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The Platelet Limbo: How Low Can You Go? Susan Montgomery Discussant: Dr. Terry Gernsheimer

The Platelet Limbo: How Low Can You Go? - Susan K. Montgomery

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Page 1: The Platelet Limbo: How Low Can You Go? - Susan K. Montgomery

The Platelet Limbo:How Low Can You Go?

Susan Montgomery

Discussant: Dr. Terry Gernsheimer

Page 2: The Platelet Limbo: How Low Can You Go? - Susan K. Montgomery

History: Lots and lots

Page 3: The Platelet Limbo: How Low Can You Go? - Susan K. Montgomery

Harker LA & Slichter SJ. New Engl J Med 1972;287:155-9

Mucosal Blood Loss and Platelet Count

History: Lots and lots

Page 4: The Platelet Limbo: How Low Can You Go? - Susan K. Montgomery

• K.D Heckman; J Clin Oncol, 15 (1997), pp. 1143–1149 (Acute Leukemia)

• H Wandt; Blood, 91 (1998), pp. 3601–3606• P Rebulla; N Engl J Med, 337 (1997), pp. 1870–

1875• M.S Zumberg; Biol Blood Marrow Transplant, 8

(2002), pp. 569–576

1970’s: favorable results for therapeutic approach to plttransfusions not relevant now given change in treatment strategies

A substantial number of studies showed safety of lowering platelet transfusion threshold from 20K to 10K in pts with AML or undergoing stem cell transplant.

History: Lots and lots

Page 5: The Platelet Limbo: How Low Can You Go? - Susan K. Montgomery

Prophylactic Platelet Transfusion Triggers: 10,000/l vs. 20,000/l in Acute Leukemia

10,000/ l 20,000/ l

Patients Major Hemorrhagic Patients Major Hemorrhagic(N) Bleeding Deaths (N) Bleeding Deaths

(%) (%) (%) (%)

Rebulla et al, 135 22 1 120 20 01997

Wandt et al, 58 18 0 47 17 01998

Heckman et al, 37 0 41 01997

Page 6: The Platelet Limbo: How Low Can You Go? - Susan K. Montgomery

• K.D Heckman; J Clin Oncol, 15 (1997), pp. 1143–1149 (Acute Leukemia)

• H Wandt; Blood, 91 (1998), pp. 3601–3606• P Rebulla; N Engl J Med, 337 (1997), pp. 1870–

1875• M.S Zumberg; Biol Blood Marrow Transplant, 8

(2002), pp. 569–576

1970’s: favorable results for therapeutic approach to plttransfusions not relevant now given change in treatment strategies

A substantial number of studies showed safety of lowering platelet transfusion threshold from 20K to 10K in pts with AML or undergoing stem cell transplant.

German group: 2 studies in mid 2000’s Small, single center studies showing safety of ppx vs

therapeutic plt transfusions in pts with AML or those undergoing stem cell transplant

History: Lots and lots

Page 7: The Platelet Limbo: How Low Can You Go? - Susan K. Montgomery

Therapeutic vs. prophylactic platelet transfusion

Lancet article, German study:

Therapeutic platelet transfusion versus routine prophylactic transfusion in patients with hematologic malignancies: an open-label, multicenter randomized study

Wandt, et al; Lancet Vol 380, Oct 13, 2012

Abstract at ASH

The effect of a no-prophylactic versus prophylactic platelet transfusion strategy on bleeding in patients with hematologic malignancies and severe thrombocytopenia (TOPPS trial)

Simon Stanworth; UK non-inferiority study

Page 8: The Platelet Limbo: How Low Can You Go? - Susan K. Montgomery

Lancet: Therapeutic vs. prophylactic platelet transfusion

German multi-center study b/w 2005-2010; n = 391 Patients had either any subtype of AML (group A) or

were undergoing autologous PBSCT (group B) Group A patients were undergoing

induction/consolidation at standard dosing: n = 190 Group B were underdoing standard high dose

chemotherapy for transplant: n = 201 60% for MM; 30% lymphoma; 10% AML

Exclusion criteria: Refractory to platelet transfusions

Previous major bleeding

Plasmatic coagulopathy

In group B: patients with pulmonary or cerebral lesions

Page 9: The Platelet Limbo: How Low Can You Go? - Susan K. Montgomery

Randomized within each group on a 1:1 basis to receive ppx plt transfusion for plt # <10 or a therapeutic transfusion at any sign of WHO gd 2 bleeding or higher

Platelets: pooled or apheresed, leukocyte reduced Ppx group were transfused one unit if plt count <10

Therapeutic group transfused with one unit at first, then additional units if the treating physician thought necessary

Petechiae or skin purpura of any size not considered clinically relevant and therefore not included

