A Primer on Hematologic Malignancies for the Non-Oncology Pharmacist

Steph’s Note: This week, we’re hosting the return of Olivia White, PharmD. You (hopefully) remember her from her recent post on Chemotherapy Induced Peripheral Neuropathy (CIPN) - and if you don’t, definitely check out her debut knowledge drop here. She’s continuing to share her love of oncology with us by breaking down the pathophysiology of the (often very confusing) hematologic malignancies. And if we all show her some love - or perhaps beg her enough - maybe we’ll be able to convince her to find time in her crazy PGY1 life to continue this topic as a series with management & treatment.

While taking my oncology course during pharmacy school, we had a very brief overview of the different hematologic malignancies (like 3 lectures). Therefore, it wasn’t until I was on my first malignant hematology rotation that I realized the intricacies and details associated with these disease states.

When you think of your classic ‘tumor’ or ‘cancer’, most people think of something solid or some sort of mass that has continuously replicated in an area of the patient’s body. However, what sets hematology apart is that these tumors are liquid in nature. None of these disease states are specific to one area of the body, but instead are ‘tumors’ of the blood - making them associated with distinct clinical presentations as well as very unique from a management perspective.

The purpose of today’s overview is not to go into the details of how we treat each of these but instead to look at what makes them stand apart. By understanding the pathophysiology of each of these disease states, it’ll make it easier for us as pharmacists to understand the ‘why’ behind ‘what’ we use to treat each of these. 

Before doing a deep dive into each of these diseases, let's talk about hematopoiesis, aka the process of developing blood cells:

This diagram is something that we’ll be continuously referencing due to each of these hematologic malignancies being derived from an upregulation of different locations in the cell lineage. (Image)

When thinking about hematopoiesis, it’s good to really consider this in two branches – the myeloid lineage and the lymphoid lineage. As a general rule of thumb, the myeloid lineage is most commonly associated with leukemias, and lymphoid lineage is a mixed bag where you have lymphomas, myelomas, and then some leukemia spill-over as well.

An additional rule of thumb is that the further down you get in cell differentiation, the more specific those cells are to their functions AND the less acute the associated disease is. There are definitely exceptions to every rule, but in the most general sense, this applies. Despite us not going into great detail today, know that with each of the cells in this diagram, there are associated hematologic diseases and that management strategies differ for each of these (which makes heme fun!).

Hematologic Malignancy Type #1: Myeloma

Let’s start with myeloma. Multiple myeloma is an incurable, biologically heterogeneous disease of the plasma cells. Multiple myeloma is the second most common hematologic malignancy, with the American Cancer Society estimating that there will be approximately 34,920 new cases and 12,410 deaths in 2021.

Similar to multiple sclerosis, multiple myeloma is considered a ‘relapsing-remitting’ disease where there is continual disease without cure. But there are also points in time where the disease is either being adequately managed or continuing to progress. Risk factors for multiple myeloma include age, sex, race, family history, obesity, and any past medical history of other plasma cell diseases.

(Image)

Multiple myeloma is believed to progress almost universally from Monoclonal Gammopathy of Undetermined Significance (MGUS). The pathogenesis of multiple myeloma is driven by the ‘activated’ and ‘abnormal’ plasma cell.

Remember, myeloma = plasma cells! (Also, please excuse Steph’s somewhat crappy crop job on this pic…)

When looking back at our hematopoietic lineage, you see that the plasma cell is the most differentiated cell on the lymphoid cell line. When thinking back to immunology and the role that plasma cells serve, you can think of these as our antibody producing B-cells. (For a more detailed review of the immune system and B cells, check this out.) When a patient has multiple myeloma, they have an abnormal production of antibodies, which is actually how we monitor for disease progression versus response to therapy.

Multiple myeloma demonstrates significant ‘intraclonal heterogeneity’ - which can make this disease very difficult to treat, because the DNA of each neoplastic cell is not the same. As more and more mutations accumulate, the disease increases in its risk of progression. 

Myeloma cells grow and expand almost exclusively in the bone marrow, and so it’s important to emphasize the bone marrow composition in these patients. In this disease state, there is a huge imbalance of bone turnover and replication of plasma cells within this space. This leads to downregulation of other cell lines.

This downregulation influences the symptoms that are classically seen with multiple myeloma. Generally these are known as the ‘CRAB’ Criteria: 

For more on hypercalcemia, review this post.

This is your friendly reminder that osteoblasts BUILD bone and osteoclasts BREAK IT DOWN. (Image)

These criteria are representative of disease progression. When thinking of the pathogenesis and how each of these symptoms manifest, the ‘C’ and ‘B’ go hand in hand. These are both due to downregulation of osteoblasts and upregulation of osteoclasts. Bone lesions and fractures are very common in patients with myeloma for this reason, and therefore, this is something we as pharmacists need to focus on. We can do this by counseling patients AND by ensuring bone health is optimized through any necessary supplementation or prescriptions.

