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Allogeneic stem cell transplantation in children


Medical editor Anders Glomstein MD
Pediatric Oncologist
Oslo University Hospital

General

An allogeneic stem cell transplant facilitates intensive treatment with chemotherapy that is sometimes combined with total body radiation for leukemia. The treatment eradicates the original bone marrow (myeloablative). This treament can cure otherwise incurable blood diseases. An immunological effect against the remaining leukemia cells is often achieved.

An allogeneic stem cell transplant is performed by transferring hematopoetic stem cells from a donor who usually has an identical tissue type but otherwise genetically different from the patient.

The patient should not have advanced disease and there must be a suitable donor. If it is possible to choose between multiple donors, it is recommended to choose a donor of the same sex. If the patient is CMV negative, the donor should preferably be CMV negative too.

Indications

Acute lymphatic leukemia

  • At the first remission with certain high risk criteria 
  • In second remission (within 6 months after finished chemotherapy). Not after isolated recurrence in CNS or testis. 

Acute myelogenous leukemia

  • In the first remission for high risk criteria 
  • Other remission

Chronic myelogenous leukemia and juvenile myelomonocytic leukemia

  • As soon as possible after the diagnosis

 Goal

  • Cure

Background

A related donor is preferable. Currently, a related donor with up to one incompatible HLA antigen can be used.

If the patient does not have a related donor, an unrelated donor with HLA A/B and DR identity can be accepted.

Stem cell transplants for leukemia with bone marrow from HLA-identical, unrelated donors gives almost as good results as using stem cells from related donors. 

Unrelated donors will, despite compatibility using serological techniques, still have small differences in HLA molecules which are of significance for GVHD (graft-versus-host disease) and rejection reactions. Genomic typing in HLA class II systems (DR, DQ, DP) is therefore carried out routinely and emphasizes the choice of the donor.  

If a live donor cannot be found for the patient, it is in rare cases, possible to find cord blood as a source for stem cells.

Harvesting of bone marrow

To harvest stem cells from a donor, the donor is given general anesthesia while lying on their abdomen. The bone marrow is aspirated by repeated punctures in the iliac crests. The aspirated bone marrow with the stem cells is transferred to blood bags containing heparin. The sufficient amount of nucleated cells to be transferred from the donor is 3 x 108 cells/kg bodyweight.  


Preparation

Tissue typing

As soon as the indication is clear and the leukemia is in remission, HLA (human leukocyte antigen) and ABO typing should be performed on the child, parents, and siblings. Rarely, typing of other relatives is necessary. If an appropriate donor is found the child and the donor must be typed again and work-up of donor started. This should take place at minimum three weeks before the planned stem cell transplant. 

If there is no suitable donor in the family and there is an indication to use an unrelated donor, the request must be sent to the Institute for Transplant Immunology at Oslo University Hospital. The request must be sent via the pediatric unit. Specimens for retyping of the patient should also be forwarded.

Work-up of donor

A related donor should have a work-up including:

  • anamnesis
  • general medical status
  • blood tests
  • thoracic X-ray
  • EKG

The donor must be informed and understand the procedure as well as possible. Sibling donors should be referred to the psychiatric section for children and youth.

Preparation for patient

The child will usually have had the work-up at the regional pediatric unit.

Retyping of the child and donor should be completed and satisfactory. 

The child should be free of infection.

The child and the family should be informed of the procedure and the prognosis. The family should be referred to the pediatric unit at Oslo University Hospital to obtain information before the transplant.

The request for the transplant should be sent to the BMT group at the pediatric unit at Oslo University Hospital.

Intravenous access

The child should have a double lumen Hickman/Chemocath central venous catheter. A venous access port cannot be used. If the patient already has a functioning single-lumen catheter, it should be used. The catheter should be inserted/changed at least 14 days before the transplant. 

Transfusion therapy

All blood products given during the time frame from one month before the transplant to at least 12 hours afterwards, must be radiated to prevent possibility of proliferation transfused T-lymphocytes in the immunosupressed patient, causing GVHD (graft versus host disease). Radiation is necessary despite always using leukocyte-filtered blood products. The absolute limit for a thrombocyte transfusion (apharesis cells) is 20 x 109/l.

