scholarly journals Continuous Complete Remission in Two Patients with Acute Lymphoblastic Leukemia and Severe Fungal Infection Following Short-Term, Dose-Reduced Chemotherapy

2021 ◽  
Vol 12 ◽  
Author(s):  
Florian Lüke ◽  
Dennis C. Harrer ◽  
Joachim Hahn ◽  
Matthias Grube ◽  
Tobias Pukrop ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Complete Remission ◽  
Residual Disease ◽  
Fungal Infections ◽  
Lymphoblastic Leukemia ◽  
Elevated Serum ◽  
Induction Treatment ◽  
Short Term ◽  
Therapy Regimen ◽  
Pulmonary Mycosis

Spontaneous remission in acute lymphoblastic leukemia (ALL) is a rare phenomenon, which typically involves a pattern of feverish or septic disease followed by quick but mostly transient remission. We report on two male patients (46-year-old (pt. 1) and 19-year-old (pt. 2)) with CD20 positive, BCR-ABL negative common B-ALL. Patient 1 had received dexamethasone and cyclophosphamide (1.2 g) as a prephase therapy, followed by rituximab and a cumulative dose of 200 mg daunorubicin combined with 2 mg vincristine as an induction therapy. Patient 2 was treated with a reduced therapy regimen (Vincristine 1 mg, dexamethasone and 80 mg daunorubicin, 12-month mercaptopurine maintenance) due to (alcohol-related) toxic liver failure and pontine myelinolysis. Both patients developed severe septic disease just few days into induction treatment. Patient 1 suffered from pulmonary mycosis, which had to be resected eventually. Histological work-up revealed invasive mucor mycosis. Patient 2 presented with elevated serum aspergillus antigen and radiographic pulmonary lesions, indicative of pulmonary mycosis. In both patients, chemotherapy had to be interrupted and could not be resumed. Both patients recovered under broad antimicrobial, antifungal and prophylactic antiviral therapy and achieved molecular complete remission. At data cut-off remissions had been on-going for 34 months (pt. 1) and 8 years (pt. 2). Short-term, reduced intensity induction chemotherapy accompanied by severe fungal infections was followed by long-lasting continuous complete remissions in ALL. Thus, we hypothesize that infection-associated immunogenic responses may not only prevent early relapse of ALL but could also eradicate minimal residual disease. The effects of combined cytotoxic therapy and severe infection may also be mimicked by biomodulatory treatment strategies aiming at reorganizing pathologically altered cellular signaling networks. This could reduce toxicity and comorbidity in adult patients requiring leukemia treatment. Therefore, these two cases should encourage systematic studies on how leukemia stroma interaction can be harnessed to achieve long lasting control of ALL.

scholarly journals Recent updates for antibody therapy for acute lymphoblastic leukemia

2020 ◽  
Vol 9 (1) ◽  
Author(s):  
Le Li ◽  
Ying Wang
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
T Cell ◽  
Complete Remission ◽  
Median Survival ◽  
Residual Disease ◽  
Hematologic Malignancy ◽  
Lymphoblastic Leukemia ◽  
Cytotoxic Agents ◽  
Great Promise ◽  
T Cell Therapy

