CLL

Question 1

Chronic lymphocytic leukemia (CLL) is the most common/ rare leukemia in the western world with an estimated 15,340 new cases expected in 2007, but only 4,500 deaths.

This is a disease with a ________ median survival, so there are currently about 80,000 people living with CLL in the United States ( = prevalence).

As with almost all lymphoid malignancies, this is a disease of _________ individuals with a median age at diagnosis in the mid 60’s. ALL and Hodgkin’s disease are notable exceptions to the older age of patients with the majority of patients with these diseases in childhood (ALL) or early adulthood (HD).

Answer 1

Chronic lymphocytic leukemia (CLL) is the most common leukemia in the western world with an estimated 15,340 new cases expected in 2007, but only 4,500 deaths.

This is a disease with a long median survival, so there are currently about 80,000 people living with CLL in the United States ( = prevalence). As with almost all lymphoid malignancies, this is a disease of older individuals with a median age at diagnosis in the mid 60’s. ALL and Hodgkin’s disease are notable exceptions to the older age of patients with the majority of patients with these diseases in childhood (ALL) or early adulthood (HD).

Question 2

The presenting symptoms of lymphoma are determined in part by the __________. In general, ______ disease tends not to cause symptoms until the disease is fairly advanced. Often, the diagnosis is made incidentally, during routine health screening. More often, patients present with painless swollen lymph node(s) which may have appeared stable for some months or have been observed to grow slowly. Fatigue can be present at diagnosis, but can be difficult to appreciate unless pronounced.

In contrast, ________ lymphomas tend to present with systemic symptoms which may occasionally precede diagnosis by months. Swollen lymph nodes may also prompt evaluation – often they appear suddenly and/or can grow over the course of days to weeks. Pain due to a lymph node stretching its capsule, pressing on a nerve, or infiltrating or obstructing an organ (blocking the ureters, for example) may be present at diagnosis.

Answer 2

The presenting symptoms of lymphoma are determined in part by the aggressiveness of the tumor. In general, indolent disease tends not to cause symptoms until the disease is fairly advanced. Often, the diagnosis is made incidentally, during routine health screening. More often, patients present with painless swollen lymph node(s) which may have appeared stable for some months or have been observed to grow slowly. Fatigue can be present at diagnosis, but can be difficult to appreciate unless pronounced.

In contrast, aggressive lymphomas tend to present with systemic symptoms which may occasionally precede diagnosis by months. Swollen lymph nodes may also prompt evaluation – often they appear suddenly and/or can grow over the course of days to weeks. Pain due to a lymph node stretching its capsule, pressing on a nerve, or infiltrating or obstructing an organ (blocking the ureters, for example) may be present at diagnosis.

Question 3

CLL is characterized by an over abundance of ________-cells, seen as the dark blue cells.

These cells have a more _________than normal cells and one can often find cells which have been ruptured as the slide was prepared, called “smudge cells”.

Answer 3

CLL is characterized by an over abundance of mature B-cells, seen as the dark blue cells.

These cells have a more fragile membrane than normal cells and one can often find cells which have been ruptured as the slide was prepared, called “smudge cells”.

In some cases the cells can be so fragile that they become difficult to count as they rupture as they flow through the cell counting machine.

Question 4

Guidelines for the diagnosis of CLL:

For the definitive diagnosis of CLL to be made, a patient must have: (4)

Answer 4

1. lymphocytosis- small mature lymphocytes
2. Bone marrow involvment with infiltration by lymphocytes
3. atypical/immature lymphoid cells in peripheral blood <50%
4. clonal expansion of abnormal B cells

Question 5

Immunohistochemistry involves staining biopsy specimens with monoclonal antibodies directed against specific protein targets (antigens). Cells of lymphoid lineage can be distinguished by the pattern of an antigen expression on their surface: ______-cells express CD2, CD3, CD4 or CD8, CD5; in contrast _____-cells express CD19, CD20, CD22, CD79a, and Ig (immunoglobulin); __________cells express CD16, CD56 and CD59.

__________can confirm expected patterns of antigen expression and also reveal abnormal patterns – such as T-cell antigens expressed on B-cells. In this way, it can be used to identify abnormal populations and diagnose lymphoid malignancies.

