A case report of a patient with AML who had undergone allogeneic stem call transplantation. She relapsed within 6 months post transplant with lineage switch to ALL. this is follwed by a sfort review of Lineage switch in acute leukemia
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Lineage switch in Acute Leukemia
1. Lineage switch in Acute
Leukemia
Dr Ankit Raiyani
Hematology Dept.
SSH
2. Case report
Mrs XX, 37 years female
Presented on 7/5/14 with symptoms of
spontaneous bruises over upper and lower limbs,
generalized weakness and
fever since 10 days.
Referred as a case of Immune thrombocytopenic
purpura, for further management
K/C/O- RA since 1 year, received Steroids/ HCQS
3. Hb-12.9, TLC- 5700, PLT-60,000 N-38%,
blasts- 12%.
Biochemistry- Normal limits, except LDH-
308.
Bone marrow aspiration and biopsy was
done- Acute leukemia with 27% (Monoblasts
+ promonocytes)
Blasts were large in size, with round nuclei,
open chromatin, 1-2 prominent nucleoli,
moderate cytoplasm with vacuolation.
4. Flowcytometry (FCM):
41.3% cells gated with moderate side scatter and
bright CD45 expression (monocyte gate).
These cells are positive for CD11c, CD14, CD15,
CD11b, CD33, CD64, CD10 (dim) and cyto MPO.
5.
6. With a diagnosis of Acute Myeloid Leukemia M4--
Patient was started on 7, 3 Induction with
Daunomycin and Cytosine
Day 14 marrow was in remission
RQ PCR AML1 ETO- Negative
RQ PCR WT1- Positive (0.047%) (5374.91)
NPM1- Negative
FLT3-ITD- Negative
Cytogenetics- normal
7. Patient was classified as intermediate risk
Acute Myeloid Leukemia
As she had HLA matched family donor
available, she was planned for matched
related donor allogeneic SCT.
Patient underwent Allo SCT (BM harvest) on
7/7/14.
Engraftment was done by 20/7/14.
GVH prophylaxis- Tacrolimus+ methotrexate
8. Patient did not develop significant GVH.
Patient was on tapering dose of
immunosuppression.
VNTR reports were s/o complete donor
chimerism
9. On 27/12/2014, patient was admitted with c/o
severe backache, rib pain, bodyache and
generalized weakness.
Her Hgm on OPD basis on 26/012/15 was
s/o- Hb-10.2, TLC- 3500, PLT- 78,000, N-
63%.
Patient underwent Bone marrow aspiration &
biopsy to rule out a relapse.
10. BMA was s/o relapse with 88% blasts.
FCM report:-
two blasts population on CD45 gating and both expressing B cell
phenotype.
Approximately 77% cells with negative CD45 and low to
intermediate SSC are gated and show co-expression on CD19,
CD10, CD34, cytoCD79a and HLADR and negative for markers
mentioned.
Other 07 % gated blasts coexpress CD10 (bright), CD19,
HLADR, CD33 and cyto CD79a.
However both tumor cell subsets are negative for cytoMPO.
Imp: Acute B lymphocytic leukemia
This is known as lineage switch in acute leukemia
12. Relapse in Acute Myeloid Leukemia (post
Allo-SCT)
Probability of acute leukemia relapsing is greatest
in the first year after SCT, and half the relapses
occur within 6 months of SCT.
Less frequently, relapse occurs late, when it is
often likely to manifest in the form of chloromas.
A sequential treatment approach for relapsed acute
leukemia patients is to begin treatment with
1. Immunosupression withdrawal,
2. Introduce chemotherapy appropriate for the disease type and
3. Follow it with a DLI or, in selected cases, a second SCT.
13. In our patient..
Immunosuppression was stopped
VNTR showed mixed chimerism of
designated markers
CSF study- No CNS involvement
Patient was started on Hyper CVAD cycle 1a
from 30/12/14
Febrile neutropenia covered by higher
antibiotics and liposomal AmphoB
15. Patient had developed right thigh cellulitis
which progressed to form an eschar at the
site.
BMA done at day 14 and day 28 were not in
remission (albeit had decreasing blast %)
Considering her poor general condition,
patient only received methotrexate ( at 2
gm/m2
)
16.
17. After discussion with relatives, it was decided
to go ahead with haplo-identical family donor
SCT.
Patient was started on conditioning regimen
But by day -1, she had developed sepsis with
shock. She was shifted to ICU, required
ventilatory and inotropic support
She succumbed on 4/3/15
19. Definition- It is the term that has been used to
describe the phenomenon of acute leukemia
that meet the standard French-American-
British system criteria for a particular lineage
upon initial diagnosis, but meet the criteria for
the opposite lineage at relapse
No timeframe defined
20. Incidence- Very rare
Seen predominantly in pediatric patients
Rarer in adult patients
Most cases are ALL AML
Rarest combination is adult patient with AML
ALL switch
Only a few cases reported.
21. American Journal of Hematology Volume 87, Issue 9, pages 890–897,
September 2012
Lineage switch in childhood acute
leukemia: An unusual event with poor
outcome
Jorge G. Rossi, et al
22. 9 cases, all with age <15 years
AML M4/M5 in all patients (either original or after switch)
Number
of cases
Average
duration
of switch
MLL
fusion
gene
Mortality
AML to
ALL
2 90 days 2 100%
ALL to
AML
7 5 100%
23. Described 8 cases
of acute leukemia
with lineage switch
Carried worst
prognosis among
all leukemia with
ambiguous linage
Gerr, H., et al. British Journal of Haematology, 149: 84–92
24. Journal of Korean Medical Science. 2011;26(6):829-831.
Lineage Switch at Relapse of Childhood Acute Leukemia: A
Report of Four Cases
Meerim Park, et al
All 4 cases ALL AML (M4 in 3 patients), pediatric
age group
3 patients achieved CR
MLL fusion gene in 2 patients. (No comments
regarding others)
Loss of CD10 &/or Tdt
25. Several hypotheses have been proposed for explaining lineage
conversions, but none proven
Leukemogenic mutation targeting early pleuripotent progenitor
cells.
NOTCH1 mutation in T cell & myeloid progenitors
MLL gene rearrangement in B lymphocyte-monocyte bipotential
stem cells
Chemotherapy might suppress or eradicate the leukemic clone
apparent at diagnosis, thereby permitting the expansion of a sub-
clone with a different phenotype.
Secondary neoplasia due to treatment
Changes in pattern for both IgH and TCRγ gene rearrangement
at relapse may suggest the emergence of a new leukemic clone
Less likely to occur in short duration
26.
27. Treatment
No established guidelines
Plan treatment regimen on case basis
Avoid using earlier used chemotherapeutic
agents. (increased toxicity, decreased
efficacy)
Stem cell transplant should be considered.