We have received the following case:

"I am a Haematologist at Peter MacCallum Cancer Centre, and would appreciate the iCMLf’s consideration of a difficult-to-treat, multiply resistant case of CML who is currently under my care. The case summary is as follows.

The patient has given her consent for this case to be put on the forum for discussion.

33 year old woman with CML diagnosed February 2009. Initial cytogenetics showed standard t(9;22), BCR-ABL 92%.
Imatinib was commenced at 400mg, poorly tolerated with fluid retention, nausea, weight gain, fatigue.
PCR after imatinib for 2 months was 23%.
PCR after imatinib for 7 months was 32%, with continuing poor tolerance.
Switched to Dasatinib on grounds of poor response to imatinib.
PCR after Dasatinib for 3 months was 16%.
PCR after Dasatinib for 5 months was 1.3%. Dasatinib intolerance with grade 4 somatic pain requiring narcotic analgesia.
Switched to Nilotinib.
PCR after Nilotinib for 3 months was 28%. Repeat at 3.5 months was 24%.
BMAT at this stage showed CML-chronic phase, Ph+ve in 41% cells, no clonal evolution. Negative for mutation testing.
Switched to Compassionate Access Bosutinib.
PCR after Bosutinib for 3 weeks was 12%. Severe intolerance with grade 3 nausea and grade 3-4 diarrhea despite maximum antinausea and antidiarrheals.
PCR after 7 weeks Bosutinib was 27%.
PCR after 11 weeks Bosutinib was 59% with rising white cell count to 30.9x10^9/L, no basophils, no splenomegaly.
BMAT at this stage confirms CML, likely early accelerated phase, cytogenetics pending.
Currently on hydroxyurea, white cell count now 17.0x10^9/L.
No sibling or matched unrelated donor available on national or international search. Patient is of Christian Lebanese origin.
A double cord unit has been identified however patient is reluctant to have cord blood transplant due to concerns regarding mortality and high risk of significant morbidity if she survives.

Her treating clinician is currently attempting to access compassionate use omacetaxine, awaiting in-vitro testing for ponatinib sensitivity which will take 3-4 weeks, and considering ponatinib study opening in 2-3 months time.

The questions for the forum include:

1. - How hard to push for cord blood transplant.
2. - Role of interferon in a young woman with history of poor tolerance to all available treatments so far.
3. - Level of optimism regarding ponatinib response in the light of resistance to imatinib, nilotinib and bosutinib without a demonstrable mutation.
4. - Level of optimism regarding omacetaxine.
5. - Other options: arsenic trioxide? Induction chemotherapy?

Yours sincerely,
Dr Kirsten Herbert MD(Hons) BSci(Med) FRACP PhD
Haematologist, Peter MacCallum Cancer Centre
Locked Bag 1, A’Beckett St. Victoria 8006 AUSTRALIA"


Please find also attached the case which carries a table of previous diagnostics.

Here are my thoughts.

I would push hard for a double cord transplant. While there isn't a lot of data in the CML setting, in acute leukemia the results appear fairly comparable to allogeneic matched transplants. I don't think any of the other agents mentioned have any chance of curing her or substantially stalling her march towards blast crisis.

Whether to induce her with chemotherapy or not depends on how fast the transplant can be performed. If she has increasing blasts, it might be best to cytoreduce before transplant. I would let the transplant center weigh in since different centers have different ideas and policies regarding blast counts prior to the transplant.


Jerald Radich, MD
Clinical Research Division
Fred Hutchinson Cancer Research Center
1100 Fairview Ave N, D4-100
Seattle, WA 98109-1024
T: 206.667.4118
F: 206.667.2917

A difficult patient indeed..I am writing my thoughts just to initiate more discussion (I hope so!).

1. I would be little hesitant in labeling this patient as multidrug resistant CML.this patient had shown a good response to Dasatinib but was intolerant to the drug. I presume there is difference between drug resistant vs drug intolerance.

2. I would consider initiating this patient again on Dasatinib ( rather than hydroxyurea) albeit at a lower dose to reduce the chances of adverse effects. May be if the levels of Dasatinib are available, I would like to perform that and try to keep in therapeutic range (I am not sure whether there is any published data on Dasatinib drug levels or its relationship with response-may be the experts can answer this).

3. Use of Interferon or omacetaxine would be again experimental and should be clearly explained to patient before using them. People who have used them had found them working in an occasional patient.

4. Going by the history and response of the patient, all drugs including Ponatinib and Dastinib would probably work only for a short period of time and may be give more time to patient to think on the ultimate option of transplantation.

5. And hence, finally the cure of CML is possible only with double cord transplanationt as has been written before and even the treating physician is well aware of that.