Blood Reviews
Volume 26, Issue 1 , Pages 25-32, January 2012

Chemoimmunotherapy in acute lymphoblastic leukemia

  • Dieter Hoelzer

      Affiliations

    • ONKOLOGIKUM, Frankfurt am Museumsufer, Frankfurt, Germany
    • Corresponding Author InformationCorresponding author at: ONKOLOGIKUM, Frankfurt am Museumsufer, Schaubstr. 16, D-60596 Frankfurt, Germany. Tel.: +49 69 650073 170; fax: +49 69 650073 180.
    • ,
  • Nicola Gökbuget

      Affiliations

    • Department of Internal Medicine II, Hematology and Oncology, Goethe University Hospital, Frankfurt, Germany

published online 30 September 2011.

Article Outline

Abstract 

ALL blast cells express a variety of specific antigens e.g. CD19, CD20, CD22, CD33, and CD52, which serve as targets for Monoclonal Antibodies (MoAbs). So far, the most experience is available for anti-CD20 (rituximab), which has been combined with chemotherapy for treatment of mature B-ALL/Burkitt's lymphoma. Studies with rituximab have also been completed in B-precursor ALL. Another antigen, CD19, is of great interest due to a very high rate of expression in ALL. It can be targeted by a bispecific monoclonal antibody, Blinatumomab, directed against CD19 and CD3. Smaller studies or case reports are also available for the anti CD52 antibody (Alemtuzumab), for anti CD22 (Epratuzumab) or anti CD33 (Gemtuzumab). Available data demonstrate that MoAb therapy in ALL is a highly promising targeted treatment. However, several details for an optimal treatment approach e.g. the required level of antigen expression, timing, schedule, dosage and stage of disease still need to be defined.

Keywords: Acute lymphoblastic leukemia, Antigen expression on ALL cells, Prognostic impact of CD20 expression, Targeted therapy with monoclonal antibodies, Experience with anti-CD20, Rituximab, New bispecific MoAbs, Older adults with ALL, Blinatumomab, Anti-CD52, Alemtuzumab, Anti-CD22, Epratuzumab

 

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1. Introduction 

Treatment outcome of adult acute lymphoblastic leukemia (ALL) has been substantially improved in the last decade, mainly by intensification and optimization of chemotherapy, risk-adapted use of stem-cell transplantation, and improved supportive care.[1], [2] Individualized treatment strategies based on prognostic factors, including the evaluation and monitoring of Minimal Residual Disease (MRD) have contributed to improved outcomes. However, results in adult patients are still considerably inferior to those in pediatric ALL and treatment related toxicity is a barrier to further intensification of standard chemotherapy, particularly in older patients. A major breakthrough in the treatment of acute lymphoblastic leukemia was the availability of targeted therapies—either targeting specific transcripts as bcr-abl fusion protein by Tyrosine Kinase Inhibitors (TKI) or by targeting specific antigens by Monoclonal Antibodies (reviewed in3).

Therapy with MoAbs is not only targeted, but also subtype-specific, and compared to chemotherapy has different mechanisms of action and side-effects. MoAbs can be administered (1) in an unconjugated form (e.g. rituximab); (2) conjugated to immunotoxins or chemotherapeutic agents, which are delivered to the target cell by the antibody; (3) conjugated to radioactive molecules, which deliver radiation selectively to malignant cells; or (4) as bispecific antibodies, which are directed to two target antigens or recruit immunologically active cells to the leukemia blasts. In addition, the synergistic effect of combined antibody and chemotherapy can be utilized. MoAb therapy will be reviewed in depth based on the available clinical experience in ALL.

1.1. Expression of surface antigens in ALL 

ALL blast cells express a variety of lineage-specific antigens and combinations of antigens are used for establishing the diagnosis and defining immunological subtypes. A prerequisite for MoAb therapy was generally the presence of the target antigen on at least 20% of the leukemic blasts, but this cut-point is not used by all investigators. Table 1 depicts the surface antigen expression with a cut of >20% positive leukemia blast cells according to ALL subtypes. The results are from two large adult ALL series including more than 500 patients each for the most relevant surface antigens and the monoclonal antibodies directed against them.

Table 1. Expression of surface antigens for potential antibody therapy in ALL.
Surface antigenALL subtypeExpression on >20% of LBCMonoclonal antibody
ThielaRaponi4
CD19B-precursor Mature B-ALL95% 94%100% 100%Blinatumomab
CD20B-precursor Mature B-ALL41%86%22–30%100%Rituximab
CD22B-precursor Mature B-ALL60–85%69%93–96%100%Epratuzumab
CD33B-precursor T-precursor Ph+ ALL23% 40% 9%17–26%Gemtuzumabb ozogamicin
CD52B-precursor T-precursor79% 77% Alemtuzumab

aData from the German Multicentre Study Group for Adult ALL (GMALL) central Immunophenotyping, E. Thiel, S. Schwartz, Berlin, Germany (personal communication).

bNot available anymore.

