Relapsed ALL: Chemotherapy vs Transplant

by Patty Feist
Source: Fall/Winter 2007 CCCF Newsletter

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. First-remission treatment for ALL is generally standardized, and 80% of children can be expected to achieve a five year event free survival. However, children who do relapse can have treatment options to chose from. Some relapses of ALL are clear cut as how to treat, while some lie in a grey area between transplant and chemotherapy. For instance, combined late relapses fall into this grey zone.

What is a combined relapse?

A combined relapse occurs in both the bone marrow (BM) and extramedullary (EM) fluid. For both Europe and North America, a combined relapse is considered to be BETTER than an isolated marrow relapse, with survival rates supporting this point of view.

What is time to relapse?

While there are numerous factors that impact the probability of achieving a second remission after a relapse, the time from fi rst remission (or if you prefer, from initial diagnosis) to relapse is one important factor. Children who relapse while on their initial treatment have been shown to have a lesser probability of achieving a second remission and subsequent fi ve year survival. These patients have also been shown to have shorter second remissions in comparison to patients who relapse after their initial treatment was complete. Additionally, the length of time that a patient was off treatment prior to the relapse also has been shown to correlate with the probability of achieving a second remission. Studies have shown that those children who relapsed more than 6 months after the completion of their initial treatment had a better fi ve year outcome as compare to those children who relapsed earlier. The European clinical trail study group known as the I-BFM or International Berlin-Frankfurt-Munster group classifi es a combined relapse that occurs after 6 months off therapy (OT) as a late relapse. In contrast, North America's clinical trial group known as the Children's Oncology Group or COG defi nes a combined relapse after 1 year OT as a late relapse.

What are the treatment options?

A stem cell transplant is the infusion of non-cancerous hemopoietic stem cells into the patient to replace their cancerous marrow. An allogeneic transplant occurs when the healthy marrow is donated by an HLA matched individual such as a sibling or matched non-related donor (MUD), after the patient has been treated with high dose chemotherapy and possibly total body radiation. An autologous transplant occurs when the patient's own marrow has been harvested and treated and then re-infused back into the patient after being given high dose chemotherapy and possibly total body radiation. A cord blood transplant uses fetal stem cells that were harvested from the umbilical cord at the time of birth.

Through the use of a high dose conditioning therapy, the bone marrow and associated leukemia cells are destroyed. The donor cells are given to rescue the patient from bone marrow failure. Without donor cells, the high dosage of chemotherapy and radiation used in conditioning for the transplant would literally kill the patient. In addition, the donor cells are also used in the attempt to stimulate a graft vs. leukemia effect so that the donor cells attack any remaining few leukemia cells in the patient, having recognizing them as foreign invaders. In contrast, treatment for relapsed ALL using chemotherapy alone involves the use of chemotherapy at dosage levels that are not in themselves a lethal dose, requiring donor stem cell rescue.

Chemotherapy alone vs. transplant?

In making a decision between transplant or chemotherapy alone, these are some factors to consider.

  • Transplant = a higher cure rate & possibly a shorter overall treatment time. However, treatment with a stem cell transplant will incur more toxicity, more treatment-related mortality, increased possibility of long term effects such as chronic graft vs. host disease (GVHD) which may result in the patient being in-hospital for a long period of time. Potential long term late effects associated with the higher intensity treatment can include sterility, growth defi - cits, late neuro-cognitive defi cits, secondary cancers, long term immunosuppression, cataracts, and other chronic health conditions.
  • Chemotherapy alone = lower cure rate and a two to three year treatment time frame. The treatment is comparatively less toxic, with less treatment-related mortality, and overall less likelihood for chronic late effects. The downside to be considered is the decreased probability of achieving a third remission if the child relapses a second time, with accumulated toxicities involved as a result of 6 years of chemotherapy treatment plus a bone marrow transplant.

Finally, another factor to consider when discussing possible transplant for the child with relapsed ALL is how different types of transplants affect the cure rate.

When you are comparing cure rates between chemo vs. transplant, make sure that you know which type of transplant it is:

  • Fully matched antigen sibling transplant
  • One (or two) antigen mismatched sibling transplant
  • Fully matched antigen unrelated donor transplant
  • One antigen mismatched unrelated donor transplant Fully matched cord blood transplant
  • One, two or three antigen mismatched cord blood transplant

All have different outcomes. Specifically:

  • Best outcome = fully matched antigens (6/6 HLA sibling transplant)
  • Outcome about 5% - 15% lower than (1) = one antigen mismatched sibling transplant and fully matched unrelated donor transplant and up to two antigen mismatch cord blood transplant
  • Outcome about 5% - 15% lower than (2) = two antigen mismatched sibling transplant and one antigen mismatch unrelated donor transplant
  • Unknown outcome = three antigen mismatched cord blood transplant

**Note: for cord blood transplants - when you read the statistics, bear in mind that these types of transplants are relatively new and late effect mortality rate for such transplants are still not known.