scholarly journals Imatinib mesylate therapy for relapse after allogeneic stem cell transplantation for chronic myelogenous leukemia

Blood ◽  
2002 ◽  
Vol 100 (5) ◽  
pp. 1590-1595 ◽  
Author(s):  
Hagop M. Kantarjian ◽  
Susan O'Brien ◽  
Jorge E. Cortes ◽  
Sergio A. Giralt ◽  
Mary Beth Rios ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Imatinib Mesylate ◽  
Allogeneic Stem Cell Transplantation ◽  
Response Rate ◽  
Chronic Phase ◽  
Complete Response ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Blastic Phase

Twenty-eight adults with chronic myelogenous leukemia (CML) that had relapsed after allogeneic stem cell transplantation (SCT) received imatinib mesylate (400-1000 mg/d). Disease was in chronic phase in 5 patients, accelerated in 15, and blastic in 8 (7 medullary, 1 extramedullary); median time from transplantation to relapse was 9 months (range, 1-137 months). Thirteen patients had undergone salvage donor lymphocyte infusion (DLI) (median time from DLI to imatinib mesylate therapy, 4 months [range, 2-39 months]). The overall response rate was 79% (22 of 28 patients); the complete hematologic response (CHR) rate was 74% (17 of 23 patients), and the cytogenetic response rate was 58% (15 of 26 patients; complete response in 9 [35%] patients). CHR rates were 100% for chronic phase, 83% for accelerated phase, and 43% for blastic phase. The patient with extramedullary blastic disease achieved complete response. Cytogenetic response rates were 63% (12 of 19 patients) for chronic or accelerated phases (complete cytogenetic response in 8) and 43% for blastic phase (3 of 7 patients). At median follow-up of 15 months, 19 patients were alive, 9 with no evidence of disease. The 1-year estimated survival rate was 74%. Five patients had recurrence of grade 3 (3 patients) or grades 1 to 2 (2 patients) graft-versus-host disease (GVHD). Severe granulocytopenia developed in 43% of patients and thrombocytopenia in 27%; both conditions reversed with dose adjustments of imatinib mesylate. We conclude that imatinib mesylate effectively controlled CML that recurred after allogeneic SCT, but it was associated with side effects including myelosuppression and recurrence of severe GVHD.

scholarly journals The role of stem cell transplantation for chronic myelogenous leukemia in the 21st century

Blood ◽  
2015 ◽  
Vol 125 (21) ◽  
pp. 3230-3235 ◽  
Author(s):  
A. John Barrett ◽  
Sawa Ito
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Chronic Myelogenous Leukemia ◽  
Kinase Inhibitors ◽  
Conditioning Regimen ◽  
Chronic Phase ◽  
Myelogenous Leukemia ◽  
Blastic Phase

Abstract The introduction of tyrosine kinase inhibitors (TKIs), a treatment of chronic myelogenous leukemia (CML), has largely replaced curative strategies based on allogeneic stem cell transplantation (SCT). Nevertheless, SCT still remains an option for accelerated/blastic-phase and selected chronic-phase CML. Transplant outcomes can be optimized by peritransplant TKIs, conditioning regimen, BCR-ABL monitoring, and relapse management. Controversies exist in transplant timing, pediatric CML, alternative donors, and economics. SCT continues to serve as a platform of “operational cure” for CML with TKIs and immunotherapies.

Imatinib Mesylate (IM), Is an Alternative to Donor Lymphocyte Infusion (DLI) for Chronic Myelogenous Leukemia (CML) in Relapse after Allogeneic Stem Cell Transplantation: A 3-Year Follow-Up Report, on the Behalf of the Société Française de Greffe de Moëlle et de Thérapie Cellulaire (SFGM-TC) and the France Intergroupe de la Leucémie Myéloïde Chronique (Fi-LMC).

