Burkitts Lymphoma : an unusual presentation in a 24yr woman

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Burkitts Lymphoma an unusual presentation in
a 24yr woman

• Kerry Williams, M.D
• Grand Rounds
• 04/20/2007

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Clinical Case

• 24 y/o Caucasian female
• No PMHx
• Presented to dentist with tooth abscess started
  on antibiotic therapy
• Noted heavy menstrual bleeding
• Presented to gynecologist performed endometrial
  biopsy.
• Underwent outpatient pelvic U/S

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Clinical Case

• Pelvic U/S bilaterally enlarged, solid ovaries,
  eccentric hypoechoic lesion in lower uterine
  canal, asymmetric myometrial wall thickening.

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Clinical Case
102
5.3
141
107
12
5.6
18
3.9
25
0.6
9.1
15.3
PTT 26.1 INR 1.18 PT 14.8
Protein 4.6 Albumin 2.9 T.Bili 0.5
MCV 85.8 RDW 13.7 ANC 2.9
FIBRINOGEN 254 LDH 962
RETIC ct 0.4 RBC FOLATE 848
HAPTOGLOBIN 54 IRON 168 TIBC lt183
FERRITIN 867 VIT B12 199
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Differential Diagnosis

• Acute leukemia AML vs ALL
• Myelophthesis lymphoma, metastatic carcinoma
• Myelosuppression drug effect
• Viral infection
• EBV, CMV, HIV, Hepatitis, HTLV, Parvovirus

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Peripheral Smear

• No circulating blasts.
• Absent myeloid cells, with residual mature
  lymphocytes and monocytes.
• Decreased platelets, no giant platelets.
• Anisopoikilocytosis, no nucleated RBC, no
  teardrops, 0-1/hpf schistocytes.

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Bone Marrow Biopsy

• Sheets of large, pleomorphic atypical cells
  infiltrating bone marrow
• CD45 ? hematopoeitic malignancy
• CD20, CD79a diffuse positivity ? B-cell lineage
• IHC TdT, Pancytokeratin, CK7, CK20, TTF-1
  negative
• Cellularity gt90, sparse maturing myeloid cells.
• Ki67 100

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Endometrial biopsy

• Round blue cell infiltrate composed of moderately
  sized, round lymphoid cells with fine chromatin,
  multiple distinct nucleoli.
• CD79a, CD10, bcl-6 positivity
• No bcl-2 expression.
• Ki67- near 100 proliferation in neoplastic
  B-cells.
• In situ hybridization for EBV RNA negative.
• FISH consistent with c-myc containing
  chromosomal rearrangement.

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Diagnosis

• Stage IV Burkitts Lymphoma

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Burkitts Lymphoma

• Highly aggressive NHL
• Denis Burkitt in Africa, in areas endemic for
  malaria (in 1958)1

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Endemic BL
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WHO Classification

• Endemic
• Sporadic
• Immunodeficiency associated
• HIV/AIDS 30-40 of NHL in HIV
• Post allotransplant
• Congenital immunodeficiency

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Sporadic BL

• Worldwide
• 1 2 of lymphoma in adults2
• Up to 40 - children in US and Western Europe
• Abdomen, especially ileocecal area
• Abdo pain, nausea, vomiting, bowel obstruction,
  GI bleeding, syndromes mimicking acute
  appendicitis, intussusception.
• Ovaries, kidneys, omentum, Waldeyers ring
• Bilateral breast involvement in association with
  onset of puberty or with lactation3

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Sporadic BL3

• LN in adults gt children
• Adults malignant pleural effusions or ascites.
• Rarely, present as leukemia ( FAB ALL L3)
• EBV in 15-30
• At diagnosis high LDH and uric acid levels,
  bulky disease

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Sporadic BL3,4

• CNS involvement in adults 13 17
• Bone marrow involvement 30 38
• 30 - limited stage disease
• 70 - widespread (Stage III/IV)

19
Blum K A, Lozanski G, Byrd J C. Adult Burkitt
Leukemia and lymphoma. Blood 20041043009-3020
20
Blum K A, Lozanski G, Byrd J C. Adult Burkitt
Leukemia and lymphoma. Blood 20041043009-3020
21
Ferry J A. Burkitts Lymphoma Clinicopathologic
Features and Differential Diagnosis. Oncologist
200611375-383
22
Bone Marrow
Lymph node
Blum K A, Lozanski G, Byrd J C. Adult Burkitt
Leukemia and lymphoma. Blood 20041043009-3020
23
Blum K A, Lozanski G, Byrd J C. Adult Burkitt
Leukemia and lymphoma. Blood 20041043009-3020
24
Blum K A, Lozanski G, Byrd J C. Adult Burkitt
Leukemia and lymphoma. Blood 20041043009-3020
25
Blum K A, Lozanski G, Byrd J C. Adult Burkitt
Leukemia and lymphoma. Blood 20041043009-3020
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TREATMENT

