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Open access peer-reviewed chapter

Use of Monoclonal Antibodies in Conditioning Regimen in Transplantation

Written By

Pervin Topcuoglu, Sinem Civriz Bozdag and Taner Demirer

Submitted: 12 March 2015 Reviewed: 11 September 2015 Published: 02 December 2015

DOI: 10.5772/61509

Progress in Stem Cell Transplantation IntechOpen
Progress in Stem Cell Transplantation Edited by Taner Demirer

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Progress in Stem Cell Transplantation

Edited by Taner Demirer

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Abstract

Monoclonal antibodies (MoAbs) alone or in the combination of conventional therapies have been used in the treatment of many benign or malign diseases. In the transplantation setting, Moabs have been generally applied as a part of conditioning regimen in the aims of the prevention of graft versus host disease and/or graft failure or treatment of underlying hematologic disease. The most frequent used moAbs for this purpose are rituximab, alemtuzumab, Gemtuzumab Ozogamicin or radioimmunoconjugates. In this chapter, we discussed the role of moAbs use in the conditioning regimens of allogeneic or autologous stem cell transplantation.

Keywords

  • Monoclonal antibodies
  • Conditioning Regimen
  • Stem Cell Transplantation

1. Introduction

Monoclonal antibodies (MoAbs) to treat a variety of benign and malignant diseases are used alone or in combination with conventional therapies. The use of MoAbs in autologous and allogeneic hematopoietic stem cell transplant (allo-HSCT) is subject to the following conditions for:

  1. In vivo purging of graft and as a part of the conditioning regimens in the autologous or allogeneic HSCTs, and/or

  2. Prevention or treatment of graft versus host disease (GvHD) developed after allo-HSCT.

The goals of the use of the MoAbs for in vivo purging of graft and/or as a part of conditioning regimens in autologous or allogeneic HSCTs are to obtain tumor-free stem cells, to reduce the recurrence, and to provide the resulting increase in the efficacy of transplantation on the underlying disease and the cure rate. Additionally, MoAbs in allo-HSCTs prevent the graft rejection and/or reduce the frequency and severity of GvHD. More frequent used MoAbs in the transplantation are: Rituximab, Radioimmunotherapeutics (RITs), Alemtuzumab, and Gemtuzumab Ozogamisin.

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2. Rituximab

Rituximab, the chimeric anti-CD20MoAb is mostly used to treat a broad variety of B-cell non-Hodgkin’s lymphomas (NHL). Rituximab shows direct activity or complement-mediated cytotoxicity and antibody-dependent cytotoxicity. There are numerous studies on the use of conditioning regimens in autologous and allogeneic HSCTs settings.

The first study was reported by Flinn et al. [1] including 25 patients with a variety of NHL (11 follicular lymphoma, 7 mantle cell lymphoma, 5 chronic lymphocytic leukemia or small lymphocytic leukemia, 1 lymphoblastic lymphoma, and 1 marginal zone lymphoma). In this study rituximab was used for in vivo purging during the stem cell mobilization with cyclophosphamide (Cy) and also added in the myeloablative (MA) conditioning regimen including mostly Cy plus total body irradiation (TBI) and a further dose given after the engraftment. As a result, rituximab was well tolerated, engraftment was fast, and temporary neutropenia developed in the mean of 99.5 days in six patients but clinically significant infection was not reported.

Following study on the addition of rituximab for the conditioning regimen in autologous HSCT has been published by Flohr et al. [2]. In this phase II study, 27 patients with a variety of B-cell NHL in both the first day of the stem cell mobilization with chemotherapy and in the conditioning regimen,-10 and -3 days at the dose of 375 mg/square meter (sqm) rituximab have been used. The overall response rate has been reported as 96%. In the median follow-up of 16 months, disease free survival (DFS) and overall survival (OS) have been estimated as 77% and 95%, respectively. Another study of Khouri et al. [3] have evaluated the efficacy of rituximab use in the stem cell mobilization and after the transplantation in a total of 67 patients with diffuse large B-cell lymphoma (DLBCL) and follicular lymphoma (FL). Rituximab (375 mg/sqm) was infused 1 day before chemotherapy and again administered 7 days after chemotherapy at 1000 mg/sqm. In addition, rituximab has been given to the patients on the first and eighth day of 1000 mg/sqm dose following the high-dose BEAM conditioning regimen for autologous HSCT. The results were retrospectively compared with those of a historical control group (n=30 patients) receiving the same preparative regimen without rituximab. Although neutrophil engraftment in the rituximab arm was late in a statistically significant proportion (median 10 days vs.11 days, p <0.05), similar incidence of infection has been shown in the patients who received rituximab compared with the control arm. In the median 20 months of follow-up, they reported that the possibilities of progression-free survival (PFS) and OS significantly prolonged in rituximab arm (PFS: 43% versus 67%, p = 0.004; OS: 53% versus 80%, p = 0.002). In a multicenter study from 10 centers associated with the Italian group, the Gruppo ItalianoTerapie Innovative nei Linfomi, when retrospectively compared the high-dose therapies with and without rituximab in the patients with DLBCL and FL undergoing autologous HSCT, either as salvage or as first-line therapy for high-risk presentation, rituximab was administered in four doses during the high-dose therapy immediately before peripheral blood collection to exploit the drug’s in vivo purging effect, and two additional doses were usually used after autologous-HSCT. They found the similar response rate and early transplant-related mortality between rituximab (+) and (-), but the 5-year projected PFS and OS were better in those with rituximab (+) (p<0.0001) [4].