Answer 5

Immunohistochemistry involves staining biopsy specimens with monoclonal antibodies directed against specific protein targets (antigens). Cells of lymphoid lineage can be distinguished by the pattern of an antigen expression on their surface: T-cells express CD2, CD3, CD4 or CD8, CD5; in contrast B-cells express CD19, CD20, CD22, CD79a, and Ig (immunoglobulin); NK cells express CD16, CD56 and CD59.

Immunohistochemistry can confirm expected patterns of antigen expression and also reveal abnormal patterns – such as T-cell antigens expressed on B-cells. In this way, immunohistochemistry can be used to identify abnormal populations and diagnose lymphoid malignancies.

Question 6

The routine availability of peripheral blood lymphocyte immunophenotyping has not only facilitated the differential diagnosis of CLL but also allowed for the subclassification of the lymphoid malignancies.

B-CLL cells resemble _____lymphocytes, and in the vast majority of cases demonstrate a signature phenotype.

The major immunophenotypic (cell surface) features that characterize CLL are:
The predominant population shares B-cell markers (CD19, CD20, and CD23), although CD20 expression is dim relative to normal B-cells and other B-cell malignancies
B-CLL expresses the T-cell marker CD____, but no other pan-T markers

The B cell is ______with regard to expression of either kappa or lamdba light chains. Recall that a B-cell presents its idiotype antibody on the surface of the cell as the receptor (Ig_) which will trigger activation.

A relatively ____ density of Ig on the surface of the cell is characteristic of CLL. Since the choice of lamba or kappa light chains is made early and irreversibly/reversibly in B-cell development, CLL cells must express either lambda or kappa light chains.

Answer 6

The routine availability of peripheral blood lymphocyte immunophenotyping has not only facilitated the differential diagnosis of CLL but also allowed for the subclassification of the lymphoid malignancies.

B-CLL cells resemble naive B lymphocytes, and in the vast majority of cases demonstrate a signature phenotype.

The major immunophenotypic (cell surface) features that characterize CLL are:
The predominant population shares B-cell markers (CD19, CD20, and CD23), although CD20 expression is dim relative to normal B-cells and other B-cell malignancies
B-CLL expresses the T-cell marker CD5, but no other pan-T markers

The B cell is monoclonal with regard to expression of either kappa or lamdba light chains. Recall that a B-cell presents its idiotype antibody on the surface of the cell as the receptor (IgD) which will trigger activation.

A relatively low density of Ig on the surface of the cell is characteristic of CLL. Since the choice of kappa or lambda light chains is made early and irreversibly in B-cell development, CLL cells must express either kappa or lambda light chains.

Question 7

Although CLL is predominantly an _____ disorder of late middle-aged or elderly individuals, the disease may cause significant morbidity. In its least aggressive pattern, patients die of causes ?

In its most aggressive form, patients may die within _____ years after diagnosis.

Answer 7

Although CLL is predominantly an indolent disorder of late middle-aged or elderly individuals, the disease may cause significant morbidity. In its least aggressive pattern, patients die of causes unrelated to CLL at a rate that closely follows actual norms for their age.

In its most aggressive form, patients may die within 1 to 2 years after diagnosis.

Question 8

At presentation, patients are often _______. Initial symptoms are generally secondary to _____ enlargement or anemia.

As the disease advances, the following may appear: increasingly ______ lymphocyte counts; progressive lymphadenopathy and hepatosplenomegaly; and more severe anemia, granulocytopenia, or thrombocytopenia.

_________ are common with disease progression and are the leading cause of death in patients with CLL. The presence of CLL has adverse regulatory consequence on the immune system. The presence of CLL may suppress normal _____ production by plasma cells resulting in critically low circulating antibodies and recurrent infection, particularly with _____________ organisms.

The presence of CLL also appears to influence the regulatory and effector arms of ___-cell immunity. As a consequence, autoimmune phenomena are often seen: hemolytic anemias, immune thrombocytopenia purpura (ITP), etc. This may be thought of as an impairment in the normal regulator function which should have maintain host tolerance.

