CASE REPORT AN UNCOMMON PRESENTATION OF CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) AT DISEASE PROGRESSION March 12th 2011 Padova Michael Mian, MD General Hospital of Bolzano
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)