It is presumed that the response to a MoAb correlates with the percentage of ALL cells expressing a specific antigen. There is also some evidence that the activity of antibodies depends on the amount of antigen expressed on the cell surface of individual cells, although only few data are available so far.[3], [4] The degree of antigen expression measured by mean fluorescence intensity (MFI) and/or the antibody capacity (ABC) very recently analyzed by Raponi et al.4 might influence the treatment outcome. Additionally B-or T-lineage ALL subtypes during different maturation stages have an individual antigen expression pattern and thus respond differentially to MoAb therapy.

Since target antigens are not expressed exclusively on malignant cells but also on the surface of normal hematopoietic cells, the cytotoxic effects are less selective and lead to MoAb specific side-effects such as profound B- or T-cell lymphopenia with related clinical consequences, particularly infections.

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2. CD20 antigen 

CD20 is a 33–37kDa non-glycosylated B-lymphocyte specific integral membrane phosphoprotein. The function of CD20 has not been clarified in detail but it seems to be involved in the regulation of transmembrane calcium conductance.5 CD20 is only very slowly internalized.

CD20 is expressed on normal and malignant B lymphocytes, but not on normal stem cells. Rituximab is a chimeric human/mouse monoclonal antibody against CD20. From in vitro studies, various mechanisms of action have been postulated, including complement-dependent cytotoxicity, antibody-dependent cellular cytotoxicity, and induction of apoptosis.6 The rationale for testing the addition of rituximab to chemotherapy in ALL was an increase in overall survival by ≥20% in high grade Non-Hodgkin Lymphoma7 studies. CD20 is found on about 30–40% of B-precursor ALL blasts, and its expression is more common in older adults with B-precursor ALL (40–50%). Furthermore CD20 is expressed in the majority of mature B-ALL blast cells (80–100%).

2.1. Prognostic impact of CD20 expression 

The prognostic impact of CD20 expression in B-precursor ALL is controversial (Table 2). In the largest series of 253 adult B-lineage ALL patients from MD Anderson Hospital,8 including 52 Ph+ ALL cases, the complete remission duration (CRD) at 3years as well as the overall survival (OS) was inferior for CD20+ ALL with 20% and 27% compared to a CRD of 55% and an overall survival of 40% for the CD20− ALL group. The outcome was particularly favorable for the CD20− younger age group. In contrast, another recent series of 143 15–60years old patients showed no significant difference between the 97 CD20− ALL patients with a complete remission (CR) rate, event free survival (EFS) and OS of 92%, 54% and 59% compared to the 46 CD20+ ALL cases with 89%, 47%, and 55%.9 However there was a negative prognostic value of CD20 expression within the high risk patients (WBC≥30×109/L) due to a higher cumulative incidence of relapse (Table 2). Similarly in a study with 169 children,10 CD20 expression was not associated with inferior outcome; EFS 84% in CD20+ vs. 78% for CD20− ALL. The most recent results from Bachanova and colleagues suggest that an adverse prognostic impact of CD20 expression in ALL can be overcome by allogeneic hematopoietic stem cell transplantation. They analyzed a total of 125 patients with pre-B-ALL after SCT and investigated both children and adults. The overall 5year DFS was 43% in CD20− and 55% in CD20+ ALL. Also the individual DFS results for children with 50% in CD20− ALL as compared to 62% for CD20+ ALL and in adults with 40% vs. 48% showed no significant difference. Similar results were obtained for the relapse rate after 3years. There was no clear difference observed in adult patients with 29% of relapse in CD20− ALL vs. 25% in CD20+ ALL. Also the difference in children with 38% in CD20− ALL vs. 17% in CD20+ ALL was statistically not significant (p=0.11).

Table 2. Prognostic impact of CD20 expression in B-lineage acute lymphoblastic leukemia.
CD20 Neg.CD20 Pos.
Jeha et al. Blood 2006 108; 3302–3304N=169
AgeChildren
<1,<10,>10years
EFS78%84%n.s.
Thomas et al. Blood 2009 113, 6330–6337N=253 (52 Ph+)
Age38 (15–80)39 (16–80)
Relapse rate33%68% intensified Hyper CVAD
35%80% conventional VAD/CVAD p=0.01
CRD 3years55%220%
OS40%227%
Maury et al. Haematologica 2010, 324–328N=143
N9746
Age36 (15–60)33 (17–60)n.s.
CR92%89%n.s.
EFS54%47%n.s.
OS59%55%n.s.
HR: WBC>30×109/L
Relapse rate24%70%p=0.006
EFS (42months)59%15%p=0.003
Bachanova et al. Blood 2011, 117: 5261–5263N=125 after allogeneic SCT
N6758
Overall
Age27 (0.6–66)n.s.
DFS 5years43%55%n.s.
2–4 acute GvHD43%38%n.s.
TRM19%18%n.s.
Children: N=5448%52%n.s.
DFS 5years50%62%n.s.
Relapse 3years38%17%n.s.
Adults: N=7161%39%n.s.
DFS 5years40%48%n.s.
Relapse 3years29%25%n.s.

