Relapsed ALL: Questions for Parents to Ask

by Patty Feist BS, MS
Source: CCCF Newsletter, Spring/Summer 2007

Relapsed acute lymphocytic leukemia (ALL) is the fourth most common childhood cancer. Treatment for relapsed ALL is one of several regimens of aggressive chemotherapy and radiation with or without a bone marrow transplant. Which regimen is advised depends on the characteristics of the relapse and, to some extent, the opinions of the doctors that you consult. Most pediatric oncology teams agree that early isolated bone marrow relapse should be treated by a bone marrow transplant, while late extramedullary (EM) relapse should be treated by chemotherapy. Other situations, for instance, a combined late relapse, are not as clear cut. Since there is not a consensus of the best treatment plan for relapsed ALL, parents often face difficult choices.

Reasons for the lack of a standard treatment plan for relapsed ALL include the limited number of patients available for studies, a variety of therapeutic strategies employed at different institutions, and the unclear role of bone marrow transplants. Even though different institutions often use widely different treatment plans, they report similar event free survival rates. The prognosis for relapsed ALL is poor, with five year survival rates for high- to low-risk ALL ranging from 10-60%.

Parents need to ask a lot of questions so that they can make an informed decision on the treatment plan. The questions (and answers) in the sections below were compiled by parents who are members of the ACOR e-mail lists: ALLkids and ALL-kids-relapsed. These parents want to help other parents in the same situation make informed choices for their child. The questions also encourage parents to find out about supportive care that might be available during their child's treatment.

Parents of children with relapsed ALL are welcome and encouraged to join the ACOR e-mail lists. The list parents are highly informed on relapsed ALL, from the details of the protocols, to which doctors they like the best, to how to deal with side effects, to all aspects of bone marrow transplants. Additionally, the parents provide emotional support for one another. Follow the links below to join one or both of the ALL lists:

listserv.acor.org/archives/all-kids-relapsed.html and listserv.acor.org/archives/all-kids.html

*A note from parents: Take a tape recorder to your meeting with the oncology team.

Type of Relapse

Question: What kind of relapse is it: bone marrow, EM (extramedullary, meaning in the spinal fluid, testes or elsewhere outside of the bone marrow), or a combination?

  • Answer: In general, isolated bone marrow relapses are considered higher risk and are treated more aggressively than are EM relapses. Some combined relapses in the bone marrow and spinal fluid are considered more favorable than strict bone marrow relapses.

Question: If the relapse is in the spinal fluid (CNS, central nervous system), how many blasts are in the spinal fluid?

  • Answer: To be considered a strict CNS relapse (so called "CNS 3"), there must be at least 5 white blood cells/microliter in the CSF and blasts must be present on cytospin. On occasion, a few white blood cells show up in the CNS and are not indicative of relapse. Ask the oncology team why they are absolutely sure that the cells in the CSF indicate relapse.

Question: Is this considered an early or a late relapse?

  • Answer: In general, early relapses are considered higher risk and are treated more aggressively. A designation of "early" or "late" depends on whether the relapse is in the bone marrow or EM. Different institutions have different definitions of early and late relapse.

Children's Oncology Group (COG) definition of early/late relapse:

  • Early marrow relapse is defined as a marrow relapse that occurs less than 3 years from initial diagnosis. COG designates this type of relapse as "high risk."
  • Late marrow relapse is defined as a marrow relapse that occurs more than 3 years after the initial diagnosis. COG designates late marrow relapse as "intermediate risk."
  • Early isolated EM relapse is defined as an EM relapse that occurs less than 18 months after the initial diagnosis. COG designates early isolated EM relapse as "intermediate risk."
  • Late isolated EM relapse is defined as an EM relapse that occurs more than 18 months after the initial diagnosis. COG designates late onset isolated EM relapse as "low risk." Note that a child can still be on frontline treatment and have a late EM relapse.

St Jude definition of early/late relapse:

  • St. Jude designates high-risk and standard-risk according to the length of the first remission, the type of cancer (T-cell or pre- B-cell), and whether the relapse is in the marrow or EM. In general, bone marrow relapses are considered "early" if they occur during the first-remission treatment or in the first 6 months after completion of treatment.

BFM (Berlin-Frankfurt-Münster Group, Germany) definition of early/late relapse:

The following table shows the relapse risk classifications of the BFM Group. The table was adapted from journal articles and from the www.cancer.gov page references at the end of this article. 

 
non T-cell ALL
T-cell ALL
  EM combined marrow/EM isolated marrow EM combined marrow/EM isolated marrow
very early (less than 18 months from diagnosis) intermediate highest highest intermediate highest highest
early (over 18 months from diagnosis and less than 6 months past completion of therapy) intermediate intermediate high intermediate highest highest
late (over 6 months past completion of treatment) standard intermediate intermediate standard highest highest

Treatment Plan: General

Question: What do we do now to get our child back into remission?