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1017-1017
Author(s):  
Cecile Pautas ◽  
Frank Nicolini ◽  
Pascal Cony-Makhoul ◽  
Stephane Giraudier ◽  
Dominique Bories ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Imatinib Mesylate ◽  
Cell Transplantation ◽  
Median Time ◽  
Allogeneic Stem Cell Transplantation ◽  
Molecular Remission ◽  
Allogeneic Hsct ◽  
Blastic Phase

Abstract DLI are an efficient treatment for CML in relapse after allogeneic stem cell transplantation, with 60 to 70% of complete response. However, major side effects such has graft-versus-host disease (GVHD) or pancytopenia are frequently observed after this treatment. Imatinib mesylate has also been shown to be effective in a such situation (Blood 2002, 100 (5): 1590–95). In the present study, we report the French experience, with a 3 years median follow-up of 26 patients in relapse of CML after allograft (21 sibling, 4 unrelated, 1 cord blood transplantations). At time of treatment with IM, twenty patients were in chronic phase and 5 only were in molecular relapse, while 4 patients were in blastic phase. Median time from graft to relapse was 36 months (3–132 months) and the median time from relapse to Imatinib was 15 months ( 1–96 months). Ten patients had already received DLI, 14 patients Interferon. Only 6 patients had no treatment prior to IM. With a median follow-up of 32 months (16–44 months), 19 patients are alive and 5 died. The majority of patients in chronic (19/20) phase are alive. At time of last follow-up : Three (11%) patients fail to respond to IM, 2 (8%) have a partial response, 12 (46%) are in CCR with 9/12 in molecular remission, and 4 (15%) patients present relapse (1 blastic phase, 3 molecular relapse). Eleven patients are evaluable for VNTR chimerism, 8(72%) achieved full donor chimerism at last follow-up. IM was well tolerated, and 2 GVHD reactivations were observed but 8 (42%) patients experienced cytopenias requiring drug modulation or withdrawal, and two grade IV toxicities (muscle cramps, cardiomyopathy). Six patients stopped IM (2 toxicities, 4 long term molecular remissions). Four of these patients experienced molecular relapse (3 after 12 months, 1 at 3 months). One patient achieved molecular remission after a new challenge with IM. In conclusion, Imatinib mesylate is efficient and safe treatment for CML in relapse after allogeneic HSCT without reactivating GVHD, and is able to restore full donor chimerism in a majority of responsive patients. A complete and sustained molecular response is obtained in about one third of patients, however molecular relapse is frequent after IM withdrawal. The place of IM and/or DLI for CML in relapse after allogeneic HSCT needs to be addressed prospectively and requires a randomized trail.

Continuous Complete Molecular Remission after Withdrawal of Imatinib Mesylate in Relapsed CML after Allogeneic Stem Cell Transplantation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4686-4686
Author(s):  
Raffaele D. Siciliano ◽  
Michael Schmid ◽  
Georg Stussi ◽  
Joerg Halter ◽  
Joerg Fehr ◽  
...  
Keyword(s):  
Stem Cell ◽  
Complete Remission ◽  
Stem Cell Transplantation ◽  
Imatinib Mesylate ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Myelogenous Leukemia ◽  
Rt Pcr ◽  
Molecular Remission ◽  
Molecular Control

Abstract Imatinib mesylate (Gleevec®) has changed the treatment of chronic myelogenous leukemia (CML), but allogeneic stem cell transplantation (SCT) is still considered the only curative therapy. Moreover, several reports indicate that imatinib mesylate may also induce complete remission in relapsed CML following SCT, but it is not known, whether imatinib mesylate can be stopped after achieving complete remission. We report a patient who is in a complete molecular remission 4 months after withdrawal of imatinib mesylate therapy. A 41-year old man was diagnosed with Philadelphia chromosome (Ph)-positive CML in first chronic phase without additional cytogenetic abnormalities. Hydroxyurea therapy was started and he received allogeneic SCT from an HLA-identical and sex-matched sibling donor within one year after the initial diagnosis. The conditioning regimen consisted of cyclophosphamide and total body irradiation (12Gy). A combination with cyclosporin A (CsA) and methotrexate was administered as a graft versus host disease (GvHD) prophylaxis. Nevertheless chronic extensive GvHD of the oral mucosa developed 3 months after SCT and resolved without further therapy. CsA was tapered after 3 and stopped after 6 months. The patient achieved complete cytogenetic remission (CCR) 9 months following SCT, but BCR-ABL remained positive by reverse transcriptase polymerase chain reaction (RT-PCR). Four years after SCT he experienced cytogenetic and morphologic relapse. Donor lymphocyte infusions were not administered, because the donor was not available, and Interferon therapy was started with an escalated dose of 9 Mio units per day. With this treatment, a second CCR and also an acceptable molecular control (BCR-ABL measurements with RT-PCR between 0.3–2.5%) was achieved. The therapy was changed to imatinib mesylate (300–400mg per day) 6 years after SCT, because of persistent molecular detection of BCR-ABL. With this treatment, complete hematologic and molecular remission were attained 5 months later and 18 months after the beginning of imatinib mesylate treatment bone marrow examination revealed no abnormalities by morphological, cytogenetic or molecular analysis. Imatinib mesylate was stopped thereafter and RT-PCR to detected residual BCR-ABL transcripts was performed monthly. Four months after stopping imatinib mesylate, the patient remains in a complete molecular remission without clinical signs of GvHD. Imatinib mesylate can induce sustained complete hematologic and molecular remission in patients with relapsed CML after allogeneic SCT. The combination of the imatinib mesylate and tumor reduction by graft versus leukemia may have synergistic effects in-vivo, and therefore facilitate the withdrawal of imatinib mesylate. Thus, the presented case shows the successful withdrawal of imatinib mesylate in a patient with relapse CML 6 years after allogeneic SCT. He continues to be in a complete molecular remission 4 months after withdrawal. However controlled studies are needed to establish the role of imatinib mesylate in the posttransplant setting.

