Therapy Of Adult Acute Lymphoblastic Leukemia Research Articles

Acute Lymphoblastic Leukemia

Acute Lymphoblastic Leukemia

Hematopoietic Cell Transplantation in the Treatment of Adult Acute Lymphoblastic Leukemia: Updated 2019 Evidence-Based Review from the American Society for Transplantation and Cellular Therapy.

The role of hematopoietic cell transplantation (HCT) in adults with acute lymphoblastic leukemia (ALL) is reviewed and critically evaluated in this systematic evidence-based review. Specific criteria were used for searching the published literature and for grading the quality and strength of the evidence and the strength of the recommendations. A panel of ALL experts developed consensus on the treatment recommendations based on the evidence. Allogeneic HCT offers a survival benefit in selected patients with ALL, and this review summarizes the standard indications as well as the areas of controversy. There is now greater experience with pediatric-inspired chemotherapy regimens that has transformed upfront therapy for adult ALL, resulting in higher remission rates and overall survival. This in turn has increased the equipoise around decision making for ALL in first complete remission (CR1) when there is no measurable residual disease (MRD) at the end of induction and/or consolidation. Randomized studies are needed for adults with ALL to compare allogeneic HCT in CR1 with pediatric-inspired chemotherapy alone. Indications for transplantation in the evolving landscape of MRD assessments and novel targeted and immune therapeutics remain important areas of investigation.

Intensified Therapy of Acute Lymphoblastic Leukemia in Adults: Report of the Randomized GRAALL-2005 Clinical Trial.

Purpose To evaluate randomly the role of hyperfractionated cyclophosphamide (hyper-C) dose intensification in adults with newly diagnosed Philadelphia chromosome-negative acute lymphoblastic leukemia treated with a pediatric-inspired protocol and to determine the upper age limit for treatment tolerability in this context. Patients and Methods A total of 787 evaluable patients (B/T lineage, 525 and 262, respectively; median age, 36.1 years) were randomly assigned to receive a standard dose of cyclophosphamide or hyper-C during first induction and late intensification. Compliance with chemotherapy was assessed by median doses actually received during each treatment phase by patients potentially exposed to the full planned doses. Results Overall complete remission (CR) rate was 91.9%. With a median follow-up of 5.2 years, the 5-year rate of event-free survival (EFS) and overall survival (OS) was 52.2% (95% CI, 48.5% to 55.7%) and 58.5% (95% CI, 54.8% to 61.9%), respectively. Randomization to the hyper-C arm did not increase the CR rate or prolong EFS or OS. As a result of worse treatment tolerance, advanced age continuously affected CR rate, EFS, and OS, with 55 years as the best age cutoff. At 5 years, EFS was 55.7% (95% CI, 51.8% to 59.4%) for patients younger than 55 years of age versus 25.8% (95% CI, 19.9% to 35.6%) in older patients (hazard ratio, 2.16; P < .001). Patients ≥ 55 years of age, in whom a lower compliance to the whole planned chemotherapy was observed, benefited significantly from hyper-C, whereas younger patients did not. Conclusion No significant benefit was associated with the introduction of a hyper-C sequence into a frontline pediatric-like adult acute lymphoblastic leukemia therapy. Overall, tolerability of an intensive pediatric-derived treatment was poor in patients ≥ 55 years of age.