• Historically similar to treatment regimens for
  ALL with induction, consolidation and maintenance
  regimens.
• High growth fraction (doubling time of 25 hours)
• Favors re-entry of cells into cell cycle and
  rapid growth btwn chemo regimens, subsequent
  development of resistance.4

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TREATMENT

• Short duration, high-intensity regimens
• CNS prophylaxis
• Tumor lysis prevention IVF, allopurinol

28
Blum K A, Lozanski G, Byrd J C. Adult Burkitt
Leukemia and lymphoma. Blood 20041043009-3020
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CODOX-M14,15,16

• Low risk Stage I-IIE, tumor mass lt10cm, normal
  serum LDH, WHO performance status 0-1
• Cyclophosphamide 800mg/m2 D1
• D 2-5 200g/m2
• Vincristine 1.5 mg/m2/day, D1 D8
• Methotrexate 1200 mg/m2 over 1 hr, and then 240
  mg/m2 for 23hrs (with leucovorin) D10
• IT cytarabine 70mg D1 D3
• IT MTX 12mg D15

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IVAC14,15,16

• Ifosfamide 1500 mg/m2/d D1-5 (with mesna)
• Etoposide 60 mg/m2/d D1-5
• Cytarabine 2000 mg/m2 every 12 hrs for 4 doses,
  D1 2
• IT methotrexate 12 mg D5

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Magrath Regimen14,15,16

• Alternating CODOX-M with IVAC for 4 cycles for
  high risk disease
• CODOX-M for 3 cycles for low risk disease
• LaCasce et al
• 14 patients with median age 47
• 86 response
• 72 alive and disease free at 21mo
• Toxicities myelosuppression
• Treatment related mortality 5 patients

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LY06 study16

• Low risk patients 3 cycles of modified CODOX-M
• High risk patients 4 cycles of alternating
  modified CODOX-M / IVAC
• 12 LR
• 40 HR
• Majority of patients completed protocol treatment
  (n41)
• Severe toxicity myelosuppression, mucositis

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Commence next cycle on day ANC gt1000
(unsupported), unsupported plt count gt75,000
34
Commence next cycle on day ANC gt1000
(unsupported), unsupported plt count gt75,000
35

• Worst WHO toxicity grade for low-risk patients (n
  12) during CODOX-M. Other toxicities included
• one grade 3 renal failure
• one grade 3 alopecia

• Worst WHO toxicity grade for high-risk patients
  (n 40) during CODOX-M/ IVAC. Other toxicities
  were as follows
• One grade 3 hemorrhage
• One grade 3 per vaginal bleeding
• One grade 3 lung toxicity
• One grade 3 sepsis
• Two grade 4 sepsis
• One grade 4 constipation
• One grade 3 alopecia

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Overall and event-free survival for all patients
(pts n 52).
Event-free survival for all patients (n
52). EFS 64.6
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Overall survival for all patients (n 52). OS
72.8 2 yr
LR patients 2yr EFS 83.3, OS 81.5 HR
patients 2yr EFS 59.5, OS 69.9
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Hyper-CVAD17
Survival and CR duration. Note all relapses but
one occurred less than 1 year from CR. 81 -
CR OS at 3 yr 49
Survival by age gt 60 yr 3 yr OS of 17 vs 77

• Worse survival
• gtage 60 years,
• hemoglobin level less than 10 g/dL
• presence of peripheral blasts

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CALGB 925119

• Prephase
• Cyclophosphamide 200mg/m2/d D1-5
• Prednisone 60mg/m2/d D1-5
• Cycle 2, 4, 6 (every 3 weeks)
• Ifosfamide, Mesna, Vincristine, Etoposide,
  Cytarabine, Methotrexate, Dexamethasone, IT MTX,
  cytarabine, hydrocortisone
• Cycle 3, 5, 7
• Cyclophosphamide, Doxorubicin, Vincristine, MTX,
  Dexamethasone, IT MTX, cytarabine and
  hydrocortisone.
• Cranial Irradiation after cycle 3