Imatinib mesylate (STI571) in the treatment of relapse of chronic myeloid leukemia after allogeneic stem cell transplantation

Blood ◽  
2002 ◽  
Vol 99 (10) ◽  
pp. 3861-3862 ◽  
Author(s):  
Eduardo Olavarria ◽  
Charles Craddock ◽  
Francesco Dazzi ◽  
David Marin ◽  
Sarah Marktel ◽  
...  
Keyword(s):  
Stem Cell ◽  
Chronic Myeloid Leukemia ◽  
Stem Cell Transplantation ◽  
Imatinib Mesylate ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Myeloid Leukemia ◽  
Specific Inhibitor ◽  
Chronic Phase ◽  
Donor Lymphocyte Infusion

Donor lymphocyte infusion (DLI) can restore durable molecular remission in a high percentage of patients with chronic myeloid leukemia (CML) who have relapses after allogeneic stem cell transplantation, but for patients who do not respond survival is poor. Imatinib mesylate (STI571) is a specific inhibitor of BCR-ABL tyrosine kinase that can induce hematologic and cytogenetic remissions in patients with CML. We report here a male patient who had a relapse to chronic phase after stem cell transplantation for CML, did not benefit from treatment with DLI, and then was administered STI571 at a dose of 400 mg daily. There was a rapid, complete hematologic response, and complete restoration of donor-type hematopoiesis (100% 46, XX marrow metaphases) was achieved after 6 months of therapy, though RT-PCR studies still detected BCR-ABL transcripts in the blood at low level. This case demonstrates that imatinib mesylate can be highly effective in the management of patients who have relapses after allograft for CML.

Durable Molecular Remissions in Patients with Relapsed CML Post Allogeneic Stem Cell Transplantation upon Treatment with Imatinib-Mesylate (Glivec®, STI-571). Follow-Up Results of a Phase II Open-Label Study.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 1004-1004
Author(s):  
G. Hess ◽  
D. Bunjes ◽  
W. Siegert ◽  
R. Schwerdtfeger ◽  
G. Ledderose ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Stem Cell ◽  
Side Effects ◽  
Stem Cell Transplantation ◽  
Imatinib Mesylate ◽  
Allogeneic Stem Cell Transplantation ◽  
Patient Population ◽  
Study Drug ◽  
Study Phase