Hick et al. have also evaluated the use of rituximab in 23 patients with relapsed FL during the mobilization of stem cells for in vivo purging and during the 8th and 24th week after autologous HSCT for a four-week maintenance treatment protocol [5]. This study showed that rituximab provided permanent molecular remission in 77% of the patients associated with significantly prolonged PFS versus those with continued polymerase chain reaction PCR positivity.

Many single-arm phase II studies including small number of patients have been reported that the addition of rituximab especially reduced intensity conditioning (RIC) regimens in allogeneic HSCT settings reduced the incidence of acute or chronic GvHD and non-relapse mortality (NRM) [7-11]. In these studies, rituximab has led to an increase of serious infections due to long-term cytopenias and prolonged hypogammaglobulinemia.

Ultimately, there is no consensus regarding the dosage and scheme of rituximab use as a part of conditioning regimen for autologous and allogeneic HSCT in these studies. In addition, it is also not sufficient in randomized controlled trials demonstrating the superiority of adding rituximab. Therefore, prospective multicenter randomized trials aiming to determinate the exact role of rituximab for in vivo purging and/or as a part of conditioning regimens should be made in lymphoma patients.

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3. Radioimmunotherapeutics

Radioimmunotherapeutics (RITs) uses monoclonal antibodies directed against specific tumor antigens labeled with a particle emitting radioisotope to deliver radiation directly to the tumor. This type of treatment gives a high dose of radiation to tumor tissue and protects uninvolved tissues and organs [12-13]. Labeled antibodies to the antigen over-expression in the target tissue with radioactive substances specifically bind. For this purpose beta- particles are the most frequently used: Radioactive particles connected the MoAb slowly give out its radiation and kill the other nearby cells. This is called as cross fire. They give high tissue distribution with high nucleotides in the target tissue and homogeneous energy and provide the myeloablation or affect the large tumor mass. To achieve a favorable biodistribution of a radiolabeled monoclonal antibody, an ideal antigen would be expressed homogeneously on the tumor cell surface and would lack expression on normal cells. Lacking such an antigen, methods to target lineage-specific hematopoietic antigens, such as CD20, CD33, and CD45, have been successfully developed in the autologous and allogeneic-HSCT setting.

Currently there are two RITs in clinical use for indolent NHL [14]: Yttrium-90 ibritumomab tiuxetan (90Y-IT) (Zevalin) and iodine-131 tositumomab (131I-T) (Bexxar). There are studies on the use of high or standard doses as a part of the conditioning regimen for the transplantation.

3.1. High-dose RITs

Studies are generally on the use of single or combined with chemotherapy in the conditioning regimen for autologous-HSCT. In the first study, Press et al. conducted the phase I study in 43 relapsed B-cell lymphoma patients, and the administration of anti-CD20 and anti-CD37 antibodies labeled 131I-T alone in the conditioning regimen was to evaluate the toxicity and efficacy (15). The maximum tolerated dose was 27.25 Gy. However, researches have shown that patients administered more than this dose had cardio-toxic effects. In addition, the biodistribution of the antibodies in the patients with the large spleen size and a large tumor mass were emphasized not to be good in the study. The overall response rate of 95% with high-dose RIT (84% complete response and 11% partial response) and tumor response were calculated as the median of 11 months. Subsequently, the same researchers have made a phase II study with anti-CD20 labeled 131I-T in 25 patients with relapse NHL [16]. In this study, they have reported that PFS was 62% and 93% of OS with the median 2-year follow-up. Similarly, Liu et al. found a median PFS of 42% and 68% of OS in median 42-month follow-up [17]. This was followed by similar studies regarding the use of the high-dose RITs. However, due to the gamma radiation emitted by 131I-T most subsequent studies had been conducted with 90Y-IT, a pure beta emitter [18-21]. There was no need to prolong strict patient isolation and contact alert in 90Y-IT in contrast to131I-T. Besides, disease statuses prior to the transplantations in those studies were also variable. Although the use of high-dose RIT was planned for the patients unable to tolerate high-dose treatment, the majority of patients in the studies was under 60 years of age and had chemosensitive relapses. Additionally, there are no prospective studies to prove RITs’ superiority to chemotherapy and/or radiotherapy. Furthermore, this treatment should be administered in specialized centers.

3.2. Standard-dose RITs

To overcome the problems related to the safe yield of high-dose RITs, the efficacies of standard-dose RITs combined with chemotherapy in preparative regimens of the transplantation have been assessed in the following studies. The results in several single-arm studies not including control group were impressive. In a randomized trial, the Blood and Marrow Transplant Clinical Trials Clinical Trials Network (BMT-CTN) 0401 in which 131I-T-BEAM or Rituximab-BEAM were given to the patients with chemosensitive relapse of DLBCL [22], disease control and survival effects of RIT could not have been shown. A randomized study compared 90Y-IT-BEAM with BEAM alone in recurrent B cell NHL was closed early by reason of the slow patient recruitment. As their evaluation with a small number of cases, it was the first randomized study that proved that higher DFS and OS were in the RIT arm. Nevertheless, the published studies do not support the routine use of standard-dose RITs in DLBCL.

Some studies in chemorefractory DLBCL patients who underwent autologous-HSCT conditioned by standard-dose RIT have been reported as two or three year PFS and OS 39%–63% and 55%–67%, respectively [23-26]. In the European Mantle Cell Network MCL-3 study 90Y-IT was given to patients younger than 66 years one week prior to BEAM or BEAC (Carmustine, Etoposide, Cytarabine and Cyclophosphamide) conditioning regimen [27]. When compared with the results of the MCL-2 study, they concluded that there was no benefit in the patients undergoing autologous-HSCTas a first-line intensification treatment.

