CASE REPORTAN UNCOMMON PRESENTATION OF CHRONIC LYMPHOCYTIC

LEUKEMIA (CLL) AT DISEASE PROGRESSION

March 12th 2011Padova

Michael Mian, MDGeneral Hospital of Bolzano

DiagnosisTherapy

Progression

Laboratory

Last FUP

DIAGNOSIS2001 2002 2003 2004

3 6 9 12 3 6 9 12 3 6 9 12 3 6 9 12

M. F. *02/1950; m

- Judoka

- Anamnesis: slight exhaustion, no B-Symptoms.

- Medical examination: bilateral laterocervical, sovraclavear and axillarylymphadenopathy (max. 2cm). Spleen palpable (1-2 cm).

- Lab: WBC 70,900/ul (N 7%, L 92%), Hb 14,6 g/dl, PLT 190,000/ul,numerous Gumprecht shadows; creatinin 0,9mg/dl; LDH<UNL, beta2-MG2,4 mg/L

- Flow cytometry: CD 19+, CD 20+, CD 22+, CD 23+, CD 5+(CD5+/Cd19+ 93%); lambda 93%

- FISH: absence of del 13q14, del11q23, del 17p13.1, trisomy12

- Ecography of the abdomen: spleen 14 cm, abdominal lymphadenopathy

=> Chronic Lymphocytic Leukemia Rai II, Binet B

Diagnosis

TherapyProgression

Laboratory

Last FUP

THERAPY I2004 2005 2006 2007

3 6 9 12 3 6 9 12 3 6 9 12 3 6 9 12

05/2004: PD (weight loss, hyperleucocytosis, increasingsplenomegaly, retroperitoneal lymphadenopathy) => PD

⇒1st line: 05-10/2004 Leukeran + Prednisone x12 cycles: SD

⇒ 2nd line: 03-09/2005 start treatment with Fludarabine mono(25mg/m2; q=28) x6: PR

08/2009: PD (Hyperleucocytosis, increasing splenomegaly andabdominal & laterocervical lymphadenopathies) => FISH: del 13q1428%, mutational analysis: IGHV unmutated

⇒3rd line: 09-12/2009 Fludarabine + Cyclophosphamide x4 cycles(no Rituximab because of recurrent infections): PR

Diagnosis

TherapyProgression

Laboratory

Last FUP

THERAPY II2010

1 2 3 4 5 6 7 8 9 10 11 12

05-06/2010 PD: Increasing spleen size, abdominal lymphadenopathy &extranodal presentation of disease: 1) subcutaneous nodule of the right arm=> excision compatible with localization of the known CLL 2) echography ofthe lower extremities: presence of pathologic tissue (2.5 cm) at the level ofthe diaphysis of the tibia with interruption of the cortical layer. 3) MR rightankle (01/07/2010): presence of a pathologic tissue

=> 4th line: 06-09/2010 R-Bendamustina (100mg/m2) x4 + start searchfor a compatible BM donor

24/09/2010: diffuse joint pain, painful swelling at the left forearm and pain ofthe right elbow (=> radiography: osteloysis), pain when chewing.⇒ PET-CT & maxillofacial CT

Maxillofacial CT: probable pathologic fracture of the anterior part of the sinusmascellaris extending to the basis of the orbita

PET-CT (28/09/2010)

Several bone lesions: right olecranon, tibial spine, right carpus; left elbow,tibial diaphysis and bilateral tarsal & metatarsali bones as well as thecalcaneus.

Diagnosis

Therapy

ProgressionLaboratory

Last FUP

PROGRESSION OF DISEASE II2008 2009 2010 2011

3 6 9 12 3 6 9 12 3 6 9 12 3 6 9 12

12/10/2010 (after the 4th cycle): The patient presents with painand swelling of the left forearm.

=> X-Rays: Pathological fracture of radius and ulna.

=> Biopsy of the fracture margin of the forearm (29/10/2011):Infiltration of the bone by the known CLL.=> Bone marrow aspirate (11/11/2011): lymphocyte infiltrationof 20% (cytofluorometry 2% of monoclonal B-cells)=> Bone marrow biopsy (11/11/2011): No evidence ofinfiltration of the bone marrow by the known CLL.

RADIOGRAPHY (12/10/2010)

Diagnosis

Therapy

Progression

LaboratoryLast FUP

LBORATORY EXAMS2010 2011

2 4 6 8 10 12 2 4 6 8 10 12 2 4 6 8

- WBC 3,520/ul (N 57%), Hb 12.7 g/dl, PLT 62,000/ul

- Ca++ 9,3mg/dl (8,5 – 10,5)- Alkaline phosphatasis 108 UI/L (30-104)- Uric acid 4.1 mg/dl (2.5-8.0)- Creatinine 0.7 mg/dl (0.8-1.3)

- Absence of Bence-Jones proteinuria.- Absence of monoclonal component in the serum-electrophoresis.- Parathormone was not measured.