AbstractAcute lymphoblastic leukemia (ALL) is a hematologic malignancy arising from precursors of the lymphoid lineage. Conventional cytotoxic chemotherapies have resulted in high cure rates of up to 90% in pediatric ALL, but the outcomes for adult patients remain suboptimal with 5-year survival rates of only 30%-40%. Current immunotherapies exploit the performance of antibodies through several different mechanisms, including naked antibodies, antibodies linked to cytotoxic agents, and T-cell re-directing antibodies. Compared with chemotherapy, the application of an antibody–drug conjugates (ADC) called inotuzumab ozogamicin in relapsed or refractory (R/R) CD22+. ALL resulted in a complete remission (CR) rate of 81% and an overall median survival of 7.7 months with reduced toxicity. Similarly, blinatumomab, the first FDA-approved bispecific antibody (BsAb), produced a 44% complete response rate and an overall median survival of 7.7 months in a widely treated ALL population. In addition, approximately 80% of patients getting complete remission with evidence of minimal residual disease (MRD) achieved a complete MRD response with the use of blinatumomab. These results highlight the great promise of antibody-based therapy for ALL. How to reasonably determine the place of antibody drugs in the treatment of ALL remains a major problem to be solved for ongoing and future researches. Meanwhile the combination of antibody-based therapy with traditional standard of care (SOC) chemotherapy, chimeric antigen receptor (CAR) T-cell therapy and HSCT is also a challenge. Here, we will review some important milestones of antibody-based therapies, including combinational strategies, and antibodies under clinical development for ALL.

scholarly journals Clinical Implication of BCR/ABL Fusion Transcript Monitoring in Addition to Ig/TCR Gene Rearrangement-Based Minimal Residual Disease in Philadelphia Chromosome-Positive Childhood Acute Lymphoblastic Leukemia

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 2258-2258
Author(s):  
Kirsten Bleckmann ◽  
Julia Alten ◽  
Anja Moericke ◽  
Andishe Attarbashi ◽  
Andrea Teigler-Schlegel ◽  
...  
Keyword(s):  
Stem Cell ◽  
Acute Lymphoblastic Leukemia ◽  
Complete Remission ◽  
Stem Cell Transplantation ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Blast Crisis ◽  
Philadelphia Chromosome ◽  
Fusion Transcript ◽  
Minimal Residual

Abstract Background: Philadelphia chromosome-positive (Ph+) acute lymphoblastic leukemia (ALL) accounts for about 3% of pediatric ALL and has a poor prognosis. Advances of treatment due to the tyrosine kinase inhibitor imatinib have improved the cure rates. According to recent guidelines in the amended European intergroup trial on Ph+ ALL (EsPhALL), patients with rapid minimal residual disease (MRD) response and negativity during further treatment are no longer eligible for allogeneic stem cell transplantation (alloSCT). This down-grading of therapy in a circumscribed patient cohort with favorable prognosis is a desirable development as stem cell transplantation still implies a considerable risk of toxicity. These guidelines refer to MRD by immunoglobulin/T-cell receptor (Ig/TCR) gene rearrangements and do not consider monitoring of the BCR/ABL fusion transcript as long as informative results for Ig/TCR MRD are available. However, discrepancies between the results of the two methods occur. This complicates the decision on alloSCT indication if Ig/TCR MRD becomes negative while the BCR/ABL fusion transcript remains detectable. Objectives/Methods: We therefore evaluated the prognostic relevance of this specific combination of findings, i.e. the continuous negativity for Ig/TCR MRD and persistently positive results for BCR/ABL after the second intensive consolidation block or later, in 16 pediatric patients with Ph+ ALL. They were identified among 139 German and Austrian Ph+ patients treated in the ALL-BFM 2000 or EsPhALL trial from August 1, 1999 to July 31, 2013. Twelve out of the 16 patients received imatinib in first-line treatment intermittently as previously described in the EsPhALL protocol (Biondi A et al Lancet Oncol. 2012) or continuously as recommended by the amended EsPhALL protocol. Results: Eight of the 16 identified patients received an alloSCT in first complete remission (1st CR), whereas the remaining eight patients were treated with chemotherapy only. Of the eight patients with alloSCT, seven are in first continuous complete remission (1st CCR) with median EFS of 7.6 years, one patient died after second relapse. In the group of eight patients without alloSCT three are in 1st CCR with a median EFS of 2.6 years, four patients are in 2nd CR after relapse (3/4 had alloSCT in 2nd CR, median EFS 4.7 years), and one patient with Down syndrome died of an infectious complication. Remarkably, two patients of the latter group (both with M-BCR) showed a protracted increase of BCR/ABL copy numbers over several years with neither morphological signs of relapse nor Ig/TCR MRD based reappearance. One of them eventually suffered a relapse 5 years after diagnosis, one is still in 1st CCR with EFS of 5.2 years. Conclusion: The data suggest that patients with Ig/TCR MRD negativity and persistently detectable BCR/ABL fusion transcript have a high risk of relapse when treated with chemotherapy only and may benefit from alloSCT. However, patient numbers are currently too small to deduce recommendations from this observation. Further investigation of a larger cohort with longer follow-up is needed to confirm the prognostic importance of BCR/ABL fusion transcript monitoring in addition to Ig/TCR MRD, especially considering a potential additional impact of the recently implemented continuous imatinib treatment. One additional patient would have met the diagnostic inclusion criteria of this analysis. He had an extensive increase of BCR/ABL fusion transcript at the end of maintenance treatment while being in morphological remission and negative for Ig/TCR MRD. This patient proved to be BCR/ABL positive in granulocytes revealing a chronic myeloid leukemia (CML) misdiagnosed as ALL during initial blast crisis. This indicates that an underlying CML might be taken into consideration also in other patients of the analyzed cohort. In consequence, BCR/ABL in granulocytes is now tested in all newly diagnosed Ph+ ALL patients in Germany to ensure the differentiation of BCR/ABL positive ALL vs. CML in blast crisis. Disclosures No relevant conflicts of interest to declare.