In allogeneic HSCT, RIT has generally been added to the RIC regimens in the refractory NHL patients. One of the first studies where Shimoni et al. gave 90Y-IT with fludarabine-based conditioning regimens to 12 patients with chemorefractory CD20+ NHL demonstrated the safety of RIT [28]. Subsequently, several studies related to adding RITs to the conditioning regimen have been published [29,30]. Although allogeneic HSCTs made by adding RITs to RIC regimes have reliability in these studies, it has not been shown to be superior to the transplantations with RIC regimens not including RIT yet.

There are some studies related to the adding of RITs to the preparative regimens in acute leukemia and myelodysplastic syndrome (MDS) as well. Initially, 131I-labeled M195, the mouse Moabs of lintuzumab (reactive with CD33) was used in 10 patients with relapsed or refractory acute myeloid leukemia in a phase I study from the Memorial Sloan Kettering Cancer Center [31]. Subsequently, 131I-labeled anti-CD33 MoAbs were added to standard myeloablative regimen in 31 patients with refractory or relapsed AML (n=16), accelerated or blastic phase chronic myeloid leukemia (CML) (n=14) or advanced myelodysplastic syndrome (MDS) (n=1) underwent allogeneic HSCT from their related donor [32]. The median survival was calculated as 4.9 months (range 0.3–90+ months). Three patients with relapsed AML remain in complete remission more than 5 years.

Based on the feasibility of MoAbs, investigators have focused on the CD45, the other antigen. The CD45 antigen, common leukocyte antigen, is expressed on the surface of virtually all hematopoietic cells, except mature red cells and platelets. In addition, CD45 expression has been detected in 85% to 90% of AML and ALL, and the antigen does not internalize after the antibody binding. In a phase I study conducted by the Fred Hutchinson Cancer Center, RIT with 131I-anti-CD45 has been implanted one week prior to the conditioning regimen including Cy-TBI in AML beyond the first complete remission (CR), acute lymphoblastic leukemia, and MDS-excess blast [33]. The patients of this study have undergone allogeneic HSCT from their human leukocyte antigen (HLA) -identical relative donors or autologous HSCT. This first study has shown that the radiation with acceptable toxicity should be given to the bone marrow and spleen. Subsequently RIT with 131I-anti-CD45 has been added to the conditioning regimen with busulfan (Bu) plus Cy (BuCy) in the patients with the first CR AML [34]. Three-year non-relapse mortality and disease-free survival in this study was calculated at 21% and 61%, respectively. They have reported that the results were comparable by the International Bone Marrow Transplantation Registry (IBMTR) data using only BuCy in allogeneic HSCT. Similarly Pagel et al. added the RIT to the RIC regimens in elderly patients with advanced stage or high risk AML and showed the reliability of RIT in a phase I study [35]. Same researches used the 131I-anti CD45 targeted radiotherapy in combination with Fludarabine plus 2 Gy TBI in younger patients (age 16 to 50 years) with advanced AML or high-risk MDS who underwent allogeneic HSCT [36]. They aimed to define the maximum tolerated dose (MTD) of radiolabeled anti-CD45 antibody in addition to non-myeloablative conditioning regimes and to create better antitumor control with minimal toxicity in comparison with standard myeloablative regimens. Their study suggested that a maximum dose of 28 Gy could be delivered to the liver and the arbitrary limit of 43 Gy to the marrow might be unnecessarily conservative. Conjugation of anti-CD45 antibody with alternative radioisotopes including 90Y is currently explored in clinical trials.

Another attempt in the studies was the use of anti-CD66 moAbs in leukemic patients. But leukemic blasts do not express CD66. Therefore, the anti-leukemic effect of CD66 RIT depends on “crossfire” from the beta-particles emitted by 188-Rhenium (Re). 188Re-labeled anti-CD66 moAbs were used as a part of the standard myeloablative conditioning regimen including total body irradiation (12 Gy) (n = 30) or busulfan (n = 27) and high-dose cyclophosphamide +/- thiotepa prior to allogeneic or autologous HSCT in 57 patients with high-risk AML or MDS [37]. In median 26 months follow-ups, disease-free survival were 64% for 44 patients in the first or second CR or in very good partial remission (less than 15% blasts in the marrow at transplantation) and only 8% for those with more than 15% blasts in the marrow at transplantation. Likewise, targeted marrow irradiation with 188Re-anti-CD66 moAbs were used in 20 patients with Philadelphia chromosome-positive acute lymphoblastic leukemia or advanced CML prior to allogeneic HSCT [38]. With a median follow-up of 54 months (range 23–81) overall and disease-free survival were 29% (95%-CI 14–58) and 25% (95%-CI 12–53), respectively. Subsequently, conjugation of anti-CD66 with 188Re or 90Y were added to a reduced intensity conditioning regimen in 20 patients with a median age of 63 years (range: 55–65 years) suffering from acute leukemia (n=17) or MDS (n=3) [39]. The probability of survival was estimated as 70% at 1 year and 52% at 2 years post-transplant. They concluded that 90Y-anti-CD66 moAbs were more feasible and less nephrotoxic than 188Re.

Briefly, the use of RIT is an attractive approach to increase conditioning prior to HSCT. The randomized studies in refractory aggressive or indolent NHL show the superiority of adding RIT. Nevertheless, the addition of standard dose RIT to the conditioning regimen in autologous transplantation is a valuable research topic. In allogeneic transplantation, until displaying the superiority of RIT-based conditioning regimen in controlled randomized studies, this approach should only be considered within clinical trials.

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4. Alemtuzumab (Campath)

Alemtuzumab is a human originated MoAbs to CD52 that normally expresses on B and T lymphocytes, macrophages, monocytes, natural killer cells, and some dendritic cells. While alemtuzumab efficiently reduces both T and B cells from the circulating blood, it has minimal or no effect on hematopoietic progenitor cells [40].