Probing the AML Surfaceome for Chimeric Antigen Receptor (CAR) Targets

Adoptive T cell therapy using chimeric antigen receptors (CARs) to redirect the specificity and function of T lymphocytes has demonstrated efficacy in patients with lymphoid malignancies, in particular acute lymphoblastic leukemia (ALL). CD19 CAR therapy can induce durable complete remissions in subjects with CD19+ malignancies for whom chemotherapies have led to drug resistance and tumor progression. We previously obtained "breakthrough designation" from the US FDA for CD19 CAR therapy for adult ALL. The success of CD19 CAR therapy bodes well for tackling other hematological malignancies, including Acute Myeloid Leukemia (AML).The challenge for developing an effective CAR therapy for AML lies in the lack of suitable CAR targets. In ALL, CD19 is expressed on most if not all tumor cells, including tumor-initiating cells, and is only expressed in the normal B cell lineage. In contrast, the AML CAR targets proposed to date (Le-Y, CD123, CD33 and folate receptor-β) do not share this profile. They have not yielded effective and safe tumor eradication in early clinical studies. The clonal heterogeneity of AML and the similarity of AML cancer stem cells to normal hematopoietic stem cells pose additional challenges. Searching for better targets is thus essential. However, the identification of CAR targets is limited by the lack of reliable tools to assess antigen expression across all human tissues.In order to identify suitable CAR targets for AML, we integrated multiple transcriptomic and proteomic data sources and created an algorithm to identify proteins that can be targeted by single and combinatorial CAR strategies. To comprehensively probe the AML surfaceome, we compiled 474 molecules identified in previous studies and 3,675 molecules we identified by membrane protein biotinylation followed by Mass-Spectometry analysis. To assess whole body antigen expression, we integrated large sets of protein and mRNA expression data and annotated the expression of each AML surface molecule in normal cell types, tissues and organs, including hematopoietic stem cells (HSCs).We then established a "quality control" filter to assign priority antigens, based on their presence in at least two protein expression datasets (Human Protein Atlas, Human Protein Map and/or Proteomics Database) and their membrane-association. This step yielded 1,694 AML molecules. We further selected molecules with low expression in 64 normal tissues/organs and excluded antigens with high expression in bone marrow HSCs. These steps reduced candidate targets to 215 proteins.From these, we identified 32 targets overexpressed in diverse AML cells and showing very low overall expression in normal tissues. We performed systematic validation analyses by flow cytometry and identified 11 top candidates with low expression in normal CD34+ and CD34+CD38- HSCs and high expression in a panel of AML cells. Further elimination of molecules expressed in T cells reduced the candidate target number to 4, including 2 G-protein coupled receptors not previously reported as CAR targets in AML.These molecules were however still minimally expressed in some normal tissues, which prompted us to search for pairs of antigens with non-overlapping expression in normal tissues as a strategy to reduce on-target/off-tumor cytotoxicity. We identified 55 such pairs. Our validation studies have so far identified 3 unique pairs of targets showing absent co-expression in normal tissues and ~100% co-expression in a small panel of AML cells. These promising pairs are targeted by T cells co-expressing a CAR specific for one antigen and a chimeric costimulatory receptor (CCR) specific for the other. In a proof-of-principle study, we demonstrate that dual-targeted CAR T cells specific for CD33 and CD70 effectively lyse AML cells with diminished reactivity relative to single-targeted CAR T cells. Further validation studies in larger AML panels are in progress.This novel discovery approach to CAR target identification should prove very useful to expand CAR therapy applications to AML and other malignancies. DisclosuresSadelain:Juno Therapeutics: Consultancy.

Adult ALL Patients Treated with Pediatric Inspired Trials Have Inacceptable Early Death but Better Relapse Free Survival Compared to Adult Trials: A Tunisian Single Center Experience