Rapid molecular response during early induction chemotherapy predicts a good outcome in childhood acute lymphoblastic leukemia

Blood ◽  
2000 ◽  
Vol 95 (3) ◽  
pp. 790-794 ◽  
Author(s):  
E. Renate Panzer-Grümayer ◽  
Monika Schneider ◽  
Simon Panzer ◽  
Karin Fasching ◽  
Helmut Gadner
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Risk Stratification ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Early Response ◽  
Response To Therapy ◽  
Childhood Acute Lymphoblastic Leukemia ◽  
Induction Treatment ◽  
Molecular Response ◽  
Significant Difference

Early response to therapy is an independent prognostic factor in childhood acute lymphoblastic leukemia. Although most patients have rapid early responses, as detected by morphology, 15% to 20% of patients have relapses. The authors evaluated residual disease by molecular methods on day 15 of minimal residual disease (MRD) therapy and compared these data with their recently established MRD-based risk stratification, defined by MRD levels 5 weeks after induction treatment and before consolidation. All 68 children treated according to current Berlin-Frankfurt-Münster (BFM) protocols went into morphologically complete remission after induction. There was a significant difference in outcome between children with rapid disease clearance and those with high levels of day-15 MRD (P = .035). Among patients with high levels of day-15 MRD, only the MRD-based risk stratification was predictive of the outcome. All patients with negative or low day-15 MRD had excellent prognoses and were in the MRD-based low-risk group. Thus, after only 2 weeks of treatment, the authors were able to identify a patient population of 20% who may benefit from the least intensive treatment.

scholarly journals Long-term follow-up of residual disease in acute lymphoblastic leukemia patients in complete remission using clonogeneic IgH probes and the polymerase chain reaction

Blood ◽  
1993 ◽  
Vol 82 (5) ◽  
pp. 1618-1625 ◽  
Author(s):  
Y Nizet ◽  
S Van Daele ◽  
P Lewalle ◽  
JL Vaerman ◽  
M Philippe ◽  
...  
Keyword(s):  
Polymerase Chain Reaction ◽  
Acute Lymphoblastic Leukemia ◽  
Complete Remission ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Clonal Evolution ◽  
Chain Reaction ◽  
Polymerase Chain