Anti-CD52 is often used in the treatment of chronic lymphocytic leukemia. But adding CD52 to the conditioning regimens in allogeneic HSCTs in many malign hematological diseases has reduced the frequency and severity of GvHD as well as decreased the risk of graft rejection [41-43]. Also alemtuzumab in combination with fludarabine and Cy in allogeneic HSCT for acquired aplastic anemia was associated with a very low incidence of chronic GvHD and excellent survival [44-49]. However, the studies have reported that alemtuzumab led to increase the frequency of opportunistic infection, in particular Cytomegalovirus, Epstein–Barr virus, and Adenovirus, and the risk for the recurrence of the underlying disease due to the reduction of graft versus tumor effects.

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5. Gemtuzumab Ozogamisin

Gemtuzumab ozogamisin (GO) is a moAbs to CD33 conjugated with human calicheamicins. It has been withdrawn from the market by the US Food and Drug Administration in 2010 because of the increasing risk of liver sinusoidal obstruction, and a lack of data for the efficacy and safety. Recently many studies have been published about the use of GO in the treatment of CD33+ AML patients as a part of induction therapy or consolidation [50-51]. Furthermore, phase I/II studies have reported that the use of GO as a part of MA or RI conditioning regimens in allo-HSCT setting could be safe and efficient in poor-risk AML patients [52-54]. In addition, a pilot study has been recently published about the administration of GO combined with azacytidine as the maintenance treatment of post-transplant relapses in AML [55].

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6. Conclusion

Although many studies have been published for the additions of MoAbs to the conditioning regimens for HSCTs, there are no sufficient data to determine the optimal dose and administration schedule of the MoAbs until now. However, rituximab recently has been widely used in many single-arm studies in NHL patients who underwent allogeneic HSCT. Another controversial issue is about the use of RITs. Randomized data do not support incorporating RITs into the conditioning regimens for either autologous or allogeneic SCT settings. The high-dose RITs should be used in refractory or advanced malign hematological disease in specialized centers though lacking randomized data. The standard-dose RIT is also a good research topic for lymphoid malignancies planning high dose therapy with autologous rescue or allogeneic SCT.

Moreover, given the reduced risk of graft failure and GvHD with alemtuzumab but increased risk of disease relapse and the incidence of opportunistic infections, the use of alemtuzumab in the allogeneic SCT should be considered in patients with matched unrelated or mismatched related donors. Owing to the shortage of studies on GO, another MoAbs, with the reuse, GO should be used in clinical trials.

In conclusion, it is anticipated that additional MoAbs to the conditioning regimens will be routinely used in the next door following by the proven clinical efficacy and safety.

