Qualitative and quantitative polymerase chain reaction monitoring of minimal residual disease in relapsed chronic lymphocytic leukemia: early assessment can predict long-term outcome after reduced intensity allogeneic transplantation.
BACKGROUND
The graft-versus-leukemia effect is able to induce clinical responses in patients with chronic lymphocytic leukemia treated with a reduced intensity conditioning regimen, followed by allogeneic stem cell transplantation. We investigated whether molecular remissions could be attained after reduced intensity conditioning and allogeneic stem cell transplantation in patients with relapsed chronic lymphocytic leukemia and whether the assessment of minimal residual disease might be used to predict the clinical outcome.


METHODS
Minimal residual disease was monitored by polymerase chain reaction using the immunoglobulin heavy-chain gene rearrangement as a molecular marker in 29 relapsed patients who achieved complete remission following reduced intensity conditioning and allogeneic stem cell transplantation. A nested-polymerase chain reaction with patient-specific primers derived from complementarity determining regions (CDR2 and CDR3) was carried out in all the patients. Real-time polymerase chain reaction was performed in patients whose nested reaction gave positive or mixed results.


RESULTS
Three patterns of minimal residual disease were observed: negative (31%), mixed (24%), and always positive (45%). The cumulative incidence of relapse according to the minimal residual disease status at 6 and 12 months after transplantation was significantly different between polymerase chain reaction-negative and -positive patients (p=0.031 and p=0.04, respectively). Two-year disease-free survival was 93% and 46% for polymerase chain reaction-negative and -positive patients at 6 months after transplantation, respectively (p=0.012). Similarly, 2-year disease-free survival was 100% and 57% for polymerase chain reaction-negative and -positive patients at 12 months, respectively (p=0.037). No clinical or biological factors were predictive of the achievement of polymerase chain reaction negativity after allogeneic stem cell transplantation. Graft-versus-host disease was more frequent in patients who did not relapse (p=0.04). Quantitative monitoring of minimal residual disease was able to identify polymerase chain reaction-positive patients with a higher risk of relapse.


CONCLUSIONS
These findings demonstrate that relapsed patients can achieve molecular remission after reduced intensity conditioning and allogeneic stem cell transplantation and suggest a minimal residual disease-driven intervention that might be useful to prevent overt hematologic relapse.
Division of Hematology-Bone Marrow Transplantation, Istituto Nazionale per lo Studio e la Cura dei Tumori, Via Venezian 1, Milan, Italy. lucia.farina@istitutotumori.mi.it
Lucia
L
Farina
Cristiana
C
Carniti
Anna
A
Dodero
Antonio
A
Vendramin
Anna
A
Raganato
Francesco
F
Spina
Francesca
F
Patriarca
Franco
F
Narni
Fabio
F
Benedetti
Attilio
A
Olivieri
Paolo
P
Corradini
D000328:Adult; D000368:Aged; D005260:Female; D015321:Gene Rearrangement; D006086:Graft vs Host Disease / Q000175:diagnosis / Q000235:genetics; D020544:Graft vs Leukemia Effect / Q000235:genetics; D018380:Hematopoietic Stem Cell Transplantation / Q000379:methods; D006801:Humans; D007143:Immunoglobulin Heavy Chains / Q000235:genetics*; D015451:Leukemia, Lymphocytic, Chronic, B-Cell / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D008297:Male; D008875:Middle Aged; D009364:Neoplasm Recurrence, Local; D018365:Neoplasm, Residual / Q000175:diagnosis / Q000235:genetics*; D017063:Outcome Assessment, Health Care / Q000379:methods; D016133:Polymerase Chain Reaction / Q000379:methods*; D011237:Predictive Value of Tests; D011379:Prognosis; D015203:Reproducibility of Results; D016019:Survival Analysis; D013997:Time Factors; D019172:Transplantation Conditioning; D014184:Transplantation, Homologous
D007143:Immunoglobulin Heavy Chains