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Radionuclide Therapy of Leukemias and Multiple Myeloma

  • Martina Sollini
  • Sara Galimberti
  • Roberto Boni
  • Paola Anna ErbaEmail author
Living reference work entry

Abstract

Monoclonal antibodies (MAbs) raised against cancer antigens may mediate antibody-dependent cell-mediated cytotoxicity. This form of cancer control arises from cytolysis of a target cell by effector lymphocytes, such as cytotoxic T lymphocytes or natural killer cells. However, most of these antibodies have low/moderate efficacy for tumor control. Antibodies targeting hormone receptors expressed by cancer have shown greater tumor control compared with other cell membrane targets. Moreover, the labeling of these antibodies with a toxin can potentiate their efficacy for tumor control. In this way, the antibody becomes an invaluable targeting vector for delivery of the toxin to the cancer cells. The toxin/antibody complex is called an immunoconjugate. Different molecules, chemicals, or radioisotopes can serve as toxins; toxins may have long half-lives in the body (e.g., ricin), thus increasing the toxicity to both the cancer cells and normal tissues.

Beta emitting radioisotopes, predominantly iodine-131, have had only modest success in radioimmunotherapy. More recently, high-linear-energy transfer (LET) radiation in the form of alpha particles has been studied: alpha radiation is ideal for killing isolated cancer cells in transit in the vascular and lymphatic systems and regressing tumors by disruption of tumor capillary networks by targeting and killing tumor capillary endothelial cells.

Over the past 20 years, the development of alpha-immunoconjugates has enabled targeted alpha therapy (TAT) to progress from in vitro studies, through in vivo experiments, to clinical trials. The dose to normal tissues limits the injected dose and that received by the tumor. However, TAT can achieve cancer regression within the maximum tolerance dose for normal tissue. TAT was originally thought to be an ideal therapy for “liquid” cancers, e.g., leukemia and micrometastases, as the short half-lives of the radioisotopes were sufficient to target these cancer cells and the short range ensured that the targeted cancer cells received the highest radiation dose. Different antibodies have been developed and tested in clinical trials as conditioning treatment, but none of them have yet been approved for RIT in MM. Additionally, bone-seeking radiopharmaceuticals are being evaluated in MM patients in the transplant setting.

Keywords

Leukemia Multiple myeloma Hematological malignancies Therapy Radioimmunotherapy 

Glossary

[18F]FDG

2-Deoxy-2-[18F]fluoro-D-glucose

ADCC

Antibody-dependent cell-mediated cytotoxicity

ALL

Acute lymphocytic leukemia

alloHSCT

Allogeneic hematopoietic stem cell transplantation

AML

Acute myeloid leukemia

APL

Acute promyelocytic leukemia

ASCO

American Society of Clinical Oncology

ASCT

Autologous stem cell transplantation

ATO

Arsenic trioxide

ATP

Adenosine 5′-triphosphate

ATRA

All-trans retinoic acid

BCP-ALL

B-cell precursor acute lymphoblastic leukemia

BCR

B-cell receptor

BMT

Bone marrow transplantation

BR

Bendamustine plus rituximab

BTK

Bruton’s tyrosine kinase

CBF

Core binding factor

cDNAs

Complementary deoxyribonucleic acid

Clb

Chlorambucil

CLL

Chronic lymphocytic leukemia

CML

Chronic myeloid leukemia

CNS

Central nervous system

CR

Complete response

CRAB

Hypercalcemia, renal failure, anemia, bone lesions

CT

Computed tomography

CTD

Cyclophosphamide/thalidomide/dexamethasone

CVAD

Cyclophosphamide, vincristine, doxorubicin, dexamethasone

DCF

Deoxycoformycin

DIC

Disseminated intravasal coagulation

DNA

Deoxyribonucleic acid

DOTA

1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetraacetic acid

DOTMP

1,4,7,10-Tetraazacyclododecane-1,4,7,10-tetramethylene-phosphonic acid

DSF

Disease free survival

DTPA

Diethylenetriaminepentaacetic acid

DVD

Doxorubicin liposomal-vincristine-dexamethasone

EBRT

External beam radiotherapy

EDTMP

Ethylenediamine tetra(methylene phosphonic acid)

EMA

European Medicines Agency

ESMO

European Society of Clinical Oncology

FCR

Chemotherapy regimen based on fludarabine cyclophosphamide, and rituximab

GMMG

German Multicenter Myeloma Group

GVHD

Graft versus host disease

Gy

Gray unit (ionizing radiation dose in the International System of Units, corresponding to the absorption of one joule of radiation energy per kilogram of matter)

HAMA

Human anti-mouse antibody

HCL

Hairy cell leukemia

HCL-V

Hairy cell leukemia variant

HD

High-dose

HLA

Human leucocyte antigen

HLA-DR

Human Leukocyte Antigen-antigen D related

HOVON

Dutch-Belgian Hemato-Oncology Cooperative Group

HR

High risk

IFN-α

Interferon-α

IMiDs

Immunomodulatory drugs

ITD

Internal tandem duplications

KIR

Killer immunoglobulin-like Receptor

LAIP

Leukemia-associated immunophenotype

LET

Linear energy transfer

MAbs

Monoclonal antibodies

MDACC

MD Anderson Cancer Center

MDR

Multidrug resistance

MDS

Myelodysplastic syndrome

MM

Multiple myeloma

MP

Melphalan and prednisone

MPR

Melphalan/prednisone/lenalidomide

MPT

Melphalan/prednisone/thalidomide

MRD

Minimal residual disease

mRNAs

Messenger ribonucleic acid

MTD

Maximum tolerable dose

NHL

Non-Hodgkin lymphomas

NLS

Nuclear localiation signal peptide

NMRI

Naval Medical Research Institute

NOD

Non-obese diabetic

NPM

Nucleophosmin

OR

Odd ratio

OS

Overall survival

PAD

Bortezomib, doxorubicin, and dexamethasone

PCR

Polymerase chain reaction

PET

Positron emission tomography

PFS

Progression-free survival

Ph+

Philadelphia positive

PRIT

Pretargeted radioimmunotherapy

R

Rituximab

RANKL

Receptor activator of nuclear factor kappa-B ligand

RIC

Dose-reduced chemotherapy intensity

RIT

Radio-immunotherapy

RT

Reverse transcriptase

RVD

Lenalidomide-bortezomib-dexamethasone

SCID

Severe combined immunodeficiency

SCT

Stem cell transplantation

SLL

Small lymphocytic leukemia

SPECT

Single-photon emission computed tomography

SR

Standard risk

TAT

Targeted alpha therapy

TBI

Total body irradiation

TD

Thalidomide-dexamethasone

TKI

Tyrosine kinase inhibitor

TRM

Treatment-related mortality

VAD

Chemotherapy regime based on vincristine, adriamycin, doxorubicin

VCD

Bortezomib-cyclophosphamide-dexamethasone

VMP

Bortezomib/melphalan/prednisone

VP

Bortezomib-prednisone

VTD

Velcade-thalidomide-dexamethasone

VTP

Bortezomib-thalidomide-prednisone

WBC

White blood cells

Radioimmunotherapy of Leukemia

Radiolabeled antibodies with affinity for hematopoietic cells may be used for myeloablative radioimmunotherapy (RIT) to increase the radiation dose to the bone marrow spearing normal cells prior to autologous stem cell transplantation (ASCT) in patients with leukemia.

This strategy relies on a well-known side effect of treatments with radiolabeled antibodies: accumulation in the bone marrow which is evident even in the presence of low burden bone marrow disease or when the targeted antigen is co-expressed on healthy hematopoietic cells. In these cases, ASCT may be required to limit severe therapy-induced cytopenia and to prevent complications such as severe infections or bleeding [1, 2, 3].

Treatment of Acute Lymphocytic Leukemia (ALL) in Adults

When the diagnosis is established, treatment should start immediately. The outcome of ALL is strictly related to the age of patient, with probability of success from 80% to 90% in childhood ALL, decreasing to <10% in elderly/frail ALL patients [4].

Currently, the use of monoclonal antibodies is a promising approach in the treatment of ALL. There are four types of monoclonal antibodies developed for ALL: (1) those destroying neoplastic cells by the antibody-dependent cell-mediated cytotoxicity (ADCC), such as rituximab, ofatumumab (anti-CD20), alemtuzumab (anti-CD52), and epratuzumab (anti-CD22); (2) antibodies conjugated with a drug, such as inotuzumab ozogamicin (anti-CD22 plus calicheamicin); (3) antibodies conjugated with a toxin, such as combotox (anti-CD22 combined with ricin A); and (4) bispecific antibodies T-cell engaging, such as blinatumomab (anti-CD19/CD3).

Epratuzumab added to conventional therapy (clofarabine and cytarabine) increased CR to 52% of patients versus 17% of the control arm [5].

Inotuzumab ozogamicin improved overall response rate (81% vs. 33%), with an evident advantage by achieving eradication of minimal residual disease (MRD) [6].

In a recent phase-3 trial, adults with relapsed or refractory ALL were randomized to receive either inotuzumab ozogamicin or standard intensive chemotherapy: the rate of CR was significantly higher in the inotuzumab ozogamicin group (81% vs. 29%), with an advantage also in terms of PFS (median, 5 vs. 2 months), but comparable OS [7].

In a series of relapsed ALL patients, blinatumomab induced 33% of CR and 82% of MRD negativity, but up to 70% of cases presented fever, hypotension, cerebellar symptoms, or encephalopathy [8].

Despite the existence of studies and meta-analyses comparing chemotherapy and allogeneic transplantation (alloSCT) [9], the indications for alloSCT in adult ALL patients in first CR is not defined and requires update. This is due to the improving results with conventional and targeted chemotherapy regimens on one hand and to the decreasing mortality and broader availability of alloSCT on the other. Several attempts have been made to provide evidence-based guidelines for indication of alloSCT [10, 11, 12, 13]: some studies reported that alloSCT when performed in first remission was superior to the conventional chemotherapy, but other authors suggest it is useful only in a second remission. A pre-phase treatment with corticosteroids (usually prednisone or dexamethasone) alone, or in combination with another drug (e.g., vincristine, cyclophosphamide), is often given together with allopurinol (sometimes rasburicase to prevent the tumor lysis syndrome) and hydration for ∼5–7 days as well as intrathecal prophylaxis. Interestingly, the response to this pre-phase therapy defines the chemosensitivity of the disease, with good responders to prednisone having a better outcome [14].

Supportive therapy should be initiated whenever necessary in particular to treat infections or to maintain circulating levels of platelets/erythrocytes. Severe neutropenia (<500/μL) is often seen at diagnosis and is most frequent (>80%) during induction therapy, causing infections and infection-related death [4]. The goal of induction therapy is the achievement of a complete response (CR) or, even better, a molecular CR or a good molecular response, usually obtained within 6–16 weeks from start of chemotherapy.

Most regimens are centered on vincristine, corticosteroids, and anthracyclines (daunorubicin, doxorubicin, idarubicin), sometimes with cyclophosphamide or cytarabine.