References

  1. 1. Flinn IW, O’Donnell PV, Goodrich A, Vogelsand G, Abrams R, Noda S, Marcelus D, Borowitz M, Jones R, Ambinde RF. Immunotherapy with Rituximab during peripheral blood stem cell transplantation for non-Hodgkin’s lymphoma. Biology of Blood and Marrow Transplantation. 2000; 6(6):628-632.
  2. 2. Flohr T, Hess G, Kolbe K, Gamm H, Nolte H, Stanislawski T, Huber C, Derigs HG. Rituximab in vivo purging is safe and effective in combination with CD34-positive selected autologous stem cell transplantation for salvage therapy in B-NHL. Bone Marrow Transplant. 2002; 29(9):769-775.
  3. 3. Khouri IF, Saliba RM, Hosing C, Okoroji GJ, Acholonu S, Anderlini P, Couriel D, De Lima M, Donato ML, Fayad L, Giralt S, Jones R, Korbling M, Maadani F, Manning JT, Pro B, Shpall E, Younes A, McLaughlin P, Champlin RE. Concurrent administration of high-dose rituximab before and after autologous stem-cell transplantation for relapsed aggressive B-cell non-Hodgkin’s lymphomas. J ClinOncol. 2005; 23(10): 2240-2247.
  4. 4. Tarella C, Zanni M, Magni M, Benedetti F, Patti C, Barbui T, Pileri A, Boccadoro M, Ciceri F, Gallamini A, Cortelazzo S, Majolino I, Mirto S, Corradini P, Passera R, Pizzolo G, Gianni AM, Rambaldi A. Rituximab improves the efficacy of high-dose chemotherapy with autograft for high-risk follicular and diffuse large B-cell lymphoma: a multicenter Gruppo Italiano Terapie Innovative nei linfomi survey. J ClinOncol. 2008; 26(19):3166-3175.
  5. 5. Hicks LK, Woods A, Buckstein R, Mangel J, Pennell N, Zhang L, Imrie K, Spaner D, Cheung MC, Boudreau A, Reis M, Crump M, Berinstein NL. Rituximab purging and maintenance combined with auto-SCT: long-term molecular remissions and prolonged hypogammaglobulinemia in relapsed follicular lymphoma. Bone Marrow Transplant. 2009; 43(9):701-708.
  6. 6. Kharfan-Dabaja MA, Pidala J, Kumar A, Terasawa T, Djulbegovic B. Comparing efficacy of reduced-toxicity allogeneic hematopoietic cell transplantation with conventional chemo-(immuno) therapy in patients with relapsed or refractory CLL: a Markov decision analysis. Bone Marrow Transplant. 2012; 47(9):1164-1170.
  7. 7. Michallet M, Socié G, Mohty M, Sobh M, Bay JO, Morisset S, Labussière-Wallet H, Tabrizi R, Milpied N, Bordigoni P, El-Cheikh J, Blaise D. Rituximab, fludarabine, and total body irradiation as conditioning regimen before allogeneic hematopoietic stem cell transplantation for advanced chronic lymphocytic leukemia: long-term prospective multicenter study. Exp Hematol. 2013; 41(2): 127-133.
  8. 8. Pidala J, Roman-Diaz J, Kim J, Nishihori T, Perkins J, Tate C, Ochoa-Bayona JL, Field T, Fernandez HF, Tomblyn M, Ayala E, Anasetti C, Kharfan-Dabaja MA. Targeted IV busulfanand fludarabine followed by post-allogeneic hematopoietic cell transplantation rituximab demonstrate encouraging activity in CD20+ lymphoid malignancies without increased risk of infectious complications. Int J Hematol. 2011; 93(2): 206-212.
  9. 9. McIver Z, Stephens N, Grim A, Barrett AJ. Rituximab administration within 6 months of T cell depleted allogeneic SCT is associated with prolonged life-threatening cytopenias. Biol Blood Marrow Transplant. 2010;16(11):1549-1556.
  10. 10. Khouri IF, Wei W, Korbling M, Turturro F, Ahmed S, Alousi A, Anderlini P, Ciurea S, Jabbour E, Oran B, Popat UR, Rondon G, Bassett RL Jr, Gulbis A. BFR (bendamustine, fludarabine, and rituximab) allogeneic conditioning for chronic lymphocytic leukemia/lymphoma: reduced myelosuppression and GVHD. Blood. 2014; 124(14): 2306-2312.
  11. 11. Shamriz O, Vilk SR, Wolf DG, Ta-Shma A, Averbuch D, Weintraub M, Stepensky P. Hematopoietic stem cell transplantation conditioning with use of rituximab in EBV related lymphoproliferative disorders. Clin Immunol. 2014;151(2): 79-83.
  12. 12. Kraeber-Bodéré F, Bodet-Milin C, Rousseau C, Eugène T, Pallardy A, Frampas E, Carlier T, Ferrer L, Gaschet J, Davodeau F, Gestin JF, Faivre-Chauvet A, Barbet J, Chére lM. Radioimmunoconjugates for the treatment of cancer. Semin Oncol. 2014; 41(5): 613-622.
  13. 13. Kawashima H. Radioimmunotherapy: a specific treatment protocol for cancer by cytotoxic radioisotopes conjugated to antibodies. Scientific World Journal. 2014; 2014: 492061.
  14. 14. Kharfan-Dabaja MA, Nishihori T, Otrock ZK, Haidar N, Mohty M, Hamadani M. Monoclonal antibodies in conditioning regimens for hematopoietic cell transplantation. Biol Blood Marrow Transplant. 2013 Sep; 19(9):1288-1300.
  15. 15. Press OW, Eary JF, Appelbaum FR, Martin PJ, Badger CC, Nelp WB, Glenn S, Butchko G, Fisher D, Porter B, Matthews DC, Fisher LD, Bernstein ID. Radiolabeled-antibody therapy of B-cell lymphoma with autologous bone marrow support. N Engl J Med. 1993; 329(17):1219 -1224.
  16. 16. Press OW, Eary JF, Appelbaum FR, Martin PJ, Nelp WB, Glenn S, Fisher DR, Porter B, Matthews DC, Gooley T. Phase II trial of 131I-B1 (anti-CD20) antibody therapy with autologous stem cell transplantation forrelapsed B cell lymphomas. Lancet. 1995; 346(8971): 336-340.
