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Allogeneic stem cell transplantation with myeloablative conditioning

Follow-up

During the first weeks after a stem cell transplantation, the patient is very susceptible to infections, especially bacterial. The patient will remain in protected isolation with positive pressure ventilation and filtered air from the fifth day after the transplantation (granulocyte count  < 0.2 x 10 9/l). The patient may come out of isolation when the granulocyte count is stable (> 0.2 x 109/l) for at least 3 consecutive days, sometimes longer.

During the period the patient is in isolation, the patient, family and health personnel must follow their respective routines to reduce the risk of infection. Certain routines are performed daily until the new marrow starts to function. The purpose of following these routines is to prevent complications and ensure that possible complications are discovered early.

Daily routines:

  • blood tests
  • rectal temperature, pulse, and blood pressure
  • weight measurement 
  • fluid balance
  • inspection of mouth, throat, and skin

For complications, it is important that treatment is initiated as soon as possible.

Platelet and erythrocyte transfusions

Transfusions of thrombocytes and erythrocytes are necessary in the weeks after the transplantation to maintain platelets and Hb at safe levels.  

ABO-incompatible donor

During a stem cell transplantation with an ABO-incompatible donor, erythrocytes of type O are given subsequent to the transplantation until the erythrocytes in the patient have changed to the donor's blood type.

Nutrition

Chemotherapy generally causes nausea and vomiting. Medications can also influence sense of taste and reduce appetite for days or weeks. Most patients also experience mucositis with considerable pain after intensive chemotherapy.   

The patient's nutritional status is monitored and the need for parenteral nutrition (TPN) is considered individually. Almost all patients need TPN for a period after conditioning and in the aplasia phase. 

Mucositis

Mucositis, both in the mouth and other mucosa and intestines, often occurs when blood values are at their lowest. The intensity of the soreness is individual. Sore mucosa in the mouth is not only an entrance for bacteria, but can also be painful. Prophylactic oral hygiene should be performed during the entire treatment. Painful mucositis may necessitate treatment with analgesics, often opiates.

For painful rectal mucosa, ointment should be liberally applied. After each toilet visit, soft toilet paper dampened with peanut oil and subsequent abundant ointment should be used. A bath with green soap will soothe the pain.

Diarrhea

Patients who have received intensive chemotherapy, and/or total body irradiation, usually experience diarrhea. This is due to temporary damage of the intestinal mucosa from the treatment. Diarrhea can be expected to last during, and a few weeks after the treatment. 

GVHD can also cause intensive diarrhea. This type of diarrhea can occur a few weeks after the transplantation, about the time when the transplantation is expected to take, but also later on.

Intensive and broad spectrum antibiotic treatment in the aplasia phase will cause changes in the intestinal flora with diarrhea. Patients are also susceptible to infection from food. 

Nutritional status is generally controlled by administering total parenteral nutrition with fluid, electrolyte, and protein substitution.

Complications

Some complications should be expected after the transplant. Complications are sometimes serious and life-threatening, and in the worst case, fatal.

Infections

Due to large doses of busulfan and cyclophosphamide, the patient will have a serious immune defect and granulocytopenia during the first few days after taking the medication. 

For serious granulocytopenia, normal signs of infection will often not be present because the patient will not create pus. In the aplasia phase, bacterial infections are almost always primary, which can quickly become very serious. The only sign of infection is often fever, which must be taken very seriously for these types of patients. 

A reliable microbiological diagnosis is obtained relatively rarely. In cases where there is bacterial growth, the treatment is adjusted according to the resistance pattern.

If the patient becomes afebrile from the antibiotic treatment, the treatment should continue for at least 3 days or until the granulocyte count is over 0.2 x 109/l.

Both GVHD prophylaxis and GVHD requiring treatment with steroids or another immunosuppressant, increase immune deficiency. Even after the patient has received sufficient granulocytes, the immune system is still impaired, with a significant risk for infections. 

Important opportunistic microbes which can cause life-threatening infections are:

  • cytomegalovirus (CMV)
  • fungus (candida og aspergillus)
  • pneumocystic jerovecii
  • various bacteria

The patient must therefore be monitored by checking for the CMV antigen or PCR. Only leukocyte-filtered products can be used. These products rarely or never transfer CMV infections. 

One should be aware of new lung infiltrates, especially in patients with chronic GVHD. It is important to try to obtain diagnostic material. The threshold for doing bronchoscopy with broncial rinsing is low.

Fungal infection

In patients who are in the aplastic phase receiving antibiotics for 5-7 days without being afebrile, or who have a new rise in temperature despite adequate antibiotic treatment, a systemic or invasive fungal infection must be considered, especially if another infection cannot be detected in a blood culture. Empirical treatment must be considered with antimycotics in a sufficient dose, often intravenously must be considered.

Pneumonia/respiratory infection

Focal infiltrates are most often due to either a bacterial or fungal infection. It is important to be aware that patients without granulocytes rarely develop obvious infiltrates. An X-ray of the lungs is often negative in the aplasia phase. HR-CT is a much more sensitive examination. Infiltrates may become visible when the granulocytes return after the cytopenia phase, with a radiologically aggravation. This may be in spite of adequate treatment and clinical improvement. It is therefore very important with close clinical observation.

