Hematology

Benign Hematology

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.
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.
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.
Article Name:  Cardiovascular Events and Intensity of Treatment in Polycythemia Vera
URL: yhttps://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.
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.
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.
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.
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)
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.
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.

Leukemia

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.
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.
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.
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.
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

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.
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.
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

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.
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.
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

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.
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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