  17. 17. Liu SY, Eary JF, Petersdorf SH, Martin PJ, Maloney DG, Appelbaum FR, Matthews DC, Bush SA, Durack LD, Fisher DR, Gooley TA, Bernstein ID, Press OW. Follow-up of relapsed B-cell lymphoma patients treated with iodine-131-labeled anti-CD20 antibody and autologous stem-cell rescue. J Clin Oncol. 1998; 16(10): 3270-3278.
  18. 18. Nademanee A, Forman S, Molina A, Fung H, Smith D, Dagis A, Kwok C, Yamauchi D, Anderson AL, Falk P, Krishnan A, Kirschbaum M, Kogut N, Nakamura R, O'donnell M, Parker P, Popplewell L, Pullarkat V, Rodriguez R, Sahebi F, Smith E, Snyder D, Stein A, Spielberger R, Zain J, White C, Raubitschek A. A phase 1/2 trial of high-dose yttrium-90-ibritumomab tiuxetan in combination with high-dose etoposide and cyclophosphamide followed by autologous stem cell transplantation in patients with poor-risk or relapsed non-Hodgkin lymphoma. Blood.2005; 106(8): 2896-2902.
  19. 19. Winter JN, Inwards DJ, Spies S, Wiseman G, Patton D, Erwin W, Rademaker AW, Weitner BB, Williams SF, Tallman MS, Micallef I, Mehta J, Singhal S, Evens AM, Zimmer M, Molina A, White CA, Gordon LI. Yttrium-90 ibritumomab tiuxetan doses calculated to deliver up to 15 Gy to critical organs may be safely combined with high-dose BEAM and autologous transplantation in relapsed or refractory B-cell non-Hodgkin’s lymphoma. J ClinOncol. 2009; 27(10):1653-1659.
  20. 20. Devizzi L, Guidetti A, Tarella C, Magni M, Matteucci P, Seregni E, Chiesa C, Bombardieri E, Di Nicola M, Carlo-Stella C, Gianni AM. High-dose yttrium-90 ibritumomab tiuxetan with tandem stem-cell reinfusion: an outpatient preparative regimen for autologous hematopoietic celltransplantation. J ClinOncol. 2008; 26(32): 5175-5182.
  21. 21. Ferrucci PF, Vanazzi A, Grana CM, Cremonesi M, Bartolomei M, Chinol M, Ferrari M, Radice D, Papi S, Martinelli G, Paganelli G. High-activity 90Y-ibritumomab tiuxetan (Zevalin) with peripheral blood progenitor cell support in patients with refractory/resistant B-cell non-Hodgkin lymphomas. Br J Haematol. 2007; 139(4): 590-599.
  22. 22. Vose JM, Carter S, Burns LJ, Ayala E, Press OW, Moskowitz CH, Stadtmauer EA, Mineshi S, Ambinder R, Fenske T, Horowitz M, Fisher R, Tomblyn M. Phase III randomized study of rituximab/carmustine, etoposide, cytarabine, and melphalan (BEAM) compared with iodine-131 tositumomab/BEAM with autologous hematopoietic cell transplantation for relapsed diffuse large B-cell lymphoma: results from the BMT CTN 0401 Trial. J Clin Oncol. 2013; 31(13):1662-1668.
  23. 23. Vose JM, Bierman PJ, Loberiza FR, Enke C, Hankins J, Bociek RG, Chan WC, Weisenburger DD, Armitage JO. Phase II trial of 131iodine tositumomab with high-dose chemotherapy and autologous stem cell transplantation for relapsed diffuse large B cell lymphoma. Biol Blood Marrow Transplant. 2013; 19(1):123-128.
  24. 24. Vose JM, Bierman PJ, Enke C, Hankins J, Bociek G, Lynch JC, Armitage JO. Phase I trial of iodine-131 tositumomab with high-dose chemotherapy and autologous stem-cell transplantation for relapsed non-Hodgkin’s lymphoma. J ClinOncol. 2005; 23(3): 461-467.
  25. 25. Shimoni A, Zwas ST, Oksman Y, Hardan I, Shem-Tov N, Yerushalmi R, Avigdor A, Ben-Bassat I, Nagler A. Yttrium-90-ibritumomab tiuxetan(Zevalin) combined with high-dose BEAM chemotherapy and autologous stem cell transplantation for chemo-refractory aggressive non-Hodgkin’s lymphoma. Exp Hematol. 2007; 35(4): 534-540.
  26. 26. Briones J, Novelli S, Garcia Marco JA, Tomas JF, Bernal T, Grande C, Canales M, Torres A, Moraleda JM, Panizo C, Palmero F, Jarque I, Hernandez M, Barca EG, Lopez D, Caballero D. Autologous stem cell transplantation with yttrium-90 ibritumomab tiuxetan (Zevalin) plus BEAM conditioning in patients with refractory non-Hodgkin diffuse large B-cell lymphoma: results of a prospective, multicenter, Phase II clinical trial. ASH Annual Meeting Abstracts. 2012; 120:1978.
  27. 27. Geisler CH, Kolstad A, Laurell A, Andersen NS, Pedersen LB, Jerkeman M, Eriksson M, Nordström M, Kimby E, Boesen AM, Kuittinen O, Lauritzsen GF, Nilsson-Ehle H, Ralfkiaer E, Akerman M, Ehinger M, Sundström C, Langholm R, Delabie J, Karjalainen-Lindsberg ML, Brown P, Elonen E. Nordic lymphoma group. Long-term progression-free survival of mantle cell lymphoma after intensive front-line immunochemotherapy with in vivo-purged stem cell rescue: a nonrandomized phase 2 multicenter study by the Nordic Lymphoma Group. Blood. 2008; 112(7): 2687-2693.
  28. 28. Shimoni A, Zwas ST, Oksman Y, Hardan I, Shem-Tov N, Rand A, Yerushalmi R, Avigdor A, Ben-Bassat I, Nagler A. Ibritumomab tiuxetan (Zevalin) combined with reduced-intensity conditioning and allogeneic stem-cell transplantation (SCT) in patients with chemorefractory non-Hodgkin’s lymphoma. Bone Marrow Transplant. 2008; 41(4): 355-361.
  29. 29. Bethge WA, Lange T, Meisner C, Von Harsdorf S, Bornhaeuser M, Federmann B, Stadler M, Uharek L, Stelljes M, Knop S, Wulf G, Trenschel R, Vucinic V, Dittmann H, Faul C, Vogel W, Kanz L, Bunjes D. Radioimmunotherapy with yttrium-90-ibritumomab tiuxetan as part of a reduced-intensity conditioning regimen for allogeneic hematopoietic cell transplantation in patients with advanced non-Hodgkin lymphoma: results of a phase 2 study. Blood. 2010; 116(10):1795-1802.
