Chapter 67: Myelodysplastic Syndromes

Michael M. Boyiadzis; Neal S. Young

INTRODUCTION

Myelodysplastic syndromes (MDSs) are clonal disorders characterized initially by ineffective hematopoiesis and subsequently by the development of acute leukemias. Peripheral blood cytopenias in combination with a hypercellular bone marrow exhibiting dysplastic changes are the hallmark of MDS

Epidemiology

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Epidemiology

Incidence: Increases with Age

Mean age: 68 years

Male-to-female ratio: 1:1

Overall:

4.1 per 100,000

Ages 50–59 years:

0.3 per 100,000

Ages 60–69 years:

15 per 100,000

Ages 70–79 years:

49 per 100,000

Ages >80 years:

89 per 100,000

Dunbar CE, Saunthararajah Y. Myelodysplastic syndromes. In: Young NS, ed. Bone Marrow Failure Syndromes. Philadelphia, PA: WB Saunders; 2000:69–98

Greenberg P et al. Blood 1997;89:2079–2088.

Erratum in: Blood 1998;91:1100. Comment in: Blood 1997;90:2843–2846, Blood 2001;98:1985

Work-up

CBC with differential

Serum liver function tests, electrolytes, serum creatinine

Bone marrow biopsy and aspiration with iron stains, flow cytometry, cytogenetics

HLA typing for patients who are candidates for allogeneic stem cell transplantation

RBC folate, serum B₁₂, serum iron/TIBC/ferritin, serum erythropoietin level (prior to RBC transfusion)

HIV testing if clinically indicated

Thyroid function tests to rule out hypothyroidism

HLA-DR15 typing to assist determination of response to immunosuppressive therapy

Evaluate patients with chronic myelomonocytic leukemia (CMML) for 5q31–33 translocations and/or PDGFRβ gene rearrangements

JAK2 mutation in patients with thrombocytosis

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Frequent Chromosomal Aberrations in MDS

Numerical

Translocations

Deletions

Cytogenetics

(%)

Cytogenetics

(%)

Cytogenetics

(%)

+ 8

inv 3

del 5q

−7

t (1;7)

del 11q

+21

t (1;3)

del 12q

−5

t (3;3)

del 20q

t (6;9)

del 7q

t (5;12)

del 13q

−, Loss of chromosome; +, additional chromosome; inv, inversion; t, translocation; del, deletion

Clonal cytogenetic abnormalities: 30–79%
Deletions are more frequent than translocations

Classification Systems for MDS

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Classification Systems for MDS

French-American-British Classification of MDS

FAB Subtype

% of Bone Marrow Blasts

% of Peripheral Blasts

Refractory anemia (RA)

Refractory anemia with ringed sideroblasts (RARS)

Refractory anemia with excess blasts (RAEB)

5–20

Refractory anemia with excess blasts in transformation (REAB-t)

≥5

21–30

Chronic myelomonocytic leukemia (CMML) (>1000 monocytes/μL blood)

5–20

Bennett JM et al. Proposals for the classification of the myelodysplastic syndromes. Br J Haematol 1982;51:189–199

2008 World Health Organization Classifi cation of MDS

Subtype

Blood

Bone Marrow

Refractory cytopenia with unilineage dysplasia (RCUD)^✫

Single or bicytopenia

Dysplasia in ≥10% of 1 cell line, <5% blasts

Refractory anemia with ring sideroblasts (RARS)

Anemia, no blasts

≥15% of erythroid precursors w/ring sideroblasts, erythroid dysplasia only, <5% blasts

Refractory cytopenia with multilineage dysplasia (RCMD)

Cytopenias, monocytes <1000/μL

Dysplasia in ≥10% of cells in ≥2 hematopoietic lineages, ±15% ring sideroblasts, <5% blasts

Refractory anemia with excess blasts-1 (RAEB-1)

Cytopenias, ≤2–4% blasts, monocytes <1000/μL

Unilineage or multilineage dysplasia, no Auer rods, 5–9%

Refractory anemia with excess blasts-2 (RAEB-2)

Cytopenias, 5–19% blasts, monocytes <1000/μL

Unilineage or multilineage dysplasia, No Auer rods ±10–9% blasts

Myelodysplastic syndrome, unclassified (MDS-U)

Cytopenias

Unilineage dysplasia or no dysplasia but characteristic MDS cytogenetics, <5% blasts

MDS associated with isolated del (5q)

Anemia, platelets normal or increased

Unilineage erythroid dysplasia, isolated del (5q), <5% blasts

^✫This category encompasses refractory anemia (RA), refractory neutropenia (RN), and refractory thrombocytopenia (RT)

Swerdlow SH, Campo E, Harris NL et al. In: World Health Organization Classification of Tumours of Haematopoietic and Lymphoid tissue. 4th ed. Lyon, France: International Agency for Research on Cancer, 2008.

Classification Systems for De Novo MDS

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Classification Systems for De Novo MDS

International Prognostic Scoring System (IPSS)

Survival and AML Evolution

Score Value

Prognostic Variable

0.5

1.0

1.5

2.0

Marrow blasts (%)

5–10

—

11–20

21–30

Karyotype^✫

Good

Intermediate

Poor

Cytopenia^†

0/1

2/3

Risk Category (% IPSS Pop.)

Overall Score

Median Survival (Years) in the Absence of Therapy

25% AML Progression (Years) in the Absence of Therapy

LOW (33)

5.7

9.4

INT-1 (38)

0.5–1.0

3.5

3.3

INT-2 (22)

1.5–2.0

1.1

HIGH (7)

≥2.5

0.4

0.2

^✫Cytogenetics:

Good = normal, −Y alone, del (5q) alone, del (20q) alone

Poor = complex (≥3 abnormalities) or chromosome 7 anomalies

Intermediate = other abnormalities

Note: Categorization excludes karyotypes t(8;21), inv 16, and t(15;17), which are considered to be AML not MDS

^†Cytopenias: neutrophil count <1800/μL, platelets <100,000/μL, Hb<10 g/dL

Greenberg P et al. Blood 1997;89:2079–2088. Erratum in: Blood 1998;91:1100. Comment in: Blood 1997;90: 2843–2846, Blood 2001;98:1985

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Classification Systems for De Novo MDS

IPSS-R, Revised International Prognostic Scoring System

Prognostic Variable

0.5

1.5

Cytogenetics^✫

Very good

—

Good

—

Intermediate

Poor

Very poor

BM blast, %

≤2

—

>2% to <5%

—

5%–10%

>10%

—

Hemoglobin

≥10

—

8 to <10

—

Platelets

≥100

50 to <100

<50

—

ANC

≥0.8

<0.8

—

—, Indicates not applicable

^✫Cytogenetics:

Very good = −Y, 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 clones

Poor = −7, inv(3)/t(3q)/del(3q), double including −7/del(7q), complex: 3 abnormalities

Very poor = complex >3 abnormalities

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Classification Systems for De Novo MDS

Risk Category

Risk Score

Very low

≤1.5

Low

>1.5–3

Intermediate

>3–4.5

High

>4.5–6

Very high

Very Low

Low

Intermediate

High

Very High

Median survival, years

8.8

5.3

3.0

1.6

0.8

(7.8–9.9)

(5.1–5.7)

(2.7–3.3)

(1.5–1.7)

(0.7–0.8)

25% AML progression, years

10.8

3.2

1.4

0.73

(14.5–NR)

(9.2–NR)

(2.8–4.4)

(1.1–1.7)

(0.7–0.9)

NR, not reached

Greenberg PL et al. Blood 2012;120:245–2465

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Classification Systems for De Novo MDS

WHO–based Prognostic Scoring System (WPSS)

Variable

Variable Scores

WHO category

RCUD, RARS, MDS, with isolated deletion (5q)

RCMD

RAEB-1

RAEB-2

Karyotype^✫

Good

Intermediate

Poor

—

Severe anemia

(Hb <9 g/dL in males or <8 g/dL in females)