REVIEW OF THE LITERATURE I (last 30years)

Report # ofpts

Age

YearsAfter

Diagnosis

WBCx10^9/l

Hb &PLT

RS MC Ca++ PTH Treatment

McMillian, BMJ 1980 1 f 73 0 28 anemia no na +/- +/- Bisphosphonates + Chlorambucil

=> PR

Rossi, BJH 1990* 2f+m

>70

na na na no na na na na

Lerner et al, L&L 1994 1 f 2 ++ na yes na ++ death of HC

Van de Casteele, AnnHematol 1994

1 m 40 12 341 anemiathrombocytope

nia

no IgM k ++ red. Bisphosphonates + CHT =>death of HC

Briones, L&L 1996 1 f 69 1,8 2 +/- yes IgG kat RS

++ +/-1,25(OH)2 D3normal

Steroids +CHOP => deathof pneumonia

In all reports, patients presented with multiple bone lesions and/or pathologic fractures.MC, Monoclonal Component; PTH, Parathormone; Hb, Hemoglobin; PLT, Platelets; CHT, chemotherapy; HC, hypercalciemia;+/-, normal; ++, elevated; f, female; m, male.

REVIEW OF THE LITERATURE II (last 30years)

Report # ofpts

Age Years AfterDiagnosis

WBCx10^9/l

Hb &PLT

RS MC Ca++ PTH Treatment

Beaudreuil, Cancer1997

2 73f +m

1 & 7 L 20 &42

na &red.

yes na ++ red.PTH-rP++

C1: Pam. + CHT =>death of septic shockC2: Pam. + CHT =>

death of septic shock

Lazarevic, L&L2006**

1 69 m 1 247 red. yes yes ++ Zoledronate + CHOP=> death of MOF

Greenfield, Eur JHaematol 2006

1 81 m 4 na na no IgGk8g/L

stable

+/- na na

**del(17p), unmutated IGHV genes

MC, Monoclonal Component; PTH, Parathormone; Hb, Hemoglobin; PLT, Platelets; CHT, chemotherapy; HC, hypercalciemia;+/-, normal; ++, elevated; f, female; m, male; Pam, Pamidronate; PTH-rP, parathormone-related peptide; MOF, multi-organfailure.

OBSERVATIONS

• Large number of osteoclasts around the tumor mass => secretion ofosteoclast activating factor by the tumor cells?

• Elevated osteoclast count (smaller than normal osteoclasts) anddramatically increase of the eroded surface ratio (4-10 fold of B-BHLwithout lytic lesions) in 8 patients affected by hematologicmalignancies (2 CLL, 4 other NHL, Mb. Waldenstöm) with lytic bonelesions and/or hypercalcemia.

• The role of numerous local & systemic factors that promoteosteoclast activation (IL1, TNF-alpha and beta, IL6, CSFs,1,25(OH)2 D3, …) in CLL is not clear: 1 case with TNF and IL-6normal; 2 cases with elevated TNFalpha and elevated IL-6 in 1 case(IL6 was also elevated in control patients without hypercalcemia).

• Parathormone-related peptide could contribute to this process (1case associated with diffuse bone reabsorption; 1 case osteolyticbone lesions)

Diagnosis

Therapy

Progression

Laboratory

Last FUP

LAST FOLLOW UP

In Trento:

- 5th line (11/2010): DHAOX x 1

- Afterwards autoimmunhaemolytic anemia => 4administrations of rituximab (lastly 21/12/11) per AEA.

- Progression of disease with hypercalcemia => monthlyBisphosphonates + C-CHOP

- The patient died due to progression of disease after the 3rd C-CHOP

2010 2011

2 4 6 8 10 12 2 4 6 8 10 12 2 4 6 8

CONCLUSIONS

• About 11 cases have been described in the last 30 years (5 cases without Richtertransformation) => lytic bone lesions are a rare complication.

• Lytic bone lesions are a sign of disease progression.

• It occurs in all ages without a specific gender predilection. At time of diagnosis it isnot strictly associated with hypercalcemia, altered blood counts.

• Determines a poor prognosis.

• Probable dysregulation of the microenviroment due to local and/or systemic factorsat time of disease progression leading to a elevated localized bone reabsorption byactivated osteoclasts.

• Treatment: bisphosphonates (+ adequate treatment for hypercalcemia if present) +chemotherapy. However, up to now there does not exist any standard treatment forCLL patients with osteolysis and the disease seems to be resistant toimmunochemotherapy.

ACKNOWLEDGEMENTS

• Prof. Sergio Cortelazzo (Ospedale diBolzano)

• Dr.ssa Cerù Silvia (Ospedale di TN)