Two studies on INF vs Fibrosis, cellularity

[EPguy]

A few 2017 studies I came across, likely some members have seen and posted before, here are some notes.

Mostly more vagueness, but covers some of the marrow discussions we’ve recently had.

-Items of note:

-CMR was correlated to reduced cellularity while PMR may not be.

-BM-CR or -PR helped prevent MF progression.

ncbi.nlm.nih.gov/pmc/articl...

BM-CR= bone marrow complete response

BM-PR= marrow partial reponse

CMR= Complete molecular response (Jak2 etc)

PMR-Partial Molec Resp.

Complete marrow response allows for up to grade 1 fibrosis, I would have expected only grade 0 qualifies:

<<Given the fact that achievements of BM-CR allows for grade 1 fibrosis in the BM…>>

BM response, partial or complete, prevented progression, but CHR also can help, from Table 2 in the report:

<<Progression to overt MF and AML occurred in 5 patients (9%; 4 MF and 1 AML), and none of these patients had a BM response. One patient who progressed to AML was holding PEG-IFN-α-2a for 6 months before transformation for unrelated reason (knee replacement surgery). None of the 4 patients were in CHR at the time of progression to MF, and all have discontinued the therapy afterwards>>

Complete Allele response helped cellularity:

<<Similarly, patients with PV who have achieved CMR have experienced significant reduction in bone marrow cellularity>>

Marrow response went from partial to complete after stopping INF:

<<Remarkably, both achieved a BM-CR after being off therapy for 32 and 36 months, and maintained their BM-CR for 30 and 24 months, still off therapy, respectively.>>

<<PEG-IFN-α-2a was capable to completely reverse BM fibrosis in up to 22% of patients, which is higher than previously observed by other investigators. BM responses were achieved after median time on therapy of 48 months, confirming the observation that a long treatment duration is necessary to achieve such a response>>

<<Importantly, none of the patients who had achieved BM-CR progressed to overt MF,…>> Repeat of above info, but above allowed for BM-PR also per Table 2.

More uncertainty, INF is still mysterious, but a plug for NextGen Sequencing:

<<Moreover, it also introduces a question about the definition of useful objective and clinically meaningful response in these patients, as simply relying on the hematologic parameters in a patient with no clinical signs of disease may not be accurate, especially after or during therapy with a biological agents such as interferon. Hopefully, with longer follow-up and better “response” assessment tools, e.g. deep genome sequencing, we will gain better insight into this dilemma.>>

<<The significance of these findings as well as the prognostic value of BM response in patients with PV and ET remains incompletely understood. Our findings further highlight the need for more elaborate approach in assessing biological effects of interferon-alfa in ET and PV, to help us understand the heterogeneity and dynamics of clinical, hematologic, molecular and morphologic responses and their significance during long-term therapy with PEG-IFN-α-2a.>>

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Another report from a different group:

This group included the older non-pegylated INF in the study, but did not break out the results between PEG and regular. With PEG considered to give better results this study may be expected to have inferior results. Also this study group was far smaller at n=15 with marrow data while the 1st study above had n=58.

With those limitations:

ncbi.nlm.nih.gov/pmc/articl...

Allele is not the end all:

<<Based on our findings, it may be premature to recommend PCR-based monitoring (for allele) of these patients as the sole criteria for treatment. In all patients with CMR, we observed progressive or persistent hypercellularity or fibrosis by marrow examination, suggesting to us a need for continued therapy in these patients.>> This conflicts with the 1st larger study.

<<Furthermore, in patients who achieved CHR and/or PHR with decrease in %V617F, we observed persistent erythroid and megakaryocytic hypercellularity and no change or progressive fibrosis.>>

Allele reduction is satisfying but don’t quit INF just because it gets lowered:

<<Our observations have unique implications for therapy. Our results question the use of JAK2V617F allele burden as the sole criterion for discontinuation of therapy. Inappropriate discontinuation of rIFNα therapy may prematurely abrogate the value of its treatment.>>

Does cellularity, fibrosis etc matter?

<<For the moment, the prognostic significance of failing to attain a morphological response (Marrow) in patients who have achieved a hematologic and/or molecular response remains unresolved. It is important to resolve these issues with longer follow up in a prospective trial, since premature discontinuation of rIFNα may allow the pathogenic mechanisms of the disease to progress unfettered.>>

There is the one actionable item here, getting a baseline BMB is a good idea:

Our findings add credence to recent World Health Organization criteria stressing the importance of the marrow biopsy at diagnosis, specifically recommended first by the Polycythemia Vera Study Group (PVSG).14 Whereas it may be argued that a baseline BM biopsy is not a necessary diagnostic procedure for patients with a significantly increased red cell count and a demonstrable JAK2V617F allele burden, a biopsy establishes initial degree of cellularity and fibrosis which should be used in clinical decision making during the course of the illness

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Interesting note, the 2nd study used either of interferon α-2b (rIFNα-2b) or pegylated rIFNα-2α (peg-rIFNα-2a) They offered no correlations to these differences however. But non-pegylated has been more troublesome, and maybe that affected their results. Also INFalpha-2a and -2b are different. I will post a bit on that later.

They missed an opportunity to compare them.

[Bluetop]

Thanks for all your work!

[Meatloaf9]

Hi ETguy, after reading, I am still trying to figure out if there is any direct relationship between allele burden and cellularity, or between cellularity and fibrosis, or between cellularity and progression. What is your take on these criteria. I think it is saying no direct relationship. Does INF decrease cellularity, I think elevated cellularity is a negative prognostic factor?

[EPguy in reply to Meatloaf9]

There is some info on these buried in there.

From above:

<<BM response, partial or complete, prevented progression, but CHR also can help, from Table 2 in the report:>>

and

<<Complete Allele response helped cellularity:...>>

with enough "if, ands or buts," this is some guidance.

My take is CMR can be quite useful, and BM-CR is really useful. CHR is good, esp for thrombotic events etc, but the progression connection seems to most benefit going thru MR and/or BM.

According to the top chart in:

healthunlocked.com/mpnvoice...

one may know of CMR by 24 months.