Long-term consequences of CLL includes transformation / evolution to a more aggressive disease, typically one that resembles aggressive ____________.

Answer 8

At presentation, patients are often asymptomatic. Initial symptoms are generally secondary to lymph node enlargement or anemia.

As the disease advances, the following may appear: increasingly elevated lymphocyte counts; progressive lymphadenopathy and hepatosplenomegaly; and more severe anemia, granulocytopenia, or thrombocytopenia.

Infections are common with disease progression and are the leading cause of death in patients with CLL. The presence of CLL has adverse regulatory consequence on the immune system.

The presence of CLL may suppress normal antibody production by plasma cells resulting in critically low circulating antibodies and recurrent infection, particularly with encapsulated organisms. The presence of CLL also appears to influence the regulatory and effector arms of T-cell immunity. As a consequence, autoimmune phenomena are often seen: hemolytic anemias, immune thrombocytopenia purpura (ITP), etc. This may be thought of as an impairment in the normal regulator function which should have maintain host tolerance.

Long-term consequences of CLL includes transformation / evolution to a more aggressive disease, typically one that resembles aggressive diffuse large B-cell lymphoma (DLBC).

Question 9

The development of ___________ is a cardinal feature of the natural history of CLL

Answer 9

autoantibodies

Question 10

In general, autoantibodies are generated against formed elements of the hematopoietic system. ___________anemia develops in between 10% and 15% of patients with CLL.

Usually, these patients are Coombs’ _____ (antibodies can be detected stuck to the host’s red blood cells), and clinical hemolysis is evident.

Pure ____ aplasia occurs less often. Patients with this autoimmune manifestation are often Coombs’ ____, despite clinical hemolysis. Examination of the bone marrow reveals a deficiency of _______ precursors. Presumably patients are Coombs’ negative because the antibodies are directed against _______ red blood cells which remain fixed in the bone marrow.

________________ is less common, occurring in 2% to 5% of patients with CLL.
Most patients with CLL do not have other autoimmune disorders, such as rheumatoid arthritis, although some investigators find these diseases more prevalent in relatives of patients with CLL.
Recall that CLL cells express CD___. Normal CD__+ B cells are usually found at the edge of germinal centers in the mantle zone of lymphoid follicles. These cells generally produce ___________autoantibodies.

The autoantibodies formed in CLL are ______ and not produced by the malignant clone. Autoimmune phenomena seem to result from interaction between (3)

Answer 10

In general, autoantibodies are generated against formed elements of the hematopoietic system. Autoimmune hemolytic anemia develops in between 10% and 15% of patients with CLL.

Usually, these patients are Coombs’ positive (antibodies can be detected stuck to the host’s red blood cells), and clinical hemolysis is evident.

Pure red cell aplasia occurs less often. Patients with this autoimmune manifestation are often Coombs’ negative, despite clinical hemolysis. Examination of the bone marrow reveals a deficiency of red blood cell precursors. Presumably patients are Coombs’ negative because the antibodies are directed against immature red blood cells which remain fixed in the bone marrow.

Immune-mediated thrombocytopenia (ie ITP) is less common, occurring in 2% to 5% of patients with CLL.
Most patients with CLL do not have other autoimmune disorders, such as rheumatoid arthritis, although some investigators find these diseases more prevalent in relatives of patients with CLL.
Recall that CLL cells express CD5. Normal CD5+ B cells are usually found at the edge of germinal centers in the mantle zone of lymphoid follicles. These cells generally produce polyreactive, low-affinity autoantibodies.

The autoantibodies formed in CLL are polyclonal and not produced by the malignant clone. Autoimmune phenomena seem to result from interaction between malignant cells, T cells, and residual normal B cells.

Question 11

As previously mentioned, severe ______ represent the leading cause of death for patients with CLL.

Increased susceptibility to infections is due both to __________

CLL evolves into a more aggressive lymphoid malignancy in about 10% to 15% of cases. Richter’s transformation is the most common of these, in which patients develop a diffuse large cell ________lymphoma. Survival is poor.

________________ occurs when the morphologic appearance of the CLL cells alters to somewhat larger cells with distinct nucleoli and less dense chromatin. This condition is refractory to typical chemotherapeutic agents.

