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.

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.

Molecular analysis of lineage-specific chimerism and minimal residual disease by RT-PCR of p210BCR-ABL and p190BCR-ABL after allogeneic bone marrow transplantation for chronic myeloid leukemia: increasing mixed myeloid chimerism and p190BCR-ABL detection precede cytogenetic relapse

Blood ◽  
2000 ◽  
Vol 95 (8) ◽  
pp. 2659-2665 ◽  
Author(s):  
Josefina Serrano ◽  
Jose Roman ◽  
Joaquin Sanchez ◽  
Antonio Jimenez ◽  
Juan A. Castillejo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Rt Pcr ◽  
Relapse Group ◽  
Minimal Residual

We studied lineage-specific chimerism and minimal residual disease (MRD) in sequential posttransplant samples from 55 patients who underwent unmanipulated (n = 44) or partially T-cell–depleted (n = 11) allogeneic bone marrow transplantation (BMT) for chronic myeloid leukemia (CML). Chimerism was assessed by polymerase chain reaction (VNTR [variable number of tandem repeats]-PCR) analysis in highly purified CD19+, CD3+, CD15+, and CD56+ cell fractions, whereas MRD was investigated in whole blood by reverse transcriptase–PCR (RT-PCR) of both p210BCR-ABL and p190BCR-ABL hybrid transcripts. Of 55 patients, 14 (including 6 T-cell–depleted patients) had cytogenetic relapse at 5-80 months and progressed to hematologic relapse, while 41 patients remained in prolonged cytogenetic remission 12-107 months post-BMT. Before leukemia recurrence, patients in the relapse group showed a consistent evolution pattern sequentially featured by persistent p210BCR-ABL positivity, increasing mixed chimerism (MC) in myeloid cells, p190BCR-ABL positivity, and, finally, cytogenetic relapse. Myeloid MC preceded cytogenetic relapse by 2-12 months, whereas p190BCR/ABL was detected 1-6 months prior to cytogenetic relapse in 11 patients and concomitant with cytogenetic relapse in 3 patients. In the remission group, all patients invariably tested negative for p190BCR-ABL; 10 patients tested positive for p210BCR-ABL at variable time-points but showed persistent full donor chimerism (DC), whereas 31 patients tested p210BCR-ABL negative and displayed full DC or transient MC due to the persistence of recipient T cells. Two patients in the relapse group were successfully reinduced into molecular remission with donor lymphocyte infusion. Sequential molecular analysis after such treatment showed the inverse pattern to that observed prior to relapse, ie, progressive disappearance of p190BCR-ABL transcripts, conversion of myeloid chimerism to donor type, and, finally, p210BCR-ABL negativity. We conclude that lineage-specific chimerism and p190BCR-ABL messenger RNA (mRNA) analyses contribute a better characterization of CML evolution after BMT and enable early identification of patients at the highest risk of relapse.

Molecular analysis of lineage-specific chimerism and minimal residual disease by RT-PCR of p210BCR-ABL and p190BCR-ABL after allogeneic bone marrow transplantation for chronic myeloid leukemia: increasing mixed myeloid chimerism and p190BCR-ABL detection precede cytogenetic relapse

Blood ◽  
2000 ◽  
Vol 95 (8) ◽  
pp. 2659-2665 ◽  
Author(s):  
Josefina Serrano ◽  
Jose Roman ◽  
Joaquin Sanchez ◽  
Antonio Jimenez ◽  
Juan A. Castillejo ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Chronic Myeloid Leukemia ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone ◽  
Rt Pcr ◽  
Relapse Group ◽  
Minimal Residual

Abstract We studied lineage-specific chimerism and minimal residual disease (MRD) in sequential posttransplant samples from 55 patients who underwent unmanipulated (n = 44) or partially T-cell–depleted (n = 11) allogeneic bone marrow transplantation (BMT) for chronic myeloid leukemia (CML). Chimerism was assessed by polymerase chain reaction (VNTR [variable number of tandem repeats]-PCR) analysis in highly purified CD19+, CD3+, CD15+, and CD56+ cell fractions, whereas MRD was investigated in whole blood by reverse transcriptase–PCR (RT-PCR) of both p210BCR-ABL and p190BCR-ABL hybrid transcripts. Of 55 patients, 14 (including 6 T-cell–depleted patients) had cytogenetic relapse at 5-80 months and progressed to hematologic relapse, while 41 patients remained in prolonged cytogenetic remission 12-107 months post-BMT. Before leukemia recurrence, patients in the relapse group showed a consistent evolution pattern sequentially featured by persistent p210BCR-ABL positivity, increasing mixed chimerism (MC) in myeloid cells, p190BCR-ABL positivity, and, finally, cytogenetic relapse. Myeloid MC preceded cytogenetic relapse by 2-12 months, whereas p190BCR/ABL was detected 1-6 months prior to cytogenetic relapse in 11 patients and concomitant with cytogenetic relapse in 3 patients. In the remission group, all patients invariably tested negative for p190BCR-ABL; 10 patients tested positive for p210BCR-ABL at variable time-points but showed persistent full donor chimerism (DC), whereas 31 patients tested p210BCR-ABL negative and displayed full DC or transient MC due to the persistence of recipient T cells. Two patients in the relapse group were successfully reinduced into molecular remission with donor lymphocyte infusion. Sequential molecular analysis after such treatment showed the inverse pattern to that observed prior to relapse, ie, progressive disappearance of p190BCR-ABL transcripts, conversion of myeloid chimerism to donor type, and, finally, p210BCR-ABL negativity. We conclude that lineage-specific chimerism and p190BCR-ABL messenger RNA (mRNA) analyses contribute a better characterization of CML evolution after BMT and enable early identification of patients at the highest risk of relapse.

