approach to heme malignancies lymphoma, multiple myeloma, acute leukemia and myeloid disorders dr....
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Approach to Heme Malignancies
Lymphoma, Multiple Myeloma, Acute Leukemia and Myeloid Disorders
Dr. Michelle GeddesUniversity of Calgary and Tom Baker Cancer Centre
Nov 26, 2015
Objectives
• Organize the approach to working up possible hematologic malignancies
• Review presenting symptoms and signs in hematologic malignancies
• Outline the approach to therapy in different hematologic malignancies
• Review disease and treatment complications
Hematopoiesis
Lymphoid Malignancies
• Lymphoproliferative disorders
• B cells 80%, T cells 20% (terrible Ts)
• Chronic lymphocytic leukemia/small lymphocytic lymphoma
• Acute leukemia (B cell ALL, T cell ALL)
Hodgkins Lymphoma
– Classical HL– Nodular lymphocyte predominant HL
NonHodgkins Lymphomas
IndolentFollicular
Gastric MALT
Small lymphocytic lymphoma
Waldenstroms
Mantle cell lymphoma
Very AggressiveBurkitt
Lymphoblastic lymphoma
AggressiveDiffuse large B
cell lymphoma
Peripheral T Cell lymphoma
Double hit lymphoma
Case 1 – possible lymphoma
• 23 year old woman with cervical lymph node present for one month
• No infectious or B symptoms• Pruritis
On exam – Temp 38 C• 3 cm left anterior cervical LN, 4 cm left
supraclavicular lymph node
Labs - CBC – normal except WBC 15, neutrophils 13.2, eosinophils 1
• LDH elevated at 420
WHAT TESTS WOULD BE HELPFUL TO DETERMINE IF LYMPHOMA?
Making a Diagnosis…• BIOPSY the Node!
– Excisional biopsy>needle core>FNA
• Other bloodwork can be helpful:– CBC
– LDH
– ESR
– B2 microglobulin
– SPEP, quant immunoglobulins
• Bone marrow biopsy usually a staging procedure, not preferred as diagnostic test
A BIOPSY IS DONE…
Hodgkins lymphoma – Reed Sternberg cell
Hodgkins LymphomaB cell lymphoma with surrounding reactive T cells
NOW WHAT?STAGING LYMPHOMA
Lymph Node Regions
Staging (Ann Arbour System)
A – no B SymptomsB – presence of B Symptoms
Staging Hodgkins Lymphoma
• Physical Exam
• History of B symptoms
• CT neck, chest, abdomen and pelvis
• ? Bone marrow biopsy– Not necessary if less than stage IIB HYL as
unlikely to be involved (unlike NHL)• Hodgkins tends to have orderly spread
• PET scan– If limited stage disease, confirm with PET scan
PET scan
Treatment and Prognosis in Hodgkins Lymphoma
Treatment and prognosis of Limited Stage HL
• Favourable risk:– ABVD (adriamycin, bleomycin, vinblastine and
dacarbazine) x2 and 30 Gy involved field RT
• Unfavourable risk:– 4 cycles ABVD and 30 Gy IFRT– If B symptoms or bulky 6 cycles ABVD and
IFRT
Treatment and prognosis of advanced stage HL
• Good risk: ABVD x 6 +/- RT• If adverse risk factors:
– Escalated dose BEACOPP• Bleomycin, etoposide, adriamycin, cyclophosphamide,
vincristine, procarbazine, prednisone• More toxicities and infertility, MDS than ABVD; ABVD used in
those with few risk factors and elderly
– PET CT scan after therapy for residual disease
•
LOW GRADE NON-HODGKINS LYMPHOMAS
Case 2
• 64 year old man comes to see his GP with an enlarged lymph node in his groin
• Feels otherwise well, no B symptoms, no symptoms related to enlarged node
• Physical exam shows 2 cm LN in both axillae• CBC, LDH, SPEP normal
• A diagnostic procedure is performed…
Follicular Lymphoma
Follicular lymphoma
• 70% of all low grade lymphomas
• Older population, usually relatively asymptomatic at diagnosis with long history of waxing and waning lymph nodes– 75% with advanced stage
• Approximately 25% will transform at some time to an aggressive DLCL
Treatment of Follicular Lymphomas
• Generally watch and wait until symptomatic– Most treatment not curative– Exception – stage 1a or IIa nonbulky contiguous disease given RT for
