Hematology

Benign Hematology

TRICC trial: Red blood cell transfusion requirements

Article Name: A Multicenter, Randomized, Controlled Clinical Trial of Transfusion Requirements in Critical Care

URL: https://www.nejm.org/doi/full/10.1056/NEJM199902113400601

Journal and year of publication: NEJM, 1999

Trial Design: Randomized controlled clinical trial

Population: 838 patients
Key inclusion criteria:
– Expected to stay in the intensive care unit more than 24 hours.
– Had a hemoglobin concentration of 9.0 g/dL or less within 72 hours after admission to the intensive care unit
– Considered to have euvolemia after initial treatment by attending physicians
Key exclusion criteria:
– Active bleeding
– Chronic anemia <9.0
– Admission after a routine cardiac surgical procedure

Intervention Studied: Restrictive strategy of transfusion (transfuse if hemoglobin below 7g/dL, goal between 7 – 9 g/dL)

Control: Liberal strategy of transfusion (transfuse if hemoglobin below 10g/dL, goal between 10 – 12 g/dL)

Outcomes:
– 30-day mortality: Overall similar in the two groups (18.7% vs. 23.3%), P= 0.11
– In patients with clinically significant cardiac disease: No significant difference
– Mortality rate during hospitalization: Significantly lower with the restrictive transfusion strategy (Restrictive strategy: 22.2% vs Liberal strategy: 28.1%; P=0.05)

The authors concluded that “A restrictive strategy of red-cell transfusion is at least as effective as and possibly superior to a liberal transfusion strategy in critically ill patients, with the possible exception of patients with acute myocardial infarction and unstable angina.“

Citation: _{Hébert PC, Wells G, Blajchman MA, Marshall J, Martin C, Pagliarello G, Tweeddale M, Schweitzer I, Yetisir E. A multicenter, randomized, controlled clinical trial of transfusion requirements in critical care. Transfusion Requirements in Critical Care Investigators, Canadian Critical Care Trials Group. N Engl J Med. 1999 Feb 11;340(6):409-17. doi: 10.1056/NEJM199902113400601. Erratum in: N Engl J Med 1999 Apr 1;340(13):1056. PMID: 9971864.}

CHOIR trial: Epoetin alfa and target hemoglobin for CKD

Article Name: Correction of Anemia with Epoetin Alfa in Chronic Kidney Disease

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa065485

Journal and year of publication: NEJM, 2006

Trial Design: Randomized controlled clinical trial

Population: 1432 patients
Key inclusion criteria:
– Have a hemoglobin level <11.0 g/dL
– Have chronic kidney disease
Key exclusion criteria:
– Uncontrolled hypertension
– Active gastrointestinal bleeding
– Iron-overload state
– Refractory iron-deficiency anemia

Intervention Studied: Epoetin alfa targeted to achieve a hemoglobin level of 13.5 g/dL

Control: Epoetin alfa targeted to achieve a hemoglobin level of 11.3 g/dL

Outcomes:
– Occurrence of composite events: (Death, MI, hospitalization for congestive HF and stroke): High-hemoglobin group: 125 events vs Low-hemoglobin group: 97 events (P=0.03)

The authors concluded that “The use of a target hemoglobin level of 13.5 g per deciliter (as compared with 11.3 g per deciliter) was associated with increased risk and no incremental improvement in the quality of life.“

Citation: _{Singh AK, Szczech L, Tang KL, Barnhart H, Sapp S, Wolfson M, Reddan D; CHOIR Investigators. Correction of anemia with epoetin alfa in chronic kidney disease. N Engl J Med. 2006 Nov 16;355(20):2085-98. doi: 10.1056/NEJMoa065485. PMID: 17108343.}

MSH trial: Hydroxyurea for sickle cell anemia

Article Name: Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia

URL: https://www.nejm.org/doi/full/10.1056/nejm199505183322001

Journal and year of publication: NEJM, 1995

Trial Design: Randomized, double-blinded, placebo-controlled clinical trial

Population: 299 patients
Key inclusion criteria:
– Sickle cell anemia
– At least 3 crises in the year before entry
Key exclusion criteria:
– Sickle cell–β+-thalassemia & sickle cell–β°-thalassemia.
– Pregnancy

Intervention Studied: Hydroxyurea

Control: Placebo

Outcomes:
– Median annual rates of crises: Hydroxyurea group: 2.5/year vs Placebo group: 4.5/year (P<0.001)
– Median time to first crisis: Hydroxyurea group: 3 months vs Placebo group: 1.5 months (P=0.01)
– Patients with hydroxyurea had fewer acute chest syndromes and underwent fewer transfusions

The authors concluded that “Hydroxyurea therapy can ameliorate the clinical course of sickle cell anemia in some adults with three or more painful crises per year. Maximal tolerated doses of hydroxyurea may not be necessary to achieve a therapeutic effect. The beneficial effects of hydroxyurea do not become manifest for several months, and its use must be carefully monitored. The long-term safety of hydroxyurea in patients with sickle cell anemia is uncertain.“

Citation: _{Charache S, Terrin ML, Moore RD, Dover GJ, Barton FB, Eckert SV, McMahon RP, Bonds DR. Effect of hydroxyurea on the frequency of painful crises in sickle cell anemia. Investigators of the Multicenter Study of Hydroxyurea in Sickle Cell Anemia. N Engl J Med. 1995 May 18;332(20):1317-22. doi: 10.1056/NEJM199505183322001. PMID: 7715639.}

CYTO-PV trial: Hemoglobin target for polycythemia vera

Article Name: Cardiovascular Events and Intensity of Treatment in Polycythemia Vera

URL: y https://www.nejm.org/doi/full/10.1056/NEJMoa1208500

Journal and year of publication: NEJM, 2013

Trial Design: Randomized clinical trial

Population: 365 patients
Key inclusion criteria:
– Diagnosis of PV according to WHO diagnostic criteria including Jak 2 V617F mutation status
Key exclusion criteria:
– Pregnant or lactating women
– Significant liver (AST or ALT > 2.5 times ULN) or renal disease (creatinine > 2 mg/ml)