Persistence of BCR-ABL genomic rearrangement in chronic myeloid leukemia patients in complete and sustained cytogenetic remission after interferon-α therapy or allogeneic bone marrow transplantation

Blood ◽  
2000 ◽  
Vol 95 (2) ◽  
pp. 404-408 ◽  
Author(s):  
Jean-Claude Chomel ◽  
Françoise Brizard ◽  
Anne Veinstein ◽  
Jérôme Rivet ◽  
Alain Sadoun ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Chronic Myeloid Leukemia ◽  
Marrow Transplantation ◽  
Myeloid Leukemia ◽  
Residual Disease ◽  
Allogeneic Bone Marrow Transplantation ◽  
Genomic Rearrangement ◽  
Allogeneic Bone ◽  
Rt Pcr

In recent years, the prognosis of chronic myeloid leukemia (CML) has been greatly improved either with interferon- (IFN-) therapy or allogeneic bone marrow transplantation (BMT). In the present study, minimal residual disease was evaluated in 21 patients in complete cytogenetic response (CCR) after such treatments. Samples from bone marrow aspirates or peripheral blood or both were analyzed by conventional cytogenetics, Southern blot, interphase fluorescent in situ hybridization (FISH), and quantitative reverse transcription-polymerase chain reaction (Q-RT-PCR). In all patients, FISH detected 1% to 12% nuclei with a BCR-ABL fusion gene, whereas Q-RT-PCR experiments were negative or weakly positive. Based on these results, we hypothesize that the BCR-ABL genomic rearrangement persists unexpressed in nonproliferating cells whatever the treatment (IFN- or BMT). These data point to the need for follow-up of CML patients in CCR over an extensive period at the DNA level (FISH) to evaluate the residual disease and at the RNA level (Q-RT-PCR) to estimate the risk of relapse.

scholarly journals Molecular analysis of relapse in chronic myeloid leukemia after allogeneic bone marrow transplantation

Blood ◽  
1987 ◽  
Vol 70 (3) ◽  
pp. 873-876 ◽  
Author(s):  
TS Ganesan ◽  
GL Min ◽  
JM Goldman ◽  
BD Young
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Chronic Myeloid Leukemia ◽  
Marrow Transplantation ◽  
Myeloid Leukemia ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone Marrow ◽  
Leukemic Cells ◽  
Allogeneic Bone ◽  
Leukemic Clone

Abstract Four patients with Philadelphia (Ph′) positive chronic myeloid leukemia (CML) were studied before, after, and on relapse following allogeneic bone marrow transplantation (BMT). Southern analysis of DNA from cells collected before and at relapse after BMT was performed in order to investigate the origin of the leukemia at relapse. Using minisatellite probes we showed that the relapse occurred in cells of host origin in all four patients and this was confirmed with a Y chromosome specific probe in two male patients who had a female donor. Furthermore, using two probes for the breakpoint cluster region (bcr) on chromosome 22, we showed that leukemic cells at relapse bore identical rearrangements to those in the disease at time of presentation of each patient. We conclude that relapse in all four patients is due to re-emergence of the original leukemic clone.

scholarly journals Molecular analysis of relapse in chronic myeloid leukemia after allogeneic bone marrow transplantation

Blood ◽  
1987 ◽  
Vol 70 (3) ◽  
pp. 873-876
Author(s):  
TS Ganesan ◽  
GL Min ◽  
JM Goldman ◽  
BD Young
Keyword(s):  
Bone Marrow ◽  
Bone Marrow Transplantation ◽  
Chronic Myeloid Leukemia ◽  
Marrow Transplantation ◽  
Myeloid Leukemia ◽  
Allogeneic Bone Marrow Transplantation ◽  
Allogeneic Bone Marrow ◽  
Leukemic Cells ◽  
Allogeneic Bone ◽  
Leukemic Clone

Four patients with Philadelphia (Ph′) positive chronic myeloid leukemia (CML) were studied before, after, and on relapse following allogeneic bone marrow transplantation (BMT). Southern analysis of DNA from cells collected before and at relapse after BMT was performed in order to investigate the origin of the leukemia at relapse. Using minisatellite probes we showed that the relapse occurred in cells of host origin in all four patients and this was confirmed with a Y chromosome specific probe in two male patients who had a female donor. Furthermore, using two probes for the breakpoint cluster region (bcr) on chromosome 22, we showed that leukemic cells at relapse bore identical rearrangements to those in the disease at time of presentation of each patient. We conclude that relapse in all four patients is due to re-emergence of the original leukemic clone.

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