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pCML - relapse post allogeneic transplant

  • Sanjay Tewari
  • Sanjay Tewari's Avatar Topic Author
4 months 4 weeks ago - 4 months 4 weeks ago #1938 by Sanjay Tewari
pCML - relapse post allogeneic transplant was created by Sanjay Tewari
Diagnosis:

CML in CP diagnosed September 2022, WCC-444
EUTOS-high risk
Cytogenetics: 46XY, t(9;22), del(7)

Treatment:

Started on Imatinib
Unable to achieve optimal response at 3 months (BCR-ABL1 >10%) with clonal evolution (+8)
Switched to Dasatinib. No evidence of clinically significant mutation detected.
In Feb’23- failure to 2nd generation TKI with rising BCR-ABL transcripts and evidence of new sub-clone (inv(16))
March 2023- Myeloid blast crisis. Started on Fla-Ida and Ponatinib added.

Transplant:

MVUD (PBSC) with Bu/Cy conditioning. CMV+/+ EBV+/+ Tox-/- (D0-02/08/23). GvHD prophylaxis: CSA+ATG 

17-year-old, Iraqi refugee, presented in September 2022 with abdominal distension, feeling unwell. Examination showed massive splenomegaly with the blood test showing a high WCC of 444, preserved platelet counts with blood film showing increased granulocytes, no excess of blasts. Diagnosed with CML in CP. The cytogenetics-46, XY,t(9;22)(q34;q11.2)[8]/46,XY,del(7)(p11),t(9;22)(q34;q11.2)[12]. 

Started on Imatinib. CHR by the end of month but failure by ELN criteria at three months (BCR-ABL>10%) on two occasions. Cytogenetics showed clonal evolution with gain of chromosome 8. No TKD mutations detected. Switched to Dasatinib in December 2022. Slight improvement in BCR-ABL ratio (16.5%) but went up again to 43.8% in February. BM in March showed 37% myeloid blasts positive for CD13 CD33 CD34 HlaDr MPO heterogeneousCD117 partial-aberrantCD7 moderateCD45 and a small blast population 4% positive for strong CD19 CD13 CD33 CD34 HLADR moderateCD45 CD79a MPO, negative for CD10 CD20 CD117 CD11b CD64 CD14 and T-cell lineage markers. Cytogenetics showed an additional chromosomal abnormality with inv(16) sub-clone. No TKD mutations detected. 

Started on Fla-Ida with Ponatinib. Had prolonged episode of FN requiring transfer to HDU at Chelsea. Not ventilated or required inotropic support. Had MUD HSCT in August. No major complications post HSCT. Engrafted neutrophils and platelets and the Day 28 BM showed morphological remission with 100% donor chimerism with BCR-ABL ratio of 0.002% (MR4.5). No GvHD. Immunosuppression weaned off. Day+100 BM done on 09/11/23 showed 0.7% myeloid blasts with BCR-ABL ratio of 10.7%. Planned for DLI but a week later presented with headaches. Diagnostic LP showed >1000 cells with flow showing 47% blasts positive for CD34 CD117 CD13 HLA-DR partial CD19 CD33. Molecular testing showing positivity for BCR-ABL. Mutation studies awaited. Started on Ponatinib and having weekly triple intrathecals.

Questions      
Thoughts about TKI +/- craniospinal irradiation   
Second transplant once in CP  
Last edit: 4 months 4 weeks ago by arlene.
  • Nirmalya Roy Moulik
  • Nirmalya Roy Moulik's Avatar Topic Author
4 months 4 weeks ago #1939 by Nirmalya Roy Moulik
Replied by Nirmalya Roy Moulik on topic pCML - relapse post allogeneic transplant
Very complex case indeed, likely to have a very grim outcome.

In case the intent of treatment is curative- will need disease clearance in the CNS and the marrow followed by allo-HSCT (better to have a different donor this time).

1. CNS clearance will be achievable by weekly TITs and TKI (ponatinib likely better than dasatinib- though CNS penetration data is limited). Should include craniospinal RT as well at some point pre-transplant.

2. Marrow disease can be controlled with- low dose chemotherapy (like Venetoclax+/- AraC or Aza) targeting AML along with TKIs and possibly FLA pre transplant.

3. Choice of TKI- Looks like he has progressed while on ponatinib- it would be important to have the kinase domain mutation reports. Was wondering if combining ponatinib with asciminib might be helpful due to synergism ( no convincing clinical data yet), given the aggressiveness of the disease. Adult CML experts may be able to help on this.
  • Jeff Lipton
  • Jeff Lipton's Avatar Topic Author
4 months 4 weeks ago - 4 months 4 weeks ago #1941 by Jeff Lipton
Replied by Jeff Lipton on topic pCML - relapse post allogeneic transplant
What an ugly case. This is a very difficult and likely poor outcome case. I credit the treating physicians for going as aggressively as they did. The two options are palliative therapy or given the age of this young man, if you get aggressive, you cannot hold back at any point.

