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A special note from parents: Take a tape recorder to your meeting with the oncology team. Update, 2011: "There is a general consensus that patients with a late isolated marrow relapse who have low levels of MRD by either flow or polymerase chain reaction techniques can be treated with chemotherapy alone without the need for stem cell transplant. European protocols tend to use a cutoff of <0.1% by PCR techniques for low-end induction MRD. There is controversy regarding the role of allogeneic stem cell transplant in patients experiencing a bone marrow or combined relapse beyond 18 months but prior to 30 months or 6 or more months from therapy completion who show <0.1% MRD at end induction. For all other patients who experience a bone marrow relapse, allogeneic transplant remains the treatment of choice." From Autotransplantation for
relapsed ALL: Going, going, gone? (pages 539-540) James Nachman and Menakshi Devidas Article first published online: 13 JUL 2011. Pediatric Blood and Cancer.
Type of Relapse
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? 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.
An isolated marrow relapse is indicated by M3 marrow. A combined marrow and EM relapse is M2 marrow plus evidence of relapse at other sites.
If the relapse is in the spinal fluid (CNS, central nervous system), ask: How many blasts are in the spinal fluid? 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. Is this considered an early or a late relapse? 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. Below are three institutions' relapse classifications, given as examples. BFM (Berlin-Frankfurt-Mnster Group, Germany) The following table shows the relapse risk classifications of the BFM Group. The table was adapted from journal articles and from the cancer.gov page references at the bottom of this article. non T-cell ALL
EM very early (less than 18 months from diagnosis) combined marrow/EM isolated marrow highest EM
T-cell ALL
combined marrow/EM isolated marrow highest
intermediate highest
intermediate highest
early (over 18 months from diagnosis and less than 6 intermediate intermediate months past completion of therapy) late (over 6 months past completion of treatment) standard intermediate
high
intermediate highest
highest
intermediate standard
highest
highest
COG
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. (Note that on some protocols, a child could still be on frontline treatment and have a late relapse.) 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. Late marrow relapse, OR a combined late marrow/EM relapse, is "intermediate risk".
St Jude
St. Judes designates high-risk and standard-risk according to the length of the first remission, the type of cancer (T- 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 firstremission treatment or in the first 6 months after completion of treatment.
Will my child be offered a study (clinical trial) for either route (transplant or no transplant)? 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. 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? 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.
Comparison of Relapse Protocols Bibliography of some pertinent relapsed-ALL articles (on the ped-onc site) abbreviations, FAQs (www.all-kids.org/faqs.html)
Will levels of MRD be measured during treatment, and will they affect the treatment plan? Will the levels direct the treatment plan? Will we be given the results of MRD testing? 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. 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? In almost all cases the original cytogenetics are seen in the relapsed clone although additional changes may be seen also. Could this possibly be a secondary leukemia? If so, would that change the way my child is treated? Less than 1% of relapses represent second malignancies induced by the original treatment. Considering the cytogenetics, and are there certain treatment plans that are known to work best with this type of leukemia? (St. Judes, for instance, has studied how to individualize treatments.)
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. Does the type of original/frontline therapy influence my child had influence which treatment is recommended? 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. How long is the relapse treatment? If transplant is recommended, what is the timing strategy for the transplant? 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. If radiation is to be included, what are the age parameters suggested at this facility? 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. If testicular relapse is diagnosed, is it necessary to have testicular radiation? 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. If CNS relapse is diagnosed, is it necessary to have CNS radiation? If so, at what dosage? 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. 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? 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.
What happens if my child does not go into remission on the protocol that you suggest? COG and other groups offer alternative re-induction protocols that can be used if the initial attempt at reinduction fails. Can a central line or port be put in as soon as possible? Most children want to have the central line placed soon to eliminate the stress of needle pokes. If child has a port and needs to go to transplant, can they keep it even if they need lines? In all likelihood, the child will have their port-a-cath replaced with a multi-line hickman. Can we start relapse therapy at a planned date and map out the schedule of chemotherapy and/or transplant? 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.) Is there any neuro-cognitive testing done prior to treatment/ transplant and what kind of follow-up is there post treatment/transplant? What are the survival statistics now? What is the five year survival rate? Final advice from parents: "Make your decision, and don't look back!"
Second Opinions
What other options are available for this kind of relapse? (COG, St. Jude's, Dana Farber or other institutions) Below are ALL specialists at several institutions.
Ching-Hon Pui, MD, St. Judes Children's Research Hospital. E-mail chinghon.pui@stjude.org. Dana-Farber Cancer Institute Grace Monaco Dr Eden (UK) Dr. William Carroll MD, New York University School of Medicine Prof Schrappe (BFM) Dr Camitta (CCG)
What types of treatment do you recommend to prevent mouth sores? (For instance, chewing gum, a glutamine supplement, or an oral gel.) Do you recommend using milk thistle, silymarin, or liver vitamins to help protect the liver?
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 pedonc bibliography, and parents' copies of treatment plans. Sources for BFM risk classifications:
Cancer.gov, excellent resource: 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 Gnter Henze for the Berlin-Frankfurt-Mnster 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