There are no randomized trials comparing different induction regimens; however, in 6617 patients from 14 studies, the weighted mean for the CR rate was 83% (62–92%) [15]. Using current approaches, the CR rate had increased to 80–90% [4], according to the risk score. There are two prevalent approaches: one includes 2 cycles of induction followed by the consolidation [4] and represents the most frequently adopted in Europe. A schematic treatment algorithm in adult ALL according to ESMO Clinical Practice Guidelines [4] is reported in Fig. 1.
Fig. 1

Diagnosis and risk assessment in adult ALL for achievement of CR and risk-oriented post-remission therapy. Major diagnostic subsets are identified within 1–2 days to allow start of pre-phase therapy, identify cases eligible to targeted therapy (TKI in Ph+ ALL), and set up the MRD study. Pre-phase therapy allows for management/prevention of metabolic/infectious/hemorrhagic complications before the start of induction therapy and checks HLA identity between patient and siblings. Induction/early consolidation therapy (incorporating CNS prophylaxis) aims to induce CR with a deep MRD response, to support subsequent risk- and MRD-oriented therapy with/without allogeneic SCT. ALL acute lymphoblastic leukemia, RT-PCR reverse transcriptase polymerase chain reaction, MRD minimal residual disease, LAIP leukemia-associated immunophenotype, WBC white blood cells, CR complete remission, CNS central nervous system, SR standard risk, HR high risk, SCT stem cell transplantation, TKI tyrosine kinase inhibitor, Ph+ Philadelphia positive, HLA human leucocyte antigen (Modified from Holzer et al. [4])

The second approach uses two different alternating intensive chemotherapy cycles, identical for induction and consolidation, accounting for a total of eight cycles, such as the hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone) protocol, preferentially used in the United States [4].

Effective prophylaxis to prevent CNS relapse is an essential part of ALL therapy: treatment modalities include CNS irradiation and intrathecal methotrexate, eventually combined with steroids or cytarabine and systemic HD therapy with either methotrexate and/or cytarabine. The combination of these measures reduces CNS relapses from 10% to <5%. Patients with CNS involvement (mostly of the leptomeninges) at diagnosis are treated with the standard chemotherapy regimen and additional intrathecal applications until there is complete blast clearance in the spinal fluid [4].

The rationale to use systemic high-dose (HD) therapy in the post-remission consolidation is to reach sufficient drug levels in sanctuary sites (e.g., CNS). Most protocols employ 6–8 cycles containing either HD methotrexate or HD cytarabine ± l-asparaginase [4].

Maintenance therapy usually consists of daily 6-mercaptopurine and weekly methotrexate; in some treatment regimens, repeated cycles of vincristine, dexamethasone, or other drugs in monthly or longer intervals are given. Treatment duration of 2.5–3 years is optimal and is usually recommended [4]. Omission of maintenance worsens outcome significantly in BCP-ALL, less in T-ALL [16], and probably not in B-ALL [17].

Nevertheless, relapses are still a major clinical challenge, especially in adults: indeed, there is no universally accepted treatment, and evidence based on randomized, controlled trials is still lacking [4]. The most commonly used regimens in Europe are fludarabine- and anthracycline-containing regimens, such as FLAG-Ida (fludarabine, high-dose ara-C, granulocyte colony-stimulating factor, and idarubicin). Despite its common use and inclusion as “standard of care” arm in several trials for relapsed ALL, there is remarkably a small number of publications in relapsed ALL [18]. Clofarabine-based regimens including cytarabine, cyclophosphamide, or etoposide are also commonly used based mostly on data in childhood ALL [19]. Liposomal vincristine [20] is licensed for the treatment of relapsed ALL. These standard chemotherapy approaches are applicable in BCP-ALL as well as in T-ALL.

Additionally, nelarabine has been licensed for this indication: it offered 31% CRs, with median DFS and OS of 20 weeks, thus demonstrating that nelarabine is well tolerated and has significant antitumor activity in relapsed or refractory T-ALL [21].

Advances have also been made in the setting of Ph’+ ALL, because of the use of tyrosine kinase inhibitors, such as imatinib, dasatinib, and ponatinib [4].

The Italian group GIMEMA treated frontline elderly ALL patients with imatinib 800 mg daily, associated to steroids without further chemotherapy: 100% obtained CR, with a median BCR-ABL1 reduction of 2 logs. No major toxicities occurred and the median survival from diagnosis was 20 months [22].

In another GIMEMA protocol , patients with Ph’+ ALL received dasatinib induction therapy for 84 days combined with steroids for the first 32 days and intrathecal chemotherapy: also in this case, all patients achieved CR by the first month, with 20-month OS of 69% and DFS of 51%. The reduction of BCR-ABL1 levels to <10–3 did significantly an impact on DFS [23].

Dasatinib was used in combination with low-intensity chemotherapy (vincristine and dexamethasone, followed by consolidation with dasatinib, reduced doses of sequential cytarabine and methotrexate for 6 months) in patients older than 55 years. CR rate was 96%, and 65% of patients achieved a 3-log reduction in BCR-ABL1 transcript levels during consolidation, with 5-year OS of 36% [24].

The MDACC recently published about the combination of the HyperCVAD regimen and ponatinib: 2-year event-free survival was 81%, with an 8% incidence of cardiovascular/thrombotic events [25].

Although targeted therapies are used increasingly in hematologic malignancies, RIT is not extensively used in ALL, even though this radiosensitive tumor expresses CD22, potentially a good target for this approach. Positive results have been published using 90Y-epratuzumab tetraxetan [26].

Chevallier et al. [27] published results of a standard 3 + 3 phase I study which evaluated 90Y-DOTA-epratuzumab RIT in refractory or relapsed CD22-positive B-cell acute lymphoblastic leukemia (with CD22 expression on at least 70% of blast cells). Treatment protocol included one cycle of 90Y-DOTA-epratuzumab on days 1 and 8 at one of four dose levels: 92.5 MBq/m2 (level 1), 185 MBq/m2 (level 2), 277.5 MBq/m2 (level 3), and 370 MBq/m2 (level 4). Seventeen patients were treated (5 at level 1, 3 at level 2, 3 at level 3, and 6 at level 4): one dose-limiting toxic effect (aplasia lasting 8 weeks) occurred at level 4, but the MTD was not reached. The most common grade 3–4 adverse events were pancytopenia and infections. Authors concluded recommending the dose of 370 MBq/m2 for two doses 1 week apart per cycle.

RIT using murine 131I-anti-CD52 mAb has been used in the conditioning regimen for allogeneic hematopoietic stem cell transplantation in recurrent refractory CD52-positive ALL preceded by 124I-labeled anti-CD52-mAb PET to evaluate dosimetry [28].

A patient with Ph’+ B-ALL in third relapse received RIT with 90Y-labeled anti-CD22 epratuzumab tetraxetan; 7 weeks after initiating therapy, the patient became BCR-ABL1 negative by quantitative PCR lasting at 6 months before alloSCT. Although with limited clinical data, 90Y-epratuzumab tetraxetan may be a promising therapeutic option for CD22+ B-ALL [26].

Treatment of Chronic Lymphocytic Leukemia

The first decision to be made in CLL is whether the patient requires therapy. A schematic treatment algorithm in adult CLL according to ESMO Clinical Practice Guidelines [29] is shown in Fig. 2.
Fig. 2

Algorithm for frontline treatment in CLL. CLL chronic lymphocytic leukemia; SLL small lymphocytic leukemia; BCR B-cell receptor; R rituximab; alloHSCT allogeneic hematopoietic stem cell transplantation; FCR fludarabine, cyclophosphamide, and rituximab; BR bendamustine plus rituximab; Clb chlorambucil (Modified from Eichhorst et al. [29])

Previous studies have shown that early treatment with chemotherapeutic agents does not translate into a survival advantage in patients with early-stage CLL. The standard treatment of patients with early disease is a watch-and-wait strategy. Blood cell counts and clinical examinations should be carried out every 3–6 months [29]. In Binet stage A and B with active disease or Binet stage C, Rai 0–II with active disease or Rai III–IV, treatment should be initiated in patients with symptomatic, active disease. Active disease is defined as significant B symptoms (weight loss, sweating, itching); cytopenias not caused by autoimmune phenomena and symptoms or complications from lymphadenopathy, splenomegaly, or hepatomegaly; lymphocyte doubling time of <6 months (only in patients with more than 30 × 109/L lymphocytes), as well as autoimmune anemia and/or thrombocytopenia poorly responsive to conventional (steroid) therapy. The presence of del(17p) or TP53 mutation without the abovementioned conditions is not an indication for treatment by itself [29].

In physically fit patients (physically active, with no major health problems, normal renal function) without TP53 deletion/mutation, fludarabine, cyclophosphamide, and rituximab (FCR) therapy is the standard first-line therapy with significantly improved OS [29, 30]. Combinations based on other purine analogues, such as cladribine [31] or pentostatin [32], have shown similar activity, but it is uncertain whether they can replace fludarabine in the FCR regimen. In fit but elderly patients, FCR was shown to be associated with a higher rate of severe infections when compared with bendamustine plus rituximab (BR) [29]. Therefore, in this group of patients, therapy with BR may be considered, although it produces fewer complete remissions than FCR [29]. In patients with relevant comorbidity, who are usually older, but without TP53 deletion/mutation, the combination of chlorambucil plus an anti-CD20 antibody (rituximab, ofatumumab, or obinutuzumab) prolongs progression-free survival when compared with monotherapy and is therefore the standard approach [33]. In a head-to-head comparison of chlorambucil-based combinations, the type II antibody obinutuzumab (GA-101) was superior to the type I antibody rituximab with regard to PFS, complete remission, and minimal residual disease remissions [29].

Nevertheless, patients with TP53 deletion/mutation have a poor prognosis even after FCR therapy [30]: therefore, it is recommended to treat them with novel inhibitors (ibrutinib, idelalisib plus rituximab) in frontline and at relapse.

Ibrutinib, an inhibitor of Bruton’s kinase, in 17p CLL patients induced objective responses in more than 80% of cases, with 2-year PFS of 60%, comparing favorably with historical treatments that offered a median PFS of 1 year [34].

Idelalisib, a BCL2 inhibitor, in combination with rituximab was able to offer 82% of overall responses and median PFS of 17 months [35].

For fit patients responding to inhibitor treatment, the option of alloSCT can be discussed, using individual and transplant-related risk factors [36].

Maintenance therapy in CLL patients with higher risk of relapse may have some benefit, but are not generally recommended [29].

At relapse, the same regimen used as first-line may be repeated if the relapse occurs at least 24 months after chemoimmunotherapy and if TP53 deletion/mutation was excluded [29]. If relapse occurs before or in case of refractory disease, the therapeutic regimen should be changed with ibrutinib or rituximab combined with idelalisib [29, 37, 38]. A schematic treatment algorithm in adult CLL according to ESMO Clinical Practice Guidelines [29] is reported in Fig. 3.
Fig. 3

Algorithm for relapse treatment in CLL. CLL chronic lymphocytic leukemia; SLL small lymphocytic leukemia; BCR B-cell receptor; R rituximab; BR bendamustine plus rituximab; FCR fludarabine, cyclophosphamide, and rituximab; alloSCT allogeneic hematopoietic stem cell transplantation (Modified from Eichhorst et al. [29])

Fit patients achieving the second remission should proceed to alloSCT [36]. On the contrary, autologous stem cell transplantation is not advantageous in CLL, but could be offered to patients achieving a good response after new drugs [29, 39].

Radiation therapy in CLL is indicated in case of large, bulky lymphoid masses causing compression symptomatology, especially if patients are unresponsive to chemotherapy. Splenic irradiation has been performed in patients with painful splenic enlargement or cytopenias related to hypersplenism, but splenectomy remains preferable. Following splenectomy, major improvements in blood counts can be achieved in 50–90% of patients [40]. Total body irradiation was used in the 1970s (response rates of 80–90%) [41] but no longer recommended since comparative studies of TBI with chemotherapy demonstrated a higher response rate with chemotherapy.

Radioimmunotherapy for the treatment of CLL has been limited by frequent extensive bone marrow involvement. Lym-1 is a radioimmunoconjugate consisting of a 131I-labeled mouse IgGk. The antibody recognizes a 31–35 kDa antigen presumed to be a polymorphic variant of the HLA-DR antigen and thought to be specific for B cells [42, 43, 44, 45, 46]. In a phase Ia trial including 10 patients, the antibody was well tolerated, but not active enough [47]. Repeated administration of 131I-Lym-1 showed a dose-limiting thrombocytopenia in up to 28% of patients, but tumor regression was documented in some cases.

