Role of MRD Monitoring in Childhood Acute Lymphoblastic Leukemia after Allogeneic Transplantation.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 983-983 ◽  
Author(s):  
Adriana Balduzzi ◽  
Sonia Bonanomi ◽  
Monica Manenti Tech ◽  
Maria Dassi ◽  
Giovanni Cazzaniga ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Hematopoietic Cell Transplantation ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Conditioning Regimen ◽  
Allogeneic Transplantation ◽  
Childhood All ◽  
Log Reduction ◽  
Long Time

Abstract Relapse of acute lymphoblastic leukemia (ALL) after allogeneic transplant has very poor prognosis; whether early prediction of relapse by means of minimal residual disease (MRD) analysis could allow effective treatment is still to be assessed. Eighteen patients at high risk of relapse were prospectively monitored in a single transplant center. MRD analysis and clinical follow up were completed for the first series of 11 patients. This includes 9 males and 2 females (median age 11ys, range 2–16) who received allogeneic hematopoietic cell transplantation (HCT) from compatible (5), one locus mismatched (1) or haploidentical (1) related or unrelated (4) donor for ALL in 1st (5), 2nd (4), or 3rd (2) complete remission (CR), after conditioning regimen containing total body irradiation (TBI) and etoposide (9) or others, and GVHD prophylaxis consisting of cyclosporine, associated with ATG in transplant from other than compatible related donor. Grafts consisted of unmanipulated bone marrow (9), containing a median of 6.6x106CD34+/Kg (range 1.7–8.6) and 57.2x106CD3+/Kg (range 24.4–96.2), or peripheral (1), containing 11x106CD34+/Kg and 174x106CD3+/Kg, or positively selected peripheral (1) containing 12x106CD34+/Kg and 0.04x106CD3+/Kg. Five patients developed grade II–IV acute GVHD, requiring ATG in 4 cases. Five of 11 patients are alive in CR at a median of 15 months (range 11–21), 1 died in CR at 7 months, 5 relapsed at a median of 8 months (range 3–23), and 3 of them died. Patients were monitored by clone-specific RQ-PCR of one (4) or two (7) Ig/TcR markers, with a sensitivity of at least 10−4. At the time of transplant 7 patients were positive at the analysis of the MRD, while 4 were negative; patients were monitored at 1, 3, 6, 9 and 12 months after transplantation, or according to clinical requirements. Among the 4 MRD negative patients, 1 remained negative and is in CR at 19 months, 1 became positive 6 months after unrelated transplant and relapsed 2 months later, 1 relapsed 30 months after haploidentical transplant, a long time after MRD monitoring had stopped, while 1 died in CR. Among the 7 MRD positive patients, 2 remained always MRD positive and relapsed 3 and 7 months after transplant, and 5 experienced MRD negativity at a certain time after transplant; 1 of 5 became MRD positive at the 6th month after transient negativity and relapsed 3 months later, 3 of 5 became negative since the 1st or 3rd month, remained negative, and are alive in CR at 9, 12, and 13 months after transplant, while the remaining 1 alternated negative and positive MRD results and is in CR at 6 months. In 5 patients quantitative MRD data allowed early immunosuppression tapering or discontinuation, yielding severe GVHD in 1, and DLI treatment was planned in 2, but refused in 1; 2 of these 5 are in CR, while 3 relapsed, despite 1 experienced transient MRD 1-log reduction and 1 negativization. In conclusion, MRD monitoring after BMT might direct either early immunosuppression tapering or DLI for prevention of relapse in high risk childhood ALL transplanted patients.

scholarly journals Outcome of Children With Hypodiploid Acute Lymphoblastic Leukemia: A Retrospective Multinational Study

2019 ◽  
Vol 37 (10) ◽  
pp. 770-779 ◽  
Author(s):  
Ching-Hon Pui ◽  
Paola Rebora ◽  
Martin Schrappe ◽  
Andishe Attarbaschi ◽  
Andre Baruchel ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Survival Rate ◽  
Hematopoietic Cell Transplantation ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Disease Free Survival ◽  
Allogeneic Transplantation ◽  
Remission Induction ◽  
Event Free Survival ◽  
Free Survival