_________may develop in patients with CLL, particularly carcinomas of the lung and gastrointestinal tract.
CLL may evolve into acute leukemia as a terminal event. When this occurs, the leukemia is ______ in origin. It is difficult to know whether the CLL led to the leukemia or whether damage from chemotherapy over time brought about the leukemia.

Answer 11

As previously mentioned, severe systemic infections represent the leading cause of death for patients with CLL.

Increased susceptibility to infections is due both to intrinsic features of the pathogenesis of CLL as well as to therapy.

CLL evolves into a more aggressive lymphoid malignancy in about 10% to 15% of cases. Richter’s transformation is the most common of these, in which patients develop a diffuse large cell immunoblastic lymphoma. Survival is poor.

Prolymphocytoid transformation occurs when the morphologic appearance of the CLL cells alters to somewhat larger cells with distinct nucleoli and less dense chromatin. This condition is refractory to typical chemotherapeutic agents.

Secondary malignancies may develop in patients with CLL, particularly carcinomas of the lung and gastrointestinal tract.
CLL may evolve into acute leukemia as a terminal event. When this occurs, the leukemia is myeloid in origin. It is difficult to know whether the CLL led to the leukemia or whether damage from chemotherapy over time brought about the leukemia.

Question 12

The options for treatment of CLL run the gamut of treatments for all hematologic malignanicies – from _________to _____________

Answer 12

The options for treatment of CLL run the gamut of treatments for all hematologic malignanicies – from symptom management to allogeneic transplant.

Question 13

In general, we want to match our treatment to the _________of the tumor. Those with low burden, low intensity disease may need no treatment for years at a time, while those with aggressive disease may suffer rapid progression and require equally aggressive treatment.

There are a number of factors that we can use to help determine how aggressive someone’s CLL will be and what impact it is likely to have on their health and life expectancy. These prognostic factors also provide a window into the biology of CLL that differentiates the low risk / indolent from high risk / aggressive patients.

Answer 13

In general, we want to match our treatment to the aggressiveness of the tumor. Those with low burden, low intensity disease may need no treatment for years at a time, while those with aggressive disease may suffer rapid progression and require equally aggressive treatment.

There are a number of factors that we can use to help determine how aggressive someone’s CLL will be and what impact it is likely to have on their health and life expectancy. These prognostic factors also provide a window into the biology of CLL that differentiates the low risk / indolent from high risk / aggressive patients.

Question 14

rai staging system:

anemia and thrombocytopenia

Answer 14

high stage

Question 15

rai staging system:

lymphadenopathy and hepatosplenomegaly

Answer 15

intermediate stage

Question 16

rai staging system:

lymphocytosis in blood /marrow

Answer 16

low staging

Question 17

Two models for leukemogenesis have been proposed for CLL.

In the first, a naïve B-cell- what does this mean? why is it naive?

suffers some oncogenic event (we don’t yet know what that might be – cosmic radiation, environmental toxins, autoimmune reactions) that transforms the naïve cell to a CLL cell. Since that cell has ________ activated via antigen recognition, it has not undergone __________. Therefore, if you sequence the immunoglobulin genes, you find that the sequence ___________from the germ line sequence. The immunoglobulin genes are called “______”.

In the second model, a naïve B-cell encounters antigen in a lymph node and become activated, it undergoes ____________in order to optimize the immune response and then enters a long term memory program. This experienced B-cell now undergoes some oncogenic hit and becomes a CLL cell. If you examine the immunoglobulin genes in this cell, you will find that there are __________ from germ line, particularly concentrated in the region coding for antigen recognition. In this case, the immunoglobulin genes are called “_______”.

Answer 17

In the first, a naïve B-cell (ie one that has rearranged immunglobulin and migrated to the lymph nodes, but has not yet recognized antigen)

suffers some oncogenic event (we don’t yet know what that might be – cosmic radiation, environmental toxins, autoimmune reactions) that transforms the naïve cell to a CLL cell. Since that cell has never been activated via antigen recognition, it has not undergone somatic hypermutation. Therefore, if you sequence the immunoglobulin genes, you find that the sequence remains essentially unchanged from the germ line sequence. The immunoglobulin genes are called “unmutated”.