90Y-ibritumomab tiuxetan and 131I-tositumomab have also been used in patients with CLL excluding patients with bone marrow involvement >25% because of safety concerns. Nevertheless, Kaminski et al. [48] reported their experience in 14 patients with SLL and a median of four prior chemotherapeutic regimens, with responses occurring in 64% of patients (including 21% complete remissions). The median duration of response was 24.7 months.

An interesting strategy under development is the reduction of bone marrow involvement prior to RIT therapy since the use of RIT in CLL is limited by the extent of bone marrow involvement. Thus, reducing the number of CLL cells in the bone marrow prior to RIT by the administration of an agent that is effective in clearing the bone marrow, such as anti-CD52 antibody (alemtuzumab), is a potentially interesting strategy.

Furthermore, 188Re-alemtuzumab has been proposed by De Decker et al. [49] in an in vitro (HuT-78 cell line) and murine study (female NMRI mice) showing excellent receptor binding as well as a fast clearance from blood (t 1/2α=4.79 h) and slower clearance from the body (t 1/2β=55.45 h). Mean radiation dose estimates, calculated for the human adults using the residence times derived from mice biodistribution data, identified the kidney (0.159–3.26 mGy/MBq), heart (0.0705–0.132 mGy/MBq), and liver (0.0602–0.220 mGy/MBq) as critical organs. The effective dose for the human reference adult was estimated to be approximately 0.0486–0.195 mSv/MBq [49, 50].

The 177Lu-DOTA-HH1 (anti-CD37 monoclonal antibody) has been tested in nude mice to evaluate the toxicity profile; results demonstrated that 177Lu-DOTA-HH1 was well tolerated at dosages about ten times above those considered relevant for RIT in patients with CLL and other non-Hodgkin lymphomas (NHL) [51].

131I-tositumomab has been used in patients in complete/partial response after induction chemotherapy; 3 months after RIT, complete response was achieved (50%) or sustained (25%), and one third of patients cleared the minimal residual disease. Hematologic toxicities were anemia (6%), neutropenia (81%), and thrombocytopenia (50%); 12% of patients developed myelodysplastic syndromes 17 and 20 months after consolidation [52].

Fourteen patients with relapsed CLL either in partial remission or in complete remission but with disease documented by flow cytometry were treated with 90Y ibritumomab tiuxetan . Grade 3 or 4 hematologic toxicity was seen in 92% of evaluable patients. In addition, myelosuppression was prolonged, with a median duration of grade 3–4 thrombocytopenia of 37 days. Five patients had persistent thrombocytopenia 3 months post-therapy. Even in patients with CLL and limited marrow involvement, the use of RIT results in unacceptable hematologic toxicity [53].

Treatment of Hairy Cell Leukemia

As with CLL, treatment for HCL is not indicated in asymptomatic patients; patients should be closely monitored with a complete history, physical examination, and complete blood cell count every 3–6 months. In contrast to CLL, asymptomatic patients, who may be diagnosed by chance, are rare, and in practice most patients need treatment shortly after diagnosis, either because of symptoms or to correct cytopenias. Treatment should be initiated in patients with symptomatic disease manifested by bulky or progressive, symptomatic splenomegaly or cytopenias (hemoglobin <10 g/dl and/or platelets <100 × 109/L and/or neutrophils <1 × 109/L), recurrent or severe infections, and/or systemic symptoms [54, 55, 56]. A schematic treatment algorithm in classical HCL (diagnosis and relapsed) and HCL variant according to ESMO Clinical Practice Guidelines [56] is reported in Figs. 4, 5, and 6, respectively.
Fig. 4

Therapeutic algorithm for newly diagnosed classical hairy cell leukemia (Modified from Robak et al. [56])

Fig. 5

Therapeutic algorithm for refractory/relapsed classical hairy cell leukemia (Modified from Robak et al. [56])

Fig. 6

Therapeutic algorithm for newly diagnosed variant hairy cell leukemia (Modified from Robak et al. [56])

Purine analogues, cladribine (2-CdA) or pentostatin (DCF), are recommended as initial treatment of symptomatic HCL patients who are young and fit. 2-CdA, subcutaneous or intravenous, induces durable and unmaintained response in 87–100% patients, including CR in 85–91%, after a single course of therapy [56]. Grade 3–4 toxicities, largely represented by neutropenia and infections, were less frequent when low doses were used (0.5 mg/kg vs. 0.7 mg/kg), with similar OR [57]. A CR following 2-CldA administration is durable even without maintenance therapy [58]. In patients demonstrating a partial remission after the first course of 2-CldA, a second course should be repeated to achieve CR at least 6 months after the end of the first course, with or without rituximab [59]. Similarly to 2-CdA, DCF induces a high rate of long-lasting CR. In patients with a normal creatinine clearance, DCF is usually given at a dose of 4 mg/m2 i.v. every second week until CR, plus one or two consolidating injections [60]. After 8–9 courses, the full blood count usually normalizes, and the bone marrow biopsy should be performed to confirm a CR. If a CR is documented, one or two further cycles are indicated [58]. DCF and 2-CdA appear to induce similar high response rates, duration of response, recurrence rates, and adverse events [58]. However, no randomized, direct comparison between the two drugs has been performed [56]. The advantage of DCF over interferon-α (IFN-α) in HCL patients has been confirmed in a multicenter, randomized trial [61]. The use of IFN-α in the treatment of HCL is limited since purine analogues produce higher and more durable remissions and are more convenient to patients [56]. However, IFN-α may still have a place in the treatment of HCL in pregnancy. It can also be used in patients presenting with very severe neutropenia [56, 62]. Relapsed patients can be successfully retreated with 2-CdA or DCF if relapse occurs after 12–18 months [63]. The alternative nucleoside analogue can be used in early relapse within 2 years after the first-line treatment [64]. The ability to attain CR decreases with each course of therapy, but CR duration appears to be similar after first-, second-, or third-line therapy [58, 65]. Rituximab given weekly (dose of 375 mg/m2 for 4–8 doses) can be used in early relapsed patients [66, 67, 68]; however, rituximab alone is inferior to purine analogues and is not the treatment of choice. Outcomes for patients with recurrent HCL appear to be better when a combination of rituximab and 2-CdA or DCF is used rather than the purine analogue alone [69, 70]. Concurrent therapy of rituximab and purine analogues induces higher response rates, and higher rates of toxic events than in the sequential administration [71]. IFN-α is also a possible option for selected patients relapsing after purine analogue therapy [72, 73]. Patients refractory to purine analogue therapy should be enrolled whenever possible on clinical trials that use new agents.

Oral fludarabine (dose of 40 mg/m2) for five consecutive days in combination with rituximab for four cycles can be a therapeutic option in relapsed or refractory patients previously treated with 2-CdA [56].

Bendamustine (70–90 mg/m2) combined with rituximab is another therapeutic option in multiple relapsed/refractory HCL and could be considered in HCL patients after the failure of standard therapies [74].

Other promising drugs active in purine analogue refractory HCL patients include moxetumomab pasudotox, an anti-CD22 recombinant immunotoxin, and vemurafenib, a BRAF V600E inhibitor [56, 75, 76]. A phase I trial of moxetumomab pasudotox in relapsed/refractory HCL induced an 86% OR rate and a 46% CR [58, 59].

Recently, the efficacy of vemurafenib was assessed in a cohort of 21 HCL patients treated outside of clinical trials: vemurafenib improved blood counts in all patients by 1.5–2 months, with a CR rate of 40% and a median EFS of 17 months [77].

The therapeutic potential of the Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib also needs to be taken into consideration in a relapse setting, given the proven in vitro activity of this drug in hairy cells [78].

Splenectomy may be indicated in patients with resistant massive symptomatic splenomegaly (>10 cm below the costal margin) with accompanied low-level bone marrow infiltration (OR rates of 60–100%) [62, 79]. Splenectomized patients respond better and faster to the subsequent chemotherapy. Splenectomy can also be considered when progressive HCL develops during pregnancy and in patients refractory to nucleoside analogues and IFN-α [62]. Systemic therapy should not be performed earlier than 6 months after splenectomy to reach full benefits of this treatment [64]. Allogeneic stem cell transplantation has a potential role in younger, heavily pretreated HCL patients who have had multiple relapses and are refractory to purine analogues and rituximab [80, 81]. In pregnant woman, treatment is indicated only when truly warranted, and the appropriate therapy depends on the stage of pregnancy, the rate of disease progression, and the response to previous therapies. IFN-α shows good tolerance, uncomplicated pregnancy, and normal child development [82].

Splenectomy is another option to consider, should INF-α fail, especially in early gestation when the risks are lower [83, 84]. Administration of 2-CdA and rituximab is not indicated in pregnancy because of the risk of teratogenic effects, although successful pregnancy has also been reported [56, 85].

The results of the treatment of hairy cell leukemia variant (HCL-V) with purine analogues are poor [56, 86]. In addition, the majority of HCL-V patients required more than 1 cycle to maintain a response. Using DCF, PR was observed in 8/15 (54%) patients, and no CR was achieved; rituximab alone, or splenectomy followed by rituximab, can also induce CR in HCL-V [87, 88, 89]. However, administration of 2-CdA immediately followed by rituximab appears to be more effective than 2-CdA alone or rituximab alone and should be considered as the initial treatment of HCL-V patients [56, 69, 90].

Alternatively, case reports suggest that alemtuzumab is an active agent in treating HCL-V, even in patients who have relapsed after rituximab [91]. Splenectomy induces clinical responses in some patients with HCL-V and is recommended because it corrects cytopenias, removes the bulk of the tumor, and may improve response to purine nucleoside analogues [56, 92]. Splenic irradiation could be performed in elderly patients with a high surgical risk of splenectomy [56]. Although limited data, clinical case reports support the use of moxetumomab pasudotox in patients with HCL-V and the use of autologous or allogeneic hematopoietic cell transplantation in refractory patients [56, 75, 93].

Treatment of Acute Myeloid Leukemia (AML)

Whenever possible, AML treatment should be offered in clinical trials and given only in experienced centers offering an adequate multidisciplinary infrastructure as well as a suitably high case load. Treatment should be planned with curative intent whenever possible. Intensive chemotherapy of AML is divided into an induction phase, consolidation, and (rarely) maintenance. Potential candidates for alloSCT (scheduled for the consolidation phase) must be identified early at diagnosis or during induction chemotherapy. Treatment of acute promyelocytic leukemia (APL) differs in several important aspects from therapy of all other AML types [94].

Patients with excessive leukocytosis at presentation and with clinical signs of leukostasis may require emergency leukapheresis coordinated with the start of chemotherapy. These patients are at particular risk of a tumor lysis syndrome under induction chemotherapy and need appropriate monitoring. In these cases, a single injection of rasburicase may be considered to prevent hyperuricemia and hence renal failure, but data are insufficient to support a firm recommendation in this respect.

In respect of a common induction regimen, the strategy of consolidation eventually followed by autologous or allogeneic transplantation depends on the cytogenetic/molecular features of disease. Induction chemotherapy usually includes an anthracycline and cytarabine in the well-known “3+7” regimen. Data on dose escalation of daunorubicin to improve AML outcome look promising, but longer follow-up is required to support a firm recommendation [95, 96, 97, 98, 99, 100, 101]. Consolidation therapy in AML is warranted once patients have reached clinical and hematological remission. There is no consensus on a single “best” post-remission treatment schedule. In good-risk AML patients in first remission, who have a relapse risk of 35% or less, alloSCT is not justified because its toxic effect and/or the risk of mortality exceed the benefit. Also, these patients may receive salvage therapy including alloSCT in second remission. Good-risk AML patients (including NPM-mutated AML with absence of internal tandem duplications of FLT3 (FLT3-ITD), core binding factor (CBF) AML, and bi-allelic mutant CEBPα AML), as well as patients who are unsuitable for alloSCT for other reasons, should receive at least one cycle of intensive consolidation chemotherapy preferably incorporating intermediate or high-dose cytarabine [94].