  30. 30. Khouri IF, Saliba RM, Erwin WD, Samuels BI, Korbling M, Medeiros LJ, Valverde R, Alousi AM, Anderlini P, Bashir Q, Ciurea S, Gulbis AM, de Lima M, Hosing C, Kebriaei P, Popat UR, Fowler N, Neelapu SS, Samaniego F, Champlin RE, Macapinlac HA. Nonmyeloablative allogeneic transplantation with or without 90 yttrium ibritumomab tiuxetan is potentially curative for relapsed follicular lymphoma: 12-year results. Blood. 2012; 119(26): 6373-6378.
  31. 31. Scheinberg DA, Lovett D, Divgi CR, Graham MC, Berman E, Pentlow K, Feirt N, Finn RD, Clarkson BD, Gee TS. A Phase I trial of monoclonal antibody M195 in acute myelogenous leukemia: specific bone marrow targeting and internalization of radionuclide. J Clin Oncol. 1991; 9(3): 478-490.
  32. 32. Burke JM1, Caron PC, Papadopoulos EB, Divgi CR, Sgouros G, Panageas KS, Finn RD, Larson SM, O'Reilly RJ, Scheinberg DA, Jurcic JG. Cytoreduction with iodine-131-anti-CD33 antibodies before bone marrow transplantation for advanced myeloid leukemias. Bone Marrow Transplant. 2003; 32(6): 549-556.
  33. 33. Matthews DC, Appelbaum FR, Eary JF, Fisher DR, Durack LD, Hui TE, Martin PJ, Mitchell D, Press OW, Storb R, Bernstein ID. Phase I study of 131I-anti-CD45 antibody plus cyclophosphamide and total body irradiation for advanced acute leukemia and myelodysplastic syndrome. Blood. 1999; 94(4): 1237-1247.
  34. 34. Horowitz MM, Press OW, Eary JF, Rajendran J, Fisher DR, Gooley T, Ruffner K, Nemecek E, Sickle E, Durack L, Carreras J, Horowitz MM, Press OW, Gopal AK, Martin PJ, Bernstein ID, Matthews DC. 131I-anti-CD45 antibody plus busulfan and cyclophosphamide before allogeneic hematopoietic cell transplantation for treatment of acute myeloid leukemia in first remission. Blood. 2006; 107(5): 2184-2191.
  35. 35. Pagel JM, Gooley TA, Rajendran J, Fisher DR, Wilson WA, Sandmaier BM, Matthews DC, Deeg HJ, Gopal AK, Martin PJ, Storb RF, Press OW, Appelbaum FR.. Allogeneic hematopoietic cell transplantation after conditioning with 131 I-anti-CD45 antibody plus fludarabine and low-dose total body irradiation for elderly patients with advanced acute myeloid leukemia or high-risk myelodysplastic Syndrome. Blood. 2009; 114(27): 5444-5453.
  36. 36. Mawad R, Gooley TA, Rajendran jG, Fisher DR, Gopal AK, Shileds AT, Sandmaier BM, Sorro ML, Deeg HJ, Strob R, Green DJ, Maloney DG, Appelbaum FR. Radioalabeled anti-CD45 Antibody with reduced-intensity conditioning and allogeneic transplantation for younger patients with advanced acute myeloid leukemia or myelodysplastic syndrome. Bio Bone Marrow Transplantation. 2014; 20: 1363-1368.
  37. 37. Bunjes D. 188Re-labeled anti-CD66 monoclonal antibody in stem cell transplantation for patients with high-risk acute myeloid leukemia. Leuk Lymphoma. 2002; 43(11): 2125-2131.
  38. 38. Zenz T, Glatting G, Schlenk RF, Buchmann I, Döhner H, Reske SN, Bunjes D. Targeted marrow irradiation with radioactively labeled anti-CD66 monoclonal antibody prior to allogeneic stem cell transplantation for patients with leukemia: results of a phase I-II study. Haematologica. 2006; 91(2): 285-286.
  39. 39. Ringhoffer M, Blumstein N, Neumaier B, Glatting G, von Harsdorf S, Buchmann I, Wiesneth M, Kotzerke J, Zenz T, Buck AK, Schauwecker P, Stilgenbauer S, Döhner H, Reske SN, Bunjes D. 188Re or 90Y-labelled anti-CD66 antibody as part of a dose-reduced conditioning regimen for patients with acute leukaemia or myelodysplastic syndrome over the age of 55: results of a phase I-II study. Br J Haematol. 2005; 130(4): 604-613.
  40. 40. Gribben JG, Hallek M. Rediscovering alemtuzumab: current and emerging therapeutic roles. Br J Haematol. 2009; 144 (6):818-831.
  41. 41. Pérez-Simón JA, Kottaridis PD, Martino R, Craddock C, Caballero D, Chopra R, García-Conde J, Milligan DW, Schey S, Urbano-Ispizua A, Parker A, Leon A, Yong K, Sureda A, Hunter A, Sierra J, Goldstone AH, Linch DC, San Miguel JF, Mackinnon S; Spanish and United Kingdom Collaborative Groups for Nonmyeloablative Transplantation. Nonmyeloablative transplantation with or without alemtuzumab: comparison between 2 prospective studies in patients with lymphoproliferative disorders. Blood. 2002; 100(9):3121-3127.
  42. 42. Hale G, Zhang MJ, Bunjes D, Spence D, Horowitz MM, Barrett AJ, Waldmann H. Improving the outcome of bone marrow transplantation by using CD52 monoclonal antibodies to prevent graft-versus-host disease and graft rejection. Blood. 1998; 92(12): 4581-4590.
  43. 43. Delgado J, Thomson K, Russell N, Ewing J, Stewart W, Cook G, Devereux S, Lovell R, Chopra R, Marks DI, Mackinnon S, Milligan DW. British Society of Blood and Marrow Transplantation. Results of alemtuzumab-based reduced-intensity allogeneic transplantation for chronic lymphocytic leukemia: a British Society of Blood and Marrow Transplantation Study. Blood. 2006; 107(4):1724-1730.
