Monoclonal B cell Lymphocytosis Diagnosis, Clinical Issues and

Management

Neil E Kay,M.D. Mayo Clinic

Kay.neil@mayo.edu

Acknowledgements

Mayo Team -  Tait Shanafelt -  Betsy LaPlant -  Tim Call -  Sameer Parikh -  Wei Ding

Thanks to our Patients and their families

Objectives •  History/Discovery of MBL

•  MBL Classification

•  Clinical and Biologic Considerations

•  Management

Initial Discovery •  Environmental health studies by CDC 1990s

•  9 of 1499 (0.6%) individuals >age 45 had monoclonal B-cell population by 2 color flow

•  Phenotype clone identical to CLL in the majority of individuals

•  Prevalence several hundred times more common than CLL and SLL

1.  Vogt BJH 139:690,2007 2.  Marti GE, Cytometry B Clin Cytom. 78:2010

MBL Has Very High Prevalence •  Subsequent studies with more sensitive flow

in healthy populations revealed MBL 1, 2 •  ~ 3% of individuals > age 40 •  ~ 5% > age 60 •  (?) 75% > age 90

1Rawstron Blood 100:635; 2Nieto Blood 114:33; 3Rawstron Blood 100:2289; 4Goldin BJH: 151:152; 5Marti Cytometry 52B:1, 6Matos BJH 147:33

•  Familial CLL –  Prevalence 13-16% among the first degree

relatives 3-5 •  Sporadic CLL

–  16% of relatives ≥ 60 6

Patients with CLL have Pre-existing MBL

•  77,469 healthy adults in PLCO screen trial

•  129 subsequently developed CLL

•  45 pre-diagnosis sample –  (mean 32 mo pre-CLL dx)

•  6 color flow and IGHV analysis by RT-PCR

•  Pre-existent MBL in 44/45 CLL patients –  Up to 6.4 year before CLL –  Both IGHV M and UM B cell clones were found

Landgren , NEJM 360:659,2009

Classification

MBL Variants •  CLL-like MBL: share the characteristic immunophenotype of CLL

–  Characterized by CD19 and CD5 concomitant expression, low surface immunoglobulin , dim CD20 expression, CD23 positive

•  Atypical CLL MBL: expressing CD5 together with bright CD20 expression and/or lack of CD23 expression

–  Extensive lymphoma work-up, with attention to FISH analysis for t(11;14), to exclude mantle cell lymphoma diagnosis

•  CD5 negative (or Non-CLL) MBL: lacking CD5 expression. –  Marginal Zone Lymphoma

•  Usually devoid of CD10 expression and other lymphoma-specific markers

–  Leukemic MCL •  small cell variant and indolent behavior are CD5-negative •  a FISH analysis for the t(11;14) may be appropriate

Diagnostic Criteria CLL-Like MBL •  Documentation of a clonal B-cell population in

peripheral blood –  (light-chain restriction [abnormal κ/λ ratio or low sIg in >25%

B cells] or heavy-chain monoclonal IGHV rearrangement).

•  B-cell count <5 × 109/L. •  CLL phenotype (CD5, CD19, CD23 positive;

CD20 and sIg dim). •  No evidence of lymphoma, infection, or

autoimmune conditions.

Marti BJH 130:325,2005

CLL Variant: MBL Types •  Clinical MBL:

–  is usually diagnosed in a clinical setting associated with lymphocytosis 1

–  Total B cells of 1500 cells per µL or greater –  Median concentration of clonal B cells is 3000 per µL –  Designated as High Count (HC) MBL

•  Population screening MBL: –  Detected during screening studies of healthy persons –  Total B cells of ≤ 50 cells per µL –  Median absolute count of clonal B cells is 1 cell per µL –  Designated as Low Count (LC) MBL

1.Rawstron N Engl J Med. 2008;359(6):575-583. 2.Daglis, Blood. 2009; 114(1):26-32. 3.Shanafelt, Leukemia. 2010;24(3):512-520 4.Rawstron, Clin. Cytometry, 78B,S19-23,2010

Risk factors for MBL Onset and Progression to CLL Requiring Therapy

Risk factors for MBL onset Risk factors for MBL progression to CLL

Family history of CLL CD38 positivity

Genetic polymorphisms (?) Unmutated IGHV

Age Deletion 17p

Infections Elevated B-cell count

Shanafelt, Leukemia ,24:512-520,2010

Biologic and Clinical Considerations

LC Vs HC MBL (FISH status)

•  LC MBL clones have a much lower frequency of chromosomal alterations –  restricted to del13q and trisomy 12

•  HC MBL –  del11q seen more often –  del17p and NOTCH1 mutations only found in HC and

CLL.