These data altogether indicate that the impact of CD20 expression as a potential adverse factor could lose its impact with better treatment outcome, particularly in children with earlier reports of inferior event-free survival (EFS) for CD20+ ALL.

2.2. Upregulation of CD20 expression 

A new observation may lead to an extended application of rituximab in ALL. Dworzak11 found CD20 upregulation in children with B-cell precursor ALL during induction treatment, most likely due to corticosteroids. This observation was confirmed in another childhood ALL study.12 Dworzak and colleagues confirmed that drug-induced modulation rather that clonal selection causes this phenomenon and that upregulation of CD20 is more persistent than that for other antigen expressions (e.g. for CD45).13

Whether this modulation of antigen expression in B-cell precursor leukemias (common and pre B-ALL) will provide a benefit for patients with <20% CD20 expression at diagnosis has to be evaluated in ongoing studies.

2.3. Rituximab in mature B-ALL and Burkitt's NHL 

The outcome of mature B-ALL and Burkitt's NHL has been improved substantially with short intensive chemotherapy regimen derived from pediatric studies. Overall survival achieved with a variety of protocols was 50–70%. In adult patients, further treatment intensifications by increased dose-intensity e.g. of methotrexate were limited. Therefore several study groups combined rituximab with chemotherapy (Table 3). The GMALL (German Multicentre Study Group for Adult ALL) study group initiated a protocol B-ALL/NHL-2002 which uses rituximab in combination with chemotherapy. The regimen includes six 5-day chemotherapy cycles based on previous GMALL studies.14 The major new feature was that rituximab was administered at a dose of 375mg/m2 on day −1 before each chemotherapy cycle and thereafter twice for consolidation in monthly intervals for a total of eight applications.

Table 3. Treatment of Burkitt lymphoma/leukemia HIV neg. or pos. with intensive chemotherapy+rituximab.
AuthorProtocolAge (range)HAARTNCROS
Thomas et al. 2006 Cancer; 106:1569–80Hyper CVAD rituximab 8×46 (17–77) 3186%89%
Hoelzer et al. 2007; Blood 110: 518GMALL B-NHL 2002 rituximab 8×36 (16–78) 227 88%
Dunleavy et al. 2007 JCO 25: 8035DA-EPOCH rituximab 6×29 (18–66)32%19100%100%
Oriol et al. 2008a Cancer 113:117–25GMALL B-NHL 2002 rituximab 8×39 (29–54)100%1984%73%
Rizzieri et al. 2010 Blood 116:#858CALGB 9251 rituximab 7×19–79 10582%73%
Barnes et al. 2011 Ann Oncol. 2011(8):1859–64CODOX-M/IVAC rituximab 4×46 (17–78)25%4090%77%

aAll patients are HIV positive.

In a pilot study 2003, 82 patients from 39 centers entered the protocol. Out of 53 evaluable patients the CR rate in mature B-ALL was 91% and in Burkitt NHL 96%; the overall survival was 70% and 80% respectively. Rituximab administration showed no excessive toxicity. In the meantime more than 227 patients have been included. The overall survival is 88% for Burkitt NHL and 70% for mature B-ALL, which is a considerable improvement compared to the previous trial.15

In a trial by Cancer and Leukemia Group B (CALGB 9251) adult patients with Burkitt or Burkitt-like leukemia/lymphoma received a similar high intensity chemotherapy and Rituximab, intensified in cycle 2 and given for a total of 8 times.16 Out of 105 enrolled patients in 75 the 7 planned courses of therapy could be completed. 82% achieved a CR and 87% of those remained in CR. There was a clear difference in outcome based on IPi score with 2year EFS and OS for low risk patients of 98% and 92% vs. 55% and 55% for high risk patients respectively.

In the approach at the MD Anderson Cancer Center rituximab was added to the hyper-CVAD regimen (cyclophosphamide/vincristine/adriamycin/dexamethasone HDMTX/HDAraC).17 Rituximab was given at the beginning and end of the first four chemotherapy cycles, for a total of eight doses rituximab. In 31 patients with newly diagnosed Burkitt's NHL or mature B-ALL, 86% complete responses were observed, and the 3-year overall survival was 89%. The authors observed a significant reduction in relapse rate and an improvement in outcome, particularly in elderly patients. Also in this study there was apparently no additional toxicity compared to the previous protocol with chemotherapy only. In the above 2 studies the improvement in overall survival was about 30%; 88%/89% vs. 50%/53%.

