Young male, was diagnosed with Ph+ CML at age of 31 years (March 2012). He had all features of CML in younger age (high WBC count, 152 G/L, splenomegaly +8cm below LCM, and his scores were Sokal 1.05, intermediate; Hasford EURO 756 low; and EUTOS 53, also low. Bone marrow was corresponding to chronic phase CML with 4% blasts, and he had 100% Ph+ mitoses. After initial leukoreduction with HU, he started imatinib 400mg in May 2012. His first evaluation was performed after 6 months of imatinib treatment in November 2012 revealing CCgR (10/10 normal). Meanwhile RQ PCR was performed revealing 0.3% IS (e.g. 9 months). After 12 months of treatment, June 2013, cytogenetics revealed better mitotic rate but 10% Ph+ (2 of 20). He admitted certain degree of noncompliance and we have decided to continue with imatinib for next 3 months. After 15 months of treatment, in September 2013 he started to decline to pancytopenia without significant splenomegaly, and repeated bone marrow biopsy revealed severe myelofibrosis, without significant rise in blast count (CD34/CD117 cells<5%). As bone marrow karyotype was not possible, patient performed FISH cytogenetics from peripheral blood in Munich Leukemia Center and it revealed severe genetic changes like +8 and deletion of p53 corresponding to iso(17). The brother was fully HLA compatible and bone marrow transplant was performed in Germany in cytogenetic progression in January 2014. He was conditioned with BuCy with classical GvHD prophylaxis. He had 100% chimerism after the grafting, and developed moderate GvHD in April 2014 when he was treated with budesonide for 3 months. During further follow up, he also had laboratory findings corresponding to GvHD in liver (rise in transaminase, gGT, AF, and ASMA antibodies), but it was not treated with steroids. In September 2014 he developed lung GvHD (BOOP) and consequently he was treated with prednisone (standard dose for 2 months with slower tapering and 10mg after 4 months), with good response within several months. His last evaluation in transplant center was at one year since grafting (January 2015) revealing chimerism 100% and RQ-PCR corresponding to MR4.5.
Patient start complaining on walking in October 2015. Standard radiography revealed no changes, but MRI was performed and shown two areas of bone infiltration (tibia and femur). Surgical biopsy with further evaluation by haematopathologist revealed myeloid sarcoma with CD34+, CD33+ and CD79+/- phenotype. Bone marrow was normal (blasts 3%) without signs of CML, but karyotype revealed reappearance of Ph+ clone with cytogenetic progression with +8, iso(17) and +19 in about 40% of analyzed mitoses. Therefore RQ PCR was not relevant (1.1% IS). Further suggestion from transplant center was to perform radiotherapy together mutation analysis and further TKI treatment, particularly ponatinib.

Well, I have certain number of questions as I have tried to find some answers within PubMed available publications. Some of issues are consequence of unavailability and formulary restrictions in Serbia. We do not have possibility for mutation analysis, and we do have only one second line TKI, nilotinib. It is reimbursed for chronic phase patients not responding to imatinib (classic second line treatment). In patients failing to keep response to nilotinib, or progress like our patient, the only possibility is stem cell grafting (sib of HLA matched unrelated). We do not have neither dasatinib nor ponatinib (both not registered, no possibility for reimbursement as unregistered). My doubts regarding this case are
1. Choice of TKI treatment if the patient would be able to find resources for several months of “salvage” TKI treatment? I suppose that imatinib is not a choice of any kind, and as far as I know nilotinib is not good choice for patients in advanced CML. How long to treat with such “salvage” TKI treatment?

2. What is the role of DLI in such a case? I have found several publications concerning DLI and also TKI and DLI together, but not in patients with overt myeloid sarcoma.

3. What is with secondary bone marrow graft? I suppose that in case of “salvage” TKI, DLI or better second graft would be feasible option?

4. In case of further leukemia dissemination, how to treat leukemia on allograft? Should we provide and what kind of chemo on blast phase of CML with such karyotype after the allograft?

I would appreciate any other comments in dealing with this demanding 34 year old patient.