Abstract Purpose: In a phase II clinical trial we have previously reported on the safety and efficacy of imatinib mesylate (IM) to induce hematologic, cytogenetic and molecular remissions in case of relapse post allogeneic stem cell transplantation (SCT) in patients with chronic myelogenous leukaemia (CML). Here we report on an extended follow-up phase, which was performed to monitor stability of responses and further disease course in patients enrolled. Patients and Methods: Within the trial, patients, transplanted in chronic phase (CP) CML with molecular or cytogenetic relapse (n=37), received IM at a starting dose of 400mg. Close monitoring was performed, which, besides evaluation of side effects, included hematology, chimerism, bone marrow analysis and quantitative/qualitative PCR for Bcr-Abl. After completion of the study phase, pts were treated by the discretion of their physician, which could include continuation or cessation of IM or application of DLI. Results: During the entire observation period the rate of reported side effects was low, only one mild reactivation of Graft versus Host Disease (GvHD) occurred upon IM treatment. Response rates reflected high efficacy of IM in this patient population: in 16/22 (72.7%) evaluable patients a complete chimerism in peripheral blood was demonstrated. Complete cytogenetic response (CCR) was seen in 11/13 (84.6%) of patients with cytogenetic relapse and follow-up samples available. Importantly, 25/37 patients (67%) achieved a complete molecular response (CMR) (defined as nested PCR-negativity for 3 consecutive samples) within the primary study phase or during follow-up. Cessation of IM in 10 patients with CMR during follow-up resulted in molecular relapse of 6 patients (60%). However, importantly in 4/10 (40%) patients, CMR were durable even after cessation of the study drug with a median follow-up of 381 days after discontinuation of IM. In 7 patients, donor lymphocyte infusions (DLI) were given without major toxicities. This established CMR in 4 of these patients. One episode of mild GvHD reactivation did occur in the context of DLI. At the median follow-up of 1.7 years, OS is 100% in the study cohort; one patient has died due to progressive disease 2 years after inclusion into the study. Conclusion: In CP-CML patients with relapse post allogeneic SCT IM treatment established CMR in a majority of patients. Importantly, CMR were noted even after cessation of the study drug, suggesting the possibility of definite tumor control in selected patients. Therefore, weighing the risk of aggravation of GvHD and/or induction of bone marrow aplasia using DLI against the favourable toxicity profile of IM, in case of MRD post allogeneic SCT relapse and primary IM-treatment seems to be justified. In particular in patients with poor performance status or active GvHD early therapy instead of postponed treatment may lead to superior results. Further clinical trials are warranted to optimize sequential or concurrent use of IM and DLI in this patient population.

Association of Hydroxyurea to Imatinib Is Effective in Patients with Chronic Myelogenous Leukemia Resistant to Imatinib Alone.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4693-4693 ◽  
Author(s):  
Roberto Latagliata ◽  
Massimo Breccia ◽  
Ida Carmosino ◽  
Chiara Sarlo ◽  
Rosa De Cuia ◽  
...  
Keyword(s):  
Chronic Myelogenous Leukemia ◽  
Chronic Phase ◽  
Complete Response ◽  
Cytogenetic Response ◽  
Myelogenous Leukemia ◽  
Hematological Toxicity ◽  
Imatinib Treatment ◽  
Duration Of Response ◽  
Wbc Count

Abstract The introduction of Imatinib in the treatment of Chronic Myelogenous Leukemia (CML) leads to the achievement of Complete Cytogenetic Response (CCR) in about 70% of patients: however, in the remaining 30% of patients there is a persistance of Ph+ cells also after standard (400 mg/day) and increased (600 mg/day) dose of Imatinib. These patients are thus cytogenetically resistant to Imatinib alone and their management is at present unclear. From 11/2002 to 11/2003, 10 patients in chronic phase (6 male and 4 female, median age 52.5 years, range 29 – 68 years) with persistance of 100% Ph+ cells (9 patients) or BCR/ABL + cells (1 patient with Ph- BCR/ABL+ CML at onset) after standard (at least 6 months of treatment) followed by increased dose (at least 3 months of treatment) of Imatinib alone, were considered resistant and added Hydroxyurea (HU) to Imatinib. Seven patients have been pretreated with IFN before Imatinib; median times from diagnosis and from Imatinib treatment to HU addition were 51 months (range 23 – 151) and 14 months (range 10 – 31), respectively. HU was given according to WBC count: patients with WBC < 10 x 109/l started HU at the dose of 1 g/day, patients with WBC > 10 x 109/l at the dose of 1.5 g/day. Imatinib was continued at the same previous dosage (600 mg/day in 6 patients and 400 mg/day in 4 patients who did not tolerate increased dosage for hematological toxicity). Three patients achieved a complete response (2 CCR after 3 and 12 months respectively and 1 molecular complete response after 9 months in the patient Ph- BCR/ABL+ at onset) and 1 patient achieved a partial CR (Ph+ < 33%) after 9 months: the remaining 6 patients were resistant with persistance of 100% Ph+ cells. Toxicity was mild and only 1 patient discontinued for 2 weeks the association due to transient thrombocytopenia: no extra-hematological toxicity has been recorded. After a median follow-up of 14 months (range 20 – 10), 2 patients (1 resistant and 1 after 5 months from the achievement of CCR) evolved in Blastic Phase (BP), 5 patients are in stable chronic phase with 100% Ph+ cells and 3 patients are still in response after 4,6 and 7 months respectively. In conclusion, the association of HU with Imatinib seems capable to induce cytogenetic response in at least one third of patients resistant to Imatinib alone, with minimal toxicity: a longer follow-up and a comparison with other associations is needed to evaluate the quality and duration of response in such group of patients.

