Transplants

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Step 5: Transplant

High-dose therapy with autologous stem cell rescue

“HDT with autologous stem cell rescue" is a standard of care for myeloma patients who are fit enough to undergo the procedure. Over the years, the proper term has been shortened to somewhat of a misnomer “transplant.” Hematopoietic (blood) stem cells are used not as treatment but to rescue the patient after the high-dose therapy. Without these blood-making cells, patients would die of overwhelming infection, anemia, and/or the inability to stop bleeding. Stem cell rescue provides white blood cells for immune response, red blood cells to transport oxygen from the lungs to the body’s organs and tissues, and platelets to help the blood clot.

In myeloma, the transplant procedure is safest for patients when their own stem cells are harvested and used as the replacement cells, which is why the procedure is called “autologous” (meaning “derived from the same individual”) stem cell transplant (ASCT). Because ASCT is the standard of care for myeloma, Step 5 will concern only that procedure.

Autologous stem cell rescue plus maintenance remains the standard of care for eligible patients

  • Autologous stem cell rescue plus Revlimid (lenalidomide) maintenance produced the longest progression-free survival (PFS) as compared with autologous stem cell rescue alone or with melphalan, prednisone, Revlimid (R) with or without Revlimid maintenance.
  • Autologous stem cell rescue after Revlimid, Velcade (bortezomib), dexamethasone (RVD) induction improved response:

--Three-year PFS: 61% RVD plus autolgous stem cell rescue as compared wtih 48% alone with a P value less than 0.0002

--Patients without upfront stem cell rescue received this procedure at relapse.

--All patients have one year of Revlimid maintenance.

  • Continuous Revlimid plus dexamethasone (Rd) as compared with four cycles of Rd plus autologous stem cell rescue had similar progression-free survival and overall survival
  • Patients should watch for evolving data.

(Sources: Palumbo, A. et al. NEJM. 2014: 371(10):895-905; Attal et al. ASH 2015 Abstract #319; Lentzch, S. et al. ASH 2015 Abstract #1975)

Types of transplant

  • Peripheral blood stem cell (PBSC) transplant – Doctors remove healthy stem cells from a patient’s circulating blood system (not from the bone marrow) and store them before the patient receives high-dose chemotherapy to destroy the cancer cells. The stem cells are then returned to the patient, where they can produce new blood cells to replace cells destroyed by the treatment. Using PBSC for autologous transplantation allows for easier and safer collection of stem cells and faster recovery after the transplant than bone marrow transplant.
  • Autologous transplant – A procedure in which stem cells are removed from a patient’s blood and then are given back to the patient following intensive treatment.
  • Bone marrow transplant – This term refers to the process of collecting stem cells from the bone marrow and infusing them into a patient. This term is used less frequently today in myeloma as stem cells are now collected from the peripheral or circulating blood.
  • Allogeneic (allograft) transplant – The infusion of bone marrow or stem cells from one individual (donor) to another (recipient). A patient receives bone marrow or stem cells from a compatible, though not genetically identical, donor. An HLA blood test is done to determine if a patient has a potential donor match. A donor may be a family member or may be obtained through a donor registry such as the National Marrow Donor Program (NMDP). Rarely, donor cells may be obtained from an umbilical cord blood bank.
  • Reduced-intensity conditioning (RIC) allo transplant – A newer and, for myeloma, safer technique than an allogeneic transplant. RIC is a non-myeloablative, reduced-intensity “mini-allo” transplant performed within 180 days after a standard autologous transplant.
  • Tandem transplant – A term used to indicate two transplants. This may be two autologous transplants or an autologous transplant followed by an allogeneic (donor) transplant. Tandem transplants are usually planned at three to six month intervals between transplants.
  • Matched unrelated donor (MUD) transplant – Refers to a stem cell transplantation procedure in which the patient and the stem cells are genetically matched but are not from family members. This procedure is not recommended for myeloma patients because it carries an unacceptably high mortality rate.
  • Syngeneic transplant – The infusion of bone marrow or stem cells from one identical twin into another.
  • Umbilical cord blood transplant – Stem cells obtained from the umbilical cords of newborns. These are frozen and stored in cord blood banks.