Absent

Present

—

Very low

Low

Intermediate

High

3–4

Very high

5–6

^✫Cytogenetics:

Good = normal, −Y alone, del (5q) alone, del (20q) alone

Poor = complex (≥3 abnormalities) or chromosome 7 anomalies

Intermediate = other abnormalities

Malcovati L et al. Hematologica 2011;95:1433–1440

Differential Diagnosis of Hypo-Productive Cytopenias

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Differential Diagnosis of Hypo-Productive Cytopenias

Hematologic Conditions

Nonhematologic Conditions

Congenital

Hereditary sideroblastic anemia

Congenital dyserythropoietic anemia

Fanconi anemia

Diamond-Blackfan syndrome

Shwachman syndrome

Kostmann syndrome
Nutritional

Vitamin B₁₂ deficiency

Folate deficiency

Iron deficiency
Aplastic anemia
Paroxysmal nocturnal hemoglobinuria
Systemic mastocytosis
Hairy cell leukemia
Large granular lymphocyte disease
Myeloproliferative neoplasms

Idiopathic myelofibrosis

Polycythemia vera

Chronic myelogenous leukemia

Essential thrombocytosis

Toxins

Alcohol

Postchemotherapy or radiation

Medications
Chronic diseases

Renal failure

Collagen-vascular diseases

Chronic infections
Viral infections

Parvovirus B19

Cytomegalovirus

Human immunodeficiency virus
Malignancy

Marrow infiltration

Paraneoplastic syndrome

International Working Group Treatment Response Criteria for MDS

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International Working Group Treatment Response Criteria for MDS

Cheson BD et al. Blood 2000;96:3671–3674

Complete remission (CR)

<5% myeloblasts with normal maturation of all cell lines
No evidence of dysplasia
Hemoglobin >11 g/dL (untranfused; patient not on cytokine support)
Neutrophils ≥1500/μL (patient not on cytokine support)
Platelets ≥100,000/μL (patient not on cytokine support)

Partial remission (PR)

Same as CR except blast decreased by 50% or more over pretreatment

Stable disease

Failure to achieve at least PR, but without evidence of progression for at least 2 months

Hematologic Improvement

Erythroid Response

Major

Pretreatment hemoglobin <11 g/dL

>2 g/dL increase in hemoglobin

RBC transfusion-dependent patients

Transfusion independence

Minor

Pretreatment hemoglobin <11 g/dL

1–2 g/dL increase in hemoglobin

RBC transfusion-dependent patients

50% decrease in transfusion requirement

Platelet Response

Major

Pretreatment platelet count <100,000/μL

Absolute increase of ≥30,000/μL in platelet count

Platelet transfusion-dependent patients

Stabilization of platelet counts and transfusion independence

Minor

Pretreatment platelet count <100,000/μL

≥50% increase in platelet count with a net increase of 10,000/μL–30,000/μL

Neutrophil Response (ANC = Absolute Neutrophil Count)

Major

Pretreatment ANC <1500/μL

≥100% increase in ANC, or an absolute increase of >500/μL whichever is greater

Minor

Pretreatment ANC <1500/μL

≥100% increase in ANC, but absolute increase <500/μL

Cytogenetic Response

Major

No detectable cytogenetic abnormality, if preexisting abnormality was present

Minor

50% or more reduction in abnormal metaphases

Treatment Options

IPSS: low/intermediate-1

WPSS: very low, low, intermediate

Patients with symptomatic anemia and del(5q) chromosomal abnormalities should receive lenalidomide. Other patients with anemia can be treated based on their levels of serum erythropoietin (sEPO). Those with levels of ≤500 mU/mL (≤500 IU/L) may be treated with recombinant human epoetin alfa or darbepoetin alfa either with or without granulocyte colony-stimulating factor. Patients with IPSS low or intermediate-1 risk, with moderate-to-severe anemia (hemoglobin below 10 g/dL), serum erythropoietin level <500 mU/mL and/or a red cell transfusion requirement <2 RBC unit per month should be considered for therapy with epoetin alfa or beta at an initial dose ranging from 30,000 to 60,000 IU/week. Patients who do not respond to epoetin alone after 8 weeks of treatment should be given granulocyte-colony stimulating factor (G-CSF 300 μg/week in 2–3 divided doses) in combination with epoetin alfa

Nonresponders should be considered for immunosuppressive therapy with equine thymocyte immune globulin (ATG; ATGAM) and cyclosporine (if there is a high likelihood of response: ≤60 years old, HLA-DR15–positive, PNH-positive clone, or hypoplastic MDS), or treatment with decitabine or azacitidine. Anemic patients with sEPO levels >500 mU/mL who have a low probability to respond to immunosuppressive therapy should be considered for treatment with lenalidomide, decitabine, or azacitidine

Patients with other serious cytopenias (thrombocytopenia, neutropenia) should be considered for treatment with decitabine or azacitidine. Nonresponders should be considered for immunosuppressive therapy with ATG and cyclosporine or allogeneic hematopoietic cell transplantation (allo-HCT)

IPSS: intermediate-2, high

WPSS: high, very high

Allogeneic HCT is the only treatment that can induce long-term remission in patients with MDS. Such therapy, however, is not applicable for many patients, because the median age at diagnosis exceeds 65 years and associated comorbidities. Allo-HCT for MDS is associated with a high rate of treatment-related death (approximately 30% at 1 year and 3 years) and suboptimal disease-free survival (approximately 40% at 1 year and 3 years). The decision to offer HCT as therapy for MDS remains an individual "personalized" decision. Age at transplantation is one of the most important prognostic factors: the older the age, the shorter the overall and disease-free survival. In addition, disease risk according to the IPSS and presence of comorbid disease are among the most relevant clinical variables to be considered in order to judge a patient's eligibility for allo-HCT

The optimal timing of myeloablative allo-HCT from HLA identical siblings was studied in patients <60 years of age. Low and intermediate-1 IPSS groups, delayed transplantation maximized overall survival. Transplantation prior to leukemic transformation was associated with a greater number of life years than transplantation at the time of leukemic progression. For intermediate-2 and high IPSS groups, transplantation at diagnosis maximized overall survival. Also, the use of reduced intensity conditioning allo-HCT regimens in de novo MDS was examined in patients aged 60-70 years. For patients with low/intermediate-1 IPSS MDS, reduced-intensity conditioning transplantation life expectancy was 38 months versus 77 months with non-transplantation approaches. For intermediate-2/high IPSS MDS, reduced-intensity conditioning transplantation life expectancy was 36 months versus 28 months for non-transplantation therapies. The study concluded that for low/intermediate-1 IPSS, non-transplantation approaches are preferred. For intermediate-2/high IPSS, reduced intensity conditioning transplantation offers overall and quality-adjusted survival benefit

For patients who are candidates for transplantation, the first choice of a donor is a HLA matched sibling, although results with HLA-matched unrelated donors have improved to levels comparable to those obtained with HLA-matched siblings. Consider intensive chemotherapy for patients who are eligible for intensive therapy but lack a stem cell donor, or those whose marrow blast count requires reduction. Patients who are not candidates for allo-HCT should receive supportive care and therapies similar to low-risk patients

Cutler CS et al. Blood 2004;104:579–585

Koreth J et al. J Clin Oncol 2013;31:2662–2670

Hellström-Lindberg E et al. Br J Haematol 1997;99:344–351

Hellström-Lindberg E et al. Br J Haematol 2003;120:1037–1046

Malcovati L et al. Blood 2013;122:2943–2964

Supportive Care

Hematopoietic cytokine support should be considered for patients with refractory symptomatic cytopenias

Aminocaproic acid and other antifibrinolytic agents may be used for bleeding episodes refractory to platelet transfusions or for profound thrombocytopenia

For patients with chronic RBC transfusion needs, serum ferritin levels and associated organ dysfunction should be monitored. Iron chelation therapy should also be considered in patients with MDS who have life expectancy of at least several years and have received at least 20 units of RBCs over 1 year or more, serum ferritin level persistently ≥1000 μg/L, clinically relevant iron overload or if allogeneic hematopoietic cell transplantation is planned

