Posttransplantation imatinib as a strategy to postpone the requirement for immunotherapy in patients undergoing reduced-intensity allografts for chronic myeloid leukemia

Blood ◽  
2007 ◽  
Vol 110 (13) ◽  
pp. 4614-4617 ◽  
Author(s):  
Eduardo Olavarria ◽  
Shamyla Siddique ◽  
Michael J. Griffiths ◽  
Sharon Avery ◽  
Jenny L. Byrne ◽  
...  
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Disease Relapse ◽  
Molecular Remission ◽  
Graft Versus Host ◽  
Novel Strategy ◽  
Kinetics Of ◽  
Reduced Intensity ◽  
Risk Of Relapse ◽  
Donor Lymphocyte Infusions

Disease relapse is a major cause of treatment failure after reduced-intensity allografts and while donor lymphocyte infusions (DLIs) can be effective salvage therapy they are associated with severe graft-versus-host disease (GVHD) when administered early after transplantation. We have therefore examined whether imatinib mesylate can delay relapse and postpone the requirement for DLI in 22 patients with chronic myeloid leukemia (CML) allografted using a reduced-intensity regimen. Imatinib was commenced on day + 35 and continued until 1 year after transplantation. Posttransplantation imatinib was well tolerated and abolished the risk of relapse during this period. Twenty-one patients completed 11 months of imatinib therapy, 15 of whom subsequently relapsed and received DLI. Ten patients to date have achieved molecular remission after DLI. Adjunctive targeted therapy allows the kinetics of disease relapse after a reduced-intensity allograft to be manipulated and represents a novel strategy by which outcome may be improved in patients who undergo transplantation for CML and other leukemias.

Kinetics of the Graft-Versus-Leukemia Response After Donor Leukocyte Infusions for Relapsed Chronic Myeloid Leukemia After Allogeneic Bone Marrow Transplantation

Blood ◽  
1998 ◽  
Vol 92 (10) ◽  
pp. 3582-3590 ◽  
Author(s):  
Herrad Baurmann ◽  
Stefan Nagel ◽  
Thomas Binder ◽  
Andreas Neubauer ◽  
Wolfgang Siegert ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Rt Pcr ◽  
Molecular Remission ◽  
Graft Versus Leukemia ◽  
Kinetics Of

Abstract Little is known about the mechanisms and the kinetics of the so-called graft-versus-leukemia (GVL) response induced by donor lymphocyte infusions (DLI) in patients with leukemic relapse after allogeneic bone marrow transplantation (BMT). We sought to elucidate this problem by sequentially studying three patients with relapsed chronic myeloid leukemia after sex-mismatched BMT from time before donor leukocyte infusion until achievement of complete molecular remission. Lineage-specific chimerism was assessed longitudinally by a combined fluorescent immunophenotyping and sex chromosome-specific in situ hybridization approach. Results were related to quantitative detection of bcr-abl transcripts by competitive differential reverse transcriptase-polymerase chain reaction (RT-PCR), qualitative bcr-abl RT-PCR, and multiplex PCR-based DNA donor/recipient chimerism. All patients had predominant donor lymphopoiesis at the time of DLI, suggesting a state of tolerance to recipient leukemic and/or normal cells. In contrast, granulopoiesis and erythropoiesis were mainly recipient derived in both patients with hematologic relapse and partly recipient derived in the patient with molecular relapse. Eighty percent, 90%, and 8% of CD34+cells, respectively, were found to be of recipient origin at relapse, and few donor stem cells predicted for cytopenia post-DLI. Responses were seen after a time lag of 5 to 13 weeks after DLI and resulted in reversal to full donor chimerism within a critical switch period of 4 to 5 weeks. A sudden decrease in recipient cells was paralleled by a sharp decrease in bcr-abl transcript numbers detectable several weeks before achievement of molecular remission and onset of clinical graft-versus-host disease (GVHD). This response pattern was confirmed by retrospective RT-PCR analysis in an additional five patients. Prospective monitoring of stem cell chimerism and response may enable us to individually tailor adoptive immunotherapy in the future.

scholarly journals Durability of responses following donor lymphocyte infusions for patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukemia

Blood ◽  
2000 ◽  
Vol 96 (8) ◽  
pp. 2712-2716 ◽  
Author(s):  
Francesco Dazzi ◽  
Richard M. Szydlo ◽  
Nicholas C. P. Cross ◽  
Charles Craddock ◽  
Jaspal Kaeda ◽  
...  
Keyword(s):  
Stem Cell ◽  
Chronic Myeloid Leukemia ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Molecular Remission ◽  
Donor Lymphocyte Infusions ◽  
Median Interval

