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1458 Fulminant Onset of Acute Leukemia (FOAL) After Total Therapies (TT) for Multiple Myeloma (MM): Absence of MDS Pathological Criteria within 3 Months of Prior MM Follow-up

Program: Oral and Poster Abstracts
Session: 611. Leukemias - Biology, Cytogenetics and Molecular Markers in Diagnosis and Prognosis: Poster I
Saturday, December 8, 2012, 5:30 PM-7:30 PM
Hall B1-B2, Level 1, Building B (Georgia World Congress Center)

Zeba N Singh, MD1, Jeffrey R Sawyer, Ph.D.1*, Ginell R. Post, MD, PhD1, Sarah Waheed, MD2, Saad Z Usmani, MD FACP2, Frits van Rhee, MD, PhD2 and Bart Barlogie, MD, PhD2

1Department of Pathology, University of Arkansas for Medical Sciences, Little Rock, AR
2Myeloma Institute for Research and Therapy, University of Arkansas for Medical Sciences, Little Rock, AR

Background: Cytogenetic abnormalities (CA) in therapy-related myeloid neoplasms (t-MN) usually correlate with nature of previous therapy and clinical presentation. t-MN following prior therapy with alkylating agents and/or radiotherapy are associated with a long latency period (> 3 years) an antecedent myelodysplastic syndrome (MDS) phase, and unbalanced translocations or a complex karyotype. Majority of t-MNs that initially present as acute leukemia (AL) are associated with prior topoisomerase II therapy, a shorter latency period (1-3 years), lack of  MDS phase and balanced translocations, commonly involving 11q23/MLL gene. In our experience the usual course of t-MN in MM patients is a prolonged MDS phase with progressive cytopenia, progressing to acute myeloid leukemia (AML) in a subset of patients. Here we report on 7 patients in complete remission (CR) for MM without cytopenia or morphologic evidence of dysplasia on bone marrow evaluation within 3 months prior to presenting with FOAL. One patient developed FOAL within 2.5 months of first documentation of MDS-associated CA (MDS-CA).

Methods: Of 3890 patients at the University of Arkansas who had received melphalan-based autograft supported high dose therapy, 69 patients developed t-MN— 63 initially presented with MDS and 13 progressed to AML. Six of the seven patients had no prior MDS-CA or morphological dysplasia, and one with MDS-CA seen <2.5 months earlier, had fulminant onset of AL.  All BM specimens at time of FOAL and within one-year period prior to FOAL were evaluated. Metaphase cytogenetic analysis was performed on unstimulated BM specimens using standard techniques. Interphase FISH was performed on BM samples using probes to detect CA commonly observed in MDS and AML.

Results: All FOAL patients were treated on Total Therapy (TT) protocols for newly diagnosed MM including 3 on TT2 with thalidomide arm, 3 on TT3A with VTD maintenance, and 1 on TT4 with VRD maintenance. At the time of FOAL all patients were in CR for MM and on maintenance therapy with dexamethasone, thalidomide, lenalidomide, and bortezomib in combination or as single agents. The clinical and laboratory features prior to and at onset of AL are shown in the table.

 

Patient No.

Parameters

1

 

2

 

3

 

4

 

5

 

6

 

7

 

Karyotype at diagnosis

62,XXX,-1,-2, +3,-4,  -5,  -6,-7, +9,+9,-13,    -13, der(14)t(11;14) (q12~13.1;q32) x2,     -16, -17, +18, +19,-21,          -22[7]/  46,XX[cp11]

42~44,X,-X, add(6)(q?22), der(12)t(1;12) (q11~12;q24.3),-13[cp9]/ 46, XX[cp11]

 

46,XY[20]

 

38~40,X,  -Y,+1, add(1)(p11), der(1;16)(q10;p10),-4,-6, t(8;14) (q24.1;q32),-8,-12,  -13,-16 [cp4]/ 70~75, idemx2, inc[cp3]/ 46,XY[cp13]

 

46,XY[20]

 

46,XY[20]

 

46,XY[20]

 

Interval from start of MM therapy

126 months

63.5 months

9.5 months

74.5 months

114 months

123 months

66 months

MM status at FOAL

Stringent CR

Stringent CR

Stringent CR

Stringent CR

Stringent CR

CR

Stringent CR

Karyotype prior to FOAL

FISH

53,XX,+X,+4,+4,+7,+8, inc[cp3]/ 46,XX[cp38]

 +7, +8

46,XX[20]

ND

46,XY[20]

Normal

 

46,XY[20]

ND

 

46,XY[20]

ND

 

46,XY[20]

Normal

46,XY[20]

ND

Leukemia subtype

ALL

ALL

AML

AML

AML

AML

AML

MDS-CA at time of FOAL

55,XX,+X,+4,+4, +der(7;9)(q10;q10), +8, del(12)(q24.2), +14,+18,+21 [cp15]/ 46,XX[5]

 

del(20q)

46,XY[20]

Complex with

-5 and -7

 

Complex

with -5,-17, and del(11q23)

 

Complex

 -5 and -7

46,XY[20]

FISH

+8, +21

del(20q)

Normal

-5, del(5q),-7

 

del(5q)

del(5q), -7, del(7q)

ND

ND= not done

 

Conclusion: In this cohort, MDS-CA (+8, del20q, -7, del7q, -5, del5q and complex karyotype) were detected in leukemic blasts in 5 of 7 patients with abnormalities of chromosomes 5 and 7 most commonly seen. In contrast to clinical and cytogenetic associations described for t-MN initially presenting as AL, none of our patients showed balanced chromosomal translocations involving 11q23, and all but one (patient 3, 9.5m) had a long latency period of 5 to 10yr. Importantly, the absence of MDS-CA on prior bone marrow evaluations in 6 of 7 of our cases indicates that FOAL cannot be predicted based on surveillance BM metaphase cytogenetics or FISH.  Studies using gene expression profile analysis of CD34 stem cells are underway to identify molecular alterations leading to FOAL.  Results of these studies may improve t-MN surveillance.

Disclosures: No relevant conflicts of interest to declare.

*signifies non-member of ASH