Abstract We sequentially studied bone marrow (BM) samples of 25 patients in complete remission of an acute lymphoblastic leukemia (ALL) using a simplified polymerase chain reaction (PCR) strategy (direct use of the PCR product as a clonogenic probe recognizing rearranged Ig heavy chain sequences) as a first approach. BM aspirates were serially investigated after obtention of a complete response. When sensitivity was less than 1:10(4), the PCR fragment was sequenced and a specific oligonucleotide was synthetized and used as a probe (five cases). Cases in which minimal residual disease (MRD) became undetectable were cross- controlled using either TCR delta rearrangement or a specific translocation to circumvent the problem of false-negative results arising from clonal evolution. The median follow-up was 30 months (3 to 51 months). Within the first 3 months of complete remission, MRD was detectable in 22 of 23 investigated patients and remained so in 19 of 21 patients examined at 6 months, regardless of the long-term clinical outcome. In patients remaining in complete remission at 30 months or more, two patterns of MRD emerged during the follow-up. Either it continuously decreased to ultimately become undetectable (five patients) or remained detectable (five patients) with an increase after discontinuation of treatment in two. In the eight patients who relapsed, MRD persisted throughout the clinical course, and eventually increased 3 to 12 months before relapse was clinically detectable. In one case, clonal evolution of the VDJ heavy chain region was observed and recurrence of MRD shown by the use of TCR delta rearrangement as a control. We conclude that the use of this simplified methodology is a valuable tool for the follow-up of MRD in a majority of ALL patients, though in a few cases, sequencing needs to be performed to achieve a relevant sensitivity. The possibility of clonal evolution requires a cross-control of any sample becoming negative whatever the initial rearrangement used to generate a probe. In patients on therapy, sequential search for MRD seems to be a good tool for predicting the long-term outcome. In addition, patients remaining positive at the time treatment is discontinued or with a high tumor burden after a few months therapy may be at a higher risk of subsequent relapse, although a longer follow-up is needed to answer this question.

scholarly journals Immunophenotypic Profile of Blast Cells as a Marker for Diagnosis of Relapsed Children Acute Lymphoblastic Leukemia

2021 ◽  
Vol 6 (1) ◽  
pp. 56-64
Author(s):  
O. A. Vynnytska ◽  
◽  
O. I. Dorosh ◽  
L. Ya. Dubey ◽  
N. V. Dubey
Keyword(s):  
Bone Marrow ◽  
Acute Lymphoblastic Leukemia ◽  
Complete Remission ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Chromosomal Translocation ◽  
Cytostatic Therapy ◽  
Blast Cells ◽  
Minimal Residual

Immunophenotyping of leukemia cells was studied in this work; minimal residual disease was monitored among children with acute lymphoblastic leukemia under conditions of relapse and complete remission after the application of ALLIC-BFM 2009 cytostatic therapy. The study showed that after application of ALLIC-BFM 2009 therapy, 88% of children had complete remission, and 12% had relapses. Among patients with relapses, the number of blast cells in the bone marrow was at a high level (more than 6%). Monitoring of patients during therapy established an increase in the minimal residual disease level of more than 1% after treatment in patients with recurrent disease. Immunophenotyping of blast cells among patients with relapse showed the expression of linear independent antigens HLA (93%), Auti-TdT (91%), CD10 (78%), CD38 (91%) and CD34 (57%) and B-linear antigens: CD19, CD22, CD58, CD79a, the highest expression was found for the CD19 antigen. A low level of expression of CD45 (28%) was recorded with relapses of acute lymphoblastic leukemia and high (89%) level was with complete remission of the disease. We did not detect expression of antigens characteristic of T-cell acute lymphoblastic leukemia in bone marrow of patients with acute lymphoblastic leukemia, both with relapses and with remission. At the same time, the expression of myeloid antigens (CD33 and CD13) was noted among acute lymphoblastic leukemia patients. Among patients, the incidence of acute lymphoblastic leukemia was the most pronounced in children aged from 3 to 6 years – 37 patients (35.2%) and aged from 6 to 9 years – 26 (24.8%) patients. The highest accidence was found among patients with chromosomal translocation TEL / AML – 22 (21%) patients with a median age 5 years. In second place, the frequency of mutations is the translocation of E2A / PBX1. BCR / ABL translocation was less common. It was noted in 1.9% of patients, but the expression of this gene indicated a bad course of the disease, as patients after cytostatic therapy under the ALLIC BFM 2009 program had a recurrence. Recurrence was also observed in patients with TEL/AML chromosomal translocation. Determination of minimal residual disease showed its increased level in patients with chromosomal aberrations BCR / ABL and TEL/AML throughout the treatment phase. In addition, patients in these groups were diagnosed with initial leukocytosis followed by leukopenia after a course of chemotherapy. Patients of all groups showed a decrease in hemoglobin. The biggest changes in clinical and laboratory parameters were found between patients with chromosomal translocations BCR/ABL and TEL/AML, as evidenced by the development of relapses in patients of these groups. The low level of association between karyotype disorders, with the formation of AF4/MLL and E2A/PBX1, and clinical and laboratory parameters in patients with acute lymphoblastic leukemia may indicate that the isolated clonal disorders are independent prognostic factors for the course of the disease