Antibiotic prophylaxis

Before starting the transplant, trimethoprim-sulfa should be given as prophylactic treatment against pneumocystic jirovecii. The medication is stopped four days before the transplant but is resumed if the graft is stable. The treatment continues for 6 months from the transplant in patients without chronic GVHD provided the granulocyte count remains over 0,5 x 109/l. Patients needing steroid treatment and/or have chronic GVHD should continue with treatment for pneumocystic carinii past 6 months.  

Aciclovir and fluconoazol are given from the day before the transplant until 3 months after. 

GVHD prophylaxis

Cyclosporin and methotrexate are given routinely to prevent acute and chronic GVHD.

Sperm banking

It is important to offer sperm banking to post-pubertal boys if practical, before starting chemotherapy. It is realistic to assume the patient will be sterile after the transplant.

Freezing of ovarian tissue

Banking ovarian tissue for older girls is still under trial, and is not offered routinely. 


Implementation

Conditioning

Bone marrow eradication treatment

For malignant blood diseases, a high-dose combination of busulfan and cylcophosphamide is given during the last 8 days before the transplant. Busulfan is given for 4 days and cyclophosphamide is given for 2 days. For acute lymphoblastic leukemia, fractionated total body radiation is given instead of busulfan for children older than 4-5 years.

Prevention of hemorrhagic cystitis

Metabolites of cyclophosphamide cause damage to and inflammation of the mucosal lining of the bladder with subsequent bleeding. To prevent this the following is administered:

  • Forced hydration – starting before the first dose of busulfan (or cyclophosphamide for total-body radiation) with continuous intravenous infusion and measurement of diuresis. Hydration is stopped approximately 20 hours after the last infusion of cyclophosphamide
  • Mesna – uroprotection given intravenously for prevention of urinary tract toxicity in connection with administration of cyclophosphamide

Nausea and treatment

Ondansetron is given to treat nausea. Other medications are used in cases where this regimen is insufficient.

Infusion of stem cells

The stem cells are transferred to the recipient via intravenous infusion, as in a normal blood transfusion.

Between 2-4 weeks, the granulocytes will start to appear in the patient's peripheral blood. Effective platelet production usually starts somewhat later.  

For ABO incompatibility between the donor and recipient, serious hemolysis may occur. Therefore, antibodies must be removed either by plasmapheresis, if the recipient has antibodies in a high titer against the donor erythrocytes, or by removing the plasma from the donor marrow if the donor has a high titer against the recipient. Sometimes erythrocytes must be removed from the stem cell product.

 


Follow-up

During the first weeks after a stem cell transplant, the child is very susceptible to infections, especially bacterial infections. The child will remain in protected isolation with positive pressure ventilation and filtered air from the day of the transplant. Strict isolation can be suspended when granulocytes are >1.0. During the period of isolation, the child/parents and health personnel must follow their respective routines to reduce the risk of infection. Parents may be allowed in during the day, but the child should preferably sleep alone in the isolation room at night.

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
  • daily temperature, pulse, and blood pressure
  • weight measurement 
  • fluid balance
  • urinalysis

Platelet and erythrocyte transfusions

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

ABO-incompatible donor

After a stem cell transplant with an ABO-incompatible donor, erythrocytes of type O are given until the child's blood type has changed into the donor's blood type.

Nutrition

Chemotherapy generally causes nausea and vomiting. Medications can also influence sense of taste and reduce appetite for days, weeks or months. Most children also experience mucositis with somewhat significant pain after intense chemotherapy.   

The child's nutritional status is monitored and the need for tube feeding and total parenteral nutrition (TPN) is assessed individually. Almost all children need tube feeding and TPN for a period after conditioning and in the aplasia phase. 

Mucositis

Mucositis, both in the mouth and other mucosal lining 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.