Abstract 4297 Background:In Tunisia children with acute lymphoblastic leukemia (ALL) are treated according to the EORTC 58951 protocol with complete remission rate (CR) of 84% and long-term survivals reaching 80% at 5 years. Survivals of adult ALL remain disappointing mainly because of the high rate of early deaths, the limited number of allografted patients performed only for those aged < 40y, and lack of access to the international bone marrow donors registry. Are the improvements made in the last decades in developed countries in the treatment of adult ALL transposable for patients diagnosed in developing countries? The aim of the present study is to report the experience of a Tunisian hematology center in the management of adult ALL. Patients and methods:Fifty one adult ALL patients were treated with three consecutive trials in the hematology department of Aziza Othmana university hospital of Tunis between January 2005 and July 2011.18 patients were treated with Tunisian LALA03 protocol (pediatric –inspired induction) between 2005 and 2007: BFM-like HR induction (PND 60mg/m2x22d, VCRx4, DNR 30mg/m2x4, ASPx8). HR patients receive 6 consolidations blocs (GRAALL03 blocs) + CNS RT+ maintenance therapy. SR patients receive EORTC AR2 consolidations (IB, interval therapy, IIAIIB) +CNS RT +maintenance therapy. This protocol led to an inacceptable rate of induction death of 38.8%. 24 and 9 patients were respectively treated with Hyper-CVAD regimen from 2008 to 2010 and GRAALL05 since 2010. Results:Male/female ratio was is 2.6. Median age was 37.5 years (21–59). Immunophenotyping revealed B-cell precursor and T-lineage ALL in respectively 60% and 35% of patients. 1 patient had biphenotypic leukemia and the immunophenotype was not precised in one case. Median baseline WBC count was 18.2 × 109/L (0.3–265 ×109/L). Three patients presented with central nervous system (CNS) disease at diagnosis. 21.5% of patients have Philadelphia positive ALL. Only 14 patients had SCT from a matched sibling donor. Complete remission rate after induction was 74.5%. Eight patients (15.6%) had early death during induction from septic shock and pneumonia in 5 and 3 cases respectively. Median overall survival (OS) was 18 months. 3 years OS was 30%. By univariate analysis, age less than 32 years (p=0.01) and bone marrow transplantation (p=0.04) had positive impact on OS. For the whole study population 3 year relapse free survival (RFS) was 20%. Despite a lower RFS with Hyper CVAD there was no significant difference between the three trials but a trend to better outcome with pediatric inspired trials i.e. LALA03 and GRAALL05. Conclusion:Pediatric-inspired protocols are associated with increased early death but prolonged remission duration compared to Hyper-CVAD. Hyper-CVAD is well tolerated but is associated to a high rate of relapse in our patients mainly because of the small number of SCT. The outcome of adult ALL in Tunisia is still unsatisfactory and can be improved with pediatric-like regimens. Effective therapy for adult ALL is feasible in our country. Controlling death induction by supportive measures and better management of myelosuppression and offering a stem cell transplant to a greater number of patients could be an option to improve on the RFS and OS. Disclosures:No relevant conflicts of interest to declare.

Which steroids should we choose for the treatment of adult acute lymphoblastic leukemia?

Corticosteroids are essential and one of the mainstays in the treatment of acute lymphoblastic leukemia (ALL). In vitro assays show that dexamethasone(DXM) is five to six times more cytotoxic to leukemic lymphoblasts than prednisolone (PDN) [1], and the use of DXM as an alternative drug for PDN is an important issue in the treatment of childhood ALL. The current randomized comparisons in childhood ALL indicated a statistically significant and clinically important decrease in rate of isolated central nervous system (CNS) relapses and an increase in event-free survival (EFS) with DXM. However, the data were limited in adult ALL. Recently, Labar et al. [2] reported their first investigation in comparison of the antileukemic activity and toxicity between DXM and PDN for adult patients with ALL and lymphoblastic lymphoma (LBL) through a randomized clinical trial (the ALL-4 trial of the EORTC Leukemia Group), and the author concluded that DXM as a steroid therapy for adult patients with ALL/LBL did not show any benefit compared with PDN, which did not support the experience from several other pediatric studies. In Labar’s observation, about 70% of adult patients were high risk (HR) ALL. Most of the patients in pediatric trials were standard risk (SR) ALL. In our study, we also evaluate the role of DXM compared with PDN during induction or subsequent phases of therapy in adult ALL with emphasis on SR group.

Adult acute lymphoblastic leukemia: concepts and strategies.

Acute lymphoblastic leukemia (ALL), a clonal expansion of hematopoietic blasts, is a highly heterogeneous disease comprising many entities for which distinct treatment strategies are pursued. Although ALL is a success story in pediatric oncology, results in adults lag behind those in children. An expansion of new drugs, more reliable immunologic and molecular techniques for the assessment of minimal residual disease, and efforts at more precise risk stratification are generating new aspects of adult ALL therapy. For this review, the authors summarized pertinent and recent literature on ALL biology and therapy, and they discuss current strategies and potential implications of novel approaches to the management of adult ALL. Cancer 2010. (c) 2010 American Cancer Society.

Outcome for Adolescents and Young Adults (AYA) with the Hyper-CVAD (with or without Rituximab) Regimens for De Novo Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma.

