Autologous Stem Cell Transplantation In Multiple Myeloma

Background. Multiple myeloma (MM) is the second most common hematologic malignancy after lymphomas In Finland: the annual incidence of MM is approximately 200. For three decades the median survival remained at 3 to 4 years from diagnosis until high-dose melphalan treatment supported by autologous stem cell transplantation (ASCT) became the standard of care for newly diagnosed MM since the mid 1990’s and the median survival increased to 5 – 6 years. This study focuses on three important aspects of ASCT, namely 1) stem cell mobilization, 2) single vs. double ASCT as initial treatment, and 3) the role of minimal residual disease (MRD) for longterm outcome. Aim. The aim of this series of studies was to evaluate the outcomes of MM patients and the ASCT procedure at the Turku University Central Hospital, Finland. First, we tried to identify which factors predict unsuccessful mobilization of autologous stem cells. Second, we compared the use of short-acting granulocyte-colony stimulating factor (GCSF) with long-acting G-CSF as mobilization agents. Third, one and two successive ASCTs were compared in 100 patients with MM. Fourth, for patients in complete response (CR) after stem cell transplantation (SCT), patient-specific probes for quantitative allele-specific oligonucleotide polymerase-chain reaction (qASO-PCR) measurements were designed to evaluate MRD and its importance for long-term outcome. Results. The quantity of previous chemotherapy and previous interferon use were significant pre-mobilization factors that predicted mobilization failure, together with some factors related to mobilization therapy itself, such as duration and degree of cytopenias and occurrence of sepsis. Short-acting and long-acting G-CSF combined with chemotherapy were comparable as stem cells mobilizers. The progression free (PFS) and overall survival (OS) tended to be longer after double ASCT than after single ASCT with a median follow-up time of 4 years, but this difference disappeared as the follow-up time increased. qASO-PCR was a good and sensitive divider of the CR patients into two prognostic groups: MRD low/negative (≤ 0.01%) and MRD high (>0.01%) groups with a significant difference in PFS and suggestively also in OS. Conclusions. When the factors prediciting a poor outcome of stem cell mobilization prevail, it is possible to identify those patients who need specific efforts to maximize the mobilization efficacy. Long-acting pegfilgrastim is a practical and effective alternative to short-acting filgrastim for mobilization therapy. There is no need to perform double ASCT on all eligible patients. MRD assessment with qASO-PCR is a sensitive method for evaluation of the depth of the CR response and can be used to predict long-term outcome after ACST.Siirretty Doriast

Luovuttajan lymfosyytti-infuusiot allogeenisen kantasolujen siirron jälkihoidossa

JOHDANTO. Allogeenisen kantasolujen siirron (ASCT) jälkihoidossa luovuttajan lymfosyytti-infuusio (DLI) on mahdollinen hoitokeino pahanlaatuisen veritaudin relapsin ehkäisemiseksi tai hoitamiseksi. Tutkimuksessa selvitettiin DLI-hoidon tehoa Tyksin kantasolujensiirtoyksikössä.AINEISTO. Tyksissä vuosina 2009-2019 allogeenisen kantasolujen siirron jälkeen DLI:n sai 46 potilasta. Lymfosyytti-infuusioita annettiin ennakoivasti, kliinisen taudin hoidoksi tai profylaktisesti suuren relapsiriskin pienentämiseksi.TULOKSET. Ennakoivan hoidon saaneiden elinikä ja taudin etenemättömyysaika olivat merkitsevästi pidemmät kuin kliinisen taudin tai profylaktisen hoidon saaneiden. DLI-hoidon merkittävin riski on käänteishyljintä. Yli puolelle tutkimuksen potilaista ei ilmaantunut akuuttia tai kroonista käänteishyljintäreaktiota, mutta toisaalta yksi potilas kuoli akuuttiin ja yksi krooniseen käänteishyljintäreaktioon.PÄÄTELMÄT. DLI on keino lisätä siirron jälkeistä graft-versus-leukemia-vaikutusta. Sen hyöty on suurin ennakoivana hoitona vähäisen tautimäärän hoidossa. DLI-hoidon tehoon ja turvallisuuteen voidaan vaikuttaa sopivilla annoksilla ja liitännäishoidoilla.</p

Monimuotoinen myelooma

Teema : Hematologiset syövät. English summaryPeer reviewe

Early CD8+-recovery independently predicts low probability of disease relapse but also associates with severe GVHD after allogeneic HSCT

In this single-center study we retrospectively evaluated the impact of early reconstitution of different lymphocyte subsets on patient outcomes after allogeneic hematopoietic stem cell transplantation (allo-HSCT). We found that CD8+ T-cell counts exceeding 50x106/l as early as on day 28 post-transplantation correlated significantly with decreased relapse risk, with three-year relapse rates of 17.0% and 55.6% (P = 0.002), but were also associated with severe acute and chronic GVHD. Incidence of grade III-IV acute GVHD was 30.5% for those with early CD8+T-cell recovery compared to 2.1% for those with lower CD8+ T-cell counts on day 28 post-transplant (HR = 20.24, P = 0.004). Early CD8+ T-cell reconstitution did not, however, affect the overall survival. Multivariate analysis showed that slow CD8+ T-cell reconstitution was strongly associated with increased risk of relapse (HR = 3.44, P = 0.026). A weaker correlation was found between CD4+ reconstitution and relapse-risk, but there was no such association with CD19+ B-cells or NK-cells. In conclusion, the early CD8+ T-cell recovery on day 28 post-transplant is associated with the lower risk of relapse but also predicts the impending severe GVHD, and thus could be useful in guiding timely treatment decisions.</p

Miten turvataan myelooman yhdenvertainen hoito tulevaisuudessa?