Patients in intermediate- and poor-risk groups with an HLA-identical sibling may be candidates for alloSCT, provided their age and performance status allow for such treatment [102, 103, 104, 105, 106, 107, 108, 109, 110, 111, 112]. Newer data suggest that alloSCT may no longer be mandatory in intermediate-risk patients, but these data need to be confirmed [96]. Patients in these risk groups without a family donor may qualify for alloSCT with an HLA-matched unrelated donor identified through an international donor registry. In fact, peripheral stem cells harvested from unrelated HLA-matched donors have become the most frequently used source of stem cells. If a killer immunoglobulin-like receptor (KIR) mismatch is present, haploidentical transplant may be considered. Conditioning regimens for alloSCT with dose-reduced chemotherapy intensity (RIC) may be used for patients in the upper age range (particularly those >50 years of age), but there is some evidence that RIC may also be used in adults at a younger age.

The role of high-dose chemotherapy with autologous stem transplantation in AML is still controversial. Recent data suggest that it may be a good option (and thus an alternative to alloSCT) in patients in the intermediate-risk group [100]. While it may prolong time to relapse or remission duration, its potential to prolong overall survival is uncertain [104, 106, 107].

Patients with significant comorbidity and elderly are often not eligible for intensive treatment; they should receive best supportive care or palliative systemic treatment. Nevertheless, recently demethylating agents have been approved for patients with 20–30% of blasts (5-azacytidine) or aged more than 65 years (decitabine) [94].

A recent retrospective study evaluated the efficacy of 5-azacitidine in a cohort of 130 elderly patients ineligible for intensive chemotherapy: patients received 5-azacitidine for a median of four cycles, with overall response rate of 36% and 37% of hematologic improvement. Median OS was 18 months for responders and 12 months for nonresponders [113].

Decitabine has been reported to offer 18%–24% of CRs, but no overall survival benefit [114].

Excessive leukocytosis due to spilling of malignant blasts into the periphery may be reduced with cytoreductive agents such as hydroxyurea or low-dose cytarabine, which, however, also can reduce also normal blood cell counts and red cells, neutrophils, or platelets. Treatment of infections due to neutropenia and transfusions to improve anemia or thrombocytopenia are important additional measures. Erythropoietin is of questionable value in patients with anemia due to extensive infiltration of the marrow with leukemia. In severely neutropenic patients, hematopoietic growth factors may be tried when neutropenic fever or infections are a problem; however, there is no evidence to support their continuous use [94, 95, 98, 104, 112].

Resistance to therapy (refractory or relapsed AML) is the major cause of treatment failure, rather than mortality due to infections and other treatment-related complications. Patients failing to respond to one or two cycles of induction are considered refractory and can be candidates for alloSCT, albeit with limited chances of success and at the cost of considerable morbidity from this procedure. For patients unsuited to this approach, best supportive care or palliative systemic treatment is often a reasonable option with, at least, limited toxic effect. The prognosis of such patients is often dismal regardless of treatment attempts. Patients presenting with relapse after a first remission may be offered intensive re-induction, with better chances of success in patients with a longer interval from first remission. Patients in second or subsequent remission may still qualify for alloSCT with a family or unrelated HLA-matched donor or with cord blood-derived stem cells [94].

Suspicion of or established diagnosis of acute promyelocytic leukemia (APL) must trigger a distinctive therapy program [115, 116, 117, 118]: oral all-trans retinoic acid (ATRA) should immediately be started, because of the high risk of bleeding caused by the disseminated intravasal coagulation (DIC) [94]. Risk assessment of APL is based on white blood cell count at presentation, where patients with a WBC count >10 × 109/L fare worse. APL induction chemotherapy consists of ATRA as a differentiating agent and idarubicin. The use of arsenic trioxide (ATO) in first-line APL therapy is promising, but long-term results are not yet available.

However, the results of ATRA-ATO combination without chemotherapy look promising, particularly in good-risk APL: in the GIMEMA APL0406 study, adults between 18 and 71 years with low- or intermediate-risk APL were randomly assigned to receive ATRA-ATO or ATRA-chemotherapy. All patients achieved CR in the ATO arm versus 97% in the chemotherapy group, with a significant advantage in terms of 4-years EFS (97% vs. 80%) and OS (99% vs. 92%) [119].

The need for daily i.v. application of ATO over a prolonged period of time, electrolyte as well as cardiac problems (including potentially fatal torsade-de-pointe ventricular arrhythmias), and case reports on secondary cancers after ATO must all be considered [120].

RIT could potentially circumvent multidrug resistance and yield remissions in drug-resistant AML. The choice of the most suitable radionuclide to label specific antibodies is based on purely clinical considerations such as the type of disease, the degree of leukemic bone marrow infiltration, and the presence of extramedullary burden. Furthermore, the decision to combine different radioimmunoconjugates may also be applied to improve the therapeutic efficacy if compared to monotherapies [121].

Radiolabeled antibodies with specificity for the antigens CD33, CD45, and CD66 have been developed and studied for myeloablative radioimmunotherapy in patients with AML or MDS. CD33 is an antigen expressed from the promyelocyte stage to the stage of mature myeloid cell and in most AML blasts. The CD45 antigen is expressed on almost all leucocytes (except plasma cells) and on 80–95% of leukemic blasts of the myeloid and lymphoid line. The CD66 antigen belongs to the group of nonspecific cross-reacting antigens and is present from the promyelocyte stage to the mature granulocyte stage, rarely on myeloid leukemic blasts. Nevertheless, none of the antibodies currently tested in clinical trials for myeloablative RIT (Table 1) are approved for this purpose. The only commercially available antibody is 99mTc-BW250/183 (IgG1; NCA 95, scintimun, besilesomab; CIS Bio International, Schering, Switzerland), but it is registered for the scintigraphic diagnosis of infections only. Preliminary results suggest that myeloablative RIT may close the gap between benefit and toxicity of conditioning therapies. When myeloablative RIT is used to condition patients scheduled for transplantation, it provides high-energy doses into the bone marrow thus inducing hypoplasia/aplasia, the rate of relapse is decreased, and normal organs that do not express the target antigen are spared from toxicity. Additionally, myeloablative RIT does not significantly increase the rate of therapy-related mortality. Generally, RIT is employed in younger patients in good general condition in addition to dose-escalated conditioning, while in patients >55 years and/or with comorbidities, it should be added to reduce the intensity of “standard” conditioning therapies [121]. 188Re-alemtuzumab RIT followed by fludarabine (150 mg/m2), busulfan (8 mg/kg), and alemtuzumab (75 mg) has been evaluated before alloSCT in a phase II trial enrolling 22 patients with advanced myeloid malignancies. The extramedullary toxicity in the first 100 days posttransplantation was limited, and all patients engrafted with complete donor chimerism. The probability of OS at 2 years was 40%. A comparison with a younger historical cohort having received the same dose of fludarabine and busulfan but neither radioimmunotherapy nor alemtuzumab showed no difference in outcome. Although the use of alemtuzumab reduced the incidence of acute graft-versus-host disease, it was associated with a relapse incidence of 40% despite the incorporation of RIT. These data confirmed the feasibility of combined RIT and reduced-intensity conditioning in elderly patients [50]. Current clinical trials for myeloablative RIT are designed to obtain an individual dosimetric study either to calculate the therapy doses or, in dose-escalating protocols, to ensure not to exceed the dose-limiting organ doses. For monotherapy in patients with AML or MDS and a low tumor load, the radiolabeled anti-CD66 mAb is considered the optimal choice, and the use of DTPA-derived chelators is suggested to improve the biodistribution profile (increased bone marrow/liver doses ratio). In patients with extensive bone marrow infiltration with blast cells or significant extramedullary disease, anti-CD33 and anti-CD45 radioimmunoconjugates are preferred [121].
Table 1

examples of antibodies developed and tested in clinical trials for leukemia and multiple myeloma

Type of antibodies

Antigen specificity

Clinical indications

Radiolabeling

M195 (IgG2a, murine)

CD33

AML

131I

HuM195 (IgG2a, humanized)

CD33

AML

90Y, 213Bi, 131I

Lintuzumab (whole antibody, humanized)

CD33

AML

225Ac

p67 (IgG, murine)

CD33

AML

131I

BC8 (IgG1, murine)

CD45

AML, MM

131I

YTH24.5 (IgG2b, rat)

CD45

AML, CML, ALL

99mTc (dosimetry)

YAML568 (IgG2a, rat)

CD45

AML, MM

90Y

BW250/183 (IgG1; murine)

CD66b

AML, MM

90Y, 188Re

Lym-1 (IgGK, murine)

HLA-DR

CCL

131I

Ibritumomab tiuxetan (IgG1, murine)

CD20

CLL

90Y

Tositumomab (IgG2a, murine)

CD20

CLL

131I

Low linear energy transfer (LET)-ionizing radiation is an important form of therapy for acute leukemias. Ionizing radiation is also a potential source of DNA damage. High LET-ionizing radiation produces structurally different forms of DNA damage and has emerged as potential treatment of metastatic and hematopoietic malignancies. Haro et al. [122] created a stable myeloid leukemia HL60 cell line radioresistant to both γ-rays or α-particles to understand possible mechanisms in radioresistance. Cross-resistance to each type of ionizing radiation was observed, but resistance to clustered, complex α-particle damage was substantially lower than that to equivalent doses of γ-rays. The resistant phenotype was driven by changes in apoptosis, late G2/M checkpoint accumulation that was indicative of increased genomic instability, stronger dependence on homology-directed repair, and more robust repair of DNA double-strand breaks and sublethal-type damage induced by γ-rays, but not by α-particles. The more potent cytotoxicity of α-particles warrants their continued investigation as therapies for leukemia and other cancers [122].

The key properties of the alpha particles generated by 225Ac are the following: (i) limited range in tissue of a few cell diameters, (ii) high linear energy transfer leading to dense radiation damage along each alpha track, (iii) a 10-day half-life, and (iv) four net alpha particles emitted per decay [123].

Treatment of Chronic Myeloid Leukemia (CML)

The introduction of tyrosine kinase inhibitors at the beginning of 2000s revolutionized the outcome of patients affected by CML, improving survival from the 40% to 90%, with a good quality of life [124]. TKIs interfere with the ATP-binding site in the BCR-ABL1 pocket blocking its uncontrolled tyrosine kinase activity. Imatinib was the first TKI to be introduced in the clinical practice on the basis of a randomized trial versus IFN-α and low-dose arabinosylcytosine (IRIS study); thus, IFN and hydroxyurea are not still recommended in treatment of CML patients.

Now, second-generation TKIs offering faster and more complete responses are available. After onset of mutations of the ABL1 that often abrogated the efficacy of the TKI, other third-generation TKIs have been designed; thus, today five different compounds are available. Each of them has a specific toxicity profile, with increased cardiovascular events for nilotinib and ponatinib, increased pleural effusion for dasatinib, diarrhea for bosutinib, and fluid retention for imatinib [125]. Consequently, European and American guidelines suggest if and when TKIs have to be changed, but not which one has to be used in the first line [126].

Moreover, no substantial progress has been made in the treatment of blast-phase disease; allogeneic transplantation is now reserved to patients failing at least 2 TKIs.