In the second model, a naïve B-cell encounters antigen in a lymph node and become activated, it undergoes hypermutation in order to optimize the immune response and then enters a long term memory program. This experienced B-cell now undergoes some oncogenic hit and becomes a CLL cell. If you examine the immunoglobulin genes in this cell, you will find that there are significant changes from germ line, particularly concentrated in the region coding for antigen recognition. In this case, the immunoglobulin genes are called “mutated”.

Question 18

Median survival was 9 years for patients without variable gene mutations (“_______”), but median survival for patients with variable gene mutations (“_______”) had not been reached (P=.0001). The unmutated / mutated convention is unfortunate and can be confusing – in the case of CLL, “___________” is a good thing!

Answer 18

Median survival was 9 years for patients without variable gene mutations (“Unmutated”), but median survival for patients with variable gene mutations (“Mutated”) had not been reached (P=.0001). The unmutated / mutated convention is unfortunate and can be confusing – in the case of CLL, “mutated” is a good thing!

Question 19

“Unmutated” arises prior to ______ (the red lightening bolt), and “Mutated” arises from an ___________

Answer 19

“Unmutated” arises prior to antigen stimulation (the red lightening bolt), and “Mutated” arises from an antigen experienced memory B-cell.

Question 20

Expression of Zap70 was identified as a ______ prognostic indicator on this basis. why?

Answer 20

Expression of Zap70 was identified as a negative prognostic indicator on this basis.

Zap70 is a tyrosine kinase normally expressed on T- and NK- cells as part of the CD3 zeta chain. Expression on CLL B-cells is abnormal and associated with worse prognosis.

Question 21

_________ using probes for the short and long arms of specific chomosomes, reveals alterations (additions or deletions) in the majority of patients with CLL.

Certain gene rearrangements, specifically deletion of the short arm of chr ____) and the long arm of chr 1____ are associated with an aggressive phenotype and short median survival (< 3 and 6 years, respectively). Similarly, _________ is associated with a better prognosis and longer survival (11+ years).

Having no cytogenetic abnormality detected on FISH was associated with an ______prognosis (median ~10 years).

Answer 21

Fluorescent in-situ hybridization using probes for the short and long arms of specific chomosomes, reveals alterations (additions or deletions) in the majority of patients with CLL.

Certain gene rearrangements, specifically deletion of the short arm of chr 17 (del 17p) and the long arm of chr 11 (del 11q) are associated with an aggressive phenotype and short median survival (< 3 and 6 years, respectively). Similarly, del 13q is associated with a better prognosis and longer survival (11+ years).

Having no cytogenetic abnormality detected on FISH was associated with an intermediate prognosis (median ~10 years).

Question 22

the top two risk factors, advanced Rai stage (stage III/IV) and deletion of ____p by FISH are associated with particularly short survival. It is not yet known whether directing more aggressive therapy toward these patients will result in any improvement in outcome.

Answer 22

the top two risk factors, advanced Rai stage (stage III/IV) and deletion of 17p by FISH are associated with particularly short survival. It is not yet known whether directing more aggressive therapy toward these patients will result in any improvement in outcome.

Question 23

We can use the prognostic factors for the management of our patients.

These factors predict strongly for____________– patients with high risk disease tend to require treatment within a few years of diagnosis while many low risk patients remain treatment free more than a decade from diagnosis.

These prognostic factors also predict for ______________ – identify those likely to die from CLL versus those who will die of other “natural causes”.

Given that we can identify high risk patients, what can we do about it?

Answer 23

We can use the prognostic factors for the management of our patients.

These factors predict strongly for time to first treatment – patients with high risk disease tend to require treatment within a few years of diagnosis while many low risk patients remain treatment free more than a decade from diagnosis.

These prognostic factors also predict for overall survival – identify those likely to die from CLL versus those who will die of other “natural causes”.

Given that we can identify high risk patients, what can we do about it? Intuitively, we can offer more aggressive treatment to those with high risk disease, particularly younger patients who will otherwise die of CLL.