Greco ,Hematological oncology. 31(1):54-55.2013

Natural History Low Count MBL •  Natural history

–  76 individuals low count MBL Val Borbera, IT –  Median age 66 –  Median follow-up 34 months

•  Clone persisted in most patients

Fazi Blood 118:6618,2011

•  No increase size B-cell clone

•  No pt develop clinical leukemia –  Including 2 pts with deletion 17p13 in >80% clonal cells at baseline

•  Life expectancy is similar to healthy normals

Summary Low Count MBL •  Practical aspects and management

–  Unlikely you will ever see these individuals in practice –  Common among elderly using very sensitive flow cytometry –  Unlikely to progress if ever to HC MBL or CLL

•  Clones persist over time in most patients but little or no expansion or conversion to CLL 1,2

•  Major research questions remain here –  Are these precursors to HC MBL? –  Even if not does this condition represent the “tip of the iceberg”

•  Highlighting unstable B cell clonal populations

1.Fazi C, Blood. 2011;118(25):6618-6625. 2.Bennett FL, ASH Annual Meeting Abstracts. 2009;114(22):59

Need To Reclassify MBL and Early Stage CLL

1. Blood. 2008 Jun 15;111(12):5446-56

The diagnosis of CLL requires the presence of at least 5 × 109 B lymphocytes/L (5000/µL) 1

Reclassifying Rai 0 CLL using IWCLL 2008 Criteria

Shanafelt Leuk Lymph 50:493,2009; Shanafelt Leuk Res 32:1458,2008

•  40% Patients classified Rai 0 CLL 1988-2007 reclassified to MBL under 2008 criteria

Reclassifying MBL/CLL

•  Olmsted County MN –  Population 144,248 –  2000-2010: 123 individuals CLL phenotype –  115 CLL and 8 MBL (1996 Criteria) –  79 CLL and 40 MBL (2008 Criteria)

0% 10% 20% 30% 40% 50% 60% 70% 80% 90%

100%

1996 Criteria 2008 Criteria

MBL CLL

Reclassifying MBL/CLL Incidence 2000-2010

(per 100,000)

CLL High Count MBL

1996 Criteria 2008 Criteria 1996 Criteria 2008 Criteria

Age and sex adjusted

10.0 6.8 0.66 3.5

Age adjusted - Male

13.2 9.8 0.95 3.9

Age adjusted - Female

7.6 4.5 0.45 3.3

Call T, Cancer. 2014 Jul 1;120(13):2000-5

Natural History CLL Is Altered Median Time to Treatment

1996 Criteria 2008 Criteria

All newly diagnosed CLL pts 9.2 years 6.5 years

Cancer. 2014 Jul 1;120(13):2000-5

Clinical Justification For Reclassifications (Time to Treatment)

0

20

40

60

80

100

0 1 2 3 4 5 6 7 8 9 10

Years since diagnosis

Untre

ated

(%)

Clinically recognized MBLRai 0 CLL, B-cell 5-10Rai 0 CLL, B-cell>10

Shanafelt, JCO 27:3959,2009; Scarfo Leukemia 26:1703,2012

MBL: 1%/yr

CLL B-cells 5-10:

3%/yr CLL

B-cells >10 5%/yr

B-cell count is the most important predictor of clinical outcome in terms of need for therapy in patients with MBL

Is ALC or B Cell Thresholds Best Predictor for Outcome ? (Rai 0)

1Shanafelt, Blood 113:4188,2009; 2Molica Haematologica 96:277,2010; 3Scarfo Leukemia 26:1703

•  B-cell count >11 x 109/L confirmed as best predictor for TFS 1

–  Evaluated OS and TFS in 459 CLL patients –  Even after controlling for novel prognostic factors

•  Two subsequent series from Italy each involving >600 patients were confirmatory 2, 3

So What Is the Natural History Of HC MBL ?

Life Expectancy: HC MBL

•  Survival compared age/sex matched population –  Influenced by biologic characteristics CLL B-cell

Shanafelt Leukemia 26:373,2010 Blood. 2015 Jul 23;126(4):454-62

Age/sex matched population

CD38- MBL

CD38+ MBL

Prognosis High Count MBL •  B-cell count single most important parameter1-3

–  Independent other prognostic markers –  belongs in classification schema and supports the use of B cell levels in

diagnostic criteria

•  Prognostic profile similar Rai 0 CLL1-5

•  Studies generally suggest markers predict outcome CLL also predict TFS high count MBL –  ZAP70; CD38; IGHV; FISH; CD49d

•  Role prognostic parameters in routine practice is debatable –  Given low rates of progression high count MBL

Shanafelt, Blood 113:4188; 2Molica Haematologica 96:277; 3Scarfo Leukemia 26:1703; 4Rossi BJH 146:64; 5Kern BJH 157:86

Do MBL Have A Clinical Phenotype Aside From Progression to CLL?

