We analyzed 563 adults ≥ 60 years of age with newly diagnosed de novo AML (excluding acute promyelocytic leukemia) whose pretreatment bone marrow (BM) or blood samples underwent HTS analysis [20]. Patients who underwent allogeneic transplantation in first complete remission (CR) were excluded as per required for the eligibility of the CALGB/Alliance protocols. HTS analysis was not performed in all patients with CBF AML because this subtype of AML represents an already recognized, curable entity and is at the top of the LLS prioritization schema. The patients were treated on CALGB trials which included a range of time from 1984 to 2013 with all receiving standard intensive treatment (Table (Table11 and further details in the Additional file 1) [2130]. As patients on the RATIFY study (CALBG 10603) were eligible only from ages 18 to 59, there are not any patients included in our analysis who received midostaurin as part of their chemotherapy regimen. All patients were considered for outcome analyses including those who suffered early death (ED), defined as death within 30 days after starting therapy irrespective of cause. Cytogenetic analyses of pretreatment BM and/or blood samples were performed by institutional CALGB/Alliance-approved laboratories. The results were confirmed by central karyotype review [31]. Patients provided written informed consent to participate in companion protocols CALGB 8461 (cytogenetic studies), CALGB 9665 (leukemia tissue bank), and CALGB 20,202 (molecular studies), which involved collection of pretreatment BM and blood samples. Treatment protocols were in accordance with the Declaration of Helsinki and approved by the institutional review boards at each center, and all patients provided written informed consent.

CALGB Protocol Chemotherapy Regimens

8321

(n = 3)

Randomized to:

*DNR Days 1–3 (45 mg/m2/day < 60 years or 30 mg/m2/day ≥ 60 years)

Ara-C Days 1–7 (100 mg/m2/day)

VERSUS

*DNR Days 1–3 (45 mg/m2/day < 60 years or 30 mg/m2/day ≥ 60 years)

Ara-C Days 1–7 (200 mg/m2/day CIV)

6-TG Days 1–10 (100 mg/m2 PO q12 hour × 10 doses)

DNR Day 57 (45 mg/m2/day < 60 years or 30 mg/m2/day ≥ 60 years)

Ara-C Days 1–10, 29–38, 57–66, 84–92 (per Induction assignment BID q12 hours × 10 doses)

VCR Days 29 and 84 (2 mg/m2 (max 2 mg))

Prednisone Days 29–33, 84–88 (40 mg/m2/day × 5 days)

8525

(n = 41)

*DNR Days 1–3 (45 mg/m2/day < 60 years or 30 mg/m2/day ≥ 60 years)

Ara-C Days 1–7 (200 mg/m2/day CIV)

Randomized to 4 Cycles:

Ara-C Days 1–5 (100 mg/m2/day CIV)

VERSUS

Days 1–5 (400 mg/m2/day CIV)

VERSUS

Days 1,3,5 (3gm/m2 every 12 h for 6 total doses)

4 Cycles:

DNR Day 1 (45 mg/m2/day)

Ara-C Days 1–5 (100 mg/m2 q12 hours SQ)

8721

(n = 1)

Ara-C Days 1,2,8,9 (3gm/m2 every 12 h – 8 doses total)

L-asparaginase Days 2, 9 (6000 IU/m2)

Allowed to repeat on Days 15,16 for both agents if no response

2 Cycles:

Ara-C Days 1,2,8,9 (3gm/m2 every 12 h – 8 doses total)

L-asparaginase Days 2, 9 (6000 IU/m2)

8821

(n = 1)

*DNR Days 1–3 (45 mg/m2/day)

Ara-C Days 1–7 (200 mg/m2/day CIV)

Randomized to Course 1 followed by Course 2 VERSUS Course 2 followed by Course 1:

Course 1: (1 cycle)

Mitoxantrone Days 1–3 (12 mg/m2/day)

Diaziquone Days 1–5 (28 mg/m2/day CIV)

Course 2: (1 cycle)

Etoposide Day 1 (2400 mg/m2 CIV)

Cytoxan Days 3–6 (50 mg/kg/day)

8923

(n = 38)

Randomized to:

*DNR Days 1–3 (45 mg/m2/day)

Ara-C Days 1–7

(200 mg/m2/day CIV)

G-CSF Starting Day 8

VERSUS

*DNR Days 1–3 (45 mg/m2/day)

Ara-C Days 1–7 (200 mg/m2/day CIV)

Placebo Starting Day 8

Course 1: (up to 4 cycles)

Ara-C Days 1–5 (100 mg/m2 CIV)

Course 2: (up to 2 cycles)

Ara-C Days 1–3 (500 mg/m2 q 12 h × 6 doses)

Mitoxantrone Days 1–3 (5 mg/m2 × 6 doses)

9420

(n = 18)

Randomized to:

*DNR Days 1–3 (dose-escalated to MTD 40 mg/m2/day)

Etoposide Days 1–3

(dose-escalated to MTD 60 mg/m2/day)