Vertaisarvioitu.• Myelooman vuosittainen ilmaantuvuus on pysynyt vakaana, mutta kehittyneiden hoitojen ansiosta potilaiden elinikä pitenee. Siksi hoidossa olevien potilaiden määrä kasvaa. • Kliinisen hematologian erikoislääkärien määrän huomattava vaje voi vaarantaa hoidon yhdenvertaisen toteutumisen. • Hoidon kustannukset kasvavat pääasiassa lääkekustannusten nousun vuoksi. Lääkekustannuksia pyritään hallitsemaan erilaisilla riskinjako- sopimuksilla. • Kliiniset lääketutkimukset tarjoavat arvokasta varhaisvaiheen käyttö- kokemusta ja konkreettista säästöä sairaaloiden lääkebudjetteihin. Niiden toteuttaminen sujuvasti rinnakkain rutiinihoidon kanssa tulisi mahdollistaa.Peer reviewe

Miten turvataan myelooman yhdenvertainen hoito tulevaisuudessa?

Vertaisarvioitu.• Myelooman vuosittainen ilmaantuvuus on pysynyt vakaana, mutta kehittyneiden hoitojen ansiosta potilaiden elinikä pitenee. Siksi hoidossa olevien potilaiden määrä kasvaa. • Kliinisen hematologian erikoislääkärien määrän huomattava vaje voi vaarantaa hoidon yhdenvertaisen toteutumisen. • Hoidon kustannukset kasvavat pääasiassa lääkekustannusten nousun vuoksi. Lääkekustannuksia pyritään hallitsemaan erilaisilla riskinjako- sopimuksilla. • Kliiniset lääketutkimukset tarjoavat arvokasta varhaisvaiheen käyttö- kokemusta ja konkreettista säästöä sairaaloiden lääkebudjetteihin. Niiden toteuttaminen sujuvasti rinnakkain rutiinihoidon kanssa tulisi mahdollistaa.Peer reviewe

Miten turvataan myelooman yhdenvertainen hoito tulevaisuudessa?

Myelooman vuosittainen ilmaantuvuus on pysynyt vakaana, mutta ­kehittyneiden hoitojen ansiosta potilaiden elinikä pitenee. Siksi hoidossa olevien potilaiden määrä kasvaa.Kliinisen hematologian erikoislääkärien määrän huomattava vaje voi vaarantaa hoidon yhdenvertaisen toteutumisen.Hoidon kustannukset kasvavat pääasiassa lääkekustannusten nousun vuoksi. Lääkekustannuksia pyritään hallitsemaan erilaisilla riskinjako-­sopimuksilla.Kliiniset lääketutkimukset tarjoavat arvokasta varhaisvaiheen käyttö­kokemusta ja konkreettista säästöä sairaaloiden lääkebudjetteihin. Niiden toteuttaminen sujuvasti rinnakkain rutiinihoidon kanssa tulisi mahdollistaa.</p

Cost analysis of a randomized stem cell mobilization study in multiple myeloma

Upfront autologous stem cell transplantation (ASCT) is the standard therapy for younger multiple myeloma (MM) patients. MM patients usually undergo stem cell mobilization with cyclophosphamide (CY) followed by granulocyte colony-stimulating factor (G-CSF), or with G-CSF alone. A limited number of randomized studies are available comparing costs of different mobilization strategies. Eighty transplant-eligible patients aged up to 70 years with untreated MM were included in this prospective study. The patients were treated with RVD induction for three 21-day cycles and randomized 1: 1 at inclusion into one of the two mobilization arms CY 2 g/m(2) + G-CSF [arm A] vs. G-CSF alone [arm B]. Plerixafor was given according to a specific algorithm if needed. Sixty-nine patients who received mobilization followed by blood graft collection were included in the cost analysis. The median total costs of the mobilization phase were significantly higher in arm A than in arm B (3855 (sic) vs. 772 (sic), pPeer reviewe

Meta-Analysis of Genome-Wide Association and Gene Expression Studies Implicates Donor T Cell Function and Cytokine Pathways in Acute GvHD

Graft-vs.-host disease (GvHD) is a major complication after allogeneic hematopoietic stem cell transplantation that causes mortality and severe morbidity. Genetic disparities in human leukocyte antigens between the recipient and donor are known contributors to the risk of the disease. However, the overall impact of genetic component is complex, and consistent findings across different populations and studies remain sparse. To gain a comprehensive understanding of the genes responsible for GvHD, we combined genome-wide association studies (GWAS) from two distinct populations with previously published gene expression studies on GvHD in a single gene-level meta-analysis. We hypothesized that genes driving GvHD should be associated in both data modalities and therefore could be detected more readily through their combined effects in the integrated analysis rather than in separate analyses. The meta-analysis yielded a total of 51 acute GvHD-associated genes (false detection rate [FDR]Peer reviewe