Infection and Cancer Risk •  Up to 50% CLL patients develop infectious

complications1

– Defects both humoral and cell-mediated immunity – Infections account for 30-50% deaths in patients CLL

•  CLL patients increased second cancers 2-3

–  OR 2.2 (and still remains elevated 9 yrs after CLL dx) –  Risk death non-lymphoid neoplasm relative population OR=1.72

•  Are these risks present in MBL?

1Francis Cancer 107:1023; 2Tsimberidou, JCO 27:904; 3Royale BJC 105:1076

Infection High Count MBL •  Hospitalization with infection:

–  Controls: 2.6% (18/689) –  MBL: 16.2% (25/154) –  CLL: 18.4% (32/174)

p<0.001

Moriera, Leukemia. 2013 Jan;27(1):136-41

•  Risk infection CLL (HR=3.2, p<0.001) and MBL (HR=3.0; p=0.001) persist after MV analysis adjusting for age, sex, treatment, comorbid health problems

Cancer Risk High Count MBL •  MBL have increased risk non-hematologic cancer

Solomon Leukemia. 2016 Feb;30(2):331-6

Survival  (%

)

60

70

80

90

100

Y ears  since  diagnosis

0 2 4 6 8 10 12

p=0.006

596 494 318 143 0 0 0120 104 76 48 32 11 0148 119 84 55 33 18 4

C ontrolMBLC LL

T ime  to  second  cancer,  outside  2  month  window

ControlMBLC L L

•  Increased risk persisted: –  After excluding concurrently diagnosed cases

(p=0.006)

–  Controls 4% (22/596) –  MBL 16% (20/125) –  CLL 13% (20/153)

•  Risk cancer in MBL (HR=2.47; p=0.02) and CLL (HR=2.1, p=0.04) persists after MV analysis after adjusting age, sex, comorbid health problems

•  Individuals with high count MBL increased risk second cancer and serious infection •  These risks > risk progression to CLL requiring

treatment

Initial Diagnostic Evaluation •   History and Physical – Yes •   Immunophenotype of lymphocytes – Yes •   CBC with differential – Yes •   FISH testing with probe for t(11;14) – Yes •   CT scan chest/abd/pelvis – No •   Bone marrow biopsy – No •   CLL prognostic testing – No

Patient Management (Counseling and Monitoring)

•  Reducing use of “leukemia” term is a good thing –  Appropriate given low risk progression; minimal impact life expectancy –  May reduce emotional distress; sense “nothing being done”

•  Annual follow-up1

–  Physical exam –  CBC –  B cell count >11 x109/L reliably predicts TFS 2

•  Recommend –  Use of Vitamin D (1000 I.U. per day) –  Vaccination recommendations

•  High dose influenza •  Prevnar 13/23 •  Avoid live vaccines

1Shanafelt Leukemia 24:512; 2Shanafelt Blood 113:4188; 3Rawstron BJH 139:845

Summary High Count MBL

•  High count MBL appears to precede overt CLL –  Progression to CLL requiring treatment ~1%/year

•  Current classification scheme has clinical relevance

•  Changes MBL:CLL diagnostic criteria have altered both incidence and natural history CLL

•  High count MBL may have clinical phenotype –  Rates serious infection >risk of progression to CLL requiring treatment –  Increased risk 2nd cancer of similar magnitude observed CLL

Special Issues •  Individuals with autoimmune cytopenia who have very small B-cell

clones (eg, normal lymphocyte counts and no lymphadenopathy) –  Recommendation was to call “MBL with autoimmune cytopenia”

instead of classifying them as CLL.

•  Stem cell and blood donor issues –  MBL transfer from the donor to recipient during SCT have been

described from both related and unrelated donors. –  Current philosophy is to conduct flow cytometry to rule out occult

MBL

Hjalgrim H Blood. 2015 Oct 22;126(17) Rachel JM, Br J Haematol. 2007 Dec;139(5):832-6 FBr J Haematol. 2007 Dec;139(5):824-31errand C Hardy NM Eur J Haematol. 2012 Mar;88(3):269-72

The End