Rituximab (R) was also added to the CODOX-M/IVAC regimen for a total of 4 doses. In the 40 R+ patient cohort the overall response/CR rate was 90%/90% compared to 85%/81% in the 47 R− patients. The progression free survival (PFS) and overall survival in the R+ arm was 70% and 73% compared to 61% and 68% in the R− arm. The outcome for the R+ patients was not statistically significant superior to the R− patients and it was discussed whether more frequent dosing of Rituximab might provide the optimal benefit. When the GMALL immunochemotherapy approach was applied in HIV positive Burkitt NHL, combined with antiretroviral HAART therapy, the survival rate improved to 77%.18 Overall, despite the one negative study, where the addition of rituximab did result in inferior results, it appears that rituximab added to short intensive chemotherapy regimen has substantially increased the survival rate of adult patients with mature ALL/Burkitt NHL also in HIV positive patients. The feasibility of rituximab is currently also explored in newly diagnosed pediatric patients with mature B-cell Non Hodgkin Lymphoma and Burkitt Leukemia.19

2.4. Rituximab in younger pts with CD20± B-precursor ALL 

Based on their positive experience with rituximab immunochemotherapy in Burkitts leukemia/lymphoma, study groups also explored rituximab in CD20+ B-precursor ALL. The effect of rituximab with a chemo induction and consolidation therapy was studied in CD20+ Ph/Bcr-abl negative B-precursor (Pre-B/Common) ALL in the GMALL Study 07/2003.20 Adult Standard Risk (SR) ALL patients (15–55years) with CD20+ B-precursor ALL (41% antigen expression of >20%) received 375mg/m2 rituximab at day −1 before each induction course (phases I and II) and before each of the six consolidation courses for a total of 8 doses. The aim was to reduce MRD load and thereby the relapse rate. High risk (HR) patients were candidates for a stem cell transplantation (SCT) in CR 1 and received rituximab three times (d −1 Ind. I/II and Cons I) in an attempt to reduce tumor load before SCT. Standard risk was defined in this setting as white blood cell count (WBC) <30,000/μL, achievement of CR≤4weeks and absence of the cytogenetic aberrations t(4;11), t(9;22) and high risk patients as having one or more of these factors21 (except t(9;22) patients treated differently).

A total of 185 CD20+ ALL patients were included in this study; 133 were SR and 52 HR patients. 117 received rituximab (R+ arm) and were compared to 70 patients recruited earlier without rituximab (R− arm), but which had identical chemo- and supportive therapy. In standard risk patients there was no difference in the CR rate of 94% and 93% in the R+ vs. R− patients, or in early death (ED) rates of 5% vs. 4% or failure/PR 1% vs. 2%. However, MRD course differed substantially. Decrease in MRD load in the R+ vs. R− arm was faster with a molecular CR (MRD <10−4) at day 21 of 60% vs. 19% and at week 16 of 89% vs. 57%. Probability for continuous complete remission (CCR) at 3years was correspondingly higher, 0.64 vs. 0.48, for R+ vs. R− pts. (p=0.009) and for overall survival 0.75 vs. 0.54. For HR pts OS at 3years was 0.54 vs. 0.32 in the R+ vs. R− group. In the 66% HR patients receiving a SCT in CR1, overall survival was superior for the R+ vs. R− arm with 0.75 vs. 0.40 (n.s.), due to fewer relapses. There was no excess toxicity in R+ vs. R− patients; death in CR 1 was 4% in R+ vs. 3% in the R− arm.

It was concluded that intensive chemo- plus immunotherapy with rituximab is feasible in adult SR and HR B-precursor ALL pts. There is a faster and higher Mol CR rate in the rituximab arm with an improvement of CCR and OS. Thus, rituximab+chemotherapy can improve outcome of younger adults with CD20+ B-precursor ALL.

The MD Anderson Hospital evaluated a modified Hyper-CVAD regimen combined with rituximab in de novo Ph- B-precursor ALL when CD20 expression was ≥20%22 (Table 4). In this study younger (<60years) as well as older patients were included. The complete remission rate was 95% in the younger (age<60years) CD20+ subset, the 3-year complete remission duration (CRD) was 70% in the modified R+ arm vs. 38% (p<0.001) in the R− arm and the overall survival was 75% vs. 47% (p=0.003). Since CRD and OS for the CD20− counterparts were unchanged with the different Hyper-CVAD modifications, it seems likely that rituximab was responsible for the CRD and OS improvement. Also in the CD20+ group the amount of patients with MRD-negativity (measured by multiparameter flow cytometry) was higher with 81% vs. 58% without rituximab. The absence of MRD was also associated with significantly better 3-year CRD (82%+R vs. 24% −R, p=0.002) but not OS rates (70% vs. 27%, P=NS) in part related to deaths in CR for the MRD-negative group. Altogether the conclusion was that younger CD20+ B-precursor ALL patients benefit from a chemoimmunotherapy with rituximab.