I will deal with the latter. I will assume that there are no comorbidities that will restrict the management. The first thing is to be sure he is in the best remission possible. Going into an allograft after relapsing post an allograft with anything less will be futile. I agree with the triple intrathecal and ponatinib (if no resistance), but there is evidence of systemic disease and I believe a re-induction with ponatinib plus chemo, say ventoclax with azacitidine or decitabine is necessary. Assuming a complete morphological remission, then allograft. If available, I would use a different donor as there was no GVH with this donor. I would use a different conditioning regimen, in this case VP16TBI building the TBI into craniospinal irradiation. I would use less intensive GVH prophylaxis as it is imperative that this man get GVL. No ATG. I would prefer CSA/MTX. ptCy may give some anti-leukemia effect, but they do not want to wipe out GVH. In the absence of GVH, start tapering the immunosuppression by 6 weeks or so and complete by 8 weeks. Restart TKI once immunosuppression is off and continue indefinitely. Give thought to additional intrathecal starting day 60-70. I would normally give 6 additional, once every 2 weeks. This plan is intensive and likely with side effects, but if he relapses again, it is game over.
Last edit: 4 months 4 weeks ago by arlene.
  • Meinolf Suttorp
  • Meinolf Suttorp's Avatar Topic Author
4 months 4 weeks ago - 4 months 4 weeks ago #1942 by Meinolf Suttorp
Replied by Meinolf Suttorp on topic pCML - relapse post allogeneic transplant
Reflections on the Case History

The case initially presents classical findings in pediatric CML-CP. Regarding the cytogenetics, monosomy 7 is a high-risk situation. Trisomy 8 is another poor prognostic marker. Clonal evolution must be diagnosed. Progression from CML-CP to 1rst CML-BP-myeloid. Ongoing clonal evolution. Early relapse post SCT as 2nd CML-BP with CNS involvement by approx. day +120. There are rare cases with different clones harboring different kinase domain mutations in the two compartments. Thus, mutation analysis of blasts from both compartments is of importance.

Questions
- (1) Thoughts about TKI +/- craniospinal irradiation
- (2) Second transplant once in CP

Answers
(1) To the best of my knowledge, in CML CNS-irradiation can be combined with ongoing TKI treatment. It has been shown in a Chinese study on lung cancer patients with brain metastasis that cranial radiotherapy can promote TKI crossing of the blood-brain barrier and improve the drug concentration of TKIs in cerebrospinal fluid (CSF), while TKIs can enhance in solid tumors the antitumor effect of radiotherapy by radiation sensitization [1,2]
In CML single cases receiving TKI and cranial irradiation are described [3,4,5]. I would recommend a dose as in AML with CNS involvement (18 Gy). Do not rely on sufficient TKI concentration in the CSF. This case illustrates that despite dasatinib treatment blasts can survive in the CNS.

(2) Yes, but it makes sense only if another CP (at least a hematological remission, better a cytogenetic remission) is achieved [6]. The shorter the interval between 1rst and 2nd SCT, the higher is the toxicity of the conditioning regimen. For 2nd SCT in the first 6 – 8 months after 1rst SCT I would recommend reduced-intensity conditioning followed by premeptive TKI and adding DLI in case MRD increases.

Hoping that these recommendations might be helpful.
Kind regards
Meinolf Suttorp


References

1. Zeng YD, Liao H, Qin T, Zhang L, Wei WD, Liang JZ, et al. Blood-brain barrier permeability of gefitinib in patients with brain metastases from non-small-cell lung cancer before and during whole brain radiation therapy. Oncotarget. 2015;6(10):8366–8376. doi: 10.18632/oncotarget.3187.
2. Zhai X, Li W, Li J, Jia W, Jing W, Tian Y, Xu S, Li Y, Zhu H, Yu J. Therapeutic effect of osimertinib plus cranial radiotherapy compared to osimertinib alone in NSCLC patients with EGFR-activating mutations and brain metastases: a retrospective study. Radiat Oncol. 2021 Dec 5;16(1):233. doi: 10.1186/s13014-021-01955-7.
3. Bin Salman AA, Zaidi ARZ, Altaf SY, AlShehry NF, Tailor IK, Motabi IH, Zaidi SZA. Prolonged Survival of a Patient with Chronic Myeloid Leukemia in Accelerated Phase with Recurrent Isolated Central Nervous System Blast Crisis. Am J Case Rep.2020 Sep 13;21:e922971. doi: 10.12659/AJCR.922971.
4. Rytting ME, Wierda WG. Central nervous system relapse in two patients with chronic myelogenous leukemia in myeloid blastic phase on imatinib mesylate therapy. Leuk Lymphoma. 2004 Aug;45(8):1623-6. doi: 10.1080/10428190410001667703. PMID: 15370215.
5. Lai SW, Huang TC, Chen JH, Wu YY, Chang PY. Dasatinib as the salvage therapy for chronic myeloid leukemia with blast crisis and central nervous system involvement: A case report. Oncol Lett. 2015 Apr;9(4):1957-1961. doi: 10.3892/ol.2015.2928. Epub 2015 Feb 3. PMID: 25789076; PMCID: PMC4356413.
6. Sembill S, Ampatzidou M, Chaudhury S, Dworzak M, Kalwak K, Karow A, Kiani A, Krumbholz M, Luesink M, Naumann-Bartsch N, De Moerloose B, Osborn M, Schultz KR, Sedlacek P, Giona F, Zwaan CM, Shimada H, Versluijs B, Millot F, Hijiya N, Suttorp M, Metzler M. Management of children and adolescents with chronic myeloid leukemia in blast phase: International pediatric CML expert panel recommendations. Leukemia. 2023 Mar;37(3):505-517. doi: 10.1038/s41375-023-01822-2
Last edit: 4 months 4 weeks ago by arlene.
  • M. A. Durosinmi
  • M. A. Durosinmi's Avatar Topic Author
4 months 4 weeks ago #1943 by M. A. Durosinmi
Replied by M. A. Durosinmi on topic pCML - relapse post allogeneic transplant
This is a very serious case. Apparently he has become resistant to all TKIs, including ponatinib. It was unfortunate he was unable to have the DLI that would have further eradicated the primitive quiescent leukemic stem cells (LSCs) following the MUD HSCT.
Clofarabine may be added to induction chemotherapy.
Asciminib and ponatinib +/+ INF-alfa may tried, followed 2nd HSCT in chronic phase
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