cure
• Rituximab-Bendamustine is mainstay of first line therapy treatment indicated– fever, night sweats, weight loss, malaise, pain– Bulky or symptomatic lymphadenopathy– Impending organ compromise (compression, pleural/pericardial
effusions, ascites)– Cytopenias secondary to bone marrow infiltration
• Maintenance rituximab given q3 months for two years to prevent relapse and improve survival
Treatment of Follicular Lymphomas
Indolent Lymphomas Follicular Lymphoma
JCO 2009: 10;1607-14
Prognosis in Follicular Lymphoma
Specific indolent lymphomas have different treatment approach
• Mantle cell lymphoma – “indolent” lymphoma but relatively aggressive course with med survival 3-5y– R-CHOP then DHAP and autologous stem cell transplant
up front, maintenance Rituximab
• Gastric MALT, cutaneous indolent lymphomas• Splenic marginal zone lymphoma ‘
– Splenectomy
• Hairy cell leukemia – Splenomegaly and cytopenias– Cladrabine single 5-7 day course: 91% CR, OS at 4y 96%
AGGRESSIVE LYMPHOMAS
Case 3
• 54 year old patient presents with rapid development over 2-3 weeks of large left supraclavicular lymph node– Fevers, drenching sweats
– Appetite poor, weight loss10 lbs
• On exam: 5 cm left supraclavicular node– Cachexia
• A diagnostic procedure is performed…
Diffuse large B cell lymphoma
Diffuse large B cell lymphoma
• Most common type of lymphoma, incidence increases with age – 25% of all NHL
• Rapidly growing LNs, 30% have B symptoms• Advanced disease>localized disease• 30% bone marrow involvement, most high LDH• Can be extranodal disease
– 5-10% risk of CNS relapse
Treatment of DLCL
• Limited stage (I-IIa non-bulky)– If 0-1 IPI risk factors: R-CHOPx3 + IFRT– If 3 risk factors: R-CHOP x 6
• Advanced stage (stage III-IV, bulky, B symptoms)– R-CHOP x6– Add IFRT to sites of prior bulk
– PET scan after completion of therapy
Prognosis - International Prognotistic Index
T cell aggressive lymphomas
• Overall, prognosis is worse than B cell aggressive lymphomas
• Can present with T symptoms – terrible B symptoms, systemic symptoms
T cell lymphoma outcomes
Foss F M et al. Blood 2011;117:6756-6767
Treatment of Aggressive T cell Lymphomas
• CHOP– Overall, response in 50-70% with 5 year
disease-free survival around 30%– Compared to 50-60% for high risk DLBCL
• CHEOP – adding etoposide may improve 3y EFS (75% vs 51%) in patients 60y
• High risk fit patients often offered autologous transplantation in 1st complete remission
HIGHLY AGGRESSIVE LYMPHOMAS
Highly Aggressive Lymphomas
• B cell lymphomas∕leukemias– Burkitts lymphoma– Precursor B lymphoblastic leukemia ∕
lymphoma
• T cell lymphomas∕leukemias– Precursor T lymphoblastic
leukemia ∕ lymphoma
Highly Aggressive Lymphomas• Aggressive and prolonged inpatient protocols of combined 4
or 5 drug chemotherapy drugs– CNS prophylaxis and CNS-penetrating chemotherapy cranial
irradiation– 25% CNS relapse without treatment
• Overall survival 60% for T lymphoblastic lymphoma and Burkitts
• Pediatric-based very aggressive 2y protocols for ALL with 60% survival <age 60y– High risk patients alloBMT
Chronic Lymphocytic Leukemia
• Indolent lymphoproliferative disorders with median survival >15y overall
• Indications for treatment: – cytopenias, B symptoms, symptomatic or bulky
lymphadenopathy, consitutional symptoms
• Cytogenetics help determine prognosis and treatment options
Current CLL treatment
Overall Survival FCR vs BR
Eichhorst B, et al. ASH 2014:19
Bruton’s tyrosing kinase inhibitorIbrutinib : duration of response
OVERALL SURVIVAL
PROGRESSION-FREE SURVIVAL
0
20%
40%
60%
80%
100%
0 6 12 18 24 30 36 42
TN
R/R+ Censored
TN R/R
30-mo PFS 96.3% 68.4%
(95% CI)(76.5-99.5)
(56.1-77.9)
Median PFSNot
reachedNot
reached