Abstract An analysis was performed of the response to treatment with donor lymphocyte infusions (DLI) and the survival in 66 consecutive patients who relapsed after primary treatment by allogeneic stem cell transplantation for BCR-ABL–positive chronic myeloid leukemia. The transplant donor was an HLA-identical sibling (n = 35) or a “matched” unrelated volunteer (n = 31). Fifty-seven patients were transplanted in chronic phase, eight in accelerated phase, and one in second chronic phase. The recognition of relapse was based on precise molecular, cytogenetic, or hematologic criteria. The median interval from transplant to relapse was 12 months (range 3-85). The median interval from relapse to initiation of DLI was 9.4 months (range 1-70). Patients received DLI from their original transplant donors on a bulk-dose (n = 34) or on an escalating-dose (n = 32) regimen. Patients were monitored serially by hematologic, cytogenetic, and molecular criteria. Molecular remission was defined by the finding of negative results by nested primer reverse transcriptase polymerase chain reaction (RT-PCR) for BCR-ABL transcripts on two consecutive occasions, subject to satisfactory controls. Forty-four patients (67%) achieved molecular remission. Patients who had relapsed to advanced phase disease and patients with short intervals between transplant and relapse had significantly lower probabilities of achieving molecular remission. Of the 44 patients who achieved molecular remission, 4 reverted to a PCR-positive status at 15, 18, 37, and 87 weeks after remission. The probability of survival for patients who achieved molecular remission was significantly better than for those who failed to do so (95% versus 53% at 3 years post-DLI,P = .0001). We conclude that the majority of molecular remissions after DLI are durable, and thus the majority of responding patients may prove to have been cured.

scholarly journals Durability of responses following donor lymphocyte infusions for patients who relapse after allogeneic stem cell transplantation for chronic myeloid leukemia

Blood ◽  
2000 ◽  
Vol 96 (8) ◽  
pp. 2712-2716
Author(s):  
Francesco Dazzi ◽  
Richard M. Szydlo ◽  
Nicholas C. P. Cross ◽  
Charles Craddock ◽  
Jaspal Kaeda ◽  
...  
Keyword(s):  
Stem Cell ◽  
Chronic Myeloid Leukemia ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Allogeneic Stem Cell Transplantation ◽  
Myeloid Leukemia ◽  
Chronic Phase ◽  
Molecular Remission ◽  
Donor Lymphocyte Infusions ◽  
Median Interval

An analysis was performed of the response to treatment with donor lymphocyte infusions (DLI) and the survival in 66 consecutive patients who relapsed after primary treatment by allogeneic stem cell transplantation for BCR-ABL–positive chronic myeloid leukemia. The transplant donor was an HLA-identical sibling (n = 35) or a “matched” unrelated volunteer (n = 31). Fifty-seven patients were transplanted in chronic phase, eight in accelerated phase, and one in second chronic phase. The recognition of relapse was based on precise molecular, cytogenetic, or hematologic criteria. The median interval from transplant to relapse was 12 months (range 3-85). The median interval from relapse to initiation of DLI was 9.4 months (range 1-70). Patients received DLI from their original transplant donors on a bulk-dose (n = 34) or on an escalating-dose (n = 32) regimen. Patients were monitored serially by hematologic, cytogenetic, and molecular criteria. Molecular remission was defined by the finding of negative results by nested primer reverse transcriptase polymerase chain reaction (RT-PCR) for BCR-ABL transcripts on two consecutive occasions, subject to satisfactory controls. Forty-four patients (67%) achieved molecular remission. Patients who had relapsed to advanced phase disease and patients with short intervals between transplant and relapse had significantly lower probabilities of achieving molecular remission. Of the 44 patients who achieved molecular remission, 4 reverted to a PCR-positive status at 15, 18, 37, and 87 weeks after remission. The probability of survival for patients who achieved molecular remission was significantly better than for those who failed to do so (95% versus 53% at 3 years post-DLI,P = .0001). We conclude that the majority of molecular remissions after DLI are durable, and thus the majority of responding patients may prove to have been cured.