Symptomatic anemic patients should receive red blood cell transfusions (using leukocyte-poor products) and for potential allogeneic hematopoietic cell transplantation candidates CMV-negative (for patients who are serologically CMV-negative) and irradiated transfused blood products

Iron depletion needs to be verified before instituting epoetin alfa or darbepoetin alfa therapy. If no response occurs with these agents alone, the addition of a granulocyte colony-stimulating factor (G-CSF) should be considered. G-CSF, and, to a lesser extent, granulocyte-macrophage colony-stimulating factor (GM-CSF) have synergistic erythropoietic activity when used in combination with erythropoiesis stimulating agents and markedly enhance erythroid responses. A predictive model for response to epoetin alfa or beta and G-CSF in MDS patients was developed and validated in prospective studies. Three groups of patients were identified (high probability of response group, intermediate, and poor) based on serum erythropoietin levels (<500 mU/mL or ≥500 mU/mL) and transfusion needs (<2 RBC units/month or ≥2 RBC units/month) with response rates according to study response criteria to treatment of 74%, 23% and 7%

Greenberg P et al. Blood 1997;89:2079–2088.

Erratum in: Blood 1998;91:1100. Comment in: Blood 1997;90:2843–2846, Blood 2001;98:1985

Greenberg PL. Br J Haematol 2010;150:131–143

Hellström-Lindberg E et al. Br J Haematol 1997;99:344–351

Hellström-Lindberg E et al. Br J Haematol 2003;120:1037–1046

Malcovati L et al. Blood 2013;122:2943–2964

Steensma DP. J Natl Compr Canc Netw 2011;9:65–75

Tefferi A, Vardiman JW. N Engl J Med 2009;361:1872–1885

REGIMEN: DECITABINE

Listen

Regimen: Decitabine

Kantarjian H et al. Blood 2007;109:52–57

Kantarjian H et al. Cancer 2006;106:1794–1803

Steensma DP et al. J Clin Oncol 2009;27:3842–3848

Decitabine 20 mg/m² per day; administer intravenously in a volume of cold^✫ 0.9% sodium chloride injection (0.9% NS), 5% dextrose injection (D5W), or lactated Ringer's injection (LRI) sufficient to result in a solution concentration within the range of 0.1–1 mg/mL, over 60 minutes for 5 consecutive days, on days 1–5, every 4 weeks (total dosage per 5-day course = 100 mg/m²)

Decitabine 15 mg/m² per dose; administer intravenously in a volume of cold^✫ 0.9% NS, D5W, or LRI sufficient to result in a solution concentration within the range of 0.1–1 mg/mL, over 3 hours, every 8 hours for 3 consecutive days (total dosage/day = 45 mg/m²; total dosage/3-day course = 135 mg/m²)

Patients should receive either regimen for a minimum of 4 cycles; however, it may take longer than 4 cycles to achieve a complete or partial response

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MINIMAL

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis may be indicated for patients with refractory symptomatic cytopenias

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is HIGH

Antimicrobial primary prophylaxis is recommended:

Antibacterial—consider fluoroquinolone prophylaxis; P. jirovecii prophylaxis is recommended (eg, cotrimoxazole)
Antifungal—recommended
Antiviral—antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir)

See Chapter 47 for more information

Patient Population Studied

Ninety-nine patients with MDS (median age: 72 years; range: 34–87 years) including IPPS risk groups: high (24%), intermediate-2 (32%), intermediate-1 (28%), and low (4%). FAB classifications: RA plus RARS (37%), RAEB plus RAEB-T (52%), CMML (11%). At baseline, 67% of patients were RBC-transfusion dependent and 15% were platelet transfusion dependent

Efficacy

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Efficacy

Response by 2006 IWG Criteria

ITT (N = 99) %

Overall complete response rate, CR + mCR

Overall response rate, CR + mCR + PR

Overall improvement rate, CR + mCR + PR + HI

Rate of stable disease or better, CR + mCR + PR + HI + SD

mCR

IWG, International Working Group; ITT, intention to treat; CR, complete response; mCR, marrow CR; PR, partial response; HI, hematologic improvement; SD, stable disease; PD, progressive disease

Activity was demonstrated across investigator-assessed IPSS risk groups, with an overall improvement rate of 50% for intermediate-1 patients, 61% for intermediate-2 patients, and 43% for high-risk patients

The 1-year survival rate for patients treated with decitabine was 66%. Median survival was 19.4 months. Patients who were classified as having CMML (n = 11) had a 73% improvement rate. Among 66 patients who were RBC transfusion-dependent at baseline, 22 patients (33%) became RBC transfusion-independent during the study. Of the 15 patients who were platelet transfusion-dependent at baseline, 6 patients (40%) became transfusion-independent during the course of the study

Adverse Effects

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Adverse Effects

Event

% of Patients

Grades 1–2

Grades ≥3

Hematologic

Neutropenia

Thrombocytopenia

Febrile neutropenia

Anemia

Nonhematologic

Fatigue

Nausea

Pyrexia

Diarrhea

Anorexia

Constipation

Pneumonia

Vomiting

Chills

Of the 619 cycles administered, 198 (32%) were delayed, primarily because of myelosuppression, with a median delay of 8 days, and there were 119 hospitalizations (19% of cycles were associated with a hospitalization)

Eleven patients (11%) died within 30 days after receiving decitabine

Treatment Modifications

REGIMEN 1: Decitabine 20 mg/m² per day; administer intravenously over 60 minutes, once daily for 5 consecutive, days 1–5, every 4 weeks (100 mg/m² per 5-day course)

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Treatment Modifications

Hematologic Adverse Effects

Cycles ≥2 (4-week cycles):

Day 1 ANC ≥1000/μL and platelets ≥50,000/μL

Begin a new treatment cycle at the same decitabine dosage and schedule previously given

Day 1 ANC <1000/μL or platelets <50,000/μL

Delay treatment and continually monitor ANC and platelet counts until recovery to ANC ≥1000/μL and platelets ≥50,000/μL, then:

Begin a new treatment cycle at the same decitabine dosage and schedule previously given

Nonhematologic Adverse Effects

Cycles ≥2, for:

Serum creatinine ≥2 mg/dL (≥177 μmol/L)
Serum ALT (SGPT) or total bilirubin ≥2 times ULN
Active or uncontrolled infection

Withhold decitabine treatment until the toxicity is resolved, then

Begin a new treatment cycle at the same decitabine dosage and schedule previously given

REGIMEN 2: Decitabine 15 mg/m² per dose; administer intravenously over 3 hours, every 8 hours for 3 consecutive days, days 1–3 (45 mg/m² per day; 135 mg/m² per 3-day course)

Hematologic Adverse Effects

Cycles ≥2, 4 weeks after a previous cycle:

If ANC ≥1000/μL and platelets ≥50,000/μL

Begin a new treatment cycle at the same decitabine dosage and schedule previously given

If ANC <1000/μL or platelets <50,000/μL

Delay treatment for up to 6 weeks after the last cycle began, and continually monitor ANC and platelet counts

Cycles ≥2, 6–8 weeks after a previous cycle:

Recovery to ANC ≥1000/μL and platelets ≥50,000/μL requiring >6 weeks, but <8 weeks

Delay treatment for up to 8 weeks after the last cycle began until ANC ≥1000/μL and platelets ≥50,000/μL, then

Begin a new treatment cycle with decitabine dosage decreased to 11 mg/m² per dose every 8 hours for 3 consecutive days (33 mg/m² per day; 99 mg/m² per 3-day course)

If ANC <1000/μL or platelets <50,000/μL

Delay treatment for up to 10 weeks after the last cycle began, and continually monitor ANC and platelet counts

Cycles ≥2, 8–10 weeks after a previous cycle:

Recovery to ANC ≥1000/μL and platelets ≥50,000/μL requiring >8 weeks, but <10 weeks