PURPOSE We determined the prognostic factors and utility of allogeneic hematopoietic cell transplantation among children with newly diagnosed hypodiploid acute lymphoblastic leukemia (ALL) treated in contemporary clinical trials. PATIENTS AND METHODS This retrospective study collected data on 306 patients with hypodiploid ALL who were enrolled in the protocols of 16 cooperative study groups or institutions between 1997 and 2013. The clinical and biologic characteristics, early therapeutic responses as determined by minimal residual disease (MRD) assessment, treatment with or without MRD-stratified protocols, and allogeneic transplantation were analyzed for their impact on outcome. RESULTS With a median follow-up of 6.6 years, the 5-year event-free survival rate was 55.1% (95% CI, 49.3% to 61.5%), and the 5-year overall survival rate was 61.2% (95% CI, 55.5% to 67.4%) for the 272 evaluable patients. Negative MRD at the end of remission induction, high hypodiploidy with 44 chromosomes, and treatment in MRD-stratified protocols were associated with a favorable prognosis, with a 5-year event-free survival rate of 75% (95% CI, 66.0% to 85.0%), 74% (95% CI, 61.0% to 89.0%), and 62% (95% CI, 55.0% to 69.0%), respectively. After exclusion of patients with high hypodiploidy with 44 chromosomes and adjustment for waiting time to transplantation and for covariables in a Poisson model, disease-free survival did not differ significantly ( P = .16) between the 42 patients who underwent transplantation and the 186 patients who received chemotherapy only, with an estimated 5-year survival rate of 59% (95% CI, 46.5% to 75.0%) versus 51.5% (95% CI, 44.7% to 59.4%), respectively. Transplantation produced no significant impact on outcome compared with chemotherapy alone, especially among the subgroup of patients who achieved a negative MRD status upon completion of remission induction. CONCLUSION MRD-stratified treatments improved the outcome for children with hypodiploid ALL. Allogeneic transplantation did not significantly improve outcome overall and, in particular, for patients who achieved MRD-negative status after induction.

Single Immunophenotypical Evaluation of Minimal Residual Disease before Autotransplantation of Non-Cryopreserved Bone Marrow Is Insufficient for Prediction of Outcome in High Risk Adult Acute Lymphoblastic Leukemia.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 4439-4439
Author(s):  
Beata M. Stella-Holowiecka ◽  
Krystyna Jagoda ◽  
Aleksandra M. Holowiecka-Goral ◽  
Tomasz Czerw ◽  
Sebastian Giebel ◽  
...  
Keyword(s):  
Bone Marrow ◽  
High Risk ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Conditioning Regimen ◽  
Long Term Results ◽  
Color Flow ◽  
Childhood All ◽  
Minimal Residual

Abstract For high-risk adult ALL patients alloHCT is a preferable option. However, a significant proportion of those not having a suitable donor may be successfully treated with autotransplantation (autoHCT). Based on our experience this treatment ensures low transplant related mortality below 3% and a reasonable overall survival and disease free survival of 60% and 45% respectively. The status of the disease before transplantation is an important factor for long term results. In childhood ALL most studies suggest that the level of minimal residual disease (MRD) after induction evaluated immunophenotypically or with bio-molecular methods is predictive for outcome after different treatments including chemotherapy, alloHCT and autoHCT. The results in adult ALL are more controversial. Patients selection. Among 1205 haematopoetic cell transplantations performed in our institution 224 (147 autologous, 77 allogeneic) were performed in 205 adults with ALL. For this study we selected an uniform group of 81 patients fulfilling following criteria’s: Ph (-) ALL, status CR1, evaluable MRD, strictly defined autoBMT procedure performed until the end of 2003. Methods. MRD was tested before autoBMT (median interval 10 days) using 2 ore 3-color flow-cytometry, as appropriate. The atypical immunophenotypes were evaluated using the “quadrans” analysis in all cases and since 2002 also the “empty spaces” technique. The sensitivity equals at least 0.0001. For all autoHSCT bone marrow was used as a source of stem cells. The CAV conditioning regimen consisted of cyclophosphamide 60mg/kg on d. -3, -2, cytarabine 2 g/m2 d. -3, -2, -1, etoposide 800 mg/m2 d. -3, -2. Bone marrow was not cryo-preserved after collection but stored in 40 C and re-transplanted after 72h. Results. In 41 patients; age med. 26 y (15–53), F/M=12/29, the MRD level was <0,001: the MRD (−) group. In 40 patients; age med. 29 y (16–53), F/M=18/22, the MRD was detected at the level =/> 0,001; MRD+ group. The ALL-immunophenotypes of MRD−/MRD+ groups were as follows; proB 4/7, preB 2/6, Common 18/19, B 0/1, preT 5/2, T 12/1). The interval from DGN to BMT was similar in both groups. The probability of LFS and OS at 10y calculated with median follow up time of 5y equaled; in the MRD(−) group 47% and 62% and in the MRD+ one 48% and 57% respectively (p=ns). The main reason of failure in both groups was a relapse which occurred after a median time of 277 days in the MRD(−) group and 134 days in MRD+ one (p=0.19). Conclusion and comment. Based on this observation we conclude that a single evaluation stratifying patients before autoBMT according to MRD level below or above 0.001 is not predictive for DFS and OS, because it informs only about the current amount of the disease but not about its opportunistic nature. In this respect a repeatedly confirmed MRD positivity should be more significant. Taking into consideration that the main reason of failures were relapses, this finding suggests also that in patients with chemotherapy-responsive ALL confirmed by stabile CR, the myeloablative CAV regimen is sufficiently strong to eliminate the residual disease at the level ranging 0.01–0.001. It may be speculated only that the 72h lasting incubation of bone marrow product before re-transplantation has also some kind of purging effect for leukemic blasts.

