 77

Pathogenesis : - BM infilatrate —> myelophtisis giving cytopenia and formation of masses. - Secretion of light chains can cause renal impairment in patients with myeloma, it is caused mainly by the toxic effects of monoclonal light chains on glomeruli and renal tubules. - The bone destruction causes hypercalcemia. - hypogammaglobulinemia as the secreted IgG are usually non functional. Clinical presentation : The most common clinical presentation is bone destruction/bone pain (70-80%). The lesions are mostly osteolytic and most commonly involve the skull, spine, and pelvis. Other important manifestations are osteoporosis and pathological fractures. 1/3 of patients are asymptomatic or have mild anemia, cytopenia. 1/3 of the patients have hypercalcemia, due to bone reabsorption, with classical neurological symptoms such as lethargy, gastrointestinal symptoms, osmotic diuresis renal failure, and nephropathy. There could also be alterations in the axonal activities. Hypercalcemia can cause the development of light chain proteinuria (Bence Jones), light chain deposition in tubules or interstitial space, irate neuropathy and amyloid glomerulopathy ; resulting in renal damage and infections. 80% of patients develop anemia, usually cytokine induced and results in erythropoietin dysfunction and myelophtisis. Less common is hemolytic anemia. Elevated levels of immunoglobulins can cause hyperviscosity syndrome and neurological symptoms due to amyloidosis in the nerves.

Question 78

What are the techniques used to diagnose MM?

Answer 78

Histopathological assessment of the BM, cytological assessment of the BM aspirate, presence of polyclonal light chains and serum/urine EF. Diagnosis through electrophoresis can shows peaks higher in the albumin zone or nothing if the patient has non secreting myeloma. Immunifixation can demonstrate the presence of k light chains in the serum/urine, normal range is 0.26 to 1.65. Immunophenotypes contributes to demonstrate clonality by assessing CD38, CD138 and CD56 positivity whereas CD19 and CD20 should be negative. Bone imaging is also used to demonstrate bone disease. Skeletal radiography, MRI, TC low dose and PET can be used.

Question 79

What are the criteria to diagnose MM?

Answer 79

Myeloma defining events CRAB : Calcium >11 mg/dl, renal failure : Crea >2 mg/dl, anemia : Hb <10 g/L or <2g/L, bone lesions in RX. If serum monoclonal protein (IgG or IgA) ≥ 30 g/L or urinary monoclonal protein ≥ 500 mg per 24h, clonal bone marrow plasma cells 10-60%, absence of myeloma-defining events or amyloidosis (no renal failure, no skeletal complications). Then MM takes the name of shouldering myeloma.

Question 80

How is MM staged?

Answer 80

Once the diagnosis is performed the next step is the staging, following the Durie and Salmon classification, which is characterized by three levels of staging (STAGE 1,2,3) defined by the level of hemoglobulin, calcium, presence of osteolytic lesions, level of immunoglobulin and urinary light chains. In addition, the three stages can be grouped into A and B based on their creatinine level: • (Stage 1,2,3) A = creatinine level < 2,0 mg/dl • (Stage 1,2,3) B = creatinine level > 2,0 mg/dl Ex. Stage I : Hb > 10 g/dl, no hypercalcemia, no osteolytic lesions, IgG > 50 g/l, IgA, Urinary k or l <4 g/24h. Stage III : Hb < 8.5 g/dL, Calcemia > 12 mg/dl, multiple osteolytic lesions (> 3), IgG > 70 g/l, IgA>50 g/l, urinary k or l >12 g/24 h

Question 81

What are the principles of therapy of the different stages of MM?

Answer 81

At the moment MM is considered a non-curable disease. There are a lot of strategies that can be used to treat this disease. It is important to distinguish multiple myeloma from smouldering myeloma because the smouldering MM is usually not treated. Isolated plasmocytoma of the bone : should be treated with radiation therapy alone, with a survival rate of after 10 years of 50%. -Radiation therapy -Chemotherapy (if M protein increases and evidence of symptomatic MM) -Dissemination in 50% of patients Extramedullary plasmacytoma : Usually treated with RT and then possible surgical resection. Indolent or stage I MM : Wait and watch approach, monitor the disease over months or years. Symptomatic or stage III MM : It is important to distinguish suitability characteristics for autologous transplant.

Question 82

How are MM patients treated?

Answer 82

After ASCT eligibility is performed we can distinguish fit or unfit patients. If fit : Patients are treated with a triplet of lenalidomide + Bortezomib and Dexamethasone. If the patient has renal failure Cyclophasphamide is used instead of lenalidomide. The therapy lasts 4 to 8 months and if the patients responds well he/she is followed up with melphalan a chemotherapic drug before undergoing ASCT. After ASCT we do lenalidomide maintenance. If unfit : Patient is approached with the triplet plus daratumumamab which is an anti CD38. Until maximal response.

Question 83

What is amyloidosis? Pathogenesis? Different types?

Answer 83

Amyloidosis is a complex condition in which extracellular deposition of proteins aggregate occurs forming insoluble fibrils called amyloid. It can be found in approximately every organ. The vast majority of this material is lipoproteins while glycoproteins constitute 5% of the material. At least 30 different proteins can aggregate to form non-branching fibrils, each formed of intertwined polypeptides in a β pleated sheet conformation. 1. Amyloid light chain : is made up of complete immunoglobulin light chains. 2. Amyloid associated : derived by proteolysis from a larger precursor in the blood called SAA (serum amyloid A). 3. Beta-amyloid protein.

Question 84

What is the mechanism behind amyloidosis?

Answer 84

Mutations in genes result in continuous stimulation of plasma cells to produce light chains. Another mechanism is in inflammation with high cytokines stimulating the production of serum amyloid proteins from the liver. In particular the production of transthyretin, which is a transport protein in the serum an CSF which carries T4, from the liver can be mutated and accumulate in other organs.

Question 85

How is amyloidosis classified?

Answer 85

Systemic amyloidosis : Primary and secondary amyloidosis associated to chronic inflammations like TB, RA or associated to cancers. Hereditary amyloidosis : Familial Mediterranean fever, familial amyloidotic neuropathies. Localized amyloidosis : Senile cerebral In Alzheimer’s, amyloidosis in medullary carcinoma of the thyroid.

Question 86

What are clinical manifestations of amyloidosis?

Answer 86

Common manifestations are weight loss, renal failure, CHF and peripheral neuropathy. Organs most commonly affected are the heart, liver and kidneys. The most important complication stem from the heart : HF, angina, sudden death, ECG abnormalities and pericardial disease.

Question 87

What is the treatment for amyloidosis?

Answer 87

Amyloidosis cannot be cured, but there are some secondary forms of amyloidosis that can be successfully treated. For the treatment we need a multidisciplinary approach since many organs can be affected. The treatment with a combination of multiple drugs is similar to the one of multiple myeloma: Melphalan + Bortezomib. In some cases the treatment of amyloidosis involves liver or heart transplant.