The whole bone-mineral axis moves on revumenib: phosphate in 51%, alkaline phosphatase in 33%, calcium in 15%
also called revumenib phosphate · menin inhibitor mineral metabolism · REVUFORJ hyperphosphataemia
Revumenib's most common laboratory abnormality is a rise in blood phosphate, seen in half of patients, alongside changes in calcium and a bone enzyme. Taken together these are the numbers a doctor would look at to check whether bone and mineral handling is being disturbed.
The same thing, for a scientist
Raised phosphate is the single most frequent laboratory abnormality on the REVUFORJ label (51%), ahead of transaminases; phosphate also fell in 25%, alkaline phosphatase rose in 33%, corrected calcium rose in 15% and intact PTH rose in 34% [E1]. Read as a set rather than as isolated rows, this is a coherent perturbation of the PTH-phosphate-calcium-bone axis, and it sits beside a juvenile-rat finding of irreversible femoral growth-plate closure that caused FDA to require monitoring of bone growth in children [E1]. The class comparison is informative and cuts both ways: the ziftomenib label's laboratory table contains no phosphate, calcium or PTH row at all, while alkaline phosphatase rose in 41% - a higher rate than revumenib's [E2].
The pattern, and why the set matters more than any row
Any one of these could be noise in a sick population. The reason to treat them together is that they are the classical panel for a single physiological axis, and four of the five moved 1:
- phosphate up 51%, down 25% (i.e. 76% of patients had phosphate move in one direction or the other)
- intact PTH up 34%
- alkaline phosphatase up 33%
- corrected calcium up 15%
PTH's principal physiological job is to raise calcium and lower phosphate. A rise in PTH alongside a rise in phosphate in half of patients is internally inconsistent with a simple primary-parathyroid story and more consistent with renal phosphate retention driving secondary PTH elevation - which is the mundane explanation and probably the right one for most patients. Creatinine rose in 38% on the same label.
Alkaline phosphatase is the interesting one because it is the bone-turnover marker in this list. It rose in 33% on revumenib and in 41% on ziftomenib 12, and the revumenib nonclinical package contains an irreversible growth-plate finding in juvenile rats 1. Raised ALP plus a growth-plate finding plus a paediatric indication is a combination that deserves a bone-specific ALP and a bone age, neither of which appears in any protocol.
The ziftomenib comparison, which is genuinely double-edged
The KOMZIFTI label's Table 4 of selected laboratory abnormalities lists AST 53%, potassium decreased 52%, albumin decreased 51%, ALT 50%, sodium decreased 49%, creatinine increased 45%, alkaline phosphatase increased 41%, bilirubin increased 27% and potassium increased 26%. There is no phosphate row, no calcium row and no parathyroid hormone row 2.
Two readings, and the data do not choose between them:
- Reassuring reading. A second menin inhibitor, in 110 patients, did not produce a phosphate or calcium abnormality large enough to reach the label's reporting threshold. If the effect were a mechanism-based class effect it should have appeared.
- Uninformative reading. Intact PTH is not a routine chemistry parameter. If it was not on the KOMET-001 laboratory schedule, its absence from the table means nothing at all. The revumenib programme reported PTH because it measured PTH.
Which reading is right is answerable by reading the KOMET-001 protocol's laboratory schedule, and until someone does, the class question is open. The honest statement is that one menin inhibitor reports a parathyroid signal and the other does not report parathyroid data.
| kind | toxicity |
|---|---|
| severity | laboratory abnormalities, largely grade 1-2; no grade 3-4 hypercalcaemia reported |
| mitigation | add bone-specific alkaline phosphatase, 25-OH vitamin D, ionised calcium and a baseline plus annual bone age to paediatric menin-inhibitor protocols; all are inexpensive and most use blood already drawn |
| open class question | whether intact PTH was on the KOMET-001 laboratory schedule at all |
affects
[ "drug-revumenib", "drug-ziftomenib" ]
revumenib rates PCT — the numbers behind the chart
{
"phosphate_increased": 51,
"phosphate_decreased": 25,
"alkaline_phosphatase_increased": 33,
"corrected_calcium_increased": 15,
"intact_pth_increased": 34,
"creatinine_increased": 38
}ziftomenib rates PCT
{
"alkaline_phosphatase_increased": 41,
"creatinine_increased": 45,
"phosphate": null,
"calcium": null,
"intact_pth": null
}- The counter-argument at full strength: a rise in phosphate together with a rise in PTH is physiologically backwards for a primary parathyroid lesion, and is exactly what renal impairment produces. Creatinine rose in 38% of the same patients. The mundane explanation covers most of the data.