Intervention Studied: Treated with phlebotomy, hydroxyurea, or both – intensive treatment (target hematocrit, <45%) (low-hematocrit group)

Control: Treated with phlebotomy, hydroxyurea, or both – less intensive treatment (target hematocrit, 45 to 50%) (high-hematocrit group)

Outcomes:
– Primary endpoint occurrence (time until death from cardiovascular causes or major thrombotic events): Low-hematocrit group: 2.7% of patients vs High-hematocrit group: 9.8% of patients (P=0.007)
– Primary end point plus superficial-vein thrombosis occurrence: Low-hematocrit group: 4.4% of patients vs High-hematocrit group: 10.9% of patients (P=0.02)

The authors concluded that “In patients with polycythemia vera, those with a hematocrit target of less than 45% had a significantly lower rate of cardiovascular death and major thrombosis than did those with a hematocrit target of 45 to 50%.“

Citation: _{Marchioli R, Finazzi G, Specchia G, Cacciola R, Cavazzina R, Cilloni D, De Stefano V, Elli E, Iurlo A, Latagliata R, Lunghi F, Lunghi M, Marfisi RM, Musto P, Masciulli A, Musolino C, Cascavilla N, Quarta G, Randi ML, Rapezzi D, Ruggeri M, Rumi E, Scortechini AR, Santini S, Scarano M, Siragusa S, Spadea A, Tieghi A, Angelucci E, Visani G, Vannucchi AM, Barbui T; CYTO-PV Collaborative Group. Cardiovascular events and intensity of treatment in polycythemia vera. N Engl J Med. 2013 Jan 3;368(1):22-33. doi: 10.1056/NEJMoa1208500. Epub 2012 Dec 8. PMID: 23216616.}

Platelet transfusions for platelet consumptive disorders

Article Name: Platelet transfusions in platelet consumptive disorders are associated with arterial thrombosis and in-hospital mortality

URL: https://ashpublications.org/blood/article/125/9/1470/34225/Platelet-transfusions-in-platelet-consumptive

Journal and year of publication: Blood, 2015

Trial Design: Retrospective study

Population: 96,936 patients
Key inclusion criteria:
– Patients with hospital admission of TTP, ITP, HIT
Key exclusion criteria:
– Hospitalizations with reported prior “history of thrombosis”
– Thrombosis/thromboembolism listed as the primary admitting diagnosis

Intervention Studied: N/A

Control: N/A

Outcomes:
– Odds of complications with platelet transfusions:
– In TTP: arterial thrombosis, acute MI, venous thrombosis, and mortality had higher odds with platelet transfusion
– In HIT: arterial thrombosis, venous thrombosis, and mortality had higher odds with platelet transfusion
– In ITP: no significant associations

The authors concluded that ” Platelet transfusions are associated with higher odds of arterial thrombosis and mortality among TTP and HIT patients.“

Citation: _{Goel R, Ness PM, Takemoto CM, Krishnamurti L, King KE, Tobian AA. Platelet transfusions in platelet consumptive disorders are associated with arterial thrombosis and in-hospital mortality. Blood. 2015 Feb 26;125(9):1470-6. doi: 10.1182/blood-2014-10-605493. Epub 2015 Jan 14. PMID: 25588677; PMCID: PMC4342358}.

IVIG and oral prednisone for ITP

Article Name: Intravenous immunoglobulin or high-dose methylprednisolone, with or without oral prednisone, for adults with untreated severe autoimmune thrombocytopenic purpura: a randomised, multicentre trial

URL: Link

Journal and year of publication: The Lancet, 2002

Trial Design: Randomized controlled trial

Population: 122 patients
Key inclusion criteria:
– Diagnosis of AITP during the 4 weeks before study entry
– Platelet count of 20×10⁹/L or less
Key exclusion criteria:
– Received any treatment known to be effective for AITP
– Presented with life-threatening gastrointestinal haemorrhage or CNS haemorrhage

Intervention Studied: To receive Intervention 1 or comparison 1, follow by intervention 2 or comparison 2
Intervention 1: Intravenous immunoglobulin
Intervention 2: Oral prednisone

Control:
Comparison 1: High-dose methyl-prednisolone
Comparison 2: Placebo

Outcomes:
– Primary outcome (number of days with platelet count greater than 50×10⁹/L within the first 21 days): IV immunoglobulin + prednisone: 18.5 days vs High-dose methylprednisolone + prednisone: 17.5 days (p=0·005)
– Percentage of patients with platelet counts over 50×10⁹/L on day 5: IV immunoglobulin: 79% of patients vs High-dose methylprednisolone: 60% of patients (p=0.04)
– Oral prednisone was more effective than placebo for all short-term endpoints

The authors concluded that ” Intravenous immunoglobulin and oral prednisone seems to be more effective than high-dose methylprednisolone and oral prednisone in adults with severe AITP, although the latter treatment is effective and well tolerated.“

Citation: _{Godeau B, Chevret S, Varet B, Lefrère F, Zini JM, Bassompierre F, Chèze S, Legouffe E, Hulin C, Grange MJ, Fain O, Bierling P; French ATIP Study Group. Intravenous immunoglobulin or high-dose methylprednisolone, with or without oral prednisone, for adults with untreated severe autoimmune thrombocytopenic purpura: a randomised, multicentre trial. Lancet. 2002 Jan 5;359(9300):23-9. doi: 10.1016/S0140-6736(02)07275-6. PMID: 11809183.}

TRAPS trial: Rivoraxaban for antiphospholipid syndrome

Article Name: Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome

URL: https://ashpublications.org/blood/article/132/13/1365/105711/Rivaroxaban-vs-warfarin-in-high-risk-patients-with

Journal and year of publication: Blood, 2018

Trial Design: Randomized controlled trial

Population: 120 patients
Key inclusion criteria:
– High-risk patients triple positive for lupus anticoagulant, anti-cardiolipin, and anti–β2-glycoprotein I antibodies of the same isotype (triple positivity)
Key exclusion criteria:
– Calculated CLCR <30 mL/min
– Concomitant treatment with other anticoagulants
– Hemorrhage risk-related criteria