For painful mucosa in the rectum, the child should be well lubricated. It is best to use soft toilet paper dampened with peanut oil and lubricate well after each toilet visit. A bath with green soap will soothe the pain.

Diarrhea

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

GVHD can also cause intense diarrhea. This type of diarrhea can occur a few weeks after the transplant, about the time when the new marrow starts to function, but also later on.

Intense and broad spectrum antibiotic treatment in the aplasia phase will cause changes in the intestinal flora with diarrhea. The child is also susceptible to infection from foodstuff. 

Nutritional status is generally controlled by feeding the child through a tube and TPN with substitution of fluid, electrolyte, and protein loss.

Complications

Serious complications should always be expected after the transplant.

Infections

Due to large doses of busulfan and cyclophosphamide, the child will have a serious immune defect and granulocytopenia during the first few days after taking the medication. Both GVHD prophylaxis and GVHD requiring treatment with steroids or other immunosupressant, aggravate the immune defect. Even after a sufficient number of granulocytes have appeared, the immune system is still weakened, with a significant risk for infections. 

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

  • cytomegalovirus (CMV)
  • fungus (candida og aspergillus)
  • pneumocystic carinii

The patient must therefore be monitored for the CMV antigen or by PCR for CMV. 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. The child should routinely receive trimethoprim-sulfa against pneumocystis carinii for at least 6 months after the transplant. Be aware of new lung infiltrates, especially in children with chronic GVHD.

In serious granulocytopenia, normal signs of infection will often be lacking because the child will not produce pus. The aplasia phase almost always involves bacterial infections which can quickly become very serious. The only signs of infection may be pain or fever, which must therefore be taken very seriously in these types of patients.

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

If the child becomes afebrile from the treatment, the treatment should continue until the granulocyte count increases and CRP is negative.

Fungal infection

In children in the aplastic phase receiving antibiotics for 5-7 days without becoming afebrile, or in children 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.

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 thorax is often negative in the aplasia phase. Infiltrates may be visible when the granulocytes return after the cytopenia phase, but worsen radiologically despite the child receiving adequate treatment and becoming better clinically. It is therefore very important to make a close clinical observation.

Interstitial pneumonia

Interstitial pneumonia is a feared complication in stem cell transplant patients. Interstitial pneumonia can occur both before and many months after the engraftment. The condition may be due to infections susceptible to treatment, for example: 

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

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

CMV infection

A cytomegalovirus infection is not uncommon after an allogeneic stem cell transplant and is often due to reactivation of a virus in sero-positive patients. Acute GVHD and its treatment increase the risk. 

The manifestations can vary from asymptomatic virus production demonstrated 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 transplant 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 transplants.

Detection of a CMV infection (positive pp65 or CMV-PCR) will usually lead to initiation of treatment with ganciclovir. The dose is reduced in case of reduced renal function. CMV-PCR should be checked at least once a week during the treatment.

Hepatic veno-occlusive disease

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

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

The treatment is expectant and symptomatic. Fluid restriction is recommended. The child must be followed clinically very closely with monitoring of fluid and electrolyte balance. 

Thrombotic microangiopathy

Microangiopathic hemolytic anemia (MAHA), hemolytic-uremic syndrome (HUS), and thrombotic thrombocytopenic purpura (TTP) occur very rarely, but carry a risk of serious complications. The pathogenesis is only partly known, but endothelial damage is a central factor. 

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 often exchanged with tacrolimus. Plasma exchange may also be tried.

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 last after the stem cell transplant. Thrombocytopenia may also be due to increased consumption of platelets from infection, GVHD, and immunization. 

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, hepatic disfunction, altered taste or medications. If the child in addition has dysphagia, esophagitis, gastritis, or a gastric or duodenal ulcer may be the cause. Intravenous feeding may in itself cause anorexia in some children.  

Hemorrhagic cystitis

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

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

Follow-up plan

The child is usually discharged to the regional pediatric unit. After returning home, the child is followed-up closely on an outpatient basis.

Routine checks at Oslo University Hospital is usually 3 and 6 months after the transplant and thereafter yearly.


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