Question 24

There is some indication that alemtuzumab may provide a better result in patients with del ______ than chemotherapy. Currently combinations of rituximab, chemotherapy and campath are under investigation.

Answer 24

There is some indication that alemtuzumab may provide a better result in patients with del 17p than chemotherapy. Currently combinations of rituximab, chemotherapy and campath are under investigation.

Question 25

First principals of treatment – CLL is a chronic disease with ________median survival for all but the highest risk patients.

Since patients with _____ disease cannot be cured, there is no advantage to beating them over the head with early treatment.

Instead, treatment is reserved until there is a _________ need: constitutional symptoms, pain, fatigue, unsightly lymphadenopathy, etc.

Answer 25

First principals of treatment – CLL is a chronic disease with long median survival for all but the highest risk patients.

Since patients with indolent disease cannot be cured, there is no advantage to beating them over the head with early treatment.

Instead, treatment is reserved until there is a symptomatic need: constitutional symptoms, pain, fatigue, unsightly lymphadenopathy, etc.

This is the same “Watch and Wait” strategy that we use in indolent NHL. I find most patients are comfortable with this recommendation when I point out that I cannot help them live longer, only better and I can’t make them feel better if they already feel fine – I can only make them sick.

Question 26

fludarabine was more effective than chlorambucil with an overall response rate of 63 vs. 37%. However, there was no overall survival advantage to either drug over the other. Both drugs remain viable single agent candidates.

Answer 26

yep

Question 27

Recall that the monoclonal anti-CD20 antibody rituximab kills tumor cells by several mechanisms:

Answer 27

mediating antibody-dependent cellular cytotoxicity, inducing apoptosis and activating complement.

Question 28

rituximab has a synergistic effect with chemo with no toxicity

Answer 28

yep

Question 29

Alemtuzumab (Campath-1H) is a monoclonal antibody directed against ______, an antigen expressed on all lymphoid cells.

Because it hits both B- and T-cells, alemtuzumab is exceptionally _____________and reactivation of latent CMV and other infections are encountered.

Answer 29

CD52

Because it hits both B- and T-cells, alemtuzumab is exceptionally immunosuppressive and reactivation of latent CMV and other infections are encountered.

Question 30

Memory T and B cells are sustained within specialized “niches” in the bone marrow – what is the benefit?

Lymphoid tumor cells appear able to capitalize on these niches to avoid ____________ So call, nurse-like cells promote survival of CLL cells and are required to get CLL to grow in in vitro cultures. An emerging therapeutic strategy aims to disrupt such cell-cell cross talk and increase sensitivity to chemotherapy.

Answer 30

Memory T and B cells are sustained within specialized “niches” in the bone marrow – micro-environments that provide anti-apoptotic and pro-survival signals through paracrine cytokines and cell-cell interactoins.

Lymphoid tumor cells appear able to capitalize on these niches to avoid death from chemotherapy and immunotherapy. So call, nurse-like cells promote survival of CLL cells and are required to get CLL to grow in in vitro cultures. An emerging therapeutic strategy aims to disrupt such cell-cell cross talk and increase sensitivity to chemotherapy.

Question 31

Lymphoid and other malignancies may co-opt these same niches to ensure their own survival. Malignant CLL cells exchange _________ and maintain cell-cell contact interactions with T-cells, mesenchymal cells and macrophages which serve to oppose _______ and likely protect the cells from ___________ and ____________.

Answer 31

Lymphoid and other malignancies may co-opt these same niches to ensure their own survival. Malignant CLL cells exchange cytokine signals and maintain cell-cell contact interactions with T-cells, mesenchymal cells and macrophages which serve to oppose apoptosis and likely protect the cells from chemotherapy and antibody attack.

Question 32

How do B-cells communicate with the microenvironment?

Answer 32

B-cells communicate with the microenvironment via contact/adhesion pathways acting via PI3k and antigen recognition via the B-cell receptor acting through Syk and BTK among other downstream kinases. These signals are integrated together and influence cell activation.

