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

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.

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

11.  Acute Myeloid Leukemia PCR panel
 NPM1- negative
 AML1/ETO -negative
 FLT-3 ITD- negative
 Inv 16 – Negative
 RT-PCR bcr-abl- negative (p190, p210, p230)

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

14. Hyper-CVAD protocol

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
)

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

18. Lineage switch in Acute leukemia
Review

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

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.

28. Thank You!!