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[gerry]

News | December 29, 2016 | Chronic Myeloid Leukemia, Hematologic Malignancies, Leukemia & Lymphoma

By Dave Levitan

Patients with chronic myeloid leukemia (CML) who have higher proportions of natural killer (NK) immune cells, and more mature NK cells, fare better when discontinuing therapy with imatinib, according to a new study.

"Recent reports suggest that approximately 40% of CML patients who have achieved optimal therapy responses (deep molecular remission) can discontinue imatinib treatment without recurrence of detectable BRC-ABL1transcripts," wrote study authors led by Satu Mustjoki, MD, PhD, of Helsinki University Hospital Comprehensive Cancer Center in Finland. Residual leukemic cells can still be detected in blood samples, however, and a complete cure would "either need to eradicate or alternatively regain the immune control of the remaining leukemic cells."

The new study aimed to elucidate the role of the immune system in successful discontinuation of tyrosine kinase inhibitor (TKI) therapy in CML patients. It was a prospective analysis, including 132 chronic-phase CML patients treated with imatinib (107 patients), dasatinib (15 patients), or nilotinib (9 patients) for at least 3 years prior to the study; only the imatinib-treated patients were included in this analysis. All patients had sustained deep molecular response for at least 1 year; these were compared with 48 healthy volunteer control patients. The results of the trial were published online ahead of print in Leukemia.

Among patients who had a relative proportion of NK cells that was higher than the median, the 6-month relapse-free survival rate was 73%; among those lower than the median, that rate was 51%, for a hazard ratio (HR) of 2.17 (P = .02). The researchers determined an optimal cutoff for the NK cell proportion; the difference between "high" and "low" NK groups was even more pronounced at 6 months, at 70% vs 43% for an HR of 2.35 (P = .009).

This association was not seen with regard to relative or absolute numbers of T and B cells, or with total monocyte, lymphocyte, or leucocyte counts.

Patients who relapsed within the first 6 months after imatinib discontinuation had a lower relative proportion of NK cells, compared with non-relapsing patients (12.8% vs 17.1%), but this was not the case among late-relapsing patients.

The researchers used detailed immunophenotyping to better understand the NK cells' role. CD56bright NK cells are considered immature; as they mature, they lose some CD56 receptors and become CD56dim NK cells. Patients with a higher than median number of the immature version had a trend toward poorer relapse-free survival; this became significant when an optimal cutoff was determined, with decrease relapse-free survival seen in patients with a lower proportion of mature NK cells.

"We hypothesize that an increased amount of mature NK cells may be capable of both directly killing the tumor cells and potentiating adaptive immune responses against leukemia, thereby maintaining remission after imatinib discontinuation," the authors wrote. "As NK modulating agents ... have already entered in the early clinical trials in other hematological malignancies, their testing in CML is warranted for increasing the proportion of patients who can discontinue imatinib treatment."

[kat73]

Wow!  I read the whole article - absolutely fascinating.  This really is very exciting.  Do you suppose we can ask our oncs to test for our NK cells?  I sure would like to know if I've got lots of the fancy, mature kind with the special tailfins.  And, looking to the future, is this something that could be introduced from the outside, like a pill or an injection or transfusion?  Or do we have to grow our own?

[gerry]

Increased proportion of mature NK cells is associated with successful imatinib discontinuation in chronic myeloid leukemia Abstract

 

Abstract

Recent studies suggest that a proportion of chronic myeloid leukemia (CML) patients in deep molecular remission can discontinue the tyrosine kinase inhibitor (TKI) treatment without disease relapse. In this multi-center, prospective clinical trial (EURO-SKI, NCT01596114) we analyzed the function and phenotype of T and NK cells and their relation to successful TKI cessation. Lymphocyte subclasses were measured from 100 imatinib-treated patients at baseline and 1 month after the discontinuation, and functional characterization of NK and T cells was done from 45 patients. The proportion of NK cells was associated with the molecular relapse-free survival as patients with higher than median NK-cell percentage at the time of drug discontinuation had better probability to stay in remission. Similar association was not found with T or B cells or their subsets. In non-relapsing patients the NK-cell phenotype was mature, whereas patients with more naïve CD56^bright NK cells had decreased relapse-free survival. In addition, the TNF-α/IFN-γ cytokine secretion by NK cells correlated with the successful drug discontinuation. Our results highlight the role of NK cells in sustaining remission and strengthen the status of CML as an immunogenic tumor warranting novel clinical trials with immunomodulating agents.