Delay treatment for up to 8 weeks after the last cycle began until ANC ≥1000/μL and platelets ≥50,000/μL
Evaluate bone marrow (BM) aspirate for evidence of disease progression (PD). If BM aspirate is negative for PD, then:
Begin a new treatment cycle with decitabine dosage decreased to 11 mg/m² per dose every 8 hours for 3 consecutive days (33 mg/m² per day; 99 mg/m² per 3-day course)
Maintain or increase decitabine dosage during subsequent cycles as clinically indicated

Nonhematologic Adverse Effects

Cycles ≥2, for:

Serum creatinine ≥2 mg/dL (≥177 μmol/L)
Serum ALT (SGPT) or total bilirubin ≥2 times ULN
Active or uncontrolled infection

Withhold decitabine treatment until the toxicity is resolved, then

Begin a new treatment cycle at the same decitabine dosage and schedule previously given

Therapy Monitoring

Complete blood counts, leukocyte differential, and platelet counts should be performed as needed to monitor response and toxicity; that is, at least once weekly
Consider bone marrow biopsy every 2 cycles until CR is confirmed
Liver chemistries and serum creatinine should be obtained prior to initiation of treatment

Notes

Decitabine is indicated for treatment of patients with myelodysplastic syndromes (MDS) including previously treated and untreated, de novo and secondary MDS of all French-American-British subtypes (refractory anemia, refractory anemia with ringed sideroblasts, refractory anemia with excess blasts, refractory anemia with excess blasts in transformation, and chronic myelomonocytic leukemia) and intermediate-1, intermediate-2, and high-risk International Prognostic Scoring System groups

REGIMEN: AZACITIDINE

Listen

Regimen: Azacitidine

Silverman LR et al. J Clin Oncol 2006;24:3895–3903

Silverman LR et al. J Clin Oncol 2002;20:2429–2440

Azacitidine 75 mg/m² per day; administer either by subcutaneous injection or intravenously for 7 consecutive days, days 1–7, every 4 weeks (total dosage/cycle = 525 mg/m²)

If a beneficial effect is not seen after 2 cycles are completed and no adverse effects other than nausea and vomiting have occurred, dosage may be increased to azacitidine 100 mg/m² per day for 7 consecutive days, days 1–7, every 4 weeks (total dosage/cycle = 700 mg/m²)
Patients should receive treatment for a minimum of 4–6 cycles; however, it may take longer than 4 cycles to achieve a complete or partial response
- Treatment may be continued as long as a patient continues to benefit
  
  Administration by subcutaneous injection
- Azacitidine is reconstituted to obtain a solution with concentration equal to 100 mg/mL
- Doses >100 mg (>4 mL) should be equally divided into 2 (or more) syringes and injected into 2 (or more) separate sites
- Rotate sites for each injection (thigh, abdomen, or upper arm)
- New injections should be given at least 1 inch from an old site and never into areas where the site is tender, bruised, red, or hard
  
  Intravenous administration
- Azacitidine is diluted in 50–100 mL 0.9% sodium chloride injection or lactated Ringer's injection
- Administer a dose over 10–40 minutes. Dose administration must be completed within 60 minutes after product preparation

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MODERATE

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis may be indicated for patients with refractory symptomatic cytopenias

Antimicrobial prophylaxis

Risk of fever and neutropenia is HIGH

Antimicrobial primary prophylaxis is recommended:

Antibacterial—P. jirovecii prophylaxis is recommended (eg, cotrimoxazole)
Antifungal—recommended
Antiviral—antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir)

See Chapter 47 for more information

Patient Population Studied

In the Cancer and Leukemia Group B (CALGB) Protocols 8421, 8921, and 9221, 268 patients were treated with azacitidine, of whom 220 were treated with subcutaneous azacitidine and 48 were treated with intravenous azacitidine; 41 patients received best supportive care on the observation arm of Protocol 9221

Efficacy

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Efficacy

Best Response for All Patients Using IWG Response Criteria for MDS in Protocols 8421, 8921, and 9221

IWG Response

Protocol 8421: IV Azacitidine (n = 48) %

Protocol 8921: SC Azacitidine (n = 70) %

Protocol 9221

Protocols 8921 and 9221: SC Azacitidine (n = 169) %

SC Azacitidine^✫ (n = 99) %

Observation Only^† (n = 41) %

SC Azacitidine After Observation (n = 51) %

HI^‡

Erythroid response, major

Erythroid response, minor

Platelet response, major

Platelet response, minor

Neutrophil response, major

Neutrophil response, minor

Overall: CR + PR + HI^‡

IWG, International Working Group; MDS, myelodysplastic syndrome; IV, intravenous; SC, subcutaneous; CR, complete remission; PR, partial remission; HI, hematologic improvement

^✫Patients randomly assigned to azacitidine

^†Patients randomly assigned to observation who did not cross over to azacitidine

^‡Patients with HI (major or minor) were counted only once in the overall response

Summary of Hematology Shifts by Maximum NCI CTC Grade Criteria (Hematology) in Protocol 9221

Maximum NCI CTC Grade Baseline Value

Post-baseline^✫ Maximum NCI CTC Grade

All Azacitidine Patients^† (n = 150)

No. of Patients

Grades 0–2 %

Grade 3 %

Grade 4 %

Hemoglobin

Grades 0–2

105

Grade 3

Grade 4

WBCs

Grades 0–2

117

Grade 3

Grade 4

100

Absolute neutrophil count

Grades 0–2

Grade 3

Grade 4

Lymphocytes

Grades 0–2

Grade 3

Grade 4

Platelets

Grades 0–2

Grade 3

Grade 4

100

NCI CTC, National Cancer Institute Common Toxicity Criteria

^✫Post-baseline toxicity grade is the maximum grade after baseline and before the end of study

^†Includes all patients exposed to azacitidine, including patients who crossed over to azacitidine from observation

Note: The number (n) for each treatment group is the number of patients with a baseline toxicity grade and at least 1 post-baseline toxicity grade

Treatment Modifications

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Treatment Modifications

For patients with baseline (start of treatment) WBC ≥3000/μL, ANC ≥1500/μL, and platelets ≥75,000/μL, adjust the dose as follows, based on nadir counts for any given cycle:

Nadir Counts

% Dose During the Next Course

ANC (/μL)

Platelets (/μL)

<500

<25,000

50%

500–1500

25,000–50,000

67%

>1500

>50,000

100%

For patients whose baseline counts are WBC <3000/μL, ANC <1500/μL, or platelets <75,000/μL, dose adjustments should be based on nadir counts and bone marrow biopsy cellularity at the time of the nadir as noted below, unless there is clear improvement in differentiation (percentage of mature granulocytes is higher and ANC is higher than at the onset of that course) at the time of the next cycle, in which case the dose of the current treatment should be continued

WBC or Platelet Nadir % Decrease in Counts from Baseline

Bone Marrow Biopsy Cellularity at Time of Nadir (%)

30–60

15–30

<115

% Dosage During the Next Course

50–75

100

>75

If a nadir has occurred as defined in the table above, the next course of treatment should be given 28 days after the start of the preceding course, provided that both the WBC and platelet counts are >25% above the nadir and rising
If a >25% increase above the nadir is not seen by day 28, counts should be reassessed every 7 days
If a 25% increase is not seen by day 42, then the patient should be treated with 50% of the scheduled dose

Toxicity

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Toxicity

Most Frequently^✫ Observed Adverse Events (NCI CTC Grades 1–4) by Patient-Years of Exposure in Protocol 9221

Adverse Event^‡

All Azacitidine Patients^† (n = 150)