scholarly journals Allogeneic transplantation for Ph+ acute lymphoblastic leukemia with posttransplantation cyclophosphamide

2020 ◽  
Vol 4 (20) ◽  
pp. 5078-5088
Author(s):  
Jonathan A. Webster ◽  
Leo Luznik ◽  
Hua-Ling Tsai ◽  
Philip H. Imus ◽  
Amy E. DeZern ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Kinase Inhibitors ◽  
De Novo ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Philadelphia Chromosome ◽  
Allogeneic Transplantation ◽  
Donor Type

Abstract Allogeneic blood or marrow transplantation (alloBMT) is standard of care for adults with Philadelphia chromosome–positive acute lymphoblastic leukemia (Ph+ ALL) in first complete remission (CR1). The routine pretransplant and posttransplant use of tyrosine kinase inhibitors (TKIs) has dramatically improved outcomes, but the optimal conditioning regimen, donor type, and TKI remain undefined. The bone marrow transplant database at Johns Hopkins was queried for adult patients with de novo Ph+ ALL who received alloBMT using posttransplantation cyclophosphamide (PTCy) as a component of graft-versus-host disease (GVHD) prophylaxis from 2008 to 2018. Among transplants for Ph+ ALL, 69 (85%) were performed in CR1, and 12 (15%) were performed in second or greater remission (CR2+). The majority of transplants (58%) were HLA haploidentical. Nearly all patients (91.4%) initiated TKI posttransplant. For patients in CR1, the 5-year relapse-free survival (RFS) was 66%. The use of nonmyeloablative conditioning, absence of measurable residual disease (MRD) according to flow cytometry at transplant, and the use of dasatinib vs imatinib at diagnosis were associated with improved overall survival (OS) and RFS. Neither donor type nor recipient age ≥60 years affected RFS. When analyzing all transplants, alloBMT in CR1 (vs CR2+) and the absence of pretransplant MRD were associated with improved RFS. Most relapses were associated with the emergence of kinase domain mutations. The cumulative incidence of grade 3 to 4 acute GVHD at 1 year was 9%, and moderate to severe chronic GVHD at 2 years was 8%. Nonmyeloablative alloBMT with PTCy for Ph+ ALL in an MRD-negative CR1 after initial treatment with dasatinib yields favorable outcomes.

Reduced Intensity Conditioning with Allogeneic Hematopoietic Cell Transplantation for the Treatment of High-Risk Acute Lymphoblastic Leukemia.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 1210-1210
Author(s):  
Ron Ram ◽  
Rainer F. Storb ◽  
David G. Maloney ◽  
Brenda M. Sandmaier ◽  
Michael Maris ◽  
...  
Keyword(s):  
Mycophenolate Mofetil ◽  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
High Intensity ◽  
Hematopoietic Cell Transplantation ◽  
Lymphoblastic Leukemia ◽  
Chronic Gvhd ◽  
Conditioning Regimen ◽  
Reduced Intensity Conditioning ◽  
Reduced Intensity