Abstract 3084Poster Board III-21AYAs aged 16–20 yrs with de novo ALL or LL have superior outcomes when treated with intensive pediatric regimens; event-free survival rates range from 60–70% compared to 30–40% after conventional adult chemotherapy [Stock W, Blood 112:1646, 2008]. This is in part attributed to higher dose intensity (and cumulative dose) of the anthracycline, vincristine [VCR], corticosteroid and asparaginase components. The intensive hyper-CVAD regimen (fractionated cyclophosphamide, VCR, doxorubicin, dexamethasone alternating with methotrexate and cytarabine) was originally modeled after childhood therapy for Burkitt lymphoma, and had been applied as frontline adult ALL therapy without age restriction since 1992. In contrast to conventional adult or pediatric ALL regimens, asparaginase is not administered during induction or consolidation phases. Modifications to the regimen have included the addition of rituximab for CD20 positive precursor B-cell ALL owing to adverse influence of CD20 expression, particularly in the younger subgroup [Thomas D, Blood 113:6330, 2009]. An adapted augmented Berlin-Frankfurt-Munster (BFM) regimen modeled after the CCG experience was developed specifically as frontline therapy for adolescents and adults up to age 30 in lieu of the hyper-CVAD regimen at our institution; accrual is ongoing. We updated the previous comparative hyper-CVAD experience in this young adult subset. One hundred seventy-six pts aged 13 to 30 yrs (median 22 yrs) with de novo ALL (n=149) or LL (n=27) were treated with hyper-CVAD (n=96) or modified hyper-CVAD (25 with anthracycline intensification, 55 without; 32 overall with rituximab). Eighty-three (47%) were less than 21 years of age (median 19 yrs). Forty-nine (29%) were CD20 positive. Overall complete remission (CR) rate was 97%; overall 3-yr CR duration (CRD) and survival (OS) rates were 65% and 70%, respectively. Rates for 3-yr CRD and OS were 68% and 75% if age 21 yrs or less, compared with 60% and 66%, respectively, if age 22 to 30 yrs (p=NS). The addition of rituximab improved the 3-yr CRD rates from 26% to 65% (p=.001) and 3-yr OS rates from 47% to 75% (p=.05) for the CD20 positive precursor B-cell ALL subsets, partly accounting for the improvement in outcomes. There were no significant differences in outcome by regimen for the CD20 negative subsets (all 3-yr rates > 70%). Outcomes with the hyper-CVAD regimens in AYAs appear to more closely resemble those of the pediatric approaches than the conventional regimens; incorporation of pegylated asparaginase and intensification of vincristine/corticosteroids (e.g., augmented hyper-CVAD) may further improve the efficacy of this regimen in the frontline setting. Incorporation of rituximab or the novel CD20 antibodies such as ofatumumab into the pediatric regimens warrants consideration. DisclosuresNo relevant conflicts of interest to declare.

Acute Lymphoblastic Leukemia (ALL) or Lymphoblastic Lymphoma (LL) after Frontline Therapy with Hyper-CVAD Regimens.

AYAs aged 16–20 with de novo ALL or LL have superior outcomes when treated with intensive pediatric regimens; event-free survival (EFS) rates range from 60–70% compared to 30–40% after conventional adult chemotherapy [Stock W, Blood 2008, e-pub]. This is in part attributed to higher dose intensity (and cumulative dose) of the anthracycline, vincristine [VCR], corticosteroid and asparaginase components. Of note, the intensive hyper-CVAD regimen (cyclophosphamide, VCR, doxorubicin, dexamethasone alternating with methotrexate/cytarabine) was originally modeled after childhood therapy for Burkitt lymphoma. It has been applied as frontline adult ALL therapy without age restriction since 1992. In contrast to conventional adult or pediatric ALL regimens, asparaginase is not administered during the induction or consolidation phases. Modifications to the regimen have included the addition of rituximab for CD20 positive precursor B-cell ALL and LL owing to adverse influence of CD20 expression, particularly in the younger subgroup [Thomas D, Blood 2008, e-pub]. An adapted augmented Berlin-Frankfurt- Munster (BFM) regimen modeled after the CCG experience was developed specifically as frontline therapy for adolescents and adults up to age 30 in lieu of the hyper-CVAD regimen at our institution; accrual is ongoing. We reviewed the previous hyper-CVAD experience in the AYA subset. One hundred two pts aged 13 to 21 yrs (median 19 yrs) with de novo ALL (n=92) or LL (n=10) were treated with hyper-CVAD (15 with rituximab). Complete remission (CR) rate was 97%; 3-yr EFS and OS rates were 65% and 70%, respectively. Preliminary reports from other investigators suggest that an intensified pediatric approach may be feasible even up to age 60. The GRAALL-2003 study reported 42-mos EFS and OS rates of 55% and 58%, respectively, in 225 de novo ALL pts aged 15– 60 (median 31 yrs) [Huget F, ASCO 2008, abstr 7005]. Median follow-up was 37 mos. A similar cohort of pts treated with the hyper-CVAD regimens included 385 pts with a slightly older median age of 35 yrs. Median follow-up was 62 mos (range, 1–180 mos). EFS and OS rates for the entire cohort were 50% and 55%, respectively. For pts below the age of 35, these rates improved to 55% and 67%. Clearly age remains a prognostic factor even with intensive chemotherapy approaches. Outcomes with the hyper-CVAD regimens appear to more closely resemble those of the pediatric approaches than the conventional regimens. Continued monitoring of ongoing prospective clinical trials using pediatric regimens in adults is paramount to delineating the optimal approach.

