Long-term transfusion independence in del(5q) MDS patients who discontinue lenalidomide

Abstract

numbers of double-sorted HSC from Npm1 þ / þ and Npm1 þ /À mice (CD45.1 þ CD45.2 þ ) were transplanted into lethally irradiated C57BL/6 (CD45.2) recipients together with competitor cells (CD45.2). Short-term (2 months) and long-term (4 months) competitive repopulating capability was studied by monitoring peripheral blood donor chimerism of recipient mice by flow cytometry. Mice transplanted with Npm1 þ /À HSC exhibited markedly lower engraftment than the recipients of Npm1 þ / þ HSC as measured by total chimerism (threefold; Figure 2a, Po0.03). The percentage total and myeloid chimerism in individual transplanted mice did not differ significantly at 2 and 4 months (data not shown). We also quantified donor chimerism in the bone marrow of the recipient mice 4 months after transplantation (Figure 2b). Similar to the results in the peripheral blood, the competitive repopulating ability of the HSC from Npm1 þ /À mice was significantly reduced (8.5-fold; Figure 2b, Po0.02) in the bone marrow of the recipient mice. Although the engraftment potential of Npm1 þ /À HSC was reduced, we did not observe any effects on the composition of donor-derived mature hematopoietic cells in the peripheral blood of recipient mice (Supplementary Figure 5). Thus, the level of NPM1 expression has a direct effect on HSC repopulating ability in vivo, but has no effect on hematopoietic fate commitment.In summary, our Npm1 þ /À mouse model indicates that NPM1 has a role in maintaining HSC number and in preserving the functional integrity of these cells in the context of competitive transplantation. However, it does not appear to have a role in regulating HSC differentiation. Npm1 haploinsufficiency did not result in significant alterations in mature blood cell numbers or significant dysplasia in our mice. These results are at some variance with a previous report, in which Npm1 heterozygosity was associated with an MDS-like phenotype in older (6-10 months) mice. 4 We cannot completely exclude the possibility that the different techniques used to generate these mutant mice may explain the differences in our results; however, both models are associated with homozygous null embryonic lethality as well as decreased Npm1 mRNA (data not shown) and protein levels in Npm1 þ /À mice. Our study did use mice in which the targeted Npm1 allele was functionally eliminated by a single-gene trap event in the NPM1 locus between exons 7 and 8 (genetic background 129/SvEvBrd  C57BL/6J), whereas in the previous study exons 2-7 were replaced by green fluorescent protein cassette introducing the stop codon after exon 2 (genetic background 129/Sv  C57BL/6). Minor genetic variability between the two different substrains used in these studies (129/Sv vs 129/SvEvBrd) might also influence their respective phenotypes. 7 Although we have no definitive explanation for the difference in phenotypes, only our study directly assessed HSC function. We speculate that the increased number of HSC in Npm þ /À mice could be an important early step in myeloid pathogenesis, as thes...

Long-Term Response in a Patient with del(5q) Myelodysplastic Syndrome Who Discontinued Lenalidomide and Obtained a Good Response and Tolerance to Rechallenge

“…In November 2009, the patient had a cytogenetic relapse remaining transfusion independent; we, however, stopped lenalidomide and observed him. Subsequently the patient was rechallenged with lenalidomide and he responded to the reintroduction of lenalidomide intervention as other cases described by Giagounidis et al [9], achieving complete cytogenetic remission after 3 cycles and continuing this dosage until the sixth course (July 2011). We continued to modulate the dose of lenalidomide on the basis of FISH analysis (table 1); in our patient, the reappearance of 5q– was not equivalent to transfusion dependence and as in other patient series he remained transfusion-free, without being exposed for many months to any medication [9].…”

“…Long-term outcome data indicate that a cytogenetic response to lenalidomide therapy might offer a survival advantage, compared with cytogenetic nonresponders, and lenalidomide treatment does not increase AML progression risk, among lower-risk, transfusion-dependent MDS patients, but instead confers a possible benefit in red blood cell transfusion-dependent patients with del(5q) low- or intermediate-1-risk MDS [9, 11]. In our patient, after 5 cycles of standard treatment, we obtained complete hematological and cytogenetic remission; we then tapered off the dose of lenalidomide, and the patient remained transfusion independent and in complete hematological and cytogenetic remission for further 9 months (fig.…”

“…Consequences of the long-term effects of continuous immunomodulation with lenalidomide are unknown, and the question whether interruption of lenalidomide treatment is beneficial for patients in remission has never been formally addressed [9]. …”

8-year-sustained response in a patient with isolated del(5q) myelodysplastic syndrome undergoing continuous treatment with lenalidomide: a case report

“…The summary of product characteristics of lenalidomide recommends treatment of del(5q) MDS patients until relapse or transfusion dependence or progressive disease [15], but there has been speculation that continuous lenalidomide may lead to selective pressure on del(5q) stem cells, potentially inducing genomic instability and resulting in progression to acute leukemic transformation [16]. In a small patient series, drug discontinuation after having achieved complete cytogenetic remission was associated with prolonged responses [17] with patients who relapsed to transfusion dependence responding to reexposure of lenalidomide. A similar observation has been reported [18] in a patient with isolated del(5q) MDS who was treated with lenalidomide, achieved complete hematologic and cytogenetic remission and relapsed to transfusion dependence after a 14-month treatment interruption.…”

How we treat lower-risk myelodysplastic syndromes

“…On the other hand, drug discontinuation in patients who have achieved complete cytogenetic response may be associated with prolonged responses. 57 Although Food and Drug Administration approved LEN in lowerrisk MDS with del 5q, the European Medicines Agency raised concern over a potential risk of LEN to trigger AML progression in some lower-risk MDS with del 5q and requested additional analyses. In the absence of prospective randomized trials, 3 retrospective analyses comparing the long-term outcome of lower-risk MDS with del 5q treated with and without LEN found no excess risk of AML with lenalidomide.…”