Are you a transplant candidate?

HDT with stem cell rescue is a treatment option for many myeloma patients but several factors must be taken into consideration.

Patient-related factors

Age is the first factor to consider. Transplant is usually considered for patients under age 65. Since high-dose chemotherapy is an intensive regimen, the patient must be medically fit enough to withstand it, with no major underlying medical issues. Some older patients are in excellent physical health and could be considered fit and transplant-eligible. Transplant eligibility is evaluated on an individual basis.

Disease-related factors

These risk-related factors include the type of myeloma, the stage of the disease, its aggressiveness and responsiveness to treatment, the levels of serum albumin and beta-2 microglobulin, and the presence or absence of certain chromosomal abnormalities in the patient’s myeloma cells. While there are similarities between patients, each patient’s disease has its own distinct characteristics. Therefore, general statements regarding patient outcomes both during the transplant procedure and post-transplant are inappropriate.

When to transplant

There is no absolute clinical data to suggest that transplantation earlier in the treatment regimen is better than waiting until later. Clinical trial results suggest that frontline therapy that includes an immunomodulatory drug and a proteasome inhibitor in combination may result in response rates and duration of response comparable to those of stem cell transplant, allowing some patients to postpone transplant until later in the course of the disease. This hypothesis is undergoing continued investigation.

It’s important to remember that even if someone is a good transplant candidate, it is ultimately the patient’s decision whether or not to have a transplant. It is possible to have stem cells harvested and saved for a later treatment, leaving the patient open to other more immediate treatment options. These are things to discuss with your physician. 

The transplant procedure

Blood stem cells are located in the bone marrow. Stem cell growth factors (also known as “colony-stimulating factors”) are injected to trigger the release of bone marrow stem cells into the bloodstream. These peripheral blood stem cells are then harvested and frozen for use within days, weeks, or years in the future. There are three main methods for collecting stem cells:

1.  Giving growth factors alone.
2.  Giving growth factors with chemotherapy.
3.  Using a stem cell mobilization agent with growth factors.

The harvesting and processing of stem cells

The removal of white cells from the blood stream (“harvesting”) is called apheresis or leukapheresis, a procedure whereby blood from the patient or donor passes through a machine that uses a centrifuge technique to separate and then remove stem cells. The rest of the blood is immediately returned to the patient or donor. The procedure lasts 3 to 4 hours each day for 1 to 5 days, and is usually done on an outpatient basis. Compared to bone marrow harvesting, this is a simple and pain-free procedure.

Side effects of apheresis are temporary and are caused by changes in the volume of the patient’s blood as it circulates in and out of the apheresis machine, as well as by the blood thinners added to keep the blood from clotting during the procedure. The most common side effects experienced during apheresis are slight dizziness and tingling sensations in the hands and feet. Less common side effects include chills, tremors, and muscle cramps.

After collection, the peripheral blood is taken to the processing laboratory for freezing (cryopreservation). The stem cells are mixed with a solution containing dimethyl sulfoxide (DMSO), then frozen and stored in liquid nitrogen. The stem cells can be stored frozen for as long as necessary until the time they are transplanted. Excellent function of stems cells is retained for at least 10 years

How many stem cells do I need?

A number of studies have been completed to determine the number of stem cells you need to safely undergo high-dose therapy. The number is quantified by a laboratory technique called “CD34+ cell analysis by flow cytometry.” A minimum number of stem cells to safely complete a transplant is 2 million CD34+ cells per kilogram of body weight. The stem cell collection process continues daily until the planned number of stem cells is collected. Most transplant physicians collect enough stem cells for two transplants (at least 4 million CD34+ cells per kilogram of body weight). The patient should discuss with the physician the pros and cons of more than one transplant performed back-to-back versus the possibility for a potential second transplant at a later time.