Projected annual 3–5-year survival rates range from 38% to 80%, with the higher values reported from more experienced centers. BMT in accelerated and/or blast-phase disease is relatively unsatisfactory; nonetheless, 15% to 20% of patients may become long-term survivors.

A recent multi-institutional randomized trial compared the use of bone marrow with peripheral blood stem cells from HLA-identical siblings for relatively favorable patients with a variety of hematologic neoplasms, including CML, undergoing transplantation. Hematologic recovery was more rapid and the 2-year OS significantly increased (70% vs. 45% of BMT). Drug treatment is superior to allogeneic stem cell transplantation in first-line therapy of CML, because of transplant-related mortality. Thus, initial allogeneic SCT cannot be recommended anymore [127].

Therapies with Radiolabeled Antibodies

Therapies with Radiolabeled Anti-CD33 mAb

Schwartz et al. [128] conducted a dose-escalation study with fractionated doses of 131I-M195 (185–7.77 MBq/m2) in 24 patients with relapsed/refractory myeloid leukemia. Post therapy whole-body scintigraphy demonstrated marked uptake of the antibody into all involved areas in every patient. A significant decrease of bone marrow blasts was observed in 83% of cases, with sufficient bone marrow cytoreduction allowing subsequent ASCT in 33% of the patients. These data suggest that a safe leukemic cytoreduction may be achieved with 131I-M195, and it may be useful as part of a myeloablative conditioning regimen. Nevertheless, in 37% of patients, human anti-mouse antibody (HAMA) was produced, preventing effective retreatment with the same murine M195 MaAb. To avoid immunogenicity leading to HAMA development [128], humanized MoAbs for the treatment of leukemia have been developed (Hu-M195). Caron et al. [129] evaluated the biodistribution profile and leukemia cell targeting, as well as safety concerning especially immunogenicity, in 13 patients with AML and CML treated with increased doses of 131I-Hu-M195. The pharmacokinetics of Hu-M195 were very similar to M195 with serum t½-a more rapid than that of the murine M195, probably because of the rapid targeting of Hu-M195 to leukemia cells (Hu-M195 affinity is 8 times higher compared to the murine form). Additionally, the amount of antibody binding to splenic targets during the “first pass” may contribute to the shorter serum t½-a . Whole-body scintigraphy also confirmed the rapid and specific binding of radiolabeled Hu-M195 to the target areas. A similar trial was reported by Appelbaum et al. [130] in patients with advanced AML using 131I-labeled p67, a murine IgG targeting CD33. However, their results were not satisfactory since the administration of a single dose of 131I-p67 due to its short marrow residence times; this was presumably due to the modulation of the antigen-antibody complex with subsequent rapid release of 131I from the marrow space [130, 131]. In fact, to be effective for myeloablation, antibodies should be retained longer in the bone marrow, as in the case of 131I-M195 and 131I-HuM195 that presented a bone marrow retention of at least 3 days [132].

Sgouros et al. [133] analyzed imaging data obtained from the phase I trial of 131I-HuMl95: response to RIT was influenced by tumor burden, antibody clearance kinetics, and the antibody-antigen interaction. Compartmental modeling analysis provided biodistribution data for absorbed dose calculations to tissues not directly sampled, to determine the optimum therapeutic dose of radiolabeled antibody for a given patient [134]. The results demonstrated a large inter- and intrapatient variability, such differences suggesting that dosimetry based upon the activity concentration at a single site may not adequately assess the potential for marrow toxicity in any patient. Red marrow dosimetry is important only if it provides a better index of potential marrow toxicity than other more easily determined parameters, such as whole-body absorbed dose or administered activity. Marrow dose estimation is critical since the biological clearance rate, fractional uptake in marrow, radionuclide half-life, and emission characteristics are accounted for in assessing absorbed dose. Both the variability in regional bone marrow radiosensitivity and the effect of treatment before absorbed dose estimates, are directly related to complication treatment-induced.

To determine the possible use of RIT in the conditioning phase, Jurcic et al. [135] associated the myeloablative action of 131I-M195 or 131I-HuM195 (4.4–14 GBq) to cyclophosphamide and busulfan in 30 patients with refractory/relapsed AML de novo or secondary to CML: no significant toxicities were reported and complete remissions were observed in 93% of patients; 19% of patients were alive and disease-free after 4.5–8 years.

A median survival of 4.9 months was also reported by Burke et al. [132] with the same treatment schedule and dose of 131I-M195 or 131I-HuM195 (4.5–16.17 MBq) combined with busulfan and cyclophosphamide; moreover, imaging confirmed good targeting of the radioimmunoconjugate to all areas of leukemic involvement, including vertebrae, pelvis and long bones, liver, and spleen. The bone marrow-absorbed radiation dose was calculated to range between 0.27 and 1.47 Gy. When comparing the performance of 131I-M195 with that of 131I-HuM195, this latest offers some advantages, including the ability to mediate antibody-dependent cellular cytotoxicity and complement-mediated cytotoxicity, the lack of immunogenicity, and the modest intrinsic antileukemic activity.

Nevertheless, 131I-labeled anti-CD33 in the setting of myeloablative RIT does not represent the optimal compound: in fact, radioiodination of antibodies decreases their ability to bind to the antigen (about 1/3 of the tyrosine residues binding 131I are located in the hypervariable regions) and thus prevents the delivery of high radiation doses to the bone marrow. Furthermore, the relatively long half-life of 131I delays transplantation, since the radionuclide retained within the bone marrow must decay totally in order to prevent injury to the grafted hematopoietic stem cells; finally, 131I requires hospitalization in a radioprotected ward. Radiometals such as 90Y and 188Re have been evaluated as alternatives to 131I: such radioisotopes offer better retention by target cells after internalization of antigen-antibody complexes, while the higher energy of their β emissions permits a lower effective dose, and the absence of γ emission reduces radioprotection restrictions [132].

Jurcic et al. [136] conducted a phase I trial to determine the safety and biological activity of 90Y-HuM195 (185–1036 MBq, as a single administration). Biodistribution and dosimetry studies were also performed after the administration of 111In-HuM195 (370 MBq). Dose-limiting toxicity (leucopenia G4) was seen at 11 MBq/kg. Scintigraphy showed uptake of 111In-HuM195 in the bone marrow, liver, and spleen within 1 hour of administration and for at least 3 days. Radiation doses to the bone marrow and liver were 0.29–0.70 Gy and 0.12–0.30 Gy, respectively. 90Y-HuM195 may overcome the limitations of 131I-anti-CD33 conjugates, being safer but still retaining a significant antileukemic activity.

The first clinical trial with 213Bi was conducted at Memorial Sloan Kettering Cancer Center in New York in collaboration with the National Institutes of Health and the Institute for Transuranium Elements in Karlsruhe [137].In this study, 18 patients with relapsed and refractory acute myelogenous leukemia or chronic myelomonocytic leukemia were treated with 10.4 to 37.0 MBq/kg of 213Bi-HuM195. Fourteen of fifteen evaluable patients (93%) had reductions in circulating blasts, and 14 of 18 patients (78%) had reductions in the percentage of bone marrow blasts. No significant extramedullary toxicity was seen. Jurcic et al. demonstrating the safety, feasibility, and antileukemic effects of 213Bi-HuM195 provided the first proof-of-concept for systemic radiometal-based RIT in patients with relapsed/refractory AML or CML [137]. Based on the encouraging results of this pioneering study, another phase I/II study was conducted to determine the maximum tolerated dose and efficacy of 213Bi-HuM195 after partially cytoreductive chemotherapy with cytarabine. Thirty-one patients with newly diagnosed (n = 13) or relapsed/refractory (n = 18) AML were treated: significant reduction in marrow blasts was seen at all dose levels and complete remissions, and partial responses were seen in 6/25 patients (24%) who received doses of ≥37 MBq/kg. Myelosuppression was tolerable, and no significant extramedullary toxicity was observed [138].

Sgouros et al. [139] analyzed the results of a phase I trial, demonstrating that 213Bi-HuM195 rapidly localized to areas of leukemic involvement and all patients developed myelosuppression with absorbed dose ratios 1000 times greater than with β-emitting radioimmunoconjugates. Moreover, 93% of evaluable patients had a reduction in circulating blasts, while 78% of patients had reductions in the percentage of bone marrow blasts [137]. Kolbert et al. [140] developed a method to provide a “whole-body” assessment of the pharmacokinetics of 213Bi-HuM195 in the patients enrolled in this phase I trial: images were acquired after multiple injections of 213Bi-HuM195 with progressively increasing antibody concentration, over 2–4 days. A linear expression to the counts in each pixel was applied to obtain parametric rate images defining clearance and uptake rates in each organ. Planar images of antibody distribution showed significant uptake in the liver, spleen, and bone marrow. The generated rate images displayed different patterns (i.e., with negative values in the liver and spleen and positive values in bone marrow), reflecting clearance and uptake rates rather than total accumulation. The inter-patient comparison developed with this method showed that rate image patterns varied based on patient-specific conditions, such as the amount of disease and previous therapies. Maximum-tolerated dose has been established for 213Bi-immunoconjugates in AML at about 37 MBq/kg [137].

Miederer et al. [141] analyzed the pharmacokinetics profile, dosimetry, and toxicity of the targetable atomic generator 225Ac-HuM195 in nonhuman primates and found severe renal toxicity and anemia at a cumulative activity of 377 kBq/kg. The longer blood t1/2 and the lack of target cell antigens in cynomolgus monkeys may increase toxicity compared with the human setting, where an activity level of 28 kBq/kg may be a safe starting dose (no toxicity at 6 months).

More recently, Maguire et al. [142] described three strategies to stably chelate 225Ac and evaluated 225Ac-HuM195 in a mouse model of leukemia (NSG) which demonstrated a lower dose-limiting toxicity (2.22 kBq) than other mouse models. Despite this aspect possibly related to the immunocompromised state of NSG mouse or to the lack of circulating antibody, reductions in tumor growth rate and a significant difference between specific and control antibodies was observed. These observations supported the hypothesis that in immunocompetent hosts, higher or repeated doses may be used, and consequently a greater absolute therapeutic effect can be achieved.

Kersemans et al. [143] recently demonstrated that 111In-HuM195 and 111In-M195 modified with peptides harboring nuclear-localizing sequences may decrease cell growth and clonogenic survival for both drug-resistant AML cell lines and primary AML patient specimens expressing MDR transporters, through the emission of Auger electrons, after CD33-mediated internalization. More than 99% of the Auger electrons emitted by 111In have a range of less than 1 μm, which obviates the cross-fire effect and yields high-linear-energy transfer comparable to that of highly cytotoxic a-emitters (i.e., 50–100 keV/mm). Targeted Auger electron RIT using 111In-NLSHuM195 and 111In-NLS-M195 may be able to overcome resistance [143, 144].

211At has been shown to be a promising, highly cytotoxic RIT in CD33-positive AML and kills tumor cells more efficiently than calicheamicin-conjugated antibody. Labeling techniques leading to higher chemical yield and specific activities have been evaluated to increase 211At-anti-CD33 therapeutic effects [145].

Clinical experience with 225Ac therapy is currently still limited. The ongoing phase I clinical trial was initiated at Memorial Sloan Kettering Cancer Center with a primary goal to define both safety and the MDT of 225Ac RIT in advanced AML patients through a dose-escalation series. The trial has been successful in demonstrating that 225Ac RIT targeted by lintuzumab had antileukemic activity across all dose levels and it is now being investigated in a multicenter USA phase I/II trial in combination with low-dose cytarabine for elderly AML patients [146].