Patients With Events Per Patient-Year of Exposure^§

No. of Patients

Total exposure, patient-years

138.2

At least 1 adverse event

1.09

150

Anemia NOS

0.77

107

Thrombocytopenia

0.74

102

Nausea

0.72

100

Pyrexia

0.56

Leukopenia NOS

0.55

Vomiting NOS

0.52

Fatigue

0.42

Constipation

0.42

Diarrhea NOS

0.39

Neutropenia

0.37

Injection site erythema

0.35

Cough

0.34

Dyspnea NOS

0.34

Ecchymosis

0.32

Weakness

0.32

Rigors

0.28

Injection site pain

0.26

Arthralgia

0.26

Headache NOS

0.25

Pain in limb

0.25

Anorexia

0.23

Pharyngitis

0.23

Contusion

0.22

NCI CTC, National Cancer Institute Common Toxicity Criteria; NOS, not otherwise specified

^✫More than or equal to 20.0% frequency

^†Includes all patients exposed to azacitidine, including patients who crossed over to azacitidine from observation

^‡Multiple reports of the same adverse event term for a patient are only counted once within each treatment group

^§Total exposure for azacitidine is the cumulative time from the first dose to the end of study (30 days after last dose), and for observation, total exposure is the cumulative time from random assignment to withdrawal from study or day before cross over

Among the 150 patients treated, infections was the cause of death in 3 patients (2%)

Therapy Monitoring

Complete blood counts, leukocyte differential, and platelet count should be performed as needed to monitor response and toxicity; that is, at least once weekly
Consider bone marrow biopsy after 8 weeks of treatment
Serum liver chemistries and creatinine should be obtained prior to initiation of treatment

Notes

Azacitidine is a nucleoside metabolic inhibitor indicated for the treatment of patients with the following FAB myelodysplastic syndrome (MDS) subtypes: refractory anemia (RA) or refractory anemia with ringed sideroblasts (RARS; if accompanied by neutropenia or thrombocytopenia or requiring transfusions), refractory anemia with excess blasts (RAEB), refractory anemia with excess blasts in transformation (RAEB-T), and chronic myelomonocytic leukemia (CMMoL)

In a phase III, international, multicenter, controlled, parallel-group, open-label trial, patients with high-risk myelodysplastic syndromes were randomly assigned, one-to-one, to receive azacitidine (75 mg/m² per day by subcutaneous injection for 7 days every 28 days) or conventional care (best supportive care, low-dose cytarabine, or intensive chemotherapy as selected by investigators before randomization)

In the study, 358 patients were randomly assigned to receive azacitidine (n = 179) or conventional care regimens (n = 179). After a median follow-up of 21.1 months (IQR 15.1–26.9), median overall survival was 24.5 months (9.9; not reached) for the azacitidine group versus 15 months (5.6–24.1) for the conventional care group (hazard ratio 0.58; 95% CI, 0.43–0.77; stratified log-rank p = 0.0001). At last follow-up, 82 patients in the azacitidine group had died, compared with 113 patients in the conventional care group

At 2 years, on the basis of Kaplan-Meier estimates, 50.8% (95% CI, 42.1–58.8) of patients in the azacitidine group were alive compared with 26.2% (18.7–34.3) in the conventional care group (p <0.0001)

Peripheral cytopenias were the most common grade 3–4 adverse events for all treatments

Fenaux P et al. Lancet Oncol 2009;10:223–232

REGIMEN: LENALIDOMIDE

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Regimen: Lenalidomide

List A et al. N Engl J Med 2006;355:1456–1465

Lenalidomide 10 mg per day; administer orally, continually (total dose/week = 70 mg)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MINIMAL–LOW

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis may be indicated for patients with refractory symptomatic cytopenias

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is HIGH

Antimicrobial primary prophylaxis is recommended:

Antibacterial—P. jirovecii prophylaxis is recommended (eg, cotrimoxazole)
Antifungal—recommended
Antiviral—antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir)

See Chapter 47 for more information

Patient Population Studied

A study of 148 patients with MDS who were treated with lenalidomide, of whom 46 were treated on the 21-day schedule and 102 received continuous daily dosing. Of the patients, 64% had either refractory anemia or refractory anemia with ringed sideroblasts, and 81% were at low or intermediate-1 risk according to the IPSS scores

Treatment Modifications

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Treatment Modifications

Dose Adjustments for Hematologic Toxicities During MDS Treatment

Platelet Counts

If thrombocytopenia develops WITHIN 4 weeks of starting treatment at 10 mg daily in MDS

If baseline ≥100,000/μL

When Platelets

Recommended Course

Fall to <50,000/μL

Interrupt lenalidomide treatment

Return to ≥50,000/μL

Resume lenalidomide at 5 mg daily

If baseline <100,000/μL

When Platelets

Recommended Course

Fall to 50% of the baseline value

Interrupt lenalidomide treatment

If baseline ≥60,000/μL and returns to ≥50,000/μL

Resume lenalidomide at 5 mg daily

If baseline <60,000/μL and returns ≥30,000/μL

Resume lenalidomide at 5 mg daily

If thrombocytopenia develops AFTER 4 weeks of starting treatment at 10 mg daily in MDS

When Platelets

<30,000/μL or <50,000/μL with platelet transfusions

Recommended Course

Interrupt lenalidomide treatment

Return to ≥30,000/μL (without hemostatic failure)

Resume lenalidomide at 5 mg daily

Patients who experience thrombocytopenia at 5 mg daily should have their dosage adjusted as follows:

If thrombocytopenia develops during treatment at 5 mg daily in MDS

When Platelets

Recommended Course

<30,000/μL or <50,000/μL with platelet transfusions

Interrupt lenalidomide treatment

Return to ≥30,000/μL (without hemostatic failure)

Resume lenalidomide at 2.5 mg daily

Patients who are dosed initially at 10 mg and experience neutropenia should have their dosage adjusted as follows:

Absolute neutrophil counts (ANC)

If neutropenia develops WITHIN 4 weeks of starting treatment at 10 mg daily in MDS

If baseline ANC ≥1000/μL

When Neutrophils

Recommended Course

Fall to <750/μL

Interrupt lenalidomide treatment

Return to ≥1000/μL

Resume lenalidomide at 5 mg daily

If baseline ANC <1000/μL

When Neutrophils

Recommended Course

Fall to <500/μL

Interrupt lenalidomide treatment

Return to ≥500/μL

Resume lenalidomide at 5 mg daily

If neutropenia develops 4 weeks AFTER starting treatment at 10 mg daily in MDS

When Neutrophils

Recommended Course

<500/μL for ≥7 days or <500/μL associated with fever (≥38.5C)

Interrupt lenalidomide treatment

Return to ≥500/μL

Resume lenalidomide at 5 mg daily

Patients who experience neutropenia at 5 mg daily should have their dosage adjusted as follows:

If neutropenia develops during treatment at 5 mg daily in MDS

When Neutrophils

Recommended Course

<500/μL for ≥ 7 days or < 500/μL associated with fever (≥38.5C)

Interrupt lenalidomide

Return to ≥500/μL

Resume lenalidomide at 2.5 mg daily

Other Grade 3/4 Toxicities in MDS

For other Grade 3/4 toxicities judged to be related to lenalidomide, hold treatment and restart at next lower dose level when toxicity has resolved to ≤ Grade 2

Starting Dose Adjustment for Renal Impairment in Myelodysplastic Syndromes (Days 1–28 of Each 28-Day Cycle)

Category

Renal Function (Cockcroft-Gault)

Dose

Moderate renal impairment

Clcr 30–60 mL/min (0.5–1 mL/s)

5 mg every 24 hours

Severe renal impairment

Clcr <30 mL/min (not requiring dialysis)

2.5 mg every 24 hours

End-stage renal disease

Clcr <30 mL/min (requiring dialysis)

2.5 mg once daily. On dialysis days, administer the dose following dialysis

Therapy Monitoring

Complete blood counts, leukocyte differential, and platelet count should be performed as needed to monitor response and toxicity; that is, at least once weekly
Consider bone marrow biopsy every 2 cycles until CR is confirmed
Serum liver chemistries and creatinine should be obtained prior to initiation of treatment

Efficacy

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Efficacy

Frequency of Cytogenetic Response According to Karyotype Complexity

Complexity

Patients Who Could be Evaluated^✫

Cytogenetic Response

Complete Cytogenetic Remission

Isolated 5q deletion–no. (%)