Intervention Studied: Rivaroxaban, 20 mg once daily

Control: Warfarin (target INR of 2.5)

Outcomes:
– Thromboembolic events: Rivaroxaban: 7 patients (12% of patients) – 4 had ischemic stroke, 3 had MI; vs Warfarin group: 0 patients (0% of patients) (p=0.01)
– Major bleeding: Rivaroxaban: 7% of patients vs Warfarin group: 3% of patients

The authors concluded that “The use of rivaroxaban in high-risk patients with antiphospholipid syndrome was associated with an increased rate of events compared with warfarin, thus showing no benefit and excess risk.“

Citation: _{Pengo V, Denas G, Zoppellaro G, Jose SP, Hoxha A, Ruffatti A, Andreoli L, Tincani A, Cenci C, Prisco D, Fierro T, Gresele P, Cafolla A, De Micheli V, Ghirarduzzi A, Tosetto A, Falanga A, Martinelli I, Testa S, Barcellona D, Gerosa M, Banzato A. Rivaroxaban vs warfarin in high-risk patients with antiphospholipid syndrome. Blood. 2018 Sep 27;132(13):1365-1371. doi: 10.1182/blood-2018-04-848333. Epub 2018 Jul 12. PMID: 30002145.}

PLASMIC score for diagnosis of TTP

Article Name: Derivation and external validation of the PLASMIC score for rapid assessment of adults with thrombotic microangiopathies: a cohort study

URL: https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(17)30026-1/fulltext

Journal and year of publication: The Lancet Haematology, 2017

Trial Design: Cohort study

Population: 214 patients
Key inclusion criteria:
– Presented with thrombocytopenia (<150×10⁹/L) and microangiopathic haemolytic anaemia
– Had an ADAMTS13 assay sent during the study period
Key exclusion criteria:
– Seen as outpatients
– Had known interferences with the ADAMTS13 assay

Intervention Studied: PLASMIC score

Control: Warfarin (target INR of 2.5)

Plasma Exchange for TTP

Article Name: Comparison of Plasma Exchange with Plasma Infusion in the Treatment of Thrombotic Thrombocytopenic Purpura

URL: https://www.nejm.org/doi/full/10.1056/nejm199108083250604

Journal and year of publication: NEJM, 1991

Trial Design: RCT

Population: 102 patients
Key inclusion criteria:
– Diagnosis of TTP without a clear alternative cause
Key exclusion criteria:

Intervention Studied: Plasma exchange

Control: Plasma infusion

Outcomes:
Higher rate of response in those receiving plasma exchange:
– Platelet count increased in: with plasma exchange: 24 of 51 patients vs with plasma infusion: 13 of 51 patients (P = 0.025)
– Death: with plasma exchange: 2 of 51 patients vs with plasma infusion: 8 of 51 patients (P = 0.035)

The authors concluded that “Plasma exchange is more effective than plasma infusion in the treatment of thrombotic thrombocytopenic purpura.“

Citation: _{Rock GA, Shumak KH, Buskard NA, Blanchette VS, Kelton JG, Nair RC, Spasoff RA. Comparison of plasma exchange with plasma infusion in the treatment of thrombotic thrombocytopenic purpura. Canadian Apheresis Study Group. N Engl J Med. 1991 Aug 8;325(6):393-7. doi: 10.1056/NEJM199108083250604. PMID: 2062330.}

AMPLIFY Trial: Apixaban for VTE

Article Name: Oral Apixaban for the Treatment of Acute Venous Thromboembolism

URL: https://www.nejm.org/doi/full/10.1056/nejmoa1302507

Journal and year of publication: NEJM, 2013

Trial Design: RCT

Population: 5395 patients
Key inclusion criteria:
– Objectively confirmed, symptomatic proximal DVT or PE
Key exclusion criteria:
– Thrombectomy, insertion of a caval filter, or use of a fibrinolytic agent
– Active bleeding, a high risk of bleeding
– Had cancer and long-term treatment with LMWH was planned
– Serum creatinine: >2.5 mg per deciliter

Intervention Studied: Apixaban (10 mg twice daily for 7 days, followed by 5 mg twice daily for 6 months)

Control: Conventional therapy (subcutaneous enoxaparin, followed by warfarin)

Outcomes:
– Primary efficacy outcome occurrence (recurrent symptomatic VTE or death related to VTE): Apixaban group: 2.3% of patients vs Conventional-therapy group: 2.7% of patients. Relative risk: 0.84 (95% CI: 0.60 to 1.18). Apixaban was non- inferior to conventional therapy (P<0.001)
– Major bleeding occurrence: Apixaban group: 0.6% of patients vs Conventional-therapy group: 1.8% of patients. Relative risk: 0.31 (95% C: 0.17 to 0.55),
P<0.001 for superiority

The authors concluded that “A fixed-dose regimen of apixaban alone was noninferior to conventional therapy for the treatment of acute venous thromboembolism and was associated with significantly less bleeding”

Citation: _{Agnelli G, Buller HR, Cohen A, Curto M, Gallus AS, Johnson M, Masiukiewicz U, Pak R, Thompson J, Raskob GE, Weitz JI; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013 Aug 29;369(9):799-808. doi: 10.1056/NEJMoa1302507. Epub 2013 Jul 1. PMID: 23808982.}

EINSTEIN Trial: Rivaroxaban for VTE

Article Name: Oral Rivaroxaban for Symptomatic Venous Thromboembolism

URL: https://www.nejm.org/doi/full/10.1056/nejmoa1007903

Journal and year of publication: NEJM, 2010

Trial Design: RCT

Population: 3,449 patients
Key inclusion criteria:
– Acute, symptomatic, objectively confirmed proximal DVT
Key exclusion criteria:
– Received therapeutic doses of LMWH, fondaparinux, or UFH for >48 hours
– Received >1 dose of a vitamin K antagonist before randomization
– Treated with thrombectomy, a vena cava filter, or a fibrinolytic agent for the current episode of thrombosis