A study of combined modalities for treating AML has been recently completed at the Memorial Sloan Kettering Cancer Center using chemotherapy to reduce the cancer load followed by RIT (213Bi- or 225Ac-immunoconjugates) [147].

213Bi-anti-CD33 exhibits its cytotoxic effects specifically in CD33-expressing AML cells via induction of the intrinsic, mitochondrial pathway of apoptosis. The abrogation of chemo- and radioresistances and the reactivation of apoptotic pathways seem to be promising for the treatment of patients with so far untreatable resistant AML and underline the importance of this emerging therapeutic approach of targeted alpha-therapies [148].

Therapies with Radiolabeled Anti-CD45 mAb

131I-BC8 (2.8–22.6 GBq) prior to transplantation in combination with cyclophosphamide and fractionated total body EBRT (12 Gy) has been used by Matthews et al. [149] in patients with advanced acute leukemia or MDS after first complete remission. Bone marrow doses obtained with this compound were up to 30 Gy, with maximum liver doses of 7 Gy [149].

A comparative study of the biodistribution and biokinetics of two other immunoconjugates, 99mTc-BW250/183 and 99mTc-YTH24.5, in patients with AML, CML, and ALL was performed by Buchmann et al. [150], who concluded that YTH24.5 is not appropriate for myeloablation because of its unfavorable biodistribution profile. Thus, YTH24.5 has been modified from IgG2b to IgG2a; this compound, named anti-CD45 MoAb YAML568, demonstrated a significant improvement of the bone marrow/liver dose ratio. Although the biodistribution and dosimetry of YAML568 are less favorable than those of BW250/183, the former represents an alternative option for leukemia patients with a high medullary tumor load or with extramedullary disease.

To improve the efficacy of RIT, Kletting et al. [151] developed a physiologically based pharmacokinetic model to describe the biodistribution of 90Y-labeled anti-CD45 antibody YAML568. Dosimetric estimates in patients receiving unlabeled antibody before the injection of 111In-labeled anti-CD45 MoAb (121±21 MBq), demonstrated that the preload with cold antibody increased selective delivery of radioactivity to the target organ as well as reducing toxicity to normal tissue [151, 152]. The method is in principle applicable also to RIT with other antibodies to decrease nonspecific binding of the labeled antibody to the liver or spleen. Validation of this model is still under evaluation.

Additionally, the conjugation with (Ab)-streptavidin and DOTA-biotin labeled with β-emitting radionuclides has been explored in AML as a strategy to decrease relapse and RIT toxicity, suggesting that anti-CD45 RIT may be highly effective and minimally toxic for treatment of AML [153].

In theory total body irradiation may be replaced by RIT in hematopoietic cell transplantation conditioning regimens, leading to positive outcomes on transplant overall survival. Anti-CD45 RIT can increase the dose of cytotoxic radiation targeted to malignant cells, while sparing normal organs. Opportunities for further optimization of CD45-targeted RIT exist, including alternate radioisotopes with different physical properties and energy characteristics. The continued combinations of innovative preclinical studies and supportive clinical trials suggest that CD45-targeted RIT will continue to develop as a critical option for improving hematopoietic cell transplantation outcomes for hematological malignancies [154].

Mawad et al. [155] used RIT with 131I-anti-CD45 antibody (332–1561 mCi) combined with fludarabine and total body irradiation (2 Gy) to improve hematopoietic cell transplantation success in advanced AML or high-risk MDS patients. Marrow doses were arbitrarily capped at 43 Gy to avoid radiation-induced stromal damage; no graft failure or evidence of stromal damage was observed. Graft-versus-host disease was observed in the majority of patients treated. Six patients (40%) were still alive after a median of 5 years (range 4.2–8.3 years), with 1-year OS of 73%. Moreover, the arbitrary limit of 43 Gy to the marrow may be unnecessarily conservative, and continued escalation of targeted radioimmunotherapy doses may be feasible to further reduce relapse [155]. The relative therapeutic efficacy and toxicity of the anti-CD45 RIT employing 90Y and 177Lu in a syngeneic, disseminated murine myeloid leukemia (B6SJLF1/J) model has been compared. 90Y-DOTA-30F11 RIT demonstrated a dose-dependent survival benefit and was associated with transient, mild myelotoxicity without hepatic or renal toxicity. Conversely, 177Lu- anti-CD45 RIT yielded no long-term survivors. Thus, in this murine leukemia model, 90Y was more effective than 177Lu for anti-CD45 RIT of AML [156]. Efficacy and toxicity of anti-CD45 RIT using 211At were positively evaluated in a disseminated murine AML model suggesting that 211At-anti-CD45 RIT in conjunction with hematopoietic stem cell transplantation may be a promising therapeutic option for AML [157].

Very recently, Orozco et al. [158] evaluated a conditioning regimen employing 90Y-anti-CD45 RIT replacing total body irradiation (TBI) before haploidentical alloSCT in a murine model, suggesting the possible introduction of RIT in clinical practice.

A phase II trial evaluated 131I-BC8, fludarabine , TBI, and donor stem cell transplant followed by cyclosporine and mycophenolate mofetil in patients with advanced AML or myelodysplastic syndrome is currently ongoing [147].

Therapies with Radiolabeled Anti-CD66 mAb

The anti-CD66 MoAb 188Re-BW250/183 (8.2±4.1 GBq) was employed in very poor prognosis childhood leukemia: the protocol consisted in a conditioning regimen including RIT, high-dose chemotherapy, and, optionally, total body EBRT before allogeneic transplantation. In this setting, the kidney was the dose-limiting organ (doses higher than the liver), and doses to the bone marrow were in the 5.5–30 Gy range. The results of this study were disappointing, since after a follow-up of 5–8 months, 6/7 patients died [159]. Subsequently, the same antibody and schedule were applied to adult AML or MDS presenting bone marrow infiltration <25% and high risk of relapse: RIT was administered at a mean activity of 11.1 GBq, associated with conventional conditioning therapy with cyclophosphamide combined with either total body EBRT (12 Gy) or busulfan. The majority of patients received T-cell depleted graft, while others had autologous transplantation. Mean bone marrow dose was 14.9 Gy, with moderate acute toxicity; the kidney was the dose-limiting organ; 18-month DFS was 45% [160, 161]. Patients with >50–60% bone marrow infiltration were excluded from treatment with 188Re-BW250/183 because specific marrow doses were lower than the nonspecific doses to the liver (Buchmann, unpublished data), probably due to low number of binding sites on the normal hematopoietic cells. Associating 188Re-BW250/183 to conditioning regimens in patients receiving BMT did not significantly increase the incidence of acute graft-versus-host disease compared to the conventional conditioning therapies [162].

A phase I/II study with the anti-CD66 MoAb BW250/183 , labeled with either 188Re or 90Y in adult patients with AML and MDS, demonstrated the feasibility and safety of RIT also in reduced dose-intensity conditioning regimens prior to alloSCT. Bone marrow doses were 21.9±8.4 Gy, with a significantly higher dose for 90Y- versus 188Re-labeling. Comparison of biodistribution profile of 188Re- and 90Y-BW250/183 suggested a more favorable profile of the 90Y-labeled MoAb, especially concerning the kidney doses. Kidney toxicity was observed in 6.4% of patients after intensified conditioning with 188Re-BW250/183, but none in patients treated with 90Y-BW250/18. Following these results, 90Y was coupled to the antibody via the chelator MX-DTPA, and further improvements had also recently been reported by Orchard et al. [163], with the use of different DTPA derivatives, such as the chelator 2B3M-DTPA [164]. Intraindividual dosimetric evaluation between PET and conventional scintigraphy, using 18F- and 99mTc-labeled anti-CD66, respectively, in a patient with high-risk leukemia, displayed a similar distribution pattern, with high preferential uptake in bone marrow. Nevertheless, urinary excretion of radioactivity after administration of 18F-anti-CD66 was faster, and bone marrow uptake was lower than after administration of 99mTc-anti-CD66 [165].

The combination of reduced-intensity conditioning, 188Re-anti-CD66 RIT, and in vivo T-cell depletion was successfully applied in elderly patients with AML or MDS; a prospective phase II protocol evaluated if a dose reduction of alemtuzumab (from 75 mg to 50 mg) would improve leukemia-free survival by reducing the incidence of relapse. Fifty-eight patients received RIT followed by fludarabine (150 mg/m2) and busulfan (8 mg/kg) combined with standard (75 mg; n = 26) or low (50 mg; n = 32) dose of alemtuzumab. The overall incidence of engraftment and the disease-free and overall survival did not differ, and the dose reduction had no positive impact on overall outcome [166].

In vitro studies showed that the human polynucleotide kinase/phosphatase inhibitor A12B4C3 radiosensitized AML cells to the DNA-damaging effects of 111In-NLS-7G3 (which recognizes the CD123+/CD131 phenotype displayed by leukemia stem cells), suggesting that the combination treatment may improve the effectiveness of Auger electron RIT of AML targeting the leukemia stem cells subpopulation [167].

The CSL360 is a chimeric IgG1 monoclonal antibody that recognizes CD123 (IL-3 receptor α-subchain) expressed in the absence of CD131 (β-subchain), an epitope that is displayed by leukemia stem cells (LSCs) and has been evaluated for RIT of AML in a model mouse (NOD/SCID mice). Additionally, microSPECT/CT has been used to assess engraftment of primary human AML specimens into NOD/SCID mice. The targeting of 111In-DTPA-NLS-CSL360 to sites of AML engraftment in the NOD/SCID mouse model is encouraging for future RIT studies [168, 169].

Treatment of Multiple Myeloma

Targeted therapies employing anti-CD45, anti-CD66, and anti-CD138 antibodies against hematopoietic or bone marrow stromal cells radiolabeled with beta-emitting radiopharmaceuticals have been developed for myeloablative RIT in MM. The CD45 antigen is overexpressed in clonogenic myeloma stem cells, and the CD66 antigen is expressed in all the intermediate stages from promyelocyte to the mature granulocyte, while anti-CD138 (syndecan-1), a heparan sulfate proteoglycan, is constantly expressed on tumor cells in MM. Different antibodies have been developed and tested in clinical trials as conditioning treatment, but none of them have yet been approved for RIT in MM (Table 1) [121]. Typically, bone marrow toxicity represents the major and dose-limiting side effect of all RIT regimens proposed so far. In fact, the radiolabeled antibodies can accumulate in the bone marrow irrespective of the severity of bone marrow infiltration or when an antibody cross-reacting with healthy hematopoietic cells is employed. Bone marrow doses of 2–8 Gy induce moderate myelosuppression, while doses >8–10 Gy induce relevant hypoplasia or aplasia. Thus, ASCT or supportive care is often required to prevent life-threatening complications. When RIT is used in the setting of conditioning regimens prior to stem cell transplantation, myelotoxicity takes on a “positive” role since it contributes to the destruction of plasma cells infiltrating the bone marrow. This option has been proposed to overcome the relative toxicity of intensified chemo- and EBRT, given the selective mechanism of action of radiolabeled antibodies. The maximum bone marrow dose applied in this clinical setting is generally limited to 35–40 Gy to avoid stromal cell damage that may affect engraftment of the transplanted stem cells. The anti-CD45 monoclonal antibody YAML568 is an option for patients with MM. Orchard et al. [163] published promising data obtained in patients with MM treated in a dose-escalated phase I trial with 90Y-labeled 2B3M-DTPA anti-CD66 BW250/183 followed by ASCT, thus prompting an ongoing phase II trial. Myeloablative RIT as conditioning treatment in patients with MM still remains difficult. It is assumed that there is a progenitor myeloma stem cell that is CD45 positive and circulates as an isolated single cell in peripheral blood. Taking these considerations into account, patients with MM should be treated beneficially with an anti-CD45 monoclonal antibody labeled with a combination of alpha-emitters (to damage the single progenitor cells circulating in the blood, the myeloma cells, and myeloma progenitor cells in the margin of the marrow) and beta-emitters (to enhance the effect in the bone marrow). Furthermore, malignant plasma cells may build clusters in the bone marrow, thus making tumor targeting more difficult. Therefore, RIT protocols should include only patients with a diffuse pattern of bone marrow infiltration and clusters <1 mL [121]. Before going into the details of the main application of RIT in MM, we will provide a brief overview on the current treatment options in MM.