Table 4. Intensified Hyper-CVAD±rituximab if CD20 expression ≥20%.22
AgeCD20 NegativeCD20 Positive
Thomas et al. JCO 2010; 28(24): 3880–9 41 (13–83)Hyper-CVADHyper-CVAD+rituximab
NN=23N=24
Response:
CR22 (96%)24 (100%)
CRp1 (4%)
Time to CR23days21days
Relapse:
Rate12 (52%)11 (46%)
Median time to relapse10months25months
Death in CR:
Overall4 (17%)3 (13%)
≥60years43
Overall survival at 3years:
Overall44%65%
≥60years0%45%

2.5. Rituximab for older adults with CD20± B-precursor ALL 

The outcome of older adults with ALL (differentially defined as >50years or >60years depending on the study) is still poor with survival rates of approximately 10% in recent trials. Since the options for chemotherapy intensification in older adults are limited, they might benefit from the addition of a non-cytotoxic approach such as rituximab. In a GMALL study CD20+ elderly ALL patients received rituximab before each cycle of a dose-reduced chemotherapy for a total of eight applications. For an interim analysis 26 patients were evaluable. The CR rate in CD20+ ALL patients was 63% and the overall survival after 1year was 54%.15 The early mortality and relapse rate in this study was still considerably higher than in younger adults for both the CD20+ as well as CD20− ALL patients. The risk of infections during induction therapy and in remission remains a major problem, although there was no clear evidence that this problem was aggravated by the rituximab therapy. Thus in elderly B-precursor ALL the combination of chemotherapy and rituximab is feasible, but long-term results are awaited.

In the MD Anderson Hospital study described above,22 the older age group with 58 patients had a CR rate of 88% with a low early death rate. The 3-year CRD was 53% and overall survival was 29%. Although the toxicity profile for CD20− and CD20+ ALL patients was similar, the number of deaths in CR in the CD20+ subset was higher, predominantly related to infections with multidrug resistant organisms during consolidation chemotherapy in the older group. Other causes of death in this subgroup included complications related to secondary myelodysplastic syndromes, cardiovascular events, or seizure-related anoxic encephalopathy. It was concluded that older patients did not benefit from rituximab-based chemoimmunotherapy.

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3. CD19 antigen 

In nearly all B-precursor ALL patients the CD19 antigen is expressed since it appears during the early stages of B-cell maturation and development. Thus CD19 seems to be an attractive target antigen. Several MoAbs targeting the CD19 antigen have been developed, most of them conjugated to immunotoxins. These antibodies are being tested in early-phase clinical trials and some have demonstrated activity3 (Table 5).

Table 5. Antigen expression and treatment results with CD19 antibodies in ALL.
AuthorAntibodyStageNTreatmentResults
Seibel et al.44Anti-CD19+PAPaDe novo childhood15Ab+CH10 CR, 2 PR
Szatrowski et al.23Anti-CD19+ricinbDe novo adult46Ab+CHNo effect on MRD
Dinndorf et al.45Anti-CD19+ricinbRefractory/relapsed childhood19Ab(I) CR
Uckun46Anti-CD19+genisteincRefractory/relapsed childhood15Ab2 CR, 1 PR

Ab, antibody; CH, chemotherapy; CR, complete remission; PR, partial remission; MRD, minimal residual disease.

aConjugate of the pokeweed antiviral protein (PAP) immunotoxin and the MoAb B43.

bConjugate of blocked ricin and the anti-CD19 MoAb.

cConjugate of the tyrosine kinase inhibitor genistein and the MoAb B43.

Most clinical experience exists with the anti-B4-bR antibody. In the CALGB 9311 trial out of 82 patients 17–82years old, 46 with CD19+ de novo ALL received this agent. The regimen consisted of two 7-day infusions after conventional induction and one block of consolidation. Treatment was feasible in most of the patients. So far a clinical benefit in terms of remission duration or survival could not be demonstrated.23 An additional interesting approach was to evaluate MRD before and after MoAb therapy. However, a decrease in MRD level could not be demonstrated. This study, although well designed, underlines the problem of evaluating the efficacy of MoAbs in the context of complex combination regimens.

3.1. Anti CD19—Blinatumomab 

Blinatumomab is a new bi-specific, single chain antibody construct specific for CD19 and CD3.24 It is designed to target CD19 expressing cells and recruit CD3 cytotoxic T-cells to lyse CD19-expressing B-cells. Thus it combines two antigen binding sites, one specific for T-cells and the other for CD19+ leukemia blast cells. It allows T cells to kill both resting and proliferating tumor cells.

3.2. Blinatumomab in relapsed non Hodgkin B-cell lymphomas 

Blinatumomab was first explored in advanced refractory B-cell Non-Hodgkin lymphomas.24 The clinical activity and safety of increasing doses of this bispecific antibody was studied in 38 patients. They received Blinatumomab at doses from 0.0005 to 0.06mg/m2/day. A total of 11 major responses (4 CR and 7 partial regressions) were observed. All occurred at doses of 0.015mg/m2 per day and higher, indicating a dose-response relationship. All seven patients treated at the latest completed dose level of 0.06mg/m2 showed objective responses occurring within 4weeks of treatment. Adverse events of Blinatumomab treatment included pyrexia, lympho- and leukopenia, chills, increase of C-reactive protein, symptoms of the central nervous system including disorientation, confusion, speech disorders, tremor, convulsions all of which were fully reversible.24

