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What Primary Care Providers Need to Know About Blood Cancers

Steven Fein, MD, MPHHematologist/OncologistMiami Cancer InstituteBaptist Health South Florida

Disclosures

Dr. Fein is on speakers’ bureaus for:Bayer, Incyte, Seattle Genetics,Janssen, and Novartis.

This lecture will not discuss off-label uses for any medications.

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Learning Objectives

• Describe common blood cancers

• Determine when abnormal CBC warrants more testing or heme referral

• Understand blood cancer treatments

Cancer By the Numbers

• 18M new cancer patients/year in the world• 10M cancer-related deaths/year in the world

• 1.8M new cancer patients/year in the U.S.• 600K cancer-related deaths/year in the U.S.• 1 in 3 of us will get cancer in our lifetime

• 17M people living with cancer in the U.S.“cancer survivors” and “cancer fighters”

How We Die in the U.S. Cancer Body Count

Cancer Statistics, 2018. CA Cancer J Clin; 68:7-30.

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Cancer Body Count Nixon 12/23/71: War on Cancer

“The time has come in America when the same kind of concentrated effort that split the atom and took man to the moon should be turned toward conquering this dread disease.”

https://dtp.cancer.gov/timeline/flash/milestones/M4_Nixon.htm

Important Book About the History of Cancer

Mukherjee, S. 2011. Emperor of All Maladies: A Biography of Cancer. Simon & Schuster Canada

Bending the Cancer Survival Curve

Source: 25 Year Decline of Cancer Death Rate. Cancer Health, American Cancer Society, January, 2019

What is the Goal of Therapy?

• Surgery if possible

• Aggressive, toxic chemotherapy

+/- radiation

• Support patients through complications

• Surgery for GI tumors

• Less toxic chemo

• Biologic therapies

• Immunotherapy

• Radiation for symptoms

• Longevity and QOL

Going for cure Palliative therapy

What is the Goal of Therapy?

• Surgery if possible

• Aggressive, toxic chemotherapy

+/- radiation

• Support patients through complications

• Surgery for GI tumors

• Less toxic chemo

• Biologic therapies

• Immunotherapy

• Radiation for symptoms

• Longevity and QOL

Going for cure Palliative therapy

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Modern Anti-Tumor Therapy Blood Cancers are 10% of the Pie

Categories of Cancer

Carcinoma

Blood cancers

Melanoma

Sarcoma

Brain tumors

What are the Blood Cancers?

• Leukemia– AML, APL, ALL, CML, CLL– PLL (Prolymphocytic leukemia)– Hairy Cell leukemia

• Lymphoma– Hodgkin’s Disease– NHL: DLBCL, FL, SLL/CLL, MCL, MZL

• Multiple Myeloma– Amyloidosis– Waldenstrom’s Disease

Potentially Curable by Chemo

APL leukemia 95%

CML leukemia 90%

Hodgkin’s lymphoma 90%

Large B cell lymphoma 60%

Adults with ALL leukemia 50%

Adults with AML leukemia 25%

What is Leukemia?

• Too many white blood cells

• Malignant tumor of the blood

• Malignant tumor of bone marrow

• Myeloid or lymphoid (lineage)

• Acute or chronic (maturation of cells, rate of growth)

Acute myeloid

AML, APL

Acute lymphoid

ALL

Chronic myeloid

Myeloproliferative

CML

PCV

ET

myelofibrosis

Chronic lymphoid

Lymphoproliferative

CLL/SLL

lymphoma

myeloma

What is Leukemia?

• Too many white blood cells

• Malignant tumor of the blood

• Malignant tumor of bone marrow

• Myeloid or lymphoid (lineage)

• Acute or chronic (maturation of cells, rate of growth)

Acute myeloid

AML, APL

Acute lymphoid

ALL

Chronic myeloid

Myeloproliferative

CML

PCV

ET

myelofibrosis

Chronic lymphoid

Lymphoproliferative

CLL/SLL

lymphoma

myeloma

One of the main reasons to do outpatient CBC’s is screening healthy people for leukemia.

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Why do screening CBC’s?

• Screening healthy people for leukemia

• Screening for “nutritional anemia” like iron deficiency

• Screening for other heme malignancy:

multiple myeloma, or MDS/MPD

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Abnormal CBC

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Which Leukemia is it?

• AML

• APL

• ALL

• CML

• CLL/SLL

• PLL

• Hairy Cell

Which Leukemia is it?

• AML

• APL

• ALL

• CML

• CLL/SLL

• PLL

• Hairy Cell

Which Leukemia is it?

• AML

• APL

• ALL

• CML

• CLL/SLL

• PLL

• Hairy Cell

Which Leukemia is it?

• AML

• APL

• ALL

• CML

• CLL/SLL

• PLL

• Hairy Cell

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Which Leukemia is it?

• AML

• APL

• ALL

• CML

• CLL

• PLL

• Hairy Cell

Which Leukemia is it?

