Page 83 - Haematologica June

A novel regimen for relapsed/refractory adult acute myeloid leukemia
each one entered the study after failure of at least 2 con- ventional regimens. One patient had undergone prior allogeneic stem cell transplant and 2 patients had under- gone autologous transplant in CR1 (on study protocols). Two patients had secondary or therapy-related AML, 14 patients had abnormal karyotypes and 4 patients were found to have KMT2A PTD molecular subtype. Clinical as well as pre-treatment cytogenetic and molecular char- acteristics of enrolled patients are summarized in Tables 2 and 3.
Dose escalation and treatment
Six patients were treated at dose level 1 due to pro- longed myelosuppression in 2 patients requiring dose expansion. However, both patients achieved CR after tox- icity “cut-off” and the protocol was amended to allow fur- ther time for count recovery as well as G-CSF to hasten count recovery. Three patients were treated on dose levels 2 and 3; 5 patients were treated on dose level 4. No other DLTs were observed.
Toxicities
As this treatment approach was intensive, patients experienced universal pancytopenia and toxicities as expected in this poor risk cohort of patients. Treatment overall was well tolerated. Diarrhea, nausea, fatigue, febrile neutropenia and elevated alanine aminotransferase were the most common occurrences for all grade toxicities occurring in 41%, 29%, 29%, 35%, and 35% of patients respectively. With regards to Grade 3 or greater toxicities, febrile neutropenia and catheter-related infections were most common at 35% and 24% of patients and are com- mon complications that occur in this patient population. A summary of all Grade toxicities and Grade 3 or greater non-hematological toxicities possibly attributable to the treatment are listed in Table 4.
Clinical responses
The overall response rate was 35% (6/17 patients) as seen in Table 3. All 6 responses by IWG criteria were CR; 3 of these 6 patients had abnormal cytogenetics and all 3 achieved a cytogenetic CR (Patients 5, 7 and 9). The medi- an number of prior therapies for patients with CR was 2 (range 1-3). Response duration assessment is compro- mised due to 4 patients subsequently receiving allogeneic transplantation (Patients 2, 5, 7, and 9). However, all patients with CR on study except one (Patient 5) eventu- ally relapsed and succumbed to complications of their underlying disease including patients who underwent allogeneic transplantation.
Count recovery for the 6 patients who achieved CR was prolonged with average absolute neutrophil count (ANC) recovery of 45 days (range Day 39-55) and average platelet recovery of 52 days (range Day 34-67). Four of the 6 patients received G-CSF to aid in count recovery with 3 patients receiving this therapy on dose level 1 and 1 patient on dose level 2. No patients had a serious adverse event (SAE) felt related to prolonged count recovery. None of the patients who were considered treatment fail- ures received any G-CSF support.
Of the 4 patients known to have KMT2A PTD muta- tions, 2 patients responded achieving cytogenetic CRs. It is interesting to note one of the KMT2A PTD responders also had a TP53 mutation with a high variant allele fre- quency (VAF), but this response may not be due to the reg- imen examined, considering recent findings with a 10-day decitabine schedule in TP53 mutated AML patients.13 It is also of interest that 2 KMT2A PTD patients (1 responder and 1 non-responder) were associated with favorable karyotypes as this has not been commonly reported. It was difficult to make any other definitive conclusions about responders and non-responders with other concur- rent mutations with such a small number of patients.
Table 3. Patient molecular mutations and responses.
Responders
Patient 2
Patient 5
Patient 6
Patient 7
Patient 9
Patient 17 Non-Responders Patient 1
Patient 3 Patient 4 Patient 8 Patient 10 Patient 11 Patient 12 Patient 13 Patient 14 Patient 15
Patient 16
KMT2A PTD +
+
Other gene mutations (VAF) Best response
FLT3-TKD, PTPN11(0.3), U2AF1(0.23) CR
None CRc DDX41(0.5), ASXL1(0.19) CR None CRc TP53(0.53) CRc FLT3-ITD (heterozygous), NRAS(0.36) CR
NPM1(.54), FLT3-ITD (hemizygous), FLT3-TKD, TET2(0.47) None
NPM1(0.35), FLT3-ITD (heterozygous)
PTPN11(0.52), RUNX1(0.41), NRAS(0.2)
PTPN11(0.14), SF1(0.13)
NPM1(0.42), FLT3-ITD (hemizygous), WT1(0.64), SF3A1(0.49) IDH2(0.21), KRAS(0.19)
FLT3-ITD (heterozygous)
RUNX1(0.39)
None
TP53(0.5)
+ +
CR: morphologic Complete Remission; CRc: morphologic and cytogenetic Complete Remission;VAF: variant allele frequency.
haematologica | 2018; 103(6)
985