Two-Year Follow-Up Results at the M.D. Anderson Hospital with Reduced-Intensity Allogeneic Stem Cell Transplantation with Fludarabine-Melphalan as Preparative Regimen in Relapsed/Refractory Hodgkin’s Lymphoma: Comparable Outcome with Matched Related and Unrelated Donors.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 3115-3115 ◽  
Author(s):  
Paolo Anderlini ◽  
Rima M. Saliba ◽  
Sandra Acholonu ◽  
Sergio A. Giralt ◽  
Issa F. Khouri ◽  
...  
Keyword(s):  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Hodgkin’S Lymphoma ◽  
Chronic Gvhd ◽  
Complete Response ◽  
Hodgkin's Lymphoma ◽  
Unrelated Donors ◽  
Reduced Intensity

Abstract BACKGROUND: Allogeneic stem cell transplantation (allo-SCT) with reduced-intensity conditioning (RIC) is gaining increasing acceptance in relapsed/refractory (R/R) Hodgkin’s lymphoma (HL), but there are little or no outcome data with matched unrelated donors (MUDs). METHODS: Fifty-eight patients with relapsed or refractory Hodgkin’s lymphoma (HL) underwent allogeneic stem cell transplantation (allo-SCT) following a reduced-intensity conditioning (RIC) regimen from a matched related donor (MRD; n=25) or a matched unrelated donor (MUD; n=33). The median age was 32 years (range 19–59). The median number of chemotherapy regimens received prior to allo-SCT was five (range 2–9). Forty-eight (83%) patients had received a prior autologous (auto) SCT. The median time to progression after auto-SCT was five months (1–34). Disease status at SCT was sensitive relapse (n=30) or refractory relapse (n=28). The conditioning regimen employed was fludarabine (125–130 mg/m sq over 4–5 days), melphalan (140 mg/m sq IV over 2 days) (FM) and antithymocyte globulin (thymoglobulin 6 mg/kg over 3 days) was added for the most recent fourteen MUD transplants. Graft-vs-host disease (GVHD) prophylaxis included tacrolimus and mini-methotrexate. RESULTS: Chimerism studies indicated 100% donor-derived engraftment in all patients (100%). Cumulative 100-day and 2-year transplant-related mortality (TRM) were 7% and 15%, respectively, (100-day TRM MRD vs. MUD 6% vs. 8%, p=ns; 2-year MRD vs. MUD 13% vs. 16%, p=ns). The cumulative incidence of acute (grade II–IV) GVHD (first 100 days) was 28% (MRD vs. MUD 12% vs. 39%, p=0.04). The cumulative incidence of chronic GVHD at any time was 74% (MRD vs. MUD 57% vs. 89%, p=0.003). Fourteen pts (24%) received a total of 25 (range 1–5) donor leukocyte infusions (DLIs) for disease progression/relapse (PD). Five of them (35%) received salvage chemotherapy as well, and nine (64%) developed acute GVHD after the DLI. Thirty-six patients (62%) are alive (23 in remission) with a median follow-up of 24 months (4–78). The f/up is 23 months (4–53) for alive pts always in remission. Twenty-two patients (38%) expired, and relapse-related mortality was 24%. Projected 2-year overall (OS) and progression-free (PFS) survival are 64% (49–76) and 32% (20–45), with projected 2-year PD at 55% (43–70). There was no statistically significant difference between MRD and MUD transplants with regard to OS (p=0.1), PFS (p=0.9) and PD (p=0.8). There was a clear trend for the response status prior to allo-SCT (complete response, complete response undefined vs. all others) to favorably impact PFS (p=0.07) and PD (p=0.049), but not OS (p=0.4). Partial responders and patients with stable or refractory disease fared similarly with regard to OS and PFS. CONCLUSIONS: Despite the expected higher incidence of acute and chronic GVHD, MUD RIC allo-SCTs had TRM, PFS, and OS comparable to MRD allo-SCTs. Day 100, 2-year TRM and OS/PFS data appear very encouraging in these very high-risk, extensively pretreated patients. Response status at transplant seems to affect outcome, and PD remains a major obstacle. The use of unrelated donors would greatly expand donor availability for these patients.

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