Intervention Studied: Oral rivaroxaban

Control: Subcutaneous enoxaparin followed by a vitamin K antagonist or placebo

Outcomes:
– Primary outcome occurrence (Recurrent venous thromboembolism): Rivaroxaban group: 36 events (2.1%) vs Enoxaparin–vitamin K antagonist group: 51 (3.0%). Hazard ratio: 0.68 (95 CI%: 0.44 to 1.04), P<0.001
– Continued-treatment study (Rivaroxaban vs Placebo). Rivaroxaban group: 8 events (1.3%) vs Placebo group: 42 events (7.1%). Hazard ratio: 0.18 (95 CI%: 0.09 to 0.39), P<0.001

The authors concluded that “Rivaroxaban offers a simple, single-drug approach to the short-term and continued treatment of venous thrombosis that may improve the benefit-to-risk profile of anticoagulation.”

Citation: ^{_{EINSTEIN Investigators; Bauersachs R, Berkowitz SD, Brenner B, Buller HR, Decousus H, Gallus AS, Lensing AW, Misselwitz F, Prins MH, Raskob GE, Segers A, Verhamme P, Wells P, Agnelli G, Bounameaux H, Cohen A, Davidson BL, Piovella F, Schellong S. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010 Dec 23;363(26):2499-510. doi: 10.1056/NEJMoa1007903. Epub 2010 Dec 3. PMID: 21128814.}}

Leukemia

ATRA for APML

Article Name: All-trans-Retinoic Acid in Acute Promyelocytic Leukemia

URL: https://www.nejm.org/doi/full/10.1056/nejm199710093371501

Journal and year of publication: NEJM, 1997

Trial Design: Randomized controlled trial

Population: 346 patients
Key inclusion criteria:
– Diagnosis of acute promyelocytic leukemia
– No prior chemotherapy except hydroxyurea
– Normal hepatic and renal function
– ECOG score of 0 to 3
– Cytogenetic evaluation for t(15;17) done
Key exclusion criteria:

Intervention Studied: All-trans-retinoic acid

Control: Daunorubicin plus cytarabine

Outcomes:
– Achieving complete remission: Chemotherapy: 69% of patients vs All-trans-retinoic acid: 72% of patients (P = 0.56)
– Overall survival (ITT analysis) :
– With Chemotherapy: At 1 year: 75% 2 years: 57% 3 years: 50%
– With all-trans-retinoic acid: At 1 year: 82% 2 years: 72% 3 years: 67%
(P = 0.003)

The authors concluded that “All-trans-retinoic acid as induction or maintenance treatment improves disease-free and overall survival as compared with chemotherapy alone and should be included in the treatment of acute promyelocytic leukemia.“

Citation: _{Tallman MS, Andersen JW, Schiffer CA, Appelbaum FR, Feusner JH, Ogden A, Shepherd L, Willman C, Bloomfield CD, Rowe JM, Wiernik PH. All-trans-retinoic acid in acute promyelocytic leukemia. N Engl J Med. 1997 Oct 9;337(15):1021-8. doi: 10.1056/NEJM199710093371501. Erratum in: N Engl J Med 1997 Nov 27;337(22):1639. PMID: 9321529.}

Lo-Coco trial: Retinoic acid + arsenic trioxide for APML

Article Name: Improved Outcomes With Retinoic Acid and Arsenic Trioxide Compared With Retinoic Acid and Chemotherapy in Non–High-Risk Acute Promyelocytic Leukemia: Final Results of the Randomized Italian-German APL0406 Trial

URL: https://ascopubs.org/doi/10.1200/JCO.2016.67.1982

Journal and year of publication: Journal of Clinical Oncology, 2016

Trial Design: Randomized controlled trial

Population: 276 patients
Key inclusion criteria:
– Low- or intermediate-risk APL
– Genetic diagnostic confirmation
Key exclusion criteria:
– PML-RARA–positive APL

Intervention Studied: ATRA-ATO (all-trans-retinoic acid and arsenic trioxide)

Control: ATRA-CHT (all-trans-retinoic acid and chemotherapy)

Outcomes:
– Response to induction:
— ATRA-ATO: 100% of patients achieved complete remission
— ATRA-CHT: 97% of patients achieved complete remission
(P = 0.12)

– Event-free survival:
— ATRA-ATO: 97.3% vs ATRA-CHT: 80%
(P < 0.001)

– Cumulative incidence of relapse:
— ATRA-ATO: 1.9% vs ATRA-CHT: 13.9%
(P = 0.0013)

– Overall survival at 50 months:
— ATRA-ATO: 99.2% vs ATRA-CHT: 92.6%
(P = 0.0073)

The authors concluded that “These results show that the advantages of ATRA-ATO over ATRA-CHT increase over time and that there is significantly greater and more sustained antileukemic efficacy of ATO-ATRA compared with ATRA-CHT in low- and intermediate-risk APL.“

Citation: _{Platzbecker U, Avvisati G, Cicconi L, Thiede C, Paoloni F, Vignetti M, Ferrara F, Divona M, Albano F, Efficace F, Fazi P, Sborgia M, Di Bona E, Breccia M, Borlenghi E, Cairoli R, Rambaldi A, Melillo L, La Nasa G, Fiedler W, Brossart P, Hertenstein B, Salih HR, Wattad M, Lübbert M, Brandts CH, Hänel M, Röllig C, Schmitz N, Link H, Frairia C, Pogliani EM, Fozza C, D’Arco AM, Di Renzo N, Cortelezzi A, Fabbiano F, Döhner K, Ganser A, Döhner H, Amadori S, Mandelli F, Ehninger G, Schlenk RF, Lo-Coco F. Improved Outcomes With Retinoic Acid and Arsenic Trioxide Compared With Retinoic Acid and Chemotherapy in Non-High-Risk Acute Promyelocytic Leukemia: Final Results of the Randomized Italian-German APL0406 Trial. J Clin Oncol. 2017 Feb 20;35(6):605-612. doi: 10.1200/JCO.2016.67.1982. Epub 2016 Oct 31. PMID: 27400939.}