49 (77)

29 (45)

5q deletion + 1 additional abnormality–no. (%)

10 (67)

6 (40)

Complex (≥3 abnormalities)–no. (%)

3 (50)

P value

0.27

0.93

^✫Patients who could be evaluated were those with at least 20 analyzable cells in metaphase at baseline and at least 1 follow-up assessment. P values are for the association between karyotypic complexity and cytogenic response or complete cytogenetic remission

Among 148 patients, 99 (67%) no longer needed transfusions by week 24; the remaining 13 patients had a reduction of 50% or greater in the number of transfusions required. The median time to transfusion independence was 4.6 weeks (range: 1–49)

The rate of transfusion independence was significantly lower among patients with baseline thrombocytopenia than among patients with platelet counts >100,000/μL at baseline (39% vs. 73%, p = 0.001)

Toxicity

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Toxicity

Grade 3 and 4 Treatment-Related Adverse Events

Adverse Event

Grade 3

Grade 4

Grades 3 and 4

Continuous Daily Dosing^✫

21-Day Dosing^✫

Continuous Daily Dosing^✫

21-Day Dosing^✫

Both Schedules

(N = 102)

(N = 46)

(N = 102)

(N = 46)

(N = 148)

Number of Patients (%)

Neutropenia

20 (20)

8 (17)

45 (44)

8 (17)

81 (55)

Thrombocytopenia

37 (36)

14 (30)

7 (7)

7 (15)

65 (44)

Anemia (not otherwise specified)

4 (4)

2 (4)

4 (4)

10 (7)

Leukopenia (not otherwise specified)

3 (3)

2 (4)

4 (4)

9 (6)

Rash

5 (5)

4 (9)

9 (6)

Febrile neutropenia

2 (2)

1 (2)

2 (2)

1 (2)

1 (1)

Pruritus

2 (2)

2 (4)

4 (3)

Fatigue

2 (2)

2 (4)

4 (3)

Muscle cramp

3 (3)

3 (2)

Pneumonia

1 (1)

2 (4)

1 (1)

4 (3)

Nausea

3 (3)

1 (2)

4 (3)

Diarrhea

4 (4)

4 (3)

Deep vein thrombosis

3 (3)

1 (2)

4 (3)

Hemorrhage

1 (1)

2 (4)

1 (1)

1 (2)

4 (3)

Hypokalemia

1 (1)

1 (2)

2 (1)

Pyrexia

1 (1)

^✫Lenalidomide 10 mg/day

Notes

Lenalidomide is indicated for patients with transfusion-dependent anemia because of low- or intermediate-1–risk myelodysplastic syndromes (MDS) associated with a deletion 5q abnormality with or without additional cytogenetic abnormalities

Lenalidomide may cause fetal harm when administered to a pregnant woman

In a phase III, randomized, double-blind study assessed the efficacy and safety of lenalidomide in 205 red-blood-cell-(RBC)-transfusion-dependent patients with International Prognostic Scoring System low-/intermediate-1–risk del5q31 MDS. Patients received lenalidomide 10 mg/day on days 1–21 (n = 69) or 5 mg/day on days 1–28 (n = 69) of 28-day cycles; or placebo (n = 67). Crossover to lenalidomide or higher dose was allowed after 16 weeks. More patients in the lenalidomide 10- and 5-mg groups achieved RBC-transfusion independence (TI) for ≥26 weeks (primary end point) versus placebo (56.1% and 42.6% vs. 5.9%; both P <0.001)

The median duration of RBC-TI was not reached (median follow-up: 1.55 years), with 60–67% of responses ongoing in patients without progression to acute myeloid leukemia (AML). Cytogenetic response rates were 50% (10 mg) versus 25% (5 mg; P = 0.066)

For the lenalidomide groups combined, 3-year overall survival and AML risk were 56.5% and 25.1%, respectively

RBC-TI for ≥8 weeks was associated with 47% and 42% reductions in the relative risks of death and AML progression or death, respectively (P = 0.021 and 0.048)

Fenaux P et al. Blood 2011;118:3765–3776

REGIMEN: LYMPHOCYTE IMMUNE GLOBULIN, ANTI-THYMOCYTE GLOBULIN [EQUINE] (ATG)

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Regimen: Lymphocyte Immune Globulin, Anti-Thymocyte Globulin [Equine] (ATG)

Atgam^® (lymphocyte immune globulin, anti-thymocyte globulin, [equine] sterile solution) November 2005 product labeling. Distributed by Pharmacia & Upjohn Co., Division of Pfizer Inc., New York, NY

Molldrem JJ et al. Ann Intern Med 2002;137:156–163

Molldrem JJ et al. Br J Haematol 1997;99:699–705

Sloand EM et al. J Clin Oncol 2008;26:2505–2511

Saunthararajah Y et al. Blood 2003;102:3025–3027

U.S. National Heart, Lung, and Blood Institute intramural clinical trial, 09-H-0183

Premedication:

Acetaminophen 650 mg; administer orally 60 minutes before each antithymocyte globulin treatment, plus

Diphenhydramine 25–50 mg; administer orally 60 minutes before each antithymocyte globulin treatment

Prednisone 1 mg/kg per day or 40 mg/day (whichever dose is greater); administer orally starting prior to the first dose of ATG

The daily prednisone dose is gradually decreased (tapered) starting on day 10 or when signs of serum sickness have resolved, whichever occurs later
Prednisone dose is tapered with a dose decrement every 2 days over the following 8 days, and then is discontinued
Patients with serum sickness may require greater prednisone doses to achieve clinical resolution and dose tapering over a longer duration

Lymphocyte immune globulin, anti-thymocyte globulin, [equine] (see Note 1 below) 40 mg/kg per day administered through a high-flow (central) vein, vascular shunt, or arteriovenous fistula in a volume of 0.9% sodium chloride injection (0.9% NS), 5% dextrose and 0.2% sodium chloride injection (D5W/0.2% NS), or 5% dextrose and 0.45% sodium chloride injection (D5W/0.45% NS) sufficient to produce a solution with antithymocyte globulin concentration ≤4 mg/mL, over at least 4 hours for 4 consecutive days, on days 1–4 (total dosage/course = 160 mg/kg)

Notes:

Lymphocyte immune globulin, anti-thymocyte globulin [equine] (ATG) product labeling recommends intradermal skin testing prior to administration. Patients with a reactive skin test may still receive antithymocyte globulin after desensitization
Always administer anti-thymocyte globulin through a 0.2–1.0-μm pore size inline filter
After dilution, ATG should be allowed to come to room temperature before administration begins
The initial infusion rate should be 10% of the total volume per hour. For example, for a total volume of 500 mL, start at a rate of 50 mL/hour for the first 30 minutes. If there are no signs of an adverse reaction, the infusion rate can be advanced to complete the infusion over no less than 4 hours

Cyclosporine orally every 12 hours, continually, starting on day 14

Patients ≥12 years of age: Cyclosporine 3 mg/kg per dose; administer orally every 12 hours (total daily dose = 6 mg/kg)

Dosing is based on actual body weight (ABW) except in obese patients (defined as a body mass index >35 kg/m² in patients >20 years of age and >95th percentile for ages 12–20 years
For obese patients, cyclosporine dosage is based on an adjusted body weight that is calculated as the midpoint between the ideal body weight (IBW) and ABW, thus:

Adjusted Body Weight = IBW + (ABW − IBW)/2
Cyclosporine is continued for 6 months, after which:
In responding patients, the dose is gradually decreased by 5% per week, and then is discontinued
In nonresponding patients, cyclosporine is discontinued
Cyclosporine doses are adjusted for increases in serum creatinine and to maintain serum cyclosporine concentrations within the range of 200–400 mcg/L (166–333 nmol/L) by radioimmunoassay