Acute lymphoblastic leukemia in adolescents and young adults in Finland

Interest has recently been paid to adolescents and young adults with acute lymphoblastic leukemia, particularly because all reports so far published indicate that these patients have a better outcome when treated with pediatric rather than adult therapeutic protocols. There are different biological subtypes of acute lymphoblastic leukemia with distinct features and prognoses; the distribution of these subtypes is not well known among adolescents. We, therefore, studied acute lymphoblastic leukemia in adolescents and young adults aged 10 to 25 years in Finland. This population-based study included 225 consecutive patients aged 10-25 years diagnosed with acute lymphoblastic leukemia during 1990-2004. One hundred and twenty-eight patients (10-16 years) were treated with pediatric Nordic (NOPHO) protocols, and 97 patients (17-25 years) with Finnish Leukemia Group National protocols. We characterized the biological subtypes, clinical features and outcome of these patients. For the whole cohort, the remission rate was 96%, 5-year event-free survival 62% and overall survival 72%. The 5-year event-free survival was 67% for the pediatric treatment group and 60% for the adult treatment group (p=n.s.). Patients with inferior outcome were those with a white blood cell count >or= 100 x 10(9)/L, the Philadelphia chromosome and MLL. Good prognostic features were TEL-AML1, hyperdiploidy, and pediatric intermediate risk stratification. Unlike all previous studies, we found that the outcome of adolescents and young adults with acute lymphoblastic leukemia treated with pediatric or adult therapeutic protocols was comparable. The success of the adult acute lymphoblastic leukemia therapy emphasizes the benefit of central referral of patients to academic centers and adherence to research protocols.

PEG-asparaginase

L-asparaginases have been established components in the treatment of acute leukemias for nearly 40 years. Their antitumor effect results from the depletion of asparagine, an amino acid essential to leukemic cells, and subsequent inhibition of protein synthesis leading to considerable cytotoxicity. The efficacy of L-asparaginases has been limited by a high rate of hypersensitivity reactions and development of anti-asparaginase antibodies, which neutralize their activity. PEG-asparaginase, a form of Escherichia coli L-asparaginase covalently linked to polyethylene glycol, was rationally synthesized to decrease immunogenicity of the enzyme and prolong its half-life. In recent years, clinical trials have established the importance of intramuscular PEG-asparaginase in frontline pediatric and adult acute lymphoblastic leukemia therapy. Present studies are evaluating the feasibility of intravenous PEG-asparaginase administration.

Thrombotic Events in Adults with Acute Lymphoblastic Leukemia.