Abstract Abstract 1210 Poster Board I-232 Allogeneic hematopoietic cell transplantation (HCT) with a conventional, high intensity conditioning regimen is an established approach for potentially curing patients (pts) with high-risk acute lymphoblastic leukemia (ALL). However, many pts are not candidates for high intensity conditioning HCT. The use of a reduced intensity conditioning (RIC) for ALL may provide an opportunity to decrease the toxicity of an intense conditioning regimen yet maintain the potential graft vs. leukemia effect. Here we describe the transplantation course and overall survival (OS) of 50 consecutive pts with high-risk ALL that were treated in a multi-center protocol of RIC and allogeneic HCT between February 2000 and August 2008. The median age was 56 (range, 7-69) years. All pts had cytogenetic analysis of bone marrow (BM) at diagnosis. 26 pts had Philadelphia chromosome positive (Ph+) ALL: 18 were in first complete remission (CR1) and 8 were in CR>1 at the time of HCT. 24 pts had Ph–ALL, 12 pts were in CR1 and 12 pts were in CR>1. Pts. were conditioned with fludarabine 90mg/m2 and 2 Gy total body irradiation. Nine pts received peripheral blood stem cells (PBSC) from HLA-identical siblings, 41 pts received grafts from unrelated donors (35 HLA-matched PBSC, 1 BM and 5 received 1-HLA-Ag mismatched PBSC). After the introduction of imatinib mesylate, 19 of the 26 pts with Ph+ALL participated in a study evaluating the safety and efficacy of imatinib starting at day +15 after HCT. Post-grafting immunosuppression consisted of combined mycophenolate mofetil and cyclosporine. Median follow up for surviving pts was 31 months (range, 12-91). One pt had graft rejection (BM recipient). 25 pts (50%) and 4 pts (8%) developed grades 2 and 3-4 acute graft-versus-host disease (GVHD), respectively. Chronic GVHD occurred in 24 pts (53% of pts surviving > 100 days); 15 pts (30%) developed extensive chronic GVHD. 19 pts (38%) relapsed at a median of 4.5 (range, 0.4-59) months. Non relapse mortality (NRM) at 2 and 5 years was 26% and 31%, respectively. Progression-free survival was very similar to OS. For all 50 pts, OS at 2 and 5 years was 37% and 27%, respectively. For pts in CR1 (n=30), OS was 52% and 41%, respectively. In contrast, OS for pts >CR1 (n=20) was significantly lower (13% and 7%, respectively, p=.003). For pts with Ph–ALL, OS was 29%, unchanged at both 2 and 5 years. Those in CR1 had improved OS compared with pts >CR1 (48% vs. 11% unchanged at both 2 and 5 years, respectively, p=0.07, Figure). OS for the 26 pts with Ph+ALL at 2 and 5 years was 45% and 27%, respectively. OS at 2 and 5 years for pts treated with imatinib after HCT was 52% and 43%, respectively, this was superior to the OS for pts with Ph+ALL that did not receive imatinib (p=0.03, Figure). For Ph+ALL pts in CR1 who had no evidence of minimal residual disease (MRD negative, detection by flow cytometry and FISH) prior to HCT and received imatinib (n=12), the OS was 67%, unchanged at both 2 and 5 years. In contrast, the pts with MRD negative Ph+ALL in CR1 who did not receive imatinib (n=4) had OS at 2 and 5 years of 50% and 0%, respectively. Imatinib after HCT was well tolerated: 3 pts required early stopping of imatinib due to associated reversible toxicity. We conclude that RIC with allogeneic HCT is a feasible treatment option that offers durable disease control, particularly for high-risk pts in CR1. The combination of post-transplant imatinib with RIC for Ph+ALL contributed to a substantially improved OS. Disclosures: Off Label Use: Imatinib - post-grafting treatment. Mycophenolate mofetil - immunosuppression after HCT.

scholarly journals Personalized therapy in pediatric high-risk B-cell acute lymphoblastic leukemia

2020 ◽  
Vol 11 ◽  
pp. 204062072092757 ◽  
Author(s):  
Seth E. Karol ◽  
Ching-Hon Pui
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
High Risk ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Pediatric Acute Lymphoblastic Leukemia ◽  
Risk Patients ◽  
Cell Acute Lymphoblastic Leukemia ◽  
Disease Stratification ◽  
Cure Rates ◽  
Minimal Residual

Although cure rates for pediatric acute lymphoblastic leukemia (ALL) have now risen to more than 90%, subsets of patients with high-risk features continue to experience high rates of treatment failure and relapse. Recent work in minimal residual disease stratification and leukemia genomics have increased the ability to identify and classify these high-risk patients. In this review, we discuss this work to identify and classify patients with high-risk ALL. Novel therapeutics, which may have the potential to improve outcomes for these patients, are also discussed.

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