Bevacizumab therapy for POEMS syndrome

Abstract

The definition of resistance is in the eye of the beholderWe appreciate the observations made by Duyster et al that relate to sensitivity of clinical alleles of FIP1L1-PDGFRA associated with hypereosinophilic syndrome to inhibition with AMN107. Our cellular and biochemical experiments are generally in agreement in showing that the FIP1L1-PDGFRA T674I imatinib mesylate resistance allele is also highly resistant to inhibition with AMN107, with more than 100-fold higher IC 50 than for FIP1L1-PDGFRA. 1 There are several potential explanations for why we observed modest effects on cell growth and tyrosine phosphorylation content of FIP1L1-PDGFRA T674I transformed cells at 1 M AMN107 compared with the results annotated here, but at most there may be a several fold difference in our estimates of cellular IC 50 .Several other points merit consideration. First, we have previously reported that PKC412 is a potent inhibitor of the FIP1L1-PDGFRA T674I allele, 2 with an IC 50 of approximately 100 nM vs approximately 376 nM reported here for AMN107. From this perspective, PKC412 may be as appropriate an alternative for FIP1L1-PDGFRA patients who develop resistance due to acquired T674I as AMN107. In this context, it is also worth noting the importance of including controls for nonspecific or off-target toxicities for tyrosine kinase inhibitors such as AMN107 or PKC412, as they are selective rather than specific. Parental Ba/F3 cells would have been 1 such control in these experiments, but in our view the most compelling controls for nonspecific toxicity or off-target effects are kinase mutations that are selected for resistance to the kinase inhibitor in question. For example, we generated a PKC412 resistance allele in the context of FIP1L1-PDGFRA with an N659D substitution. 2 We observed that cells stably transduced with FIP1L1-PDGFRA N659D were resistant to the effects of PKC412, establishing FIP1L1-PDGFRA as the critical target for cellular cytotoxicity mediated by PKC412 in this context, rather than off-target or nonspecific effects. Indeed, the finding of the FIP1L1-PDGFRA T674I imatinib mesylate resistance mutation in a patient with clinically resistant HES provides the most compelling evidence that FIP1L1-PDGFRA causes HES and is the target of imatinib mesylate. It would be useful to have comparable controls for AMN107 as well, although it seems most likely that the cytotoxic effects of AMN107 treatment are attributable to inhibition of the T674I allele.Second, we completely agree that relative resistance of FIP1L1-PDGFRA T674I to AMN107 does not exclude potential clinical applicability and efficacy if adequate plasma concentrations can be achieved. It may be of value to consider either AMN107 or PKC412 as second-line agents. For the time being, the point is moot, as neither of these drugs is Food and Drug Administration (FDA) approved for any indication, but could potentially be accessed through compassionate use mechanisms.It may be, as suggested by the authors, that FIP1L1-PDGFRA T674I will emerge as an important...

POEMS syndrome: Update on diagnosis, risk‐stratification, and management

“…Two other patients using it as "salvage" improved, but relapsed and died despite continued therapy, normal VEGF at 3.5 and 5.5 years. Six other cases of use with or after other alkylator based therapy yielded one death and 4 patients with improvement [22][23][24][25][26][27]176] High-dose chemotherapy with peripheral blood stem cell transplant can also be quite effective, but selection basis may confound these reports. Case series suggest 100% of patients achieve at least some neurologic improvement [18,54,87,140,[149][150][151][152][153][154][155][156][181][182][183][184][185].…”

“…Although an anti-VEGF strategy is appealing, the results with bevacizumab have been mixed [22][23][24][25][26][27]. Five patients who had also received either radiation or alkylator during and/or predating the bevacizumab had benefit [24][25][26]187], including three who had improvement, but was then consolidated with high-dose chemotherapy with autologous stem cell transplant [25,187].…”

“…Five patients who had also received either radiation or alkylator during and/or predating the bevacizumab had benefit [24][25][26]187], including three who had improvement, but was then consolidated with high-dose chemotherapy with autologous stem cell transplant [25,187]. Three patients receiving bevacizumab died [21,22,27].…”

“…To date, VEGF is the cytokine that correlates best with disease activity [11][12][13][14][15][16][17][18][19][20], although it may not be the driving force of the disease based on the mixed results seen with anti-VEGF therapy [21][22][23][24][25][26][27][28]. VEGF is known to target endothelial cells, induce a rapid and reversible increase in vascular permeability, and be important in angiogenesis.…”

Intracranial hemangiomas in a patient with POEMS syndrome

“…Nevertheless, a still elevated VEGF suggests an active disease, also reflected by the appearance of hemangiomas and intracranial hypertension. In consideration of different clinical reports focussing on experimental therapeutic strategies such as anti-VEGF antibodies (bevacizumab, with contradictory results, [2,11,13]), further -6 -investigation concerning the role of VEGF in this complex disease is needed and will provide valuable information towards a better understanding of its pathophysiology. …”