IRIS trial: Imatinib for CML

Article Name: Imatinib Compared with Interferon and Low-Dose Cytarabine for Newly Diagnosed Chronic-Phase Chronic Myeloid Leukemia

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa022457

Journal and year of publication: NEJM, 2003

Trial Design: Randomized controlled trial

Population: 1,106 patients
Key inclusion criteria:
– Diagnosis of chronic-phase, Ph-positive CML within the last six months
Key exclusion criteria:
– Extramedullary disease other than hepatosplenomegaly
– ECOG 3 or higher
– Undergone hematopoietic-cell transplantation
– <100,000 platelets /cubic millimeter

Intervention Studied: Imatinib

Control: Interferon alfa plus low-dose cytarabine

Outcomes:
– Estimated rate of a major cytogenetic response at 18 months:
– Imatinib: 87.1% (95% CI: 84.1 to 90.0)
– Interferon alfa + low-dose cytarabine: 34.7% (95% CI: 29.3 to 40.0)
(P<0.001)

– Estimated rates of complete cytogenetic response:
– Imatinib: 76.2% (95% CI: 72.5 to 79.9)
– Interferon alfa + low-dose cytarabine: 14.5% (95% CI: 10.5 to 18.5)
(P<0.001)

The authors concluded that ” In terms of hematologic and cytogenetic responses, tolerability, and the likelihood of progression to accelerated-phase or blast-crisis CML, imatinib was superior to interferon alfa plus low-dose cytarabine as first-line therapy in newly diagnosed chronic-phase CML.“

Citation: _{O’Brien SG, Guilhot F, Larson RA, Gathmann I, Baccarani M, Cervantes F, Cornelissen JJ, Fischer T, Hochhaus A, Hughes T, Lechner K, Nielsen JL, Rousselot P, Reiffers J, Saglio G, Shepherd J, Simonsson B, Gratwohl A, Goldman JM, Kantarjian H, Taylor K, Verhoef G, Bolton AE, Capdeville R, Druker BJ; IRIS Investigators. Imatinib compared with interferon and low-dose cytarabine for newly diagnosed chronic-phase chronic myeloid leukemia. N Engl J Med. 2003 Mar 13;348(11):994-1004. doi: 10.1056/NEJMoa022457. PMID: 12637609.}

Ibrutinib-Rituximab for CLL

Article Name: Ibrutinib–Rituximab or Chemoimmunotherapy for Chronic Lymphocytic Leukemia

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1817073

Journal and year of publication: NEJM, 2019

Trial Design: Randomized controlled trial

Population: 529 patients
Key inclusion criteria:
– Previously untreated patients with CLL or the small lymphocytic lymphoma (SLL) subtype of CLL
– 70 years of age or younger
– No previous use of glucocorticoids for autoimmune complications that have developed since the initial diagnosis of CLL
Key exclusion criteria:
– Patients with chromosome 17p13 deletion

Intervention Studied: Ibrutinib and rituximab for six cycles (after a single cycle of ibrutinib alone), followed by ibrutinib until disease progression

Control: 6 cycles of chemoimmunotherapy with fludarabine, cyclophosphamide, and rituximab

Outcomes:
– Progression-free survival at 3 years: Ibrutinib–rituximab: 89.4% vs chemoimmunotherapy: 72.9% (P<0.001)
– Overall survival at 3 years: Ibrutinib–rituximab: 98.8% vs chemoimmunotherapy: 91.5% (P<0.001)

The authors concluded that “The ibrutinib–rituximab regimen resulted in progression-free survival and overall survival that were superior to those with a standard chemoimmunotherapy regimen among patients 70 years of age or younger with previously untreated CLL.“

Citation: _{Shanafelt TD, Wang XV, Kay NE, Hanson CA, O’Brien S, Barrientos J, Jelinek DF, Braggio E, Leis JF, Zhang CC, Coutre SE, Barr PM, Cashen AF, Mato AR, Singh AK, Mullane MP, Little RF, Erba H, Stone RM, Litzow M, Tallman M. Ibrutinib-Rituximab or Chemoimmunotherapy for Chronic Lymphocytic Leukemia. N Engl J Med. 2019 Aug 1;381(5):432-443. doi: 10.1056/NEJMoa1817073. PMID: 31365801; PMCID: PMC6908306.}

How Long trial: Antibiotics for febrile neutropenia

Article Name: Optimisation of empirical antimicrobial therapy in patients with haematological malignancies and febrile neutropenia (How Long study): an open-label, randomised, controlled phase 4 trial

URL: https://www.thelancet.com/journals/lanhae/article/PIIS2352-3026(17)30211-9/fulltext

Journal and year of publication: The Lancet Hematology, 2017

Trial Design: Randomized controlled trial

Population: 157 patients
Key inclusion criteria:
– Receiving treatment for haematological malignancies or undergoing haemopoietic stemcell transplantation
– high-risk febrile neutropenia (defined as expected neutropenia of ≤0·5×10⁹ cells per L for ≥7 days)
Key exclusion criteria:
– Patients with an aetiological diagnosis of the fever were excluded
– Patients receiving antimicrobial therapy for any reason before onset of fever were also excluded

Intervention Studied: Antipseudomonal β-lactam drug as monotherapy (ceftazidime or cefepime, meropenem or imipenem, or piperacillin-tazobactam) – withdrawn after 72 h or more of apyrexia plus clinical recovery

Control: Combination therapy (with an aminoglycoside, fluoroquinolone, or glycopeptide) – withdrawn when the neutrophil count was also 0·5 × 10⁹ cells per L or higher

Outcomes:
– The mean number of EAT-free days (empirical antimicrobial therapy): Experimental group: 16.1 vs Control group: 13.6 (p=0.026)
– Severe events: Experimental group: 18 vs Control group: 38
– Deaths: Experimental group: 1 death vs Control group: 3 deaths