Retinal bleeding without visual impairment not included

Any new headache or neurologic symptoms prompted CT to assess for CNS hemorrhage

Page 10: The Platelet Limbo: How Low Can You Go? - Susan K. Montgomery

WHO bleeding scale

Page 11: The Platelet Limbo: How Low Can You Go? - Susan K. Montgomery

WHO bleeding scale

Page 12: The Platelet Limbo: How Low Can You Go? - Susan K. Montgomery

WORLD  HEALTH  ORGANIZATION  (WHO)Bleeding Grades

BleedingGrade Type of Bleeding

0 None

1 Petechiae, ecchymosis, occult blood, mild vaginal spotting

2 Gross hemorrhage not requiring RBC transfusion                   

epistaxis, hematuria, hematemesis

3 Hemorrhage requiring transfusion of ≥ 1 unit RBCs

4 Life‐threatening hemorrhage                                                            massive bleeding causing hemodynamic compromise bleeding into a vital organ

Page 13: The Platelet Limbo: How Low Can You Go? - Susan K. Montgomery

Primary outcome:

Number of platelet transfusions given during a standardized observation period of 14 days per patient

Secondary outcomes:

Clinically relevant bleeding

# of RBC transfusions required

Days with platelet count <20

Side effects of transfusions

Length of hospital stay

Survival

Page 14: The Platelet Limbo: How Low Can You Go? - Susan K. Montgomery

Results Primary endpoint: 33.5% less plt transfusions in the

therapeutic gp across Groups A & B (p = <0.0001).

Secondary Endpoints: no statistically significant difference b/w therapeutic and ppx groups, including overall survival

Exception: clinically relevant bleeding

Page 15: The Platelet Limbo: How Low Can You Go? - Susan K. Montgomery

Clinically relevant bleeding:

Risk of grade 2+ bleeding higher in therapeutic group in both groups A & B Group A: p = <0.0001

Group B: p = 0.0005

Group A: more grade 4 bleeding in therapeutic group vs the prophylactic group; 7% vs 2%, p = 0.0095

Group B: no evidence of grade 4 bleeding

Page 16: The Platelet Limbo: How Low Can You Go? - Susan K. Montgomery

Group A; AML Overall, bleeding

risk higher in AML group vs SCT gp 37% vs 18%,

p<0.0001

More grade 2 and 4 bld in therapeutic gp

13 gd 4 blds 11 controlled by

timely transfusions

7 w/plt >10

2 died of cerebral hemorrhage 1 with plt ~11;

pulm fungal infxn, ? Cerebral lesion

1 with plt >10; thrombocytopenia

Page 17: The Platelet Limbo: How Low Can You Go? - Susan K. Montgomery

Group B; transplant Overall, bleeding

risk higher in AML group vs SCT gp 37% vs 18%,

p<0.0001

No grade 4 bleeds

More grade 2 bleeding in therapeutic gp vs ppx gp

Page 18: The Platelet Limbo: How Low Can You Go? - Susan K. Montgomery

Take home for Lancet Article

Decreased # of plt transfusion in the therapeutic gp (by 1/3)

Increase risk of grade 2 or higher bleeding in therapeutic vs ppx platelet transfusion across AML and transplant pts

Grade 2 or higher bleeding was roughly 2x higher in the therapeutic vs the ppx approach

~93% of bleeds were only grade 2 bleeds, therefore Bleeding was tolerated

Most were controlled by timely platelet transfusions

Grade 4 bleeding only seen in the AML (group A) group, and of those, majority in therapeutic group

Conclusion: OK for therapeutic approach in stable transplant patients but should continue ppx approach for patients with AML undergoing induction or consolidative chemotherapy

Page 19: The Platelet Limbo: How Low Can You Go? - Susan K. Montgomery

TOPPS trial: UK non-inferiority study

The effect of a no-prophylactic versus prophylactic platelet transfusion strategy on bleeding in patients with hematologic malignancies and severe thrombocytopenia (TOPPS trial)

Primary outcome: proportion of patients with clinically relevant bleed, gd 2 or higher, up to 30days after randomization

No ppx: n = 301; ppx: n = 299; 70% of patients in each gp undergoing autologous SCT

Fewer plt transfusions in the no ppx group

Page 20: The Platelet Limbo: How Low Can You Go? - Susan K. Montgomery

TOPPS results

Grade 2-4 bleeding occurred in 50% of patients in the no-ppx groups vs 43% in the ppx group; p = 0.06

Negative trial: did not prove that a no-ppx approach is non-inferior to a ppx approach No-ppx gp had more days with gd 2 or high bleeding

and shorter time to first bleed 6/300 gd 3-4 blds in the no-ppx group vs 1/298 in ppx

group: not statistically significant Only 2 of 7 of these pts had a plt count <10

Both pts receiving induction chemotherapy for AML

Needs further subgroup analysis

Page 21: The Platelet Limbo: How Low Can You Go? - Susan K. Montgomery

Thank you

Dr. Terry Gernsheimer

Dr. Mazyar Shadman

Dr. Aaron Gerds