3.3. Blinatumomab in MRD± adult ALL 

Blinatumomab was first investigated in adult B-precursor ALL patients in hematological complete remission who had detectable minimal residual disease using clone specific PCR methods to monitor the malignant clones (MRD+). This study included patients who had persistence of MRD despite clinical remission or patients who had molecular relapse after ≥3cycles of chemotherapy.25 Blinatumomab was given at a dose of 50μg/m2/day as a continuous infusion for four weeks with a two week break between cycles. Patient achieving molecular CR received 3 consolidation cycles. Molecular stable disease patients may have received 6 additional cycles in an attempt to achieve molecular CR. The primary aim of this study was to convert MRD+ by Blinatumomab into a MRD− state using a quantitative PCR with a sensitivity of ≥1×10−4. Secondary endpoints were time to hematologic relapse and incidence of severity of adverse events.26

In this GMALL study 21 patients were evaluable27 (see Table 6). Out of 14 BCR-abl negative, MRD+ ALL patients, 12 became MRD−. This included some very high risk patients: of two t(4;11) patients, one became MRD− and out of 5 BCR-abl positive, 3 became MRD− (including one patient with t315I abl kinase mutation). This accounts for an overall MRD response rate of 80%. Most patients showed a rapid response, occurring within the first cycle of treatment. The probability for relapse free survival is 78% with a median follow up of 405days. Non-hematological toxicity such as infections, nervous system disorders (1 syncope/convulsion, 1 seizure, 1 headache, and 1 somnolence) were rare,27 most likely due to the lower dose of Blinatumomab.

Table 6. Blinatumomab in MRD pos. B-precursor adult ALL patients.
Topp et al. ASH 2010 #174Topp et al. JCO 2011;20(18):2403–8
GMALL study
Number of patients enrolled21 (20 evaluable)
Age/range47 (range 20–77)
Female/male12/9

Disease characteristics
ALL subtype/MRD statusNumber of patients N=20Response MRD negative CR N
Bcr/abl negative (individual rearrangements)1412
Bcr/abl negative; t(4;11)21
Bcr/abl positive53
MRD response16/2080%
Relapses post MRD negativity4

3.4. Blinatumomab in refractory/relapsed ALL 

Blinatumomab was also evaluated in a few children and adults with relapsed/refractory ALL (Table 7). Three children were diagnosed with far advanced B-precursor ALL and recurrence after allo-MUD (Matched Unrelated Donor) SCT. All children achieved a molecular remission after Blinatumomab with tolerable toxicity.28 In an interim analysis of an ongoing study 7 adult patients 18–77years with relapsed/refractory B-precursor ALL received Blinatumomab at two different dose levels; 15 or 5μg/m²/day for the first 7days, followed by 15μg/m²/day for week 2 in both groups. Four out of five evaluable patients had a CR and 3 of them with MRD negativity. Side effects, including cytokine release syndrome (1 patient) and CNS event (1 patient) were manageable and reversible29 (Table 7).

Table 7. Blinatumomab in relapsed/refractory ALL.
Patient/
diagnosis		Age/
gender		Previous
Tx		Blinatumomab
Tx		Response
Handgretinger et. al. 2011 Leukemia: 25, 181–184Case 1
HR-B prec. ALL		7years, mCOALL->CR 2years
ALL Rez. BFM
Allo SCT MUD Clofa/Cyclo/Elop. Melph/Cytara
→ 3% LBC		15μg/m2/day cont. i.v. for 5weeks– MRD neg.
– 2nd allo SCT
hapl.
– 23months in
Mol. neg. CR
Case 2
B-prec. ALL		12years, m.ALL-BFM2000
→ CR32 months
ALL-Rez BFM
Allo SCT MUD
→2nd rel. 21months
→3d rel. 11months
Refract. 23% LBC		15μg/m2/day cont. i.v. for 6weeks– Aplasia
– Mol. neg. CR
– Second Allo
SCT MUD
Relapse
→death
Case 3
Ph+ B-prec. ALL		15years, mALL-BFM 2000
Allo SCT sib CR
1year, 1. relapse
Allo SCT MUD 2nd relapse, 2years
Dasa, Clofa, Ara C
Allo SCT
Rel. BM+ CNS
3% LBC		15μg/m2/day cont. i.v. for 4weeks– MRD neg. CR after 4weeks of Blinatumomab
– MRD pos. reoccurred 4weeks after the 4th course
Topp et al. EHA 2011
Abstract #844		7 patients
5 evaluable		18–77yearsPrior HSCT permitted15μg/m2/day i.v. for four weeks
Responders receive up to 4 cycles		– 4/5 patients achieved CR
– 3/5 became MRD negative
– 1 had an extra-medullary rel.

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4. CD52 antigen 

CD52 is a cell surface glycoprotein on most lymphoid cells of both T- and B-cell lineage, which may have a higher expression in more mature subtypes of B- or T-lineage ALL. CD52 antibodies have been first used for ex-vivo T-cell depletion of allogeneic bone-marrow grafts in order to prevent graft-versus-host disease (GvHD) without further GvHD prophylaxis, since CD52 is not expressed on hematopoietic stem cells.