The authors concluded that “In high-risk patients with haematological malignancies and febrile neutropenia, EAT can be discontinued after 72 h of apyrexia and clinical recovery irrespective of their neutrophil count. This clinical approach reduces unnecessary exposure to antimicrobials and it is safe.“

Citation: _{Aguilar-Guisado M, Espigado I, Martín-Peña A, Gudiol C, Royo-Cebrecos C, Falantes J, Vázquez-López L, Montero MI, Rosso-Fernández C, de la Luz Martino M, Parody R, González-Campos J, Garzón-López S, Calderón-Cabrera C, Barba P, Rodríguez N, Rovira M, Montero-Mateos E, Carratalá J, Pérez-Simón JA, Cisneros JM. Optimisation of empirical antimicrobial therapy in patients with haematological malignancies and febrile neutropenia (How Long study): an open-label, randomised, controlled phase 4 trial. Lancet Haematol. 2017 Dec;4(12):e573-e583. doi: 10.1016/S2352-3026(17)30211-9. Epub 2017 Nov 15. PMID: 29153975.}

Lymphoma

ABVD chemotherapy for Hodgkin’s Lymphoma

Article Name: Chemotherapy of Advanced Hodgkin’s Disease with MOPP, ABVD, or MOPP Alternating with ABVD

URL: https://www.nejm.org/doi/full/10.1056/NEJM199211193272102

Journal and year of publication: NEJM, 1992

Trial Design: Randomized controlled trial

Population: 157 patients
Key inclusion criteria:
– Biopsy-proved Hodgkin’s disease
– Previously untreated and in clinical and pathological Stage IIIAd, IIIB, IVA or IVB
Key exclusion criteria:
– Not clear per manuscript

Intervention Studied:
1) MOPP (mechlorethamine, vincristine, procarbazine, and prednisone)
2) MOPP alternating with ABVD
3) ABVD (doxorubicin, bleomycin, vinblastine, and dacarbazine)

Control: See above

Outcomes:
– Overall (Complete) response rate:
MOPP: 67% vs MOPP – ABVD: 83% vs ABVD: 82%
(P = 0.006 for the comparison of MOPP with the other two regimens)
– Overall survival (at five years):
MOPP: 66% vs MOPP – ABVD: 75% vs ABVD: 73%
(P = 0.28 for the comparison of MOPP with the doxorubicin regimens)
– More severe toxic effects on bone marrow with MOPP (vs ABVD) and more reductions in prescribed dose in MOPP

The authors concluded that “In this trial, ABVD therapy for 6 to 8 months was as effective as 12 months of MOPP alternating with ABVD, and both were superior to MOPP alone in the treatment of advanced Hodgkin’s disease. ABVD was less myelotoxic than MOPP or ABVD alternating with MOPP.“

Citation: _{Canellos GP, Anderson JR, Propert KJ, Nissen N, Cooper MR, Henderson ES, Green MR, Gottlieb A, Peterson BA. Chemotherapy of advanced Hodgkin’s disease with MOPP, ABVD, or MOPP alternating with ABVD. N Engl J Med. 1992 Nov 19;327(21):1478-84. doi: 10.1056/NEJM199211193272102. PMID: 1383821.}

ECHELON-1 trial: Brentuximab for Hodgkin’s Lymphoma

Article Name: Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin’s Lymphoma

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1708984

Journal and year of publication: NEJM, 2018

Trial Design: Randomized controlled trial

Population: 1,334 patients
Key inclusion criteria:
– Histologically confirmed advanced classic Hodgkin’s lymphoma (Ann Arbor stage III or IV)
– Not been previously treated with systemic chemotherapy or radiotherapy
Key exclusion criteria:
– Nodular lymphocyte-predominant Hodgkin’s lymphoma
– Peripheral sensory or motor neuropathy
– Known cerebral or meningeal disease

Intervention Studied: brentuximab vedotin, doxorubicin, vinblastine, dacarbazine (A+AVD)

Control: doxorubicin, bleomycin,vinblastine, dacarbazine (ABVD)

Outcomes:
– 2-year modified progression-free survival rate: A+AVD: 82.1% vs ABVD: 77.2% (P=0.04)
– Deaths: A+AVD: 28 vs ABVD: 39 (P=0.20)

The authors concluded that “A+AVD had superior efficacy to ABVD in the treatment of patients with advanced-stage Hodgkin’s lymphoma, with a 4.9 percentage-point lower combined risk of progression, death, or noncomplete response and use of subsequent anticancer therapy at 2 years.“

Citation: _{Connors JM, Jurczak W, Straus DJ, Ansell SM, Kim WS, Gallamini A, Younes A, Alekseev S, Illés Á, Picardi M, Lech-Maranda E, Oki Y, Feldman T, Smolewski P, Savage KJ, Bartlett NL, Walewski J, Chen R, Ramchandren R, Zinzani PL, Cunningham D, Rosta A, Josephson NC, Song E, Sachs J, Liu R, Jolin HA, Huebner D, Radford J; ECHELON-1 Study Group. Brentuximab Vedotin with Chemotherapy for Stage III or IV Hodgkin’s Lymphoma. N Engl J Med. 2018 Jan 25;378(4):331-344. doi: 10.1056/NEJMoa1708984. Epub 2017 Dec 10. Erratum in: N Engl J Med. 2018 Mar 1;378(9):878. PMID: 29224502; PMCID: PMC5819601.}

R-CHOP for non-Hodgkin’s Lymphoma

Article Name: CHOP Chemotherapy plus Rituximab Compared with CHOP Alone in Elderly Patients with Diffuse Large-B-Cell Lymphoma

URL: https://www.nejm.org/doi/full/10.1056/nejmoa011795

Journal and year of publication: NEJM, 2002

Trial Design: Randomized controlled trial

Population: 398 patients
Key inclusion criteria:
– Untreated diffuse large-B-cell lymphoma of stage II, III, or IV disease
Key exclusion criteria:
– T-cell lymphoma
– History of indolent lymphoma
– CNS involvement

