Quinine Improves Results of Intensive Chemotherapy (IC) in Myelodysplastic Syndromes (MDS) Expressing P-Glycoprotein (PGP)

Wattel, Éric; Solary, Éric; Hecquet, B; Caillot, Denis; Ifrah, Norbert; Brion, Annie; Milpied, Noël; Janvier, Maud; Guerci, Agnès; Rochant, H; Cordonnier, C.; Dreyfus, François; Veil, A.; Hoang-Ngoc, L.; Stoppa, A. M.; Gratecos, N; Sadoun, A.; Tilly, H; Brice, P.; Lioure, Bruno; Desablens, B; Pignon, B.; Abgrall, J.; Leporrier, M; Fenaux, Pierre

doi:10.1007/978-1-4615-4811-9_5

Cited by 28 publications

(26 citation statements)

References 36 publications

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“…101 Human growth hormone (GH) can sensitize the AML cell line U937 to TNF or anthracyclin-induced apoptosis via inhibition of NF-kB. 105 Similarly, erythropoietin 106 can sensitize U937 cells to daunorubicin-induced apoptosis. This effect involves an EPO-induced activation of JAK2 and stabilization of IkB.…”

Section: Therapeutic Strategies Targeting Nf-jbmentioning

confidence: 99%

Targeting NF-κB in hematologic malignancies

et al. 2006

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The transcription factor nuclear factor kappa B (NF-jB) can intervene in oncogenesis by virtue of its capacity to regulate the expression of a plethora of genes that modulate apoptosis, and cell survival as well as proliferation, inflammation, tumor metastasis and angiogenesis. Different reports demonstrate the intrinsic activation of NF-jB in lymphoid and myeloid malignancies, including preneoplastic conditions such as myelodysplastic syndromes, underscoring its implication in malignant transformation. Targeting intrinsic NF-jB activation, as well as its upstream and downstream regulators, may hence constitute an additional approach to the oncologist's armamentarium. Several small inhibitors of the NF-jB-activatory kinase IjB kinase, of the proteaseome, or of the DNA binding of NF-jB subunits are under intensive investigation. Currently used cytotoxic agents can induce NF-jB activation as an unwarranted side effect, which confers apoptosis suppression and hence resistance to these drugs. Thus, NF-jB inhibitory molecules may be clinically useful, either as single therapeutic agents or in combination with classical chemotherapeutic agents, for the treatment of hematological malignancies.

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Section: Therapeutic Strategies Targeting Nf-jbmentioning

confidence: 99%

Targeting NF-κB in hematologic malignancies

et al. 2006

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“…16 Recently, our two groups, the Groupe Ouest-Est d'étude des Leucémies aiguës myé-loïdes (Goelams group) and the Groupe Français des Myélo-dysplasies (French MDS group: GFM), found in a randomized study that modulation of mdr expression by quinine improved CR rates obtained with intensive chemotherapy in MDS patients expressing the mdr gene. 17 Intensive chemotherapy, in MDS and AML following MDS, also gives shorter CR duration than in de novo AML, and a very low proportion of long-term survivors (14% at 4 years in our experience) is observed. [1][2][3]7,8,[8][9][10][11][12][13][14] Therefore, in an attempt to improve long-term outcome, several groups have performed autologous stem cell transplantation, [18][19][20][21] either bone marrow (ABMT) or peripheral stem cell transplantation (APSCT), as consolidation treatment in MDS patients who achieved CR after intensive chemotherapy.…”

Section: Introductionmentioning

confidence: 77%

“…17 Fifty-seven patients (43.5%) achieved CR, including 47% of the patients who received quinine and 41% of the patients who did not receive quinine.…”

Section: Resultsmentioning

confidence: 98%

“…17 This trial had been approved by the ethical committee of Dijon (France) according to French law. Inclusion criteria were: (1) MDS, according to FAB criteria; (2) age р65 years; (3) marrow blasts у5%, ie refractory anemia with excess blasts (RAEB), RAEB in transformation (RAEB-T), chronic myelomonocytic leukemia (CMML, or MDS having progressed to AML (AML post MDS); (4) no previous chemotherapy; (5) absence of an HLA-identical sibling; (6) patient diagnosed in a center where PGP expression was assessable or adequate material was sent to a referral center; and (7) 3 , hemoglobin Ͼ10 g without transfusion requirement; (3) normalization of the karyotype if initially abnormal (at least 10 mitoses examined); (4) disappearance of major myelodysplastic features in the bone marrow (with the exception of mild dysplasia, as seen after chemotherapy).…”

Section: Methodsmentioning

confidence: 99%

“…In the largest reported study where 79 patients received ABMT, the treatment-related mortality was 9% and the 2 year disease-free survival (DFS) post ABMT was 34%. 21 In a study of intensive chemotherapy in MDS and AML post MDS, undertaken by the Goelams and GFM groups, 17 patients younger than 55 years who achieved CR and had no HLA-identical sibling were scheduled to receive autologous stem cell transplantation. We present here the results of this prospective study.…”

Section: Introductionmentioning

confidence: 99%

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A prospective study of autologous bone marrow or peripheral blood stem cell transplantation after intensive chemotherapy in myelodysplastic syndromes

Wattel¹,

Solary

Leleu³

et al. 1999

Leukemia

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We prospectively assessed autologous stem cell transplantation for consolidation treatment in a trial of intensive chemotherapy in high risk myelodysplastic syndromes (MDS). In this trial, patients aged 55 years or less with no HLA-identical sibling and achieving CR were scheduled to receive unmanipulated autologous bone marrow transplantation (ABMT) preceded by a consolidation chemotherapy course. Forty-two of the 83 patients aged 55 years or less included in the trial (51%) achieved CR. Three were allografted in CR. Twenty-four of the remaining 39 patients who achieved CR (62%) received ABMT (16 patients) or autologous peripheral blood stem cell transplantation (APSCT) (eight patients). Indeed, as bone marrow harvest was often insufficient, APSCT was subsequently proposed after mobilization by consolidation chemotherapy followed by G-CSF. The conditioning regimen combined cyclophosphamide and busulfan. ABMT and APSCT were performed 1-7 months (median 3) after CR achievement. Hematological reconstitution occurred in all patients and tended to be faster after APSCT than ABMT although not significantly. Three patients died from the procedure, nine relapsed after 2-26 months and 12 (50%) were still in CR after 8-55 months. In autografted patients, median Kaplan-Meier disease-free survival and survival were 29 and 33 months from the autograft, respectively. Thus, ABMT or APSCT can be performed in almost two-thirds of MDS patients who achieve CR with intensive chemotherapy. PBSC collection may yield higher numbers of stem cells than marrow collection in some cases, and could improve the percentage of MDS patients autografted in CR. Longer follow-up is required to determine if autograft will prolong CR duration in at least some patients.

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