4.1. Anti-CD-52 Alemtuzumab (Campath-1H) 

Campath-1H is a genetically engineered, humanized, IgG1 kappa monoclonal antibody, which is specific for the 21–28kDa lymphocyte surface glycoprotein CD52. The humanized antibody Campath-1H showed antitumor activity in CLL, T-PLL and other T-NHLs. In a few cases clinical effects were observed with a single-drug treatment in relapsed adult ALL.3

In a Cancer and Leukemia Group B study (CALGB 10102) 24 CR1 patients received single agent Alemtuzumab30 as their fourth treatment module during a Phase I portion of the study. The median age was 37years (18–77years); 80% had precursor B-cell ALL; 19% had precursor T-cell ALL. Non-hematologic toxicities were mild. Grade 3–4 myelosuppression was reported during 4weeks of Alemtuzumab treatment in 4 patients; 2 had Grade 3–4 lymphopenia. During subsequent post-remission therapy, 8 patients developed CMV viremia, 2 had Herpes simplex infections, and 3 Herpes zoster reactivation. Serial assessment of MRD using quantitative clone-specific PCR was possible in 11/24 cases. There was a median 1-log decrease in MRD during Alemtuzumab therapy. For the 14 surviving patients the median disease free survival (DFS) was 53months and median OS was 55months. Pharmacokinetic analysis revealed rising Alemtuzumab serum levels during treatment in all dose cohorts, and levels were still detectable in some patients 10weeks after completing Alemtuzumab. There was however no significant correlation between serum Alemtuzumab level and change in MRD. The authors concluded that since the DFS results were encouraging, they will be confirmed in an additional 70 patients in a Phase II portion of this study.

In 2006 the MD-Anderson Cancer Center reported six patients with advanced ALL.31 Patients were included if they had 20% CD52+ leukemic blast cells and Alemtuzumab was given 30mg IV 3 times a week for a total of 4 to 12weeks. Out of the 6 ALL patients, among them 3 with recurrent Philadelphia chromosome-positive disease, four were early withdrawn from treatment since they had progressive disease. Alemtuzumab was found to be myelosuppressive in all patients and infectious complications occurred in most of them. It was concluded that the combination of Alemtuzumab with other active agents needs further investigation.

From these studies, it appears that Alemtuzumab may have activity in both B- and T-cell precursor ALL. The optimal dose seems to be 30mg i.v. 3×/week for 4weeks or even better up to 3months. Although DFS in small selected cohorts might be encouraging it has to be outweighed against a high rate of infectious complications, despite adequate antiviral and antibacterial supportive therapy. Close follow-up of CMV-viremia seem to be required. The definitive role of Alemtuzumab in the treatment of adult ALL e.g. combinations, the setting, consolidation, or maintenance is however as yet not defined.

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5. Epratuzumab, anti-CD22 

Epratuzumab is a humanized anti-CD22 monoclonal antibody, which binds to the third extracellular domain of CD22. After binding, the receptor/antigen complex is internalized. Epratuzumab appears to modulate B-cell activation and signaling. Mechanisms of action include antibody-dependent cellular cytotoxicity, CD22 phosphorylation, and proliferation inhibition with cross linking.32

Epratuzumab is only rarely explored in ALL. In a Childrens Oncology Group Pilot study chemoimmunotherapy reinduction with epratuzumab was explored in 15 children with acute lymphoblastic leukemia and bone marrow relapse. Patients received four doses of epratuzumab, 360mg/m2/dose IV, twice weekly during the 14-day reduction phase, followed by four weekly doses, 360mg/m2/dose, administered with block 1 chemotherapy32 (Table 8).

Table 8. Epratuzumab in relapsed ALL.
Chemoimmunotherapy reinduction with epratuzumab in children with acute lymphoblastic leukemia in marrow relapse: a Children's Oncology Group Pilot Study
Raetz et al. JCO 200832
NStage of diseaseEpratuzumab doseResponse
CRMRD neg CR
15: 8m, 7f
10years (median)		11 first relapse
4s relapse		360mg/m2/day i.v. 3× weekly
Later weekly+ind. chemo		97

Toxicity; dose limiting 2.

1 Grade 4 seizure, 1 grade 3 ALT elevative.

Response to chemoimmunotherapy was determined at the end of block 1. Two patients died as a result of infections, one was removed from protocol. Nine patients achieved a complete remission and seven of these nine achieving a morphologic CR had also no detectable MRD. Of the 12 patients fully assessable for toxicity it was overall acceptable with grade 1 or 2 infusion reaction characterized by rigors, fever, and nausea. Two patients had experienced dose-limiting toxicity, 1 had a grade 4 seizure and the second patient experienced a grade 3 ALT elevation that returned.

Epratuzumab was selected for this study because of high CD22 expression levels in B-precursor ALL and by the fact that the mechanism of action may be distinct from cytotoxic agents and therefore could allow a combination with dose-intensive chemotherapy. The favorable rate of MRD negativity after administration of chemotherapy with epratuzumab suggested that the antibody may enhance response to a cytotoxic chemotherapy.