When considering renal insufficiency, the primary contributor to this symptom is the overproduction of protein in the form of antibodies. Because of this increased production, the antibodies can infiltrate an area (in this case your kidneys), causing a ‘clogging’ effect, and therefore leading to dysfunction.

And then lastly, similar to the downregulation of other cells, these patients can be anemic due to a downregulation of red blood cell production.

Following the discovery of bone lesions and associated symptoms, a diagnostic workup for myeloma will be completed. This includes a variety of laboratory tests that assess severity of disease (including amount of protein in the blood), urine tests to assess secretion of protein, bone marrow biopsies, and radiographic imaging. Following this assessment, the patient will typically be initiated on a 3-drug regimen and closely monitored for disease progression.

I will add, the management of multiple myeloma is somewhat of a ‘hot’ topic at the current moment. Therefore, standards of care and management of these patients could drastically change in years to come due to the vast amount of research that’s currently ongoing. 

Hematologic Malignancy Type #2: Lymphomas

Now that we’ve had the opportunity to discuss myelomas, we’ll transition into our curable disease states, with the first being lymphomas. I like to think of lymphomas as our most ‘solid tumor-like’ liquid tumors. In general, lymphomas impact your lymphoid tissues (example, the lymph nodes), and therefore, there is a solid structure or organ group that is directly impacted by this disease (in comparison to the very fluid leukemias or myelomas). 

(Image)

Of all the hematologic malignancy groups discussed today, lymphomas are by FAR the most vast in presentation. The World Health Organization’s classification of lymphoma includes more than 90 (NINETY!) subtypes of the disease. In the most basic sense, these can be separated into Non-Hodgkin lymphomas and Hodgkin Lymphoma. Furthermore, your Non-Hodgkin lymphomas can be separated into T-cell lymphomas and B-cell lymphomas.

Additionally, lymphomas are classified by the aggressiveness of the disease (check out the table to the right). Of the most common lymphomas listed in the table, the aggressive lymphomas include Burkitt’s, Diffuse large B-cell (or DLBCL), Precursor B-cell, and Peripheral T-cell. The more indolent lymphomas commonly include Follicular, Marginal Zone, and Mycosis Fungoides. 

Risk factors for lymphomas include first-degree relatives with lymphoma, rheumatoid arthritis, systemic lupus erythematosus, Sjogren syndrome, dermatomyositis, celiac disease, tobacco use, obesity, and long-term pesticide exposure.

The primary symptom associated with lymphoma is painless adenopathy. In indolent lymphomas that progress over long periods of time, this adenopathy can wax and wane. Additionally, for patients who have fairly progressed disease, patients will complain of what we like to call ‘B Symptoms’ – these include fever, unexplained weight loss, and night sweats. The location of the adenopathy is also important to delineate the type of lymphoma that can be present. Most Hodgkin lymphomas are supradiaphragmatic, while Non-Hodgkin lymphomas can originate anywhere in the body.

Remember, lymphoma = lymphoid cell lines!

Because lymphomas are so variable depending on the presentation, it makes it rather difficult to discuss the exact pathogenesis of this disease. However, when thinking of our hematopoietic lineage, for lymphoma, no matter the disease, we are ALWAYS talking about the lymphoid chain. The most common lymphoma is Diffuse large B cell or DLBCL, which is considered an aggressive, B-cell lymphoma.

Similar to other oncologic diseases, lymphomas occur due to the loss of regulation of cell production. Patients with aggressive lymphomas can see a rapid increase in the size of their lymph nodes or other affected lymphoid tissues. This is generally due to a genetic mutation, with specific mutations being associated with different types of lymphomas. Specifically for B-cell lymphomas, the involved neoplastic cells usually express the CD20 receptor, which influences our treatment options and diagnosis (i.e., we usually use a CD20 inhibitor such as rituximab).

One other thing to consider with rapid changes in nodal size is compression of other organs. Patients, especially those with aggressive disease, are commonly at risk for Superior Vena Cava Syndrome or other compressive complications, including spinal cord compression and bowel obstruction.

Once lymphoma is confirmed by imaging and biopsy of the nodal site, it can then be further classified based on the location within the node (germinal center versus proximal) and classified into the type of lymphoma that we will then aim to treat.

Hematologic Malignancy Type #3: Leukemias

The last hematologic malignancy we’ll discuss (and my personal favorite) are leukemias. The word leukemia actually means ‘leukocytes in the blood’, and so you can think of this as the general presentation for all of our different disease states under this umbrella. 

Leukemias are a heterogeneous group of malignancies that all derive from dysfunction in proliferation of leukocytes. When thinking about our hematopoietic progression, leukemias can present from both sides of the lineage, but you can break them down based on acuity and involved cells. Similar to lymphomas, we can divide these diseases into ‘acute’ and ‘chronic’.