Question 33

Ibrutinib is an oral inhibitor of ________ which is reversible/irreversible

Answer 33

Bruton’s Tyrosine Kinase and it is irreversible

Question 34

Bruton’s Tyrosine Kinase are required for ____________ and mutations could lead to ___________

Answer 34

Bruton’s Tyrosine Kinase are required for B-cell survival and mutations could lead to x-linked agammaglobulinemia

Question 35

Deletion ________results in resistance to apoptosis induced by chemotherapy and radiation

Answer 35

17p (TP53)

Question 36

Signaling though BCR and integrins _____________apoptosis via BCL2

Answer 36

downregulates

Question 37

Venetoclax inhibits BCL2, triggering

Answer 37

apoptosis

Question 38

Treatment for patients with CLL can now be directed according to _______ status (whether deleted – ie del17p, or mutated). Patient with del/mut _____ are relatively resistance to chemotherapy as functional________ is essential for detecting DNA damage – cells which lack ________ activity will not trigger apoptosis following chemotherapy or radiation – they can, in essence, ignore the fact that they have been damaged. Therefore, patients with del/mut _______ or those whom are otherwise unfit to receive chemotherapy due to age or co-morbidity, should receive targeted therapy as first line.

Younger, fitter patients, and in particular those with ___________ (who remain chemosensitive) should receive a combination of alkylator-based chemotherapy (ie fludarabine+cyclophosphamide or bendamustine) and an anti-CD20 monoclonal antibody (ie rituximab or obinatuzumab).

Answer 38

Treatment for patients with CLL can now be directed according to p53 status (whether deleted – ie del17p, or mutated). Patient with del/mut p53 are relatively resistance to chemotherapy as functional p53 is essential for detecting DNA damage – cells which lack p53 activity will not trigger apoptosis following chemotherapy or radiation – they can, in essence, ignore the fact that they have been damaged. Therefore, patients with del/mut p53 or those whom are otherwise unfit to receive chemotherapy due to age or co-morbidity, should receive targeted therapy as first line.

Younger, fitter patients, and in particular those with del11q (who remain chemosensitive) should receive a combination of alkylator-based chemotherapy (ie fludarabine+cyclophosphamide or bendamustine) and an anti-CD20 monoclonal antibody (ie rituximab or obinatuzumab).

Question 39

is a proliferation of small, mature lymphocytes with compact chromatin, revealing barely any cytoplasm. ________ cells may be fragile and easily “smudge” when being smeared on a slide. ______ is associated with multiple cytogenetic abnormalities, notably del 17p, del 13q and trisomy 12p. About 20% will have no detectable cytogenetic defect. Cytogenetic changes have prognostic importance, but do not appear directly related to malignant transformation. The median survival for patients with ________ is 8 years, with some subgroups enjoying much longer survival. While the appearance of acute leukemia is reported with ________, it remains a rare event and may be related more to the therapy (chemotherapy) than to the underlying ________ itself. Finally, there are no targeted therapies currently available for ________ (nor are there any consistent molecular targets to go after!).

Answer 39

CLL

Question 40

is a clonal proliferation of a myeloid stem cell which retains the ability to differentiate. Maturation predominantly follows the neutrophil lineage with accumulation of myelocytes, metamyelocytes, bands and neutrophils, but may also result in thrombocytosis (high platelet count) and basophilia (accumulation of basophils). ______ is associate with a very specific chromosomal translocation, among the first identified in association with disease, the Philadelphia chromosome, t(9;22) which results in fusion of BCR and ABL, leading to constitutive activation of the Abelson kinase. Untreated, _________ is associated with a high risk of transformation to incurable acute leukemia (AML)– 25% per year. Finally, there are currently 3 FDA-approved tyrosine kinase inhibitors specifically targeting the BCR-ABL fusion product.

Answer 40

CML

Question 41

is a monotonous population of small cells (similar in size to the red blood cells), with dense, dark cytplasms and very little cytoplasm. Some cells may have irregular nuclear contours such as the cleft marked with the arrow.

Answer 41

CLL

Question 42

marked variation – visible are many large, myeloid cells in various stages of maturation from blast to mature neutrophil. A basophil is noted. Note the more abundant, granular cytoplasms in the neutrophils.

Answer 42

CML