Interstitial pneumonia

Interstitial pneumonia is a lung infection with numerous small areas of infection. The condition is a feared complication in stem cell transplanted patients. Interstitial pneumonia can occur both before and many months after the engraftment. The mortality is high. The condition may be due is due to infections sensitive to treatment. 

  • CMV infection
  • Pneumocystic jerovecii (observed rarely during trimetoprim-sulfa prophylaxis)

It is therefore very important to initiate the correct treatment. Patients with interstitial pneumonia can quickly become dependent on a respirator and must be followed closely with a pulse oxymeter and by monitoration of arterial blood gases.  

CMV infection

A CMV infection is not uncommon after an allogeneic stem cell transplantation and is often due to reactivation of a virus in sero-positive patients. Acute GVHD and treatment of this increases the risk. 

The manifestations can vary from asymptomatic virus production via thrombocytopenia and leukopenia, to unexplained fever, hepatitis or gastrointestinal symptoms with life-threatening interstitial pneumonia. 

CMV pneumonitis typically occurs 40-60 days after the transplantation but can also occur later on. The fear of CMV pneumonitis is one of the reasons leukocyte-filtered products are used for allogeneic stem cell transplantations.

Detection of a CMV infection (positive pp65 or CMV-PCR) will usually lead to starting treatment with ganciclovir. The dose is reduced for reduced renal function. For granulocytes under 0.7 x 109/l, foscarnet is given instead. pp65 or CMV-PCR should be monitored at least once a week during the treatment.

Hepatic veno-occlusive disease

This condition is due to chemotherapy and/or total body irradiation. An obstruction of sinusoidal blood flow is due to damaged terminal hepatic vessels and sublobular veins. The condition is rare and is often observed 3-4 weeks after the transplant. 

The elevation of transaminase at the time of the transplantation causes an increased risk for hepatic veno-occlusive disease. The first sign is often gradual weight increase and increased need for platelet infusion. The patient may have intense abdominal pain, especially in the epigastrium and right hypochondrium, elevated bilirubin, and transaminase, with enlarged liver and soreness. Ascites may appear with weight gain, encephalopathy, and coagulopathy. At a later stage, the patient may develop hepatorenal syndrome.    

The treatment is expectative and symptomatic. The patient must be followed clinically very closely with monitoration of fluid and electrolyte balance. The prognosis is poor for serious involvement.

Thrombotic microangiopathy

These conditions occur rarely, but are potentially serious complications which affect about 5% of patients. The pathogenesis is only partly known, but endothelial damage is a central factor.

  • Microangiopathic hemolytic anemia (MAHA)
  • Hemolytic-uremic syndrome (HUS)
  • Thrombotic thrombocytopenic purpura (TTP)

 Symptoms are:

  • serious hemolysis 
  • renal failure
  • thrombocytopenia
  • neurological manifestations due to reduced circulation in capillaries

The benefit of therapeutic measures is controversial. Cyclosporin A is replaced with mycopholate or tacrolimus. A problem is that tracrolimus can also cause thrombocytopenia. It is also possible, but seldom effective, to perform plasma exchange.

Acute GVHD

Graft-versus-host disease is a condition where T-lymphocytes from the donor attack cells and tissue of the patient.

Bone marrow failure

Bone marrow failure refers to lasting anemia, leukopenia, and thrombocytopenia. Causes for bone marrow failure may be: 

  • rejection of bone marrow
  • delayed engraftment
  • infection (CMV among others)
  • bone marrow-toxic medications
  • GVHD

Megakaryocyte function is restored often lastly restored after the stem cell transplantation. Thrombocytopenia may also be due to enhanced consumption of platelets from infection, GVHD, and immunizing. 

In addition to reduced marrow function, anemia may be due to bleeding and/or hemolysis. For ABO incompatibility, a significant delay of adequate erythropoiesis is often observed (up to one year).

Long-term anorexia

Anorexia may be due to infection, GVHD, renal dysfunction, or medications. If the patient in addition has problems with swallowing, esophagitis, gastritis, or an ulcer may be the cause. The nutritional status should be maintained intravenously, as needed, which itself may cause anorexia in some patients.  

Hemorrhagic cystitis

Hemorrhagic cystitis is primarily due to high doses of cyclophosphamide, however, high doses of busulfan also play a role. Despite prophylactic measures with forced hydration and mesna, some patients still develop hematuria/dysuria/pollakisuria. The symptoms generally appear during or in the first three days after a cyclophosphamide infusion. Some patients can also develop hemorrhagic cystitis later on, possibly as a manifestation of GVHD, but also from a viral infection (CMV, adenovirus, BK virus).

The treatment is to continue or resume forced hydration/diuresis. Analgesics or antiviral treatment is started if necessary. 

Recurrence after allogeneic stem cell transplantation

For recurrence after a transplantation for CML, it has been shown that an infusion of T-lymphocytes from the donor causes complete remission in about 70% of patients who recur to a chronic phase. This GVL (graft-versus-leukemia) effect is more poorly documented in recurrence after transplantation for acute leukemia.

Further follow-up

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