• AML

• APL

• ALL

• CML

• CLL/SLL

• PLL

• Hairy Cell

Which Leukemia is it?

• AML

• APL

• ALL

• CML

• CLL/SLL

• PLL

• Hairy Cell

What to do With Patients who haveHigh WBC Count but No Infection

• Look at clinical picture, chronicity

• Look at WBC differential

• Look at plt count (high plt count=MPD)

• Flow cytometry ONLY FOR LYMPHS

• Consider imaging if lymphoma suspected

Abnormal CBC

29Diagnosis: CML

Chronic Myeloid Leukemia

Acute myeloid

AML, APL

Acute lymphoid

ALL

Chronic myeloid

Myeloproliferative

CML

PCV

ET

myelofibrosis

Chronic lymphoid

Lymphoproliferative

CLL/SLL

lymphoma

myeloma

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Normal Chronic phase CML

CML Blood Smear

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1 2 3 4 5

6 7 8 10 119 12

13 14 15 16 17 18

19 20 21 22X Y

Cytogenetic Abnormality of CML: Philadelphia Chromosome

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• Imatinib mesylate—a specific inhibitor of a small family of tyrosine kinases, including Bcr-Abl

TKI Medications Target BCR-ABL CML Survival / “Cure”

Mughal, T. (2016). Chronic Myeloid Leukemia: Reminiscences and Dreams. Hematologica; 101: 541-558.

Chronic Lymphocytic Leukemia

Acute myeloid

AML, APL

Acute lymphoid

ALL

Chronic myeloid

Myeloproliferative

CML

PCV

ET

myelofibrosis

Chronic lymphoid

Lymphoproliferative

CLL/SLL

lymphoma

myeloma

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Chronic Lymphocytic Leukemia

• Usually indolent

5-10 years

• May be best to postpone treatment

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CLL Treatments

Chemotherapy Immunotherapy Biologic Therapy

Cyclophosphamide Rituximab Ibrutinib

Fludarabine Obinatuzimab Idelasilib

Chlorambucil Ofatumamab Develisib

Acute Myeloid Leukemia?

Acute myeloid

AML, APL

Acute lymphoid

ALL

Chronic myeloid

Myeloproliferative

CML

PCV

ET

myelofibrosis

Chronic lymphoid

Lymphoproliferative

CLL/SLL

lymphoma

myeloma

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AML Bad Actors

• Older people >75yo

• FLT3 mutation positive (25%)

• MDS/AML (MDS mutations found)

• Prior cancer (secondary AML)

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What to do When AML is Found

• Assess patient’s ability to be treated– Age, performance status, comorbidities, social factors

• Assess patient’s ability to be cured– Bad actor AML presentations

• Admit/transfer patient to leukemia unit

• Stabilize pt: r/o DIC, infection, bleeding– Don’t miss window to treat AML while waiting for antibiotics to

treat presumed infection

Recent Drug Approvals for AML

• Liposomal daunorubicin/cytarabine• Gemtuzamab: anti-CD33 antibody• Midostaurin: FLT3 inhibitor• Gilteritinib: FLT3 inhibitor• Ivosidenib: IDH1 inhibitor• Enasidenib: IDH2 inhibitor• Venetoclax: BCL2 inhibitor• Glasdegib: Hedgehog inhibitor

APL Leukemia is CurableBUT Deadly if Missed

Lococo, F. et al. (2013). Retinoic Acid and Arsenic Trioxide for Acute Promyelocytic Leukemia. NEJM 369: 111-121.

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Don’t Miss an APL patient

• Most APL patients are young <50yo• Low WBC (neutropenia) OR high WBC• Any new or abnormal bleeding/bruising• High PTT and low fibrinogen• Can have “spontaneous” intracranial bleeding

• Have high index of suspicion for patients with low plt<50 with bleeding

APL Leukemia Patients

What We do if APL is Suspected

• Start round-the-clock plt and cryo transfusions

• Start empiric tretinoin treatment

• Request FISH for PML-RARa mutation

• If high WBC start hydroxyurea

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What is MDS?

• Abnormal blood counts

• Abnormal bone marrow function

• Clonal stem cell disorder, “pre-leukemia”

• Can cause severe anemia requiring transfusions

• Can cause bleeding requiring transfusions

• Can cause immunocomprimised state

• Can lead to hospitalizations and death

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What MDS Looks Like

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When to Suspect MDS

• Usually hospitalized for “other” things• 15,000 new MDS patients per year in U.S.

• “Community acquired pneumonia”– Why is my patient immunocompromised?

• Anemia assumed a benign problem• Bleeding tendency and bruising may be ignored• Abnormal blood counts should not be ignored

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MDS RBC Dysfunction

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Diagnosis of MDS

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Explaining MDS is an Art

• “What caused me to get this?”• Abnormal counts “missed” or ignored by prior

doctors• “Pre-leukemia” hard to explain and digest• “Bone marrow dysfunction” may be better

understood• Need for chemotherapy means it is like cancer• Decision to treat is not straightforward

– Usually older people with comorbidities– Not curable, so hard to justify aggressive treatment

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Myeloproliferative Disorders

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Blood Disorders Overlap Who Needs a Bone Marrow Biopsy?