  • Answer: Treatment is likely to begin immediately. Ask exactly what the treatment will be, if it is part of a protocol, and if any treatment given would prevent your child from taking part in a clinical trial.

Question: What treatment plan do you advise for our child and why?

  • Answer: Treatment will be chemotherapy with or without bone marrow transplant and often includes radiation. Many factorsdetermine which treatment plan will be recommended, including early or late relapse, site of relapse, type of leukemia, and the availability of a suitable bone marrow donor. Some cases are clear-cut as to which treatment is preferred, and some cases might be treated with similar expected outcomes by different protocols.

Question: Explain why you advise either the chemotherapy alone or transplant.

  • Answer: There are advantages and disadvantages to each of these types of treatment. Transplant may mean a higher cure rate, but incurs more toxicity, treatment-related mortality, and possibility of long term effects. The nontransplant nontransplant route can mean a slightly lower cure rate, a longer treatment, but is less likely to cause treatment-related mortality and long term effects. For a more comprehensive discussion regarding this issue please see: www.all-kids.org/chemovstrans.html.

Question: Will my child be offered a study (clinical trial) for either route (transplant or no transplant)?

  • Answer: Clinical trials, or studies, are investigative treatment plans that have several arms. If a study is offered, ask if it a phase I (usually indicated in patients who have relapsed multiple times), II, or III trial. For a more comprehensive explanation of the various clinical trial phases, please see the Candlelighters' article on Clinical Trials.

Question: If my child is not on a clinical trial, will the protocol be followed completely in relation to drugs given and the schedule of chemotherapy and/or transplant?

  • Answer: The best treatment arm of completed clinical trial protocols usually becomes the standard treatment plan for future generations of patients. Oncologists have the option to follow these standard treatment plans to the letter, or to modify them as their experience and knowledge dictate. Ask the team for a copy of the protocol your child is being placed on, as well as the rationale behind any modified treatment that they propose.

Treatment Plan: Specifics

Question: Will levels of minimal residual disease (MRD) be measured during treatment? Will the levels direct the treatment plan? Will we be given the results of MRD testing?

  • Answer: Only a few institutions have MRD studies on relapsed patients (for instance, St Jude and BFM) and use the results to direct treatment. COG trials routinely measure MRD levels at certain times during relapse treatment, but as of 2007, the MRD levels do not direct the treatment itself.

Question: What are the cytogenetics/molecular diagnostics of the relapsed leukemia? Is the relapse showing the same cytogenetics as the initial diagnosis? If different, what does that mean for treatment?

  • Answer: In almost all cases the original cytogenetics are seen in the relapsed clone although additional changes may be seen also.

Question: Could this possibly be a secondary leukemia? If so, would that change the way my child is treated?

  • Answer: Less than 1% of "relapses" represent second malignancies induced by the original treatment.

Question: What are the cytogenetics, and are there certain treatment plans that are known to work best with this type of leukemia? (St. Jude and COG, for instance, have studied how to individualize treatments.)

  • Answer: In contrast to initial diagnosis, in general, the cytogenetics at relapse do not dictate the type of therapy. Philadelphia positive (Ph+) cases at diagnosis and relapse are likely to be treated with drugs targeted to this defect.

Question: Does the type of original/frontline therapy my child had influence which treatment is recommended?

  • Answer: It has not been proven that there is a better outlook for those who were on low-risk treatment in frontline therapy. The gold standard for prognosis in relapse is still time to relapse and site of relapse, as well as whether it is T-cell or pre-B cell leukemia. Thus, the type of frontline therapy, aggressive or less-aggressive, will not influence relapse treatment except in the case where the maximum cumulative dose for any of the chemotherapy agents has been reached.

Question: If transplant is recommended, what is the timing strategy for the transplant?

  • Answer: Optimal timing for relapse is when the disease burden is minimal (after two or three cycles of chemotherapy) and when the donor is available. In general the time of transplant is three months or so after the start of re-treatment.

Question: If radiation is to be included, what are the age parameters suggested at this facility?

  • Answer: Total body irradiation has been shown in many circumstances to be an optimal component of the "preparative" regimen for bone marrow transplant. However in very young children under three years of age other approaches may be considered.

Question: If testicular relapse is diagnosed, is it necessary to have testicular radiation?