  44. 44. Peggs KS, Sureda A, Qian W, Caballero D, Hunter A, Urbano-Ispizua A, Cavet J, Ribera JM, Parker A, Canales M, Mahendra P, Garcia-Conde J, Milligan D, Sanz G, Thomson K, Arranz R, Goldstone AH, Alvarez I, Linch DC, Sierra J, Mackinnon S. UK and Spanish Collaborative Groups. Reduced-intensity conditioning for allogeneic haematopoietic stem cell transplantation in relapsed and refractory Hodgkin lymphoma: impact of alemtuzumab and donor lymphocyte infusions on long-term outcomes. Br J Haematol. 2007; 139(1):70-80.
  45. 45. Gandhi S, Kulasekararaj AG, Mufti GJ, Marsh JC. Allogeneic stem cell transplantation using alemtuzumab-containing regimens in severe aplastic anemia. Int J Hematol. 2013; 97(5): 573-580.
  46. 46. March JC, Gupta V, Lim Z, Ho AY, Ireland RM, Hayden J, Potter V, Koh MB, Islam MS, Russel N, Marks DI, Mufti GJ and Pagliuca A. Alemtuzumab with fludarabine and cyclophosphamide reduces Chronic graft-versus-host disease after allogeneic stem cell transplantation for acquired aplastic anemia. Blood. 2011; 118)(8): 2351-2357
  47. 47. De Lima M, Champlin RE, Thall PF, Wang X, Martin TG 3rd, Cook JD, McCormick G, Qazilbash M, Kebriaei P, Couriel D, Shpall EJ, Khouri I, Anderlini P, Hosing C, Chan KW, Andersson BS, Patah PA, Caldera Z, Jabbour E, Giralt S. Phase I/II study of gemtuzumab ozogamicin added to fludarabine, melphalan and allogeneic hematopoietic stem cell transplantation for high-risk CD33-positive myeloid leukemias and myelodysplastic syndrome. Leukemia. 2008; 22 (2):258-264.
  48. 48. Marsh JC, Pearce RM, Koh MB, Lim Z, Pagliuca A, Mufti GJ, Perry J, Snowden JA, Vora AJ, Wynn RT, Russell N, Gibson B, Gilleece M, Milligan D, Veys P, Samarasinghe S, McMullin M, Kirkland K, Cook G. British Society for Blood and Marrow Transplantation, Clinical Trials Committee. Retrospective study of alemtuzumab vs ATG-based conditioning without irradiation for unrelated and matched sibling donor transplants in acquired severe aplastic anemia: a study from the British Society for Blood and Marrow Transplantation. Bone Marrow Transplant. 2014 Jan; 49(1):42-48.
  49. 49. Hamad N, Del Bel R, Messner HA, Kim D, Kuruvilla J, Lipton JH, Uhm J, Seftel M, Alam N, Xu W, Gupta V. Outcomes of hematopoietic cell transplantation in adult patients with acquired aplastic anemia using intermediate-dose alemtuzumab-based conditioning. Biol Blood Marrow Transplant. 2014; 20(11):1722-1728.
  50. 50. Castaigne S, Pautas C, Terre C, Raffoux E, Bordessoule D, Bastie JN, Legrand O, Thomas X, Turlure P, Reman O, De Revel T, Gastaud L, de Gunzburg N, Contentin N, Henry E, Marolleau JP, Aljijakli A, Rousselot P, Fenaux P, Preudhomme C, Chevret S, Dombret H; Acute Leukemia French Association. Effect of gemtuzumab ozogamicin on survival of adult patients with de-novo acute myeloid leukaemia(ALFA-0701): a randomised, open-label, phase 3 study. Lancet. 2012; 379(9825):1508-1516.
  51. 51. [51]Petersdorf SH, Kopecky KJ, Slovak M, Willman C, Nevill T, Brandwein J, Larson RA, Erba HP, Stiff PJ, Stuart RK, Walter RB, Tallman MS, Stenke L, Appelbaum FR. A phase 3 study of gemtuzumab ozogamicin during induction and postconsolidation therapy in younger patients with acute myeloid leukemia. Blood 2013; 121(24): 4854–4860.
  52. 52. Kharfan-Dabaja MA, Hamadani M, Reljic T, Pyngolil R, Komrokji RS, Lancet JE, Fernandez HF, Djulbegovic B, Kumar A. Gemtuzumab ozogamicin for treatment of newly diagnosed acute myeloid leukaemia: a systematic review and meta-analysis. Br J Haematol 2013; 163(3): 315-325.
  53. 53. Bornhäuser M, Illmer T, Oelschlaegel U, Schetelig J, Ordemann R, Schaich M, Hänel M, Schuler U, Thiede C, Kiani A, Platzbecker U, Ehninger G. gemtuzumab ozogamicin as part of reduced-intensity conditioning for allogeneic hematopoietic cell transplantation in patients with relapsed acute myeloid leukemia. Clin Cancer Res. 2008; 14 (17):5585-5593.
  54. 54. Satwani P, Bhatia M, Garvin JHJr, George D, Dela Cruz F, Le Gall J, Jin Z, Schwartz J, Duffy D, Van de Ven C, Foley S, Hawks R, Morris E, Baxter-Lowe LA, Cairo MS. A Phase I study of gemtuzumabozogamicin (GO) in combination with busulfan and cyclophosphamide (Bu/Cy) and allogeneic stem cell transplantation in children with poor-risk CD33(+) AML: a new targeted immunochemotherapy myeloablative conditioning (MAC) regimen. Biol Blood Marrow Transplant. 2012; 18(2):324-329.
  55. 55. Oshikawa G1, Kakihana K, Saito M, Aoki J, Najima Y, Kobayashi T, Doki N, Sakamaki H, Ohashi K. Post-transplant maintenance therapy with azacitidine and gemtuzumab ozogamicin for high-risk acute myeloid leukaemia. Br J Haematol. 2014 Dec 17. doi: 10.1111/bjh.13248 [Epub ahead of print].

Written By

Pervin Topcuoglu, Sinem Civriz Bozdag and Taner Demirer

Submitted: 12 March 2015 Reviewed: 11 September 2015 Published: 02 December 2015

© 2015 The Author(s). Licensee IntechOpen. This chapter is distributed under the terms of the Creative Commons Attribution 3.0 License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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