Intervention Studied: CHOP + rituximab

Control: CHOP alone

Outcomes:
– Rate of complete response: CHOP + rituximab: 76% vs CHOP: 63% (P=0.005)
– Event-free survival and overall survival (median follow up of 2 years):
Significantly higher CHOP + rituximab
For event-free survival: P<0.001 For overall survival P=0.007

The authors concluded that “The addition of rituximab to the CHOP regimen increases the complete-response rate and prolongs event-free and overall survival in elderly patients with diffuse large-B-cell lymphoma, without a clinically significant increase in toxicity.“

Citation: _{Coiffier B, Lepage E, Briere J, Herbrecht R, Tilly H, Bouabdallah R, Morel P, Van Den Neste E, Salles G, Gaulard P, Reyes F, Lederlin P, Gisselbrecht C. CHOP chemotherapy plus rituximab compared with CHOP alone in elderly patients with diffuse large-B-cell lymphoma. N Engl J Med. 2002 Jan 24;346(4):235-42. doi: 10.1056/NEJMoa011795. PMID: 11807147.}

Plasma Cell Disorders

APEX trial: Bortezomib for Multiple Myeloma

Article Name: Bortezomib or High-Dose Dexamethasone for Relapsed Multiple Myeloma

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa043445

Journal and year of publication: NEJM, 2005

Trial Design: Randomized controlled trial

Population: 669 patients
Key inclusion criteria:
– Measurable progressive multiple myeloma after one to three previous treatments
Key exclusion criteria:
– Had a disease that was refractory to high-dose dexamethasone
– Grade 2 peripheral neuropathy

Intervention Studied: Bortezomib

Control: High-dose dexamethasone

Outcomes:
– Combined complete and partial response rates: Bortezomib: 38% vs Dexamethasone: 18% (P<0.001)
– Median time to progression: Bortezomib: 189 days vs Dexamethasone: 106 days
Hazard ratio: 0.55 (P<0.001)
– One-year survival rate: Bortezomib: 80% vs Dexamethasone: 66% (P=0.003)

The authors concluded that “Bortezomib is superior to high-dose dexamethasone for the treatment of patients with multiple myeloma who have had a relapse after one to three previous therapies.“

Citation: _{Richardson PG, Sonneveld P, Schuster MW, Irwin D, Stadtmauer EA, Facon T, Harousseau JL, Ben-Yehuda D, Lonial S, Goldschmidt H, Reece D, San-Miguel JF, Bladé J, Boccadoro M, Cavenagh J, Dalton WS, Boral AL, Esseltine DL, Porter JB, Schenkein D, Anderson KC; Assessment of Proteasome Inhibition for Extending Remissions (APEX) Investigators. Bortezomib or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med. 2005 Jun 16;352(24):2487-98. doi: 10.1056/NEJMoa043445. PMID: 15958804.}

Lenalidomide for Multiple Myeloma

Article Name: Lenalidomide plus Dexamethasone for Relapsed or Refractory Multiple Myeloma

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa070594

Journal and year of publication: NEJM, 2007

Trial Design: Randomized, placebo controlled trial

Population: 351 patients
Key inclusion criteria:
– Multiple myeloma, had been treated with at least one previous antimyeloma regimen
Key exclusion criteria:
– Disease progression during previous therapy containing high-dose dexamethasone

Intervention Studied: Lenalidomide + Dexamethasone

Control: Placebo + Dexamethasone

Outcomes:
– Complete or partial response rates: Lenalidomide group: 60.2% vs Placebo group: 24.0% (P<0.001)
– Overall survival: Significantly improved in the lenalidomide group (Hazard ratio for death: 0.66, P=0.03)

The authors concluded that “Lenalidomide plus dexamethasone is more effective than high-dose dexamethasone alone in relapsed or refractory multiple myeloma.“

Citation: _{Dimopoulos M, Spencer A, Attal M, Prince HM, Harousseau JL, Dmoszynska A, San Miguel J, Hellmann A, Facon T, Foà R, Corso A, Masliak Z, Olesnyckyj M, Yu Z, Patin J, Zeldis JB, Knight RD; Multiple Myeloma (010) Study Investigators. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 2007 Nov 22;357(21):2123-32. doi: 10.1056/NEJMoa070594. Erratum in: N Engl J Med. 2009 Jul 30;361(5):544. PMID: 18032762.}

Stem cell transplantation + RVD for Multiple Myeloma

Article Name: Triplet Therapy, Transplantation, and Maintenance until Progression in Myeloma

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa2204925

Journal and year of publication: NEJM, 2022

Trial Design: Randomized controlled trial

Population: 722 patients
Key inclusion criteria:
– Newly diagnosed myeloma
Key exclusion criteria:
– Previous use of systemic therapy for myeloma
– Central nervous system involvement
– Inadequate hematologic, hepatic, renal, or cardiac function

Intervention Studied: RVD alone (lenalidomide, bortezomib, and dexamethasone)

Control: RVD + autologous stem-cell transplantation (ASCT)

Outcomes:
– Events of disease progression or death (at a median follow-up of 76.0 months):
Risk was 53% higher in the RVD-alone group . Hazard ratio: 1.53 (95% CI: 1.23 to 1.91), P<0.001
– Treatment-related adverse events occurrence (grade 3 or higher): RVD-alone group: 78.2% of patients vs Transplantation group: 94.2% of patients

The authors concluded that “Among adults with multiple myeloma, RVD plus ASCT was associated with longer progression-free survival than RVD alone. No overall survival benefit was observed.”