5.1. Ytttrium-90 (90y) epratuzumab tetraxetan (humanized anti-CD22 antibody) 

Anti-CD22 fractionated radioimmunotherapy was recently evaluated in a Multicenter phase I/II study in Non-Hodgkins lymphoma.33 64 patients with relapsed/refractory NHL including 17 with prior autologous stem cell transplantation received a maximum total (90) Y dose of 45mCi/m2. The overall response rate and median progression free survival for all 61 evaluable patients was 62% and 9.5months and in patients with bulky disease 71% respectively. Whether these favorable results will also apply to adult ALL patients with bulky disease after relapse remains open.

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6. CD33 antigen 

A humanized anti-CD33 antibody which is conjugated to calicheamicin, an antitumor antibiotic (Gemtuzumab ozogamicin), was intensively tested in relapsed acute myeloid leukemia (AML). Expression at 20% or more was detected in 17–26% of B-precursor- and 40% of T-ALL (Table 1). It was higher in TEL/AML1 (40%) and BCR-ABL pos. (38%) ALL.34 Therapeutic activity in ALL was demonstrated by in-vitro and in-vivo experiments.35 Several case reports found responses to anti-CD33 in pediatric ALL and in a few cases of relapsed adult ALL.[36], [37] Cases responding to Gemtuzumab had a very high >90% CD33 expression.

It would have been of interest to further investigate this agent in CD33+ ALL, particular relevant in early subtypes e.g. pro-B-ALL or early T-ALL which comprise a considerable proportion of cases with co-expression of myeloid antigens.[38], [39], [40]

In conclusion, in contrast to theoretical considerations and few positive case reports anti CD33 Gemtuzumab was only rarely used in adult ALL although toxicities are limited. The obvious reason was its limited availability.

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7. T-cell antibodies 

In T-lineage ALL antibody therapy has been far less intensively explored, which may be due to the fact that immunotherapy was first developed for treatment of B-lineage NHL as a more frequent disease. In addition to Alemtuzumab which was described above, immunotoxins directed to CD25, CD7, CD5 and CD3/CD7 have been tested in the treatment of cutaneous T-cell lymphoma, other T-cell lymphomas and for treatment of GvHD.41

Several antibodies bind the CD25 antigen (IL-2 receptor) which is often over-expressed on activated and malignant lymphocytes, particularly T lymphocytes. CD25 antibodies were conjugated to different toxins and showed activity in treatment of acute GvHD. One of these antibodies induced CRs in single patients with adult T-cell leukemia/lymphoma (reviewed in3).

Other antibodies that have demonstrated activity in T-cell leukemias either in vitro or in vivo are anti-CD7-Ricin, antiCD7-PAP, antiCD2, OKT3 or a humanized anti-CD3 MoAb. Overall experience with MoAbs in T-cell ALL – except for anti-CD52 Alemtuzumab – is scarce.

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8. New MoAbs 

There is an increasing number of new MoAbs available, many directed against CD20. One of these is GA101, a Fc-engineered, type II humanized IgG1 anti-CD20 antibody.42 Ofatumomab binds to a novel epitope of CD20 and with greater avidity than rituximab.43 These MoAbs and several others that have been developed recently are first being explored in Non-Hodgkin-Lymphomas. If they have significant activity, they will be tested in the treatment of ALL patients. Given the small numbers overall of adults and children with ALL, investigators will need to select carefully the most promising antibodies for clinical trial testing. Cooperative international trials of carefully defined ALL patient populations will be needed to explore their optimal value and to define their role in improving treatment outcome for our patients with ALL. The research agenda shows that there are still substantial questions for MoAb-therapy that need to be solved.

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9. Practice points 


•Rituximab (anti-CD20) plus intensive chemo cycles (6–8) improves outcome in Burkitt lymphoma/leukemia.

•Rituximab (anti-CD20) in induction and consolidation improves outcome in CD20+ B-precursor ALL.

•Blinatumomab (CD3 and CD17) is effective in MRD pos. relapsed/refractory B-precursor ALL.

•Achievement of MRD negativity seems the best endpoint.

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10. Research Agenda 


•Is the antigen expression per cell relevant?

•Is the potential upregulation of CD20 by corticosteroids clinically useful?

•Is rituximab maintenance – as in NHL – beneficial in B-precursor ALL?

•Is the combination of MoAbs with Tyrosine Kinase Inhibitors a new treatment option for Ph+ ALL?

•Will reduction of pre-transplant tumor load or maintenance with MoAbs improve outcome of SCT?

•Is monotherapy with MoAbs a treatment option for elderly/frail patients?

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Conflict of interest statement 

None declared.

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Funding 

None.

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References 

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PII: S0268-960X(11)00065-8

doi:10.1016/j.blre.2011.08.001

Blood Reviews
Volume 26, Issue 1 , Pages 25-32, January 2012

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