Ara-C Days 1–7 (100 mg/m2/day CIV)

PSC-833 1.5gm/kg IV Days 1–3 for 2 h, followed by 10 mg/kg/day CIV for 72 h

VERSUS

*DNR Days 1–3 (dose-escalated to MTD 40 mg/m2/day)

Etoposide Days 1–3

(dose-escalated to MTD 60 mg/m2/day)

Ara-C Days 1–7 (100 mg/m2/day CIV)

No PSC-833

Randomized to 1 Cycle:

DNR Days 1–2 (30 mg/m2/day)

Etoposide Days 1–2 (60 mg/m2/day)

Ara-C Days 1–5 (100 mg/m2/day CIV)

PSC-833 1.5gm/kg IV Days 1–3 for 2 h, followed by 10 mg/kg/day CIV for 72 h

VERSUS

DNR Days 1–2 (30 mg/m2/day)

Etoposide Days 1–2 (60 mg/m2/day)

Ara-C Days 1–5 (100 mg/m2/day CIV)

No PSC-833 (based on initial induction assignment)

Randomized to:

R-IL2 (0.9 × 106 SQ Days 1–14, 19–28, 33–42, 47–56, 61–70, 75–90 and 12 × 106 Day 15–17,29–31, 43–45, 57–59, 71–73)

VERSUS

No maintenance

9720

(n = 233)

Randomized to:

*DNR Days 1–3 (40 mg/m2/day)

Etoposide Days 1–3 (60 mg/m2/day)

Ara-C Days 1–7

(100 mg/m2/day CIV)

PSC-833 1.5gm/kg IV Days 1–3 for 2 h, followed by 10 mg/kg/day CIV for 72 h

VERSUS

*DNR Days 1–3 (40 mg/m2/day)

Etoposide Days 1–3 (60 mg/m2/day)

Ara-C Days 1–7 (100 mg/m2/day CIV)

No PSC-833

Randomized to 1 Cycle:

DNR Days 1–2 (30 mg/m2/day)

Etoposide Days 1–2 (60 mg/m2/day)

Ara-C Days 1–5 (100 mg/m2/day CIV)

PSC-833 Days 1–3 (1.5gm/kg IV for 2 h, followed by 10 mg/kg/day CIV for 72 h)

VERSUS

DNR Days 1–2 (30 mg/m2/day)

Etoposide Days 1–2 (60 mg/m2/day)

Ara-C Days 1–5 (100 mg/m2/day CIV)

No PSC-833 (based on initial induction assignment)

Randomized to:

R-IL2 (0.9 × 106 SQ Days 1–14, 19–28, 33–42, 47–56, 61–70, 75–90 and 12 × 106 Day 15–17,29–31, 43–45, 57–59, 71–73)

VERSUS

No maintenance

Randomized to:

*DNR Days 4–6 (60 mg/m2/day)

Ara-C Days 4–10 (100 mg/m2/day CIV)

Oblimersen Days 1–10 (7 mg/kg/day CIV) VERSUS

*DNR Days 4–6 (60 mg/m2/day)

Ara-C Days 4–10 (100 mg/m2/day CIV)

No Oblimersen

Randomized to 2 Cycles:

Ara-C Days 4–8 (2000 mg/m2/daily)

Oblimersen Days 1–8 (7 mg/kg/day CIV)

VERSUS

Ara-C Days 4–8 (2000 mg/m2/daily)

No Oblimersen

10502

(n = 35)

*DNR Days 1–3 (60 mg/m2/day)

Ara-C Days 1–7 (100 mg/m2/day CIV)

Bortezomib 1.3 mg/m2 Days 1,4,8,11

2 Cycles:

Ara-C Days 1–5 (2gm/m2/day)

Bortezomib per dose escalation Days 1,4,8,11

10801

(n = 13)

*DNR Days 1–3 (60 mg/m2/day)

Ara-C Days 1–7 (200 mg/m2/day CIV)

Dasatinib Days 8–21 (100 mg PO Daily)

4 cycles:

Ara-C Days 1,3,5 (3 gm/m2 q12 hours < 60 years and 1gm/m2 q12 hours ≥ 60 years)

Dasatinib Days 1–26 (100 mg PO daily)

11001

(n = 11)

*DNR Days 1–3 (60 mg/m2/day)

Ara-C Days 1–7 (100 mg/m2/day CIV)

Sorafenib Days 1–7 (400 mg daily)

2 Cycles:

Ara-C Days 1–5 (2 gm/m2/day)

Sorafenib Days 1–28 (400 mg PO BID)

Ara-C, cytarabine; BID, twice daily; CIV, continuous intravenous infusion; DNR, daunorubicin; gm, gram; h, hour; IU, international units; kg, kilogram; m, meter; mg, milligram; MTD, maximum tolerated dose; n, number; n/a, not applicable; PO, orally; q12, every 12; SQ, subcutaneous; VCR, vincristine; 6-TG, 6-Thioguanine

*Reinduction therapy allowed

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