- The second approved menin inhibitor's label shows no phosphate, calcium or PTH abnormality, which is real counter-evidence to a class effect even though it may only reflect a different laboratory panel.
- Chasing a mineral-axis signal could generate unnecessary imaging and parathyroid referrals in children whose real problem is relapsed leukaemia; the right response is to add three cheap assays to existing protocols, not to change treatment.
- Was intact PTH on the KOMET-001 or cAMeLot-1 laboratory schedule? Until this is known the ziftomenib label's silence cannot be used as evidence either way, and it is answerable by reading two protocols.
- Is the raised alkaline phosphatase on both menin inhibitors hepatic or bone in origin? A bone-specific ALP fraction on stored samples would answer it.
- Does phosphate rise before or after PTH in individual patients? The temporal order distinguishes renal phosphate retention driving PTH from a primary parathyroid effect, and the data to answer it already exist in both sponsors' databases.
- E1established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
On the REVUFORJ label, phosphate increased is the most frequent laboratory abnormality at 51%, with phosphate decreased in 25%, alkaline phosphatase increased in 33%, corrected calcium increased in 15%, intact PTH increased in 34% and creatinine increased in 38%; separately, in 6-7 week old rats treated for 13 weeks an irreversible increase in femur growth plate closure was observed at approximately 2 times the human exposure, prompting the instruction to monitor bone growth and development in paediatric patients.
REVUFORJ (revumenib) tablets, for oral use - US full prescribing information (NDA 218944) · Syndax Pharmaceuticals / US FDA · DailyMed / Drugs@FDA (NDA 218944) 2025What this evidence cannot show
Read verbatim from DailyMed on 2026-09-18 (Table 8 and section 8.4 Animal Data). Single-arm, uncontrolled; no background rate for an equivalently pretreated leukaemia population is available, and hyperphosphataemia is common with renal impairment and with tumour lysis. The label gives no grade 3-4 rates for phosphate, PTH or ALP, and no bone-specific ALP.
Evidence that argues against this (1)
- Phosphate moves in BOTH directions in the same population - increased in 51% and decreased in 25% - which argues against a single clean drug effect on phosphate handling. Bidirectional laboratory abnormality at high frequency is the signature of a population with tumour lysis, variable renal function, transfusion and nutritional swings, all of which are present here. The entry should not read 51% as a mineral-axis mechanism without a baseline-adjusted, timing-resolved analysis. FDA Drugs@FDA 2024
- E2established confidence 5 of 5: Multiple independent lines of evidence; treated as settled in the field.database
The KOMZIFTI (ziftomenib) label's table of selected new or worsening laboratory abnormalities (denominator 108-110) lists AST increased 53%, potassium decreased 52%, albumin decreased 51%, ALT increased 50%, sodium decreased 49%, creatinine increased 45%, alkaline phosphatase increased 41%, bilirubin increased 27% and potassium increased 26%, and contains no phosphate, calcium or parathyroid hormone row.
KOMZIFTI (ziftomenib) capsules, for oral use - US full prescribing information · Kura Oncology / US FDA · DailyMed / Drugs@FDA 2025What this evidence cannot show
Read verbatim from the DailyMed full prescribing information on 2026-09-18. Crucially, the label does not state which analytes were on the KOMET-001 laboratory schedule, so an absent row may mean 'measured and below threshold' or 'never measured'. The two trials also differ in population (ziftomenib label population is 112 adults with NPM1-mutant AML; no paediatric patients) and in dose intensity, so a direct comparison of rates is not valid.
Evidence that argues against this (1)
- The absence of a parathyroid row on the ziftomenib label is the best available published counter-evidence to a class effect, and it should be weighed at full strength. If a second menin inhibitor in over a hundred patients produces no reportable calcium or phosphate abnormality, the simplest explanation of the revumenib pattern is renal and phosphate physiology in sick patients rather than menin biology. Kura Oncology / US FDA 2025
- related to →Intact PTH rises in 34% of patients on revumenib, and hyperparathyroidism is on the label
the PTH rise sits inside a wider mineral-axis disturbance that has a mundane renal explanation
the ziftomenib label reports no phosphate, calcium or PTH row - counter-evidence to a class effect, or a different laboratory panel
Biochemical mismatch: the mouse Men1 parathyroid phenotype is hypercalcaemia WITH hypophosphataemia, whereas revumenib raises phosphate in 51%; the human pattern resembles renal secondary hyperparathyroidism more than primary parathyroid autonomy