scholarly journals Blinatumomab for minimal residual disease in adults with B-cell precursor acute lymphoblastic leukemia

Blood ◽  
2018 ◽  
Vol 131 (14) ◽  
pp. 1522-1531 ◽  
Author(s):  
Nicola Gökbuget ◽  
Hervé Dombret ◽  
Massimiliano Bonifacio ◽  
Albrecht Reichle ◽  
Carlos Graux ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
Complete Remission ◽  
B Cell ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Cell Precursor ◽  
Hematopoietic Stem ◽  
Grade 3 ◽  
Minimal Residual

Abstract Approximately 30% to 50% of adults with acute lymphoblastic leukemia (ALL) in hematologic complete remission after multiagent therapy exhibit minimal residual disease (MRD) by reverse transcriptase–polymerase chain reaction or flow cytometry. MRD is the strongest predictor of relapse in ALL. In this open-label, single-arm study, adults with B-cell precursor ALL in hematologic complete remission with MRD (≥10−3) received blinatumomab 15 µg/m2 per day by continuous IV infusion for up to 4 cycles. Patients could undergo allogeneic hematopoietic stem-cell transplantation any time after cycle 1. The primary end point was complete MRD response status after 1 cycle of blinatumomab. One hundred sixteen patients received blinatumomab. Eighty-eight (78%) of 113 evaluable patients achieved a complete MRD response. In the subgroup of 110 patients with Ph-negative ALL in hematologic remission, the Kaplan-Meier estimate of relapse-free survival (RFS) at 18 months was 54%. Median overall survival (OS) was 36.5 months. In landmark analyses, complete MRD responders had longer RFS (23.6 vs 5.7 months; P = .002) and OS (38.9 vs 12.5 months; P = .002) compared with MRD nonresponders. Adverse events were consistent with previous studies of blinatumomab. Twelve (10%) and 3 patients (3%) had grade 3 or 4 neurologic events, respectively. Four patients (3%) had cytokine release syndrome grade 1, n = 2; grade 3, n = 2), all during cycle 1. After treatment with blinatumomab in a population of patients with MRD-positive B-cell precursor ALL, a majority achieved a complete MRD response, which was associated with significantly longer RFS and OS compared with MRD nonresponders. This study is registered at www.clinicaltrials.gov as #NCT01207388.

scholarly journals CD20 up-regulation in pediatric B-cell precursor acute lymphoblastic leukemia during induction treatment: setting the stage for anti-CD20 directed immunotherapy

Blood ◽  
2008 ◽  
Vol 112 (10) ◽  
pp. 3982-3988 ◽  
Author(s):  
Michael N. Dworzak ◽  
Angela Schumich ◽  
Dieter Printz ◽  
Ulrike Pötschger ◽  
Zvenyslava Husak ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cells ◽  
Induction Treatment ◽  
Cell Precursor ◽  
Anti Cd20 ◽  
The Impact

