This week’s question comes from Sarah, who asks, “A close relative of mine had leukemia years ago and recently relapsed, developing a type of leukemia known as AML. He received a bone marrow transplant from his brother a long time ago and was treated with DLI this time around. But, in the weeks that followed his chemo and DLI, he developed a potentially serious complication known as GVHD. Can you explain how leukemias happen in the first place, DLI, and GVHD/other common complications of treatment?”
Well, Sarah, before we dive into the complexities of leukemias, we should first introduce the various types and how they differ. Generally, leukemia is a cancer of the blood that specifically produces too many immature white blood cells, known generically as “blasts.” Because these white blood cells are immature, they cannot function properly and effectively take up space, eventually preventing production and function of mature, life-sustaining blood cells. This is different from the similar sounding lymphoma, which also involves immune cells but can create solid tumors that usually occur in the lymphatic tissue and organs. The difference between them is not important for this discussion, but it is important that you know they are largely discrete diseases. Leukemias, like most cancers, happen due to a genetic predisposition or mutation. Sometimes, leukemias can be caused by exposure to chemicals or radiation, but most often are a result of a natural genetic alteration (birth defect, ie. Philadelphia Chromosome translocation, or acquired via viral infection, ie. Epstein-Barr Virus).
Leukemias are divided into two major categories, acute and chronic. Acute refers to the fact that the disease comes on and progresses rapidly. Chronic, on the other hand, is the opposite. The disease may take months or years to progress fully. Either way, the abnormally high production of immature white blood cells is serious and left untreated can result in grave illness and eventually death.
Acute and chronic leukemias are further divided into lymphoblastic/lymphocytic and myelogenous. Lymphoblastic/lymphocytic leukemias specifically involve the bone marrow precursor cells that produce lymphocytes, more commonly known as B or T cells. In practice, lymphoblastic/lymphocytic leukemias can develop into lymphomas, so the diseases do have a link. Myelogenous leukemias, on the other hand, involve the bone marrow precursor cells involved in producing other parts of the blood besides lymphocytes, which include other white blood cells, platelets, and red blood cells.
So, by this classification, we end up with four major types of leukemia. Granted, these are not all the types that exist, but for the sake of brevity these are the four on which we will concentrate. The four types are:
- Acute Lymphoblastic Leukemia (ALL)
- Chronic Lymphocytic Leukemia (CLL)
- Acute Myelogenous Leukemia (AML)
- Chronic Myelogenous Leukemia (CML)
Given the brief introduction in the previous paragraph, it should be fair easy to understand generally what is involved in each of the four. If you’re curious about a more in-depth explanation of each, feel free to view the sources at the bottom. On the whole though, each presents its own dangers and are each treated differently.
On the topic of treatment, it is important that we understand that not all leukemias are created equal. Some leukemias have a nearly 100% survival rate, such as a subset of CLL known as hairy cell leukemia, while others require dramatic treatment measures to even provide a 50-50 chance at survival. Many leukemias can now be treated directly with drugs. CML, for example, is treated with a drug that targets the protein responsible for overactive production. This drug, imatinib (trade name: Gleevec), has turned CML from a slow death sentence into a chronic, manageable disease for a vast majority of patients. Likewise, chemotherapy is often successful for most AML, ALL, and CLL patients.
However, a fair number of patients after initial successful treatment relapse and a minority of patients fail first line treatments like chemotherapy, radiation, and medications. These people are then treated with bone marrow transplants, which can come from relatives or unrelated “matches” from the general population. Bone marrow transplants are tricky business, primarily because they first involve the total destruction of the patient’s own bone marrow. Without bone marrow, the patient cannot create new blood cells, including red blood cells, platelets, and immune cells. Once irradiated, they reach a point of no return, so the donor bone marrow must be as close to a “match” as possible.
I put match in quotations because no one from the general population, save for an identical twin, will ever have the same exact genetic markers necessary to prevent rejection. Interestingly and likely not surprisingly due to the genetic component, bone marrow donated from an identical twin was found to have a higher rate of relapse but lower mortality due to the lack of rejection. But for the rest of us, bone marrow must come from someone who is, by definition, genetically different. And so, rigid genetic testing is required before the marrow can be transplanted. This involves human leukocyte antigen (HLA) markers, ten of which have been identified as necessary for a true compatible donation. HLA markers are a type of major histocompatibility complex, which we have discussed before, and identify tissues throughout the body as “self.” The more matching HLA markers, the lower the likelihood of rejection or an adverse reaction. This is true regardless of transplant type, but is especially important for bone marrow transplants.
Over time, however, relapses can happen even with bone marrow transplants. Sometimes the cancer is not always completely eliminated by the new immune system. If the cancer returns in a patient who has already received a bone marrow transplant, the options are more limited. DLI, or direct lymphocyte infusion, is one of the main options available alongside standard chemotherapy and redoing the bone marrow transplant. DLI puts more of the the same donor’s T-cells directly into the blood stream to take advantage of the graft versus tumor effect, which is a fancy way of saying cancer fighting capabilities. This is often a successful treatment, given that the graft is stable.
However, there is the possibility of problems with the transplant in the first place. In this circumstance, one of two things tend to happen, graft rejection or graft versus host disease (GVHD). Graft rejection involves lingering patient immune cells recognizing the new transplant as foreign and attacking it. The risk of this can be significantly reduced with pre-treatment (chemotherapy, radiation, etc.) to thoroughly eliminate the original immune cells, but it still remains a distinct possibility following transplantation. This is a serious, often lethal, complication because the patient is left largely defenseless and without the ability to make blood products effectively.
Graft versus host disease (GVHD) is a different, and in many cases not quite so serious, complication of the bone marrow transplant. It can also be induced through DLI because of the large T-cell infusion. GVHD involves the new immune cells attacking the patient’s tissues because the new cells identify the old ones as foreign or “non-self.” Essentially, GVHD flips HLA markers on their head: instead of the body attacking the transplant, the transplant now attacks the body. It often attacks the skin, mucosa, and GI system (liver and GI tract) , which can be severely painful and debilitating. Less severe versions of GVHD can be controlled with steroids, while more severe cases have shown to be responsive to injectable antibody medications that block the signaling pathways associated with the disease. New treatments for GVHD that doesn’t respond to steroids are being developed, but by and large the use of steroids or injectable antibody medications tend to successfully manage this complication.
Hope this helped, Sarah. Thank you for sharing this deeply personal question. I highly recommend everyone join the national bone marrow registry at Be The Match. Five minutes of your time may save someone’s life.
Till next time,