When only one osteolytic bone lesion is seen in the presence of 10% or more clonal plasma cells, no clear indication is present for systemic therapy if no other criteria are met for active myeloma. This circumstance is rare, and we recommend that patients could be given radiation therapy and observed. Clinical trials to determine the value of adjuvant systemic therapy for these patients are being planned [170]. Treatment should be initiated in all patients with active myeloma fulfilling the CRAB criteria and in those symptomatic due to the underlying disease [171]. A major discriminant among the different treatment options for high-risk patients is the possibility to perform high-dose chemotherapy regimens plus either autologous stem cell transplantation (ASCT) or allogeneic bone marrow transplantation (Fig. 7). Initial treatment for newly diagnosed MM (induction therapy) was historically performed with high-dose melphalan. Given the possibility of such initial therapy to adversely affect the ability to collect stem cells and considering the recent introduction of new class of drugs in transplant eligible patients, thalidomide/lenalidomide and bortezomib-based regimens are currently preferred to single agent dexamethasone and VAD (vincristine, adriamycin, doxorubicin), with strong recommendation for the use of bortezomib-containing regimens in high-risk patients. Oral combinations of melphalan and prednisone (MP) plus novel agents or lenalidomide and steroid are considered as standards of care for elderly patients (non-transplant setting) [171] (Fig. 8). The two following options are recommended (level IA): melphalan/prednisone/thalidomide (MPT) [173] and bortezomib/melphalan/prednisone (VMP) [174]; both are approved in this setting by the European Medicines Agency (EMA). Bendamustine plus prednisone is another regimen that is also approved by the EMA in patients who have clinical neuropathy at time of diagnosis precluding the use of thalidomide (MPT regimen) or bortezomib (VMP regimen) [175]. Melphalan/prednisone/lenalidomide (MPR) allowed 81% of patients to achieve at least a partial response, and to about half of them to achieve a very good partial response, to 24% to reach a CR, with 12-month EFS of 92% and OS of 100% [176]. Moreover, in a randomized trial comparing MPR followed by lenalidomide as maintenance versus MPR without maintenance versus MP, MPR-R significantly prolonged progression-free survival (median, 31 months) as compared with MPR (median, 14 months) and MP (median, 13 months), but without any significant impact on OS. At least a very good partial response was reported in 33% in the MPR-R and MPR groups versus 12% in the MP group. Even in this trial, OS was not different among the 3 arms [177]. Cyclophosphamide/thalidomide/dexamethasone (CTD) combination has also been compared with MP and is superior in terms of response rates, but does not induce a clear survival advantage over MP [178]. In patients in good clinical condition (e.g., fit patients), induction followed by high-dose therapy with autologous stem cell transplantation (ASCT) is the standard treatment (level IIb) [171]. ASCT improves complete response and prolongs median overall survival by approximately 24 months, though with an intrinsic mortality rate ranging from 1% to 2%. Response rates to induction therapy have been significantly increased by the use of novel agent-based combinations. Bortezomib-dexamethasone, which is superior to the classical VAD regimen (vincristine, adriamycin, and high-dose dexamethasone) [179], has become the backbone of induction therapy before ASCT (level IIb) [171]. The addition of a third agent to bortezomib-dexamethasone, e.g., thalidomide (VTD), doxorubicin (DVD or PAD), lenalidomide (RVD), or cyclophosphamide (VCD), has shown to offer higher response rates in phase II trials [180]. Three prospective studies have already shown that VTD is superior to TD or bortezomib-dexamethasone [181, 182, 183]. Based on response rates, depth of response, and PFS as surrogate markers for outcome, three-drug combinations including at least bortezomib and dexamethasone are currently the standard of care before ASCT. Three to four courses are recommended before proceeding to stem cell collection [171]. Melphalan (200 mg/m2 i.v.) is the standard preparative regimen before ASCT [184] (level IIb) [171]. Peripheral blood progenitor cells are the preferred source of stem cells, rather than BM [171]. Tandem ASCT has been evaluated before the era of novel agents. The benefit of tandem ASCT was observed in patients that were not reaching very good partial response after the first ASCT [185]. In a recent study phase III (Hovon 65-GMMG HD4 trial) in the context of bortezomib induction and maintenance treatment, OS was better in the GMMG group, which carried out tandem ASCT in contrast to HOVON (single ASCT) [186]. Nevertheless, the trial was not powered to compare single versus double high-dose melphalan. Ongoing trials running both in Europe and the USA comparing prospectively single versus tandem ASCT in the era of novel agents will solve this important issue. Allogeneic stem cell transplantation should only be carried out in the context of a clinical trial and only in patients with good response before transplant [171]. Myeloablation as part of radioimmunotherapy (RIT, see above) can be used 10–14 days before transplantation to reduce the dose of the conditioning treatment. Ongoing studies aim at assessing whether the conditioning regimen can be improved by the addition of bone-seeking radiopharmaceuticals such as 166Ho-DOTMP or 153Sm-EDTMP. A second sequential ASCT has been investigated as additional consolidation therapy to further reduce disease burden. Such tandem ASCT seems to be beneficial for patients who have failed to achieve good partial response after the first ASCT. Allogeneic stem cell transplantation is not recommended as part of initial therapy, but can be considered in young patients at high risk achieving a good response after the first ASCT. Indeed, notwithstanding the new conditioning strategies and the possibility of employing sibling or unrelated donors, the treatment-related mortality (TRM) rate is still about 10–20%, in addition to the high probability of graft versus host disease (GVHD) [187]. Thus far, in the era of novel agent-based induction therapy, there is still not enough evidence that consolidation therapy should be systematically applied [171]; even some studies suggest that consolidation after ASCT could be advantageous in terms of OS and PFS [188]. In elderly patients following induction, three randomized trials have explored the benefit of maintenance therapy in terms of OS using either immunomodulatory drugs (IMiDs) or bortezomib: MP versus MPR versus MPR-R [177], bortezomib-melphalan-prednisone-thalidomide/bortezomib-thalidomide versus VMP [189], VMP versus VTP followed by either bortezomib-prednisone (VP) or VP maintenance [190]. Due to the trial design, the benefit in OS is not well established. Therefore, systematic maintenance therapy is not recommended in elderly patients [171]. In young patients following ASCT, phase III randomized trials have demonstrated that maintenance therapy with IMiDs, either thalidomide or lenalidomide, prolongs PFS [191, 192], but the OS benefit is still unclear. Bortezomib maintenance is also under evaluation [186]. These three agents are not approved in this setting; therefore, systematic maintenance therapy is not recommended [171]. The choice of therapy in the relapse setting depends on several parameters, such as age; performance status; comorbidities; the type, efficacy, and tolerance of the previous treatment; the number of prior treatment lines; the available remaining treatment options; and the interval since the last therapy [171]. The EMA has approved lenalidomide in combination with dexamethasone [193, 194] and bortezomib either alone as single agent [195] or in combination with pegylated doxorubicin [196]. Thalidomide and bendamustine are effective drugs, often used, but not approved [197]. Triplet combinations have proved effective in phase II trials, but only one single randomized trial has shown the superiority of VTD over TD for PFS in patients relapsing following ASCT [198]. In young patients, a second ASCT may be considered, provided the patient responded well to the previous ASCT and had a PFS of more than 24 months [199]. In the relapse setting, allogeneic SCT should only be carried out in the context of a clinical trial. When possible, patients should be offered participation in clinical trials. Pomalidomide, the third-in-class IMiD, and carfilzomib [197] are now available in Europe also. Moreover, monoclonal antibodies, such as daratumumab and elotuzumab, are very promising options: daratumumab as single agent offered overall response to one third of patients refractory either to IMIDs or to bortezomib, with median duration of response of 7.4 months and 12 months OS of 65% and good tolerability [200]. Intravenous elotuzumab, in combination with lenalidomide and dexamethasone, offered to more than 90% of resistant patients a response and to more than 40% a very good partial response [201]. In a recently published phase 3 trial, refractory or relapsed MM patients were randomized to receive ixazomib (oral proteasome inhibitor) plus lenalidomide and dexamethasone or placebo plus lenalidomide and dexamethasone. PFS was 21 months in the ixazomib group versus 15 months in the control group, with similar percentage of serious adverse events [202]. Finally, histone-deacetylase inhibitors, such as panobinostat, have been licensed in association with bortezomib for relapsed patients: in the PANORAMA 2 trial, panobinostat was administered to relapsed MM patients in combination with bortezomib and dexamethasone (overall response rate of 34%, with PFS of 6 months for responsive cases) [203]. Supportive care with bisphosphonates can decrease bone pain as wells as reduce the progression of osteolytic lesions and prevent pathologic fractures. The exact time of start and optimal duration of treatment are still under investigation. However, according to ASCO recommendations, such therapy should be started in the presence of significant bone loss or of pathological spine fractures (lower bone density leads to weaker bones) and should continue for no longer than 2 years [204, 205]. A fully humanized mAb to RANKL (denosumab, which binds and inhibits the RANK ligand thus reducing bone resorption markers) is still under clinical investigation. Erythropoietin or darbepoetin is useful in patients with persistent symptomatic anemia. Indication for prophylactic antibiotic therapy in patients undergoing chemotherapy is still debated, while it should be considered in all patients receiving high-dose steroid therapy [205]. Intravenous immunoglobulin administration is indicated if patients have recurrent severe infections associated with severe hypogammaglobulinemia. Plasmapheresis is useful in patients with the hyperviscosity syndrome. Vertebroplasty and kyphoplasty generally result in rapid and long-lasting reduction of bone pain and improvement in functional activity in patients with vertebral compression fractures. The standard treatments for cord or cauda equina compression are steroids and radiation therapy, whereas surgical decompression is rarely necessary. Radiotherapy is generally used for the treatment of painful bone lesions or to prevent complications and is performed at least once in about 70% of patients with MM. Typically, doses <30 Gy are preferred, to avoid permanent side effects which could jeopardize subsequent chemotherapy or ASCT [205, 206]. Among the radionuclide therapies for MM, CXCR4-targeted radiotherapy with pentixather appears to be a promising novel treatment option in combination with cytotoxic chemotherapy and autologous stem cell transplantation, especially for patients with advanced MM as recently reported in a first in human experience [207].
Fig. 7

Treatment options for multiple myeloma (Adapted from Rajkumar et al. [170] and Moreau et al. [171])

Fig. 8

Special considerations prior to therapy in elderly or frail patients. In multiple myeloma patients with newly diagnosed or refractory disease, a detailed geriatric and functional assessment helps to define more precisely “fit” versus “frail” patients and to evaluate patients’ risk for treatment toxicity and treatment discontinuation. These definitions of fit, unfit, and frail patients are anticipated to influence selection of therapeutics, as well as the correct allocation to intensive or nonintensive treatment should reduce side effects/SAEs and treatment toxicity (Modified from Terpos et al. [172])

Radioimmunotherapy in Multiple Myeloma

In 1999 Couturier O. et al. [208] evaluated RIT in MM targeting a specific monoclonal antibody (B-B4) coupled to 213Bi by a chelating agent (pentaacetic triamine diethylene p-aminobenzyl acid). The efficacy of alpha-RIT was assessed in vitro by analysis of thymidine incorporation, cell mortality, apoptosis of myeloma cells, and the study of nonspecific irradiation of hematopoietic cell lines not recognized by B-B4-pentaacetic triamine diethylene p-aminobenzyl acid immunoconjugate. B-B4 has been shown to induce apoptotic death of more than 40% of myeloma cells at a dose of 7.4 kBq/105 cells. Similarly, Burtun et al. [209] explored the biochemical nature and potential of MUC1 as antigenic target in MM. MA5 mAb was strongly reactive with 6/8 human MM cell lines as shown by flow cytometry. In 7/8 MM patient samples (bone marrow and/or peripheral blood), reactivity was found in 10–90% of the cells, whereas normal control (n = 5) and leukemia and lymphoma (n = 5) cells showed only 0–6% reactivity. 125I-labeled MA5 whole-cell binding studies showed quantitatively similar amounts of binding between strongly positive MM lines and high-MUC1-expressing breast carcinoma lines. MM cell lines were positive for mRNA expression (Northern blotting and reverse transcription-PCR), with strong similarity in the sizes of the mRNAs and cDNAs.