Kinetics of the Graft-Versus-Leukemia Response After Donor Leukocyte Infusions for Relapsed Chronic Myeloid Leukemia After Allogeneic Bone Marrow Transplantation

Blood ◽  
1998 ◽  
Vol 92 (10) ◽  
pp. 3582-3590 ◽  
Author(s):  
Herrad Baurmann ◽  
Stefan Nagel ◽  
Thomas Binder ◽  
Andreas Neubauer ◽  
Wolfgang Siegert ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Rt Pcr ◽  
Molecular Remission ◽  
Graft Versus Leukemia ◽  
Kinetics Of

Little is known about the mechanisms and the kinetics of the so-called graft-versus-leukemia (GVL) response induced by donor lymphocyte infusions (DLI) in patients with leukemic relapse after allogeneic bone marrow transplantation (BMT). We sought to elucidate this problem by sequentially studying three patients with relapsed chronic myeloid leukemia after sex-mismatched BMT from time before donor leukocyte infusion until achievement of complete molecular remission. Lineage-specific chimerism was assessed longitudinally by a combined fluorescent immunophenotyping and sex chromosome-specific in situ hybridization approach. Results were related to quantitative detection of bcr-abl transcripts by competitive differential reverse transcriptase-polymerase chain reaction (RT-PCR), qualitative bcr-abl RT-PCR, and multiplex PCR-based DNA donor/recipient chimerism. All patients had predominant donor lymphopoiesis at the time of DLI, suggesting a state of tolerance to recipient leukemic and/or normal cells. In contrast, granulopoiesis and erythropoiesis were mainly recipient derived in both patients with hematologic relapse and partly recipient derived in the patient with molecular relapse. Eighty percent, 90%, and 8% of CD34+cells, respectively, were found to be of recipient origin at relapse, and few donor stem cells predicted for cytopenia post-DLI. Responses were seen after a time lag of 5 to 13 weeks after DLI and resulted in reversal to full donor chimerism within a critical switch period of 4 to 5 weeks. A sudden decrease in recipient cells was paralleled by a sharp decrease in bcr-abl transcript numbers detectable several weeks before achievement of molecular remission and onset of clinical graft-versus-host disease (GVHD). This response pattern was confirmed by retrospective RT-PCR analysis in an additional five patients. Prospective monitoring of stem cell chimerism and response may enable us to individually tailor adoptive immunotherapy in the future.

Complete molecular responses are achieved after reduced intensity stem cell transplantation and donor lymphocyte infusion in chronic myeloid leukemia

Blood ◽  
2008 ◽  
Vol 111 (10) ◽  
pp. 5252-5255 ◽  
Author(s):  
Nicholas B. Heaney ◽  
Mhairi Copland ◽  
Karen Stewart ◽  
Judith Godden ◽  
Anne N. Parker ◽  
...  
Keyword(s):  
Stem Cell ◽  
Chronic Myeloid Leukemia ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Chronic Phase ◽  
Viral Reactivation ◽  
Reduced Intensity ◽  
Donor Lymphocyte Infusions

Abstract Patients with newly diagnosed chronic phase chronic myeloid leukemia were treated with imatinib mesylate (IM) for 6 to 12 months to establish disease control, before reduced intensity stem cell transplantation (RISCT). Escalating doses of donor lymphocyte infusions were given from 6 months after transplantation to eradicate residual disease. A total of 18 patients entered the study and 15 received RISCT (median follow-up, 31 months). RISCT was well tolerated with rapid engraftment, short inpatient stays, and few readmissions. Viral reactivation was common, although extensive graft-versus-host disease occurred infrequently. Donor lymphocyte infusions were given as part of the RISCT protocol in 13 of 15 patients. BCR-ABL transcripts continued to decrease after RISCT, and 8 (53%) patients achieved sustained undetectable levels. All patients are currently off IM. Although IM is now established as first-line therapy for chronic phase chronic myeloid leukemia, this protocol is a safe, well-tolerated, and effective strategy in these patients. This study is registered at http://www.controlled-trials.com as ISRCTN86187144.

Donor Lymphocyte Infusions for Chronic Myeloid Leukemia Relapsing after Allogeneic Stem Cell Transplant: May We Predict Graft vs Leukemia without Graft vs Host Disease?.

