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We have an interesting case for which and opinion is needed.
Patient diagnosed as CML in 1998 : age of 10 years . Started on Hydroxyurea . Received from 1998 to 2001.
August 2001 Accelerated Phase and was started on Imatinib.
Allogenic BMT (with sister as donor - MRD, Bu + Cy conditioning)
1. Day+33 Chimerism studies showed mixed chimera (80% donor, 20% recipient Ph+ve cells) .
2. day+73, he developed pain left ankle, MRI showed joint effusion - given Local RT for pain relief >> resolved
3. Day+144, skin GHVD: treated >> responded
4. Day+160 BM studies showed 35% bcr-abl fusion.
5. Day+263 BM showed 74% bcr abl fusion . started on T. Imatinib (DLI was not feasible due to young donor age)
Chimerism analysis (2006): 100% donor cells.
Imatinib was stopped in 2006 and was on 3 monthly molecular monitoring.
RQ-PCR done in April, 2009 : Negative
April 2012: : RQ -PCR for bcr abl of 8.86% s/o relapsed CML.
Restarted on Imatinib in 2012.
Maintaining MMR with yearly RQ-PCR monitoring.
April 2018: patient asymptomatic, counts normal. RQ-PCR 22.29% : relapse. He is 29 years of age
No imatinib mutation found
CBC: Hb-8.7, TLC-106800,Plt-35000, uric acid-12.7
BM: 18% blasts,
IPT : 13% myeloid blasts s/o AP
Started on hydroxyurea + dasatinib >> hydroxyurea stopped. dasatinib continued
June 28, 2018: chicken pox with pancytopenia . Treated conservatively >> responded
BMA/Biopsy (Jun 30 2018): CML, with < 5% blasts
Chimerism (STR, Jul 2018): Donor 76%, Recipient: 24%
Chimerism (FISH, Jun 30, 2018)): XX:72%, XO:28% ( loss of Y)
Karyotype (Jun 2018): 47,XY,del(Y)(q11.22), t(9;22)(q34;q11.2), +der(22)t(9;22) / 48,XY,del(Y) (q11.22),t(9;22),+2mar/ 46,XX. S/O CLONAL EVOLUTION
CML at age of 10 years. did well on allo SCT which was done for AP
TFR x 6 years , Molecular relapse >> did well again on imatinib for 6 years>> progressed into AP
1.Continue dasatinib alone
2.DLI with same sister donor ( as still he has 76% donor cells in BM and CML is the disease which responds well to DLI.)
3.Second full transplant with same sister donor ( no other sibling)
4.Haplo SCT with one of the parents : considering that the sister cells have sat in his BM for 16 years and adding some more sister DLI cells may not cause any benefit
5.MUD transplant : totally new immune system
The patient was diagnosed with CML-CP 20 years ago in 1998 when he was 10 years old. He underwent SCT from his sister in CML-AP at the age of 13 years in 2001 (Bus Cy conditioning) after short treatment with imatinib. He relapsed by day 160 and imatinib was restarted. Imatinib was stopped in 2006 and he maintained complete molecular response until 2012 (by then 24 years old).
In April 2012 he experienced 2nd relapse with CML-CP (bcr abl of 8.86%) and imatinib was restarted on Imatinib. He achieved and maintained Major mol Response until April 2018 when the RQ-PCR rose to 22.29% and 3rd relapse was diagnosed at the Age of 29 years. He now showed clonal evolution (BM: 18% blasts,
CML-AP) but no imatinib mutation was detected and he was put on dasatinib. He responded and achieved hematological remission (BMA/Biopsy (Jun 30 2018): CML with < 5% blasts, and the karyogram showed clonal evolution (Karyotype (Jun 2018): 47,XY,del(Y)(q11.22), t(9;22)(q34;q11.2), +der(22)t(9;22) / 48,XY,del(Y) (q11.22),t(9;22),+2mar/ 46,XX. S/O CLONAL EVOLUTION). Chimerism is around 70% female donor cells and 30% recipient cells/ Ph+ cells.
As a pediatrian I would continue with dasatinib for another three months because the patients has responded well so far. However because of clonal evolution this should be followed by DLI from my Point of view. Most importanty the molecular and cytogenegtic Response should be monitoired quantitatively. As the patient is a young adult since more than a decade by now, please also ask the colleagues from internal medicine/hematology.
Prof. Meinolf Suttorp
Pediatric Hematology and Oncology. Dresden, Germany
Very unfortunate case of a now 29year old man who was diagnosed with CML-CP in 1998. Treated briefly with imatinib and then underwent sibiling allograft in 2001. Molecular relapse at day 160 post allograft and imatinib restarted and continued until 2006 with patient in TFR. Molecular relapse in 2012 and patient diagnosed in CP and imatinib restarted. MMR sustained until April 2018, when at that time with clonal progression and diagnosis of AP. Switched to Dasatinib at that time. Achieved CHR but with ongoing evidence of clonal progression. What to do now?
Patient has shown clonal progression while on therapy. No mutation detected. The only question that is really relevant at this time is whether we think this individual can sustain his response indefinitely. I think the answer here is a definite no. Although counts may be controlled for a period of time, the likelihood of a molecular response is very small and not durable. Given that he has already seen one AP, he is at very high risk for going into blast crisis. The only drug that might give him a longer response, but not likelihood permanent might be ponatinib. Given his age, I believe the most aggressive response should be taken before blast phase develops. Whether a 3-month course of ponatinib can be given to further down stage the disease pre-allograft, could be considered.
Let us look at the options suggested.
1. Sustained Dasatinib is only a very temporary fix.
2. DLI likely not effective with this degree of bulk and with chimerism only 72% donor, there is a risk of rendering him aplastic.
3. Significant immunosuppression required to do a haplo will eliminate a lot of the chance of a GVL effect, essential in allografting for CML.
4. New allograft with MUD donor is an option. I am not sure what the chances of finding a good match with his ethnicity, but if a 10/10 available would consider.
5. Second transplant from the same donor sister.
I favor a second allograft as soon as possible. He did get a lengthy response the first time with some GVHD and since the sister appears available, would use her. Would do a full myeloablative regimen with PBSC whether sister or MUD (more GVH/GVL than bone marrow) and consider tapering immunosuppression completely by day 60 in the absence of any GVHD. If GVHD does develop, would not treat immediately unless very symptomatic grade 2 or higher, allowing as long a chance for GVL as possible.
Although no real evidence in AP disease, could consider re-adding Dasatinib (or ponatinib if it was used) after immunosuppression discontinued and continue for a minimum of 2 years. There is some evidence, at least in blast phase disease or Ph-positive ALL when transplanted in CP or AP, that post-transplant TKI may improve DFS.