Finally, biodistribution experiments were carried out with 131I-labeled MA5 versus a nonbinding control 125I-labeled mAb in a MM xenograft model. Selective MM tumor uptake of the MA5 mAb was demonstrated, with a potential for delivering a tumor radiation absorbed dose of 8540 cGy/mCi of injected dose compared with 3099 cGy/mCi of tumor-absorbed dose delivered by nonspecific antibody. Results of a direct comparison between B-B4 and MA5 labeled with iodine-131 and bismuth-213 in vitro have been demonstrated that B-B4 RIT might be more effective than MA5 and suggested that alpha-RIT might be more suitable than beta-RIT for treating single-cell tumor models [210]. Different mechanisms (cell cycle synchronization, DNA damage, and apoptosis) that might underlie potential synergy between chemotherapy (paclitaxel or doxorubicin) and RIT with alpha radionuclides have been analyzed in three different MM cell lines (LP1, RMI 8226, and U266). Cells were treated with 213Bi-B-B4 24 hours after paclitaxel (1 nmol/L) or doxorubicin (10 nmol/L) treatment; radiation enhancement ratio showed that paclitaxel and doxorubicin were synergistic with alpha RIT. After a 24-h incubation, paclitaxel and doxorubicin arrested all cell lines in the G2-M phase of the cell cycle. Doxorubicin combined with alpha RIT increased tail DNA in the RPMI 8226 cell line but not the LP1 or U266 cell lines compared with doxorubicin alone or alpha RIT alone. Neither doxorubicin nor paclitaxel combined with alpha RIT increased the level of apoptosis induced by either drug alone or alpha RIT alone. Both cell cycle arrest in the G2-M phase and an increase in DNA double-strand breaks could lead to radiosensitization of cells by doxorubicin or paclitaxel, but apoptosis would not be involved in radiosensitization mechanisms [211].

In myeloma xenografts models, treatment with 213Bi-anti-CD38-MAb suppressed tumor growth via induction of apoptosis in tumor tissue and significantly prolonged survival compared to controls [212, 213].

In order to define where alpha-RIT stands in MM treatment, melphalan was compared with alpha-RIT using a 213Bi-anti-CD38-MAb in a syngeneic MM mouse model. Fifty percent of untreated mice died by day 63 after MM engraftment. In mice treated with melphalan alone, 200 μg improved median survival. No animal was cured after melphalan treatment, whereas 60% of the mice survived with RIT alone at day 22 after tumor engraftment, with only slight and reversible hematological radiotoxicity. No therapeutic effect was observed with alpha-RIT 25 days after engraftment. Melphalan and alpha-RIT combination does not improve overall survival compared to RIT alone, resulting in increased leukocyte and red blood cell toxicity. Based on these data, alpha-RIT seems to be a good alternative to melphalan, while their association provides no benefit [214].

To promote an efficient and long-lasting antitumor response, combining α-RIT (213Bi-radiolabeled anti-CD138 antibody) and adoptive T-cell transfer (ovalbumin-specific CD8+ T cells) have been evaluated in an animal model. Animals treated with the combination had significant tumor growth control and an improved survival compared to control mice or the ones that received RIT alone or adoptive T-cell transfer alone [215].

Pretargeting with biotin may improve RIT efficacy. A comparison between conventional RIT using anti-CD38-MAb and streptavidin-biotin pretargeted RIT (PRIT) demonstrated more favorable results for PRIT. Particularly, PRIT demonstrated better biodistribution with a very high tumor-to-blood ratio (638:1 24 h after PRIT; ratios never exceeded 1:1 with conventional RIT). Objective remissions were observed within 7 days in 100% of the mice treated with PRIT (800–1200 μCi of anti-CD38 pretargeted 90Y-DOTA-biotin), including 100% of complete remissions by day 23. Furthermore, 100% of animals bearing NCI-H929 multiple myeloma tumor treated with 800 μCi of anti-CD38 pretargeted 90Y-DOTA-biotin achieved long-term myeloma-free survival (>70 days) compared with none of the control animals [216].

More recently, preliminary biodistribution and dosimetry results were obtained in refractory MM patients in a phase I/II RIT study using 131I-B-B4. Four patients at the fourth relapse received 370 MBq (20 mg/m2) of 131I-B-B4: each patient underwent three-point images (day 0, day 1, and day 3–4) to assess doses absorbed by organs and the bone marrow. Images obtained 1 h after 131I-B-B4 injection showed high bone marrow and liver uptake without kidney uptake. The bone marrow uptake confirmed the bone marrow involvement as detected by [18F]FDG-PET/CT. Absorbed doses were calculated at 2.03 ± 0.3 mGy/MBq for the liver, 1.10 ± 0.9 mGy/MBq for the kidney, and 0.52 ± 0.20 mGy/MBq for the bone marrow. Grade III thrombocytopenia was documented in two cases (highest bone marrow-absorbed doses), and no grade IV hematological toxicity was observed. One patient experienced partial response, with 60% reduction of M-spike on serum electrophoresis, and total relief of pain, lasting for 1 year. This proof-of-concept study based on dosimetry demonstrated the feasibility of the anti-CD138 antibody RIT [217]. Animal model studies confirmed the efficacy of 213Bi-labeled anti-mCD138 for the treatment of residual disease in the case of MM, with only moderate and transient toxicity [213].

Promising results have been reported also by using 131I-Radretumab . Radretumab is a fully human antibody binding the extradomain-B splice variant of fibronectin. Strong extradomain-B expression in almost all lymphoma subtypes and in the bone marrow from MM patients has also been reported [218].

Based on these preclinical data, a phase I/II study was performed in patients with solid tumors and hematological malignancies . Two MM patients were treated with 3.7 GBq and 1.85 GBq of 131I-Radretumab, respectively, achieving disease stabilization lasting few months [219].

The newly synthetized te2a-Ph-NCS has been conjugated to a new anti-CD138 mAb (9E7.4) to evaluate its in vivo behavior and potentiality as bifunctional chelating agents and to explore a first attempt of PET-phenotypic imaging in MM (64Cu-9E7.4-CSN-Ph-te2a). Animal experiments were carried out on 5 T33-Luc(+) tumor bearing mice: a millimetric bone uptake was localized in the sacroiliac myeloma. Nonspecific uptakes were observed at 2 h postinjection, but, unlike for the tumor, a significant decrease was observed at 20 h postinjection [220].

Very recently, the therapeutic efficacy of RIT in the 5 T33 murine MM model using 9E7.4 labeled either with 213Bi for α-RIT or 177Lu for β-RIT has been evaluated. α-RIT performed with 3.7 MBq of 213Bi-9E7.4 increased median survival to 80 days compared to untreated control (37 days) and effected cure in 45% of animals. β-RIT performed with 18.5 MBq of 177Lu-9E7.4 mAb was well tolerated and significantly increased mouse survival (54 vs. 37 days in the control group); however, no mice were cured with this treatment [221].

Radiotherapy with Bone-Seeking Radionuclides

Bone-seeking radiopharmaceuticals, although used more widely in the palliation of bone pain for patients with metastases from prostate or breast cancer, are also being evaluated in MM patients in the transplant setting.

In vitro studies showed that myeloma cell lines treated with 153Sm-EDTMP showed a 50% decrease in clonogenic activity and mice who received treatment improved median survival from 18 to 25 days (p<0.001) [222].

A phase II trial using high-dose 153Sm-EDTMP conducted at the Mayo Clinic included 46 patients treated with melphalan 200 mg/m2 and 40 Gy of 153Sm-EDTMP: engraftment was comparable to that seen after conventional ASCT. No dose-related toxicity or cases of thrombotic thrombocytopenic purpura, radiation nephritis, or bladder toxicity were observed with a median follow-up of 14.2 months [223].

In another study, the clinical impact and quality of life after treatment with 153Sm-EDTMP (2 GBq every 12 weeks) and zoledronic acid (4 mg every 28 days) for symptomatic refractory MM were evaluated in elderly patients. A single course of 153Sm-EDTMP plus zoledronic acid prolonged duration of the clinical response (reduction of MM-related symptoms). No significant hematological or non-hematological side effects were observed [224]. This combination is therefore safe and may be useful in the setting of refractory bone pain for MM patients with bone disease. It is currently ongoing a phase I/II trial which evaluates the efficacy and side effects of 153Sm-lexidronam pentasodium when given together with zoledronic acid or pamidronate [147]. More recent studies also showed that many of the newer agents (including bortezomib, thalidomide, and arsenic trioxide) have a radiosensitizing effect, possibly through inhibitory effects on the NF-κB pathway that usually upregulates the anti-apoptotic signaling following exposure to ionizing radiation [222, 225, 226].

Very interesting results were obtained by a phase I dose-escalation study assessing the safety, tolerability, and efficacy of 153Sm-lexidronam combined with bortezomib (as radiosensitizing agent) for patients with relapsed/refractory MM: the maximum tolerated was not reached and no dose-limiting toxicities were observed. Responses occurred in five (21%) patients, including three (12.5%) complete and two (8.3%) minimal responses. These results suggested that bortezomib combined with 153Sm-lexidronam is a well-tolerated regimen and it might be effective in patients with relapsed or refractory MM [227].

Results of a phase I/II trial evaluating the side effects and best activity of samarium 153Sm-lexidronam when given together with high-dose melphalan in patients with MM undergoing stem cell transplant are not available [147]. However, therapy with 186Re-HEDP used as part of an intensified conditioning regimen before allogeneic stem cell transplantation has been reported in two patients with advanced ALL during the second partial or third complete remission [228]. After a pre-therapeutic dynamic scintigraphy with 99mTc-Mag3 showing normal renal function, a dynamic bone scintigraphy with 99mTc-MDP was used to calculate the expected bone marrow and kidney doses, with effective doses equal to 2.1 Gy and 1.6 Gy, respectively. No unexpected complications occurred after completing conditioning and allogeneic stem cell transplantation, and no deterioration of renal function was noticed. The authors therefore concluded that 186Re-HEDP is expected to increase the total additional bone marrow dose without inducing clinically significant nephrotoxicity; in these conditions, doses near 10 Gy to the bone marrow can be achieved.

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Copyright information

© Springer International Publishing Switzerland 2016

Authors and Affiliations

  • Martina Sollini
    • 1
  • Sara Galimberti
    • 2
  • Roberto Boni
    • 3
  • Paola Anna Erba
    • 3
    Email author
  1. 1.Department of Biomedical SciencesHumanitas UniversityRozzano, MilanItaly
  2. 2.Hematology UnitUniversity of PisaPisaItaly
  3. 3.Regional Center of Nuclear MedicineUniversity of PisaPisaItaly

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