0
20%
40%
60%
80%
100%
0 6 12 18 24 30 36
Months
TN
R/R
+ Censored
TN R/R
30-month OS
96.6% 79.9%
(95% CI)(77.9-99.5)
(69.0-87.3)
Median OSNot
reachedNot
reached
O’Brien S, et al. ASCO 2014; Oral/Abstract #7014
Idelalisib + rituximab
Furman et al NEJM 2014
Idelalisib + R improves overall survival
Furman et al NEJM 2014
Lymphoma Summary
• Divided into indolent, aggressive and highly aggressive malignancies
• Indolent lymphomas are not generally curable with chemo and less symptomatic– often diagnosed in advanced stage but with long survival
ie follicular– watch and wait, less intensive chemotherapy
• Aggressive lymphomas often curable with chemoradiation and are more symptomatic– more often diagnosed in early stages– chemotherapy IFRT given at diagnosis for cure
Case 4
• 60yo man presents with pathologic fracture of the humerus
• Fatigued, generally unwell for 6 months• Labs:
– Hb 90, remainder of CBC normal– Ca+ 2.7, creatinine 160, total protein 90
– What further investigations would you need to do?
Further investigations– SPEP shows IgG kappa monoclonal protein 32g, – B2 microglobulin 4.2, albumin 30, CRP high, Ig levels shows high
IgG – Serum free light chain index elevated at 326– Skeletal survey – multiple lytic bony lesions– Urine protein electropheresis and creatinine clearance
• Dipstick may not be positive (picks up albumin)
– A bone scan is not helpful!• Osteoclastic activity not osteoblastic in myeloma, does not light up on
bone scan
Diagnosis
CRAB (A)
• Calcium (>2.7)• Renal failure (>176)• Anemia (Hb<110)• Bony lesions• (Amyloidosis)
Cytogenetics and flow cytometry are sent for prognostic markers on bone marrow aspiration
Staging multiple myeloma
• Always comes out of an MGUS
• FISH for: t(14;16), t(4;14), deletion 17 (17p-) and del13q are prognostically important on bone marrow aspiration
Stage B2Microglobulin
Albumin Median Survival(months)
I <3.5 and 35 62
II ≥3.5 and <5.5 and/or <35 44
III ≥5.5 29
Treatment Approach in Myeloma
• Transplant eligible
• Non-transplant eligible
Treatment algorithm
Stem cell mobilization, autologous stem cell transplant then VRD x 2 cycles
Maintenance with lenalidomide until progression or bortezomib for 2 years
or
All patients IV bisphosphonatemonthly x2y
Prognosis post transplant in MM
Al-Mansour, et al. Adv Hematol. 2014; 2014: 652395.
Age >65y Age <65y
In non-transplant eligible, OS 60-70% at 4y
Myeloid disorders• Myelodysplastic syndromes• Myeloproliferative disorders
– Essential thrombocytosis, polycythemia vera, myelofibrosis– CML – tyrosine kinase inhibitors
• Acute myeloid leukemia– Intensive inpatient protocols with allogeneic transplantation
in high risk patients– Hypomethylating agents or low dose cytarabine in the
elderly
What raises a red flag that there is a myeloid disorder?
• Reasons to refer urgently: – Blasts – always!
– Nucleated red blood cells
– >1 unexplained cytopenia or a severe cytopenia
– Unexplained elevated blood counts:• Hb >185 in men or Hb>165 in women – check epo levels, jak2V617F
mutation if no obvious explanation for high Hb
• Thrombocytosis >450 persistent – look for reactive causes, iron deficiency
• Elevated white blood cells with left shift
Myelodysplastic Syndromes
• Clonal disorders of the bone marrow characterized by:– Low blood counts– Ineffective production of blood cells– Abnormal red cells, neutrophils and platelets– Increased risk of developing AML
Mr. G. Olfer
• 72 yo man with anemia for 4 years• Mildly low neutrophil count, no infections• Platelets normal, no bleeding• Now hemoglobin down to 60s, transfusion
dependent with 4u red cells transfused• Bone marrow biopsy shows MDS
• Refractory anemia with ringed sideroblasts
• What does this mean for him?