Blood ◽  
2006 ◽  
Vol 108 (11) ◽  
pp. 263-263
Author(s):  
Cesare Guglielmi ◽  
Stefania Bergantini ◽  
Simona Iacobelli ◽  
Anja van Biezen ◽  
Eduardo Olavarria ◽  
...  
Keyword(s):  
Stem Cell ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Stem Cell Transplant ◽  
Chronic Gvhd ◽  
Cell Transplant ◽  
Molecular Remission ◽  
Hematopoietic Stem ◽  
Cell Dose ◽  
Donor Lymphocyte Infusions

Abstract Donor lymphocyte infusions (DLI) have radically changed the prognosis of patients relapsing after allogeneic hematopoietic stem cell transplant (SCT) for chronic myeloid leukemia (CML). Major obstacles to success with DLI are represented by leukemia resistance and by secondary GvHD (GvHD2). The best result of is when a patient treated with DLI achieve a durable molecular remission without experiencing GvHD2. It is unclear which factors may predict for such a favourable outcome when CML patients are treated with DLI. We retrospectively identified 500 patients (59% males, median age 39 years, range 4–64), treated with DLI for CML relapse (81 molecular [16%], 150 cytogenetic [30%], 211 hematological chronic [42%], and 58 hematological accelerated [12%]) at 68 EBMT centers before 2004 with adequate information collected on disease response, GvHD2 and survival after DLI. Donor was an HLA-identical sibling in 73%, unrelated in 27%. DLI started with a cell dose <2×107 CD3+ cells/Kg in 62% of the cases; 208 patients (42%) received 2 or more additional infusions of donor cells. Cumulative cell dose ranged from 1×105 CD3+ cells/Kg to 1.4×109 (median 7×107). Molecular remission and/or cytogenetic complete remission was achieved in 340 patients (68%) in a median of 7.5 months (95% within 41 months). GvHD2 occurred in 60% of patients at a median of 3 months from 1st transfusion of donor lymphocytes (95% within 24 months). Sixteen recurred at a median of 19 months (range 3–48). Actuarial probability of being alive and responsive to DLI without experiencing any GvHD2 was 29% (95% confidence interval [95CI]: 27–31%) and 27% (95CI: 24–30%) at 5 and 10 years after DLI, respectively. We studied the prognostic effect of following factors: patient age at DLI, donor type, donor sex, sex mismatch with the donor, phase at SCT, stem cell source, T-depletion, total body irradiation in the conditioning regimen, GvHD prior to DLI, interval from SCT to DLI, type of relapse. Multivariate analysis with a Cox model adjusted for the period of DLI (≤1997 vs >1997), showed that chronic GvHD after transplant and prior to relapse (hazard ratio [HR]: 1.5, 95CI: 1.2–1.9, p<0.001), an interval from SCT to DLI <1 year (HR: 1.7, 95CI: 1.3–2.2, p<0.001), and hematological relapse (HR: 1.6, 95CI: 1.2–2.0, p<0.001), were adverse features. 94 patients (20%), 222 (48%), 133 (28%), and 17 (4%) had 0, 1, 2, and 3 adverse features, respectively. Survival in remission without experiencing GvHD2 at 5 years improved from 14%, 30%, to 56% in patients with 2–3, 1, and 0 adverse features, respectively. We conclude that:“pure” GvL effect (ie. durable remission without GvHD2) was observed in more than 25% of patients treated with DLI for CML relapsing after allogeneic SCT;occurrence of chronic GvHD prior to relapse, the interval from SCT to DLI, and the type of relapse are the main factors associated with the chance of a “pure” GvL effect;patients treated with DLI beyond 1 year from SCT for a molecular/cytogenetic relapse that was not preceded by chronic GvHD have more than 50% chance of exploiting the “pure” GvL effect.

scholarly journals Recurrence of Chronic Myeloid Leukemia during Pregnancy Subsequently Achieving Complete Medical Remission

2017 ◽  
Vol 2017 ◽  
pp. 1-3
Author(s):  
Sasha Mikhael ◽  
Ashlee Pascoe ◽  
Joseph Prezzato
Keyword(s):  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Animal Studies ◽  
Kinase Inhibitors ◽  
Adverse Outcomes ◽  
High Dose ◽  
Molecular Remission ◽  
Successful Pregnancy ◽  
Pregnancy And Delivery ◽  
Reproductive Aged Women

The treatment of chronic myeloid leukemia (CML) with tyrosine kinase inhibitors (TKIs) in reproductive-aged women poses major dilemmas concerning its associated teratogenicity as observed in many animal studies. Much controversy exists regarding continuation versus discontinuation of its use in pregnancy with some studies suggesting safety of TKIs before and during pregnancy and others reporting toxicity and adverse outcomes. TKIs have become a well-established treatment option for CML, significantly improving prognosis, and yet have been reported to be fetotoxic. We present a case of a 25-year-old woman who achieved successful pregnancy and delivery after withholding treatment, meanwhile relapsing, eventually achieving complete molecular remission after reinitiation of high dose dasatinib.

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