 

Introduction

Chronic myeloid leukemia (CML) is a myeloproliferative cancer that seeds from a translocation (9;22) in the hematopoietic stem cell resulting in constitutively active BCR-ABL1 oncokinase. The inhibition of BCR-ABL1 with tyrosine kinase inhibitors (TKIs) has revolutionized the prognosis of CML.^{1, 2, 3, 4} The first TKI developed for the treatment of CML (imatinib) has now been in use for 15 years. However, TKIs are not considered to be curative as the majority of patients still have residual disease left after years on treatment.⁵ Even though therapy responses to TKIs are generally very good, the life-long medication creates physiological, mental and economical burden.⁶ In addition, the prevalence of CML is increasing due to the improved treatment results.⁷ Therefore, there is a significant need to find novel treatment strategies aiming for cure. Recent reports suggest that approximately 40% of CML patients who have achieved optimal therapy response (deep molecular remission) can discontinue imatinib treatment without recurrence of detectable BCR-ABL1 transcripts.^8, 9, 10 Similarly dasatinib discontinuation after sustained deep molecular response has shown to be successful in 50% of patients.¹¹ However, with more sensitive DNA-based methods residual leukemic cells can still be detected in blood samples from these patients.⁹ To be able to cure CML we would either need to eradicate or alternatively regain the immune control of the remaining leukemic cells.

We set up an immunological study within the framework of the pan-European TKI stopping study (EURO-SKI) in order to understand whether the immune system has a role in the successful discontinuation of the TKI treatment. Here we show that a high proportion of mature NK cells is related to the successful imatinib discontinuation highlighting the importance of NK cells when considering future treatment strategies.

 

Paste this link into your browser to get it to work properly for the remainder of the article  http://www.nature.co...u2016104a.html 

[Trey]

It is likely a piece of the puzzle but I doubt it is the entire story.  The data is not entirely convincing:

 

"Patients who relapsed within the first 6 months after imatinib discontinuation had a lower relative proportion of NK cells, compared with non-relapsing patients (12.8% vs 17.1%), but this was not the case among late-relapsing patients."

 

First, the 13% vs 17% is not very convincing statistically speaking since that is not a large difference.  Also, the study used relative cell proportions (percentages of neutrophils vs lymphocytes, etc) which doesn't mean much as we with leukemia know -- we only trust absolute cell counts such as ANC, etc, but this study does not deal with absolute NK numbers.  Secondly, the late relapse issue does not make any sense if the NK cells are enabling cessation success.  But the study just offers that little tidbit and then ignores it as "oh well".  Also, the numbers of Sprycel and Tasigna patients are too low to offer any useful data.

Edited by Trey, 29 December 2016 - 09:20 PM.

[gerry]

Maybe you just don't talk too much about the things that don't meet your theory. lol

[Trey]

Right.  If a person has low neutrophils then their NK numbers will be "relatively" high even if at normal levels.  Researchers "forget" we have low myeloid cell counts due partly to the TKIs themselves, which makes relative cell counts unreliable as indicators, especially if they are lymphoid counts compared to myeloid counts. 

 

I think there is some piece of truth in there somewhere, I just don't like this researcher's methodology.  And then there is that "not true for late relapse" thingy, which means late relapsing patients had relatively high NK numbers but still relapsed.  Not impressed with that little tidbit. 

Edited by Trey, 30 December 2016 - 10:35 AM.

[Trey]

No way to directly increase NK cells.  They are produced as the body thinks they are needed. 

 

The NK cells only attack leukemic cells if they are told to attack by dendritic helper cells.  If the dendritic cells do not activate the NK cells against leukemic cells, the NK will leave it alone.  So it may be more about getting the dendritic (helper) cells to recognize CML cells as targets, then tell the NK cells to attack them.  Some think the NK cells can learn over time if prodded enough by the dendritic cells, but the knowledge of such things is limited.

 

https://www.scienced...40206075307.htm

 

http://www.nature.co.../cmi20131a.html