  • Answer: Some studies have shown that the use of high dose methotrexate can replace the need for irradiation. This approach is being explored by COG investigators and others.

Question: If CNS relapse is diagnosed, is it necessary to have CNS radiation? If so, at what dosage?

  • Answer: In almost all cases, some irradiation will be necessary but it may be limited to cranial as opposed to craniospinal radiation (XRT) and in some protocols the dose has also been lowered.

Question: In an early bone marrow relapse, a child will likely be put on a protocol to get them into remission and then a bone marrow transplant will be advised. What happens if a match for the transplant is not found?

  • Answer: While many children may not have a suitable family donor (usually a brother or sister) a "matched unrelated donor" (MUD) is likely to be identified in national and international bone marrow data banks. Certain ethnic groups however are under-represented in these banks and therefore it may be more difficult in these circumstances.

Question: What happens if my child does not go into remission on the protocol that you suggest?

  • Answer: COG and other groups offer alternative re-induction protocols that can be used if the initial attempt at reinduction fails.

Question: Can a central line or port be put in as soon as possible?

  • Answer: Most children want to have the central line placed soon to eliminate the stress of needle pokes.

Question: If child has a port and needs to go to transplant, can they keep it even if they need lines?

  • Answer: In all likelihood, the child will have their port-a-cath replaced with a multi-line hickman.

In addition to the above general questions and answers, the following questions are encouraged to be discussed with your child's oncologist, with answers specific to the various treating institutions.

Question: Can we start relapse therapy at a planned date and map out the schedule of chemotherapy and/or transplant?

Question: What supportive services for associated health services are available? How do we contact the people responsible for these services? (This includes a hospital school, social worker, psychologist, and physiotherapist.)

Question: Is there any neuro-cognitive testing done prior to treatment/ transplant and what kind of follow-up is there post treatment/ transplant?

Question: What are the survival statistics now? What is the five year survival rate?

Coping with/lessening side effects (additional questions to ask your child's oncologist).

Question: Can my child be given dexrazoxane to protect his/her heart from anthracyclines?

Question: What types of treatment do you recommend to prevent mouth sores? (For example: chewing gum, a glutamine supplement, or an oral gel.)

Question: Do you recommend using milk thistle, silymarin, or liver vitamins to help protect the liver?

Final advice from other parents who have been through an ALL relapse with their child: "Make your decision, and don't look back!"

Research:

Question: How can my child's relapsed biopsy be saved and used for future genetic research?

  • Answer: The best opportunity to treat relapse is to prevent it in the first place. Understanding the biological mechanisms that account for drug resistance offers the best hope of finding new treatments. Investigators have now uncovered certain pathways operative in relapsed blasts that distinguish them from the initial diagnosis. These pathways are now being targeted in laboratory experiments to see if interrupting these pathways could improve the ability to eradicate these resistant cells. These and similar types of research studies depend on analyzing blast cells at relapse. Scientists depend on tumor banks for this research. To assist with this important research initiative to help future relapsed ALL children, ask your doctor if a sample of your child's relapsed biopsy can be sent to a central tumor bank so that this important research can continue.

Second Opinions:

What other options are available for this kind of relapse? Below is the contact information for ALL specialists at two institutions regarding second opinions. 

  • Ching-Hon Pui, MD, St. Jude Children's Research Hospital
  • Dr. William Carroll MD, New York University School of Medicine

Special section if a transplant is recommended:

Questions to ask the transplant team (on the ALL-kids web site)

Sources for BFM risk classifications (the table in the first part of this article):

  • www.cancer.gov (excellent resource: go to "recurrent ALL")
  • Journal of Clinical Oncology, Vol 23, No 31 (November 1), 2005: pp. 7942-7950.
  • Blood. 2003 May 15;101(10):3835-9. Anja Borgmann, Arend von Stackelberg, Reinhard Hartmann, Wolfram Ebell, Thomas Klingebiel, Christina Peters, and Günter Henze for the Berlin-Frankfurt-Münster Relapse Study Group. Unrelated donor stem cell transplantation compared with chemotherapy for children with acute lymphoblastic leukemia in a second remission: a matched-pair analysis.
  • Roy A, Cargill A, Love S, et al.: Outcome after first relapse in childhood acute lymphoblastic leukaemia - lessons from the United Kingdom R2 trial. Br J Haematol 130 (1): 67-75, 2005

This article was written by Patty Feist with the help of several members of the ALL-kids-relapsed e-mail list. We are not health care professionals. Medical references include Childhood Leukemia by Chng-Hon Pui, seminars on the St Judes Cure4Kids web site, journal articles listed in the ped-onc bibliography, and parents' copies of treatment plans.