Leukemia nomenclature is easy to follow since the associated acuity of each neoplasm is in the name of the disease. Therefore, our predominant acute leukemias include Acute Myeloid Leukemia (AML) and Acute Lymphoid Leukemia (ALL). ALL can be further separated into T-cell and B-cell ALL, with B-cell being more common. When thinking of our chronic leukemias, our predominant classifications include chronic myeloid leukemia (CML) and chronic lymphoid leukemia (CLL). 

Remember, acute leukemias = less mature cells!

Similar to what was mentioned earlier, the acute leukemias generally impact cells higher up on the lineage (see left). Risk factors for acute leukemias include age, chemical exposures, EBV (specific to ALL), and having a familial history of leukemia. Notably, age associated with risk of disease is distributed in somewhat of a bi-modal pattern. AML is more common in the older population (except for one specific subset of AML — APML), while ALL is the most common leukemia in children. 

When you open a patient’s chart to pre-round and see a white blood count of 130. (Image)

Both AML and ALL are acute in nature, meaning that these diseases develop over weeks to months. Acute leukemias derive from our less mature cells, commonly referred to as ‘blasts’. They begin to progress when these cells are stalled in the progenitor phase of maturation and then have uncontrolled replication. When thinking of the classic presentation of a patient with acute leukemia, these patients have an extremely high white count (I’ve seen up to the 130s before!).

Additionally, due to the ‘stalling’ of these blasts in the immature phase, there’s a downregulation of the more mature myeloid cells. This can lead to thrombocytopenia and anemia in patients who are uncontrolled or who have disease progression. Also, due to the rapid cell turnover, these patients are at a high risk of Tumor Lysis Syndrome. Therefore, in these patients we like to watch their electrolytes and uric acid closely, especially when initiating therapy. The presence of blast ‘spill-over’ from the bone marrow into the blood can cause the blood to be viscous and lead to patients experiencing leukostasis and signs/symptoms of DVT or PE. Lastly, when considering the functionality of these cells, these cells lack the ability to fulfill their true function as immune defense. Therefore, these patients are essentially immunosuppressed on presentation due to their lack of mature, functioning leukocytes.

Despite acute leukemias sounding complex, the fortunate fact is that these diseases are fairly rare. Furthermore, depending on the genetic profile of the disease, patients can be associated with favorable outcomes and have a fairly high overall survival rate depending on age and other risk factors. These diseases are curable in nature (unlike myeloma at this time) with the potential for stem cell transplant in patients who are able to tolerate it. Our diagnosis of any type of leukemia includes bone marrow biopsy as well as genetic sequencing to determine prognosis.

Remember, chronic leukemias = more differentiated cells!

Switching from the acute leukemias, I think it is also extremely important to discuss the chronic leukemias that we see more in the ambulatory setting. These leukemias are typically separated into Chronic Myeloid Leukemia (CML) and Chronic Lymphoid Leukemia (CLL). Of note, the chronic leukemias generally impact the cells farther down in the hematopoietic lineage. Because of this, the cells generally aren’t as fast at cloning (think years versus months). Additionally, when considering the chronic leukemic cells, these are a little bit more mature and thus have some residual function in comparison to the acute blasts. 

CML in particular has a very distinct pathophysiology. This disease state is specifically linked to chromosomal abnormalities that occur in the hematopoietic stem cells, thereby causing mutations in the granulocytes. This mutation is commonly referred to as the Philadelphia Chromosome, and it involves a translocation of chromosomes 9 and 22. Following this translocation occurrence, there is a fusion of the BCR protein on chromosome 22 and ABL1 on chromosome 9. This fusion leads to a dysregulated tyrosine kinase (i.e., the Philadelphia Chromosome). This genetic mutation is commonly targeted in CML treatment, and the majority of these patients will receive a BCR-ABL Tyrosine Kinase Inhibitor (TKI) as initial therapy.

Notably, this genetic abnormality is not specific to CML. It can actually be seen in ALL as well, and therefore you can see ALL patients initiated on BCR-ABL TKIs in addition to their standard chemotherapy.

One other thing that is notable about CML is that when comparing it to indolent lymphomas, CML can actually progress into a phase labeled ‘blast crisis’. In this state, it is then possible to continue progression into acute leukemia. This in particular is what sets our leukemias apart from lymphomas. Lymphomas aren’t fluid enough (get it…) to really change from one classification to the next in comparison to the leukemia disease states.

The tl;dr of Hematologic Malignancies

In summary, despite many hematologic malignancies presenting similarly, there are key pathophysiologic features that can help you delineate between them. As pharmacists, it is always important to understand pathophysiology because with this knowledge in our back pocket, we are more able to recommend life-saving therapies and understand the mechanisms that drive our decisions. 

The vast majority of hematologic diseases can be further separated into specific diagnoses based on histology, genetic mutations, and degree of progression. However, knowing the basics of these diseases and what causes each of these to proliferate is key to understanding the intricacies and details that set each of these apart.