A strong link between asparaginase-containing (ase +) chemotherapy regimens and venous thrombotic events (VTE) has been established for pediatric acute lymphoblastic leukemia (ALL), but this association has not been studied in adult ALL. We recently adopted as our first-line therapy for adult ALL a treatment protocol (DFCI 00–01) that employs weekly high-dose ase throughout a 27 week intensification phase. We reviewed the records of 92 adult patients consecutively accrued at Princess Margaret Hospital (from Jan 2000 to Dec 2003) for venous thrombotic events (VTE). Median age at diagnosis of ALL was 41±17 y, or 19±3 y for those who presented after a history of pediatric ALL (n=6), and 42±16 y for adults who presented with de novo ALL (n=86). Thirty-five (37%) were female, 59 (63%) male. Twenty-four (26%) were Philadelphia-chromosome positive; 71% of these received regimens containing imatinib. At least 1 symptomatic, radiologically confirmed VTE was seen in 19 patients (21%), with 3 (3%) diagnosed prior to any antileukemic therapy. Overall survival (OS) versus thrombosis-free survival (TFS) is illustrated in the Kaplan-Meier curve below. Median time to VTE was 94±92 d [95% CI]. Average age of patients with VTE was 44 ±15y; no events were observed in patients with a prior pediatric history of ALL. The sites of VTE were: 10/22 (46%) in the lower extremities, 5/22 (23%) propagating from central venous access catheters (CVAC), 4/22 (18%) as pulmonary emboli (2 in isolation), and 3/22 (14%) CNS (2 cerebral venous sinus and 1 retinal venous thrombus). The first antileukemic regimen administered was DFCI 00–01 ± imatinib in 79/92 (86%), HyperCVAD ± imatinib in 7 (8%), an unclassified ase+ regimen in 1 (1%), or an unclassified asparaginase-excluding (ase−) regimen in 5 (5%). A significant difference in the rate of ase-dependent VTE was observed when all regimens (1° or subsequent) were counted, with 18 VTE during 103 ase+ regimens (17.5%), versus only 1 VTE in 32 ase− regimens (3.1%), [p=0.04]. Median time to VTE in DFCI 00-01was 109±98d, most often occurring during the intensification phase. The odds ratio for VTE with any T-cell subtype of ALL compared to any B-cell subtype was 4.6 [p=0.0043].Conclusions: A high, significant VTE rate (~18%) was observed in adults with ALL undergoing ase+ antileukemic therapy, nearly 6X the rate observed either prior to treatment or during ase− regimens (~3%). Ase is thus strongly associated with VTE, warranting improved surveillance and antithrombotic prophylaxis. Risk factors (underlying thrombophilias, leukemic subtypes) similarly deserve further study. [Display omitted]

Prognostic Factors in Adult Acute Lymphoblastic Leukemia

The prognosis of patients with acute lymphoblastic leukemia (ALL), treated with modern chemotherapeutic regimens, is dependent on a number of variables. The major prognostic factors for survival in adult ALL are age, cytogenetic abnormalities, immunologic subtype, white blood cell (WBC) count, and time to achieve complete remission (CR). Determination of these factors is crucial for adapting post remission therapy in adult ALL. Indeed, risk-adapted strategies based on those biologic and clinical features are currently being applied to improve survival.In this review, we report the different prognostic factors described in adult ALL and discuss the controversies in current adult ALL management in relation with these different features. The data reported are derived from the medical literature and from the experience of the authors. Prognostic factors appear to be time-dependent. This emphasizes their determination according to the phase of treatment. The use of time-segmented multivariate analysis able to distinguish prognostic factors associated with the induction phase and those associated with the post-induction phase of treatment seems suitable to define accurately prognostic models.

Adult acute lymphoblastic leukemia: results of the Iowa HOP-L protocol.

Fifty-nine consecutive previously untreated adult patients with acute lymphoblastic leukemia (ALL) were entered onto a prospective single-arm trial of doxorubicin, vincristine, prednisone, and asparaginase (HOP-L) induction therapy followed by CNS prophylaxis and 3 years of maintenance therapy. Consolidation therapy was not administered. The study population included a large number of older (greater than 50 years) patients. Seventy-five percent of patients achieved complete remission. With a median follow-up of 6 years, the median duration of complete remission is greater than 4 years, with 53% of patients expected to remain in remission at both 3 and 5 years. Overall, median survival duration is 27.9 months, with 45% and 35% of all patients expected to survive 3 and 5 years, respectively. Multivariate analysis identified patients with T-cell disease and mediastinal masses (P less than .001) and those with low values of lactic dehydrogenase (LDH) (P = .057) as being at greatest risk of relapse. Therapy was well tolerated by patients under age 35, but older patients suffered appreciable mortality. We conclude that this treatment program is effective therapy for adult ALL, yielding a large proportion of durable remissions despite the exclusion of consolidation therapy.