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CALGB 925119

• 54 evaluable patients
• CR 80
• 4 yr DFS 50
• Toxicities
• Severe neurological toxicity (transverse
  myelitis, peripheral neuropathy, aphasia,
  cortical blindness, dementia) 10 / 74 patients
  enrolled. attributed to high dose MTX, triple IT
  chemo and WBRT (24Gy)
• gt 50 yrs
• mortality (21 vs 9), disease progression (32
  vs 3), toxicity (16 vs 9),

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ASCT

• Upfront autologous SCT (in CR-1)
• 3 yr OS rates of 60 - 72 have been reported ?
  similar to rates obtained with chemo alone.4
• Increased morbidity and mortality with ASCT vs
  chemo alone.
• French LMB trial 54 (7/13 pts) in CR-1 ? SCT (6
  allo, 7 auto) survived vs 89 (40/45) with chemo
  alone.6
• No role for SCT in CR-1

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Prognosis

• Most patients attain CR within 4-6 weeks of
  initiating therapy.
• Hyper-CVAD17
• median time to CR 22 days
• 70 CR within 1st 4 wks
• Relapse within 1st year
• Failure to achieve CR-1 poor prognostic sign
• PR or relapsed disease - ???? salvage

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Salvage

• Cytarabine, ifosfamide, or cisplatin
• ?? Auto vs allo SCT in salvage setting
• Disease status at time of SCT (CR-1 or
  chemosensivity) significant effect on OS
• No effect of graft-vs-lymphoma ? no effect on OS

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New Modalities

• Rituximab
• Hyper-CVAD regimen
• Days 1 and 11 of cycles 1,3
• Days 1 and 8 of cycles 2,4
• MD Anderson18
• 20 pts
• CR in 89
• Most patients with advanced disease, some HIV
  positive patients.

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R-HyperCVAD

• Thomas et al20
• Cancer April 2006
• 31 patients with newly diagnosed BL or B-ALL
• R-HyperCVAD
• CR 86
• OS at 3 yr 89
• EFS at 3yr 80
• DFS at 3yr 88

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Thomas, et al. Cancer 20061061569-80
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• Survival with hyper-CVAD plus rituximab compared
  with hyper-CVAD
• Overall

(B) Age lt 60
(C) Age gt 60
Thomas, et al. Cancer 20061061569-80
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Summary

• Rare disease, aggressive NHL
• Short duration, high-intensity regimens
• CNS prophylaxis, tumor lysis prevention
• Still no standard treatment regimen
• Role of rituximab
• Role of SCT
• auto vs allo
• CR-1 ??

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Our Patient

• Received module A of R-HyperCVAD
• Hospital course complicated by febrile
  neutropenia, clostridium difficile colitis, and
  ongoing vaginal bleeding.
• Discharged home with growth factor support.
• Vaginal bleeding resolving, ANC slowly
  recovering.
• Readmitted 04/18/07 for module B ..

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References

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  200611375-383.
• Blum K A, Lozanski G, Byrd J C. Adult Burkitt
  Leukemia and lymphoma. Blood 20041043009-3020.
• Bernstein J, Coleman C, Strickler J, Dorfman R,
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References

• 11. Divine M, Cassasus P, Koscielny S et
  al. Adult Burkitt lymphoma. A prospective
  multicenter trial with the LMB protocol. Proc Am
  Soc Clin Oncol. abstract 20001980.
• 12. Hoelzer D, Ludwig W D, Thiel E et al.
  Improved outcome in adult B-cell acute
  lymphoblastic leukemia. Blood 199687495-508.
• 13. Todeschini G, Tecchio C, Degani D et
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  advanced Burkitts lymphoma/leukemia no
  differences in outcome between pediatric and
  adult patients treated with the same intensive
  pediatric protocol. Ann Oncol 19978S77-S81.
• 14. Adde M, Shad A, Venzon D et al.
  Additional chemotherapy agents improve treatment
  outcome for children and adults with advanced
  B-cell lymphoma. Semin Oncol 19982533-39.
• 15. LaCasce A, Howard O, Li S, Fisher D,
  Neuberg D, Shipp M. The Magrath Regimen is
  effective in older adults with Burkitts and
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• 16. Mead G, Sydes M, Walewski J, et al. An
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• 17. Thomas D, Cortes J, OBrien S et al.
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  1999172461-2470.
• 18. Cabanillas M, Thomas D, Cortes J et al.
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  Proc Am Soc Clin Oncol. abstract. 2003222309.
  
• 19. Lee E, Petroni G, Schiffer C et al.
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• Thomas D, Faderl S, OBrien S, Bueso-Ramos C et
  al. Chemoimmunotherapy with Hyper-CVAD plus
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