WHO 2008 Classification – A collection of myelodysplastic
syndromesRefractory Cytopenias with Unilineage Dysplasia (RCUD)
Refractory Anemia with Ring Sideroblasts (RARS)
Refractory Cytopenia with Multilineage Dysplasia
Refractory Anemia with Excess Blasts-1 (RAEB-1) (5-9% BM blasts)
Refractory Anemia with Excess Blasts-2 (RAEB-2) (10-19% BM blasts)
Myelodysplastic Syndrome - Unclassified
MDS Associated with Isolated del(5q)
< 20% blasts
WHO Classification of Tumours of Haematopoietic and Lymphoid Tissues, 4 th edition. 2008.
Goals of Therapy
• Prolong survival
• Quality of life
• Improve symptoms
• Reduce transformation to acute leukemia
How do we decide if patients have lower risk or higher risk MDS?
• Blood counts
• Chromosome analysis
• Blast counts in bone marrow
• Age
• Type of MDS
IPSS-RRevised International Prognostic Scoring System
Greenberg P, Tuechler H, Schanz J, et al. Blood. 2012;120(12):2454
Very good = del(11q)Good = Normal, del(5q), del(12p), del(20q), double including del(5q)Intermediate = del(7q), 8, 19, i(17q), any other single or double independent clonesPoor = inv(3)/t(3q)/del(3q), double including 7/del(7q), complex: 3 abnormalitiesVery poor = Complex: 3 abnormalities
Lower risk MDS• Growth factors i.e. erythropoietin
– increase red cells and reduce transfusions
• Transfusions, antibiotics, supportive care
• Iron chelation for iron overload from transfusions– Usually if ferritin>1000 and/or 20
transfusions red cells
Del 5q syndrome• 10-15% of MDS
– Anemia– Mild low white blood cells– Atypical megakaryocytes, normal to elevated
platelets– Transfusion dependence– Normal blast count
Extended survival with low frequency of AML transformation (10%)
Lenalidomide: RBC Transfusion Independence in Del(5q) MDS
Erythroid Response Rate (N=148) n (%) 95% CI
Transfusion independence* 99 (67) 59–74
≥50% decrease in no. transfusions 13 (9) 5–15
Total transfusion response 112 (76) 68–82
Transfusion Independence
Response Characteristics
Median Range
Time to response (wk) 46 1–49
Hgb increase† (g/dL) 54 11–114
N Eng J Med, 2006; 355: 1456
Mr. G. Olfer
• After 2 years, his platelets drop to 14 and he starts to have blasts in his peripheral blood
• Bone marrow biopsy shows refractory anemia with excess blasts-2• Blasts 11%, complex cytogenetics• Higher risk MDS
• What treatment options does he have?
Higher risk MDS
• Supportive care, transfusions
• Azacytidine Intermediate-2 and High risk MDS, low blast count AML– 7d subcutaneous injections every 4 weeks– Associated with improved survival, lower rate
of developing acute leukemia– Improved quality of life
Overall Survival: Azacitidine vs Conventional Care Regimen
Lancet Oncol 2009; 10:223-32.
p=0.0001p=0.0001
0 5 10 15 20 25 30 35 40
Time (months) from RandomizationTime (months) from Randomization
0.0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1.0
Pro
po
rtio
n S
urv
ivin
gP
rop
ort
ion
Su
rviv
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ConventionalCare
AZA
Survival Difference 9.4 monthsSurvival Difference 9.4 monthsOral azacytidine in developmentOral azacytidine in development
Between a rock and a hard place
Transplantation iscurrently the only curative therapyfor many hematologic malignancies
Median age at diagnosis is 65-70Toxicity of transplantation can be prohibitive
Role of Clinical Trials
Other supports available
• Home care• Wellspring• AAMAC• Leukemia and lymphoma society• Psychosocial services• Dieticians• Social work, home care, mobile lab
Questions?
Blood Moon
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