Citation: _{Richardson PG, Jacobus SJ, Weller EA, Hassoun H, Lonial S, Raje NS, Medvedova E, McCarthy PL, Libby EN, Voorhees PM, Orlowski RZ, Anderson LD Jr, Zonder JA, Milner CP, Gasparetto C, Agha ME, Khan AM, Hurd DD, Gowin K, Kamble RT, Jagannath S, Nathwani N, Alsina M, Cornell RF, Hashmi H, Campagnaro EL, Andreescu AC, Gentile T, Liedtke M, Godby KN, Cohen AD, Openshaw TH, Pasquini MC, Giralt SA, Kaufman JL, Yee AJ, Scott E, Torka P, Foley A, Fulciniti M, Hebert K, Samur MK, Masone K, Maglio ME, Zeytoonjian AA, Nadeem O, Schlossman RL, Laubach JP, Paba-Prada C, Ghobrial IM, Perrot A, Moreau P, Avet-Loiseau H, Attal M, Anderson KC, Munshi NC; DETERMINATION Investigators. Triplet Therapy, Transplantation, and Maintenance until Progression in Myeloma. N Engl J Med. 2022 Jul 14;387(2):132-147. doi: 10.1056/NEJMoa2204925. Epub 2022 Jun 5. PMID: 35660812.}

Prognosis of MGUS

Article Name: Long-Term Follow-up of Monoclonal Gammopathy of Undetermined Significance

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1709974

Journal and year of publication: NEJM, 2018

Trial Design: Retrospective cohort study

Population: 1,384 patients
Key inclusion criteria:
– Persons with MGUS
– M protein concentration of 3 g/dL or less
– 10% or fewer plasma cells in the bone marrow (if assessed)
Key exclusion criteria:
– Light-chain MGUS were not included

Outcomes:
– Primary endpoint (progression to multiple myeloma or another plasma-cell or lymphoid disorder): MGUS progression was 6.5 times the rate in the control population (95% CI: 5.5 to 7.7)
– Risk of progression without accounting for death due to competing causes:
At 10 years: 10%; at 20 years: 18%; at 30 years: 28%; at 35 years: 36%
– Median survival: MGUS: 8.1 years vs control population: 12.4 years (P<0.001)

The authors concluded that “Lenalidomide plus dexamethasone is more effective than high-dose dexamethasone alone in relapsed or refractory multiple myeloma.“

Citation: _{Kyle RA, Larson DR, Therneau TM, Dispenzieri A, Kumar S, Cerhan JR, Rajkumar SV. Long-Term Follow-up of Monoclonal Gammopathy of Undetermined Significance. N Engl J Med. 2018 Jan 18;378(3):241-249. doi: 10.1056/NEJMoa1709974. PMID: 29342381; PMCID: PMC5852672.}

Other hematologic disorders

Peripheral blood stem cells for marrow transplant

Article Name: Peripheral-Blood Stem Cells versus Bone Marrow from Unrelated Donors

URL: https://www.nejm.org/doi/full/10.1056/NEJMoa1203517

Journal and year of publication: NEJM, 2012

Trial Design: Randomized controlled trial

Population: 551 patients
Key inclusion criteria:
– Less than 66 years of age
– Planning to undergo transplantation for acute leukemia, myelodysplasia, chronic myeloid or myelomonocytic leukemia, or myelofibrosis
Key exclusion criteria:
– Donor-specific anti-HLA antibodies
– Prior allogeneic or autologous transplantation
– HIV infection

Intervention Studied: Transplantation of peripheral-blood stem cells

Control: Bone marrow transplant from unrelated donors

Outcomes:
– Overall survival rate (at 2 years): Peripheral-blood group: 51% vs Bone marrow group: 46% (P=0.29)
– Incidence of graft failure: Peripheral-blood group: 3% vs Bone marrow group: 9% (P=0.002)
– Incidence of chronic GVHD (at 2 years): Peripheral-blood group: 53% vs Bone marrow group: 1% (P=0.01)

The authors concluded that “We did not detect significant survival differences between peripheral-blood stem-cell and bone marrow transplantation from unrelated donors. Exploratory analyses of secondary end points indicated that peripheral-blood stem cells may reduce the risk of graft failure, whereas bone marrow may reduce the risk of chronic GVHD.“

Citation: _{Anasetti C, Logan BR, Lee SJ, Waller EK, Weisdorf DJ, Wingard JR, Cutler CS, Westervelt P, Woolfrey A, Couban S, Ehninger G, Johnston L, Maziarz RT, Pulsipher MA, Porter DL, Mineishi S, McCarty JM, Khan SP, Anderlini P, Bensinger WI, Leitman SF, Rowley SD, Bredeson C, Carter SL, Horowitz MM, Confer DL; Blood and Marrow Transplant Clinical Trials Network. Peripheral-blood stem cells versus bone marrow from unrelated donors. N Engl J Med. 2012 Oct 18;367(16):1487-96. doi: 10.1056/NEJMoa1203517. PMID: 23075175; PMCID: PMC3816375.}

Lenalidomide for MDS

Article Name: Efficacy of Lenalidomide in Myelodysplastic Syndromes

URL: https://www.nejm.org/doi/full/10.1056/nejmoa041668

Journal and year of publication: NEJM, 2005

Trial Design: Single arm clinical trial

Population: 43 patients
Key inclusion criteria:
– Histologically confirmed diagnosis of a primary myelodysplastic syndrome AND
– Symptomatic anemia OR Transfusion-dependent anemia
Key exclusion criteria:
– Severe neutropenia
– Severe thrombocytopenia
– Treatment-related myelodysplastic syndromes

Intervention Studied: Lenalidomide

Control: N/a

Outcomes:
– Response: 24 patients had a response, 20 had sustained independence from transfusion
– Adverse Events: Neutropenia: 65%; Thrombocytopenia: 74%; 58% of patients needed interruption or dose reduction of treatment

The authors concluded that “Lenalidomide has hematologic activity in patients with low-risk myelodysplastic syndromes who have no response to erythropoietin or who are unlikely to benefit from conventional therapy.“

Citation: _{List A, Kurtin S, Roe DJ, Buresh A, Mahadevan D, Fuchs D, Rimsza L, Heaton R, Knight R, Zeldis JB. Efficacy of lenalidomide in myelodysplastic syndromes. N Engl J Med. 2005 Feb 10;352(6):549-57. doi: 10.1056/NEJMoa041668. PMID: 15703420.}

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Benign Hematology

Leukemia

Lymphoma

Plasma Cell Disorders

Other hematologic disorders

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