• Known or suspected leukemia

• Unexplained low blood counts

• Myeloproliferative disorder (MPD)

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What is Lymphoma?

• Usually lymph nodes and bone marrow

• Systemic disease, may affect any organ

Hodgkin’s

Disease

Non-Hodgkin’s LymphomaDiffuse Large B cell lymphoma

Follicular lymphoma (FL)

Small lymphocytic lymphoma (SLL/CLL)

Mantle cell lymphoma (MCL)

Marginal zone lymphoma (MZL)

T cell lymphoma

Burkitt lymphoma

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NHL Bad Actors

• “Double hit” DLBCL (5%): BCL2/6 & c-myc

• Stage 4 (brain, lungs, bones)

• ABC subtype (Activated B Cell)

• High IPI score (APLES)– Age>60, PS>1, high LDH, extranodal, stage >2

Targeted biologic therapies• Ibrutinib: CLL/SLL, Mantle Cell, Splenic Marginal Zone• Idelalisib: CLL/SLL and Follicular Lymphoma• Acalabrutinib: Mantle Cell Lymphoma• Copanlisib: Relapsed Follicular Lymphoma• Duvelisib: Relapsed CLL/SLL and Follicular Lymphoma

Monoclonal antibodies• Obinutuzimab: CLL and Follicular lymphoma• Brentuximab: Hodgkin’s Lymphoma and T cell lymphoma• Nivolumab: Hodgkin’s Lymphoma after autologous HSCT• Pembrolizumab: Refractory Hodgkin’s Lymphoma

Recent Drug Approvals for Lymphoma

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How Lymphoma is Treated

• Indolent lymphoma may be “observed”

• Chemotherapy/immunotherapy – Rituximab (B cell)

– Brentuximab (T cell)

• Radiation therapy for big tumors or stage 1-2

• Autologous stem cell transplant

• Radioimmunotherapy

• CAR-T immunotherapy

Immunotherapy: CAR-T

The Car T cell revolution: What does it offer, and can we afford it? Cancerworld January, 2018.

What is Multiple Myeloma?

• Means something different to each MM patient• A “blood cancer” like leukemia• A “bone cancer” like leukemia/lymphoma• “Too much protein” in the blood• Sometimes aggressive disease treated by crisis

prevention and management• Sometimes chronic disease treated by cautious

use of anti-myeloma therapy

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Sarah Newbury…the First Known Multiple Myeloma Patient 1844

Kyle, R. (2000). Multiple Myeloma: An Odyssey of Discovery. British Hournal of Hematology, 111, 1035-44

Monoclonal Plasma Cells Secrete Monoclonal “M” Protein

Henry Bence Jones: Bone Fracturesand Abnormal Urine Protein

https://en.wikipedia.org/wiki/Henry_Bence_Jones

Light Chain Deposition Disease

Korngold and Lapiri 1956

Why it’s Called Multiple Myeloma

• Bone tumors throughout the skeleton

• Can be “missed” by a bone biopsy

• Confusing because many patients don’t have actual bone tumors– Diffuse bone infiltration

– Soft tissue variants

– Light chain deposition dz

– Systemic amyloidosis

Explaining Myeloma is an Art

• Variable presentation, tempo, sequelae

• Sometimes young, healthy people

• Always a shock to patients and families

• Sometimes “missed” by prior doctors/ER’s

• Usually several weeks/months of symptoms

• Diagnosis usually made during a crisis

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Myeloma is a Systemic Disease

CRAB Symptoms:

HyperCalcemiaRenal FailureAnemiaBone Tumor/Fracture

Bone Pain May be the Initial Crisis

• Severe bone pain is common– Fracture without trauma = pathologic fracture

– Lytic bone lesions without fracture

– Back pain: r/o spinal cord compression

• Bone pain hurts only while moving, so patients will stay still and become immobile

• Usually myeloma patients are older people who fear becoming addicted to opiate meds

Recent Drug Approvals for Multiple Myeloma

• Pomalidomide (oral) biologic therapy

• Carfilzomib (IV) chemotherapy

• Elotuzamab (IV) immunotherapy

• Daratumamab (IV) immunotherapy

• Ixazomib (oral) chemotherapy

• Selinexor (oral) biologic therapy

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Take Home Messages

• Blood cancers account for 10% of new cancer– Leukemia, lymphoma, and multiple myeloma

• Abnormal “screening” CBC should trigger testing– WBC Differential, fibrinogen, flow cytometry, SPEP

• Multiple myeloma is a blood cancer that affects each patient differently, usually starts with a crisis

• Blood cancer patients who are not cured need expert palliative care to live longer and better

References

• Acute Myeloid Leukemia review– NEJM 9/17/15; 373: 1136-1152.

• Adult Primary Care after Childhood ALL– NEJM 10/13/11; 365:1417-1424