Abstract CD20 is expressed in approximately one- half of pediatric acute lymphoblastic leukemia (ALL) cases with B-cell precursor (BCP) origin. We observed that it is occasionally up-regulated during treatment. To understand the impact of this on the potential effectiveness of anti-CD20 immunotherapy, we studied 237 CD10+ pediatric BCP-ALL patients with Berlin-Frankfurt-Munster (BFM)–type therapy. We analyzed CD20 expression changes from diagnosis to end-induction, focusing on sample pairs with more than or equal to 0.1% residual leukemic blasts, and assessed complement-induced cytotoxicity by CD20-targeting with rituximab in vitro. CD20-positivity significantly increased from 45% in initial samples to 81% at end-induction (day 15, 71%). The levels of expression also increased; 52% of cases at end-induction had at least 90% CD20pos leukemic cells, as opposed to 5% at diagnosis (day 15, 20%). CD20 up-regulation was frequent in high-risk patients, patients with high minimal residual disease at end-induction, and patients who suffered later from relapse, but not in TEL/AML1 cases. Notably, up-regulation occurred in viable cells sustaining chemotherapy. In vitro, CD20 up-regulation significantly enhanced rituximab cytotoxicity and could be elicited on prednisolone incubation. In conclusion, CD20 up-regulation is frequently induced in BCP-ALL during induction, and this translates into an acquired state of higher sensitivity to rituximab. This study was registered at http://www.clinicaltrials.gov as #NCT00430118.

CD20 up-Regulation in Childhood B-Cell Precursor Acute Lymphoblastic Leukemia during Induction Treatment Translates into Higher Rituximab-Sensitivity.

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 906-906
Author(s):  
Andishe Attarbaschi ◽  
Angela Schumich ◽  
Georg Mann ◽  
Oskar A. Haas ◽  
Helmut Gadner ◽  
...  
Keyword(s):  
Acute Lymphoblastic Leukemia ◽  
B Cell ◽  
Induction Therapy ◽  
Residual Disease ◽  
Lymphoblastic Leukemia ◽  
Leukemic Cells ◽  
Remission Induction ◽  
Induction Treatment ◽  
Cell Precursor ◽  
The Impact

Abstract CD20 is expressed in about one half of childhood acute lymphoblastic leukemia (ALL) cases with B-cell precursor (BCP) origin. We recently observed that this phenotypic marker is further up-regulated in some patients during remission induction treatment containing corticosteroids for up to 5 weeks. To understand the impact of this phenomenon on the potential effectiveness of anti-CD20 immunotherapy (i.e., Rituximab), we studied 237 CD10-positive childhood BCP-ALL patients consecutively enrolled onto the trial AIEOP-BFM-ALL 2000. The analysis included the assessment of CD20 expression changes from diagnosis to the end of induction therapy and complement-induced cytotoxicity by CD20-targeting with Rituximab in-vitro. CD20-positivity significantly increased from diagnosis to the end of induction therapy with respect to the number of positive cases as well as to the levels of expression. After completion of induction therapy, one half of cases showed ≥ 90% CD20pos. leukemic cells, as opposed to 5% at diagnosis and 20% after 2 weeks of chemotherapy. Notably, up-regulation occurred in viable cells sustaining chemotherapy, most probably as a consequence of steroid-induced modulation of gene expression. Rituximab-cytotoxicity was significantly enhanced by CD20 up-regulation and depended on high expression levels. Importantly, CD20 up-regulation was frequent in high-risk patients (mainly poor prednisone responders), patients with high minimal residual disease levels at the end of induction therapy, and patients who suffered later from relapse, but not in TEL/AML1-positive cases. In conclusion, CD20 up-regulation is frequently induced in BCP-ALL during induction therapy and this translates into an acquired state of higher sensitivity to Rituximab.

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