Comments to your questions are below. Could you also clarify if bone marrow in Sept 2013 showed +8 and iso (17) was seen in Ph+ clone? Based on the 12 months cytogenetic data I presume that these cytogenetic changes were seen in Ph+ clone. This would suggest clonal evolution and hence accelerated phase. Secondly response only lasted for ~20 months following sibling allogeneic SCT. Did this patient repeat bone marrow after sibling allogeneic SCT such as on D+30, 3 months or 12 month time point following SCT and what were the results?


1. Choice of TKI treatment if the patient would be able to find resources for several months of “salvage” TKI treatment? I suppose that imatinib is not a choice of any kind, and as far as I know nilotinib is not good choice for patients in advanced CML. How long to treat with such “salvage” TKI treatment?

This patient would need salvage TKI, choice does depend upon mutation profiling. If mutation profiling is not helpful then my preference would be ponatinib or dasatinib. Duration of TKI will be long-term as long he is responding/tolerating and as a bridge to definitive procedure such as second allograft (if that option is available).

2. What is the role of DLI in such a case? I have found several publications concerning DLI and also TKI and DLI together, but not in patients with overt myeloid sarcoma.

DLI does have role in this situation but I shall caution that this patient had BOOP as evidence of GVHD but still developed relapse. Hence DLI could worsen BOOP with limited benefit in disease control. Worth considering is not going for second allograft.

3. What is with secondary bone marrow graft? I suppose that in case of “salvage” TKI, DLI or better second graft would be feasible option?

If patient is fit then SCT from MUD donor is a better option than DLI with TKI +/- chemotherapy as a bridge to SCT.

4. In case of further leukemia dissemination, how to treat leukemia on allograft? Should we provide and what kind of chemo on blast phase of CML with such karyotype after the allograft?

Chemotherapy such as FLAG-Ida and allograft

Horrible situation and quite frankly, the likelihood of a successful outcome with any intervention is not in the cards.
His BOOP was a manifestation of chronic GVHD and therefore the GVL that is associated with this was insufficient to control the disease. In order for DLI or a second allograft to have a chance of even temporarily controlling the disease, he would again need to have GVHD and this would have a very high chance of being fatal. Of all the malignancies that may benefit from the GVL effect, CML has always been the best target, but as is seen here, it doesn't always work. Even if you get control of the disease, he will likely be left with severe disabling chronic GVHD that may not be adequate to control the CML. Use of a reduced intensity protocol would not eliminate the GVHD. One might argue that the GVL from this donor was inadequate and should a second donor be considered? Same arguments as above.
If a second allograft is considered, better control of the disease before hand is essential. I think if only an isolated TKI is still considered, then only ponatinib is the choice. Personally for CML BC and most people will consider this BC, I favor a combination of chemotherapy plus TKI, such as the FLAG-Ida plus ponatinib suggested previously. I would also do a diagnostic LP at some point.
Given all this, it is necessary to think about what you want to do with therapy. Cure is an unlikely possibility. Aggressive therapy is gong to have an impact on quality of life and may shorten his life. Personally, I would favor single agent ponatinib for as long as it can control the disease and not consider a second transplant or DLI. In the end of course, it is what the patient wants after hearing the chances and the risks, and what can be done within the limits of institutional/reimbursement options.

This is indeed a very challenging case, and I'm afraid there is no good solution to offer. Involved field radiation to the myeloid sarcoma may provide some local control, but obviously will have no impact on the systemic disease. Given the limited availability of TKIs, I would start nilotinib. However, it is unclear how much BCR-ABL is driving the leukemia now, in light of the additional clonal cytogenetic abnormalities.
Intensive AML induction chemotherapy (e.g. FLAG-Ida) followed by DLI at the nadir is an approach that we have used at our center for this situation. There is about a 20% chance of a meaningful remission.
We would consider a second allogeneic transplant, with reduced intensity conditioning, if you can achieve some type of remission.
However, given the severity and extent of GVHD that he experienced, the potential for a second transplant, and even for DLI to induce significant GVHD is high.