Notes:
- Avoid other nephrotoxic drugs concurrent with cyclosporine treatment
- Granulocyte-colony stimulating factors (G-CSF) should be administered as clinically indicated, usually for evidence of infection such as fever or localized inflammation in the setting of severe inflammation. Emergence of monosomy 7 has been linked to exogenous use of G-CSF

Allergy skin testing prior to ATG administration:

Anti-thymocyte globulin (equine) is freshly diluted (1:1000) with 0.9% sodium chloride injection (0.9% NS), to a concentration of 5 mcg/0.1 mL, and administered intradermally
Administer 0.1 mL 0.9% NS, intradermally in a contralateral extremity as a control
Observe every 15–20 minutes during the first hour after intradermal injection
1. A local reaction ≥10 mm with a wheal, erythema, or both, ± pseudopod formation and itching or a marked local swelling is considered a positive test. For patients who exhibit a positive test result, consider desensitization prior to therapy
  
  Notes:
  - Advise patients to avoid using H₁-receptor antagonists for 72 hours before skin testing
  - The predictive value of skin testing has not been proved clinically; that is, allergic reactions including anaphylaxis have occurred in patients whose skin test result is negative
  - If antithymocyte globulin is administered after a locally positive skin test, administration should only be attempted in a setting where intensive life-support facilities are immediately available and with the attendance of a physician familiar with the treatment of potentially life-threatening allergic reactions
  - Systemic reactions preclude antithymocyte globulin administration; for example, generalized rash, tachycardia, dyspnea, hypotension, or anaphylaxis

Guidelines for administering antithymocyte globulin (ATG):

Severity and frequency of toxicities (rigors, fevers, oxygen desaturation, hypotension, nausea, vomiting, anaphylaxis) are greatest during the first day of infusion and diminish with each subsequent day. Toxicities generally subside after completing treatment
Adverse effects generally can be managed while continuing antithymocyte globulin infusion
Most patients receiving ATG will develop fever. Most fevers are not infectious in origin

Monitoring during ATG administration:

Patients should remain under continual surveillance
Assess peripheral vascular access sites for thrombophlebitis every 8 hours
Monitor vital signs and assess for adverse reactions (flushing, hives, itching, SOB, difficulty breathing, chest tightness) before starting administration, then:
- During initial dose: Continually during the first 15 minutes, then every 30 minutes × 2, then at least every hour until administration is completed
- During subsequent doses: 30 minutes after initiating ATG infusion

Supportive Care

Antimicrobial prophylaxis

Risk of fever and neutropenia is HIGH

Antimicrobial primary prophylaxis is recommended:

Antibacterial—P. jirovecii prophylaxis is recommended (eg, cotrimoxazole or aerosolized pentamidine)
- Begin during the first month of therapy, and continue throughout the duration of cyclosporine use
Antifungal—recommended
Antiviral—antiherpes antivirals (eg, acyclovir, famciclovir, valacyclovir)

See Chapter 47 for more information

Toxicity

Twelve patients required temporary admission to an intensive care unit during ATG treatment. Six patients did not complete 4 planned days of ATG treatment: 3 developed shaking chills, 2 experienced hypotension associated with shaking chills, and 1 died from alveolar hemorrhage associated with leukemic pulmonary infiltrates. One patient died shortly after receiving ATG from alveolar hemorrhage

Infusional toxicities of antithymocyte globulin:

Severity and frequency of toxicities are greatest during the first day of ATG administration and diminish with each subsequent day. Toxicities generally subside after completing treatment

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Toxicity

Adverse Events

Interventions

Rigors

Antihistamines (eg, diphenhydramine 25–50 mg, intravenously or orally every 6 hours as needed)

Meperidine 12.5–50 mg, intravenously may be repeated every 10 minutes

Nausea, vomiting

Antiemetic rescue. Then give antiemetic prophylaxis during subsequent antithymocyte globulin treatments (secondary prophylaxis)

Anaphylaxis^✫

Immediately STOP administration; administer steroids; assist respiration; and provide other resuscitative measures. DO NOT resume treatment

Thrombocytopenia, anemia

Blood product transfusions as needed^†

Fever and neutropenia^‡

Broad-spectrum antibiotics empirically, if ANC <500/mm³. May give acetaminophen 650 mg orally every 4 hours

Hypotension

Fluid resuscitation

Refractory hypotension

May indicate anaphylaxis. Stop antithymocyte globulin administration and stabilize blood pressure. Intensive Care Unit support

Oxygen desaturation

Oxygen therapy

Refractory oxygen desaturation

Discontinue antithymocyte globulin. Intensive Care Unit support

Respiratory distress

Discontinue antithymocyte globulin. If distress persists, administer an antihistamine, epinephrine, steroids

Rash, pruritus, urticaria

Administer antihistamines and/or topical steroids for prophylaxis and treatment

Serum sickness-like symptoms^§

Administer prophylactic glucocorticoids

Hepatotoxicity

Monitor LFTs

^✫Anaphylaxis (<3% of patients) more frequently occurs within the first hour after starting antithymocyte globulin infusion. After the first hour, adverse effects occur as result of a delayed immune response and generally can be managed while continuing the antithymocyte globulin infusion

^†Concurrent administration of blood products should be avoided with antithymocyte globulin infusions to avoid confusing transfusion reactions with reactions to antithymocyte globulin

^‡Most patients who receive antithymocyte globulin will develop fever as a result of the drug. Most fevers are not infectious in origin

^§Type II hypersensitivity reactions/serum sickness consisting of fever, rash, and arthralgia develops in approximately 85% of patients between 7 and 14 days after ATG treatment. These symptoms can be managed with steroids

An isolated increase in serum alanine aminotransferase (ALT) frequently has no clinical significance. Generally, liver function abnormalities are transient and return to normal within 1 month

Bevans MF, Shalabi RA. Clin J Oncol Nurs 2004;8:377–382

Patient Population Studied

Sixteen patients had low IPSS risk, 94 patients intermediate-1 (int-1) IPSS, 13 patients int-2 IPSS, and 6 patients high risk IPSS. Seventy-four patients received equine ATG, 42 patients received a combination of ATG and cyclosporine (maintaining cyclosporine levels >100 mcg/L [>83 nmol/L] for up to 6 months), and 13 patients received cyclosporine alone on the same schedule

Efficacy

Eighteen (24%) of 74 patients (95% CI, 14–34%) responded to ATG, 20 (45%) of 42 patients (95% CI, 32–63%) responded to ATG plus cyclosporine (P = 0.01), and 1 (8%) of 13 patients responded to cyclosporine. Thirty-one percent (12 of 39 patients; 95% CI, 16–46%) of the responses were complete, resulting in near-normal blood counts and transfusion independence; 32 (82%) of 39 (95% CI, 70–94%) of the responders achieved either bi-lineage or tri-lineage responses. Of the partial responders, all but 1 became transfusion independent

In multivariate analysis, young age was the most significant factor favoring response to therapy. Other favorable factors affecting response were HLA-DR15 positivity and combination ATG plus cyclosporine treatment (P = 0.001 and P = 0.048, respectively). Patients were seen at yearly follow-up from the start of IST. Seventy patients survive with a median follow-up of 3 years. Patients treated with ATG plus cyclosporine had superior response rates compared with patients treated with ATG alone, although there were no survival differences between these groups

Therapy Monitoring

During antithymocyte globulin infusion: CBC with differential, LFTs, electrolytes
After antithymocyte globulin therapy: CBC monitoring is dependent on blood counts. If WBC, ANC, and platelet counts are stable, a CBC with differential may be as infrequent as once every 2–3 weeks. Patients who require platelets may need more frequent CBCs, but not more than twice weekly and usually only once weekly
Six months after the start of therapy: Bone marrow biopsy and aspiration. If patients are stable based on blood counts, bone marrow biopsy may not need to be repeated

Therapeutic drug monitoring for cyclosporine:

When initiating cyclosporine treatment and after any dose adjustments, monitor cyclosporine trough concentrations (sampled at the end of a dosing interval) every 4–7 days until stable concentrations are achieved
For patients on a stable cyclosporine regimen, monitor trough levels every 2 weeks
More frequent cyclosporine monitoring is recommended whenever cyclosporine dosage adjustments are made, serum creatinine increases, and when a patient's concomitantly administered medication regimen is changed (be wary of drugs that potentially perturb cytochrome P450 CYP3A subfamily enzymes expression, availability, or activity)
Cyclosporine doses are adjusted to maintain blood concentrations with the range of 200–400 mcg/L (166–333 nmol/L) by radioimmunoassay

REGIMEN: ALEMTUZUMAB

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Regimen: Alemtuzumab

Sloand EM et al. J Clin Oncol 2010;28:5166–5173

Premedication given before all alemtuzumab doses including test doses:

Diphenhydramine 25–50 mg orally or intravenously 30 minutes prior to alemtuzumab injection, and

Acetaminophen 650 mg; orally 30 minutes before alemtuzumab

Test dose: Alemtuzumab 1 mg intravenously in 100 mL 0.9% sodium chloride injection (0.9% NS) or 5% dextrose injection (D5W) over 1 hour on the day before the first full (10-mg) dose of alemtuzumab is administered

Treatment: If a test dose was tolerated, give alemtuzumab 10 mg/day intravenously in 100 mL 0.9% NS or D5W over 2 hours for 10 consecutive days, on days 1–10 (total dose/10-day course, including a test dose = 101 mg)

Supportive Care

Antiemetic prophylaxis

Emetogenic potential is MINIMAL

See Chapter 39 for antiemetic recommendations

Hematopoietic growth factor (CSF) prophylaxis

Primary prophylaxis may be indicated

Note: In the study by Sloand et al, the use of erythropoietin-stimulating agents and/or granulocyte colony-stimulating factor (G-CSF) to treat severe anemia and/or neutropenia was permitted, but hematologic responses were ascertained after 4 weeks of withholding erythropoietin-stimulating agents and/or G-CSF

See Chapter 43 for more information

Antimicrobial prophylaxis

Risk of fever and neutropenia is HIGH

Antimicrobial primary prophylaxis is recommended:

Antibacteria—Pentamidine 300 mg; administer aerosolized pentamidine by inhalation every 4 weeks beginning the first month of alemtuzumab therapy, and continue for at least 6 months. If at 6 months CD4+ cells are <200/μL, continue Pneumocystis jirovecii prophylaxis until CD4+ cells >200/μL
Ciprofloxacin 500 mg orally twice daily until ANC >500/μL
Antiviral—Valacyclovir 500 mg orally once daily for at least 2 months regardless of HSV serology status. If at 2 months CD4+ cells are <200/μL, continue antiviral prophylaxis until CD4+ cells ≥200/μL

See Chapter 47 for more information

Patient Population Studied

Study of 31 evaluable patients (median age: 57 years) with de novo MDS without known preceding aplastic anemia or prior chemotherapy. According to IPSS, 2 patients were classified as low risk, 22 patients were classified as intermediate-1 (Int-1) risk, and 7 patients were classified as intermediate-2 (Int-2) risk

For study entry, 1 or more of the following criteria were necessary: transfusion dependence (≥2 units RBCs or ≥5 units of platelets per month for 8 weeks before enrollment), thrombocytopenia (platelet count ≤50,000/μL), neutropenia (neutrophil count ≤500/μL), and anemia (hemoglobin <9 g/dL or absolute reticulocyte count of <60,000 cells/μL) based on the mean of 3 blood counts within 2 weeks before enrollment. HLA-DR1-–negative patients in whom the sum of the age plus months of RBC transfusion dependence was <58 and HLA-DR15-positive patients in whom the sum of the age plus months of RBC transfusion dependence was <72 were eligible for the study

Treatment Modification

Withhold alemtuzumab during serious infection or other serious adverse reaction until resolution

Toxicity (N = 31)

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Toxicity (N = 31)

SAE

No. of Patients

No. of Days to SAE

Infection

Bacterial pneumonia

Cellulitis

428

Clostridium difficile diarrhea

78,123

Neutropenia and fever

7,31,329

Fever without neutropenia

35,162

Shingles

381

Sinusitis

173

URI symptoms

Infusion reaction

Hypotension

Hematologic

Autoimmune thrombocytopenia

Dermatologic

Molluscum contagiosum skin lesion

217

SAE, severe adverse event; URI, upper respiratory tract infection

Nonhematologic AEs

No. of Patients

Cardiovascular

Hypertension

Constitutional

Asthenia

Fatigue

Stiffness

Dermatology/skin

Facial flushing

Pruritus

Rash

Urticaria

Diarrhea

Nausea

Infusion reaction

Infection/febrile neutropenia

Orchitis

Pilonidal cyst

Upper respiratory tract

Mycobacterium chelonae

Lymphatic

Hand swelling

Metabolic

Decreased phosphate

Elevated AST, ALT

Elevated LDH

Elevated creatinine

Neurologic

Dizziness

Pain

Headache

Muscle cramps

Neuropathic

Renal/genitourinary

Darkened urine

AE, adverse even; LDH, lactate dehydrogenase; URI, upper respiratory tract infection

Twenty-four patients had infusion reactions of rigors, malaise, and elevated transaminases, and 1 patient developed hypotension after the first alemtuzumab dose. Infusion reactions were seen most frequently with the initial test dose, but became attenuated with successive infusions

Among 31 evaluable patients, all were seropositive for EBV, and 22 (71%) were seropositive for CMV. Of the EBV patients, 15 experienced reactivation of EBV. Of the CMV-seropositive patients, 5 (23%) experienced CMV reactivation. All reactivations were subclinical and self-limited; no patient developed EBV- or CMV-related disease or required pre-emptive antiviral therapy

Efficacy

Twenty-one patients (68%) achieved either hematologic improvement in 1 or more lineages or a CR

Seventeen (77%) of 22 evaluable patients with Int-1 MDS and 4 (57%) of 7 patients with Int-2 MDS responded to treatment

Median time to response was 3 months. Among the responders, 2 (11%) of 18 patients had a CR at 3 months, 3 (18%) of 17 evaluable responders had a CR at 6 months, and 5 (56%) of 9 evaluable responders had a CR at 12 months

Of the 25 patients who were RBC transfusion dependent before treatment, 10 (40%) achieved transfusion independence by 3 months. Seven (78%) of 9 of responders evaluable at 1 year were transfusion independent

Thirteen (65%) of 20 neutropenic patients had hematologic improvement or complete neutrophil response and 9 (38%) of 24 thrombocytopenic patients had a platelet response

Four of 7 responding patients with abnormal karyotype before treatment had cytogenetic CRs by 1 year

Therapy Monitoring

On treatment monitoring: CBC with differential (daily) and renal, hepatic function every other day

Post treatment monitoring: Complete blood counts with differential, renal, hepatic function should be evaluated as needed to monitor response and toxicity; ie, at least once weekly

Bone marrow biopsy and aspiration at 6 months post-treatment

EBV and CMV monitoring: EBV and CMV PCR in the blood prior to treatment, repeated weekly for the first month, then every other week in the second month, monthly for another 6 months, and at 12 months. In case of a positive PCR for CMV, treatment will be instituted when clinical symptoms are attributed to CMV. EBV positivity by PCR will also be placed in context of clinical signs and symptoms

Notes

Patients who experienced relapse 3 months after an initial response to alemtuzumab were eligible to receive cyclosporine, unless otherwise contraindicated: cyclosporine 5 mg/kg per dose orally every 12 hours, continually (total dosage/day = 10 mg/kg). No-responders were removed from study at 6 months

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Chapter 67: Myelodysplastic Syndromes

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INTRODUCTION

REGIMEN: DECITABINE

REGIMEN: AZACITIDINE

REGIMEN: LENALIDOMIDE

REGIMEN: LYMPHOCYTE IMMUNE GLOBULIN, ANTI-THYMOCYTE GLOBULIN [EQUINE] (ATG)

REGIMEN: ALEMTUZUMAB

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