Administering high-dose chemotherapy

After the harvested stem cells are frozen, the patient is ready to receive high-dose chemotherapy to destroy the myeloma cells. High-dose chemotherapy kills myeloma cells inside the patient’s body more effectively than standard-dose chemotherapy. Depending on the treatment center, type of myeloma, and other factors, some patients may receive a second transplant 3 to 6 months after the first transplant. 

Autologous stem cell transplant or infusion

Since high-dose treatment destroys the normal bone marrow in addition to the myeloma cells, the collected stem cells are unfrozen and given back given back into the bloodstream through a catheter one to two days after administration of the high-dose chemotherapy. This infusion is often referred to as the transplant. It is not a surgical procedure and usually takes place in the patient’s room over the course of 1 to 4 hours. Infused stem cells travel through the bloodstream to the bone marrow, where they begin to produce new blood cells, a process called “engraftment.” It takes 10 to 14 days for the newly produced blood cells to enter the bloodstream in substantial numbers, and the patient may be given growth factors to speed up this process. The average time for the chemotherapy, transplant, and recovery is approximately 3 weeks. Not all transplant centers require that patients remain in the hospital after the infusion of stem cells.

In addition to obliterating the bone marrow, high-dose chemotherapy can cause other severe side effects, which may require hospitalization for treatment during this period. Some of the more common side effects include nausea, vomiting, diarrhea, mouth sores, skin rashes, hair loss, fever or chills, and infection. Medications are given to prevent or lessen some of the expected side effects, and patients are closely monitored during and after the administration of high-dose chemotherapy. 

Preventing infection

Until engraftment of the stem cells takes place, the body’s immune system is weakened by the effects of the high-dose chemotherapy, and patients are very susceptible to developing infections. Even a minor infection like the common cold can lead to serious problems. Therefore, special precautions are necessary during recovery. Patients may remain in the hospital until the white blood cell counts reach a level safe enough for the patient to be discharged. Patients and their caregivers are given instructions for maintaining a safe environment at home to help prevent infection while the immune system continues to recover. The following measures may be required:

To prevent infection, the following supportive care measures may be required:

  • Antibiotics are often prescribed to help prevent infection.
  • Visitors should wash their hands and may be asked to wear masks, gowns, and rubber gloves to protect the patient.
  • Fresh fruits, vegetables, and flowers may be prohibited from the patient’s room as these can carry bacteria and fungi.
  • If infection or fever occurs (as the result of lowered white cell counts), the patient may be admitted to the hospital and be given intravenous antibiotics.

Engraftment and recovery

After the transplant, many transplant centers use white blood cell growth factors (e.g., Neupogen®, Neulasta®, Leukine®) to help stimulate the bone marrow to produce normal blood cells. These injections continue until the white blood cell count returns to normal. During this time, red blood cell and/or platelet transfusions may be necessary. Once symptoms resolve and the risk of serious infections is reduced, transfusions will no longer be needed.

Although patients may be well enough to leave the hospital, the recovery process will continue at home for 1 to 4 months, and patients usually cannot resume normal activities for up to 3 to 6 months, although this varies from individual to individual. Having a support network is very important during this time. Waiting for the transplanted stem cells to engraft, for blood counts to return to safe levels, and for side effects to disappear is often the most difficult time for both patients and their loved ones. It is important to take things one day at a time: one day a patient may feel much better, but the next day feel too weak to do much more than sleep. 

Psychosocial issues

High-dose chemotherapy with stem cell rescue can place physical, psychological, emotional, and financial stresses on patients and their families. You may experience feelings of anger, depression, and anxiety over an unknown future and a lack of control. We urge you to take advantage of support services offered through the hospital and other organizations, including myeloma support groups, or to seek a referral from your oncologist for psychological counseling or psychiatric consultation.